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SECTION 1. SHORT TITLE.
This Act may be cited as the ``DTV Border Fix Act''.
SEC. 2. CONTINUATION OF ANALOG BROADCASTING ALONG COMMON BORDER WITH
MEXICO.
Section 309(j)(14) of the Communications Act of 1934 (47 U.S.C.
309(j)(14)) is amended by adding at the end the following:
``(D) Continuation of analog broadcasting along
common border with mexico.--
``(i) In general.--Notwithstanding any
other provision of this section, any television
station that has been granted a full-power
television broadcast license that authorizes
analog television service prior to February 17,
2009, that is licensed by the Commission to
serve communities located within 50 miles of
the United States common border with Mexico,
and that can establish to the satisfaction of
the Commission that such station's continued
broadcasting of television service in analog is
in the public interest, shall during the period
beginning on the date of enactment of the DTV
Border Fix Act, and ending February 17, 2014--
``(I) be entitled to the renewal of
such station's television broadcast
license authorizing analog television
service; and
``(II) operate such television
service on a channel between 2 and 51.
``(ii) Conditions.--The rights, privileges,
and obligations described under clause (i)
shall only be extended if the following
requirements are satisfied:
``(I) Any channel used for the
distribution of analog television
service shall not--
``(aa) prevent the auction
of recovered spectrum pursuant
to paragraph (15);
``(bb) prevent the use of
recovered spectrum for any
public safety service pursuant
to section 337(a)(1); and
``(cc) encumber or
interfere with any channel
reserved for public safety use,
as such channels are designated
in ET Docket No. 97-157.
``(II) Each station described in
clause (i) operates on its assigned
analog channel, as of February 16,
2009, if such channel--
``(aa) is between 2 and 51;
``(bb) has not previously
been assigned to such station
or any another station for
digital operation after the
digital transition required
under subparagraph (A); and
``(cc) could be used by
such station for broadcasting
analog television service after
the digital transition required
under subparagraph (A) without
causing interference to any
previously authorized digital
television stations.
``(III) If such station does not
meet the requirements under subclause
(II) for operation on its assigned
analog channel, as of February 16,
2009, such station may request, and the
Commission shall promptly act upon such
request, to be assigned a new channel
for broadcasting analog television
service, provided that such newly
requested channel shall--
``(aa) be between channels
2 and 51; and
``(bb) allow such station
to operate on a primary basis
without causing interference
to--
``(AA) any other
analog or digital
television station; or
``(BB) any station
licensed to operate in
any other radio service
that also operates on
channels between 2 and
51.
``(iii) Mutually exclusive applications.--
If mutually exclusive applications are
submitted for the right to use a channel in
order to broadcast analog television service
pursuant to this subparagraph, the Commission
shall--
``(I) award the authority to use
such channel for such purpose through
the application of the procedures
established under this section; and
``(II) give due consideration to
any resolution procedures established
by the Commission.''. | DTV Border Fix Act - Amends the Communications Act of 1934 to allow the renewal of a full-power analog television broadcasting license through February 17, 2014, for stations located within 50 miles of the U.S. border with Mexico, provided certain requirements are met, including that the renewal does not prevent the auction of recovered spectrum or encumber or interfere with any channel reserved for public safety use.
Requires the Federal Communications Commission (FCC), if mutually exclusive applications are submitted to use a channel under the amendments made by this Act, to award the authority to use the channel through competitive bidding under existing procedures. | <s>[INST]SECTION 1. SHORT TITLE.
This Act may be cited as the ``DTV Border Fix Act''.
SEC. 2. CONTINUATION OF ANALOG BROADCASTING ALONG COMMON BORDER WITH
MEXICO.
Section 309(j)(14) of the Communications Act of 1934 (47 U.S.C.
309(j)(14)) is amended by adding at the end the following:
``(D) Continuation of analog broadcasting along
common border with mexico.--
``(i) In general.--Notwithstanding any
other provision of this section, any television
station that has been granted a full-power
television broadcast license that authorizes
analog television service prior to February 17,
2009, that is licensed by the Commission to
serve communities located within 50 miles of
the United States common border with Mexico,
and that can establish to the satisfaction of
the Commission that such station's continued
broadcasting of television service in analog is
in the public interest, shall during the period
beginning on the date of enactment of the DTV
Border Fix Act, and ending February 17, 2014--
``(I) be entitled to the renewal of
such station's television broadcast
license authorizing analog television
service; and
``(II) operate such television
service on a channel between 2 and 51.
``(ii) Conditions.--The rights, privileges,
and obligations described under clause (i)
shall only be extended if the following
requirements are satisfied:
``(I) Any channel used for the
distribution of analog television
service shall not--
``(aa) prevent the auction
of recovered spectrum pursuant
to paragraph (15);
``(bb) prevent the use of
recovered spectrum for any
public safety service pursuant
to section 337(a)(1); and
``(cc) encumber or
interfere with any channel
reserved for public safety use,
as such channels are designated
in ET Docket No. 97-157.
``(II) Each station described in
clause (i) operates on its assigned
analog channel, as of February 16,
2009, if such channel--
``(aa) is between 2 and 51;
``(bb) has not previously
been assigned to such station
or any another station for
digital operation after the
digital transition required
under subparagraph (A); and
``(cc) could be used by
such station for broadcasting
analog television service after
the digital transition required
under subparagraph (A) without
causing interference to any
previously authorized digital
television stations.
``(III) If such station does not
meet the requirements under subclause
(II) for operation on its assigned
analog channel, as of February 16,
2009, such station may request, and the
Commission shall promptly act upon such
request, to be assigned a new channel
for broadcasting analog television
service, provided that such newly
requested channel shall--
``(aa) be between channels
2 and 51; and
``(bb) allow such station
to operate on a primary basis
without causing interference
to--
``(AA) any other
analog or digital
television station; or
``(BB) any station
licensed to operate in
any other radio service
that also operates on
channels between 2 and
51.
``(iii) Mutually exclusive applications.--
If mutually exclusive applications are
submitted for the right to use a channel in
order to broadcast analog television service
pursuant to this subparagraph, the Commission
shall--
``(I) award the authority to use
such channel for such purpose through
the application of the procedures
established under this section; and
``(II) give due consideration to
any resolution procedures established
by the Commission.''.[/INST]DTV Border Fix Act - Amends the Communications Act of 1934 to allow the renewal of a full-power analog television broadcasting license through February 17, 2014, for stations located within 50 miles of the U.S. border with Mexico, provided certain requirements are met, including that the renewal does not prevent the auction of recovered spectrum or encumber or interfere with any channel reserved for public safety use.
Requires the Federal Communications Commission (FCC), if mutually exclusive applications are submitted to use a channel under the amendments made by this Act, to award the authority to use the channel through competitive bidding under existing procedures.</s> |
SECTION 1. SHORT TITLE.
This Act may be cited as the ``Fulfilling the Potential of Women in
Academic Science and Engineering Act of 2011''.
SEC. 2. FINDINGS.
The Congress finds the following:
(1) Many reports over the past decade have found that it is
critical to our Nation's economic leadership and global
competitiveness that we educate and train more scientists and
engineers.
(2) In its 2007 report entitled ``Beyond Bias and
Barriers'', the National Academies stated that, in order to
maintain its scientific and engineering leadership amid
increasing economic and educational globalization, the United
States must aggressively pursue the innovative capacity of all
of its people--women and men.
(3) Research shows that the number of women who are
interested in science, technology, engineering, and mathematics
(STEM) careers is reduced at every educational transition, from
high school on through full professorships.
(4) According to data compiled by National Science
Foundation in 2006, women now earn about half of all science
and engineering bachelor's degrees, but major variations
persist among fields. For example, women still receive only 20
percent of all bachelor's degrees awarded in engineering and
physics.
(5) Even in science and engineering fields with a higher
representation of women, such as the social and behavioral
sciences, women remain underrepresented among university
faculty. According to data compiled by the National Science
Foundation, for over 30 years women have made up over 30
percent of the doctorates in social sciences and behavioral
sciences and over 20 percent in the life sciences. Yet, at the
top research institutions, only 15.4 percent of the full
professors in the social and behavioral sciences and 14.8
percent in the life sciences are women.
(6) Across fields, women remain a small portion of the
science and engineering faculty members at major research
universities, and they typically receive fewer institutional
resources for their research activities than their male
colleagues.
(7) Studies have not found any significant biological
differences between men and women in performing science and
mathematics that can account for the lower representation of
women in academic faculty and scientific leadership positions
in these fields.
(8) A substantial body of evidence establishes that most
people hold implicit biases. Decades of cognitive psychology
research reveals that most people carry prejudices of which
they are unaware but that nonetheless play a large role in
evaluations of people and their work. Unintentional biases and
outmoded institutional structures are hindering the access for
women to, and advancement of women in, science and engineering.
(9) Workshops held to educate faculty about unintentional
biases have demonstrated success in raising awareness of such
biases.
(10) The Federal Government provides over 60 percent of
research funding at institutions of higher education, and
through its grant making policies has had significant influence
on institution of higher education policies, including policies
related to institutional culture and structure.
SEC. 3. FULFILLING THE POTENTIAL OF WOMEN IN ACADEMIC SCIENCE AND
ENGINEERING.
(a) Definitions.--In this section--
(1) the term ``Federal science agency'' means any Federal
agency that is responsible for at least 2 percent of total
Federal research and development funding to institutions of
higher education, according to the most recent data available
from the National Science Foundation;
(2) the term ``institution of higher education'' has the
meaning given such term in section 101(a) of the Higher
Education Act of 1965 (20 U.S.C. 1001(a));
(3) the term ``STEM'' means science, technology,
engineering, and mathematics; and
(4) the term ``United States'' means the several States,
the District of Columbia, the Commonwealth of Puerto Rico, the
Virgin Islands, Guam, American Samoa, the Commonwealth of the
Northern Mariana Islands, and any other territory or possession
of the United States.
(b) Workshops To Enhance Gender Equity in Academic Science and
Engineering.--
(1) In general.--Not later than 6 months after the date of
enactment of this Act, the Director of the Office of Science
and Technology Policy shall develop a uniform policy for all
Federal science agencies to carry out a program of workshops
that educate program officers, members of grant review panels,
institution of higher education STEM department chairs, and
other federally funded researchers about methods that minimize
the effects of gender bias in evaluation of Federal research
grants and in the related academic advancement of actual and
potential recipients of these grants, including hiring, tenure,
promotion, and selection for any honor based in part on the
recipient's research record.
(2) Interagency coordination.--The Director of the Office
of Science and Technology Policy shall ensure that programs of
workshops across the Federal science agencies are coordinated
and supported jointly as appropriate. As part of this process,
the Director of the Office of Science and Technology Policy
shall ensure that at least 1 workshop is supported every 2
years among the Federal science agencies in each of the major
science and engineering disciplines supported by those
agencies.
(3) Organizations eligible to carry out workshops.--Federal
science agencies may carry out the program of workshops under
this subsection by making grants to eligible organizations. In
addition to any other organizations made eligible by the
Federal science agencies, the following organizations are
eligible for grants under this subsection:
(A) Nonprofit scientific and professional societies
and organizations that represent one or more STEM
disciplines.
(B) Nonprofit organizations that have the primary
mission of advancing the participation of women in
STEM.
(4) Characteristics of workshops.--The workshops shall have
the following characteristics:
(A) Invitees to workshops shall include at least--
(i) the chairs of departments in the
relevant discipline from at least the top 50
institutions of higher education, as determined
by the amount of Federal research and
development funds obligated to each institution
of higher education in the prior year based on
data available from the National Science
Foundation;
(ii) members of any standing research grant
review panel appointed by the Federal science
agencies in the relevant discipline;
(iii) in the case of science and
engineering disciplines supported by the
Department of Energy, the individuals from each
of the Department of Energy National
Laboratories with personnel management
responsibilities comparable to those of an
institution of higher education department
chair; and
(iv) Federal science agency program
officers in the relevant discipline, other than
program officers that participate in comparable
workshops organized and run specifically for
that agency's program officers.
(B) Activities at the workshops shall include
research presentations and interactive discussions or
other activities that increase the awareness of the
existence of gender bias in the grant-making process
and the development of the academic record necessary to
qualify as a grant recipient, including recruitment,
hiring, tenure review, promotion, and other forms of
formal recognition of individual achievement, and
provide strategies to overcome such bias.
(C) Research presentations and other workshop
programs, as appropriate, shall include a discussion of
the unique challenges faced by women who are members of
historically underrepresented groups.
(D) Workshop programs shall include information on
best practices and the value of mentoring undergraduate
and graduate women students as well as outreach to
girls earlier in their STEM education.
(5) Report.--
(A) In general.--Not later than 5 years after the
date of enactment of this Act, the Director of the
Office of Science and Technology Policy shall transmit
to the Committee on Science, Space, and Technology of
the House of Representatives and the Committee on
Commerce, Science, and Transportation of the Senate a
report evaluating the effectiveness of the program
carried out under this subsection to reduce gender bias
towards women engaged in research funded by the Federal
Government. The Director of the Office of Science and
Technology Policy shall include in this report any
recommendations for improving the evaluation process
described in subparagraph (B).
(B) Minimum criteria for evaluation.--In
determining the effectiveness of the program, the
Director of the Office of Science and Technology Policy
shall consider, at a minimum--
(i) the rates of participation by invitees
in the workshops authorized under this
subsection;
(ii) the results of attitudinal surveys
conducted on workshop participants before and
after the workshops;
(iii) any relevant institutional policy or
practice changes reported by participants; and
(iv) for individuals described in paragraph
(4)(A) (i) or (iii) who participated in at
least 1 workshop 3 or more years prior to the
due date for the report, trends in the data for
the department represented by the chair or
employee including faculty data related to
gender as described in section 4.
(C) Institutional attendance at workshops.--As part
of the report under subparagraph (A), the Director of
the Office of Science and Technology Policy shall
include a list of institutions of higher education
science and engineering departments whose
representatives attended the workshops required under
this subsection.
(6) Minimizing costs.--To the extent practicable, workshops
shall be held in conjunction with national or regional
disciplinary meetings to minimize costs associated with
participant travel.
(c) Extended Research Grant Support and Interim Technical Support
for Caregivers.--
(1) Policies for caregivers.--Not later than 6 months after
the date of enactment of this Act, the Director of the Office
of Science and Technology Policy shall develop a uniform policy
to--
(A) extend the period of grant support for
federally funded researchers who have caregiving
responsibilities; and
(B) provide funding for interim technical staff
support for federally funded researchers who take a
leave of absence for caregiving responsibilities.
(2) Report.--Upon developing the policy required under
paragraph (1), the Director of the Office of Science and
Technology Policy shall transmit a copy of the policy to the
Committee on Science, Space, and Technology of the House of
Representatives and to the Committee on Commerce, Science, and
Transportation of the Senate.
(d) Collection of Data on Federal Research Grants.--
(1) In general.--Each Federal science agency shall collect
standardized annual composite information on demographics,
field, award type and budget request, review score, and funding
outcome for all applications for research and development
grants to institutions of higher education supported by that
agency.
(2) Reporting of data.--
(A) The Director of the Office of Science and
Technology Policy shall establish a policy to ensure
uniformity and standardization of data collection
required under paragraph (1).
(B) Not later than 2 years after the date of
enactment of this Act, and annually thereafter, each
Federal science agency shall submit data collected
under paragraph (1) to the National Science Foundation.
(C) The National Science Foundation shall be
responsible for storing and publishing all of the grant
data submitted under subparagraph (B), disaggregated
and cross-tabulated by race, ethnicity, and gender, in
conjunction with the biennial report required under
section 37 of the Science and Engineering Equal
Opportunities Act (42 U.S.C. 1885d).
(e) Publication of List of Institutional Participation in Workshops
To Enhance Gender Equity in Academic Science and Engineering.--The
Director of the Office of Science and Technology Policy, on the basis
of data reported by the Federal science agencies, shall publish
annually a list of institutions of higher education science and
engineering departments represented by individuals who attend the
workshops described in this section. The list shall be publicly
available through the Web site of the Office of Science and Technology
Policy. Any institution of higher education science and engineering
department that is publicized on the list may publicize its receipt of
such recognition on its Web site, in printed materials, or through
other means.
SEC. 4. COLLECTION OF DATA ON DEMOGRAPHICS OF FACULTY.
(a) Collection of Data.--The Director of the National Science
Foundation shall report, in conjunction with the biennial report
required under section 37 of the Science and Engineering Equal
Opportunities Act (42 U.S.C. 1885d), statistical summary data on the
demographics of STEM discipline faculty at institutions of higher
education in the United States, disaggregated and cross-tabulated by
race, ethnicity, and gender. At a minimum, the Director shall
consider--
(1) the number and percent of faculty by gender, race, and
age;
(2) the number and percent of faculty at each rank, by
gender, race, and age;
(3) the number and percent of faculty who are in nontenure-
track positions, including teaching and research, by gender,
race, and age;
(4) the number of faculty who are reviewed for promotion,
including tenure, and the percentage of that number who are
promoted, by gender, race, and age;
(5) faculty years in rank by gender, race, and age;
(6) faculty attrition by gender, race, and age;
(7) the number and percent of faculty hired by rank,
gender, race, and age; and
(8) the number and percent of faculty in leadership
positions, including endowed or named chairs, serving on
promotion and tenure committees, by gender, race, and age.
(b) Recommendations.--The Director of the National Science
Foundation shall solicit input and recommendations from relevant
stakeholders, including representatives from institutions of higher
education and nonprofit organizations, on the collection of data
required under subsection (a), including the development of standard
definitions on the terms and categories to be used in the collection of
such data.
(c) Report to Congress.--Not later than 2 years after the date of
enactment of this Act, the Director of the National Science Foundation
shall submit a report to Congress on how the National Science
Foundation will gather the demographic data on STEM faculty,
including--
(1) a description of the data to be reported and the
sources of those data;
(2) justification for the exclusion of any data described
in paragraph (1); and
(3) a list of the definitions for the terms and categories,
such as ``faculty'' and ``leadership positions'', to be applied
in the reporting of all data described in paragraph (1). | Fulfilling the Potential of Women in Academic Science and Engineering Act of 2011 - Defines a "federal science agency" as any federal agency responsible for at least 2% of total federal research and development funding to institutions of higher education (IHEs), according to National Science Foundation (NSF) data.
Requires the Director of the Office of Science and Technology Policy (OSTP) to develop a policy for federal science agencies to carry out a program of workshops that educate specified federally funded researchers about methods that minimize the effects of gender bias in the evaluation of federal research grants and in the related academic advancement of the recipients of these grants.
Authorizes federal science agencies to make grants to eligible organizations to carry out workshops.
Requires OSTP to support at least one workshop every two years among the federal science agencies in the major science and engineering disciplines.
Requires the Director to develop a policy to extend research grant support and provide interim technical support for federally funded researchers who are caregivers.
Requires federal science agencies to collect specified standardized annual data for all applications for research and development grants to IHEs and to submit the data collected to the NSF.
Requires NSF to report statistical summary data on the demographics of STEM (science, technology, engineering, and mathematics) faculty at IHEs in the United States and report to Congress on how NSF will gather such data. | <s>[INST]SECTION 1. SHORT TITLE.
This Act may be cited as the ``Fulfilling the Potential of Women in
Academic Science and Engineering Act of 2011''.
SEC. 2. FINDINGS.
The Congress finds the following:
(1) Many reports over the past decade have found that it is
critical to our Nation's economic leadership and global
competitiveness that we educate and train more scientists and
engineers.
(2) In its 2007 report entitled ``Beyond Bias and
Barriers'', the National Academies stated that, in order to
maintain its scientific and engineering leadership amid
increasing economic and educational globalization, the United
States must aggressively pursue the innovative capacity of all
of its people--women and men.
(3) Research shows that the number of women who are
interested in science, technology, engineering, and mathematics
(STEM) careers is reduced at every educational transition, from
high school on through full professorships.
(4) According to data compiled by National Science
Foundation in 2006, women now earn about half of all science
and engineering bachelor's degrees, but major variations
persist among fields. For example, women still receive only 20
percent of all bachelor's degrees awarded in engineering and
physics.
(5) Even in science and engineering fields with a higher
representation of women, such as the social and behavioral
sciences, women remain underrepresented among university
faculty. According to data compiled by the National Science
Foundation, for over 30 years women have made up over 30
percent of the doctorates in social sciences and behavioral
sciences and over 20 percent in the life sciences. Yet, at the
top research institutions, only 15.4 percent of the full
professors in the social and behavioral sciences and 14.8
percent in the life sciences are women.
(6) Across fields, women remain a small portion of the
science and engineering faculty members at major research
universities, and they typically receive fewer institutional
resources for their research activities than their male
colleagues.
(7) Studies have not found any significant biological
differences between men and women in performing science and
mathematics that can account for the lower representation of
women in academic faculty and scientific leadership positions
in these fields.
(8) A substantial body of evidence establishes that most
people hold implicit biases. Decades of cognitive psychology
research reveals that most people carry prejudices of which
they are unaware but that nonetheless play a large role in
evaluations of people and their work. Unintentional biases and
outmoded institutional structures are hindering the access for
women to, and advancement of women in, science and engineering.
(9) Workshops held to educate faculty about unintentional
biases have demonstrated success in raising awareness of such
biases.
(10) The Federal Government provides over 60 percent of
research funding at institutions of higher education, and
through its grant making policies has had significant influence
on institution of higher education policies, including policies
related to institutional culture and structure.
SEC. 3. FULFILLING THE POTENTIAL OF WOMEN IN ACADEMIC SCIENCE AND
ENGINEERING.
(a) Definitions.--In this section--
(1) the term ``Federal science agency'' means any Federal
agency that is responsible for at least 2 percent of total
Federal research and development funding to institutions of
higher education, according to the most recent data available
from the National Science Foundation;
(2) the term ``institution of higher education'' has the
meaning given such term in section 101(a) of the Higher
Education Act of 1965 (20 U.S.C. 1001(a));
(3) the term ``STEM'' means science, technology,
engineering, and mathematics; and
(4) the term ``United States'' means the several States,
the District of Columbia, the Commonwealth of Puerto Rico, the
Virgin Islands, Guam, American Samoa, the Commonwealth of the
Northern Mariana Islands, and any other territory or possession
of the United States.
(b) Workshops To Enhance Gender Equity in Academic Science and
Engineering.--
(1) In general.--Not later than 6 months after the date of
enactment of this Act, the Director of the Office of Science
and Technology Policy shall develop a uniform policy for all
Federal science agencies to carry out a program of workshops
that educate program officers, members of grant review panels,
institution of higher education STEM department chairs, and
other federally funded researchers about methods that minimize
the effects of gender bias in evaluation of Federal research
grants and in the related academic advancement of actual and
potential recipients of these grants, including hiring, tenure,
promotion, and selection for any honor based in part on the
recipient's research record.
(2) Interagency coordination.--The Director of the Office
of Science and Technology Policy shall ensure that programs of
workshops across the Federal science agencies are coordinated
and supported jointly as appropriate. As part of this process,
the Director of the Office of Science and Technology Policy
shall ensure that at least 1 workshop is supported every 2
years among the Federal science agencies in each of the major
science and engineering disciplines supported by those
agencies.
(3) Organizations eligible to carry out workshops.--Federal
science agencies may carry out the program of workshops under
this subsection by making grants to eligible organizations. In
addition to any other organizations made eligible by the
Federal science agencies, the following organizations are
eligible for grants under this subsection:
(A) Nonprofit scientific and professional societies
and organizations that represent one or more STEM
disciplines.
(B) Nonprofit organizations that have the primary
mission of advancing the participation of women in
STEM.
(4) Characteristics of workshops.--The workshops shall have
the following characteristics:
(A) Invitees to workshops shall include at least--
(i) the chairs of departments in the
relevant discipline from at least the top 50
institutions of higher education, as determined
by the amount of Federal research and
development funds obligated to each institution
of higher education in the prior year based on
data available from the National Science
Foundation;
(ii) members of any standing research grant
review panel appointed by the Federal science
agencies in the relevant discipline;
(iii) in the case of science and
engineering disciplines supported by the
Department of Energy, the individuals from each
of the Department of Energy National
Laboratories with personnel management
responsibilities comparable to those of an
institution of higher education department
chair; and
(iv) Federal science agency program
officers in the relevant discipline, other than
program officers that participate in comparable
workshops organized and run specifically for
that agency's program officers.
(B) Activities at the workshops shall include
research presentations and interactive discussions or
other activities that increase the awareness of the
existence of gender bias in the grant-making process
and the development of the academic record necessary to
qualify as a grant recipient, including recruitment,
hiring, tenure review, promotion, and other forms of
formal recognition of individual achievement, and
provide strategies to overcome such bias.
(C) Research presentations and other workshop
programs, as appropriate, shall include a discussion of
the unique challenges faced by women who are members of
historically underrepresented groups.
(D) Workshop programs shall include information on
best practices and the value of mentoring undergraduate
and graduate women students as well as outreach to
girls earlier in their STEM education.
(5) Report.--
(A) In general.--Not later than 5 years after the
date of enactment of this Act, the Director of the
Office of Science and Technology Policy shall transmit
to the Committee on Science, Space, and Technology of
the House of Representatives and the Committee on
Commerce, Science, and Transportation of the Senate a
report evaluating the effectiveness of the program
carried out under this subsection to reduce gender bias
towards women engaged in research funded by the Federal
Government. The Director of the Office of Science and
Technology Policy shall include in this report any
recommendations for improving the evaluation process
described in subparagraph (B).
(B) Minimum criteria for evaluation.--In
determining the effectiveness of the program, the
Director of the Office of Science and Technology Policy
shall consider, at a minimum--
(i) the rates of participation by invitees
in the workshops authorized under this
subsection;
(ii) the results of attitudinal surveys
conducted on workshop participants before and
after the workshops;
(iii) any relevant institutional policy or
practice changes reported by participants; and
(iv) for individuals described in paragraph
(4)(A) (i) or (iii) who participated in at
least 1 workshop 3 or more years prior to the
due date for the report, trends in the data for
the department represented by the chair or
employee including faculty data related to
gender as described in section 4.
(C) Institutional attendance at workshops.--As part
of the report under subparagraph (A), the Director of
the Office of Science and Technology Policy shall
include a list of institutions of higher education
science and engineering departments whose
representatives attended the workshops required under
this subsection.
(6) Minimizing costs.--To the extent practicable, workshops
shall be held in conjunction with national or regional
disciplinary meetings to minimize costs associated with
participant travel.
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in the reporting of all data described in paragraph (1).[/INST]Fulfilling the Potential of Women in Academic Science and Engineering Act of 2011 - Defines a "federal science agency" as any federal agency responsible for at least 2% of total federal research and development funding to institutions of higher education (IHEs), according to National Science Foundation (NSF) data.
Requires the Director of the Office of Science and Technology Policy (OSTP) to develop a policy for federal science agencies to carry out a program of workshops that educate specified federally funded researchers about methods that minimize the effects of gender bias in the evaluation of federal research grants and in the related academic advancement of the recipients of these grants.
Authorizes federal science agencies to make grants to eligible organizations to carry out workshops.
Requires OSTP to support at least one workshop every two years among the federal science agencies in the major science and engineering disciplines.
Requires the Director to develop a policy to extend research grant support and provide interim technical support for federally funded researchers who are caregivers.
Requires federal science agencies to collect specified standardized annual data for all applications for research and development grants to IHEs and to submit the data collected to the NSF.
Requires NSF to report statistical summary data on the demographics of STEM (science, technology, engineering, and mathematics) faculty at IHEs in the United States and report to Congress on how NSF will gather such data.</s> |
darboux transformations are a well known tool in the theory of integrable systems @xcite .
the classical darboux transformation @xcite deals with a sturm liouville problem ( the one dimensional stationary schrdinger equation ) generating , at the same time , new potentials and new wave functions from given ones thus providing solutions to the korteweg de vries hierarchy of @xmath0 dimensional integrable systems . however , as it is clearly stated in @xcite , it was an earlier work of moutard @xcite which inspired darboux . in that work one can find the proper transformation that applies to @xmath1 dimensional integrable systems .
note that the initial area of applications of the darboux transformations , which preceded the theory of integrable systems , was the theory of conjugate and asymptotic nets where the large body of results on darboux transformations was formulated @xcite .
most of the techniques that allow us to find solutions of integrable non - linear differential equations have been successfully applied to difference equations .
these include mutually interrelated methods such as bilinearization method @xcite and the sato approach @xcite , direct linearization method @xcite , inverse scattering method @xcite , the nonlocal @xmath2 dressing method @xcite , the algebro - geometric techniques @xcite .
also the method of the darboux transformation has been successfully applied to the discrete integrable systems .
the present paper aims to review application of the darboux transformation technique for the equations that can be regarded as discretizations of second order linear differential equations in two dimensions , their distinguished subclasses and systems of such equations . while presenting the results we are trying to keep the relation with continuous case .
however , we are aware of weak points of this way of exposition .
the theory of discrete integrable systems @xcite is reacher but also , in a sense , simpler then the corresponding theory of integrable partial differential equations . in the course of a limiting procedure , which gives differential systems from the discrete ones , various symmetries and relations between different discrete systems
the classical example is provided ( see , for example @xcite ) by the hierarchy of the kadomsev
petviashvilii ( kp ) equations , which can be obtained from a single hirota
miwa equation the opposite way , from differential to discrete , involves all equations of the hierarchy @xcite .
the structure of the paper is as follows . in section [ dodane ]
we expose main ideas in the theory of darboux transformations in multidimension . in section [ sec:6p ]
we present the construction of the darboux transformation for the discrete second order linear problem the 6-point scheme which can be considered as a discretization of the general second order linear partial differential equation in two variables .
then we discuss various specifications and reductions of the 6-point scheme .
we separately present in section [ sec : s - a ] the darboux transformations for discrete self - adjoint two dimensional linear systems on the square , triangular and the honeycomb lattices , and their relation to the discrete moutard transformation .
section [ sec:4p ] is devoted to detailed presentation of the darboux transformations for systems of the 4-point linear problems , their various specifications and the corresponding permutability theorems .
sec:4p - red ] is dedicated to reductions of the fundamental transformation compatible with additional restrictions on the form of the four point scheme .
finally , in section [ 3p - sch ] we review the darboux transformations for the 3-point linear problem , and the corresponding celebrated hirota s discrete kp nonlinear system .
the main idea included in the paper has its origin in jonas paper @xcite where fundamental transformation for conjugate nets has been presented . neglecting the geometrical context of jonas paper we only would like to say that the fundamental transformation acts on solutions of compatible system of second order linear differential equations on function @xmath3 @xmath4 where coefficients @xmath5 and @xmath6 are functions of @xmath7 , and for @xmath8 they have to obey a nonlinear differential equation ( compatibility conditions ) ; we use notation that subscript preceded by coma denotes partial differentiation with respect to indicated variables .
every fundamental transformation @xmath9 can be presented as composition of suitably chosen 1 .
radial transformation @xmath10 @xmath11 2 .
combescure transformation @xmath12 @xmath13 3 .
radial transformation @xmath14 @xmath15 we refer interested reader to eisenhart book @xcite for further details .
as the practice shows the fundamental transformation is indeed fundamental - in the sense that most ( if not all ) of the darboux transformations are reductions of the fundamental transformation . here
we follow this basic idea discovered almost one hundred years ago .
we start from presenting two dimensional difference operators @xmath16 ( and corresponding difference equations @xmath17 , where @xmath18 is function of discrete variables @xmath19 and @xmath20 ) together with the transformation @xmath21 which is composition of 1 .
gauge transformation @xmath22 ( see subsection [ ge ] ) @xmath23 where @xmath24 is a solution of @xmath25 whereas @xmath26 is a solution of @xmath27 where @xmath28 denotes operator formally adjoint to operator @xmath16 .
we emphasize that this particular choice of functions @xmath24 and @xmath26 is essential , for it guarantees existence of function @xmath29 in the next transformation 2 .
transformations @xmath30 that take either the form ( details are given in the text below ) @xmath31 = \left [ \begin{matrix } \alpha & \beta\cr \gamma & \delta \end{matrix } \right ] \left [ \begin{matrix } { \delta_1}\psi_r \cr { \delta_2}\psi_r \end{matrix } \right ] \end{array}\ ] ] or the form @xmath32 = \left [ \begin{matrix } \alpha & \beta\cr \gamma & \delta \end{matrix } \right ] \left [ \begin{matrix } { \delta_{-1}}\psi_r \cr { \delta_{-2}}\psi_r \end{matrix } \right ] \end{array}\ ] ] where @xmath33 , @xmath34 denote forward difference operators @xmath35 , @xmath36 , whereas @xmath37 , @xmath38 denote backward difference operators @xmath39 , @xmath40 .
3 . gauge transformation @xmath41 @xmath42 where in general @xmath43 and @xmath44 are arbitrary functions ( which should be specified when reductions or specifications of the transformations are considered ) .
( 620,400 ) ( 90,360)(215,90 ) ( -10,375)(40,10)[l]6-point ( 80,390 ) ( 73,380)(87,380 ) ( 66,370)(80,370 ) ( 94,370 ) ( 120,375)(40,10)[l]sect .
[ gc ] ( -10,325)(50,10)[l]@xmath45 ( -10,350)(50,10)[l]@xmath46 ( 90,310)(0,-1)55 ( 15,285)(50,10)[l]specification ( 0,270)(50,10)[l]@xmath47 , @xmath48 ( 20,250)(0,-1)80 ( 160,250)(0,-1)80 ( 20,250)(1,0)140 ( 20,170)(1,0)140 ( 30,225)(40,10)[l]4-point ( 78,235)(88,235 ) ( 78,225)(88,225 ) ( 100,225)(40,10)[l]sect .
[ sec:4p-6p ] , [ sec : fund ] ( 30,200)(50,10)[l]@xmath49 ( 30,175)(50,10)[l]@xmath50 ( 90,165)(0,-1)55 ( 15,140)(50,10)[l]specification ( 30,125)(50,10)[l]@xmath51 ( 30,105)(0,-1)70 ( 150,105)(0,-1)70 ( 30,105)(1,0)120 ( 30,35)(1,0)120 ( 40,85)(40,10)[l]3-point ( 78,95)(92,95 ) ( 85,85 ) ( 100,85)(40,10)[l]sect . [ 3mn ] , [ 3p - sch ] ( 40,65)(50,10)[l]@xmath52 ( 40,45)(50,10)[l]@xmath53 ( 165,240)(40,10)[l]ribaucour reduction ( 165,230)(1,0)90 ( 255,230)(0,-1)15 ( 210,210)(0,-1)60 ( 300,210)(0,-1)60 ( 210,210)(1,0)90 ( 210,150)(1,0)90 ( 220,195)(40,10)[l]see section [ qr ] ( 215,175)(40,10)[l]@xmath18 lies on a quadric ( 215,160)(40,10)[l]@xmath54 lies on a quadric ( 145,130)(0,1)35 ( 425,130)(-1,0)280 ( 425,130)(0,1)15 ( 330,135)(50,10)[l]moutard reduction ( 330,210)(0,-1)60 ( 423,210)(0,-1)60 ( 330,210)(1,0)93 ( 330,150)(1,0)93 ( 340,195)(50,10)[l]discrete moutard ( 345,185)(40,10)[l]sect . [ mr ] , [ bkp ] ( 332,170)(50,10)[l]@xmath55 ( 350,155)(50,10)[l]@xmath56 ( 423,180)(1,0)4 ( 427,210)(0,-1)60 ( 527,210)(0,-1)60 ( 427,210)(1,0)100 ( 427,150)(1,0)100 ( 440,195)(50,10)[l]adjoint discrete ( 478,185)(50,10)[l]sect . [ mr ] ( 430,185)(50,10)[l]moutard , ( 428,170)(50,10)[l]@xmath57 ( 447,155)(50,10)[l]@xmath56 ( 335,365)(135,70 ) ( 273,385 ) ( 60,10)[l]7-point ( 268,375 ) ( 60,10)[l]selfadjoint ( 328,395)(342,395 ) ( 321,385)(335,385 ) ( 349,385 ) ( 328,375)(342,375 ) ( 355,380)(40,10)[l]sect .
[ 7ps ] ( 270,360)(100,10)[l]@xmath58 ( 270,350)(100,10)[l]@xmath59 ( 272,335)(100,10)[l]@xmath60 ( 475,365)(135,70 ) ( 415,380)(50,10)[l]honeycomb ( 483,395)(497,395 ) ( 476,385 ) ( 504,385 ) ( 483,375)(497,375 ) ( 410,355)(50,10)[l]see section [ hcb ] for details ( 405,215)(0,1)115 ( 405,330)(-1,0)10 ( 260,315)(50,10)[l]specification @xmath61 ( 405,330)(1,0)10 ( 350,325)(0,-1)10 ( 410,275)(50,10)[l]sublattice approach ( 410,265)(50,10)[l]on quasi - regular ( 410,255)(50,10)[l ] rhombic lattice ( 380,215)(0,1)20 ( 290,225)(50,10)[l]sublattice approach ( 290,215)(50,10)[l]on square lattice ( 335,275)(130,70 ) ( 276,295 ) ( 60,10)[l]5-point ( 271,285 ) ( 60,10)[l]selfadjoint ( 334,305 ) ( 324,295 ) ( 334,295)(344,295 ) ( 334,285 ) ( 352,290)(40,10)[l]sect .
[ 5r ] ( 290,270)(100,10)[l]@xmath62 ( 290,260)(100,10)[l]@xmath63 ( 290,245)(100,10)[l]@xmath64 ( 125,120)(0,1)45 ( 595,120)(-1,0)470 ( 595,120)(0,1)25 ( 510,125)(50,10)[l]goursat reduction ( 550,235)(0,-1)85 ( 640,235)(0,-1)85 ( 550,235)(1,0)90 ( 550,150)(1,0)90 ( 557,225)(50,10)[l]discrete goursat ( 560,215)(40,10)[l]sect .
[ gr ] , [ ckp ] ( 551,200)(100,10)[l ] @xmath65 ( 551,185)(100,10)[l ] @xmath66 ( 551,170)(100,10)[l ] @xmath67 ( 551,150)(100,10)[l ] @xmath68
we pay special attention to subclasses of operators @xmath16 that admit darboux transformations .
a trivial , from the point of view of integrable systems , examples are subclasses obtained by fixing a gauge ( see section [ ge ] ) .
very important classes of operators are obtained by imposing conditions on the mentioned above functions @xmath24 and @xmath26 .
for example in the case of self - adjoint 7-point scheme we discuss in section [ 7ps ] , the relation is @xmath69 .
we refer to such procedures as to reductions .
the further examples of reductions are given in sections [ gr ] , [ mr ] and [ sec:4p - red ] .
we reserve separate name `` specification '' to the cases when the operator is reduced , whereas the transformations remain essentially unaltered ( i.e. no constraint on functions @xmath24 and @xmath26 is necessary ) .
examples of specifications are given in sections [ sec:4p-6p ] , [ 5r ] and [ 3mn ] . with the notion of `` specification '' another important issue appears , since continuous counterparts of the specifications presented here can be viewed as a choice of particular gauge and independent variables .
the interesting ( because not well understood ) aspects of discrete integrable systems come from the fact there is no theory how to change discrete independent variables so that not to destroy underlying integrable phenomena .
sublattice approach , widely used in theoretical physics , can be regarded , to some extent , as counterpart of change of independent variables . to some extent , because the only case studied in detail from the point of view of darboux transformations is the case of self - adjoint equation , which in the discrete case consists of moutard case ( section [ mr ] ) , self - adjoint case ( section [ sec : s - a ] ) and their mutual relations ( c.f .
interrelations between results presented here are summarized in figure 1 .
large part of the paper is dedicated to the specification in which the matrix in is diagonal . in this case
one can consider systems of four point operators defined on lattices with arbitrary number of independent variables .
the multidimensional lattices are extensively discussed in sections [ sec:4p ] and [ sec:4p - red ] , where compact elegant expressions for superpositions of fundamental transformations are presented either .
in this section we present discretizations of equation and its subclasses covariant under darboux transformations . out of the schemes that can serve as a discretization of the 2d equation @xmath70 the following 6-point scheme @xmath71 deserve a special attention ( coefficients @xmath72 , @xmath73 etc .
and dependent variable @xmath18 are functions on @xmath74 , subscript in brackets denote shift operators , @xmath75 , @xmath76 , @xmath77 , @xmath78 and @xmath79 ) .
the scheme admits decomposition @xmath80\psi=0 $ ] ( where @xmath81 and @xmath82 are forward shift operators in first and second direction respectively ) and therefore its laplace transformations can be constructed ( see @xcite and section [ sec : laplace - tr ] for the notion of the laplace transformations of multidimensional linear operators ) . what more important from the point of view of this review the scheme is covariant under a fundamental darboux transformation @xcite ( the transformation is often referred to as binary darboux transformation in soliton literature ) .
indeed , [ th:6p - dt ] given a non - vanishing solution @xmath24 of @xmath83 and a non - vanishing solution @xmath26 of the equation adjoint to equation @xmath84 ( negative integers in brackets in subscript denote backward shift e.g. @xmath85 etc . ) the existence of auxiliary function @xmath86 is guaranteed @xmath87 then equation can be rewritten as @xmath88+\\ { \delta_1}\left [ a{_{(-1)}}\phi{_{(-1)}}\theta{_{(1)}}{\delta_1}\left(\frac{\psi}{\theta } \right ) -(p{_{(-1)}}- c{_{(-1)}})\phi{_{(-1)}}\theta{_{(2 ) } } ) { \delta_2}\left(\frac{\psi}{\theta } \right ) \right]=0 \end{array}\ ] ] which in turn guarantees the existence of functions @xmath89 such that @xmath90 = \left [ \begin{matrix } ( c{_{(-2)}}+ p{_{(-2)}})\phi{_{(-2)}}\theta{_{(1 ) } } & b{_{(-2)}}\phi{_{(-2)}}\theta{_{(2)}}\cr -a{_{(-1)}}\phi{_{(-1)}}\theta{_{(1)}}&(p{_{(-1)}}- c{_{(-1)}})\phi{_{(-1)}}\theta{_{(2)}}\end{matrix } \right ] \left [ \begin{matrix } { \delta_1}\left(\frac{\psi}{\theta } \right)\cr { \delta_2}\left(\frac{\psi}{\theta } \right ) \end{matrix } \right ] \end{array}\ ] ] assuming that matrix in is invertible on the whole lattice , i.e. everywhere and finally on introducing @xmath91 via @xmath92 and taking the opportunity of multiplying resulting equation by non - vanishing function @xmath43 , we arrive at the conclusion that the function @xmath91 satisfies equation of the form but with new coefficients @xmath93 the family of maps @xmath94 given by - we refer to as darboux transformations of equation .
we say that two linear operators @xmath16 and @xmath95 are gauge equivalent if one can find functions say @xmath26 and @xmath24 such that @xmath96 ( where @xmath97 stands for composition of operators ) .
the idea to consider equivalence classes of linear operators with respect to gauge rather than single operator itself , goes to laplace and darboux papers @xcite . in the continuous case it reflects in the fact that one can confine himself e.g. to equations ( the so called affine gauge ) @xmath98 or to ( in this case we would like to introduce the name _ basic gauge _ ) @xmath99 without loss of generality .
the darboux transformation can be viewed as transformation acting on equivalence classes ( with respect to gauge ) of equation ( compare @xcite ) .
therefore one can confine himself to particular elements of equivalence class .
commonly used choice is to confine oneself to the affine gauge i.e. to equations that obeys @xmath100 if one puts s = const in ( this condition is not necessary ) then the above constraint is preserved under the darboux transformation .
one can consider further specification of the gauge @xmath101 this choice of gauge we would like to refer as to basic gauge of equation .
note that if the equation is in a basic gauge its formal adjoint is in a basic gauge too . in the continuous case due to possibility of changing independent variables one can reduce , provided equation
is hyperbolic , to canonical form @xmath102 in the discrete case similar result can be obtained in a different way . taking a glance at ( [ dcoef ] )
we can notice that coefficients @xmath72 , @xmath73 and @xmath103 transform in a very simple manner .
in particular , if any of these coefficients equals zero then its transform equals zero too .
let us stress that in this case if we do so , we do not impose any constraints on transformation data , transformations remains essentially the same .
first we shall concentrate on the case when two out of three mentioned functions vanish .
if we put @xmath104 then from equation @xmath105 and one can adjust the function @xmath43 so that @xmath106 so we arrive at the 4-point scheme @xmath107 and its fundamental transformation c.f . @xcite .
we observe that the form of equation is covariant under the gauge @xmath108 and to identify whether two equations are equivalent or not we use the invariants of the gauge @xmath109 two equations are equivalent if their corresponding invariants @xmath110 and @xmath20 are equal @xcite . in this subsection
we discuss the discretization of class of equations @xmath111 which is referred to as goursat equation . the discrete counterpart of goursat equation arose from the surveys on egorov lattices @xcite and symmetric lattices @xcite and can be written in the form @xcite @xmath112 where functions @xmath113 and @xmath114 are related via @xmath115 the gauge invariant characterization of the discrete goursat equation is either @xmath116 or @xmath117 the goursat equation can be isolated from the others 4-point schemes in the similar way that goursat did it over hundred years ago @xcite i.e. as the equation such that one of its laplace transformations maps solutions of the equation to solutions of the adjoint equation . therefore in this case
if @xmath24 obeys @xmath118 then its laplace transformation @xmath119 is a solution of equation adjoint to equation @xcite .
equation is the constraint we impose on transformation data ( i.e. functions @xmath24 and @xmath26 ) in the fundamental transformation , ( we recall we have already put @xmath72 and @xmath73 equal to zero ) .
in addition if @xmath24 obeys then @xmath120\ ] ] and as a result there exists function @xmath121 such that @xmath122 now it can be shown that one can put @xmath123 { _ { ( 2)}}-{\vartheta}{_{(2)}}\ ] ] and the transformation takes form @xmath124 = \left [ \begin{matrix } \sqrt{\frac{\tau { _ { ( 2)}}}{\tau { _ { ( 1)}}}}\frac{\sqrt{{\delta_1}{\vartheta}{\delta_2}{\vartheta}}}{q } -{\vartheta } & 0 \cr 0 & - { \vartheta}{_{(2)}}\end{matrix } \right ] \left [ \begin{matrix } { \delta_1}\left(\sqrt{\frac{{\tau}}{{\tau { _ { ( 2 ) } } } } } \frac{\psi}{\sqrt{{\delta_2}{\vartheta}}}\right)\cr { \delta_2}\left(\sqrt{\frac{{\tau}}{{\tau { _ { ( 2 ) } } } } } \frac{\psi}{\sqrt{{\delta_2}{\vartheta } } } \right ) \end{matrix } \right ] \end{array}\ ] ] which is the discrete version of goursat transformation @xcite .
the transformation rule for the field @xmath114 is @xmath125 in this subsection we discuss discretization moutard equation and its ( moutard ) transformation @xcite @xmath126 moutard equation is self - adjoint equation ( which allowed us to impose reduction @xmath69 in the continuous analogue of transformation c.f .
the point is that opposite to the continuous case there is no appropriate self - adjoint 4-point scheme we do have the reduction of fundamental transformation that can be regarded as discrete counterpart of moutard transformation .
namely , class of equations that can be written in the form @xmath127 we refer nowadays to as discrete moutard equation .
it appeared in the context of integrable systems in @xcite and then its moutard transformations have been studied in detail in @xcite .
gauge invariant characterization of the class of discrete moutard equations is @xcite @xmath128 let us trace this reduction on the level of fundamental transformation
. putting @xmath129 and @xmath130 the equations , and take respectively form @xmath131 @xmath132 @xmath133 the crucial observation is : if the function @xmath24 satisfies equation then the function @xmath26 given by @xmath134 satisfies equation @xcite .
if we put @xmath135 then equations will be automatically satisfied .
if in addition we put in @xmath136 then darboux transformation takes form ( c.f .
@xcite ) @xmath137 = \left [ \begin{matrix } \theta \theta { _ { ( 1 ) } } & 0\cr 0 & -\theta \theta { _ { ( 2)}}\end{matrix } \right ] \left [ \begin{matrix } { \delta_1}\frac{\psi}{\theta}\cr { \delta_2}\frac{\psi}{\theta } \end{matrix } \right]\ ] ] and it serves as transformation @xmath94 that maps solutions of equation into solutions of another discrete moutard equation @xmath138 we recall that @xmath24 an arbitrary non - vanishing fixed solution of the equation @xmath139 every equation that is gauge equivalent to we refer to as an adjoint discrete equation moutard equation , its gauge invariant characterization is @xcite @xmath140 equation can be regarded as potential version of equation in the continuous case there is direct reduction of the fundamental transformation for equation to the moutard type transformation for self - adjoint equation @xcite @xmath141 in this section we present difference analogues of equation which allow for the darboux transformation.opposite to the continuous case the transformation will not be direct reduction of the fundamental transformation for the 6-point scheme .
the self - adjoint discrete operators studied below are however intimately related to discrete moutard equation which provides the link between their darboux transformations and the fundamental transformation for equation . the following 7-point linear system @xmath142 allows for the darboux transformation @xcite .
[ th : tp - d ] given scalar solution @xmath143 of the linear equation , then @xmath144 given as solution of the following system @xmath145 satisfies the 7-point scheme with the new fields given by @xmath146 @xmath147 where @xmath148 as it was shown in @xcite the self - adjoint 7-point scheme can be obtained from the system of moutard equations imposed consistently on quadrilaterals of the bipartite quasi - regular rhombic tiling ( see fig .
[ fig : qrrt ] ) , which is a particular case of the approach considered in @xcite .
then the moutard transformations can be also restricted to the triangular sublattice leading to theorem [ th : tp - d ] .
the 7-point scheme admits specification @xmath61 ( alternatively one can put @xmath149 or @xmath150 ) and as result we obtain specification to 5-point self - adjoint scheme @xcite .
@xmath151 the self - adjoint 5-point scheme and its darboux transformation can be also obtained form the moutard equation on the ( bipartite ) square lattice @xcite .
it is well known that the triangular and honeycomb grids are dual to each other ( see fig .
[ fig : qrrt ] ) .
restriction of the system of the moutard equations on the rhombic tiling to the honeycomb sublattice gives @xcite the following linear system @xmath152 because @xmath153 and @xmath154 satisfy separately the self - adjoint 7-point schemes , but with different coefficients , then the linear problem - can be considered as a relation between two equations .
this is the laplace transformation between self - adjoint 7-point schemes studied in @xcite .
the corresponding restriction of the moutard transformation gives the darboux transformation for the honeycomb linear problem .
[ th : dt - hc ] given scalar solution @xmath155 of the honeycomb linear system - then the solution @xmath156 of the system @xmath157 with @xmath158 given by @xmath159 satisfies a new honeycomb linear system with the coefficients @xmath160 we end the review of two - dimensional case with specification to the 3-point scheme i.e. to a discretization of first order differential equation @xmath161 if we put @xmath162 then according to @xmath163 it means that the fundamental transformation is also the darboux transformation for the 3-point scheme @xcite @xmath164 this elementary scheme is the simplest one from the class considered here , but it deserves a special attention , because it leads to one of the most studied integrable discrete equation @xcite .
we confine ourselves to recalling briefly in section [ 3p - sch ] main results in this field . to the end
let us rewrite the 3-point scheme in the basic gauge @xmath165
in this section we present the darboux transformations for the four point scheme ( the discrete laplace equation ) from the point of view of systems of such equations , and the corresponding permutability theorems . to keep the paper of reasonable size and in order to present the results from a simple algebraic perspective we do not discuss important relations of the subject to incidence and difference geometry @xcite ( see also @xcite and earlier works @xcite ) , application of analytic @xcite and algebro - geometric @xcite techniques of the integrable systems theory to construct large classes of solutions of the linear systems in question and solutions of the corresponding nonlinear discrete equations . in order to simplify discussion of the darboux transformations for systems of the 4-point schemes we fix ( without loss of generality @xcite ) the gauge to the affine one @xmath166 where @xmath167 are some functions constrained by the compatibility of the system .
it is also convenient @xcite to replace the second order linear system by a first order system as follows .
the compatibility of allows for definition of the potentials ( the lam coefficients ) @xmath168 such that @xmath169 the new wave functions @xmath170 given by the decomposition @xmath171 satisfy the first order linear system @xmath172 where the functions @xmath173 , called the rotation coefficients , are calculated from the equation @xmath174 which is called adjoint to .
both the equations and are compatible provided the fields @xmath173 satisfy the discrete darboux equations @xcite @xmath175 [ cor:4p - psi - i ] due to the function @xmath170 satisfies itself the four point equation @xmath176 while the function @xmath177 satifies the adjoint of in the sense of .
the discrete darboux equations imply existence of the potentials @xmath178 given as solutions of the compatible system @xmath179 and yet another potential @xmath114 such that @xmath180 in terms of the @xmath114-function and the functions @xmath181 the meaning of which will be given in section [ sec : laplace - tr ] , equations and can be rewritten @xcite in the bilinear form @xmath182 we start with a simple algebraic fact , whose consequences will be discussed throughout the remaining part of this section .
[ th : vect - darb ] given the solution @xmath183 , of the linear system , and given the solution @xmath184 , of the adjoint linear system .
these allow to construct the linear operator valued potential @xmath185 : \mathbb{z}^n\to \mathrm{l}({{\mathbb w}},{{\mathbb u}})$ ] , defined by @xmath186 = \boldsymbol{\phi}_i \otimes \boldsymbol{\phi}^*_{i(i ) } , \qquad i = 1,\dots , n.\ ] ] if @xmath187 and the potential @xmath188 is invertible , @xmath185\in\mathrm{gl}({{\mathbb w}})$ ] , then @xmath189^{-1}{\boldsymbol{\phi}}_i , \;\ ; \ ; i=1, ... ,n , \label{eq : haty}\\ \tilde{{\boldsymbol{\phi}}}^*_i&={\boldsymbol{\phi}}^*_i{\boldsymbol{\omega}}[{\boldsymbol{\phi}},{\boldsymbol{\phi}}^*]^{-1},\;\;\ ; i=1, ... ,n,\label{eq : haty*}\end{aligned}\ ] ] satisfy the linear systems - correspondingly , with the fields @xmath190^{-1}|{\boldsymbol{\phi}}_i \rangle , \;\;\ ; i , j=1,\dots , n , \;\;i\neq j , \label{eq : hatq}.\ ] ] in addition , @xmath191 = c - { \boldsymbol{\omega}}[{\boldsymbol{\phi}},{\boldsymbol{\phi}}^*]^{-1},\ ] ] where @xmath192 is a constant operator .
notice that because of we have @xmath193 $ ] . the potentials @xmath178 and the @xmath114-function transform according to @xmath194^{-1 } { \boldsymbol{\phi}}_i),\\ \tilde{\tau } & = \tau \det\boldsymbol{\omega}[{\boldsymbol{\phi}},{\boldsymbol{\phi}}^*].\end{aligned}\ ] ] applying the above transformation one can produce new compatible ( affine ) four point linear problems from the old ones .
to obtain conventional transformation formulas consider @xcite the following splitting of the vector space @xmath195 of theorem [ th : vect - darb ] : @xmath196 if @xmath197 then , the corresponding potential matrix is of the form @xmath198 = \begin{pmatrix } { { \mathbb i}}_{{\mathbb e } } & { \boldsymbol{\omega}}[{\boldsymbol{\psi}},{\boldsymbol{\theta}}^ * ] & { \boldsymbol{\omega}}[{\boldsymbol{\psi } } , { \boldsymbol{\psi}}^ * ] \\ 0 & { \boldsymbol{\omega}}[{\boldsymbol{\theta}},{\boldsymbol{\theta}}^ * ] & { \boldsymbol{\omega}}[{\boldsymbol{\theta } } , { \boldsymbol{\psi}}^ * ] \\ 0 & 0 & { { \mathbb i}}_{{\mathbb f}}\end{pmatrix}\ ] ] and its inverse is @xmath198^{-1 } = \begin{pmatrix } { { \mathbb i}}_{{\mathbb e } } & -{\boldsymbol{\omega}}[{\boldsymbol{\psi}},{\boldsymbol{\theta}}^ * ] { \boldsymbol{\omega}}[{\boldsymbol{\theta}},{\boldsymbol{\theta}}^*]^{-1 } & -{\boldsymbol{\omega}}[{\boldsymbol{\psi } } , { \boldsymbol{\psi}}^ * ] + { \boldsymbol{\omega}}[{\boldsymbol{\psi}},{\boldsymbol{\theta}}^*]{\boldsymbol{\omega}}[{\boldsymbol{\theta}},{\boldsymbol{\theta}}^*]^{-1}{\boldsymbol{\omega}}[{\boldsymbol{\theta } } , { \boldsymbol{\psi}}^ * ] \\ 0 & { \boldsymbol{\omega}}[{\boldsymbol{\theta}},{\boldsymbol{\theta}}^*]^{-1 } & - { \boldsymbol{\omega}}[{\boldsymbol{\theta}},{\boldsymbol{\theta}}^*]^{-1}{\boldsymbol{\omega}}[{\boldsymbol{\theta } } , { \boldsymbol{\psi}}^ * ] \\ 0 & 0 & { { \mathbb i}}_{{\mathbb f}}\end{pmatrix}.\ ] ] let us consider the case of @xmath199-dimensional transformation data space , @xmath200 , and @xmath201 , @xmath202 , then the transformed solution @xmath203 $ ] of the four point scheme ( recall that @xmath204 $ ] ) up to a constant vector reads @xmath205{\boldsymbol{\omega } } [ { \boldsymbol{\theta } } , { \boldsymbol{\theta}}^*]^{-1 } { \boldsymbol{\omega } } [ { \boldsymbol{\theta } } , h],\ ] ] where the corresponding transformed solutions @xmath206 of the linear problem and @xmath207 of the adjoint linear problem are given by equations @xmath208 { \boldsymbol{\omega}}[{\boldsymbol{\theta}},{\boldsymbol{\theta}}^*]^{-1}{\boldsymbol{\theta}}_i , \\
\tilde{h}_i & = h_i - { \boldsymbol{\theta}}^*_i { \boldsymbol{\omega}}[{\boldsymbol{\theta}},{\boldsymbol{\theta}}^*]^{-1}{\boldsymbol{\omega}}[{\boldsymbol{\theta } } , h],\end{aligned}\ ] ] and @xmath209^{-1}{\boldsymbol{\theta}}_i.\ ] ] the scalar ( @xmath210 ) fundamental transformation in the above form was given in @xcite . to connect the above formalism to the results of section [ sec:6p ] notice that given scalar solution @xmath211 of the linear system then the potential @xmath212 $ ] is the scalar solution of the system of second order linear equations
moreover , given the solution @xmath213 , of the adjoint linear system then the functions @xmath214 satisfy @xcite the linear system @xmath215 equations imply that the functions @xmath216 satisfy the corresponding equations @xmath217 adjoint of equations . in the case
@xmath218 we obtain therefore the data of the transformation being the solution @xmath24 of the linear problem and the solution @xmath219 of its adjoint , thus we recover results of theorem [ th:6p - dt ] with the four point specification in the affine gauge ; see @xcite for more detailed description . notice that in order to describe fundamental transformation in the second order formalism for @xmath220 one should consider in addition the algebraic relations @xmath221 which are consequences of definition .
it is important to notice that the vectorial fundamental transformation can be obtained as a superposition of @xmath199 scalar transformations , which follows from the following observation .
[ th : perm - fund ] assume the following splitting of the data of the vectorial fundamental transformation @xmath222 associated with the partition @xmath223 , which implies the following splitting of the potentials @xmath224 = \left ( \begin{array}{c } \boldsymbol{\omega}[{\boldsymbol{\theta}}^a , h ] \\ \boldsymbol{\omega}[{\boldsymbol{\theta}}^b , h ] \end{array } \right ) , \qquad \boldsymbol{\omega}[{\boldsymbol{\theta}},{\boldsymbol{\theta}}^ * ] = \left ( \begin{array}{cc } \boldsymbol{\omega}[{\boldsymbol{\theta}}^a,{\boldsymbol{\theta}}_a^ * ] & \boldsymbol{\omega}[{\boldsymbol{\theta}}^a,{\boldsymbol{\theta}}_b^ * ] \\ \boldsymbol{\omega}[{\boldsymbol{\theta}}^b,{\boldsymbol{\theta}}_a^ * ] & \boldsymbol{\omega}[{\boldsymbol{\theta}}^b,{\boldsymbol{\theta}}_b^*]\end{array } \right),\ ] ] @xmath225 = \left ( \begin{array}{cc } \boldsymbol{\omega}[\boldsymbol{\psi},{\boldsymbol{\theta}}_a^ * ] & \boldsymbol{\omega}[\boldsymbol{\psi},{\boldsymbol{\theta}}_b^*]\end{array } \right).\ ] ] then the vectorial fundamental transformation is equivalent to the following superposition of vectorial fundamental transformations : + 1 ] transformation @xmath226 with the data @xmath227 , @xmath228 and the corresponding potentials @xmath229 $ ] , @xmath230 $ ] , @xmath231 $ ] @xmath232 \boldsymbol{\omega}[{\boldsymbol{\theta}}^a,{\boldsymbol{\theta}}^*_a]^{-1 } \boldsymbol{\omega}[{\boldsymbol{\theta}}^a , h],\\ \boldsymbol{\psi}_i^{\{a\ } } & = \boldsymbol{\psi}_i - \boldsymbol{\omega}[\boldsymbol{\psi},{\boldsymbol{\theta}}^*_a ] \boldsymbol{\omega}[{\boldsymbol{\theta}}^a,{\boldsymbol{\theta}}^*_a]^{-1 } { \boldsymbol{\theta}}^a_i , \\ h_i^{\{a\ } } & = h_i - { \boldsymbol{\theta}}^*_{i a } \boldsymbol{\omega}[{\boldsymbol{\theta}}^a,{\boldsymbol{\theta}}^*_a]^{-1 } \boldsymbol{\omega}[{\boldsymbol{\theta}}^a , h].\end{aligned}\ ] ] 2 ] application on the result the vectorial fundamental transformation with the transformed data @xmath233 \boldsymbol{\omega}[{\boldsymbol{\theta}}^a,{\boldsymbol{\theta}}^*_a]^{-1 } { \boldsymbol{\theta}}^a_i , \\ { { \boldsymbol{\theta}}}_{i b}^{*\{a\ } } & = { \boldsymbol{\theta}}_{i b}^ * - { \boldsymbol{\theta}}^*_{i a } \boldsymbol{\omega}[{\boldsymbol{\theta}}^a,{\boldsymbol{\theta}}^*_a]^{-1 } \boldsymbol{\omega}[{\boldsymbol{\theta}}^a , { \boldsymbol{\theta}}_{b}^*],\end{aligned}\ ] ] and potentials @xmath234^{\{a\ } } & = \boldsymbol{\omega}[{\boldsymbol{\theta}}^b , h ] - \boldsymbol{\omega}[{\boldsymbol{\theta}}^b,{\boldsymbol{\theta}}^*_a ] \boldsymbol{\omega}[{\boldsymbol{\theta}}^a,{\boldsymbol{\theta}}^*_a]^{-1 } \boldsymbol{\omega}[{\boldsymbol{\theta}}^a , h]= \boldsymbol{\omega}[{{\boldsymbol{\theta}}}^{b\{a\}},h^{\{a\ } } ] , \\ { \boldsymbol{\omega}}[{\boldsymbol{\theta}}^b,{\boldsymbol{\theta}}^*_b]^{\{a\ } } & = \boldsymbol{\omega}[{\boldsymbol{\theta}}^b,{\boldsymbol{\theta}}^*_b ] - \boldsymbol{\omega}[{\boldsymbol{\theta}}^b,{\boldsymbol{\theta}}^*_a ] \boldsymbol{\omega}[{\boldsymbol{\theta}}^a,{\boldsymbol{\theta}}^*_a]^{-1 } \boldsymbol{\omega}[{\boldsymbol{\theta}}^a,{\boldsymbol{\theta}}^*_b]= \boldsymbol{\omega}[{{\boldsymbol{\theta}}}^{b\{a\}},{{\boldsymbol{\theta}}}_b^{*\{a\ } } ] , \\ { \boldsymbol{\omega}}[\boldsymbol{\psi},{\boldsymbol{\theta}}^*_b]^{\{a\ } } & = \boldsymbol{\omega}[\boldsymbol{\psi},{\boldsymbol{\theta}}^*_b ] - \boldsymbol{\omega}[\boldsymbol{\psi},{\boldsymbol{\theta}}^*_a ] \boldsymbol{\omega}[{\boldsymbol{\theta}}^a,{\boldsymbol{\theta}}^*_a]^{-1 } \boldsymbol{\omega}[{\boldsymbol{\theta}}^a,{\boldsymbol{\theta}}^*_b]= \boldsymbol{\omega}[{\boldsymbol{\psi}}^{\{a\}},{{\boldsymbol{\theta}}}_b^{*\{a\ } } ] , \label{eq : fund - vect - potentials - slit}\end{aligned}\ ] ] i.e. , @xmath235^{\{a\ } } [ { \boldsymbol{\omega}}[{\boldsymbol{\theta}}^b,{\boldsymbol{\theta}}^*_b]^{\{a\}}]^{-1 } { \boldsymbol{\omega}}[{\boldsymbol{\theta}}^b , h]^{\{a\}}.\ ] ] the above formulas , apart from existence of the @xmath114-function , remain valid ( eventually one needs the proper ordering of some factors ) if , instead of the real field @xmath236 , we consider @xcite arbitrary division ring .
notice , that because the structure of the transformation formulas is a consequence of equation then the formulas may be expressed in terms of quasi - determinants @xcite ( recall , that roughly speaking , a quasi - determinant is the inverse of an element of the inverse of a matrix with entries in a division ring ) .
let us list basic reductions of the ( scalar ) fundamental transformation .
we follow the nomenclature of @xcite which has origins in geometric terminology of transformations of conjugate nets @xcite .
we provide also the terminology of modern theory of integrable systems @xcite , where the fundamental transformation is called the binary darboux transformation .
all the transformations presented in this section can be derived @xcite from the fundamental transformation through limiting procedures .
given a scalar solution @xmath211 of the linear problem the lvy transform of @xmath237 $ ] is then given by @xmath238}{\theta_i } { \boldsymbol{\psi}}_i.\ ] ] the transformed lam coefficients and new wave functions are of the form @xmath239 \ ; , \\ { { \mathcal l}}_i(h_j ) & = h_j - \frac{q_{ij}}{\theta_i}{\boldsymbol{\omega}}[\theta , h ] \ ; , \\ { { \mathcal l}}_i({\boldsymbol{\psi}}_i ) & = -{\boldsymbol{\psi}}_{i(i ) } + \frac{\theta_{i(i)}}{\theta_i}{\boldsymbol{\psi}}_i \ ; , \\ { { \mathcal l}}_i({\boldsymbol{\psi}}_j ) & = { \boldsymbol{\psi}}_j - \frac{\theta_j}{\theta_i}{\boldsymbol{\psi}}_i \ ; .\end{aligned}\ ] ] within the nonlocal @xmath240-dressing method the elementary darboux transformation was introduced in @xcite .
given a scalar solution @xmath213 of the adjoint linear problem the adjoint lvy transform @xmath241 of @xmath242 is given by @xmath243.\ ] ] the new lam coefficients and the wave functions are of the form @xmath244 \ ; , \\ { { \mathcal l}}^*_i({\boldsymbol{\psi}}_j ) & = { \boldsymbol{\psi}}_j - \frac{q_{ji}}{\theta_i^*}{\boldsymbol{\omega}}[{\boldsymbol{\psi}},\theta^ * ] \ ; .\end{aligned}\ ] ] as it was shown in @xcite , the scalar fundamental transformation can be obtained as superposition of the lvy transformation and its adjoint .
the closed formulae for iterations of the lvy transformations in terms of casorati determinants , and analogous result for the adjoint lvy transformation , was given in @xcite .
the description of the lvy transformation and its adjoint in the homogeneous formalism in the case of @xmath218 is given in @xcite . from analytic @xcite and geometric @xcite point of view
one can distinguish also the so called _ combescure transformation _
, whose algebraic description is however very simple ( the wave functions @xmath170 are invariant ) . the combescure transformation supplemented by the _ projective ( or radial _ transformation ,
whose algebraic description is also trivial @xcite ) , generate the fundamental transformation .
see also section [ dodane ] and [ gc ] for generalization of the combescure transformation .
the following transformations does not involve any functional parameters , and can be considered as further degeneration of the lvy ( or its adjoint ) reduction .
the laplace transformation of @xmath242 is given by @xmath245 the lam coefficients of the transformed linear problems read @xmath246 and the new wave functions read @xmath247 the laplace transformations satisfy generically the following identities @xmath248 the laplace transformation for the four point affine scheme was introduced in @xcite following the geometric ideas of @xcite and independently in @xcite using the factorization approach .
the generalization for systems of four point schemes ( quadrilateral lattices ) was given in @xcite . as it was shown in @xcite
the functions @xmath249 defined by equation are @xmath114-functions of the transformed four point schemes @xmath250 @xmath251 which , due to , leads @xcite to the discrete toda system @xcite .
in this section we study ( systems of ) four point linear equations subject to additional constraints , and we provide corresponding reductions of the fundamental transformation .
the basic algebraic idea behind such reduced transformations lies in a relationships between solutions of the linear problem and its adjoint , which should be preserved by the fundamental transformation ( see , for example , application of this technique in @xcite to reductions of the binary darboux transformation for the toda system ) .
some results presented here have been partially covered in section [ sec:4p-6p ] but in a different setting .
consider the system of discrete moutard equations ( the discrete bkp linear problem @xcite ) @xmath252 for suitable functions @xmath253 .
compatibility of the system implies existence of the potential @xmath254 , in terms of which the functions @xmath255 can be written as @xmath256 which satisfies system of miwa s discrete bkp equations @xcite @xmath257 the discrete moutard system can be given @xcite the first order formulation - upon introducing the lam coefficients @xmath258 and the rotation coefficients ( below we assume @xmath259 ) @xmath260 which in view of , gives the familiar relation between the @xmath114-functions of the kp and bkp hierarchies @xmath261 the corresponding reduction of the fundamental transformation was given in @xcite , where also a link with earlier work @xcite on the discrete moutard transformation has been established .
[ prop : vect - fund - red - bql ] given solution @xmath262 of the linear problem corresponding to the moutard linear system and its first order form - .
denote by @xmath263 $ ] the corresponding potential , which is also new vectorial solution of the linear problem .
+ 1 ) then @xmath264 provides a vectorial solution of the adjoint linear problem , and the corresponding potential @xmath265 $ ] allows for the following constraint @xmath266 + \boldsymbol{\omega}[\boldsymbol{\theta},\boldsymbol{\theta}^*]^t = 2 \boldsymbol{\theta}\otimes \boldsymbol{\theta}^t.\ ] ] 2 ) the fundamental vectorial transform @xmath267 of @xmath242 , given by with the potentials @xmath188 restricted as above satisfies moutard linear system and can be considered as the superposition of @xmath199 scalar reduced fundamental transforms . in the scalar case and for
@xmath268 inserting in equations and the functions @xmath269 and @xmath270 given by and correspondingly , we obtain the formula in the gauge @xmath271 ( modulo the corresponding change of sign ) . notice that given @xmath272 then , because of the constraint , to construct @xmath273 we need only its antisymmetric part @xmath274 , which satisfies the system @xmath275 this observation is the key element of the connection of the above reduction of the fundamental transformation with earlier results @xcite on the vectorial moutard transformation for the system , where the formulas using pfaffians were obtained ( recall that determinant of a skew - symmetric matrix is a square of pfaffian ) .
in particular , the transformation rule for the @xmath276-function can be recovered @xmath277 consider the linear problem subject to the constraint @xcite which arose from studies on the egorov lattices @xcite @xmath278 then the discrete darboux equations can be rewritten @xcite in the following quartic form @xmath279 which can be identified with equation derived in @xcite in connection with the star - triangle relation in the ising model . according to @xcite , the above equation can be obtained from the ckp hierarchy via successive application of the corresponding reduction of the binary darboux transformations .
construction @xcite of the reduction of the fundamental transformations which preserves the constraint makes use the following observation .
the following conditions are equivalent : + 1 ) the functions @xmath173 , @xmath178 satisfy constraint ; + 2 ) given a nontrivial solution @xmath280 of the adjoint linear problem then @xmath281 provides a solution of the linear problem ; + 3 ) the corresponding potential @xmath185 $ ] allows for the constraint @xmath282^t= \boldsymbol{\omega}[\boldsymbol{\phi},\boldsymbol{\phi}^*].\ ] ] when the data @xmath283 , @xmath284 , @xmath285 $ ] of the fundamental transformation satisfy conditions - then the new functions @xmath286 , @xmath287 found by equations , are constrained by , i.e. @xmath288 the corresponding permutability principle has been proved in @xcite . to connect the symmetric reduction with the goursat equation and the corresponding transformation
( see section [ gr ] ) notice that because of corollary [ cor:4p - psi - i ] and equations - the function @xmath289 satisfies equation with @xmath290 .
then , due to the same corollary and condition , given scalar solution @xmath291 of the four point equation of @xmath289 then the function @xmath292 satisfies its adjoint ; in the lat equation we have used the linear problem and equation . consider the system of four point equations which solution @xmath242 is subject to the following quadratic constraint @xmath293 here @xmath294 is a non - degenerate symmetric matrix , @xmath295 is a constant vector , @xmath296 is a scalar .
notice that unlike in two previous reductions we fix ( by giving the quadratic equation ) the dimension of @xmath242 . double discrete differentiation of equation in @xmath297 directions gives , after some algebra , the condition @xmath298 analogous to that obtained in @xcite in order to characterize circular lattices @xcite .
it implies @xcite , in particular , that @xmath299 satisfy the same equation as the potentials @xmath178 . as in two above reductions
, the quadratic condition allows for a relation between solutions of the linear system and its adjoint .
the following proposition can be easily derived from analogous results of @xcite , where as the basic ingredient of the transformation was used the potential @xmath300 $ ] , but we present here its direct proof in the spirit of corresponding results found for the circular lattice @xcite . given a nontrivial solution @xmath301 of the adjoint linear problem corresponding to the system of four point equations which solution @xmath242 is subject to the constraint then @xmath302_{(i ) } + { \boldsymbol{\omega}}[{\boldsymbol{\psi } } , { \boldsymbol{\theta}}^*])^t q { \boldsymbol{\psi}}_i\ ] ] provides a solution of the corresponding linear problem .
after some algebra using the equations satisfied by @xmath303 and @xmath170 one gets @xmath304 which vanishes due to .
the following result gives the discrete ribaucour reduction of the fundamental transformation .
given solution @xmath305 of the adjoint linear problem corresponding to the quadratic constraint .
+ 1 ) then the potentials @xmath300 $ ] , @xmath306 $ ] and @xmath307 $ ] , where @xmath283 is the solution of the linear problem constructed from @xmath284 by means of formula , allow for the constraints @xmath308^t & = 2 { \boldsymbol{\psi}}^t q { \boldsymbol{\omega}}[{\boldsymbol{\psi } } , { \boldsymbol{\theta}}^ * ] + { \boldsymbol{a}}^t { \boldsymbol{\omega}}[{\boldsymbol{\psi } } , { \boldsymbol{\theta}}^ * ] \ ; \ ; , \\ \label{eq : bphic - qv } { \boldsymbol{\omega}}[{\boldsymbol{\theta } } , { \boldsymbol{\theta}}^ * ] + { \boldsymbol{\omega}}[{\boldsymbol{\theta } } , { \boldsymbol{\theta}}^*]^t & = 2 { \boldsymbol{\omega}}[{\boldsymbol{\psi } } , { \boldsymbol{\theta}}^*]^t q { \boldsymbol{\omega}}[{\boldsymbol{\psi } } , { \boldsymbol{\theta}}^ * ] \ ; .\end{aligned}\ ] ] 2 ) the ribaucour reduction of the fundamental vectorial transform @xmath267 of @xmath242 , given by with the potentials @xmath188 restricted as above satisfies the quadratic constraint and can be considered as the superposition of @xmath199 scalar ribaucour transformations . as it was explained in @xcite ,
the ribaucour transformations @xcite of the circular lattice @xcite can be derived from the above approach after the stereographic projection from the mbius sphere .
the superposition principle for the ribaucour transformation of circular lattices was derived also in @xcite .
in this final section we present the vectorial darboux transformations for the three point scheme .
the corresponding nonlinear difference system , known as the hirota miwa equation , is perhaps the most important and widely studied integrable discrete system .
it was discovered by hirota @xcite , who called it the discrete analogue of the two dimensional toda lattice ( see also @xcite ) , as a culmination of his studies on the bilinear form of nonlinear integrable equations .
general feature of hirota s equation was uncovered by miwa @xcite who found a remarkable transformation which connects the equation to the kp hierarchy @xcite .
the hirota - miwa equation , called also the discrete kp equation , can be encountered in various branches of theoretical physics @xcite and mathematics @xcite .
consider the linear system @xcite @xmath309 whose compatibility leads to the following parametrization of the field @xmath310 in terms of the potentials @xmath311 @xmath312 and then to existence of the @xmath114 function @xmath313 and , finally to the the discrete kp system @xcite @xmath314 the same nonlinear systems arises from compatibility of @xmath315 called the adjoint of .
we present the darboux transformation for the three point scheme in the way similar to that of section [ sec : fund ] following the approach of @xcite , see however early works on the subject @xcite .
[ th : vect - darb - kp ] given the solution @xmath316 , of the linear system , and given the solution @xmath317 , of the adjoint linear system .
these allow to construct the linear operator valued potential @xmath318 : \mathbb{z}^n\to \mathrm{l}({{\mathbb w}},{{\mathbb u}})$ ] , defined by @xmath319 = \boldsymbol{\phi } \otimes \boldsymbol{\phi}^*_{(i ) } , \qquad i = 1,\dots , n.\ ] ] if @xmath187 and the potential @xmath188 is invertible , @xmath318\in\mathrm{gl}({{\mathbb w}})$ ] , then @xmath320^{-1}\boldsymbol{\phi } , \label{eq : hatp}\\ \tilde{\boldsymbol{\phi}}^*&=\boldsymbol{\phi}^ * { \boldsymbol{\omega}}[{\boldsymbol{\phi}},{\boldsymbol{\phi}}^*]^{-1},\label{eq : hatp*}\end{aligned}\ ] ] satisfy the linear systems and , correspondingly , with the fields @xmath321^{-1 } \boldsymbol{\phi})_{(i ) } + ( \boldsymbol{\phi}^ * { \boldsymbol{\omega}}[\boldsymbol{\phi},\boldsymbol{\phi}^*]^{-1 } \boldsymbol{\phi})_{(j)}.\ ] ] in addition , @xmath322 = c - { \boldsymbol{\omega}}[\boldsymbol{\phi},\boldsymbol{\phi}^*]^{-1},\ ] ] where @xmath192 is a constant operator .
the transformation rule for the potentials @xmath311 reads @xmath323^{-1 } \boldsymbol{\phi } ) , \ ] ] while using the technique of the bordered determinants @xcite one can show that @xcite @xmath324 \label{eq : hat - tau - dkp}.\ ] ] more standard transformation formulas arise , when one splits , like in section [ sec : fund ] , the vector space @xmath195 of theorem [ th : vect - darb - kp ] as follows @xmath325 if @xmath326 then the corresponding potential matrix and its inverse have the structure like those in section [ sec : fund ] , which gives @xcite @xmath327 { \boldsymbol{\omega}}[{\boldsymbol{\theta}},{\boldsymbol{\theta}}^*]^{-1}{\boldsymbol{\theta}},\\ \tilde{\boldsymbol{\psi}}^ * & = \boldsymbol{\psi}^ * - { \boldsymbol{\theta}}^ * { \boldsymbol{\omega}}[{\boldsymbol{\theta}},{\boldsymbol{\theta}}^*]^{-1}{\boldsymbol{\omega}}[{\boldsymbol{\theta } } , \boldsymbol{\psi}^*],\\ \tilde{u}_{ij } & = u_{ij } - ( { \boldsymbol{\theta}}^ * { \boldsymbol{\omega}}[{\boldsymbol{\theta}},{\boldsymbol{\theta}}^*]^{-1 } { \boldsymbol{\theta}})_{(i ) } + ( { \boldsymbol{\theta}}^ * { \boldsymbol{\omega}}[{\boldsymbol{\theta}},{\boldsymbol{\theta}}^*]^{-1 } { \boldsymbol{\theta}})_{(j)}.\end{aligned}\ ] ] notice that one can consider @xcite the three point linear problem in associative algebras .
then the structure of the transformation formulas implies the quasi - determinant interpretation @xcite of the above equations .
the permutability property for the darboux transformations of the three point scheme @xcite can be formulated exactly ( cancel subscripts @xmath328 ) like theorem [ th : perm - fund ] .
finally we remark that the binary darboux transformation for the three point linear problem can be decomposed @xcite into superposition of the elementary darboux transformation and its adjoint , which can be described as follows . given a scalar solution @xmath24 of the linear problem then the elementary darboux transformation @xmath329\ ; , \\ { { \mathcal d}}(\tau ) & = \theta \tau\end{aligned}\ ] ] leaves equations and invariant .
analogously , given a scalar solution @xmath330 of the linear problem then the adjoint elementary darboux @xmath331 , \\ { { \mathcal d}}^*(\boldsymbol{\psi}^ * ) & = - \boldsymbol{\psi}^*_{(-i ) } + \frac{\theta^*_{(-i)}}{\theta^ * } \boldsymbol{\psi}^ * , \\ { { \mathcal d}}^*(\tau ) & = \theta^ * \tau\end{aligned}\ ] ] leaves equations and invariant .
the above transformations allow for vectorial forms , which can be conveniently written @xcite in terms of casorati determinants .
in the paper we aimed to present results on darboux transformations of linear operators on two dimensional regular lattices . to put some order into the review we started from the six point scheme ( and its darboux transformation ) as the master linear problem .
the path between its various specifications and reductions has been visualized in figure [ 5p ] .
we considered also in more detail the corresponding theory of the darboux transformations of the systems of the four point schemes and their reductions .
finally , we briefly discussed the multidimensional aspects of the three point schemes .
it is worth to mention that for systems of the three or four point schemes the darboux transformations can be interpreted as a way to generate new dimensions .
this is very much connected to the permutability of the transformations , which is a core of integrability of the corresponding nonlinear systems .
separate issue touched here is such extention of four point schemes that can be regarded as an analogue of discretization of a diferential equation in arbitrary parametrization .
more precisely we discussed here such an extension of general ( akp ) case ( section [ gc ] ) and moutard selfadjoint ( bkp ) case ( sections [ mr ] and [ sec : s - a ] ) .
goursat and ribaucour reductions have not been investigated from this point of view .
the multidimensional schemes that mimic equations governing conjugate nets ( and their reductions ) with arbitrary change of independend variables have been not exploited either .
we also mentioned another approach to the problem of construction of the unified theory of the darboux transformations .
it consists in isolating basic `` bricks '' in order to use their combinations to construct more involved linear operators together with their darboux transformations .
such an idea has been applied to derive , starting from the moutard reduction of the four point scheme , the self - adjoint operators on the square ( the five point scheme ) , triangular ( the seven point scheme ) and the honeycomb grids .
recently it was shown in @xcite that the theory of systems of four point linear equations and their laplace transformations follows from the theory of the three point systems .
this means , that also the transformations of the four point scheme can be , in principle , derived from the three point scheme .
an open question is if the six point scheme and its transformations can be decomposed in a similar way .
finally , we would like to mention possibility of considering ( hierarchies of ) continuous deformations of the above lattice linear problems , which would lead to ( hierarchies of ) discrete - differential integrable by construction equations .
some aspects of deformations of the self - adjoint seven and five linear systems have been elaborated in @xcite .
the authors thank the isaac newton institute for mathematical sciences ( cambridge , uk ) for hospitality during the programme _ discrete integrable systems_. a. i. bobenko , ch .
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kluwer academic publishers , 1993 , pp . 193206 . | darboux transformations for linear operators on regular two dimensional lattices are reviewed .
the six point scheme is considered as the master linear problem , whose various specifications , reductions , and their sublattice combinations lead to other linear operators together with the corresponding darboux transformations . the second part of the review deals with multidimensional aspects of ( basic reductions of ) the four point scheme , as well as the three point scheme . | <s>[INST]darboux transformations are a well known tool in the theory of integrable systems @xcite .
the classical darboux transformation @xcite deals with a sturm liouville problem ( the one dimensional stationary schrdinger equation ) generating , at the same time , new potentials and new wave functions from given ones thus providing solutions to the korteweg de vries hierarchy of @xmath0 dimensional integrable systems . however , as it is clearly stated in @xcite , it was an earlier work of moutard @xcite which inspired darboux . in that work one can find the proper transformation that applies to @xmath1 dimensional integrable systems .
note that the initial area of applications of the darboux transformations , which preceded the theory of integrable systems , was the theory of conjugate and asymptotic nets where the large body of results on darboux transformations was formulated @xcite .
most of the techniques that allow us to find solutions of integrable non - linear differential equations have been successfully applied to difference equations .
these include mutually interrelated methods such as bilinearization method @xcite and the sato approach @xcite , direct linearization method @xcite , inverse scattering method @xcite , the nonlocal @xmath2 dressing method @xcite , the algebro - geometric techniques @xcite .
also the method of the darboux transformation has been successfully applied to the discrete integrable systems .
the present paper aims to review application of the darboux transformation technique for the equations that can be regarded as discretizations of second order linear differential equations in two dimensions , their distinguished subclasses and systems of such equations . while presenting the results we are trying to keep the relation with continuous case .
however , we are aware of weak points of this way of exposition .
the theory of discrete integrable systems @xcite is reacher but also , in a sense , simpler then the corresponding theory of integrable partial differential equations . in the course of a limiting procedure , which gives differential systems from the discrete ones , various symmetries and relations between different discrete systems
the classical example is provided ( see , for example @xcite ) by the hierarchy of the kadomsev
petviashvilii ( kp ) equations , which can be obtained from a single hirota
miwa equation the opposite way , from differential to discrete , involves all equations of the hierarchy @xcite .
the structure of the paper is as follows . in section [ dodane ]
we expose main ideas in the theory of darboux transformations in multidimension . in section [ sec:6p ]
we present the construction of the darboux transformation for the discrete second order linear problem the 6-point scheme which can be considered as a discretization of the general second order linear partial differential equation in two variables .
then we discuss various specifications and reductions of the 6-point scheme .
we separately present in section [ sec : s - a ] the darboux transformations for discrete self - adjoint two dimensional linear systems on the square , triangular and the honeycomb lattices , and their relation to the discrete moutard transformation .
section [ sec:4p ] is devoted to detailed presentation of the darboux transformations for systems of the 4-point linear problems , their various specifications and the corresponding permutability theorems .
sec:4p - red ] is dedicated to reductions of the fundamental transformation compatible with additional restrictions on the form of the four point scheme .
finally , in section [ 3p - sch ] we review the darboux transformations for the 3-point linear problem , and the corresponding celebrated hirota s discrete kp nonlinear system .
the main idea included in the paper has its origin in jonas paper @xcite where fundamental transformation for conjugate nets has been presented . neglecting the geometrical context of jonas paper we only would like to say that the fundamental transformation acts on solutions of compatible system of second order linear differential equations on function @xmath3 @xmath4 where coefficients @xmath5 and @xmath6 are functions of @xmath7 , and for @xmath8 they have to obey a nonlinear differential equation ( compatibility conditions ) ; we use notation that subscript preceded by coma denotes partial differentiation with respect to indicated variables .
every fundamental transformation @xmath9 can be presented as composition of suitably chosen 1 .
radial transformation @xmath10 @xmath11 2 .
combescure transformation @xmath12 @xmath13 3 .
radial transformation @xmath14 @xmath15 we refer interested reader to eisenhart book @xcite for further details .
as the practice shows the fundamental transformation is indeed fundamental - in the sense that most ( if not all ) of the darboux transformations are reductions of the fundamental transformation . here
we follow this basic idea discovered almost one hundred years ago .
we start from presenting two dimensional difference operators @xmath16 ( and corresponding difference equations @xmath17 , where @xmath18 is function of discrete variables @xmath19 and @xmath20 ) together with the transformation @xmath21 which is composition of 1 .
gauge transformation @xmath22 ( see subsection [ ge ] ) @xmath23 where @xmath24 is a solution of @xmath25 whereas @xmath26 is a solution of @xmath27 where @xmath28 denotes operator formally adjoint to operator @xmath16 .
we emphasize that this particular choice of functions @xmath24 and @xmath26 is essential , for it guarantees existence of function @xmath29 in the next transformation 2 .
transformations @xmath30 that take either the form ( details are given in the text below ) @xmath31 = \left [ \begin{matrix } \alpha & \beta\cr \gamma & \delta \end{matrix } \right ] \left [ \begin{matrix } { \delta_1}\psi_r \cr { \delta_2}\psi_r \end{matrix } \right ] \end{array}\ ] ] or the form @xmath32 = \left [ \begin{matrix } \alpha & \beta\cr \gamma & \delta \end{matrix } \right ] \left [ \begin{matrix } { \delta_{-1}}\psi_r \cr { \delta_{-2}}\psi_r \end{matrix } \right ] \end{array}\ ] ] where @xmath33 , @xmath34 denote forward difference operators @xmath35 , @xmath36 , whereas @xmath37 , @xmath38 denote backward difference operators @xmath39 , @xmath40 .
3 . gauge transformation @xmath41 @xmath42 where in general @xmath43 and @xmath44 are arbitrary functions ( which should be specified when reductions or specifications of the transformations are considered ) .
( 620,400 ) ( 90,360)(215,90 ) ( -10,375)(40,10)[l]6-point ( 80,390 ) ( 73,380)(87,380 ) ( 66,370)(80,370 ) ( 94,370 ) ( 120,375)(40,10)[l]sect .
[ gc ] ( -10,325)(50,10)[l]@xmath45 ( -10,350)(50,10)[l]@xmath46 ( 90,310)(0,-1)55 ( 15,285)(50,10)[l]specification ( 0,270)(50,10)[l]@xmath47 , @xmath48 ( 20,250)(0,-1)80 ( 160,250)(0,-1)80 ( 20,250)(1,0)140 ( 20,170)(1,0)140 ( 30,225)(40,10)[l]4-point ( 78,235)(88,235 ) ( 78,225)(88,225 ) ( 100,225)(40,10)[l]sect .
[ sec:4p-6p ] , [ sec : fund ] ( 30,200)(50,10)[l]@xmath49 ( 30,175)(50,10)[l]@xmath50 ( 90,165)(0,-1)55 ( 15,140)(50,10)[l]specification ( 30,125)(50,10)[l]@xmath51 ( 30,105)(0,-1)70 ( 150,105)(0,-1)70 ( 30,105)(1,0)120 ( 30,35)(1,0)120 ( 40,85)(40,10)[l]3-point ( 78,95)(92,95 ) ( 85,85 ) ( 100,85)(40,10)[l]sect . [ 3mn ] , [ 3p - sch ] ( 40,65)(50,10)[l]@xmath52 ( 40,45)(50,10)[l]@xmath53 ( 165,240)(40,10)[l]ribaucour reduction ( 165,230)(1,0)90 ( 255,230)(0,-1)15 ( 210,210)(0,-1)60 ( 300,210)(0,-1)60 ( 210,210)(1,0)90 ( 210,150)(1,0)90 ( 220,195)(40,10)[l]see section [ qr ] ( 215,175)(40,10)[l]@xmath18 lies on a quadric ( 215,160)(40,10)[l]@xmath54 lies on a quadric ( 145,130)(0,1)35 ( 425,130)(-1,0)280 ( 425,130)(0,1)15 ( 330,135)(50,10)[l]moutard reduction ( 330,210)(0,-1)60 ( 423,210)(0,-1)60 ( 330,210)(1,0)93 ( 330,150)(1,0)93 ( 340,195)(50,10)[l]discrete moutard ( 345,185)(40,10)[l]sect . [ mr ] , [ bkp ] ( 332,170)(50,10)[l]@xmath55 ( 350,155)(50,10)[l]@xmath56 ( 423,180)(1,0)4 ( 427,210)(0,-1)60 ( 527,210)(0,-1)60 ( 427,210)(1,0)100 ( 427,150)(1,0)100 ( 440,195)(50,10)[l]adjoint discrete ( 478,185)(50,10)[l]sect . [ mr ] ( 430,185)(50,10)[l]moutard , ( 428,170)(50,10)[l]@xmath57 ( 447,155)(50,10)[l]@xmath56 ( 335,365)(135,70 ) ( 273,385 ) ( 60,10)[l]7-point ( 268,375 ) ( 60,10)[l]selfadjoint ( 328,395)(342,395 ) ( 321,385)(335,385 ) ( 349,385 ) ( 328,375)(342,375 ) ( 355,380)(40,10)[l]sect .
[ 7ps ] ( 270,360)(100,10)[l]@xmath58 ( 270,350)(100,10)[l]@xmath59 ( 272,335)(100,10)[l]@xmath60 ( 475,365)(135,70 ) ( 415,380)(50,10)[l]honeycomb ( 483,395)(497,395 ) ( 476,385 ) ( 504,385 ) ( 483,375)(497,375 ) ( 410,355)(50,10)[l]see section [ hcb ] for details ( 405,215)(0,1)115 ( 405,330)(-1,0)10 ( 260,315)(50,10)[l]specification @xmath61 ( 405,330)(1,0)10 ( 350,325)(0,-1)10 ( 410,275)(50,10)[l]sublattice approach ( 410,265)(50,10)[l]on quasi - regular ( 410,255)(50,10)[l ] rhombic lattice ( 380,215)(0,1)20 ( 290,225)(50,10)[l]sublattice approach ( 290,215)(50,10)[l]on square lattice ( 335,275)(130,70 ) ( 276,295 ) ( 60,10)[l]5-point ( 271,285 ) ( 60,10)[l]selfadjoint ( 334,305 ) ( 324,295 ) ( 334,295)(344,295 ) ( 334,285 ) ( 352,290)(40,10)[l]sect .
[ 5r ] ( 290,270)(100,10)[l]@xmath62 ( 290,260)(100,10)[l]@xmath63 ( 290,245)(100,10)[l]@xmath64 ( 125,120)(0,1)45 ( 595,120)(-1,0)470 ( 595,120)(0,1)25 ( 510,125)(50,10)[l]goursat reduction ( 550,235)(0,-1)85 ( 640,235)(0,-1)85 ( 550,235)(1,0)90 ( 550,150)(1,0)90 ( 557,225)(50,10)[l]discrete goursat ( 560,215)(40,10)[l]sect .
[ gr ] , [ ckp ] ( 551,200)(100,10)[l ] @xmath65 ( 551,185)(100,10)[l ] @xmath66 ( 551,170)(100,10)[l ] @xmath67 ( 551,150)(100,10)[l ] @xmath68
we pay special attention to subclasses of operators @xmath16 that admit darboux transformations .
a trivial , from the point of view of integrable systems , examples are subclasses obtained by fixing a gauge ( see section [ ge ] ) .
very important classes of operators are obtained by imposing conditions on the mentioned above functions @xmath24 and @xmath26 .
for example in the case of self - adjoint 7-point scheme we discuss in section [ 7ps ] , the relation is @xmath69 .
we refer to such procedures as to reductions .
the further examples of reductions are given in sections [ gr ] , [ mr ] and [ sec:4p - red ] .
we reserve separate name `` specification '' to the cases when the operator is reduced , whereas the transformations remain essentially unaltered ( i.e. no constraint on functions @xmath24 and @xmath26 is necessary ) .
examples of specifications are given in sections [ sec:4p-6p ] , [ 5r ] and [ 3mn ] . with the notion of `` specification '' another important issue appears , since continuous counterparts of the specifications presented here can be viewed as a choice of particular gauge and independent variables .
the interesting ( because not well understood ) aspects of discrete integrable systems come from the fact there is no theory how to change discrete independent variables so that not to destroy underlying integrable phenomena .
sublattice approach , widely used in theoretical physics , can be regarded , to some extent , as counterpart of change of independent variables . to some extent , because the only case studied in detail from the point of view of darboux transformations is the case of self - adjoint equation , which in the discrete case consists of moutard case ( section [ mr ] ) , self - adjoint case ( section [ sec : s - a ] ) and their mutual relations ( c.f .
interrelations between results presented here are summarized in figure 1 .
large part of the paper is dedicated to the specification in which the matrix in is diagonal . in this case
one can consider systems of four point operators defined on lattices with arbitrary number of independent variables .
the multidimensional lattices are extensively discussed in sections [ sec:4p ] and [ sec:4p - red ] , where compact elegant expressions for superpositions of fundamental transformations are presented either .
in this section we present discretizations of equation and its subclasses covariant under darboux transformations . out of the schemes that can serve as a discretization of the 2d equation @xmath70 the following 6-point scheme @xmath71 deserve a special attention ( coefficients @xmath72 , @xmath73 etc .
and dependent variable @xmath18 are functions on @xmath74 , subscript in brackets denote shift operators , @xmath75 , @xmath76 , @xmath77 , @xmath78 and @xmath79 ) .
the scheme admits decomposition @xmath80\psi=0 $ ] ( where @xmath81 and @xmath82 are forward shift operators in first and second direction respectively ) and therefore its laplace transformations can be constructed ( see @xcite and section [ sec : laplace - tr ] for the notion of the laplace transformations of multidimensional linear operators ) . what more important from the point of view of this review the scheme is covariant under a fundamental darboux transformation @xcite ( the transformation is often referred to as binary darboux transformation in soliton literature ) .
indeed , [ th:6p - dt ] given a non - vanishing solution @xmath24 of @xmath83 and a non - vanishing solution @xmath26 of the equation adjoint to equation @xmath84 ( negative integers in brackets in subscript denote backward shift e.g. @xmath85 etc . ) the existence of auxiliary function @xmath86 is guaranteed @xmath87 then equation can be rewritten as @xmath88+\\ { \delta_1}\left [ a{_{(-1)}}\phi{_{(-1)}}\theta{_{(1)}}{\delta_1}\left(\frac{\psi}{\theta } \right ) -(p{_{(-1)}}- c{_{(-1)}})\phi{_{(-1)}}\theta{_{(2 ) } } ) { \delta_2}\left(\frac{\psi}{\theta } \right ) \right]=0 \end{array}\ ] ] which in turn guarantees the existence of functions @xmath89 such that @xmath90 = \left [ \begin{matrix } ( c{_{(-2)}}+ p{_{(-2)}})\phi{_{(-2)}}\theta{_{(1 ) } } & b{_{(-2)}}\phi{_{(-2)}}\theta{_{(2)}}\cr -a{_{(-1)}}\phi{_{(-1)}}\theta{_{(1)}}&(p{_{(-1)}}- c{_{(-1)}})\phi{_{(-1)}}\theta{_{(2)}}\end{matrix } \right ] \left [ \begin{matrix } { \delta_1}\left(\frac{\psi}{\theta } \right)\cr { \delta_2}\left(\frac{\psi}{\theta } \right ) \end{matrix } \right ] \end{array}\ ] ] assuming that matrix in is invertible on the whole lattice , i.e. everywhere and finally on introducing @xmath91 via @xmath92 and taking the opportunity of multiplying resulting equation by non - vanishing function @xmath43 , we arrive at the conclusion that the function @xmath91 satisfies equation of the form but with new coefficients @xmath93 the family of maps @xmath94 given by - we refer to as darboux transformations of equation .
we say that two linear operators @xmath16 and @xmath95 are gauge equivalent if one can find functions say @xmath26 and @xmath24 such that @xmath96 ( where @xmath97 stands for composition of operators ) .
the idea to consider equivalence classes of linear operators with respect to gauge rather than single operator itself , goes to laplace and darboux papers @xcite . in the continuous case it reflects in the fact that one can confine himself e.g. to equations ( the so called affine gauge ) @xmath98 or to ( in this case we would like to introduce the name _ basic gauge _ ) @xmath99 without loss of generality .
the darboux transformation can be viewed as transformation acting on equivalence classes ( with respect to gauge ) of equation ( compare @xcite ) .
therefore one can confine himself to particular elements of equivalence class .
commonly used choice is to confine oneself to the affine gauge i.e. to equations that obeys @xmath100 if one puts s = const in ( this condition is not necessary ) then the above constraint is preserved under the darboux transformation .
one can consider further specification of the gauge @xmath101 this choice of gauge we would like to refer as to basic gauge of equation .
note that if the equation is in a basic gauge its formal adjoint is in a basic gauge too . in the continuous case due to possibility of changing independent variables one can reduce , provided equation
is hyperbolic , to canonical form @xmath102 in the discrete case similar result can be obtained in a different way . taking a glance at ( [ dcoef ] )
we can notice that coefficients @xmath72 , @xmath73 and @xmath103 transform in a very simple manner .
in particular , if any of these coefficients equals zero then its transform equals zero too .
let us stress that in this case if we do so , we do not impose any constraints on transformation data , transformations remains essentially the same .
first we shall concentrate on the case when two out of three mentioned functions vanish .
if we put @xmath104 then from equation @xmath105 and one can adjust the function @xmath43 so that @xmath106 so we arrive at the 4-point scheme @xmath107 and its fundamental transformation c.f . @xcite .
we observe that the form of equation is covariant under the gauge @xmath108 and to identify whether two equations are equivalent or not we use the invariants of the gauge @xmath109 two equations are equivalent if their corresponding invariants @xmath110 and @xmath20 are equal @xcite . in this subsection
we discuss the discretization of class of equations @xmath111 which is referred to as goursat equation . the discrete counterpart of goursat equation arose from the surveys on egorov lattices @xcite and symmetric lattices @xcite and can be written in the form @xcite @xmath112 where functions @xmath113 and @xmath114 are related via @xmath115 the gauge invariant characterization of the discrete goursat equation is either @xmath116 or @xmath117 the goursat equation can be isolated from the others 4-point schemes in the similar way that goursat did it over hundred years ago @xcite i.e. as the equation such that one of its laplace transformations maps solutions of the equation to solutions of the adjoint equation . therefore in this case
if @xmath24 obeys @xmath118 then its laplace transformation @xmath119 is a solution of equation adjoint to equation @xcite .
equation is the constraint we impose on transformation data ( i.e. functions @xmath24 and @xmath26 ) in the fundamental transformation , ( we recall we have already put @xmath72 and @xmath73 equal to zero ) .
in addition if @xmath24 obeys then @xmath120\ ] ] and as a result there exists function @xmath121 such that @xmath122 now it can be shown that one can put @xmath123 { _ { ( 2)}}-{\vartheta}{_{(2)}}\ ] ] and the transformation takes form @xmath124 = \left [ \begin{matrix } \sqrt{\frac{\tau { _ { ( 2)}}}{\tau { _ { ( 1)}}}}\frac{\sqrt{{\delta_1}{\vartheta}{\delta_2}{\vartheta}}}{q } -{\vartheta } & 0 \cr 0 & - { \vartheta}{_{(2)}}\end{matrix } \right ] \left [ \begin{matrix } { \delta_1}\left(\sqrt{\frac{{\tau}}{{\tau { _ { ( 2 ) } } } } } \frac{\psi}{\sqrt{{\delta_2}{\vartheta}}}\right)\cr { \delta_2}\left(\sqrt{\frac{{\tau}}{{\tau { _ { ( 2 ) } } } } } \frac{\psi}{\sqrt{{\delta_2}{\vartheta } } } \right ) \end{matrix } \right ] \end{array}\ ] ] which is the discrete version of goursat transformation @xcite .
the transformation rule for the field @xmath114 is @xmath125 in this subsection we discuss discretization moutard equation and its ( moutard ) transformation @xcite @xmath126 moutard equation is self - adjoint equation ( which allowed us to impose reduction @xmath69 in the continuous analogue of transformation c.f .
the point is that opposite to the continuous case there is no appropriate self - adjoint 4-point scheme we do have the reduction of fundamental transformation that can be regarded as discrete counterpart of moutard transformation .
namely , class of equations that can be written in the form @xmath127 we refer nowadays to as discrete moutard equation .
it appeared in the context of integrable systems in @xcite and then its moutard transformations have been studied in detail in @xcite .
gauge invariant characterization of the class of discrete moutard equations is @xcite @xmath128 let us trace this reduction on the level of fundamental transformation
. putting @xmath129 and @xmath130 the equations , and take respectively form @xmath131 @xmath132 @xmath133 the crucial observation is : if the function @xmath24 satisfies equation then the function @xmath26 given by @xmath134 satisfies equation @xcite .
if we put @xmath135 then equations will be automatically satisfied .
if in addition we put in @xmath136 then darboux transformation takes form ( c.f .
@xcite ) @xmath137 = \left [ \begin{matrix } \theta \theta { _ { ( 1 ) } } & 0\cr 0 & -\theta \theta { _ { ( 2)}}\end{matrix } \right ] \left [ \begin{matrix } { \delta_1}\frac{\psi}{\theta}\cr { \delta_2}\frac{\psi}{\theta } \end{matrix } \right]\ ] ] and it serves as transformation @xmath94 that maps solutions of equation into solutions of another discrete moutard equation @xmath138 we recall that @xmath24 an arbitrary non - vanishing fixed solution of the equation @xmath139 every equation that is gauge equivalent to we refer to as an adjoint discrete equation moutard equation , its gauge invariant characterization is @xcite @xmath140 equation can be regarded as potential version of equation in the continuous case there is direct reduction of the fundamental transformation for equation to the moutard type transformation for self - adjoint equation @xcite @xmath141 in this section we present difference analogues of equation which allow for the darboux transformation.opposite to the continuous case the transformation will not be direct reduction of the fundamental transformation for the 6-point scheme .
the self - adjoint discrete operators studied below are however intimately related to discrete moutard equation which provides the link between their darboux transformations and the fundamental transformation for equation . the following 7-point linear system @xmath142 allows for the darboux transformation @xcite .
[ th : tp - d ] given scalar solution @xmath143 of the linear equation , then @xmath144 given as solution of the following system @xmath145 satisfies the 7-point scheme with the new fields given by @xmath146 @xmath147 where @xmath148 as it was shown in @xcite the self - adjoint 7-point scheme can be obtained from the system of moutard equations imposed consistently on quadrilaterals of the bipartite quasi - regular rhombic tiling ( see fig .
[ fig : qrrt ] ) , which is a particular case of the approach considered in @xcite .
then the moutard transformations can be also restricted to the triangular sublattice leading to theorem [ th : tp - d ] .
the 7-point scheme admits specification @xmath61 ( alternatively one can put @xmath149 or @xmath150 ) and as result we obtain specification to 5-point self - adjoint scheme @xcite .
@xmath151 the self - adjoint 5-point scheme and its darboux transformation can be also obtained form the moutard equation on the ( bipartite ) square lattice @xcite .
it is well known that the triangular and honeycomb grids are dual to each other ( see fig .
[ fig : qrrt ] ) .
restriction of the system of the moutard equations on the rhombic tiling to the honeycomb sublattice gives @xcite the following linear system @xmath152 because @xmath153 and @xmath154 satisfy separately the self - adjoint 7-point schemes , but with different coefficients , then the linear problem - can be considered as a relation between two equations .
this is the laplace transformation between self - adjoint 7-point schemes studied in @xcite .
the corresponding restriction of the moutard transformation gives the darboux transformation for the honeycomb linear problem .
[ th : dt - hc ] given scalar solution @xmath155 of the honeycomb linear system - then the solution @xmath156 of the system @xmath157 with @xmath158 given by @xmath159 satisfies a new honeycomb linear system with the coefficients @xmath160 we end the review of two - dimensional case with specification to the 3-point scheme i.e. to a discretization of first order differential equation @xmath161 if we put @xmath162 then according to @xmath163 it means that the fundamental transformation is also the darboux transformation for the 3-point scheme @xcite @xmath164 this elementary scheme is the simplest one from the class considered here , but it deserves a special attention , because it leads to one of the most studied integrable discrete equation @xcite .
we confine ourselves to recalling briefly in section [ 3p - sch ] main results in this field . to the end
let us rewrite the 3-point scheme in the basic gauge @xmath165
in this section we present the darboux transformations for the four point scheme ( the discrete laplace equation ) from the point of view of systems of such equations , and the corresponding permutability theorems . to keep the paper of reasonable size and in order to present the results from a simple algebraic perspective we do not discuss important relations of the subject to incidence and difference geometry @xcite ( see also @xcite and earlier works @xcite ) , application of analytic @xcite and algebro - geometric @xcite techniques of the integrable systems theory to construct large classes of solutions of the linear systems in question and solutions of the corresponding nonlinear discrete equations . in order to simplify discussion of the darboux transformations for systems of the 4-point schemes we fix ( without loss of generality @xcite ) the gauge to the affine one @xmath166 where @xmath167 are some functions constrained by the compatibility of the system .
it is also convenient @xcite to replace the second order linear system by a first order system as follows .
the compatibility of allows for definition of the potentials ( the lam coefficients ) @xmath168 such that @xmath169 the new wave functions @xmath170 given by the decomposition @xmath171 satisfy the first order linear system @xmath172 where the functions @xmath173 , called the rotation coefficients , are calculated from the equation @xmath174 which is called adjoint to .
both the equations and are compatible provided the fields @xmath173 satisfy the discrete darboux equations @xcite @xmath175 [ cor:4p - psi - i ] due to the function @xmath170 satisfies itself the four point equation @xmath176 while the function @xmath177 satifies the adjoint of in the sense of .
the discrete darboux equations imply existence of the potentials @xmath178 given as solutions of the compatible system @xmath179 and yet another potential @xmath114 such that @xmath180 in terms of the @xmath114-function and the functions @xmath181 the meaning of which will be given in section [ sec : laplace - tr ] , equations and can be rewritten @xcite in the bilinear form @xmath182 we start with a simple algebraic fact , whose consequences will be discussed throughout the remaining part of this section .
[ th : vect - darb ] given the solution @xmath183 , of the linear system , and given the solution @xmath184 , of the adjoint linear system .
these allow to construct the linear operator valued potential @xmath185 : \mathbb{z}^n\to \mathrm{l}({{\mathbb w}},{{\mathbb u}})$ ] , defined by @xmath186 = \boldsymbol{\phi}_i \otimes \boldsymbol{\phi}^*_{i(i ) } , \qquad i = 1,\dots , n.\ ] ] if @xmath187 and the potential @xmath188 is invertible , @xmath185\in\mathrm{gl}({{\mathbb w}})$ ] , then @xmath189^{-1}{\boldsymbol{\phi}}_i , \;\ ; \ ; i=1, ... ,n , \label{eq : haty}\\ \tilde{{\boldsymbol{\phi}}}^*_i&={\boldsymbol{\phi}}^*_i{\boldsymbol{\omega}}[{\boldsymbol{\phi}},{\boldsymbol{\phi}}^*]^{-1},\;\;\ ; i=1, ... ,n,\label{eq : haty*}\end{aligned}\ ] ] satisfy the linear systems - correspondingly , with the fields @xmath190^{-1}|{\boldsymbol{\phi}}_i \rangle , \;\;\ ; i , j=1,\dots , n , \;\;i\neq j , \label{eq : hatq}.\ ] ] in addition , @xmath191 = c - { \boldsymbol{\omega}}[{\boldsymbol{\phi}},{\boldsymbol{\phi}}^*]^{-1},\ ] ] where @xmath192 is a constant operator .
notice that because of we have @xmath193 $ ] . the potentials @xmath178 and the @xmath114-function transform according to @xmath194^{-1 } { \boldsymbol{\phi}}_i),\\ \tilde{\tau } & = \tau \det\boldsymbol{\omega}[{\boldsymbol{\phi}},{\boldsymbol{\phi}}^*].\end{aligned}\ ] ] applying the above transformation one can produce new compatible ( affine ) four point linear problems from the old ones .
to obtain conventional transformation formulas consider @xcite the following splitting of the vector space @xmath195 of theorem [ th : vect - darb ] : @xmath196 if @xmath197 then , the corresponding potential matrix is of the form @xmath198 = \begin{pmatrix } { { \mathbb i}}_{{\mathbb e } } & { \boldsymbol{\omega}}[{\boldsymbol{\psi}},{\boldsymbol{\theta}}^ * ] & { \boldsymbol{\omega}}[{\boldsymbol{\psi } } , { \boldsymbol{\psi}}^ * ] \\ 0 & { \boldsymbol{\omega}}[{\boldsymbol{\theta}},{\boldsymbol{\theta}}^ * ] & { \boldsymbol{\omega}}[{\boldsymbol{\theta } } , { \boldsymbol{\psi}}^ * ] \\ 0 & 0 & { { \mathbb i}}_{{\mathbb f}}\end{pmatrix}\ ] ] and its inverse is @xmath198^{-1 } = \begin{pmatrix } { { \mathbb i}}_{{\mathbb e } } & -{\boldsymbol{\omega}}[{\boldsymbol{\psi}},{\boldsymbol{\theta}}^ * ] { \boldsymbol{\omega}}[{\boldsymbol{\theta}},{\boldsymbol{\theta}}^*]^{-1 } & -{\boldsymbol{\omega}}[{\boldsymbol{\psi } } , { \boldsymbol{\psi}}^ * ] + { \boldsymbol{\omega}}[{\boldsymbol{\psi}},{\boldsymbol{\theta}}^*]{\boldsymbol{\omega}}[{\boldsymbol{\theta}},{\boldsymbol{\theta}}^*]^{-1}{\boldsymbol{\omega}}[{\boldsymbol{\theta } } , { \boldsymbol{\psi}}^ * ] \\ 0 & { \boldsymbol{\omega}}[{\boldsymbol{\theta}},{\boldsymbol{\theta}}^*]^{-1 } & - { \boldsymbol{\omega}}[{\boldsymbol{\theta}},{\boldsymbol{\theta}}^*]^{-1}{\boldsymbol{\omega}}[{\boldsymbol{\theta } } , { \boldsymbol{\psi}}^ * ] \\ 0 & 0 & { { \mathbb i}}_{{\mathbb f}}\end{pmatrix}.\ ] ] let us consider the case of @xmath199-dimensional transformation data space , @xmath200 , and @xmath201 , @xmath202 , then the transformed solution @xmath203 $ ] of the four point scheme ( recall that @xmath204 $ ] ) up to a constant vector reads @xmath205{\boldsymbol{\omega } } [ { \boldsymbol{\theta } } , { \boldsymbol{\theta}}^*]^{-1 } { \boldsymbol{\omega } } [ { \boldsymbol{\theta } } , h],\ ] ] where the corresponding transformed solutions @xmath206 of the linear problem and @xmath207 of the adjoint linear problem are given by equations @xmath208 { \boldsymbol{\omega}}[{\boldsymbol{\theta}},{\boldsymbol{\theta}}^*]^{-1}{\boldsymbol{\theta}}_i , \\
\tilde{h}_i & = h_i - { \boldsymbol{\theta}}^*_i { \boldsymbol{\omega}}[{\boldsymbol{\theta}},{\boldsymbol{\theta}}^*]^{-1}{\boldsymbol{\omega}}[{\boldsymbol{\theta } } , h],\end{aligned}\ ] ] and @xmath209^{-1}{\boldsymbol{\theta}}_i.\ ] ] the scalar ( @xmath210 ) fundamental transformation in the above form was given in @xcite . to connect the above formalism to the results of section [ sec:6p ] notice that given scalar solution @xmath211 of the linear system then the potential @xmath212 $ ] is the scalar solution of the system of second order linear equations
moreover , given the solution @xmath213 , of the adjoint linear system then the functions @xmath214 satisfy @xcite the linear system @xmath215 equations imply that the functions @xmath216 satisfy the corresponding equations @xmath217 adjoint of equations . in the case
@xmath218 we obtain therefore the data of the transformation being the solution @xmath24 of the linear problem and the solution @xmath219 of its adjoint , thus we recover results of theorem [ th:6p - dt ] with the four point specification in the affine gauge ; see @xcite for more detailed description . notice that in order to describe fundamental transformation in the second order formalism for @xmath220 one should consider in addition the algebraic relations @xmath221 which are consequences of definition .
it is important to notice that the vectorial fundamental transformation can be obtained as a superposition of @xmath199 scalar transformations , which follows from the following observation .
[ th : perm - fund ] assume the following splitting of the data of the vectorial fundamental transformation @xmath222 associated with the partition @xmath223 , which implies the following splitting of the potentials @xmath224 = \left ( \begin{array}{c } \boldsymbol{\omega}[{\boldsymbol{\theta}}^a , h ] \\ \boldsymbol{\omega}[{\boldsymbol{\theta}}^b , h ] \end{array } \right ) , \qquad \boldsymbol{\omega}[{\boldsymbol{\theta}},{\boldsymbol{\theta}}^ * ] = \left ( \begin{array}{cc } \boldsymbol{\omega}[{\boldsymbol{\theta}}^a,{\boldsymbol{\theta}}_a^ * ] & \boldsymbol{\omega}[{\boldsymbol{\theta}}^a,{\boldsymbol{\theta}}_b^ * ] \\ \boldsymbol{\omega}[{\boldsymbol{\theta}}^b,{\boldsymbol{\theta}}_a^ * ] & \boldsymbol{\omega}[{\boldsymbol{\theta}}^b,{\boldsymbol{\theta}}_b^*]\end{array } \right),\ ] ] @xmath225 = \left ( \begin{array}{cc } \boldsymbol{\omega}[\boldsymbol{\psi},{\boldsymbol{\theta}}_a^ * ] & \boldsymbol{\omega}[\boldsymbol{\psi},{\boldsymbol{\theta}}_b^*]\end{array } \right).\ ] ] then the vectorial fundamental transformation is equivalent to the following superposition of vectorial fundamental transformations : + 1 ] transformation @xmath226 with the data @xmath227 , @xmath228 and the corresponding potentials @xmath229 $ ] , @xmath230 $ ] , @xmath231 $ ] @xmath232 \boldsymbol{\omega}[{\boldsymbol{\theta}}^a,{\boldsymbol{\theta}}^*_a]^{-1 } \boldsymbol{\omega}[{\boldsymbol{\theta}}^a , h],\\ \boldsymbol{\psi}_i^{\{a\ } } & = \boldsymbol{\psi}_i - \boldsymbol{\omega}[\boldsymbol{\psi},{\boldsymbol{\theta}}^*_a ] \boldsymbol{\omega}[{\boldsymbol{\theta}}^a,{\boldsymbol{\theta}}^*_a]^{-1 } { \boldsymbol{\theta}}^a_i , \\ h_i^{\{a\ } } & = h_i - { \boldsymbol{\theta}}^*_{i a } \boldsymbol{\omega}[{\boldsymbol{\theta}}^a,{\boldsymbol{\theta}}^*_a]^{-1 } \boldsymbol{\omega}[{\boldsymbol{\theta}}^a , h].\end{aligned}\ ] ] 2 ] application on the result the vectorial fundamental transformation with the transformed data @xmath233 \boldsymbol{\omega}[{\boldsymbol{\theta}}^a,{\boldsymbol{\theta}}^*_a]^{-1 } { \boldsymbol{\theta}}^a_i , \\ { { \boldsymbol{\theta}}}_{i b}^{*\{a\ } } & = { \boldsymbol{\theta}}_{i b}^ * - { \boldsymbol{\theta}}^*_{i a } \boldsymbol{\omega}[{\boldsymbol{\theta}}^a,{\boldsymbol{\theta}}^*_a]^{-1 } \boldsymbol{\omega}[{\boldsymbol{\theta}}^a , { \boldsymbol{\theta}}_{b}^*],\end{aligned}\ ] ] and potentials @xmath234^{\{a\ } } & = \boldsymbol{\omega}[{\boldsymbol{\theta}}^b , h ] - \boldsymbol{\omega}[{\boldsymbol{\theta}}^b,{\boldsymbol{\theta}}^*_a ] \boldsymbol{\omega}[{\boldsymbol{\theta}}^a,{\boldsymbol{\theta}}^*_a]^{-1 } \boldsymbol{\omega}[{\boldsymbol{\theta}}^a , h]= \boldsymbol{\omega}[{{\boldsymbol{\theta}}}^{b\{a\}},h^{\{a\ } } ] , \\ { \boldsymbol{\omega}}[{\boldsymbol{\theta}}^b,{\boldsymbol{\theta}}^*_b]^{\{a\ } } & = \boldsymbol{\omega}[{\boldsymbol{\theta}}^b,{\boldsymbol{\theta}}^*_b ] - \boldsymbol{\omega}[{\boldsymbol{\theta}}^b,{\boldsymbol{\theta}}^*_a ] \boldsymbol{\omega}[{\boldsymbol{\theta}}^a,{\boldsymbol{\theta}}^*_a]^{-1 } \boldsymbol{\omega}[{\boldsymbol{\theta}}^a,{\boldsymbol{\theta}}^*_b]= \boldsymbol{\omega}[{{\boldsymbol{\theta}}}^{b\{a\}},{{\boldsymbol{\theta}}}_b^{*\{a\ } } ] , \\ { \boldsymbol{\omega}}[\boldsymbol{\psi},{\boldsymbol{\theta}}^*_b]^{\{a\ } } & = \boldsymbol{\omega}[\boldsymbol{\psi},{\boldsymbol{\theta}}^*_b ] - \boldsymbol{\omega}[\boldsymbol{\psi},{\boldsymbol{\theta}}^*_a ] \boldsymbol{\omega}[{\boldsymbol{\theta}}^a,{\boldsymbol{\theta}}^*_a]^{-1 } \boldsymbol{\omega}[{\boldsymbol{\theta}}^a,{\boldsymbol{\theta}}^*_b]= \boldsymbol{\omega}[{\boldsymbol{\psi}}^{\{a\}},{{\boldsymbol{\theta}}}_b^{*\{a\ } } ] , \label{eq : fund - vect - potentials - slit}\end{aligned}\ ] ] i.e. , @xmath235^{\{a\ } } [ { \boldsymbol{\omega}}[{\boldsymbol{\theta}}^b,{\boldsymbol{\theta}}^*_b]^{\{a\}}]^{-1 } { \boldsymbol{\omega}}[{\boldsymbol{\theta}}^b , h]^{\{a\}}.\ ] ] the above formulas , apart from existence of the @xmath114-function , remain valid ( eventually one needs the proper ordering of some factors ) if , instead of the real field @xmath236 , we consider @xcite arbitrary division ring .
notice , that because the structure of the transformation formulas is a consequence of equation then the formulas may be expressed in terms of quasi - determinants @xcite ( recall , that roughly speaking , a quasi - determinant is the inverse of an element of the inverse of a matrix with entries in a division ring ) .
let us list basic reductions of the ( scalar ) fundamental transformation .
we follow the nomenclature of @xcite which has origins in geometric terminology of transformations of conjugate nets @xcite .
we provide also the terminology of modern theory of integrable systems @xcite , where the fundamental transformation is called the binary darboux transformation .
all the transformations presented in this section can be derived @xcite from the fundamental transformation through limiting procedures .
given a scalar solution @xmath211 of the linear problem the lvy transform of @xmath237 $ ] is then given by @xmath238}{\theta_i } { \boldsymbol{\psi}}_i.\ ] ] the transformed lam coefficients and new wave functions are of the form @xmath239 \ ; , \\ { { \mathcal l}}_i(h_j ) & = h_j - \frac{q_{ij}}{\theta_i}{\boldsymbol{\omega}}[\theta , h ] \ ; , \\ { { \mathcal l}}_i({\boldsymbol{\psi}}_i ) & = -{\boldsymbol{\psi}}_{i(i ) } + \frac{\theta_{i(i)}}{\theta_i}{\boldsymbol{\psi}}_i \ ; , \\ { { \mathcal l}}_i({\boldsymbol{\psi}}_j ) & = { \boldsymbol{\psi}}_j - \frac{\theta_j}{\theta_i}{\boldsymbol{\psi}}_i \ ; .\end{aligned}\ ] ] within the nonlocal @xmath240-dressing method the elementary darboux transformation was introduced in @xcite .
given a scalar solution @xmath213 of the adjoint linear problem the adjoint lvy transform @xmath241 of @xmath242 is given by @xmath243.\ ] ] the new lam coefficients and the wave functions are of the form @xmath244 \ ; , \\ { { \mathcal l}}^*_i({\boldsymbol{\psi}}_j ) & = { \boldsymbol{\psi}}_j - \frac{q_{ji}}{\theta_i^*}{\boldsymbol{\omega}}[{\boldsymbol{\psi}},\theta^ * ] \ ; .\end{aligned}\ ] ] as it was shown in @xcite , the scalar fundamental transformation can be obtained as superposition of the lvy transformation and its adjoint .
the closed formulae for iterations of the lvy transformations in terms of casorati determinants , and analogous result for the adjoint lvy transformation , was given in @xcite .
the description of the lvy transformation and its adjoint in the homogeneous formalism in the case of @xmath218 is given in @xcite . from analytic @xcite and geometric @xcite point of view
one can distinguish also the so called _ combescure transformation _
, whose algebraic description is however very simple ( the wave functions @xmath170 are invariant ) . the combescure transformation supplemented by the _ projective ( or radial _ transformation ,
whose algebraic description is also trivial @xcite ) , generate the fundamental transformation .
see also section [ dodane ] and [ gc ] for generalization of the combescure transformation .
the following transformations does not involve any functional parameters , and can be considered as further degeneration of the lvy ( or its adjoint ) reduction .
the laplace transformation of @xmath242 is given by @xmath245 the lam coefficients of the transformed linear problems read @xmath246 and the new wave functions read @xmath247 the laplace transformations satisfy generically the following identities @xmath248 the laplace transformation for the four point affine scheme was introduced in @xcite following the geometric ideas of @xcite and independently in @xcite using the factorization approach .
the generalization for systems of four point schemes ( quadrilateral lattices ) was given in @xcite . as it was shown in @xcite
the functions @xmath249 defined by equation are @xmath114-functions of the transformed four point schemes @xmath250 @xmath251 which , due to , leads @xcite to the discrete toda system @xcite .
in this section we study ( systems of ) four point linear equations subject to additional constraints , and we provide corresponding reductions of the fundamental transformation .
the basic algebraic idea behind such reduced transformations lies in a relationships between solutions of the linear problem and its adjoint , which should be preserved by the fundamental transformation ( see , for example , application of this technique in @xcite to reductions of the binary darboux transformation for the toda system ) .
some results presented here have been partially covered in section [ sec:4p-6p ] but in a different setting .
consider the system of discrete moutard equations ( the discrete bkp linear problem @xcite ) @xmath252 for suitable functions @xmath253 .
compatibility of the system implies existence of the potential @xmath254 , in terms of which the functions @xmath255 can be written as @xmath256 which satisfies system of miwa s discrete bkp equations @xcite @xmath257 the discrete moutard system can be given @xcite the first order formulation - upon introducing the lam coefficients @xmath258 and the rotation coefficients ( below we assume @xmath259 ) @xmath260 which in view of , gives the familiar relation between the @xmath114-functions of the kp and bkp hierarchies @xmath261 the corresponding reduction of the fundamental transformation was given in @xcite , where also a link with earlier work @xcite on the discrete moutard transformation has been established .
[ prop : vect - fund - red - bql ] given solution @xmath262 of the linear problem corresponding to the moutard linear system and its first order form - .
denote by @xmath263 $ ] the corresponding potential , which is also new vectorial solution of the linear problem .
+ 1 ) then @xmath264 provides a vectorial solution of the adjoint linear problem , and the corresponding potential @xmath265 $ ] allows for the following constraint @xmath266 + \boldsymbol{\omega}[\boldsymbol{\theta},\boldsymbol{\theta}^*]^t = 2 \boldsymbol{\theta}\otimes \boldsymbol{\theta}^t.\ ] ] 2 ) the fundamental vectorial transform @xmath267 of @xmath242 , given by with the potentials @xmath188 restricted as above satisfies moutard linear system and can be considered as the superposition of @xmath199 scalar reduced fundamental transforms . in the scalar case and for
@xmath268 inserting in equations and the functions @xmath269 and @xmath270 given by and correspondingly , we obtain the formula in the gauge @xmath271 ( modulo the corresponding change of sign ) . notice that given @xmath272 then , because of the constraint , to construct @xmath273 we need only its antisymmetric part @xmath274 , which satisfies the system @xmath275 this observation is the key element of the connection of the above reduction of the fundamental transformation with earlier results @xcite on the vectorial moutard transformation for the system , where the formulas using pfaffians were obtained ( recall that determinant of a skew - symmetric matrix is a square of pfaffian ) .
in particular , the transformation rule for the @xmath276-function can be recovered @xmath277 consider the linear problem subject to the constraint @xcite which arose from studies on the egorov lattices @xcite @xmath278 then the discrete darboux equations can be rewritten @xcite in the following quartic form @xmath279 which can be identified with equation derived in @xcite in connection with the star - triangle relation in the ising model . according to @xcite , the above equation can be obtained from the ckp hierarchy via successive application of the corresponding reduction of the binary darboux transformations .
construction @xcite of the reduction of the fundamental transformations which preserves the constraint makes use the following observation .
the following conditions are equivalent : + 1 ) the functions @xmath173 , @xmath178 satisfy constraint ; + 2 ) given a nontrivial solution @xmath280 of the adjoint linear problem then @xmath281 provides a solution of the linear problem ; + 3 ) the corresponding potential @xmath185 $ ] allows for the constraint @xmath282^t= \boldsymbol{\omega}[\boldsymbol{\phi},\boldsymbol{\phi}^*].\ ] ] when the data @xmath283 , @xmath284 , @xmath285 $ ] of the fundamental transformation satisfy conditions - then the new functions @xmath286 , @xmath287 found by equations , are constrained by , i.e. @xmath288 the corresponding permutability principle has been proved in @xcite . to connect the symmetric reduction with the goursat equation and the corresponding transformation
( see section [ gr ] ) notice that because of corollary [ cor:4p - psi - i ] and equations - the function @xmath289 satisfies equation with @xmath290 .
then , due to the same corollary and condition , given scalar solution @xmath291 of the four point equation of @xmath289 then the function @xmath292 satisfies its adjoint ; in the lat equation we have used the linear problem and equation . consider the system of four point equations which solution @xmath242 is subject to the following quadratic constraint @xmath293 here @xmath294 is a non - degenerate symmetric matrix , @xmath295 is a constant vector , @xmath296 is a scalar .
notice that unlike in two previous reductions we fix ( by giving the quadratic equation ) the dimension of @xmath242 . double discrete differentiation of equation in @xmath297 directions gives , after some algebra , the condition @xmath298 analogous to that obtained in @xcite in order to characterize circular lattices @xcite .
it implies @xcite , in particular , that @xmath299 satisfy the same equation as the potentials @xmath178 . as in two above reductions
, the quadratic condition allows for a relation between solutions of the linear system and its adjoint .
the following proposition can be easily derived from analogous results of @xcite , where as the basic ingredient of the transformation was used the potential @xmath300 $ ] , but we present here its direct proof in the spirit of corresponding results found for the circular lattice @xcite . given a nontrivial solution @xmath301 of the adjoint linear problem corresponding to the system of four point equations which solution @xmath242 is subject to the constraint then @xmath302_{(i ) } + { \boldsymbol{\omega}}[{\boldsymbol{\psi } } , { \boldsymbol{\theta}}^*])^t q { \boldsymbol{\psi}}_i\ ] ] provides a solution of the corresponding linear problem .
after some algebra using the equations satisfied by @xmath303 and @xmath170 one gets @xmath304 which vanishes due to .
the following result gives the discrete ribaucour reduction of the fundamental transformation .
given solution @xmath305 of the adjoint linear problem corresponding to the quadratic constraint .
+ 1 ) then the potentials @xmath300 $ ] , @xmath306 $ ] and @xmath307 $ ] , where @xmath283 is the solution of the linear problem constructed from @xmath284 by means of formula , allow for the constraints @xmath308^t & = 2 { \boldsymbol{\psi}}^t q { \boldsymbol{\omega}}[{\boldsymbol{\psi } } , { \boldsymbol{\theta}}^ * ] + { \boldsymbol{a}}^t { \boldsymbol{\omega}}[{\boldsymbol{\psi } } , { \boldsymbol{\theta}}^ * ] \ ; \ ; , \\ \label{eq : bphic - qv } { \boldsymbol{\omega}}[{\boldsymbol{\theta } } , { \boldsymbol{\theta}}^ * ] + { \boldsymbol{\omega}}[{\boldsymbol{\theta } } , { \boldsymbol{\theta}}^*]^t & = 2 { \boldsymbol{\omega}}[{\boldsymbol{\psi } } , { \boldsymbol{\theta}}^*]^t q { \boldsymbol{\omega}}[{\boldsymbol{\psi } } , { \boldsymbol{\theta}}^ * ] \ ; .\end{aligned}\ ] ] 2 ) the ribaucour reduction of the fundamental vectorial transform @xmath267 of @xmath242 , given by with the potentials @xmath188 restricted as above satisfies the quadratic constraint and can be considered as the superposition of @xmath199 scalar ribaucour transformations . as it was explained in @xcite ,
the ribaucour transformations @xcite of the circular lattice @xcite can be derived from the above approach after the stereographic projection from the mbius sphere .
the superposition principle for the ribaucour transformation of circular lattices was derived also in @xcite .
in this final section we present the vectorial darboux transformations for the three point scheme .
the corresponding nonlinear difference system , known as the hirota miwa equation , is perhaps the most important and widely studied integrable discrete system .
it was discovered by hirota @xcite , who called it the discrete analogue of the two dimensional toda lattice ( see also @xcite ) , as a culmination of his studies on the bilinear form of nonlinear integrable equations .
general feature of hirota s equation was uncovered by miwa @xcite who found a remarkable transformation which connects the equation to the kp hierarchy @xcite .
the hirota - miwa equation , called also the discrete kp equation , can be encountered in various branches of theoretical physics @xcite and mathematics @xcite .
consider the linear system @xcite @xmath309 whose compatibility leads to the following parametrization of the field @xmath310 in terms of the potentials @xmath311 @xmath312 and then to existence of the @xmath114 function @xmath313 and , finally to the the discrete kp system @xcite @xmath314 the same nonlinear systems arises from compatibility of @xmath315 called the adjoint of .
we present the darboux transformation for the three point scheme in the way similar to that of section [ sec : fund ] following the approach of @xcite , see however early works on the subject @xcite .
[ th : vect - darb - kp ] given the solution @xmath316 , of the linear system , and given the solution @xmath317 , of the adjoint linear system .
these allow to construct the linear operator valued potential @xmath318 : \mathbb{z}^n\to \mathrm{l}({{\mathbb w}},{{\mathbb u}})$ ] , defined by @xmath319 = \boldsymbol{\phi } \otimes \boldsymbol{\phi}^*_{(i ) } , \qquad i = 1,\dots , n.\ ] ] if @xmath187 and the potential @xmath188 is invertible , @xmath318\in\mathrm{gl}({{\mathbb w}})$ ] , then @xmath320^{-1}\boldsymbol{\phi } , \label{eq : hatp}\\ \tilde{\boldsymbol{\phi}}^*&=\boldsymbol{\phi}^ * { \boldsymbol{\omega}}[{\boldsymbol{\phi}},{\boldsymbol{\phi}}^*]^{-1},\label{eq : hatp*}\end{aligned}\ ] ] satisfy the linear systems and , correspondingly , with the fields @xmath321^{-1 } \boldsymbol{\phi})_{(i ) } + ( \boldsymbol{\phi}^ * { \boldsymbol{\omega}}[\boldsymbol{\phi},\boldsymbol{\phi}^*]^{-1 } \boldsymbol{\phi})_{(j)}.\ ] ] in addition , @xmath322 = c - { \boldsymbol{\omega}}[\boldsymbol{\phi},\boldsymbol{\phi}^*]^{-1},\ ] ] where @xmath192 is a constant operator .
the transformation rule for the potentials @xmath311 reads @xmath323^{-1 } \boldsymbol{\phi } ) , \ ] ] while using the technique of the bordered determinants @xcite one can show that @xcite @xmath324 \label{eq : hat - tau - dkp}.\ ] ] more standard transformation formulas arise , when one splits , like in section [ sec : fund ] , the vector space @xmath195 of theorem [ th : vect - darb - kp ] as follows @xmath325 if @xmath326 then the corresponding potential matrix and its inverse have the structure like those in section [ sec : fund ] , which gives @xcite @xmath327 { \boldsymbol{\omega}}[{\boldsymbol{\theta}},{\boldsymbol{\theta}}^*]^{-1}{\boldsymbol{\theta}},\\ \tilde{\boldsymbol{\psi}}^ * & = \boldsymbol{\psi}^ * - { \boldsymbol{\theta}}^ * { \boldsymbol{\omega}}[{\boldsymbol{\theta}},{\boldsymbol{\theta}}^*]^{-1}{\boldsymbol{\omega}}[{\boldsymbol{\theta } } , \boldsymbol{\psi}^*],\\ \tilde{u}_{ij } & = u_{ij } - ( { \boldsymbol{\theta}}^ * { \boldsymbol{\omega}}[{\boldsymbol{\theta}},{\boldsymbol{\theta}}^*]^{-1 } { \boldsymbol{\theta}})_{(i ) } + ( { \boldsymbol{\theta}}^ * { \boldsymbol{\omega}}[{\boldsymbol{\theta}},{\boldsymbol{\theta}}^*]^{-1 } { \boldsymbol{\theta}})_{(j)}.\end{aligned}\ ] ] notice that one can consider @xcite the three point linear problem in associative algebras .
then the structure of the transformation formulas implies the quasi - determinant interpretation @xcite of the above equations .
the permutability property for the darboux transformations of the three point scheme @xcite can be formulated exactly ( cancel subscripts @xmath328 ) like theorem [ th : perm - fund ] .
finally we remark that the binary darboux transformation for the three point linear problem can be decomposed @xcite into superposition of the elementary darboux transformation and its adjoint , which can be described as follows . given a scalar solution @xmath24 of the linear problem then the elementary darboux transformation @xmath329\ ; , \\ { { \mathcal d}}(\tau ) & = \theta \tau\end{aligned}\ ] ] leaves equations and invariant .
analogously , given a scalar solution @xmath330 of the linear problem then the adjoint elementary darboux @xmath331 , \\ { { \mathcal d}}^*(\boldsymbol{\psi}^ * ) & = - \boldsymbol{\psi}^*_{(-i ) } + \frac{\theta^*_{(-i)}}{\theta^ * } \boldsymbol{\psi}^ * , \\ { { \mathcal d}}^*(\tau ) & = \theta^ * \tau\end{aligned}\ ] ] leaves equations and invariant .
the above transformations allow for vectorial forms , which can be conveniently written @xcite in terms of casorati determinants .
in the paper we aimed to present results on darboux transformations of linear operators on two dimensional regular lattices . to put some order into the review we started from the six point scheme ( and its darboux transformation ) as the master linear problem .
the path between its various specifications and reductions has been visualized in figure [ 5p ] .
we considered also in more detail the corresponding theory of the darboux transformations of the systems of the four point schemes and their reductions .
finally , we briefly discussed the multidimensional aspects of the three point schemes .
it is worth to mention that for systems of the three or four point schemes the darboux transformations can be interpreted as a way to generate new dimensions .
this is very much connected to the permutability of the transformations , which is a core of integrability of the corresponding nonlinear systems .
separate issue touched here is such extention of four point schemes that can be regarded as an analogue of discretization of a diferential equation in arbitrary parametrization .
more precisely we discussed here such an extension of general ( akp ) case ( section [ gc ] ) and moutard selfadjoint ( bkp ) case ( sections [ mr ] and [ sec : s - a ] ) .
goursat and ribaucour reductions have not been investigated from this point of view .
the multidimensional schemes that mimic equations governing conjugate nets ( and their reductions ) with arbitrary change of independend variables have been not exploited either .
we also mentioned another approach to the problem of construction of the unified theory of the darboux transformations .
it consists in isolating basic `` bricks '' in order to use their combinations to construct more involved linear operators together with their darboux transformations .
such an idea has been applied to derive , starting from the moutard reduction of the four point scheme , the self - adjoint operators on the square ( the five point scheme ) , triangular ( the seven point scheme ) and the honeycomb grids .
recently it was shown in @xcite that the theory of systems of four point linear equations and their laplace transformations follows from the theory of the three point systems .
this means , that also the transformations of the four point scheme can be , in principle , derived from the three point scheme .
an open question is if the six point scheme and its transformations can be decomposed in a similar way .
finally , we would like to mention possibility of considering ( hierarchies of ) continuous deformations of the above lattice linear problems , which would lead to ( hierarchies of ) discrete - differential integrable by construction equations .
some aspects of deformations of the self - adjoint seven and five linear systems have been elaborated in @xcite .
the authors thank the isaac newton institute for mathematical sciences ( cambridge , uk ) for hospitality during the programme _ discrete integrable systems_. a. i. bobenko , ch .
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[ in : ] p. a. clarkson ( ed . ) , _ application of analytic and geometric methods to nonlinear differential equations _ ,
kluwer academic publishers , 1993 , pp . 193206 .[/INST] darboux transformations for linear operators on regular two dimensional lattices are reviewed .
the six point scheme is considered as the master linear problem , whose various specifications , reductions , and their sublattice combinations lead to other linear operators together with the corresponding darboux transformations . the second part of the review deals with multidimensional aspects of ( basic reductions of ) the four point scheme , as well as the three point scheme . </s> |
solid epithelial tumors are complex structures in which associated stromal cells , including fibroblasts , support cancer cells . during metastatic progression ,
cancer cells disseminate from their tissue of origin to re - establish the tumor structure in distant organs .
efficient metastasis requires the expression of specific molecules , such as postn and tnc , within the local microenvironment ( malanchi et al . , 2012 ,
therefore , a favorable microenvironment , or niche , is a crucial early requirement for metastatic progression ( sleeman , 2012 ) .
cancer cells display heterogeneity in intrinsic tumorigenic potential ; only a small subset of cells within tumors retains the ability of sustaining long - term growth ( hermann et al .
cancer cells with the stem cell - like property of self - renewal can be defined functionally as cancer - initiating cells ( cics ) for their capacity to elicit tumor growth .
moreover , metastatic initiating cells ( mics ) can be distinguished from the bulk of cancer cells for their ability to establish metastasis .
the functional assay for mics involves determining the extent to which single cells can grow in a foreign tissue and is more challenging than the equivalent orthotopic transplantation assay used to assess the ability of cics to initiate tumor growth .
although self - renewal ability is a common requirement for the re - initiation of a cancer cell mass at either primary or secondary sites , additional characteristics that discriminate mics from cics have not been explored .
mics have been identified previously in the mouse breast cancer model where mouse mammary tumor virus promoter controls the expression of the polyomavirus middle t antigen ( mmtv - pymt ) ( malanchi et al . , 2012 ) .
we hypothesized that , in addition to intrinsic tumorigenic potential , mics would exhibit a higher capacity for interacting with their niche by activating naive cells at distant sites ( malanchi , 2013 ) .
one strategy adopted by carcinoma cells to disseminate from the primary tumor mass is the activation of the developmental program epithelial - to - mesenchymal transition ( emt ) . during emt ,
epithelial cells undergo a global change in cell architecture , leading to the loss of cell - cell adhesions in favor of cell - extracellular matrix ( ecm ) interactions and cell migration ( thiery et al . , 2009 ) .
notably , emt modulations are not binary , but a graded range of intermediate states exists .
the process is initiated by the activation of the emt core transcription factors ( tfs ) snail , zeb , and twist1 ( peinado et al . , 2007 ) , which drive epithelial cancer cells to switch off the expression of epithelial markers such as the adherens junction protein e - cadherin and
the tyrosine kinase axl is a downstream effector of the emt program ( vuoriluoto et al . , 2011 ) .
emt in breast cancer cells triggers an increase in axl expression , and inhibition of axl reduces the invasive and tumorigenic behavior of cancer cells ( gjerdrum et al . , 2010 , holland et al . , 2010 , sheridan , 2013 , paccez et al . ,
interestingly , the induction of emt tfs correlates with the emergence of stem cell - like properties ( mani et al . , 2008 ,
this suggests that the gain of mesenchymal characteristics might not only affect dissemination from primary tumors but also boost the stem cell properties required for metastatic outgrowth .
however , epithelial characteristics are re - acquired at metastatic locations via mesenchymal - to - epithelial transitions ( mets ) , typically leading to the establishment of secondary tumors with epithelial phenotypes ( tsai et al .
the potential advantage of a more mesenchymal state of cancer cells at the metastatic site and the origin of their epithelial plasticity remain unclear . in this study , we use breast cancer models to demonstrate that the emt program is a key regulator of the enhanced niche activation capacity of mics at secondary sites .
we identify thrombospondin 2 ( thbs2 ) as a mesenchymal state - dependent effector of cancer cells that promotes stromal niche activation .
subsequently , the newly activated stroma promotes cancer cells to shift toward a more epithelial , bmp - dependent state compatible with proliferation .
we elucidated a biphasic temporal regulation during metastatic colonization whereby the mesenchymal status of cancer cells promotes stromal activation , which , in turn , promotes cancer cell epithelial plasticity and their reversion to a more epithelium - like phenotype .
in the mouse breast cancer mmtv - pymt model , mics were identified by co - expression of the cd24 and cd90 markers ( malanchi et al . , 2012 ) .
the gene expression profile of mics ( cd24cd90 ) was compared to that of non - mics ( cd24cd90 ) to generate a mic signature ( figure s1a ) .
we verified that high levels of wnt signaling are a hallmark of metastatic cancer stem cells ( malanchi et al .
, 2008 , malanchi et al . , 2012 , nguyen et al . , 2009 , reya and clevers , 2005 , vermeulen et al . , 2010 ) , along with other characteristics associated with their high metastatic potential , such as active transforming growth factor ( tgf- ) signaling ( padua et al . , 2008 ) and yap / taz activity ( diepenbruck et al . , 2014 ) .
we also found that the mic signature exhibited characteristic features of emt and its related extracellular matrix remodeling ( figure 1a and s1b ) . in line with this , mics freshly isolated from primary tumors displayed a mesenchymal phenotype with higher expression of vimentin and the emt - related receptor axl as well as reduced e - cadherin levels ( figures 1b and 1c ) .
this more mesenchymal phenotype was corroborated functionally using matrigel collagen matrices where mics , either in pure or mixed non - mic / mic spheroids , displayed enhanced single - cell invasive behavior compared with non - mics ( figures 1d , 1e , and s1c ) .
the capacity of mics for invasion correlated with increased expression levels of actin cytoskeleton regulators and extracellular matrix components ( figures s1d and s1e ) .
emt in mics was further confirmed by the higher expression and nuclear localization of emt tfs ( figures s1f and s1 g ) .
however , the high level of heterogeneity within the mic population suggests a graded emt with intermediate
partial emt states rather than a simple binary transition . the mic expression signature also correlated with different secretome gene sets ( figure 1a ) . some of these secreted factors have been reported previously to play a role in metastasis , such as tnc , sparc , or ccl2 ( oskarsson et al .
we went on to investigate the influence that the observed partial emt status of mics has on their capacity for metastatic initiation following dissemination .
because the metastatic behavior of mmtv - pymt mics might be regulated by the activity of other pathways , such as wnt ( figure 1a ) , we selected a broader mesenchymal cancer cell pool expressing axl , including the mic ( cd24cd90 ) population ( figure s2a ) .
as expected , the cd24axl population isolated from primary tumors displayed partial mesenchymal features ( figures s2b and s2c ) .
we next tested cd24axl cells for their cancer initiation and metastatic initiation potential using orthotopic transplantation and tail vein injection , respectively ( figures 1f and 1 g ) .
both assays require cancer cell stemness to reinitiate and sustain a cancer cell mass , either in a collective challenge within their organ of origin with favorable niches or when seeded via circulation as single cells in a likely less favorable foreign organ .
we observed no difference in primary tumor growth for cd24axl and cd24axl cells , indicating that the subpools exhibit a comparable capacity for cancer initiation ( figure 1h ) .
indeed , for mmtv - pymt tumor cells , more mesenchymal characteristics do not appear to influence tumor initiation ability .
the more epithelial cd24sca1 subpool ( figures s2d s2f ) identified previously for their tumor initiation capacity ( liu et al .
, 2007 ) displayed a similar tumor initiation potential as the more mesenchymal cd24axl or mic pools ( figures s2g s2i ) .
strikingly , cd24axl cancer cells show a higher lung metastasis competence compared with their more epithelial counterparts ( figure 1i ) .
this suggests that the common mesenchymal characteristics observed within the cd24axl and mic cd24cd90 cancer cells might be linked functionally to their metastatic competence , independent of an advantage in intrinsic stemness potential displayed in a favorable microenvironment .
the highly secretory mesenchymal status of mics might provide an increased capacity of generating a favorable environment , or niche , in distant sites ( figure 1a ) .
we examined this suggestion by analyzing the activation of lung stromata around disseminated axl or axl cancer cell early after their extravasation into the lungs .
in line with our hypothesis , cd24axl cells are surrounded by higher numbers of smooth muscle actin ( sma)-activated fibroblastic stroma compared with cd24axl cells .
we observed no difference in their tissue localization , in particular in their proximity to lung endothelial cells ( figures 2a2d ) . to test whether niche activation ability is a common advantage conferred by the mesenchymal status of cd24axl and mic pools , we measured the ability of isolated mics to trigger features of cancer - associated fibroblasts ( cafs ) in normal lung fibroblasts ex vivo . sorted mics or non - mics with a gfp - labeled normal lung fibroblast cell line ( nlf3 ) were plated and monitored for the induction of early fibroblast activation markers ( figure 2e ) . because all cancer cells are capable of fibroblast activation to some extent , we used low cell numbers to increase the assay s sensitivity .
after 24 hr , fibroblasts co - cultured with mics exhibited early nuclear yap translocation , required for caf induction , and higher fibroblast activation protein ( fap ) expression compared with fibroblasts cultured with non - mics ( figures 2f2h ; calvo et al . , 2013 ) . to verify that the induction of these markers represents fibroblast activation , we performed functional gel contraction assays to examine the ability of fibroblasts to physically remodel the ecm .
limited numbers of cell - sorted mics or non - mics from primary tumors were seeded in the upper chamber of a trans - well dish . in the lower chamber of the co - culture , normal lung fibroblasts ( nfs ) freshly isolated from wild - type mouse lungs were embedded in collagen - matrigel matrices ( figure 2i ) .
importantly , we observed that mics trigger significantly greater fibroblast - driven gel contraction compared with the other primary cancer cells ( figures 2j ) . in parallel , a gain of a caf gene expression signature was induced in fibroblast co - cultured with mics .
collectively , these data provide direct evidence that cancer cells displaying partial emt characteristics show an enhanced ability to generate activated fibroblasts , a crucial component of the metastatic niche .
to understand the mechanism underlying the enhanced capacity for fibroblast activation , we tested several mic - specific secreted proteins for their ability to activate fibroblasts ( figures s3a and s3b ) .
we found that purified recombinant thbs2 significantly enhanced the gel contraction capacity of fibroblasts ( figure 3a ) .
we observed that exposure of lung fibroblasts to purified thbs2 led to activation of integrin 1 and the phosphorylation of its downstream effector focal adhesion kinase ( pfak ) ( figures 3b and 3c ) .
importantly , a specific integrin 1-blocking antibody ( 1ba ) arrested the thbs2-dependent integrin cascade as well as fibroblast activation ( figures 3b3d ) . to examine the role thbs2
might play in tumorigenicity , we used a specific short hairpin rna ( shrna ) targeting thbs2 mrna ( shthbs2 ) to knock down its expression in primary mmtv - pymt cancer cells ( pymt ) ( figure 3e ) .
importantly , thbs2 depletion rendered cancer cells less able to activate lung fibroblasts ( figure 3f ) .
furthermore , shthbs2 cancer cells were reduced dramatically in their capacity for lung metastatic colonization upon intravenous injection ( figure 3h ) . however
, this is unlikely to be due to an effect on intrinsic cancer cell stemness because shthsb2 pymt cells maintained their ability to initiate early primary tumor growth in vivo or form spheres in vitro ( figure 3 g and s3c ) .
similar findings were obtained using a second shrna to block thbs2 secretion ( figures s3d s3h ) . because thbs2 is highly expressed in only a subset of pymt cells , we tested the consequence of exogenous thbs2 gene expression in all pymt cells .
importantly , broad thbs2 secretion resulted in increased early metastatic growth in the lungs upon direct seeding ( figure 3i ) .
these data support the clinical correlation of high thbs2 expression with poor prognosis in advanced - stage human breast cancers ( figure s3i ) .
together , these results suggest that mics mediate efficient fibroblast activation through thbs2 secretion and that this is critical for efficient metastatic initiation within the secondary tissue .
interestingly , we also found that their partial emt phenotype defined by axl expression was sufficient to determine their metastatic competence ( figure 1i ) .
therefore , we investigated whether the high niche activation ability of mics is linked functionally to their axl mesenchymal status .
first we used the axl - specific small molecule inhibitor r428 ( holland et al . , 2010 ) , and second we used an shrna to target axl mrna ( gjerdrum et al . , 2010 ) .
brief exposure of mics to r428 triggered an overall shift toward a more epithelial phenotype with lower vimentin and axl expression and higher e - cadherin levels ( figures 4a , 4b , and s4a ) .
accordingly , we detected a reduction in the expression of emt - tfs and motility in mics ( figures s4b and s4c ) .
similar phenotypic changes occurred in the basal human breast cancer cell line mda - mb-231 ( mda231 ) following treatment with r428 . indeed ,
although mda231 cells , which homogeneously express axl , typically display mesenchyme - like features , a single pulse of r428 reduced the expression of axl and vimentin and cell motility for up to 48 hr ( figures s4d
interestingly , upon r428-mediated mesenchymal inhibition , cancer cells also reduced the expression of secreted factors , including thbs2 ( figures 4c and s4h ) .
concomitantly , the fibroblast activation ability of r428-treated metastatic cells was impaired dramatically ( figure 4d ) . because similar results were found using an shrna against axl mrna in primary pymt cells ( figure s5a )
indeed , shrna - induced axl downregulation in pymt cells reduced thbs2 secretion and ex vivo fibroblast activation abilities ( figures 4e and 4f ) .
notably , the expression of thbs2 appears to be highly linked to the expression of the axl and twist1 genes in human tumor biopsies ( figure s4i ) .
these data demonstrate that the mesenchymal status of mics is directly related to their enhanced capacity for fibroblast activation .
we showed that mics isolated from primary tumors are in an axl - positive mesenchymal state .
therefore , we went on to examine the mesenchymal status of cancer cells at the target site by monitoring axl expression during early colonization .
we detected two distinct phases of axl expression : a first phase , where the pymt emt mic subpool maintains axl , and a second phase , where the axl - positive phenotype is lost coincidentally with mic expansion in the lungs ( figure 5a ) .
similar biphasic axl expression was observed in the mda231 cell line ( figure 5b ) . because the ability of cancer cells to trigger the niche is crucial for metastatic establishment ( figure 3 ) and dependent on the mesenchymal phenotype ( figure 4 ) , we assessed whether the maintenance of axl is required for the first phase of metastatic colonization . to do this
, we inhibited axl activity only during the first colonization phase by pre - treating cancer cells with the r428 inhibitor prior to intravenous injection and continued treatment in vivo for 7 days ( figure 5c and s5b ) . notably , although r428 pre - treatment did not alter cancer cell extravasation ( figure s5c ) , it did significantly reduce metastasis after 5 weeks ( figures 5d5f ) .
remarkably , only r428 pre - treatment 24 hr before seeding into the lung was sufficient to inhibit metastatic establishment ( figure 5e ) , suggesting that axl mesenchymal features are required early after metastatic cell arrival to new tissue .
although short - term inhibition of axl decreased metastatic competence , this had no effect on proliferation , self - renewal , and 3d cancer cell mass growth in vitro ( figures s5d5 g ) , or primary tumor initiation in vivo ( figure s5h ) .
interestingly , enhancing thbs2 expression in the mda - mb-231 cell line partially rescued metastasis upon axl inhibition in spite of the fact that thbs2 overexpression only provided a positive trend toward metastasis in these cells ( figures 5 g , s5i , and s5j ) .
this result is in line with the observation that axl - mesenchymal cells show a thbs2-mediated advantage in niche activation .
we also observed a block in metastasis upon axl inhibition using shrna knockdown in pymt cells ( figures 5h and 5i ) .
furthermore , treatment of a second mouse breast cancer cell line ( 4t1 ) with shthbs2 or shaxl also reduced the metastatic ability of 4t1 cells ( figures s5k and s5l ) . together
, these results suggest that the first phase of metastatic colonization requires the niche activation capacity provided by the axl mesenchymal characteristics .
the previous results highlight the requirement of a mesenchymal state for metastatic initiation upon seeding at the target site .
however , when cancer cells start growing within the metastatic tissue , axl expression is downregulated ( figures 5a , 5b , and 6a ) .
imagestream analysis showed that , coincident with axl downregulation , gfp cancer cells growing in the lungs exhibit reduced expression of the emt transcription factor twist1 ( figures 6b , 6c , s6a , and s6b ) .
this suggests that the previously reported emt inhibition at the secondary site ( tsai et al . ,
therefore , we investigated the changes that occur in metastatic cells during this time period .
ex vivo co - culture ( as shown in figure 2e ) demonstrated that , concomitant with fibroblast activation ( figures 2f2h ) , mics express lower levels of axl , twist1 ( figures 6d and 6e ) , and overall emt tf mrna ( figure s6c ) . to track the phenotypic changes during this time , cancer cells were co - cultured with cafs for 24 hr under adherence conditions ( figure s6d ) .
here we found that mics reduced expression of vimentin and axl and increased expression of e - cadherin ( figures s6e and s6f ) .
these results suggest that crosstalk between fibroblasts and cancer cells triggers alterations in both compartments ; namely , activation of fibroblasts and consequent reacquisition of epithelial characteristics by cancer cells . to functionally validate these changes in the mic emt state
, we analyzed their 3d invasion modality as they first come in contact with cafs .
in line with previous studies ( gaggioli et al . , 2007 , yu et al . , 2014 )
, carcinoma cells in a non - invasive epithelial state ( non - mics ) activated both single and collective cell invasion modalities . strikingly , in line with the downregulation of mesenchymal markers , mics displayed a notable reduction in single - cell migration when surrounded by cafs ( figures 6f and 6 g ) .
we next investigated the potential molecular mechanism of caf - driven changes in cancer cells .
tgf- signaling has been implicated extensively in metastasis ( padua et al . , 2008 ) .
high tgf- signaling favors early metastatic colonization , whereas its subsequent reduction is important for metastatic outgrowth ( giampieri et al . , 2009 ) .
because tgf- signaling , which is active in mics ( figure 1a and s1b ) , could be linked functionally to their mesenchymal status ( diepenbruck et al . , 2014 ) , we assessed whether modulation of tgf- signaling in mics associates with the reacquisition of more epithelial characteristics . using imagestream analysis , we monitored the dynamics of activation of the tgf- effector smad2 - 3 in metastasizing cells in vivo .
as axl mesenchymal cells in the lung transit from the first to the second phase of colonization , the number and staining intensity of psmad2 - 3 cells decreased similarly to twist1 expression ( figure 6h , s6 g , and s6i ) .
these data are in agreement with the previous evidence showing that a reduction in tgf- signaling is required for the acquisition of the proliferative status necessary for metastatic outgrowth ( massagu , 2008 ) .
conversely , the activation levels of bmp - dependent psmad1 - 5 was maintained during the second phase of colonization , and the number of psmad1 - 5 cells increased ( figures 6i , s6h , and s6j ) . in line with this , we observed that the levels of inhibitor of differentiation 1 ( id1 ) , a bmp / psmad1 - 5 target gene needed for cell proliferation during metastatic outgrowth ( gupta et al . , 2007 ) , were maintained , in particular in twist1 cells ( figures 6j and 6k ) .
notably , this modulation of id1 in cancer cells could be recapitulated in vitro by exposure to caf - conditioned medium ( cacm ) , which increases the levels of id1 in a bmp - dependent manner ( figures 6l and 6 m ) .
importantly , treatment with the specific inhibitor ldn193189 in vivo resulted in reduced metastatic capacity ( figures 6n and 6o ) , suggesting that bmp / psmad1 - 5 activity does indeed play a significant role in the second phase of colonization .
together , these data show that , in the second colonization phase , the phenotypic changes observed in metastasizing cancer cells toward a more epithelial state correlate with an inhibition of tgf- signaling and the enhanced bmp signaling necessary for metastatic outgrowth .
we showed that the mesenchymal status of cancer cells during the first phase of colonization is required for metastatic establishment .
however , when cd24axl mesenchymal cancer cells accumulate in the lung , they revert to an axl - negative , more epithelial state ( figure 5 ) following interaction with newly activated fibroblasts ( figure 6 ) .
if these two events were linked causally , then it would be expected that a temporal regulation of epithelial plasticity is critical for metastatic outgrowth .
initially , to probe this hypothesis , we induced an early mesenchymal reversion of metastatic cells by r428 treatment during the second phase of colonization ( figure 7a ) .
this axl inhibition no longer blocks the metastatic establishment of mda231 cells ( figure s7a ) and increases metastasis of primary pymt cells ( figures 7b and 7c ) , suggesting that inhibiting emt in this phase promotes metastasis .
we observed that axl inhibition in late - stage metastases did not alter the number of metastatic nodules ( figures 7a and 7b ) .
next , we delayed mesenchymal reversion in vivo by exogenous expression of the axl gene ( ltr - axl ) in cancer cells ( figure 7d ) .
this leads to an exacerbated axl - positive mesenchymal phenotype ( figures 7 g , 7j , and s7b ) without altering the proliferation capacity ( figure s7c ) .
importantly , preventing early axl downregulation in metastasizing ltr - axl - expressing cells delayed initial growth in the lungs ( figures 7e and 7f ) and , ultimately , led to a reduction in the metastatic potential of both pymt and mda231 cancer cells ( figures 7h , 7i , and 7k ) .
these data support the idea that downregulation of axl is required during the second colonization phase to allow the transition to a more epithelial proliferative state .
interestingly , the overexpression of axl in cancer cells led to a reduction in metastatic capacity specifically because an enhancement of primary tumor growth was detected ( figure s7d ) .
this is likely due to an increase in axl tyrosine kinase receptor activity at the early stages of tumor initiation , leading to the generation of larger tumors without obvious histologic changes after tumor establishment ( figures s7e and s7f ) .
successful establishment of metastases requires cancer cells with self - renewal properties to disseminate from their tissue of origin and re - initiate growth at secondary sites . the evidence that experimental induction of emt in epithelial cells triggers stem cell characteristics suggests a unified mechanism for cancer metastasis .
however , the plasticity of the emt program from dissemination to distant colonization during the metastatic process makes the direct relationship between emt and stemness controversial ( tsai et al . , 2012 ,
mani et al . , 2008 , morel et al . , 2008 ,
, 2009 , brabletz , 2012 , nieto , 2013 ) and suggests that metastatic cancer cells are likely to undergo a partial emt that can be modulated toward a more mesenchymal or epithelial state ( ombrato and malanchi , 2014 ) .
furthermore , although the requirement of an emt inhibition at the metastatic site has been reported previously ( tsai et al . , 2012 ) , the dynamic regulation of the mesenchymal / epithelial transition is currently unknown . using breast cancer models , we highlight the importance of the more mesenchymal phenotype of mics during the early phase of metastatic colonization .
moreover , we demonstrate the requirement for axl mesenchymal state - dependent thbs2 secretion in mediating enhanced niche activation .
we also identify a subsequent phase of colonization where the mesenchymal phenotype of cancer cells is downmodulated by the interaction with the newly induced niche .
this crosstalk leads to inhibition of tgf- signaling and psmad1 - 5-dependent outgrowth , shifting cancer cells toward a more epithelial and proliferative state .
blocking the effectors of these pathways during this biphasic process reduces metastasis : thbs2 expression during the first phase or psmad1 - 5 activity during the second phase . here
we identify epithelial plasticity as a crucial determinant of metastatic colonization and describe how disruption of axl - dependent phenotypic modulation is sufficient to reduce metastatic efficiency . in agreement with the previously observed link between the emt program and the gain in stemness ( mani et al .
, 2008 , morel et al . , 2008 ) , we found that the mics of the mmtv - pymt tumor model ( malanchi et al . , 2012 )
however , using the emt downstream effector axl as a marker for mesenchymal cancer cells , we demonstrate that , within the mmtv - pymt hierarchy , the mesenchymal features per se do not confer a differential tumor initiation ability ( figure 1h and s2 ) .
nonetheless , a more mesenchymal state promotes growth at a less favorable distant environment ( figure 1i ) .
this correlates with a higher capacity of cd24axl cells to induce stromal activation early after infiltration of the secondary tissue ( figures 2a2d ) .
our work suggests that the increased intrinsic ability to trigger a favorable microenvironment at the naive target site provides a metastatic initiation advantage .
indeed , both the mic subpool of mmtv - pymt cancer cells as well as the metastatic human mda - mb-231 cell line show higher niche component activation ability according to their mesenchymal phenotype ( figures 2 and 4 ) and thbs2 secretion ( figure 3 ) .
we show here that thbs2 is capable of triggering fibroblast activation via integrin signaling and enhancing early metastatic colonization ( figure 3i ) .
this finding is supported by computational analyses defining thbs2 as one of the three genes associated with a stromal desmoplastic reaction and high metastatic risk ( kim et al . ,
2010 ) as well as by the clinical evidence of its correlation with poor prognosis in high - grade human breast cancers ( figure s3i )
. however , in rare circulating cancer cell clusters that exhibit high metastatic potential , the mechanism we describe may be circumvented ( aceto et al . , 2014 ) . in this context
, the cells within the cluster may create their own favorable niche and , therefore , bypass the requirement for a mesenchymal state and associated niche activation .
our results support the concept that stemness is unperturbed by the mesenchymal / epithelial plasticity of metastatic cells and correlate with a flexible partial emt state rather than with a stable binary emt program .
we confirmed that , to efficiently generate a cancer cell mass at a distant site , cells regain a more epithelial phenotype ( tsai et al . , 2012 ) .
notably , we now show that this modulation is controlled temporally during the second phase of metastatic colonization ( figure 7 ) .
indeed , prolonged axl gene activation in cancer cells strongly reduces metastatic ability ( figures 7h and 7k ) .
axl expression in the context of breast cancer lung metastasis opposes primary tumor initiation ( figures 7g7k and s7d ) , likely because of differences in the requirement of its tyrosine kinase receptor function , which is also crucial for other cancer types ( ben - batalla et al . , 2013 ) .
remarkably , we provide experimental evidence that epithelial plasticity is mediated by crosstalk between the cancer cell and stroma ( figure 6 ) . during the second colonization phase ,
the newly activated fibroblasts generated during the first phase induce a phenotype switch in mics .
bmp - dependent id1 activation in cancer cells is triggered by exposure to cacm ( figures 6l and 6 m ) .
this effect , observed in vitro , is corroborated in vivo by the enhancement of psmad1 - 5 activity and downmodulation of tgf- signaling in favor of an id1-positive proliferative state .
indeed , treatment of mice with the specific bmp inhibitor ldn193189 during the second colonization phase inhibits metastasis ( figures 6n and 6o ) .
overall , this study provides a refined definition of distant colonization by more mesenchymal cancer cells where their niche - activation capacity is linked to their mesenchymal status and thbs2 secretion .
this model highlights the importance of cancer cell - stroma crosstalk in modulating the optimal phenotype for cancer cells during the dynamic metastatic process .
p values were obtained from two - tailed student s t tests with paired or unpaired adjustment .
one - tailed t test was used for figure 4e . where indicated , two - way anova was used to perform multiple comparisons or multiple variables analysis between experimental groups .
graphs show the symbols describing the p value ( p < 0.05 , p < 0.01 , p < 0.001 , p < 0.0001 ) .
all experimental procedures involving mice were performed in accordance with united kingdom regulations under project license ppl 80/2531 .
lungs or matrigel collagen gels from co - culture experiments were digested and dissociated to obtain a single - cell suspension , stained with a live / dead fixable dye , fixed , and stained with the indicated primary antibodies ( antibody descriptions and working dilutions can be found in table s4 and in the supplemental experimental procedures ) .
y.p.m . designed and performed most of the experiments , analyzed data , and contributed to manuscript preparation .
designed and supervised some experiments , provided crucial conceptual advice , and revised the manuscript .
i.m . designed and supervised the study , interpreted data , and wrote the manuscript . | summaryduring metastatic colonization , tumor cells must establish a favorable microenvironment or niche that will sustain their growth .
however , both the temporal and molecular details of this process remain poorly understood . here
, we found that metastatic initiating cells ( mics ) exhibit a high capacity for lung fibroblast activation as a result of thrombospondin 2 ( thbs2 ) expression .
importantly , inhibiting the mesenchymal phenotype of mics by blocking the epithelial - to - mesenchymal transition ( emt)-associated kinase axl reduces thbs2 secretion , niche - activating ability , and , consequently , metastatic competence .
subsequently , disseminated metastatic cells revert to an axl - negative , more epithelial phenotype to proliferate and decrease the phosphorylation levels of tgf--dependent smad2 - 3 in favor of bmp / smad1 - 5 signaling .
remarkably , newly activated fibroblasts promote this transition . in summary ,
our data reveal a crosstalk between cancer cells and their microenvironment whereby the emt status initially triggers and then is regulated by niche activation during metastatic colonization . | <s>[INST]solid epithelial tumors are complex structures in which associated stromal cells , including fibroblasts , support cancer cells . during metastatic progression ,
cancer cells disseminate from their tissue of origin to re - establish the tumor structure in distant organs .
efficient metastasis requires the expression of specific molecules , such as postn and tnc , within the local microenvironment ( malanchi et al . , 2012 ,
therefore , a favorable microenvironment , or niche , is a crucial early requirement for metastatic progression ( sleeman , 2012 ) .
cancer cells display heterogeneity in intrinsic tumorigenic potential ; only a small subset of cells within tumors retains the ability of sustaining long - term growth ( hermann et al .
cancer cells with the stem cell - like property of self - renewal can be defined functionally as cancer - initiating cells ( cics ) for their capacity to elicit tumor growth .
moreover , metastatic initiating cells ( mics ) can be distinguished from the bulk of cancer cells for their ability to establish metastasis .
the functional assay for mics involves determining the extent to which single cells can grow in a foreign tissue and is more challenging than the equivalent orthotopic transplantation assay used to assess the ability of cics to initiate tumor growth .
although self - renewal ability is a common requirement for the re - initiation of a cancer cell mass at either primary or secondary sites , additional characteristics that discriminate mics from cics have not been explored .
mics have been identified previously in the mouse breast cancer model where mouse mammary tumor virus promoter controls the expression of the polyomavirus middle t antigen ( mmtv - pymt ) ( malanchi et al . , 2012 ) .
we hypothesized that , in addition to intrinsic tumorigenic potential , mics would exhibit a higher capacity for interacting with their niche by activating naive cells at distant sites ( malanchi , 2013 ) .
one strategy adopted by carcinoma cells to disseminate from the primary tumor mass is the activation of the developmental program epithelial - to - mesenchymal transition ( emt ) . during emt ,
epithelial cells undergo a global change in cell architecture , leading to the loss of cell - cell adhesions in favor of cell - extracellular matrix ( ecm ) interactions and cell migration ( thiery et al . , 2009 ) .
notably , emt modulations are not binary , but a graded range of intermediate states exists .
the process is initiated by the activation of the emt core transcription factors ( tfs ) snail , zeb , and twist1 ( peinado et al . , 2007 ) , which drive epithelial cancer cells to switch off the expression of epithelial markers such as the adherens junction protein e - cadherin and
the tyrosine kinase axl is a downstream effector of the emt program ( vuoriluoto et al . , 2011 ) .
emt in breast cancer cells triggers an increase in axl expression , and inhibition of axl reduces the invasive and tumorigenic behavior of cancer cells ( gjerdrum et al . , 2010 , holland et al . , 2010 , sheridan , 2013 , paccez et al . ,
interestingly , the induction of emt tfs correlates with the emergence of stem cell - like properties ( mani et al . , 2008 ,
this suggests that the gain of mesenchymal characteristics might not only affect dissemination from primary tumors but also boost the stem cell properties required for metastatic outgrowth .
however , epithelial characteristics are re - acquired at metastatic locations via mesenchymal - to - epithelial transitions ( mets ) , typically leading to the establishment of secondary tumors with epithelial phenotypes ( tsai et al .
the potential advantage of a more mesenchymal state of cancer cells at the metastatic site and the origin of their epithelial plasticity remain unclear . in this study , we use breast cancer models to demonstrate that the emt program is a key regulator of the enhanced niche activation capacity of mics at secondary sites .
we identify thrombospondin 2 ( thbs2 ) as a mesenchymal state - dependent effector of cancer cells that promotes stromal niche activation .
subsequently , the newly activated stroma promotes cancer cells to shift toward a more epithelial , bmp - dependent state compatible with proliferation .
we elucidated a biphasic temporal regulation during metastatic colonization whereby the mesenchymal status of cancer cells promotes stromal activation , which , in turn , promotes cancer cell epithelial plasticity and their reversion to a more epithelium - like phenotype .
in the mouse breast cancer mmtv - pymt model , mics were identified by co - expression of the cd24 and cd90 markers ( malanchi et al . , 2012 ) .
the gene expression profile of mics ( cd24cd90 ) was compared to that of non - mics ( cd24cd90 ) to generate a mic signature ( figure s1a ) .
we verified that high levels of wnt signaling are a hallmark of metastatic cancer stem cells ( malanchi et al .
, 2008 , malanchi et al . , 2012 , nguyen et al . , 2009 , reya and clevers , 2005 , vermeulen et al . , 2010 ) , along with other characteristics associated with their high metastatic potential , such as active transforming growth factor ( tgf- ) signaling ( padua et al . , 2008 ) and yap / taz activity ( diepenbruck et al . , 2014 ) .
we also found that the mic signature exhibited characteristic features of emt and its related extracellular matrix remodeling ( figure 1a and s1b ) . in line with this , mics freshly isolated from primary tumors displayed a mesenchymal phenotype with higher expression of vimentin and the emt - related receptor axl as well as reduced e - cadherin levels ( figures 1b and 1c ) .
this more mesenchymal phenotype was corroborated functionally using matrigel collagen matrices where mics , either in pure or mixed non - mic / mic spheroids , displayed enhanced single - cell invasive behavior compared with non - mics ( figures 1d , 1e , and s1c ) .
the capacity of mics for invasion correlated with increased expression levels of actin cytoskeleton regulators and extracellular matrix components ( figures s1d and s1e ) .
emt in mics was further confirmed by the higher expression and nuclear localization of emt tfs ( figures s1f and s1 g ) .
however , the high level of heterogeneity within the mic population suggests a graded emt with intermediate
partial emt states rather than a simple binary transition . the mic expression signature also correlated with different secretome gene sets ( figure 1a ) . some of these secreted factors have been reported previously to play a role in metastasis , such as tnc , sparc , or ccl2 ( oskarsson et al .
we went on to investigate the influence that the observed partial emt status of mics has on their capacity for metastatic initiation following dissemination .
because the metastatic behavior of mmtv - pymt mics might be regulated by the activity of other pathways , such as wnt ( figure 1a ) , we selected a broader mesenchymal cancer cell pool expressing axl , including the mic ( cd24cd90 ) population ( figure s2a ) .
as expected , the cd24axl population isolated from primary tumors displayed partial mesenchymal features ( figures s2b and s2c ) .
we next tested cd24axl cells for their cancer initiation and metastatic initiation potential using orthotopic transplantation and tail vein injection , respectively ( figures 1f and 1 g ) .
both assays require cancer cell stemness to reinitiate and sustain a cancer cell mass , either in a collective challenge within their organ of origin with favorable niches or when seeded via circulation as single cells in a likely less favorable foreign organ .
we observed no difference in primary tumor growth for cd24axl and cd24axl cells , indicating that the subpools exhibit a comparable capacity for cancer initiation ( figure 1h ) .
indeed , for mmtv - pymt tumor cells , more mesenchymal characteristics do not appear to influence tumor initiation ability .
the more epithelial cd24sca1 subpool ( figures s2d s2f ) identified previously for their tumor initiation capacity ( liu et al .
, 2007 ) displayed a similar tumor initiation potential as the more mesenchymal cd24axl or mic pools ( figures s2g s2i ) .
strikingly , cd24axl cancer cells show a higher lung metastasis competence compared with their more epithelial counterparts ( figure 1i ) .
this suggests that the common mesenchymal characteristics observed within the cd24axl and mic cd24cd90 cancer cells might be linked functionally to their metastatic competence , independent of an advantage in intrinsic stemness potential displayed in a favorable microenvironment .
the highly secretory mesenchymal status of mics might provide an increased capacity of generating a favorable environment , or niche , in distant sites ( figure 1a ) .
we examined this suggestion by analyzing the activation of lung stromata around disseminated axl or axl cancer cell early after their extravasation into the lungs .
in line with our hypothesis , cd24axl cells are surrounded by higher numbers of smooth muscle actin ( sma)-activated fibroblastic stroma compared with cd24axl cells .
we observed no difference in their tissue localization , in particular in their proximity to lung endothelial cells ( figures 2a2d ) . to test whether niche activation ability is a common advantage conferred by the mesenchymal status of cd24axl and mic pools , we measured the ability of isolated mics to trigger features of cancer - associated fibroblasts ( cafs ) in normal lung fibroblasts ex vivo . sorted mics or non - mics with a gfp - labeled normal lung fibroblast cell line ( nlf3 ) were plated and monitored for the induction of early fibroblast activation markers ( figure 2e ) . because all cancer cells are capable of fibroblast activation to some extent , we used low cell numbers to increase the assay s sensitivity .
after 24 hr , fibroblasts co - cultured with mics exhibited early nuclear yap translocation , required for caf induction , and higher fibroblast activation protein ( fap ) expression compared with fibroblasts cultured with non - mics ( figures 2f2h ; calvo et al . , 2013 ) . to verify that the induction of these markers represents fibroblast activation , we performed functional gel contraction assays to examine the ability of fibroblasts to physically remodel the ecm .
limited numbers of cell - sorted mics or non - mics from primary tumors were seeded in the upper chamber of a trans - well dish . in the lower chamber of the co - culture , normal lung fibroblasts ( nfs ) freshly isolated from wild - type mouse lungs were embedded in collagen - matrigel matrices ( figure 2i ) .
importantly , we observed that mics trigger significantly greater fibroblast - driven gel contraction compared with the other primary cancer cells ( figures 2j ) . in parallel , a gain of a caf gene expression signature was induced in fibroblast co - cultured with mics .
collectively , these data provide direct evidence that cancer cells displaying partial emt characteristics show an enhanced ability to generate activated fibroblasts , a crucial component of the metastatic niche .
to understand the mechanism underlying the enhanced capacity for fibroblast activation , we tested several mic - specific secreted proteins for their ability to activate fibroblasts ( figures s3a and s3b ) .
we found that purified recombinant thbs2 significantly enhanced the gel contraction capacity of fibroblasts ( figure 3a ) .
we observed that exposure of lung fibroblasts to purified thbs2 led to activation of integrin 1 and the phosphorylation of its downstream effector focal adhesion kinase ( pfak ) ( figures 3b and 3c ) .
importantly , a specific integrin 1-blocking antibody ( 1ba ) arrested the thbs2-dependent integrin cascade as well as fibroblast activation ( figures 3b3d ) . to examine the role thbs2
might play in tumorigenicity , we used a specific short hairpin rna ( shrna ) targeting thbs2 mrna ( shthbs2 ) to knock down its expression in primary mmtv - pymt cancer cells ( pymt ) ( figure 3e ) .
importantly , thbs2 depletion rendered cancer cells less able to activate lung fibroblasts ( figure 3f ) .
furthermore , shthbs2 cancer cells were reduced dramatically in their capacity for lung metastatic colonization upon intravenous injection ( figure 3h ) . however
, this is unlikely to be due to an effect on intrinsic cancer cell stemness because shthsb2 pymt cells maintained their ability to initiate early primary tumor growth in vivo or form spheres in vitro ( figure 3 g and s3c ) .
similar findings were obtained using a second shrna to block thbs2 secretion ( figures s3d s3h ) . because thbs2 is highly expressed in only a subset of pymt cells , we tested the consequence of exogenous thbs2 gene expression in all pymt cells .
importantly , broad thbs2 secretion resulted in increased early metastatic growth in the lungs upon direct seeding ( figure 3i ) .
these data support the clinical correlation of high thbs2 expression with poor prognosis in advanced - stage human breast cancers ( figure s3i ) .
together , these results suggest that mics mediate efficient fibroblast activation through thbs2 secretion and that this is critical for efficient metastatic initiation within the secondary tissue .
interestingly , we also found that their partial emt phenotype defined by axl expression was sufficient to determine their metastatic competence ( figure 1i ) .
therefore , we investigated whether the high niche activation ability of mics is linked functionally to their axl mesenchymal status .
first we used the axl - specific small molecule inhibitor r428 ( holland et al . , 2010 ) , and second we used an shrna to target axl mrna ( gjerdrum et al . , 2010 ) .
brief exposure of mics to r428 triggered an overall shift toward a more epithelial phenotype with lower vimentin and axl expression and higher e - cadherin levels ( figures 4a , 4b , and s4a ) .
accordingly , we detected a reduction in the expression of emt - tfs and motility in mics ( figures s4b and s4c ) .
similar phenotypic changes occurred in the basal human breast cancer cell line mda - mb-231 ( mda231 ) following treatment with r428 . indeed ,
although mda231 cells , which homogeneously express axl , typically display mesenchyme - like features , a single pulse of r428 reduced the expression of axl and vimentin and cell motility for up to 48 hr ( figures s4d
interestingly , upon r428-mediated mesenchymal inhibition , cancer cells also reduced the expression of secreted factors , including thbs2 ( figures 4c and s4h ) .
concomitantly , the fibroblast activation ability of r428-treated metastatic cells was impaired dramatically ( figure 4d ) . because similar results were found using an shrna against axl mrna in primary pymt cells ( figure s5a )
indeed , shrna - induced axl downregulation in pymt cells reduced thbs2 secretion and ex vivo fibroblast activation abilities ( figures 4e and 4f ) .
notably , the expression of thbs2 appears to be highly linked to the expression of the axl and twist1 genes in human tumor biopsies ( figure s4i ) .
these data demonstrate that the mesenchymal status of mics is directly related to their enhanced capacity for fibroblast activation .
we showed that mics isolated from primary tumors are in an axl - positive mesenchymal state .
therefore , we went on to examine the mesenchymal status of cancer cells at the target site by monitoring axl expression during early colonization .
we detected two distinct phases of axl expression : a first phase , where the pymt emt mic subpool maintains axl , and a second phase , where the axl - positive phenotype is lost coincidentally with mic expansion in the lungs ( figure 5a ) .
similar biphasic axl expression was observed in the mda231 cell line ( figure 5b ) . because the ability of cancer cells to trigger the niche is crucial for metastatic establishment ( figure 3 ) and dependent on the mesenchymal phenotype ( figure 4 ) , we assessed whether the maintenance of axl is required for the first phase of metastatic colonization . to do this
, we inhibited axl activity only during the first colonization phase by pre - treating cancer cells with the r428 inhibitor prior to intravenous injection and continued treatment in vivo for 7 days ( figure 5c and s5b ) . notably , although r428 pre - treatment did not alter cancer cell extravasation ( figure s5c ) , it did significantly reduce metastasis after 5 weeks ( figures 5d5f ) .
remarkably , only r428 pre - treatment 24 hr before seeding into the lung was sufficient to inhibit metastatic establishment ( figure 5e ) , suggesting that axl mesenchymal features are required early after metastatic cell arrival to new tissue .
although short - term inhibition of axl decreased metastatic competence , this had no effect on proliferation , self - renewal , and 3d cancer cell mass growth in vitro ( figures s5d5 g ) , or primary tumor initiation in vivo ( figure s5h ) .
interestingly , enhancing thbs2 expression in the mda - mb-231 cell line partially rescued metastasis upon axl inhibition in spite of the fact that thbs2 overexpression only provided a positive trend toward metastasis in these cells ( figures 5 g , s5i , and s5j ) .
this result is in line with the observation that axl - mesenchymal cells show a thbs2-mediated advantage in niche activation .
we also observed a block in metastasis upon axl inhibition using shrna knockdown in pymt cells ( figures 5h and 5i ) .
furthermore , treatment of a second mouse breast cancer cell line ( 4t1 ) with shthbs2 or shaxl also reduced the metastatic ability of 4t1 cells ( figures s5k and s5l ) . together
, these results suggest that the first phase of metastatic colonization requires the niche activation capacity provided by the axl mesenchymal characteristics .
the previous results highlight the requirement of a mesenchymal state for metastatic initiation upon seeding at the target site .
however , when cancer cells start growing within the metastatic tissue , axl expression is downregulated ( figures 5a , 5b , and 6a ) .
imagestream analysis showed that , coincident with axl downregulation , gfp cancer cells growing in the lungs exhibit reduced expression of the emt transcription factor twist1 ( figures 6b , 6c , s6a , and s6b ) .
this suggests that the previously reported emt inhibition at the secondary site ( tsai et al . ,
therefore , we investigated the changes that occur in metastatic cells during this time period .
ex vivo co - culture ( as shown in figure 2e ) demonstrated that , concomitant with fibroblast activation ( figures 2f2h ) , mics express lower levels of axl , twist1 ( figures 6d and 6e ) , and overall emt tf mrna ( figure s6c ) . to track the phenotypic changes during this time , cancer cells were co - cultured with cafs for 24 hr under adherence conditions ( figure s6d ) .
here we found that mics reduced expression of vimentin and axl and increased expression of e - cadherin ( figures s6e and s6f ) .
these results suggest that crosstalk between fibroblasts and cancer cells triggers alterations in both compartments ; namely , activation of fibroblasts and consequent reacquisition of epithelial characteristics by cancer cells . to functionally validate these changes in the mic emt state
, we analyzed their 3d invasion modality as they first come in contact with cafs .
in line with previous studies ( gaggioli et al . , 2007 , yu et al . , 2014 )
, carcinoma cells in a non - invasive epithelial state ( non - mics ) activated both single and collective cell invasion modalities . strikingly , in line with the downregulation of mesenchymal markers , mics displayed a notable reduction in single - cell migration when surrounded by cafs ( figures 6f and 6 g ) .
we next investigated the potential molecular mechanism of caf - driven changes in cancer cells .
tgf- signaling has been implicated extensively in metastasis ( padua et al . , 2008 ) .
high tgf- signaling favors early metastatic colonization , whereas its subsequent reduction is important for metastatic outgrowth ( giampieri et al . , 2009 ) .
because tgf- signaling , which is active in mics ( figure 1a and s1b ) , could be linked functionally to their mesenchymal status ( diepenbruck et al . , 2014 ) , we assessed whether modulation of tgf- signaling in mics associates with the reacquisition of more epithelial characteristics . using imagestream analysis , we monitored the dynamics of activation of the tgf- effector smad2 - 3 in metastasizing cells in vivo .
as axl mesenchymal cells in the lung transit from the first to the second phase of colonization , the number and staining intensity of psmad2 - 3 cells decreased similarly to twist1 expression ( figure 6h , s6 g , and s6i ) .
these data are in agreement with the previous evidence showing that a reduction in tgf- signaling is required for the acquisition of the proliferative status necessary for metastatic outgrowth ( massagu , 2008 ) .
conversely , the activation levels of bmp - dependent psmad1 - 5 was maintained during the second phase of colonization , and the number of psmad1 - 5 cells increased ( figures 6i , s6h , and s6j ) . in line with this , we observed that the levels of inhibitor of differentiation 1 ( id1 ) , a bmp / psmad1 - 5 target gene needed for cell proliferation during metastatic outgrowth ( gupta et al . , 2007 ) , were maintained , in particular in twist1 cells ( figures 6j and 6k ) .
notably , this modulation of id1 in cancer cells could be recapitulated in vitro by exposure to caf - conditioned medium ( cacm ) , which increases the levels of id1 in a bmp - dependent manner ( figures 6l and 6 m ) .
importantly , treatment with the specific inhibitor ldn193189 in vivo resulted in reduced metastatic capacity ( figures 6n and 6o ) , suggesting that bmp / psmad1 - 5 activity does indeed play a significant role in the second phase of colonization .
together , these data show that , in the second colonization phase , the phenotypic changes observed in metastasizing cancer cells toward a more epithelial state correlate with an inhibition of tgf- signaling and the enhanced bmp signaling necessary for metastatic outgrowth .
we showed that the mesenchymal status of cancer cells during the first phase of colonization is required for metastatic establishment .
however , when cd24axl mesenchymal cancer cells accumulate in the lung , they revert to an axl - negative , more epithelial state ( figure 5 ) following interaction with newly activated fibroblasts ( figure 6 ) .
if these two events were linked causally , then it would be expected that a temporal regulation of epithelial plasticity is critical for metastatic outgrowth .
initially , to probe this hypothesis , we induced an early mesenchymal reversion of metastatic cells by r428 treatment during the second phase of colonization ( figure 7a ) .
this axl inhibition no longer blocks the metastatic establishment of mda231 cells ( figure s7a ) and increases metastasis of primary pymt cells ( figures 7b and 7c ) , suggesting that inhibiting emt in this phase promotes metastasis .
we observed that axl inhibition in late - stage metastases did not alter the number of metastatic nodules ( figures 7a and 7b ) .
next , we delayed mesenchymal reversion in vivo by exogenous expression of the axl gene ( ltr - axl ) in cancer cells ( figure 7d ) .
this leads to an exacerbated axl - positive mesenchymal phenotype ( figures 7 g , 7j , and s7b ) without altering the proliferation capacity ( figure s7c ) .
importantly , preventing early axl downregulation in metastasizing ltr - axl - expressing cells delayed initial growth in the lungs ( figures 7e and 7f ) and , ultimately , led to a reduction in the metastatic potential of both pymt and mda231 cancer cells ( figures 7h , 7i , and 7k ) .
these data support the idea that downregulation of axl is required during the second colonization phase to allow the transition to a more epithelial proliferative state .
interestingly , the overexpression of axl in cancer cells led to a reduction in metastatic capacity specifically because an enhancement of primary tumor growth was detected ( figure s7d ) .
this is likely due to an increase in axl tyrosine kinase receptor activity at the early stages of tumor initiation , leading to the generation of larger tumors without obvious histologic changes after tumor establishment ( figures s7e and s7f ) .
successful establishment of metastases requires cancer cells with self - renewal properties to disseminate from their tissue of origin and re - initiate growth at secondary sites . the evidence that experimental induction of emt in epithelial cells triggers stem cell characteristics suggests a unified mechanism for cancer metastasis .
however , the plasticity of the emt program from dissemination to distant colonization during the metastatic process makes the direct relationship between emt and stemness controversial ( tsai et al . , 2012 ,
mani et al . , 2008 , morel et al . , 2008 ,
, 2009 , brabletz , 2012 , nieto , 2013 ) and suggests that metastatic cancer cells are likely to undergo a partial emt that can be modulated toward a more mesenchymal or epithelial state ( ombrato and malanchi , 2014 ) .
furthermore , although the requirement of an emt inhibition at the metastatic site has been reported previously ( tsai et al . , 2012 ) , the dynamic regulation of the mesenchymal / epithelial transition is currently unknown . using breast cancer models , we highlight the importance of the more mesenchymal phenotype of mics during the early phase of metastatic colonization .
moreover , we demonstrate the requirement for axl mesenchymal state - dependent thbs2 secretion in mediating enhanced niche activation .
we also identify a subsequent phase of colonization where the mesenchymal phenotype of cancer cells is downmodulated by the interaction with the newly induced niche .
this crosstalk leads to inhibition of tgf- signaling and psmad1 - 5-dependent outgrowth , shifting cancer cells toward a more epithelial and proliferative state .
blocking the effectors of these pathways during this biphasic process reduces metastasis : thbs2 expression during the first phase or psmad1 - 5 activity during the second phase . here
we identify epithelial plasticity as a crucial determinant of metastatic colonization and describe how disruption of axl - dependent phenotypic modulation is sufficient to reduce metastatic efficiency . in agreement with the previously observed link between the emt program and the gain in stemness ( mani et al .
, 2008 , morel et al . , 2008 ) , we found that the mics of the mmtv - pymt tumor model ( malanchi et al . , 2012 )
however , using the emt downstream effector axl as a marker for mesenchymal cancer cells , we demonstrate that , within the mmtv - pymt hierarchy , the mesenchymal features per se do not confer a differential tumor initiation ability ( figure 1h and s2 ) .
nonetheless , a more mesenchymal state promotes growth at a less favorable distant environment ( figure 1i ) .
this correlates with a higher capacity of cd24axl cells to induce stromal activation early after infiltration of the secondary tissue ( figures 2a2d ) .
our work suggests that the increased intrinsic ability to trigger a favorable microenvironment at the naive target site provides a metastatic initiation advantage .
indeed , both the mic subpool of mmtv - pymt cancer cells as well as the metastatic human mda - mb-231 cell line show higher niche component activation ability according to their mesenchymal phenotype ( figures 2 and 4 ) and thbs2 secretion ( figure 3 ) .
we show here that thbs2 is capable of triggering fibroblast activation via integrin signaling and enhancing early metastatic colonization ( figure 3i ) .
this finding is supported by computational analyses defining thbs2 as one of the three genes associated with a stromal desmoplastic reaction and high metastatic risk ( kim et al . ,
2010 ) as well as by the clinical evidence of its correlation with poor prognosis in high - grade human breast cancers ( figure s3i )
. however , in rare circulating cancer cell clusters that exhibit high metastatic potential , the mechanism we describe may be circumvented ( aceto et al . , 2014 ) . in this context
, the cells within the cluster may create their own favorable niche and , therefore , bypass the requirement for a mesenchymal state and associated niche activation .
our results support the concept that stemness is unperturbed by the mesenchymal / epithelial plasticity of metastatic cells and correlate with a flexible partial emt state rather than with a stable binary emt program .
we confirmed that , to efficiently generate a cancer cell mass at a distant site , cells regain a more epithelial phenotype ( tsai et al . , 2012 ) .
notably , we now show that this modulation is controlled temporally during the second phase of metastatic colonization ( figure 7 ) .
indeed , prolonged axl gene activation in cancer cells strongly reduces metastatic ability ( figures 7h and 7k ) .
axl expression in the context of breast cancer lung metastasis opposes primary tumor initiation ( figures 7g7k and s7d ) , likely because of differences in the requirement of its tyrosine kinase receptor function , which is also crucial for other cancer types ( ben - batalla et al . , 2013 ) .
remarkably , we provide experimental evidence that epithelial plasticity is mediated by crosstalk between the cancer cell and stroma ( figure 6 ) . during the second colonization phase ,
the newly activated fibroblasts generated during the first phase induce a phenotype switch in mics .
bmp - dependent id1 activation in cancer cells is triggered by exposure to cacm ( figures 6l and 6 m ) .
this effect , observed in vitro , is corroborated in vivo by the enhancement of psmad1 - 5 activity and downmodulation of tgf- signaling in favor of an id1-positive proliferative state .
indeed , treatment of mice with the specific bmp inhibitor ldn193189 during the second colonization phase inhibits metastasis ( figures 6n and 6o ) .
overall , this study provides a refined definition of distant colonization by more mesenchymal cancer cells where their niche - activation capacity is linked to their mesenchymal status and thbs2 secretion .
this model highlights the importance of cancer cell - stroma crosstalk in modulating the optimal phenotype for cancer cells during the dynamic metastatic process .
p values were obtained from two - tailed student s t tests with paired or unpaired adjustment .
one - tailed t test was used for figure 4e . where indicated , two - way anova was used to perform multiple comparisons or multiple variables analysis between experimental groups .
graphs show the symbols describing the p value ( p < 0.05 , p < 0.01 , p < 0.001 , p < 0.0001 ) .
all experimental procedures involving mice were performed in accordance with united kingdom regulations under project license ppl 80/2531 .
lungs or matrigel collagen gels from co - culture experiments were digested and dissociated to obtain a single - cell suspension , stained with a live / dead fixable dye , fixed , and stained with the indicated primary antibodies ( antibody descriptions and working dilutions can be found in table s4 and in the supplemental experimental procedures ) .
y.p.m . designed and performed most of the experiments , analyzed data , and contributed to manuscript preparation .
designed and supervised some experiments , provided crucial conceptual advice , and revised the manuscript .
i.m . designed and supervised the study , interpreted data , and wrote the manuscript .[/INST]summaryduring metastatic colonization , tumor cells must establish a favorable microenvironment or niche that will sustain their growth .
however , both the temporal and molecular details of this process remain poorly understood . here
, we found that metastatic initiating cells ( mics ) exhibit a high capacity for lung fibroblast activation as a result of thrombospondin 2 ( thbs2 ) expression .
importantly , inhibiting the mesenchymal phenotype of mics by blocking the epithelial - to - mesenchymal transition ( emt)-associated kinase axl reduces thbs2 secretion , niche - activating ability , and , consequently , metastatic competence .
subsequently , disseminated metastatic cells revert to an axl - negative , more epithelial phenotype to proliferate and decrease the phosphorylation levels of tgf--dependent smad2 - 3 in favor of bmp / smad1 - 5 signaling .
remarkably , newly activated fibroblasts promote this transition . in summary ,
our data reveal a crosstalk between cancer cells and their microenvironment whereby the emt status initially triggers and then is regulated by niche activation during metastatic colonization .</s> |
SECTION 1. SHORT TITLE.
This Act may be cited as the ``Life Insurance Fairness for
Travelers Act of 2005''.
SEC. 2. AMENDMENTS TO TRIA.
The Terrorism Risk Insurance Act of 2002 (Public Law 107-297; 116
Stat. 2322) is amended by adding at the end the following new title:
``TITLE IV--FAIRNESS FOR LIFE INSURANCE PURCHASERS
``SEC. 401. CONGRESSIONAL FINDINGS AND PURPOSES.
``(a) Findings.--The Congress finds that--
``(1) life insurance companies are increasingly using the
future plans of Americans to engage in lawful foreign travel as
a reason to either deny persons life insurance or to charge
premiums that are not commensurate with the risk of such
travel; and
``(2) that such denials of insurance and disproportionate
premiums may deter Americans from purchasing insurance that
they and their families may need.
``(b) Purpose.--The purpose of this title is to establish uniform
rules relating to the use of foreign travel as a factor in setting life
insurance eligibility and rating.
``SEC. 402. PROHIBITION AGAINST DISCRIMINATION IN LIFE INSURANCE
POLICIES BASED ON FUTURE FOREIGN TRAVEL PLANS.
``(a) In General.--It shall be unlawful for any insurer to deny any
person life insurance, or to otherwise discriminate in the issuance,
cancellation, amount of coverage, or conditions of life insurance,
based upon the intent of such person to engage in future lawful foreign
travel.
``(b) Insurance Rates.--It shall be unlawful for any insurer to
charge rates for life insurance which are excessive or unfairly
discriminatory in relation to the actuarial risk associated with future
lawful foreign travel of such person.
``SEC. 403. ADMINISTRATIVE ENFORCEMENT.
``(a) State Enforcement.--In addition to such other remedies as are
provided under State law, the chief law enforcement officer of a State,
or an official or agency designated by a State, may bring an action to
enjoin any person who has violated or is violating this title.
``(b) Enforcement by the Secretary.--The Secretary shall enforce
this Act in any State that the Secretary determines does not have a
comparable State law or a law that the Secretary has determined is not
inconsistent under section 405.
``SEC. 404. EFFECT ON STATE LAWS.
``(a) In General.--This title does not annul, alter, or affect, or
exempt any insurer subject to the provisions of this title from
complying with the laws of any State with respect to the use of
prospective lawful foreign travel for the purposes of underwriting or
rating life insurance except to the extent that such laws are
inconsistent with any provision of this title and then only to the
extent of the inconsistency. The Secretary is authorized to determine
whether such inconsistencies exist. The Secretary may not determine
that any State law is inconsistent with any provision of this title if
the Secretary determines that such law gives greater protection to the
insured.
``(b) State Exemptions.--The Secretary shall, by regulation, exempt
from the requirements of this title any class of insurance transactions
within any State if the Secretary determines that under the law of that
State that class of transaction is subject to requirements
substantially similar to those imposed under this title or that such
law gives greater protection to the consumer, and that there is
adequate provision for enforcement.
``SEC. 405. DEFINITIONS.
``In this title, the following definitions shall apply:
``(1) Insurer.--The term `insurer' means any entity,
including any affiliate thereof, that is licensed or admitted
to engage in the business of providing life insurance in any
State.
``(2) Insured.--The term `insured' means any natural person
who purchases, or attempts to purchase, life insurance.
``(3) Life insurance.--
``(A) In general.--The term `life insurance' means
insurance for which the probabilities of the duration
of human life or the rate of mortality are an element
or condition of insurance.
``(B) Included insurance.--Such term includes the
granting of--
``(i) endowment benefits;
``(ii) additional benefits in the event of
death by accident or accidental means;
``(iii) disability income benefits;
``(iv) additional disability benefits that
operate to safeguard the contract from lapse or
to provide a special surrender value, or
special benefit in the event of total and
permanent disability;
``(v) benefits that provide payment or
reimbursement for long-term home health care,
or long-term care in a nursing home or other
related facility;
``(vi) burial insurance; and
``(vii) optional modes of settlement of
proceeds of life insurance.
``(C) Exclusions.--Such term does not include
property and casualty insurance, health insurance or
workers compensation insurance.
``(4) Secretary.--The term `Secretary' means the Secretary
of the Treasury.
``SEC. 406. REGULATIONS.
`` The Secretary shall issue regulations to carry out the purposes
of this title.
``SEC. 407. APPLICABILITY.
``This title shall apply to any policy for life insurance coverage
issued, renewed, altered, or modified or canceled after the expiration
of the 6-month period beginning on the date of the enactment of the
Life Insurance Fairness for Travelers Act of 2005.''.
SEC. 3. TIMING OF REGULATIONS.
The Secretary of the Treasury shall issue the regulations required
by section 406 of the Terrorism Risk Insurance Act of 2002, as added by
section 2 of this Act, not later than the expiration of the 6-month
period beginning on the date of the enactment of this Act.
SEC. 4. TECHNICAL AMENDMENT.
The table of contents in section 1(b) of the Terrorism Risk
Insurance Act of 2002 (15 U.S.C. 6701 note) is amended by adding at the
end the following new items:
``TITLE IV--FAIRNESS FOR LIFE INSURANCE PURCHASERS
``Sec. 401. Congressional findings and purposes.
``Sec. 402. Prohibition against discrimination in life insurance
policies based on future foreign travel
plans.
``Sec. 403. Administrative enforcement.
``Sec. 404. Effect on State laws.
``Sec. 405. Definitions.
``Sec. 406. Regulations.
``Sec. 407. Applicability.''. | Life Insurance Fairness for Travelers Act of 2005 - Amends the Terrorism Risk Insurance Act of 2002 to make it unlawful for any insurer to: (1) deny any person life insurance, or to otherwise discriminate in the issuance, cancellation, amount of coverage, or conditions of life insurance, based upon the person's intent to engage in future lawful foreign travel; and (2) charge rates for life insurance which are excessive or unfairly discriminatory in relation to the actuarial risk associated with future lawful foreign travel of such person.
Provides for administrative enforcement of this Act by either: (1) the chief law enforcement officer of a state, or an official or agency designated by a state; or (2) the Secretary of the Treasury. | <s>[INST]SECTION 1. SHORT TITLE.
This Act may be cited as the ``Life Insurance Fairness for
Travelers Act of 2005''.
SEC. 2. AMENDMENTS TO TRIA.
The Terrorism Risk Insurance Act of 2002 (Public Law 107-297; 116
Stat. 2322) is amended by adding at the end the following new title:
``TITLE IV--FAIRNESS FOR LIFE INSURANCE PURCHASERS
``SEC. 401. CONGRESSIONAL FINDINGS AND PURPOSES.
``(a) Findings.--The Congress finds that--
``(1) life insurance companies are increasingly using the
future plans of Americans to engage in lawful foreign travel as
a reason to either deny persons life insurance or to charge
premiums that are not commensurate with the risk of such
travel; and
``(2) that such denials of insurance and disproportionate
premiums may deter Americans from purchasing insurance that
they and their families may need.
``(b) Purpose.--The purpose of this title is to establish uniform
rules relating to the use of foreign travel as a factor in setting life
insurance eligibility and rating.
``SEC. 402. PROHIBITION AGAINST DISCRIMINATION IN LIFE INSURANCE
POLICIES BASED ON FUTURE FOREIGN TRAVEL PLANS.
``(a) In General.--It shall be unlawful for any insurer to deny any
person life insurance, or to otherwise discriminate in the issuance,
cancellation, amount of coverage, or conditions of life insurance,
based upon the intent of such person to engage in future lawful foreign
travel.
``(b) Insurance Rates.--It shall be unlawful for any insurer to
charge rates for life insurance which are excessive or unfairly
discriminatory in relation to the actuarial risk associated with future
lawful foreign travel of such person.
``SEC. 403. ADMINISTRATIVE ENFORCEMENT.
``(a) State Enforcement.--In addition to such other remedies as are
provided under State law, the chief law enforcement officer of a State,
or an official or agency designated by a State, may bring an action to
enjoin any person who has violated or is violating this title.
``(b) Enforcement by the Secretary.--The Secretary shall enforce
this Act in any State that the Secretary determines does not have a
comparable State law or a law that the Secretary has determined is not
inconsistent under section 405.
``SEC. 404. EFFECT ON STATE LAWS.
``(a) In General.--This title does not annul, alter, or affect, or
exempt any insurer subject to the provisions of this title from
complying with the laws of any State with respect to the use of
prospective lawful foreign travel for the purposes of underwriting or
rating life insurance except to the extent that such laws are
inconsistent with any provision of this title and then only to the
extent of the inconsistency. The Secretary is authorized to determine
whether such inconsistencies exist. The Secretary may not determine
that any State law is inconsistent with any provision of this title if
the Secretary determines that such law gives greater protection to the
insured.
``(b) State Exemptions.--The Secretary shall, by regulation, exempt
from the requirements of this title any class of insurance transactions
within any State if the Secretary determines that under the law of that
State that class of transaction is subject to requirements
substantially similar to those imposed under this title or that such
law gives greater protection to the consumer, and that there is
adequate provision for enforcement.
``SEC. 405. DEFINITIONS.
``In this title, the following definitions shall apply:
``(1) Insurer.--The term `insurer' means any entity,
including any affiliate thereof, that is licensed or admitted
to engage in the business of providing life insurance in any
State.
``(2) Insured.--The term `insured' means any natural person
who purchases, or attempts to purchase, life insurance.
``(3) Life insurance.--
``(A) In general.--The term `life insurance' means
insurance for which the probabilities of the duration
of human life or the rate of mortality are an element
or condition of insurance.
``(B) Included insurance.--Such term includes the
granting of--
``(i) endowment benefits;
``(ii) additional benefits in the event of
death by accident or accidental means;
``(iii) disability income benefits;
``(iv) additional disability benefits that
operate to safeguard the contract from lapse or
to provide a special surrender value, or
special benefit in the event of total and
permanent disability;
``(v) benefits that provide payment or
reimbursement for long-term home health care,
or long-term care in a nursing home or other
related facility;
``(vi) burial insurance; and
``(vii) optional modes of settlement of
proceeds of life insurance.
``(C) Exclusions.--Such term does not include
property and casualty insurance, health insurance or
workers compensation insurance.
``(4) Secretary.--The term `Secretary' means the Secretary
of the Treasury.
``SEC. 406. REGULATIONS.
`` The Secretary shall issue regulations to carry out the purposes
of this title.
``SEC. 407. APPLICABILITY.
``This title shall apply to any policy for life insurance coverage
issued, renewed, altered, or modified or canceled after the expiration
of the 6-month period beginning on the date of the enactment of the
Life Insurance Fairness for Travelers Act of 2005.''.
SEC. 3. TIMING OF REGULATIONS.
The Secretary of the Treasury shall issue the regulations required
by section 406 of the Terrorism Risk Insurance Act of 2002, as added by
section 2 of this Act, not later than the expiration of the 6-month
period beginning on the date of the enactment of this Act.
SEC. 4. TECHNICAL AMENDMENT.
The table of contents in section 1(b) of the Terrorism Risk
Insurance Act of 2002 (15 U.S.C. 6701 note) is amended by adding at the
end the following new items:
``TITLE IV--FAIRNESS FOR LIFE INSURANCE PURCHASERS
``Sec. 401. Congressional findings and purposes.
``Sec. 402. Prohibition against discrimination in life insurance
policies based on future foreign travel
plans.
``Sec. 403. Administrative enforcement.
``Sec. 404. Effect on State laws.
``Sec. 405. Definitions.
``Sec. 406. Regulations.
``Sec. 407. Applicability.''.[/INST]Life Insurance Fairness for Travelers Act of 2005 - Amends the Terrorism Risk Insurance Act of 2002 to make it unlawful for any insurer to: (1) deny any person life insurance, or to otherwise discriminate in the issuance, cancellation, amount of coverage, or conditions of life insurance, based upon the person's intent to engage in future lawful foreign travel; and (2) charge rates for life insurance which are excessive or unfairly discriminatory in relation to the actuarial risk associated with future lawful foreign travel of such person.
Provides for administrative enforcement of this Act by either: (1) the chief law enforcement officer of a state, or an official or agency designated by a state; or (2) the Secretary of the Treasury.</s> |
Despite never really showing much interest in fashion up to now, Tobey Maguire is the new face of Prada menswear in ads shot by David Sims. Huh. Random. Maybe they finally saw that horrible dance sequence from Spider-Man 3 and decided he needed their help. They also gave him some promotional copy to read verbatim when Vogue U.K. asked him what the hell he was doing. "A great supporter of the arts, Miuccia Prada has inspired a culture of creativity that is woven through every aspect of her company," Maguire said, adding: "I have such admiration for her artistry." My ass, he does. I'm guessing this is going to tie in with his upcoming role in The Great Gatsby somehow. Either that or, judging from these pictures, he's playing a young Robert Smith in a Cure biopic. Two full images after the jump. ||||| ACTOR Tobey Maguire is Prada's new menswear campaign face for autumn/winter 2011-12, shot in New York by David Sims.
"A great supporter of the Arts, Miuccia Prada has inspired a culture of creativity that is woven through every aspect of her company, from her collections, her campaigns, to every design detail in her stores," Maguire said. "I have such admiration for her artistry and I'm thrilled to be a part of Prada's fall campaign."
Made famous by his role as the unlikely hero, Peter Parker, who becomes Spider Man, Maguire is set to return to our screens in Baz Luhrmann's The Great Gatsby next year.
YOU SHOULD SEE: The latest Prada menswear collection....
YOU SHOULD SEE: How much did Miuccia Prada get paid last year?
YOU SHOULD SEE: Prada's latest catwalk show... | – When you think Prada, you probably don’t think Tobey Maguire. Yet Spider-Man himself is in fact the new face of the company’s menswear campaign, Vogue reports. On AdWeek, David Kiefaber finds the whole thing a little “random,” he writes, but “maybe they finally saw that horrible dance sequence from Spider-Man 3 and decided he needed their help.” Click to see two of the ads shot by David Sims, in which Maguire looks “really quite sullen” and sort of like “a young Robert Smith.” | <s>[INST]Despite never really showing much interest in fashion up to now, Tobey Maguire is the new face of Prada menswear in ads shot by David Sims. Huh. Random. Maybe they finally saw that horrible dance sequence from Spider-Man 3 and decided he needed their help. They also gave him some promotional copy to read verbatim when Vogue U.K. asked him what the hell he was doing. "A great supporter of the arts, Miuccia Prada has inspired a culture of creativity that is woven through every aspect of her company," Maguire said, adding: "I have such admiration for her artistry." My ass, he does. I'm guessing this is going to tie in with his upcoming role in The Great Gatsby somehow. Either that or, judging from these pictures, he's playing a young Robert Smith in a Cure biopic. Two full images after the jump. ||||| ACTOR Tobey Maguire is Prada's new menswear campaign face for autumn/winter 2011-12, shot in New York by David Sims.
"A great supporter of the Arts, Miuccia Prada has inspired a culture of creativity that is woven through every aspect of her company, from her collections, her campaigns, to every design detail in her stores," Maguire said. "I have such admiration for her artistry and I'm thrilled to be a part of Prada's fall campaign."
Made famous by his role as the unlikely hero, Peter Parker, who becomes Spider Man, Maguire is set to return to our screens in Baz Luhrmann's The Great Gatsby next year.
YOU SHOULD SEE: The latest Prada menswear collection....
YOU SHOULD SEE: How much did Miuccia Prada get paid last year?
YOU SHOULD SEE: Prada's latest catwalk show...[/INST]– When you think Prada, you probably don’t think Tobey Maguire. Yet Spider-Man himself is in fact the new face of the company’s menswear campaign, Vogue reports. On AdWeek, David Kiefaber finds the whole thing a little “random,” he writes, but “maybe they finally saw that horrible dance sequence from Spider-Man 3 and decided he needed their help.” Click to see two of the ads shot by David Sims, in which Maguire looks “really quite sullen” and sort of like “a young Robert Smith.”</s> |
HBO
Ed Sheeran, a singer/celebrity, made a cameo appearance on Game of Thrones today. He was there because the actress who plays Arya, Maisie Williams, is a big fan. But some fans complained that the scene felt forced, and memes are already circulating making fun of the cameo.
Did you like the scene? Let us know in the comments below, after you see the best tweets and reactions to Sheeran’s scene.
First, here’s the scene in question:
Here is Ed Sheeran's special appearance on #GameOfThrones pic.twitter.com/3Rnnos5gYe — Hi! Watch This (@HiWatchThis) July 17, 2017
Some fans liked the song, but still felt like his scene took away from the show’s realism:
When Ed Sheeran's presence in #GoTS7 throws you off but the song he was singing is a bop. pic.twitter.com/KuGXzcueyP — cookies&Corinthians (@AKempChronicles) July 17, 2017
All I know is Ed Sheeran needs to gtf outta here — G Daddy (@sorryimgina) July 17, 2017
And some fans are finding some creative ways to work in song lyrics:
At some point in the season I hope Ed Sheeran meets Bran and tells him "When your legs don't work like they used to before" — Manta Rays Children (@868ball_is_life) July 17, 2017
Some fans were hoping for a special surprise from Sheeran’s appearance:
ok but what if ed sheeran ripped off his face and he was jaqen h'ghar pic.twitter.com/L57Vtjj02F — Dana Schwartz (@DanaSchwartzzz) July 17, 2017
If Arya kills Ed Sheeran it'll be worth it — Vann R. Newkirk II (@fivefifths) July 17, 2017
And this reaction is just priceless:
Arya: "That's a pretty song."
Ed Sheeran: "It's a new one… off my brand new album, 'Divide,' in stores now!!!!"#GameOfThrones pic.twitter.com/nsAumXug7K — Zach Goins (@zach_goins) July 17, 2017
But not everyone was upset. Some people were really happy to see him:
Ed Sheeran drinking wine with Arya Stark #WinterIsHere pic.twitter.com/YAbqTuTaSS — Cool Down 💦 (@jadineloveydove) July 17, 2017
What did you think about his cameo? Let us know in the comments below. ||||| Twitter shades Ed Sheeran's 'Game of Thrones' cameo
Skip in Skip x Embed x Share CLOSE Season 7's premiere of Game of Thrones was packed with drama and shockers. We go over the top 3 that we saw. USA TODAY
Game of Thrones fans did a lot of Thinking Out Loud with regard to Sunday's Season 7 premiere featuring Ed Sheeran.
Ed Sheeran performs on NBC's 'Today' on July 6, 2017 in New York City. (Photo: ANGELA WEISS, AFP/Getty Images)
While some enjoyed his singing character, others were vocally disgruntled with the Galway Girl artist's stint.
There were users who were generally confused.
Ed Sheeran what are you doing here? — Chay (@OhMyChay) July 17, 2017
loool why was ed sheeran on game of thrones 😭😭 — dom (@ddominic_) July 17, 2017
There were the mildly annoyed.
Was half thinking of getting back into watching GoT but I just saw that ed sheeran sings in the new episode so nah buddy, thanks. — Rebecca (@Becca92_) July 17, 2017
The only bad part about first ep of season 7 Game of Thrones was Ed Sheeran 👎 — 「ｋｉｙｏｓｈｉ」 (@KiyoshiFiraga) July 17, 2017
Those seemingly more irritated.
Why did they put Ed Sheeran in GoT... it feels less authentic and cheap 😡 — James Joyce (@bustamoby_) July 17, 2017
With the addition of Ed Sheeran, can we now officially say that #GameOfThrones has jumped the shark? — Randi Lee (@lee_randi) July 17, 2017
it was a good episode, the ed sheeran scene was completely forced , no need for that at all, took me completely out of it ,terrible. — n0BBsiemagic (@n0BBsiemagic) July 17, 2017
Exactly! The focus was on the fact that he is Ed Sheeran, not on the plot - there wasn't even an attempt at a character! — Stephanie Soteriou (@StephanieRiou) July 17, 2017
Ed Sheeran in GOT is one of the most ridiculously out of place things since...well David Beckham in that King Arthur movie. — Liam Donovan (@LJDonovan11) July 17, 2017
Some were pretty much beside themselves.
Why is ed sheeran in GOT? can I not enjoy anything in life — g (@sxulpturs) July 17, 2017
Ed Sheeran was so unnecessary. Don't do it again #GameOfThrones This is not Gossip Girl guys ☕️🐸 #GoTS7 — Ken Decaumartin (@iamverystylish) July 17, 2017
And because this is Twitter we're talking about, some saw it as the perfect opportunity to make a joke.
Friends, please tell me more about how seeing Ed Sheeran in your dragon show is unrealistic. — Ronald Funches (@RonFunches) July 17, 2017
Ed Sheeran on #GoTS7...
The club isn't the best place to find a lover, so the Riverlands is where I go..." pic.twitter.com/0EvQHRODnN — ∞ Aoife Mairéad ॐ (@TriggerHippieTV) July 17, 2017
Ed Sheeran's going to meet Brandon Stark and be like "when your legs don't work like they used to before".#GoTS7 — Alina Khan (@thealinamahsud) July 17, 2017
For more Game of Thrones, sign up for USA TODAY's newsletter, "Postcards From Westeros" here.
Read or Share this story: https://usat.ly/2v9jbwg ||||| Veteran TV director Jeremy Podeswa has helmed some of Game of Thrones’ moodiest, most striking moments over the past two seasons: Jon Snow’s resurrection, Sansa’s Winterfell wedding to Ramsay, and Melisandre’s jaw-dropping reveal of her true age, among others. For Season 7, he was tasked with both Sunday’s premiere and the finale — and the show’s biggest, most divisive musician cameo yet.
Pop singer Ed Sheeran appears midway through “Dragonstone” as a nameless Lannister soldier, serenading his comrades at a campfire with a little ditty about Tyrion Lannister and his secret, now dead ex-love, Shae. Arya Stark (played by real-life Sheeran superfan Maisie Williams, who inspired showrunners David Benioff and D.B. Weiss to cast him as a surprise) stumbles across Sheeran as he sings “Hands of Gold” and stops to chat with the group over roasted squirrel and blackberry wine.
The scene was meant as one of the show’s “grace notes,” says Podeswa — a rare offbeat moment of empathy and understanding between Arya and a group of young men that, in any other instance, she would have killed without a second thought. For many though, Sheeran’s instantly-recognizable face and voice proved too distracting. The cameo drew sharp criticism from myriad corners of the internet (not this corner; we were fine with it), and seems to have prompted a short-lived social media break from the singer.
All of which has baffled Podeswa. “I’m a bit surprised that people have made that much fuss about it,” he tells the Daily Beast. “To me, he does seem quite organic, in his own way, to the show.”
“The truth is, everybody on the show is famous now,” he laughs. “So it doesn't mean anything to me. It’s about, are they appropriate for the role? Are they doing a good job? And it was yes, yes, yes to all those questions with him.”
We talked to Podeswa about Sheeran’s polarizing cameo and fans’ responses, Arya’s triumphant revenge on the Freys, and what it was like to finally film Daenerys Targaryen’s homecoming to Dragonstone.
What was it like directing Ed Sheeran?
Delightful! Genuinely. He is a lovely person; he’s really down-to-earth. If you didn't know that he was a pop star or an entertainer of any kind, you would think he’s just one of the guys. And he is. He really just wanted to do a great job. He’s been acting for a little while; he takes it very seriously. And he was a real trouper, too. We were shooting in the middle of nowhere in Northern Ireland. He sat around outside with the cast and crew all day long, and just kind of hung out and was good-humored and lovely. He took direction well. He really could not have been nicer.
Maisie Williams cracks a very natural-looking smile when she sees him from the road. What was her reaction to the whole thing like as a superfan?
I think she was really happy to have him there, and they do have a lovely rapport. But the great thing is he kind of deserved to be there, in a way, because he’s a lovely performer. The role required gifts that he has. And he looks right in the show; he fits into the fabric of the show. And he was very happy to just kind of be a part of the ensemble. So Maisie obviously enjoyed working with him, but we all did. I think it was really lovely for everybody, for all the other Lannister soldiers who were sitting around spending the day with him, and for the crew. It was really, really nice. But it was also unexceptional, in a certain way. He didn’t bring any hoo-ha at all. He just brings himself and he’s very, as I said, eager to please and eager to do a good job. So it was a really lovely day actually.
I didn’t find him overly distracting but I know many other people did, saying it overshadowed some of the nuance of the scene. What did you think?
It is a funny thing because I really, genuinely believe that if you didn’t know who he was, you would have just thought he was one of the gang, effortlessly. And for me, I myself don’t bring a lot of baggage to who he is, or anybody on the show. And the truth is, everybody on the show is famous now. (Laughs.) So it’s like, it doesn’t mean anything to me. It’s about, are they appropriate for the role? Are they doing a good job? And it was yes, yes, yes to all those questions with him so, I don’t know. For me, I’m actually a bit surprised that people have made that much fuss about it. Because he… I don’t know. To me, he does seem quite organic, in his own way, to the show.
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Apart from the Ed Sheeran of it all, that scene was kind of remarkable. It’s about these regular Lannister soldiers, the kind you usually only see in the background, connecting as people with Arya. Can you talk about what that scene meant?
Yeah, for sure. I mean, this is one of those lovely grace notes of the show — of which there are a number. I think the scene with The Hound at the farmhouse was another one. And these scenes, they advance plot somewhat but they’re not really plot-driven scenes. They’re scenes about character, and about tone. What’s lovely about that scene for Arya is she’s been so hell-bent on vengeance — the previous scene is her killing all the Freys — that you forget sometimes that she’s just a young girl who’s trying to make her way through the world and is becoming a young woman. And here she is with a group of guys who should be her enemies. In any other instance, she might just kill them all. But there’s a kind of unexpected identification she has with them because they’re all young men, like her in a way. They’re kind of thrown into this world and fighting somebody else’s war. But they are just like a bunch of kids, as she is.
So there’s an interesting empathy she finds in herself for these guys. And we see the commonality [between them.] It is one of those things about fate and about the wars that people wage that you are always fighting someone else’s war, and you’re just a pawn in this big gamesmanship that’s going on. And the fact that we can see Lannister soldiers and her having to grapple with many of the same things — they are both victims of other people’s need to have power — I think it’s a very interesting parallel. Dan and Dave wrote a beautiful scene there. It’s touching and it’s funny and unexpected. We all really loved it in the writing; we loved the execution. We loved Maisie’s performance. I think all the guys, including Ed, are great in it. It has a very lovely tone about it and I think it’s quite memorable.
This episode also started out with the rare cold open, with Arya’s revenge on the Freys. But it wasn’t originally filmed as the cold open, right?
Yes, in fact it was originally supposed to be the first scene after the credits and there was another cold open. Originally in the script, the army of the dead, Bran’s vision, was the opening. Actually, I’m not even sure I recall if that was meant to be before the credits or the first thing after the credits, but it was meant to be the first scene. But it was interesting because Dan and David and I independently came to the conclusion that the scene with Arya would be great as a cold open. I know that they were thinking that way, not knowing that I was also thinking that way. Because when we shot that scene, it was just so strong and then the editing was even stronger.
Also, the funny thing is this is actually one of the few times I really thought about an audience reaction. I thought about sitting at the premiere, and that scene playing on the big screen and the audience going crazy. (Laughs.) I literally thought about that when we edited it. And that’s actually what happened! We screened it at [the Walt Disney Concert Hall] a few days before the broadcast premiere, and the audience just so enjoyed that scene before the credits. People were cheering when the credits started, and I was just so happy about that. It was really funny that it felt like it would elicit that reaction. Maisie is so great in that scene and it has so many associations for people who remember the Red Wedding and are invested in the show and know what it all means. It has great twists in it, and I was so pleased with how it all played.
The other huge thing in this episode was Daenerys coming home to Dragonstone. That scene felt very reverential with her team marching in procession, and was left mostly silent—
It was completely silent. (Laughs.)
Right. That was like a holy grail moment, something the whole show has built to over six seasons. How do you begin putting that together?
Well, it’s interesting. Reading that on the page, it was one thing. It was very moving, her coming home. As a concept, it was really lovely. And then, again, it’s one of those things where people who follow the show and are really invested in it — everybody knows fully what that all means and what that journey has been for her to get back there. So we knew people were gonna bring a lot of emotional value to the material. And then it was a matter of like, OK well where are we gonna shoot it? And what’s it gonna look like? It’s got to have this epic quality about it. The return home should be as spectacular as you hope it can be. So then when I saw the locations that were being considered for it, I was blown away. They were so unusual and incredibly beautiful and they have a kind of specificity to them. They weren’t generic beaches or generic hills. Everything about it was so specific and almost looked like it was created by the visual effects department, but it wasn’t. It was stitched together by the visual effects department — not all those places exist in one place. But those actual places exist.
Just standing on that beach in Zumaia or standing in San Juan [de Gaztelugatxe] and seeing that incredible staircase that goes up that hill, it is magical. It was like, “This is exactly what it should feel like. It has to be this spectacular, and it is.” And then the sets that [production designer] Deb Riley built, which are really unique to the show, I don’t think they’ve ever built sets quite like that. They’re enormous and incredibly detailed. The conceptual architectural design is spectacular. I know it’s one of Deb’s favorite things that she’s built for the show. We were all blown away by what she came up with. So once we knew we had all those component pieces, I just felt it was gonna be a beautiful sequence. And of course, it’s really sold by Emilia [Clarke.] Her face — everything is in her face. That look that she gives when she’s on the beach and she puts her hand in the sand and looks up to Dragonstone, it’s all there.
And you’re also going to direct the finale this season, which is a big deal. What should we expect from that one?
Oh, that I can’t tell you. All will be revealed in seven weeks! ||||| Following his controversial guest appearance on HBO’s “Game of Thrones” Season 7 premiere, Ed Sheeran has been making waves on social media.
After his ill-timed deletion of his Twitter account, followed by its almost immediate return, the singer is shedding some light on the issue.
Sheeran took to his Instagram account on Wednesday to address some reports that he deleted his Twitter account in the wake of the negative backlash his appearance on “Thrones” received from fans.
“Last I’ll say on this,” he wrote. “I came off Twitter Coz [sic] I was always intending to come off Twitter, had nothing to do with what people said about my game of thrones cameo, because I am in game of thrones, why the hell would I worry what people thought about that. It’s clearly f-----’ awesome. Timing was just a coincidence, but believe what you want.”
The idea that Sheeran’s Twitter deletion had nothing to do with his “Thrones” appearance might seem convenient, but the singer did previously rail against the social network while speaking to The Sun.
He told the outlet that he only uses his Twitter now to post his Instagram photos and finds it nothing but a place for people to say “mean things.” | – Twitter exploded after Game of Thrones fans got a surprise cameo on Sunday night's season premiere: English singer Ed Sheeran playing a Lannister soldier. Heavy rounds up some of the best memes about his appearance, while USA Today gathers up a range of the reactions, ranging from bafflement ("Ed Sheeran what are you doing here") to annoyance ("Ed Sheeran in GOT is one of the most ridiculously out of place things since...well David Beckham in that King Arthur movie") to people making fun of those who were annoyed ("Friends, please tell me more about how seeing Ed Sheeran in your dragon show is unrealistic"). But on Wednesday, Jeremy Podeswa, who directed the episode, defended Sheeran's appearance in an interview with the Daily Beast. "I really, genuinely believe that if you didn’t know who he was, you would have just thought he was one of the gang, effortlessly," Podeswa says. "I’m actually a bit surprised that people have made that much fuss about it. Because he … I don’t know. To me, he does seem quite organic, in his own way, to the show." (Maisie Williams, who appeared in the scene as her character Arya Stark, is a real-life fan of Sheeran's and convinced showrunners to cast him.) Podeswa adds that "the role required gifts that he has"; Sheeran's character performed a song on the show. Sheeran briefly left Twitter after the episode aired, but also Wednesday, he clarified that the uproar over his appearance was not the reason: "I was always intending to come off Twitter," he insisted, though Fox News notes he quickly returned to the platform. | <s>[INST]HBO
Ed Sheeran, a singer/celebrity, made a cameo appearance on Game of Thrones today. He was there because the actress who plays Arya, Maisie Williams, is a big fan. But some fans complained that the scene felt forced, and memes are already circulating making fun of the cameo.
Did you like the scene? Let us know in the comments below, after you see the best tweets and reactions to Sheeran’s scene.
First, here’s the scene in question:
Here is Ed Sheeran's special appearance on #GameOfThrones pic.twitter.com/3Rnnos5gYe — Hi! Watch This (@HiWatchThis) July 17, 2017
Some fans liked the song, but still felt like his scene took away from the show’s realism:
When Ed Sheeran's presence in #GoTS7 throws you off but the song he was singing is a bop. pic.twitter.com/KuGXzcueyP — cookies&Corinthians (@AKempChronicles) July 17, 2017
All I know is Ed Sheeran needs to gtf outta here — G Daddy (@sorryimgina) July 17, 2017
And some fans are finding some creative ways to work in song lyrics:
At some point in the season I hope Ed Sheeran meets Bran and tells him "When your legs don't work like they used to before" — Manta Rays Children (@868ball_is_life) July 17, 2017
Some fans were hoping for a special surprise from Sheeran’s appearance:
ok but what if ed sheeran ripped off his face and he was jaqen h'ghar pic.twitter.com/L57Vtjj02F — Dana Schwartz (@DanaSchwartzzz) July 17, 2017
If Arya kills Ed Sheeran it'll be worth it — Vann R. Newkirk II (@fivefifths) July 17, 2017
And this reaction is just priceless:
Arya: "That's a pretty song."
Ed Sheeran: "It's a new one… off my brand new album, 'Divide,' in stores now!!!!"#GameOfThrones pic.twitter.com/nsAumXug7K — Zach Goins (@zach_goins) July 17, 2017
But not everyone was upset. Some people were really happy to see him:
Ed Sheeran drinking wine with Arya Stark #WinterIsHere pic.twitter.com/YAbqTuTaSS — Cool Down 💦 (@jadineloveydove) July 17, 2017
What did you think about his cameo? Let us know in the comments below. ||||| Twitter shades Ed Sheeran's 'Game of Thrones' cameo
Skip in Skip x Embed x Share CLOSE Season 7's premiere of Game of Thrones was packed with drama and shockers. We go over the top 3 that we saw. USA TODAY
Game of Thrones fans did a lot of Thinking Out Loud with regard to Sunday's Season 7 premiere featuring Ed Sheeran.
Ed Sheeran performs on NBC's 'Today' on July 6, 2017 in New York City. (Photo: ANGELA WEISS, AFP/Getty Images)
While some enjoyed his singing character, others were vocally disgruntled with the Galway Girl artist's stint.
There were users who were generally confused.
Ed Sheeran what are you doing here? — Chay (@OhMyChay) July 17, 2017
loool why was ed sheeran on game of thrones 😭😭 — dom (@ddominic_) July 17, 2017
There were the mildly annoyed.
Was half thinking of getting back into watching GoT but I just saw that ed sheeran sings in the new episode so nah buddy, thanks. — Rebecca (@Becca92_) July 17, 2017
The only bad part about first ep of season 7 Game of Thrones was Ed Sheeran 👎 — 「ｋｉｙｏｓｈｉ」 (@KiyoshiFiraga) July 17, 2017
Those seemingly more irritated.
Why did they put Ed Sheeran in GoT... it feels less authentic and cheap 😡 — James Joyce (@bustamoby_) July 17, 2017
With the addition of Ed Sheeran, can we now officially say that #GameOfThrones has jumped the shark? — Randi Lee (@lee_randi) July 17, 2017
it was a good episode, the ed sheeran scene was completely forced , no need for that at all, took me completely out of it ,terrible. — n0BBsiemagic (@n0BBsiemagic) July 17, 2017
Exactly! The focus was on the fact that he is Ed Sheeran, not on the plot - there wasn't even an attempt at a character! — Stephanie Soteriou (@StephanieRiou) July 17, 2017
Ed Sheeran in GOT is one of the most ridiculously out of place things since...well David Beckham in that King Arthur movie. — Liam Donovan (@LJDonovan11) July 17, 2017
Some were pretty much beside themselves.
Why is ed sheeran in GOT? can I not enjoy anything in life — g (@sxulpturs) July 17, 2017
Ed Sheeran was so unnecessary. Don't do it again #GameOfThrones This is not Gossip Girl guys ☕️🐸 #GoTS7 — Ken Decaumartin (@iamverystylish) July 17, 2017
And because this is Twitter we're talking about, some saw it as the perfect opportunity to make a joke.
Friends, please tell me more about how seeing Ed Sheeran in your dragon show is unrealistic. — Ronald Funches (@RonFunches) July 17, 2017
Ed Sheeran on #GoTS7...
The club isn't the best place to find a lover, so the Riverlands is where I go..." pic.twitter.com/0EvQHRODnN — ∞ Aoife Mairéad ॐ (@TriggerHippieTV) July 17, 2017
Ed Sheeran's going to meet Brandon Stark and be like "when your legs don't work like they used to before".#GoTS7 — Alina Khan (@thealinamahsud) July 17, 2017
For more Game of Thrones, sign up for USA TODAY's newsletter, "Postcards From Westeros" here.
Read or Share this story: https://usat.ly/2v9jbwg ||||| Veteran TV director Jeremy Podeswa has helmed some of Game of Thrones’ moodiest, most striking moments over the past two seasons: Jon Snow’s resurrection, Sansa’s Winterfell wedding to Ramsay, and Melisandre’s jaw-dropping reveal of her true age, among others. For Season 7, he was tasked with both Sunday’s premiere and the finale — and the show’s biggest, most divisive musician cameo yet.
Pop singer Ed Sheeran appears midway through “Dragonstone” as a nameless Lannister soldier, serenading his comrades at a campfire with a little ditty about Tyrion Lannister and his secret, now dead ex-love, Shae. Arya Stark (played by real-life Sheeran superfan Maisie Williams, who inspired showrunners David Benioff and D.B. Weiss to cast him as a surprise) stumbles across Sheeran as he sings “Hands of Gold” and stops to chat with the group over roasted squirrel and blackberry wine.
The scene was meant as one of the show’s “grace notes,” says Podeswa — a rare offbeat moment of empathy and understanding between Arya and a group of young men that, in any other instance, she would have killed without a second thought. For many though, Sheeran’s instantly-recognizable face and voice proved too distracting. The cameo drew sharp criticism from myriad corners of the internet (not this corner; we were fine with it), and seems to have prompted a short-lived social media break from the singer.
All of which has baffled Podeswa. “I’m a bit surprised that people have made that much fuss about it,” he tells the Daily Beast. “To me, he does seem quite organic, in his own way, to the show.”
“The truth is, everybody on the show is famous now,” he laughs. “So it doesn't mean anything to me. It’s about, are they appropriate for the role? Are they doing a good job? And it was yes, yes, yes to all those questions with him.”
We talked to Podeswa about Sheeran’s polarizing cameo and fans’ responses, Arya’s triumphant revenge on the Freys, and what it was like to finally film Daenerys Targaryen’s homecoming to Dragonstone.
What was it like directing Ed Sheeran?
Delightful! Genuinely. He is a lovely person; he’s really down-to-earth. If you didn't know that he was a pop star or an entertainer of any kind, you would think he’s just one of the guys. And he is. He really just wanted to do a great job. He’s been acting for a little while; he takes it very seriously. And he was a real trouper, too. We were shooting in the middle of nowhere in Northern Ireland. He sat around outside with the cast and crew all day long, and just kind of hung out and was good-humored and lovely. He took direction well. He really could not have been nicer.
Maisie Williams cracks a very natural-looking smile when she sees him from the road. What was her reaction to the whole thing like as a superfan?
I think she was really happy to have him there, and they do have a lovely rapport. But the great thing is he kind of deserved to be there, in a way, because he’s a lovely performer. The role required gifts that he has. And he looks right in the show; he fits into the fabric of the show. And he was very happy to just kind of be a part of the ensemble. So Maisie obviously enjoyed working with him, but we all did. I think it was really lovely for everybody, for all the other Lannister soldiers who were sitting around spending the day with him, and for the crew. It was really, really nice. But it was also unexceptional, in a certain way. He didn’t bring any hoo-ha at all. He just brings himself and he’s very, as I said, eager to please and eager to do a good job. So it was a really lovely day actually.
I didn’t find him overly distracting but I know many other people did, saying it overshadowed some of the nuance of the scene. What did you think?
It is a funny thing because I really, genuinely believe that if you didn’t know who he was, you would have just thought he was one of the gang, effortlessly. And for me, I myself don’t bring a lot of baggage to who he is, or anybody on the show. And the truth is, everybody on the show is famous now. (Laughs.) So it’s like, it doesn’t mean anything to me. It’s about, are they appropriate for the role? Are they doing a good job? And it was yes, yes, yes to all those questions with him so, I don’t know. For me, I’m actually a bit surprised that people have made that much fuss about it. Because he… I don’t know. To me, he does seem quite organic, in his own way, to the show.
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Apart from the Ed Sheeran of it all, that scene was kind of remarkable. It’s about these regular Lannister soldiers, the kind you usually only see in the background, connecting as people with Arya. Can you talk about what that scene meant?
Yeah, for sure. I mean, this is one of those lovely grace notes of the show — of which there are a number. I think the scene with The Hound at the farmhouse was another one. And these scenes, they advance plot somewhat but they’re not really plot-driven scenes. They’re scenes about character, and about tone. What’s lovely about that scene for Arya is she’s been so hell-bent on vengeance — the previous scene is her killing all the Freys — that you forget sometimes that she’s just a young girl who’s trying to make her way through the world and is becoming a young woman. And here she is with a group of guys who should be her enemies. In any other instance, she might just kill them all. But there’s a kind of unexpected identification she has with them because they’re all young men, like her in a way. They’re kind of thrown into this world and fighting somebody else’s war. But they are just like a bunch of kids, as she is.
So there’s an interesting empathy she finds in herself for these guys. And we see the commonality [between them.] It is one of those things about fate and about the wars that people wage that you are always fighting someone else’s war, and you’re just a pawn in this big gamesmanship that’s going on. And the fact that we can see Lannister soldiers and her having to grapple with many of the same things — they are both victims of other people’s need to have power — I think it’s a very interesting parallel. Dan and Dave wrote a beautiful scene there. It’s touching and it’s funny and unexpected. We all really loved it in the writing; we loved the execution. We loved Maisie’s performance. I think all the guys, including Ed, are great in it. It has a very lovely tone about it and I think it’s quite memorable.
This episode also started out with the rare cold open, with Arya’s revenge on the Freys. But it wasn’t originally filmed as the cold open, right?
Yes, in fact it was originally supposed to be the first scene after the credits and there was another cold open. Originally in the script, the army of the dead, Bran’s vision, was the opening. Actually, I’m not even sure I recall if that was meant to be before the credits or the first thing after the credits, but it was meant to be the first scene. But it was interesting because Dan and David and I independently came to the conclusion that the scene with Arya would be great as a cold open. I know that they were thinking that way, not knowing that I was also thinking that way. Because when we shot that scene, it was just so strong and then the editing was even stronger.
Also, the funny thing is this is actually one of the few times I really thought about an audience reaction. I thought about sitting at the premiere, and that scene playing on the big screen and the audience going crazy. (Laughs.) I literally thought about that when we edited it. And that’s actually what happened! We screened it at [the Walt Disney Concert Hall] a few days before the broadcast premiere, and the audience just so enjoyed that scene before the credits. People were cheering when the credits started, and I was just so happy about that. It was really funny that it felt like it would elicit that reaction. Maisie is so great in that scene and it has so many associations for people who remember the Red Wedding and are invested in the show and know what it all means. It has great twists in it, and I was so pleased with how it all played.
The other huge thing in this episode was Daenerys coming home to Dragonstone. That scene felt very reverential with her team marching in procession, and was left mostly silent—
It was completely silent. (Laughs.)
Right. That was like a holy grail moment, something the whole show has built to over six seasons. How do you begin putting that together?
Well, it’s interesting. Reading that on the page, it was one thing. It was very moving, her coming home. As a concept, it was really lovely. And then, again, it’s one of those things where people who follow the show and are really invested in it — everybody knows fully what that all means and what that journey has been for her to get back there. So we knew people were gonna bring a lot of emotional value to the material. And then it was a matter of like, OK well where are we gonna shoot it? And what’s it gonna look like? It’s got to have this epic quality about it. The return home should be as spectacular as you hope it can be. So then when I saw the locations that were being considered for it, I was blown away. They were so unusual and incredibly beautiful and they have a kind of specificity to them. They weren’t generic beaches or generic hills. Everything about it was so specific and almost looked like it was created by the visual effects department, but it wasn’t. It was stitched together by the visual effects department — not all those places exist in one place. But those actual places exist.
Just standing on that beach in Zumaia or standing in San Juan [de Gaztelugatxe] and seeing that incredible staircase that goes up that hill, it is magical. It was like, “This is exactly what it should feel like. It has to be this spectacular, and it is.” And then the sets that [production designer] Deb Riley built, which are really unique to the show, I don’t think they’ve ever built sets quite like that. They’re enormous and incredibly detailed. The conceptual architectural design is spectacular. I know it’s one of Deb’s favorite things that she’s built for the show. We were all blown away by what she came up with. So once we knew we had all those component pieces, I just felt it was gonna be a beautiful sequence. And of course, it’s really sold by Emilia [Clarke.] Her face — everything is in her face. That look that she gives when she’s on the beach and she puts her hand in the sand and looks up to Dragonstone, it’s all there.
And you’re also going to direct the finale this season, which is a big deal. What should we expect from that one?
Oh, that I can’t tell you. All will be revealed in seven weeks! ||||| Following his controversial guest appearance on HBO’s “Game of Thrones” Season 7 premiere, Ed Sheeran has been making waves on social media.
After his ill-timed deletion of his Twitter account, followed by its almost immediate return, the singer is shedding some light on the issue.
Sheeran took to his Instagram account on Wednesday to address some reports that he deleted his Twitter account in the wake of the negative backlash his appearance on “Thrones” received from fans.
“Last I’ll say on this,” he wrote. “I came off Twitter Coz [sic] I was always intending to come off Twitter, had nothing to do with what people said about my game of thrones cameo, because I am in game of thrones, why the hell would I worry what people thought about that. It’s clearly f-----’ awesome. Timing was just a coincidence, but believe what you want.”
The idea that Sheeran’s Twitter deletion had nothing to do with his “Thrones” appearance might seem convenient, but the singer did previously rail against the social network while speaking to The Sun.
He told the outlet that he only uses his Twitter now to post his Instagram photos and finds it nothing but a place for people to say “mean things.”[/INST]– Twitter exploded after Game of Thrones fans got a surprise cameo on Sunday night's season premiere: English singer Ed Sheeran playing a Lannister soldier. Heavy rounds up some of the best memes about his appearance, while USA Today gathers up a range of the reactions, ranging from bafflement ("Ed Sheeran what are you doing here") to annoyance ("Ed Sheeran in GOT is one of the most ridiculously out of place things since...well David Beckham in that King Arthur movie") to people making fun of those who were annoyed ("Friends, please tell me more about how seeing Ed Sheeran in your dragon show is unrealistic"). But on Wednesday, Jeremy Podeswa, who directed the episode, defended Sheeran's appearance in an interview with the Daily Beast. "I really, genuinely believe that if you didn’t know who he was, you would have just thought he was one of the gang, effortlessly," Podeswa says. "I’m actually a bit surprised that people have made that much fuss about it. Because he … I don’t know. To me, he does seem quite organic, in his own way, to the show." (Maisie Williams, who appeared in the scene as her character Arya Stark, is a real-life fan of Sheeran's and convinced showrunners to cast him.) Podeswa adds that "the role required gifts that he has"; Sheeran's character performed a song on the show. Sheeran briefly left Twitter after the episode aired, but also Wednesday, he clarified that the uproar over his appearance was not the reason: "I was always intending to come off Twitter," he insisted, though Fox News notes he quickly returned to the platform.</s> |
GAITHERSBURG, Md. (AP) — A small, private jet has crashed into a house in Maryland's Montgomery County on Monday, killing at least three people on board, authorities said.
Preliminary information indicates at least three people were on board and didn't survive the Monday crash into home in Gaithersburg, a Washington, D.C. suburb, said Pete Piringer, a Montgomery County Fire and Rescue spokesman.
He said a fourth person may have been aboard.
Piringer said the jet crashed into one home around 11 a.m., setting it and two others on fire. Crews had the fire under control within an hour and were searching for anyone who may have been in the homes.
Television news footage of the scene showed one home nearly destroyed, with a car in the driveway. Witnesses told television news crews that they saw the airplane appear to struggle to maintain altitude before going into a nosedive and crashing.
An FAA spokesman said preliminary information shows the Embraer EMB-500/Phenom 100 twin-engine jet was on approach at the nearby Montgomery County Airpark. The National Transportation Safety Board is sending an investigator to the scene. ||||| Gemmell family (Photo: Facebook)
GAITHERSBURG, Md. (WUSA9) -- The investigations into a plane crash that left six people dead in Gaithersburg on Monday evening are just beginning.
A mother and her two young children are three of the six lives lost in the crash.
Marie Gemmell, 36, her three-year-old son Cole and her infant-son Devin were inside their home when a corporate jet crashed into it. Their bodies were found on the second floor hours after the crash. The father and a third child were not home at the time of the crash.
Michael Rosenberg was on the jet that crashed (Photo: Health Decisions)
Three people on the jet were also killed, according to Montgomery County fire officials. One of those victims has been identified as Michael Rosenberg, CEO of Health Decisions. You can read their statement here.
An Embraer EMB-500/Phenom 100 crashed into a house in the 19700 block of Drop Forge Lane off Snouffer School Road in the neighborhood of Hunters Woods around 10:45 a.m., according to the NTSB. The plane was coming from Chapel Hill, NC and approaching the Montgomery County Air Park.
The NTSB has sent a go-team to the site, where three homes were damaged. Firefighters used foam to battle fires all around the scene. The fuselage of the jet is parallel to a second house, and the tail of the airplane is at the front door. One of the wings was catapulted into the Gemmell's house, causing a huge fire and the majority of the damage, according to the NTSB. Senior Investigator Timothy LeBaron is leading the go-team.
Investigators are looking at operations, including crew experience, training and procedures, the functionality of the engines, the weather, air traffic control and more, NTSB spokesperson Robert L. Sumwalt said at a press confrence.
"Our mission is to find out not only what happened, but why it happened because we want to make sure something like this never happens again," Sumwalt said.
MORE: Woman says community feared plane crash
NTSB investigators are currently collecting perishable evidence, not determining the cause. They'll be conducting interviews and documenting the wreckage. Investigators could be on the scene for three to seven days for what they call the "fact-finding" phase.
The black box, which has recordings from the crash, has been recovered. It is in good condition and has been rushed to labs, Sumwalt said.
The first call about the crash came in at 10:44 a.m. from the National Guard Armory for the report of an explosion, and units were on the scene in approximately seven minutes, Montgomery County Fire Chief Steve Lohr said at an initial press conference. Utility crews were also on the scene and Lorh said it is safe for residents in the area. Electricity has been temporarily cut off.
Recordings of the 911-calls from the crash were released on Monday evening. In the recordings neighbors and witnesses describe the scene where the plane crashed in the Gaithersburg neighborhood.
Recordings of the 911 calls from the Gaithersburg plane crash were released on Monday evening.
"We just heard a giant explosion we looked out the window and there's... it looks like a house is on fire, we've got some people running over there to see if people are okay," one caller described.
RAW: Fire Chief Steve Lohr speaks on plane crash
A woman who was traveling into the area after taking a test at Montgomery College tells WUSA9 that she could see the smoke from the crash from I-370. As she got closer, she saw all the emergency response vehicles and called her husband. He told her that the smoke was coming from the area where her mother and stepfather lived and she says she got worried. She discovered the house that was struck was their neighbors' house. She says there are "three little ones" who live in that house.
One person reported seeing the plane "wobble" before it crashed into the house. Other neighbors reported hearing repeated booms and feeling their houses shake from the impact of the plane.
Something went wrong with the jet heading to the Montgomery County airport and it went into a house in Gaithersburg
WUSA9 spoke with an eyewitness named Jocelyn Brown who said she first heard the plane sputtering, making a sound that planes that go over the area normally don't make flying over the houses. She says she and her mother became concerned and went to investigate. They then saw the plane hit the side of a house. She reported seeing a "mushroom effect of smoke" and also hearing three explosions after the plane hit.
Jocelyn says they also heard screams in the area of the home. She says she does not know whether they were coming from inside the house or behind them.
Jocelyn lives in the area and says she knows the mother that lives there. She described her as a "sweet woman" who walks with her kids in the area all the time and speaks to everyone.
He said the plane sounded like it was "puttering" and then saw fire
A woman posted video from the ground of the scene of the plane crash on YouTube.
.
The FAA has released the following information:
"This is preliminary information about an Embraer EMB-500/Phenom 100 twin-engine jet that crashed one mile north of the Montgomery County Airport, Gaithersburg, MD at 11am today. The aircraft was on approach to Runway 14 at the airport when the accident occurred. Please contact local authorities for information on passengers and the situation on the ground. The FAA will investigate. We will update this statement when new information is available. "
Photo of plane from FlightAware (Photo: FlightAware)
An FAA source says the jet was waiting for a much slower single engine aircraft, possibly a Cessna, to make its turn so it could make its approach. That information has not been confirmed by the NTSB.
The Montgomery County Air Park is within 1/2 to 3/4 of a mile of the crash. The airport does not have a tower, so communication would have been with Washington Air Traffic Control Section, not the airport.
The FAA registry shows that the plane was a corporate Phenom jet with tail number N100EQ. It's registered to Sage Aviation LLC out of Chapel Hill, NC which makes replacement parts for the aviation industry.
MORE: Gaithersburg plane crash at Drop Forge Lane, 3 houses suffering some sort of damage, this one the worst @WNEWpic.twitter.com/vihz4k5eYE — JimMacKayWNEW (@JimMacKayWNEW) December 8, 2014
Snouffer School Road was closed between Centerway Road and Goshen Road following the crash. Drivers and pedestrians are being urged to avoid the area. It is likely to remain closed throughout the night and possibly Tuesday.
She says something has to be done about planes flying low directly over homes.
Read or Share this story: http://on.wusa9.com/1A8PzKE | – A twin-engine Embraer jet that the FAA describes as "on approach to Runway 14" at the Montgomery County Airpark in Gaithersburg, Maryland, crashed into a home this morning, engulfing that home in flames and setting two others on fire. Three people are dead, but the count could grow. A Montgomery County Fire rep says three fliers were killed in the crash, but notes the corporate plane may have had a fourth person on board, reports the AP. A relative of the owner of the home that was hit tells WUSA 9 that a mother with three children pre-school age and under should have been home at the time; there's no word on the family's whereabouts. The crash occurred around 11am on Drop Forge Lane, and the fire was extinguished within an hour. Crews are now searching the wreckage. A witness noted the plane appeared to "wobble" before the crash; the airport is no more than 3/4 mile from the crash scene. NTSB and FAA will investigate. | <s>[INST]GAITHERSBURG, Md. (AP) — A small, private jet has crashed into a house in Maryland's Montgomery County on Monday, killing at least three people on board, authorities said.
Preliminary information indicates at least three people were on board and didn't survive the Monday crash into home in Gaithersburg, a Washington, D.C. suburb, said Pete Piringer, a Montgomery County Fire and Rescue spokesman.
He said a fourth person may have been aboard.
Piringer said the jet crashed into one home around 11 a.m., setting it and two others on fire. Crews had the fire under control within an hour and were searching for anyone who may have been in the homes.
Television news footage of the scene showed one home nearly destroyed, with a car in the driveway. Witnesses told television news crews that they saw the airplane appear to struggle to maintain altitude before going into a nosedive and crashing.
An FAA spokesman said preliminary information shows the Embraer EMB-500/Phenom 100 twin-engine jet was on approach at the nearby Montgomery County Airpark. The National Transportation Safety Board is sending an investigator to the scene. ||||| Gemmell family (Photo: Facebook)
GAITHERSBURG, Md. (WUSA9) -- The investigations into a plane crash that left six people dead in Gaithersburg on Monday evening are just beginning.
A mother and her two young children are three of the six lives lost in the crash.
Marie Gemmell, 36, her three-year-old son Cole and her infant-son Devin were inside their home when a corporate jet crashed into it. Their bodies were found on the second floor hours after the crash. The father and a third child were not home at the time of the crash.
Michael Rosenberg was on the jet that crashed (Photo: Health Decisions)
Three people on the jet were also killed, according to Montgomery County fire officials. One of those victims has been identified as Michael Rosenberg, CEO of Health Decisions. You can read their statement here.
An Embraer EMB-500/Phenom 100 crashed into a house in the 19700 block of Drop Forge Lane off Snouffer School Road in the neighborhood of Hunters Woods around 10:45 a.m., according to the NTSB. The plane was coming from Chapel Hill, NC and approaching the Montgomery County Air Park.
The NTSB has sent a go-team to the site, where three homes were damaged. Firefighters used foam to battle fires all around the scene. The fuselage of the jet is parallel to a second house, and the tail of the airplane is at the front door. One of the wings was catapulted into the Gemmell's house, causing a huge fire and the majority of the damage, according to the NTSB. Senior Investigator Timothy LeBaron is leading the go-team.
Investigators are looking at operations, including crew experience, training and procedures, the functionality of the engines, the weather, air traffic control and more, NTSB spokesperson Robert L. Sumwalt said at a press confrence.
"Our mission is to find out not only what happened, but why it happened because we want to make sure something like this never happens again," Sumwalt said.
MORE: Woman says community feared plane crash
NTSB investigators are currently collecting perishable evidence, not determining the cause. They'll be conducting interviews and documenting the wreckage. Investigators could be on the scene for three to seven days for what they call the "fact-finding" phase.
The black box, which has recordings from the crash, has been recovered. It is in good condition and has been rushed to labs, Sumwalt said.
The first call about the crash came in at 10:44 a.m. from the National Guard Armory for the report of an explosion, and units were on the scene in approximately seven minutes, Montgomery County Fire Chief Steve Lohr said at an initial press conference. Utility crews were also on the scene and Lorh said it is safe for residents in the area. Electricity has been temporarily cut off.
Recordings of the 911-calls from the crash were released on Monday evening. In the recordings neighbors and witnesses describe the scene where the plane crashed in the Gaithersburg neighborhood.
Recordings of the 911 calls from the Gaithersburg plane crash were released on Monday evening.
"We just heard a giant explosion we looked out the window and there's... it looks like a house is on fire, we've got some people running over there to see if people are okay," one caller described.
RAW: Fire Chief Steve Lohr speaks on plane crash
A woman who was traveling into the area after taking a test at Montgomery College tells WUSA9 that she could see the smoke from the crash from I-370. As she got closer, she saw all the emergency response vehicles and called her husband. He told her that the smoke was coming from the area where her mother and stepfather lived and she says she got worried. She discovered the house that was struck was their neighbors' house. She says there are "three little ones" who live in that house.
One person reported seeing the plane "wobble" before it crashed into the house. Other neighbors reported hearing repeated booms and feeling their houses shake from the impact of the plane.
Something went wrong with the jet heading to the Montgomery County airport and it went into a house in Gaithersburg
WUSA9 spoke with an eyewitness named Jocelyn Brown who said she first heard the plane sputtering, making a sound that planes that go over the area normally don't make flying over the houses. She says she and her mother became concerned and went to investigate. They then saw the plane hit the side of a house. She reported seeing a "mushroom effect of smoke" and also hearing three explosions after the plane hit.
Jocelyn says they also heard screams in the area of the home. She says she does not know whether they were coming from inside the house or behind them.
Jocelyn lives in the area and says she knows the mother that lives there. She described her as a "sweet woman" who walks with her kids in the area all the time and speaks to everyone.
He said the plane sounded like it was "puttering" and then saw fire
A woman posted video from the ground of the scene of the plane crash on YouTube.
.
The FAA has released the following information:
"This is preliminary information about an Embraer EMB-500/Phenom 100 twin-engine jet that crashed one mile north of the Montgomery County Airport, Gaithersburg, MD at 11am today. The aircraft was on approach to Runway 14 at the airport when the accident occurred. Please contact local authorities for information on passengers and the situation on the ground. The FAA will investigate. We will update this statement when new information is available. "
Photo of plane from FlightAware (Photo: FlightAware)
An FAA source says the jet was waiting for a much slower single engine aircraft, possibly a Cessna, to make its turn so it could make its approach. That information has not been confirmed by the NTSB.
The Montgomery County Air Park is within 1/2 to 3/4 of a mile of the crash. The airport does not have a tower, so communication would have been with Washington Air Traffic Control Section, not the airport.
The FAA registry shows that the plane was a corporate Phenom jet with tail number N100EQ. It's registered to Sage Aviation LLC out of Chapel Hill, NC which makes replacement parts for the aviation industry.
MORE: Gaithersburg plane crash at Drop Forge Lane, 3 houses suffering some sort of damage, this one the worst @WNEWpic.twitter.com/vihz4k5eYE — JimMacKayWNEW (@JimMacKayWNEW) December 8, 2014
Snouffer School Road was closed between Centerway Road and Goshen Road following the crash. Drivers and pedestrians are being urged to avoid the area. It is likely to remain closed throughout the night and possibly Tuesday.
She says something has to be done about planes flying low directly over homes.
Read or Share this story: http://on.wusa9.com/1A8PzKE[/INST]– A twin-engine Embraer jet that the FAA describes as "on approach to Runway 14" at the Montgomery County Airpark in Gaithersburg, Maryland, crashed into a home this morning, engulfing that home in flames and setting two others on fire. Three people are dead, but the count could grow. A Montgomery County Fire rep says three fliers were killed in the crash, but notes the corporate plane may have had a fourth person on board, reports the AP. A relative of the owner of the home that was hit tells WUSA 9 that a mother with three children pre-school age and under should have been home at the time; there's no word on the family's whereabouts. The crash occurred around 11am on Drop Forge Lane, and the fire was extinguished within an hour. Crews are now searching the wreckage. A witness noted the plane appeared to "wobble" before the crash; the airport is no more than 3/4 mile from the crash scene. NTSB and FAA will investigate.</s> |
in the standard model ( sm ) , electroweak symmetry breaking , whereby the @xmath12 and @xmath13 bosons and the quarks and leptons acquire mass , gives rise to a higgs boson , @xmath14 . however , the value of @xmath15 is quadratically sensitive to the cutoff scale of the theory , @xmath16 , especially through top quark loops which give a one - loop correction of ^2=-34 ^ 2 ^ 2v^2 ^ 2 , where @xmath16 is the high energy cutoff and @xmath17 . for @xmath16 of order
the gut scale , @xmath18 , or the planck scale , @xmath19 , an extreme cancellation between the one - loop contribution(s ) and the bare higgs mass is required in order that the physical higgs mass be below a @xmath20 , as required in order for the scattering of longitudinally polarized @xmath12 bosons to obey unitarity in a perturbative fashion .
supersymmetric ( susy ) models , such as the minimal supersymmetric model ( mssm ) , cure this naturalness / hierarchy problem associated with the quadratically divergent 1-loop corrections via the introduction of superpartners for each sm particle .
because the spin of the superpartners differs by 1/2 unit from that of the corresponding sm particle , the 1-loop correction from the superpartner will cancel that of the sm particle once the energy scale being integrated over in the loop is above the mass of the ( presumed to be heavier ) superpartner .
so long as the superpartners have mass somewhat below @xmath21 ( say @xmath22 ) , the cancellation is not particularly extreme and the hierarchy / naturalness problem associated with the quadratic divergences is ameliorated .
however , there remains the question of how finely the gut - scale parameters must be adjusted in order to get appropriate electroweak symmetry breaking , that is to say correctly predict the observed value of @xmath23 .
it is here that lep limits on a sm - like higgs boson play a crucial role .
supersymmetric models most naturally predict that the lightest higgs boson , generically @xmath24 , is sm - like and that it has a mass closely correlated to @xmath23 , typically lying in the range @xmath25 for stop masses @xmath26 , with an upper bound , for example , of @xmath27 in the mssm for stop masses @xmath28 and large stop mixing . if the stop masses are large , the predicted value of @xmath23 is very sensitive to the gut scale parameters
. such sensitivity is termed fine tuning. models with minimal fine tuning provide a much more natural explanation of the @xmath13 mass than those with a high level of fine tuning .
the degree of fine tuning required is thus quite closely related to the constraints on a sm - like @xmath24 , and these in turn depend on how it decays .
the sm and the mssm predict that @xmath5 decays are dominant and lep has placed strong constraints on @xmath29 . the limits on ( hbb )
are shown in fig .
[ zbblimits ] ( from ref .
@xcite ) . from this plot ,
one concludes that @xmath30 is excluded for a sm - like @xmath24 that decays primarily to @xmath31 .
in fact , because of the manner in which the analysis is done , at a first level of approximation this limit applies for an @xmath24 that decays to any combination of @xmath32 and @xmath33 . for @xmath34 and @xmath35 ( with @xmath36 channels making up the rest ) @xmath37
is excluded .
this will be important later . in the case of the cp - conserving mssm
, one always obtains @xmath38 . for @xmath39
, most of parameter space will yield @xmath30 and thus be ruled out by the sm - like higgs lep limit .
the remaining part of mssm parameter space either has at least one very large parameter , most typically a soft - susy - breaking stop mass close to a tev at scale @xmath23 , or else large mixing in the stop sector . in the former case
, one always finds that to predict the observed @xmath23 requires very careful adjustment , fine - tuning , of the gut - scale parameters with accuracies better than 1% . in the latter case , fine - tuning
can be reduced to the 3% level . to achieve small fine - tuning ,
let us say no worse than 10% , the soft - susy - breaking parameters that affect the higgs sector should be well below a tev , in which case the lightest cp - even mssm higgs boson would have mass @xmath40 . as suggested in @xcite , the simplest way to allow a higgs mass of order @xmath0 , thus making possible a light susy spectrum and low fine - tuning ,
is to modify higgs decays so that the @xmath31 branching ratio is small and primary decays are to channel(s ) to which lep is less sensitive .
this is very natural in models in which the higgs sector is extended and higgs to higgs decays are kinematically allowed .
the decay widths for higgs to higgs decays can easily exceed the very small width for the @xmath31 channel .
the simplest supersymmetric model that gives rise to this possibility is the next - to - minimal supersymmetric model ( nmssm ) .
the nmssm yields a preferred value of @xmath6 purely on the basis of minimizing fine - tuning .
a higgs mass near @xmath0 is also strongly preferred by precision electroweak measurements .
further , there is a well - known @xmath41 excess in the @xmath42 channel in the lep data for @xmath43 when a final state that contains two or more @xmath44 is assumed to contain exactly 2 @xmath44 .
if the higgs decays only to @xmath31 then this excess and limits on the @xmath45 final state would apply to @xmath46 defined by = [ g_zzh^2/g_zz^2](hbb ) .
[ cbbdef ] the excess is apparent in the higher observed vs. expected @xmath46 limits for a test higgs mass of @xmath6 shown in fig .
[ zbblimits ] .
this excess is particularly apparent in the @xmath47 result ( fig . 7 of @xcite ) obtained after combining all four lep experiments . from ref .
@xcite are shown vs. @xmath48 .
also plotted are the predictions for the nmssm parameter cases discussed in @xcite having fixed @xmath49 , @xmath50 that give fine - tuning measure @xmath51 and @xmath52 and that are consistent with higgs constraints obtained using the preliminary lhwg analysis code @xcite.,width=230 ] in a previous paper @xcite , we have shown that the above excess is consistent with a scenario in which the higgs boson has sm - like @xmath53 coupling , but has reduced @xmath54 by virtue of the presence of @xmath24 decays to a pair of lighter higgs bosons , @xmath1 , where @xmath55 is small , as is automatic if @xmath56 so that @xmath57 or light quarks and gluons . is dominant , as occurs for @xmath58 , then , as noted earlier in the text , @xmath59 is required by lep data @xcite . ]
( the importance of such decays was first emphasized in @xcite , and later in @xcite , followed by extensive work in @xcite . ) for example , if the @xmath53 coupling is full sm strength , then @xmath60 with @xmath61 and @xmath62 fits the observed @xmath63 excess nicely .
meanwhile , there are no current limits on the @xmath64 final state for @xmath65 @xcite . and limits in the case of @xmath66 run out at slightly lower @xmath48 . as already stressed and as described below in more detail , we are particularly led to the above interpretation of lep data since fine - tuning within the nmssm is absent for model parameters that yield precisely this kind of scenario @xcite . while various alternative interpretations of this excess in terms of a non - sm higgs sector have been suggested @xcite , the nmssm scenario has the lowest fine tuning of any such scenario and has particularly strong theoretical motivation .
the nmssm is an extremely attractive model @xcite .
first , it provides a very elegant solution to the @xmath67 problem of the mssm via the introduction of a singlet superfield @xmath68 . for the simplest possible scale invariant form of the superpotential
, the scalar component of @xmath68 naturally acquires a vacuum expectation value of the order of the breaking scale , giving rise to a value of @xmath67 of order the electroweak scale .
the nmssm is the simplest supersymmetric extension of the standard model in which the electroweak scale originates from the breaking scale only .
hence , the nmssm deserves very serious consideration .
apart from the usual quark and lepton yukawa couplings , the scale invariant superpotential of the nmssm is @xmath69 depending on two dimensionless couplings @xmath70 , @xmath71 beyond the mssm .
[ hatted ( unhatted ) capital letters denote superfields ( scalar superfield components ) . ]
the associated trilinear soft terms are @xmath72 the final two input parameters are @xmath73 and @xmath74 where @xmath75 , @xmath76 and @xmath77 .
the higgs sector of the nmssm is thus described by the six parameters @xmath78 in addition , values must be input for the gaugino masses and for the soft terms related to the ( third generation ) squarks and sleptons that contribute to the radiative corrections in the higgs sector and to the higgs decay widths .
the particle content of the nmssm differs from the mssm by the addition of one cp - even and one cp - odd state in the neutral higgs sector ( assuming cp conservation ) , and one additional neutralino .
the result is three cp - even higgs bosons ( @xmath79 ) two cp - odd higgs bosons ( @xmath80 ) and a total of five neutralinos @xmath81 .
it will be convenient to denote the cp - even and cp - odd neutral higgs bosons of the mssm as @xmath82 and @xmath83 , respectively , while those of the nmssm will be denoted by @xmath84 and @xmath85 , respectively . in the latter case
, our focus will be on the lightest states @xmath86 and @xmath87 .
the nmhdecay program @xcite , which includes most lep constraints , allows easy exploration of higgs phenomenology in the nmssm .
( top ) , @xmath48 ( middle ) and @xmath88 ( bottom ) for randomly generated mssm parameter choices with @xmath49 and @xmath50 .
blue pluses correspond to parameter choices such that @xmath30 .
red crosses are points with @xmath89.,width=230 ] ( top ) , @xmath48 ( middle ) and @xmath88 ( bottom ) for randomly generated mssm parameter choices with @xmath49 and @xmath50 .
blue pluses correspond to parameter choices such that @xmath30 .
red crosses are points with @xmath89.,width=230 ] ( top ) , @xmath48 ( middle ) and @xmath88 ( bottom ) for randomly generated mssm parameter choices with @xmath49 and @xmath50 .
blue pluses correspond to parameter choices such that @xmath30 .
red crosses are points with @xmath89.,width=230 ] in @xcite , we presented a first study of the fine - tuning issues for the nmssm vs. the mssm .
we define the fine - tuning measure to be f = max_p f_p _ p|dd p| , where the parameters @xmath90 comprise all gut - scale soft - susy - breaking parameters .
in this section , we will consider scenarios associated with minimal fine tuning in the mssm and the nmssm . in the following section
, we will give a broader overview of all types of nmssm scenarios and will show how it is that one is lead to the nmssm scenarios considered in this section .
we discuss fine tuning for the mssm first . in this case , the gut scale parameters comprise : : @xmath91 , @xmath67 , @xmath92 , @xmath93 , @xmath94 , @xmath95 , @xmath96 , @xmath97 , @xmath98 , @xmath99 , @xmath88 , @xmath100 , and @xmath101 . in principle , soft masses squared for the first two generations should be included above , but they have negligible effect upon @xmath23 . in our approach , we choose @xmath23-scale values for all the squark and slepton soft masses squared at scale @xmath23 , for the gaugino masses , @xmath102 , and for @xmath103 , @xmath104 and @xmath105 ( with no requirement of universality at the gut scale ) .
we also choose @xmath23-scale values for @xmath7 , @xmath67 and @xmath106 ; these uniquely determine @xmath107 .
the vevs @xmath108 and @xmath109 at scale @xmath23 are fixed by @xmath7 and @xmath23 via @xmath110 ( where @xmath111 ) .
finally , @xmath112 and @xmath113 are determined from the two potential minimization conditions .
[ from here on , all parameters displayed without an explicit argument are @xmath23-scale values , although we sometimes give them an explicit @xmath114 argument for emphasis .
all gut - scale parameters will be specifically indicated using an explicit argument @xmath115 . ]
we then evolve all parameters to the mssm gut scale ( including @xmath67 and @xmath92 ) .
next , we shift each of the gut - scale parameters in turn , evolve back down to scale @xmath23 , and re - minimize the higgs potential using the shifted values of @xmath67 , @xmath92 , @xmath98 and @xmath99 .
this gives new values for @xmath108 and @xmath109 from which we compute a new value for @xmath23 ( and @xmath7 ) .
it is not difficult to understand why fine tuning is typically large in the mssm given lep constraints .
minimization of the higgs potential gives ( at scale @xmath23 ) ^2=-^2 + -^2 ^ 2 - 1 .
[ mzsquared ] the @xmath23-scale @xmath116 parameters can be determined from the gut - scale values of all susy - breaking parameters via the renormalization group equations .
the result for @xmath49 ( similar to the @xmath117 results in refs .
@xcite ) is ^2&~&-2.0 ^ 2()+5.9m_3 ^ 2()+0.8 ( ) + & & + 0.6 ( ) -1.2 ( ) + & & -0.7m_3()a_t()+0.2 a_t^2()+ [mzfromgut ] all of the above terms aside from @xmath118 and @xmath119 arise from the rge evolution result for @xmath120 .
similarly , one can expand @xmath23-scale values for soft - susy - breaking parameters in terms of gut - scale parameters .
in particular , one finds ( at @xmath49 ) a_t()&~ & -2.3 m_3()+0.24 a_t()[atmz ] + m_3()&~ & 3 m_3()[m3mz ] + ^2()&~ & 5.0 m_3 ^ 2()+0.6 ^2 ( ) + & & + 0.2 a_t()m_3()[mstopbarmz ] .
[ rgeatm3 ] in the above , ^1/2 .
[ mstopbardef ] unless there are large cancellations ( fine - tuning ) , one would expect that ~,,m_h^ , where @xmath121 is similar in size to @xmath67 .
we would need a very light gluino , and a rather light stop , to avoid fine - tuning .
more precisely , if @xmath122 , then it is clear from eq .
( [ mzfromgut ] ) that the minimum of @xmath123 is determined by the @xmath124 term , which would give @xmath125 for @xmath126 . allowing for small positive @xmath127
reduces this minimum @xmath123 somewhat , as will be illustrated below .
of course , in specific models you can also have correlations among the gut - scale parameters that would reduce @xmath123 .
the problem is that the small @xmath88 value required for minimal @xmath123 does not yield a mssm higgs mass @xmath48 above the @xmath128 lep limit unless @xmath129 is very large ( which causes a high level of fine - tuning , @xmath130 ) . to maximize @xmath48 at moderate @xmath129
, one should consider parameters corresponding to @xmath131 , termed an @xmath48-max scenario. for such choices it is also possible to obtain @xmath89 . to simultaneously minimize @xmath123 , the sign of @xmath88 must be chosen negative . to understand this
, we first note that @xmath89 can be achieved with @xmath132 or @xmath133 and @xmath134 .
given eq .
( [ rgeatm3 ] ) , this translates to @xmath135 or @xmath136 , respectively .
in both cases , @xmath123 will be determined by the @xmath137 term in eq .
( [ rgeatm3 ] ) , yielding f~0.2 a^2_t()^2
. obviously the case of @xmath136 case will correspond to very large fine tuning , roughly @xmath138 . for the @xmath135 case ,
@xmath139 is obtained .
similar values of @xmath123 can be obtained for much smaller @xmath140 values provided one allows for moderate @xmath141 @xcite .
the above generic features are apparent in the numerical results presented in fig .
[ fvsmhmssm ] for the case of @xmath142 and @xmath50 .
we scan randomly over @xmath103 , @xmath104 , @xmath105 and 3rd generation squark and slepton soft masses - squared above @xmath143 , as well as over @xmath144 , @xmath145 and over @xmath146 .
for such values of @xmath106 , the @xmath24 is quite sm - like and only allowed by lep data if @xmath147 .
if lower values of @xmath106 are allowed , in particular @xmath148 , lower values of @xmath149 can be obtained for experimentally allowed scenarios . in these latter scenarios ,
the @xmath150 is typically fairly sm - like but will have mass above @xmath128 while the @xmath151 can have mass below @xmath128 by virtue having weak @xmath152 coupling .
these scenarios are characterized by mixing among the higgs bosons .
analogous mixed - higgs scenarios are also possible in the nmssm .
the mssm and nmssm mixed - higgs scenarios will be considered in a separate paper @xcite .
the fine tuning in nmssm mixed - higgs scenarios have also been discussed in @xcite .
the main drawback of mixed - higgs scenarios is that they require adjustments in other parameters besides those necessary for correct electroweak symmetry breaking .
returning to fig .
[ fvsmhmssm ] , the top plot gives @xmath123 as a function of @xmath129 .
the latter enters into the computation of the radiative correction to the sm - like light higgs mass @xmath48 . in the middle plot
, we display @xmath123 as a function of @xmath48 . and ,
in the bottom plot we display @xmath123 as a function of @xmath88 .
we first of all note that the very smallest values of @xmath123 are achieved for @xmath153 $ ] , @xmath154 and @xmath155 $ ] . as stated above , for @xmath146 , as considered here
, the @xmath24 is fairly sm - like in all its couplings to sm particles .
thus , points with @xmath30 , plotted as ( blue ) @xmath156 s , are excluded by lep data , whereas those with @xmath89 , plotted as ( red ) @xmath157 s , are not excluded by lep .
although very modest values of @xmath123 ( of order @xmath158 ) are possible for @xmath30 , the smallest @xmath123 value found for @xmath159 is of order @xmath160 , as explained earlier .
the increase of the smallest achievable @xmath123 with @xmath48 is illustrated in the middle plot .
the modest @xmath161 values are achieved for special parameter choices , namely , @xmath134 and @xmath162 corresponding to a large ratio of @xmath163 ; see earlier discussion .
a value of @xmath160 corresponds to roughly @xmath164 fine tuning . generally speaking , however
, it would obviously be nicer if the @xmath6 points with @xmath158 were not excluded by lep . vs. @xmath129 , @xmath165 and @xmath88 for nmhdecay - accepted scenarios with @xmath49 and @xmath50 .
points marked by blue @xmath156 s are consistent with lep limits on the @xmath166 channel and the @xmath167 channel @xcite , considered separately , _ but not necessarily with lep limits on the combined @xmath166 and @xmath167 channels ) . _
points marked by red @xmath157 s escape lep limits due to @xmath168 .
, width=230 ] vs. @xmath129 , @xmath165 and @xmath88 for nmhdecay - accepted scenarios with @xmath49 and @xmath50 .
points marked by blue @xmath156 s are consistent with lep limits on the @xmath166 channel and the @xmath167 channel @xcite , considered separately , _ but not necessarily with lep limits on the combined @xmath166 and @xmath167 channels ) .
_ points marked by red @xmath157 s escape lep limits due to @xmath168 .
, width=230 ] vs. @xmath129 , @xmath165 and @xmath88 for nmhdecay - accepted scenarios with @xmath49 and @xmath50 .
points marked by blue @xmath156 s are consistent with lep limits on the @xmath166 channel and the @xmath167 channel @xcite , considered separately , _ but not necessarily with lep limits on the combined @xmath166 and @xmath167 channels ) .
_ points marked by red @xmath157 s escape lep limits due to @xmath168 .
, width=230 ] we now compare these results to what is found in the nmssm .
plots analogous to those for the mssm appear in fig .
[ fvsmh1nmssm1 ] .
let us first first define our conventions ( we follow those of ref .
@xcite ) and discuss a few theoretical points .
the superpotential for the higgs fields is w = _ u _ d + ^3 , where _ u _ d = _ u^+ _ d^- - _ u^0
_ d^0 . for the soft breaking terms
we take v_&= & m_^2 | h_u |^2 + m_^2 | h_d |^2 + m_^2 | s |^2 + & + & ( a _ h_u h_d s + a _
( above , we have not written the usual terms involving higgs fields and quark / squark fields . ) assuming that the parameters of the potential are real , @xmath12 and @xmath169 together yield a full potential for the neutral components of the @xmath170 , @xmath171 and @xmath172 scalar fields of the form v & = & ^2 ( h_u^2 s^2 + h_d^2 s^2 + h_u^2 h_d^2 ) + ^2 s^4 + g^2 ( h_u^2 - h_d^2)^2 + & & - 2 h_u h_d s^2 - 2a _
h_d s + a_s^3 + & & + m_h_u^2 h_u^2 + m_h_d^2 h_d^2 + m_s^2 s^2 .
[ vhiggs ] there are now three minimization conditions = 0,=0,=0 which are to be solved for @xmath173 , @xmath174 and @xmath175 in terms of the vevs and other parameters appearing in .
one combination of the minimization equations yields the mssm - like expression for @xmath176 in terms of @xmath177 , @xmath7 , @xmath98 and @xmath99 with @xmath67 replaced by @xmath178 .
however , a second combination gives an expression for @xmath178 in terms of @xmath23 and other higgs potential parameters : & & ( m_h_d^2 - m_h_u^2 ) - ^2 ( m_h_d^2 - m_h_u^2 ) + & & = ^2 + & & + _ eff a_^2 ( - ) [ mzform_s ] . eliminating @xmath178 , we arrive at an equation of the form @xmath179 , with solution @xmath180 , where @xmath181 and @xmath182 are given in terms of the soft susy breaking parameters , @xmath183 , @xmath71 and @xmath7 .
only one of the solutions to the quadratic equation applies for any given set of parameter choices . to explore fine tuning numerically ,
we proceed analogously to the manner described for the mssm . at scale
@xmath23 , we fixed @xmath7 and scanned over all allowed values of @xmath183 ( @xmath184 by convention and @xmath185 is required for perturbativity up to the gut scale ) and @xmath186 , and over @xmath187 , @xmath188 .
we also choose @xmath23-scale values for the soft - susy - breaking parameters @xmath189 , @xmath190 , @xmath191 , @xmath192 , @xmath193 , @xmath194 , @xmath93 , @xmath94 , @xmath95 , @xmath96 , and @xmath97 , all of which enter into the evolution equations .
we process each such choice through nmhdecay to check that the scenario satisfies all theoretical and experimental constraints , with the exception that we plot some points that are consistent with lep limits on the @xmath166 and @xmath167 channels considered separately as in @xcite , but inconsistent with the lep constraints on the @xmath45 final states , where @xmath195 .
we shall return to this point shortly . for accepted cases
, we then evolve to determine the gut - scale values of all the above parameters .
the fine - tuning derivative for each parameter is determined by shifting the gut - scale value for that parameter by a small amount , evolving all parameters back down to @xmath23 , redetermining the potential minimum ( which gives new values @xmath196 and @xmath197 ) and finally computing a new value for @xmath176 using @xmath198 . and
@xmath199 as a functions of @xmath165 for nmhdecay - accepted scenarios with @xmath49 and @xmath50
. point notation as in fig .
[ fvsmh1nmssm1].,width=230 ] and @xmath199 as a functions of @xmath165 for nmhdecay - accepted scenarios with @xmath49 and @xmath50 .
point notation as in fig .
[ fvsmh1nmssm1].,width=230 ] vs. @xmath200 and vs. @xmath201 for nmhdecay - accepted scenarios with @xmath49 and @xmath50 .
point notation as in fig .
[ fvsmh1nmssm1].,width=230 ] vs. @xmath200 and vs. @xmath201 for nmhdecay - accepted scenarios with @xmath49 and @xmath50 .
point notation as in fig .
[ fvsmh1nmssm1].,width=230 ] our basic results are displayed in fig . [ fvsmh1nmssm1 ] .
the density of points of a given type should not be taken as having any significance it simply reflects the nature of the scanning procedures employed for the various cases . in particular , the scans used to obtain results presented in this section were designed to focus on parameter regions with @xmath202 .
further , we focused a lot of our scans on keeping only points with @xmath203 . in fig .
[ fvsmh1nmssm1 ] , one sees a lot of similarity between the nmssm plots and those for the mssm , with differences to be noted below .
again , one finds that @xmath204 ( no worse than 10% fine - tuning of gut scale parameters ) is easily achieved in the nmssm for the present modest gluino mass of @xmath205 if the mean stop mass is of order @xmath206 which yields @xmath165 @xmath40 ( for the case of @xmath49 variation with @xmath7 will be noted later ) .
the associated @xmath88 values are of very modest size , lying in the range @xmath207 $ ] .
further , as described in more detail later , the low-@xmath123 scenarios are once again such that the @xmath86 is quite sm - like as regards its couplings to @xmath208 , @xmath152 and @xmath209 .
the difference between these plots and the earlier mssm plots is that many ( but not all , as we shall explain ) of the @xmath210 points plotted escape all lep limits . of course , points with @xmath168 escape lep limits simply by being above the maximum lep - excluded mass .
let us next discuss in more detail the points with @xmath210 .
they are plotted in fig .
[ fvsmh1nmssm1 ] provided that they are consistent with lep limits on the @xmath166 and @xmath167 channels , considered separately as plotted and tabulated in @xcite , but not necessarily the combined @xmath45 limit .
all the plotted @xmath210 points pass the @xmath166 and @xmath167 separate channel limits by virtue of the fact that @xmath211 is large enough that @xmath212 is sufficiently suppressed that @xmath213 lies below the lep @xmath166 limit , while simultaneously @xmath214 lies below the @xmath167 limit .
the values of @xmath46 and @xmath199 are plotted in fig .
[ nmssmceff ] as functions of @xmath165 . in the @xmath199 plot one finds two classes of points with @xmath210 .
the first class has large @xmath199 ( but still below lep limits for this individual channel ) by virtue of the fact that @xmath211 is large _ and _ @xmath215 .
the second class of points has zero @xmath199 since @xmath52 .
@xmath123 as a function of @xmath211 is shown in the top plot of fig .
[ nmssmbrhaa ] .
however , the plotted @xmath210 points with non - zero @xmath199 are mostly not consistent with the lep data .
nmhdecay allows these points because it does not take into account the need to combine @xmath166 and @xmath167 final states in confronting the lep limits , which are effectively ( at least roughly ) on the sum of these two final states . for those @xmath210 points with non - zero @xmath199 ,
the sum of @xmath46 and @xmath199 is typically large and one expects such points to have too large a net @xmath45 rate , where @xmath195 . indeed , for the limited number of points that were analyzed using the full lep higgs working group code one indeed finds @xcite that those points with @xmath216 that have large @xmath211 _ and _ @xmath215 ( implying @xmath217 predominantly ) are inconsistent with lep limits on the net @xmath45 rate . without analyzing every one of our @xmath215 points using the full code , we can not be sure that this same statement applies to all of them . with this proviso , we thus find that when @xmath210 , one needs large @xmath211 _ and _ @xmath52 to evade lep limits .
the bottom plot of fig . [ nmssmbrhaa ] shows that it is easy to obtain very low @xmath123 points that satisfy both criteria .
( the less frequent occurrence of @xmath218 points in this plot is purely an artifact of our scan procedure . )
we will turn to a discussion of this in more detail shortly . as regards @xmath219 points ( which are not subject to lep limits ) , returning to fig .
[ fvsmh1nmssm1 ] , we find that @xmath123 values as low as @xmath220 ( only @xmath221 tuning of gut - scale parameters ) can be achieved for the special choices of @xmath134 and @xmath162 .
this is the same region of stop parameter space that yields a minimum @xmath160 with @xmath168 in the mssm .
we have also found another type of point with low @xmath123 and @xmath222 that escapes published lep limits as follows .
first , for these points @xmath211 is large , @xmath223 , so that @xmath224 , implying a perfectly acceptable lep rate in the @xmath225 channel .
second , the @xmath87 is highly singlet and decays mainly into two photons , @xmath226 .
thus , there is negligible contribution to the @xmath227 channel .
thirdly , @xmath201 is typically fairly substantial for these points , @xmath228 .
however , these points are highly fine - tuned in the sense that the highly singlet nature of the @xmath87 required for large @xmath229 is very sensitive to gut scale parameters .
this is why they do not appear in the random scans discussed above .
locating such points requires an extremely fine scan over a carefully chosen part of parameter space
. we will give more details regarding these points later .
we now briefly describe a third class of points that manage to have relatively low fine - tuning .
generically , in the nmssm it is easy to have @xmath210 without violating lep limits simply by choosing parameters so that the @xmath86 has substantial singlet @xmath172 component . in this way
, the @xmath230 coupling is suppressed and the @xmath231 production rate is reduced to an allowed level even if @xmath232 decays are dominant . in such scenarios , it is typically the @xmath233 that is the most sm - like cp - even higgs boson , but @xmath234 and lep constraints do not apply to the @xmath233 . we have performed a broad scan over nmssm parameter space to look for and investigate the fine tuning associated with scenarios of this type .
we find that not all the points of this type found in our scans are highly fine - tuned .
there is a specific parameter region that produces points of this type that are only moderately fine - tuned and for which the @xmath86 escapes lep limits by virtue of small @xmath230 coupling .
the lowest @xmath123 value that we have found for such points is @xmath149 . in a separate paper @xcite
, we will describe these scenarios and their fine - tuning in detail and compare to similar mssm scenarios that are found when @xmath148 points are included in the mssm parameter scans . for @xmath49 , @xmath235 and @xmath236 for points with @xmath237 , taking @xmath50 .
small black @xmath157 points are those obtained after requiring a global and local minimum , no landau pole before @xmath18 and a neutralino lsp .
the green o s are those that in addition satisfy experimental limits on stops and charginos , but not necessarily higgs limits .
the blue @xmath238 s are the points that remain after imposing all lep single channel higgs limits , in particular limits @xcite on the @xmath166 and @xmath167 channels considered separately .
the yellow fancy crosses are the blue square points that remain after requiring @xmath52 , so that lep limits on @xmath45 , where @xmath195 , are not violated .
, width=230 ] for @xmath49 , @xmath235 and @xmath236 for points with @xmath237 , taking @xmath50 .
small black @xmath157 points are those obtained after requiring a global and local minimum , no landau pole before @xmath18 and a neutralino lsp .
the green o s are those that in addition satisfy experimental limits on stops and charginos , but not necessarily higgs limits .
the blue @xmath238 s are the points that remain after imposing all lep single channel higgs limits , in particular limits @xcite on the @xmath166 and @xmath167 channels considered separately .
the yellow fancy crosses are the blue square points that remain after requiring @xmath52 , so that lep limits on @xmath45 , where @xmath195 , are not violated .
, width=230 ] for @xmath49 , @xmath235 and @xmath236 for points with @xmath237 , taking @xmath50 .
small black @xmath157 points are those obtained after requiring a global and local minimum , no landau pole before @xmath18 and a neutralino lsp .
the green o s are those that in addition satisfy experimental limits on stops and charginos , but not necessarily higgs limits .
the blue @xmath238 s are the points that remain after imposing all lep single channel higgs limits , in particular limits @xcite on the @xmath166 and @xmath167 channels considered separately .
the yellow fancy crosses are the blue square points that remain after requiring @xmath52 , so that lep limits on @xmath45 , where @xmath195 , are not violated .
, width=230 ]
armed with this overview , we now return to the parameter region of the nmssm that allows for the lowest possible fine tuning , as studied earlier in section [ sec : compare ] for @xmath49 . here , we consider also @xmath235 and @xmath236 .
these scans are focused very much on parameter choices that can yield the lowest @xmath123 values .
the relevant plots are presented in fig .
[ fvsmh1 ] .
we present our results in a somewhat different manner than in sec .
[ sec : compare ] so as to stress the remarkable preference for @xmath239 in order to achieve the very lowest @xmath123 values at @xmath49 , with corresponding preferences for @xmath240 at @xmath236 and @xmath241 at @xmath235 .
first , we stress that the above @xmath165 values are the largest ones consistent with low @xmath123 in an unbiased ( before applying experimental constraints of any kind ) scan over the part of parameter space that is simply theoretically consistent ( see below ) .
once one imposes lower bounds on the stop ( and chargino ) masses , @xmath123 shows a distinct minimum at the above @xmath165 values .
the preference for these values of @xmath165 to achieve low @xmath123 becomes progressively more apparent as one imposes in addition : ( a ) lep constraints on higgs bosons , including the important @xmath166 channel and @xmath167 channels , considered separately ( as plotted and tabulated in @xcite ) , but not the combined @xmath166 and @xmath167 channels ; and ( b ) lep constraints on the combined @xmath166 and @xmath167 channels .
let us first focus on the @xmath49 case .
four different types of points are displayed .
the black crosses show @xmath123 as a function of @xmath165 after requiring only that the scenario be theoretically consistent , but before any experimental constraints whatsoever are imposed .
the most important components of the theoretical consistency are : ( 1 ) that the vacuum corresponds to a proper electroweak symmetry breaking vacuum at a true minimum of the potential ; and ( 2 ) that the couplings remain perturbative during evolution up to the gut scale .
the black crosses already single out @xmath239 as the point above which @xmath123 rises rapidly .
black points with low @xmath165 typically have a rather low value for @xmath242 that is clearly inconsistent with lep and tevatron limits .
the minimum @xmath123 for these low-@xmath165 black cross points is fairly independent of @xmath165 .
the ( green ) circles correspond to the black crosses that survive after imposing experimental limits on @xmath242 and @xmath243 and similar non - higgs constraints .
we immediately see a striking preference for @xmath239 in order to achieve minimum @xmath123 .
the ( blue ) squares indicate the points that survive after requiring _ in addition _ that the scenario be consistent with lep higgs limits , including the @xmath166 and @xmath167 final state limits considered separately @xcite , _ but before imposing a limit on the combined @xmath45 ( @xmath195 ) final state_. in the case of @xmath49 , these blue squares are the union of the @xmath237 red @xmath157 s and blue @xmath156 s of the middle plot of fig . [ fvsmh1nmssm1 ] .
the blue - square points now show a very strong preference for @xmath222 , even before , but especially after , focusing on minimal @xmath123 .
the final large ( yellow ) crosses are the @xmath210 points among the ( blue ) square points that have @xmath52 so that there is no contribution to the @xmath167 channel from the @xmath244 decay that , in turn , has a sufficiently large branching ratio to allow these points to escape the @xmath166 channel lep limit . now @xmath239 is clearly singled out . in the plots for the @xmath235 and @xmath236 cases , we did not bother to generate points with low @xmath242 .
so the black cross points in these cases simply indicate the presence of a few scenarios with @xmath242 above experimental limits but with @xmath243 below existing limits or some other non - higgs experimental inconsistency . the green - circle , blue - square and yellow - cross are as described above . the large number of blue - square points with very low @xmath123 indicate that a significant fraction of the very lowest @xmath123 scenarios are such that @xmath86 decays primarily into a pair of the lightest cp - odd higgs bosons of the model , @xmath244 .
the yellow crosses show that low-@xmath123 points with large @xmath211 _ and _ @xmath52 are often found . for such points , @xmath245 ( or @xmath246 if @xmath247 ) thereby allowing consistency with lep constraints on the @xmath45 channel and , in many cases , the lep excess in the @xmath232 channel for higgs mass of order @xmath0 .
given that low @xmath123 can be easily achieved without violating lep constraints if @xmath52 , an important issue is whether obtaining small @xmath201 requires fine - tuning of gut - scale parameters .
in fact , a light @xmath248 is natural in the nmssm in the @xmath249 limit .
this can be understood as a consequence of a global @xmath250 symmetry of the scalar potential ( in the limit @xmath251 ) which is spontaneously broken by the vevs , resulting in a nambu - goldstone boson in the spectrum @xcite .
is to have a slightly broken peccei - quinn symmetry .
however , the models with low @xmath123 are not close to the peccei - quinn symmetry limit . ]
this symmetry is explicitly broken by the trilinear soft terms so that for small @xmath252 the lightest cp odd higgs boson is naturally much lighter than other higgs bosons .
in fact , as discussed in depth in @xcite , the values of @xmath252 needed to have @xmath52 , @xmath253 and low @xmath123 are quite natural in the context of the nmssm starting from small or zero values of @xmath254 and @xmath255 . in particular , large @xmath211 is essentially automatic for typical rge generated values of @xmath256 and @xmath257 ( @xmath258 and @xmath259 ) and it is only a question of whether the requirement @xmath52 is naturally achieved . in @xcite , we found that essentially no tuning of @xmath256 and @xmath257 is required in many model contexts .
for example , in the case of @xmath49 tuning of the gut - scale parameters needed to achieve appropriate @xmath256 and @xmath257 is likely to be minimal for scenarios in which the @xmath87 is about 10% non - singlet at the state - mixing , amplitude level , 1% at the probability level .
more precisely , let us define = a_mssm+a_s , where @xmath260 is the usual two - doublet cp - odd state and @xmath261 is the cp - odd state coming from the @xmath172 field .
then , the mass of the lightest cp - odd higgs boson in the simplest approximation is given by : @xmath262 we see that the @xmath256 contribution to @xmath201 is suppressed relative to the @xmath257 contribution for small @xmath263 and large @xmath7 and an appropriate balance between the contributions is naturally achieved .
in @xcite , we defined a measure called @xmath264 that encapsulates the amount of tuning at the gut scale that is likely to be needed to achieve small @xmath201
. @xmath264 is defined using , as g\ { max,|+|}. as shown in @xcite , small @xmath264 implies it is quite natural to get small @xmath201 even for fairly general @xmath18-scale boundary conditions .
for example , if eq .
( [ eq : ma1_first ] ) is approximately correct , so that @xmath265 is linear in @xmath256 and @xmath257 , and if @xmath256 and @xmath257 are primarily sensitive to a single gut - scale parameter @xmath90 , then , if @xmath266 is small , sensitivity of @xmath265 to @xmath90 is guaranteed to cancel .
nonetheless , the measure @xmath264 should not be overemphasized since specific boundary condition choices can give small @xmath201 even when @xmath264 is large .
scenarios that are fully consistent with all lep constraints , we plot @xmath264 vs. @xmath263 taking @xmath267 and @xmath49 ( top ) , @xmath268 ( middle ) and @xmath269 ( bottom ) .
the point coding is : black @xmath270 ; dark grey ( red ) @xmath271 ; light grey ( green ) @xmath272 ; and darkest grey ( blue ) = @xmath273.,title="fig:",width=230 ] scenarios that are fully consistent with all lep constraints , we plot @xmath264 vs. @xmath263 taking @xmath267 and @xmath49 ( top ) , @xmath268 ( middle ) and @xmath269 ( bottom ) .
the point coding is : black @xmath270 ; dark grey ( red ) @xmath271 ; light grey ( green ) @xmath272 ; and darkest grey ( blue ) = @xmath273.,title="fig:",width=230 ] scenarios that are fully consistent with all lep constraints , we plot @xmath264 vs. @xmath263 taking @xmath267 and @xmath49 ( top ) , @xmath268 ( middle ) and @xmath269 ( bottom ) .
the point coding is : black @xmath270 ; dark grey ( red ) @xmath271 ; light grey ( green ) @xmath272 ; and darkest grey ( blue ) = @xmath273.,title="fig:",width=230 ] in fig .
[ gvscta ] , we plot @xmath264 as a function of @xmath263 for parameters choices that yield @xmath274 , taking @xmath49 , 3 , and 50 .
the results are displayed using different shadings ( colors ) for different ranges of @xmath201 , as delineated in the figure caption . for @xmath49 , we see that @xmath264 is minimal for @xmath275 , not much above the rough lower bound of @xmath276 .
this lower bound is a direct consequence of the _ combined _ requirements that : 1 ) @xmath211 be so large that @xmath212 is small enough to escape the lep limit on the @xmath166 channel ; and 2 ) that @xmath52 so that @xmath87 does not decay to @xmath31 and there is no @xmath277 decay contribution to the net @xmath45 channel .
we also note that small @xmath264 is only achieved for @xmath278 , with @xmath279 preferred . for @xmath235
, there is again a preference for larger @xmath201 in order to achieve small @xmath264 .
however , small @xmath264 can be achieved for a much larger range of @xmath263 . of course
, one should also notice that all the low-@xmath123 solutions have @xmath280 , with lower bound of @xmath281 .
the bottom of the three plots shows that if @xmath236 then it is much more difficult to find solutions with low @xmath123 that also have low @xmath264 .
the lower bound on @xmath282 needed to achieve large @xmath211 shifts downwards slightly to about @xmath283 .
one should note that the coupling of the @xmath87 to @xmath31 is proportional to @xmath284 times the usual sm - like @xmath285 coupling strength . the lower limits on @xmath282 at @xmath49 , @xmath268 , @xmath269 are such that @xmath286 , @xmath287 , @xmath288 .
this means that the @xmath31 coupling is not particularly suppressed , and can even be enhanced with respect to the sm - like @xmath289 value .
( of course , the @xmath290 coupling of the @xmath87 , proportional to @xmath291 , is very suppressed . )
the fact that the @xmath31 coupling is always significant implies that there is always a significant branching ratio for @xmath292 ( where the @xmath293 can be the @xmath294 , @xmath295 or @xmath296 state ) so long as there is adequate phase space for the decay .
the predictions for @xmath297 and further discussion appear in @xcite . and
a fixed value of @xmath49 . notation as in fig .
[ fvsmh1].,width=230 ] the minimum value of @xmath123 that can be achieved is , of course , dependent upon @xmath194 ( and is essentially independent of @xmath192 and @xmath193 ) .
indeed , the largest gut - scale parameter derivative is very frequently that with respect to @xmath298 . to explore this sensitivity ,
we have also performed a ( somewhat less dense ) parameter scan for the case of @xmath299 at @xmath49 .
the results for @xmath123 as a function of @xmath165 are presented in fig .
[ fvsmh1meq126 ] .
we find a minimum value of @xmath300 at @xmath301 , the latter being somewhat higher than the @xmath239 location in the corresponding @xmath49 , @xmath267 case .
a sm - like @xmath86 with @xmath301 is only consistent with lep limits if @xmath211 is large and @xmath52 ( the large ( yellow ) crosses ) .
the @xmath301 location of the minimal @xmath123 is less consistent with the @xmath302 excess in the lep data . however , to have @xmath239 in the @xmath299 case is possible for @xmath303 , which is barely different from the @xmath300 minimum value .
one other point of interest is that @xmath52 points are more easily achieved at larger @xmath304 when @xmath305 than for @xmath306 .
this can be understood by considering the special case of @xmath307 , @xmath308 and @xmath309 . in this case
, we find @xmath310 let us consider the @xmath311 case ( by convention , @xmath184 ) , for which it can be shown that @xmath312 is required @xcite to get @xmath313 . from eqs .
( [ akrun ] ) , ( [ atmz ] ) and ( [ m3mz ] ) , one finds that @xmath314 , implying that increasingly negative @xmath103 is required to achieve @xmath312 as @xmath315 increases . from eq .
( [ eq : ma1_first ] ) , a small value of @xmath265 will be easily achieved in the present case of @xmath316 if @xmath317 so that the @xmath318 and @xmath319 terms tend to cancel .
( [ alrun ] ) , ( [ atmz ] ) and ( [ m3mz ] ) imply @xmath320 which gives @xmath317 for increasingly negative @xmath103 as @xmath315 increases . in short , the larger @xmath315 is the more negative @xmath103 can be while requiring small @xmath265 .
the more negative @xmath103 , the larger stop mixing is at fixed @xmath129 and therefore the larger @xmath165 .
we will now discuss in more detail other properties of the low-@xmath123 scenarios with @xmath239 and @xmath52 , focusing first on the case of @xmath49 and @xmath50 .
first , we recall our earlier results from @xcite . there , we studied in detail the @xmath51 points from our earliest @xmath49 scans as plotted in fig .
[ zbblimits ] .
the plot shows the @xmath46 predictions for all parameter choices in our scan that had @xmath51 and @xmath52 and that are consistent with the experimental and theoretical constraints built into nmhdecay as well as with limits from the preliminary lhwg full analysis code @xcite , which in particular incorporates limits on the @xmath45 combined channel .
eight @xmath204 points are singled out .
as we have emphasized , these latter points cluster near @xmath321 . in @xcite , we found the remarkable result that not only are these @xmath204 @xmath52 points consistent with lep limits , but also most are such that @xmath165 and @xmath212 are appropriate for explaining the @xmath46 excess .
we wish to emphasize that in our scan there are many , many points that satisfy all constraints and have @xmath52 .
the remarkable result is that those with @xmath204 have a substantial probability that they predict the higgs boson properties that would imply a lep @xmath322 s excess of the sort seen .
we stress again that the @xmath204 points with @xmath201 substantially above @xmath323 all predict a net @xmath324 s signal that is ruled out at better than @xmath325 cl by lep data .
indeed , all such @xmath51 points have a net @xmath326 s branching ratio , @xmath327 , which is too large for lep consistency . in our larger scans , as represented by the @xmath46 results of fig .
[ nmssmceff ] , we see a huge number of @xmath52 points with approximately the correct @xmath46 to explain the lep @xmath0 excess . for @xmath236 , @xmath50 , the preference for @xmath240 to achieve low @xmath123 will again imply that many of the lowest @xmath123 scenarios will provide a natural explanation of the @xmath166 lep excess . at @xmath235 , the very lowest @xmath123 values , @xmath328 , consistent with lep limits are achieved for @xmath329 , as shown in the middle plot of fig .
[ fvsmh1 ] .
such an @xmath86 mass is too low to provide a natural explanation of the @xmath166 excess .
however , this same plot shows that the very slightly higher value of @xmath330 is possible for @xmath239 .
thus , the lep @xmath166 excess is fully consistent with low fine - tuning scenarios that pass all lep higgs limits for all @xmath331 .
( we have not explored still lower values . ) of course , it is equally true that at @xmath49 and @xmath236 , only a very modest increase in @xmath123 would be needed for @xmath165 to take on a value that is not perfectly correlated with the location at @xmath302 of the @xmath166 lep excess .
( top ) and vs. @xmath332 ( bottom ) for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1].,width=230 ] ( top ) and vs. @xmath332 ( bottom ) for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1].,width=230 ] ( top ) , @xmath333 ( middle ) and @xmath334 ( bottom ) for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1].,width=230 ] ( top ) , @xmath333 ( middle ) and @xmath334 ( bottom ) for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1].,width=230 ] ( top ) , @xmath333 ( middle ) and @xmath334 ( bottom ) for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1].,width=230 ] ( top ) and vs. @xmath332 ( bottom ) for points with @xmath237 taking @xmath50 and @xmath236 .
point notation as in fig .
[ fvsmh1].,width=230 ] ( top ) and vs. @xmath332 ( bottom ) for points with @xmath237 taking @xmath50 and @xmath236 .
point notation as in fig .
[ fvsmh1].,width=230 ] ( top ) , @xmath333 ( middle ) and @xmath334 ( bottom ) for points with @xmath237 taking @xmath50 and @xmath236 .
point notation as in fig .
[ fvsmh1].,width=230 ] ( top ) , @xmath333 ( middle ) and @xmath334 ( bottom ) for points with @xmath237 taking @xmath50 and @xmath236 .
point notation as in fig .
[ fvsmh1].,width=230 ] ( top ) , @xmath333 ( middle ) and @xmath334 ( bottom ) for points with @xmath237 taking @xmath50 and @xmath236 .
point notation as in fig .
[ fvsmh1].,width=230 ] another interesting question is whether there is any correlation between @xmath123 and @xmath201 or between @xmath123 and the masses of the heavier higgs bosons , @xmath332 , @xmath335 , @xmath333 and @xmath334 .
the plots for @xmath49 appear in figs .
[ fvsma1andmhplus ] and [ fvsma2mh2mh3 ] .
there , we observe that @xmath123 depends very weakly on @xmath201 ( once @xmath52 ) , but that lower values of @xmath336 are definitely preferred to obtain small @xmath123 and that to obtain fully allowed yellow fancy crosses with @xmath204 requires @xmath337 $ ] , @xmath338 $ ] , @xmath339 $ ] and @xmath340 $ ] .
the corresponding plots for @xmath236 appear in figs .
[ fvsma1andmhplustb50 ] and [ fvsma2mh2mh3tb50 ] .
again , we observe that @xmath123 depends very weakly on @xmath201 , and that lower values of @xmath336 are definitely preferred to obtain small @xmath123 . for @xmath236 , to obtain fully allowed yellow fancy crosses with @xmath204 requires @xmath341 $ ] , @xmath338 $ ] , @xmath342 $ ] and @xmath343 $ ] .
these results have implications for the lhc and ilc . at the lhc ,
the main processes for producing and detecting these heavier higgs bosons are @xmath344 ( where @xmath345 ) and @xmath346 , with , for example , @xmath347 .
one finds @xcite that detection becomes possible when the @xmath348 and @xmath349 couplings are enhanced by large @xmath7 .
the mass ranges for the heavier higgs bosons preferred for obtaining low @xmath123 are such that if @xmath49 they will be on the margin of detectability at the lhc , whereas if @xmath236 they will certainly be detectable .
( at @xmath235 the small-@xmath123 mass ranges for the @xmath350 are similar , but @xmath7 is definitely too small for the above lhc modes to be detectable . ) for the lowest part of the mass ranges , a signal for @xmath344 might also emerge at the tevatron if @xmath236 .
it is also important to note that the low-@xmath123 mass ranges of the @xmath351 are such that their pair production would mostly be outside the kinematical reach of a @xmath352 ilc , but that a substantial portion of the mass ranges are such that pair production would be possible at a @xmath353 ilc .
we next turn to a detailed discussion of various correlations among the nmssm parameters that are associated with low-@xmath123 scenarios having large @xmath211 and @xmath52 , the points indicated by the large yellow crosses in the previous figures .
we call such points `` fully ok '' .
we first present some figures to illustrate how the fully ok points compare to points that are either experimentally excluded or else have sufficiently large @xmath165 ( roughly @xmath354 ) as to avoid lep constraints on the @xmath45 channel .
these latter points are the ( blue ) squares , ( green ) circles and black @xmath157 s of the earlier plots .
( top ) and vs. @xmath127 ( bottom ) for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1].,width=230 ] ( top ) and vs. @xmath127 ( bottom ) for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1].,width=230 ] ( top ) and vs. @xmath127 ( bottom ) for points with @xmath237 taking @xmath50 and @xmath236 .
point notation as in fig .
[ fvsmh1].,width=230 ] ( top ) and vs. @xmath127 ( bottom ) for points with @xmath237 taking @xmath50 and @xmath236 .
point notation as in fig .
[ fvsmh1].,width=230 ] first consider @xmath88 .
plots of f as a function of @xmath103 and @xmath127 are given in figs .
[ fvsat ] and [ fvsattb50 ] for @xmath49 and @xmath236 , respectively .
these show that rather well - defined ( and rather @xmath7-independent ) values are needed to achieve the very lowest @xmath123 values , especially after imposing higgs boson experimental limits . at scale @xmath23 the preferred @xmath103 is of order @xmath355 .
the corresponding @xmath127 is of order @xmath356 .
the lowest @xmath123 values are of course those associated with @xmath239 .
this is consistent with our earlier discussion .
the @xmath49 points with large negative @xmath103 values that escape lep limits by virtue of @xmath168 are the dark ( blue ) squares that begin at @xmath300 and @xmath357 . for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1].,width=230 ] for points with @xmath237 taking @xmath50 and @xmath236 .
point notation as in fig .
[ fvsmh1].,width=230 ] in figs .
[ fvsmueff ] and [ fvsmuefftb50 ] , we plot @xmath123 as a function of @xmath178 ( which in the case of the nmssm is only defined at scale @xmath23 where ewsb has occurred ) for the cases of @xmath49 and @xmath236 , respectively . as one could easily anticipate from eq .
( [ mzsquared ] ) ( with @xmath67 replaced by @xmath178 ) , fine - tuning is smallest for the the smallest values of @xmath178 .
this figure also shows that @xmath358 values below about @xmath0 are eliminated by the lep limit on the mass of the lightest chargino . ,
@xmath359 and @xmath360 for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1].,width=230 ] , @xmath359 and @xmath360 for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1].,width=230 ] , @xmath359 and @xmath360 for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1].,width=230 ] , @xmath359 and @xmath360 for points with @xmath237 taking @xmath50 and @xmath236 .
point notation as in fig .
[ fvsmh1].,width=230 ] , @xmath359 and @xmath360 for points with @xmath237 taking @xmath50 and @xmath236 .
point notation as in fig .
[ fvsmh1].,width=230 ] , @xmath359 and @xmath360 for points with @xmath237 taking @xmath50 and @xmath236 .
point notation as in fig .
[ fvsmh1].,width=230 ] , @xmath361 and @xmath362 for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1 ] .
negative values indicate cases for which @xmath363 in which case the plot gives @xmath364.,width=230 ] , @xmath361 and @xmath362 for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1 ] .
negative values indicate cases for which @xmath363 in which case the plot gives @xmath364.,width=230 ] , @xmath361 and @xmath362 for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1 ] .
negative values indicate cases for which @xmath363 in which case the plot gives @xmath364.,width=230 ] , @xmath361 and @xmath362 for points with @xmath237 taking @xmath50 and @xmath236 .
point notation as in fig .
[ fvsmh1 ] .
negative values indicate cases for which @xmath363 in which case the plot gives @xmath364.,width=230 ] , @xmath361 and @xmath362 for points with @xmath237 taking @xmath50 and @xmath236 .
point notation as in fig .
[ fvsmh1 ] .
negative values indicate cases for which @xmath363 in which case the plot gives @xmath364.,width=230 ] , @xmath361 and @xmath362 for points with @xmath237 taking @xmath50 and @xmath236 .
point notation as in fig .
[ fvsmh1 ] .
negative values indicate cases for which @xmath363 in which case the plot gives @xmath364.,width=230 ] next , let us examine the soft squark masses @xmath365 , @xmath366 , and @xmath367 of the third generation .
values for these at scale @xmath23 are plotted in figs .
[ fvsmqmz ] and [ fvsmqmztb50 ] for @xmath49 and @xmath236 , respectively .
we see that to obey limits on stop masses , there is a fairly definite lower bound on @xmath368 and @xmath360 , although low values for @xmath359 are possible . and , to achieve @xmath274 and satisfy all experimental limits requires all these soft masses to lie in a very well defined band .
the corresponding gut - scale values are given in figs .
[ fvsmqgut ] and [ fvsmqguttb50 ] .
points with @xmath274 satisfying all limits again have soft masses squared at the gut scale that fall within narrow bands ( and are sometimes negative and sometimes positive ) . vs. @xmath369 and @xmath370 ( upper two plots ) and @xmath370 vs. @xmath369 ( lower plot ) for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1 ] .
, width=230 ] vs. @xmath369 and @xmath370 ( upper two plots ) and @xmath370 vs. @xmath369 ( lower plot ) for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1 ] .
, width=230 ] vs. @xmath369 and @xmath370 ( upper two plots ) and @xmath370 vs. @xmath369 ( lower plot ) for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1 ] .
, width=230 ] next , we examine , for the case of @xmath49 , @xmath256 and @xmath257 at scale @xmath23 . fig .
[ akmzalmzplotsflt50 ] gives some results .
the upper plot shows that @xmath274 can be achieved for a wide range of @xmath369 , with points that obey all limits requiring a minimum value of @xmath371 .
the middle plot shows that fully ok points require @xmath370 in a rather narrow band with @xmath372 .
the bottom plot shows the correlation between @xmath370 and @xmath369 that is required to get small @xmath52 , as discussed earlier .
note that either both must be negative or both positive for any point that is fully consistent with experimental limits .
the lower bounds on their absolute values for the fully ok points the large yellow crosses are those required to have large enough @xmath211 to escape the @xmath45 lep limits for @xmath239 .
similar results are obtained for @xmath236 .
all these results can be understood analytically as discussed in @xcite .
vs. @xmath369 and @xmath370 for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1 ] .
, width=230 ] vs. @xmath369 and @xmath370 for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1 ] . ,
width=230 ] fig .
[ ma1vsalakmzplotsflt50 ] shows the dependence on @xmath201 on @xmath369 and @xmath370 in the case of @xmath49 .
one observes that large @xmath201 can be achieved for these same ranges of @xmath369 and @xmath370 just as easily as small @xmath201 .
it is just that cases with large @xmath215 and small @xmath123 , which requires @xmath239 , are not consistent with lep limits on the net @xmath45 channel , as we have discussed .
similar results are found for @xmath236 .
vs. @xmath255 and @xmath254 ( upper two plots ) and @xmath254 vs. @xmath255 ( lower plot ) for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1 ] .
, width=230 ] vs. @xmath255 and @xmath254 ( upper two plots ) and @xmath254 vs. @xmath255 ( lower plot ) for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1 ] .
, width=230 ] vs. @xmath255 and @xmath254 ( upper two plots ) and @xmath254 vs. @xmath255 ( lower plot ) for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1 ] .
, width=230 ] , @xmath373 and @xmath374 for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1 ] .
, width=230 ] , @xmath373 and @xmath374 for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1 ] . ,
width=230 ] , @xmath373 and @xmath374 for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1 ] .
, width=230 ] plots of the gut - scale parameters , @xmath255 and @xmath254 , appear in fig .
[ akgutalgutplotsflt50 ] .
these show that the lowest-@xmath123 scenarios that are fully consistent with experiment are often achieved for small values of these parameters . in terms of model building , these soft - susy - breaking parameters are thus close to values associated with no - scale soft - susy - breaking . ,
@xmath373 and @xmath374 for points with @xmath237 taking @xmath50 and @xmath236 .
point notation as in fig .
[ fvsmh1 ] .
, width=230 ] , @xmath373 and @xmath374 for points with @xmath237 taking @xmath50 and @xmath236 .
point notation as in fig .
[ fvsmh1 ] .
, width=230 ] , @xmath373 and @xmath374 for points with @xmath237 taking @xmath50 and @xmath236 .
point notation as in fig .
[ fvsmh1 ] .
, width=230 ] probably the most interesting parameter correlation is that regarding the soft - susy - breaking higgs masses squared at the gut scale . these are plotted in figs .
[ fvsmhsqgutflt50 ] and [ fvsmhsqgutflt50tb50 ] for the cases of @xmath49 and @xmath236 , respectively .
these plots show that the fully ok scenarios with smallest @xmath123 have very modest soft masses squared at the gut scale , especially in the case of @xmath98 .
thus , something close to a no - scale model for soft higgs masses squared at the gut scale is preferred for low @xmath123 .
taking @xmath50 and @xmath49 .
point notation : dark ( red ) @xmath375 ; light grey ( cyan ) @xmath373 ; darker grey ( green ) @xmath374 .
points plotted are the yellow fancy cross points from fig .
[ fvsmhsqgutflt50].,width=230 ] this preference for a no - scale type of boundary condition for the higgs soft masses squared at the gut - scale is further emphasized by the @xmath49 plot of fig .
[ fvsmhsqgut ] , where we overlap the values of @xmath375 , @xmath373 and @xmath374 for @xmath237 yellow fancy cross scenarios of fig .
[ fvsmhsqgutflt50 ] . for @xmath49 .
point notation as in fig .
[ fvsmh1].,width=230 ] we have said in many places that for the fully ok scenarios the @xmath86 has quite sm - like @xmath376 coupling .
this is illustrated in fig .
[ fvscv ] where we plot @xmath123 as a function of c_v , for the case of @xmath49 ( results for @xmath236 are similar ) .
we see that the fully ok yellow fancy crosses all have @xmath377 .
in fact , for @xmath237 scenarios , @xmath377 also for the ( blue ) square points that are not also yellow fancy crosses , those points obtained if one only requires that the scenario is consistent with experimental limits that include the @xmath166 channel ( that is , before requiring @xmath52 as needed to avoid the limits on the combined @xmath45 channel ) . suppressed @xmath378 values only appear in these plots if the higgs experimental limits are removed . as discussed later , there are some very special points for which this is not true that will be considered in a follow - up paper . in this subsection , we consider at a still more detailed level the fully ok yellow points having large @xmath211 and @xmath52 that also have @xmath204 .
we will present results only for the case of @xmath49 and @xmath379 .
in general , the other @xmath7 values give similar correlations aside from the shift in the value of @xmath165 that gives the lowest @xmath123 value . in the plots presented in this section
we will use blue @xmath156 s in place of the yellow crosses , since the latter do not display well on their own .
hopefully , there are few enough points on the following plots that the reader can match points from one plot to another . for the large ( yellow )
cross points ( for clarity , we use blue @xmath156 s in their place in this and succeeding plots ) with @xmath204 taking @xmath50 and @xmath49 .
the lower plot shows @xmath123 vs. @xmath201 .
, width=230 ] for the large ( yellow ) cross points ( for clarity , we use blue @xmath156 s in their place in this and succeeding plots ) with @xmath204 taking @xmath50 and @xmath49 .
the lower plot shows @xmath123 vs. @xmath201 .
, width=230 ] first , we show @xmath123 as a function of @xmath165 and @xmath201 in fig .
[ fvsmhimai ] . in the upper plot
, we see again the preference for @xmath165 near @xmath0 .
the lower plot shows that the very smallest @xmath123 values occur at @xmath201 values above @xmath380 , implying that the @xmath245 channel is the dominant @xmath87 decay .
we note that the @xmath381 part of the @xmath52 fully ok zone was also found in the companion paper @xcite to be preferred in order to avoid fine - tuning associated with getting small @xmath201 .
( which equals @xmath46 since @xmath382 when @xmath52 ) vs. @xmath123 for the large ( yellow ) cross points with @xmath204 taking @xmath50 and @xmath49.,width=230 ] one important prediction of any given parameter set is that for @xmath383 , where ^2(z+b s ) & & g_zz^2 g_zz^2 .
[ xisqdef ] for the fully ok points one has @xmath52 and thus @xmath384 .
more generally , @xmath383 is the net rate for lep production of @xmath166 _ and _ @xmath167 final states relative to the rate that one would obtain for a sm higgs boson which decayed entirely to @xmath31 .
of particular interest is the correlation between @xmath383 and @xmath123 .
thus , an important comparison is the model prediction for @xmath383 relative to the excess found at lep in the vicinity of @xmath31 mass @xmath40 .
the value of @xmath384 as a function of @xmath165 is plotted in fig .
[ xisqvsf ] .
we observe that the points with @xmath204 lie in the range @xmath385 with many of the very lowest @xmath123 points having @xmath386 $ ] , the range most consistent with the lep excess at @xmath387 mass @xmath388 .
vs. @xmath263 ( upper ) and @xmath123 vs. @xmath389 ( lower ) for the large ( yellow ) cross points with @xmath204 taking @xmath50 and @xmath49.,width=230 ] vs. @xmath263 ( upper ) and @xmath123 vs. @xmath389 ( lower ) for the large ( yellow ) cross points with @xmath204 taking @xmath50 and @xmath49.,width=230 ] next , we wish to illustrate the relative mssm vs. singlet composition of the @xmath87 and @xmath86 for the @xmath204 points .
this composition has obvious implications for their couplings to sm particles .
the more pure mssm the @xmath86 is , the more sm - like will be its couplings . the more singlet the @xmath87 is , the more weakly it will be coupled to sm particles . in particular ,
its couplings to sm down - type fermions and leptons are given by @xmath284 times the sm - like weight in which @xmath390 is replaced by @xmath391 , for example .
these compositions are shown in fig .
[ fvscta ] .
the upper plot illustrates that there is a lower bound on @xmath282 that arises from the joint requirements of large @xmath211 and @xmath52 . as noted earlier , this guarantees that the @xmath31 ( and @xmath392 ) coupling strengths of the @xmath87 are sufficiently large that the decays of the @xmath87 are dominated by the heaviest fermionic states , @xmath393 for @xmath394 and @xmath395 for @xmath396 , with @xmath397 also being important . for @xmath398
, @xmath397 is the dominant decay .
note the preference for @xmath399 for the very lowest @xmath123 points .
the lower plot of fig .
[ fvscta ] shows the singlet component , @xmath389 , of the @xmath86 for the fully ok solutions .
the @xmath86 can be as much as @xmath400 singlet at the amplitude level , but this means it is still @xmath401 non - singlet in the amplitude - squared sense . as a result , all plotted points have @xmath377 .
the very lowest @xmath123 points are clearly associated with very small @xmath389 .
we now turn to the gut - scale parameters associated with @xmath204 large yellow fancy cross points ( plotted as blue @xmath156 s for these figures ) that pass all experimental constraints and the correlations among them . for large ( yellow ) cross points with @xmath204 taking @xmath50 and @xmath49 .
the lower plot shows @xmath402 as a function of @xmath403.,width=230 ] for large ( yellow ) cross points with @xmath204 taking @xmath50 and @xmath49 .
the lower plot shows @xmath402 as a function of @xmath403.,width=230 ] first , we consider @xmath402 and @xmath403 in fig .
[ fvslgut ] .
we see that the very lowest @xmath123 values have fairly small @xmath403 and significantly larger @xmath404 . for fully ok points with @xmath204 taking @xmath50 and @xmath49 .
the lower plot shows @xmath254 as a function of @xmath255.,width=230 ] for fully ok points with @xmath204 taking @xmath50 and @xmath49 .
the lower plot shows @xmath254 as a function of @xmath255.,width=230 ] we consider @xmath254 and @xmath255 in fig .
[ fvslgut ] .
we see that the very lowest @xmath123 values have fairly small @xmath255 and @xmath254 , , as noted earlier , both are close to being consistent with no - scale boundary conditions at @xmath18 . for fully ok points with @xmath204 taking @xmath50 and @xmath49 .
the middle plot shows @xmath405 as a function of @xmath406 .
the bottom plot shows @xmath407 as a function of @xmath406 .
our convention is that if an @xmath408 is negative then we plot @xmath409.,width=230 ] for fully ok points with @xmath204 taking @xmath50 and @xmath49 .
the middle plot shows @xmath405 as a function of @xmath406 .
the bottom plot shows @xmath407 as a function of @xmath406 .
our convention is that if an @xmath408 is negative then we plot @xmath409.,width=230 ] for fully ok points with @xmath204 taking @xmath50 and @xmath49 .
the middle plot shows @xmath405 as a function of @xmath406 .
the bottom plot shows @xmath407 as a function of @xmath406 .
our convention is that if an @xmath408 is negative then we plot @xmath409.,width=230 ] we consider @xmath406 , @xmath405 and @xmath407 in fig .
[ fvsmsqgut ] .
we see that the very lowest @xmath123 values have fairly small gut - scale values for all the scalar higgs mass squared values , again close to being consistent with no - scale boundary conditions at @xmath18 .
however , our scans did not locate any fully ok points for which @xmath406 , @xmath405 and @xmath407 were all simultaneously small .
we are unsure at this time as to whether this is an artifact of limited computer time for scanning or something deeper .
decays and low @xmath123 , we plot : @xmath123 vs. @xmath165 ( top ) ; and @xmath201 vs. @xmath165 ( bottom ) .
note that there are a number of degeneracies where exactly the same @xmath123 and @xmath165 are predicted for somewhat different parameter choices in the scan.,width=211 ] decays and low @xmath123 , we plot : @xmath123 vs. @xmath165 ( top ) ; and @xmath201 vs. @xmath165 ( bottom ) .
note that there are a number of degeneracies where exactly the same @xmath123 and @xmath165 are predicted for somewhat different parameter choices in the scan.,width=211 ] decays and low @xmath123 , we plot : @xmath123 vs. @xmath263 ( top ) ; @xmath412 vs. @xmath263 ( middle ) ; and @xmath383 vs. @xmath165 ( bottom ) .
since @xmath123 depends primarily on @xmath263 , there are a number of points in the @xmath123 vs. @xmath263 plot that are actually multiple repetitions of exactly the same @xmath123 at a given @xmath263 value but with @xmath412 and @xmath383 varying slightly because of sensitivity to other parameters of the scan.,width=211 ] decays and low @xmath123 , we plot : @xmath123 vs. @xmath263 ( top ) ; @xmath412 vs. @xmath263 ( middle ) ; and @xmath383 vs. @xmath165 ( bottom ) .
since @xmath123 depends primarily on @xmath263 , there are a number of points in the @xmath123 vs. @xmath263 plot that are actually multiple repetitions of exactly the same @xmath123 at a given @xmath263 value but with @xmath412 and @xmath383 varying slightly because of sensitivity to other parameters of the scan.,width=211 ] decays and low @xmath123 , we plot : @xmath123 vs. @xmath263 ( top ) ; @xmath412 vs. @xmath263 ( middle ) ; and @xmath383 vs. @xmath165 ( bottom ) .
since @xmath123 depends primarily on @xmath263 , there are a number of points in the @xmath123 vs. @xmath263 plot that are actually multiple repetitions of exactly the same @xmath123 at a given @xmath263 value but with @xmath412 and @xmath383 varying slightly because of sensitivity to other parameters of the scan.,width=211 ] decays and low @xmath123 , we plot : @xmath413 vs. @xmath263 ( top ) ; and @xmath414 as a function of @xmath263 ( bottom ) .
( many of the points have the same @xmath414 value.),width=211 ] decays and low @xmath123 , we plot : @xmath413 vs. @xmath263 ( top ) ; and @xmath414 as a function of @xmath263 ( bottom ) .
( many of the points have the same @xmath414 value.),width=211 ] let us now turn to the special class of points mentioned in section [ sec : compare ] .
these are the low-@xmath123 points with a sm - like @xmath86 of mass @xmath40 and for which @xmath415 . for these points , @xmath416 and @xmath417 . for this to occur
, the @xmath87 must be highly singlet in nature so that the tree - level decays to fermion - antifermion are highly suppressed , in which case the chargino loop - induced decay to @xmath10 can be dominant .
( the relevant couplings are present even when the @xmath87 is purely singlet . )
this combination of features allows consistency with the lep limits on the @xmath45 channel .
we have not been able to determine if there are relevant limits on the @xmath418 channel .
this channel would have quite a high rate and most probably these relatively spectacular events would have been noticed .
these points are also disfavored theoretically since , as detailed shortly , a very high level of fine tuning of gut - scale parameters is required in order to achieve @xmath419 as required ( for @xmath49 ) for @xmath420 to be the dominant @xmath87 decay channel .
nonetheless , they should not be entirely discarded as a possible class and so we give some details regarding them in the following .
these points were found using an extremely fine grid scanning approach of the type detailed in @xcite with fixed @xmath421 , @xmath422 and @xmath49 .
basic plots for this scenario appear in fig .
[ 4gamplots1 ] .
the top plot of this figure gives @xmath123 as a function of @xmath165 .
we see again that @xmath239 gives the lowest @xmath123 value , @xmath423 in this case .
the lower plot shows that @xmath424 is required for this kind of scenario , with the lowest @xmath123 obtained for @xmath425 .
[ 4gam_braxisq ] shows @xmath123 vs. @xmath263 as the top plot , @xmath412 as a function of @xmath263 as the middle plot and @xmath383 vs. @xmath165 as the bottom plot .
the top plot is useful for correlating @xmath123 with the value of @xmath263 .
however , note that there is some degeneracy : essentially the same values of @xmath123 and @xmath263 are sometimes obtained even though the basic scan parameters are different .
the middle plot shows that @xmath426 for these points , with @xmath427 for the @xmath423 points .
as expected , very small @xmath263 is required in order for the @xmath428 decays to be dominant .
the bottom plot of the figure shows @xmath383 as a function of @xmath165 .
we observe that @xmath383 is of the right general magnitude to explain the lep excess for the lowest @xmath123 points that have @xmath240 .
we note that @xmath383 receives contributions from both the @xmath166 final state from direct @xmath429 decay and also the @xmath167 from @xmath430 where @xmath431 due to the competition from the @xmath428 decays .
the careful reader may wonder why it is that we can have small @xmath263 for these points whereas the @xmath52 points have a lower bound on @xmath263 . in fact , it is precisely the _ combination _ of the requirements that @xmath52 and @xmath432 which forces a lower bound on @xmath263 .
values of @xmath263 small enough to yield large @xmath412 while at the same time @xmath433 is maintained are only possible for relatively large @xmath201 .
the fine - tuning required in @xmath256 and @xmath257 to achieve very small @xmath263 can be quantified via the derivatives , , where all parameters are defined at scale @xmath23 .
understanding of these quantities can be gleaned from the approximate formula _ a - m_12 ^ 2m_11 ^ 2-m_22 ^ 2- , [ ctaform ] where we used @xmath434 eq .
( [ ctaform ] ) shows that there will be great sensitivity of @xmath263 to the value of @xmath256 relative to @xmath435 , and almost no sensitivity to @xmath257 .
both are confirmed by the numerical results we now present for fixed @xmath267 , @xmath49 , @xmath436 , @xmath437 , @xmath438 , @xmath439 ( for the relevant 3rd generation ) .
different points are obtained by scanning in @xmath440 .
( obviously , many more @xmath441 points could be found if the fixed parameters are allowed to vary .
however , large @xmath442 is essential to get small @xmath123 for such points . ) in fig .
[ 4gam_fcalvscta ] , we plot @xmath413 vs. @xmath263 and @xmath414 vs. @xmath263 .
the top plot shows that @xmath413 must be small for small @xmath263 ( and there is a strong linear relation ) .
the bottom plot shows that such small values of @xmath263 imply rather large values of @xmath414 .
given eq .
( [ alrun ] ) , high sensitivity to the @xmath23-scale value of @xmath256 implies a high level of fine - tuning for @xmath256 ( at scale @xmath23 ) with respect to @xmath255 , @xmath127 and @xmath298 .
one should also note that the @xmath414 tuning measure for @xmath256 is largest ( @xmath443 ) for the point for which the ewsb fine tuning measure @xmath123 is smallest and vice - versa
. decays and low @xmath123 , we plot : @xmath186 vs. @xmath183 ( top ) ; and @xmath257 vs. @xmath256 ( bottom ) .
, width=211 ] decays and low @xmath123 , we plot : @xmath186 vs. @xmath183 ( top ) ; and @xmath257 vs. @xmath256 ( bottom ) .
, width=211 ] finally , the two plots of fig . [ 4gamplots2 ] show that these points require largish @xmath186 and @xmath183 that are fairly closely correlated , while @xmath257 must be quite small .
there is strong motivation for a supersymmetric model with an extended higgs sector containing one or more extra higgs singlet superfields .
these motivations range from string theory model building , where it is known that sm - singlets are abundant in string theory compactifications , to the purely phenomenological , including the fact that adding anything other than sm singlets to the mssm will typically destroy gauge coupling unification . in this paper , we have studied in detail the next - to - minimal supersymmetric model , which contains exactly one singlet higgs superfield in addition to the two higgs doublet superfields of the mssm .
we have shown that there is a portion of nmssm parameter space with an abundance of attractive features , no outstanding problems and which leads to an important set of predictions that should be taken quite seriously .
there are many ways in which the nmssm is a better benchmark theory than the mssm , since it has important flexibilities that are currently leading to problematical issues for the mssm .
the attractive features of the nmssm include : a natural explanation for the @xmath67 parameter is provided since all superpotential couplings are dimensionless in the nmssm , the scale of @xmath67 is given by the scale of soft - susy - breaking , which ( see below ) can be well below a tev ; the supersymmetric context provides a highly satisfactory solution of the naturalness / hierarchy problem if the squark masses ( in particular , the stop masses ) and the gluino mass are well below a tev ( implying possible discovery at the tevatron and very plentiful production at the lhc ) ; low squark masses imply that the lightest higgs boson , the @xmath86 , will most naturally be sm - like in its couplings to sm particles and have a mass of order @xmath0 , close to the ideal value for satisfying precision electroweak constraints ; lep data is fully consistent with such an @xmath86 provided it decays mostly via @xmath444 ( requiring @xmath394 ) or @xmath445 ( when @xmath273 ) , where the @xmath87 is primarily the cp - odd component of the extra complex scalar higgs singlet field ; the optimal scenarios fit nicely with choices for the gut - scale values of the soft - susy - breaking higgs masses squared and @xmath83 parameters that are quite modest in size , as might be associated with an approximate no - scale model for susy breaking ; in the natural scenarios above , the heavier higgs bosons of the model ( two cp - even and one cp - odd neutral higgs bosons and the charged higgs boson ) have relatively modest masses that would make them accessible at a hadron collider if @xmath7 is large enough and mostly accessible at a 1 tev linear @xmath451 collider ; the @xmath87 could allow for adequate annihilation in the early universe of very light neutralinos @xcite .
the attractiveness of this scenario suggests that the lep groups should push a re - analysis of the @xmath453 channel in the hope of either ruling out the @xmath454 scenario , or finding an excess consistent with it for @xmath165 in the vicinity of @xmath0 .
either a positive or negative result would have very important implications for higgs searches at the tevatron and lhc .
we also stress that @xmath181 factory experiments should attempt to search for a @xmath455 signal down to the lowest possible branching ratio ( the predicted minimum in the nmssm context being of order @xmath456 ) .
we speculate that similar results could emerge in other supersymmetric models with a higgs sector that , like the case of the nmssm , is more complicated than that of the mssm .
many such models can be constructed .
thus , much of the discussion above regarding higgs discovery is quite generic . in general
, there might be quite a few light @xmath8 s , all of which could appear in the decay of a light sm - like @xmath24 and all of which would provide potential signals in reanalyzed lep data and in @xmath457 decays . there is a potential gold - mine of discovery if one digs deeply enough . however , whether the @xmath8 is truly the nmssm cp - odd @xmath87 or just a lighter higgs boson into which the sm - like @xmath24 pair - decays , hadron collider detection of the @xmath24 in its @xmath1 decay mode will be very challenging .
discovery modes that one can hope to demonstrate to be viable include : diffractive production @xcite , @xmath461 , with @xmath460 .
this latter mode looks very promising @xcite .
unfortunately , it seems very doubtful that viable discovery signals would be possible for the analogous modes with @xmath462 ( that would be the only ones available if @xmath463 ) .
although @xmath464 is somewhat preferred by naturalness arguments in the nmssm case , one should be prepared for the possibility that the lhc will discover a plethora of supersymmetric particles , and perhaps some heavy higgs bosons ( if @xmath7 is large enough ) but fail to see the sm - like light higgs most closely associated with electroweak symmetry breaking . the only lhc evidence for its existence
would then be that @xmath208 scattering would be found to be fully perturbative , as predicted if there is a light @xmath24 with sm - like couplings to @xmath208 . at a linear collider , detection of @xmath465 production
using the @xmath466 missing mass @xmath467 approach will be completely straightforward .
a @xmath0 @xmath24 with sm coupling to @xmath152 will result in many events forming a sharp peak in @xmath467 , quite independently of how the @xmath24 decays .
the decays can then be analyzed to see what is present and with what branching ratio .
detection of an @xmath24 with unexpected decays at a photon collider will also be reasonably straightforward @xcite .
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j. c * 33 * , 261 ( 2004 ) [ arxiv : hep - ph/0311023 ] .
gunion , v. khoze , a. deroeck , m. ryskin , in preparation . | we present an extended study of how the next to minimal supersymmetric model easily avoids fine - tuning in electroweak symmetry breaking for a sm - like light higgs with mass in the vicinity of @xmath0 , as beautifully consistent with precision electroweak data , while escaping lep constraints due to the dominance of @xmath1 decays with @xmath2 so that @xmath3 or jets .
the residual @xmath4 branching ratio for @xmath5 explains perfectly the well - known lep excess at @xmath6 .
details of model parameter correlations and requirements are discussed as a function @xmath7 .
comparisons of fine - tuning in the nmssm to that in the mssm are presented .
we also discuss fine - tuning associated with scenarios in which the @xmath8 is essentially pure singlet , has mass @xmath9 , and decays primarily to @xmath10 leading to an @xmath11 higgs signal . | <s>[INST]in the standard model ( sm ) , electroweak symmetry breaking , whereby the @xmath12 and @xmath13 bosons and the quarks and leptons acquire mass , gives rise to a higgs boson , @xmath14 . however , the value of @xmath15 is quadratically sensitive to the cutoff scale of the theory , @xmath16 , especially through top quark loops which give a one - loop correction of ^2=-34 ^ 2 ^ 2v^2 ^ 2 , where @xmath16 is the high energy cutoff and @xmath17 . for @xmath16 of order
the gut scale , @xmath18 , or the planck scale , @xmath19 , an extreme cancellation between the one - loop contribution(s ) and the bare higgs mass is required in order that the physical higgs mass be below a @xmath20 , as required in order for the scattering of longitudinally polarized @xmath12 bosons to obey unitarity in a perturbative fashion .
supersymmetric ( susy ) models , such as the minimal supersymmetric model ( mssm ) , cure this naturalness / hierarchy problem associated with the quadratically divergent 1-loop corrections via the introduction of superpartners for each sm particle .
because the spin of the superpartners differs by 1/2 unit from that of the corresponding sm particle , the 1-loop correction from the superpartner will cancel that of the sm particle once the energy scale being integrated over in the loop is above the mass of the ( presumed to be heavier ) superpartner .
so long as the superpartners have mass somewhat below @xmath21 ( say @xmath22 ) , the cancellation is not particularly extreme and the hierarchy / naturalness problem associated with the quadratic divergences is ameliorated .
however , there remains the question of how finely the gut - scale parameters must be adjusted in order to get appropriate electroweak symmetry breaking , that is to say correctly predict the observed value of @xmath23 .
it is here that lep limits on a sm - like higgs boson play a crucial role .
supersymmetric models most naturally predict that the lightest higgs boson , generically @xmath24 , is sm - like and that it has a mass closely correlated to @xmath23 , typically lying in the range @xmath25 for stop masses @xmath26 , with an upper bound , for example , of @xmath27 in the mssm for stop masses @xmath28 and large stop mixing . if the stop masses are large , the predicted value of @xmath23 is very sensitive to the gut scale parameters
. such sensitivity is termed fine tuning. models with minimal fine tuning provide a much more natural explanation of the @xmath13 mass than those with a high level of fine tuning .
the degree of fine tuning required is thus quite closely related to the constraints on a sm - like @xmath24 , and these in turn depend on how it decays .
the sm and the mssm predict that @xmath5 decays are dominant and lep has placed strong constraints on @xmath29 . the limits on ( hbb )
are shown in fig .
[ zbblimits ] ( from ref .
@xcite ) . from this plot ,
one concludes that @xmath30 is excluded for a sm - like @xmath24 that decays primarily to @xmath31 .
in fact , because of the manner in which the analysis is done , at a first level of approximation this limit applies for an @xmath24 that decays to any combination of @xmath32 and @xmath33 . for @xmath34 and @xmath35 ( with @xmath36 channels making up the rest ) @xmath37
is excluded .
this will be important later . in the case of the cp - conserving mssm
, one always obtains @xmath38 . for @xmath39
, most of parameter space will yield @xmath30 and thus be ruled out by the sm - like higgs lep limit .
the remaining part of mssm parameter space either has at least one very large parameter , most typically a soft - susy - breaking stop mass close to a tev at scale @xmath23 , or else large mixing in the stop sector . in the former case
, one always finds that to predict the observed @xmath23 requires very careful adjustment , fine - tuning , of the gut - scale parameters with accuracies better than 1% . in the latter case , fine - tuning
can be reduced to the 3% level . to achieve small fine - tuning ,
let us say no worse than 10% , the soft - susy - breaking parameters that affect the higgs sector should be well below a tev , in which case the lightest cp - even mssm higgs boson would have mass @xmath40 . as suggested in @xcite , the simplest way to allow a higgs mass of order @xmath0 , thus making possible a light susy spectrum and low fine - tuning ,
is to modify higgs decays so that the @xmath31 branching ratio is small and primary decays are to channel(s ) to which lep is less sensitive .
this is very natural in models in which the higgs sector is extended and higgs to higgs decays are kinematically allowed .
the decay widths for higgs to higgs decays can easily exceed the very small width for the @xmath31 channel .
the simplest supersymmetric model that gives rise to this possibility is the next - to - minimal supersymmetric model ( nmssm ) .
the nmssm yields a preferred value of @xmath6 purely on the basis of minimizing fine - tuning .
a higgs mass near @xmath0 is also strongly preferred by precision electroweak measurements .
further , there is a well - known @xmath41 excess in the @xmath42 channel in the lep data for @xmath43 when a final state that contains two or more @xmath44 is assumed to contain exactly 2 @xmath44 .
if the higgs decays only to @xmath31 then this excess and limits on the @xmath45 final state would apply to @xmath46 defined by = [ g_zzh^2/g_zz^2](hbb ) .
[ cbbdef ] the excess is apparent in the higher observed vs. expected @xmath46 limits for a test higgs mass of @xmath6 shown in fig .
[ zbblimits ] .
this excess is particularly apparent in the @xmath47 result ( fig . 7 of @xcite ) obtained after combining all four lep experiments . from ref .
@xcite are shown vs. @xmath48 .
also plotted are the predictions for the nmssm parameter cases discussed in @xcite having fixed @xmath49 , @xmath50 that give fine - tuning measure @xmath51 and @xmath52 and that are consistent with higgs constraints obtained using the preliminary lhwg analysis code @xcite.,width=230 ] in a previous paper @xcite , we have shown that the above excess is consistent with a scenario in which the higgs boson has sm - like @xmath53 coupling , but has reduced @xmath54 by virtue of the presence of @xmath24 decays to a pair of lighter higgs bosons , @xmath1 , where @xmath55 is small , as is automatic if @xmath56 so that @xmath57 or light quarks and gluons . is dominant , as occurs for @xmath58 , then , as noted earlier in the text , @xmath59 is required by lep data @xcite . ]
( the importance of such decays was first emphasized in @xcite , and later in @xcite , followed by extensive work in @xcite . ) for example , if the @xmath53 coupling is full sm strength , then @xmath60 with @xmath61 and @xmath62 fits the observed @xmath63 excess nicely .
meanwhile , there are no current limits on the @xmath64 final state for @xmath65 @xcite . and limits in the case of @xmath66 run out at slightly lower @xmath48 . as already stressed and as described below in more detail , we are particularly led to the above interpretation of lep data since fine - tuning within the nmssm is absent for model parameters that yield precisely this kind of scenario @xcite . while various alternative interpretations of this excess in terms of a non - sm higgs sector have been suggested @xcite , the nmssm scenario has the lowest fine tuning of any such scenario and has particularly strong theoretical motivation .
the nmssm is an extremely attractive model @xcite .
first , it provides a very elegant solution to the @xmath67 problem of the mssm via the introduction of a singlet superfield @xmath68 . for the simplest possible scale invariant form of the superpotential
, the scalar component of @xmath68 naturally acquires a vacuum expectation value of the order of the breaking scale , giving rise to a value of @xmath67 of order the electroweak scale .
the nmssm is the simplest supersymmetric extension of the standard model in which the electroweak scale originates from the breaking scale only .
hence , the nmssm deserves very serious consideration .
apart from the usual quark and lepton yukawa couplings , the scale invariant superpotential of the nmssm is @xmath69 depending on two dimensionless couplings @xmath70 , @xmath71 beyond the mssm .
[ hatted ( unhatted ) capital letters denote superfields ( scalar superfield components ) . ]
the associated trilinear soft terms are @xmath72 the final two input parameters are @xmath73 and @xmath74 where @xmath75 , @xmath76 and @xmath77 .
the higgs sector of the nmssm is thus described by the six parameters @xmath78 in addition , values must be input for the gaugino masses and for the soft terms related to the ( third generation ) squarks and sleptons that contribute to the radiative corrections in the higgs sector and to the higgs decay widths .
the particle content of the nmssm differs from the mssm by the addition of one cp - even and one cp - odd state in the neutral higgs sector ( assuming cp conservation ) , and one additional neutralino .
the result is three cp - even higgs bosons ( @xmath79 ) two cp - odd higgs bosons ( @xmath80 ) and a total of five neutralinos @xmath81 .
it will be convenient to denote the cp - even and cp - odd neutral higgs bosons of the mssm as @xmath82 and @xmath83 , respectively , while those of the nmssm will be denoted by @xmath84 and @xmath85 , respectively . in the latter case
, our focus will be on the lightest states @xmath86 and @xmath87 .
the nmhdecay program @xcite , which includes most lep constraints , allows easy exploration of higgs phenomenology in the nmssm .
( top ) , @xmath48 ( middle ) and @xmath88 ( bottom ) for randomly generated mssm parameter choices with @xmath49 and @xmath50 .
blue pluses correspond to parameter choices such that @xmath30 .
red crosses are points with @xmath89.,width=230 ] ( top ) , @xmath48 ( middle ) and @xmath88 ( bottom ) for randomly generated mssm parameter choices with @xmath49 and @xmath50 .
blue pluses correspond to parameter choices such that @xmath30 .
red crosses are points with @xmath89.,width=230 ] ( top ) , @xmath48 ( middle ) and @xmath88 ( bottom ) for randomly generated mssm parameter choices with @xmath49 and @xmath50 .
blue pluses correspond to parameter choices such that @xmath30 .
red crosses are points with @xmath89.,width=230 ] in @xcite , we presented a first study of the fine - tuning issues for the nmssm vs. the mssm .
we define the fine - tuning measure to be f = max_p f_p _ p|dd p| , where the parameters @xmath90 comprise all gut - scale soft - susy - breaking parameters .
in this section , we will consider scenarios associated with minimal fine tuning in the mssm and the nmssm . in the following section
, we will give a broader overview of all types of nmssm scenarios and will show how it is that one is lead to the nmssm scenarios considered in this section .
we discuss fine tuning for the mssm first . in this case , the gut scale parameters comprise : : @xmath91 , @xmath67 , @xmath92 , @xmath93 , @xmath94 , @xmath95 , @xmath96 , @xmath97 , @xmath98 , @xmath99 , @xmath88 , @xmath100 , and @xmath101 . in principle , soft masses squared for the first two generations should be included above , but they have negligible effect upon @xmath23 . in our approach , we choose @xmath23-scale values for all the squark and slepton soft masses squared at scale @xmath23 , for the gaugino masses , @xmath102 , and for @xmath103 , @xmath104 and @xmath105 ( with no requirement of universality at the gut scale ) .
we also choose @xmath23-scale values for @xmath7 , @xmath67 and @xmath106 ; these uniquely determine @xmath107 .
the vevs @xmath108 and @xmath109 at scale @xmath23 are fixed by @xmath7 and @xmath23 via @xmath110 ( where @xmath111 ) .
finally , @xmath112 and @xmath113 are determined from the two potential minimization conditions .
[ from here on , all parameters displayed without an explicit argument are @xmath23-scale values , although we sometimes give them an explicit @xmath114 argument for emphasis .
all gut - scale parameters will be specifically indicated using an explicit argument @xmath115 . ]
we then evolve all parameters to the mssm gut scale ( including @xmath67 and @xmath92 ) .
next , we shift each of the gut - scale parameters in turn , evolve back down to scale @xmath23 , and re - minimize the higgs potential using the shifted values of @xmath67 , @xmath92 , @xmath98 and @xmath99 .
this gives new values for @xmath108 and @xmath109 from which we compute a new value for @xmath23 ( and @xmath7 ) .
it is not difficult to understand why fine tuning is typically large in the mssm given lep constraints .
minimization of the higgs potential gives ( at scale @xmath23 ) ^2=-^2 + -^2 ^ 2 - 1 .
[ mzsquared ] the @xmath23-scale @xmath116 parameters can be determined from the gut - scale values of all susy - breaking parameters via the renormalization group equations .
the result for @xmath49 ( similar to the @xmath117 results in refs .
@xcite ) is ^2&~&-2.0 ^ 2()+5.9m_3 ^ 2()+0.8 ( ) + & & + 0.6 ( ) -1.2 ( ) + & & -0.7m_3()a_t()+0.2 a_t^2()+ [mzfromgut ] all of the above terms aside from @xmath118 and @xmath119 arise from the rge evolution result for @xmath120 .
similarly , one can expand @xmath23-scale values for soft - susy - breaking parameters in terms of gut - scale parameters .
in particular , one finds ( at @xmath49 ) a_t()&~ & -2.3 m_3()+0.24 a_t()[atmz ] + m_3()&~ & 3 m_3()[m3mz ] + ^2()&~ & 5.0 m_3 ^ 2()+0.6 ^2 ( ) + & & + 0.2 a_t()m_3()[mstopbarmz ] .
[ rgeatm3 ] in the above , ^1/2 .
[ mstopbardef ] unless there are large cancellations ( fine - tuning ) , one would expect that ~,,m_h^ , where @xmath121 is similar in size to @xmath67 .
we would need a very light gluino , and a rather light stop , to avoid fine - tuning .
more precisely , if @xmath122 , then it is clear from eq .
( [ mzfromgut ] ) that the minimum of @xmath123 is determined by the @xmath124 term , which would give @xmath125 for @xmath126 . allowing for small positive @xmath127
reduces this minimum @xmath123 somewhat , as will be illustrated below .
of course , in specific models you can also have correlations among the gut - scale parameters that would reduce @xmath123 .
the problem is that the small @xmath88 value required for minimal @xmath123 does not yield a mssm higgs mass @xmath48 above the @xmath128 lep limit unless @xmath129 is very large ( which causes a high level of fine - tuning , @xmath130 ) . to maximize @xmath48 at moderate @xmath129
, one should consider parameters corresponding to @xmath131 , termed an @xmath48-max scenario. for such choices it is also possible to obtain @xmath89 . to simultaneously minimize @xmath123 , the sign of @xmath88 must be chosen negative . to understand this
, we first note that @xmath89 can be achieved with @xmath132 or @xmath133 and @xmath134 .
given eq .
( [ rgeatm3 ] ) , this translates to @xmath135 or @xmath136 , respectively .
in both cases , @xmath123 will be determined by the @xmath137 term in eq .
( [ rgeatm3 ] ) , yielding f~0.2 a^2_t()^2
. obviously the case of @xmath136 case will correspond to very large fine tuning , roughly @xmath138 . for the @xmath135 case ,
@xmath139 is obtained .
similar values of @xmath123 can be obtained for much smaller @xmath140 values provided one allows for moderate @xmath141 @xcite .
the above generic features are apparent in the numerical results presented in fig .
[ fvsmhmssm ] for the case of @xmath142 and @xmath50 .
we scan randomly over @xmath103 , @xmath104 , @xmath105 and 3rd generation squark and slepton soft masses - squared above @xmath143 , as well as over @xmath144 , @xmath145 and over @xmath146 .
for such values of @xmath106 , the @xmath24 is quite sm - like and only allowed by lep data if @xmath147 .
if lower values of @xmath106 are allowed , in particular @xmath148 , lower values of @xmath149 can be obtained for experimentally allowed scenarios . in these latter scenarios ,
the @xmath150 is typically fairly sm - like but will have mass above @xmath128 while the @xmath151 can have mass below @xmath128 by virtue having weak @xmath152 coupling .
these scenarios are characterized by mixing among the higgs bosons .
analogous mixed - higgs scenarios are also possible in the nmssm .
the mssm and nmssm mixed - higgs scenarios will be considered in a separate paper @xcite .
the fine tuning in nmssm mixed - higgs scenarios have also been discussed in @xcite .
the main drawback of mixed - higgs scenarios is that they require adjustments in other parameters besides those necessary for correct electroweak symmetry breaking .
returning to fig .
[ fvsmhmssm ] , the top plot gives @xmath123 as a function of @xmath129 .
the latter enters into the computation of the radiative correction to the sm - like light higgs mass @xmath48 . in the middle plot
, we display @xmath123 as a function of @xmath48 . and ,
in the bottom plot we display @xmath123 as a function of @xmath88 .
we first of all note that the very smallest values of @xmath123 are achieved for @xmath153 $ ] , @xmath154 and @xmath155 $ ] . as stated above , for @xmath146 , as considered here
, the @xmath24 is fairly sm - like in all its couplings to sm particles .
thus , points with @xmath30 , plotted as ( blue ) @xmath156 s , are excluded by lep data , whereas those with @xmath89 , plotted as ( red ) @xmath157 s , are not excluded by lep .
although very modest values of @xmath123 ( of order @xmath158 ) are possible for @xmath30 , the smallest @xmath123 value found for @xmath159 is of order @xmath160 , as explained earlier .
the increase of the smallest achievable @xmath123 with @xmath48 is illustrated in the middle plot .
the modest @xmath161 values are achieved for special parameter choices , namely , @xmath134 and @xmath162 corresponding to a large ratio of @xmath163 ; see earlier discussion .
a value of @xmath160 corresponds to roughly @xmath164 fine tuning . generally speaking , however
, it would obviously be nicer if the @xmath6 points with @xmath158 were not excluded by lep . vs. @xmath129 , @xmath165 and @xmath88 for nmhdecay - accepted scenarios with @xmath49 and @xmath50 .
points marked by blue @xmath156 s are consistent with lep limits on the @xmath166 channel and the @xmath167 channel @xcite , considered separately , _ but not necessarily with lep limits on the combined @xmath166 and @xmath167 channels ) . _
points marked by red @xmath157 s escape lep limits due to @xmath168 .
, width=230 ] vs. @xmath129 , @xmath165 and @xmath88 for nmhdecay - accepted scenarios with @xmath49 and @xmath50 .
points marked by blue @xmath156 s are consistent with lep limits on the @xmath166 channel and the @xmath167 channel @xcite , considered separately , _ but not necessarily with lep limits on the combined @xmath166 and @xmath167 channels ) .
_ points marked by red @xmath157 s escape lep limits due to @xmath168 .
, width=230 ] vs. @xmath129 , @xmath165 and @xmath88 for nmhdecay - accepted scenarios with @xmath49 and @xmath50 .
points marked by blue @xmath156 s are consistent with lep limits on the @xmath166 channel and the @xmath167 channel @xcite , considered separately , _ but not necessarily with lep limits on the combined @xmath166 and @xmath167 channels ) .
_ points marked by red @xmath157 s escape lep limits due to @xmath168 .
, width=230 ] we now compare these results to what is found in the nmssm .
plots analogous to those for the mssm appear in fig .
[ fvsmh1nmssm1 ] .
let us first first define our conventions ( we follow those of ref .
@xcite ) and discuss a few theoretical points .
the superpotential for the higgs fields is w = _ u _ d + ^3 , where _ u _ d = _ u^+ _ d^- - _ u^0
_ d^0 . for the soft breaking terms
we take v_&= & m_^2 | h_u |^2 + m_^2 | h_d |^2 + m_^2 | s |^2 + & + & ( a _ h_u h_d s + a _
( above , we have not written the usual terms involving higgs fields and quark / squark fields . ) assuming that the parameters of the potential are real , @xmath12 and @xmath169 together yield a full potential for the neutral components of the @xmath170 , @xmath171 and @xmath172 scalar fields of the form v & = & ^2 ( h_u^2 s^2 + h_d^2 s^2 + h_u^2 h_d^2 ) + ^2 s^4 + g^2 ( h_u^2 - h_d^2)^2 + & & - 2 h_u h_d s^2 - 2a _
h_d s + a_s^3 + & & + m_h_u^2 h_u^2 + m_h_d^2 h_d^2 + m_s^2 s^2 .
[ vhiggs ] there are now three minimization conditions = 0,=0,=0 which are to be solved for @xmath173 , @xmath174 and @xmath175 in terms of the vevs and other parameters appearing in .
one combination of the minimization equations yields the mssm - like expression for @xmath176 in terms of @xmath177 , @xmath7 , @xmath98 and @xmath99 with @xmath67 replaced by @xmath178 .
however , a second combination gives an expression for @xmath178 in terms of @xmath23 and other higgs potential parameters : & & ( m_h_d^2 - m_h_u^2 ) - ^2 ( m_h_d^2 - m_h_u^2 ) + & & = ^2 + & & + _ eff a_^2 ( - ) [ mzform_s ] . eliminating @xmath178 , we arrive at an equation of the form @xmath179 , with solution @xmath180 , where @xmath181 and @xmath182 are given in terms of the soft susy breaking parameters , @xmath183 , @xmath71 and @xmath7 .
only one of the solutions to the quadratic equation applies for any given set of parameter choices . to explore fine tuning numerically ,
we proceed analogously to the manner described for the mssm . at scale
@xmath23 , we fixed @xmath7 and scanned over all allowed values of @xmath183 ( @xmath184 by convention and @xmath185 is required for perturbativity up to the gut scale ) and @xmath186 , and over @xmath187 , @xmath188 .
we also choose @xmath23-scale values for the soft - susy - breaking parameters @xmath189 , @xmath190 , @xmath191 , @xmath192 , @xmath193 , @xmath194 , @xmath93 , @xmath94 , @xmath95 , @xmath96 , and @xmath97 , all of which enter into the evolution equations .
we process each such choice through nmhdecay to check that the scenario satisfies all theoretical and experimental constraints , with the exception that we plot some points that are consistent with lep limits on the @xmath166 and @xmath167 channels considered separately as in @xcite , but inconsistent with the lep constraints on the @xmath45 final states , where @xmath195 .
we shall return to this point shortly . for accepted cases
, we then evolve to determine the gut - scale values of all the above parameters .
the fine - tuning derivative for each parameter is determined by shifting the gut - scale value for that parameter by a small amount , evolving all parameters back down to @xmath23 , redetermining the potential minimum ( which gives new values @xmath196 and @xmath197 ) and finally computing a new value for @xmath176 using @xmath198 . and
@xmath199 as a functions of @xmath165 for nmhdecay - accepted scenarios with @xmath49 and @xmath50
. point notation as in fig .
[ fvsmh1nmssm1].,width=230 ] and @xmath199 as a functions of @xmath165 for nmhdecay - accepted scenarios with @xmath49 and @xmath50 .
point notation as in fig .
[ fvsmh1nmssm1].,width=230 ] vs. @xmath200 and vs. @xmath201 for nmhdecay - accepted scenarios with @xmath49 and @xmath50 .
point notation as in fig .
[ fvsmh1nmssm1].,width=230 ] vs. @xmath200 and vs. @xmath201 for nmhdecay - accepted scenarios with @xmath49 and @xmath50 .
point notation as in fig .
[ fvsmh1nmssm1].,width=230 ] our basic results are displayed in fig . [ fvsmh1nmssm1 ] .
the density of points of a given type should not be taken as having any significance it simply reflects the nature of the scanning procedures employed for the various cases . in particular , the scans used to obtain results presented in this section were designed to focus on parameter regions with @xmath202 .
further , we focused a lot of our scans on keeping only points with @xmath203 . in fig .
[ fvsmh1nmssm1 ] , one sees a lot of similarity between the nmssm plots and those for the mssm , with differences to be noted below .
again , one finds that @xmath204 ( no worse than 10% fine - tuning of gut scale parameters ) is easily achieved in the nmssm for the present modest gluino mass of @xmath205 if the mean stop mass is of order @xmath206 which yields @xmath165 @xmath40 ( for the case of @xmath49 variation with @xmath7 will be noted later ) .
the associated @xmath88 values are of very modest size , lying in the range @xmath207 $ ] .
further , as described in more detail later , the low-@xmath123 scenarios are once again such that the @xmath86 is quite sm - like as regards its couplings to @xmath208 , @xmath152 and @xmath209 .
the difference between these plots and the earlier mssm plots is that many ( but not all , as we shall explain ) of the @xmath210 points plotted escape all lep limits . of course , points with @xmath168 escape lep limits simply by being above the maximum lep - excluded mass .
let us next discuss in more detail the points with @xmath210 .
they are plotted in fig .
[ fvsmh1nmssm1 ] provided that they are consistent with lep limits on the @xmath166 and @xmath167 channels , considered separately as plotted and tabulated in @xcite , but not necessarily the combined @xmath45 limit .
all the plotted @xmath210 points pass the @xmath166 and @xmath167 separate channel limits by virtue of the fact that @xmath211 is large enough that @xmath212 is sufficiently suppressed that @xmath213 lies below the lep @xmath166 limit , while simultaneously @xmath214 lies below the @xmath167 limit .
the values of @xmath46 and @xmath199 are plotted in fig .
[ nmssmceff ] as functions of @xmath165 . in the @xmath199 plot one finds two classes of points with @xmath210 .
the first class has large @xmath199 ( but still below lep limits for this individual channel ) by virtue of the fact that @xmath211 is large _ and _ @xmath215 .
the second class of points has zero @xmath199 since @xmath52 .
@xmath123 as a function of @xmath211 is shown in the top plot of fig .
[ nmssmbrhaa ] .
however , the plotted @xmath210 points with non - zero @xmath199 are mostly not consistent with the lep data .
nmhdecay allows these points because it does not take into account the need to combine @xmath166 and @xmath167 final states in confronting the lep limits , which are effectively ( at least roughly ) on the sum of these two final states . for those @xmath210 points with non - zero @xmath199 ,
the sum of @xmath46 and @xmath199 is typically large and one expects such points to have too large a net @xmath45 rate , where @xmath195 . indeed , for the limited number of points that were analyzed using the full lep higgs working group code one indeed finds @xcite that those points with @xmath216 that have large @xmath211 _ and _ @xmath215 ( implying @xmath217 predominantly ) are inconsistent with lep limits on the net @xmath45 rate . without analyzing every one of our @xmath215 points using the full code , we can not be sure that this same statement applies to all of them . with this proviso , we thus find that when @xmath210 , one needs large @xmath211 _ and _ @xmath52 to evade lep limits .
the bottom plot of fig . [ nmssmbrhaa ] shows that it is easy to obtain very low @xmath123 points that satisfy both criteria .
( the less frequent occurrence of @xmath218 points in this plot is purely an artifact of our scan procedure . )
we will turn to a discussion of this in more detail shortly . as regards @xmath219 points ( which are not subject to lep limits ) , returning to fig .
[ fvsmh1nmssm1 ] , we find that @xmath123 values as low as @xmath220 ( only @xmath221 tuning of gut - scale parameters ) can be achieved for the special choices of @xmath134 and @xmath162 .
this is the same region of stop parameter space that yields a minimum @xmath160 with @xmath168 in the mssm .
we have also found another type of point with low @xmath123 and @xmath222 that escapes published lep limits as follows .
first , for these points @xmath211 is large , @xmath223 , so that @xmath224 , implying a perfectly acceptable lep rate in the @xmath225 channel .
second , the @xmath87 is highly singlet and decays mainly into two photons , @xmath226 .
thus , there is negligible contribution to the @xmath227 channel .
thirdly , @xmath201 is typically fairly substantial for these points , @xmath228 .
however , these points are highly fine - tuned in the sense that the highly singlet nature of the @xmath87 required for large @xmath229 is very sensitive to gut scale parameters .
this is why they do not appear in the random scans discussed above .
locating such points requires an extremely fine scan over a carefully chosen part of parameter space
. we will give more details regarding these points later .
we now briefly describe a third class of points that manage to have relatively low fine - tuning .
generically , in the nmssm it is easy to have @xmath210 without violating lep limits simply by choosing parameters so that the @xmath86 has substantial singlet @xmath172 component . in this way
, the @xmath230 coupling is suppressed and the @xmath231 production rate is reduced to an allowed level even if @xmath232 decays are dominant . in such scenarios , it is typically the @xmath233 that is the most sm - like cp - even higgs boson , but @xmath234 and lep constraints do not apply to the @xmath233 . we have performed a broad scan over nmssm parameter space to look for and investigate the fine tuning associated with scenarios of this type .
we find that not all the points of this type found in our scans are highly fine - tuned .
there is a specific parameter region that produces points of this type that are only moderately fine - tuned and for which the @xmath86 escapes lep limits by virtue of small @xmath230 coupling .
the lowest @xmath123 value that we have found for such points is @xmath149 . in a separate paper @xcite
, we will describe these scenarios and their fine - tuning in detail and compare to similar mssm scenarios that are found when @xmath148 points are included in the mssm parameter scans . for @xmath49 , @xmath235 and @xmath236 for points with @xmath237 , taking @xmath50 .
small black @xmath157 points are those obtained after requiring a global and local minimum , no landau pole before @xmath18 and a neutralino lsp .
the green o s are those that in addition satisfy experimental limits on stops and charginos , but not necessarily higgs limits .
the blue @xmath238 s are the points that remain after imposing all lep single channel higgs limits , in particular limits @xcite on the @xmath166 and @xmath167 channels considered separately .
the yellow fancy crosses are the blue square points that remain after requiring @xmath52 , so that lep limits on @xmath45 , where @xmath195 , are not violated .
, width=230 ] for @xmath49 , @xmath235 and @xmath236 for points with @xmath237 , taking @xmath50 .
small black @xmath157 points are those obtained after requiring a global and local minimum , no landau pole before @xmath18 and a neutralino lsp .
the green o s are those that in addition satisfy experimental limits on stops and charginos , but not necessarily higgs limits .
the blue @xmath238 s are the points that remain after imposing all lep single channel higgs limits , in particular limits @xcite on the @xmath166 and @xmath167 channels considered separately .
the yellow fancy crosses are the blue square points that remain after requiring @xmath52 , so that lep limits on @xmath45 , where @xmath195 , are not violated .
, width=230 ] for @xmath49 , @xmath235 and @xmath236 for points with @xmath237 , taking @xmath50 .
small black @xmath157 points are those obtained after requiring a global and local minimum , no landau pole before @xmath18 and a neutralino lsp .
the green o s are those that in addition satisfy experimental limits on stops and charginos , but not necessarily higgs limits .
the blue @xmath238 s are the points that remain after imposing all lep single channel higgs limits , in particular limits @xcite on the @xmath166 and @xmath167 channels considered separately .
the yellow fancy crosses are the blue square points that remain after requiring @xmath52 , so that lep limits on @xmath45 , where @xmath195 , are not violated .
, width=230 ]
armed with this overview , we now return to the parameter region of the nmssm that allows for the lowest possible fine tuning , as studied earlier in section [ sec : compare ] for @xmath49 . here , we consider also @xmath235 and @xmath236 .
these scans are focused very much on parameter choices that can yield the lowest @xmath123 values .
the relevant plots are presented in fig .
[ fvsmh1 ] .
we present our results in a somewhat different manner than in sec .
[ sec : compare ] so as to stress the remarkable preference for @xmath239 in order to achieve the very lowest @xmath123 values at @xmath49 , with corresponding preferences for @xmath240 at @xmath236 and @xmath241 at @xmath235 .
first , we stress that the above @xmath165 values are the largest ones consistent with low @xmath123 in an unbiased ( before applying experimental constraints of any kind ) scan over the part of parameter space that is simply theoretically consistent ( see below ) .
once one imposes lower bounds on the stop ( and chargino ) masses , @xmath123 shows a distinct minimum at the above @xmath165 values .
the preference for these values of @xmath165 to achieve low @xmath123 becomes progressively more apparent as one imposes in addition : ( a ) lep constraints on higgs bosons , including the important @xmath166 channel and @xmath167 channels , considered separately ( as plotted and tabulated in @xcite ) , but not the combined @xmath166 and @xmath167 channels ; and ( b ) lep constraints on the combined @xmath166 and @xmath167 channels .
let us first focus on the @xmath49 case .
four different types of points are displayed .
the black crosses show @xmath123 as a function of @xmath165 after requiring only that the scenario be theoretically consistent , but before any experimental constraints whatsoever are imposed .
the most important components of the theoretical consistency are : ( 1 ) that the vacuum corresponds to a proper electroweak symmetry breaking vacuum at a true minimum of the potential ; and ( 2 ) that the couplings remain perturbative during evolution up to the gut scale .
the black crosses already single out @xmath239 as the point above which @xmath123 rises rapidly .
black points with low @xmath165 typically have a rather low value for @xmath242 that is clearly inconsistent with lep and tevatron limits .
the minimum @xmath123 for these low-@xmath165 black cross points is fairly independent of @xmath165 .
the ( green ) circles correspond to the black crosses that survive after imposing experimental limits on @xmath242 and @xmath243 and similar non - higgs constraints .
we immediately see a striking preference for @xmath239 in order to achieve minimum @xmath123 .
the ( blue ) squares indicate the points that survive after requiring _ in addition _ that the scenario be consistent with lep higgs limits , including the @xmath166 and @xmath167 final state limits considered separately @xcite , _ but before imposing a limit on the combined @xmath45 ( @xmath195 ) final state_. in the case of @xmath49 , these blue squares are the union of the @xmath237 red @xmath157 s and blue @xmath156 s of the middle plot of fig . [ fvsmh1nmssm1 ] .
the blue - square points now show a very strong preference for @xmath222 , even before , but especially after , focusing on minimal @xmath123 .
the final large ( yellow ) crosses are the @xmath210 points among the ( blue ) square points that have @xmath52 so that there is no contribution to the @xmath167 channel from the @xmath244 decay that , in turn , has a sufficiently large branching ratio to allow these points to escape the @xmath166 channel lep limit . now @xmath239 is clearly singled out . in the plots for the @xmath235 and @xmath236 cases , we did not bother to generate points with low @xmath242 .
so the black cross points in these cases simply indicate the presence of a few scenarios with @xmath242 above experimental limits but with @xmath243 below existing limits or some other non - higgs experimental inconsistency . the green - circle , blue - square and yellow - cross are as described above . the large number of blue - square points with very low @xmath123 indicate that a significant fraction of the very lowest @xmath123 scenarios are such that @xmath86 decays primarily into a pair of the lightest cp - odd higgs bosons of the model , @xmath244 .
the yellow crosses show that low-@xmath123 points with large @xmath211 _ and _ @xmath52 are often found . for such points , @xmath245 ( or @xmath246 if @xmath247 ) thereby allowing consistency with lep constraints on the @xmath45 channel and , in many cases , the lep excess in the @xmath232 channel for higgs mass of order @xmath0 .
given that low @xmath123 can be easily achieved without violating lep constraints if @xmath52 , an important issue is whether obtaining small @xmath201 requires fine - tuning of gut - scale parameters .
in fact , a light @xmath248 is natural in the nmssm in the @xmath249 limit .
this can be understood as a consequence of a global @xmath250 symmetry of the scalar potential ( in the limit @xmath251 ) which is spontaneously broken by the vevs , resulting in a nambu - goldstone boson in the spectrum @xcite .
is to have a slightly broken peccei - quinn symmetry .
however , the models with low @xmath123 are not close to the peccei - quinn symmetry limit . ]
this symmetry is explicitly broken by the trilinear soft terms so that for small @xmath252 the lightest cp odd higgs boson is naturally much lighter than other higgs bosons .
in fact , as discussed in depth in @xcite , the values of @xmath252 needed to have @xmath52 , @xmath253 and low @xmath123 are quite natural in the context of the nmssm starting from small or zero values of @xmath254 and @xmath255 . in particular , large @xmath211 is essentially automatic for typical rge generated values of @xmath256 and @xmath257 ( @xmath258 and @xmath259 ) and it is only a question of whether the requirement @xmath52 is naturally achieved . in @xcite , we found that essentially no tuning of @xmath256 and @xmath257 is required in many model contexts .
for example , in the case of @xmath49 tuning of the gut - scale parameters needed to achieve appropriate @xmath256 and @xmath257 is likely to be minimal for scenarios in which the @xmath87 is about 10% non - singlet at the state - mixing , amplitude level , 1% at the probability level .
more precisely , let us define = a_mssm+a_s , where @xmath260 is the usual two - doublet cp - odd state and @xmath261 is the cp - odd state coming from the @xmath172 field .
then , the mass of the lightest cp - odd higgs boson in the simplest approximation is given by : @xmath262 we see that the @xmath256 contribution to @xmath201 is suppressed relative to the @xmath257 contribution for small @xmath263 and large @xmath7 and an appropriate balance between the contributions is naturally achieved .
in @xcite , we defined a measure called @xmath264 that encapsulates the amount of tuning at the gut scale that is likely to be needed to achieve small @xmath201
. @xmath264 is defined using , as g\ { max,|+|}. as shown in @xcite , small @xmath264 implies it is quite natural to get small @xmath201 even for fairly general @xmath18-scale boundary conditions .
for example , if eq .
( [ eq : ma1_first ] ) is approximately correct , so that @xmath265 is linear in @xmath256 and @xmath257 , and if @xmath256 and @xmath257 are primarily sensitive to a single gut - scale parameter @xmath90 , then , if @xmath266 is small , sensitivity of @xmath265 to @xmath90 is guaranteed to cancel .
nonetheless , the measure @xmath264 should not be overemphasized since specific boundary condition choices can give small @xmath201 even when @xmath264 is large .
scenarios that are fully consistent with all lep constraints , we plot @xmath264 vs. @xmath263 taking @xmath267 and @xmath49 ( top ) , @xmath268 ( middle ) and @xmath269 ( bottom ) .
the point coding is : black @xmath270 ; dark grey ( red ) @xmath271 ; light grey ( green ) @xmath272 ; and darkest grey ( blue ) = @xmath273.,title="fig:",width=230 ] scenarios that are fully consistent with all lep constraints , we plot @xmath264 vs. @xmath263 taking @xmath267 and @xmath49 ( top ) , @xmath268 ( middle ) and @xmath269 ( bottom ) .
the point coding is : black @xmath270 ; dark grey ( red ) @xmath271 ; light grey ( green ) @xmath272 ; and darkest grey ( blue ) = @xmath273.,title="fig:",width=230 ] scenarios that are fully consistent with all lep constraints , we plot @xmath264 vs. @xmath263 taking @xmath267 and @xmath49 ( top ) , @xmath268 ( middle ) and @xmath269 ( bottom ) .
the point coding is : black @xmath270 ; dark grey ( red ) @xmath271 ; light grey ( green ) @xmath272 ; and darkest grey ( blue ) = @xmath273.,title="fig:",width=230 ] in fig .
[ gvscta ] , we plot @xmath264 as a function of @xmath263 for parameters choices that yield @xmath274 , taking @xmath49 , 3 , and 50 .
the results are displayed using different shadings ( colors ) for different ranges of @xmath201 , as delineated in the figure caption . for @xmath49 , we see that @xmath264 is minimal for @xmath275 , not much above the rough lower bound of @xmath276 .
this lower bound is a direct consequence of the _ combined _ requirements that : 1 ) @xmath211 be so large that @xmath212 is small enough to escape the lep limit on the @xmath166 channel ; and 2 ) that @xmath52 so that @xmath87 does not decay to @xmath31 and there is no @xmath277 decay contribution to the net @xmath45 channel .
we also note that small @xmath264 is only achieved for @xmath278 , with @xmath279 preferred . for @xmath235
, there is again a preference for larger @xmath201 in order to achieve small @xmath264 .
however , small @xmath264 can be achieved for a much larger range of @xmath263 . of course
, one should also notice that all the low-@xmath123 solutions have @xmath280 , with lower bound of @xmath281 .
the bottom of the three plots shows that if @xmath236 then it is much more difficult to find solutions with low @xmath123 that also have low @xmath264 .
the lower bound on @xmath282 needed to achieve large @xmath211 shifts downwards slightly to about @xmath283 .
one should note that the coupling of the @xmath87 to @xmath31 is proportional to @xmath284 times the usual sm - like @xmath285 coupling strength . the lower limits on @xmath282 at @xmath49 , @xmath268 , @xmath269 are such that @xmath286 , @xmath287 , @xmath288 .
this means that the @xmath31 coupling is not particularly suppressed , and can even be enhanced with respect to the sm - like @xmath289 value .
( of course , the @xmath290 coupling of the @xmath87 , proportional to @xmath291 , is very suppressed . )
the fact that the @xmath31 coupling is always significant implies that there is always a significant branching ratio for @xmath292 ( where the @xmath293 can be the @xmath294 , @xmath295 or @xmath296 state ) so long as there is adequate phase space for the decay .
the predictions for @xmath297 and further discussion appear in @xcite . and
a fixed value of @xmath49 . notation as in fig .
[ fvsmh1].,width=230 ] the minimum value of @xmath123 that can be achieved is , of course , dependent upon @xmath194 ( and is essentially independent of @xmath192 and @xmath193 ) .
indeed , the largest gut - scale parameter derivative is very frequently that with respect to @xmath298 . to explore this sensitivity ,
we have also performed a ( somewhat less dense ) parameter scan for the case of @xmath299 at @xmath49 .
the results for @xmath123 as a function of @xmath165 are presented in fig .
[ fvsmh1meq126 ] .
we find a minimum value of @xmath300 at @xmath301 , the latter being somewhat higher than the @xmath239 location in the corresponding @xmath49 , @xmath267 case .
a sm - like @xmath86 with @xmath301 is only consistent with lep limits if @xmath211 is large and @xmath52 ( the large ( yellow ) crosses ) .
the @xmath301 location of the minimal @xmath123 is less consistent with the @xmath302 excess in the lep data . however , to have @xmath239 in the @xmath299 case is possible for @xmath303 , which is barely different from the @xmath300 minimum value .
one other point of interest is that @xmath52 points are more easily achieved at larger @xmath304 when @xmath305 than for @xmath306 .
this can be understood by considering the special case of @xmath307 , @xmath308 and @xmath309 . in this case
, we find @xmath310 let us consider the @xmath311 case ( by convention , @xmath184 ) , for which it can be shown that @xmath312 is required @xcite to get @xmath313 . from eqs .
( [ akrun ] ) , ( [ atmz ] ) and ( [ m3mz ] ) , one finds that @xmath314 , implying that increasingly negative @xmath103 is required to achieve @xmath312 as @xmath315 increases . from eq .
( [ eq : ma1_first ] ) , a small value of @xmath265 will be easily achieved in the present case of @xmath316 if @xmath317 so that the @xmath318 and @xmath319 terms tend to cancel .
( [ alrun ] ) , ( [ atmz ] ) and ( [ m3mz ] ) imply @xmath320 which gives @xmath317 for increasingly negative @xmath103 as @xmath315 increases . in short , the larger @xmath315 is the more negative @xmath103 can be while requiring small @xmath265 .
the more negative @xmath103 , the larger stop mixing is at fixed @xmath129 and therefore the larger @xmath165 .
we will now discuss in more detail other properties of the low-@xmath123 scenarios with @xmath239 and @xmath52 , focusing first on the case of @xmath49 and @xmath50 .
first , we recall our earlier results from @xcite . there , we studied in detail the @xmath51 points from our earliest @xmath49 scans as plotted in fig .
[ zbblimits ] .
the plot shows the @xmath46 predictions for all parameter choices in our scan that had @xmath51 and @xmath52 and that are consistent with the experimental and theoretical constraints built into nmhdecay as well as with limits from the preliminary lhwg full analysis code @xcite , which in particular incorporates limits on the @xmath45 combined channel .
eight @xmath204 points are singled out .
as we have emphasized , these latter points cluster near @xmath321 . in @xcite , we found the remarkable result that not only are these @xmath204 @xmath52 points consistent with lep limits , but also most are such that @xmath165 and @xmath212 are appropriate for explaining the @xmath46 excess .
we wish to emphasize that in our scan there are many , many points that satisfy all constraints and have @xmath52 .
the remarkable result is that those with @xmath204 have a substantial probability that they predict the higgs boson properties that would imply a lep @xmath322 s excess of the sort seen .
we stress again that the @xmath204 points with @xmath201 substantially above @xmath323 all predict a net @xmath324 s signal that is ruled out at better than @xmath325 cl by lep data .
indeed , all such @xmath51 points have a net @xmath326 s branching ratio , @xmath327 , which is too large for lep consistency . in our larger scans , as represented by the @xmath46 results of fig .
[ nmssmceff ] , we see a huge number of @xmath52 points with approximately the correct @xmath46 to explain the lep @xmath0 excess . for @xmath236 , @xmath50 , the preference for @xmath240 to achieve low @xmath123 will again imply that many of the lowest @xmath123 scenarios will provide a natural explanation of the @xmath166 lep excess . at @xmath235 , the very lowest @xmath123 values , @xmath328 , consistent with lep limits are achieved for @xmath329 , as shown in the middle plot of fig .
[ fvsmh1 ] .
such an @xmath86 mass is too low to provide a natural explanation of the @xmath166 excess .
however , this same plot shows that the very slightly higher value of @xmath330 is possible for @xmath239 .
thus , the lep @xmath166 excess is fully consistent with low fine - tuning scenarios that pass all lep higgs limits for all @xmath331 .
( we have not explored still lower values . ) of course , it is equally true that at @xmath49 and @xmath236 , only a very modest increase in @xmath123 would be needed for @xmath165 to take on a value that is not perfectly correlated with the location at @xmath302 of the @xmath166 lep excess .
( top ) and vs. @xmath332 ( bottom ) for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1].,width=230 ] ( top ) and vs. @xmath332 ( bottom ) for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1].,width=230 ] ( top ) , @xmath333 ( middle ) and @xmath334 ( bottom ) for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1].,width=230 ] ( top ) , @xmath333 ( middle ) and @xmath334 ( bottom ) for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1].,width=230 ] ( top ) , @xmath333 ( middle ) and @xmath334 ( bottom ) for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1].,width=230 ] ( top ) and vs. @xmath332 ( bottom ) for points with @xmath237 taking @xmath50 and @xmath236 .
point notation as in fig .
[ fvsmh1].,width=230 ] ( top ) and vs. @xmath332 ( bottom ) for points with @xmath237 taking @xmath50 and @xmath236 .
point notation as in fig .
[ fvsmh1].,width=230 ] ( top ) , @xmath333 ( middle ) and @xmath334 ( bottom ) for points with @xmath237 taking @xmath50 and @xmath236 .
point notation as in fig .
[ fvsmh1].,width=230 ] ( top ) , @xmath333 ( middle ) and @xmath334 ( bottom ) for points with @xmath237 taking @xmath50 and @xmath236 .
point notation as in fig .
[ fvsmh1].,width=230 ] ( top ) , @xmath333 ( middle ) and @xmath334 ( bottom ) for points with @xmath237 taking @xmath50 and @xmath236 .
point notation as in fig .
[ fvsmh1].,width=230 ] another interesting question is whether there is any correlation between @xmath123 and @xmath201 or between @xmath123 and the masses of the heavier higgs bosons , @xmath332 , @xmath335 , @xmath333 and @xmath334 .
the plots for @xmath49 appear in figs .
[ fvsma1andmhplus ] and [ fvsma2mh2mh3 ] .
there , we observe that @xmath123 depends very weakly on @xmath201 ( once @xmath52 ) , but that lower values of @xmath336 are definitely preferred to obtain small @xmath123 and that to obtain fully allowed yellow fancy crosses with @xmath204 requires @xmath337 $ ] , @xmath338 $ ] , @xmath339 $ ] and @xmath340 $ ] .
the corresponding plots for @xmath236 appear in figs .
[ fvsma1andmhplustb50 ] and [ fvsma2mh2mh3tb50 ] .
again , we observe that @xmath123 depends very weakly on @xmath201 , and that lower values of @xmath336 are definitely preferred to obtain small @xmath123 . for @xmath236 , to obtain fully allowed yellow fancy crosses with @xmath204 requires @xmath341 $ ] , @xmath338 $ ] , @xmath342 $ ] and @xmath343 $ ] .
these results have implications for the lhc and ilc . at the lhc ,
the main processes for producing and detecting these heavier higgs bosons are @xmath344 ( where @xmath345 ) and @xmath346 , with , for example , @xmath347 .
one finds @xcite that detection becomes possible when the @xmath348 and @xmath349 couplings are enhanced by large @xmath7 .
the mass ranges for the heavier higgs bosons preferred for obtaining low @xmath123 are such that if @xmath49 they will be on the margin of detectability at the lhc , whereas if @xmath236 they will certainly be detectable .
( at @xmath235 the small-@xmath123 mass ranges for the @xmath350 are similar , but @xmath7 is definitely too small for the above lhc modes to be detectable . ) for the lowest part of the mass ranges , a signal for @xmath344 might also emerge at the tevatron if @xmath236 .
it is also important to note that the low-@xmath123 mass ranges of the @xmath351 are such that their pair production would mostly be outside the kinematical reach of a @xmath352 ilc , but that a substantial portion of the mass ranges are such that pair production would be possible at a @xmath353 ilc .
we next turn to a detailed discussion of various correlations among the nmssm parameters that are associated with low-@xmath123 scenarios having large @xmath211 and @xmath52 , the points indicated by the large yellow crosses in the previous figures .
we call such points `` fully ok '' .
we first present some figures to illustrate how the fully ok points compare to points that are either experimentally excluded or else have sufficiently large @xmath165 ( roughly @xmath354 ) as to avoid lep constraints on the @xmath45 channel .
these latter points are the ( blue ) squares , ( green ) circles and black @xmath157 s of the earlier plots .
( top ) and vs. @xmath127 ( bottom ) for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1].,width=230 ] ( top ) and vs. @xmath127 ( bottom ) for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1].,width=230 ] ( top ) and vs. @xmath127 ( bottom ) for points with @xmath237 taking @xmath50 and @xmath236 .
point notation as in fig .
[ fvsmh1].,width=230 ] ( top ) and vs. @xmath127 ( bottom ) for points with @xmath237 taking @xmath50 and @xmath236 .
point notation as in fig .
[ fvsmh1].,width=230 ] first consider @xmath88 .
plots of f as a function of @xmath103 and @xmath127 are given in figs .
[ fvsat ] and [ fvsattb50 ] for @xmath49 and @xmath236 , respectively .
these show that rather well - defined ( and rather @xmath7-independent ) values are needed to achieve the very lowest @xmath123 values , especially after imposing higgs boson experimental limits . at scale @xmath23 the preferred @xmath103 is of order @xmath355 .
the corresponding @xmath127 is of order @xmath356 .
the lowest @xmath123 values are of course those associated with @xmath239 .
this is consistent with our earlier discussion .
the @xmath49 points with large negative @xmath103 values that escape lep limits by virtue of @xmath168 are the dark ( blue ) squares that begin at @xmath300 and @xmath357 . for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1].,width=230 ] for points with @xmath237 taking @xmath50 and @xmath236 .
point notation as in fig .
[ fvsmh1].,width=230 ] in figs .
[ fvsmueff ] and [ fvsmuefftb50 ] , we plot @xmath123 as a function of @xmath178 ( which in the case of the nmssm is only defined at scale @xmath23 where ewsb has occurred ) for the cases of @xmath49 and @xmath236 , respectively . as one could easily anticipate from eq .
( [ mzsquared ] ) ( with @xmath67 replaced by @xmath178 ) , fine - tuning is smallest for the the smallest values of @xmath178 .
this figure also shows that @xmath358 values below about @xmath0 are eliminated by the lep limit on the mass of the lightest chargino . ,
@xmath359 and @xmath360 for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1].,width=230 ] , @xmath359 and @xmath360 for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1].,width=230 ] , @xmath359 and @xmath360 for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1].,width=230 ] , @xmath359 and @xmath360 for points with @xmath237 taking @xmath50 and @xmath236 .
point notation as in fig .
[ fvsmh1].,width=230 ] , @xmath359 and @xmath360 for points with @xmath237 taking @xmath50 and @xmath236 .
point notation as in fig .
[ fvsmh1].,width=230 ] , @xmath359 and @xmath360 for points with @xmath237 taking @xmath50 and @xmath236 .
point notation as in fig .
[ fvsmh1].,width=230 ] , @xmath361 and @xmath362 for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1 ] .
negative values indicate cases for which @xmath363 in which case the plot gives @xmath364.,width=230 ] , @xmath361 and @xmath362 for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1 ] .
negative values indicate cases for which @xmath363 in which case the plot gives @xmath364.,width=230 ] , @xmath361 and @xmath362 for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1 ] .
negative values indicate cases for which @xmath363 in which case the plot gives @xmath364.,width=230 ] , @xmath361 and @xmath362 for points with @xmath237 taking @xmath50 and @xmath236 .
point notation as in fig .
[ fvsmh1 ] .
negative values indicate cases for which @xmath363 in which case the plot gives @xmath364.,width=230 ] , @xmath361 and @xmath362 for points with @xmath237 taking @xmath50 and @xmath236 .
point notation as in fig .
[ fvsmh1 ] .
negative values indicate cases for which @xmath363 in which case the plot gives @xmath364.,width=230 ] , @xmath361 and @xmath362 for points with @xmath237 taking @xmath50 and @xmath236 .
point notation as in fig .
[ fvsmh1 ] .
negative values indicate cases for which @xmath363 in which case the plot gives @xmath364.,width=230 ] next , let us examine the soft squark masses @xmath365 , @xmath366 , and @xmath367 of the third generation .
values for these at scale @xmath23 are plotted in figs .
[ fvsmqmz ] and [ fvsmqmztb50 ] for @xmath49 and @xmath236 , respectively .
we see that to obey limits on stop masses , there is a fairly definite lower bound on @xmath368 and @xmath360 , although low values for @xmath359 are possible . and , to achieve @xmath274 and satisfy all experimental limits requires all these soft masses to lie in a very well defined band .
the corresponding gut - scale values are given in figs .
[ fvsmqgut ] and [ fvsmqguttb50 ] .
points with @xmath274 satisfying all limits again have soft masses squared at the gut scale that fall within narrow bands ( and are sometimes negative and sometimes positive ) . vs. @xmath369 and @xmath370 ( upper two plots ) and @xmath370 vs. @xmath369 ( lower plot ) for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1 ] .
, width=230 ] vs. @xmath369 and @xmath370 ( upper two plots ) and @xmath370 vs. @xmath369 ( lower plot ) for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1 ] .
, width=230 ] vs. @xmath369 and @xmath370 ( upper two plots ) and @xmath370 vs. @xmath369 ( lower plot ) for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1 ] .
, width=230 ] next , we examine , for the case of @xmath49 , @xmath256 and @xmath257 at scale @xmath23 . fig .
[ akmzalmzplotsflt50 ] gives some results .
the upper plot shows that @xmath274 can be achieved for a wide range of @xmath369 , with points that obey all limits requiring a minimum value of @xmath371 .
the middle plot shows that fully ok points require @xmath370 in a rather narrow band with @xmath372 .
the bottom plot shows the correlation between @xmath370 and @xmath369 that is required to get small @xmath52 , as discussed earlier .
note that either both must be negative or both positive for any point that is fully consistent with experimental limits .
the lower bounds on their absolute values for the fully ok points the large yellow crosses are those required to have large enough @xmath211 to escape the @xmath45 lep limits for @xmath239 .
similar results are obtained for @xmath236 .
all these results can be understood analytically as discussed in @xcite .
vs. @xmath369 and @xmath370 for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1 ] .
, width=230 ] vs. @xmath369 and @xmath370 for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1 ] . ,
width=230 ] fig .
[ ma1vsalakmzplotsflt50 ] shows the dependence on @xmath201 on @xmath369 and @xmath370 in the case of @xmath49 .
one observes that large @xmath201 can be achieved for these same ranges of @xmath369 and @xmath370 just as easily as small @xmath201 .
it is just that cases with large @xmath215 and small @xmath123 , which requires @xmath239 , are not consistent with lep limits on the net @xmath45 channel , as we have discussed .
similar results are found for @xmath236 .
vs. @xmath255 and @xmath254 ( upper two plots ) and @xmath254 vs. @xmath255 ( lower plot ) for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1 ] .
, width=230 ] vs. @xmath255 and @xmath254 ( upper two plots ) and @xmath254 vs. @xmath255 ( lower plot ) for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1 ] .
, width=230 ] vs. @xmath255 and @xmath254 ( upper two plots ) and @xmath254 vs. @xmath255 ( lower plot ) for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1 ] .
, width=230 ] , @xmath373 and @xmath374 for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1 ] .
, width=230 ] , @xmath373 and @xmath374 for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1 ] . ,
width=230 ] , @xmath373 and @xmath374 for points with @xmath237 taking @xmath50 and @xmath49 .
point notation as in fig .
[ fvsmh1 ] .
, width=230 ] plots of the gut - scale parameters , @xmath255 and @xmath254 , appear in fig .
[ akgutalgutplotsflt50 ] .
these show that the lowest-@xmath123 scenarios that are fully consistent with experiment are often achieved for small values of these parameters . in terms of model building , these soft - susy - breaking parameters are thus close to values associated with no - scale soft - susy - breaking . ,
@xmath373 and @xmath374 for points with @xmath237 taking @xmath50 and @xmath236 .
point notation as in fig .
[ fvsmh1 ] .
, width=230 ] , @xmath373 and @xmath374 for points with @xmath237 taking @xmath50 and @xmath236 .
point notation as in fig .
[ fvsmh1 ] .
, width=230 ] , @xmath373 and @xmath374 for points with @xmath237 taking @xmath50 and @xmath236 .
point notation as in fig .
[ fvsmh1 ] .
, width=230 ] probably the most interesting parameter correlation is that regarding the soft - susy - breaking higgs masses squared at the gut scale . these are plotted in figs .
[ fvsmhsqgutflt50 ] and [ fvsmhsqgutflt50tb50 ] for the cases of @xmath49 and @xmath236 , respectively .
these plots show that the fully ok scenarios with smallest @xmath123 have very modest soft masses squared at the gut scale , especially in the case of @xmath98 .
thus , something close to a no - scale model for soft higgs masses squared at the gut scale is preferred for low @xmath123 .
taking @xmath50 and @xmath49 .
point notation : dark ( red ) @xmath375 ; light grey ( cyan ) @xmath373 ; darker grey ( green ) @xmath374 .
points plotted are the yellow fancy cross points from fig .
[ fvsmhsqgutflt50].,width=230 ] this preference for a no - scale type of boundary condition for the higgs soft masses squared at the gut - scale is further emphasized by the @xmath49 plot of fig .
[ fvsmhsqgut ] , where we overlap the values of @xmath375 , @xmath373 and @xmath374 for @xmath237 yellow fancy cross scenarios of fig .
[ fvsmhsqgutflt50 ] . for @xmath49 .
point notation as in fig .
[ fvsmh1].,width=230 ] we have said in many places that for the fully ok scenarios the @xmath86 has quite sm - like @xmath376 coupling .
this is illustrated in fig .
[ fvscv ] where we plot @xmath123 as a function of c_v , for the case of @xmath49 ( results for @xmath236 are similar ) .
we see that the fully ok yellow fancy crosses all have @xmath377 .
in fact , for @xmath237 scenarios , @xmath377 also for the ( blue ) square points that are not also yellow fancy crosses , those points obtained if one only requires that the scenario is consistent with experimental limits that include the @xmath166 channel ( that is , before requiring @xmath52 as needed to avoid the limits on the combined @xmath45 channel ) . suppressed @xmath378 values only appear in these plots if the higgs experimental limits are removed . as discussed later , there are some very special points for which this is not true that will be considered in a follow - up paper . in this subsection , we consider at a still more detailed level the fully ok yellow points having large @xmath211 and @xmath52 that also have @xmath204 .
we will present results only for the case of @xmath49 and @xmath379 .
in general , the other @xmath7 values give similar correlations aside from the shift in the value of @xmath165 that gives the lowest @xmath123 value . in the plots presented in this section
we will use blue @xmath156 s in place of the yellow crosses , since the latter do not display well on their own .
hopefully , there are few enough points on the following plots that the reader can match points from one plot to another . for the large ( yellow )
cross points ( for clarity , we use blue @xmath156 s in their place in this and succeeding plots ) with @xmath204 taking @xmath50 and @xmath49 .
the lower plot shows @xmath123 vs. @xmath201 .
, width=230 ] for the large ( yellow ) cross points ( for clarity , we use blue @xmath156 s in their place in this and succeeding plots ) with @xmath204 taking @xmath50 and @xmath49 .
the lower plot shows @xmath123 vs. @xmath201 .
, width=230 ] first , we show @xmath123 as a function of @xmath165 and @xmath201 in fig .
[ fvsmhimai ] . in the upper plot
, we see again the preference for @xmath165 near @xmath0 .
the lower plot shows that the very smallest @xmath123 values occur at @xmath201 values above @xmath380 , implying that the @xmath245 channel is the dominant @xmath87 decay .
we note that the @xmath381 part of the @xmath52 fully ok zone was also found in the companion paper @xcite to be preferred in order to avoid fine - tuning associated with getting small @xmath201 .
( which equals @xmath46 since @xmath382 when @xmath52 ) vs. @xmath123 for the large ( yellow ) cross points with @xmath204 taking @xmath50 and @xmath49.,width=230 ] one important prediction of any given parameter set is that for @xmath383 , where ^2(z+b s ) & & g_zz^2 g_zz^2 .
[ xisqdef ] for the fully ok points one has @xmath52 and thus @xmath384 .
more generally , @xmath383 is the net rate for lep production of @xmath166 _ and _ @xmath167 final states relative to the rate that one would obtain for a sm higgs boson which decayed entirely to @xmath31 .
of particular interest is the correlation between @xmath383 and @xmath123 .
thus , an important comparison is the model prediction for @xmath383 relative to the excess found at lep in the vicinity of @xmath31 mass @xmath40 .
the value of @xmath384 as a function of @xmath165 is plotted in fig .
[ xisqvsf ] .
we observe that the points with @xmath204 lie in the range @xmath385 with many of the very lowest @xmath123 points having @xmath386 $ ] , the range most consistent with the lep excess at @xmath387 mass @xmath388 .
vs. @xmath263 ( upper ) and @xmath123 vs. @xmath389 ( lower ) for the large ( yellow ) cross points with @xmath204 taking @xmath50 and @xmath49.,width=230 ] vs. @xmath263 ( upper ) and @xmath123 vs. @xmath389 ( lower ) for the large ( yellow ) cross points with @xmath204 taking @xmath50 and @xmath49.,width=230 ] next , we wish to illustrate the relative mssm vs. singlet composition of the @xmath87 and @xmath86 for the @xmath204 points .
this composition has obvious implications for their couplings to sm particles .
the more pure mssm the @xmath86 is , the more sm - like will be its couplings . the more singlet the @xmath87 is , the more weakly it will be coupled to sm particles . in particular ,
its couplings to sm down - type fermions and leptons are given by @xmath284 times the sm - like weight in which @xmath390 is replaced by @xmath391 , for example .
these compositions are shown in fig .
[ fvscta ] .
the upper plot illustrates that there is a lower bound on @xmath282 that arises from the joint requirements of large @xmath211 and @xmath52 . as noted earlier , this guarantees that the @xmath31 ( and @xmath392 ) coupling strengths of the @xmath87 are sufficiently large that the decays of the @xmath87 are dominated by the heaviest fermionic states , @xmath393 for @xmath394 and @xmath395 for @xmath396 , with @xmath397 also being important . for @xmath398
, @xmath397 is the dominant decay .
note the preference for @xmath399 for the very lowest @xmath123 points .
the lower plot of fig .
[ fvscta ] shows the singlet component , @xmath389 , of the @xmath86 for the fully ok solutions .
the @xmath86 can be as much as @xmath400 singlet at the amplitude level , but this means it is still @xmath401 non - singlet in the amplitude - squared sense . as a result , all plotted points have @xmath377 .
the very lowest @xmath123 points are clearly associated with very small @xmath389 .
we now turn to the gut - scale parameters associated with @xmath204 large yellow fancy cross points ( plotted as blue @xmath156 s for these figures ) that pass all experimental constraints and the correlations among them . for large ( yellow ) cross points with @xmath204 taking @xmath50 and @xmath49 .
the lower plot shows @xmath402 as a function of @xmath403.,width=230 ] for large ( yellow ) cross points with @xmath204 taking @xmath50 and @xmath49 .
the lower plot shows @xmath402 as a function of @xmath403.,width=230 ] first , we consider @xmath402 and @xmath403 in fig .
[ fvslgut ] .
we see that the very lowest @xmath123 values have fairly small @xmath403 and significantly larger @xmath404 . for fully ok points with @xmath204 taking @xmath50 and @xmath49 .
the lower plot shows @xmath254 as a function of @xmath255.,width=230 ] for fully ok points with @xmath204 taking @xmath50 and @xmath49 .
the lower plot shows @xmath254 as a function of @xmath255.,width=230 ] we consider @xmath254 and @xmath255 in fig .
[ fvslgut ] .
we see that the very lowest @xmath123 values have fairly small @xmath255 and @xmath254 , , as noted earlier , both are close to being consistent with no - scale boundary conditions at @xmath18 . for fully ok points with @xmath204 taking @xmath50 and @xmath49 .
the middle plot shows @xmath405 as a function of @xmath406 .
the bottom plot shows @xmath407 as a function of @xmath406 .
our convention is that if an @xmath408 is negative then we plot @xmath409.,width=230 ] for fully ok points with @xmath204 taking @xmath50 and @xmath49 .
the middle plot shows @xmath405 as a function of @xmath406 .
the bottom plot shows @xmath407 as a function of @xmath406 .
our convention is that if an @xmath408 is negative then we plot @xmath409.,width=230 ] for fully ok points with @xmath204 taking @xmath50 and @xmath49 .
the middle plot shows @xmath405 as a function of @xmath406 .
the bottom plot shows @xmath407 as a function of @xmath406 .
our convention is that if an @xmath408 is negative then we plot @xmath409.,width=230 ] we consider @xmath406 , @xmath405 and @xmath407 in fig .
[ fvsmsqgut ] .
we see that the very lowest @xmath123 values have fairly small gut - scale values for all the scalar higgs mass squared values , again close to being consistent with no - scale boundary conditions at @xmath18 .
however , our scans did not locate any fully ok points for which @xmath406 , @xmath405 and @xmath407 were all simultaneously small .
we are unsure at this time as to whether this is an artifact of limited computer time for scanning or something deeper .
decays and low @xmath123 , we plot : @xmath123 vs. @xmath165 ( top ) ; and @xmath201 vs. @xmath165 ( bottom ) .
note that there are a number of degeneracies where exactly the same @xmath123 and @xmath165 are predicted for somewhat different parameter choices in the scan.,width=211 ] decays and low @xmath123 , we plot : @xmath123 vs. @xmath165 ( top ) ; and @xmath201 vs. @xmath165 ( bottom ) .
note that there are a number of degeneracies where exactly the same @xmath123 and @xmath165 are predicted for somewhat different parameter choices in the scan.,width=211 ] decays and low @xmath123 , we plot : @xmath123 vs. @xmath263 ( top ) ; @xmath412 vs. @xmath263 ( middle ) ; and @xmath383 vs. @xmath165 ( bottom ) .
since @xmath123 depends primarily on @xmath263 , there are a number of points in the @xmath123 vs. @xmath263 plot that are actually multiple repetitions of exactly the same @xmath123 at a given @xmath263 value but with @xmath412 and @xmath383 varying slightly because of sensitivity to other parameters of the scan.,width=211 ] decays and low @xmath123 , we plot : @xmath123 vs. @xmath263 ( top ) ; @xmath412 vs. @xmath263 ( middle ) ; and @xmath383 vs. @xmath165 ( bottom ) .
since @xmath123 depends primarily on @xmath263 , there are a number of points in the @xmath123 vs. @xmath263 plot that are actually multiple repetitions of exactly the same @xmath123 at a given @xmath263 value but with @xmath412 and @xmath383 varying slightly because of sensitivity to other parameters of the scan.,width=211 ] decays and low @xmath123 , we plot : @xmath123 vs. @xmath263 ( top ) ; @xmath412 vs. @xmath263 ( middle ) ; and @xmath383 vs. @xmath165 ( bottom ) .
since @xmath123 depends primarily on @xmath263 , there are a number of points in the @xmath123 vs. @xmath263 plot that are actually multiple repetitions of exactly the same @xmath123 at a given @xmath263 value but with @xmath412 and @xmath383 varying slightly because of sensitivity to other parameters of the scan.,width=211 ] decays and low @xmath123 , we plot : @xmath413 vs. @xmath263 ( top ) ; and @xmath414 as a function of @xmath263 ( bottom ) .
( many of the points have the same @xmath414 value.),width=211 ] decays and low @xmath123 , we plot : @xmath413 vs. @xmath263 ( top ) ; and @xmath414 as a function of @xmath263 ( bottom ) .
( many of the points have the same @xmath414 value.),width=211 ] let us now turn to the special class of points mentioned in section [ sec : compare ] .
these are the low-@xmath123 points with a sm - like @xmath86 of mass @xmath40 and for which @xmath415 . for these points , @xmath416 and @xmath417 . for this to occur
, the @xmath87 must be highly singlet in nature so that the tree - level decays to fermion - antifermion are highly suppressed , in which case the chargino loop - induced decay to @xmath10 can be dominant .
( the relevant couplings are present even when the @xmath87 is purely singlet . )
this combination of features allows consistency with the lep limits on the @xmath45 channel .
we have not been able to determine if there are relevant limits on the @xmath418 channel .
this channel would have quite a high rate and most probably these relatively spectacular events would have been noticed .
these points are also disfavored theoretically since , as detailed shortly , a very high level of fine tuning of gut - scale parameters is required in order to achieve @xmath419 as required ( for @xmath49 ) for @xmath420 to be the dominant @xmath87 decay channel .
nonetheless , they should not be entirely discarded as a possible class and so we give some details regarding them in the following .
these points were found using an extremely fine grid scanning approach of the type detailed in @xcite with fixed @xmath421 , @xmath422 and @xmath49 .
basic plots for this scenario appear in fig .
[ 4gamplots1 ] .
the top plot of this figure gives @xmath123 as a function of @xmath165 .
we see again that @xmath239 gives the lowest @xmath123 value , @xmath423 in this case .
the lower plot shows that @xmath424 is required for this kind of scenario , with the lowest @xmath123 obtained for @xmath425 .
[ 4gam_braxisq ] shows @xmath123 vs. @xmath263 as the top plot , @xmath412 as a function of @xmath263 as the middle plot and @xmath383 vs. @xmath165 as the bottom plot .
the top plot is useful for correlating @xmath123 with the value of @xmath263 .
however , note that there is some degeneracy : essentially the same values of @xmath123 and @xmath263 are sometimes obtained even though the basic scan parameters are different .
the middle plot shows that @xmath426 for these points , with @xmath427 for the @xmath423 points .
as expected , very small @xmath263 is required in order for the @xmath428 decays to be dominant .
the bottom plot of the figure shows @xmath383 as a function of @xmath165 .
we observe that @xmath383 is of the right general magnitude to explain the lep excess for the lowest @xmath123 points that have @xmath240 .
we note that @xmath383 receives contributions from both the @xmath166 final state from direct @xmath429 decay and also the @xmath167 from @xmath430 where @xmath431 due to the competition from the @xmath428 decays .
the careful reader may wonder why it is that we can have small @xmath263 for these points whereas the @xmath52 points have a lower bound on @xmath263 . in fact , it is precisely the _ combination _ of the requirements that @xmath52 and @xmath432 which forces a lower bound on @xmath263 .
values of @xmath263 small enough to yield large @xmath412 while at the same time @xmath433 is maintained are only possible for relatively large @xmath201 .
the fine - tuning required in @xmath256 and @xmath257 to achieve very small @xmath263 can be quantified via the derivatives , , where all parameters are defined at scale @xmath23 .
understanding of these quantities can be gleaned from the approximate formula _ a - m_12 ^ 2m_11 ^ 2-m_22 ^ 2- , [ ctaform ] where we used @xmath434 eq .
( [ ctaform ] ) shows that there will be great sensitivity of @xmath263 to the value of @xmath256 relative to @xmath435 , and almost no sensitivity to @xmath257 .
both are confirmed by the numerical results we now present for fixed @xmath267 , @xmath49 , @xmath436 , @xmath437 , @xmath438 , @xmath439 ( for the relevant 3rd generation ) .
different points are obtained by scanning in @xmath440 .
( obviously , many more @xmath441 points could be found if the fixed parameters are allowed to vary .
however , large @xmath442 is essential to get small @xmath123 for such points . ) in fig .
[ 4gam_fcalvscta ] , we plot @xmath413 vs. @xmath263 and @xmath414 vs. @xmath263 .
the top plot shows that @xmath413 must be small for small @xmath263 ( and there is a strong linear relation ) .
the bottom plot shows that such small values of @xmath263 imply rather large values of @xmath414 .
given eq .
( [ alrun ] ) , high sensitivity to the @xmath23-scale value of @xmath256 implies a high level of fine - tuning for @xmath256 ( at scale @xmath23 ) with respect to @xmath255 , @xmath127 and @xmath298 .
one should also note that the @xmath414 tuning measure for @xmath256 is largest ( @xmath443 ) for the point for which the ewsb fine tuning measure @xmath123 is smallest and vice - versa
. decays and low @xmath123 , we plot : @xmath186 vs. @xmath183 ( top ) ; and @xmath257 vs. @xmath256 ( bottom ) .
, width=211 ] decays and low @xmath123 , we plot : @xmath186 vs. @xmath183 ( top ) ; and @xmath257 vs. @xmath256 ( bottom ) .
, width=211 ] finally , the two plots of fig . [ 4gamplots2 ] show that these points require largish @xmath186 and @xmath183 that are fairly closely correlated , while @xmath257 must be quite small .
there is strong motivation for a supersymmetric model with an extended higgs sector containing one or more extra higgs singlet superfields .
these motivations range from string theory model building , where it is known that sm - singlets are abundant in string theory compactifications , to the purely phenomenological , including the fact that adding anything other than sm singlets to the mssm will typically destroy gauge coupling unification . in this paper , we have studied in detail the next - to - minimal supersymmetric model , which contains exactly one singlet higgs superfield in addition to the two higgs doublet superfields of the mssm .
we have shown that there is a portion of nmssm parameter space with an abundance of attractive features , no outstanding problems and which leads to an important set of predictions that should be taken quite seriously .
there are many ways in which the nmssm is a better benchmark theory than the mssm , since it has important flexibilities that are currently leading to problematical issues for the mssm .
the attractive features of the nmssm include : a natural explanation for the @xmath67 parameter is provided since all superpotential couplings are dimensionless in the nmssm , the scale of @xmath67 is given by the scale of soft - susy - breaking , which ( see below ) can be well below a tev ; the supersymmetric context provides a highly satisfactory solution of the naturalness / hierarchy problem if the squark masses ( in particular , the stop masses ) and the gluino mass are well below a tev ( implying possible discovery at the tevatron and very plentiful production at the lhc ) ; low squark masses imply that the lightest higgs boson , the @xmath86 , will most naturally be sm - like in its couplings to sm particles and have a mass of order @xmath0 , close to the ideal value for satisfying precision electroweak constraints ; lep data is fully consistent with such an @xmath86 provided it decays mostly via @xmath444 ( requiring @xmath394 ) or @xmath445 ( when @xmath273 ) , where the @xmath87 is primarily the cp - odd component of the extra complex scalar higgs singlet field ; the optimal scenarios fit nicely with choices for the gut - scale values of the soft - susy - breaking higgs masses squared and @xmath83 parameters that are quite modest in size , as might be associated with an approximate no - scale model for susy breaking ; in the natural scenarios above , the heavier higgs bosons of the model ( two cp - even and one cp - odd neutral higgs bosons and the charged higgs boson ) have relatively modest masses that would make them accessible at a hadron collider if @xmath7 is large enough and mostly accessible at a 1 tev linear @xmath451 collider ; the @xmath87 could allow for adequate annihilation in the early universe of very light neutralinos @xcite .
the attractiveness of this scenario suggests that the lep groups should push a re - analysis of the @xmath453 channel in the hope of either ruling out the @xmath454 scenario , or finding an excess consistent with it for @xmath165 in the vicinity of @xmath0 .
either a positive or negative result would have very important implications for higgs searches at the tevatron and lhc .
we also stress that @xmath181 factory experiments should attempt to search for a @xmath455 signal down to the lowest possible branching ratio ( the predicted minimum in the nmssm context being of order @xmath456 ) .
we speculate that similar results could emerge in other supersymmetric models with a higgs sector that , like the case of the nmssm , is more complicated than that of the mssm .
many such models can be constructed .
thus , much of the discussion above regarding higgs discovery is quite generic . in general
, there might be quite a few light @xmath8 s , all of which could appear in the decay of a light sm - like @xmath24 and all of which would provide potential signals in reanalyzed lep data and in @xmath457 decays . there is a potential gold - mine of discovery if one digs deeply enough . however , whether the @xmath8 is truly the nmssm cp - odd @xmath87 or just a lighter higgs boson into which the sm - like @xmath24 pair - decays , hadron collider detection of the @xmath24 in its @xmath1 decay mode will be very challenging .
discovery modes that one can hope to demonstrate to be viable include : diffractive production @xcite , @xmath461 , with @xmath460 .
this latter mode looks very promising @xcite .
unfortunately , it seems very doubtful that viable discovery signals would be possible for the analogous modes with @xmath462 ( that would be the only ones available if @xmath463 ) .
although @xmath464 is somewhat preferred by naturalness arguments in the nmssm case , one should be prepared for the possibility that the lhc will discover a plethora of supersymmetric particles , and perhaps some heavy higgs bosons ( if @xmath7 is large enough ) but fail to see the sm - like light higgs most closely associated with electroweak symmetry breaking . the only lhc evidence for its existence
would then be that @xmath208 scattering would be found to be fully perturbative , as predicted if there is a light @xmath24 with sm - like couplings to @xmath208 . at a linear collider , detection of @xmath465 production
using the @xmath466 missing mass @xmath467 approach will be completely straightforward .
a @xmath0 @xmath24 with sm coupling to @xmath152 will result in many events forming a sharp peak in @xmath467 , quite independently of how the @xmath24 decays .
the decays can then be analyzed to see what is present and with what branching ratio .
detection of an @xmath24 with unexpected decays at a photon collider will also be reasonably straightforward @xcite .
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we also discuss fine - tuning associated with scenarios in which the @xmath8 is essentially pure singlet , has mass @xmath9 , and decays primarily to @xmath10 leading to an @xmath11 higgs signal . </s> |
specimen collection - mosquito collections were carried out in a range
of natural and artificial habitats in the forest environment within a 10 km
circumference of the tbs , yasun biosphere reserve and national park , orellana province ,
ecuador ( fig .
s1 ) . collections ( n = 121 ) of immature mosquitoes were carried out in aquatic habitats within
the forest , including permanent standing water bodies ( e.g. , stream margins , lakes ) ,
temporary water bodies ( e.g. , ground pools , tree holes ) and container habitats ( e.g. ,
rainwater collections in bromeliad and heliconia axils as well as
artificial containers and oviposition traps ) .
each discreet habitat was registered as a
separate collection and detailed notes on habitat and locality information noted on a
standardised collection form , which can be downloaded from the walter reed
biosystematics unit ( wrbu ) website ( wrbu.si.edu/techniques.html ) . where gaps in the
forest canopy permitted , gps readings were taken .
otherwise , detailed notes on each
locality were documented in relation to positions along the tbs trails , allowing
retrospective georeferencing using google earth .
all coordinates were converted to
decimal degrees ( foley et al . 2009 ) and
distributions records are freely available in mosquitomap ( mosquitomap.org ) . depending on habitat ,
immature mosquitoes were collected using either a standard larval
dipper ( bioquip , ca , usa ) or a turkey baster and carefully transferred to a
whirlpak plastic bag , using wide - mouth glass pipettes for transport to
the laboratory .
specimens were individually link - reared to adults , following the
modified procedures of belkin et al .
( 1965 )
summarised in gaffigan and pecor ( 1997 ) ,
ensuring a good series of high - quality morphological voucher adult specimens ( of both
sexes ) with associated larval and/or pupal skins upon which to undertake the
morphological assessment .
the associated immature exuviae were preserved in 80% ethanol and
subsequently mounted on microscope slides .
a subset of male genitalia were clipped and
mounted on microscope slides for further taxonomic verification .
in addition to
morphological vouchers , some whole larvae and reared adult specimens ( particularly
males ) of perceived morphotaxa were preserved in 100% ethanol for later dna
analysis .
human landing catches were not carried out in this study , but a few individuals found
landing on the collectors whilst up the tower in the canopy were collected using manual
aspirators and later pinned ( ec126 , ec168 ) .
in addition , three shannon traps ( ec124 ,
ec139 , ec259 ) , one indoor resting ( ec219 ) and one outdoor resting ( ec127 ) collection
yielded adults ( fig .
s1 , supplementary data 1 ) .
in some cases , identification was impossible due to poor quality ( rubbed ) specimens and
lack of differentiating characters in the adult female life stage .
only those adults
identified with certainty are reported to species herein ; all others are identified to
subgenera .
morphological identification - there is no single morphological key to
facilitate the identification of all known mosquitoes of ecuador .
the multi - entry
web - based keys developed by the wrbu for south america
( wrbu.si.edu/southcom_mqkeys.html ) were used to determine generic level identifications
and species level identification for some better - known taxa .
these multi - entry keys
facilitate identification of damaged specimens by the ability to skip questions directed
at missing or damaged body parts .
in addition , available dichotomous keys and original
species descriptions of all life stages and the male genitalia were compiled through
literature freely available on the wrbu website ( wrbu.org ) .
important references used for species identifications by taxonomic groups included :
tribe aedini ( berlin 1969 ,
schick 1970 , zavortink 1972 , arnell 1973 ) ,
anopheles ( cova - garcia 1961
, zavortink 1973 , faran 1980 , faran & linthicum
1981 , wilkerson & sallum 1999 ,
gonzlez & carrejo 2007 ) ,
chagasia ( harbach & howard
2009 ) , culex ( rozeboom
& komp 1950 , bram 1967 , valencia 1973 , berlin & belkin 1980 , pecor et al .
1992 , sallum & forattini 1996 ) ,
haemagogus ( zavortink 1972
, arnell 1973 ) , onirion ( harbach & peyton 2000 ) ,
psorophora ( guedes & souza
1964 ) , sabethes ( harbach
1991 , hall et al . 1999 ) ,
trichoprosopon ( stone 1944 ,
zavortink 1979a , b ) and wyeomyia ( judd 1998 ) .
authors associated with species names , along with standardised generic and subgeneric
abbreviations , are given in the final ecuador species list ( supplementary data 2 ) .
molecular identification - dna from single legs plucked from pinned
adults or whole ethanol - preserved larva or adults were extracted using the
qiagen dneasy blood & tissue kit on the biosprint 96 automated dna
extraction platform ( qiagen , germantown , md , usa ) . a 710-bp amplicon ( 658-bp
less primers ) corresponding to the universal barcoding region of the mitochondrial
coi
i gene was amplified using the lco1490 & hco2198 primers of
folmer et al .
( 1994 ) , using the standard protocol of the mosquito barcoding initiative
( headed by y - ml and rcw ) .
each pcr contained 1 l of dna template , 1 x nh4
buffer , 0.5 mm of each deoxynucleotide triphosphate , 2 mm mgcl , 0.3 m each primer , 0.2
u of taq polymerase ( bioline , taunton , ma , usa ) , made up to a total volume of 10 l
using ddh20 . the polymerase chain reaction ( pcr ) cycle was : 95c for 5 min ,
35 cycles of 95c for 30 s , 48c for 30 min and 72c for 30 s , 72c for 5 min and a 10c
hold .
two microlitres of the pcr product was removed and mixed with 2 l of 5 x loading dye
before loading into wells in a 1.5% agarose gel containing 0.5 mg / ml of ethidium
bromide .
pcr
products were cleaned by adding 2 l of exosap - it ( usb co , cleveland , oh ,
usa ) , diluted 1:4 with ddh20 , to the remaining 8 l of positive pcr products .
samples were put back into the thermocycler and run at 37c for 30 min , followed by 80c
for 20 min .
bi - directional sequencing was carried out on an abi 3730 automated sequencer ( pe applied
biosystems , warrington , england ) using the original pcr primers and the
big dye terminator kit ( pe applied biosystems ) .
sequences were
edited in sequencher v.4.8 ( genes codes co , ann arbor , mi , usa ) .
similarities with publicly available sequences were assessed using basic local alignment
search tool ( blast.ncbi.nlm.nih.gov/blast.cgi ) .
comparisons with unpublished barcode
records were checked through the identification system of the barcode of life database
( bold ) ( barcodinglife.org/index.php/ids_openidengine ) .
intra
and interspecific variation was calculated using kimura two - parameter distance algorithm
( kimura 1980 ) in mega v.5.2.2 ( tamura et al . 2011 ) .
sixty variable nucleotide sequences were detected in
the 21 species dataset and all nucleotides were included in pairwise comparisons .
voucher specimens - details of voucher specimens stored in the culicid
and frozen collections of the smithsonian institution , national museum of natural
history ( nmnh ) , including associated exuviae , genitalia preps and dna , are explicitly
listed by species in supplementary data 3 .
full collection site details , including
georeferences and species determined by collection site are listed in supplementary data
1 .
collection numbers run sequentially , but ec101 - 102 , ec109 , ec119 , ec129 , ec182 ,
ec185 , ec190 - 192 , ec211 , ec260 - 261 and ec265 yielded no specimens and are omitted .
fully digitised specimen level data records and the original collection sheets are held
in the wrbu accession acc1682 and are incorporated into the mosquitomap section of
vectormap ( vectormap.org ) ( headed by dhf ) . a schematic map of the trails surrounding tbs
is available from y - ml on request .
details of specimens used for dna , along with
coi barcode sequences and the original chromatograms can be accessed
through the bold ( boldsystems.org ) under the project mosquitoes of the ecuadorian
amazon .
dna sequences are available in genbank ( ncbi.nlm.nih.gov/genbank ) under
accessions kf670990-kf671024 and kf671027-kf671044 .
mosquito collections were carried out in the forest environs around the tbs between 29
october-13 november 1998 ( wrbu acc1682 ; collections ec100-ec219 ) and 25 may-2 june 1999
( wrbu acc1682 ; collections ec254-ec270 ) .
these focussed primarily on collections of
immatures for link - rearing , but also included a few adult collections ( shannon trap ,
incidental human landing , indoor resting and outdoor resting ) .
a total of 2,284 voucher
specimens are preserved and these are housed in the mosquito collections of the
smithsonian institution , nmnh . of these ,
1,671 specimens have associated immature
exuviae , all but 108 of which are slide mounted . to further verify species
identifications ,
the male genitalia of 121 individuals were softened overnight , then
clipped , cleared and permanently mounted on slides .
slide - mounted exuviae and male
genitalia preps are labelled with the same unique specimen numbers as their associated
adults .
full details of associated life stages ( including genbank accessions for
sequenced specimens ) are listed in supplementary data 3 .
biodiversity survey ( morphology and dna barcodes ) - this study
identified 68 unique taxa belonging to 17 genera and 27 subgenera as follow :
anopheles ( an . ) [ subgenera anopheles
( ano . ) , kerteszia ( ker .
) , lophopodomyia ( lph . ) , nyssorhynchus
( nys . ) , stethomyia (
ste . ) ] , chagasia ( ch . ) ,
culex ( cx . ) [ subgenera anoedioporpa
( and . ) , carrollia ( car .
) , culex ( cux . ) , melanoconion (
mel . ) , microculex ( mcx . )
] ,
haemagogus ( hg . ) [ subgenus haemagogus
( hag . ) ] , limatus ( li .
) , lutzia ( lt . ) [ subgenus lutzia
( lut . ) ] , ochlerotatus ( oc . )
[ subgenera chrysoconops ( chs . ) , protoculex
( pcx . ) , protomacleaya (
pro . ) ] , onirion ( on . ) ,
orthopodomyia ( or . ) , psorophora
( ps . )
[ subgenera grabhamia (
gra . ) , janthinosoma ( jan . ) ] ,
runchomyia ( ru . ) [ subgenus ctenogoeldia
( cte . ) ] , sabethes ( sa .
) [ subgenera peytonulus ( pey . ) , sabethes
( sab . ) ] , toxorhynchites (
tx . ) [ subgenus lynchiella (
lyn . ) ] , trichoprosopon ( tr . ) ,
uranotaenia ( ur . )
[ subgenus uranotaenia
( ura . ) ] and wyeomyi a (
wy . )
[ subgenera decamyia ( dec .
) , dodecamyia ( dod . ) , hystatomyia
( hys . ) , miamyia ( mia . ) ,
wyeomyia ( wyo . ) ] . a quantitative list of all
confirmed species are given ( fig .
s1 ,
supplementary data 3 ) along with information on bionomics and collection localities
( fig .
s1 , supplementary data 1 ) . in conjunction with morphological analysis of available life stages
, dna barcodes were
generated for 58 questionable specimens and used to determine their specific identity .
coi sequences were compared with topotypic and/or expertly
identified specimens in the databank of the mosquito barcoding initiative and those
available in genbank .
comparison of these 58 sequences allowed the verification of 20
species in nine genera , including five of the new species discovered :
an .
somewhat incredibly , 37 of the 68 species confirmed here from yasun national park
comprise new country records for ecuador .
these include 12 species new to science and
one further undetermined species in ano- pheles (
stethomyia ) , a subgenus not previously reported from ecuador
( supplementary data 2 ) . more than half of all specimens collected ( 53.3% ) comprised the
following five species : wy .
subfamily anophelinae - anopheles : eight species of
anopheles were collected , representing five subgenera :
anopheles , kerteszia ,
lophopodomyia , nyssorhynchus and
stethomyia .
konderi and three specimens of an undetermined species of
anopheles subgenus stethomyia ( fig .
the specific identification of three specimens as belonging to
anopheles subgenus stethomyia , a new subgeneric
record for ecuador , was hampered as only two females remain .
the only male exemplar ,
stored in ethanol , was wholly destroyed in an earlier dna study and therefore its
genitalia could not be examined .
tip1 ) were unique with regard to others in
bold or genbank , thus it remains unclear whether the specimens collected represent a new
species or corresponds to one of the five already described species within the subgenus
stethomyia ( an .
thomasi shannon ) .
while it was not possible to positively confirm the identity of the species detected
here , coi sequence comparison with the three available
stethomyia species sequences have excluded an .
fluminensis was originally described from itaperuna ,
state of rio de janeiro , brazil and has never been reported from ecuador .
fluminensis ? by
morphology showed 2.75 - 3.77% sequence differences from two unpublished brazilian
specimens of an .
fluminensis in the mosquito barcoding initiative ( mbi )
dataset in bold ( mbii823 - 09 and mbii825 - 09 ) from pariquera ac , state of so paulo ,
brazil .
retrospective comparisons with brazilian specimens revealed morphological
differences and the species , designated herein as an .
these clustered together , varying by
only 0.2 - 0.61% over the 658-bp fragment , indicating these comprised the same species .
sequences were 99.01 - 100% identical to a new species determined from colombia ( caquet ) ,
ecuador ( orellana ) and peru ( madre de dios , loreto ) in ruiz - lopez et al .
( 2013 ) and 98.32% identical to genbank entry jf437965
( ac18 - 16 of sallum & laporta from acre brazil , listed as an .
oswaldoi ( ruiz - lopez et al .
2013 ) inadvertently uncovered the presence of more than one species in the
specimens listed in the neotype description ( flores - mendoza et al .
our specimens here correspond to one of the
species barcoded from the neotype series , but it remains unclear whether this is true
efforts are underway to sequence the neotype , but in
the meantime we designate this species an .
( ano . ) costai ( 95.17 - 96.18% identity , jx205127 and hm022403 from
colombia ) .
squamifemur
and the undetermined anopheles ( ste . )
species comprise six new country records for anopheles in ecuador .
, two specimens were found to be highly genetically distinct ( minimum 10.84%
sequence divergence ) .
retrospective detailed morphological study confirmed morphological
differences and showed this novel taxa was most similar to ch .
subfamily culicinae - tribe aedini - eight species of the tribe aedini
were collected in this study , representing three genera and six subgenera , as follow :
hg .
tribe culicini - twenty - six species of tribe culicini were collected
in this study ( fig .
culex : twenty - five species of culex were
collected , representing five subgenera : cx .
ten
species of culex are reported from ecuador for the first time :
cx .
( and . )
browni ( n = 1 ) , cx .
bonnei ( n = 2 ;
intra - specific distance , 0.15% ) , cx .
urichii [ n = 6 ; mean
distance , 0.18% ( range 0 - 0.46% ) and cx .
mean intra - specific distances within culex
species ranged from 0 - 0.62% ( mean 0.21% ) whereas inter - specific differences ranged from
9.0 - 15.69% ( mean 13% ) .
conservator , was compared against unpublished
sequences in the mbi dataset generated from near topotypic specimens from trinidad .
browni
coi sequence shared 96.77 - 96.93% sequence similarity with the
unpublished mbi cx .
( cux . ) coronator
group . of the six recognised species in this complex ( cx .
usquatissimus dyar ) ( bram 1967 ) , the presence of only cx .
usquatus ( n = 3 ) were verified
through examination of slide - mounted male genitalia .
the remaining specimens from yasun
national park and the group as a whole need further examination .
(
lut . ) allostigma collected herein represent the
first report of this species in ecuador ( fig .
s1 ,
supplementary data 3 ) . heinemann and belkin
( 1979 ) previously reported an undetermined species of the genus ( as
culex subgenus lutzia ) , but it is unclear whether
these were lt .
all specimens collected here were found in
water collected in palm bracts on the ground or in bamboo stumps filled with boiled leaf
water ( fig .
intra - specific
variation ranged from 0.15 - 0.31% and was closest to the published sequence of
cx .
fascipes were collected as immatures in a small tree
hole ( n = 2 , ec175 ) and one in the internode of fallen , living bamboo ( ec197 ) ( fig .
tribe sabethini - limatus : two species of the genus
limatus were recorded : li .
this is the first public barcode available for this species and while it
100% matched six undetermined specimens in bold , the next most similar unpublished
sequence was that of li .
magna was identified , reared from a pupa collected in
ground seepage ( ec130 ) .
sabethes : a new species , sa .
( pey . ) sp . nr . luxodens , was discovered as
immatures in a bamboo internode ( ec132 , n = 4 ) , along with an adult female , identifiable
only to subgenus sabethes ( ec219 ) .
digitatum ( n = 279 ) was the second most numerous species
collected in this study .
digitatum ( 0.62% difference ) ; these comprise the first published
trichoprosopon
coi sequences .
lampropus were collected from water collected in a palm bract ,
lying on the ground ( supplementary data 1 , 3 ) .
wyeomyia : due to lack
of updated keys , species of the genus wyeomyia are notoriously
difficult to identify .
many wyeomyia specimens have been identified
only to subgenus and these specimens form part of a larger revisionary study of the
genus by chp .
of the 12 wyeomyia species identified herein , six were
new to science : wy .
oblita ] , all but
wy . ( dod . ) aphobema are new country records for ecuador ( fig .
( dec . ) ulocoma ( n = 8 ; mean distance 0.7 , range 0 - 1.55% ) ,
wy . ( dod . )
nr . aphobema ( n = 1 ) , with the latter
discovered by dna .
sequence variation between the three species sequenced ranged from
4.6 - 10.66% ( mean 9.94% ) .
tribe toxorhynchitini - toxorhynchites : two species
of the toxorhynchites subgenus lynchiella were
identified : tx .
bambusicola reported here were collected in three separate collections
( ec197 , ec203 , ec254 ) and these comprise a new country record for ecuador ( fig .
only one dna barcode
was determined for an undetermined species of toxorhynchites ( as
toxorhynchites sp . tip1 in figure ) .
this sequence was most similar ( 87.7% ) to the published sequence of
tx .
figurebootstrap consensus tree of cytochrome c oxidase sequences ( n = 58 )
inferred using the neighbour - joining method of saitou and nei ( 1987 ) .
branches corresponding
to partitions reproduced in less than 50% of replicates are collapsed .
percentage of replicate trees in which the associated taxa clustered together
in the bootstrap test is shown next to the branches .
evolutionary distances
were calculated using kimura two - parameter distance algorithm ( kimura 1980 ) .
calosomata collected as pupae in the large lake
( ec112 ) form another new country record ( fig .
an integrated morphological and molecular approach such as advocated here facilitates
robust identification for the species found in amazonian ecuador .
dna barcodes were
useful in the discovery of several new species , which were at first overlooked by
morphological assessment alone .
efforts will continue to obtain species - diagnostic dna
barcode signatures for all other species documented in this collection and elsewhere in
ecuador .
a reference library of dna sequences , generated from well - vouchered
morphological specimens , will invariably facilitate the correct identification of adult
specimens , the stage most commonly captured in vector surveillance studies and currently
most difficult to identify using morphology alone .
bionomics - immature habitats - mosquito species are often highly
specific in their choice of oviposition site . in this study
, larval habitats could be
grouped into temporary and permanent groundwater habitats , artificial containers and
natural ( plant ) containers ( fig .
( ker . )
bambusicola ( exclusive to bamboo internodes ) and an .
( ker . )
lepidotus ( exclusive to bromeliads ) , immatures of all other species of
anopheles and chagasia were collected with ground
water habitats : an .
culex ( mel . ) immatures were
all recovered from ground water habitats , including ground pools , seepage and lake ,
swamp and stream margins ( fig .
s1 ) . permanent water bodies ( lakes , swamps , stream margins ) in the forest environs of the tbs
yielded a high diversity of taxa .
species collected at the edge of the four - hectare lake
( ec112 , ec199 , ec263 ) included an .
eighteen collections carried out
at stream margins ( ec100 , ec125 , ec127 , ec128 , ec145 , ec146 , ec152 , ec153 , ec163 , ec169 ,
ec170 , ec172 , ec198 , ec216 , ec257 , ec258 , ec260 , ec266 ) yielded immatures of the
following taxa : an .
( ano . ) and
chagasia were found at the edges of a large swamp ( ec255 , ec269 ) .
ground pools ( ec137 , ec148 , ec200 ) were occupied by an .
magna were collected from ground
seepage in open sunlight ( ec130 , ec134 ) ( fig .
many species were found occupying a variety of natural and artificial habitats at ground
level .
lampropus were collected
in small rainwater pools in palm bracts on the ground ( ec103 , ec110 , ec113 - 7 , ec120 - 1 ,
ec140 - 1 , ec143 , ec171 , ec175 , ec186 - 7 , ec194 ) .
aphobema were collected from rainwater pockets in a folded
tarpaulin on the forest floor ( ec157 ) .
digitatum were collected in a tree
hole in a fallen tree ( ec118 ) .
durhamii were collected in
a discarded 1.5 l plastic bottle lying on the forest floor ( ec188 ) in which rainwater
had collected .
dark plastic oviposition traps were placed at different heights up a tower in the
forest : at ground level ( ec209 , ec212 ) , at 5 m ( ec210 ) , at 8 m ( ec164 , ec167 ) , at 25 m
( ec213 ) and at the top of the tower ( 34 m , ec208 ) .
digitatum was
collected in the oviposition cups ( ovi - cup ) placed at every height ( ec167 , ec208 , ec209 ,
ec210 , ec213 ) .
an undetermined species of toxorhynchites w as reared
from an ovi - cup ( ec212 ) at ground level , cx .
digitatum
were collected together in an ovi - cup placed 34 m up at the top of the tower
( ec208 ) .
bamboo offers many discrete microhabitats for immature stages of forest mosquitoes ;
these microhabitats appear to be closely associated with certain mosquito species .
mollis were
collected from inside bamboo into which a hole had been artificially cut ( ec154 ) and
from cut , dry bamboo lying on the ground ( ec136 ) , along with li .
split aged bamboo sections were filled with boiled leaf water
and left on the forest floor to promote oviposition ( ec177 - 181 , ec183 - 184 , ec214 - 215 ,
ec217 ) .
haemorrhoidalis were collected from
internodes in dead bamboo ( ec202 - 203 , ec206 , ec270 ) whereas an .
( mia )
oblita were collected from internodes in living bamboo ( ec131 - 133 ,
ec196 , ec204 ) .
fascipes
were collected from a bamboo internode in fallen , living bamboo ( ec197 ) and
cx .
wilsoni from a bamboo internode in fallen , cut bamboo ( ec205 ) .
digitatum were collected from bamboo stumps ( ec155 , ec174 , ec201 ) ( fig .
anopheles mosquitoes of the subgenus kertezsia breed
almost exclusively in plant containers and serve as highly effective malaria vectors in
forested areas ( zavortink 1973 ) . whereas
an .
( ker . ) bambusicolus ( ec131 , ec254 ) was collected from internodes
in standing bamboo , we found that immatures of an .
lepidotus
were restricted to bromeliad axils ( ec104 , ec151 , ec166 , ec256 ) .
digitatum , it seems likely that this collection was
also a bromeliad axil collected from the tower .
water collections from bromeliad axils yielded a high diversity of mosquito species
including : an .
( ec104 - 105 , ec108 ,
ec135 , ec138 , ec147 , ec151 , ec156 , ec161 , ec166 , ec207 , ec256 , ec268 )
bambusicola were
all collected from bromeliad axils in high ( > 30 m ) in the forest canopy ( ec166 ,
ec207 , ec256 ) , accessed from the tower and canopy walkway .
bromeliad axils that fall to
the ground ( ec122 - 123 ) seem to loose their exclusivity and are occupied instead by
non - bromeliad - specific species such as culex ( car . )
( lut . ) allostigma , which appear to occupy almost all ground habitats .
excluding the fallen bromeliads ,
nine species were collected in this unique habitat ,
including three of the new wyeomyia species .
species found in the axils of heliconia plants ( ec106 , ec107 , ec144 ,
ec158 - 160 , ec173 , ec189 , ec193 , ec195 , ec218 , ec264 ) were limited to tr .
digitatum and wyeomyia ( dec . ) species
namely wy . ( dec . )
( cux . ) mollis , hg . ( hag . ) janthinomys , oc .
argyrothorax , or . fascipes and
wy .
( dec . )
ulocoma were collected in holes in living trees ( ec111 , ec142 , ec162 ,
ec173 ) .
mollis
females opportunistically laid egg rafts in rearing pans in the laboratory
( ec149 - 150 ) ( supplementary data 1 ) .
adult collections - due to the paucity of diagnostic female
characteristics , little effort was placed on collection of adults so only 142 adults
were collected in seven discrete collections .
three collections were carried out using
shannon traps ( ec124 , ec139 , ec259 ) , two human landing collections ( ec126 , ec168 ) , one
indoor resting ( ec219 ) and one outdoor resting collection ( ec127 ) ( supplementary data
1 ) .
only those indisputable specific identifications are listed , with most adult females
being identified to subgeneric level only ( supplementary data 3 ) .
an un - baited shannon trap set some 1.5 m above the ground ( ec124 ) yielded only one
lt .
allostigma , whereas setting the trap near a gas lantern
resulted in the collection of many more specimens as well as a wider variety taxa
( ec259 , n = 84 ) : an . ( nys . )
, hg . (
hag . ) sp . undet . , oc . ( chs . ) fulvus ,
oc .
, ps . ( jan . ) albipes and tr .
digitatum .
another shannon trap ( ec139 ) set high in the forest canopy ( c.
34 m at the top of the tower ) collected oc .
lanei
( n = 1 ) detected in this study ( supplementary data 1 , 3 ) .
digitatum was collected outdoor resting near the edge of a stream
( ec127 ) and indoor resting within the research station , along with undetermined species
of cx .
lepidotus was collected on two separate occasions trying to bite the
collectors some 34 m up in the canopy on the tower ( ec126 , ec168 ) ( supplementary data
1 ) . despite the unfocussed collecting effort , five of the 68 species reported ( 7.3% )
were collected only as adults , showing that adult collections are a valuable addition to
biodiversity surveys in this region .
current list of ecuadorian culicidae - given the relatively narrow
spatial and temporal range of this study , the biodiversity of mosquitoes collected was
quite remarkable . that more 16% of all taxa identified from the yasun national park in
these snapshot collections were new to science and 54% are new country records clearly
indicates that taxonomic study of ecuadorian fauna has been woefully neglected , at least
in the eastern amazonian region .
this prompted the authors to review the available
literature and to determine a current faunal list for the mosquitoes of ecuador
( supplementary data 2 ) . by far
the most productive mosquito taxonomist in ecuadorian history was roberto
levi - castillo , who published several species lists ( lev - castillo 1945 , 1949 , 1953 ) and many new species in the 40s and 50s , 30
of which remain valid species today ( supplementary data 2 ) .
levi - castillo published
several reports ( e.g. , lev - castillo 1956 ) in
which he listed species collected in ecuador , but these were composite lists , without
associated collection data or specimens . while there is no doubting his contribution to
the understanding of the mosquito fauna of ecuador , his disregard for preserving voucher
specimens has previously been highlighted ( e.g. , zavortink 1979a ) ( p. 13 ) . in their revisionary work ,
a catalog of the
mosquitoes of the world , knight and stone ( 1977 )
included the distributions of only verifiable records . to create this updated species list for ecuador , we used knight and stone ( 1977 ) as a basis and included all species reported in
verified peer reviewed publications since , reflecting revisions in taxonomy ( knight 1978 , faran
1979 , heinemann & belkin 1979 ,
zavortink 1979a , b , berlin & belkin 1980 ,
sirivanakarn 1982 , ward 1984 , forattini & sallum
1989 , hall et al . 1999 ,
our findings show that 179 mosquito
species have been recorded in ecuador to date , representing 26 genera and 39 subgenera
( supplementary data 2 ) .
this is the first published list of ecuadorian culicidae since
lev - castillo ( 1953 ) and we hope this serves
as a useful systematics platform for future work on the mosquitoes of ecuador .
s1 : mosquito taxa identified from forest habitat in the ecuadorian amazon ,
detailing diversity in larvae habitats and adult collections methodology .
some
68 unique taxa , representing 17 genera and 27 subgenera and 12 species new to
science , were collected in this study .
two undetermined species representing
new subgeneric records for anopheles (
stethomyia ) and sabethes (
sabethes ) are also included .
anopheles sp . nr . konderi
is the same taxa as in ruiz - lopez et al . (
usquatus have been unequivocally
confirmed using slide - mounted genitalia and are listed separately .
habitat details and associated species per collection
all collections were carried out in the environs of the tbs by rcw .
ec100 . harpa trail 750 m : stream margin , slow clear water , heavy shade .
wy . (
dec . ) ulocoma [ -0.637087 , -76.150089 ]
( as ec106 ) wy . ( dec . ) ulocoma , wy .
( dec . )
pseudopecten ,
wy . ( dod . ) aphobema , wy .
undet . , ur . (
ura . ) calosomata [ -0.637087 , -76.150089 ] .
harpa trail 750 m : stream margin , heavy shade , in leaves and debris .
harpa trail 800 m : stream margin , heavy shade , turbid water . 02.xi.1998 .
. fluminensis
( immatures ) , tr . digitatum ( adult resting ) [ -0.630179 ,
-76.145504 ] .
rio tiputini ( c. 8 km from tiputini biodiversity station ) : seepage area ( 1 m
x 3 m ) , standing , turbid water in direct sunlight . 03.xi.1998 .
( as ec130 ) seepage area ( 0.5 m x 0.5 m x 0.05 m deep ) , clear water in direct
sunlight . cx .
( as ec135 ) small shallow ground pool , turbid water in direct sunlight .
undet . , oc . ( chs . ) fulvus , ps .
( gra . ) cingulata , ps .
ec140 . only georeference and habitat data recorded , fallen palm bract . 04.xi.1998 .
( as ec140 ) small stream margin ( c.1 m ) , in floating leaves and debris , clear
water , heavy shade . an .
( as ec140 ) small stream margin ( c.2 m ) , in floating leaves and debris , clear
water , heavy shade
( as ec147 ) ground pool at base of fallen tree ( 1 m x 2 m x 0.05 m )
harpa trail 800 m : small stream margin ( c.1 m wide ) , slow - moving clear water ,
heavy shade , no aquatic vegetation .
harpa trail 350 m : stream margin ( c.3 m wide ) , moderate flow , clear water , heavy
shade , no aquatic vegetation . 05.xi.1998 .
( as ec106 ) water collected in artificially cut hole in bamboo , partial shade .
07.xi.1998 .
( as ec158 ) wy . ( dec . ) ulocoma , wy .
( as ec158 ) wy . ( dec . ) ulocoma , wy .
( as ec156 ) wy . ( dec . ) ulocoma , wy .
rio tiputini , blackwater area ( c. 3.5 km from tiputini biodiversity station ) :
large stream margin ( c.15 m wide ) leading to flooded area , turbid water , partial shade .
harpa trail 750 m : small stream margin , semi - permanent , slow - moving , heavy
shade .
matapalo trail 450 m : small stream margin , semi - permanent , slow - moving , heavy
shade .
main camp at chorongo trail : aged bamboo internode , filled with boiled leaf
water .
maquisapa trail 6,300 m : small stream margin ( c.2 m wide ) , slow - moving turbid
water , heavy shade , in floating leaves and debris .
maquisapa trail 7,200 m : ground pool ( 1 m x 1 m ) , clear , standing water , heavy
shade , no aquatic vegetation .
( as ec104 ) bromeliad axil , c. 30 m up in tree . 14.xi.1998 .
( as ec169 ) large stream leading to swampy area , permanent turbid water , partial
shade .
wy . (
dec . ) ulocoma , wy . ( dec . )
rio tiputini ( 6 km from tiputini biodiversity station ) : bamboo internodes ( c.15 ) .
rio tiputini , blackwater area ( nr tiputini biodiversity station ) : large swampy
area ( c.10 hectares ) , permanent slow - moving clear water , partial shade .
( as ec104 ) bromeliad axils ( c.10 ) , nr top of 32 m tower .
harpa trail 750 m : small stream margin ( c.1 m wide ) , permanent slow - moving clear
water , heavy shade , in floating leaves and debris .
undet . , oc . ( chs . ) fulvus , oc .
sp . undet . , ps . ( jan . ) albipes ,
tr
guacamayo trail 550 m : small stream margin ( c.1 m wide ) , permanent , slow - moving
clear water , heavy shade .
ec263 . lake ( c. 4 hectares ) : permanent , standing turbid water , partial shade . 29.v.1999 .
an .
chorongo trail 1,100 m : small stream margin ( c.1 m wide ) , permanent slow - moving
clear water , heavy shade .
chorongo trail 800 m : palm frond , heavy shade . 01.vi.1999 . tx .
maquisapa trail 5,300 m : large swamp , permanent standing clear water , heavy
shade , in debris . 02.vi.1999 .
revised systematic checklist of 179 species of ecuadorian culicidae . species listed
include those published since the last major revision of world taxa by knight and stone ( 1977 ) ( knight 1978 , faran 1979 ,
heinemann & belkin 1979 , sirivanakarn 1979 , zavortink 1979a , b , berlin & belkin 1980 , ward 1984 , forattini & sallum
1989 , hall et al .
2004 , harbach &
howard 2007 , zavortink & chaverri
2009 , gonzlez et al .
species identified in this study are
underlined ; those underlined and in boldface comprise 37 new additions to the mosquito
records from ecuador .
the
classification used here follows that of zavortink ( 1979a , b ) , reinert et al .
( 2004 , 2005 ,
2006 , 2008 , 2009 ) and harbach and howard ( 2007 ) .
voucher specimens examined
morphological identifications are listed alphabetically by genus , subgenus and species .
undetermined specimens are listed as sp . undet . under the relevant generic or
subgeneric heading .
specimens are listed both by collection number , e.g. , ec118 and
unique rearing number , e.g. , ec118 - 003 .
numbers and letters following these codes
indicate the presence of associated larval le
exuviae
denoted in rounded brackets , e.g. ( lepe ) indicate skins are unmounted ; all others are
slide mounted .
m for male and
f for female , where this information was not deducible a ?
square brackets
[ e.g. ( m ) ] indicate that this life stage was preserved in ethanol for dna studies .
( 2005 ) , reinert
( 2009 ) and the abbreviation summary on the wrbu website
( mosquitocatalog.org/abbreviations.aspx ) .
specimens for which dna barcodes have been
generated are followed by their respective bold and genbank accessions in
parenthesis .
( ano . )
forattinii ( n = 13 ) , ec128 - 100pe[m ] ( wrbue070 - 10 ; kf670990 ) ; ec266[l ] ,
ec266 - 001(lepe ) [ ? ] , ec266 - 002(lepe)[m ] , ec266 - 003(lepe)m , ec266 - 004(lepe)f ,
ec266 - 005(lepe)f , ec266 - 006(lepe)f , ec266 - 007(lepe)f , ec266 - 008(lepe)f , ec266 - 100(pe)f ,
ec266 - 101(pe)f , ec266 - 102(pe)m ; an .
( ano . )
mattogrossensis ( n = 1 ) , ec263 - 002lepef ; an .
fluminensis ( n = 83 ) ,
ec125 - 001lepef , ec125 - 002lepem , ec125 - 003lepef , ec125 - 004lepef , ec125 - 005lepef ,
ec125 - 006lepef , ec125 - 007lepem , ec125 - 009lepef , ec125 - 010lepem , ec125 - 011lepef ,
ec125 - 014lepef , ec125 - 101pef , ec125 - 106pef , ec125 - 110pef , ec127 - 001lepef ,
ec127 - 002lepem , ec127 - 100pem , ec128 - 001lepef , ec128 - 002lepem , ec128 - 101pe[m]gen01/64
( mbii891 - 09 ; kf670994 ) , ec128 - 102pem , ec128 - 103pef , ec128 - 104pe[m ] , ec128 - 106pe[m ]
( wrbue083 - 10 ; kf670996 ) , ec128 - 115pef , ec128 - 116pem , ec145 - 001lepef , ec145 - 003lepem ,
ec145 - 004lepem , ec145 - 005lepem , ec145 - 102pef , ec146 - 001lepem , ec146 - 002lepem ,
ec146 - 003lepef , ec146 - 005lepef , ec148 - 001lepef , ec148 - 002lepef , ec148 - 003lepef ,
ec148 - 004lepef , ec148 - 005lepem , ec148 - 008lepem , ec148 - 100pe[m ] ( wrbue084 - 10 ; kf670995 ) ,
ec148 - 104pe[m ] ( wrbue089 - 10 ; kf670992 ) , ec152 - 001lepem , ec152 - 002lepef , ec152 - 003lepem ,
ec152 - 004lepef , ec152 - 005lepef , ec152 - 006lepef , ec152 - 007lepef , ec152 - 008lepem ,
ec152 - 009lepef , ec152 - 100pem , ec152 - 102pef , ec152 - 103pem , ec163 - 001lepem ,
ec169 - 011lepe[f ] , ec170 - 001lepem , ec170 - 002lepef , ec170 - 005lepef , ec172 - 001lepef ,
ec172 - 002lepe[m ] ( wrbue116 - 10 ; kf670993 ) , ec200 - 001lepef , ec200 - 002lepef ,
ec200 - 003lepem , ec200 - 004lepem , ec200 - 005lepef , ec200 - 006lepef , ec200 - 007lepef ,
ec200 - 008lepef , ec200 - 100pef , ec200 - 101pef , ec216 - 117pef , ec216 - 118pef , ec216 - 124pef ,
ec216 - 146pef ,
ec269 - 005lepef , ec269 - 006lepem , ec269 - 015lepef , ec269 - 016lepem ,
ec269 - 017lepe [ ? ] , ec269 - 107pef , ec152 - 010lepe[m ] ; an .
( n = 4 ) , ec123 - 006lepem , ec255 - 002lepe[m ] ,
ec255 - 007lepe[m ] , ec263[l ] ; an . ( ker . )
bambusicolus ( n = 7 ) , ec131 - 001lepemgen01/63 , ec254 - 003lepe[m]gen01/58 ,
ec254 - 004lepe[m]gen01/59 , ec254 - 009lepem , ec254 - 012lepem , ec254 - 103pef , ec254 - 106pef ;
an .
( ker . ) lepidotus ( n = 34 ) ,
ec104 - 002lepef , ec104 - 003lepe , ec126(a)[f ] ( wrbue079 - 10 ; kf670991 ) ,
ec151 - 001lepe[m]gen99/01 ( mbii893 - 09 ; jq041286 ) , ec151 - 002lepem , ec151 - 003lepem ,
ec151 - 004lepem , ec151 - 005lepe[m]gen99/02 ( lepho001 - 11 ; jq041283 ) , ec151 - 009lepem ,
ec151 - 010lepem , ec151 - 100pef , ec151 - 101pem , ec151 - 102pef , ec151 - 103pem ,
ec165 - 102(pe)[m ] , ec166 - 002lepef , ec166 - 003lepef , ec166 - 004pemgen99/05 , ec166 - 006lepef ,
ec166 - 101pemgen99/03 , ec166 - 102pemgen99/04 ( lepho002 - 11 ; jq041285 ) , ec168a[f ]
( mbii894 - 09 ; jq041282 ) , ec168b[f ] ( mbii895 - 09 ; jq041284 ) , ec168[f ] , ec168[f ] , ec168[f ] ,
ec207 - 002lepem , ec256 - 001lepef , ec256 - 002lepef , ec256 - 003lepef , ec256 - 104pem ,
ec256 - 105pef , ec256 - 106pem , ec256 - 107pem ; an .
( lph .
) squamifemur ( n = 9 ) , ec125 - 107pe[m]gen01/65 , ec169 - 001lepe[m ] ,
ec169 - 132pem , ec169 - 133pe[m]gen01/66 , ec216 - 013lepef , ec216 - 017lepem , ec216 - 018lepe[f ] ,
ec216 - 019lepef , ec216 - 020lepef ; an .
konderi ( n = 154 ) , ec112 - 008lepef , ec128 - 117pemgen01/132
( wrbue114 - 10 ; kf670997 ) , ec145 - 002lepe[m ] ( wrbue101 - 10 ; kf670998 ) , ec169 - 002(lepe)[f ]
( wrbue105 - 10 ; kf671001 ) , ec169 - 004lepe[m ] ( wrbue109 - 10 ; kf671002 ) , ec169 - 005(lepe)f ,
ec169 - 007lepe[m ] ( wrbue112 - 10 ; kf671000 ) , ec169 - 008lepem , ec169 - 012(lepe)f ,
ec169 - 013lepem , ec169 - 014(lepe)f , ec169 - 015lepem , ec169 - 126(pe)[m ] ( wrbue111 - 10 ;
kf670999 ) , ec216[8l ] , ec216 - 001lepef , ec216 - 002lepef , ec216 - 003lepef , ec216 - 004lepef ,
ec216 - 005lepef , ec216 - 006lepef , ec216 - 007lepef , ec216 - 008lepef , ec216 - 009lepef ,
ec216 - 010lepe[m]gen01/68 , ec216 - 011lepef , ec216 - 012lepef , ec216 - 014lepef ,
ec216 - 015lepem , ec216 - 016lepef , ec216 - 021lepem , ec216 - 022lepef , ec216 - 023lepef ,
ec216 - 100pef , ec216 - 104pem , ec216 - 105pem , ec216 - 106pef , ec216 - 108pe[m ] , ec216 - 109pef ,
ec216 - 110pe[m ] , ec216 - 111pef , ec216 - 112pem , ec216 - 113pem , ec216 - 114pem ,
ec216 - 115pe[m]gen01/67 , ec216 - 116pef , ec216 - 119pef , ec216 - 120pef , ec216 - 121pef ,
ec216 - 122pe[m ] , ec216 - 123pef , ec216 - 125pem , ec216 - 126pef , ec216 - 127pef , ec216 - 128pef ,
ec216 - 129pem , ec216 - 130pem , ec216 - 135pef , ec216 - 136pef , ec216 - 137pem , ec216 - 138pef ,
ec216 - 140pef , ec216 - 141pe[m ] , ec216 - 142pem , ec216 - 143pem , ec216 - 144pef , ec216 - 147pef ,
ec216 - 148pef , ec216 - 149pem , ec216 - 150pef , ec255[20l ] , ec255[30l ] , ec255 - 001lepe[m ] ,
ec255 - 003lepe[m ] , ec255 - 004lepem , ec255 - 005lepef , ec255 - 006lepem , ec255 - 008lepef ,
ec255 - 009lepem , ec255 - 010lepef , ec255 - 011lepef , ec255 - 012lepef , ec255 - 013lepem ,
ec255 - 014lepem , ec255 - 015lepef , ec255 - 016lepef , ec255 - 104pef , ec255 - 105pem ,
ec255 - 106(pe)m , ec255 - 107(pe)f , ec259(1f ) , ec269 - 001lepem , ec269 - 007lepef ,
ec269 - 008lepef , ec269 - 009lepef , ec269 - 010lepef , ec269 - 014lepef , ec269 - 018lepem ,
ec269 - 103pef , ec269 - 106pef ; an .
( n = 3 ) , ec269 - 100pe [ ? ] , ec269 - 101pe [ ? ] , ec269 - 102pe [ ? ] ; an .
( n = 3 ) , ec125 - 103pe[m ]
( wrbue074 - 10 ; kf671003 ) , ec125 - 105pe[f ] ( wrbue081 - 10 ; kf671004 ) , ec128 - 109pef .
bonneae ( n = 97 ) , ec169[30l ] ,
ec169 - 003lepef , ec169 - 006(lepe)f , ec169 - 009lepem , ec169 - 010(lepe)f , ec169 - 100pe[m ]
( wrbue097 - 10 ; kf671008 ) , ec169 - 101pe[m ] ( wrbue100 - 10 ; kf671007 ) , ec169 - 102(pe)f ,
ec169 - 103(pe)m , ec169 - 104(pe)f , ec169 - 105(pe)f , ec169 - 106(pe)f , ec169 - 107(pe)f ,
ec169 - 108pe[m ] ( wrbue104 - 10 ; kf671010 ) , ec169 - 109(pe)f , ec169 - 110(pe)f , ec169 - 111(pe)[m ]
( wrbue106 - 10 & soie296 - 13 ; kf671011 ) , ec169 - 112(pe)f , ec169 - 113(pe)m ,
ec169 - 114(pe)f , ec169 - 115(pe)[m ] ( wrbue108 - 10 ; kf671006 ) ,
ec169 - 116(pe)m ,
ec169 - 117(pe)m , ec169 - 118(pe)f , ec169 - 119(pe)f , ec169 - 120(pe)[m ] ( wrbue107 - 10 ;
kf671005 ) , ec169 - 121(pe)m , ec169 - 122(pe)m , ec169 - 123(pe)f , ec169 - 124(pe)f ,
ec169 - 125(pe)[m ] ( wrbue110 - 10 ; kf671009 ) , ec169 - 127(pe)m , ec169 - 128(pe)m ,
ec169 - 129(pe)f , ec169 - 130(pe)f , ec169 - 131(pe)f , ec169a[f ] , ec170 - 103pem , ec172 - 003lepef ,
ec216[20l ] , ec216 - 131pef , ec216 - 132pem , ec216 - 133pef , ec216 - 134pem , ec216 - 139pem ,
ec216 - 145pem , ec216 - 151pem , ec258 - 001lepem , ec260 - 100pem ; ch .
.
fajardoi ( n = 12 ) , ec125 - 104pe[f ] ( wrbue077 - 10 ; kf671012 ) ,
ec153 - 001lepef , ec153 - 100pef , ec170 - 003lepef , ec170 - 004lepef , ec170 - 100(pe)f ,
ec170 - 101(pe)f , ec170 - 102pe[m ] ( wrbue115 - 10 ; kf671013 ) , ec257 - 001lepem , ec257 - 002lepem ,
ec257 - 003lepem , ec257 - 004lepef ; ch .
bamborum ( n = 7 ) , ec131 - 002lepem , ec131 - 003lepef , ec131 - 004lepem ,
ec133 - 005lepef , ec254 - 007lepemgen05/58 , ec254 - 100pef , ec254 - 105pef ; cx .
browni ( n = 2 ) , ec118 - 004lepe[m ]
( wrbue091 - 10 ; kf671016 ) , ec133 - 002lepef ; cx .
. conservator ( n = 38 ) , ec110 - 001lepemgen01/14 ,
ec118 - 001lepemgen01/28 , ec118 - 005lepef , ec118 - 006lepef , ec118 - 007lepem , ec118 - 009lepef ,
ec118 - 010lepem , ec118 - 011lepem , ec118 - 014lepe[m ] ( wrbue094 - 10 ; kf671017 ) ,
ec118 - 016lepef , ec118 - 017lepem , ec118 - 019lepef , ec118 - 020lepem , ec118 - 021lepef ,
ec118 - 022lepef , ec118 - 023lepef , ec118 - 026lepef , ec118 - 027lepem , ec118 - 028lepef ,
ec118 - 029lepem , ec118 - 030lepef , ec118 - 032lepef , ec118 - 033lepem , ec118 - 036lepemgen01/29 ,
ec118 - 038lepem , ec118 - 040lepef , ec118 - 100pef , ec118 - 101pef , ec118 - 102pef , ec118 - 103pef ,
ec118 - 104pem , ec118 - 105pem , ec118 - 106pef , ec118 - 108pem , ec118 - 109pem , ec118 - 113pef ,
ec118 - 115pem , ec118 - 132pef ; cx .
bonnei ( n = 36 ) , ec123 - 024lepemgen01/38 , ec123 - 025lepef , ec136 - 004lepem ,
ec136 - 005lepem , ec136 - 006lepef , ec136 - 009lepef , ec136 - 010lepef , ec136 - 011lepef ,
ec136 - 012lepef , ec136 - 013lepef , ec136 - 014lepe[m ] ( wrbue119 - 10 ; kf671015 ) ,
ec136 - 015lepef , ec136 - 016lepem , ec136 - 017lepemgen02/26 , ec136 - 018lepem , ec136 - 100pef ,
ec136 - 101pe[m ] ( wrbue078 - 10 ; kf671014 ) , ec136 - 102pef , ec136 - 103pef , ec136 - 104pem ,
ec136 - 106pef , ec136 - 110pef , ec136 - 111pef , ec136 - 112pef , ec136 - 113pef , ec136 - 114pem ,
ec136 - 115pem , ec136 - 116pem , ec136 - 117pem , ec136 - 118pem , ec136 - 119pem , ec136 - 120pem ,
ec136 - 121pef , ec136 - 122pef , ec136 - 123pef , ec154 - 004lepem ; cx . (
car . ) iridescens ( n = 4 ) , ec270 - 002lepef ,
ec270 - 003lepem , ec270 - 004lepem , ec270 - 100pem ; culex (
car . ) secundus
( n = 4 ) , ec254 - 002lepem ,
ec254 - 010lepemgen05/57 , ec254 - 102pef , ec254 - 104pem ; cx . (
car . )
urichii ( n = 141 ) , ec103 - 001lepemgen01/02 ,
ec103 - 002lepem , ec103 - 003lepem , ec103 - 004lepem , ec103 - 005lepem , ec103 - 006lepem ,
ec103 - 007lepem , ec103 - 008lepef , ec103 - 009lepef , ec103 - 010lepef , ec103 - 011lepef ,
ec103 - 012lepef , ec103 - 013lepem , ec103 - 014lepef , ec103 - 015lepef , ec103 - 016lepef ,
ec103 - 017lepef , ec103 - 018lepef , ec103 - 019lepef , ec103 - 020lepem , ec103 - 021lepem ,
ec103 - 022lepef , ec103 - 023lepem , ec103 - 024lepef , ec103 - 025lepef , ec103 - 026lepef ,
ec103 - 027lepem , ec103 - 028lepem , ec103 - 029lepef , ec103 - 030lepem , ec103 - 031lepem ,
ec103 - 032lepem , ec103 - 033lepef , ec103 - 100pem ,
ec103 - 101pe[m ] ( wrbue068 - 10 ; kf671019 ) ,
ec103 - 102pef , ec103 - 103pef , ec103 - 104pef , ec103 - 105pe[m ] ( wrbue085 - 10 ; kf671022 ) ,
ec103 - 106pef , ec110 - 100pef , ec113 - 002f , ec114 - 002pe , ec114 - 006lepem , ec115 - 001lepe[m ]
( wrbue087 - 10 ; kf671021 ) , ec115 - 002lepef , ec115 - 003lepemgen01/22 , ec115 - 010lepe[m ]
( wrbue102 - 10 ; kf671023 ) , ec115 - 011lepem , ec115 - 013lepef , ec115 - 014lepem , ec115 - 015lepem ,
ec115 - 016lepem , ec115 - 017lepef , ec115 - 018lepef , ec115 - 019lepem , ec115 - 020lepem ,
ec115 - 021lepef , ec115 - 022lepef , ec115 - 023lepef , ec115 - 024lepem , ec115 - 025lepef ,
ec115 - 026lepem , ec115 - 027lepem , ec115 - 028lepef , ec115 - 029lepem , ec115 - 030lepem ,
ec115 - 031lepef , ec115 - 032lepef , ec115 - 033lepef , ec115 - 034lepef , ec115 - 035lepem ,
ec115 - 036lepem , ec115 - 037lepef , ec115 - 038lepef , ec115 - 039lepef , ec115 - 040lepem ,
ec115 - 041lepef , ec115 - 042lepef , ec115 - 043lepem , ec115 - 044lepem , ec115 - 045lepef ,
ec115 - 105pem , ec115 - 106pem , ec115 - 107pef , ec116 - 001lepef , ec116 - 002lepef ,
ec116 - 004lepem , ec116 - 005lepef , ec116 - 006lepem , ec116 - 007lepef , ec116 - 008lepem ,
ec116 - 009lepef , ec116 - 010lepef , ec116 - 011lepemgen01/24 , ec116 - 012lepef , ec116 - 013lepem ,
ec116 - 014lepef , ec116 - 015lepef , ec116 - 016lepef , ec116 - 017lepef , ec116 - 018lepem ,
ec116 - 019lepem , ec116 - 100pemgen01/25 , ec116 - 101pem , ec116 - 102pem , ec116 - 103pem ,
ec116 - 104pem , ec116 - 105pef , ec120 - 001lepef , ec121 - 001lepef , ec121 - 002lepe[m ]
( wrbue093 - 10 ; kf671020 ) , ec121 - 009lepemgen01/33 , ec121 - 010lepem , ec121 - 011lepef ,
ec121 - 012lepef , ec121 - 013lepef , ec121 - 100pef , ec121 - 108[?](wrbue069 - 10 ; kf671024 ) ,
ec121 - 109pef , ec121 - 111pef , ec121 - 113pef , ec121 - 114f , ec121 - 118pem , ec122 - 002lepef ,
ec122 - 003f , ec122 - 101pef , ec122 - 102f , ec123 - 005lepem , ec133 - 001f , ec135 - 001lepem ,
ec140 - 001lepef , ec140 - 002lepef , ec140 - 003lepem , ec140 - 004lepem , ec140 - 005lepem ,
ec140 - 006lepem , ec140 - 007lepem , ec140 - 100pem , ec140 - 101pef , ec140 - 102pem ; cx .
wilsoni ( n = 23 ) ,
ec196 - 003lepemgen02/30 , ec196 - 006lepem , ec205 - 001lepem , ec206[3l ] , ec206 - 001lepem ,
ec206 - 002lepem , ec206 - 003lepem , ec206 - 004lepemgen02/18 , ec206 - 005lepef , ec206 - 006lepem ,
ec206 - 007lepef , ec206 - 008lepef , ec206 - 009lepef , ec206 - 010lepef , ec206 - 011lepef ,
ec206 - 012lepem , ec206 - 013lepef , ec206 - 014lepem , ec206 - 015lepef , ec206 - 016lepef ,
ec206 - 100pem ; cx .
bonneae
( n = 21 ) , ec149[15l ] , ec149 - 001lepemgen02/27 , ec149 - 002lepem , ec149 - 003lepem ,
ec149 - 004lepem , ec149 - 005lepef , ec149 - 006lepef , ec166 - 005lepef ; cx .
(
cux . ) camposi ( n = 3 ) , ec130 - 102pemgen05/59 ,
ec134 - 005lepemgen05/34 , ec134 - 102pe[m]gen13/02 ; cx .
( n = 50 ) , ec130 - 001lepef ,
ec130 - 002lepef , ec130 - 003lepef , ec130 - 004lepef , ec130 - 101pef , ec134[15l ] ,
ec134 - 001lepef , ec134 - 002lepef , ec134 - 003lepef , ec134 - 004lepef , ec134 - 006lepef ,
ec134 - 007lepef , ec134 - 008lepef , ec134 - 009lepef , ec134 - 012lepef , ec134 - 013lepef ,
ec134 - 014lepem , ec134 - 015lepem , ec134 - 016lepef , ec134 - 017lepef , ec134 - 018lepef ,
ec134 - 019lepem , ec134 - 020lepef , ec134 - 021lepef , ec134 - 100pef , ec134 - 101pef ,
ec134 - 103pef , ec134 - 104pef , ec134 - 105pem , ec134 - 106pem , ec134 - 107pem , ec134 - 108pef ,
ec134 - 109pef , ec134 - 110pef , ec134 - 111pem , ec137 - 100pem ; cx .
(
cux . ) mollis ( n = 181 ) , ec113 - 001lepef ,
ec113 - 100pemgen01/20 , ec113 - 101pef , ec113 - 102pem , ec115 - 108pef , ec116 - 003lepemgen01/23 ,
ec118 - 002lepemgen01/30 , ec118 - 003lepef , ec118 - 008lepef , ec118 - 012lepem , ec118 - 013lepef ,
ec118 - 015lepef , ec118 - 018lepef , ec118 - 024lepem , ec118 - 031lepem , ec118 - 034lepef ,
ec118 - 035lepef , ec118 - 107pem , ec118 - 110pef , ec118 - 111pem , ec118 - 112pef , ec118 - 114pem ,
ec118 - 116pef , ec118 - 117pem , ec118 - 118pem , ec118 - 119pef , ec118 - 120pef , ec118 - 121apef ,
ec118 - 121bpef , ec118 - 122pem , ec118 - 123pem , ec118 - 124pem , ec118 - 125pem , ec118 - 126pem ,
ec118 - 127pem , ec118 - 128pem , ec118 - 129pem , ec118 - 130pef , ec118 - 131pem , ec120 - 101pef ,
ec120 - 103pef , ec121 - 003lepem , ec121 - 004lepem , ec121 - 005lepef , ec121 - 006lepem ,
ec121 - 007lepef , ec121 - 008lepem , ec121 - 101pef , ec121 - 102pef , ec121 - 103pef , ec121 - 104pef ,
ec121 - 105pef , ec121 - 112pem , ec121 - 115 m , ec121 - 116pef , ec121 - 117pef , ec122 - 001lepef ,
ec123 - 001lepemgen01/37 , ec123 - 002lepef , ec123 - 003f , ec123 - 004lepef , ec123 - 007lepef ,
ec123 - 008lepem , ec123 - 009lepef , ec123 - 010lepef , ec123 - 011lepef , ec123 - 012lepef ,
ec123 - 013lepemgen01/36 , ec123 - 014lepef , ec123 - 015lepem , ec123 - 016lepem , ec123 - 017lepem ,
ec123 - 018lepemgen01/35 , ec123 - 019lepem , ec123 - 020lepef , ec123 - 021lepef , ec123 - 022lepef ,
ec123 - 023lepef , ec123 - 100pef , ec123 - 101pef , ec123 - 102pem , ec123 - 103pef , ec123 - 104pef ,
ec123 - 105pem , ec123 - 106pem , ec123 - 107pem , ec123 - 108pem , ec123 - 109pem , ec123 - 110pem ,
ec123 - 111pem , ec123 - 112pef , ec123 - 113pem , ec123 - 114pem , ec123 - 115pem , ec136 - 002lepef ,
ec136 - 003lepemgen02/25 , ec136 - 007lepef , ec136 - 008lepef , ec141 - 001lepem ,
ec141 - 002lepemgen05/35 , ec141 - 003lepem , ec141 - 004lepem , ec141 - 005lepef , ec141 - 006lepef ,
ec141 - 100pem , ec141 - 101pem , ec143 - 001lepemgen02/62 , ec150[10l ] , ec150 - 002lepef ,
ec150 - 003lepef , ec150 - 004lepem , ec150 - 005lepef , ec150 - 006lepef , ec150 - 007lepef ,
ec150 - 008lepef , ec150 - 009lepef , ec150 - 100pem , ec150 - 101pem , ec150 - 102pemgen02/21 ,
ec150 - 103pem , ec150 - 104pem , ec150 - 105pem , ec150 - 106pem , ec150 - 107pem , ec150 - 108pem ,
ec150 - 109pem , ec150 - 110pem , ec150 - 111pem , ec150 - 112pem , ec150 - 113pem , ec150 - 114pem ,
ec150 - 115pem , ec150 - 116pef , ec150 - 117pem , ec150 - 118pef , ec150 - 119pem , ec150 - 120pem ,
ec150 - 121pem , ec150 - 122pem , ec150 - 123pem , ec150 - 124pem , ec150 - 125pem , ec150 - 126pem ,
ec150 - 127pem , ec150 - 128pem , ec150 - 129pem , ec150 - 130pem , ec150 - 131pem , ec150 - 132pem ,
ec154 - 001lepem , ec154 - 002lepef , ec154 - 003lepem , ec154 - 100pemgen05/37 ,
ec157 - 100pemgen05/38 , ec157 - 101pem , ec157 - 102pem , ec157 - 103pem , ec157 - 104pef ,
ec157 - 105pef , ec157 - 106pef , ec157 - 107pef , ec162 - 100pef ,
ec183 - 001lepemgen05/42 ,
ec183 - 002lepef , ec183 - 003lepef , ec183 - 004lepef , ec183 - 005lepef , ec183 - 100lepem ,
ec183 - 101lepem , ec183 - 102lepem , ec183 - 103lepem , ec121 - 110mgen01/34 ; cx .
usquatus ( n = 2 ) ,
ec134 - 010lepe[m]gen13/01 , ec134 - 011lepemgen05/61 ; cx .
( n = 17 ) , ec139(3f ) , ec259(9f ) , ec219(2f ) ,
ec219(3f ) ; cx .
chryselatus
( n = 22 ) , ec105 - 001lepemgen01/03 , ec105 - 003lepef , ec105 - 004lepef , ec105 - 005lepem ,
ec105 - 100pemgen01/04 , ec105 - 101pem , ec105 - 102pem , ec166 - 001lepef , ec207 - 003lepef ,
ec207 - 101pem , ec207 - 102pem , ec207 - 103pem , ec208 - 003pemgen02/31 , ec208 - 004pef ,
ec208 - 005pef , ec208 - 006pemgen05/47 , ec208 - 007pef , ec208 - 008pef , ec208 - 009pem ,
ec208 - 010pem , ec208 - 011pef , ec208 - 012pef ; cx .
( mcx .
) pleuristriatus ( n = 11 ) , ec164 - 001lepef , ec164 - 002(lepe)f ,
ec164 - 003(lepe)f , ec164 - 004(lepe)f , ec164 - 005(lepe)f , ec164 - 100(pe)f , ec164 - 101pem ,
ec164 - 102(pe)mgen02/20 , ec196 - 001lepem , ec196 - 002lepef , ec196 - 004lepem , ec196 - 005lepef ,
ec196 - 007lepemgen02/29 , ec196 - 008lepef , ec196 - 009lepe ; cx .
( n = 3 ) , ec256 - 100pef , ec268 - 102pef ,
ec207 - 001lepef ; cx .
eastor ( n = 4 ) , ec112 - 016lepef , ec112 - 102pem , ec112 - 108pemgen01/19 ,
ec112 - 109pef ; cx .
elevator
( n = 45 ) , ec100 - 001lepemgen01/01 , ec100 - 002lepem , ec100 - 003lepem , ec100 - 004lepef ,
ec100 - 100pem , ec100 - 101pemgen01/43 , ec125 - 013lepef , ec125 - 015lepef , ec125 - 016lepef ,
ec125 - 017lepef , ec125 - 018lepef , ec125 - 100pem , ec125 - 102pemgen01/40 , ec125 - 108pef ,
ec125 - 109pef , ec125 - 111pem , ec125 - 112pef , ec125 - 113pemgen01/41 , ec125 - 114pem ,
ec125 - 115pem , ec125 - 116pef , ec125 - 117pef , ec125 - 118pef , ec125 - 119pem , ec125 - 120pef ,
ec125 - 121pef , ec125 - 122pem , ec125 - 123pef , ec125 - 125pemgen01/42 , ec125 - 127pef ,
ec125 - 129pef , ec125 - 130pef , ec125 - 131pef , ec128 - 105pem , ec128 - 107pef , ec128 - 108pef ,
ec128 - 110pem , ec128 - 111pem , ec128 - 112pemgen02/24 , ec128 - 113pem , ec128 - 114pem ,
ec145 - 100pemgen02/64 , ec145 - 101pem , ec152 - 101pemgen05/36 , ec198 - 001lepemgen05/44 ;
cx .
evansae ( n = 8) ,
ec146 - 004lepemgen02/65 , ec148 - 108pef , ec148 - 109pemgen02/67 , ec148 - 110pemgen02/22 ,
ec148 - 111pem , ec148 - 112pem , ec148 - 113pem , ec148 - 114pem ; cx .
iolambdis ( n = 5 ) , ec125 - 008lepemgen01/39 ,
ec125 - 012lepef , ec125 - 124pem , ec125 - 126pem , ec125 - 128pem ; cx .
pilosus ( n = 18 ) , ec130 - 100pemgen05/60 ,
ec199 - 001lepem , ec199 - 003lepef , ec199 - 004lepef , ec199 - 005lepem , ec199 - 100pem ,
ec199 - 101pef , ec199 - 102pem , ec199 - 103pef , ec199 - 104pef , ec199 - 105pef , ec199 - 106pem ,
ec199 - 107pem , ec199 - 108pem , ec199 - 109pemgen02/19 , ec199 - 110pem , ec199 - 111pem ,
ec259mgen12/13 ; cx .
serratimarge ( n = 19 ) , ec112 - 001lepem , ec112 - 002lepef , ec112 - 003lepef ,
ec112 - 004lepef , ec112 - 005lepemgen01/15 , ec112 - 006lepef , ec112 - 007lepe[m ] ( wrbue088 - 10 ;
kf671018 ) , ec112 - 009lepef , ec112 - 011lepem , ec112 - 012lepef , ec112 - 013lepef ,
ec112 - 014lepemgen01/16 , ec112 - 017lepem , ec112 - 018lepef , ec112 - 100pemgen01/18 ,
ec112 - 101pem , ec112 - 103pem , ec112 - 106pef , ec112 - 107pem ; cx .
(
mel . ) symbletos ( n = 2 ) , ec112 - 015lepemgen01/17 ,
ec112 - 111pem ; cx . ( mel . )
theobaldi
( n = 9 ) , ec199 - 002lepemgen05/45 , ec199 - 112pef , ec216 - 107pef , ec255 - 100pem ,
ec255 - 101pem , ec255 - 102pem , ec255 - 103pem , ec259mgen12/14 , ec259mgen12/15 ; cx .
( n = 75 ) , ec112 - 110pem ,
ec148 - 115pem , ec256 - 101pef , ec256 - 103pef , ec259(1f ) , ec259(25f ) , ec259(38 m ) ,
ec269 - 011lepem , ec269 - 012lepem , ec148 - 006lepef , ec148 - 007lepef , ec269 - 013lepem ,
ec269 - 104pef , ec269 - 105pef .
( hag . )
janthinomys ( n = 1 ) , ec111 - 001lepef ; hg .
durhamii ( n = 61 ) , ec120 - 100pemgen01/31 ,
ec136 - 109pef , ec155 - 001lepef , ec155 - 002lepef , ec155 - 003lepef , ec155 - 004lepef ,
ec155 - 005lepef , ec155 - 006lepem , ec155 - 007lepem , ec155 - 008lepem , ec155 - 009lepem ,
ec155 - 010lepef , ec155 - 011lepem , ec155 - 012lepef , ec155 - 013lepem , ec155 - 014lepem ,
ec155 - 015lepef , ec155 - 016lepem , ec155 - 017lepem , ec155 - 018lepem , ec155 - 019lepef ,
ec155 - 020lepef , ec155 - 021lepef , ec155 - 022lepef , ec155 - 023lepem , ec155 - 024lepem ,
ec155 - 025lepem , ec155 - 026lepem , ec155 - 027lepem , ec155 - 028lepem , ec155 - 029lepem ,
ec155 - 030lepef , ec155 - 031lepef , ec155 - 100pef , ec155 - 101pem , ec155 - 102pef , ec155 - 103pef ,
ec155 - 104pef , ec155 - 105pem , ec155 - 106pem , ec155 - 107pem , ec155 - 108pef , ec155 - 109pef ,
ec155 - 110pef , ec155 - 111pem , ec155 - 112pem , ec155 - 113pem , ec155 - 114pef , ec155 - 115pem ,
ec155 - 116pef , ec188[3l ] , ec188 - 001lepef , ec188 - 002lepef , ec188 - 003lepef , ec188 - 100pef ,
ec188 - 101pem , ec188 - 102pef , ec188 - 103pe ; li
. flavisetosus ( n = 29 ) ,
ec115 - 004lepem , ec115 - 005lepem , ec115 - 006lepem , ec115 - 007lepem , ec115 - 008lepem ,
ec115 - 009lepef , ec115 - 012lepe[m](wrbue103 - 10 ; kf671027 ) , ec115 - 100pem ,
ec115 - 101pemgen01/21 , ec115 - 102pef , ec115 - 103pef , ec115 - 104pef , ec115 - 109pef ,
ec115 - 110pef , ec115 - 111pe[m ] , ec115 - 112pem , ec115 - 113pem , ec115 - 114pef , ec118 - 025lepef ,
ec120 - 102pemgen01/32 , ec136 - 105pef , ec136 - 107pef , ec136 - 108pem , ec171 - 001lepef ,
ec175 - 001lepef , ec175 - 100pef , ec201 - 001lepef , ec201 - 100pef , ec201 - 101pef ; li .
( lut . )
allostigma ( n = 14 ) , ec114 - 001lepe[m ] ( wrbue076 - 10 ; kf671030 ) ,
ec114 - 003lepef , ec114 - 004lepef , ec114 - 005lepef , ec114 - 007lepem , ec114 - 100pef ,
ec114 - 101pef , ec121 - 106pef , ec121 - 107pef , ec122 - 100pe[m ] ( wrbue071 - 10 ; kf671029 ) ,
ec124[f ] ( wrbue065 - 10 ; kf671028 ) , ec217 - 100pem , ec217 - 101pem , ec217 - 102pef .
( chs . ) fulvus ( n = 27 ) ,
ec259(1f ) , ec139(26f ) ; oc .
( pcx . )
serratus ( n = 5 ) , ec148 - 101pef , ec148 - 102pef , ec148 - 103pef , ec148 - 105pef ,
ec148 - 106pef ; oc .
argyrothorax ( n = 2 ) , ec142 - 001lepef , ec142 - 002lepef ; oc .
imparis ( n = 5 ) , ec202 - 001lepef ,
ec202 - 002f , ec202 - 003lepem , ec202 - 004lepef , ec254 - 005lepemgen05/32 .
orthopodomyia - or . fascipes ( n = 3 ) , ec176 - 100pef ,
ec176 - 101pem , ec197 - 002lepef .
( jan .
) albipes ( n = 1 ) , ec259(1f ) ; ps .
albigenu ( n = 4 ) , ec139(3f ) , ec148 - 107pef ;
ps .
lanei ( n = 1 ) ,
ec139(1f ) ; ps . ( jan . ) sp . undet .
( cte . )
magna ( n = 1 ) , ec130 - 005lepef .
.
luxodens ( n = 4 ) , ec132 - 003lepef , ec132 - 004lepem , ec132 - 005lepef ,
ec132 - 007lepemgen02/59 ; sa .
bambusicola ( n = 3 ) , ec197 - 001lepemgen05/63 , ec203 - 001lepef ,
ec254 - 011lepef ; tx .
haemorrhoidalis ( n = 9 ) , ec267 - 001lepe [ ? ] , ec267 - 002lepe [ ? ] , ec267 - 003lepem ,
ec267 - 004 m , ec267 - 005f , ec267 - 006lepem , ec267 - 007 m , ec267 - 008lepef , ec270 - 001lepem ;
tx .
( n = 2 ) , ec212 - 001lepe[m](wrbue090 - 10 ;
kj671031 ) , ec256 - 102pef .
digitatum ( n = 279 ) ,
ec117 - 001lepemgen01/26 , ec117 - 002lepef , ec117 - 003lepef , ec117 - 004lepem , ec117 - 005lepef ,
ec117 - 006lepef , ec117 - 007lepef , ec117 - 008lepef , ec117 - 009lepef , ec117 - 010lepem ,
ec117 - 011lepem , ec117 - 012lepef , ec117 - 013lepef , ec117 - 014lepef , ec117 - 015lepef ,
ec117 - 016lepem , ec117 - 017lepem , ec117 - 018lepef , ec117 - 019lepem , ec117 - 020lepef ,
ec117 - 021lepef , ec117 - 100pe[m ] ( wrbue113 - 10 ; kf671032 ) , ec118 - 037lepemgen01/27 ,
ec118 - 039lepem , ec118 - 041lepe , ec118 - 042lepem , ec127(a)[f ] ( wrbue080 - 10 ; kf671033 ) ,
ec139(1f ) , ec157 - 001lepem , ec157 - 002lepem , ec157 - 003lepem , ec157 - 004lepef , ec157 - 108pem ,
ec157 - 109pef , ec157 - 110pef , ec165 - 001lepem , ec165 - 002lepef , ec167 - 001lepem ,
ec167 - 002lepem , ec165 - 003(lepe)f , ec165 - 004(lepe)f , ec165 - 005(lepe)f , ec165 - 006(lepe)f ,
ec165 - 100(pe)m , ec165 - 101(pe)m , ec165 - 103(pe)m , ec165 - 104(pe)m , ec165 - 105(pe)m ,
ec165 - 106(pe)m , ec165 - 107(pe)f , ec165 - 108(pe)f , ec165 - 109(pe)f , ec165 - 110(pe)f ,
ec165 - 111(pe)f , ec165 - 112(pe)f , ec167[15l ] , ec167 - 003(lepe)m , ec167 - 004(lepe)f ,
ec167 - 005(lepe)m , ec167 - 006(lepe)f , ec167 - 007(lepe)f , ec167 - 008(lepe)m ,
ec167 - 009(lepe)m , ec167 - 010(lepe)f , ec167 - 011(lepe)f , ec167 - 012(lepe)f ,
ec167 - 013(lepe)f , ec167 - 014(lepe)f , ec167 - 015(lepe)f , ec167 - 016(lepe)f ,
ec167 - 017(lepe)f , ec167 - 018(lepe)f , ec167 - 100(pe)m , ec167 - 101(pe)m , ec167 - 102(pe)m ,
ec167 - 103(pe)m , ec167 - 104(pe)m , ec174 - 001lepem , ec174 - 002lepem , ec174 - 003(lepe)m ,
ec174 - 004(lepe)f , ec174 - 005(lepe)f , ec174 - 100(pe)m , ec177 - 001lepem , ec177 - 002lepem ,
ec177 - 003lepef , ec177 - 004lepef , ec177 - 005lepem , ec177 - 006lepef , ec177 - 100pem ,
ec177 - 101pef , ec178[5l ] , ec178[7l ] , ec178 - 001lepem , ec178 - 002lepem , ec178 - 003lepem ,
ec178 - 100pem , ec178 - 101pem , ec178 - 102pem , ec178 - 103pem , ec178 - 104pem , ec179 - 001lepef ,
ec179 - 002lepef , ec179 - 100 m , ec179 - 101pef , ec179 - 102pem , ec179 - 103pef , ec179 - 104pem ,
ec179 - 105pem , ec180 - 001lepem , ec180 - 002lepem , ec180 - 003lepef , ec180 - 004lepef ,
ec180 - 005lepef , ec180 - 006lepem , ec180 - 007lepem , ec180 - 008lepef , ec180 - 009lepef ,
ec180 - 010lepef , ec180 - 011lepef , ec180 - 012lepef , ec180 - 013lepef , ec180 - 100pem ,
ec180 - 101pem , ec180 - 102pem , ec180 - 103pef , ec180 - 104pef , ec180 - 105pem , ec181[10lp ] ,
ec181 - 001lepef , ec181 - 002lepem , ec181 - 003lepem , ec181 - 004lepef , ec181 - 100pem ,
ec181 - 101pef , ec181 - 102pem , ec181 - 103pem , ec184 - 001lepem , ec184 - 002lepef ,
ec184 - 003lepem , ec184 - 004lepef , ec184 - 005lepem , ec184 - 006lepem , ec184 - 007lepef ,
ec184 - 008lepef , ec184 - 009lepef , ec184 - 010lepef , ec184 - 100pem , ec184 - 101pef ,
ec184 - 102pef , ec184 - 103pemgen05/41 , ec184 - 104 m , ec184 - 105pem , ec186 - 001lepef ,
ec186 - 002lepef , ec186 - 003lepef , ec186 - 004lepef , ec186 - 005lepef , ec186 - 006lepef ,
ec186 - 007lepem , ec186 - 100pef , ec186 - 101pem , ec186 - 102pem , ec186 - 103pem , ec186 - 104pem ,
ec186 - 105pem , ec186 - 106pem , ec186 - 107pem , ec186 - 108pem , ec186 - 109pef , ec186 - 110pef ,
ec186 - 111pem , ec186 - 112pem , ec186 - 113pem , ec186 - 114pef , ec186 - 115pef , ec187 - 001lepem ,
ec187 - 002lepem , ec187 - 003lepef , ec187 - 004lepem , ec187 - 005lepem , ec187 - 006lepef ,
ec187 - 007lepef , ec187 - 008lepef , ec187 - 009lepef , ec187 - 010lepef , ec187 - 011lepef ,
ec187 - 012lepef , ec187 - 013lepef , ec187 - 014lepef , ec187 - 015lepef , ec187 - 016lepef ,
ec187 - 017lepef , ec187 - 018lepef , ec187 - 019lepef , ec187 - 020lepef , ec187 - 021lepem ,
ec187 - 022lepef , ec187 - 023lepef , ec187 - 100pem , ec187 - 101pem , ec187 - 102pem , ec187 - 103pem ,
ec187 - 104pem , ec187 - 105pem , ec187 - 106pem , ec187 - 107pem , ec187 - 108pem , ec187 - 109pem ,
ec187 - 110pem , ec187 - 111pem , ec187 - 112pem , ec189 - 002lepem , ec189 - 003lepef , ec208 - 001pem ,
ec208 - 002pef , ec209 - 100pef , ec209 - 101pef , ec210 - 001lepef , ec213 - 001lepem ,
ec213 - 002lepem , ec213 - 003lepem , ec214 - 001lepem , ec214 - 002lepem , ec214 - 003lepem ,
ec214 - 004lepem , ec214 - 005lepef , ec214 - 006lepef , ec214 - 007lepef , ec214 - 008lepef ,
ec214 - 009lepem , ec214 - 010lepef , ec214 - 011lepem , ec214 - 100pem , ec214 - 101pef ,
ec214 - 102pef , ec214 - 103pem , ec217 - 103pem , ec219(4f ) , ec259(2f ) , ec264 - 002(lepe)f ,
ec264 - 003(lepe)f ; tr .
nr . lampropus ( n = 2 ) ,
ec194 - 003lepemgen05/43 , ec194 - 004lepef .
. ( ura . )
calosomata ( n = 2 ) , ec112 - 104pem , ec112 - 105pe[m ] ( wrbue098 - 10 ;
kf671034 ) .
wyeomyia - wy .
( dec . )
pseudopecten ( n = 19 ) , ec108 - 001lepemgen01/11 , ec144 - 001lepem ,
ec144 - 002lepef , ec144 - 003lepef , ec144 - 004lepem , ec144 - 005lepef , ec144 - 006lepef ,
ec144 - 007lepef , ec144 - 100pem , ec144 - 101pef , ec144 - 102pem , ec144 - 103pemgen02/63 ,
ec144 - 104pem , ec144 - 105pef , ec144 - 106pem , ec144 - 107pem , ec144 - 108pef , ec144 - 109pef ,
ec195 - 100pemgencp ; wy . ( dec . ) ulocoma
( n = 462 ) , ec106[20l ] , ec106[50l ] , ec106 - 001lepemgen01/05 , ec106 - 002lepem ,
ec106 - 003lepem , ec106 - 004lepef , ec106 - 005lepem , ec106 - 006lepef , ec106 - 007lepef ,
ec106 - 008lepef , ec106 - 009lepem , ec106 - 010lepef , ec106 - 011lepe[f ] ( wrbue066 - 10 ;
kf671040 ) , ec106 - 012lepef , ec106 - 013lepef , ec106 - 014lepef , ec106 - 015lepef ,
ec106 - 016lepef , ec106 - 017lepef , ec106 - 018lepef , ec106 - 019lepem , ec106 - 020lepem ,
ec106 - 021lepe[m ] ( wrbue075 - 10 ; kf671039 ) , ec106 - 022lepem , ec106 - 023lepef ,
ec106 - 024lepef , ec106 - 025lepef , ec106 - 026lepef , ec106 - 027lepef , ec106 - 028lepem ,
ec106 - 029lepef , ec106 - 030lepef , ec106 - 031lepef , ec106 - 032lepef , ec106 - 033lepef ,
ec106 - 034lepef , ec106 - 035lepef , ec106 - 036lepef , ec106 - 037lepef , ec106 - 100pef ,
ec106 - 101pemgen01/08 , ec106 - 102pef , ec106 - 103pef , ec106 - 104pef , ec106 - 105pemgen01/06 ,
ec106 - 106pef , ec106 - 107pef , ec106 - 108pem , ec106 - 109pem , ec106 - 110pef , ec106 - 111pe[m ]
( wrbue072 - 10 ; kf671038 ) , ec106 - 112pe[m ] ( soie294 - 13 ; kf671042 ) , ec106 - 113pem ,
ec106 - 114pef , ec106 - 115pef , ec106 - 116pem , ec106 - 117pef , ec106 - 118pem , ec106 - 119pem ,
ec106 - 120pem , ec106 - 121pe[m ] ( soie293 - 13 ; kf671043 ) , ec106 - 122pem , ec106 - 123pemgen01/07 ,
ec106 - 124pem , ec106 - 125pem , ec106 - 126pem , ec107 - 001lepem , ec107 - 003lepemgen01/09 ,
ec107 - 004lepef , ec107 - 005lepem , ec107 - 006lepem , ec107 - 007lepef , ec107 - 008lepem ,
ec107 - 010lepef , ec107 - 011lepef , ec107 - 012lepemgencp , ec107 - 013lepef , ec107 - 014lepem ,
ec107 - 015lepef , ec107 - 017lepef , ec107 - 018lepem , ec107 - 020lepem , ec107 - 021lepem ,
ec107 - 023lepem , ec107 - 025lepef , ec107 - 026lepem , ec107 - 027lepef , ec107 - 028lepem ,
ec107 - 100pef , ec107 - 102pem , ec107 - 103pem , ec107 - 104pef , ec107 - 105pem , ec107 - 106pef ,
ec107 - 108pef , ec107 - 109pem , ec107 - 110pef , ec107 - 111pef , ec107 - 112pem , ec107 - 113pem ,
ec107 - 114pem , ec107 - 115pem , ec107 - 116pe[m ] ( wrbue073 - 10 ; kf671044 ) , ec107 - 118pem ,
ec107 - 119pem , ec107 - 120pem , ec107 - 121pem , ec107 - 122pem , ec107 - 123pem , ec107 - 124pem ,
ec107 - 125pef , ec107 - 126pem , ec107 - 127pem , ec107 - 128pem , ec158 - 002lepef , ec158 - 003lepef ,
ec158 - 004lepem , ec158 - 005lepef , ec158 - 006lepem , ec158 - 007lepem , ec158 - 010lepef ,
ec158 - 011lepef , ec158 - 100pef , ec158 - 101pe[m ] ( wrbue096 - 10 ; kf671037 ) , ec158 - 102pem ,
ec158 - 103pe , ec158 - 104pem , ec158 - 105pem , ec159 - 001lepef , ec159 - 002lepef , ec159 - 003lepef ,
ec159 - 004lepem , ec159 - 005lepef , ec159 - 006lepef , ec159 - 007lepem , ec159 - 008lepef ,
ec159 - 010lepem , ec159 - 011lepem , ec159 - 013lepef , ec159 - 016lepef , ec159 - 017lepef ,
ec159 - 018lepef , ec159 - 019lepef , ec159 - 019lepef , ec159 - 020lepef , ec159 - 021lepef ,
ec159 - 022lepef , ec159 - 023lepef , ec159 - 100pem , ec159 - 101pem , ec159 - 102pem , ec159 - 103pem ,
ec159 - 104pem , ec159 - 105pef , ec159 - 106pef , ec159 - 107pem , ec159 - 108pem , ec159 - 109pem ,
ec159 - 110pem , ec159 - 111pem , ec160[15l ] , ec160[15l ] , ec160 - 001lepe ,
ec160 - 002lepemgen05/39 , ec160 - 003lepef , ec160 - 004lepem , ec160 - 005lepem , ec160 - 006lepem ,
ec160 - 007lepef , ec160 - 008lepef , ec160 - 100pef , ec160 - 102pe[m ] ( wrbue095 - 10 ; kf671041 ) ,
ec160 - 103pef , ec160 - 104pef , ec160 - 106pef , ec160 - 107pem , ec160 - 108pef , ec160 - 109pem ,
ec160 - 110pem , ec160 - 111pef , ec160 - 112pem , ec160 - 113pef , ec160 - 114pem , ec160 - 115pem ,
ec160 - 116pef , ec160 - 117pef , ec160 - 118pem , ec160 - 119pef , ec160 - 120pef , ec160 - 121pef ,
ec160 - 122pem , ec160 - 123pem , ec160 - 124pem , ec160 - 125pem , ec160 - 126pem , ec160 - 127pef ,
ec160 - 128pef , ec160 - 129pem , ec160 - 130pem , ec160 - 131pef , ec160 - 132pem , ec160 - 133pef ,
ec160 - 134pef , ec161 - 001(lepe)m , ec161 - 002(lepe)f , ec161 - 003(lepe)f , ec161 - 004(lepe)f ,
ec161 - 005(lepe)f , ec161 - 102(pe)m , ec173 - 001lepem , ec173 - 100(pe)f , ec173 - 101pem ,
ec215 - 001lepef , ec215 - 002lepemgen05/48 , ec215 - 003lepef , ec215 - 100pem , ec218 - 001lepe ,
ec218 - 002lepef , ec218 - 003f , ec218 - 004lepef , ec218 - 005lepef , ec218 - 100pef , ec218 - 102pem ,
ec218 - 104pef , ec218 - 106pem , ec218 - 107pef , ec218 - 108pef , ec218 - 109pef , ec218 - 110pef ,
ec218 - 112pef , ec218 - 113pef , ec264(64 m ) , ec264(68f ) , ec264 - 104pemgencp ,
ec264 - 105pemgencp , ec264mgen12/11 , ec264mgen12/12 ; wy .
( n = 77 ) , ec158 - 001lepef , ec158 - 008lepem ,
ec158 - 009lepef , ec158 - 106pem , ec159 - 009lepem , ec159 - 012lepem , ec159 - 014lepem ,
ec159 - 015lepef , ec160 - 101pem , ec160 - 105pef , ec161 - 100pem , ec161 - 101(pe)mgen05/40 ,
ec189 - 001lepem , ec189 - 100pemgen05/62 , ec189 - 101pef , ec189 - 102pef , ec189 - 103pem ,
ec189 - 104pem , ec189 - 105pef , ec189 - 106pem , ec193[20l ] , ec193 - 001lepef , ec193 - 002lepem ,
ec193 - 003lepef , ec193 - 004lepef , ec193 - 005lepef , ec193 - 006lepef , ec193 - 007lepef ,
ec193 - 008lepef , ec193 - 009lepef , ec193 - 010lepef , ec193 - 011lepef , ec193 - 012lepe ,
ec193 - 013lepef , ec193 - 014lepef , ec193 - 015lepef , ec193 - 016lepef , ec193 - 100pem ,
ec193 - 101pef , ec193 - 102pef , ec193 - 103pef , ec193 - 104pem , ec193 - 105pef , ec195 - 101pef ,
ec218 - 101pef , ec218 - 103pef , ec218 - 105pem , ec218 - 111pe , ec107 - 002lepef , ec107 - 009lepef ,
ec107 - 016lepef , ec107 - 019lepef , ec107 - 022lepem , ec107 - 024lepem , ec107 - 101pem ,
ec107 - 107pef , ec107 - 117pem , ec108 - 100lepem ; wy . (
dod . ) aphobema ( n = 35 ) , ec108 - 002lepemgen01/12 ,
ec108 - 003lepef , ec108 - 004lepef , ec108 - 005lepef , ec108 - 006lepef , ec108 - 007lepef ,
ec108 - 008lepef , ec108 - 009lepef , ec108 - 010lepem , ec108 - 011lepem , ec108 - 012lepef ,
ec108 - 013lepef , ec108 - 014lepemgen01/13 , ec108 - 101pef , ec108 - 102pem , ec108 - 104pem ,
ec108 - 105pef , ec135 - 004lepef , ec138 - 001lepem , ec138 - 002lepef , ec138 - 003lepef ,
ec138 - 004lepef , ec138 - 005lepem , ec138 - 100pef , ec147 - 001lepem , ec147 - 007lepef ,
ec147 - 008lepem , ec147 - 009lepef , ec147 - 011lepem , ec147 - 100pe[m ] ( wrbue092 - 10 ; kf671035 ) ,
ec156 - 001lepem , ec161 - 006lepef , ec268 - 001lepem , ec268 - 100pem , ec268 - 101pem ; wy .
. aphobema ( n = 1 ) ,
ec156 - 100pe[m ] ( wrbue099 - 10 ; kf671036 ) ; wy .
autocratica ( n = 3 ) , ec105 - 002pef , ec105 - 006pef ,
ec105 - 103pemgencp ; wy .
lamellata ( n = 1 ) , ec108 - 103pemgen01/10 ; wy . (
hys . )
( n = 2 ) , ec207 - 004lepemgen05/46 , ec207 - 100pef ;
wy .
codiocampa ( n =
11 ) , ec132 - 001lepef , ec132 - 002lepem , ec132 - 006lepemgen05/28 , ec132 - 008lepemgen02/60 ,
ec132 - 009lepef , ec132 - 011lepef , ec132 - 015lepef , ec132 - 100pef , ec132 - 101pef ,
ec204 - 002lepem , ec204 - 003lepef ; wy .
oblita ( n = 3 ) , ec133 - 003lepemgen05/30 , ec133 - 004lepem , ec204 - 001lepem ;
wy .
nr . codiocampa
( n = 1 ) , ec132 - 019lepemgencp ; wy .
( n = 11 ) , ec132 - 010lepef , ec132 - 012f , ec132 - 013lepef , ec132 - 014mgen05/29 ,
ec132 - 016lepef , ec132 - 017f , ec132 - 018mgen02/61 , ec132 - 020lepef , ec132 - 021lepef ,
ec132 - 022lepef ; wy .
nr .
albosquamata ( n = 4 ) , ec135 - 003lepem , ec147 - 003lepemgencp , ec147 - 004lepem ,
ec147 - 006lepef ; wy .
.
medioalbipes ( n = 1 ) , ec104 - 001lepef ; wy .
( n = 6 ) , ec135 - 002lepef , ec147 - 002lepemgen02/66 ,
ec147 - 005lepef , ec147 - 010lepef , ec147 - 101pef , ec147 - 102pef . | two snapshot surveys to establish the diversity and ecological preferences of
mosquitoes ( diptera : culicidae ) in the terra firme primary rain
forest surrounding the tiputini biodiversity station in the unesco yasun biosphere
reserve of eastern amazonian ecuador were carried out in november 1998 and may 1999 .
the mosquito fauna of this region is poorly known ; the focus of this study was to
obtain high quality link - reared specimens that could be used to unequivocally confirm
species level diversity through integrated systematic study of all life stages and
dna sequences .
a total of 2,284 specimens were preserved ; 1,671 specimens were
link - reared with associated immature exuviae , all but 108 of which are slide mounted .
this study identified 68 unique taxa belonging to 17 genera and 27 subgenera . of
these , 12 are new to science and 37 comprise new country records .
dna barcodes
[ 658-bp of the mtdna cytochrome c oxidase ( coi ) i gene ] are
presented for 58 individuals representing 20 species and nine genera .
dna barcoding
proved useful in uncovering and confirming new species and we advocate an integrated
systematics approach to biodiversity studies in future .
associated bionomics of all
species collected are discussed .
an updated systematic checklist of the mosquitoes of
ecuador ( n = 179 ) is presented for the first time in 60 years . | <s>[INST]specimen collection - mosquito collections were carried out in a range
of natural and artificial habitats in the forest environment within a 10 km
circumference of the tbs , yasun biosphere reserve and national park , orellana province ,
ecuador ( fig .
s1 ) . collections ( n = 121 ) of immature mosquitoes were carried out in aquatic habitats within
the forest , including permanent standing water bodies ( e.g. , stream margins , lakes ) ,
temporary water bodies ( e.g. , ground pools , tree holes ) and container habitats ( e.g. ,
rainwater collections in bromeliad and heliconia axils as well as
artificial containers and oviposition traps ) .
each discreet habitat was registered as a
separate collection and detailed notes on habitat and locality information noted on a
standardised collection form , which can be downloaded from the walter reed
biosystematics unit ( wrbu ) website ( wrbu.si.edu/techniques.html ) . where gaps in the
forest canopy permitted , gps readings were taken .
otherwise , detailed notes on each
locality were documented in relation to positions along the tbs trails , allowing
retrospective georeferencing using google earth .
all coordinates were converted to
decimal degrees ( foley et al . 2009 ) and
distributions records are freely available in mosquitomap ( mosquitomap.org ) . depending on habitat ,
immature mosquitoes were collected using either a standard larval
dipper ( bioquip , ca , usa ) or a turkey baster and carefully transferred to a
whirlpak plastic bag , using wide - mouth glass pipettes for transport to
the laboratory .
specimens were individually link - reared to adults , following the
modified procedures of belkin et al .
( 1965 )
summarised in gaffigan and pecor ( 1997 ) ,
ensuring a good series of high - quality morphological voucher adult specimens ( of both
sexes ) with associated larval and/or pupal skins upon which to undertake the
morphological assessment .
the associated immature exuviae were preserved in 80% ethanol and
subsequently mounted on microscope slides .
a subset of male genitalia were clipped and
mounted on microscope slides for further taxonomic verification .
in addition to
morphological vouchers , some whole larvae and reared adult specimens ( particularly
males ) of perceived morphotaxa were preserved in 100% ethanol for later dna
analysis .
human landing catches were not carried out in this study , but a few individuals found
landing on the collectors whilst up the tower in the canopy were collected using manual
aspirators and later pinned ( ec126 , ec168 ) .
in addition , three shannon traps ( ec124 ,
ec139 , ec259 ) , one indoor resting ( ec219 ) and one outdoor resting ( ec127 ) collection
yielded adults ( fig .
s1 , supplementary data 1 ) .
in some cases , identification was impossible due to poor quality ( rubbed ) specimens and
lack of differentiating characters in the adult female life stage .
only those adults
identified with certainty are reported to species herein ; all others are identified to
subgenera .
morphological identification - there is no single morphological key to
facilitate the identification of all known mosquitoes of ecuador .
the multi - entry
web - based keys developed by the wrbu for south america
( wrbu.si.edu/southcom_mqkeys.html ) were used to determine generic level identifications
and species level identification for some better - known taxa .
these multi - entry keys
facilitate identification of damaged specimens by the ability to skip questions directed
at missing or damaged body parts .
in addition , available dichotomous keys and original
species descriptions of all life stages and the male genitalia were compiled through
literature freely available on the wrbu website ( wrbu.org ) .
important references used for species identifications by taxonomic groups included :
tribe aedini ( berlin 1969 ,
schick 1970 , zavortink 1972 , arnell 1973 ) ,
anopheles ( cova - garcia 1961
, zavortink 1973 , faran 1980 , faran & linthicum
1981 , wilkerson & sallum 1999 ,
gonzlez & carrejo 2007 ) ,
chagasia ( harbach & howard
2009 ) , culex ( rozeboom
& komp 1950 , bram 1967 , valencia 1973 , berlin & belkin 1980 , pecor et al .
1992 , sallum & forattini 1996 ) ,
haemagogus ( zavortink 1972
, arnell 1973 ) , onirion ( harbach & peyton 2000 ) ,
psorophora ( guedes & souza
1964 ) , sabethes ( harbach
1991 , hall et al . 1999 ) ,
trichoprosopon ( stone 1944 ,
zavortink 1979a , b ) and wyeomyia ( judd 1998 ) .
authors associated with species names , along with standardised generic and subgeneric
abbreviations , are given in the final ecuador species list ( supplementary data 2 ) .
molecular identification - dna from single legs plucked from pinned
adults or whole ethanol - preserved larva or adults were extracted using the
qiagen dneasy blood & tissue kit on the biosprint 96 automated dna
extraction platform ( qiagen , germantown , md , usa ) . a 710-bp amplicon ( 658-bp
less primers ) corresponding to the universal barcoding region of the mitochondrial
coi
i gene was amplified using the lco1490 & hco2198 primers of
folmer et al .
( 1994 ) , using the standard protocol of the mosquito barcoding initiative
( headed by y - ml and rcw ) .
each pcr contained 1 l of dna template , 1 x nh4
buffer , 0.5 mm of each deoxynucleotide triphosphate , 2 mm mgcl , 0.3 m each primer , 0.2
u of taq polymerase ( bioline , taunton , ma , usa ) , made up to a total volume of 10 l
using ddh20 . the polymerase chain reaction ( pcr ) cycle was : 95c for 5 min ,
35 cycles of 95c for 30 s , 48c for 30 min and 72c for 30 s , 72c for 5 min and a 10c
hold .
two microlitres of the pcr product was removed and mixed with 2 l of 5 x loading dye
before loading into wells in a 1.5% agarose gel containing 0.5 mg / ml of ethidium
bromide .
pcr
products were cleaned by adding 2 l of exosap - it ( usb co , cleveland , oh ,
usa ) , diluted 1:4 with ddh20 , to the remaining 8 l of positive pcr products .
samples were put back into the thermocycler and run at 37c for 30 min , followed by 80c
for 20 min .
bi - directional sequencing was carried out on an abi 3730 automated sequencer ( pe applied
biosystems , warrington , england ) using the original pcr primers and the
big dye terminator kit ( pe applied biosystems ) .
sequences were
edited in sequencher v.4.8 ( genes codes co , ann arbor , mi , usa ) .
similarities with publicly available sequences were assessed using basic local alignment
search tool ( blast.ncbi.nlm.nih.gov/blast.cgi ) .
comparisons with unpublished barcode
records were checked through the identification system of the barcode of life database
( bold ) ( barcodinglife.org/index.php/ids_openidengine ) .
intra
and interspecific variation was calculated using kimura two - parameter distance algorithm
( kimura 1980 ) in mega v.5.2.2 ( tamura et al . 2011 ) .
sixty variable nucleotide sequences were detected in
the 21 species dataset and all nucleotides were included in pairwise comparisons .
voucher specimens - details of voucher specimens stored in the culicid
and frozen collections of the smithsonian institution , national museum of natural
history ( nmnh ) , including associated exuviae , genitalia preps and dna , are explicitly
listed by species in supplementary data 3 .
full collection site details , including
georeferences and species determined by collection site are listed in supplementary data
1 .
collection numbers run sequentially , but ec101 - 102 , ec109 , ec119 , ec129 , ec182 ,
ec185 , ec190 - 192 , ec211 , ec260 - 261 and ec265 yielded no specimens and are omitted .
fully digitised specimen level data records and the original collection sheets are held
in the wrbu accession acc1682 and are incorporated into the mosquitomap section of
vectormap ( vectormap.org ) ( headed by dhf ) . a schematic map of the trails surrounding tbs
is available from y - ml on request .
details of specimens used for dna , along with
coi barcode sequences and the original chromatograms can be accessed
through the bold ( boldsystems.org ) under the project mosquitoes of the ecuadorian
amazon .
dna sequences are available in genbank ( ncbi.nlm.nih.gov/genbank ) under
accessions kf670990-kf671024 and kf671027-kf671044 .
mosquito collections were carried out in the forest environs around the tbs between 29
october-13 november 1998 ( wrbu acc1682 ; collections ec100-ec219 ) and 25 may-2 june 1999
( wrbu acc1682 ; collections ec254-ec270 ) .
these focussed primarily on collections of
immatures for link - rearing , but also included a few adult collections ( shannon trap ,
incidental human landing , indoor resting and outdoor resting ) .
a total of 2,284 voucher
specimens are preserved and these are housed in the mosquito collections of the
smithsonian institution , nmnh . of these ,
1,671 specimens have associated immature
exuviae , all but 108 of which are slide mounted . to further verify species
identifications ,
the male genitalia of 121 individuals were softened overnight , then
clipped , cleared and permanently mounted on slides .
slide - mounted exuviae and male
genitalia preps are labelled with the same unique specimen numbers as their associated
adults .
full details of associated life stages ( including genbank accessions for
sequenced specimens ) are listed in supplementary data 3 .
biodiversity survey ( morphology and dna barcodes ) - this study
identified 68 unique taxa belonging to 17 genera and 27 subgenera as follow :
anopheles ( an . ) [ subgenera anopheles
( ano . ) , kerteszia ( ker .
) , lophopodomyia ( lph . ) , nyssorhynchus
( nys . ) , stethomyia (
ste . ) ] , chagasia ( ch . ) ,
culex ( cx . ) [ subgenera anoedioporpa
( and . ) , carrollia ( car .
) , culex ( cux . ) , melanoconion (
mel . ) , microculex ( mcx . )
] ,
haemagogus ( hg . ) [ subgenus haemagogus
( hag . ) ] , limatus ( li .
) , lutzia ( lt . ) [ subgenus lutzia
( lut . ) ] , ochlerotatus ( oc . )
[ subgenera chrysoconops ( chs . ) , protoculex
( pcx . ) , protomacleaya (
pro . ) ] , onirion ( on . ) ,
orthopodomyia ( or . ) , psorophora
( ps . )
[ subgenera grabhamia (
gra . ) , janthinosoma ( jan . ) ] ,
runchomyia ( ru . ) [ subgenus ctenogoeldia
( cte . ) ] , sabethes ( sa .
) [ subgenera peytonulus ( pey . ) , sabethes
( sab . ) ] , toxorhynchites (
tx . ) [ subgenus lynchiella (
lyn . ) ] , trichoprosopon ( tr . ) ,
uranotaenia ( ur . )
[ subgenus uranotaenia
( ura . ) ] and wyeomyi a (
wy . )
[ subgenera decamyia ( dec .
) , dodecamyia ( dod . ) , hystatomyia
( hys . ) , miamyia ( mia . ) ,
wyeomyia ( wyo . ) ] . a quantitative list of all
confirmed species are given ( fig .
s1 ,
supplementary data 3 ) along with information on bionomics and collection localities
( fig .
s1 , supplementary data 1 ) . in conjunction with morphological analysis of available life stages
, dna barcodes were
generated for 58 questionable specimens and used to determine their specific identity .
coi sequences were compared with topotypic and/or expertly
identified specimens in the databank of the mosquito barcoding initiative and those
available in genbank .
comparison of these 58 sequences allowed the verification of 20
species in nine genera , including five of the new species discovered :
an .
somewhat incredibly , 37 of the 68 species confirmed here from yasun national park
comprise new country records for ecuador .
these include 12 species new to science and
one further undetermined species in ano- pheles (
stethomyia ) , a subgenus not previously reported from ecuador
( supplementary data 2 ) . more than half of all specimens collected ( 53.3% ) comprised the
following five species : wy .
subfamily anophelinae - anopheles : eight species of
anopheles were collected , representing five subgenera :
anopheles , kerteszia ,
lophopodomyia , nyssorhynchus and
stethomyia .
konderi and three specimens of an undetermined species of
anopheles subgenus stethomyia ( fig .
the specific identification of three specimens as belonging to
anopheles subgenus stethomyia , a new subgeneric
record for ecuador , was hampered as only two females remain .
the only male exemplar ,
stored in ethanol , was wholly destroyed in an earlier dna study and therefore its
genitalia could not be examined .
tip1 ) were unique with regard to others in
bold or genbank , thus it remains unclear whether the specimens collected represent a new
species or corresponds to one of the five already described species within the subgenus
stethomyia ( an .
thomasi shannon ) .
while it was not possible to positively confirm the identity of the species detected
here , coi sequence comparison with the three available
stethomyia species sequences have excluded an .
fluminensis was originally described from itaperuna ,
state of rio de janeiro , brazil and has never been reported from ecuador .
fluminensis ? by
morphology showed 2.75 - 3.77% sequence differences from two unpublished brazilian
specimens of an .
fluminensis in the mosquito barcoding initiative ( mbi )
dataset in bold ( mbii823 - 09 and mbii825 - 09 ) from pariquera ac , state of so paulo ,
brazil .
retrospective comparisons with brazilian specimens revealed morphological
differences and the species , designated herein as an .
these clustered together , varying by
only 0.2 - 0.61% over the 658-bp fragment , indicating these comprised the same species .
sequences were 99.01 - 100% identical to a new species determined from colombia ( caquet ) ,
ecuador ( orellana ) and peru ( madre de dios , loreto ) in ruiz - lopez et al .
( 2013 ) and 98.32% identical to genbank entry jf437965
( ac18 - 16 of sallum & laporta from acre brazil , listed as an .
oswaldoi ( ruiz - lopez et al .
2013 ) inadvertently uncovered the presence of more than one species in the
specimens listed in the neotype description ( flores - mendoza et al .
our specimens here correspond to one of the
species barcoded from the neotype series , but it remains unclear whether this is true
efforts are underway to sequence the neotype , but in
the meantime we designate this species an .
( ano . ) costai ( 95.17 - 96.18% identity , jx205127 and hm022403 from
colombia ) .
squamifemur
and the undetermined anopheles ( ste . )
species comprise six new country records for anopheles in ecuador .
, two specimens were found to be highly genetically distinct ( minimum 10.84%
sequence divergence ) .
retrospective detailed morphological study confirmed morphological
differences and showed this novel taxa was most similar to ch .
subfamily culicinae - tribe aedini - eight species of the tribe aedini
were collected in this study , representing three genera and six subgenera , as follow :
hg .
tribe culicini - twenty - six species of tribe culicini were collected
in this study ( fig .
culex : twenty - five species of culex were
collected , representing five subgenera : cx .
ten
species of culex are reported from ecuador for the first time :
cx .
( and . )
browni ( n = 1 ) , cx .
bonnei ( n = 2 ;
intra - specific distance , 0.15% ) , cx .
urichii [ n = 6 ; mean
distance , 0.18% ( range 0 - 0.46% ) and cx .
mean intra - specific distances within culex
species ranged from 0 - 0.62% ( mean 0.21% ) whereas inter - specific differences ranged from
9.0 - 15.69% ( mean 13% ) .
conservator , was compared against unpublished
sequences in the mbi dataset generated from near topotypic specimens from trinidad .
browni
coi sequence shared 96.77 - 96.93% sequence similarity with the
unpublished mbi cx .
( cux . ) coronator
group . of the six recognised species in this complex ( cx .
usquatissimus dyar ) ( bram 1967 ) , the presence of only cx .
usquatus ( n = 3 ) were verified
through examination of slide - mounted male genitalia .
the remaining specimens from yasun
national park and the group as a whole need further examination .
(
lut . ) allostigma collected herein represent the
first report of this species in ecuador ( fig .
s1 ,
supplementary data 3 ) . heinemann and belkin
( 1979 ) previously reported an undetermined species of the genus ( as
culex subgenus lutzia ) , but it is unclear whether
these were lt .
all specimens collected here were found in
water collected in palm bracts on the ground or in bamboo stumps filled with boiled leaf
water ( fig .
intra - specific
variation ranged from 0.15 - 0.31% and was closest to the published sequence of
cx .
fascipes were collected as immatures in a small tree
hole ( n = 2 , ec175 ) and one in the internode of fallen , living bamboo ( ec197 ) ( fig .
tribe sabethini - limatus : two species of the genus
limatus were recorded : li .
this is the first public barcode available for this species and while it
100% matched six undetermined specimens in bold , the next most similar unpublished
sequence was that of li .
magna was identified , reared from a pupa collected in
ground seepage ( ec130 ) .
sabethes : a new species , sa .
( pey . ) sp . nr . luxodens , was discovered as
immatures in a bamboo internode ( ec132 , n = 4 ) , along with an adult female , identifiable
only to subgenus sabethes ( ec219 ) .
digitatum ( n = 279 ) was the second most numerous species
collected in this study .
digitatum ( 0.62% difference ) ; these comprise the first published
trichoprosopon
coi sequences .
lampropus were collected from water collected in a palm bract ,
lying on the ground ( supplementary data 1 , 3 ) .
wyeomyia : due to lack
of updated keys , species of the genus wyeomyia are notoriously
difficult to identify .
many wyeomyia specimens have been identified
only to subgenus and these specimens form part of a larger revisionary study of the
genus by chp .
of the 12 wyeomyia species identified herein , six were
new to science : wy .
oblita ] , all but
wy . ( dod . ) aphobema are new country records for ecuador ( fig .
( dec . ) ulocoma ( n = 8 ; mean distance 0.7 , range 0 - 1.55% ) ,
wy . ( dod . )
nr . aphobema ( n = 1 ) , with the latter
discovered by dna .
sequence variation between the three species sequenced ranged from
4.6 - 10.66% ( mean 9.94% ) .
tribe toxorhynchitini - toxorhynchites : two species
of the toxorhynchites subgenus lynchiella were
identified : tx .
bambusicola reported here were collected in three separate collections
( ec197 , ec203 , ec254 ) and these comprise a new country record for ecuador ( fig .
only one dna barcode
was determined for an undetermined species of toxorhynchites ( as
toxorhynchites sp . tip1 in figure ) .
this sequence was most similar ( 87.7% ) to the published sequence of
tx .
figurebootstrap consensus tree of cytochrome c oxidase sequences ( n = 58 )
inferred using the neighbour - joining method of saitou and nei ( 1987 ) .
branches corresponding
to partitions reproduced in less than 50% of replicates are collapsed .
percentage of replicate trees in which the associated taxa clustered together
in the bootstrap test is shown next to the branches .
evolutionary distances
were calculated using kimura two - parameter distance algorithm ( kimura 1980 ) .
calosomata collected as pupae in the large lake
( ec112 ) form another new country record ( fig .
an integrated morphological and molecular approach such as advocated here facilitates
robust identification for the species found in amazonian ecuador .
dna barcodes were
useful in the discovery of several new species , which were at first overlooked by
morphological assessment alone .
efforts will continue to obtain species - diagnostic dna
barcode signatures for all other species documented in this collection and elsewhere in
ecuador .
a reference library of dna sequences , generated from well - vouchered
morphological specimens , will invariably facilitate the correct identification of adult
specimens , the stage most commonly captured in vector surveillance studies and currently
most difficult to identify using morphology alone .
bionomics - immature habitats - mosquito species are often highly
specific in their choice of oviposition site . in this study
, larval habitats could be
grouped into temporary and permanent groundwater habitats , artificial containers and
natural ( plant ) containers ( fig .
( ker . )
bambusicola ( exclusive to bamboo internodes ) and an .
( ker . )
lepidotus ( exclusive to bromeliads ) , immatures of all other species of
anopheles and chagasia were collected with ground
water habitats : an .
culex ( mel . ) immatures were
all recovered from ground water habitats , including ground pools , seepage and lake ,
swamp and stream margins ( fig .
s1 ) . permanent water bodies ( lakes , swamps , stream margins ) in the forest environs of the tbs
yielded a high diversity of taxa .
species collected at the edge of the four - hectare lake
( ec112 , ec199 , ec263 ) included an .
eighteen collections carried out
at stream margins ( ec100 , ec125 , ec127 , ec128 , ec145 , ec146 , ec152 , ec153 , ec163 , ec169 ,
ec170 , ec172 , ec198 , ec216 , ec257 , ec258 , ec260 , ec266 ) yielded immatures of the
following taxa : an .
( ano . ) and
chagasia were found at the edges of a large swamp ( ec255 , ec269 ) .
ground pools ( ec137 , ec148 , ec200 ) were occupied by an .
magna were collected from ground
seepage in open sunlight ( ec130 , ec134 ) ( fig .
many species were found occupying a variety of natural and artificial habitats at ground
level .
lampropus were collected
in small rainwater pools in palm bracts on the ground ( ec103 , ec110 , ec113 - 7 , ec120 - 1 ,
ec140 - 1 , ec143 , ec171 , ec175 , ec186 - 7 , ec194 ) .
aphobema were collected from rainwater pockets in a folded
tarpaulin on the forest floor ( ec157 ) .
digitatum were collected in a tree
hole in a fallen tree ( ec118 ) .
durhamii were collected in
a discarded 1.5 l plastic bottle lying on the forest floor ( ec188 ) in which rainwater
had collected .
dark plastic oviposition traps were placed at different heights up a tower in the
forest : at ground level ( ec209 , ec212 ) , at 5 m ( ec210 ) , at 8 m ( ec164 , ec167 ) , at 25 m
( ec213 ) and at the top of the tower ( 34 m , ec208 ) .
digitatum was
collected in the oviposition cups ( ovi - cup ) placed at every height ( ec167 , ec208 , ec209 ,
ec210 , ec213 ) .
an undetermined species of toxorhynchites w as reared
from an ovi - cup ( ec212 ) at ground level , cx .
digitatum
were collected together in an ovi - cup placed 34 m up at the top of the tower
( ec208 ) .
bamboo offers many discrete microhabitats for immature stages of forest mosquitoes ;
these microhabitats appear to be closely associated with certain mosquito species .
mollis were
collected from inside bamboo into which a hole had been artificially cut ( ec154 ) and
from cut , dry bamboo lying on the ground ( ec136 ) , along with li .
split aged bamboo sections were filled with boiled leaf water
and left on the forest floor to promote oviposition ( ec177 - 181 , ec183 - 184 , ec214 - 215 ,
ec217 ) .
haemorrhoidalis were collected from
internodes in dead bamboo ( ec202 - 203 , ec206 , ec270 ) whereas an .
( mia )
oblita were collected from internodes in living bamboo ( ec131 - 133 ,
ec196 , ec204 ) .
fascipes
were collected from a bamboo internode in fallen , living bamboo ( ec197 ) and
cx .
wilsoni from a bamboo internode in fallen , cut bamboo ( ec205 ) .
digitatum were collected from bamboo stumps ( ec155 , ec174 , ec201 ) ( fig .
anopheles mosquitoes of the subgenus kertezsia breed
almost exclusively in plant containers and serve as highly effective malaria vectors in
forested areas ( zavortink 1973 ) . whereas
an .
( ker . ) bambusicolus ( ec131 , ec254 ) was collected from internodes
in standing bamboo , we found that immatures of an .
lepidotus
were restricted to bromeliad axils ( ec104 , ec151 , ec166 , ec256 ) .
digitatum , it seems likely that this collection was
also a bromeliad axil collected from the tower .
water collections from bromeliad axils yielded a high diversity of mosquito species
including : an .
( ec104 - 105 , ec108 ,
ec135 , ec138 , ec147 , ec151 , ec156 , ec161 , ec166 , ec207 , ec256 , ec268 )
bambusicola were
all collected from bromeliad axils in high ( > 30 m ) in the forest canopy ( ec166 ,
ec207 , ec256 ) , accessed from the tower and canopy walkway .
bromeliad axils that fall to
the ground ( ec122 - 123 ) seem to loose their exclusivity and are occupied instead by
non - bromeliad - specific species such as culex ( car . )
( lut . ) allostigma , which appear to occupy almost all ground habitats .
excluding the fallen bromeliads ,
nine species were collected in this unique habitat ,
including three of the new wyeomyia species .
species found in the axils of heliconia plants ( ec106 , ec107 , ec144 ,
ec158 - 160 , ec173 , ec189 , ec193 , ec195 , ec218 , ec264 ) were limited to tr .
digitatum and wyeomyia ( dec . ) species
namely wy . ( dec . )
( cux . ) mollis , hg . ( hag . ) janthinomys , oc .
argyrothorax , or . fascipes and
wy .
( dec . )
ulocoma were collected in holes in living trees ( ec111 , ec142 , ec162 ,
ec173 ) .
mollis
females opportunistically laid egg rafts in rearing pans in the laboratory
( ec149 - 150 ) ( supplementary data 1 ) .
adult collections - due to the paucity of diagnostic female
characteristics , little effort was placed on collection of adults so only 142 adults
were collected in seven discrete collections .
three collections were carried out using
shannon traps ( ec124 , ec139 , ec259 ) , two human landing collections ( ec126 , ec168 ) , one
indoor resting ( ec219 ) and one outdoor resting collection ( ec127 ) ( supplementary data
1 ) .
only those indisputable specific identifications are listed , with most adult females
being identified to subgeneric level only ( supplementary data 3 ) .
an un - baited shannon trap set some 1.5 m above the ground ( ec124 ) yielded only one
lt .
allostigma , whereas setting the trap near a gas lantern
resulted in the collection of many more specimens as well as a wider variety taxa
( ec259 , n = 84 ) : an . ( nys . )
, hg . (
hag . ) sp . undet . , oc . ( chs . ) fulvus ,
oc .
, ps . ( jan . ) albipes and tr .
digitatum .
another shannon trap ( ec139 ) set high in the forest canopy ( c.
34 m at the top of the tower ) collected oc .
lanei
( n = 1 ) detected in this study ( supplementary data 1 , 3 ) .
digitatum was collected outdoor resting near the edge of a stream
( ec127 ) and indoor resting within the research station , along with undetermined species
of cx .
lepidotus was collected on two separate occasions trying to bite the
collectors some 34 m up in the canopy on the tower ( ec126 , ec168 ) ( supplementary data
1 ) . despite the unfocussed collecting effort , five of the 68 species reported ( 7.3% )
were collected only as adults , showing that adult collections are a valuable addition to
biodiversity surveys in this region .
current list of ecuadorian culicidae - given the relatively narrow
spatial and temporal range of this study , the biodiversity of mosquitoes collected was
quite remarkable . that more 16% of all taxa identified from the yasun national park in
these snapshot collections were new to science and 54% are new country records clearly
indicates that taxonomic study of ecuadorian fauna has been woefully neglected , at least
in the eastern amazonian region .
this prompted the authors to review the available
literature and to determine a current faunal list for the mosquitoes of ecuador
( supplementary data 2 ) . by far
the most productive mosquito taxonomist in ecuadorian history was roberto
levi - castillo , who published several species lists ( lev - castillo 1945 , 1949 , 1953 ) and many new species in the 40s and 50s , 30
of which remain valid species today ( supplementary data 2 ) .
levi - castillo published
several reports ( e.g. , lev - castillo 1956 ) in
which he listed species collected in ecuador , but these were composite lists , without
associated collection data or specimens . while there is no doubting his contribution to
the understanding of the mosquito fauna of ecuador , his disregard for preserving voucher
specimens has previously been highlighted ( e.g. , zavortink 1979a ) ( p. 13 ) . in their revisionary work ,
a catalog of the
mosquitoes of the world , knight and stone ( 1977 )
included the distributions of only verifiable records . to create this updated species list for ecuador , we used knight and stone ( 1977 ) as a basis and included all species reported in
verified peer reviewed publications since , reflecting revisions in taxonomy ( knight 1978 , faran
1979 , heinemann & belkin 1979 ,
zavortink 1979a , b , berlin & belkin 1980 ,
sirivanakarn 1982 , ward 1984 , forattini & sallum
1989 , hall et al . 1999 ,
our findings show that 179 mosquito
species have been recorded in ecuador to date , representing 26 genera and 39 subgenera
( supplementary data 2 ) .
this is the first published list of ecuadorian culicidae since
lev - castillo ( 1953 ) and we hope this serves
as a useful systematics platform for future work on the mosquitoes of ecuador .
s1 : mosquito taxa identified from forest habitat in the ecuadorian amazon ,
detailing diversity in larvae habitats and adult collections methodology .
some
68 unique taxa , representing 17 genera and 27 subgenera and 12 species new to
science , were collected in this study .
two undetermined species representing
new subgeneric records for anopheles (
stethomyia ) and sabethes (
sabethes ) are also included .
anopheles sp . nr . konderi
is the same taxa as in ruiz - lopez et al . (
usquatus have been unequivocally
confirmed using slide - mounted genitalia and are listed separately .
habitat details and associated species per collection
all collections were carried out in the environs of the tbs by rcw .
ec100 . harpa trail 750 m : stream margin , slow clear water , heavy shade .
wy . (
dec . ) ulocoma [ -0.637087 , -76.150089 ]
( as ec106 ) wy . ( dec . ) ulocoma , wy .
( dec . )
pseudopecten ,
wy . ( dod . ) aphobema , wy .
undet . , ur . (
ura . ) calosomata [ -0.637087 , -76.150089 ] .
harpa trail 750 m : stream margin , heavy shade , in leaves and debris .
harpa trail 800 m : stream margin , heavy shade , turbid water . 02.xi.1998 .
. fluminensis
( immatures ) , tr . digitatum ( adult resting ) [ -0.630179 ,
-76.145504 ] .
rio tiputini ( c. 8 km from tiputini biodiversity station ) : seepage area ( 1 m
x 3 m ) , standing , turbid water in direct sunlight . 03.xi.1998 .
( as ec130 ) seepage area ( 0.5 m x 0.5 m x 0.05 m deep ) , clear water in direct
sunlight . cx .
( as ec135 ) small shallow ground pool , turbid water in direct sunlight .
undet . , oc . ( chs . ) fulvus , ps .
( gra . ) cingulata , ps .
ec140 . only georeference and habitat data recorded , fallen palm bract . 04.xi.1998 .
( as ec140 ) small stream margin ( c.1 m ) , in floating leaves and debris , clear
water , heavy shade . an .
( as ec140 ) small stream margin ( c.2 m ) , in floating leaves and debris , clear
water , heavy shade
( as ec147 ) ground pool at base of fallen tree ( 1 m x 2 m x 0.05 m )
harpa trail 800 m : small stream margin ( c.1 m wide ) , slow - moving clear water ,
heavy shade , no aquatic vegetation .
harpa trail 350 m : stream margin ( c.3 m wide ) , moderate flow , clear water , heavy
shade , no aquatic vegetation . 05.xi.1998 .
( as ec106 ) water collected in artificially cut hole in bamboo , partial shade .
07.xi.1998 .
( as ec158 ) wy . ( dec . ) ulocoma , wy .
( as ec158 ) wy . ( dec . ) ulocoma , wy .
( as ec156 ) wy . ( dec . ) ulocoma , wy .
rio tiputini , blackwater area ( c. 3.5 km from tiputini biodiversity station ) :
large stream margin ( c.15 m wide ) leading to flooded area , turbid water , partial shade .
harpa trail 750 m : small stream margin , semi - permanent , slow - moving , heavy
shade .
matapalo trail 450 m : small stream margin , semi - permanent , slow - moving , heavy
shade .
main camp at chorongo trail : aged bamboo internode , filled with boiled leaf
water .
maquisapa trail 6,300 m : small stream margin ( c.2 m wide ) , slow - moving turbid
water , heavy shade , in floating leaves and debris .
maquisapa trail 7,200 m : ground pool ( 1 m x 1 m ) , clear , standing water , heavy
shade , no aquatic vegetation .
( as ec104 ) bromeliad axil , c. 30 m up in tree . 14.xi.1998 .
( as ec169 ) large stream leading to swampy area , permanent turbid water , partial
shade .
wy . (
dec . ) ulocoma , wy . ( dec . )
rio tiputini ( 6 km from tiputini biodiversity station ) : bamboo internodes ( c.15 ) .
rio tiputini , blackwater area ( nr tiputini biodiversity station ) : large swampy
area ( c.10 hectares ) , permanent slow - moving clear water , partial shade .
( as ec104 ) bromeliad axils ( c.10 ) , nr top of 32 m tower .
harpa trail 750 m : small stream margin ( c.1 m wide ) , permanent slow - moving clear
water , heavy shade , in floating leaves and debris .
undet . , oc . ( chs . ) fulvus , oc .
sp . undet . , ps . ( jan . ) albipes ,
tr
guacamayo trail 550 m : small stream margin ( c.1 m wide ) , permanent , slow - moving
clear water , heavy shade .
ec263 . lake ( c. 4 hectares ) : permanent , standing turbid water , partial shade . 29.v.1999 .
an .
chorongo trail 1,100 m : small stream margin ( c.1 m wide ) , permanent slow - moving
clear water , heavy shade .
chorongo trail 800 m : palm frond , heavy shade . 01.vi.1999 . tx .
maquisapa trail 5,300 m : large swamp , permanent standing clear water , heavy
shade , in debris . 02.vi.1999 .
revised systematic checklist of 179 species of ecuadorian culicidae . species listed
include those published since the last major revision of world taxa by knight and stone ( 1977 ) ( knight 1978 , faran 1979 ,
heinemann & belkin 1979 , sirivanakarn 1979 , zavortink 1979a , b , berlin & belkin 1980 , ward 1984 , forattini & sallum
1989 , hall et al .
2004 , harbach &
howard 2007 , zavortink & chaverri
2009 , gonzlez et al .
species identified in this study are
underlined ; those underlined and in boldface comprise 37 new additions to the mosquito
records from ecuador .
the
classification used here follows that of zavortink ( 1979a , b ) , reinert et al .
( 2004 , 2005 ,
2006 , 2008 , 2009 ) and harbach and howard ( 2007 ) .
voucher specimens examined
morphological identifications are listed alphabetically by genus , subgenus and species .
undetermined specimens are listed as sp . undet . under the relevant generic or
subgeneric heading .
specimens are listed both by collection number , e.g. , ec118 and
unique rearing number , e.g. , ec118 - 003 .
numbers and letters following these codes
indicate the presence of associated larval le
exuviae
denoted in rounded brackets , e.g. ( lepe ) indicate skins are unmounted ; all others are
slide mounted .
m for male and
f for female , where this information was not deducible a ?
square brackets
[ e.g. ( m ) ] indicate that this life stage was preserved in ethanol for dna studies .
( 2005 ) , reinert
( 2009 ) and the abbreviation summary on the wrbu website
( mosquitocatalog.org/abbreviations.aspx ) .
specimens for which dna barcodes have been
generated are followed by their respective bold and genbank accessions in
parenthesis .
( ano . )
forattinii ( n = 13 ) , ec128 - 100pe[m ] ( wrbue070 - 10 ; kf670990 ) ; ec266[l ] ,
ec266 - 001(lepe ) [ ? ] , ec266 - 002(lepe)[m ] , ec266 - 003(lepe)m , ec266 - 004(lepe)f ,
ec266 - 005(lepe)f , ec266 - 006(lepe)f , ec266 - 007(lepe)f , ec266 - 008(lepe)f , ec266 - 100(pe)f ,
ec266 - 101(pe)f , ec266 - 102(pe)m ; an .
( ano . )
mattogrossensis ( n = 1 ) , ec263 - 002lepef ; an .
fluminensis ( n = 83 ) ,
ec125 - 001lepef , ec125 - 002lepem , ec125 - 003lepef , ec125 - 004lepef , ec125 - 005lepef ,
ec125 - 006lepef , ec125 - 007lepem , ec125 - 009lepef , ec125 - 010lepem , ec125 - 011lepef ,
ec125 - 014lepef , ec125 - 101pef , ec125 - 106pef , ec125 - 110pef , ec127 - 001lepef ,
ec127 - 002lepem , ec127 - 100pem , ec128 - 001lepef , ec128 - 002lepem , ec128 - 101pe[m]gen01/64
( mbii891 - 09 ; kf670994 ) , ec128 - 102pem , ec128 - 103pef , ec128 - 104pe[m ] , ec128 - 106pe[m ]
( wrbue083 - 10 ; kf670996 ) , ec128 - 115pef , ec128 - 116pem , ec145 - 001lepef , ec145 - 003lepem ,
ec145 - 004lepem , ec145 - 005lepem , ec145 - 102pef , ec146 - 001lepem , ec146 - 002lepem ,
ec146 - 003lepef , ec146 - 005lepef , ec148 - 001lepef , ec148 - 002lepef , ec148 - 003lepef ,
ec148 - 004lepef , ec148 - 005lepem , ec148 - 008lepem , ec148 - 100pe[m ] ( wrbue084 - 10 ; kf670995 ) ,
ec148 - 104pe[m ] ( wrbue089 - 10 ; kf670992 ) , ec152 - 001lepem , ec152 - 002lepef , ec152 - 003lepem ,
ec152 - 004lepef , ec152 - 005lepef , ec152 - 006lepef , ec152 - 007lepef , ec152 - 008lepem ,
ec152 - 009lepef , ec152 - 100pem , ec152 - 102pef , ec152 - 103pem , ec163 - 001lepem ,
ec169 - 011lepe[f ] , ec170 - 001lepem , ec170 - 002lepef , ec170 - 005lepef , ec172 - 001lepef ,
ec172 - 002lepe[m ] ( wrbue116 - 10 ; kf670993 ) , ec200 - 001lepef , ec200 - 002lepef ,
ec200 - 003lepem , ec200 - 004lepem , ec200 - 005lepef , ec200 - 006lepef , ec200 - 007lepef ,
ec200 - 008lepef , ec200 - 100pef , ec200 - 101pef , ec216 - 117pef , ec216 - 118pef , ec216 - 124pef ,
ec216 - 146pef ,
ec269 - 005lepef , ec269 - 006lepem , ec269 - 015lepef , ec269 - 016lepem ,
ec269 - 017lepe [ ? ] , ec269 - 107pef , ec152 - 010lepe[m ] ; an .
( n = 4 ) , ec123 - 006lepem , ec255 - 002lepe[m ] ,
ec255 - 007lepe[m ] , ec263[l ] ; an . ( ker . )
bambusicolus ( n = 7 ) , ec131 - 001lepemgen01/63 , ec254 - 003lepe[m]gen01/58 ,
ec254 - 004lepe[m]gen01/59 , ec254 - 009lepem , ec254 - 012lepem , ec254 - 103pef , ec254 - 106pef ;
an .
( ker . ) lepidotus ( n = 34 ) ,
ec104 - 002lepef , ec104 - 003lepe , ec126(a)[f ] ( wrbue079 - 10 ; kf670991 ) ,
ec151 - 001lepe[m]gen99/01 ( mbii893 - 09 ; jq041286 ) , ec151 - 002lepem , ec151 - 003lepem ,
ec151 - 004lepem , ec151 - 005lepe[m]gen99/02 ( lepho001 - 11 ; jq041283 ) , ec151 - 009lepem ,
ec151 - 010lepem , ec151 - 100pef , ec151 - 101pem , ec151 - 102pef , ec151 - 103pem ,
ec165 - 102(pe)[m ] , ec166 - 002lepef , ec166 - 003lepef , ec166 - 004pemgen99/05 , ec166 - 006lepef ,
ec166 - 101pemgen99/03 , ec166 - 102pemgen99/04 ( lepho002 - 11 ; jq041285 ) , ec168a[f ]
( mbii894 - 09 ; jq041282 ) , ec168b[f ] ( mbii895 - 09 ; jq041284 ) , ec168[f ] , ec168[f ] , ec168[f ] ,
ec207 - 002lepem , ec256 - 001lepef , ec256 - 002lepef , ec256 - 003lepef , ec256 - 104pem ,
ec256 - 105pef , ec256 - 106pem , ec256 - 107pem ; an .
( lph .
) squamifemur ( n = 9 ) , ec125 - 107pe[m]gen01/65 , ec169 - 001lepe[m ] ,
ec169 - 132pem , ec169 - 133pe[m]gen01/66 , ec216 - 013lepef , ec216 - 017lepem , ec216 - 018lepe[f ] ,
ec216 - 019lepef , ec216 - 020lepef ; an .
konderi ( n = 154 ) , ec112 - 008lepef , ec128 - 117pemgen01/132
( wrbue114 - 10 ; kf670997 ) , ec145 - 002lepe[m ] ( wrbue101 - 10 ; kf670998 ) , ec169 - 002(lepe)[f ]
( wrbue105 - 10 ; kf671001 ) , ec169 - 004lepe[m ] ( wrbue109 - 10 ; kf671002 ) , ec169 - 005(lepe)f ,
ec169 - 007lepe[m ] ( wrbue112 - 10 ; kf671000 ) , ec169 - 008lepem , ec169 - 012(lepe)f ,
ec169 - 013lepem , ec169 - 014(lepe)f , ec169 - 015lepem , ec169 - 126(pe)[m ] ( wrbue111 - 10 ;
kf670999 ) , ec216[8l ] , ec216 - 001lepef , ec216 - 002lepef , ec216 - 003lepef , ec216 - 004lepef ,
ec216 - 005lepef , ec216 - 006lepef , ec216 - 007lepef , ec216 - 008lepef , ec216 - 009lepef ,
ec216 - 010lepe[m]gen01/68 , ec216 - 011lepef , ec216 - 012lepef , ec216 - 014lepef ,
ec216 - 015lepem , ec216 - 016lepef , ec216 - 021lepem , ec216 - 022lepef , ec216 - 023lepef ,
ec216 - 100pef , ec216 - 104pem , ec216 - 105pem , ec216 - 106pef , ec216 - 108pe[m ] , ec216 - 109pef ,
ec216 - 110pe[m ] , ec216 - 111pef , ec216 - 112pem , ec216 - 113pem , ec216 - 114pem ,
ec216 - 115pe[m]gen01/67 , ec216 - 116pef , ec216 - 119pef , ec216 - 120pef , ec216 - 121pef ,
ec216 - 122pe[m ] , ec216 - 123pef , ec216 - 125pem , ec216 - 126pef , ec216 - 127pef , ec216 - 128pef ,
ec216 - 129pem , ec216 - 130pem , ec216 - 135pef , ec216 - 136pef , ec216 - 137pem , ec216 - 138pef ,
ec216 - 140pef , ec216 - 141pe[m ] , ec216 - 142pem , ec216 - 143pem , ec216 - 144pef , ec216 - 147pef ,
ec216 - 148pef , ec216 - 149pem , ec216 - 150pef , ec255[20l ] , ec255[30l ] , ec255 - 001lepe[m ] ,
ec255 - 003lepe[m ] , ec255 - 004lepem , ec255 - 005lepef , ec255 - 006lepem , ec255 - 008lepef ,
ec255 - 009lepem , ec255 - 010lepef , ec255 - 011lepef , ec255 - 012lepef , ec255 - 013lepem ,
ec255 - 014lepem , ec255 - 015lepef , ec255 - 016lepef , ec255 - 104pef , ec255 - 105pem ,
ec255 - 106(pe)m , ec255 - 107(pe)f , ec259(1f ) , ec269 - 001lepem , ec269 - 007lepef ,
ec269 - 008lepef , ec269 - 009lepef , ec269 - 010lepef , ec269 - 014lepef , ec269 - 018lepem ,
ec269 - 103pef , ec269 - 106pef ; an .
( n = 3 ) , ec269 - 100pe [ ? ] , ec269 - 101pe [ ? ] , ec269 - 102pe [ ? ] ; an .
( n = 3 ) , ec125 - 103pe[m ]
( wrbue074 - 10 ; kf671003 ) , ec125 - 105pe[f ] ( wrbue081 - 10 ; kf671004 ) , ec128 - 109pef .
bonneae ( n = 97 ) , ec169[30l ] ,
ec169 - 003lepef , ec169 - 006(lepe)f , ec169 - 009lepem , ec169 - 010(lepe)f , ec169 - 100pe[m ]
( wrbue097 - 10 ; kf671008 ) , ec169 - 101pe[m ] ( wrbue100 - 10 ; kf671007 ) , ec169 - 102(pe)f ,
ec169 - 103(pe)m , ec169 - 104(pe)f , ec169 - 105(pe)f , ec169 - 106(pe)f , ec169 - 107(pe)f ,
ec169 - 108pe[m ] ( wrbue104 - 10 ; kf671010 ) , ec169 - 109(pe)f , ec169 - 110(pe)f , ec169 - 111(pe)[m ]
( wrbue106 - 10 & soie296 - 13 ; kf671011 ) , ec169 - 112(pe)f , ec169 - 113(pe)m ,
ec169 - 114(pe)f , ec169 - 115(pe)[m ] ( wrbue108 - 10 ; kf671006 ) ,
ec169 - 116(pe)m ,
ec169 - 117(pe)m , ec169 - 118(pe)f , ec169 - 119(pe)f , ec169 - 120(pe)[m ] ( wrbue107 - 10 ;
kf671005 ) , ec169 - 121(pe)m , ec169 - 122(pe)m , ec169 - 123(pe)f , ec169 - 124(pe)f ,
ec169 - 125(pe)[m ] ( wrbue110 - 10 ; kf671009 ) , ec169 - 127(pe)m , ec169 - 128(pe)m ,
ec169 - 129(pe)f , ec169 - 130(pe)f , ec169 - 131(pe)f , ec169a[f ] , ec170 - 103pem , ec172 - 003lepef ,
ec216[20l ] , ec216 - 131pef , ec216 - 132pem , ec216 - 133pef , ec216 - 134pem , ec216 - 139pem ,
ec216 - 145pem , ec216 - 151pem , ec258 - 001lepem , ec260 - 100pem ; ch .
.
fajardoi ( n = 12 ) , ec125 - 104pe[f ] ( wrbue077 - 10 ; kf671012 ) ,
ec153 - 001lepef , ec153 - 100pef , ec170 - 003lepef , ec170 - 004lepef , ec170 - 100(pe)f ,
ec170 - 101(pe)f , ec170 - 102pe[m ] ( wrbue115 - 10 ; kf671013 ) , ec257 - 001lepem , ec257 - 002lepem ,
ec257 - 003lepem , ec257 - 004lepef ; ch .
bamborum ( n = 7 ) , ec131 - 002lepem , ec131 - 003lepef , ec131 - 004lepem ,
ec133 - 005lepef , ec254 - 007lepemgen05/58 , ec254 - 100pef , ec254 - 105pef ; cx .
browni ( n = 2 ) , ec118 - 004lepe[m ]
( wrbue091 - 10 ; kf671016 ) , ec133 - 002lepef ; cx .
. conservator ( n = 38 ) , ec110 - 001lepemgen01/14 ,
ec118 - 001lepemgen01/28 , ec118 - 005lepef , ec118 - 006lepef , ec118 - 007lepem , ec118 - 009lepef ,
ec118 - 010lepem , ec118 - 011lepem , ec118 - 014lepe[m ] ( wrbue094 - 10 ; kf671017 ) ,
ec118 - 016lepef , ec118 - 017lepem , ec118 - 019lepef , ec118 - 020lepem , ec118 - 021lepef ,
ec118 - 022lepef , ec118 - 023lepef , ec118 - 026lepef , ec118 - 027lepem , ec118 - 028lepef ,
ec118 - 029lepem , ec118 - 030lepef , ec118 - 032lepef , ec118 - 033lepem , ec118 - 036lepemgen01/29 ,
ec118 - 038lepem , ec118 - 040lepef , ec118 - 100pef , ec118 - 101pef , ec118 - 102pef , ec118 - 103pef ,
ec118 - 104pem , ec118 - 105pem , ec118 - 106pef , ec118 - 108pem , ec118 - 109pem , ec118 - 113pef ,
ec118 - 115pem , ec118 - 132pef ; cx .
bonnei ( n = 36 ) , ec123 - 024lepemgen01/38 , ec123 - 025lepef , ec136 - 004lepem ,
ec136 - 005lepem , ec136 - 006lepef , ec136 - 009lepef , ec136 - 010lepef , ec136 - 011lepef ,
ec136 - 012lepef , ec136 - 013lepef , ec136 - 014lepe[m ] ( wrbue119 - 10 ; kf671015 ) ,
ec136 - 015lepef , ec136 - 016lepem , ec136 - 017lepemgen02/26 , ec136 - 018lepem , ec136 - 100pef ,
ec136 - 101pe[m ] ( wrbue078 - 10 ; kf671014 ) , ec136 - 102pef , ec136 - 103pef , ec136 - 104pem ,
ec136 - 106pef , ec136 - 110pef , ec136 - 111pef , ec136 - 112pef , ec136 - 113pef , ec136 - 114pem ,
ec136 - 115pem , ec136 - 116pem , ec136 - 117pem , ec136 - 118pem , ec136 - 119pem , ec136 - 120pem ,
ec136 - 121pef , ec136 - 122pef , ec136 - 123pef , ec154 - 004lepem ; cx . (
car . ) iridescens ( n = 4 ) , ec270 - 002lepef ,
ec270 - 003lepem , ec270 - 004lepem , ec270 - 100pem ; culex (
car . ) secundus
( n = 4 ) , ec254 - 002lepem ,
ec254 - 010lepemgen05/57 , ec254 - 102pef , ec254 - 104pem ; cx . (
car . )
urichii ( n = 141 ) , ec103 - 001lepemgen01/02 ,
ec103 - 002lepem , ec103 - 003lepem , ec103 - 004lepem , ec103 - 005lepem , ec103 - 006lepem ,
ec103 - 007lepem , ec103 - 008lepef , ec103 - 009lepef , ec103 - 010lepef , ec103 - 011lepef ,
ec103 - 012lepef , ec103 - 013lepem , ec103 - 014lepef , ec103 - 015lepef , ec103 - 016lepef ,
ec103 - 017lepef , ec103 - 018lepef , ec103 - 019lepef , ec103 - 020lepem , ec103 - 021lepem ,
ec103 - 022lepef , ec103 - 023lepem , ec103 - 024lepef , ec103 - 025lepef , ec103 - 026lepef ,
ec103 - 027lepem , ec103 - 028lepem , ec103 - 029lepef , ec103 - 030lepem , ec103 - 031lepem ,
ec103 - 032lepem , ec103 - 033lepef , ec103 - 100pem ,
ec103 - 101pe[m ] ( wrbue068 - 10 ; kf671019 ) ,
ec103 - 102pef , ec103 - 103pef , ec103 - 104pef , ec103 - 105pe[m ] ( wrbue085 - 10 ; kf671022 ) ,
ec103 - 106pef , ec110 - 100pef , ec113 - 002f , ec114 - 002pe , ec114 - 006lepem , ec115 - 001lepe[m ]
( wrbue087 - 10 ; kf671021 ) , ec115 - 002lepef , ec115 - 003lepemgen01/22 , ec115 - 010lepe[m ]
( wrbue102 - 10 ; kf671023 ) , ec115 - 011lepem , ec115 - 013lepef , ec115 - 014lepem , ec115 - 015lepem ,
ec115 - 016lepem , ec115 - 017lepef , ec115 - 018lepef , ec115 - 019lepem , ec115 - 020lepem ,
ec115 - 021lepef , ec115 - 022lepef , ec115 - 023lepef , ec115 - 024lepem , ec115 - 025lepef ,
ec115 - 026lepem , ec115 - 027lepem , ec115 - 028lepef , ec115 - 029lepem , ec115 - 030lepem ,
ec115 - 031lepef , ec115 - 032lepef , ec115 - 033lepef , ec115 - 034lepef , ec115 - 035lepem ,
ec115 - 036lepem , ec115 - 037lepef , ec115 - 038lepef , ec115 - 039lepef , ec115 - 040lepem ,
ec115 - 041lepef , ec115 - 042lepef , ec115 - 043lepem , ec115 - 044lepem , ec115 - 045lepef ,
ec115 - 105pem , ec115 - 106pem , ec115 - 107pef , ec116 - 001lepef , ec116 - 002lepef ,
ec116 - 004lepem , ec116 - 005lepef , ec116 - 006lepem , ec116 - 007lepef , ec116 - 008lepem ,
ec116 - 009lepef , ec116 - 010lepef , ec116 - 011lepemgen01/24 , ec116 - 012lepef , ec116 - 013lepem ,
ec116 - 014lepef , ec116 - 015lepef , ec116 - 016lepef , ec116 - 017lepef , ec116 - 018lepem ,
ec116 - 019lepem , ec116 - 100pemgen01/25 , ec116 - 101pem , ec116 - 102pem , ec116 - 103pem ,
ec116 - 104pem , ec116 - 105pef , ec120 - 001lepef , ec121 - 001lepef , ec121 - 002lepe[m ]
( wrbue093 - 10 ; kf671020 ) , ec121 - 009lepemgen01/33 , ec121 - 010lepem , ec121 - 011lepef ,
ec121 - 012lepef , ec121 - 013lepef , ec121 - 100pef , ec121 - 108[?](wrbue069 - 10 ; kf671024 ) ,
ec121 - 109pef , ec121 - 111pef , ec121 - 113pef , ec121 - 114f , ec121 - 118pem , ec122 - 002lepef ,
ec122 - 003f , ec122 - 101pef , ec122 - 102f , ec123 - 005lepem , ec133 - 001f , ec135 - 001lepem ,
ec140 - 001lepef , ec140 - 002lepef , ec140 - 003lepem , ec140 - 004lepem , ec140 - 005lepem ,
ec140 - 006lepem , ec140 - 007lepem , ec140 - 100pem , ec140 - 101pef , ec140 - 102pem ; cx .
wilsoni ( n = 23 ) ,
ec196 - 003lepemgen02/30 , ec196 - 006lepem , ec205 - 001lepem , ec206[3l ] , ec206 - 001lepem ,
ec206 - 002lepem , ec206 - 003lepem , ec206 - 004lepemgen02/18 , ec206 - 005lepef , ec206 - 006lepem ,
ec206 - 007lepef , ec206 - 008lepef , ec206 - 009lepef , ec206 - 010lepef , ec206 - 011lepef ,
ec206 - 012lepem , ec206 - 013lepef , ec206 - 014lepem , ec206 - 015lepef , ec206 - 016lepef ,
ec206 - 100pem ; cx .
bonneae
( n = 21 ) , ec149[15l ] , ec149 - 001lepemgen02/27 , ec149 - 002lepem , ec149 - 003lepem ,
ec149 - 004lepem , ec149 - 005lepef , ec149 - 006lepef , ec166 - 005lepef ; cx .
(
cux . ) camposi ( n = 3 ) , ec130 - 102pemgen05/59 ,
ec134 - 005lepemgen05/34 , ec134 - 102pe[m]gen13/02 ; cx .
( n = 50 ) , ec130 - 001lepef ,
ec130 - 002lepef , ec130 - 003lepef , ec130 - 004lepef , ec130 - 101pef , ec134[15l ] ,
ec134 - 001lepef , ec134 - 002lepef , ec134 - 003lepef , ec134 - 004lepef , ec134 - 006lepef ,
ec134 - 007lepef , ec134 - 008lepef , ec134 - 009lepef , ec134 - 012lepef , ec134 - 013lepef ,
ec134 - 014lepem , ec134 - 015lepem , ec134 - 016lepef , ec134 - 017lepef , ec134 - 018lepef ,
ec134 - 019lepem , ec134 - 020lepef , ec134 - 021lepef , ec134 - 100pef , ec134 - 101pef ,
ec134 - 103pef , ec134 - 104pef , ec134 - 105pem , ec134 - 106pem , ec134 - 107pem , ec134 - 108pef ,
ec134 - 109pef , ec134 - 110pef , ec134 - 111pem , ec137 - 100pem ; cx .
(
cux . ) mollis ( n = 181 ) , ec113 - 001lepef ,
ec113 - 100pemgen01/20 , ec113 - 101pef , ec113 - 102pem , ec115 - 108pef , ec116 - 003lepemgen01/23 ,
ec118 - 002lepemgen01/30 , ec118 - 003lepef , ec118 - 008lepef , ec118 - 012lepem , ec118 - 013lepef ,
ec118 - 015lepef , ec118 - 018lepef , ec118 - 024lepem , ec118 - 031lepem , ec118 - 034lepef ,
ec118 - 035lepef , ec118 - 107pem , ec118 - 110pef , ec118 - 111pem , ec118 - 112pef , ec118 - 114pem ,
ec118 - 116pef , ec118 - 117pem , ec118 - 118pem , ec118 - 119pef , ec118 - 120pef , ec118 - 121apef ,
ec118 - 121bpef , ec118 - 122pem , ec118 - 123pem , ec118 - 124pem , ec118 - 125pem , ec118 - 126pem ,
ec118 - 127pem , ec118 - 128pem , ec118 - 129pem , ec118 - 130pef , ec118 - 131pem , ec120 - 101pef ,
ec120 - 103pef , ec121 - 003lepem , ec121 - 004lepem , ec121 - 005lepef , ec121 - 006lepem ,
ec121 - 007lepef , ec121 - 008lepem , ec121 - 101pef , ec121 - 102pef , ec121 - 103pef , ec121 - 104pef ,
ec121 - 105pef , ec121 - 112pem , ec121 - 115 m , ec121 - 116pef , ec121 - 117pef , ec122 - 001lepef ,
ec123 - 001lepemgen01/37 , ec123 - 002lepef , ec123 - 003f , ec123 - 004lepef , ec123 - 007lepef ,
ec123 - 008lepem , ec123 - 009lepef , ec123 - 010lepef , ec123 - 011lepef , ec123 - 012lepef ,
ec123 - 013lepemgen01/36 , ec123 - 014lepef , ec123 - 015lepem , ec123 - 016lepem , ec123 - 017lepem ,
ec123 - 018lepemgen01/35 , ec123 - 019lepem , ec123 - 020lepef , ec123 - 021lepef , ec123 - 022lepef ,
ec123 - 023lepef , ec123 - 100pef , ec123 - 101pef , ec123 - 102pem , ec123 - 103pef , ec123 - 104pef ,
ec123 - 105pem , ec123 - 106pem , ec123 - 107pem , ec123 - 108pem , ec123 - 109pem , ec123 - 110pem ,
ec123 - 111pem , ec123 - 112pef , ec123 - 113pem , ec123 - 114pem , ec123 - 115pem , ec136 - 002lepef ,
ec136 - 003lepemgen02/25 , ec136 - 007lepef , ec136 - 008lepef , ec141 - 001lepem ,
ec141 - 002lepemgen05/35 , ec141 - 003lepem , ec141 - 004lepem , ec141 - 005lepef , ec141 - 006lepef ,
ec141 - 100pem , ec141 - 101pem , ec143 - 001lepemgen02/62 , ec150[10l ] , ec150 - 002lepef ,
ec150 - 003lepef , ec150 - 004lepem , ec150 - 005lepef , ec150 - 006lepef , ec150 - 007lepef ,
ec150 - 008lepef , ec150 - 009lepef , ec150 - 100pem , ec150 - 101pem , ec150 - 102pemgen02/21 ,
ec150 - 103pem , ec150 - 104pem , ec150 - 105pem , ec150 - 106pem , ec150 - 107pem , ec150 - 108pem ,
ec150 - 109pem , ec150 - 110pem , ec150 - 111pem , ec150 - 112pem , ec150 - 113pem , ec150 - 114pem ,
ec150 - 115pem , ec150 - 116pef , ec150 - 117pem , ec150 - 118pef , ec150 - 119pem , ec150 - 120pem ,
ec150 - 121pem , ec150 - 122pem , ec150 - 123pem , ec150 - 124pem , ec150 - 125pem , ec150 - 126pem ,
ec150 - 127pem , ec150 - 128pem , ec150 - 129pem , ec150 - 130pem , ec150 - 131pem , ec150 - 132pem ,
ec154 - 001lepem , ec154 - 002lepef , ec154 - 003lepem , ec154 - 100pemgen05/37 ,
ec157 - 100pemgen05/38 , ec157 - 101pem , ec157 - 102pem , ec157 - 103pem , ec157 - 104pef ,
ec157 - 105pef , ec157 - 106pef , ec157 - 107pef , ec162 - 100pef ,
ec183 - 001lepemgen05/42 ,
ec183 - 002lepef , ec183 - 003lepef , ec183 - 004lepef , ec183 - 005lepef , ec183 - 100lepem ,
ec183 - 101lepem , ec183 - 102lepem , ec183 - 103lepem , ec121 - 110mgen01/34 ; cx .
usquatus ( n = 2 ) ,
ec134 - 010lepe[m]gen13/01 , ec134 - 011lepemgen05/61 ; cx .
( n = 17 ) , ec139(3f ) , ec259(9f ) , ec219(2f ) ,
ec219(3f ) ; cx .
chryselatus
( n = 22 ) , ec105 - 001lepemgen01/03 , ec105 - 003lepef , ec105 - 004lepef , ec105 - 005lepem ,
ec105 - 100pemgen01/04 , ec105 - 101pem , ec105 - 102pem , ec166 - 001lepef , ec207 - 003lepef ,
ec207 - 101pem , ec207 - 102pem , ec207 - 103pem , ec208 - 003pemgen02/31 , ec208 - 004pef ,
ec208 - 005pef , ec208 - 006pemgen05/47 , ec208 - 007pef , ec208 - 008pef , ec208 - 009pem ,
ec208 - 010pem , ec208 - 011pef , ec208 - 012pef ; cx .
( mcx .
) pleuristriatus ( n = 11 ) , ec164 - 001lepef , ec164 - 002(lepe)f ,
ec164 - 003(lepe)f , ec164 - 004(lepe)f , ec164 - 005(lepe)f , ec164 - 100(pe)f , ec164 - 101pem ,
ec164 - 102(pe)mgen02/20 , ec196 - 001lepem , ec196 - 002lepef , ec196 - 004lepem , ec196 - 005lepef ,
ec196 - 007lepemgen02/29 , ec196 - 008lepef , ec196 - 009lepe ; cx .
( n = 3 ) , ec256 - 100pef , ec268 - 102pef ,
ec207 - 001lepef ; cx .
eastor ( n = 4 ) , ec112 - 016lepef , ec112 - 102pem , ec112 - 108pemgen01/19 ,
ec112 - 109pef ; cx .
elevator
( n = 45 ) , ec100 - 001lepemgen01/01 , ec100 - 002lepem , ec100 - 003lepem , ec100 - 004lepef ,
ec100 - 100pem , ec100 - 101pemgen01/43 , ec125 - 013lepef , ec125 - 015lepef , ec125 - 016lepef ,
ec125 - 017lepef , ec125 - 018lepef , ec125 - 100pem , ec125 - 102pemgen01/40 , ec125 - 108pef ,
ec125 - 109pef , ec125 - 111pem , ec125 - 112pef , ec125 - 113pemgen01/41 , ec125 - 114pem ,
ec125 - 115pem , ec125 - 116pef , ec125 - 117pef , ec125 - 118pef , ec125 - 119pem , ec125 - 120pef ,
ec125 - 121pef , ec125 - 122pem , ec125 - 123pef , ec125 - 125pemgen01/42 , ec125 - 127pef ,
ec125 - 129pef , ec125 - 130pef , ec125 - 131pef , ec128 - 105pem , ec128 - 107pef , ec128 - 108pef ,
ec128 - 110pem , ec128 - 111pem , ec128 - 112pemgen02/24 , ec128 - 113pem , ec128 - 114pem ,
ec145 - 100pemgen02/64 , ec145 - 101pem , ec152 - 101pemgen05/36 , ec198 - 001lepemgen05/44 ;
cx .
evansae ( n = 8) ,
ec146 - 004lepemgen02/65 , ec148 - 108pef , ec148 - 109pemgen02/67 , ec148 - 110pemgen02/22 ,
ec148 - 111pem , ec148 - 112pem , ec148 - 113pem , ec148 - 114pem ; cx .
iolambdis ( n = 5 ) , ec125 - 008lepemgen01/39 ,
ec125 - 012lepef , ec125 - 124pem , ec125 - 126pem , ec125 - 128pem ; cx .
pilosus ( n = 18 ) , ec130 - 100pemgen05/60 ,
ec199 - 001lepem , ec199 - 003lepef , ec199 - 004lepef , ec199 - 005lepem , ec199 - 100pem ,
ec199 - 101pef , ec199 - 102pem , ec199 - 103pef , ec199 - 104pef , ec199 - 105pef , ec199 - 106pem ,
ec199 - 107pem , ec199 - 108pem , ec199 - 109pemgen02/19 , ec199 - 110pem , ec199 - 111pem ,
ec259mgen12/13 ; cx .
serratimarge ( n = 19 ) , ec112 - 001lepem , ec112 - 002lepef , ec112 - 003lepef ,
ec112 - 004lepef , ec112 - 005lepemgen01/15 , ec112 - 006lepef , ec112 - 007lepe[m ] ( wrbue088 - 10 ;
kf671018 ) , ec112 - 009lepef , ec112 - 011lepem , ec112 - 012lepef , ec112 - 013lepef ,
ec112 - 014lepemgen01/16 , ec112 - 017lepem , ec112 - 018lepef , ec112 - 100pemgen01/18 ,
ec112 - 101pem , ec112 - 103pem , ec112 - 106pef , ec112 - 107pem ; cx .
(
mel . ) symbletos ( n = 2 ) , ec112 - 015lepemgen01/17 ,
ec112 - 111pem ; cx . ( mel . )
theobaldi
( n = 9 ) , ec199 - 002lepemgen05/45 , ec199 - 112pef , ec216 - 107pef , ec255 - 100pem ,
ec255 - 101pem , ec255 - 102pem , ec255 - 103pem , ec259mgen12/14 , ec259mgen12/15 ; cx .
( n = 75 ) , ec112 - 110pem ,
ec148 - 115pem , ec256 - 101pef , ec256 - 103pef , ec259(1f ) , ec259(25f ) , ec259(38 m ) ,
ec269 - 011lepem , ec269 - 012lepem , ec148 - 006lepef , ec148 - 007lepef , ec269 - 013lepem ,
ec269 - 104pef , ec269 - 105pef .
( hag . )
janthinomys ( n = 1 ) , ec111 - 001lepef ; hg .
durhamii ( n = 61 ) , ec120 - 100pemgen01/31 ,
ec136 - 109pef , ec155 - 001lepef , ec155 - 002lepef , ec155 - 003lepef , ec155 - 004lepef ,
ec155 - 005lepef , ec155 - 006lepem , ec155 - 007lepem , ec155 - 008lepem , ec155 - 009lepem ,
ec155 - 010lepef , ec155 - 011lepem , ec155 - 012lepef , ec155 - 013lepem , ec155 - 014lepem ,
ec155 - 015lepef , ec155 - 016lepem , ec155 - 017lepem , ec155 - 018lepem , ec155 - 019lepef ,
ec155 - 020lepef , ec155 - 021lepef , ec155 - 022lepef , ec155 - 023lepem , ec155 - 024lepem ,
ec155 - 025lepem , ec155 - 026lepem , ec155 - 027lepem , ec155 - 028lepem , ec155 - 029lepem ,
ec155 - 030lepef , ec155 - 031lepef , ec155 - 100pef , ec155 - 101pem , ec155 - 102pef , ec155 - 103pef ,
ec155 - 104pef , ec155 - 105pem , ec155 - 106pem , ec155 - 107pem , ec155 - 108pef , ec155 - 109pef ,
ec155 - 110pef , ec155 - 111pem , ec155 - 112pem , ec155 - 113pem , ec155 - 114pef , ec155 - 115pem ,
ec155 - 116pef , ec188[3l ] , ec188 - 001lepef , ec188 - 002lepef , ec188 - 003lepef , ec188 - 100pef ,
ec188 - 101pem , ec188 - 102pef , ec188 - 103pe ; li
. flavisetosus ( n = 29 ) ,
ec115 - 004lepem , ec115 - 005lepem , ec115 - 006lepem , ec115 - 007lepem , ec115 - 008lepem ,
ec115 - 009lepef , ec115 - 012lepe[m](wrbue103 - 10 ; kf671027 ) , ec115 - 100pem ,
ec115 - 101pemgen01/21 , ec115 - 102pef , ec115 - 103pef , ec115 - 104pef , ec115 - 109pef ,
ec115 - 110pef , ec115 - 111pe[m ] , ec115 - 112pem , ec115 - 113pem , ec115 - 114pef , ec118 - 025lepef ,
ec120 - 102pemgen01/32 , ec136 - 105pef , ec136 - 107pef , ec136 - 108pem , ec171 - 001lepef ,
ec175 - 001lepef , ec175 - 100pef , ec201 - 001lepef , ec201 - 100pef , ec201 - 101pef ; li .
( lut . )
allostigma ( n = 14 ) , ec114 - 001lepe[m ] ( wrbue076 - 10 ; kf671030 ) ,
ec114 - 003lepef , ec114 - 004lepef , ec114 - 005lepef , ec114 - 007lepem , ec114 - 100pef ,
ec114 - 101pef , ec121 - 106pef , ec121 - 107pef , ec122 - 100pe[m ] ( wrbue071 - 10 ; kf671029 ) ,
ec124[f ] ( wrbue065 - 10 ; kf671028 ) , ec217 - 100pem , ec217 - 101pem , ec217 - 102pef .
( chs . ) fulvus ( n = 27 ) ,
ec259(1f ) , ec139(26f ) ; oc .
( pcx . )
serratus ( n = 5 ) , ec148 - 101pef , ec148 - 102pef , ec148 - 103pef , ec148 - 105pef ,
ec148 - 106pef ; oc .
argyrothorax ( n = 2 ) , ec142 - 001lepef , ec142 - 002lepef ; oc .
imparis ( n = 5 ) , ec202 - 001lepef ,
ec202 - 002f , ec202 - 003lepem , ec202 - 004lepef , ec254 - 005lepemgen05/32 .
orthopodomyia - or . fascipes ( n = 3 ) , ec176 - 100pef ,
ec176 - 101pem , ec197 - 002lepef .
( jan .
) albipes ( n = 1 ) , ec259(1f ) ; ps .
albigenu ( n = 4 ) , ec139(3f ) , ec148 - 107pef ;
ps .
lanei ( n = 1 ) ,
ec139(1f ) ; ps . ( jan . ) sp . undet .
( cte . )
magna ( n = 1 ) , ec130 - 005lepef .
.
luxodens ( n = 4 ) , ec132 - 003lepef , ec132 - 004lepem , ec132 - 005lepef ,
ec132 - 007lepemgen02/59 ; sa .
bambusicola ( n = 3 ) , ec197 - 001lepemgen05/63 , ec203 - 001lepef ,
ec254 - 011lepef ; tx .
haemorrhoidalis ( n = 9 ) , ec267 - 001lepe [ ? ] , ec267 - 002lepe [ ? ] , ec267 - 003lepem ,
ec267 - 004 m , ec267 - 005f , ec267 - 006lepem , ec267 - 007 m , ec267 - 008lepef , ec270 - 001lepem ;
tx .
( n = 2 ) , ec212 - 001lepe[m](wrbue090 - 10 ;
kj671031 ) , ec256 - 102pef .
digitatum ( n = 279 ) ,
ec117 - 001lepemgen01/26 , ec117 - 002lepef , ec117 - 003lepef , ec117 - 004lepem , ec117 - 005lepef ,
ec117 - 006lepef , ec117 - 007lepef , ec117 - 008lepef , ec117 - 009lepef , ec117 - 010lepem ,
ec117 - 011lepem , ec117 - 012lepef , ec117 - 013lepef , ec117 - 014lepef , ec117 - 015lepef ,
ec117 - 016lepem , ec117 - 017lepem , ec117 - 018lepef , ec117 - 019lepem , ec117 - 020lepef ,
ec117 - 021lepef , ec117 - 100pe[m ] ( wrbue113 - 10 ; kf671032 ) , ec118 - 037lepemgen01/27 ,
ec118 - 039lepem , ec118 - 041lepe , ec118 - 042lepem , ec127(a)[f ] ( wrbue080 - 10 ; kf671033 ) ,
ec139(1f ) , ec157 - 001lepem , ec157 - 002lepem , ec157 - 003lepem , ec157 - 004lepef , ec157 - 108pem ,
ec157 - 109pef , ec157 - 110pef , ec165 - 001lepem , ec165 - 002lepef , ec167 - 001lepem ,
ec167 - 002lepem , ec165 - 003(lepe)f , ec165 - 004(lepe)f , ec165 - 005(lepe)f , ec165 - 006(lepe)f ,
ec165 - 100(pe)m , ec165 - 101(pe)m , ec165 - 103(pe)m , ec165 - 104(pe)m , ec165 - 105(pe)m ,
ec165 - 106(pe)m , ec165 - 107(pe)f , ec165 - 108(pe)f , ec165 - 109(pe)f , ec165 - 110(pe)f ,
ec165 - 111(pe)f , ec165 - 112(pe)f , ec167[15l ] , ec167 - 003(lepe)m , ec167 - 004(lepe)f ,
ec167 - 005(lepe)m , ec167 - 006(lepe)f , ec167 - 007(lepe)f , ec167 - 008(lepe)m ,
ec167 - 009(lepe)m , ec167 - 010(lepe)f , ec167 - 011(lepe)f , ec167 - 012(lepe)f ,
ec167 - 013(lepe)f , ec167 - 014(lepe)f , ec167 - 015(lepe)f , ec167 - 016(lepe)f ,
ec167 - 017(lepe)f , ec167 - 018(lepe)f , ec167 - 100(pe)m , ec167 - 101(pe)m , ec167 - 102(pe)m ,
ec167 - 103(pe)m , ec167 - 104(pe)m , ec174 - 001lepem , ec174 - 002lepem , ec174 - 003(lepe)m ,
ec174 - 004(lepe)f , ec174 - 005(lepe)f , ec174 - 100(pe)m , ec177 - 001lepem , ec177 - 002lepem ,
ec177 - 003lepef , ec177 - 004lepef , ec177 - 005lepem , ec177 - 006lepef , ec177 - 100pem ,
ec177 - 101pef , ec178[5l ] , ec178[7l ] , ec178 - 001lepem , ec178 - 002lepem , ec178 - 003lepem ,
ec178 - 100pem , ec178 - 101pem , ec178 - 102pem , ec178 - 103pem , ec178 - 104pem , ec179 - 001lepef ,
ec179 - 002lepef , ec179 - 100 m , ec179 - 101pef , ec179 - 102pem , ec179 - 103pef , ec179 - 104pem ,
ec179 - 105pem , ec180 - 001lepem , ec180 - 002lepem , ec180 - 003lepef , ec180 - 004lepef ,
ec180 - 005lepef , ec180 - 006lepem , ec180 - 007lepem , ec180 - 008lepef , ec180 - 009lepef ,
ec180 - 010lepef , ec180 - 011lepef , ec180 - 012lepef , ec180 - 013lepef , ec180 - 100pem ,
ec180 - 101pem , ec180 - 102pem , ec180 - 103pef , ec180 - 104pef , ec180 - 105pem , ec181[10lp ] ,
ec181 - 001lepef , ec181 - 002lepem , ec181 - 003lepem , ec181 - 004lepef , ec181 - 100pem ,
ec181 - 101pef , ec181 - 102pem , ec181 - 103pem , ec184 - 001lepem , ec184 - 002lepef ,
ec184 - 003lepem , ec184 - 004lepef , ec184 - 005lepem , ec184 - 006lepem , ec184 - 007lepef ,
ec184 - 008lepef , ec184 - 009lepef , ec184 - 010lepef , ec184 - 100pem , ec184 - 101pef ,
ec184 - 102pef , ec184 - 103pemgen05/41 , ec184 - 104 m , ec184 - 105pem , ec186 - 001lepef ,
ec186 - 002lepef , ec186 - 003lepef , ec186 - 004lepef , ec186 - 005lepef , ec186 - 006lepef ,
ec186 - 007lepem , ec186 - 100pef , ec186 - 101pem , ec186 - 102pem , ec186 - 103pem , ec186 - 104pem ,
ec186 - 105pem , ec186 - 106pem , ec186 - 107pem , ec186 - 108pem , ec186 - 109pef , ec186 - 110pef ,
ec186 - 111pem , ec186 - 112pem , ec186 - 113pem , ec186 - 114pef , ec186 - 115pef , ec187 - 001lepem ,
ec187 - 002lepem , ec187 - 003lepef , ec187 - 004lepem , ec187 - 005lepem , ec187 - 006lepef ,
ec187 - 007lepef , ec187 - 008lepef , ec187 - 009lepef , ec187 - 010lepef , ec187 - 011lepef ,
ec187 - 012lepef , ec187 - 013lepef , ec187 - 014lepef , ec187 - 015lepef , ec187 - 016lepef ,
ec187 - 017lepef , ec187 - 018lepef , ec187 - 019lepef , ec187 - 020lepef , ec187 - 021lepem ,
ec187 - 022lepef , ec187 - 023lepef , ec187 - 100pem , ec187 - 101pem , ec187 - 102pem , ec187 - 103pem ,
ec187 - 104pem , ec187 - 105pem , ec187 - 106pem , ec187 - 107pem , ec187 - 108pem , ec187 - 109pem ,
ec187 - 110pem , ec187 - 111pem , ec187 - 112pem , ec189 - 002lepem , ec189 - 003lepef , ec208 - 001pem ,
ec208 - 002pef , ec209 - 100pef , ec209 - 101pef , ec210 - 001lepef , ec213 - 001lepem ,
ec213 - 002lepem , ec213 - 003lepem , ec214 - 001lepem , ec214 - 002lepem , ec214 - 003lepem ,
ec214 - 004lepem , ec214 - 005lepef , ec214 - 006lepef , ec214 - 007lepef , ec214 - 008lepef ,
ec214 - 009lepem , ec214 - 010lepef , ec214 - 011lepem , ec214 - 100pem , ec214 - 101pef ,
ec214 - 102pef , ec214 - 103pem , ec217 - 103pem , ec219(4f ) , ec259(2f ) , ec264 - 002(lepe)f ,
ec264 - 003(lepe)f ; tr .
nr . lampropus ( n = 2 ) ,
ec194 - 003lepemgen05/43 , ec194 - 004lepef .
. ( ura . )
calosomata ( n = 2 ) , ec112 - 104pem , ec112 - 105pe[m ] ( wrbue098 - 10 ;
kf671034 ) .
wyeomyia - wy .
( dec . )
pseudopecten ( n = 19 ) , ec108 - 001lepemgen01/11 , ec144 - 001lepem ,
ec144 - 002lepef , ec144 - 003lepef , ec144 - 004lepem , ec144 - 005lepef , ec144 - 006lepef ,
ec144 - 007lepef , ec144 - 100pem , ec144 - 101pef , ec144 - 102pem , ec144 - 103pemgen02/63 ,
ec144 - 104pem , ec144 - 105pef , ec144 - 106pem , ec144 - 107pem , ec144 - 108pef , ec144 - 109pef ,
ec195 - 100pemgencp ; wy . ( dec . ) ulocoma
( n = 462 ) , ec106[20l ] , ec106[50l ] , ec106 - 001lepemgen01/05 , ec106 - 002lepem ,
ec106 - 003lepem , ec106 - 004lepef , ec106 - 005lepem , ec106 - 006lepef , ec106 - 007lepef ,
ec106 - 008lepef , ec106 - 009lepem , ec106 - 010lepef , ec106 - 011lepe[f ] ( wrbue066 - 10 ;
kf671040 ) , ec106 - 012lepef , ec106 - 013lepef , ec106 - 014lepef , ec106 - 015lepef ,
ec106 - 016lepef , ec106 - 017lepef , ec106 - 018lepef , ec106 - 019lepem , ec106 - 020lepem ,
ec106 - 021lepe[m ] ( wrbue075 - 10 ; kf671039 ) , ec106 - 022lepem , ec106 - 023lepef ,
ec106 - 024lepef , ec106 - 025lepef , ec106 - 026lepef , ec106 - 027lepef , ec106 - 028lepem ,
ec106 - 029lepef , ec106 - 030lepef , ec106 - 031lepef , ec106 - 032lepef , ec106 - 033lepef ,
ec106 - 034lepef , ec106 - 035lepef , ec106 - 036lepef , ec106 - 037lepef , ec106 - 100pef ,
ec106 - 101pemgen01/08 , ec106 - 102pef , ec106 - 103pef , ec106 - 104pef , ec106 - 105pemgen01/06 ,
ec106 - 106pef , ec106 - 107pef , ec106 - 108pem , ec106 - 109pem , ec106 - 110pef , ec106 - 111pe[m ]
( wrbue072 - 10 ; kf671038 ) , ec106 - 112pe[m ] ( soie294 - 13 ; kf671042 ) , ec106 - 113pem ,
ec106 - 114pef , ec106 - 115pef , ec106 - 116pem , ec106 - 117pef , ec106 - 118pem , ec106 - 119pem ,
ec106 - 120pem , ec106 - 121pe[m ] ( soie293 - 13 ; kf671043 ) , ec106 - 122pem , ec106 - 123pemgen01/07 ,
ec106 - 124pem , ec106 - 125pem , ec106 - 126pem , ec107 - 001lepem , ec107 - 003lepemgen01/09 ,
ec107 - 004lepef , ec107 - 005lepem , ec107 - 006lepem , ec107 - 007lepef , ec107 - 008lepem ,
ec107 - 010lepef , ec107 - 011lepef , ec107 - 012lepemgencp , ec107 - 013lepef , ec107 - 014lepem ,
ec107 - 015lepef , ec107 - 017lepef , ec107 - 018lepem , ec107 - 020lepem , ec107 - 021lepem ,
ec107 - 023lepem , ec107 - 025lepef , ec107 - 026lepem , ec107 - 027lepef , ec107 - 028lepem ,
ec107 - 100pef , ec107 - 102pem , ec107 - 103pem , ec107 - 104pef , ec107 - 105pem , ec107 - 106pef ,
ec107 - 108pef , ec107 - 109pem , ec107 - 110pef , ec107 - 111pef , ec107 - 112pem , ec107 - 113pem ,
ec107 - 114pem , ec107 - 115pem , ec107 - 116pe[m ] ( wrbue073 - 10 ; kf671044 ) , ec107 - 118pem ,
ec107 - 119pem , ec107 - 120pem , ec107 - 121pem , ec107 - 122pem , ec107 - 123pem , ec107 - 124pem ,
ec107 - 125pef , ec107 - 126pem , ec107 - 127pem , ec107 - 128pem , ec158 - 002lepef , ec158 - 003lepef ,
ec158 - 004lepem , ec158 - 005lepef , ec158 - 006lepem , ec158 - 007lepem , ec158 - 010lepef ,
ec158 - 011lepef , ec158 - 100pef , ec158 - 101pe[m ] ( wrbue096 - 10 ; kf671037 ) , ec158 - 102pem ,
ec158 - 103pe , ec158 - 104pem , ec158 - 105pem , ec159 - 001lepef , ec159 - 002lepef , ec159 - 003lepef ,
ec159 - 004lepem , ec159 - 005lepef , ec159 - 006lepef , ec159 - 007lepem , ec159 - 008lepef ,
ec159 - 010lepem , ec159 - 011lepem , ec159 - 013lepef , ec159 - 016lepef , ec159 - 017lepef ,
ec159 - 018lepef , ec159 - 019lepef , ec159 - 019lepef , ec159 - 020lepef , ec159 - 021lepef ,
ec159 - 022lepef , ec159 - 023lepef , ec159 - 100pem , ec159 - 101pem , ec159 - 102pem , ec159 - 103pem ,
ec159 - 104pem , ec159 - 105pef , ec159 - 106pef , ec159 - 107pem , ec159 - 108pem , ec159 - 109pem ,
ec159 - 110pem , ec159 - 111pem , ec160[15l ] , ec160[15l ] , ec160 - 001lepe ,
ec160 - 002lepemgen05/39 , ec160 - 003lepef , ec160 - 004lepem , ec160 - 005lepem , ec160 - 006lepem ,
ec160 - 007lepef , ec160 - 008lepef , ec160 - 100pef , ec160 - 102pe[m ] ( wrbue095 - 10 ; kf671041 ) ,
ec160 - 103pef , ec160 - 104pef , ec160 - 106pef , ec160 - 107pem , ec160 - 108pef , ec160 - 109pem ,
ec160 - 110pem , ec160 - 111pef , ec160 - 112pem , ec160 - 113pef , ec160 - 114pem , ec160 - 115pem ,
ec160 - 116pef , ec160 - 117pef , ec160 - 118pem , ec160 - 119pef , ec160 - 120pef , ec160 - 121pef ,
ec160 - 122pem , ec160 - 123pem , ec160 - 124pem , ec160 - 125pem , ec160 - 126pem , ec160 - 127pef ,
ec160 - 128pef , ec160 - 129pem , ec160 - 130pem , ec160 - 131pef , ec160 - 132pem , ec160 - 133pef ,
ec160 - 134pef , ec161 - 001(lepe)m , ec161 - 002(lepe)f , ec161 - 003(lepe)f , ec161 - 004(lepe)f ,
ec161 - 005(lepe)f , ec161 - 102(pe)m , ec173 - 001lepem , ec173 - 100(pe)f , ec173 - 101pem ,
ec215 - 001lepef , ec215 - 002lepemgen05/48 , ec215 - 003lepef , ec215 - 100pem , ec218 - 001lepe ,
ec218 - 002lepef , ec218 - 003f , ec218 - 004lepef , ec218 - 005lepef , ec218 - 100pef , ec218 - 102pem ,
ec218 - 104pef , ec218 - 106pem , ec218 - 107pef , ec218 - 108pef , ec218 - 109pef , ec218 - 110pef ,
ec218 - 112pef , ec218 - 113pef , ec264(64 m ) , ec264(68f ) , ec264 - 104pemgencp ,
ec264 - 105pemgencp , ec264mgen12/11 , ec264mgen12/12 ; wy .
( n = 77 ) , ec158 - 001lepef , ec158 - 008lepem ,
ec158 - 009lepef , ec158 - 106pem , ec159 - 009lepem , ec159 - 012lepem , ec159 - 014lepem ,
ec159 - 015lepef , ec160 - 101pem , ec160 - 105pef , ec161 - 100pem , ec161 - 101(pe)mgen05/40 ,
ec189 - 001lepem , ec189 - 100pemgen05/62 , ec189 - 101pef , ec189 - 102pef , ec189 - 103pem ,
ec189 - 104pem , ec189 - 105pef , ec189 - 106pem , ec193[20l ] , ec193 - 001lepef , ec193 - 002lepem ,
ec193 - 003lepef , ec193 - 004lepef , ec193 - 005lepef , ec193 - 006lepef , ec193 - 007lepef ,
ec193 - 008lepef , ec193 - 009lepef , ec193 - 010lepef , ec193 - 011lepef , ec193 - 012lepe ,
ec193 - 013lepef , ec193 - 014lepef , ec193 - 015lepef , ec193 - 016lepef , ec193 - 100pem ,
ec193 - 101pef , ec193 - 102pef , ec193 - 103pef , ec193 - 104pem , ec193 - 105pef , ec195 - 101pef ,
ec218 - 101pef , ec218 - 103pef , ec218 - 105pem , ec218 - 111pe , ec107 - 002lepef , ec107 - 009lepef ,
ec107 - 016lepef , ec107 - 019lepef , ec107 - 022lepem , ec107 - 024lepem , ec107 - 101pem ,
ec107 - 107pef , ec107 - 117pem , ec108 - 100lepem ; wy . (
dod . ) aphobema ( n = 35 ) , ec108 - 002lepemgen01/12 ,
ec108 - 003lepef , ec108 - 004lepef , ec108 - 005lepef , ec108 - 006lepef , ec108 - 007lepef ,
ec108 - 008lepef , ec108 - 009lepef , ec108 - 010lepem , ec108 - 011lepem , ec108 - 012lepef ,
ec108 - 013lepef , ec108 - 014lepemgen01/13 , ec108 - 101pef , ec108 - 102pem , ec108 - 104pem ,
ec108 - 105pef , ec135 - 004lepef , ec138 - 001lepem , ec138 - 002lepef , ec138 - 003lepef ,
ec138 - 004lepef , ec138 - 005lepem , ec138 - 100pef , ec147 - 001lepem , ec147 - 007lepef ,
ec147 - 008lepem , ec147 - 009lepef , ec147 - 011lepem , ec147 - 100pe[m ] ( wrbue092 - 10 ; kf671035 ) ,
ec156 - 001lepem , ec161 - 006lepef , ec268 - 001lepem , ec268 - 100pem , ec268 - 101pem ; wy .
. aphobema ( n = 1 ) ,
ec156 - 100pe[m ] ( wrbue099 - 10 ; kf671036 ) ; wy .
autocratica ( n = 3 ) , ec105 - 002pef , ec105 - 006pef ,
ec105 - 103pemgencp ; wy .
lamellata ( n = 1 ) , ec108 - 103pemgen01/10 ; wy . (
hys . )
( n = 2 ) , ec207 - 004lepemgen05/46 , ec207 - 100pef ;
wy .
codiocampa ( n =
11 ) , ec132 - 001lepef , ec132 - 002lepem , ec132 - 006lepemgen05/28 , ec132 - 008lepemgen02/60 ,
ec132 - 009lepef , ec132 - 011lepef , ec132 - 015lepef , ec132 - 100pef , ec132 - 101pef ,
ec204 - 002lepem , ec204 - 003lepef ; wy .
oblita ( n = 3 ) , ec133 - 003lepemgen05/30 , ec133 - 004lepem , ec204 - 001lepem ;
wy .
nr . codiocampa
( n = 1 ) , ec132 - 019lepemgencp ; wy .
( n = 11 ) , ec132 - 010lepef , ec132 - 012f , ec132 - 013lepef , ec132 - 014mgen05/29 ,
ec132 - 016lepef , ec132 - 017f , ec132 - 018mgen02/61 , ec132 - 020lepef , ec132 - 021lepef ,
ec132 - 022lepef ; wy .
nr .
albosquamata ( n = 4 ) , ec135 - 003lepem , ec147 - 003lepemgencp , ec147 - 004lepem ,
ec147 - 006lepef ; wy .
.
medioalbipes ( n = 1 ) , ec104 - 001lepef ; wy .
( n = 6 ) , ec135 - 002lepef , ec147 - 002lepemgen02/66 ,
ec147 - 005lepef , ec147 - 010lepef , ec147 - 101pef , ec147 - 102pef .[/INST]two snapshot surveys to establish the diversity and ecological preferences of
mosquitoes ( diptera : culicidae ) in the terra firme primary rain
forest surrounding the tiputini biodiversity station in the unesco yasun biosphere
reserve of eastern amazonian ecuador were carried out in november 1998 and may 1999 .
the mosquito fauna of this region is poorly known ; the focus of this study was to
obtain high quality link - reared specimens that could be used to unequivocally confirm
species level diversity through integrated systematic study of all life stages and
dna sequences .
a total of 2,284 specimens were preserved ; 1,671 specimens were
link - reared with associated immature exuviae , all but 108 of which are slide mounted .
this study identified 68 unique taxa belonging to 17 genera and 27 subgenera . of
these , 12 are new to science and 37 comprise new country records .
dna barcodes
[ 658-bp of the mtdna cytochrome c oxidase ( coi ) i gene ] are
presented for 58 individuals representing 20 species and nine genera .
dna barcoding
proved useful in uncovering and confirming new species and we advocate an integrated
systematics approach to biodiversity studies in future .
associated bionomics of all
species collected are discussed .
an updated systematic checklist of the mosquitoes of
ecuador ( n = 179 ) is presented for the first time in 60 years .</s> |
extracardiac shunts ( ecs ) are commonly used for the palliation of patients with congenital heart disease ( chd ) who are not candidates for early complete repair .
after placement of a palliative ecs , a period of months may be required to achieve sufficient somatic growth , pulmonary artery growth , and fall in pulmonary vascular resistance to allow candidacy for definitive intracardiac repair . during that time
clotting factors and platelets used at the time of surgical placement of ecs predispose to early layering of thrombus within the lumen of ecs , which potentially leads to cellular ingrowth and a higher propensity toward occlusion .
histopathologic studies have shown that early thrombus deposition may lead to luminal ingrowth consisting of fibrous tissue . in a nonrandomized observational study of infants with systemic to pulmonary ecs ,
in another study , occlusion > 50% was noted in 23% of ecs examined at the time of elective take down .
efforts to maintain ecs patency have the potential to limit morbidity and mortality in chd .
imageguided high mechanical index ( mi ) impulses from a modified diagnostic ultrasound ( us ) system during a systemic microbubble ( mb ) infusion dissolve intravascular thrombi without the need for fibrinolytic therapy .
cavitation and resultant shear forces that lead to a microstreaming phenomenon are proposed mechanisms for sonothrombolysis .
contrast mbs serve as nuclei for cavitation , lowering the peak negative pressure threshold required to induce cavitation , thus enhancing the thrombolytic effects of us . recently ,
the effectiveness of mbenhanced us lysis has been shown in dissolving thrombi that formed on central venous catheters in vivo .
however , no studies to date have examined whether this technique could prevent thrombus formation in vessels or shunts at higher risk for this .
based on these studies of thrombi dissolution , we hypothesized that the microstreaming induced by mb cavitation may be an effective method to prevent the early thrombus accumulation ( thromboprophylaxis ) on surgically placed grafts that lead to subsequent intimal hyperplasia within the graft and resultant occlusion .
accordingly , the specific aim of this study was to examine the effectiveness of thromboprophylaxis using usguided mb treatments in arteriovenous ( av ) , and arterioarterial ( aa ) shunts placed in a porcine model .
the study was approved by the institutional animal care and use committee of the university of nebraska medical center and was in compliance with the standards in the guide for the care and use of laboratory animals .
the pig was fasted overnight and preanesthetized with an intramuscular mixture of telazol ( 4.4 mg / kg ) , ketamine ( 2.2 mg / kg ) , and xylazine ( 2.2 mg / kg ) .
intramuscular atropine ( 0.05 mg / kg ) was used to dry oraltracheal secretions and prevent bradycardia during intubation . following placement of a venous line in the lateral or medial auricular vein ,
the pig was intubated and isoflurane inhalation anesthesia ( induction at 4% , maintained at 1.0% to 1.8% ) administered .
the animal was placed on a ventilator at a volume of 11 cc / kg of air and at a rate of 15 breaths / minute .
after the pig was placed under anesthesia and after preparation of the surgical site , a midline cervical incision was made . through the incision ,
two 4mm diameter , 2.5 cm long , heparinbonded expanded polytetrafluoroethylene shunts ( propaten vascular graft ; gore medical ) were implanted : one interposition within the left carotid ( arterioarterial , aa ) , and one sidetoside av shunt from the right carotid artery to the right internal jugular vein .
this shunt type is commonly used in standard of care clinical practice in humans . for
the interposition shunt , each vessel was clamped proximally and distally and a 2.5 cm segment of vessel was excised . each anastomosis was created with running 60 polypropylene suture ( prolene ; ethicon ) .
both anastomoses were completed before releasing the vessel clamps , ie , the graft was not clamped . for the av shunt ,
4 clamps were applied to the artery and the vein both proximally and distally and all were removed when both anastomoses were completed .
the grafts were observed until hemostasis , and then the incision was closed with a subcutaneous and a skin suture layer ( figure 1 ) .
representative examples of surgically implanted rightsided arteriovenous ( av ) shunt from the right carotid artery to the right internal jugular vein , and left sided arterioarterial ( aa ) interposition shunt within the left carotid artery ( black arrows ) .
these mb have a diameter of 1.00.1 m , and concentration of 1.5 to 3.010/ml .
the mb infusion was prepared by diluting 2 ml of the mrx801 in 100 ml of 0.9% saline and infused at a rate of 1.0 ml / min .
a commercially available us system ( ie33 ; philips medical systems ) and diagnostic transducer ( s51 ; philips ) were used .
the us system had low mi contrast sensitive imaging pulse sequences ( power modulation ) that were applied in between high mi impulses to assist in the detection of mb .
the 3 randomized groups tested were : ( 1 ) 2d intermittent guided high mi with intravenous mb ( group 1 ) ; ( 2 ) 2dguided high mi us with intravenous 0.9% saline ( group 2 ) ; and ( 3 ) controls that received no treatment ( group 3 ) .
randomized transcutaneous treatment groups ( 1 or 2 ) and controls were assigned immediately after surgical placement of ecs . the first treatment regimen ( in groups 1 and 2 )
was begun within 2 hours of placement of the ecs , because it is anticipated that this is when significant initial platelet and fibrin deposition occurs .
thirtyminute treatments were given separately to each side ( av shunt on the right side , aa shunt on the left ) .
the mb or 0.9% saline were infused through a peripheral vein . in group 1 ,
the application of brief high mi impulses ( 1.1 mi ; pulse duration 20 s ; frame rate 20 hz ) was guided to allow replenishment of mb within the region of interest .
this frequency and pulse duration for therapeutic us application was chosen based on previous in vitro work from our laboratory .
pulmonary hypertension , mediated by the vasoconstrictor thromboxane has been reported in pigs after exposure to intravenous mb .
this reaction is presumed to be secondary to speciesrelated pulmonary intravascular macrophages ; the macrophage phagocytotic process resulting in the release of thromboxane causing pulmonary hypertension .
ketorolac 60 mg and methylprednisolone 40 mg to prevent pulmonary hypertensive responses to mb were administered intravenously in groups 1 and 2 prior to each treatment .
oxygen saturation by pulse oximetry , arterial blood pressure , and 3lead electrocardiograms were measured before , during , and for 30 minutes after us and mb therapy .
the shunts were imaged using color doppler us ( 4vc1 vascular transducer ; siemens ) before and after each treatment ( figure 2 ) .
a single experienced echocardiographer ( jw ) recorded doppler data as good , reduced , or absent based on color doppler information obtained from within the shunt .
settings of low 2dimensional gain , high color gain , small color overlay , zoom mode , and a single focal zone were used to maximize the sampling rate . as the doppler angles were inconsistent between the implanted shunts ,
the arteriovenous ( left panels ) and arterioarterial ( right panels ) shunts are demonstrated ( asterisks ) on 2dimensional and color doppler imaging , and during thromboprophylactic application of microbubbles and high mechanical index pulse sequences to insonify each shunt .
aa indicates arterioarterial ; av , arteriovenous . each animal was sacrificed at the completion of 4 treatments in groups 1 and 2 , and at a similar time point in group 3 .
each ecs was removed and placed in 10% neutral buffered formalin immediately , and processed according to standard tissue processing techniques .
the shunts were embedded in paraffin wax , sectioned , stained with hematoxylin and eosin for microscopy and reviewed by a pathologist ( sjr ) .
digital images of each section were taken through the iscan coreo slide scanner ( ventana medical systems inc ) at 20 magnification .
images of histopathologic sections from the explanted ecs were reviewed by the pathologist ( sjr ) , and under the pathologist 's direction , a blinded experienced observer ( jra ) performed quantitation of the inlumen residue in each shunt using ventana image viewer 3.1 software .
the area inside the endothelial cell lining of the tunica intima was included in the measurement .
areas calculated for each shunt section were added up to quantify thrombus accumulation ( figure 3 ) .
a , section of an av shunt in a group 1 animal with minimal intimal thickening and no luminal thrombus .
b , section of an av shunt with a mixture of blood , platelets and fibrin partially occluding its lumen .
the luminal composition was a mixture of platelets and fibrin with some endothelial cell ingrowth .
in addition , mononuclear cells , collagen and areas of calcification were seen in some of the sections that were occluded .
therefore , median thrombus burden was reported for us with mb , us with saline , and control groups , and the kruskalwallis test was applied to assess differences among these groups .
the student 's t test was used for comparison of hemodynamic measurements in treatment groups 1 and 2 . to assess the interobserver agreement ,
histopathologic thrombus burden measurements were repeated in 10 randomly chosen aa and av shunts by a second blinded observer .
blandaltman plots were derived to identify possible bias ( mean divergence ) and the limits of agreement ( 2 standard deviation of the divergence ) .
statistical analysis was performed using commercially available software ( minitab version 16.1 ; minitab inc ) .
the study was approved by the institutional animal care and use committee of the university of nebraska medical center and was in compliance with the standards in the guide for the care and use of laboratory animals .
the pig was fasted overnight and preanesthetized with an intramuscular mixture of telazol ( 4.4 mg / kg ) , ketamine ( 2.2 mg / kg ) , and xylazine ( 2.2 mg / kg ) .
intramuscular atropine ( 0.05 mg / kg ) was used to dry oraltracheal secretions and prevent bradycardia during intubation . following placement of a venous line in the lateral or medial auricular vein ,
the pig was intubated and isoflurane inhalation anesthesia ( induction at 4% , maintained at 1.0% to 1.8% ) administered .
the animal was placed on a ventilator at a volume of 11 cc / kg of air and at a rate of 15 breaths / minute .
after the pig was placed under anesthesia and after preparation of the surgical site , a midline cervical incision was made . through the incision ,
two 4mm diameter , 2.5 cm long , heparinbonded expanded polytetrafluoroethylene shunts ( propaten vascular graft ; gore medical ) were implanted : one interposition within the left carotid ( arterioarterial , aa ) , and one sidetoside av shunt from the right carotid artery to the right internal jugular vein .
this shunt type is commonly used in standard of care clinical practice in humans . for
the interposition shunt , each vessel was clamped proximally and distally and a 2.5 cm segment of vessel was excised . each anastomosis was created with running 60 polypropylene suture ( prolene ; ethicon ) .
both anastomoses were completed before releasing the vessel clamps , ie , the graft was not clamped . for the av shunt ,
4 clamps were applied to the artery and the vein both proximally and distally and all were removed when both anastomoses were completed .
the grafts were observed until hemostasis , and then the incision was closed with a subcutaneous and a skin suture layer ( figure 1 ) .
representative examples of surgically implanted rightsided arteriovenous ( av ) shunt from the right carotid artery to the right internal jugular vein , and left sided arterioarterial ( aa ) interposition shunt within the left carotid artery ( black arrows ) .
these mb have a diameter of 1.00.1 m , and concentration of 1.5 to 3.010/ml .
the mb infusion was prepared by diluting 2 ml of the mrx801 in 100 ml of 0.9% saline and infused at a rate of 1.0 ml / min .
a commercially available us system ( ie33 ; philips medical systems ) and diagnostic transducer ( s51 ; philips ) were used .
the us system had low mi contrast sensitive imaging pulse sequences ( power modulation ) that were applied in between high mi impulses to assist in the detection of mb .
the 3 randomized groups tested were : ( 1 ) 2d intermittent guided high mi with intravenous mb ( group 1 ) ; ( 2 ) 2dguided high mi us with intravenous 0.9% saline ( group 2 ) ; and ( 3 ) controls that received no treatment ( group 3 ) .
randomized transcutaneous treatment groups ( 1 or 2 ) and controls were assigned immediately after surgical placement of ecs . the first treatment regimen ( in groups 1 and 2 )
was begun within 2 hours of placement of the ecs , because it is anticipated that this is when significant initial platelet and fibrin deposition occurs .
thirtyminute treatments were given separately to each side ( av shunt on the right side , aa shunt on the left ) .
the mb or 0.9% saline were infused through a peripheral vein . in group 1 ,
the application of brief high mi impulses ( 1.1 mi ; pulse duration 20 s ; frame rate 20 hz ) was guided to allow replenishment of mb within the region of interest .
this frequency and pulse duration for therapeutic us application was chosen based on previous in vitro work from our laboratory .
pulmonary hypertension , mediated by the vasoconstrictor thromboxane has been reported in pigs after exposure to intravenous mb .
this reaction is presumed to be secondary to speciesrelated pulmonary intravascular macrophages ; the macrophage phagocytotic process resulting in the release of thromboxane causing pulmonary hypertension .
ketorolac 60 mg and methylprednisolone 40 mg to prevent pulmonary hypertensive responses to mb were administered intravenously in groups 1 and 2 prior to each treatment .
oxygen saturation by pulse oximetry , arterial blood pressure , and 3lead electrocardiograms were measured before , during , and for 30 minutes after us and mb therapy .
the shunts were imaged using color doppler us ( 4vc1 vascular transducer ; siemens ) before and after each treatment ( figure 2 ) .
a single experienced echocardiographer ( jw ) recorded doppler data as good , reduced , or absent based on color doppler information obtained from within the shunt .
settings of low 2dimensional gain , high color gain , small color overlay , zoom mode , and a single focal zone were used to maximize the sampling rate . as the doppler angles were inconsistent between the implanted shunts ,
the arteriovenous ( left panels ) and arterioarterial ( right panels ) shunts are demonstrated ( asterisks ) on 2dimensional and color doppler imaging , and during thromboprophylactic application of microbubbles and high mechanical index pulse sequences to insonify each shunt .
each animal was sacrificed at the completion of 4 treatments in groups 1 and 2 , and at a similar time point in group 3 .
each ecs was removed and placed in 10% neutral buffered formalin immediately , and processed according to standard tissue processing techniques .
the shunts were embedded in paraffin wax , sectioned , stained with hematoxylin and eosin for microscopy and reviewed by a pathologist ( sjr ) .
digital images of each section were taken through the iscan coreo slide scanner ( ventana medical systems inc ) at 20 magnification .
images of histopathologic sections from the explanted ecs were reviewed by the pathologist ( sjr ) , and under the pathologist 's direction , a blinded experienced observer ( jra ) performed quantitation of the inlumen residue in each shunt using ventana image viewer 3.1 software .
the area inside the endothelial cell lining of the tunica intima was included in the measurement .
areas calculated for each shunt section were added up to quantify thrombus accumulation ( figure 3 ) .
representative examples of residual thrombi within av shunt . a , section of an av shunt in a group 1 animal with minimal intimal thickening and no luminal thrombus .
b , section of an av shunt with a mixture of blood , platelets and fibrin partially occluding its lumen .
the luminal composition was a mixture of platelets and fibrin with some endothelial cell ingrowth .
in addition , mononuclear cells , collagen and areas of calcification were seen in some of the sections that were occluded .
therefore , median thrombus burden was reported for us with mb , us with saline , and control groups , and the kruskalwallis test was applied to assess differences among these groups .
the student 's t test was used for comparison of hemodynamic measurements in treatment groups 1 and 2 . to assess the interobserver agreement ,
histopathologic thrombus burden measurements were repeated in 10 randomly chosen aa and av shunts by a second blinded observer .
blandaltman plots were derived to identify possible bias ( mean divergence ) and the limits of agreement ( 2 standard deviation of the divergence ) .
statistical analysis was performed using commercially available software ( minitab version 16.1 ; minitab inc ) .
a total of 18 pigs had a placement of 36 ecs ( 12 pigs for thromboprophylaxis protocols and 6 controls ) .
table 1 shows the hemodynamic measurements in all animals prior to , during , and after the treatments summarized for all 4 treatments . there were no significant differences in hemodynamic parameters between groups 1 and 2 with any of the randomized therapies .
color doppler assessments of the shunts showed reduced or absent color doppler flow during 5 of 24 treatments in 2 group 1 pigs : absent flow was noted during 2 treatments in 1 and reduced flow was seen for 3 treatments in the second pig . among the group 2 pigs , absent or reduced flow
these included 6 instances of absent flow in 2 pigs and 2 instances of reduced flow in a third pig .
these color doppler flow changes in both groups were mostly observed during the third and fourth treatments .
hemodynamic indices compared between groups 1 and 2 for all treatments act indicates activated clotting time ; dbp , diastolic blood pressure ; hr , heart rate ; mb , microbubble ; sbp , systolic blood pressure ; spo2 , systemic oxygen saturation ; us indicates ultrasound . in the untreated animals ( group 3 ) , the median thrombus burden in av shunts was 5.10 mm compared with 4.05 mm in aa shunts ( p=0.199 ) . in the av shunts , group 1
had less median thrombus burden ( 2.5 mm ) in the av shunts compared with group 2 ( 5.6 mm ) and group 3 ( 7.5 mm ) pigs ( p=0.006 ; table 2 ) . among the explanted av shunts ,
no total lumen occlusions were observed in group 1 , whereas one av shunt total occlusion was seen in groups 2 and 3 .
differences in thrombus burden for explanted shunts compared between groups aa indicates arterioarterial ; av , arteriovenous ; mb , microbubble ; us indicates ultrasound .
the luminal composition was predominantly a mixture of organized blood , platelets , and fibrin ; collagen , mononuclear cells , and areas of calcification were also seen in the sections that were occluded ( figure 3 ) .
sections of av shunt histology in pigs treated with guided us with mbs showed reductions in thrombus formation along the entire circumference of the vessel . no difference in median thrombus burden
was seen among the 3 groups for aa shunts ( 4.05 mm in group 1 , 4.25 mm in group 2 , 4.50 mm in group 3 , p=0.895 ) .
blandaltman analysis showed good interobserver agreement for thrombus burden measurements as represented in figure 4 .
blandaltman analysis of interobserver agreement of residual thrombus burden in 10 randomly chosen aa and av shunts .
in the untreated animals ( group 3 ) , the median thrombus burden in av shunts was 5.10 mm compared with 4.05 mm in aa shunts ( p=0.199 ) . in the av shunts ,
group 1 had less median thrombus burden ( 2.5 mm ) in the av shunts compared with group 2 ( 5.6 mm ) and group 3 ( 7.5 mm ) pigs ( p=0.006 ; table 2 ) . among the explanted av shunts ,
no total lumen occlusions were observed in group 1 , whereas one av shunt total occlusion was seen in groups 2 and 3 .
differences in thrombus burden for explanted shunts compared between groups aa indicates arterioarterial ; av , arteriovenous ; mb , microbubble ; us indicates ultrasound .
the luminal composition was predominantly a mixture of organized blood , platelets , and fibrin ; collagen , mononuclear cells , and areas of calcification were also seen in the sections that were occluded ( figure 3 ) .
sections of av shunt histology in pigs treated with guided us with mbs showed reductions in thrombus formation along the entire circumference of the vessel . no difference in median thrombus burden
was seen among the 3 groups for aa shunts ( 4.05 mm in group 1 , 4.25 mm in group 2 , 4.50 mm in group 3 , p=0.895 ) .
blandaltman analysis showed good interobserver agreement for thrombus burden measurements as represented in figure 4 .
blandaltman analysis of interobserver agreement of residual thrombus burden in 10 randomly chosen aa and av shunts .
the clinical implications of thrombosis after surgical procedures in chd , including systemic to pulmonary shunts , bidirectional cavopulmonary shunts , and fontan palliation are significant .
thrombotic lumen occlusion is the usual cause for ecs failure ; this development leads to significant acute mortality and morbidity in chd .
no published randomized controlled trials are available to guide the thromboprophylactic management of patients with ecs , so use of anticoagulation is a subject of debate . although antiplatelet therapy has been studied extensively in adults , evidence for its benefit in infants and young children is limited .
while the use of aspirin was associated with a reduction in ecs thrombosis in some studies , others have failed to demonstrate a beneficial effect . in theory
, aspirin alone may be insufficient to prevent arterial thrombosis because it inhibits only one pathway ( cyclooxygenase ) of platelet activation , and would have minimal effect in treating thrombi that would be expected in ecs .
moreover , the optimal pediatric dose of aspirin for inhibition of platelet aggregation is unknown .
aspirin is associated with reye syndrome in infants and children , and may cause bleeding complications , particularly in the presence of an underlying hemostatic defect or with concurrent thrombolytic therapy .
the use of fibrinolytic drugs has not been established in children , and carries significant risk of major hemorrhage .
attempted recanalization of acutely thrombosed ecs by cathetermediated thrombus disruption or rheolytic thrombectomy has been met with some success .
subacute ecs occlusion develops from neointimal proliferation in addition to thrombus formation within the shunt , so recanalization is more difficult in such cases . therefore , treatments designed to locally prevent thrombus formation / reduce thrombus burden and maintain ecs patency would be ideal , and avoid these systemic complications .
mbs coupled with us have been used to dissolve thrombi without thrombolytic agents , and also have been shown to enhance the effectiveness of exogenous tissue plasminogen activator . in in vivo models , successful dissolution of arterial and venous thrombi is achievable with guided high mi impulses delivered from a diagnostic us transducer .
the advantage of this approach is that it permits simultaneous low mi mb sensitive imaging pulse sequence schemes to detect the mb with the same transducer , and allows one to control the region in which therapy is desired .
the present study describes the application of this treatment for thromboprophylaxis of ecs in vivo .
an imageguided approach ensured the presence of mb near the shunt when the high mi impulses were applied .
the arteriovenous connection generates an intravascular pressure differential , similar to the blalockthomastaussig shunt or sano shunt used for chd palliation .
these shunts are subject to intimal proliferation due to shear forces of turbulent blood flow , and subsequent thrombus deposition on the irregular surface where blood flow slows .
this was presumably because of the ( 1 ) higher baseline flow rates and consequently lower predisposition for stasisrelated thrombus formation , and ( 2 ) the relatively short duration ( 4 weeks ) of placement .
we speculate that the interposition shunts within the carotid artery ( aa ) had improved flow compared to the sideside connected av shunts . for the av shunts
, there is the possibility of narrowing at the sidetoside anastomoses and turbulence of flow due to pressure differences between the vessels , which may have led to increased thrombogenesis .
the safety and success of this noninvasive thromboprophylactic application in our porcine model increase the potential for translation to av shunts in the human . besides chd , a potential therapeutic application of av shunt thromboprophylaxis is in patients with endstage renal disease where the use of such shunts is very common
. the application may also be particularly advantageous in infants and children because of the proximity of vascular structures to allow improved penetration of transcutaneously applied us impulses .
moreover , recent clinical trials have indicated that us contrast agents are safe and effective in children and young adults .
comparisons of efficacy between usmb thromboprophylaxis and pharmacologic ( antiplatelet or anticoagulant ) prophylaxis require further study . the number of animals studied was relatively small and the duration of placement of shunts prior to explantation and histopathologic examination was 4 weeks . considering that av shunts in the human are placed for substantially longer periods of time , whether the same results could be extrapolated for longer durations / older shunts
the purpose of this study was to explore the feasibility of ultrasound and microbubble prophylaxis , but further work is needed to explore this treatment approach in shunts placed for longer periods of time .
evaluation for the possibility of soft tissue injury due to bioeffects associated with highmi impulses from the transducer requires further investigation .
there is potential for unwanted us mechanical bioeffects at mi>1.0 , however , these are likely to be minimal because the us application used in the study was with a commercially available diagnostic transducer , and the highmi therapeutic pulses were significantly lower than the food and drug administration recommended mi limit for clinical use .
the mbs used in this study have been successfully used in human trials as adjuvant for arterial sonothrombolysis .
although these mbs are not yet commercially available , they are similar in shell composition and mb size to commercially available lipid encapsulated mbs . finally , these results would only be applicable to av shunts .
other palliative connections in chd are also subject to thrombotic occlusion , and the role of thromboprophylaxis with us and mb must be explored in such settings , where attenuation of the us beam may play a role in achieving adequate inertial cavitation of the mb .
the number of animals studied was relatively small and the duration of placement of shunts prior to explantation and histopathologic examination was 4 weeks . considering that av shunts in the human are placed for substantially longer periods of time , whether the same results could be extrapolated for longer durations / older shunts
the purpose of this study was to explore the feasibility of ultrasound and microbubble prophylaxis , but further work is needed to explore this treatment approach in shunts placed for longer periods of time .
evaluation for the possibility of soft tissue injury due to bioeffects associated with highmi impulses from the transducer requires further investigation .
there is potential for unwanted us mechanical bioeffects at mi>1.0 , however , these are likely to be minimal because the us application used in the study was with a commercially available diagnostic transducer , and the highmi therapeutic pulses were significantly lower than the food and drug administration recommended mi limit for clinical use .
the mbs used in this study have been successfully used in human trials as adjuvant for arterial sonothrombolysis .
although these mbs are not yet commercially available , they are similar in shell composition and mb size to commercially available lipid encapsulated mbs . finally , these results would only be applicable to av shunts .
other palliative connections in chd are also subject to thrombotic occlusion , and the role of thromboprophylaxis with us and mb must be explored in such settings , where attenuation of the us beam may play a role in achieving adequate inertial cavitation of the mb .
transcutaneous us and intravenous mb are capable of decreasing thrombus burden in arteriovenous shunts without the need for antiplatelet agents , and may be a method of preventing progressive occlusion of a highflow , small diameter expanded polytetrafluoroethylene tube graft such as the modified blalock shunt or the sano shunt .
we appreciate the expert technical assistance of elizabeth stolze , lucas drvol , and gretchen fry of the joint cardiovascular research laboratory of the university of nebraska medical center . | backgroundpalliative shunts in congenital heart disease patients are vulnerable to thrombotic occlusion
. high mechanical index ( mi ) impulses from a modified diagnostic ultrasound ( us ) transducer during a systemic microbubble ( mb ) infusion have been used to dissolve intravascular thrombi without anticoagulation , and we sought to determine whether this technique could be used prophylactically to reduce thrombus burden and prevent occlusion of surgically placed extracardiac shunts.methods and resultsheparinbonded eptfe tubular vascular shunts of 4 mm2.5 cm ( propaten ; w.l gore ) were surgically placed in 18 pigs : a rightsided sidetoside arteriovenous ( av , carotidjugular ) shunt , and a leftsided arterioarterial ( aa , carotidcarotid ) interposition shunt in each animal . after shunt implantation , animals were randomly assigned to one of 3 groups .
transcutaneous , weekly 30minute treatments ( total of 4 treatments ) of either guided high mi us+mb ( group 1 ; n=6 ) using a 3% mrx801 mb infusion , or us alone ( group 2 ; n=6 ) were given separately to each shunt .
the third group of 6 pigs received no treatments .
the shunts were explanted after 4 weeks and analyzed by histopathology to quantify luminal thrombus area ( mm2 ) for the length of each shunt .
no pigs received antiplatelet agents or anticoagulants during the treatment period .
the median overall thrombus burden in the 3 groups for av shunts was 5.10 mm2 compared with 4.05 mm2 in aa ( p=0.199 ) .
group 1 pigs had significantly less thrombus burden in the av shunts ( median 2.5 mm2 ) compared with group 2 ( median 5.6 mm2 ) and group 3 ( median 7.5 mm2 ) pigs ( p=0.006 )
. no difference in thrombus burden was seen between groups for aa shunts.conclusiontranscutaneous us with intravenous mb is capable of preventing thrombus accumulation in arteriovenous shunts without the need for antiplatelet agents , and may be a method of preventing progressive occlusion of palliative shunts . | <s>[INST]extracardiac shunts ( ecs ) are commonly used for the palliation of patients with congenital heart disease ( chd ) who are not candidates for early complete repair .
after placement of a palliative ecs , a period of months may be required to achieve sufficient somatic growth , pulmonary artery growth , and fall in pulmonary vascular resistance to allow candidacy for definitive intracardiac repair . during that time
clotting factors and platelets used at the time of surgical placement of ecs predispose to early layering of thrombus within the lumen of ecs , which potentially leads to cellular ingrowth and a higher propensity toward occlusion .
histopathologic studies have shown that early thrombus deposition may lead to luminal ingrowth consisting of fibrous tissue . in a nonrandomized observational study of infants with systemic to pulmonary ecs ,
in another study , occlusion > 50% was noted in 23% of ecs examined at the time of elective take down .
efforts to maintain ecs patency have the potential to limit morbidity and mortality in chd .
imageguided high mechanical index ( mi ) impulses from a modified diagnostic ultrasound ( us ) system during a systemic microbubble ( mb ) infusion dissolve intravascular thrombi without the need for fibrinolytic therapy .
cavitation and resultant shear forces that lead to a microstreaming phenomenon are proposed mechanisms for sonothrombolysis .
contrast mbs serve as nuclei for cavitation , lowering the peak negative pressure threshold required to induce cavitation , thus enhancing the thrombolytic effects of us . recently ,
the effectiveness of mbenhanced us lysis has been shown in dissolving thrombi that formed on central venous catheters in vivo .
however , no studies to date have examined whether this technique could prevent thrombus formation in vessels or shunts at higher risk for this .
based on these studies of thrombi dissolution , we hypothesized that the microstreaming induced by mb cavitation may be an effective method to prevent the early thrombus accumulation ( thromboprophylaxis ) on surgically placed grafts that lead to subsequent intimal hyperplasia within the graft and resultant occlusion .
accordingly , the specific aim of this study was to examine the effectiveness of thromboprophylaxis using usguided mb treatments in arteriovenous ( av ) , and arterioarterial ( aa ) shunts placed in a porcine model .
the study was approved by the institutional animal care and use committee of the university of nebraska medical center and was in compliance with the standards in the guide for the care and use of laboratory animals .
the pig was fasted overnight and preanesthetized with an intramuscular mixture of telazol ( 4.4 mg / kg ) , ketamine ( 2.2 mg / kg ) , and xylazine ( 2.2 mg / kg ) .
intramuscular atropine ( 0.05 mg / kg ) was used to dry oraltracheal secretions and prevent bradycardia during intubation . following placement of a venous line in the lateral or medial auricular vein ,
the pig was intubated and isoflurane inhalation anesthesia ( induction at 4% , maintained at 1.0% to 1.8% ) administered .
the animal was placed on a ventilator at a volume of 11 cc / kg of air and at a rate of 15 breaths / minute .
after the pig was placed under anesthesia and after preparation of the surgical site , a midline cervical incision was made . through the incision ,
two 4mm diameter , 2.5 cm long , heparinbonded expanded polytetrafluoroethylene shunts ( propaten vascular graft ; gore medical ) were implanted : one interposition within the left carotid ( arterioarterial , aa ) , and one sidetoside av shunt from the right carotid artery to the right internal jugular vein .
this shunt type is commonly used in standard of care clinical practice in humans . for
the interposition shunt , each vessel was clamped proximally and distally and a 2.5 cm segment of vessel was excised . each anastomosis was created with running 60 polypropylene suture ( prolene ; ethicon ) .
both anastomoses were completed before releasing the vessel clamps , ie , the graft was not clamped . for the av shunt ,
4 clamps were applied to the artery and the vein both proximally and distally and all were removed when both anastomoses were completed .
the grafts were observed until hemostasis , and then the incision was closed with a subcutaneous and a skin suture layer ( figure 1 ) .
representative examples of surgically implanted rightsided arteriovenous ( av ) shunt from the right carotid artery to the right internal jugular vein , and left sided arterioarterial ( aa ) interposition shunt within the left carotid artery ( black arrows ) .
these mb have a diameter of 1.00.1 m , and concentration of 1.5 to 3.010/ml .
the mb infusion was prepared by diluting 2 ml of the mrx801 in 100 ml of 0.9% saline and infused at a rate of 1.0 ml / min .
a commercially available us system ( ie33 ; philips medical systems ) and diagnostic transducer ( s51 ; philips ) were used .
the us system had low mi contrast sensitive imaging pulse sequences ( power modulation ) that were applied in between high mi impulses to assist in the detection of mb .
the 3 randomized groups tested were : ( 1 ) 2d intermittent guided high mi with intravenous mb ( group 1 ) ; ( 2 ) 2dguided high mi us with intravenous 0.9% saline ( group 2 ) ; and ( 3 ) controls that received no treatment ( group 3 ) .
randomized transcutaneous treatment groups ( 1 or 2 ) and controls were assigned immediately after surgical placement of ecs . the first treatment regimen ( in groups 1 and 2 )
was begun within 2 hours of placement of the ecs , because it is anticipated that this is when significant initial platelet and fibrin deposition occurs .
thirtyminute treatments were given separately to each side ( av shunt on the right side , aa shunt on the left ) .
the mb or 0.9% saline were infused through a peripheral vein . in group 1 ,
the application of brief high mi impulses ( 1.1 mi ; pulse duration 20 s ; frame rate 20 hz ) was guided to allow replenishment of mb within the region of interest .
this frequency and pulse duration for therapeutic us application was chosen based on previous in vitro work from our laboratory .
pulmonary hypertension , mediated by the vasoconstrictor thromboxane has been reported in pigs after exposure to intravenous mb .
this reaction is presumed to be secondary to speciesrelated pulmonary intravascular macrophages ; the macrophage phagocytotic process resulting in the release of thromboxane causing pulmonary hypertension .
ketorolac 60 mg and methylprednisolone 40 mg to prevent pulmonary hypertensive responses to mb were administered intravenously in groups 1 and 2 prior to each treatment .
oxygen saturation by pulse oximetry , arterial blood pressure , and 3lead electrocardiograms were measured before , during , and for 30 minutes after us and mb therapy .
the shunts were imaged using color doppler us ( 4vc1 vascular transducer ; siemens ) before and after each treatment ( figure 2 ) .
a single experienced echocardiographer ( jw ) recorded doppler data as good , reduced , or absent based on color doppler information obtained from within the shunt .
settings of low 2dimensional gain , high color gain , small color overlay , zoom mode , and a single focal zone were used to maximize the sampling rate . as the doppler angles were inconsistent between the implanted shunts ,
the arteriovenous ( left panels ) and arterioarterial ( right panels ) shunts are demonstrated ( asterisks ) on 2dimensional and color doppler imaging , and during thromboprophylactic application of microbubbles and high mechanical index pulse sequences to insonify each shunt .
aa indicates arterioarterial ; av , arteriovenous . each animal was sacrificed at the completion of 4 treatments in groups 1 and 2 , and at a similar time point in group 3 .
each ecs was removed and placed in 10% neutral buffered formalin immediately , and processed according to standard tissue processing techniques .
the shunts were embedded in paraffin wax , sectioned , stained with hematoxylin and eosin for microscopy and reviewed by a pathologist ( sjr ) .
digital images of each section were taken through the iscan coreo slide scanner ( ventana medical systems inc ) at 20 magnification .
images of histopathologic sections from the explanted ecs were reviewed by the pathologist ( sjr ) , and under the pathologist 's direction , a blinded experienced observer ( jra ) performed quantitation of the inlumen residue in each shunt using ventana image viewer 3.1 software .
the area inside the endothelial cell lining of the tunica intima was included in the measurement .
areas calculated for each shunt section were added up to quantify thrombus accumulation ( figure 3 ) .
a , section of an av shunt in a group 1 animal with minimal intimal thickening and no luminal thrombus .
b , section of an av shunt with a mixture of blood , platelets and fibrin partially occluding its lumen .
the luminal composition was a mixture of platelets and fibrin with some endothelial cell ingrowth .
in addition , mononuclear cells , collagen and areas of calcification were seen in some of the sections that were occluded .
therefore , median thrombus burden was reported for us with mb , us with saline , and control groups , and the kruskalwallis test was applied to assess differences among these groups .
the student 's t test was used for comparison of hemodynamic measurements in treatment groups 1 and 2 . to assess the interobserver agreement ,
histopathologic thrombus burden measurements were repeated in 10 randomly chosen aa and av shunts by a second blinded observer .
blandaltman plots were derived to identify possible bias ( mean divergence ) and the limits of agreement ( 2 standard deviation of the divergence ) .
statistical analysis was performed using commercially available software ( minitab version 16.1 ; minitab inc ) .
the study was approved by the institutional animal care and use committee of the university of nebraska medical center and was in compliance with the standards in the guide for the care and use of laboratory animals .
the pig was fasted overnight and preanesthetized with an intramuscular mixture of telazol ( 4.4 mg / kg ) , ketamine ( 2.2 mg / kg ) , and xylazine ( 2.2 mg / kg ) .
intramuscular atropine ( 0.05 mg / kg ) was used to dry oraltracheal secretions and prevent bradycardia during intubation . following placement of a venous line in the lateral or medial auricular vein ,
the pig was intubated and isoflurane inhalation anesthesia ( induction at 4% , maintained at 1.0% to 1.8% ) administered .
the animal was placed on a ventilator at a volume of 11 cc / kg of air and at a rate of 15 breaths / minute .
after the pig was placed under anesthesia and after preparation of the surgical site , a midline cervical incision was made . through the incision ,
two 4mm diameter , 2.5 cm long , heparinbonded expanded polytetrafluoroethylene shunts ( propaten vascular graft ; gore medical ) were implanted : one interposition within the left carotid ( arterioarterial , aa ) , and one sidetoside av shunt from the right carotid artery to the right internal jugular vein .
this shunt type is commonly used in standard of care clinical practice in humans . for
the interposition shunt , each vessel was clamped proximally and distally and a 2.5 cm segment of vessel was excised . each anastomosis was created with running 60 polypropylene suture ( prolene ; ethicon ) .
both anastomoses were completed before releasing the vessel clamps , ie , the graft was not clamped . for the av shunt ,
4 clamps were applied to the artery and the vein both proximally and distally and all were removed when both anastomoses were completed .
the grafts were observed until hemostasis , and then the incision was closed with a subcutaneous and a skin suture layer ( figure 1 ) .
representative examples of surgically implanted rightsided arteriovenous ( av ) shunt from the right carotid artery to the right internal jugular vein , and left sided arterioarterial ( aa ) interposition shunt within the left carotid artery ( black arrows ) .
these mb have a diameter of 1.00.1 m , and concentration of 1.5 to 3.010/ml .
the mb infusion was prepared by diluting 2 ml of the mrx801 in 100 ml of 0.9% saline and infused at a rate of 1.0 ml / min .
a commercially available us system ( ie33 ; philips medical systems ) and diagnostic transducer ( s51 ; philips ) were used .
the us system had low mi contrast sensitive imaging pulse sequences ( power modulation ) that were applied in between high mi impulses to assist in the detection of mb .
the 3 randomized groups tested were : ( 1 ) 2d intermittent guided high mi with intravenous mb ( group 1 ) ; ( 2 ) 2dguided high mi us with intravenous 0.9% saline ( group 2 ) ; and ( 3 ) controls that received no treatment ( group 3 ) .
randomized transcutaneous treatment groups ( 1 or 2 ) and controls were assigned immediately after surgical placement of ecs . the first treatment regimen ( in groups 1 and 2 )
was begun within 2 hours of placement of the ecs , because it is anticipated that this is when significant initial platelet and fibrin deposition occurs .
thirtyminute treatments were given separately to each side ( av shunt on the right side , aa shunt on the left ) .
the mb or 0.9% saline were infused through a peripheral vein . in group 1 ,
the application of brief high mi impulses ( 1.1 mi ; pulse duration 20 s ; frame rate 20 hz ) was guided to allow replenishment of mb within the region of interest .
this frequency and pulse duration for therapeutic us application was chosen based on previous in vitro work from our laboratory .
pulmonary hypertension , mediated by the vasoconstrictor thromboxane has been reported in pigs after exposure to intravenous mb .
this reaction is presumed to be secondary to speciesrelated pulmonary intravascular macrophages ; the macrophage phagocytotic process resulting in the release of thromboxane causing pulmonary hypertension .
ketorolac 60 mg and methylprednisolone 40 mg to prevent pulmonary hypertensive responses to mb were administered intravenously in groups 1 and 2 prior to each treatment .
oxygen saturation by pulse oximetry , arterial blood pressure , and 3lead electrocardiograms were measured before , during , and for 30 minutes after us and mb therapy .
the shunts were imaged using color doppler us ( 4vc1 vascular transducer ; siemens ) before and after each treatment ( figure 2 ) .
a single experienced echocardiographer ( jw ) recorded doppler data as good , reduced , or absent based on color doppler information obtained from within the shunt .
settings of low 2dimensional gain , high color gain , small color overlay , zoom mode , and a single focal zone were used to maximize the sampling rate . as the doppler angles were inconsistent between the implanted shunts ,
the arteriovenous ( left panels ) and arterioarterial ( right panels ) shunts are demonstrated ( asterisks ) on 2dimensional and color doppler imaging , and during thromboprophylactic application of microbubbles and high mechanical index pulse sequences to insonify each shunt .
each animal was sacrificed at the completion of 4 treatments in groups 1 and 2 , and at a similar time point in group 3 .
each ecs was removed and placed in 10% neutral buffered formalin immediately , and processed according to standard tissue processing techniques .
the shunts were embedded in paraffin wax , sectioned , stained with hematoxylin and eosin for microscopy and reviewed by a pathologist ( sjr ) .
digital images of each section were taken through the iscan coreo slide scanner ( ventana medical systems inc ) at 20 magnification .
images of histopathologic sections from the explanted ecs were reviewed by the pathologist ( sjr ) , and under the pathologist 's direction , a blinded experienced observer ( jra ) performed quantitation of the inlumen residue in each shunt using ventana image viewer 3.1 software .
the area inside the endothelial cell lining of the tunica intima was included in the measurement .
areas calculated for each shunt section were added up to quantify thrombus accumulation ( figure 3 ) .
representative examples of residual thrombi within av shunt . a , section of an av shunt in a group 1 animal with minimal intimal thickening and no luminal thrombus .
b , section of an av shunt with a mixture of blood , platelets and fibrin partially occluding its lumen .
the luminal composition was a mixture of platelets and fibrin with some endothelial cell ingrowth .
in addition , mononuclear cells , collagen and areas of calcification were seen in some of the sections that were occluded .
therefore , median thrombus burden was reported for us with mb , us with saline , and control groups , and the kruskalwallis test was applied to assess differences among these groups .
the student 's t test was used for comparison of hemodynamic measurements in treatment groups 1 and 2 . to assess the interobserver agreement ,
histopathologic thrombus burden measurements were repeated in 10 randomly chosen aa and av shunts by a second blinded observer .
blandaltman plots were derived to identify possible bias ( mean divergence ) and the limits of agreement ( 2 standard deviation of the divergence ) .
statistical analysis was performed using commercially available software ( minitab version 16.1 ; minitab inc ) .
a total of 18 pigs had a placement of 36 ecs ( 12 pigs for thromboprophylaxis protocols and 6 controls ) .
table 1 shows the hemodynamic measurements in all animals prior to , during , and after the treatments summarized for all 4 treatments . there were no significant differences in hemodynamic parameters between groups 1 and 2 with any of the randomized therapies .
color doppler assessments of the shunts showed reduced or absent color doppler flow during 5 of 24 treatments in 2 group 1 pigs : absent flow was noted during 2 treatments in 1 and reduced flow was seen for 3 treatments in the second pig . among the group 2 pigs , absent or reduced flow
these included 6 instances of absent flow in 2 pigs and 2 instances of reduced flow in a third pig .
these color doppler flow changes in both groups were mostly observed during the third and fourth treatments .
hemodynamic indices compared between groups 1 and 2 for all treatments act indicates activated clotting time ; dbp , diastolic blood pressure ; hr , heart rate ; mb , microbubble ; sbp , systolic blood pressure ; spo2 , systemic oxygen saturation ; us indicates ultrasound . in the untreated animals ( group 3 ) , the median thrombus burden in av shunts was 5.10 mm compared with 4.05 mm in aa shunts ( p=0.199 ) . in the av shunts , group 1
had less median thrombus burden ( 2.5 mm ) in the av shunts compared with group 2 ( 5.6 mm ) and group 3 ( 7.5 mm ) pigs ( p=0.006 ; table 2 ) . among the explanted av shunts ,
no total lumen occlusions were observed in group 1 , whereas one av shunt total occlusion was seen in groups 2 and 3 .
differences in thrombus burden for explanted shunts compared between groups aa indicates arterioarterial ; av , arteriovenous ; mb , microbubble ; us indicates ultrasound .
the luminal composition was predominantly a mixture of organized blood , platelets , and fibrin ; collagen , mononuclear cells , and areas of calcification were also seen in the sections that were occluded ( figure 3 ) .
sections of av shunt histology in pigs treated with guided us with mbs showed reductions in thrombus formation along the entire circumference of the vessel . no difference in median thrombus burden
was seen among the 3 groups for aa shunts ( 4.05 mm in group 1 , 4.25 mm in group 2 , 4.50 mm in group 3 , p=0.895 ) .
blandaltman analysis showed good interobserver agreement for thrombus burden measurements as represented in figure 4 .
blandaltman analysis of interobserver agreement of residual thrombus burden in 10 randomly chosen aa and av shunts .
in the untreated animals ( group 3 ) , the median thrombus burden in av shunts was 5.10 mm compared with 4.05 mm in aa shunts ( p=0.199 ) . in the av shunts ,
group 1 had less median thrombus burden ( 2.5 mm ) in the av shunts compared with group 2 ( 5.6 mm ) and group 3 ( 7.5 mm ) pigs ( p=0.006 ; table 2 ) . among the explanted av shunts ,
no total lumen occlusions were observed in group 1 , whereas one av shunt total occlusion was seen in groups 2 and 3 .
differences in thrombus burden for explanted shunts compared between groups aa indicates arterioarterial ; av , arteriovenous ; mb , microbubble ; us indicates ultrasound .
the luminal composition was predominantly a mixture of organized blood , platelets , and fibrin ; collagen , mononuclear cells , and areas of calcification were also seen in the sections that were occluded ( figure 3 ) .
sections of av shunt histology in pigs treated with guided us with mbs showed reductions in thrombus formation along the entire circumference of the vessel . no difference in median thrombus burden
was seen among the 3 groups for aa shunts ( 4.05 mm in group 1 , 4.25 mm in group 2 , 4.50 mm in group 3 , p=0.895 ) .
blandaltman analysis showed good interobserver agreement for thrombus burden measurements as represented in figure 4 .
blandaltman analysis of interobserver agreement of residual thrombus burden in 10 randomly chosen aa and av shunts .
the clinical implications of thrombosis after surgical procedures in chd , including systemic to pulmonary shunts , bidirectional cavopulmonary shunts , and fontan palliation are significant .
thrombotic lumen occlusion is the usual cause for ecs failure ; this development leads to significant acute mortality and morbidity in chd .
no published randomized controlled trials are available to guide the thromboprophylactic management of patients with ecs , so use of anticoagulation is a subject of debate . although antiplatelet therapy has been studied extensively in adults , evidence for its benefit in infants and young children is limited .
while the use of aspirin was associated with a reduction in ecs thrombosis in some studies , others have failed to demonstrate a beneficial effect . in theory
, aspirin alone may be insufficient to prevent arterial thrombosis because it inhibits only one pathway ( cyclooxygenase ) of platelet activation , and would have minimal effect in treating thrombi that would be expected in ecs .
moreover , the optimal pediatric dose of aspirin for inhibition of platelet aggregation is unknown .
aspirin is associated with reye syndrome in infants and children , and may cause bleeding complications , particularly in the presence of an underlying hemostatic defect or with concurrent thrombolytic therapy .
the use of fibrinolytic drugs has not been established in children , and carries significant risk of major hemorrhage .
attempted recanalization of acutely thrombosed ecs by cathetermediated thrombus disruption or rheolytic thrombectomy has been met with some success .
subacute ecs occlusion develops from neointimal proliferation in addition to thrombus formation within the shunt , so recanalization is more difficult in such cases . therefore , treatments designed to locally prevent thrombus formation / reduce thrombus burden and maintain ecs patency would be ideal , and avoid these systemic complications .
mbs coupled with us have been used to dissolve thrombi without thrombolytic agents , and also have been shown to enhance the effectiveness of exogenous tissue plasminogen activator . in in vivo models , successful dissolution of arterial and venous thrombi is achievable with guided high mi impulses delivered from a diagnostic us transducer .
the advantage of this approach is that it permits simultaneous low mi mb sensitive imaging pulse sequence schemes to detect the mb with the same transducer , and allows one to control the region in which therapy is desired .
the present study describes the application of this treatment for thromboprophylaxis of ecs in vivo .
an imageguided approach ensured the presence of mb near the shunt when the high mi impulses were applied .
the arteriovenous connection generates an intravascular pressure differential , similar to the blalockthomastaussig shunt or sano shunt used for chd palliation .
these shunts are subject to intimal proliferation due to shear forces of turbulent blood flow , and subsequent thrombus deposition on the irregular surface where blood flow slows .
this was presumably because of the ( 1 ) higher baseline flow rates and consequently lower predisposition for stasisrelated thrombus formation , and ( 2 ) the relatively short duration ( 4 weeks ) of placement .
we speculate that the interposition shunts within the carotid artery ( aa ) had improved flow compared to the sideside connected av shunts . for the av shunts
, there is the possibility of narrowing at the sidetoside anastomoses and turbulence of flow due to pressure differences between the vessels , which may have led to increased thrombogenesis .
the safety and success of this noninvasive thromboprophylactic application in our porcine model increase the potential for translation to av shunts in the human . besides chd , a potential therapeutic application of av shunt thromboprophylaxis is in patients with endstage renal disease where the use of such shunts is very common
. the application may also be particularly advantageous in infants and children because of the proximity of vascular structures to allow improved penetration of transcutaneously applied us impulses .
moreover , recent clinical trials have indicated that us contrast agents are safe and effective in children and young adults .
comparisons of efficacy between usmb thromboprophylaxis and pharmacologic ( antiplatelet or anticoagulant ) prophylaxis require further study . the number of animals studied was relatively small and the duration of placement of shunts prior to explantation and histopathologic examination was 4 weeks . considering that av shunts in the human are placed for substantially longer periods of time , whether the same results could be extrapolated for longer durations / older shunts
the purpose of this study was to explore the feasibility of ultrasound and microbubble prophylaxis , but further work is needed to explore this treatment approach in shunts placed for longer periods of time .
evaluation for the possibility of soft tissue injury due to bioeffects associated with highmi impulses from the transducer requires further investigation .
there is potential for unwanted us mechanical bioeffects at mi>1.0 , however , these are likely to be minimal because the us application used in the study was with a commercially available diagnostic transducer , and the highmi therapeutic pulses were significantly lower than the food and drug administration recommended mi limit for clinical use .
the mbs used in this study have been successfully used in human trials as adjuvant for arterial sonothrombolysis .
although these mbs are not yet commercially available , they are similar in shell composition and mb size to commercially available lipid encapsulated mbs . finally , these results would only be applicable to av shunts .
other palliative connections in chd are also subject to thrombotic occlusion , and the role of thromboprophylaxis with us and mb must be explored in such settings , where attenuation of the us beam may play a role in achieving adequate inertial cavitation of the mb .
the number of animals studied was relatively small and the duration of placement of shunts prior to explantation and histopathologic examination was 4 weeks . considering that av shunts in the human are placed for substantially longer periods of time , whether the same results could be extrapolated for longer durations / older shunts
the purpose of this study was to explore the feasibility of ultrasound and microbubble prophylaxis , but further work is needed to explore this treatment approach in shunts placed for longer periods of time .
evaluation for the possibility of soft tissue injury due to bioeffects associated with highmi impulses from the transducer requires further investigation .
there is potential for unwanted us mechanical bioeffects at mi>1.0 , however , these are likely to be minimal because the us application used in the study was with a commercially available diagnostic transducer , and the highmi therapeutic pulses were significantly lower than the food and drug administration recommended mi limit for clinical use .
the mbs used in this study have been successfully used in human trials as adjuvant for arterial sonothrombolysis .
although these mbs are not yet commercially available , they are similar in shell composition and mb size to commercially available lipid encapsulated mbs . finally , these results would only be applicable to av shunts .
other palliative connections in chd are also subject to thrombotic occlusion , and the role of thromboprophylaxis with us and mb must be explored in such settings , where attenuation of the us beam may play a role in achieving adequate inertial cavitation of the mb .
transcutaneous us and intravenous mb are capable of decreasing thrombus burden in arteriovenous shunts without the need for antiplatelet agents , and may be a method of preventing progressive occlusion of a highflow , small diameter expanded polytetrafluoroethylene tube graft such as the modified blalock shunt or the sano shunt .
we appreciate the expert technical assistance of elizabeth stolze , lucas drvol , and gretchen fry of the joint cardiovascular research laboratory of the university of nebraska medical center .[/INST]backgroundpalliative shunts in congenital heart disease patients are vulnerable to thrombotic occlusion
. high mechanical index ( mi ) impulses from a modified diagnostic ultrasound ( us ) transducer during a systemic microbubble ( mb ) infusion have been used to dissolve intravascular thrombi without anticoagulation , and we sought to determine whether this technique could be used prophylactically to reduce thrombus burden and prevent occlusion of surgically placed extracardiac shunts.methods and resultsheparinbonded eptfe tubular vascular shunts of 4 mm2.5 cm ( propaten ; w.l gore ) were surgically placed in 18 pigs : a rightsided sidetoside arteriovenous ( av , carotidjugular ) shunt , and a leftsided arterioarterial ( aa , carotidcarotid ) interposition shunt in each animal . after shunt implantation , animals were randomly assigned to one of 3 groups .
transcutaneous , weekly 30minute treatments ( total of 4 treatments ) of either guided high mi us+mb ( group 1 ; n=6 ) using a 3% mrx801 mb infusion , or us alone ( group 2 ; n=6 ) were given separately to each shunt .
the third group of 6 pigs received no treatments .
the shunts were explanted after 4 weeks and analyzed by histopathology to quantify luminal thrombus area ( mm2 ) for the length of each shunt .
no pigs received antiplatelet agents or anticoagulants during the treatment period .
the median overall thrombus burden in the 3 groups for av shunts was 5.10 mm2 compared with 4.05 mm2 in aa ( p=0.199 ) .
group 1 pigs had significantly less thrombus burden in the av shunts ( median 2.5 mm2 ) compared with group 2 ( median 5.6 mm2 ) and group 3 ( median 7.5 mm2 ) pigs ( p=0.006 )
. no difference in thrombus burden was seen between groups for aa shunts.conclusiontranscutaneous us with intravenous mb is capable of preventing thrombus accumulation in arteriovenous shunts without the need for antiplatelet agents , and may be a method of preventing progressive occlusion of palliative shunts .</s> |
SECTION 1. SHORT TITLE.
This Act may be cited as the ``Defense of the Environment Act of
1997''.
SEC. 2. FINDINGS AND PURPOSE.
(a) Findings.--Congress finds that provisions that reduce
protection of the environment have been included in legislation without
adequate consideration and an opportunity for Members to vote on the
provisions and have been included in major rules adopted by Federal
agencies without adequate analysis.
(b) Purpose.--The purposes of this Act are to--
(1) require Members of Congress to vote in House of
Representatives and the Senate on provisions included in
legislation that reduce protection of the environment; and
(2) require the Office of Management and Budget to ensure
that an adequate analysis is conducted for provisions included
in major rules that reduce protection of the environment.
SEC. 3. APPLICABLE PROVISIONS.
(a) In General.--This Act shall apply to any provision in a bill,
joint resolution, amendment, or conference report before Congress, or
in any major rule, that reduces protection of the environment.
(b) Provisions Reducing Protection.--A provision shall be
considered to reduce protection of the environment if the provision
meets the criteria of one or more of the following paragraphs:
(1) Defense of clean air and water.--The provision may
allow increased pollution of ambient air, indoor air, surface
water, ground water, the oceans, or other terrestrial or
aquatic resources.
(2) Defense of national parks and public lands.--The
provision may--
(A) cause adverse impacts on the environmental
quality of national parks or other public lands,
including the effect of decreasing the quantity or
quality of outdoor educational or recreational
opportunities on such lands; or
(B) diminish protection of species that may be
endangered.
(3) Defense of children's environmental health.--The
provision may increase children's exposure to environmental
contaminants and other environmental risks.
(c) Other Provisions.--A provision shall also be considered to
reduce protection of the environment if the provision may have the
effect of shielding any violators of environmental laws from penalties
or limiting judicial review of agency action under the authority of any
environmental law.
(d) Baseline for Effects.--The baseline for determining the effects
of a provision described in subsection (b) or (c) shall be the
circumstances that would exist if the provision were not enacted.
SEC. 4. DUTIES OF CONGRESSIONAL COMMITTEES.
(a) In General.--When a committee of the House of Representatives
or Senate or a committee of conference reports a bill or joint
resolution of public character that includes any provision that reduces
protection of the environment, the report of the committee accompanying
the bill or joint resolution (or the statement of managers accompanying
the conference report) shall contain each of the following:
(1) An identification and description of any provision in
the bill or joint resolution or conference report that reduces
protection of the environment.
(2) A qualitative and, if practicable, a quantitative
assessment of the extent of the reduction in protection of the
environment.
(3) A description of the actions, if any, taken by the
committee to avoid the reduction in protection of the
environment.
(4) Any statement received under section 5.
SEC. 5. DUTIES OF THE COMPTROLLER GENERAL.
(a) Statement.--For each bill or joint resolution of a public
character reported by any committee of the House of Representatives or
the Senate, and for each report by a committee of conference, the
Comptroller General of the United States, upon a request of the
committee or a majority of the members of the minority party or
majority party of the committee, shall, prior to the filing of the
report, prepare and submit to the committee a statement assessing the
extent to which the provisions of the bill, joint resolution, or
conference report reduce protection of the environment.
(b) Assistance to Committees and Studies.--At the request of any
committee of the Senate or the House of Representatives, the
Comptroller General shall, to the extent practicable, consult with and
assist such committee in assessing the extent to which the provisions
of a bill, joint resolution, or conference report reduce the protection
of the environment.
SEC. 6. DUTIES OF OFFICE OF MANAGEMENT AND BUDGET.
(a) In General.--The Director of the Office of Management and
Budget shall ensure that, before proposing or promulgating any major
rule, the department or agency of the United States responsible for
such rule has conducted an analysis that contains each of the
following:
(1) An identification and description of any provision in
the rule that reduces protection of the environment.
(2) A qualitative and, if practicable, a quantitative
assessment of the extent of the reduction in protection of the
environment.
(3) A description of the actions, if any, taken by the
department or agency to avoid the reduction in protection of
the environment.
(b) Notice.--In proposing or promulgating any major rule, the
department or agency of the United States responsible for such rule
shall include in the Federal Register, together with notice of such
proposal or promulgation, a detailed summary of the analysis conducted
under subsection (a).
(c) Definition of Major Rule.--For purposes of this section the
term ``major rule'' shall have the same meaning as when used in
Executive Order No. 12866.
SEC. 7. LEGISLATION SUBJECT TO POINT OF ORDER.
(a) In General.--It shall not be in order in the House of
Representatives or the Senate to consider any bill, joint resolution,
or conference report that is reported by a committee unless the
committee has complied with section 4.
(b) Procedure in the House of Representatives.--It shall not be in
order in the House of Representatives to consider a rule or order that
waives the application of subsection (a).
SEC. 8. DEBATE ON PROVISIONS REDUCING PROTECTION.
(a) Amendment of House Rules.--Rule XVI of the Rules of the House
of Representatives is amended by adding at the end the following:
``(11) Notwithstanding the adoption of any rule or motion to limit
or close debate it shall always be in order, as question of high
privilege, to move to strike from any bill, joint resolution, or
amendment any provision that reduces protection of the environment
(within the meaning of section 3 of the Defense of the Environment Act
of 1997). Such motion shall take precedence over a motion for the
previous question on such bill, joint resolution, or amendment and it
shall be in order to debate any such motion for 40 minutes, one-half of
such time shall be given to debate in favor of, and one-half of such
times in opposition to, such motion.''.
(b) Vote in Senate.--Notwithstanding the adoption of any rule or
motion to limit or close debate it shall always be in order, as
question of high privilege in the Senate, to move to strike from any
bill, joint resolution, amendment, or conference report any provision
that reduces protection of the environment (within the meaning of
section 3 of the Defense of the Environment Act of 1997). Such motion
shall take precedence over a motion for the previous question on such
bill, joint resolution, amendment, or conference report, and it shall
be in order to debate any such motion for 40 minutes, one-half of such
time shall be given to debate in favor of, and one-half of such times
in opposition to, such motion.
(c) Conference Reports and Senate Amendments.--
(1) Conference reports.--Clause (4) of Rule XXVIII of the
Rules of the House of Representatives is amended as follows:
(A) In subsection (a) after ``if such matter has
been offered as an amendment in the House'' by
inserting ``or containing any provision that reduces
protection of the environment (within the meaning of
section 3 of the Defense of the Environment Act of
1997)''.
(B) In subsections (a), (b), and (c), by striking
out ``nongermane matter'' in each place it appears and
inserting ``matter or provision''.
(2) Senate amendments.--Clause (5) of Rule XXVII of the
Rules of the House of Representatives is amended as follows:
(A) In subsection (a) after ``if such matter had
been offered as an amendment in the House'' by
inserting ``or that reduces protection of the
environment (within the meaning of section 3 of the
Defense of the Environment Act of 1997)''.
(B) In subsections (a), (b), and (c), by striking
out ``nongermane matter'' in each place it appears and
inserting ``matter or provision''.
(d) Exercise of Rulemaking Powers.--The provisions of this section
and sections 4 and 7 are enacted by Congress--
(1) as an exercise of the rulemaking power of the House of
Representatives and the Senate, respectively, and as such they
shall be considered as part of the rules of such House,
respectively, and such rules shall supersede other rules only
to the extent that they are inconsistent therewith; and
(2) with full recognition of the constitutional right of
either House to change such rules (so far as relating to such
House) at any time, in the same manner, and to the same extent
as in the case of any other rule of each House.
SEC. 9. EFFECTIVE DATE.
This Act shall take effect on the date of enactment. | Defense of the Environment Act of 1997 - Requires any report of a congressional committee or committee of conference accompanying a public bill or joint resolution that includes any provision that reduces environmental protection to contain: (1) an identification and description of the provision; (2) an assessment of the extent of such reduction; (3) a description of any actions to avoid such reduction; and (4) any statement received from the Comptroller General, upon request of the committee or a majority of either the minority or majority members of the committee, assessing the reduction.
Deems a provision to reduce environmental protection if it may: (1) allow increased pollution; (2) adversely affect the environmental quality of public lands or diminish protection of species that may be endangered; (3) increase children's exposure to environmental contaminants and other environmental risks; or (4) have the effect of shielding environmental law violators or limiting judicial review of agency action under authority of any environmental law.
Provides for consultation and assistance of the Comptroller General at the request of any committee. Requires the Director of the Office of Management and Budget to ensure that, before proposing or promulgating any major rule, the responsible agency has conducted an analysis of any provision that reduces environmental protection.
Makes out of order in the House of Representatives and the Senate the consideration of any reported bill or joint resolution, or conference report, unless the committee has complied with the identification and assessment provisions of this Act. Makes any rule waiving these provisions out of order in the House.
Amends the Rules of the House of Representatives with respect to the consideration and striking of provisions reducing environmental protection within the meaning of this Act. Provides Senate procedures for the striking of such provisions. | <s>[INST]SECTION 1. SHORT TITLE.
This Act may be cited as the ``Defense of the Environment Act of
1997''.
SEC. 2. FINDINGS AND PURPOSE.
(a) Findings.--Congress finds that provisions that reduce
protection of the environment have been included in legislation without
adequate consideration and an opportunity for Members to vote on the
provisions and have been included in major rules adopted by Federal
agencies without adequate analysis.
(b) Purpose.--The purposes of this Act are to--
(1) require Members of Congress to vote in House of
Representatives and the Senate on provisions included in
legislation that reduce protection of the environment; and
(2) require the Office of Management and Budget to ensure
that an adequate analysis is conducted for provisions included
in major rules that reduce protection of the environment.
SEC. 3. APPLICABLE PROVISIONS.
(a) In General.--This Act shall apply to any provision in a bill,
joint resolution, amendment, or conference report before Congress, or
in any major rule, that reduces protection of the environment.
(b) Provisions Reducing Protection.--A provision shall be
considered to reduce protection of the environment if the provision
meets the criteria of one or more of the following paragraphs:
(1) Defense of clean air and water.--The provision may
allow increased pollution of ambient air, indoor air, surface
water, ground water, the oceans, or other terrestrial or
aquatic resources.
(2) Defense of national parks and public lands.--The
provision may--
(A) cause adverse impacts on the environmental
quality of national parks or other public lands,
including the effect of decreasing the quantity or
quality of outdoor educational or recreational
opportunities on such lands; or
(B) diminish protection of species that may be
endangered.
(3) Defense of children's environmental health.--The
provision may increase children's exposure to environmental
contaminants and other environmental risks.
(c) Other Provisions.--A provision shall also be considered to
reduce protection of the environment if the provision may have the
effect of shielding any violators of environmental laws from penalties
or limiting judicial review of agency action under the authority of any
environmental law.
(d) Baseline for Effects.--The baseline for determining the effects
of a provision described in subsection (b) or (c) shall be the
circumstances that would exist if the provision were not enacted.
SEC. 4. DUTIES OF CONGRESSIONAL COMMITTEES.
(a) In General.--When a committee of the House of Representatives
or Senate or a committee of conference reports a bill or joint
resolution of public character that includes any provision that reduces
protection of the environment, the report of the committee accompanying
the bill or joint resolution (or the statement of managers accompanying
the conference report) shall contain each of the following:
(1) An identification and description of any provision in
the bill or joint resolution or conference report that reduces
protection of the environment.
(2) A qualitative and, if practicable, a quantitative
assessment of the extent of the reduction in protection of the
environment.
(3) A description of the actions, if any, taken by the
committee to avoid the reduction in protection of the
environment.
(4) Any statement received under section 5.
SEC. 5. DUTIES OF THE COMPTROLLER GENERAL.
(a) Statement.--For each bill or joint resolution of a public
character reported by any committee of the House of Representatives or
the Senate, and for each report by a committee of conference, the
Comptroller General of the United States, upon a request of the
committee or a majority of the members of the minority party or
majority party of the committee, shall, prior to the filing of the
report, prepare and submit to the committee a statement assessing the
extent to which the provisions of the bill, joint resolution, or
conference report reduce protection of the environment.
(b) Assistance to Committees and Studies.--At the request of any
committee of the Senate or the House of Representatives, the
Comptroller General shall, to the extent practicable, consult with and
assist such committee in assessing the extent to which the provisions
of a bill, joint resolution, or conference report reduce the protection
of the environment.
SEC. 6. DUTIES OF OFFICE OF MANAGEMENT AND BUDGET.
(a) In General.--The Director of the Office of Management and
Budget shall ensure that, before proposing or promulgating any major
rule, the department or agency of the United States responsible for
such rule has conducted an analysis that contains each of the
following:
(1) An identification and description of any provision in
the rule that reduces protection of the environment.
(2) A qualitative and, if practicable, a quantitative
assessment of the extent of the reduction in protection of the
environment.
(3) A description of the actions, if any, taken by the
department or agency to avoid the reduction in protection of
the environment.
(b) Notice.--In proposing or promulgating any major rule, the
department or agency of the United States responsible for such rule
shall include in the Federal Register, together with notice of such
proposal or promulgation, a detailed summary of the analysis conducted
under subsection (a).
(c) Definition of Major Rule.--For purposes of this section the
term ``major rule'' shall have the same meaning as when used in
Executive Order No. 12866.
SEC. 7. LEGISLATION SUBJECT TO POINT OF ORDER.
(a) In General.--It shall not be in order in the House of
Representatives or the Senate to consider any bill, joint resolution,
or conference report that is reported by a committee unless the
committee has complied with section 4.
(b) Procedure in the House of Representatives.--It shall not be in
order in the House of Representatives to consider a rule or order that
waives the application of subsection (a).
SEC. 8. DEBATE ON PROVISIONS REDUCING PROTECTION.
(a) Amendment of House Rules.--Rule XVI of the Rules of the House
of Representatives is amended by adding at the end the following:
``(11) Notwithstanding the adoption of any rule or motion to limit
or close debate it shall always be in order, as question of high
privilege, to move to strike from any bill, joint resolution, or
amendment any provision that reduces protection of the environment
(within the meaning of section 3 of the Defense of the Environment Act
of 1997). Such motion shall take precedence over a motion for the
previous question on such bill, joint resolution, or amendment and it
shall be in order to debate any such motion for 40 minutes, one-half of
such time shall be given to debate in favor of, and one-half of such
times in opposition to, such motion.''.
(b) Vote in Senate.--Notwithstanding the adoption of any rule or
motion to limit or close debate it shall always be in order, as
question of high privilege in the Senate, to move to strike from any
bill, joint resolution, amendment, or conference report any provision
that reduces protection of the environment (within the meaning of
section 3 of the Defense of the Environment Act of 1997). Such motion
shall take precedence over a motion for the previous question on such
bill, joint resolution, amendment, or conference report, and it shall
be in order to debate any such motion for 40 minutes, one-half of such
time shall be given to debate in favor of, and one-half of such times
in opposition to, such motion.
(c) Conference Reports and Senate Amendments.--
(1) Conference reports.--Clause (4) of Rule XXVIII of the
Rules of the House of Representatives is amended as follows:
(A) In subsection (a) after ``if such matter has
been offered as an amendment in the House'' by
inserting ``or containing any provision that reduces
protection of the environment (within the meaning of
section 3 of the Defense of the Environment Act of
1997)''.
(B) In subsections (a), (b), and (c), by striking
out ``nongermane matter'' in each place it appears and
inserting ``matter or provision''.
(2) Senate amendments.--Clause (5) of Rule XXVII of the
Rules of the House of Representatives is amended as follows:
(A) In subsection (a) after ``if such matter had
been offered as an amendment in the House'' by
inserting ``or that reduces protection of the
environment (within the meaning of section 3 of the
Defense of the Environment Act of 1997)''.
(B) In subsections (a), (b), and (c), by striking
out ``nongermane matter'' in each place it appears and
inserting ``matter or provision''.
(d) Exercise of Rulemaking Powers.--The provisions of this section
and sections 4 and 7 are enacted by Congress--
(1) as an exercise of the rulemaking power of the House of
Representatives and the Senate, respectively, and as such they
shall be considered as part of the rules of such House,
respectively, and such rules shall supersede other rules only
to the extent that they are inconsistent therewith; and
(2) with full recognition of the constitutional right of
either House to change such rules (so far as relating to such
House) at any time, in the same manner, and to the same extent
as in the case of any other rule of each House.
SEC. 9. EFFECTIVE DATE.
This Act shall take effect on the date of enactment.[/INST]Defense of the Environment Act of 1997 - Requires any report of a congressional committee or committee of conference accompanying a public bill or joint resolution that includes any provision that reduces environmental protection to contain: (1) an identification and description of the provision; (2) an assessment of the extent of such reduction; (3) a description of any actions to avoid such reduction; and (4) any statement received from the Comptroller General, upon request of the committee or a majority of either the minority or majority members of the committee, assessing the reduction.
Deems a provision to reduce environmental protection if it may: (1) allow increased pollution; (2) adversely affect the environmental quality of public lands or diminish protection of species that may be endangered; (3) increase children's exposure to environmental contaminants and other environmental risks; or (4) have the effect of shielding environmental law violators or limiting judicial review of agency action under authority of any environmental law.
Provides for consultation and assistance of the Comptroller General at the request of any committee. Requires the Director of the Office of Management and Budget to ensure that, before proposing or promulgating any major rule, the responsible agency has conducted an analysis of any provision that reduces environmental protection.
Makes out of order in the House of Representatives and the Senate the consideration of any reported bill or joint resolution, or conference report, unless the committee has complied with the identification and assessment provisions of this Act. Makes any rule waiving these provisions out of order in the House.
Amends the Rules of the House of Representatives with respect to the consideration and striking of provisions reducing environmental protection within the meaning of this Act. Provides Senate procedures for the striking of such provisions.</s> |
SECTION 1. SHORT TITLE.
This Act may be cited as the ``Border and Port Security Act''.
SEC. 2. ADDITIONAL U.S. CUSTOMS AND BORDER PROTECTION PERSONNEL.
(a) Officers.--The Commissioner of U.S. Customs and Border
Protection shall every fiscal year hire, train, and assign not fewer
than 500 new officers above the level as of September 30 of the
immediately preceding fiscal year until the total number of officers
equals the requirements identified each year in the Workload Staffing
Model developed by the Commissioner.
(b) Agricultural Specialists.--The Commissioner of U.S. Customs and
Border Protection shall every fiscal year hire, train, and assign not
fewer than 100 new agricultural specialists above the level as of
September 30 of the immediately preceding fiscal year until the total
number of officers equals the requirements identified each year in the
Agriculture Resource Allocation Model developed by the Commissioner.
(c) Investigators.--The Commissioner of U.S. Customs and Border
Protection shall every fiscal year hire, train, and assign 30 new full-
time investigators within the Office of Professional Responsibility of
U.S. Customs and Border Protection until the total number of
investigators enables the Office to fulfill its mission proportionate
to the number of new personnel hired in accordance with subsections (a)
and (b).
(d) Support Staff.--The Commissioner of U.S. Customs and Border
Protection is authorized to hire, train, and assign support staff,
including technicians, to perform non-law enforcement administrative
functions to support the new officers hired pursuant to subsection (a).
(e) Traffic Forecasts.--In calculating the number of officers
needed at each land, air, and maritime port of entry through the
Workload Staffing Model, the Office of Field Operations of U.S. Customs
and Border Protection shall--
(1) rely on data collected regarding the inspections and
other activities conducted at each such port of entry; and
(2) consider volume from seasonal surges, other projected
changes in commercial and passenger volumes, the most current
commercial forecasts, and other relevant information.
(f) Amendment.--Subparagraph (A) of section 411(g)(5) of the
Homeland Security Act of 2002 (6 U.S.C. 211(g)(5)) is amended--
(1) by striking ``model'' and inserting ``models'';
(2) by inserting ``agricultural specialists,'' before ``and
support personnel''; and
(3) by inserting before the period at the end the
following: ``, and information concerning the progress made
toward meeting officer, agriculture specialist, and support
staff hiring targets, while accounting for attrition''.
(g) GAO Report.--If by September 30, 2020, the Commissioner of U.S.
Customs and Border Protection has not hired at least 500 additional
officers authorized under subsection (a) or at least 50 additional
agriculture specialists authorized under subsection (b), and in any
subsequent fiscal year in which the staffing levels specified in the
Workload Staffing Model or Agriculture Resource Allocation Model for
the Office of Field Operations have not been achieved, the Comptroller
General of the United States shall--
(1) conduct a review of U.S. Customs and Border Protection
hiring policies and processes to identify factors contributing
to such levels not being achieved and any other issues related
to hiring by U.S. Customs and Border Protection;
(2) consider attrition levels within the Office of Field
Operations to identify associated factors contributing to
attrition within the workforce of such Office; and
(3) submit to the Committee on Homeland Security of the
House of Representatives and the Committee on Homeland Security
and Governmental Affairs of the Senate a report that describes
the results of the review and consideration under paragraphs
(1) and (2), respectively, and that contains recommendations to
enhance the likelihood of achieving such staffing levels.
SEC. 3. PORTS OF ENTRY INFRASTRUCTURE ENHANCEMENT REPORT.
Not later than 90 days after the date of the enactment of this Act,
the Commissioner of U.S. Customs and Border Protection shall submit to
the Committee on Homeland Security of the House of Representatives and
the Committee on Homeland Security and Governmental Affairs of the
Senate a report that identifies--
(1) infrastructure improvements at ports of entry that
would enhance the ability of U.S. Customs and Border Protection
officers to detect, interdict, disrupt, and prevent fentanyl,
other synthetic opioids, and other narcotics and psychoactive
substances and associated contraband from entering the United
States, including a description of circumstances in which
effective technology in use at certain ports of entry cannot be
implemented at other ports of entry;
(2) detection equipment that would improve the ability of
such officers to identify such drugs and other dangers that are
being illegally transported into the United States; and
(3) safety equipment that would protect such officers from
accidental exposure to such drugs or other dangers associated
with the inspection of potential drug traffickers.
SEC. 4. AUTHORIZATION OF APPROPRIATIONS.
There is authorized to be appropriated to carry out this Act
$82,775,000 in fiscal year 2018 and $93,095,000 for each of the fiscal
years 2019 through 2024. | Border and Port Security Act This bill requires U.S. Customs and Border Protection (CBP), every fiscal year, to hire, train, and assign at least 500 new officers above the level as of September 30 of the immediately preceding fiscal year until the total number of officers equals the requirements identified each year in the Workload Staffing Model developed by the CBP. The CBP shall, every fiscal year, hire, train, and assign specified levels of new agricultural specialists, full-time investigators within its Office of Professional Responsibility, and support staff, including technicians, to perform non-law enforcement administrative functions. In calculating the number of officers needed at each port of entry through the Workload Staffing Model, the Office of Field Operations of the CBP shall: (1) rely on data collected regarding the inspections and other activities conducted at each such port of entry; and (2) consider volume from seasonal surges, other projected changes in commercial and passenger volumes, the most current commercial forecasts, and other relevant information. The bill amends the Homeland Security Act of 2002 to require CBP's annual report on staffing to include information on how many agricultural specialists are assigned to each field office and port of entry and information concerning the progress made toward meeting officer, agricultural specialist, and support staff hiring targets, while accounting for attrition. The CBP must also report on infrastructure and equipment needed to prevent the illegal transportation of opioids and other drugs through U.S. ports of entry. | <s>[INST]SECTION 1. SHORT TITLE.
This Act may be cited as the ``Border and Port Security Act''.
SEC. 2. ADDITIONAL U.S. CUSTOMS AND BORDER PROTECTION PERSONNEL.
(a) Officers.--The Commissioner of U.S. Customs and Border
Protection shall every fiscal year hire, train, and assign not fewer
than 500 new officers above the level as of September 30 of the
immediately preceding fiscal year until the total number of officers
equals the requirements identified each year in the Workload Staffing
Model developed by the Commissioner.
(b) Agricultural Specialists.--The Commissioner of U.S. Customs and
Border Protection shall every fiscal year hire, train, and assign not
fewer than 100 new agricultural specialists above the level as of
September 30 of the immediately preceding fiscal year until the total
number of officers equals the requirements identified each year in the
Agriculture Resource Allocation Model developed by the Commissioner.
(c) Investigators.--The Commissioner of U.S. Customs and Border
Protection shall every fiscal year hire, train, and assign 30 new full-
time investigators within the Office of Professional Responsibility of
U.S. Customs and Border Protection until the total number of
investigators enables the Office to fulfill its mission proportionate
to the number of new personnel hired in accordance with subsections (a)
and (b).
(d) Support Staff.--The Commissioner of U.S. Customs and Border
Protection is authorized to hire, train, and assign support staff,
including technicians, to perform non-law enforcement administrative
functions to support the new officers hired pursuant to subsection (a).
(e) Traffic Forecasts.--In calculating the number of officers
needed at each land, air, and maritime port of entry through the
Workload Staffing Model, the Office of Field Operations of U.S. Customs
and Border Protection shall--
(1) rely on data collected regarding the inspections and
other activities conducted at each such port of entry; and
(2) consider volume from seasonal surges, other projected
changes in commercial and passenger volumes, the most current
commercial forecasts, and other relevant information.
(f) Amendment.--Subparagraph (A) of section 411(g)(5) of the
Homeland Security Act of 2002 (6 U.S.C. 211(g)(5)) is amended--
(1) by striking ``model'' and inserting ``models'';
(2) by inserting ``agricultural specialists,'' before ``and
support personnel''; and
(3) by inserting before the period at the end the
following: ``, and information concerning the progress made
toward meeting officer, agriculture specialist, and support
staff hiring targets, while accounting for attrition''.
(g) GAO Report.--If by September 30, 2020, the Commissioner of U.S.
Customs and Border Protection has not hired at least 500 additional
officers authorized under subsection (a) or at least 50 additional
agriculture specialists authorized under subsection (b), and in any
subsequent fiscal year in which the staffing levels specified in the
Workload Staffing Model or Agriculture Resource Allocation Model for
the Office of Field Operations have not been achieved, the Comptroller
General of the United States shall--
(1) conduct a review of U.S. Customs and Border Protection
hiring policies and processes to identify factors contributing
to such levels not being achieved and any other issues related
to hiring by U.S. Customs and Border Protection;
(2) consider attrition levels within the Office of Field
Operations to identify associated factors contributing to
attrition within the workforce of such Office; and
(3) submit to the Committee on Homeland Security of the
House of Representatives and the Committee on Homeland Security
and Governmental Affairs of the Senate a report that describes
the results of the review and consideration under paragraphs
(1) and (2), respectively, and that contains recommendations to
enhance the likelihood of achieving such staffing levels.
SEC. 3. PORTS OF ENTRY INFRASTRUCTURE ENHANCEMENT REPORT.
Not later than 90 days after the date of the enactment of this Act,
the Commissioner of U.S. Customs and Border Protection shall submit to
the Committee on Homeland Security of the House of Representatives and
the Committee on Homeland Security and Governmental Affairs of the
Senate a report that identifies--
(1) infrastructure improvements at ports of entry that
would enhance the ability of U.S. Customs and Border Protection
officers to detect, interdict, disrupt, and prevent fentanyl,
other synthetic opioids, and other narcotics and psychoactive
substances and associated contraband from entering the United
States, including a description of circumstances in which
effective technology in use at certain ports of entry cannot be
implemented at other ports of entry;
(2) detection equipment that would improve the ability of
such officers to identify such drugs and other dangers that are
being illegally transported into the United States; and
(3) safety equipment that would protect such officers from
accidental exposure to such drugs or other dangers associated
with the inspection of potential drug traffickers.
SEC. 4. AUTHORIZATION OF APPROPRIATIONS.
There is authorized to be appropriated to carry out this Act
$82,775,000 in fiscal year 2018 and $93,095,000 for each of the fiscal
years 2019 through 2024.[/INST]Border and Port Security Act This bill requires U.S. Customs and Border Protection (CBP), every fiscal year, to hire, train, and assign at least 500 new officers above the level as of September 30 of the immediately preceding fiscal year until the total number of officers equals the requirements identified each year in the Workload Staffing Model developed by the CBP. The CBP shall, every fiscal year, hire, train, and assign specified levels of new agricultural specialists, full-time investigators within its Office of Professional Responsibility, and support staff, including technicians, to perform non-law enforcement administrative functions. In calculating the number of officers needed at each port of entry through the Workload Staffing Model, the Office of Field Operations of the CBP shall: (1) rely on data collected regarding the inspections and other activities conducted at each such port of entry; and (2) consider volume from seasonal surges, other projected changes in commercial and passenger volumes, the most current commercial forecasts, and other relevant information. The bill amends the Homeland Security Act of 2002 to require CBP's annual report on staffing to include information on how many agricultural specialists are assigned to each field office and port of entry and information concerning the progress made toward meeting officer, agricultural specialist, and support staff hiring targets, while accounting for attrition. The CBP must also report on infrastructure and equipment needed to prevent the illegal transportation of opioids and other drugs through U.S. ports of entry.</s> |
The virtual currency bitcoin suffered the biggest setback in its five-year history after a major exchange shut down on Tuesday, stoking concern about the future of a digital form of money traded by professional investors and ordinary people, but regulated by no one.
The abrupt closure of Tokyo-based Mt. Gox underscored the risks of a virtual currency that has seen a meteoric rise in the past year. Unlike a U.S. bank failure, in which deposits are insured by the government, there may be little recourse for people whose money... ||||| NEW YORK (MarketWatch) — Bitcoin prices recovered Wednesday from the declines spurred by the sudden closure of Tokyo-based bitcoin exchange Mt. Gox, as authorities in the U.S. and Japan began looking into the matter.
Meanwhile, Mt. Gox Chief Executive Mark Karpeles said Wednesday on the exchange’s website that he is working on the exchange’s problems but told users that they should stop asking questions because staff members are not allowed to respond.
Bitcoin rose 5.5% to $564.02 Wednesday from Tuesday’s close on the CoinDesk Bitcoin Price Index, which takes into account prices on the Bitstamp and BTC-e bitcoin exchanges. The CoinDesk bitcoin price index was in the $400s early Tuesday after it became apparent that trading on Mt. Gox had been halted. The Mt. Gox website was subsequently wiped clean of information.
“I am still in Japan, and working very hard with the support of different parties to find a solution to our recent issues,” said Karpeles in the statement. “Furthermore I would like to kindly ask that people refrain from asking questions to our staff: they have been instructed not to give any response or information.”
Mt. Gox
After initially remaining silent on Tuesday’s shuttering of Mt. Gox, a move that shocked the virtual-currency market, Japanese officials said they were looking into the matter.
“At this stage the relevant financial authorities — the police, the Finance Ministry and others — are gathering information on the case,” Chief Cabinet Secretary Yoshihide Suga said at a regular news conference Wednesday, according to a Reuters translation of his remarks. Suga declined to comment further.
Late Tuesday, The Wall Street Journal reported that federal prosecutors based in New York had served Mt. Gox with a subpoena earlier this month. The report, citing an unnamed person familiar with the matter, said the subpoena included an order for Mt. Gox to preserve certain documents.
It’s unclear how much money was tied up on Mt. Gox, once the dominant exchange for bitcoin. Its collapse has triggered calls for regulation of the virtual currency and the exchanges tied to it, even as supporters have said bitcoin, which advocates have touted as a long-term alternative to government-issued currencies, remains viable.
The virtual currency has attracted the attention — and cash — of venture capitalists such as Marc Andreessen, who has called it transformational technology, Tyler and Cameron Winklevoss, who may be best known for their lawsuit against Mark Zuckerberg over the origins of Facebook, and Fred Wilson, whose Union Square Ventures counts Coinbase as a portfolio company.
For its own part, Mt. Gox has offered little explanation for its closure. In a terse statement on its website Tuesday, it cited “recent news reports and the potential repercussions on Mt. Gox’s operations and the market” as the reason for halting transactions “for the time being.”
Tuesday’s complete trading halt on Mt. Gox was the latest in a series of halts and delays that have plagued the exchange in the past year.
A widely cited document leaked to the bitcoin entrepreneur and blogger Ryan Selkis alleges that just less than 750,000 bitcoin are missing from Mt. Gox. The bitcoins had been stolen over “several years” due to an issue in the way the exchange wrote its software that could allow for duplicate transactions.
Reuters said Wednesday that Karpeles had told the news agency in an email: “We should have an official announcement ready soon-ish. We are currently at a turning point for the business. I can’t tell much more for now as this also involves other parties.”
However, Karpeles didn’t offer further details or disclose his location at the time.
More MarketWatch news:
Who are the big investors in bitcoin ventures?
Warren Buffett dishes out investment advice
Bank of America’s legal problems pile up
Providing critical information for the U.S. trading day. Subscribe to MarketWatch's free Need to Know newsletter. Sign up here. ||||| Bitcoin exchange Mt. Gox has received a subpoena from federal prosecutors in New York, according to a person familiar with the matter, dealing another blow to the embattled marketplace for buyers and sellers of the virtual currency.
Mt. Gox, one of the largest bitcoin exchanges, shut down on Tuesday, underscoring the risks of bitcoin, the virtual currency that has seen a meteoric rise in the past year. The subpoena was sent this... | – Federal prosecutors in New York have sent a subpoena to Mt. Gox, the once-mighty bitcoin exchange that vanished yesterday, the Wall Street Journal reports. Prosecutors demanded that the site preserve certain documents, a source said. Mt. Gox is based out of Tokyo, but if its employees sent emails or financial transfers through New York, federal prosecutors can claim jurisdiction. Soon after the Journal report hit, Japanese authorities said they too were looking into the matter, Reuters reports. "The police, the Finance Ministry, and others are gathering information on the case," Japan's chief Cabinet secretary said. Mt. Gox CEO Mark Karpeles told Reuters the site would have an official announcement "soon-ish," adding, "We are currently at a turning point for the business." On the barren page where the site once stood, Karpeles wrote that he was still in Japan and working to fix things. Despite the uproar, bitcoin prices actually spiked today to $575, after dropping to $515 yesterday, MarketWatch reports. | <s>[INST]The virtual currency bitcoin suffered the biggest setback in its five-year history after a major exchange shut down on Tuesday, stoking concern about the future of a digital form of money traded by professional investors and ordinary people, but regulated by no one.
The abrupt closure of Tokyo-based Mt. Gox underscored the risks of a virtual currency that has seen a meteoric rise in the past year. Unlike a U.S. bank failure, in which deposits are insured by the government, there may be little recourse for people whose money... ||||| NEW YORK (MarketWatch) — Bitcoin prices recovered Wednesday from the declines spurred by the sudden closure of Tokyo-based bitcoin exchange Mt. Gox, as authorities in the U.S. and Japan began looking into the matter.
Meanwhile, Mt. Gox Chief Executive Mark Karpeles said Wednesday on the exchange’s website that he is working on the exchange’s problems but told users that they should stop asking questions because staff members are not allowed to respond.
Bitcoin rose 5.5% to $564.02 Wednesday from Tuesday’s close on the CoinDesk Bitcoin Price Index, which takes into account prices on the Bitstamp and BTC-e bitcoin exchanges. The CoinDesk bitcoin price index was in the $400s early Tuesday after it became apparent that trading on Mt. Gox had been halted. The Mt. Gox website was subsequently wiped clean of information.
“I am still in Japan, and working very hard with the support of different parties to find a solution to our recent issues,” said Karpeles in the statement. “Furthermore I would like to kindly ask that people refrain from asking questions to our staff: they have been instructed not to give any response or information.”
Mt. Gox
After initially remaining silent on Tuesday’s shuttering of Mt. Gox, a move that shocked the virtual-currency market, Japanese officials said they were looking into the matter.
“At this stage the relevant financial authorities — the police, the Finance Ministry and others — are gathering information on the case,” Chief Cabinet Secretary Yoshihide Suga said at a regular news conference Wednesday, according to a Reuters translation of his remarks. Suga declined to comment further.
Late Tuesday, The Wall Street Journal reported that federal prosecutors based in New York had served Mt. Gox with a subpoena earlier this month. The report, citing an unnamed person familiar with the matter, said the subpoena included an order for Mt. Gox to preserve certain documents.
It’s unclear how much money was tied up on Mt. Gox, once the dominant exchange for bitcoin. Its collapse has triggered calls for regulation of the virtual currency and the exchanges tied to it, even as supporters have said bitcoin, which advocates have touted as a long-term alternative to government-issued currencies, remains viable.
The virtual currency has attracted the attention — and cash — of venture capitalists such as Marc Andreessen, who has called it transformational technology, Tyler and Cameron Winklevoss, who may be best known for their lawsuit against Mark Zuckerberg over the origins of Facebook, and Fred Wilson, whose Union Square Ventures counts Coinbase as a portfolio company.
For its own part, Mt. Gox has offered little explanation for its closure. In a terse statement on its website Tuesday, it cited “recent news reports and the potential repercussions on Mt. Gox’s operations and the market” as the reason for halting transactions “for the time being.”
Tuesday’s complete trading halt on Mt. Gox was the latest in a series of halts and delays that have plagued the exchange in the past year.
A widely cited document leaked to the bitcoin entrepreneur and blogger Ryan Selkis alleges that just less than 750,000 bitcoin are missing from Mt. Gox. The bitcoins had been stolen over “several years” due to an issue in the way the exchange wrote its software that could allow for duplicate transactions.
Reuters said Wednesday that Karpeles had told the news agency in an email: “We should have an official announcement ready soon-ish. We are currently at a turning point for the business. I can’t tell much more for now as this also involves other parties.”
However, Karpeles didn’t offer further details or disclose his location at the time.
More MarketWatch news:
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Providing critical information for the U.S. trading day. Subscribe to MarketWatch's free Need to Know newsletter. Sign up here. ||||| Bitcoin exchange Mt. Gox has received a subpoena from federal prosecutors in New York, according to a person familiar with the matter, dealing another blow to the embattled marketplace for buyers and sellers of the virtual currency.
Mt. Gox, one of the largest bitcoin exchanges, shut down on Tuesday, underscoring the risks of bitcoin, the virtual currency that has seen a meteoric rise in the past year. The subpoena was sent this...[/INST]– Federal prosecutors in New York have sent a subpoena to Mt. Gox, the once-mighty bitcoin exchange that vanished yesterday, the Wall Street Journal reports. Prosecutors demanded that the site preserve certain documents, a source said. Mt. Gox is based out of Tokyo, but if its employees sent emails or financial transfers through New York, federal prosecutors can claim jurisdiction. Soon after the Journal report hit, Japanese authorities said they too were looking into the matter, Reuters reports. "The police, the Finance Ministry, and others are gathering information on the case," Japan's chief Cabinet secretary said. Mt. Gox CEO Mark Karpeles told Reuters the site would have an official announcement "soon-ish," adding, "We are currently at a turning point for the business." On the barren page where the site once stood, Karpeles wrote that he was still in Japan and working to fix things. Despite the uproar, bitcoin prices actually spiked today to $575, after dropping to $515 yesterday, MarketWatch reports.</s> |
given a proliferating population of cells starting from one or more progenitors , a natural quantity of interest in cell biology is the average number of divisions per cell since the initial progenitors , i.e. the average generation of presently living cells . the average generation is related to the population s turn - over rate and can potentially be used to quantify dynamics and aging of the immune system @xcite , to better understand the evolution and risk of cancer @xcite , and to rank cell types in hierarchies of complex differentiation programs @xcite .
estimating average generation is a simple matter if cell lifetimes are all equal and the division time is known or , alternatively , if total cell counts can be measured and there is no cell death . if , however , lifetimes are heterogeneous , the population is subject to death as well as division or total cell counts are not available , the issue is more involved . in these settings ,
several experimental techniques can be employed to estimate average generation , including time lapse microscopy , division diluting fluorescent dyes , and inference from somatic mutations and telomere length .
the most unambiguous measurement technique is _ in vitro _
time lapse microscopy as it affords nearly direct determination of lineage trees and cell generation .
time lapse microscopy has been used to study many cell systems including bacteria , lymphocytes , embryonic development , gut development , to name but a few , e.g. @xcite .
even it , however , has limitations as filming is not continuous , cells can leave the field of vision or form three dimensional structures that inhibit tracking .
the complexity of image segmentation increases with cell numbers , and so time lapse microscopy has proved challenging if more than approximately @xmath0 generations are to be followed .
another popular experimental approach , particularly in immunology , is to stain starting cells with a fluorescent dye such as carboxyfluorescein succinimidyl ester @xcite , celltrace@xmath1 violet or cell proliferation dye efluor 670 @xcite . with each division , cells inherit approximately half of their parent s dye and so fluoresce with half their intensity .
a cell s generation can thus be determined by its luminous intensity via flow cytometry .
this approach is used both _ in vitro _ and _ in vivo _ , and allows the experimenter to start with a large number of progenitors without difficulty .
it enables 6 - 10 generations to be followed before dye dilution is such that the signal - to - noise ratio is too high for a cell s generation to be reliably determined . determining generation _ in vivo _ remains challenging as often it can not be achieved by direct observation or cell stain methods .
estimating replicative history , cell depth and lineage trees has been proposed by measurement of average telomere length @xcite or by the number of somatic mutations , which are introduced during dna duplication @xcite . while methods in this direction rely on inference rather than direct observation , they offer the possibility of tracing more than 10 generations in a wide range of species , including humans .
in the present paper , we provide a novel average generation estimator that is designed with the _ in vivo _ setting in mind .
the estimator is suitable for systems where cells undergo an unlikely , heritable division - linked label change with a determinable probability , where the label serves only as a marker and does not impact on cell dynamics .
chief amongst the estimator s desirable properties are that : ( 1 ) it requires no information on cell lifetime distributions ; ( 2 ) the population can be subject to death as well as division ; and ( 3 ) only a proportion of label - positive to total cells needs to be measured .
the present article introduces the estimator , analytically establishes its fundamental properties , validates its applicability by comparison with simulation and comparison with published data , proposes an experimental realization , and demonstrates its utility . in section [ sec : estover ] we describe the estimator and explain how it can be used .
the estimator appropriateness is a consequence of theorems that are presented in detail in section [ sec : math ] , with a heuristic explanation and overview of them appearing first in section [ sec : mathsum ] . in section [ sec : val_sim ] ,
validation using simulated data , we use monte carlo simulations to assess the estimator s performance for physiological parameterizations . in section [ sec : val_data ] , validation using published data , we use several sources of publicly available data to illustrate the estimator s applicability .
we avail of complete lineage tree data for the development of _ c. elegans _ , as determined from time - lapse microscopy @xcite , stochastically labeling it . applying the estimator results in accurate inference of the average generation in comparison to the directly observed quantity .
we also take data from two distinct experimental studies , one on human colorectal cancer cells @xcite and one on murine embryonic fibroblasts @xcite , that employ micro - satellite mutation fluorescent reporter systems .
micro - satellite mutation is an unlikely division linked change and the fluorescence of cells in these systems serves as a label suitable for average generation estimation .
the results show consistency between average generation estimates , measured quantities and values reported in the literature . as an illustrative example , in section [ sec : expdes ] ,
experiment design , we propose a genetic construct , based on existing pieces , to facilitate average generation inference .
we describe how the probability of label - loss could be measured and how the method could be validated . in section [ sec :
disc ] , discussion , we conclude with experimental designs where the method would prove biologically informative .
we consider a system where cells are subject to a division - linked , heritable label change that serves as a measurable distinguishing marker , but does not influence population dynamics .
the method is appropriate regardless of whether initial cells are label - negative and can gain the label , which is then inherited by their offspring , or are label - positive and can lose the label , with their offspring not regaining the label . for a consistent description ,
we phrase the paper in terms of the latter , but the results all hold _ mutatis mutandis_. during each cell s lifetime , assume that a label - positive cell becomes label - negative with a known , small likelihood , @xmath2 .
let @xmath3 be the total live cell count at time @xmath4 and @xmath5 be the live cell count of label - positive cells .
assume that the initial cells at @xmath6 are all label - positive and that at some time @xmath4 the fraction of label positive cells to total cells , @xmath7 , can be measured . with @xmath8 denoting the sum of the generations of all cells living at time @xmath4 and with @xmath9 defined to be @xmath10 , then given there are label - positive cells in the system at @xmath4 , i.e. @xmath11 , we establish that the average generation of cells alive at time @xmath4 satisfies the following relationship @xmath12 that is , the average generation of the population can be estimated directly from the proportion of label - positive cells if the delabeling probability is known .
perhaps unexpectedly the formula does not depend on several difficult - to - measure factors such as cell - lifetime distributions and total cell counts .
moreover the right hand side of requires only a proportional measurement of label - positive cells , which can be determined from a sample , and the relationship holds even though the population could be subject to death as well as division . for the validity of
, we have assumed that at @xmath6 all cells are label - positive . as a result @xmath13 and
so both the right and left hand side of are @xmath10 at @xmath6 , agreeing irrespective of the initial starting number . if , however , not all cells are initially label - positive , the estimator and the average generation would not agree .
this can be rectified if measurements of the proportion of positively labeled cells are available at two time - points , @xmath14 .
then , irrespective of the initial composition of label - positive and label - negative cells , so long as @xmath15 , @xmath16 this two - measurement estimator has an additional advantage when initial cell numbers are small .
if the culture is started , as an extreme example , with a single progenitor , then the right hand side of can be subject to stochastic fluctuations at shorter time - scales ( see the monte carlo simulations in section [ sec : val_sim ] ) . as established rigorously in section [ sec : math ] , with @xmath17 , the two - sample estimator in is more accurate than as it removes the influence of the timing of early cell events on the estimate .
the estimators and have non - obvious forms . utilising expansion properties of cumulant generating functions , results in the following section show that the relationships hold , in expectation , for an arbitrary familial relationship .
this includes , in particular , estimation of average generation for heterogeneous cell populations with distinct , potentially interdependent , proliferation characteristics . in the absence of a generative model of family trees , however , that derivation can not provide information about the development in time of the average generation of a family of cells .
nor can it be used to determine time - dependent properties of the estimators on a developing population . for a more detailed analysis of sample - path , multi - progenitor and time - dependent properties ,
a general mathematical framework for capturing the stochastic dynamics of a proliferating cell system subject to division and death , as well as heterogeneous cell life times , is that of age dependent branching processes @xcite where cells have random lifetimes as well as random numbers of offspring . since the seminal work of bellman and harris @xcite
, it has been known that if cells are more likely to divide then die , given the cell population does not die out , the number of cells living at time @xmath4 grows exponentially in time , @xmath18 , at a rate , @xmath19 , dubbed the malthus parameter , that depends on the lifetime and offspring number distributions of cells .
this result is known to be robust , for example , to sibling dependencies @xcite . in a cell system experiencing heritable one - way label - changes
, label - positive cells can become label negative - cells , but the reverse is not possible .
thus the number of label - positive cells at time @xmath4 also satisfies the branching process result , @xmath20 , but with a malthus parameter that is smaller than that for the total label - independent population of cells , @xmath21 .
the difference @xmath22 depends on the likelihood , @xmath2 , that a label - positive cell loses its label .
fewer results have been established regarding the total generation of a cell population , the sum of the generations of all cells living at time @xmath4 , @xmath8 , for which new theorems can be found in section [ sec : math ] . for the label - independent population , in substantial generality
we prove that @xmath23 .
that is , the total generation increases faster than the total population size by a factor of @xmath4 . recalling that @xmath24 , for a general age - dependent branching process , the average generation of the population grows linearly in time @xmath25 for some @xmath26 . in the following section we give a deterministic result to provide non - probabilistic intuition for why this is so before considering the stochastic system .
the clinching result quantitatively relates the phenomena of stochastic delabeling to generational expansion .
so long as label - positive cells remain @xmath27 so that for @xmath2 small @xmath28 this identification holds for any age dependent branching process and does not depend upon the details of life - time distributions or the possibility of cell death , so long as populations do not go extinct . the estimators are related through stochastic quantities and are subject to sample - path fluctuations , particularly at early time - points . establishing that estimates , as a function of time on individual sample paths , converge to the true average generation underlies the development of the two time - point estimator in equation .
that methodology circumvents this issue of small number variability by eliminating the early fluctuations on a path - by - path basis . as a supporting result
, we also prove that the path - to - path variability of estimates decreases inversely proportionally to the number of progenitors , supporting the precision of estimates for experimental systems that are initiated with multiple cells , which is typically the case .
we begin by deriving a version of based on averages over realisations of the delabeling process .
this derivation has the advantage that it requires no assumptions regarding the family tree and so holds in complete generality , but it is not informative with regards individual realisations .
sample - path , time - dependent properties of the estimators arise as a consequence of involved theorems in the context of the most well established generative model of family trees , age dependent branching processes , which follow this derivation .
at some time @xmath4 , consider a collection of @xmath3 cells , whose familial relationship need not be known .
the generation of a cell is defined to be the number of ancestors it possesses , with initial cells being defined to be in generation @xmath10 .
denote each of the generations of the @xmath3 cells by @xmath29 .
of the generations of all living cells being denoted by @xmath30 knowing @xmath2 we wish to estimate the average generation of presently living cells , i.e. @xmath31 , by observation of the proportion @xmath7 .
if initial cells are label positive and with each division the label is lost independently with probability @xmath2 , the probability cell @xmath32 is still label positive in generation @xmath33 is @xmath34 . with @xmath5 denoting the number of label positive cells , by linearity of expectation the average proportion of label - positive cells in the population is @xmath35 identifying @xmath36 , this can be re - written in a form that identifies it with a moment generating function , e.g. @xcite , @xmath37 where @xmath38 is uniformly selected in @xmath39 . as both the moment generating function and the cumulant generating function , @xmath40 , are real analytic , we can take a taylor expansion of the latter around the origin , giving @xmath41 so that @xmath42 taking @xmath43 is equivalent to taking @xmath44 . thus noting that @xmath45 , we obtain @xmath46 which is formula , albeit with an expectation over stochastic delabelings . while this result is not as strong as others we shall prove , it illustrates both how the unusual formulation arises and that , averaged over delabeling processes , the relationship holds for arbitrary family tree structure . to determine sample path properties of the generation counting estimator
, we must establish two quantitative relationships in a general age - dependent branching process : ( 1 ) relating the growth rates of labeled and unlabeled populations when the probability of delabeling per cell division is small ; and ( 2 ) for the relationship between the number of cells alive and the sum of the generations of all living cells .
for the quantitative relationship between the growth - rates of the labeled and unlabeled populations when the delabeling probability per cell division is small and label - state does not impact on population dynamics , we leverage well - know single type results @xcite . for the relationship between the number of cells alive and the sum of the generations of all living cells ,
there are some results indirectly available from @xcite , but to identify more properties of our estimator we find it beneficial to provide an analysis of the joint probability generating function of number of cells alive and their total generation number .
our initial mathematical study treats systems that start with a single initiating progenitor . from these results , systems that start with several statistically equivalent progenitors with indistinguishable progeny
can be deduced .
in addition , we provide results on the behavior of the estimator for a system with numerous progenitors , establishing that that variances behave inversely proportionally to the number of progenitors .
we begin by considering a standard age dependent branching process , e.g. @xcite , with the usual assumptions on the distribution of a lifetime , a non - negative random variable @xmath47 , and the number of offspring , @xmath48 a non - negative integer valued random variable , at the end of a lifetime . in the circumstances of interest to us , proliferating cell populations , @xmath48 will take values in @xmath49 indicating that cells die or divide into two at the end of their lives , but we will prove the results in greater generality .
[ ass:1 ] the lifetime distribution , @xmath50 for @xmath51 , is non - lattice and satisfies @xmath52 .
the probability generating function of the number of offspring , @xmath53 for @xmath54 , is finite in a neighborhood of @xmath55 .
we denote its expected value by @xmath56 .
a key quantity in the study of age - dependent branching processes is the malthus parameter , @xmath57 , which is defined to be the solution of the following equation , should the solution exist , @xmath58 if @xmath57 exists , it is then the , possibly negative , asymptotic exponential growth rate of the expected population size .
the dependence of the malthus parameter , @xmath57 , on the expected number of offspring of a cell , @xmath59 , is not usually made explicit , but will prove essential for us as we shall be interested in relating the growth rate of the label - positive population and of the total population , which will differ .
for that purpose , we have the following result on the range of mean offspring , @xmath60 , for which the malthus parameter exists and its smoothness as a function of @xmath60 .
we expect that this proposition is known , but can not find a reference in the literature and so present a proof here .
[ prop : malder ] define @xmath61 where @xmath62 , then there exists a real analytic function @xmath63 , the malthus parameter , such that @xmath64 in particular , for @xmath65 , the first two derivatives of @xmath57 as a function of the average number of offspring @xmath60 are @xmath66 and @xmath67 consider the function @xmath68 $ ] defined by @xmath69 we wish to identify the range of @xmath60 such that @xmath57 exists satisfying @xmath70 , and to determine its smoothness properties as a function of @xmath59 . when @xmath71 , @xmath72 and so @xmath73 . as @xmath74 is the moment generating function of a non - negative random variable , @xmath47 , evaluated at @xmath75 , it is a real analytic function on the interior of the domain on which it is finite , i.e. for @xmath76
therefore as @xmath77 defined in is a product of real analytic functions , it is also real analytic on @xmath78 . as @xmath77 is a monotonic decreasing function of @xmath79 , for any @xmath80 there exists a unique @xmath79 such that @xmath81 .
thus we can apply the real analytic version of the implicit function theorem , e.g. theorem 1.8.3 @xcite .
this establishes that @xmath57 satisfying exists for @xmath80 , that @xmath19 is real analytic for @xmath65 , and that its first derivative satisfies @xmath82 which gives . to obtain
, one differentiates .
the real analyticity of @xmath57 allows us to characterize the difference in growth rates of two populations in terms of the taylor expansion of @xmath57 .
this will be useful as if there is small probability of label - loss , then the label - positive and total populations have similar , but non - identical , average offspring number .
we will relate the difference in their growth rates to the dynamics of the average generation of the population .
we consider a two - type reducible age - dependent branching process previously studied , for example , in @xcite .
that is , we consider a cell system that starts with a single progenitor that is positive for a label so that @xmath83 and @xmath84 , and define the total population at time @xmath4 to be @xmath85 .
each cell is assumed to have an independent and identically distributed lifetime at the end of which they independently give rise to a random number of offspring .
positive label cells can become negative label cells , but the reverse does not happen .
we are interested in populations where the label does not indicate a phenotypic change so that lifetime distributions do not depend on the label . depending upon the experimental system and marker employed
, the process of delabeling can occur in different ways and so one may have distinct models .
thus we make a general assumption that encompasses several of these .
notationally , let the random variable @xmath86 define the number of label - positive offspring of a label - positive cell , where @xmath87 captures the probability of delabeling .
we will make a technical assumption that ensures that the distribution of the number of label - positive offspring of a label - positive cell is less than its total ( i.e. label positive and negative ) offspring and that as @xmath2 drops to @xmath10 we assume that we recover the random variable describing the total ( i.e. label independent ) offspring of a cell , denoted @xmath88 .
[ ass:2 ] lifetimes are independent and identically distributed , and independent of independent and identically distributed type - dependent offspring numbers .
the lifetime distribution for cells , @xmath50 for @xmath51 , is non - lattice and satisfies @xmath52 .
if @xmath89 , the number of label - positive offspring of a label - positive cell is less than its total number of offspring : @xmath86 is strictly stochastically dominated by @xmath90 , i.e. @xmath91 for all @xmath92 and @xmath93 for some @xmath94 .
thus , defining @xmath95 , @xmath96 for all @xmath89 .
we assume that @xmath53 for @xmath54 , is finite in a neighborhood of @xmath55 , that @xmath97 , and that @xmath98 is real analytic in @xmath2 .
_ example 1 : _ delabeling occurs immediately prior to a cell s division , independently with probability @xmath2 . in this case
the offspring of a label - positive cell s are either all labeled or all delabeled . thus with @xmath48 denoting the label - independent offspring random variable , @xmath99 and , in particular , @xmath100 .
_ example 2 : _ delabeling of the offspring of a label - positive cell occurs independently with probability @xmath2 at birth . in this case
@xmath101 so that again @xmath102 , but higher order moments are smaller than those in example 1 .
_ example 3 : _ the offspring of a label - positive cell experience asymmetric label - loss .
there are genetic constructs where , on division , labels are lost asymmetrically @xcite .
that is , if a label - positive cell divides in two and one of its two offspring loses its label , then the other does not . as a result ,
if @xmath2 is the probability of delabeling and @xmath103 is the probability that a division rather than death occurs , then @xmath104 @xmath105 and the mean number of label positive offspring is @xmath106 . in all three of these examples
@xmath98 is a linear function of @xmath2 , so that assumption [ ass:2 ] holds .
based on results in @xcite in conjunction with proposition [ prop : malder ] , the following theorem can be deduced .
[ thm : twopop ] if @xmath107 , under assumption [ ass:2 ] , if @xmath108 , then almost surely @xmath109 where @xmath110 and , in particular , if @xmath108 , then almost surely @xmath111 the asymptotic behavior of @xmath5 and @xmath3 follow directly from @xcite . by proposition [ prop : malder ]
, @xmath57 is real analytic for @xmath65 and @xmath112 , and , by assumption [ ass:2 ] , @xmath98 is real analytic with @xmath97 .
thus @xmath113 is real analytic and we can take a taylor expansion of @xmath113 in @xmath2 around @xmath10 and so holds .
the relationship in follows from taking the limit as @xmath2 tends to @xmath10 . for comparison with these two - population results ,
we need to establish properties of the total generation , the sum of the generations of living cells , for a single - type population . in order to precisely define the total generation of a branching process , some unwieldy definitions are necessary .
these shall be largely side - stepped in the analysis , but are included to precisely define the objects of interest to us .
we use a modification of ideas in @xcite to do so and consider a single - type construction as that is sufficient for our needs .
the generation of an object is defined to be the number of ancestors it possesses . as such
, it is natural to begin with a single object at time @xmath10 defined to be in generation @xmath10 .
let @xmath114 denote the length of the life of the @xmath115-th object in the @xmath32-th generation and let @xmath116 denote the number of offspring of the @xmath115-th object in the @xmath32-th generation . starting with a single object , the total number of objects that will ,
at any stage , exist in the @xmath94-th generation is governed by a galton - watson recursion : @xmath117 where the empty sum is defined to be @xmath10 .
that is , the number of objects that will ever be in generation @xmath55 is the offspring number of the first object , @xmath118 .
the number of offspring that will ever exist in generation @xmath119 is the sum of the number offspring of those members of generation @xmath55 , and so forth , leading to the above recursion for @xmath120 .
each object in generation @xmath94 is defined by a life - history , @xmath121 , where this object is the @xmath122-th child of the @xmath123-child of the @xmath124-th child and so forth back to @xmath125 .
the indices run over objects that exist , so that @xmath126
. the birth time of the object @xmath121 is the sum of lifetime of its ancestors , @xmath127 the time the object ceases to be is @xmath128 . in terms of these definitions ,
the total number of objects present at time @xmath4 can be identified as all objects of any generation that are alive at time @xmath4 , @xmath129 where @xmath130 is the indicator function .
that is , the population alive at time @xmath4 is all those objects whose birth time is before or equal to @xmath4 and whose death time is after @xmath4 .
the generation of an object @xmath121 is @xmath94 and thus the sum of the generations of all objects existing at time @xmath4 is @xmath131 that is , for each object alive at time @xmath4 in generation @xmath94 , the total generation at that time is incremented by @xmath94 . before considering the probabilistic system , we begin with a fundamental , non - probabilistic lemma that will give an indication as to why one expects that the total generation of all living cells @xmath132 to grow in a similar fashion to @xmath133 , where @xmath134 is the number of presently living cells , assuming that cells can either die or divide into two at the end of their lives . [
lem : min ] for a binary family tree beginning with a single progenitor in generation @xmath10 , if there are @xmath135 cells alive then the average generation per cell satisfies @xmath136 .
consider a family tree with @xmath137 cells alive ( i.e. @xmath134 leaves ) , where @xmath92 and @xmath138 .
the minimal @xmath132 given @xmath134 is attained is when @xmath139 cells are in generation @xmath94 and @xmath140 cells are in generation @xmath141 , which can be formally established using the equations given above .
thus @xmath142 if @xmath143 or @xmath144 , these are equal and so the difference between the two is zero at each @xmath145 and one needs to be delicate with one s estimates . a rearrangement of terms gives @xmath146 if and only if @xmath147 a sufficient condition for this to be true is to relax the problem , letting @xmath148 with @xmath149 $ ] , and establish that @xmath150 , \end{aligned}\ ] ] which is readily achieved by calculus . in a system with death , in general there is no equivalent upper bound to lemma [ lem : min ] as it s possible that there is only one cell alive , @xmath151 , and the generation of that cell , and hence @xmath132 , can be arbitrarily large . for branching processes , however , under general conditions the population either dies out or ultimately grows in a somewhat regular fashion , @xcite , and so lemma [ lem : min ] anticipates that , in a suitable sense , @xmath152 becomes constant if the population survives . indeed , amongst other results , this is something we shall establish .
it is not possible to study the total generation of living cells , @xmath8 , separately from the total population , @xmath3 , as they are strongly coupled and their dynamics are intertwined .
this relationship appears as a cross term in when we consider the evolution of the joint probability generating function of the two , giving rise to an integral equation of unusual form . despite this form , it is , in general , susceptible to analysis .
[ ass:3 ] lifetimes are independent and identically distributed and independent of independent and identically distributed offspring numbers .
the lifetime distribution , @xmath50 for @xmath51 , is non - lattice and satisfies @xmath52 .
the probability generating function of the number of offspring , @xmath53 for @xmath54 , is finite in a neighborhood of @xmath55 .
we denote its first and second derivative at one by @xmath153 [ thm : ggen ] under assumption [ ass:3 ] , starting with @xmath154 , the joint probability generating function of @xmath155 , @xmath156 satisfies the integral equation @xmath157 for @xmath158 , define @xmath159 where @xmath57 and @xmath160 are defined in the statement of proposition [ prop : malder ] . for @xmath158 , @xmath161 and @xmath162 if @xmath163 ,
with @xmath164 defined in , defining @xmath165 in addition we have that @xmath166 we first establish that holds .
begin with a family tree starting with a single cell at time @xmath10 , @xmath167 , defined to be in generation @xmath10 , so that @xmath168 .
consider the impact of altering this initial condition so that the founding cell is in generation @xmath55 at @xmath6 , @xmath169 .
we will write @xmath170 for the process counting the total generation of living cells starting with @xmath169 , so that , in particular , @xmath171 , and retain @xmath8 for total generation given @xmath168 . the key observation , which can be established using equations and , is that @xmath172 this can be understood by noting that , leaving all other aspects of the family tree unchanged , the move from @xmath168 to @xmath169 causes the generation of every living cell to increase by @xmath55 .
thus , taking expectations over the lifetime of the initial cell and using the independence and identical distribution of the sub - trees generated by the first birth , but noting they start with cells that are in generation @xmath55 , we obtain @xmath173 giving .
the uniqueness of @xmath174 for @xmath175 and @xmath176 follows from analogous arguments to those in @xcite , chapter vi , utilizing the ideas in @xcite . to establish , note that using @xmath177 where we have used the equivalent , well known integral equation for @xmath178 to obtain the final equality .
we wish to study the asymptotics of this equation , dividing it by @xmath179 and taking limits as @xmath180 . to this end
, we employ a result from renewal theory , @xcite theorem 6.2(a ) , using the fact that by construction @xmath181 is a probability measure , @xmath182 should the limits on the right hand side exist .
the existence of the first limit follows from results in @xcite , @xmath183 consider @xmath184 .
if @xmath185 , then the limit automatically exists and is @xmath10 . if @xmath186 , select @xmath187 such that @xmath188 . from proposition [ prop :
malder ] , we are guaranteed the existence of such a @xmath79 as @xmath65 . as @xmath189 ,
as in the chernoff bound we have that @xmath190 as @xmath191 , this ensures that @xmath192 hence , using , @xmath193 as required . to obtain ,
one uses in conjunction with .
consider now , with a little re - arranging of terms , @xmath194 we wish to establish that the limit @xmath195 exists and identify its limit .
using and @xmath196 which can be found in @xcite , it is clear that only the last term on the right hand side of could be non - zero .
as @xmath197 is a defective probability measure , that is @xmath198 , an application of the renewal theorem for defective measures @xcite in conjunction with the dominated convergence theorem leads us to @xmath199 a similar argument reveals the other equality . from and , in theorems
[ thm : twopop ] and [ thm : ggen ] respectively , we have our cornerstone result relating the average generation of the population to the proportion of positively labeled cells , justifying and .
[ prop : result ] under assumptions [ ass:1 ] and [ ass:2 ] , if @xmath108 , then @xmath200 almost surely .
consider the delabeling possibilities described after assumption [ ass:2 ] . in examples 1 and 2 , where delabeling occurs with probability @xmath2 at the end of a lifetime or independently with probability @xmath2 for each offspring , @xmath201 and we have that @xmath202 almost surely , if @xmath108 .
whereas , as in example 3 , if delabeling occurs via an asymmetric division construct , @xmath203 so that @xmath204 almost surely if @xmath108 .
we have proved results for @xmath205 , experimentally we would wish to know @xmath206 , the average generation per progenitor .
thus we wish to establish that these results are a good approximation for the latter .
to achieve this we use the standard approach , e.g. @xcite , of taking a taylor expansion of the ratio around the ratio of the expectations , and quantifying how the expectation of its leading order terms behave . using the first and second order terms of the taylor expansion
, we have @xmath207 using the results in theorem [ thm : ggen ] , if @xmath65 @xmath208 thus using the ratio of the expectations as an approximation to the expectation of the ratio is reasonable .
we can also use the taylor approximation to determine the approximate behavior of the variance of @xmath31 .
namely , to first order @xmath209 using the results in theorem [ thm : ggen ] , if @xmath210 , this shows that the variance is becoming small , @xmath211 thus we expect the average generation of a population of cells to be a stochastically well behaved process ; a phenomenon we will observe in simulations described later .
cultures are typically started with more than a single progenitor and so one expects that the estimator s accuracy will improve by laws of large numbers . here , by means that have nothing to do with branching processes , we establish that this is indeed the case and that , in particular , the ratios are both asymptotically normal , e.g. @xcite , and the variance decreases as one over the number of progenitors . in order to state the result , recall that a sequence of random variables @xmath212 is said to be asymptotically normal , e.g. @xcite , with means @xmath213 and variances @xmath214 if @xmath215 for all @xmath94 sufficiently large and the sequence @xmath216 converges in distribution to @xmath217 , the gaussian distribution with mean @xmath10 and variance @xmath55 .
[ thm : largen ] let @xmath218 be a bivariate i.i.d sequence of possibly correlated random variables , representing the label - positive and total cell population at time @xmath4 from progenitor @xmath32 , and let @xmath219 be an independent copy .
if the probability generating function of @xmath219 is finite in a neighbourhood of @xmath220 , then @xmath221 is asymptotically normal with @xmath222 where @xmath223 and @xmath224 .
let @xmath225 be a bivariate i.i.d sequence of possibly correlated random variables , representing the total generation and total cell population at time @xmath4 from progenitor @xmath32 , and let @xmath226 be an independent copy .
if the probability generating function of @xmath226 is finite in a neighbourhood of @xmath220 , then @xmath227 is asymptotically normal with @xmath228 both results start with an application of the multi - variate central limit theorem , e.g. @xcite , to the partial sums of @xmath218 and @xmath225 to establish their asymptotic normality .
application of the delta method , the corollary on page 124 of @xcite , with the function @xmath229 then establishes asymptotic normality of the ratios of the sums .
an additional application of the delta method with the function @xmath230 establishes the asymptotic normality of the logarithm of the ratio of sums . as a result of this theorem
, we anticipate the variability in the average generation number , as well as the variability in estimator , to decrease significantly as the number of progenitors increases .
here we use monte carlo simulations of age dependent branching processes @xcite to validate the method , investigating its appropriateness on individual stochastic sample paths for parameter values of the order one would anticipate experimentally . define @xmath5 to be the number of label - positive live cells at time @xmath4 , @xmath3 to be the total number of living cells at time @xmath4 , @xmath8 to be the sum of the generations of all living cells at time @xmath4 , so that @xmath31 is the average generation of living cells at time @xmath4 . in this section each cell s lifetime is drawn independently from the same distribution and , at the end of their life , each cell independently either dies or gives rise to two cells .
we assume that label - positive cells delabel immediately prior to division with probability @xmath2 .
one of the estimator s primary features is that it can be used in practice without knowledge of the lifetime distribution or death rates .
thus we performed stochastic simulations over a range of conditions , including lifetime distributions such as lag - exponential , lag - log - normal and lag - gamma , and parameter values such as @xmath231 , @xmath232 $ ] hours and the average number of offspring of a cell , @xmath233 , in @xmath234 .
these values include those typically encountered in cell cycle experiments @xcite and demonstrated the merits of the method , even for @xmath4 being relatively small , at a few days , and @xmath2 of order @xmath235 per cell per generation .
to illustrate the insights gained from the simulation study , we report on a specific , representative example , where lifetime distribution is lognormal , which is found to be a good fit in @xcite .
figures [ fig : single_progenitor_gam ] and [ fig : mult_progenitor_gam ] are the equivalents of [ fig : single_progenitor ] and [ fig : multiple_progenitors ] , but for delayed - gamma distributed cell lifetimes .
the results for both of these settings , as well as others that we have explored , are qualitatively similar . for the lifetime distribution
we assume a log - normal distribution with parameter values based on data from long - term video microscopy of murine b lymphocytes proliferating in response to cpg dna @xcite , @xmath47 is log - normally distributed with mean @xmath236 hours and standard deviation @xmath237 hours .
we consider populations that are , on average , expanding . for the probability of delabeling
, we adopt estimates related to existing division - linked labeling systems , namely cre - induced mitotic recombination @xcite and micro - satellite mutation induced label activation @xcite .
the probability of cre induced mitotic recombination has been estimated for a specific construct as @xmath238 per cell per generation @xcite , while mutation rates in human micro - satellites were inferred to be in the @xmath239 range per locus per generation @xcite .
cell populations are simulated for @xmath240 hours . at the end of a cell s lifetime
, it divides into two cells with probability @xmath241 and dies with probability @xmath242 , giving an average number of offspring @xmath243 .
this leads to an average expansion by a factor of approximately @xmath244 at @xmath245 hours and an average increase in the generation number of more than 25 .
note that 25 generations is far beyond what current experimental method , such as continuous observation or division - diluting dyes , are able to measure .
the mathematical results hold for sample population ratios where label - positive cells persist . if at some time
@xmath246 $ ] @xmath247 , we do not report the path from @xmath4 on as this represent samples for which the experimenter would have no estimate beyond that time .
systems that start with a single label - positive cell are subject to the greatest variability at early times and thus this situation is the one that poses the greatest difficulties for estimation . while most experimental systems will start with more than a single progenitor
and we know from the mathematical results in section [ subsec : largeno ] that they are better behaved , with variance in estimates decreasing inversely proportional to starting cell number , we begin by considering this most challenging circumstance . starting with a single label - positive progenitor at @xmath83 , panels ( a ) and
( b ) of plot @xmath248 realizations of both the average generation @xmath31 ( orange lines ) and the estimate of it , @xmath249 ( blue lines ) .
the average generation across realizations is consistent , even for early times , and grows linearly in time as theorem [ thm : ggen ] predicts .
in contrast , the per - realization estimates , the blue lines , which the sample path theory establishes will ultimately grow with the same slope as the average orange line , exhibit substantial variability at short time - scales .
two dynamical properties contribute to these fluctuations . at the beginning , there are no label - negative cells and so the logarithm of the ratio is @xmath10 .
when the first label - negative cells appear , the ratio of label - positive to total cell population can dramatically change , especially if the population size is small . in effect , the theorem is not in force until both the label positive and label negative populations are large enough for average behavior to become dominant , which only happens after at least an order of @xmath250 division events have occured .
as one might expect , by decreasing @xmath2 from @xmath238 to @xmath251 this effect is amplified , as can also be seen in ( a ) and ( b ) . in this
setting , the typical behavior is initially for underestimation as can be seen in the inter - quartile range plot of panels ( c ) and ( d ) of for @xmath252 simulations .
this can be understood as there is no estimate prior to at least one cell delabeling , which requires , on average , @xmath250 divisions to occur .
as @xmath2 is assumed small , typically one does not intially get an estimate and this delay explains the observed lag in the blue lines . on the other hand , in the unlikely event that an early cell delabels , then the approximation initially gives signifcant over - estimates .
this bias , which we have observed consistently across other simulations , suggests that if starting with a single progenitor family , only becomes accurate at longer time - frames , i.e. after several generations have passed .
note that the mean value of the estimator at early times over multiple runs is effected by outliers , hence the mean lies outside the inter - quartile range .
results in section [ sec : math ] for the time - dependent sample paths of estimates suggest that one way to mitigate this initial variability in the single time - point estimate @xmath249 is to make two measurements at distinct times , @xmath253 and use their difference to estimate @xmath31 via the approximation in section [ sec : intro ] : @xmath254 the effect of this difference measurement is the removal of the initial fluctuations on a path - by - path basis .
this is illustrated in , panels ( e ) and ( f ) .
using monte carlo methods and a standard kernel estimation method , the plots compare three values : the actual average generation @xmath255 at @xmath256 hours ( orange ) ; the single time - point estimates @xmath257 ( blue ) ; and , with @xmath256 and an extra measurement at @xmath258 hours , the two time point estimates in with @xmath259 hours .
the two - point estimate is not only more symmetrically distributed around the true value , but its variability is significantly less than the single time - point estimates .
while the method works well for single progenitors , experiments are typically seeded with multiple progenitors .
theorem [ thm : largen ] establishes that the variability decreases inverse linearly with the number of progenitors , @xmath260 , and so one expects that starting with even a small number of cells will eradicate the early time variability and here we demonstrate that this is , indeed , the case . for @xmath261 , panels ( a ) and ( b ) correspond with those of .
the orange lines , showing the per - realization of the average generation , remain largely unchanged , but the accuracy of the single time point estimates ( blue ) are greatly improved .
this comes about as even if an individual progenitor s family generates label - negative cells relatively late this is balanced by another progenitor s family where delabeling happened relatively early .
thus both @xmath5 and @xmath3 rapidly become sufficiently substantial for the limit theorem to be in force and for the estimator to be precise .
panels ( c ) and ( d ) show monte carlo created box plots of the per - sample average generation , the single time - point estimate and the two time - point estimate for a range of initial progenitor numbers .
sample - to - sample variation is greatly reduced even with as few as @xmath0 progenitors .
thus in standard experimental systems , which are often seeded with hundreds or thousands of cells , the estimator is expected to be precise .
the simulations of the previous section show that the estimator works well for parameterizations akin to those found in experimental systems and provide insight into the impact of a number of factors , such as the delabeling probability and the number of progenitors , on the quality of the estimates .
here we use a range of published data to further investigate the estimator s applicability .
the first application takes lineage trees of the early development of _ c. elegans _ determined by time - lapse microscopy and reported on in @xcite .
as the entire family tree is known , we have direct access to measurements of average generation as a function of time . simulating a stochastic delabeling process on this tree , as would be experimentally possible via a division linked mosaic
construct similar to the one introduced in @xcite or the one we propose in section [ sec : expdes ] , we can directly investigate the estimator s accuracy .
\(a ) shows the embryonic lineage tree of the nematode _ caenorhabditis elegans _ as constructed from data published by richards et al .
@xcite . in their study ,
a reference lineage tree was constructed based on output from automated tracking of nuclei in @xmath262 embryos , recorded over approximately six hours at 1.5 minute intervals by three - dimensional resonance - scanning confocal microscopy .
each node in the figure represents a cell division and the tree contains information about all parent - daughter relationships and gives the timing of more than @xmath263 division events during an embryo s development .
this leads to a population size of approximately 600 cells , ( b ) . from the timing of the division events ,
lifetimes are readily computed , shown in ( c ) . for this tree ,
lifetime durations correlate positively with both generation and with the time of birth relative to fertilization , ( d ) , illustrating a lack of homogeneity .
regarding independence , there are correlations throughout the tree .
( e ) demonstrates , for example , that lifetimes of siblings are positively correlated .
these features are not in line with the assumptions under which some of the the sample path properties of the estimator were established , but are consistent with the derivation via properties of the cumulant generating function in section [ sec : math ] .
to test the accuracy of the estimator , we stochastically decorated the tree . beginning with a single label - positive progenitor , daughters are delabeled with probability @xmath2 .
should they remain label - positive , their daughters are delabeled independently with probability @xmath2 and so on for the whole tree . ( a ) illustrates one such random decoration , with blue indicating label positive and white label negative .
for @xmath252 independent monte carlo realizations of this delabeling process , ( f ) shows the average ( blue ) and the inter - quartile range of the estimates ( blue ) , using , at each time point during the first six hours of the development as well as the true average generation number of the embryo in orange , proving to be accurate . as explained in section [ sec : estover ] , if not all cells are initially label - positive one can estimate average generation from proportion measurements at two distinct times . to mimic this , we considered the development of the labeled trees after @xmath264 minutes . at @xmath264 minutes one measurement is taken , giving the proportion of label - positive cells and the approximation to determine the average generation growth since @xmath265 to the time of a later measurement to determine the average generation since @xmath265 .
the results are plotted in ( g ) , which show accuracy .
existing micro - satellite reporter systems implement division - linked labeling and are suitable for both _ in vitro _ and _ in vivo _
applications @xcite .
micro - satellites are short repeating motifs found in dna that , with small probability per cell division , are subject to insertion or deletion of copies of the motif .
mutation reporter systems possess an initially out of frame gene for a fluorescent protein .
micro - satellite mutation on division results in the gene becoming in frame , with the cell becoming fluorescent .
this fluorescent state is inherited by offspring and is either irreversible , as in @xcite , or has a reportedly negligible likelihood of reversion @xcite .
thus with micro - satellite mutation acting as a driver of rare division linked change , cell fluorescence serves as a label for average generation estimation .
the two data sets we analyze are from studies published by gasche et al .
@xcite on human colorectal cancer cells ( hct116 ) and kozar et al .
@xcite on mouse embryonic fibroblast ( mef ) .
the probability that a cell becomes fluorescent as a result of a micro - satellite mutation is estimated as @xmath266 and @xmath267 in each study , respectively . for generation estimation ,
these values serve as @xmath2 , the probability of delabeling per cell division .
the data sets consist of measurements of proportions of labeled cells over several days from in vitro proliferating cell lines that carry transgenic micro - satellite mutation reporter cassettes , allowing us to estimate the average generation of the cell population .
in addition to the proportions , @xcite also provides the growth curve , which is exponential from day one to day four before slowing down , probably as a consequence of cell confluence @xcite , while @xcite reports an exponential growth for the whole time - course of their experiment . applying the estimator @xmath249 with the proportions , @xmath7 , recapitulated in ( a - b ) , and label loss probabilities provided in the studies
, we can estimate the average generation @xmath31 as a function of time , ( c ) . for both data sets ,
the estimated average generation increases linearly over time at a rate of approximately one per day .
direct validation of the method with this data would require knowledge of the average generation , which is not reported in the above studies .
the growth curve ( d ) , however , allows an alternate method to estimate this quantity for comparison .
we directly estimate the average from this curve by assuming for exponentially distributed life - times and the absence of cell death as in this special case one can show that @xmath268 , where @xmath269 is the malthus parameter @xcite .
estimating @xmath269 from the growth curve from day one up to day four , using linear regression on @xmath270 , predicts that the increase of average generation relative to the first time point as @xmath271 .
this predictions matches closely the estimated average generation , ( c ) . taken together
, the analysis of these data shows that inferring the average generation from the proportion of labeled cells carrying micro - satellite mutation reporter cassettes is an experimentally feasible approach .
as an illustrative example of an ideal experiment including estimation of the probability of label - loss @xmath2 , we describe one possible implementation of a division - linked one - way labeling system via a genetic construct , ( a ) , that combines existing experimental techniques : expression of a fluorescent protein such as blue fluorescent protein ( bfp ) ; the use of a cell - cycle specific promoter to create division - linked changes @xcite ; and site - specific recombination @xcite .
the construct is composed of two elements .
first cre recombinase expression is placed under the control of a cell - cycle specific promoter @xcite .
the cell - cycle promoter is employed to ensure a division linked expression of cre recombinase .
then , two loxp sites are placed at each end of the bfp gene . as cells enter cell cycle cre recombinase
is expressed , site - specific recombination will occur probabilistically between the two loxp recombination sites @xcite and the bfp gene is excised . for average generation inference ,
the desirable likelihood of recombination should be small , which can be achieved with a low efficiency cre recombinase .
thus bfp+ cells are regarded as label positive and bfp- cells are label negative .
this design is similar in spirit to an existing one used to create mosaics in zebrafish @xcite , which employs micro - satellites as a division linked probabilistic driver and a kaloop in lieu of site - specific recombination .
the proportion of label - positive cells in a cell system incorporating this construct can be readily determined via fluorescence - activated cell sorting ( facs ) .
the essential remaining ingredient for average generation inference is the determination of the probability of label - loss .
this can be achieved by a _ in vitro _
facs experiment , as illustrated by the _ in silico _ simulated experiment in ( b)-(c ) .
a collection of cells that incorporate the construct are stained with a division diluting dye , such as cfse @xcite , with noise added for illustrative purposes .
after division , cells are gated based on their generation , and the proportion of label - positive cells per - generation determined by their fluorescence . with @xmath272 being the measured proportion of label - positive cells in generation @xmath94 , in the presence of a large number of initial progenitors the probability label - loss , @xmath2 ,
irrespective of whether deaths occur , is @xmath273 , which should be the same for every @xmath94 . in particular , if all initial cells are bfp+ , then @xmath274 and @xmath275 , the proportion of bfp negative cells in generation @xmath55 .
thus the probability of label - loss can be readily determined experimentally .
for this simulation , an estimated value of @xmath2 is determined using this measurement for @xmath276 , @xmath277 .
the accuracy of the method can then be checked during or after the experiment by comparing the average generation as determined by the division diluting dye with the value estimated via equation with the measured @xmath2 , ( d ) .
once @xmath2 is known , similar cell stain experiments with distinct cell lines or distinct stimulii can be performed to validate the method s inference before its use _ in vivo _ and for generation counts beyond the range possible with division diluting dyes or fluorescence microscopy . the construct described in this section
is intended as an exemplar , creatable with present technology .
further experimental possibilities , including those based on naturally occurring mutations , can be found in the following discussion .
the estimators introduced in this article , and , offer means to estimate a biologically significant quantity , the average generation of cell populations , for cell systems where direct measurement poses a significant challenge .
their appropriateness is not intuitively apparent and their development requires several mathematical results . throughout the development of those results
we assume that the label change is one - way , which can be shown not to be essential for the cumulant generating function derivation of the estimators , but is relied on in establishing the sample - path results as if the label change is reversible , so that labels can be gained as well as lost , then asymptotically it is known that the growth rate of the number of label - positive cells equals the growth rate of the total number of cells @xcite . despite its less than obvious genesis
, the estimator has highly desirable features : it allows the population to be subject to death and division ; it does not need to know the number of progenitors ; it does not require knowledge of cell - cycle distributions ; and , subject to knowing the per - division label - change probability , only requires the measurement of proportions .
comparison of estimates for simulations suggest that the estimator is accurate for physiological reasonable parameterizations . the estimators and depend on the proportion of label - positive cells in the population , where the label can be any of the cell s properties that is lost with a small probability during its division cycle .
several naturally occurring and engineered cellular processes exist that approximately match this requirement .
somatic mutation is probably the best studied natural process of this kind . in this case
germ - line cells are defined to be label - positive , while label - negative cells correspond to those with mutations in their dna .
the proportion of label - positive cells can be assessed by next generation sequencing . in humans
there is a high rate of fidelity in dna replication , giving an error rate of @xmath278 per base per division @xcite and so using only a single nucleotide location as a label appears impractical .
considering instead the full germ - line genome as a positive label , even though each nucleotide may suffer mutations with distinct rates , and potentially in concert , there is still an over - all probability of label - change that has been estimated in human sperm cells as approximately @xmath279 @xcite . in principle
, this rate could be used as the probability of delabeling for our estimator .
alternatively , hotspots of mutation could also be analyzed .
for example , micro - satellites , short repetitive sequences of dna , mutate in humans with @xmath2 in the range @xmath239 , which we have used for the parameterization to evaluate the performance of our estimator .
the use of hotspots of mutation as a label suffers from the difficulty that delabeled cells could relabel due to the occurrence of further mutations .
the impact of this can be ameliorated by creating an asymmetry in the likelihood of relabeling to delabeling .
one selects a set of @xmath48 sites for measurement , each having their own probability of mutation , @xmath280 .
one defines the label - positive cells as those that have germ - line values at all sites .
the likelihood of a labeled cell delabeling is the likelihood that any of the sites mutate away from germ - line , @xmath281 , if the individual @xmath280 are small .
the likelihood that a cell with a single mutation relabels is @xmath282 , creating a significant asymmetry .
moreover , for a cell that has had several mutations , the likelihood that all revert , which is necessary for relabeling , is smaller still . while it seems likely that one must rely on naturally occurring processes to estimate the average generation of a cell population for humans , genetically modified cell lines and animals have the advantage that measuring the proportion of label - positive cells can be directly facilitated by fluorescent markers .
the construct described in the experiment design section could be built or existing constructions , such as cre - mediated sister chromatid recombination @xcite and micro - satellite mutation induced label activation @xcite , can be adapted , so that reversion does not occur . using fluorescence - activated cell sorting or live imaging technologies and the estimators developed in this article it could be possible to follow the average generation of specific cell populations , like neoplastic tissue or the skin , in living organisms over long periods of time .
recent evidence from _ in vivo _ cell lineage tracing techniques such as cellular barcoding @xcite has demonstrated that apparently homogeneous progenitors give rise to heterogeneous families in cancer , immunology and hematopoesis , e.g. @xcite .
theoretical work developing methodologies to interrogate data from these experiments is ongoing , but one key difficulty that must be overcome is that the generation of individual families is unknown @xcite .
combining any of the above experimental methodologies and using the estimator developed in the present article would allow inference of the per progenitor average generation , enhancing the deductive power of these techniques , which have already proved invaluable .
having established the estimators and validating them through simulations and comparison with published data , we believe these are promising avenues . * acknowledgments : * the authors thank sren asmussen ( aarhus university ) for drawing their attention to @xcite .
the work of t.w .
, l.p . and
k.d . was supported by human frontier science program grant rgp0060/2012 .
was also supported by science foundation ireland grant 12 ip 1263 .
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s. l. weinrich , r. pruzan , l. ma , m. ouellette , v. m. tesmer , s. e. holt , a. g. bodnar , s. lichtsteiner , n. w. kim , j. b. trager , r. d. taylor , r. carlos , w. h. andrews , w. e. wright , j. w. shay , c. b. harley , and g. b. morin .
reconstitution of human telomerase with the template rna component htr and the catalytic protein subunit htrt .
, 17(4):498502 , 1997 . , start with a single label - positive cell at time @xmath10 .
plots shown for two label - change probabilities , @xmath283 ( top row ) and @xmath284 ( bottom row ) .
for @xmath248 independent realizations , orange lines display the actual average generation , @xmath31 .
blue lines display the estimates @xmath249 from , which ultimately increase linearly with the same slope as the average generation , but initially show significant variability .
( c)-(d ) for @xmath285 independent realizations of the process , the dashed line reveals that the empirical average of the estimates is close to the true value .
the blue region is an inter - quartile plot of the @xmath249 estimates , with the upper boundary being where 25 of the realizations are larger and the lower boundary being where 25 of realizations are smaller , which typically exhibits under - estimation .
( e)-(f ) using monte carlo methods and a standard kernel estimator , these panels show , for @xmath256 hours , the density of observations of @xmath255 in orange , the single time - point estimate @xmath257 in blue , and the two time - point estimate in grey with an additional time point at @xmath258 hours .
the additional time - point improves the estimate by removing early variability on a realization - by - realization basis . ]
( top row ) and @xmath284 ( bottom row ) .
( a)-(b ) sample paths of @xmath248 independent realizations with @xmath285 progenitors .
orange lines correspond to average generation , @xmath31 .
blue lines display the estimates @xmath249 , whose early time fluctuation is significantly less pronounced than with a single progenitor , as in ( a)-(b ) .
( c)-(d ) for 1 , 10 and 100 progenitors , monte carlo generated box plots of average generation ( orange ) and single time - point estimates ( blue ) at @xmath286 hours , and two time - point estimates ( grey ) , with the additional measurement at @xmath258 hours . as predicted by theory , accuracy improves substantially , in a @xmath2 dependent fashion , as the number of progenitors increases . ] .
( a ) lineage tree of c. elegans embryos , for first nine generations .
the lowest node represents the progenitor present in the first frame , while the uppermost nodes represent cells alive in the last frame .
each node in between represents a division event , and its vertical position corresponds to the frame in which it was recorded .
the color of the nodes , blue for label - positive at division and white for label - negative at division , illustrate one possible random delabeling of the trees .
( b ) total population , @xmath3 , as a function of time , @xmath4 , shows a step - wise increase in cell numbers followed by a reduction in growth rate that is not consistent with a homogeneous age dependent branching process .
( c ) histogram of the cell lifetime shows a multi - modal distribution , partly explained by the fact that lifetimes appear to lengthen with time of birth or generation .
( d ) box plot of the lifetimes as a function of generation , which shows lifetimes increasing with generation .
( e ) sibling lifetimes are highly correlated , with many dividing during the same frame .
( f ) comparison of average generation @xmath31 ( orange ) with its estimate @xmath287 ( blue ) .
monte carlo determined inter - quartile ranges based on @xmath252 samples .
( g ) same as ( f ) , but starting at @xmath264 and computing the difference of the average generation @xmath31 ( orange ) since @xmath265 via the approximation . ] over several days of culture for genetically modified clones of mef cells ( a , @xcite ) and hct116 cells ( b , @xcite ) carrying micro - satellite mutation reporter cassettes .
the mutation probabilities , as reported in the respective studies are @xmath288 @xcite and @xmath289 @xcite , which we use for @xmath2 , the probability of delabeling per cell division .
data are represented as mean @xmath290 sem . for the hct116 data ,
the mean at each time point is over three clones .
( c ) inferred relative average generation g(t)/z(t ) from the proportions of unlabeled cells and @xmath2 using the estimator @xmath291 ( mef , open circles ; hct116 , filled circles ) .
for both data sets the average generation increases linearly with time , as expected from the theory .
in addition , the slope is close to one generation per day , even thought the mutation probability @xmath2 differs by a factor of six .
the orange dashed line shows the increase in average generation as estimated directly from the growth curve @xmath3 ( panel d ) assuming exponentially distributed life - times and no cell death ( for details see main text ) , demonstrating the accuracy of the estimator .
the blue dashed regression lines ( @xmath292 for both sets ) highlight the linear increase of average generation estimates during the exponential growth phase .
( d ) population size @xmath3 of cultured mef cells ( open circles , @xcite ) and exponential growth fit to first four time points ( dashed line , @xmath293 ) .
[ fig : ms ] ] .
the simulation is parameterized as in section [ sec : val_sim ] .
@xmath294 bfp+ cells are labeled with a division diluting dye such as cfse , which is green , and cultured until they divide . at each division
, cfse is shared evenly between daughters and the bfp label is lost with probability @xmath295 .
( b)-(c ) simulated facs plots , ten and 40 hours after cfse labeling .
the fluorescence signals were set to realistic experimental values @xcite and noise was added to initial cfse levels for illustrative purposes . the gates in ( b ) and ( c ) capture the proportion of label - positive cells , @xmath272 , in each generation , @xmath94 . from these , the label - loss probability , @xmath2 , can be experimentally determined via the formula @xmath296 . as all cells in the zeroth generation express bfp , @xmath297 , and so @xmath298 , the proportion of bfp negative cells in generation @xmath55 .
( d ) the orange line plots the average generation of the population , determined from the simulated cfse data , a function of time .
the blue line is estimate determined using the method described in the present paper with a label - loss parameter , @xmath299 , obtained from ( b ) .
the cfse determined value and the estimate exhibit excellent concordance . ] | for proliferating cells subject to both division and death , how can one estimate the average generation number of the living population without continuous observation or a division - diluting dye ? in this paper we provide a method for cell systems such that at each division there is an unlikely , heritable one - way label change that has no impact other than to serve as a distinguishing marker . if the probability of label change per cell generation can be determined and the proportion of labeled cells at a given time point can be measured , we establish that the average generation number of living cells can be estimated . crucially , the estimator does not depend on knowledge of the statistics of cell cycle , death rates or total cell numbers .
we validate the estimator and illustrate its features through comparison with published data and physiologically parameterized stochastic simulations , using it to suggest new experimental designs . | <s>[INST]given a proliferating population of cells starting from one or more progenitors , a natural quantity of interest in cell biology is the average number of divisions per cell since the initial progenitors , i.e. the average generation of presently living cells . the average generation is related to the population s turn - over rate and can potentially be used to quantify dynamics and aging of the immune system @xcite , to better understand the evolution and risk of cancer @xcite , and to rank cell types in hierarchies of complex differentiation programs @xcite .
estimating average generation is a simple matter if cell lifetimes are all equal and the division time is known or , alternatively , if total cell counts can be measured and there is no cell death . if , however , lifetimes are heterogeneous , the population is subject to death as well as division or total cell counts are not available , the issue is more involved . in these settings ,
several experimental techniques can be employed to estimate average generation , including time lapse microscopy , division diluting fluorescent dyes , and inference from somatic mutations and telomere length .
the most unambiguous measurement technique is _ in vitro _
time lapse microscopy as it affords nearly direct determination of lineage trees and cell generation .
time lapse microscopy has been used to study many cell systems including bacteria , lymphocytes , embryonic development , gut development , to name but a few , e.g. @xcite .
even it , however , has limitations as filming is not continuous , cells can leave the field of vision or form three dimensional structures that inhibit tracking .
the complexity of image segmentation increases with cell numbers , and so time lapse microscopy has proved challenging if more than approximately @xmath0 generations are to be followed .
another popular experimental approach , particularly in immunology , is to stain starting cells with a fluorescent dye such as carboxyfluorescein succinimidyl ester @xcite , celltrace@xmath1 violet or cell proliferation dye efluor 670 @xcite . with each division , cells inherit approximately half of their parent s dye and so fluoresce with half their intensity .
a cell s generation can thus be determined by its luminous intensity via flow cytometry .
this approach is used both _ in vitro _ and _ in vivo _ , and allows the experimenter to start with a large number of progenitors without difficulty .
it enables 6 - 10 generations to be followed before dye dilution is such that the signal - to - noise ratio is too high for a cell s generation to be reliably determined . determining generation _ in vivo _ remains challenging as often it can not be achieved by direct observation or cell stain methods .
estimating replicative history , cell depth and lineage trees has been proposed by measurement of average telomere length @xcite or by the number of somatic mutations , which are introduced during dna duplication @xcite . while methods in this direction rely on inference rather than direct observation , they offer the possibility of tracing more than 10 generations in a wide range of species , including humans .
in the present paper , we provide a novel average generation estimator that is designed with the _ in vivo _ setting in mind .
the estimator is suitable for systems where cells undergo an unlikely , heritable division - linked label change with a determinable probability , where the label serves only as a marker and does not impact on cell dynamics .
chief amongst the estimator s desirable properties are that : ( 1 ) it requires no information on cell lifetime distributions ; ( 2 ) the population can be subject to death as well as division ; and ( 3 ) only a proportion of label - positive to total cells needs to be measured .
the present article introduces the estimator , analytically establishes its fundamental properties , validates its applicability by comparison with simulation and comparison with published data , proposes an experimental realization , and demonstrates its utility . in section [ sec : estover ] we describe the estimator and explain how it can be used .
the estimator appropriateness is a consequence of theorems that are presented in detail in section [ sec : math ] , with a heuristic explanation and overview of them appearing first in section [ sec : mathsum ] . in section [ sec : val_sim ] ,
validation using simulated data , we use monte carlo simulations to assess the estimator s performance for physiological parameterizations . in section [ sec : val_data ] , validation using published data , we use several sources of publicly available data to illustrate the estimator s applicability .
we avail of complete lineage tree data for the development of _ c. elegans _ , as determined from time - lapse microscopy @xcite , stochastically labeling it . applying the estimator results in accurate inference of the average generation in comparison to the directly observed quantity .
we also take data from two distinct experimental studies , one on human colorectal cancer cells @xcite and one on murine embryonic fibroblasts @xcite , that employ micro - satellite mutation fluorescent reporter systems .
micro - satellite mutation is an unlikely division linked change and the fluorescence of cells in these systems serves as a label suitable for average generation estimation .
the results show consistency between average generation estimates , measured quantities and values reported in the literature . as an illustrative example , in section [ sec : expdes ] ,
experiment design , we propose a genetic construct , based on existing pieces , to facilitate average generation inference .
we describe how the probability of label - loss could be measured and how the method could be validated . in section [ sec :
disc ] , discussion , we conclude with experimental designs where the method would prove biologically informative .
we consider a system where cells are subject to a division - linked , heritable label change that serves as a measurable distinguishing marker , but does not influence population dynamics .
the method is appropriate regardless of whether initial cells are label - negative and can gain the label , which is then inherited by their offspring , or are label - positive and can lose the label , with their offspring not regaining the label . for a consistent description ,
we phrase the paper in terms of the latter , but the results all hold _ mutatis mutandis_. during each cell s lifetime , assume that a label - positive cell becomes label - negative with a known , small likelihood , @xmath2 .
let @xmath3 be the total live cell count at time @xmath4 and @xmath5 be the live cell count of label - positive cells .
assume that the initial cells at @xmath6 are all label - positive and that at some time @xmath4 the fraction of label positive cells to total cells , @xmath7 , can be measured . with @xmath8 denoting the sum of the generations of all cells living at time @xmath4 and with @xmath9 defined to be @xmath10 , then given there are label - positive cells in the system at @xmath4 , i.e. @xmath11 , we establish that the average generation of cells alive at time @xmath4 satisfies the following relationship @xmath12 that is , the average generation of the population can be estimated directly from the proportion of label - positive cells if the delabeling probability is known .
perhaps unexpectedly the formula does not depend on several difficult - to - measure factors such as cell - lifetime distributions and total cell counts .
moreover the right hand side of requires only a proportional measurement of label - positive cells , which can be determined from a sample , and the relationship holds even though the population could be subject to death as well as division . for the validity of
, we have assumed that at @xmath6 all cells are label - positive . as a result @xmath13 and
so both the right and left hand side of are @xmath10 at @xmath6 , agreeing irrespective of the initial starting number . if , however , not all cells are initially label - positive , the estimator and the average generation would not agree .
this can be rectified if measurements of the proportion of positively labeled cells are available at two time - points , @xmath14 .
then , irrespective of the initial composition of label - positive and label - negative cells , so long as @xmath15 , @xmath16 this two - measurement estimator has an additional advantage when initial cell numbers are small .
if the culture is started , as an extreme example , with a single progenitor , then the right hand side of can be subject to stochastic fluctuations at shorter time - scales ( see the monte carlo simulations in section [ sec : val_sim ] ) . as established rigorously in section [ sec : math ] , with @xmath17 , the two - sample estimator in is more accurate than as it removes the influence of the timing of early cell events on the estimate .
the estimators and have non - obvious forms . utilising expansion properties of cumulant generating functions , results in the following section show that the relationships hold , in expectation , for an arbitrary familial relationship .
this includes , in particular , estimation of average generation for heterogeneous cell populations with distinct , potentially interdependent , proliferation characteristics . in the absence of a generative model of family trees , however , that derivation can not provide information about the development in time of the average generation of a family of cells .
nor can it be used to determine time - dependent properties of the estimators on a developing population . for a more detailed analysis of sample - path , multi - progenitor and time - dependent properties ,
a general mathematical framework for capturing the stochastic dynamics of a proliferating cell system subject to division and death , as well as heterogeneous cell life times , is that of age dependent branching processes @xcite where cells have random lifetimes as well as random numbers of offspring . since the seminal work of bellman and harris @xcite
, it has been known that if cells are more likely to divide then die , given the cell population does not die out , the number of cells living at time @xmath4 grows exponentially in time , @xmath18 , at a rate , @xmath19 , dubbed the malthus parameter , that depends on the lifetime and offspring number distributions of cells .
this result is known to be robust , for example , to sibling dependencies @xcite . in a cell system experiencing heritable one - way label - changes
, label - positive cells can become label negative - cells , but the reverse is not possible .
thus the number of label - positive cells at time @xmath4 also satisfies the branching process result , @xmath20 , but with a malthus parameter that is smaller than that for the total label - independent population of cells , @xmath21 .
the difference @xmath22 depends on the likelihood , @xmath2 , that a label - positive cell loses its label .
fewer results have been established regarding the total generation of a cell population , the sum of the generations of all cells living at time @xmath4 , @xmath8 , for which new theorems can be found in section [ sec : math ] . for the label - independent population , in substantial generality
we prove that @xmath23 .
that is , the total generation increases faster than the total population size by a factor of @xmath4 . recalling that @xmath24 , for a general age - dependent branching process , the average generation of the population grows linearly in time @xmath25 for some @xmath26 . in the following section we give a deterministic result to provide non - probabilistic intuition for why this is so before considering the stochastic system .
the clinching result quantitatively relates the phenomena of stochastic delabeling to generational expansion .
so long as label - positive cells remain @xmath27 so that for @xmath2 small @xmath28 this identification holds for any age dependent branching process and does not depend upon the details of life - time distributions or the possibility of cell death , so long as populations do not go extinct . the estimators are related through stochastic quantities and are subject to sample - path fluctuations , particularly at early time - points . establishing that estimates , as a function of time on individual sample paths , converge to the true average generation underlies the development of the two time - point estimator in equation .
that methodology circumvents this issue of small number variability by eliminating the early fluctuations on a path - by - path basis . as a supporting result
, we also prove that the path - to - path variability of estimates decreases inversely proportionally to the number of progenitors , supporting the precision of estimates for experimental systems that are initiated with multiple cells , which is typically the case .
we begin by deriving a version of based on averages over realisations of the delabeling process .
this derivation has the advantage that it requires no assumptions regarding the family tree and so holds in complete generality , but it is not informative with regards individual realisations .
sample - path , time - dependent properties of the estimators arise as a consequence of involved theorems in the context of the most well established generative model of family trees , age dependent branching processes , which follow this derivation .
at some time @xmath4 , consider a collection of @xmath3 cells , whose familial relationship need not be known .
the generation of a cell is defined to be the number of ancestors it possesses , with initial cells being defined to be in generation @xmath10 .
denote each of the generations of the @xmath3 cells by @xmath29 .
of the generations of all living cells being denoted by @xmath30 knowing @xmath2 we wish to estimate the average generation of presently living cells , i.e. @xmath31 , by observation of the proportion @xmath7 .
if initial cells are label positive and with each division the label is lost independently with probability @xmath2 , the probability cell @xmath32 is still label positive in generation @xmath33 is @xmath34 . with @xmath5 denoting the number of label positive cells , by linearity of expectation the average proportion of label - positive cells in the population is @xmath35 identifying @xmath36 , this can be re - written in a form that identifies it with a moment generating function , e.g. @xcite , @xmath37 where @xmath38 is uniformly selected in @xmath39 . as both the moment generating function and the cumulant generating function , @xmath40 , are real analytic , we can take a taylor expansion of the latter around the origin , giving @xmath41 so that @xmath42 taking @xmath43 is equivalent to taking @xmath44 . thus noting that @xmath45 , we obtain @xmath46 which is formula , albeit with an expectation over stochastic delabelings . while this result is not as strong as others we shall prove , it illustrates both how the unusual formulation arises and that , averaged over delabeling processes , the relationship holds for arbitrary family tree structure . to determine sample path properties of the generation counting estimator
, we must establish two quantitative relationships in a general age - dependent branching process : ( 1 ) relating the growth rates of labeled and unlabeled populations when the probability of delabeling per cell division is small ; and ( 2 ) for the relationship between the number of cells alive and the sum of the generations of all living cells .
for the quantitative relationship between the growth - rates of the labeled and unlabeled populations when the delabeling probability per cell division is small and label - state does not impact on population dynamics , we leverage well - know single type results @xcite . for the relationship between the number of cells alive and the sum of the generations of all living cells ,
there are some results indirectly available from @xcite , but to identify more properties of our estimator we find it beneficial to provide an analysis of the joint probability generating function of number of cells alive and their total generation number .
our initial mathematical study treats systems that start with a single initiating progenitor . from these results , systems that start with several statistically equivalent progenitors with indistinguishable progeny
can be deduced .
in addition , we provide results on the behavior of the estimator for a system with numerous progenitors , establishing that that variances behave inversely proportionally to the number of progenitors .
we begin by considering a standard age dependent branching process , e.g. @xcite , with the usual assumptions on the distribution of a lifetime , a non - negative random variable @xmath47 , and the number of offspring , @xmath48 a non - negative integer valued random variable , at the end of a lifetime . in the circumstances of interest to us , proliferating cell populations , @xmath48 will take values in @xmath49 indicating that cells die or divide into two at the end of their lives , but we will prove the results in greater generality .
[ ass:1 ] the lifetime distribution , @xmath50 for @xmath51 , is non - lattice and satisfies @xmath52 .
the probability generating function of the number of offspring , @xmath53 for @xmath54 , is finite in a neighborhood of @xmath55 .
we denote its expected value by @xmath56 .
a key quantity in the study of age - dependent branching processes is the malthus parameter , @xmath57 , which is defined to be the solution of the following equation , should the solution exist , @xmath58 if @xmath57 exists , it is then the , possibly negative , asymptotic exponential growth rate of the expected population size .
the dependence of the malthus parameter , @xmath57 , on the expected number of offspring of a cell , @xmath59 , is not usually made explicit , but will prove essential for us as we shall be interested in relating the growth rate of the label - positive population and of the total population , which will differ .
for that purpose , we have the following result on the range of mean offspring , @xmath60 , for which the malthus parameter exists and its smoothness as a function of @xmath60 .
we expect that this proposition is known , but can not find a reference in the literature and so present a proof here .
[ prop : malder ] define @xmath61 where @xmath62 , then there exists a real analytic function @xmath63 , the malthus parameter , such that @xmath64 in particular , for @xmath65 , the first two derivatives of @xmath57 as a function of the average number of offspring @xmath60 are @xmath66 and @xmath67 consider the function @xmath68 $ ] defined by @xmath69 we wish to identify the range of @xmath60 such that @xmath57 exists satisfying @xmath70 , and to determine its smoothness properties as a function of @xmath59 . when @xmath71 , @xmath72 and so @xmath73 . as @xmath74 is the moment generating function of a non - negative random variable , @xmath47 , evaluated at @xmath75 , it is a real analytic function on the interior of the domain on which it is finite , i.e. for @xmath76
therefore as @xmath77 defined in is a product of real analytic functions , it is also real analytic on @xmath78 . as @xmath77 is a monotonic decreasing function of @xmath79 , for any @xmath80 there exists a unique @xmath79 such that @xmath81 .
thus we can apply the real analytic version of the implicit function theorem , e.g. theorem 1.8.3 @xcite .
this establishes that @xmath57 satisfying exists for @xmath80 , that @xmath19 is real analytic for @xmath65 , and that its first derivative satisfies @xmath82 which gives . to obtain
, one differentiates .
the real analyticity of @xmath57 allows us to characterize the difference in growth rates of two populations in terms of the taylor expansion of @xmath57 .
this will be useful as if there is small probability of label - loss , then the label - positive and total populations have similar , but non - identical , average offspring number .
we will relate the difference in their growth rates to the dynamics of the average generation of the population .
we consider a two - type reducible age - dependent branching process previously studied , for example , in @xcite .
that is , we consider a cell system that starts with a single progenitor that is positive for a label so that @xmath83 and @xmath84 , and define the total population at time @xmath4 to be @xmath85 .
each cell is assumed to have an independent and identically distributed lifetime at the end of which they independently give rise to a random number of offspring .
positive label cells can become negative label cells , but the reverse does not happen .
we are interested in populations where the label does not indicate a phenotypic change so that lifetime distributions do not depend on the label . depending upon the experimental system and marker employed
, the process of delabeling can occur in different ways and so one may have distinct models .
thus we make a general assumption that encompasses several of these .
notationally , let the random variable @xmath86 define the number of label - positive offspring of a label - positive cell , where @xmath87 captures the probability of delabeling .
we will make a technical assumption that ensures that the distribution of the number of label - positive offspring of a label - positive cell is less than its total ( i.e. label positive and negative ) offspring and that as @xmath2 drops to @xmath10 we assume that we recover the random variable describing the total ( i.e. label independent ) offspring of a cell , denoted @xmath88 .
[ ass:2 ] lifetimes are independent and identically distributed , and independent of independent and identically distributed type - dependent offspring numbers .
the lifetime distribution for cells , @xmath50 for @xmath51 , is non - lattice and satisfies @xmath52 .
if @xmath89 , the number of label - positive offspring of a label - positive cell is less than its total number of offspring : @xmath86 is strictly stochastically dominated by @xmath90 , i.e. @xmath91 for all @xmath92 and @xmath93 for some @xmath94 .
thus , defining @xmath95 , @xmath96 for all @xmath89 .
we assume that @xmath53 for @xmath54 , is finite in a neighborhood of @xmath55 , that @xmath97 , and that @xmath98 is real analytic in @xmath2 .
_ example 1 : _ delabeling occurs immediately prior to a cell s division , independently with probability @xmath2 . in this case
the offspring of a label - positive cell s are either all labeled or all delabeled . thus with @xmath48 denoting the label - independent offspring random variable , @xmath99 and , in particular , @xmath100 .
_ example 2 : _ delabeling of the offspring of a label - positive cell occurs independently with probability @xmath2 at birth . in this case
@xmath101 so that again @xmath102 , but higher order moments are smaller than those in example 1 .
_ example 3 : _ the offspring of a label - positive cell experience asymmetric label - loss .
there are genetic constructs where , on division , labels are lost asymmetrically @xcite .
that is , if a label - positive cell divides in two and one of its two offspring loses its label , then the other does not . as a result ,
if @xmath2 is the probability of delabeling and @xmath103 is the probability that a division rather than death occurs , then @xmath104 @xmath105 and the mean number of label positive offspring is @xmath106 . in all three of these examples
@xmath98 is a linear function of @xmath2 , so that assumption [ ass:2 ] holds .
based on results in @xcite in conjunction with proposition [ prop : malder ] , the following theorem can be deduced .
[ thm : twopop ] if @xmath107 , under assumption [ ass:2 ] , if @xmath108 , then almost surely @xmath109 where @xmath110 and , in particular , if @xmath108 , then almost surely @xmath111 the asymptotic behavior of @xmath5 and @xmath3 follow directly from @xcite . by proposition [ prop : malder ]
, @xmath57 is real analytic for @xmath65 and @xmath112 , and , by assumption [ ass:2 ] , @xmath98 is real analytic with @xmath97 .
thus @xmath113 is real analytic and we can take a taylor expansion of @xmath113 in @xmath2 around @xmath10 and so holds .
the relationship in follows from taking the limit as @xmath2 tends to @xmath10 . for comparison with these two - population results ,
we need to establish properties of the total generation , the sum of the generations of living cells , for a single - type population . in order to precisely define the total generation of a branching process , some unwieldy definitions are necessary .
these shall be largely side - stepped in the analysis , but are included to precisely define the objects of interest to us .
we use a modification of ideas in @xcite to do so and consider a single - type construction as that is sufficient for our needs .
the generation of an object is defined to be the number of ancestors it possesses . as such
, it is natural to begin with a single object at time @xmath10 defined to be in generation @xmath10 .
let @xmath114 denote the length of the life of the @xmath115-th object in the @xmath32-th generation and let @xmath116 denote the number of offspring of the @xmath115-th object in the @xmath32-th generation . starting with a single object , the total number of objects that will ,
at any stage , exist in the @xmath94-th generation is governed by a galton - watson recursion : @xmath117 where the empty sum is defined to be @xmath10 .
that is , the number of objects that will ever be in generation @xmath55 is the offspring number of the first object , @xmath118 .
the number of offspring that will ever exist in generation @xmath119 is the sum of the number offspring of those members of generation @xmath55 , and so forth , leading to the above recursion for @xmath120 .
each object in generation @xmath94 is defined by a life - history , @xmath121 , where this object is the @xmath122-th child of the @xmath123-child of the @xmath124-th child and so forth back to @xmath125 .
the indices run over objects that exist , so that @xmath126
. the birth time of the object @xmath121 is the sum of lifetime of its ancestors , @xmath127 the time the object ceases to be is @xmath128 . in terms of these definitions ,
the total number of objects present at time @xmath4 can be identified as all objects of any generation that are alive at time @xmath4 , @xmath129 where @xmath130 is the indicator function .
that is , the population alive at time @xmath4 is all those objects whose birth time is before or equal to @xmath4 and whose death time is after @xmath4 .
the generation of an object @xmath121 is @xmath94 and thus the sum of the generations of all objects existing at time @xmath4 is @xmath131 that is , for each object alive at time @xmath4 in generation @xmath94 , the total generation at that time is incremented by @xmath94 . before considering the probabilistic system , we begin with a fundamental , non - probabilistic lemma that will give an indication as to why one expects that the total generation of all living cells @xmath132 to grow in a similar fashion to @xmath133 , where @xmath134 is the number of presently living cells , assuming that cells can either die or divide into two at the end of their lives . [
lem : min ] for a binary family tree beginning with a single progenitor in generation @xmath10 , if there are @xmath135 cells alive then the average generation per cell satisfies @xmath136 .
consider a family tree with @xmath137 cells alive ( i.e. @xmath134 leaves ) , where @xmath92 and @xmath138 .
the minimal @xmath132 given @xmath134 is attained is when @xmath139 cells are in generation @xmath94 and @xmath140 cells are in generation @xmath141 , which can be formally established using the equations given above .
thus @xmath142 if @xmath143 or @xmath144 , these are equal and so the difference between the two is zero at each @xmath145 and one needs to be delicate with one s estimates . a rearrangement of terms gives @xmath146 if and only if @xmath147 a sufficient condition for this to be true is to relax the problem , letting @xmath148 with @xmath149 $ ] , and establish that @xmath150 , \end{aligned}\ ] ] which is readily achieved by calculus . in a system with death , in general there is no equivalent upper bound to lemma [ lem : min ] as it s possible that there is only one cell alive , @xmath151 , and the generation of that cell , and hence @xmath132 , can be arbitrarily large . for branching processes , however , under general conditions the population either dies out or ultimately grows in a somewhat regular fashion , @xcite , and so lemma [ lem : min ] anticipates that , in a suitable sense , @xmath152 becomes constant if the population survives . indeed , amongst other results , this is something we shall establish .
it is not possible to study the total generation of living cells , @xmath8 , separately from the total population , @xmath3 , as they are strongly coupled and their dynamics are intertwined .
this relationship appears as a cross term in when we consider the evolution of the joint probability generating function of the two , giving rise to an integral equation of unusual form . despite this form , it is , in general , susceptible to analysis .
[ ass:3 ] lifetimes are independent and identically distributed and independent of independent and identically distributed offspring numbers .
the lifetime distribution , @xmath50 for @xmath51 , is non - lattice and satisfies @xmath52 .
the probability generating function of the number of offspring , @xmath53 for @xmath54 , is finite in a neighborhood of @xmath55 .
we denote its first and second derivative at one by @xmath153 [ thm : ggen ] under assumption [ ass:3 ] , starting with @xmath154 , the joint probability generating function of @xmath155 , @xmath156 satisfies the integral equation @xmath157 for @xmath158 , define @xmath159 where @xmath57 and @xmath160 are defined in the statement of proposition [ prop : malder ] . for @xmath158 , @xmath161 and @xmath162 if @xmath163 ,
with @xmath164 defined in , defining @xmath165 in addition we have that @xmath166 we first establish that holds .
begin with a family tree starting with a single cell at time @xmath10 , @xmath167 , defined to be in generation @xmath10 , so that @xmath168 .
consider the impact of altering this initial condition so that the founding cell is in generation @xmath55 at @xmath6 , @xmath169 .
we will write @xmath170 for the process counting the total generation of living cells starting with @xmath169 , so that , in particular , @xmath171 , and retain @xmath8 for total generation given @xmath168 . the key observation , which can be established using equations and , is that @xmath172 this can be understood by noting that , leaving all other aspects of the family tree unchanged , the move from @xmath168 to @xmath169 causes the generation of every living cell to increase by @xmath55 .
thus , taking expectations over the lifetime of the initial cell and using the independence and identical distribution of the sub - trees generated by the first birth , but noting they start with cells that are in generation @xmath55 , we obtain @xmath173 giving .
the uniqueness of @xmath174 for @xmath175 and @xmath176 follows from analogous arguments to those in @xcite , chapter vi , utilizing the ideas in @xcite . to establish , note that using @xmath177 where we have used the equivalent , well known integral equation for @xmath178 to obtain the final equality .
we wish to study the asymptotics of this equation , dividing it by @xmath179 and taking limits as @xmath180 . to this end
, we employ a result from renewal theory , @xcite theorem 6.2(a ) , using the fact that by construction @xmath181 is a probability measure , @xmath182 should the limits on the right hand side exist .
the existence of the first limit follows from results in @xcite , @xmath183 consider @xmath184 .
if @xmath185 , then the limit automatically exists and is @xmath10 . if @xmath186 , select @xmath187 such that @xmath188 . from proposition [ prop :
malder ] , we are guaranteed the existence of such a @xmath79 as @xmath65 . as @xmath189 ,
as in the chernoff bound we have that @xmath190 as @xmath191 , this ensures that @xmath192 hence , using , @xmath193 as required . to obtain ,
one uses in conjunction with .
consider now , with a little re - arranging of terms , @xmath194 we wish to establish that the limit @xmath195 exists and identify its limit .
using and @xmath196 which can be found in @xcite , it is clear that only the last term on the right hand side of could be non - zero .
as @xmath197 is a defective probability measure , that is @xmath198 , an application of the renewal theorem for defective measures @xcite in conjunction with the dominated convergence theorem leads us to @xmath199 a similar argument reveals the other equality . from and , in theorems
[ thm : twopop ] and [ thm : ggen ] respectively , we have our cornerstone result relating the average generation of the population to the proportion of positively labeled cells , justifying and .
[ prop : result ] under assumptions [ ass:1 ] and [ ass:2 ] , if @xmath108 , then @xmath200 almost surely .
consider the delabeling possibilities described after assumption [ ass:2 ] . in examples 1 and 2 , where delabeling occurs with probability @xmath2 at the end of a lifetime or independently with probability @xmath2 for each offspring , @xmath201 and we have that @xmath202 almost surely , if @xmath108 .
whereas , as in example 3 , if delabeling occurs via an asymmetric division construct , @xmath203 so that @xmath204 almost surely if @xmath108 .
we have proved results for @xmath205 , experimentally we would wish to know @xmath206 , the average generation per progenitor .
thus we wish to establish that these results are a good approximation for the latter .
to achieve this we use the standard approach , e.g. @xcite , of taking a taylor expansion of the ratio around the ratio of the expectations , and quantifying how the expectation of its leading order terms behave . using the first and second order terms of the taylor expansion
, we have @xmath207 using the results in theorem [ thm : ggen ] , if @xmath65 @xmath208 thus using the ratio of the expectations as an approximation to the expectation of the ratio is reasonable .
we can also use the taylor approximation to determine the approximate behavior of the variance of @xmath31 .
namely , to first order @xmath209 using the results in theorem [ thm : ggen ] , if @xmath210 , this shows that the variance is becoming small , @xmath211 thus we expect the average generation of a population of cells to be a stochastically well behaved process ; a phenomenon we will observe in simulations described later .
cultures are typically started with more than a single progenitor and so one expects that the estimator s accuracy will improve by laws of large numbers . here , by means that have nothing to do with branching processes , we establish that this is indeed the case and that , in particular , the ratios are both asymptotically normal , e.g. @xcite , and the variance decreases as one over the number of progenitors . in order to state the result , recall that a sequence of random variables @xmath212 is said to be asymptotically normal , e.g. @xcite , with means @xmath213 and variances @xmath214 if @xmath215 for all @xmath94 sufficiently large and the sequence @xmath216 converges in distribution to @xmath217 , the gaussian distribution with mean @xmath10 and variance @xmath55 .
[ thm : largen ] let @xmath218 be a bivariate i.i.d sequence of possibly correlated random variables , representing the label - positive and total cell population at time @xmath4 from progenitor @xmath32 , and let @xmath219 be an independent copy .
if the probability generating function of @xmath219 is finite in a neighbourhood of @xmath220 , then @xmath221 is asymptotically normal with @xmath222 where @xmath223 and @xmath224 .
let @xmath225 be a bivariate i.i.d sequence of possibly correlated random variables , representing the total generation and total cell population at time @xmath4 from progenitor @xmath32 , and let @xmath226 be an independent copy .
if the probability generating function of @xmath226 is finite in a neighbourhood of @xmath220 , then @xmath227 is asymptotically normal with @xmath228 both results start with an application of the multi - variate central limit theorem , e.g. @xcite , to the partial sums of @xmath218 and @xmath225 to establish their asymptotic normality .
application of the delta method , the corollary on page 124 of @xcite , with the function @xmath229 then establishes asymptotic normality of the ratios of the sums .
an additional application of the delta method with the function @xmath230 establishes the asymptotic normality of the logarithm of the ratio of sums . as a result of this theorem
, we anticipate the variability in the average generation number , as well as the variability in estimator , to decrease significantly as the number of progenitors increases .
here we use monte carlo simulations of age dependent branching processes @xcite to validate the method , investigating its appropriateness on individual stochastic sample paths for parameter values of the order one would anticipate experimentally . define @xmath5 to be the number of label - positive live cells at time @xmath4 , @xmath3 to be the total number of living cells at time @xmath4 , @xmath8 to be the sum of the generations of all living cells at time @xmath4 , so that @xmath31 is the average generation of living cells at time @xmath4 . in this section each cell s lifetime is drawn independently from the same distribution and , at the end of their life , each cell independently either dies or gives rise to two cells .
we assume that label - positive cells delabel immediately prior to division with probability @xmath2 .
one of the estimator s primary features is that it can be used in practice without knowledge of the lifetime distribution or death rates .
thus we performed stochastic simulations over a range of conditions , including lifetime distributions such as lag - exponential , lag - log - normal and lag - gamma , and parameter values such as @xmath231 , @xmath232 $ ] hours and the average number of offspring of a cell , @xmath233 , in @xmath234 .
these values include those typically encountered in cell cycle experiments @xcite and demonstrated the merits of the method , even for @xmath4 being relatively small , at a few days , and @xmath2 of order @xmath235 per cell per generation .
to illustrate the insights gained from the simulation study , we report on a specific , representative example , where lifetime distribution is lognormal , which is found to be a good fit in @xcite .
figures [ fig : single_progenitor_gam ] and [ fig : mult_progenitor_gam ] are the equivalents of [ fig : single_progenitor ] and [ fig : multiple_progenitors ] , but for delayed - gamma distributed cell lifetimes .
the results for both of these settings , as well as others that we have explored , are qualitatively similar . for the lifetime distribution
we assume a log - normal distribution with parameter values based on data from long - term video microscopy of murine b lymphocytes proliferating in response to cpg dna @xcite , @xmath47 is log - normally distributed with mean @xmath236 hours and standard deviation @xmath237 hours .
we consider populations that are , on average , expanding . for the probability of delabeling
, we adopt estimates related to existing division - linked labeling systems , namely cre - induced mitotic recombination @xcite and micro - satellite mutation induced label activation @xcite .
the probability of cre induced mitotic recombination has been estimated for a specific construct as @xmath238 per cell per generation @xcite , while mutation rates in human micro - satellites were inferred to be in the @xmath239 range per locus per generation @xcite .
cell populations are simulated for @xmath240 hours . at the end of a cell s lifetime
, it divides into two cells with probability @xmath241 and dies with probability @xmath242 , giving an average number of offspring @xmath243 .
this leads to an average expansion by a factor of approximately @xmath244 at @xmath245 hours and an average increase in the generation number of more than 25 .
note that 25 generations is far beyond what current experimental method , such as continuous observation or division - diluting dyes , are able to measure .
the mathematical results hold for sample population ratios where label - positive cells persist . if at some time
@xmath246 $ ] @xmath247 , we do not report the path from @xmath4 on as this represent samples for which the experimenter would have no estimate beyond that time .
systems that start with a single label - positive cell are subject to the greatest variability at early times and thus this situation is the one that poses the greatest difficulties for estimation . while most experimental systems will start with more than a single progenitor
and we know from the mathematical results in section [ subsec : largeno ] that they are better behaved , with variance in estimates decreasing inversely proportional to starting cell number , we begin by considering this most challenging circumstance . starting with a single label - positive progenitor at @xmath83 , panels ( a ) and
( b ) of plot @xmath248 realizations of both the average generation @xmath31 ( orange lines ) and the estimate of it , @xmath249 ( blue lines ) .
the average generation across realizations is consistent , even for early times , and grows linearly in time as theorem [ thm : ggen ] predicts .
in contrast , the per - realization estimates , the blue lines , which the sample path theory establishes will ultimately grow with the same slope as the average orange line , exhibit substantial variability at short time - scales .
two dynamical properties contribute to these fluctuations . at the beginning , there are no label - negative cells and so the logarithm of the ratio is @xmath10 .
when the first label - negative cells appear , the ratio of label - positive to total cell population can dramatically change , especially if the population size is small . in effect , the theorem is not in force until both the label positive and label negative populations are large enough for average behavior to become dominant , which only happens after at least an order of @xmath250 division events have occured .
as one might expect , by decreasing @xmath2 from @xmath238 to @xmath251 this effect is amplified , as can also be seen in ( a ) and ( b ) . in this
setting , the typical behavior is initially for underestimation as can be seen in the inter - quartile range plot of panels ( c ) and ( d ) of for @xmath252 simulations .
this can be understood as there is no estimate prior to at least one cell delabeling , which requires , on average , @xmath250 divisions to occur .
as @xmath2 is assumed small , typically one does not intially get an estimate and this delay explains the observed lag in the blue lines . on the other hand , in the unlikely event that an early cell delabels , then the approximation initially gives signifcant over - estimates .
this bias , which we have observed consistently across other simulations , suggests that if starting with a single progenitor family , only becomes accurate at longer time - frames , i.e. after several generations have passed .
note that the mean value of the estimator at early times over multiple runs is effected by outliers , hence the mean lies outside the inter - quartile range .
results in section [ sec : math ] for the time - dependent sample paths of estimates suggest that one way to mitigate this initial variability in the single time - point estimate @xmath249 is to make two measurements at distinct times , @xmath253 and use their difference to estimate @xmath31 via the approximation in section [ sec : intro ] : @xmath254 the effect of this difference measurement is the removal of the initial fluctuations on a path - by - path basis .
this is illustrated in , panels ( e ) and ( f ) .
using monte carlo methods and a standard kernel estimation method , the plots compare three values : the actual average generation @xmath255 at @xmath256 hours ( orange ) ; the single time - point estimates @xmath257 ( blue ) ; and , with @xmath256 and an extra measurement at @xmath258 hours , the two time point estimates in with @xmath259 hours .
the two - point estimate is not only more symmetrically distributed around the true value , but its variability is significantly less than the single time - point estimates .
while the method works well for single progenitors , experiments are typically seeded with multiple progenitors .
theorem [ thm : largen ] establishes that the variability decreases inverse linearly with the number of progenitors , @xmath260 , and so one expects that starting with even a small number of cells will eradicate the early time variability and here we demonstrate that this is , indeed , the case . for @xmath261 , panels ( a ) and ( b ) correspond with those of .
the orange lines , showing the per - realization of the average generation , remain largely unchanged , but the accuracy of the single time point estimates ( blue ) are greatly improved .
this comes about as even if an individual progenitor s family generates label - negative cells relatively late this is balanced by another progenitor s family where delabeling happened relatively early .
thus both @xmath5 and @xmath3 rapidly become sufficiently substantial for the limit theorem to be in force and for the estimator to be precise .
panels ( c ) and ( d ) show monte carlo created box plots of the per - sample average generation , the single time - point estimate and the two time - point estimate for a range of initial progenitor numbers .
sample - to - sample variation is greatly reduced even with as few as @xmath0 progenitors .
thus in standard experimental systems , which are often seeded with hundreds or thousands of cells , the estimator is expected to be precise .
the simulations of the previous section show that the estimator works well for parameterizations akin to those found in experimental systems and provide insight into the impact of a number of factors , such as the delabeling probability and the number of progenitors , on the quality of the estimates .
here we use a range of published data to further investigate the estimator s applicability .
the first application takes lineage trees of the early development of _ c. elegans _ determined by time - lapse microscopy and reported on in @xcite .
as the entire family tree is known , we have direct access to measurements of average generation as a function of time . simulating a stochastic delabeling process on this tree , as would be experimentally possible via a division linked mosaic
construct similar to the one introduced in @xcite or the one we propose in section [ sec : expdes ] , we can directly investigate the estimator s accuracy .
\(a ) shows the embryonic lineage tree of the nematode _ caenorhabditis elegans _ as constructed from data published by richards et al .
@xcite . in their study ,
a reference lineage tree was constructed based on output from automated tracking of nuclei in @xmath262 embryos , recorded over approximately six hours at 1.5 minute intervals by three - dimensional resonance - scanning confocal microscopy .
each node in the figure represents a cell division and the tree contains information about all parent - daughter relationships and gives the timing of more than @xmath263 division events during an embryo s development .
this leads to a population size of approximately 600 cells , ( b ) . from the timing of the division events ,
lifetimes are readily computed , shown in ( c ) . for this tree ,
lifetime durations correlate positively with both generation and with the time of birth relative to fertilization , ( d ) , illustrating a lack of homogeneity .
regarding independence , there are correlations throughout the tree .
( e ) demonstrates , for example , that lifetimes of siblings are positively correlated .
these features are not in line with the assumptions under which some of the the sample path properties of the estimator were established , but are consistent with the derivation via properties of the cumulant generating function in section [ sec : math ] .
to test the accuracy of the estimator , we stochastically decorated the tree . beginning with a single label - positive progenitor , daughters are delabeled with probability @xmath2 .
should they remain label - positive , their daughters are delabeled independently with probability @xmath2 and so on for the whole tree . ( a ) illustrates one such random decoration , with blue indicating label positive and white label negative .
for @xmath252 independent monte carlo realizations of this delabeling process , ( f ) shows the average ( blue ) and the inter - quartile range of the estimates ( blue ) , using , at each time point during the first six hours of the development as well as the true average generation number of the embryo in orange , proving to be accurate . as explained in section [ sec : estover ] , if not all cells are initially label - positive one can estimate average generation from proportion measurements at two distinct times . to mimic this , we considered the development of the labeled trees after @xmath264 minutes . at @xmath264 minutes one measurement is taken , giving the proportion of label - positive cells and the approximation to determine the average generation growth since @xmath265 to the time of a later measurement to determine the average generation since @xmath265 .
the results are plotted in ( g ) , which show accuracy .
existing micro - satellite reporter systems implement division - linked labeling and are suitable for both _ in vitro _ and _ in vivo _
applications @xcite .
micro - satellites are short repeating motifs found in dna that , with small probability per cell division , are subject to insertion or deletion of copies of the motif .
mutation reporter systems possess an initially out of frame gene for a fluorescent protein .
micro - satellite mutation on division results in the gene becoming in frame , with the cell becoming fluorescent .
this fluorescent state is inherited by offspring and is either irreversible , as in @xcite , or has a reportedly negligible likelihood of reversion @xcite .
thus with micro - satellite mutation acting as a driver of rare division linked change , cell fluorescence serves as a label for average generation estimation .
the two data sets we analyze are from studies published by gasche et al .
@xcite on human colorectal cancer cells ( hct116 ) and kozar et al .
@xcite on mouse embryonic fibroblast ( mef ) .
the probability that a cell becomes fluorescent as a result of a micro - satellite mutation is estimated as @xmath266 and @xmath267 in each study , respectively . for generation estimation ,
these values serve as @xmath2 , the probability of delabeling per cell division .
the data sets consist of measurements of proportions of labeled cells over several days from in vitro proliferating cell lines that carry transgenic micro - satellite mutation reporter cassettes , allowing us to estimate the average generation of the cell population .
in addition to the proportions , @xcite also provides the growth curve , which is exponential from day one to day four before slowing down , probably as a consequence of cell confluence @xcite , while @xcite reports an exponential growth for the whole time - course of their experiment . applying the estimator @xmath249 with the proportions , @xmath7 , recapitulated in ( a - b ) , and label loss probabilities provided in the studies
, we can estimate the average generation @xmath31 as a function of time , ( c ) . for both data sets ,
the estimated average generation increases linearly over time at a rate of approximately one per day .
direct validation of the method with this data would require knowledge of the average generation , which is not reported in the above studies .
the growth curve ( d ) , however , allows an alternate method to estimate this quantity for comparison .
we directly estimate the average from this curve by assuming for exponentially distributed life - times and the absence of cell death as in this special case one can show that @xmath268 , where @xmath269 is the malthus parameter @xcite .
estimating @xmath269 from the growth curve from day one up to day four , using linear regression on @xmath270 , predicts that the increase of average generation relative to the first time point as @xmath271 .
this predictions matches closely the estimated average generation , ( c ) . taken together
, the analysis of these data shows that inferring the average generation from the proportion of labeled cells carrying micro - satellite mutation reporter cassettes is an experimentally feasible approach .
as an illustrative example of an ideal experiment including estimation of the probability of label - loss @xmath2 , we describe one possible implementation of a division - linked one - way labeling system via a genetic construct , ( a ) , that combines existing experimental techniques : expression of a fluorescent protein such as blue fluorescent protein ( bfp ) ; the use of a cell - cycle specific promoter to create division - linked changes @xcite ; and site - specific recombination @xcite .
the construct is composed of two elements .
first cre recombinase expression is placed under the control of a cell - cycle specific promoter @xcite .
the cell - cycle promoter is employed to ensure a division linked expression of cre recombinase .
then , two loxp sites are placed at each end of the bfp gene . as cells enter cell cycle cre recombinase
is expressed , site - specific recombination will occur probabilistically between the two loxp recombination sites @xcite and the bfp gene is excised . for average generation inference ,
the desirable likelihood of recombination should be small , which can be achieved with a low efficiency cre recombinase .
thus bfp+ cells are regarded as label positive and bfp- cells are label negative .
this design is similar in spirit to an existing one used to create mosaics in zebrafish @xcite , which employs micro - satellites as a division linked probabilistic driver and a kaloop in lieu of site - specific recombination .
the proportion of label - positive cells in a cell system incorporating this construct can be readily determined via fluorescence - activated cell sorting ( facs ) .
the essential remaining ingredient for average generation inference is the determination of the probability of label - loss .
this can be achieved by a _ in vitro _
facs experiment , as illustrated by the _ in silico _ simulated experiment in ( b)-(c ) .
a collection of cells that incorporate the construct are stained with a division diluting dye , such as cfse @xcite , with noise added for illustrative purposes .
after division , cells are gated based on their generation , and the proportion of label - positive cells per - generation determined by their fluorescence . with @xmath272 being the measured proportion of label - positive cells in generation @xmath94 , in the presence of a large number of initial progenitors the probability label - loss , @xmath2 ,
irrespective of whether deaths occur , is @xmath273 , which should be the same for every @xmath94 . in particular , if all initial cells are bfp+ , then @xmath274 and @xmath275 , the proportion of bfp negative cells in generation @xmath55 .
thus the probability of label - loss can be readily determined experimentally .
for this simulation , an estimated value of @xmath2 is determined using this measurement for @xmath276 , @xmath277 .
the accuracy of the method can then be checked during or after the experiment by comparing the average generation as determined by the division diluting dye with the value estimated via equation with the measured @xmath2 , ( d ) .
once @xmath2 is known , similar cell stain experiments with distinct cell lines or distinct stimulii can be performed to validate the method s inference before its use _ in vivo _ and for generation counts beyond the range possible with division diluting dyes or fluorescence microscopy . the construct described in this section
is intended as an exemplar , creatable with present technology .
further experimental possibilities , including those based on naturally occurring mutations , can be found in the following discussion .
the estimators introduced in this article , and , offer means to estimate a biologically significant quantity , the average generation of cell populations , for cell systems where direct measurement poses a significant challenge .
their appropriateness is not intuitively apparent and their development requires several mathematical results . throughout the development of those results
we assume that the label change is one - way , which can be shown not to be essential for the cumulant generating function derivation of the estimators , but is relied on in establishing the sample - path results as if the label change is reversible , so that labels can be gained as well as lost , then asymptotically it is known that the growth rate of the number of label - positive cells equals the growth rate of the total number of cells @xcite . despite its less than obvious genesis
, the estimator has highly desirable features : it allows the population to be subject to death and division ; it does not need to know the number of progenitors ; it does not require knowledge of cell - cycle distributions ; and , subject to knowing the per - division label - change probability , only requires the measurement of proportions .
comparison of estimates for simulations suggest that the estimator is accurate for physiological reasonable parameterizations . the estimators and depend on the proportion of label - positive cells in the population , where the label can be any of the cell s properties that is lost with a small probability during its division cycle .
several naturally occurring and engineered cellular processes exist that approximately match this requirement .
somatic mutation is probably the best studied natural process of this kind . in this case
germ - line cells are defined to be label - positive , while label - negative cells correspond to those with mutations in their dna .
the proportion of label - positive cells can be assessed by next generation sequencing . in humans
there is a high rate of fidelity in dna replication , giving an error rate of @xmath278 per base per division @xcite and so using only a single nucleotide location as a label appears impractical .
considering instead the full germ - line genome as a positive label , even though each nucleotide may suffer mutations with distinct rates , and potentially in concert , there is still an over - all probability of label - change that has been estimated in human sperm cells as approximately @xmath279 @xcite . in principle
, this rate could be used as the probability of delabeling for our estimator .
alternatively , hotspots of mutation could also be analyzed .
for example , micro - satellites , short repetitive sequences of dna , mutate in humans with @xmath2 in the range @xmath239 , which we have used for the parameterization to evaluate the performance of our estimator .
the use of hotspots of mutation as a label suffers from the difficulty that delabeled cells could relabel due to the occurrence of further mutations .
the impact of this can be ameliorated by creating an asymmetry in the likelihood of relabeling to delabeling .
one selects a set of @xmath48 sites for measurement , each having their own probability of mutation , @xmath280 .
one defines the label - positive cells as those that have germ - line values at all sites .
the likelihood of a labeled cell delabeling is the likelihood that any of the sites mutate away from germ - line , @xmath281 , if the individual @xmath280 are small .
the likelihood that a cell with a single mutation relabels is @xmath282 , creating a significant asymmetry .
moreover , for a cell that has had several mutations , the likelihood that all revert , which is necessary for relabeling , is smaller still . while it seems likely that one must rely on naturally occurring processes to estimate the average generation of a cell population for humans , genetically modified cell lines and animals have the advantage that measuring the proportion of label - positive cells can be directly facilitated by fluorescent markers .
the construct described in the experiment design section could be built or existing constructions , such as cre - mediated sister chromatid recombination @xcite and micro - satellite mutation induced label activation @xcite , can be adapted , so that reversion does not occur . using fluorescence - activated cell sorting or live imaging technologies and the estimators developed in this article it could be possible to follow the average generation of specific cell populations , like neoplastic tissue or the skin , in living organisms over long periods of time .
recent evidence from _ in vivo _ cell lineage tracing techniques such as cellular barcoding @xcite has demonstrated that apparently homogeneous progenitors give rise to heterogeneous families in cancer , immunology and hematopoesis , e.g. @xcite .
theoretical work developing methodologies to interrogate data from these experiments is ongoing , but one key difficulty that must be overcome is that the generation of individual families is unknown @xcite .
combining any of the above experimental methodologies and using the estimator developed in the present article would allow inference of the per progenitor average generation , enhancing the deductive power of these techniques , which have already proved invaluable .
having established the estimators and validating them through simulations and comparison with published data , we believe these are promising avenues . * acknowledgments : * the authors thank sren asmussen ( aarhus university ) for drawing their attention to @xcite .
the work of t.w .
, l.p . and
k.d . was supported by human frontier science program grant rgp0060/2012 .
was also supported by science foundation ireland grant 12 ip 1263 .
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r. lu , n. f. neff , s. r. quake , and i. l. weissman . tracking single hematopoietic stem cells in vivo using high - throughput sequencing in conjunction with viral genetic barcoding .
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, 17(4):498502 , 1997 . , start with a single label - positive cell at time @xmath10 .
plots shown for two label - change probabilities , @xmath283 ( top row ) and @xmath284 ( bottom row ) .
for @xmath248 independent realizations , orange lines display the actual average generation , @xmath31 .
blue lines display the estimates @xmath249 from , which ultimately increase linearly with the same slope as the average generation , but initially show significant variability .
( c)-(d ) for @xmath285 independent realizations of the process , the dashed line reveals that the empirical average of the estimates is close to the true value .
the blue region is an inter - quartile plot of the @xmath249 estimates , with the upper boundary being where 25 of the realizations are larger and the lower boundary being where 25 of realizations are smaller , which typically exhibits under - estimation .
( e)-(f ) using monte carlo methods and a standard kernel estimator , these panels show , for @xmath256 hours , the density of observations of @xmath255 in orange , the single time - point estimate @xmath257 in blue , and the two time - point estimate in grey with an additional time point at @xmath258 hours .
the additional time - point improves the estimate by removing early variability on a realization - by - realization basis . ]
( top row ) and @xmath284 ( bottom row ) .
( a)-(b ) sample paths of @xmath248 independent realizations with @xmath285 progenitors .
orange lines correspond to average generation , @xmath31 .
blue lines display the estimates @xmath249 , whose early time fluctuation is significantly less pronounced than with a single progenitor , as in ( a)-(b ) .
( c)-(d ) for 1 , 10 and 100 progenitors , monte carlo generated box plots of average generation ( orange ) and single time - point estimates ( blue ) at @xmath286 hours , and two time - point estimates ( grey ) , with the additional measurement at @xmath258 hours . as predicted by theory , accuracy improves substantially , in a @xmath2 dependent fashion , as the number of progenitors increases . ] .
( a ) lineage tree of c. elegans embryos , for first nine generations .
the lowest node represents the progenitor present in the first frame , while the uppermost nodes represent cells alive in the last frame .
each node in between represents a division event , and its vertical position corresponds to the frame in which it was recorded .
the color of the nodes , blue for label - positive at division and white for label - negative at division , illustrate one possible random delabeling of the trees .
( b ) total population , @xmath3 , as a function of time , @xmath4 , shows a step - wise increase in cell numbers followed by a reduction in growth rate that is not consistent with a homogeneous age dependent branching process .
( c ) histogram of the cell lifetime shows a multi - modal distribution , partly explained by the fact that lifetimes appear to lengthen with time of birth or generation .
( d ) box plot of the lifetimes as a function of generation , which shows lifetimes increasing with generation .
( e ) sibling lifetimes are highly correlated , with many dividing during the same frame .
( f ) comparison of average generation @xmath31 ( orange ) with its estimate @xmath287 ( blue ) .
monte carlo determined inter - quartile ranges based on @xmath252 samples .
( g ) same as ( f ) , but starting at @xmath264 and computing the difference of the average generation @xmath31 ( orange ) since @xmath265 via the approximation . ] over several days of culture for genetically modified clones of mef cells ( a , @xcite ) and hct116 cells ( b , @xcite ) carrying micro - satellite mutation reporter cassettes .
the mutation probabilities , as reported in the respective studies are @xmath288 @xcite and @xmath289 @xcite , which we use for @xmath2 , the probability of delabeling per cell division .
data are represented as mean @xmath290 sem . for the hct116 data ,
the mean at each time point is over three clones .
( c ) inferred relative average generation g(t)/z(t ) from the proportions of unlabeled cells and @xmath2 using the estimator @xmath291 ( mef , open circles ; hct116 , filled circles ) .
for both data sets the average generation increases linearly with time , as expected from the theory .
in addition , the slope is close to one generation per day , even thought the mutation probability @xmath2 differs by a factor of six .
the orange dashed line shows the increase in average generation as estimated directly from the growth curve @xmath3 ( panel d ) assuming exponentially distributed life - times and no cell death ( for details see main text ) , demonstrating the accuracy of the estimator .
the blue dashed regression lines ( @xmath292 for both sets ) highlight the linear increase of average generation estimates during the exponential growth phase .
( d ) population size @xmath3 of cultured mef cells ( open circles , @xcite ) and exponential growth fit to first four time points ( dashed line , @xmath293 ) .
[ fig : ms ] ] .
the simulation is parameterized as in section [ sec : val_sim ] .
@xmath294 bfp+ cells are labeled with a division diluting dye such as cfse , which is green , and cultured until they divide . at each division
, cfse is shared evenly between daughters and the bfp label is lost with probability @xmath295 .
( b)-(c ) simulated facs plots , ten and 40 hours after cfse labeling .
the fluorescence signals were set to realistic experimental values @xcite and noise was added to initial cfse levels for illustrative purposes . the gates in ( b ) and ( c ) capture the proportion of label - positive cells , @xmath272 , in each generation , @xmath94 . from these , the label - loss probability , @xmath2 , can be experimentally determined via the formula @xmath296 . as all cells in the zeroth generation express bfp , @xmath297 , and so @xmath298 , the proportion of bfp negative cells in generation @xmath55 .
( d ) the orange line plots the average generation of the population , determined from the simulated cfse data , a function of time .
the blue line is estimate determined using the method described in the present paper with a label - loss parameter , @xmath299 , obtained from ( b ) .
the cfse determined value and the estimate exhibit excellent concordance . ][/INST] for proliferating cells subject to both division and death , how can one estimate the average generation number of the living population without continuous observation or a division - diluting dye ? in this paper we provide a method for cell systems such that at each division there is an unlikely , heritable one - way label change that has no impact other than to serve as a distinguishing marker . if the probability of label change per cell generation can be determined and the proportion of labeled cells at a given time point can be measured , we establish that the average generation number of living cells can be estimated . crucially , the estimator does not depend on knowledge of the statistics of cell cycle , death rates or total cell numbers .
we validate the estimator and illustrate its features through comparison with published data and physiologically parameterized stochastic simulations , using it to suggest new experimental designs . </s> |
mitomap is a comprehensive database of human mtdna variation and its relation to human evolution and disease .
the need for a curated and thus reliable database of mitochondrial gene sequence variation with easily used web - based query tools is becoming increasingly essential as the importance of mtdna variation in the common age - related metabolic and neurodegenerative diseases , aging and cancer is elucidated .
the mtdna encompasses the 13 core polypeptide genes that define the efficiency of the mitochondrial energy generating system oxidative phosphorylation ( oxphos ) , the trnas and rrnas for their expression , and a 1121 np control region that regulates mtdna transcription and replication .
the mtdna also has a unique genetics , being maternally inherited , present in thousands of copies per cell , and capable of encompassing various percentages of mutant and normal molecules ( or heteroplasmy ) ( 1 ) .
hence , the mtdna imparts a quantitative genetics to the vital , systemic function of energy production ( 1,2 ) .
the 16 569 nt pairs ( np ) of the closed circular mtdna are each numbered sequentially and the
standard base at each position ( 3 ) is specified in the revised cambridge reference sequence ( rcrs ) , genbank j01415.2 .
this permits any new mtdna sequence to be unambiguously defined by specifying only the deviant positions and bases relative to the rcrs .
the human mtdna has a very high mutation rate , and this has generated three classes of sequence variants : pathogenic , adaptive and neutral .
pathogenic mutations damage conserved gene functions and as the deleterious mutation increases in its percentage heteroplasmy , it erodes systemic cellular energy output .
this deficiency is acted on by natural selection and the mutation is soon eliminated from the population as hereditary disease .
adaptive mtdna mutations also alter conserved functions but these alterations are advantageous in certain environments . consequently , they become established in the individual ( or homoplasmic ) and increase in the population that occupies the compatible environment .
neutral mutations accumulate by chance , but those linked to advantageous mutations can become enriched in particular populations by hitchhiking .
mutations in the mtdna not only arise in the female germline , but also accumulate in the post - mitotic cells of the body with age .
these somatic mtdna mutations now appear to be the aging clock and may also be important in the etiology of certain cancers ( 1,2 ) .
pathogenic mtdna mutations can be divided into those that alter more than one gene ( inter - gene or contiguous gene defects ) and those that affect only one gene ( intra - gene or single gene defects ) .
the intra - gene mutations can either alter polypeptide coding genes or protein synthesis ( rrna and trna ) genes .
the functional severity of pathogenic nucleotide substitutions can be estimated , in part , through the inter - species conservation index ( ci ) and for rrna or trna genes by the effect of the base change on the rna secondary structure .
since the clinical effect of a mutation is the product of both the severity of the mutation and its percentage of heteroplasmy , the clinical phenotypes of heteroplasmic mtdna mutations can be highly variable among the maternal relatives ( 1,2 ) .
since mtdna mutations can arise in both the germline and somatic tissues , they have been associated with both degenerative diseases and cancers ( 46 ) .
moreover , since they are retained in the population by selection , they are frequently ancient and present at polymorphic frequencies .
about 25% of the polypeptide amino acid substitution ( missense ) mutations present in the human mtdna phylogenetic tree are adaptive ( 7,8 ) , 1020% of trna mutations appear to be adaptive , as do various rrna variants ( 9 ) .
many of these same mutations have also been reported as somatic mutations in cancer cells suggesting that tumors adapt to their changing energetic environment through the evolution of mtdna variation ( 10 ) .
a surprisingly high proportion of cancer control region somatic mutations are also population polymorphisms ( 10 ) , suggesting that modulation of mtdna replication and transcription is an important adaptive strategy .
since mtdna mutations accumulate sequentially along maternal mtdna lineages , the mtdnas of region - specific branches of the mtdna tree are founded by a common mtdna haplotype and thus share a set of common polymorphisms . from this founder
, additional mutations are added sequentially over time forming groups of related haplotypes is called a haplogroup . since selection may have caused the haplogroup to flourish in the new environment , different haplogroups may be functionally different ( 8,9 ) .
evidence that haplogroups can be functionally different comes from the fact that haplogroups are associated with predilection to or protection from various clinical phenotypes .
for instance , haplogroup j increases the risk of developing blindness in association with the milder leber hereditary optic neuropathy ( lhon ) mutations ( 1113 ) and haplogroup
t increases risk for depression ( 14 ) . however , other haplogroups are protective against alzheimer disease ( 1517 ) and parkinson disease ( 1719 ) and are associated with increased longevity ( 8,2024 ) . throughout the evolution of the symbiosis between the nuclear - cytosol and the mitochondrial organisms , sequences from the mtdna
have been transferred to the ndna with the result that the vast majority of mitochondrial genes are now located in the nucleus .
the transfer of mtdna sequences to the ndna continues today , but differences in the mtdna genetic code that arose prior to the origin of the fungal - animal mtdna lineage render the mtdna sequences unintelligible to the nuclear - cytosol system ( 2 ) .
consequently , all recent mtdna transfers into the human ndna have resulted in nuclear - mtdna pseudogenes ( numts ) ( 25 ) .
numts are potentially problematic since they can be inadvertently amplified using the polymerase chain reaction ( pcr ) , sequenced , and the pseudogene variants mistaken for pathogenic mtdna mutations ( 26,27 ) . while the mtdna retains the 13 central oxphos proton and electron carries for the oxphos circuitry , all of the structural genes necessary to assemble the mitochondrial oxphos complexes as well as all of the genes needed to create a mitochondrion are now encoded by the nucleus , a total of 1500 mitochondrial genes .
therefore , many mutations that affect mitochondrial function are the result of ndna mutations ( 1,2 ) .
a number of factors must be considered when evaluating the nucleotide variants observed in a new mtdna sequence relative to the rcrs .
these include the association between different variants on particular branches of the mtdna tree ( the haplogroup ) , the time in human mtdna radiation that the variant appeared and the position of the variant in the protein or rna gene .
all of these considerations were utilized in developing our sequential mutational phylogenetic tree of the human mtdna .
our mtdna tree encompasses the information in 2959 mtdna coding region sequences , using the rcrs ( genbank j01415.2 ) as the reference . while our tree was assembled primarily using mtdna coding region single nucleotide polymorphisms ( snps ) , informative control region snps are also being incorporated when available .
however , this dataset is incomplete since the control region sequences have not been reported for many of the published mtdna sequences used in building the tree .
each sequence was analyzed for possible sequencing errors , identified by base changes inconsistent with the most likely haplogroup .
black polymorphisms represent nonsynonymous mutations ( amino acid , position , amino acid , gene ) , red synonymous mutations ( gene ) , green trna or rrna mutations ( gene ) , blue indicates non - coding nucleotides in the coding region and underlined yellow represent pathological mutations .
large blue letters indicate a haplogroup designation and large black letters allow for navigation of the tree at low magnification .
for example , 4(55 ) indicates howell 's article ( 4 is the code for this article ) and 55 is the number of the sequence in the article ) .
( b ) magnification of blue box in figure1a showing details of the tree for subhaplogroup j2b .
the core topology of the tree was generated by the neighbor - joining program from mega ( 28 ) using 1060 human mtdna sequences .
the branching order used is highly robust as demonstrated by its consistency within 1000 bootstrap iterations .
separate neighbor - joining trees were also built for each major haplogroup , again with the branching order being robust based in 1000 bootstrap iterations . then using sequence alignment and sequence comparisons ,
the positions of the individual nucleotide changes were incorporated into the various branches and nodes of the tree .
since the core tree encompasses all of the major mtdna haplogroups , new mtdna sequences can be continually incorporated into the existing tree manually without necessity for further computer analysis .
atypical variants such as insertion - deletions are also added manually and unsolved parallel mutations are resolved by network analysis .
the overall branching order of the human mtdna tree has been clear for many years ( 2932 ) .
however , the presence of identical mutations in multiple different parts of the phylogeny was initially puzzling .
this was resolved when we concluded that many of these recurrent mutations were due to convergent evolution resulting from adaptive selection acting on specific functional variants ( 8,9 ) .
the letters were assigned as the mtdna lineages became apparent . because native americans were found to have a limited number of mtdna lineages ( 33 ) , the four major native american haplogroups were designated a , b , c and d ( 34,35 ) .
subsequent analysis added haplogroups in europe ( h , i , j , t , u , uk , v , w and x ) ( 36,37 ) , asia ( many derivatives of macro - haplogroups m and n which radiated out - of - africa ) ( 38,39 ) and africa ( haplogroups l0 , l1 , l2 and l3 ) ( 7,40,41 ) .
a fifth native american haplogroup was also found to be related to eurasian mtdna haplogroup x ( 42 ) .
the sub - branching order of the haplogroups has been further refined by incorporating subsequent nomenclatural proposals ( 43 ) and application of the information derived from complete mtdna sequences ( 7,44,45 ) .
since the african mtdnas lie at the root of the mtdna phylogeny ( 2931 ) , the african haplogroups are presented at the beginning ( top ) of the phylogenetic tree ( figure 1 ) .
the complete phylogeny with all of the ordered snps requires 126 pages to print . to make the tree more accessible , it was integrated and transferred into the canvas x ( acd systems , inc
, the entire tree can be viewed at any resolution desired , from ultra - low resolution , where all of the branches can be observed but no detail can be perceived , to ultra - high resolution , where the branching order is lost but the individual nucleotide changes can be seen ( figure 1 ) .
the nucleotide position of each change is located in the tree in the order that they arose , and the nature of the mutation , transition versus transversion , given . if the nucleotide change alters a trna or an rrna gene , the mutation is presented in green with the gene designated . if the mutation alters a polypeptide gene , but is synonymous , then it is presented in red with the gene identified .
however , if the mutation alters the amino acid sequence of a polypeptide gene , the mutation is presented in black with the affected gene identified and the codon position and amino acid substitution reported . non - coding variants are shown in blue , and few representative pathogenic mutations are included in the tree in yellow . in this way , all of the common mtdna sequence changes , their relationship to each other and their potential significance can easily be observed . because of how our tree was developed , it is invaluable for analyzing the nature of the nucleotide differences found in any new mtdna sequence relative to the rcrs . by tracing the nucleotide variants in the new mtdna sequence along the branching order of our tree ,
the new sequence 's haplogroup is defined , the time that each variant arose ( ancient versus recent ) is determined and the effect of the sequence variant on the polypeptide or rna gene revealed .
ancient functional variants associated with a new sequence may be adaptive variants and may have also arisen independently in other branches of the phylogeny .
variants that do not appear in our phylogenetic tree are likely to be relatively recent mutations . if the mtdna sequence is from a potentially maternally inherited disease patient and the new mutation is potentially functionally significant , the mutation becomes a candidate for a pathogenic mutation .
neutral variants can be either ancient or recent , but do not alter an important mitochondrial function . with these rules , a mtdna sequence from a patient with a potentially maternally inherited disease would be analyzed by first comparing the sequence to the rcrs , and all differences will be listed .
these variants would then be used to trace down the various branches of the phylogenetic tree until you arrive at the end of a terminal branch .
any variants that are left over must be recent and require additional analysis . if a residual nucleotide change alters an amino acid in a mtdna polypeptide or the sequence of a trna or rrna ,
calculation of the ci of the variant amino acid can give further insight into pathogenicity ( 8) . similarly , for a trna or rrna sequence change , if the variant alters a conserved nucleotide and/or affects the secondary structure of the rna then it becomes a candidate for a pathogenic mutation ( 9 ) .
additional criteria suggesting pathogenicity could include the presence of heteroplasmy and a correlation between the severity of the pathogenic mutation and the percentage of mutant mtdnas present in various family members along a maternal lineage
. another criterion could be the similarity between the pathological presentation of the mutation and that of a similar type of pathogenic mutation that presents with a similar phenotype .
in certain cases , multiple patients from unrelated families may be found that have closely related mtdna haplotypes . in these situations , it is possible that the background mtdna haplogroup is also contributing to the pathogenicity of the deleterious mutation .
this type of phenomenon has been documented for the milder pathogenic mutations at nt g11778a , t14484c , and t10663c which cause lhon , which are preferentially associated with mtdna haplogroups j and t ( 1113 ) .
one strong criterion for identifying a pathogenic mtdna mutation would be if the same mutation had been identified in other patients with similar clinical presentation . to facilitate this type of comparison ,
the current searchable tables are divided into three major classes : ( i ) mutations associated with lhon , ( ii ) mutations that affect polypeptide sequences but present with other phenotypes and ( iii ) mutations that alter trnas and rrnas and present with a various multi - system clinical problems . these tables and the associated clinical diseases
are explained in depth in our various clinical reviews ( 2,46,47 ) . as an example , the lhon disease mutations have been sub - classified into two main categories .
the first category includes well characterized and causative mutations designated the top 10 primary lhon mutations .
this group includes the three most common lhon mutations ( g3460a , g11778a and t14484c ) with account for 95% of lhon patients .
the second mutation category includes mutations that have been reported in a single family and thus require additional independent reports to confirm their causal association with lhon .
if in the process of analyzing an mtdna sequence from a patient , one of the recent sequence differences is also present in one of the pathogenic mutational tables , then this mutation becomes a good likely candidate for the disease mutation .
however , it must be remembered that the mtdna haplogroup background can be a contributing factor in some diseases such as lhon .
hence , it is important that the role of the mutation be considered in the larger context of what we know about human mitochondrial genetics ( 2 ) .
while the mtdna encodes 37 critical genes for oxphos ( 13 polypeptides , 22 trnas and 2 rrnas ) the ndna encodes in the order of 1500 additional mitochondrial proteins and mutations in these genes can also cause mitochondrial disease . hence , many of the more severe mitochondrial diseases can be caused by mutations in ndna encoded genes for the structural or assembly proteins of the oxphos complexes and a spectrum of disorders can result from ndna mutations that affect mtdna replication ( 48 ) . to alert mitomap users to these important classes of mitochondrial disease ,
mitomap now includes summary tables of the known ndna - encoded mitochondrial diseases ( 2 ) .
the ndna also encodes 247 fragments of the mtdna of sufficiently recent origin to be easily mistaken for legitimate mtdna sequences . inadvertent pcr amplification of one of these sequences during a clinical study can result in the erroneous conclusion that the sequence variants within the numt pseudogene are the cause of the disease ( 26,27 ) . to address this problem ,
we have developed a mitomap human numt database ( 25 ) . by scanning the numt sequences that encompass the same region as that of clinical interest , the potential ndna pseudogene variants can be identified .
the mitomap database currently encompasses over 5100 references . these pertain to the mtdna sequence , sequence variation and mitochondrial role in a wide variety of diseases .
all of the data for mitomap is now managed in postgresql ( ) , an open - source database management system ( i.e. dbms ) with object - relational modeling capabilities .
data for mitomap are initially extracted by the database curators and stored , formatted and screened in excel spreadsheets .
updated versions of the curated data are then periodically uploaded to the server , where perl programs implementing the parseexcel and dbi modules are used to parse the values from the spreadsheets and populate the data structures implemented in postgresql .
the mitomap servers are located at the university of california , irvine , on a dual - processor server running redhat linux as its operating system .
by adding the mtdna mutational tree , updating the depth and breadth of the mtdna disease mutation tables and creating a numt pseudogene sequence database , we have now generated the informational infrastructure that will permit mitomap to evolve from a simple factual database to an intelligent analytical system . the sequential mutation mtdna phylogenetic tree places all of the factual information about mtdna sequence variation into an evolutionary and functional context .
this single integrated entity thus automatically sorts mtdna variants into ancient versus recent mutations , defines the gene affected and provides preliminary information on the potential functional implications of the mutation . from this foundation
, mitomap is now poised to implement our much more powerful data integration and analysis system , mitomaster .
the mitomap - mitomaster system will permit the user to up - load a new mtdna sequence , and the system will automatically identify the sequence variants relative to the rcrs , determine the mtdna haplogroup , indicate the potentially functional variants , check for numt pseudogene variants and provide a list of potential disease causing mutations .
hence mitomap - mitomaster will soon be an important bioinformatics tool in the analysis of human mtdna sequence variation . | the mitomap ( ) data system for the human mitochondrial genome has been greatly enhanced by the addition of a navigable mutational mitochondrial dna ( mtdna ) phylogenetic tree of 3000 mtdna coding region sequences plus expanded pathogenic mutation tables and a nuclear - mtdna pseudogene ( numt ) data base . the phylogeny reconstructs the entire mutational history of the human mtdna , thus defining the mtdna haplogroups and differentiating ancient from recent mtdna mutations .
pathogenic mutations are classified by both genotype and phenotype , and the numt sequences permits detection of spurious inclusion of pseudogene variants during mutation analysis .
these additions position mitomap for the implementation of our automated mtdna sequence analysis system , mitomaster . | <s>[INST]mitomap is a comprehensive database of human mtdna variation and its relation to human evolution and disease .
the need for a curated and thus reliable database of mitochondrial gene sequence variation with easily used web - based query tools is becoming increasingly essential as the importance of mtdna variation in the common age - related metabolic and neurodegenerative diseases , aging and cancer is elucidated .
the mtdna encompasses the 13 core polypeptide genes that define the efficiency of the mitochondrial energy generating system oxidative phosphorylation ( oxphos ) , the trnas and rrnas for their expression , and a 1121 np control region that regulates mtdna transcription and replication .
the mtdna also has a unique genetics , being maternally inherited , present in thousands of copies per cell , and capable of encompassing various percentages of mutant and normal molecules ( or heteroplasmy ) ( 1 ) .
hence , the mtdna imparts a quantitative genetics to the vital , systemic function of energy production ( 1,2 ) .
the 16 569 nt pairs ( np ) of the closed circular mtdna are each numbered sequentially and the
standard base at each position ( 3 ) is specified in the revised cambridge reference sequence ( rcrs ) , genbank j01415.2 .
this permits any new mtdna sequence to be unambiguously defined by specifying only the deviant positions and bases relative to the rcrs .
the human mtdna has a very high mutation rate , and this has generated three classes of sequence variants : pathogenic , adaptive and neutral .
pathogenic mutations damage conserved gene functions and as the deleterious mutation increases in its percentage heteroplasmy , it erodes systemic cellular energy output .
this deficiency is acted on by natural selection and the mutation is soon eliminated from the population as hereditary disease .
adaptive mtdna mutations also alter conserved functions but these alterations are advantageous in certain environments . consequently , they become established in the individual ( or homoplasmic ) and increase in the population that occupies the compatible environment .
neutral mutations accumulate by chance , but those linked to advantageous mutations can become enriched in particular populations by hitchhiking .
mutations in the mtdna not only arise in the female germline , but also accumulate in the post - mitotic cells of the body with age .
these somatic mtdna mutations now appear to be the aging clock and may also be important in the etiology of certain cancers ( 1,2 ) .
pathogenic mtdna mutations can be divided into those that alter more than one gene ( inter - gene or contiguous gene defects ) and those that affect only one gene ( intra - gene or single gene defects ) .
the intra - gene mutations can either alter polypeptide coding genes or protein synthesis ( rrna and trna ) genes .
the functional severity of pathogenic nucleotide substitutions can be estimated , in part , through the inter - species conservation index ( ci ) and for rrna or trna genes by the effect of the base change on the rna secondary structure .
since the clinical effect of a mutation is the product of both the severity of the mutation and its percentage of heteroplasmy , the clinical phenotypes of heteroplasmic mtdna mutations can be highly variable among the maternal relatives ( 1,2 ) .
since mtdna mutations can arise in both the germline and somatic tissues , they have been associated with both degenerative diseases and cancers ( 46 ) .
moreover , since they are retained in the population by selection , they are frequently ancient and present at polymorphic frequencies .
about 25% of the polypeptide amino acid substitution ( missense ) mutations present in the human mtdna phylogenetic tree are adaptive ( 7,8 ) , 1020% of trna mutations appear to be adaptive , as do various rrna variants ( 9 ) .
many of these same mutations have also been reported as somatic mutations in cancer cells suggesting that tumors adapt to their changing energetic environment through the evolution of mtdna variation ( 10 ) .
a surprisingly high proportion of cancer control region somatic mutations are also population polymorphisms ( 10 ) , suggesting that modulation of mtdna replication and transcription is an important adaptive strategy .
since mtdna mutations accumulate sequentially along maternal mtdna lineages , the mtdnas of region - specific branches of the mtdna tree are founded by a common mtdna haplotype and thus share a set of common polymorphisms . from this founder
, additional mutations are added sequentially over time forming groups of related haplotypes is called a haplogroup . since selection may have caused the haplogroup to flourish in the new environment , different haplogroups may be functionally different ( 8,9 ) .
evidence that haplogroups can be functionally different comes from the fact that haplogroups are associated with predilection to or protection from various clinical phenotypes .
for instance , haplogroup j increases the risk of developing blindness in association with the milder leber hereditary optic neuropathy ( lhon ) mutations ( 1113 ) and haplogroup
t increases risk for depression ( 14 ) . however , other haplogroups are protective against alzheimer disease ( 1517 ) and parkinson disease ( 1719 ) and are associated with increased longevity ( 8,2024 ) . throughout the evolution of the symbiosis between the nuclear - cytosol and the mitochondrial organisms , sequences from the mtdna
have been transferred to the ndna with the result that the vast majority of mitochondrial genes are now located in the nucleus .
the transfer of mtdna sequences to the ndna continues today , but differences in the mtdna genetic code that arose prior to the origin of the fungal - animal mtdna lineage render the mtdna sequences unintelligible to the nuclear - cytosol system ( 2 ) .
consequently , all recent mtdna transfers into the human ndna have resulted in nuclear - mtdna pseudogenes ( numts ) ( 25 ) .
numts are potentially problematic since they can be inadvertently amplified using the polymerase chain reaction ( pcr ) , sequenced , and the pseudogene variants mistaken for pathogenic mtdna mutations ( 26,27 ) . while the mtdna retains the 13 central oxphos proton and electron carries for the oxphos circuitry , all of the structural genes necessary to assemble the mitochondrial oxphos complexes as well as all of the genes needed to create a mitochondrion are now encoded by the nucleus , a total of 1500 mitochondrial genes .
therefore , many mutations that affect mitochondrial function are the result of ndna mutations ( 1,2 ) .
a number of factors must be considered when evaluating the nucleotide variants observed in a new mtdna sequence relative to the rcrs .
these include the association between different variants on particular branches of the mtdna tree ( the haplogroup ) , the time in human mtdna radiation that the variant appeared and the position of the variant in the protein or rna gene .
all of these considerations were utilized in developing our sequential mutational phylogenetic tree of the human mtdna .
our mtdna tree encompasses the information in 2959 mtdna coding region sequences , using the rcrs ( genbank j01415.2 ) as the reference . while our tree was assembled primarily using mtdna coding region single nucleotide polymorphisms ( snps ) , informative control region snps are also being incorporated when available .
however , this dataset is incomplete since the control region sequences have not been reported for many of the published mtdna sequences used in building the tree .
each sequence was analyzed for possible sequencing errors , identified by base changes inconsistent with the most likely haplogroup .
black polymorphisms represent nonsynonymous mutations ( amino acid , position , amino acid , gene ) , red synonymous mutations ( gene ) , green trna or rrna mutations ( gene ) , blue indicates non - coding nucleotides in the coding region and underlined yellow represent pathological mutations .
large blue letters indicate a haplogroup designation and large black letters allow for navigation of the tree at low magnification .
for example , 4(55 ) indicates howell 's article ( 4 is the code for this article ) and 55 is the number of the sequence in the article ) .
( b ) magnification of blue box in figure1a showing details of the tree for subhaplogroup j2b .
the core topology of the tree was generated by the neighbor - joining program from mega ( 28 ) using 1060 human mtdna sequences .
the branching order used is highly robust as demonstrated by its consistency within 1000 bootstrap iterations .
separate neighbor - joining trees were also built for each major haplogroup , again with the branching order being robust based in 1000 bootstrap iterations . then using sequence alignment and sequence comparisons ,
the positions of the individual nucleotide changes were incorporated into the various branches and nodes of the tree .
since the core tree encompasses all of the major mtdna haplogroups , new mtdna sequences can be continually incorporated into the existing tree manually without necessity for further computer analysis .
atypical variants such as insertion - deletions are also added manually and unsolved parallel mutations are resolved by network analysis .
the overall branching order of the human mtdna tree has been clear for many years ( 2932 ) .
however , the presence of identical mutations in multiple different parts of the phylogeny was initially puzzling .
this was resolved when we concluded that many of these recurrent mutations were due to convergent evolution resulting from adaptive selection acting on specific functional variants ( 8,9 ) .
the letters were assigned as the mtdna lineages became apparent . because native americans were found to have a limited number of mtdna lineages ( 33 ) , the four major native american haplogroups were designated a , b , c and d ( 34,35 ) .
subsequent analysis added haplogroups in europe ( h , i , j , t , u , uk , v , w and x ) ( 36,37 ) , asia ( many derivatives of macro - haplogroups m and n which radiated out - of - africa ) ( 38,39 ) and africa ( haplogroups l0 , l1 , l2 and l3 ) ( 7,40,41 ) .
a fifth native american haplogroup was also found to be related to eurasian mtdna haplogroup x ( 42 ) .
the sub - branching order of the haplogroups has been further refined by incorporating subsequent nomenclatural proposals ( 43 ) and application of the information derived from complete mtdna sequences ( 7,44,45 ) .
since the african mtdnas lie at the root of the mtdna phylogeny ( 2931 ) , the african haplogroups are presented at the beginning ( top ) of the phylogenetic tree ( figure 1 ) .
the complete phylogeny with all of the ordered snps requires 126 pages to print . to make the tree more accessible , it was integrated and transferred into the canvas x ( acd systems , inc
, the entire tree can be viewed at any resolution desired , from ultra - low resolution , where all of the branches can be observed but no detail can be perceived , to ultra - high resolution , where the branching order is lost but the individual nucleotide changes can be seen ( figure 1 ) .
the nucleotide position of each change is located in the tree in the order that they arose , and the nature of the mutation , transition versus transversion , given . if the nucleotide change alters a trna or an rrna gene , the mutation is presented in green with the gene designated . if the mutation alters a polypeptide gene , but is synonymous , then it is presented in red with the gene identified .
however , if the mutation alters the amino acid sequence of a polypeptide gene , the mutation is presented in black with the affected gene identified and the codon position and amino acid substitution reported . non - coding variants are shown in blue , and few representative pathogenic mutations are included in the tree in yellow . in this way , all of the common mtdna sequence changes , their relationship to each other and their potential significance can easily be observed . because of how our tree was developed , it is invaluable for analyzing the nature of the nucleotide differences found in any new mtdna sequence relative to the rcrs . by tracing the nucleotide variants in the new mtdna sequence along the branching order of our tree ,
the new sequence 's haplogroup is defined , the time that each variant arose ( ancient versus recent ) is determined and the effect of the sequence variant on the polypeptide or rna gene revealed .
ancient functional variants associated with a new sequence may be adaptive variants and may have also arisen independently in other branches of the phylogeny .
variants that do not appear in our phylogenetic tree are likely to be relatively recent mutations . if the mtdna sequence is from a potentially maternally inherited disease patient and the new mutation is potentially functionally significant , the mutation becomes a candidate for a pathogenic mutation .
neutral variants can be either ancient or recent , but do not alter an important mitochondrial function . with these rules , a mtdna sequence from a patient with a potentially maternally inherited disease would be analyzed by first comparing the sequence to the rcrs , and all differences will be listed .
these variants would then be used to trace down the various branches of the phylogenetic tree until you arrive at the end of a terminal branch .
any variants that are left over must be recent and require additional analysis . if a residual nucleotide change alters an amino acid in a mtdna polypeptide or the sequence of a trna or rrna ,
calculation of the ci of the variant amino acid can give further insight into pathogenicity ( 8) . similarly , for a trna or rrna sequence change , if the variant alters a conserved nucleotide and/or affects the secondary structure of the rna then it becomes a candidate for a pathogenic mutation ( 9 ) .
additional criteria suggesting pathogenicity could include the presence of heteroplasmy and a correlation between the severity of the pathogenic mutation and the percentage of mutant mtdnas present in various family members along a maternal lineage
. another criterion could be the similarity between the pathological presentation of the mutation and that of a similar type of pathogenic mutation that presents with a similar phenotype .
in certain cases , multiple patients from unrelated families may be found that have closely related mtdna haplotypes . in these situations , it is possible that the background mtdna haplogroup is also contributing to the pathogenicity of the deleterious mutation .
this type of phenomenon has been documented for the milder pathogenic mutations at nt g11778a , t14484c , and t10663c which cause lhon , which are preferentially associated with mtdna haplogroups j and t ( 1113 ) .
one strong criterion for identifying a pathogenic mtdna mutation would be if the same mutation had been identified in other patients with similar clinical presentation . to facilitate this type of comparison ,
the current searchable tables are divided into three major classes : ( i ) mutations associated with lhon , ( ii ) mutations that affect polypeptide sequences but present with other phenotypes and ( iii ) mutations that alter trnas and rrnas and present with a various multi - system clinical problems . these tables and the associated clinical diseases
are explained in depth in our various clinical reviews ( 2,46,47 ) . as an example , the lhon disease mutations have been sub - classified into two main categories .
the first category includes well characterized and causative mutations designated the top 10 primary lhon mutations .
this group includes the three most common lhon mutations ( g3460a , g11778a and t14484c ) with account for 95% of lhon patients .
the second mutation category includes mutations that have been reported in a single family and thus require additional independent reports to confirm their causal association with lhon .
if in the process of analyzing an mtdna sequence from a patient , one of the recent sequence differences is also present in one of the pathogenic mutational tables , then this mutation becomes a good likely candidate for the disease mutation .
however , it must be remembered that the mtdna haplogroup background can be a contributing factor in some diseases such as lhon .
hence , it is important that the role of the mutation be considered in the larger context of what we know about human mitochondrial genetics ( 2 ) .
while the mtdna encodes 37 critical genes for oxphos ( 13 polypeptides , 22 trnas and 2 rrnas ) the ndna encodes in the order of 1500 additional mitochondrial proteins and mutations in these genes can also cause mitochondrial disease . hence , many of the more severe mitochondrial diseases can be caused by mutations in ndna encoded genes for the structural or assembly proteins of the oxphos complexes and a spectrum of disorders can result from ndna mutations that affect mtdna replication ( 48 ) . to alert mitomap users to these important classes of mitochondrial disease ,
mitomap now includes summary tables of the known ndna - encoded mitochondrial diseases ( 2 ) .
the ndna also encodes 247 fragments of the mtdna of sufficiently recent origin to be easily mistaken for legitimate mtdna sequences . inadvertent pcr amplification of one of these sequences during a clinical study can result in the erroneous conclusion that the sequence variants within the numt pseudogene are the cause of the disease ( 26,27 ) . to address this problem ,
we have developed a mitomap human numt database ( 25 ) . by scanning the numt sequences that encompass the same region as that of clinical interest , the potential ndna pseudogene variants can be identified .
the mitomap database currently encompasses over 5100 references . these pertain to the mtdna sequence , sequence variation and mitochondrial role in a wide variety of diseases .
all of the data for mitomap is now managed in postgresql ( ) , an open - source database management system ( i.e. dbms ) with object - relational modeling capabilities .
data for mitomap are initially extracted by the database curators and stored , formatted and screened in excel spreadsheets .
updated versions of the curated data are then periodically uploaded to the server , where perl programs implementing the parseexcel and dbi modules are used to parse the values from the spreadsheets and populate the data structures implemented in postgresql .
the mitomap servers are located at the university of california , irvine , on a dual - processor server running redhat linux as its operating system .
by adding the mtdna mutational tree , updating the depth and breadth of the mtdna disease mutation tables and creating a numt pseudogene sequence database , we have now generated the informational infrastructure that will permit mitomap to evolve from a simple factual database to an intelligent analytical system . the sequential mutation mtdna phylogenetic tree places all of the factual information about mtdna sequence variation into an evolutionary and functional context .
this single integrated entity thus automatically sorts mtdna variants into ancient versus recent mutations , defines the gene affected and provides preliminary information on the potential functional implications of the mutation . from this foundation
, mitomap is now poised to implement our much more powerful data integration and analysis system , mitomaster .
the mitomap - mitomaster system will permit the user to up - load a new mtdna sequence , and the system will automatically identify the sequence variants relative to the rcrs , determine the mtdna haplogroup , indicate the potentially functional variants , check for numt pseudogene variants and provide a list of potential disease causing mutations .
hence mitomap - mitomaster will soon be an important bioinformatics tool in the analysis of human mtdna sequence variation .[/INST]the mitomap ( ) data system for the human mitochondrial genome has been greatly enhanced by the addition of a navigable mutational mitochondrial dna ( mtdna ) phylogenetic tree of 3000 mtdna coding region sequences plus expanded pathogenic mutation tables and a nuclear - mtdna pseudogene ( numt ) data base . the phylogeny reconstructs the entire mutational history of the human mtdna , thus defining the mtdna haplogroups and differentiating ancient from recent mtdna mutations .
pathogenic mutations are classified by both genotype and phenotype , and the numt sequences permits detection of spurious inclusion of pseudogene variants during mutation analysis .
these additions position mitomap for the implementation of our automated mtdna sequence analysis system , mitomaster .</s> |
epigenetic regulation
of gene expression is mediated through at
least five series of events involving changes of chromatin at the
molecular level : dna modifications , histone modifications , histone
variants , noncoding rnas , and nucleosome remodeling .
epigenetic control of transcription is essential to drive cells
toward their normal phenotype , and epigenetic deregulation could lead
to initiation and progression of human diseases including cancer .
in contrast to genetic origins of cancer , epigenetic aberrations
are reversible events that occur at early stages in tumor genesis ,
and in the past decade , many interactions and connections have been
reported between genetic and epigenetic changes that highlight the
complex , multifactorial nature of such disease . among the five epigenetic events ,
three dna methyltransferases ( dnmts ) , dnmt1 ,
dnmt3a , and dnmt3b , catalyze the transfer of a methyl group from s - adenosyl - l - methionine ( adomet ) to the c5-position
of cytosine predominantly in cpg dinucleotides .
the maintenance methyltransferase
dnmt1 is most abundant in somatic cells and has a greater activity
for hemi- rather than unmethylated substrates .
differently ,
de novo methyltransferase dnmt3a is only present in low amounts in
somatic cells and shows no preference for hemi- or unmethylated dna . in normal cells ,
dna methylation plays
a key role in many physiological
events ( genomic imprinting control , x - chromosome inactivation , maintenance
of chromosomal stability , silencing of genes and endogenous retroviruses ,
and embryonic development ) , following a pattern according to which
certain genomic sites are hypermethylated ( gene silencing ) , whereas
other sites , such as cpg islands , are hypomethylated ( gene transcription ) . in cancer cells ,
aberrant dna methylation leads to hypermethylation
at cpg islands , joined to a global hypomethylation , giving rise to
genomic instability and inactivation of tumor - suppressor genes .
hypermethylation of cpg islands is so biologically relevant and
specific that for each cancer a typical hypermethylome can be drawn .
in addition to cancer , very recently aberrant
dna methylation has been linked to premature senescence and aging
diseases such as hutchinson gilford progeria and werner syndrome , to neural plasticity and gabaergic signaling modulation , and to heart failure and atrial fibrillation through methylation
of the homeobox gene pitx2c .
moreover , dnmt1 and dnmt3a proteins have been found to be overexpressed
in rheumatoid arthritis and osteoarthritis .
dnmt inhibitors ( dnmti ) have been validated as useful tools
to
reactivate tumor - suppressor genes and to reprogram cancer cells toward
growth arrest and death .
two nucleoside analogue dnmti ( azacytidine and decitabine , chart 1 ) have been approved by the u.s .
fda for clinical
use against hematological malignancies , but despite their high efficacy ,
such drugs suffer from poor bioavailability , chemical instability ,
and toxic side effects . some non - nucleoside compounds
have been reported as dnmti ( chart 1 ) , but
they typically share low potency and/or low selectivity for dnmts ,
and their mechanism of inhibition is unknown . among non - nucleoside inhibitors ,
sgi-1027 ( 1 ) ( figure 1 ) , identified
among a series of quinoline - based
compounds developed as anticancer drugs , has attracted our attention
because of its high potency in both enzyme and cell assays . because the structure of 1 shows
four fragments ( 4-aminoquinoline + 4-aminobenzoic acid + 1,4-phenylenediamine
+ 2,4-diamino-6-methylpyrimidine ) linked in sequence with para / para
orientation , we prepared a series of regioisomers of 1 by shifting each fragment s linkage from the para to the
meta or ortho position ( figure 1 ) and obtained
compounds 29 ( figure 1 ) .
in addition , we prepared two related compounds ( 10 and 11 ) showing either a bis - quinoline or bis - pyrimidine
structure and two truncated compounds ( 12 and 13 ) lacking the
chemical
structures of sgi-1027 ( 1 ) and related analogues 213 described in this study . their ic50 values ( m ) from nanoscale hts against human dnmt1
are reported in the brackets .
compounds 19 were prepared by
coupling the 2- , 3- , or 4-(quinolin-4-ylamino)benzoic acid , 14a c , with the n-(2- , 3- , or 4-aminophenyl)-6-methylpyrimidine-2,4-diamine , 15a c , in the presence of benzotriazol-1-yl - oxytripyrrolidinophosphonium
hexafluorophosphate ( pybop ) and triethylamine in dry n , n - dimethylformamide as solvent ( scheme 1 ) . intermediate compounds 14a c were prepared by reaction between 4-chloroquinoline with
the appropriate ethyl 2- , 3- , or 4-aminobenzoate and 37% hydrochloric
acid in ethanol at 80 c .
the obtained ethyl benzoates , 16a c , underwent basic hydrolysis using
2 n potassium hydroxide to afford the corresponding acids , 14a c .
the same reaction conducted with 4-chloro-6-methylpyrimidin-2-amine
and the opportune 2- , 3- , or 4-nitroanilines in the presence of 37%
hydrochloric acid and ethanol at 80 c furnished the nitro - intermediates , 17a c , which were in turn reduced with
stannous chloride dihydrate and 37% hydrochloric acid in ethanol to
the corresponding anilines , 15a c .
chemical and physical data of final compounds 113 ( table s1 ) as
well as those
of intermediate compounds 1422 ( table s2 ) are listed in the supporting information .
reagents and conditions :
( a )
37% hcl , ch3ch2oh , 80 c , 2 h ; ( b ) 2 n
koh , ch3ch2oh ; ( c ) stannous chloride dihydrate ,
37% hcl , ch3ch2oh , 1 h , 80 c ; ( d ) ( c2h5)3n , pybop , anhydrous dmf , n2 atmosphere , room temperature , 1 h. reagents and conditions : ( a )
37% hcl , ch3ch2oh , 80 c , 2 h ; ( b ) stannous
chloride dihydrate , 37% hcl , ch3ch2oh , 80 c ,
1 h ; ( c ) ( c2h5)3n , pybop , anhydrous
dmf , n2 atmosphere , room temperature , 1 h ; ( d ) 2 n koh ,
ch3ch2oh .
bisquinoline 10 was obtained by treating 4-chloroquinoline
with 4-nitroaniline and , after reduction of the nitro group of the
resulting intermediate 18 to the corresponding aniline 19 , by coupling 19 with 16c ( scheme 2a ) .
treatment of 4-chloro-6-methylpyrimidin-2-amine
with ethyl 4-aminobenzoate afforded intermediate ester 20 , which was hydrolyzed to acid 21 and was then coupled
with 17c to furnish bispyrimidine 11 ( scheme 2b ) .
truncated compounds 12 and 13 were prepared by reaction of 16c with 4-phenylendiamine
( 12 ) or by reaction of 17c with 4-nitrobenzoic
acid and subsequent reduction of the nitro group of intermediate 22 to the corresponding amine ( 13 ) ( scheme 3 ) .
reagents and conditions : ( a )
( c2h5)3n , pybop , anhydrous dmf , n2 atmosphere , room temperature , 1 h ; ( b ) stannous chloride
dihydrate , 37% hcl , ch3ch2oh , 80 c , 1
h.
from a nanoscale prescreen performed
on 113 against human dnmt1 using
poly(di dc ) as substrate ,
compounds 2 , 4 , and 5 , obtained
by replacing either or both the para with the meta linkages in the
structure of 1 , emerged as highly efficient dnmt1 inhibitors ,
whereas the ortho regioisomers were less potent ( 3 and 68 ) or totally inactive ( 9 ) .
bisquinoline 10 displayed a similar potency as 1 against dnmt1 , whereas bispyrimidine 11 was
slightly less efficient , and truncated compounds 12 and 13 showed a severe drop in inhibition ( figure 1 ) . to perform a more wide and accurate inhibition assay
against dnmts , we tested the most potent compounds , 2 , 4 , 5 , 10 , and 11 , in comparison with 1 against human dnmt1 using a hemimethylated
substrate and against the human dnmt3a2/dnmt3l complex using an unmethylated
substrate ( figure 2 ) . under these assay conditions ,
meta / meta analogue 5 ( ic50 = 9 m ) displayed
a 4-fold higher activity than 1 against dnmt1 , whereas
the para / meta ( 2 ) and meta / para ( 4 ) analogues
were 1.5- and 7.6-fold less potent , respectively .
bisquinoline 10 showed the same dnmt1 inhibiting activity as 1 , whereas bispyrimidine 11 was 2-fold less potent . against dnmt3a2/dnmt3l ,
all of the inhibitors were more efficient
than against dnmt1 , and 5 was again the most potent ,
with ic50 = 2.8 m [ ic50 ( 1 ) = 10 m ] . among the remaining compounds , 11 and 2 were 2-fold , 10 was 3-fold , and 4 was 4-fold less potent than 1 ( figure 2 ) .
inhibitory activities of 1 , 2 , 4 , 5 , 10 , and 11 against
human dnmt1 ( hemimethylated substrate ) and the dnmt3a2/dnmt3l complex
( unmethylated substrate ) . to determine the mechanism of dnmt1 inhibition by compound 5 , we carried out competition experiments by varying the concentration
of either adomet or dna , and we used both the ic50 and
the velocity plot methods to analyze the data .
as shown in figure 3 , the ic50 analysis of 5 against the adomet concentration shows nearly constant ic50 values as the adomet concentration increases ( figure 3a , b ) , suggesting a noncompetitive inhibition .
differently , the ic50 of 5 increases
linearly with dna concentration , suggesting a dna - competitive behavior
( figure 3c , d ) .
these deformations have been described by copeland and horiuchi and are explained by potential nonspecific substrate inhibitor
interactions ( dna interactions ) , tight - binding , or a time - dependent
inhibitor .
competition studies performed
on structurally different compound 11 gave similar results
( figure s1 in the supporting
information ) .
competition experiments performed with compound 5 on
dnmt1 by varying adomet concentrations at a near - saturating dna concentration
( a , b ) or by varying dna concentrations at a near - saturating adomet
concentration ( c , d ) .
( b ) velocity plot against [ adomet ] for different concentrations
of compound 5 .
( d ) velocity
plot against [ dna ] for different concentrations of 5 .
the lines represent the nonlinear regressions with sigmoidal dose response .
on each graph ,
the mean of two independent experiments is represented
sem . to determine the specificity
of 1 , 2 , 4 , 5 , 10 , and 11 for
dnmts among other adomet - dependent enzymes
, we tested them against
prmt1 , a protein arginine methyltransferase , and g9a - like protein ( glp ) , a histone h3 lysine 9 methyltransferase . under the tested conditions
, the new derivatives showed very low
( if any ) prmt1- and glp - inhibiting activities , resulting in the tested compounds being more dnmt - selective than 1 , which displayed only 4- and 1.9-fold lower activities against prmt1
and glp , respectively , when compared with dnmt1 inhibition .
in contrast , 5 was 33- and 11-fold less potent against prmt1 and glp than
against dnmt1 ( table 1 ) .
the dnmt1 selectivity
( as the
prmt1 or glp / dnmt1 ic50 ratio ) for each compound is reported .
the errors in the determinations
of ic50 s are within 20% of their values . to delineate better the mechanism(s )
for the inhibitory potency
of 5 against dnmt1
in particular , compound 5 was docked in two different
dnmt1 structures available in the protein data bank ( pdb ) : dnmt1 ( residues
6001600 ) crystallized in complex with sinefungin ( pdb 3swr , hashimoto and cheng ,
unpublished data ) and dnmt1 ( residues 6461600 ) in complex
with both adohcy and a 19 bp dna duplex ( pdb 3pta ) .
these two dnmt1 structures share a similar overall 3d arrangement ,
with some conformational differences mainly in the dna - binding cxxc
domain region ( residues 646692 , figure
s2 in the supporting information ) .
the latter is adjacent to the methyltransferase domain , which
is the putative inhibitor binding site , and in principle its conformation
could influence the inhibitor binding .
therefore , we decided to dock 5 in both of the aforementioned structures by employing the
glide program of the schrdinger package .
docking results achieved on the dnmt1 structure alone
( unbound to dna ) revealed that in the lowest - energy binding conformation
( docking score 6.95 ) 5 should be able to span
between the adomet binding site and the cxxc region ( figure 4 ) .
indeed , changing one or both the para / meta linkages
( 1 , 2 , 4 , and 5 ) with ortho ones ( 3 and 69 ) by modifying the ligand shape from a stretched to a more
condensed one should prevent the ligand from spanning between the
two sites , explaining why the presence of ortho linkages is not productive
in terms of inhibitory potency .
as depicted in figure 4 , the 4-aminoquinoline fragment of 5 is embedded
in a lipophilic region normally occupied by the adomet adenine ring ,
establishing hydrophobic contacts with i1167 , m1169 , p1225 , and i1247
as well as a t - shaped interaction with f1145 . in this position ,
substitution
of the quinoline ring with a smaller pyrimidine one ( 11 ) or with a hydrogen ( 13 ) would cause a partial loss
of the interactions within the aforementioned cleft , thus explaining
the drop in inhibitory potency .
also , the attached central fragment
( 3-aminobenzoic acid + 1,3-phenylenediamine ) of 5 is
embedded in a region in which cation and
interactions are established with r1574 and w1170 , respectively .
the
intrinsic rigidity of this fragment allows to project the 2,4-diamino-6-methylpyrimidine
terminal at the crevice between the cxxc and methyltransferase domains .
in this position , the terminal hydrophilic head of 5 forms
three h - bonds with the m694 and p692 backbone co and with the d1571
side chain .
given the critical role of the cxxc region for the dnmt1
enzymatic activity , it might be speculated
that favorable ligand interactions with this region should also be
critical for inhibitory potency , thus explaining why replacement of
the 2,4-diamino-6-methylpyrimidine ( 5 ) fragment with
a quinoline ( 10 ) one or with an hydrogen ( 12 ) does not enhance dnmt1 inhibition
. predicted binding mode of 5 in the dnmt1 structure
unbound to dna ( pdb 3swr ) .
compound 5 is depicted as orange sticks , and the
enzyme catalytic and cxxc domains are depicted as cyan ( right side )
and brown ( left side ) ribbons and sticks , respectively .
interestingly , the same calculations did not succeed in suggesting
a well - defined binding pose for compound 5 in the enzyme / dna
structure .
indeed , in the dnmt1/dna complex , when merging the coordinates
of 5 achieved in the absence of dna , it seems clear that
the subtle rearrangements of the cxxc domain induced by the presence
of dna would sterically hamper 5 from spanning from the
adomet interaction site to the crevice between the cxxc and methyltransferase
domains ( figure s4b in the supporting information ) .
results of analogous
docking studies performed on 1 are reported in the supporting information ( figures
s3 and s4a ) .
almost the same binding orientations were obtained
either in the free dnmt1 or in the dnmt1/dna structure , suggesting
that , whereas 5 can in principle be recognized by the
dna - unbound enzyme conformation ( i.e. , in a dna - competitive binding
mode ) , 1 should be able to bind dnmt1 independently from
the presence of dna .
competition experiments also outline that
the inhibitory potency
of 5 is not affected by increasing concentrations of
the adomet cofactor .
these data might suggest that either the ligand
is also able to adapt to binding sites that are different from that
of the cofactor or the same compound can also bind the enzyme / cofactor
complex . in this respect , the dnmt1 structures ( pdb 3pta and 3swr ) were also searched
for different binding sites with the sitemap software available within
the maestro suite .
results of these predictions
demonstrate that the most probable site is the one occupied by the
cofactor , whereas four additional less probable sites could exist
( figure s5a ) . nevertheless , when glide
was employed to predict a possible binding position of 5 in these enzyme regions , weak binding affinities were predicted
( docking scores below 5.0 ) , mainly because the selected clefts , being
rather shallow and solvent - exposed , are less prone to provide efficient
ligand interactions .
this would suggest that the highest affinity
dnmt1 binding site is the cofactor one .
we then attempted to dock 5 in the dnmt1/adohcy ( mimicking adomet substrate analogue )
complex to probe whether the ligand is still able to bind this complex .
indeed , these studies suggest that in the presence of the cofactor
the ligand would still positively interact with the enzyme complex ,
adopting a conformation ( docking score 6.76 , figure s5b ) in which the ligand is sandwiched between the
substrate and part of the enzyme cxxc domain region ( residues 646650 ) .
this might rationalize why increasing adomet concentrations do not
abrogate the ligand inhibition efficiency . to study the effects
of these dnmti in a cellular context , we tested 1 , 2 , 4 , 5 , 10 , and 11 in a panel of cancer cells ( histiocytic lymphoma ,
u-937 ; breast cancer , mda - mb-231 ; burkitt s lymphoma , raji ;
and prostate cancer , pc-3 ) .
trypan blue exclusion assays were carried
out to determine their effects on cell proliferation and viability .
the effect of the tested compounds in peripheral blood mononuclear
cells ( pbmcs ) was also determined to assess for differential toxicity .
in full agreement with their dnmt - inhibition potency
, compounds 1 , 2 , and 5 displayed the highest
antiproliferative effects and the strongest cell - death induction in
all of the cancer cells tested ( figure 5a d ) .
compounds 4 , 10 , and 11 showed
both lower activity and cytotoxicity in these assays ( figure s6 in the supporting
information ) .
compounds 1 and 5 showed
comparable potency against tumor cells , but 5 was the
less toxic in pbmcs ( figure 5e , f ) .
nuclear
morphological changes were further observed by fluorescence microscopy
after hoechst and propidium iodide ( pi ) staining in both u-937 and
raji cells treated with increasing doses of 5 to assess
the levels of necrosis and apoptosis induced by the compound ( figure 5 g ) . in u-937 cells , 5 displayed massive
apoptosis at 10 m followed by necrosis at 25 m , whereas
in raji cells , 5 mainly led to necrosis at 25 m
without triggering any apoptotic response at lower concentrations .
( a e ) antiproliferative
effects ( left ) and cell - death induction ( right ) of 1 , 2 , and 5 on u-937 ( a ) , raji ( b ) , mda - mb-231 ( c ) ,
pc-3 ( d ) , and pbm ( e ) cells .
( f ) ic50 values of cell viability
relative to the above cells treated with 1 , 2 , and 5 for 48 h. ( g ) nuclear - morphology analysis after
hoechst and pi staining in u-937 and raji cells treated with increasing
doses of 5 for 72 h. data represent the mean ( sd )
of at least three independent experiments .
dna methylation also plays a key role
in cancer stem cells : a comparison of the epigenomes of normal and
cancer stem cells and pluripotent and differentiated states revealed
a clear link between dnmts and transcribed loci . in cancer stem cells , the effect of dnmt inhibitors
azacytidine has been shown to reactivate sall4 expression and transcription in acute promyelocytic
leukemia nb4 cells as well as in colorectal
cancers through dnmt inhibition . in idh1
mutant glioma cells , decitabine induced a dramatic loss of stemlike
properties and efficient adoption of markers of differentiation as
well as decreased replicative potential and tumor growth in vivo . to date , no non - nucleoside dnmti has been tested
in a cancer stem cell context .
we tested compounds 2 and 5 at different dosages in mouse mbscs , a cancer stem cell
line expressing high levels of dnmts ( figure s7 in the supporting information ) , to determine
their effects on cell proliferation and differentiation . in these
assays ,
compound 5 arrested the mbsc clonogenic activity ,
induced cell adhesion and differentiation , and impaired significantly
the mbsc growth rate , evaluated by both quantifying pcna levels and
mtt assay ( figure 6a , b ) , whereas 2 was less effective . in mbscs differentiation assays , evaluated by
both iii - tubulin rt - pcr and phase - contrast images ( figure 6c ,
d ) , 2 showed the highest differentiation
effect after treatment with lower doses ( 10 m ) , whereas 5 required higher concentrations ( 50 m ) to reach significance .
to the best of our knowledge , 2 and 5
are
the first examples of non - nucleoside dnmti tested in cancer stem cells
( cscs ) .
( a ) pcna
mrna levels and ( b ) mtt assay of mbscs after 48 h of 2 and 5 treatment or dmso as control ( ctr ) . * p < 0.05 versus untreated cells ( ctr ) .
( c ) mrna levels
of iii - tubulin ( iiitub ) in 2- and 5-treated mbscs for 48 h. dmso was used as control.*p < 0.05 versus untreated cells ( ctr ) .
( d ) representative
bright - field images of mbscs after 2 or 5 treatment ( 48 h , 10 m ) or dmso as control .
through chemical manipulation
applied on the structure of 1 , we identified compound 5 , a novel non - nucleoside
dnmti more potent than 1 and more selective toward other
adomet - dependent protein methyltransferases ( prmt1 and glp ) . tested
on a panel of cancer cells ( leukemia , u937 ; breast cancer , mda - mb-231 ;
burkitt s lymphoma , raji ; and prostate cancer , pc-3 ) as well
as on pbmcs , compound 5 displayed comparable activity
as 1 and with less toxicity .
in mbscs at 10 m , 5 significantly blocked proliferation but required higher
doses ( 50 m ) to induce differentiation , whereas related compound 2 , which was less potent as an antiproliferative agent , showed
high differentiating activity . the anticancer activity displayed by 2 and 5 in the tested cancer cells , including
in cancer stem cells , suggests their use as potent and selective non - nucleoside
dnmti for cancer therapy .
melting points were determined on a buchi
530 melting - point apparatus and are uncorrected .
h nmr
and c nmr spectra were recorded at 400 mhz on a bruker
ac 400 spectrometer ; chemical shifts are reported in ( ppm )
units relative to the internal reference , tetramethylsilane ( me4si ) .
eims spectra were recorded with a fisons trio 1000 spectrometer ;
only molecular ions ( m ) and base peaks are given .
all
compounds were routinely checked by tlc , h nmr , and c nmr spectra .
tlc was performed on aluminum - backed silica
gel plates ( merck dc , alufolien kieselgel 60 f254 ) with spots visualized
by uv light .
all solvents were reagent grade and , when necessary ,
were purified and dried by standard methods .
concentration of solutions
after reactions and extractions involved the use of a rotary evaporator
operating at reduced pressure of ca .
elemental analysis was used to
determine the purity of the described compounds , which was found to
be > 95% . analytical results are within 0.40% of the theoretical
values .
all chemicals were purchased from aldrich chimica , milan ( italy ) ,
or from alfa aesar , milan ( italy ) , and were of the highest purity .
4-chloroquinoline ( 6.05 mmol , 0.99 g ) , ethyl
3-aminobenzoate ( 6.05 mmol , 1 g ) , and a catalytic amount ( 4 drops )
of 37% hydrochloric acid were refluxed for 2 h. the reaction was allowed
to cool to room temperature , and the precipitated solid was filtered
off , washed with water ( 3 5 ml ) , and recrystallized by methanol
to afford pure 16b as a hydrochloride salt .
h nmr ( dmso - d6 , 400 mhz ) 1.34
( t , 3h , j = 7.2 hz , cooch2ch3 ) , 4.36 ( q , 2h , j = 7.2 hz ,
cooch2ch3 ) , 6.88 ( d ,
1h , j = 5.2 hz , quinoline proton ) , 7.74 ( m , 2h , benzene
protons ) , 7.84 ( t , 1h , j = 7.4 hz , benzene proton ) ,
8.00 ( d , 1h , j = 8.2 hz , quinoline proton ) , 8.068.12
( m , 3h , quinoline and benzene protons ) , 8.56 ( d , 1h , j = 8.2 hz , quinoline proton ) , 8.81 ( d , 1h , j = 5.2
hz , quinoline proton ) , 11.08 ( bs , 1h , nh ) ,
14.68 ( bs , 1h , h ) .
c nmr
( dmso - d6 , 100 mhz ) 14.1 , 60.9 ,
112.8 , 114.2 , 119.9 , 121.6 , 122.1 , 124.2 , 125.7 , 129.2 , 129.6 , 130.9 ,
133.7 , 138.7 , 142.3 , 149.7 , 151.6 , 165.9 .
ms ( ei ) m / z [ m ] calcd for c18h16n2o2 , 292.1212 ; found , 292.1218 .
a solution of ethyl 3-(quinolin-4-ylamino)benzoate 16b ( 1.71 mmol , 0.5 g ) and 2 n koh ( 6.84 mmol , 0.38 g ) in
ethanol ( 15 ml ) was stirred overnight at room temperature .
then , the
solvent was evaporated , and 2 n hcl was slowly added until ph 5.0
was obtained .
the colorless solid was filtered , washed with water
( 3 5 ml ) , and recrystallized from methanol to obtain pure 14b .
h nmr ( dmso - d6 , 400 mhz ) 7.00 ( d , 1h , j = 5.2 hz , quinoline
proton ) , 7.517.58 ( m , 2h , quinoline and benzene protons ) ,
7.63 ( d , 1h , benzene proton ) , 7.687.75 ( m , 2h , quinoline and
benzene protons ) , 7.907.93 ( m , 2h , quinoline and benzene protons ) ,
8.39 ( d , 1h , j = 8.0 hz , quinoline proton ) , 8.51
( d , 1h , j = 5.2 hz , quinoline proton ) , 9.17 ( bs ,
1h , nh ) , 12.0 ( bs , 1h , cooh ) . c nmr
( dmso - d6 , 100 mhz ) 112.8 , 119.5
( 2c ) , 120.2 , 121.6 , 124.2 , 125.7 , 129.2 , 129.6 , 131.1 ( 2c ) , 138.7 ,
149.7 , 151.1 , 151.6 , 169.3 . ms ( ei ) m / z [ m ] calcd for c16h12n2o2 , 264.0899 ; found , 264.0902 .
to a cooled solution of 6-methyl - n-(3-nitrophenyl)pyrimidine-2,4-diamine 17b ( 1.63 mmol , 0.5 g ) and stannous chloride dihydrate ( 8.15
mmol , 1.84 g ) in ethanol ( 10 ml ) was slowly added a 37% hydrochloric
acid solution ( 0.3 ml ) at 0 c .
the reaction was then kept at
80 c for 1 h. afterward , the reaction was quenched at room temperature
by a 2 n sodium carbonate solution ( 20 ml ) , and the mixture was extracted
with ethyl acetate ( 3 30 ml ) , washed with brine ( 3 30
ml ) , dried with anhydrous sodium sulfate , filtered , and concentrated
under reduced pressure .
h nmr ( dmso - d6 , 400 mhz ) 2.06 ( s , 3h , ch3 ) , 4.92 ( bs , 2h , nh2-aniline ) , 5.87 ( s , 1h , pyrimidine proton ) , 5.97 ( bs ,
2h , -nh2-pyrimidine ) , 6.19 ( d , 1h , j = 8.0 hz , aniline proton ) , 6.80 ( d , 1h , j = 8.0 hz , aniline proton ) , 6.876.91 ( m , 2h , aniline protons ) ,
8.64 ( bs , 1h , nh ) .
c nmr ( dmso - d6 , 100 mhz ) 23.9 , 93.8 , 102.7 , 105.0 ,
107.8 , 130.3 , 143.2 , 147.8 , 163.1 , 164.5 , 170.2 .
ms ( ei ) m / z [ m ] calcd for c11h13n5 , 215.1171 ; found , 215.1167 .
triethylamine ( 3.04 mmol , 0.42 ml ) and benzotriazol-1-yl - oxytripyrrolidinophosphonium
hexafluorophosphate ( pybop ) ( 0.91 mmol , 0.47 g ) were added to a solution
of 3-(quinolin-4-ylamino)benzoic acid 14b ( 0.76 mmol ,
0.2 g ) in anhydrous n , n - dimethylformamide
( 5 ml ) under a nitrogen atmosphere .
the resulting mixture was stirred
for 30 min at room temperature followed by the addition of n-(3-aminophenyl)-6-methylpyrimidine-2,4-diamine 15b ( 0.76 mmol , 0.16 g ) under a nitrogen atmosphere , and the
reaction was stirred overnight .
the reaction was quenched with water
( 50 ml ) and extracted with ethyl acetate ( 3 30 ml ) .
the combined
organic extracts were dried , and the residue obtained upon evaporation
of solvent was purified by column chromatography ( sio2 eluting
with ethyl acetate / methanol 10:1 ) to provide pure 5 .
h nmr ( dmso - d6 , 400 mhz )
2.10 ( s , 3h , ch3 ) , 5.94 ( s , 1h ,
pyrimidine proton ) , 6.07 ( bs , 2h , nh2-pyrimidine ) , 7.06 ( d , 1h , j = 4.8 hz , quinoline
proton ) , 7.26 ( t , 1h , j = 8.0 hz , benzene proton ) ,
7.35 ( d , 1h , j = 7.6 hz , quinoline proton ) , 7.557.61
( m , 4h , benzene and quinoline protons ) , 7.727.75 ( m , 2h , benzene
protons ) , 7.91 ( d , 1h , j = 8.0 hz , quinoline proton ) ,
7.95 ( s , 1h , benzene proton ) , 8.03 ( s , 1h , benzene proton ) , 8.42 ( d ,
1h , j = 8.4 hz , quinoline proton ) , 8.52 ( d , 1h , j = 5.6 hz , quinoline proton ) , 9.04 ( bs , 1h , nh - pyrimidine ) , 9.16 ( bs , 1h , nh - quinoline ) , 10.18 ( s , 1h , conh ) .
c nmr ( dmso - d6 , 100 mhz )
23.9 , 93.8 , 108.0 , 111.6 , 111.8 , 112.8 , 113.4 , 117.5 , 121.2 , 121.6 ,
124.2 , 125.7 , 129.2 , 129.6 , 129.7 , 133.9 , 135.0 , 136.7 , 138.7 , 142.5 ,
142.6 , 149.7 , 151.6 , 163.1 , 164.5 , 164.7 , 170.2 . ms ( ei ) m / z [ m ] calcd for c27h23n7o , 461.1964 ; found , 461.1969 .
h nmr ( dmso - d6 , 400 mhz ) 2.10 ( s , 3h , ch3 ) , 5.88 ( s , 1h , pyrimidine proton ) , 6.14 ( bs ,
2h , nh2-pyrimidine ) , 7.21 ( d ,
1h , j = 5.4 hz , quinoline proton ) , 7.487.81
( m , 8h , benzene and quinoline protons ) , 7.938.03 ( m , 3h , benzene
and quinoline protons ) , 8.42 ( d , 1h , j = 8.4 hz ,
quinoline proton ) , 8.52 ( d , 1h , j = 5.6 hz , quinoline
proton ) , 8.97 ( bs , 1h , nh - pyrimidine ) , 9.25
( bs , 1h , nh - quinoline ) , 10.06 ( bs , 1h , conh ) .
c nmr ( dmso - d6 , 100 mhz ) 23.9 , 93.8 , 111.4 ( 2c ) , 112.8 , 117.7 ( 2c ) ,
121.6 , 122.4 ( 2c ) , 124.2 ( 2c ) , 125.7 , 127.9 , 129.2 , 129.6 , 130.2 ( 2c ) ,
136.5 , 138.7 , 149.3 , 149.7 , 151.6 , 163.1 , 164.5 , 164.7 , 170.2 .
ms
( ei ) m / z [ m ] calcd for
c27h23n7o , 461.1964 ; found , 461.1969 .
h nmr ( dmso - d6 , 400 mhz ) 2.10 ( s , 3h , ch3 ) , 5.95 ( s , 1h , pyrimidine proton ) , 6.07 ( bs , 2h , nh2-pyrimidine ) , 7.217.25 ( m , 2h , benzene
and quinoline protons ) , 7.37 ( d , 1h , j = 8.2 hz ,
benzene proton ) , 7.507.61 ( m , 4h , benzene and quinoline protons ) ,
7.75 ( t , 1h , j = 7.4 hz , quinoline proton ) , 7.938.03
( m , 4h , benzene and quinoline protons ) , 8.42 ( d , 1h , j = 8.4 hz , quinoline proton ) , 8.52 ( d , 1h , j = 5.6
hz , quinoline proton ) , 9.03 ( bs , 1h , nh - pyrimidine ) ,
9.25 ( bs , 1h , nh - quinoline ) , 10.05 ( bs , 1h ,
conh ) .
c nmr ( dmso - d6 , 100 mhz ) 23.9 , 93.8 , 108.0 , 111.4
( 2c ) , 111.6 , 112.8 , 113.4 , 121.6 , 124.2 ( 2c ) , 125.7 , 129.2 , 129.6 ,
129.7 , 130.2 ( 2c ) , 136.7 , 138.7 , 142.6 , 149.3 , 149.7 , 151.6 , 163.1 ,
164.5 , 164.7 , 170.2 .
ms ( ei ) m / z [ m ] calcd for c27h23n7o , 461.1964 ; found , 461.1969 .
h nmr ( dmso - d6 , 400 mhz ) 2.09 ( s , 3h , ch3 ) , 5.88 ( s , 1h , pyrimidine proton ) , 6.31 ( bs , 2h , nh2-pyrimidine ) , 7.187.22 ( m , 2h , benzene
and quinoline protons ) , 7.377.50 ( m , 4h ) , 7.587.65
( m , 2h benzene and quinoline protons ) , 7.727.77 ( m , 2h , benzene
protons ) , 7.947.96 ( m , 2h , quinoline protons ) , 8.37 ( d , 1h , j = 7.6 hz , quinoline proton ) , 8.55 ( bs , 1h , nh - pyrimidine ) , 8.58 ( d , 1h , j = 4.8 hz ,
quinoline proton ) , 9.25 ( bs , 1h , nh - quinoline ) ,
10.15 ( bs , 1h , conh ) .
c nmr ( dmso - d6 , 100 mhz ) 23.9 ,
93.8 , 111.4 ( 2c ) , 112.8 , 118.9 , 121.6 , 122.8 , 124.2 ( 2c ) , 125.5 , 125.7 ,
126.1 , 129.2 , 129.6 , 130.2 ( 2c ) , 137.9 , 138.7 , 147.6 , 149.3 , 149.7 ,
151.6 , 163.1 , 164.5 , 170.2 , 172.5 .
ms ( ei ) m / z [ m ] calcd for c27h23n7o , 461.1964 ; found , 461.1969 .
h nmr ( dmso - d6 , 400 mhz ) 2.08 ( s , 3h , ch3 ) , 5.87 ( s , 1h , pyrimidine proton ) , 6.10 ( bs , 2h , nh2-pyrimidine ) , 7.06 ( d , 1h , j = 5.6 hz , quinoline proton ) , 7.547.74 ( m , 9h , benzene and
quinoline protons ) , 7.90 ( d , 1h , j = 8.4 hz quinoline
proton ) , 8.01 ( s , 1h , benzene proton ) , 8.46 ( d , 1h , j = 8.4 hz , quinoline proton ) , 8.51 ( d , 1h , j = 4.0
hz , quinoline proton ) , 9.01 ( bs , 1h , nh - pyrimidine ) ,
9.28 ( bs , 1h , nh - quinoline ) , 10.30 ( s , 1h ,
conh ) .
c nmr ( dmso - d6 , 100 mhz ) 23.9 , 93.8 , 111.8 , 112.8 ,
117.5 , 117.7 ( 2c ) , 121.2 , 121.6 , 122.4 ( 2c ) , 124.2 , 125.7 , 127.9 ,
129.2 , 129.6 , 133.9 , 135.0 , 136.5 , 138.7 , 142.5 , 149.7 , 151.6 , 163.1 ,
164.5 , 164.7 , 170.2 .
ms ( ei ) m / z [ m ] calcd for c27h23n7o , 461.1964 ; found , 461.1969 .
h nmr ( dmso - d6 , 400 mhz ) 2.05 ( s , 3h , ch3 ) , 5.86 ( s , 1h , pyrimidine proton ) , 6.23 ( bs , 2h , nh2-pyrimidine ) , 7.04 ( d , 1h , j = 5.6 hz , quinoline proton ) , 7.20 ( m , 2h , benzene and quinoline
protons ) , 7.517.74 ( m , 7h , benzene and quinoline protons ) ,
7.907.92 ( m , 2h , benzene and quinoline protons ) , 8.40 ( d ,
1h , j = 8.4 hz , quinoline proton ) , 8.47 ( bs , 1h ,
nh - pyrimidine ) , 8.51 ( d , 1h , j = 5.4 quinoline proton ) , 9.11 ( bs , 1h , nh - quinoline ) , 10.19 ( bs , 1h , conh ) .
c nmr ( dmso - d6 , 100 mhz )
23.9 , 93.8 , 111.8 , 112.8 , 117.5 , 118.9 , 121.2 , 121.6 , 122.8 , 124.2 ,
125.5 , 125.7 , 126.1 , 129.2 , 129.6 , 133.9 , 135.0 , 137.9 , 138.7 , 142.5 ,
147.6 , 149.7 , 151.6 , 163.1 , 164.5 , 164.7 , 170.2 .
ms ( ei ) m / z [ m ] calcd for c27h23n7o , 461.1964 ; found , 461.1969 .
h nmr ( dmso - d6 , 400 mhz ) 2.07 ( s , 3h , ch3 ) , 5.85 ( s , 1h , pyrimidine proton ) , 6.08 ( bs , 2h , nh2-pyrimidine ) , 7.15 ( d , 1h , j = 5.4 hz , quinoline proton ) , 7.26
( t , 1h , j = 6.8
hz , quinoline proton ) , 7.487.75 ( m , 8h , benzene and quinoline
protons ) , 7.92 ( m , 2h , quinoline protons ) , 8.16 ( d , 1h , j = 8.0 hz , quinoline proton ) , 8.55 ( d , 1h , j = 4.0
hz , quinoline proton ) , 8.95 ( bs,1h , nh - pyrimidine ) ,
10.26 ( bs , 1h , nh- quinoline ) , 10.41 ( bs ,
1h , conh ) .
c nmr ( dmso - d6 , 100 mhz ) 23.9 , 93.8 , 112.8 , 116.4 ,
117.7 ( 2c ) , 117.9 , 118.8 , 121.6 , 122.4 ( 2c ) , 124.2 , 125.7 , 127.9 ,
128.3 , 129.2 , 129.6 , 132.9 , 136.5 , 138.7 , 149.7 , 151.6 , 151.9 , 163.1 ,
164.5 , 167.5 , 170.2 .
ms ( ei ) m / z [ m ] calcd for c27h23n7o , 461.1964 ; found , 461.1969 .
h nmr ( dmso - d6 , 400 mhz ) 2.08 ( s , 3h , ch3 ) , 5.91 ( s , 1h , pyrimidine proton ) , 6.05 ( bs , 2h , nh2-pyrimidine ) , 7.127.28 ( m , 3h , benzene
and quinoline protons ) , 7.617.73 ( m , 3h , benzene and quinoline
protons ) , 7.717.76 ( m , 3h , benzene protons ) , 7.917.96
( m , 2h , benzene and quinoline protons ) , 8.16 ( d , 1h , j = 8.0 hz , quinoline proton ) , 8.55 ( d , 1h , j = 4.8
hz , quinoline proton ) , 9.02 ( bs , 1h , nh - pyrimidine ) ,
10.10 ( bs , 1h , nh - quinoline ) , 10.40 ( bs ,
1h , conh ) .
c nmr ( dmso - d6 , 100 mhz ) 23.9 , 93.8 , 108.0 , 111.6 ,
112.8 , 113.4 , 116.4 , 117.9 , 118.8 , 121.6 , 124.2 , 125.7 , 128.3 , 129.2 ,
129.6 , 129.7 , 132.9 , 136.7 , 138.7 , 142.6 , 149.7 , 151.6 , 151.9 , 163.1 ,
164.5 , 167.5 , 170.2 .
ms ( ei ) m / z [ m ] calcd for c27h23n7o , 461.1964 ; found , 461.1969 .
h nmr ( dmso - d6 , 400 mhz ) 2.01 ( s , 3h , ch3 ) , 5.81 ( s , 1h , pyrimidine proton ) , 6.27 ( s , 2h , nh2-pyrimidine ) , 7.127.24 ( m , 4h , benzene
and quinoline protons ) , 7.48 ( d , 1h , j = 7.6 hz ,
benzene proton ) , 7.547.61 ( m , 3h , benzene protons ) , 7.717.76
( m , 2h , benzene and quinoline protons ) , 7.927.97 ( m , 2h , benzene
and quinoline protons ) , 8.08 ( d , 1h , j = 8.8 hz ,
quinoline protons ) , 8.57 ( m , 2h , quinoline and nh - pyrimidine protons ) , 10.44 ( bs , 1h , nh - quinoline ) ,
10.57 ( bs , 1h , conh ) .
c nmr ( dmso - d6 , 100 mhz ) 23.9 ,
93.8 , 112.8 , 116.4 , 117.9 , 118.8 , 118.9 , 121.6 , 122.8 , 124.2 , 125.5 ,
125.7 , 126.1 , 128.3 , 129.2 , 129.6 , 132.9 , 137.9 , 138.7 , 147.6 , 149.7 ,
151.6 , 151.9 , 163.1 , 164.5 , 167.5 , 170.2 .
ms ( ei ) m / z [ m ] calcd for c27h23n7o , 461.1964 ; found , 461.1969 .
h nmr ( dmso - d6 , 400 mhz ) 6.83 ( d , 1h , j =
6.0 hz , quinoline proton ) , 7.20 ( d , 1h , j = 4.8 hz ,
quinoline proton ) , 7.42 ( d , 2h , j = 8.8 hz , benzene
protons ) , 7.53 ( d , 2h , j = 8.4 hz , benzene protons ) ,
7.607.68 ( m , 2h , quinoline protons ) , 7.79 ( t , 1h , j = 7.2 hz , quinoline proton ) , 7.83 ( t , 1h , j = 7.2 hz , quinoline proton ) , 7.947.97 ( m , 4h , benzene and
quinoline protons ) , 8.07 ( d , 2h , j = 7.6 hz , benzene
protons ) , 8.458.49 ( m , 2h , quinoline protons ) , 8.578.61
( m , 2h , quinoline protons ) , 9.49 ( bs , 1h , nh - quinoline ) , 9.82 ( bs , 1h , nh - quinoline ) ,
10.35 ( bs , 1h , conh ) .
c nmr ( dmso - d6 , 100 mhz ) 111.4
( 2c ) , 112.8 ( 2c ) , 117.7 ( 2c ) , 121.6 ( 2c ) , 122.4 ( 2c ) , 124.2 ( 3c ) ,
125.7 ( 2c ) , 127.9 , 129.2 ( 2c ) , 129.6 ( 2c ) , 130.2 ( 2c ) , 138.7 ( 2c ) ,
141.5 , 149.3 , 149.7 ( 2c ) , 151.6 ( 2c ) , 164.7 .
ms ( ei ) m / z [ m ] calcd for c31h23n5o , 481.1903 ; found , 481.1908 .
h nmr ( dmso - d6 , 400 mhz ) 2.09 ( s , 3h , ch3 ) , 2.13 ( s , 3h , ch3 ) , 5.86 ( s , 1h , pyrimidine proton ) , 5.95 ( s , 1h , pyrimidine proton ) ,
6.10 ( bs , 2h , nh2-pyrimidine ) ,
6.26 ( bs , 2h , nh2-pyrimidine ) ,
7.65 ( m , 4h , benzene protons ) , 7.89 ( m , 4h , benzene protons ) , 8.91
( bs , 1h , nh - pyrimidine ) , 9.32 ( bs , 1h , nh - pyrimidine ) , 9.96 ( bs , 1h , conh ) .
c nmr ( dmso - d6 , 100 mhz ) 23.9 ( 2c ) , 93.8 ( 2c ) , 111.4 ( 2c ) , 117.7 ( 2c ) ,
122.4 ( 2c ) , 124.2 , 127.9 , 130.2 ( 2c ) , 136.5 , 144.3 , 163.1 ( 2c ) , 164.5 ,
164.7 , 167.0 , 167.7 , 170.2 . ms ( ei ) m / z [ m ] calcd for c23h23n9o , 441.2026 ; found , 441.2023 .
h nmr ( dmso - d6 , 400 mhz ) 4.91 ( bs , 2h , nh2-benzene ) , 6.56 ( d , 2h , j = 7.6 hz ,
benzene protons ) , 7.18 ( d , 1h , j = 4.8 hz , quinoline
proton ) , 7.38 ( d , 2h , j = 8.4 hz , benzene protons ) ,
7.46 ( d , 2h , j = 8.4 hz , benzene protons ) , 7.60 ( t ,
1h , j = 7.2 hz , quinoline proton ) , 7.74 ( t , 1h , j = 7.2 hz , quinoline proton ) , 7.93 ( d , 1h , j = 8.0 hz , quinoline proton ) , 7.97 ( d , 2h , j = 8.4
hz , benzene protons ) , 8.38 ( d , 1h , j = 8.4 hz , quinoline
proton ) , 8.57 ( d , 1h , j = 4.4 hz , quinoline proton ) ,
9.20 ( bs , 1h , nh - quinoline ) , 9.79 ( bs , 1h ,
conh ) .
c nmr ( dmso - d6 , 100 mhz ) 111.4 ( 2c ) , 112.8 , 116.5
( 2c ) , 121.6 , 122.4 ( 2c ) , 124.2 ( 2c ) , 125.7 , 127.9 , 129.2 , 129.6 , 130.2
( 2c ) , 138.7 , 144.0 , 149.3 , 149.7 , 151.6 , 164.7 . ms ( ei ) m / z [ m ] calcd for c22h18n4o , 354.1481 ; found , 354.1486 .
h nmr ( dmso - d6 , 400 mhz ) 2.06 ( s , 3h , ch3 ) , 5.71 ( bs , 2h , nh2-benzene ) , 5.85 ( s , 1h , pyrimidine proton ) , 6.08 ( bs , 2h , nh2-pyrimidine ) , 6.60 ( d , 2h , j = 8.4 hz , benzene protons ) , 7.597.64 ( m , 4h , benzene protons ) ,
7.71 ( d , 2h , j = 8.4 hz , benzene protons ) , 8.88 ( bs ,
1h , nh - pyrimidine ) , 9.66 ( bs , 1h , conh ) .
c nmr ( dmso - d6 , 100 mhz ) 23.9 , 93.8 , 114.3 ( 2c ) , 117.7 ( 2c ) , 122.4
( 2c ) , 124.2 , 127.9 , 130.2 ( 2c ) , 136.5 , 151.8 , 163.1 , 164.5 , 164.7 ,
170.2 .
ms ( ei ) m / z [ m ] calcd for c18h18n6o , 334.1542 ;
found , 334.1545 .
compounds 113 were
tested in 10-dose ic50 mode with 2-fold serial dilutions
at a starting concentration of
500 m against human dnmt1 using poly(di dc ) ( 0.001 mg / ml )
as a substrate in the presence of adomet ( 1 m ) as a cofactor .
control compounds , adohcy ( s-(5-adenosyl)-l - homocysteine )
and sinefungin , were tested in 10-dose ic50 mode with 3-fold
serial dilutions starting at 100 m .
the expression and purification
of human dnmt1 with an n - terminal deletion of 600 residues ( residues
6011600 ) and the human dnmt3a2/dnmt3l complex have been described .
recombinant rat prmt1 and the human g9a - like protein ( glp ) c - terminal fragment containing
both the ankyrin repeats and catalytic set domain ( residues 7341235 ;
pxc758 ) were purified as described . for dnmt1 , methyl transfer activity
inhibition assays were performed in 20 l reactions containing
4.6 mm [ methyl - h]-adomet ( 10.0 ci / mmol ; perkinelmer ) ,
1.0 mm dna oligonucleotides , 0.2 m dnmt1 , 1 mm edta , and 50
mm tris - hcl , ph 7.5 .
enzymes were preincubated with adomet and various
concentrations of inhibitors for 5 min at 37 c before the addition
of substrate dna . after a 15 min incubation
, the reactions were terminated
by the addition of 1% sds and 1 mg / ml of protease k and heating at
50 c for 15 min .
the reaction mixtures were spotted on de81
paper circles ( whatman ) , washed with 5 ml of cold 0.2 m nh4hco3 ( twice ) , 5 ml of deionized water ( twice ) , and 5 ml
of ethanol ( once ) .
all curves were fit individually
using origin 7.5 software ( originlab ) . for the dnmt3a2/3l complex
,
the inhibition assays were performed 20 l reactions containing
4.6 mm [ methyl - h]-adomet , 1.0 mm dna oligonucleotides ,
0.3 m enzyme , 0.5 mm tris(2-carboxyethyl)phosphine ( tcep ) ,
2.5% ( v / v ) glycerol , and 50 mm tris - hcl , ph 7.5 .
the dna substrates
were 28 bp and contained two cpg sites : 5-aca gta cgt caa gat ctt gacgta ctg t-3 and the complementary strand .
for histone methylation
inhibitions , the assays were performed in 20 l reactions containing
4.6 mm [ methyl - h]-adomet , 50 g / ml histone from
calf thymus ( sigma ) , 12 g / ml ( 0.3 m ) prmt1 or 10 g / ml
( 0.17 m ) glp , 100 mm kcl , 5 mm dithiothreitol ( dtt ) , and 50
mm tris - hcl , ph 8.5 .
enzymes were preincubated with adomet and various
concentrations of inhibitors for 5 min at 37 c ( for prmt1 ) or
30 c ( for glp ) before the addition of histone substrates .
after
incubation ( 6.5 min for prmt1 or 5 min for glp ) , the reactions were
terminated by the addition of 20% trichloroacetic acid ( tca , fisher
scientific ) .
the reaction mixtures were spotted on gf / a paper circles
( whatman ) and washed three times with 3 ml of 10% tca and once with
3 ml of ethanol .
briefly , the reaction was started by the addition of 94.5 nm dnmt1
to a mix containing the tested compound ( up to 1% dmso ) , an adomet/[methyl - h]-adomet mix in a ratio of 3:1 ( isotopic dilution 1*:3 ) ,
and biotinylated dna duplex in a 10 l final volume . in adomet
competition studies , adomet was varied between 0.5 and 15 m
while dna was kept at a near - saturating concentration . in dna competition
studies
, dna was varied between 0.1 and 0.6 m while adomet
was kept at a near - saturating concentration .
the tested compounds
were spanned from ic10 to ic80 . for each substrate
concentration ,
the ic50 of the tested compound was calculated
by nonlinear regression fitting with sigmoidal dose response ( variable
slope ) .
the linear regressions of ic50 against [ dna]/km or [ adomet]/km were displayed only if their slopes
were significantly different from 0 .
velocity plots were fitted by
michaelis menten regression or nonlinear regression fitting
with sigmoidal dose response ( variable slope ) .
prior to docking calculations , epik
software was used to calculate the most
relevant ionization and tautomeric state of compounds 5 and 1 .
then , the glide program of the schrdinger
package was used to dock these compounds
into the two selected dnmt1 x - ray structures ( pdb 3swr , hashimoto and cheng ,
unpublished data , and pdb 3pta(32 ) ) .
the receptor grid generation
was performed for the box with a center in the putative binding sites
of the two structures .
the geometry of the ligand binding
site of the complex between 5 ( or 1 ) and
the dnmt1 structures was then optimized .
the binding site was defined
as 5 ( or 1 ) and all amino acid residues
located within 8 from the ligands .
all of the receptor residues
located within 2 from the binding site were used as a shell .
water was used as an implicit solvent , and a
maximum of 5000 iterations of the polak
ribier conjugate gradient
minimization method was used with a convergence threshold of 0.01
kj mol .
u-937 ( histiocytic lymphoma ) , raji ( burkitt s
lymphoma ) , pc-3
( prostate cancer ) , mda - mb-231 ( breast cancer ) cell lines were purchased
from deutsche sammlung fr mikroorganismen and zellkulturen
( dszm ) .
cells were cultured in rpmi 1640 ( lonza ) supplemented with
10% fetal calf serum ( lonza ) and 1% antibiotic
peripheral blood mononuclear cells ( pbmcs ) were isolated
and cultured as previously described .
proliferation and viability were assessed
by trypan blue exclusion analysis at the indicated time points .
mbscs were isolated and cultivated
as described . in detail , mbscs were isolated
from fresh tumor specimens from ptch1 .
cells were
obtained after mechanical and enzymatic dissociation and cultured
in serum - free dmem - f12 supplemented with glucose ( 0.6% ) , insulin ( 25
mg / ml ) , n - acetyl - l - cystein ( 60 mg / ml ) , heparin
( 2 mg / ml ) , b27 ( 1 ) , egf ( 20 ng / ml ) , and bfgf ( 20 ng / ml ) .
mbscs
were also treated to differentiate in vitro after withdrawal of egf / bfgf
and addition of differentiating factors ( platelet derived growth factor ,
pdgf ) for 48 h. compounds 2 and 5 were resuspended
in dmso at 1 mm .
cells were treated with increasing concentration
of 2 or 5 ( 1 , 10 , and 50 m ) for 48
h , and dmso was used as control . unless otherwise indicated , media
and supplements were purchased from gibco - invitrogen ( life science ) ,
and chemicals were from sigma - aldrich ( st .
total rna was isolated
with tri - reagent ( ambion ) according to the manufacturer s procedure ,
and sample quantification was done using a nanodrop spectophotometer
( thermo scientific ) .
the reverse transcription was performed using
a high - capacity cdna reverse - transcription kit ( applied biosystem ) ,
and quantitative rt - pcr analysis of iii - tubulin , pcna , dnmt1 ,
dnmt3a , and dnmt3b was performed using a taqman assay from lifetech .
mrna expression was analyzed using the abi prism 7900ht sequence detection
system ( applied biosystem ) with a taqman gene - expression assay according
to the manufacturer s protocol ( applied biosystem ) .
each amplification
reaction was performed in triplicate , and the average of the three
threshold - cycle values was used to calculate the relative amount of
transcripts in the sample ( sds 2.3 software , applied biosystem ) .
mrna
quantification was expressed , in arbitrary units , as the ratio of
the sample quantity to the calibrator or to the mean values of control
samples .
all values were normalized to three endogenous controls :
-actin , 2-microglobulin , and hprt .
cells were lysed using ripa buffer
( tris - hcl , ph 7.6 , 50 mm , deoxycholic acid sodium salt 0.5% , nacl
140 mm , np40 1% , edta 5 mm , naf 100 mm , sodium pyrophosphate 2 mm )
and protease inhibitors .
the following antibodies
were used : anti - dnmt1 ( sc-20701 ; santa cruz biotechnology ) , anti - dnmt3a
( sc-365769 ; santa cruz biotechnology ) , and anti - dnmt3b ( sc-10236 ;
santa cruz biotechnology ) .
mbsc were treated with
1 , 10 , and 50 m
of compound 2 or 5 for 48 h. the growth
of drug - treated cells relative to untreated cells was measured by
mtt assay . | dna
methyltransferases ( dnmts ) are important enzymes involved in
epigenetic control of gene expression and represent valuable targets
in cancer chemotherapy .
a number of nucleoside dnmt inhibitors ( dnmti )
have been studied in cancer , including in cancer stem cells , and two
of them ( azacytidine and decitabine ) have been approved for treatment
of myelodysplastic syndromes . however
, only a few non - nucleoside dnmti
have been identified so far , and even fewer have been validated in
cancer . through a process of hit - to - lead optimization , we report here
the discovery of compound 5 as a potent non - nucleoside
dnmti that is also selective toward other adomet - dependent protein
methyltransferases .
compound 5 was potent at single - digit
micromolar concentrations against a panel of cancer cells and was
less toxic in peripheral blood mononuclear cells than two other compounds
tested . in mouse
medulloblastoma stem cells , 5 inhibited
cell growth , whereas related compound 2 showed high cell
differentiation . to the best of our knowledge , 2 and 5
are the first non - nucleoside dnmti tested in a cancer stem
cell line . | <s>[INST]epigenetic regulation
of gene expression is mediated through at
least five series of events involving changes of chromatin at the
molecular level : dna modifications , histone modifications , histone
variants , noncoding rnas , and nucleosome remodeling .
epigenetic control of transcription is essential to drive cells
toward their normal phenotype , and epigenetic deregulation could lead
to initiation and progression of human diseases including cancer .
in contrast to genetic origins of cancer , epigenetic aberrations
are reversible events that occur at early stages in tumor genesis ,
and in the past decade , many interactions and connections have been
reported between genetic and epigenetic changes that highlight the
complex , multifactorial nature of such disease . among the five epigenetic events ,
three dna methyltransferases ( dnmts ) , dnmt1 ,
dnmt3a , and dnmt3b , catalyze the transfer of a methyl group from s - adenosyl - l - methionine ( adomet ) to the c5-position
of cytosine predominantly in cpg dinucleotides .
the maintenance methyltransferase
dnmt1 is most abundant in somatic cells and has a greater activity
for hemi- rather than unmethylated substrates .
differently ,
de novo methyltransferase dnmt3a is only present in low amounts in
somatic cells and shows no preference for hemi- or unmethylated dna . in normal cells ,
dna methylation plays
a key role in many physiological
events ( genomic imprinting control , x - chromosome inactivation , maintenance
of chromosomal stability , silencing of genes and endogenous retroviruses ,
and embryonic development ) , following a pattern according to which
certain genomic sites are hypermethylated ( gene silencing ) , whereas
other sites , such as cpg islands , are hypomethylated ( gene transcription ) . in cancer cells ,
aberrant dna methylation leads to hypermethylation
at cpg islands , joined to a global hypomethylation , giving rise to
genomic instability and inactivation of tumor - suppressor genes .
hypermethylation of cpg islands is so biologically relevant and
specific that for each cancer a typical hypermethylome can be drawn .
in addition to cancer , very recently aberrant
dna methylation has been linked to premature senescence and aging
diseases such as hutchinson gilford progeria and werner syndrome , to neural plasticity and gabaergic signaling modulation , and to heart failure and atrial fibrillation through methylation
of the homeobox gene pitx2c .
moreover , dnmt1 and dnmt3a proteins have been found to be overexpressed
in rheumatoid arthritis and osteoarthritis .
dnmt inhibitors ( dnmti ) have been validated as useful tools
to
reactivate tumor - suppressor genes and to reprogram cancer cells toward
growth arrest and death .
two nucleoside analogue dnmti ( azacytidine and decitabine , chart 1 ) have been approved by the u.s .
fda for clinical
use against hematological malignancies , but despite their high efficacy ,
such drugs suffer from poor bioavailability , chemical instability ,
and toxic side effects . some non - nucleoside compounds
have been reported as dnmti ( chart 1 ) , but
they typically share low potency and/or low selectivity for dnmts ,
and their mechanism of inhibition is unknown . among non - nucleoside inhibitors ,
sgi-1027 ( 1 ) ( figure 1 ) , identified
among a series of quinoline - based
compounds developed as anticancer drugs , has attracted our attention
because of its high potency in both enzyme and cell assays . because the structure of 1 shows
four fragments ( 4-aminoquinoline + 4-aminobenzoic acid + 1,4-phenylenediamine
+ 2,4-diamino-6-methylpyrimidine ) linked in sequence with para / para
orientation , we prepared a series of regioisomers of 1 by shifting each fragment s linkage from the para to the
meta or ortho position ( figure 1 ) and obtained
compounds 29 ( figure 1 ) .
in addition , we prepared two related compounds ( 10 and 11 ) showing either a bis - quinoline or bis - pyrimidine
structure and two truncated compounds ( 12 and 13 ) lacking the
chemical
structures of sgi-1027 ( 1 ) and related analogues 213 described in this study . their ic50 values ( m ) from nanoscale hts against human dnmt1
are reported in the brackets .
compounds 19 were prepared by
coupling the 2- , 3- , or 4-(quinolin-4-ylamino)benzoic acid , 14a c , with the n-(2- , 3- , or 4-aminophenyl)-6-methylpyrimidine-2,4-diamine , 15a c , in the presence of benzotriazol-1-yl - oxytripyrrolidinophosphonium
hexafluorophosphate ( pybop ) and triethylamine in dry n , n - dimethylformamide as solvent ( scheme 1 ) . intermediate compounds 14a c were prepared by reaction between 4-chloroquinoline with
the appropriate ethyl 2- , 3- , or 4-aminobenzoate and 37% hydrochloric
acid in ethanol at 80 c .
the obtained ethyl benzoates , 16a c , underwent basic hydrolysis using
2 n potassium hydroxide to afford the corresponding acids , 14a c .
the same reaction conducted with 4-chloro-6-methylpyrimidin-2-amine
and the opportune 2- , 3- , or 4-nitroanilines in the presence of 37%
hydrochloric acid and ethanol at 80 c furnished the nitro - intermediates , 17a c , which were in turn reduced with
stannous chloride dihydrate and 37% hydrochloric acid in ethanol to
the corresponding anilines , 15a c .
chemical and physical data of final compounds 113 ( table s1 ) as
well as those
of intermediate compounds 1422 ( table s2 ) are listed in the supporting information .
reagents and conditions :
( a )
37% hcl , ch3ch2oh , 80 c , 2 h ; ( b ) 2 n
koh , ch3ch2oh ; ( c ) stannous chloride dihydrate ,
37% hcl , ch3ch2oh , 1 h , 80 c ; ( d ) ( c2h5)3n , pybop , anhydrous dmf , n2 atmosphere , room temperature , 1 h. reagents and conditions : ( a )
37% hcl , ch3ch2oh , 80 c , 2 h ; ( b ) stannous
chloride dihydrate , 37% hcl , ch3ch2oh , 80 c ,
1 h ; ( c ) ( c2h5)3n , pybop , anhydrous
dmf , n2 atmosphere , room temperature , 1 h ; ( d ) 2 n koh ,
ch3ch2oh .
bisquinoline 10 was obtained by treating 4-chloroquinoline
with 4-nitroaniline and , after reduction of the nitro group of the
resulting intermediate 18 to the corresponding aniline 19 , by coupling 19 with 16c ( scheme 2a ) .
treatment of 4-chloro-6-methylpyrimidin-2-amine
with ethyl 4-aminobenzoate afforded intermediate ester 20 , which was hydrolyzed to acid 21 and was then coupled
with 17c to furnish bispyrimidine 11 ( scheme 2b ) .
truncated compounds 12 and 13 were prepared by reaction of 16c with 4-phenylendiamine
( 12 ) or by reaction of 17c with 4-nitrobenzoic
acid and subsequent reduction of the nitro group of intermediate 22 to the corresponding amine ( 13 ) ( scheme 3 ) .
reagents and conditions : ( a )
( c2h5)3n , pybop , anhydrous dmf , n2 atmosphere , room temperature , 1 h ; ( b ) stannous chloride
dihydrate , 37% hcl , ch3ch2oh , 80 c , 1
h.
from a nanoscale prescreen performed
on 113 against human dnmt1 using
poly(di dc ) as substrate ,
compounds 2 , 4 , and 5 , obtained
by replacing either or both the para with the meta linkages in the
structure of 1 , emerged as highly efficient dnmt1 inhibitors ,
whereas the ortho regioisomers were less potent ( 3 and 68 ) or totally inactive ( 9 ) .
bisquinoline 10 displayed a similar potency as 1 against dnmt1 , whereas bispyrimidine 11 was
slightly less efficient , and truncated compounds 12 and 13 showed a severe drop in inhibition ( figure 1 ) . to perform a more wide and accurate inhibition assay
against dnmts , we tested the most potent compounds , 2 , 4 , 5 , 10 , and 11 , in comparison with 1 against human dnmt1 using a hemimethylated
substrate and against the human dnmt3a2/dnmt3l complex using an unmethylated
substrate ( figure 2 ) . under these assay conditions ,
meta / meta analogue 5 ( ic50 = 9 m ) displayed
a 4-fold higher activity than 1 against dnmt1 , whereas
the para / meta ( 2 ) and meta / para ( 4 ) analogues
were 1.5- and 7.6-fold less potent , respectively .
bisquinoline 10 showed the same dnmt1 inhibiting activity as 1 , whereas bispyrimidine 11 was 2-fold less potent . against dnmt3a2/dnmt3l ,
all of the inhibitors were more efficient
than against dnmt1 , and 5 was again the most potent ,
with ic50 = 2.8 m [ ic50 ( 1 ) = 10 m ] . among the remaining compounds , 11 and 2 were 2-fold , 10 was 3-fold , and 4 was 4-fold less potent than 1 ( figure 2 ) .
inhibitory activities of 1 , 2 , 4 , 5 , 10 , and 11 against
human dnmt1 ( hemimethylated substrate ) and the dnmt3a2/dnmt3l complex
( unmethylated substrate ) . to determine the mechanism of dnmt1 inhibition by compound 5 , we carried out competition experiments by varying the concentration
of either adomet or dna , and we used both the ic50 and
the velocity plot methods to analyze the data .
as shown in figure 3 , the ic50 analysis of 5 against the adomet concentration shows nearly constant ic50 values as the adomet concentration increases ( figure 3a , b ) , suggesting a noncompetitive inhibition .
differently , the ic50 of 5 increases
linearly with dna concentration , suggesting a dna - competitive behavior
( figure 3c , d ) .
these deformations have been described by copeland and horiuchi and are explained by potential nonspecific substrate inhibitor
interactions ( dna interactions ) , tight - binding , or a time - dependent
inhibitor .
competition studies performed
on structurally different compound 11 gave similar results
( figure s1 in the supporting
information ) .
competition experiments performed with compound 5 on
dnmt1 by varying adomet concentrations at a near - saturating dna concentration
( a , b ) or by varying dna concentrations at a near - saturating adomet
concentration ( c , d ) .
( b ) velocity plot against [ adomet ] for different concentrations
of compound 5 .
( d ) velocity
plot against [ dna ] for different concentrations of 5 .
the lines represent the nonlinear regressions with sigmoidal dose response .
on each graph ,
the mean of two independent experiments is represented
sem . to determine the specificity
of 1 , 2 , 4 , 5 , 10 , and 11 for
dnmts among other adomet - dependent enzymes
, we tested them against
prmt1 , a protein arginine methyltransferase , and g9a - like protein ( glp ) , a histone h3 lysine 9 methyltransferase . under the tested conditions
, the new derivatives showed very low
( if any ) prmt1- and glp - inhibiting activities , resulting in the tested compounds being more dnmt - selective than 1 , which displayed only 4- and 1.9-fold lower activities against prmt1
and glp , respectively , when compared with dnmt1 inhibition .
in contrast , 5 was 33- and 11-fold less potent against prmt1 and glp than
against dnmt1 ( table 1 ) .
the dnmt1 selectivity
( as the
prmt1 or glp / dnmt1 ic50 ratio ) for each compound is reported .
the errors in the determinations
of ic50 s are within 20% of their values . to delineate better the mechanism(s )
for the inhibitory potency
of 5 against dnmt1
in particular , compound 5 was docked in two different
dnmt1 structures available in the protein data bank ( pdb ) : dnmt1 ( residues
6001600 ) crystallized in complex with sinefungin ( pdb 3swr , hashimoto and cheng ,
unpublished data ) and dnmt1 ( residues 6461600 ) in complex
with both adohcy and a 19 bp dna duplex ( pdb 3pta ) .
these two dnmt1 structures share a similar overall 3d arrangement ,
with some conformational differences mainly in the dna - binding cxxc
domain region ( residues 646692 , figure
s2 in the supporting information ) .
the latter is adjacent to the methyltransferase domain , which
is the putative inhibitor binding site , and in principle its conformation
could influence the inhibitor binding .
therefore , we decided to dock 5 in both of the aforementioned structures by employing the
glide program of the schrdinger package .
docking results achieved on the dnmt1 structure alone
( unbound to dna ) revealed that in the lowest - energy binding conformation
( docking score 6.95 ) 5 should be able to span
between the adomet binding site and the cxxc region ( figure 4 ) .
indeed , changing one or both the para / meta linkages
( 1 , 2 , 4 , and 5 ) with ortho ones ( 3 and 69 ) by modifying the ligand shape from a stretched to a more
condensed one should prevent the ligand from spanning between the
two sites , explaining why the presence of ortho linkages is not productive
in terms of inhibitory potency .
as depicted in figure 4 , the 4-aminoquinoline fragment of 5 is embedded
in a lipophilic region normally occupied by the adomet adenine ring ,
establishing hydrophobic contacts with i1167 , m1169 , p1225 , and i1247
as well as a t - shaped interaction with f1145 . in this position ,
substitution
of the quinoline ring with a smaller pyrimidine one ( 11 ) or with a hydrogen ( 13 ) would cause a partial loss
of the interactions within the aforementioned cleft , thus explaining
the drop in inhibitory potency .
also , the attached central fragment
( 3-aminobenzoic acid + 1,3-phenylenediamine ) of 5 is
embedded in a region in which cation and
interactions are established with r1574 and w1170 , respectively .
the
intrinsic rigidity of this fragment allows to project the 2,4-diamino-6-methylpyrimidine
terminal at the crevice between the cxxc and methyltransferase domains .
in this position , the terminal hydrophilic head of 5 forms
three h - bonds with the m694 and p692 backbone co and with the d1571
side chain .
given the critical role of the cxxc region for the dnmt1
enzymatic activity , it might be speculated
that favorable ligand interactions with this region should also be
critical for inhibitory potency , thus explaining why replacement of
the 2,4-diamino-6-methylpyrimidine ( 5 ) fragment with
a quinoline ( 10 ) one or with an hydrogen ( 12 ) does not enhance dnmt1 inhibition
. predicted binding mode of 5 in the dnmt1 structure
unbound to dna ( pdb 3swr ) .
compound 5 is depicted as orange sticks , and the
enzyme catalytic and cxxc domains are depicted as cyan ( right side )
and brown ( left side ) ribbons and sticks , respectively .
interestingly , the same calculations did not succeed in suggesting
a well - defined binding pose for compound 5 in the enzyme / dna
structure .
indeed , in the dnmt1/dna complex , when merging the coordinates
of 5 achieved in the absence of dna , it seems clear that
the subtle rearrangements of the cxxc domain induced by the presence
of dna would sterically hamper 5 from spanning from the
adomet interaction site to the crevice between the cxxc and methyltransferase
domains ( figure s4b in the supporting information ) .
results of analogous
docking studies performed on 1 are reported in the supporting information ( figures
s3 and s4a ) .
almost the same binding orientations were obtained
either in the free dnmt1 or in the dnmt1/dna structure , suggesting
that , whereas 5 can in principle be recognized by the
dna - unbound enzyme conformation ( i.e. , in a dna - competitive binding
mode ) , 1 should be able to bind dnmt1 independently from
the presence of dna .
competition experiments also outline that
the inhibitory potency
of 5 is not affected by increasing concentrations of
the adomet cofactor .
these data might suggest that either the ligand
is also able to adapt to binding sites that are different from that
of the cofactor or the same compound can also bind the enzyme / cofactor
complex . in this respect , the dnmt1 structures ( pdb 3pta and 3swr ) were also searched
for different binding sites with the sitemap software available within
the maestro suite .
results of these predictions
demonstrate that the most probable site is the one occupied by the
cofactor , whereas four additional less probable sites could exist
( figure s5a ) . nevertheless , when glide
was employed to predict a possible binding position of 5 in these enzyme regions , weak binding affinities were predicted
( docking scores below 5.0 ) , mainly because the selected clefts , being
rather shallow and solvent - exposed , are less prone to provide efficient
ligand interactions .
this would suggest that the highest affinity
dnmt1 binding site is the cofactor one .
we then attempted to dock 5 in the dnmt1/adohcy ( mimicking adomet substrate analogue )
complex to probe whether the ligand is still able to bind this complex .
indeed , these studies suggest that in the presence of the cofactor
the ligand would still positively interact with the enzyme complex ,
adopting a conformation ( docking score 6.76 , figure s5b ) in which the ligand is sandwiched between the
substrate and part of the enzyme cxxc domain region ( residues 646650 ) .
this might rationalize why increasing adomet concentrations do not
abrogate the ligand inhibition efficiency . to study the effects
of these dnmti in a cellular context , we tested 1 , 2 , 4 , 5 , 10 , and 11 in a panel of cancer cells ( histiocytic lymphoma ,
u-937 ; breast cancer , mda - mb-231 ; burkitt s lymphoma , raji ;
and prostate cancer , pc-3 ) .
trypan blue exclusion assays were carried
out to determine their effects on cell proliferation and viability .
the effect of the tested compounds in peripheral blood mononuclear
cells ( pbmcs ) was also determined to assess for differential toxicity .
in full agreement with their dnmt - inhibition potency
, compounds 1 , 2 , and 5 displayed the highest
antiproliferative effects and the strongest cell - death induction in
all of the cancer cells tested ( figure 5a d ) .
compounds 4 , 10 , and 11 showed
both lower activity and cytotoxicity in these assays ( figure s6 in the supporting
information ) .
compounds 1 and 5 showed
comparable potency against tumor cells , but 5 was the
less toxic in pbmcs ( figure 5e , f ) .
nuclear
morphological changes were further observed by fluorescence microscopy
after hoechst and propidium iodide ( pi ) staining in both u-937 and
raji cells treated with increasing doses of 5 to assess
the levels of necrosis and apoptosis induced by the compound ( figure 5 g ) . in u-937 cells , 5 displayed massive
apoptosis at 10 m followed by necrosis at 25 m , whereas
in raji cells , 5 mainly led to necrosis at 25 m
without triggering any apoptotic response at lower concentrations .
( a e ) antiproliferative
effects ( left ) and cell - death induction ( right ) of 1 , 2 , and 5 on u-937 ( a ) , raji ( b ) , mda - mb-231 ( c ) ,
pc-3 ( d ) , and pbm ( e ) cells .
( f ) ic50 values of cell viability
relative to the above cells treated with 1 , 2 , and 5 for 48 h. ( g ) nuclear - morphology analysis after
hoechst and pi staining in u-937 and raji cells treated with increasing
doses of 5 for 72 h. data represent the mean ( sd )
of at least three independent experiments .
dna methylation also plays a key role
in cancer stem cells : a comparison of the epigenomes of normal and
cancer stem cells and pluripotent and differentiated states revealed
a clear link between dnmts and transcribed loci . in cancer stem cells , the effect of dnmt inhibitors
azacytidine has been shown to reactivate sall4 expression and transcription in acute promyelocytic
leukemia nb4 cells as well as in colorectal
cancers through dnmt inhibition . in idh1
mutant glioma cells , decitabine induced a dramatic loss of stemlike
properties and efficient adoption of markers of differentiation as
well as decreased replicative potential and tumor growth in vivo . to date , no non - nucleoside dnmti has been tested
in a cancer stem cell context .
we tested compounds 2 and 5 at different dosages in mouse mbscs , a cancer stem cell
line expressing high levels of dnmts ( figure s7 in the supporting information ) , to determine
their effects on cell proliferation and differentiation . in these
assays ,
compound 5 arrested the mbsc clonogenic activity ,
induced cell adhesion and differentiation , and impaired significantly
the mbsc growth rate , evaluated by both quantifying pcna levels and
mtt assay ( figure 6a , b ) , whereas 2 was less effective . in mbscs differentiation assays , evaluated by
both iii - tubulin rt - pcr and phase - contrast images ( figure 6c ,
d ) , 2 showed the highest differentiation
effect after treatment with lower doses ( 10 m ) , whereas 5 required higher concentrations ( 50 m ) to reach significance .
to the best of our knowledge , 2 and 5
are
the first examples of non - nucleoside dnmti tested in cancer stem cells
( cscs ) .
( a ) pcna
mrna levels and ( b ) mtt assay of mbscs after 48 h of 2 and 5 treatment or dmso as control ( ctr ) . * p < 0.05 versus untreated cells ( ctr ) .
( c ) mrna levels
of iii - tubulin ( iiitub ) in 2- and 5-treated mbscs for 48 h. dmso was used as control.*p < 0.05 versus untreated cells ( ctr ) .
( d ) representative
bright - field images of mbscs after 2 or 5 treatment ( 48 h , 10 m ) or dmso as control .
through chemical manipulation
applied on the structure of 1 , we identified compound 5 , a novel non - nucleoside
dnmti more potent than 1 and more selective toward other
adomet - dependent protein methyltransferases ( prmt1 and glp ) . tested
on a panel of cancer cells ( leukemia , u937 ; breast cancer , mda - mb-231 ;
burkitt s lymphoma , raji ; and prostate cancer , pc-3 ) as well
as on pbmcs , compound 5 displayed comparable activity
as 1 and with less toxicity .
in mbscs at 10 m , 5 significantly blocked proliferation but required higher
doses ( 50 m ) to induce differentiation , whereas related compound 2 , which was less potent as an antiproliferative agent , showed
high differentiating activity . the anticancer activity displayed by 2 and 5 in the tested cancer cells , including
in cancer stem cells , suggests their use as potent and selective non - nucleoside
dnmti for cancer therapy .
melting points were determined on a buchi
530 melting - point apparatus and are uncorrected .
h nmr
and c nmr spectra were recorded at 400 mhz on a bruker
ac 400 spectrometer ; chemical shifts are reported in ( ppm )
units relative to the internal reference , tetramethylsilane ( me4si ) .
eims spectra were recorded with a fisons trio 1000 spectrometer ;
only molecular ions ( m ) and base peaks are given .
all
compounds were routinely checked by tlc , h nmr , and c nmr spectra .
tlc was performed on aluminum - backed silica
gel plates ( merck dc , alufolien kieselgel 60 f254 ) with spots visualized
by uv light .
all solvents were reagent grade and , when necessary ,
were purified and dried by standard methods .
concentration of solutions
after reactions and extractions involved the use of a rotary evaporator
operating at reduced pressure of ca .
elemental analysis was used to
determine the purity of the described compounds , which was found to
be > 95% . analytical results are within 0.40% of the theoretical
values .
all chemicals were purchased from aldrich chimica , milan ( italy ) ,
or from alfa aesar , milan ( italy ) , and were of the highest purity .
4-chloroquinoline ( 6.05 mmol , 0.99 g ) , ethyl
3-aminobenzoate ( 6.05 mmol , 1 g ) , and a catalytic amount ( 4 drops )
of 37% hydrochloric acid were refluxed for 2 h. the reaction was allowed
to cool to room temperature , and the precipitated solid was filtered
off , washed with water ( 3 5 ml ) , and recrystallized by methanol
to afford pure 16b as a hydrochloride salt .
h nmr ( dmso - d6 , 400 mhz ) 1.34
( t , 3h , j = 7.2 hz , cooch2ch3 ) , 4.36 ( q , 2h , j = 7.2 hz ,
cooch2ch3 ) , 6.88 ( d ,
1h , j = 5.2 hz , quinoline proton ) , 7.74 ( m , 2h , benzene
protons ) , 7.84 ( t , 1h , j = 7.4 hz , benzene proton ) ,
8.00 ( d , 1h , j = 8.2 hz , quinoline proton ) , 8.068.12
( m , 3h , quinoline and benzene protons ) , 8.56 ( d , 1h , j = 8.2 hz , quinoline proton ) , 8.81 ( d , 1h , j = 5.2
hz , quinoline proton ) , 11.08 ( bs , 1h , nh ) ,
14.68 ( bs , 1h , h ) .
c nmr
( dmso - d6 , 100 mhz ) 14.1 , 60.9 ,
112.8 , 114.2 , 119.9 , 121.6 , 122.1 , 124.2 , 125.7 , 129.2 , 129.6 , 130.9 ,
133.7 , 138.7 , 142.3 , 149.7 , 151.6 , 165.9 .
ms ( ei ) m / z [ m ] calcd for c18h16n2o2 , 292.1212 ; found , 292.1218 .
a solution of ethyl 3-(quinolin-4-ylamino)benzoate 16b ( 1.71 mmol , 0.5 g ) and 2 n koh ( 6.84 mmol , 0.38 g ) in
ethanol ( 15 ml ) was stirred overnight at room temperature .
then , the
solvent was evaporated , and 2 n hcl was slowly added until ph 5.0
was obtained .
the colorless solid was filtered , washed with water
( 3 5 ml ) , and recrystallized from methanol to obtain pure 14b .
h nmr ( dmso - d6 , 400 mhz ) 7.00 ( d , 1h , j = 5.2 hz , quinoline
proton ) , 7.517.58 ( m , 2h , quinoline and benzene protons ) ,
7.63 ( d , 1h , benzene proton ) , 7.687.75 ( m , 2h , quinoline and
benzene protons ) , 7.907.93 ( m , 2h , quinoline and benzene protons ) ,
8.39 ( d , 1h , j = 8.0 hz , quinoline proton ) , 8.51
( d , 1h , j = 5.2 hz , quinoline proton ) , 9.17 ( bs ,
1h , nh ) , 12.0 ( bs , 1h , cooh ) . c nmr
( dmso - d6 , 100 mhz ) 112.8 , 119.5
( 2c ) , 120.2 , 121.6 , 124.2 , 125.7 , 129.2 , 129.6 , 131.1 ( 2c ) , 138.7 ,
149.7 , 151.1 , 151.6 , 169.3 . ms ( ei ) m / z [ m ] calcd for c16h12n2o2 , 264.0899 ; found , 264.0902 .
to a cooled solution of 6-methyl - n-(3-nitrophenyl)pyrimidine-2,4-diamine 17b ( 1.63 mmol , 0.5 g ) and stannous chloride dihydrate ( 8.15
mmol , 1.84 g ) in ethanol ( 10 ml ) was slowly added a 37% hydrochloric
acid solution ( 0.3 ml ) at 0 c .
the reaction was then kept at
80 c for 1 h. afterward , the reaction was quenched at room temperature
by a 2 n sodium carbonate solution ( 20 ml ) , and the mixture was extracted
with ethyl acetate ( 3 30 ml ) , washed with brine ( 3 30
ml ) , dried with anhydrous sodium sulfate , filtered , and concentrated
under reduced pressure .
h nmr ( dmso - d6 , 400 mhz ) 2.06 ( s , 3h , ch3 ) , 4.92 ( bs , 2h , nh2-aniline ) , 5.87 ( s , 1h , pyrimidine proton ) , 5.97 ( bs ,
2h , -nh2-pyrimidine ) , 6.19 ( d , 1h , j = 8.0 hz , aniline proton ) , 6.80 ( d , 1h , j = 8.0 hz , aniline proton ) , 6.876.91 ( m , 2h , aniline protons ) ,
8.64 ( bs , 1h , nh ) .
c nmr ( dmso - d6 , 100 mhz ) 23.9 , 93.8 , 102.7 , 105.0 ,
107.8 , 130.3 , 143.2 , 147.8 , 163.1 , 164.5 , 170.2 .
ms ( ei ) m / z [ m ] calcd for c11h13n5 , 215.1171 ; found , 215.1167 .
triethylamine ( 3.04 mmol , 0.42 ml ) and benzotriazol-1-yl - oxytripyrrolidinophosphonium
hexafluorophosphate ( pybop ) ( 0.91 mmol , 0.47 g ) were added to a solution
of 3-(quinolin-4-ylamino)benzoic acid 14b ( 0.76 mmol ,
0.2 g ) in anhydrous n , n - dimethylformamide
( 5 ml ) under a nitrogen atmosphere .
the resulting mixture was stirred
for 30 min at room temperature followed by the addition of n-(3-aminophenyl)-6-methylpyrimidine-2,4-diamine 15b ( 0.76 mmol , 0.16 g ) under a nitrogen atmosphere , and the
reaction was stirred overnight .
the reaction was quenched with water
( 50 ml ) and extracted with ethyl acetate ( 3 30 ml ) .
the combined
organic extracts were dried , and the residue obtained upon evaporation
of solvent was purified by column chromatography ( sio2 eluting
with ethyl acetate / methanol 10:1 ) to provide pure 5 .
h nmr ( dmso - d6 , 400 mhz )
2.10 ( s , 3h , ch3 ) , 5.94 ( s , 1h ,
pyrimidine proton ) , 6.07 ( bs , 2h , nh2-pyrimidine ) , 7.06 ( d , 1h , j = 4.8 hz , quinoline
proton ) , 7.26 ( t , 1h , j = 8.0 hz , benzene proton ) ,
7.35 ( d , 1h , j = 7.6 hz , quinoline proton ) , 7.557.61
( m , 4h , benzene and quinoline protons ) , 7.727.75 ( m , 2h , benzene
protons ) , 7.91 ( d , 1h , j = 8.0 hz , quinoline proton ) ,
7.95 ( s , 1h , benzene proton ) , 8.03 ( s , 1h , benzene proton ) , 8.42 ( d ,
1h , j = 8.4 hz , quinoline proton ) , 8.52 ( d , 1h , j = 5.6 hz , quinoline proton ) , 9.04 ( bs , 1h , nh - pyrimidine ) , 9.16 ( bs , 1h , nh - quinoline ) , 10.18 ( s , 1h , conh ) .
c nmr ( dmso - d6 , 100 mhz )
23.9 , 93.8 , 108.0 , 111.6 , 111.8 , 112.8 , 113.4 , 117.5 , 121.2 , 121.6 ,
124.2 , 125.7 , 129.2 , 129.6 , 129.7 , 133.9 , 135.0 , 136.7 , 138.7 , 142.5 ,
142.6 , 149.7 , 151.6 , 163.1 , 164.5 , 164.7 , 170.2 . ms ( ei ) m / z [ m ] calcd for c27h23n7o , 461.1964 ; found , 461.1969 .
h nmr ( dmso - d6 , 400 mhz ) 2.10 ( s , 3h , ch3 ) , 5.88 ( s , 1h , pyrimidine proton ) , 6.14 ( bs ,
2h , nh2-pyrimidine ) , 7.21 ( d ,
1h , j = 5.4 hz , quinoline proton ) , 7.487.81
( m , 8h , benzene and quinoline protons ) , 7.938.03 ( m , 3h , benzene
and quinoline protons ) , 8.42 ( d , 1h , j = 8.4 hz ,
quinoline proton ) , 8.52 ( d , 1h , j = 5.6 hz , quinoline
proton ) , 8.97 ( bs , 1h , nh - pyrimidine ) , 9.25
( bs , 1h , nh - quinoline ) , 10.06 ( bs , 1h , conh ) .
c nmr ( dmso - d6 , 100 mhz ) 23.9 , 93.8 , 111.4 ( 2c ) , 112.8 , 117.7 ( 2c ) ,
121.6 , 122.4 ( 2c ) , 124.2 ( 2c ) , 125.7 , 127.9 , 129.2 , 129.6 , 130.2 ( 2c ) ,
136.5 , 138.7 , 149.3 , 149.7 , 151.6 , 163.1 , 164.5 , 164.7 , 170.2 .
ms
( ei ) m / z [ m ] calcd for
c27h23n7o , 461.1964 ; found , 461.1969 .
h nmr ( dmso - d6 , 400 mhz ) 2.10 ( s , 3h , ch3 ) , 5.95 ( s , 1h , pyrimidine proton ) , 6.07 ( bs , 2h , nh2-pyrimidine ) , 7.217.25 ( m , 2h , benzene
and quinoline protons ) , 7.37 ( d , 1h , j = 8.2 hz ,
benzene proton ) , 7.507.61 ( m , 4h , benzene and quinoline protons ) ,
7.75 ( t , 1h , j = 7.4 hz , quinoline proton ) , 7.938.03
( m , 4h , benzene and quinoline protons ) , 8.42 ( d , 1h , j = 8.4 hz , quinoline proton ) , 8.52 ( d , 1h , j = 5.6
hz , quinoline proton ) , 9.03 ( bs , 1h , nh - pyrimidine ) ,
9.25 ( bs , 1h , nh - quinoline ) , 10.05 ( bs , 1h ,
conh ) .
c nmr ( dmso - d6 , 100 mhz ) 23.9 , 93.8 , 108.0 , 111.4
( 2c ) , 111.6 , 112.8 , 113.4 , 121.6 , 124.2 ( 2c ) , 125.7 , 129.2 , 129.6 ,
129.7 , 130.2 ( 2c ) , 136.7 , 138.7 , 142.6 , 149.3 , 149.7 , 151.6 , 163.1 ,
164.5 , 164.7 , 170.2 .
ms ( ei ) m / z [ m ] calcd for c27h23n7o , 461.1964 ; found , 461.1969 .
h nmr ( dmso - d6 , 400 mhz ) 2.09 ( s , 3h , ch3 ) , 5.88 ( s , 1h , pyrimidine proton ) , 6.31 ( bs , 2h , nh2-pyrimidine ) , 7.187.22 ( m , 2h , benzene
and quinoline protons ) , 7.377.50 ( m , 4h ) , 7.587.65
( m , 2h benzene and quinoline protons ) , 7.727.77 ( m , 2h , benzene
protons ) , 7.947.96 ( m , 2h , quinoline protons ) , 8.37 ( d , 1h , j = 7.6 hz , quinoline proton ) , 8.55 ( bs , 1h , nh - pyrimidine ) , 8.58 ( d , 1h , j = 4.8 hz ,
quinoline proton ) , 9.25 ( bs , 1h , nh - quinoline ) ,
10.15 ( bs , 1h , conh ) .
c nmr ( dmso - d6 , 100 mhz ) 23.9 ,
93.8 , 111.4 ( 2c ) , 112.8 , 118.9 , 121.6 , 122.8 , 124.2 ( 2c ) , 125.5 , 125.7 ,
126.1 , 129.2 , 129.6 , 130.2 ( 2c ) , 137.9 , 138.7 , 147.6 , 149.3 , 149.7 ,
151.6 , 163.1 , 164.5 , 170.2 , 172.5 .
ms ( ei ) m / z [ m ] calcd for c27h23n7o , 461.1964 ; found , 461.1969 .
h nmr ( dmso - d6 , 400 mhz ) 2.08 ( s , 3h , ch3 ) , 5.87 ( s , 1h , pyrimidine proton ) , 6.10 ( bs , 2h , nh2-pyrimidine ) , 7.06 ( d , 1h , j = 5.6 hz , quinoline proton ) , 7.547.74 ( m , 9h , benzene and
quinoline protons ) , 7.90 ( d , 1h , j = 8.4 hz quinoline
proton ) , 8.01 ( s , 1h , benzene proton ) , 8.46 ( d , 1h , j = 8.4 hz , quinoline proton ) , 8.51 ( d , 1h , j = 4.0
hz , quinoline proton ) , 9.01 ( bs , 1h , nh - pyrimidine ) ,
9.28 ( bs , 1h , nh - quinoline ) , 10.30 ( s , 1h ,
conh ) .
c nmr ( dmso - d6 , 100 mhz ) 23.9 , 93.8 , 111.8 , 112.8 ,
117.5 , 117.7 ( 2c ) , 121.2 , 121.6 , 122.4 ( 2c ) , 124.2 , 125.7 , 127.9 ,
129.2 , 129.6 , 133.9 , 135.0 , 136.5 , 138.7 , 142.5 , 149.7 , 151.6 , 163.1 ,
164.5 , 164.7 , 170.2 .
ms ( ei ) m / z [ m ] calcd for c27h23n7o , 461.1964 ; found , 461.1969 .
h nmr ( dmso - d6 , 400 mhz ) 2.05 ( s , 3h , ch3 ) , 5.86 ( s , 1h , pyrimidine proton ) , 6.23 ( bs , 2h , nh2-pyrimidine ) , 7.04 ( d , 1h , j = 5.6 hz , quinoline proton ) , 7.20 ( m , 2h , benzene and quinoline
protons ) , 7.517.74 ( m , 7h , benzene and quinoline protons ) ,
7.907.92 ( m , 2h , benzene and quinoline protons ) , 8.40 ( d ,
1h , j = 8.4 hz , quinoline proton ) , 8.47 ( bs , 1h ,
nh - pyrimidine ) , 8.51 ( d , 1h , j = 5.4 quinoline proton ) , 9.11 ( bs , 1h , nh - quinoline ) , 10.19 ( bs , 1h , conh ) .
c nmr ( dmso - d6 , 100 mhz )
23.9 , 93.8 , 111.8 , 112.8 , 117.5 , 118.9 , 121.2 , 121.6 , 122.8 , 124.2 ,
125.5 , 125.7 , 126.1 , 129.2 , 129.6 , 133.9 , 135.0 , 137.9 , 138.7 , 142.5 ,
147.6 , 149.7 , 151.6 , 163.1 , 164.5 , 164.7 , 170.2 .
ms ( ei ) m / z [ m ] calcd for c27h23n7o , 461.1964 ; found , 461.1969 .
h nmr ( dmso - d6 , 400 mhz ) 2.07 ( s , 3h , ch3 ) , 5.85 ( s , 1h , pyrimidine proton ) , 6.08 ( bs , 2h , nh2-pyrimidine ) , 7.15 ( d , 1h , j = 5.4 hz , quinoline proton ) , 7.26
( t , 1h , j = 6.8
hz , quinoline proton ) , 7.487.75 ( m , 8h , benzene and quinoline
protons ) , 7.92 ( m , 2h , quinoline protons ) , 8.16 ( d , 1h , j = 8.0 hz , quinoline proton ) , 8.55 ( d , 1h , j = 4.0
hz , quinoline proton ) , 8.95 ( bs,1h , nh - pyrimidine ) ,
10.26 ( bs , 1h , nh- quinoline ) , 10.41 ( bs ,
1h , conh ) .
c nmr ( dmso - d6 , 100 mhz ) 23.9 , 93.8 , 112.8 , 116.4 ,
117.7 ( 2c ) , 117.9 , 118.8 , 121.6 , 122.4 ( 2c ) , 124.2 , 125.7 , 127.9 ,
128.3 , 129.2 , 129.6 , 132.9 , 136.5 , 138.7 , 149.7 , 151.6 , 151.9 , 163.1 ,
164.5 , 167.5 , 170.2 .
ms ( ei ) m / z [ m ] calcd for c27h23n7o , 461.1964 ; found , 461.1969 .
h nmr ( dmso - d6 , 400 mhz ) 2.08 ( s , 3h , ch3 ) , 5.91 ( s , 1h , pyrimidine proton ) , 6.05 ( bs , 2h , nh2-pyrimidine ) , 7.127.28 ( m , 3h , benzene
and quinoline protons ) , 7.617.73 ( m , 3h , benzene and quinoline
protons ) , 7.717.76 ( m , 3h , benzene protons ) , 7.917.96
( m , 2h , benzene and quinoline protons ) , 8.16 ( d , 1h , j = 8.0 hz , quinoline proton ) , 8.55 ( d , 1h , j = 4.8
hz , quinoline proton ) , 9.02 ( bs , 1h , nh - pyrimidine ) ,
10.10 ( bs , 1h , nh - quinoline ) , 10.40 ( bs ,
1h , conh ) .
c nmr ( dmso - d6 , 100 mhz ) 23.9 , 93.8 , 108.0 , 111.6 ,
112.8 , 113.4 , 116.4 , 117.9 , 118.8 , 121.6 , 124.2 , 125.7 , 128.3 , 129.2 ,
129.6 , 129.7 , 132.9 , 136.7 , 138.7 , 142.6 , 149.7 , 151.6 , 151.9 , 163.1 ,
164.5 , 167.5 , 170.2 .
ms ( ei ) m / z [ m ] calcd for c27h23n7o , 461.1964 ; found , 461.1969 .
h nmr ( dmso - d6 , 400 mhz ) 2.01 ( s , 3h , ch3 ) , 5.81 ( s , 1h , pyrimidine proton ) , 6.27 ( s , 2h , nh2-pyrimidine ) , 7.127.24 ( m , 4h , benzene
and quinoline protons ) , 7.48 ( d , 1h , j = 7.6 hz ,
benzene proton ) , 7.547.61 ( m , 3h , benzene protons ) , 7.717.76
( m , 2h , benzene and quinoline protons ) , 7.927.97 ( m , 2h , benzene
and quinoline protons ) , 8.08 ( d , 1h , j = 8.8 hz ,
quinoline protons ) , 8.57 ( m , 2h , quinoline and nh - pyrimidine protons ) , 10.44 ( bs , 1h , nh - quinoline ) ,
10.57 ( bs , 1h , conh ) .
c nmr ( dmso - d6 , 100 mhz ) 23.9 ,
93.8 , 112.8 , 116.4 , 117.9 , 118.8 , 118.9 , 121.6 , 122.8 , 124.2 , 125.5 ,
125.7 , 126.1 , 128.3 , 129.2 , 129.6 , 132.9 , 137.9 , 138.7 , 147.6 , 149.7 ,
151.6 , 151.9 , 163.1 , 164.5 , 167.5 , 170.2 .
ms ( ei ) m / z [ m ] calcd for c27h23n7o , 461.1964 ; found , 461.1969 .
h nmr ( dmso - d6 , 400 mhz ) 6.83 ( d , 1h , j =
6.0 hz , quinoline proton ) , 7.20 ( d , 1h , j = 4.8 hz ,
quinoline proton ) , 7.42 ( d , 2h , j = 8.8 hz , benzene
protons ) , 7.53 ( d , 2h , j = 8.4 hz , benzene protons ) ,
7.607.68 ( m , 2h , quinoline protons ) , 7.79 ( t , 1h , j = 7.2 hz , quinoline proton ) , 7.83 ( t , 1h , j = 7.2 hz , quinoline proton ) , 7.947.97 ( m , 4h , benzene and
quinoline protons ) , 8.07 ( d , 2h , j = 7.6 hz , benzene
protons ) , 8.458.49 ( m , 2h , quinoline protons ) , 8.578.61
( m , 2h , quinoline protons ) , 9.49 ( bs , 1h , nh - quinoline ) , 9.82 ( bs , 1h , nh - quinoline ) ,
10.35 ( bs , 1h , conh ) .
c nmr ( dmso - d6 , 100 mhz ) 111.4
( 2c ) , 112.8 ( 2c ) , 117.7 ( 2c ) , 121.6 ( 2c ) , 122.4 ( 2c ) , 124.2 ( 3c ) ,
125.7 ( 2c ) , 127.9 , 129.2 ( 2c ) , 129.6 ( 2c ) , 130.2 ( 2c ) , 138.7 ( 2c ) ,
141.5 , 149.3 , 149.7 ( 2c ) , 151.6 ( 2c ) , 164.7 .
ms ( ei ) m / z [ m ] calcd for c31h23n5o , 481.1903 ; found , 481.1908 .
h nmr ( dmso - d6 , 400 mhz ) 2.09 ( s , 3h , ch3 ) , 2.13 ( s , 3h , ch3 ) , 5.86 ( s , 1h , pyrimidine proton ) , 5.95 ( s , 1h , pyrimidine proton ) ,
6.10 ( bs , 2h , nh2-pyrimidine ) ,
6.26 ( bs , 2h , nh2-pyrimidine ) ,
7.65 ( m , 4h , benzene protons ) , 7.89 ( m , 4h , benzene protons ) , 8.91
( bs , 1h , nh - pyrimidine ) , 9.32 ( bs , 1h , nh - pyrimidine ) , 9.96 ( bs , 1h , conh ) .
c nmr ( dmso - d6 , 100 mhz ) 23.9 ( 2c ) , 93.8 ( 2c ) , 111.4 ( 2c ) , 117.7 ( 2c ) ,
122.4 ( 2c ) , 124.2 , 127.9 , 130.2 ( 2c ) , 136.5 , 144.3 , 163.1 ( 2c ) , 164.5 ,
164.7 , 167.0 , 167.7 , 170.2 . ms ( ei ) m / z [ m ] calcd for c23h23n9o , 441.2026 ; found , 441.2023 .
h nmr ( dmso - d6 , 400 mhz ) 4.91 ( bs , 2h , nh2-benzene ) , 6.56 ( d , 2h , j = 7.6 hz ,
benzene protons ) , 7.18 ( d , 1h , j = 4.8 hz , quinoline
proton ) , 7.38 ( d , 2h , j = 8.4 hz , benzene protons ) ,
7.46 ( d , 2h , j = 8.4 hz , benzene protons ) , 7.60 ( t ,
1h , j = 7.2 hz , quinoline proton ) , 7.74 ( t , 1h , j = 7.2 hz , quinoline proton ) , 7.93 ( d , 1h , j = 8.0 hz , quinoline proton ) , 7.97 ( d , 2h , j = 8.4
hz , benzene protons ) , 8.38 ( d , 1h , j = 8.4 hz , quinoline
proton ) , 8.57 ( d , 1h , j = 4.4 hz , quinoline proton ) ,
9.20 ( bs , 1h , nh - quinoline ) , 9.79 ( bs , 1h ,
conh ) .
c nmr ( dmso - d6 , 100 mhz ) 111.4 ( 2c ) , 112.8 , 116.5
( 2c ) , 121.6 , 122.4 ( 2c ) , 124.2 ( 2c ) , 125.7 , 127.9 , 129.2 , 129.6 , 130.2
( 2c ) , 138.7 , 144.0 , 149.3 , 149.7 , 151.6 , 164.7 . ms ( ei ) m / z [ m ] calcd for c22h18n4o , 354.1481 ; found , 354.1486 .
h nmr ( dmso - d6 , 400 mhz ) 2.06 ( s , 3h , ch3 ) , 5.71 ( bs , 2h , nh2-benzene ) , 5.85 ( s , 1h , pyrimidine proton ) , 6.08 ( bs , 2h , nh2-pyrimidine ) , 6.60 ( d , 2h , j = 8.4 hz , benzene protons ) , 7.597.64 ( m , 4h , benzene protons ) ,
7.71 ( d , 2h , j = 8.4 hz , benzene protons ) , 8.88 ( bs ,
1h , nh - pyrimidine ) , 9.66 ( bs , 1h , conh ) .
c nmr ( dmso - d6 , 100 mhz ) 23.9 , 93.8 , 114.3 ( 2c ) , 117.7 ( 2c ) , 122.4
( 2c ) , 124.2 , 127.9 , 130.2 ( 2c ) , 136.5 , 151.8 , 163.1 , 164.5 , 164.7 ,
170.2 .
ms ( ei ) m / z [ m ] calcd for c18h18n6o , 334.1542 ;
found , 334.1545 .
compounds 113 were
tested in 10-dose ic50 mode with 2-fold serial dilutions
at a starting concentration of
500 m against human dnmt1 using poly(di dc ) ( 0.001 mg / ml )
as a substrate in the presence of adomet ( 1 m ) as a cofactor .
control compounds , adohcy ( s-(5-adenosyl)-l - homocysteine )
and sinefungin , were tested in 10-dose ic50 mode with 3-fold
serial dilutions starting at 100 m .
the expression and purification
of human dnmt1 with an n - terminal deletion of 600 residues ( residues
6011600 ) and the human dnmt3a2/dnmt3l complex have been described .
recombinant rat prmt1 and the human g9a - like protein ( glp ) c - terminal fragment containing
both the ankyrin repeats and catalytic set domain ( residues 7341235 ;
pxc758 ) were purified as described . for dnmt1 , methyl transfer activity
inhibition assays were performed in 20 l reactions containing
4.6 mm [ methyl - h]-adomet ( 10.0 ci / mmol ; perkinelmer ) ,
1.0 mm dna oligonucleotides , 0.2 m dnmt1 , 1 mm edta , and 50
mm tris - hcl , ph 7.5 .
enzymes were preincubated with adomet and various
concentrations of inhibitors for 5 min at 37 c before the addition
of substrate dna . after a 15 min incubation
, the reactions were terminated
by the addition of 1% sds and 1 mg / ml of protease k and heating at
50 c for 15 min .
the reaction mixtures were spotted on de81
paper circles ( whatman ) , washed with 5 ml of cold 0.2 m nh4hco3 ( twice ) , 5 ml of deionized water ( twice ) , and 5 ml
of ethanol ( once ) .
all curves were fit individually
using origin 7.5 software ( originlab ) . for the dnmt3a2/3l complex
,
the inhibition assays were performed 20 l reactions containing
4.6 mm [ methyl - h]-adomet , 1.0 mm dna oligonucleotides ,
0.3 m enzyme , 0.5 mm tris(2-carboxyethyl)phosphine ( tcep ) ,
2.5% ( v / v ) glycerol , and 50 mm tris - hcl , ph 7.5 .
the dna substrates
were 28 bp and contained two cpg sites : 5-aca gta cgt caa gat ctt gacgta ctg t-3 and the complementary strand .
for histone methylation
inhibitions , the assays were performed in 20 l reactions containing
4.6 mm [ methyl - h]-adomet , 50 g / ml histone from
calf thymus ( sigma ) , 12 g / ml ( 0.3 m ) prmt1 or 10 g / ml
( 0.17 m ) glp , 100 mm kcl , 5 mm dithiothreitol ( dtt ) , and 50
mm tris - hcl , ph 8.5 .
enzymes were preincubated with adomet and various
concentrations of inhibitors for 5 min at 37 c ( for prmt1 ) or
30 c ( for glp ) before the addition of histone substrates .
after
incubation ( 6.5 min for prmt1 or 5 min for glp ) , the reactions were
terminated by the addition of 20% trichloroacetic acid ( tca , fisher
scientific ) .
the reaction mixtures were spotted on gf / a paper circles
( whatman ) and washed three times with 3 ml of 10% tca and once with
3 ml of ethanol .
briefly , the reaction was started by the addition of 94.5 nm dnmt1
to a mix containing the tested compound ( up to 1% dmso ) , an adomet/[methyl - h]-adomet mix in a ratio of 3:1 ( isotopic dilution 1*:3 ) ,
and biotinylated dna duplex in a 10 l final volume . in adomet
competition studies , adomet was varied between 0.5 and 15 m
while dna was kept at a near - saturating concentration . in dna competition
studies
, dna was varied between 0.1 and 0.6 m while adomet
was kept at a near - saturating concentration .
the tested compounds
were spanned from ic10 to ic80 . for each substrate
concentration ,
the ic50 of the tested compound was calculated
by nonlinear regression fitting with sigmoidal dose response ( variable
slope ) .
the linear regressions of ic50 against [ dna]/km or [ adomet]/km were displayed only if their slopes
were significantly different from 0 .
velocity plots were fitted by
michaelis menten regression or nonlinear regression fitting
with sigmoidal dose response ( variable slope ) .
prior to docking calculations , epik
software was used to calculate the most
relevant ionization and tautomeric state of compounds 5 and 1 .
then , the glide program of the schrdinger
package was used to dock these compounds
into the two selected dnmt1 x - ray structures ( pdb 3swr , hashimoto and cheng ,
unpublished data , and pdb 3pta(32 ) ) .
the receptor grid generation
was performed for the box with a center in the putative binding sites
of the two structures .
the geometry of the ligand binding
site of the complex between 5 ( or 1 ) and
the dnmt1 structures was then optimized .
the binding site was defined
as 5 ( or 1 ) and all amino acid residues
located within 8 from the ligands .
all of the receptor residues
located within 2 from the binding site were used as a shell .
water was used as an implicit solvent , and a
maximum of 5000 iterations of the polak
ribier conjugate gradient
minimization method was used with a convergence threshold of 0.01
kj mol .
u-937 ( histiocytic lymphoma ) , raji ( burkitt s
lymphoma ) , pc-3
( prostate cancer ) , mda - mb-231 ( breast cancer ) cell lines were purchased
from deutsche sammlung fr mikroorganismen and zellkulturen
( dszm ) .
cells were cultured in rpmi 1640 ( lonza ) supplemented with
10% fetal calf serum ( lonza ) and 1% antibiotic
peripheral blood mononuclear cells ( pbmcs ) were isolated
and cultured as previously described .
proliferation and viability were assessed
by trypan blue exclusion analysis at the indicated time points .
mbscs were isolated and cultivated
as described . in detail , mbscs were isolated
from fresh tumor specimens from ptch1 .
cells were
obtained after mechanical and enzymatic dissociation and cultured
in serum - free dmem - f12 supplemented with glucose ( 0.6% ) , insulin ( 25
mg / ml ) , n - acetyl - l - cystein ( 60 mg / ml ) , heparin
( 2 mg / ml ) , b27 ( 1 ) , egf ( 20 ng / ml ) , and bfgf ( 20 ng / ml ) .
mbscs
were also treated to differentiate in vitro after withdrawal of egf / bfgf
and addition of differentiating factors ( platelet derived growth factor ,
pdgf ) for 48 h. compounds 2 and 5 were resuspended
in dmso at 1 mm .
cells were treated with increasing concentration
of 2 or 5 ( 1 , 10 , and 50 m ) for 48
h , and dmso was used as control . unless otherwise indicated , media
and supplements were purchased from gibco - invitrogen ( life science ) ,
and chemicals were from sigma - aldrich ( st .
total rna was isolated
with tri - reagent ( ambion ) according to the manufacturer s procedure ,
and sample quantification was done using a nanodrop spectophotometer
( thermo scientific ) .
the reverse transcription was performed using
a high - capacity cdna reverse - transcription kit ( applied biosystem ) ,
and quantitative rt - pcr analysis of iii - tubulin , pcna , dnmt1 ,
dnmt3a , and dnmt3b was performed using a taqman assay from lifetech .
mrna expression was analyzed using the abi prism 7900ht sequence detection
system ( applied biosystem ) with a taqman gene - expression assay according
to the manufacturer s protocol ( applied biosystem ) .
each amplification
reaction was performed in triplicate , and the average of the three
threshold - cycle values was used to calculate the relative amount of
transcripts in the sample ( sds 2.3 software , applied biosystem ) .
mrna
quantification was expressed , in arbitrary units , as the ratio of
the sample quantity to the calibrator or to the mean values of control
samples .
all values were normalized to three endogenous controls :
-actin , 2-microglobulin , and hprt .
cells were lysed using ripa buffer
( tris - hcl , ph 7.6 , 50 mm , deoxycholic acid sodium salt 0.5% , nacl
140 mm , np40 1% , edta 5 mm , naf 100 mm , sodium pyrophosphate 2 mm )
and protease inhibitors .
the following antibodies
were used : anti - dnmt1 ( sc-20701 ; santa cruz biotechnology ) , anti - dnmt3a
( sc-365769 ; santa cruz biotechnology ) , and anti - dnmt3b ( sc-10236 ;
santa cruz biotechnology ) .
mbsc were treated with
1 , 10 , and 50 m
of compound 2 or 5 for 48 h. the growth
of drug - treated cells relative to untreated cells was measured by
mtt assay .[/INST]dna
methyltransferases ( dnmts ) are important enzymes involved in
epigenetic control of gene expression and represent valuable targets
in cancer chemotherapy .
a number of nucleoside dnmt inhibitors ( dnmti )
have been studied in cancer , including in cancer stem cells , and two
of them ( azacytidine and decitabine ) have been approved for treatment
of myelodysplastic syndromes . however
, only a few non - nucleoside dnmti
have been identified so far , and even fewer have been validated in
cancer . through a process of hit - to - lead optimization , we report here
the discovery of compound 5 as a potent non - nucleoside
dnmti that is also selective toward other adomet - dependent protein
methyltransferases .
compound 5 was potent at single - digit
micromolar concentrations against a panel of cancer cells and was
less toxic in peripheral blood mononuclear cells than two other compounds
tested . in mouse
medulloblastoma stem cells , 5 inhibited
cell growth , whereas related compound 2 showed high cell
differentiation . to the best of our knowledge , 2 and 5
are the first non - nucleoside dnmti tested in a cancer stem
cell line .</s> |
at the end of the evolution of low- and intermediate - mass stars , pre - planetary nebulae ( ppns ) are seen associated with post asymptotic giant branch ( post - agb ) stars .
they will turn into planetary nebulae ( pns ) in less than 1000 years as the post - agb stars become hot white dwarfs .
their shaping mechanism is still unclear and is closely related to the mass - loss processes during the end phases of the evolution .
many ppns and young pns were found to have highly aspherical shapes , with a significant fraction having highly collimated bipolar or multipolar lobes @xcite .
point symmetry , rather than axisymmetry , better characterizes the geometry of the majority of these objects [ striking examples are he2 - 115 @xcite and he3 - 1475 @xcite ] . as a result , instead of spherical fast winds as in the generalized interacting stellar winds ( gisw ) model ( see e.g. , review by * ? ? ?
* ) , collimated fast winds have been proposed to operate during the post - agb phase ( and even earlier during the late agb phase ) , and be the primary agents for the shaping of ppns and young pns @xcite . collimated fast wind ( cfw ) models have been used to account for the morphology and kinematics of a few well - studied ppns and pns , with some assuming a radial wind with a small opening angle ( lee & sahai 2003 , hereafter @xcite ; * ? ? ?
* ) , some assuming a cylindrical jet either unmagnetized @xcite or magnetized @xcite , and some assuming a bullet ( a massive clump ) along the outflow axis @xcite .
this paper is a follow - up to our previous study of cfw models for the well - studied ppn crl 618 @xcite .
crl 618 is located at a distance of 900 pc @xcite .
it shows several narrow lobes at different orientations in hst images @xcite and belongs to the multipolar " morphological classification @xcite , perhaps resulting from multiple ejections at different orientations .
the general structures of the different lobes are similar and we focus only on the northwestern ( w1 ) lobe , which seems to be better separated from other lobes . in @xcite , we compared our cfw models with optical observations of crl 618 in atomic and ionic lines and found that a cfw with a small opening angle can readily reproduce the highly collimated shape of the w1 lobe and the bow - like structure seen at its tip @xcite .
however , it may have difficulties in reproducing properly the high - velocity optical emission along the body of the lobe . in this paper
, we compare our cfw models with recent observations of crl 618 in 2 1 - 0 s(1 ) @xcite , co j=2 - 1 @xcite and j=6 - 5 @xcite .
we find that our cfw models also have difficulties in reproducing the high - velocity molecular emission in the w1 lobe and the cfw is required to have a different physical structure .
the two - dimensional hydrodynamic code , zeus 2d , is used for the simulations of our models , as in @xcite .
this code has been now modified to include molecular cooling and the time dependent chemistry of hydrogen by solving the following equations ( see also * ? ? ?
* ) : @xmath0 where @xmath1 , @xmath2 , @xmath3 , and @xmath4 are the internal energy density , thermal pressure , velocity , and temperature , respectively .
also , @xmath5 is the hydrogen nuclei density , @xmath6 is the fractional part of hydrogen molecules with @xmath7 ( i.e. , @xmath8 for atomic / ionic gas and @xmath9 for molecular gas ) , and @xmath10 is the fractional part of ionized hydrogen with @xmath11 .
helium is included as a neutral component with @xmath12 and thus @xmath13 , where @xmath14 and @xmath15 are the mass density and the mass of atomic hydrogen , respectively . here
@xmath16 and @xmath17 are dissociation and ressociation rates of molecular hydrogen , respectively ( see * ? ? ?
* and reference therein ) , @xmath18 and @xmath19 are ionization and recombination rates of atomic hydrogen , respectively .
@xmath20 is the optically thin radiative cooling from atoms and ions ( as in * ? ? ?
* ) , with the cooling at high temperature from @xcite and low temperature from @xcite .
@xmath21 is the optically thin radiative cooling from molecules , including 2 @xcite and co @xcite .
the chemistry of co is not included .
the co abundance is assumed to be constant and equal to 2@xmath22 of the number of hydrogen molecules , as in @xcite .
we believe this assumption does not significantly affect our conclusions , it only affects the small - scale structure of the co emission .
the equations of state and material coefficients are ( for similar derivation see * ? ? ?
* ) : @xmath23 where @xmath24 , @xmath25 , and @xmath26 are the boltzmann constant , mean molecular weight , and specific heat , respectively . a scalar color tracer @xmath27 is also included in the simulations to track the fast wind , it is one for the fast wind , zero for the agb wind , and a value between one and zero for a mixture of the fast wind and agb wind . as in @xcite ,
the simulations are performed in spherical coordinates but presented in cylindrical coordinates ( z , r ) , with the z - axis being the outflow axis .
our cfw models are based on models 1 and 4 in @xcite , which were found to be the best models for the w1 lobe of crl 618 as seen at optical wavelengths . in these models , a cfw with a small opening angle is assumed to emanate radially from the vicinity of the post - agb star , interacting with a spherical agb wind ( for details see * ? ? ?
* ) . in our simulations ,
the cfw is launched from the inner boundary of the simulation domain , which is at 5@xmath28 cm ( @xmath29 333 au ) away from the post - agb star .
the agb wind is assumed to be molecular with a temperature of 10 k and have a mass - loss rate of @xmath30 m@xmath31 yr@xmath32 with an expansion velocity of @xmath33 km s@xmath32 .
the cfw is assumed to have a mass - loss rate of 2.5@xmath34 m@xmath31 yr@xmath32 , a speed of 300 km s@xmath32 , and an opening angle of @xmath35 .
it can either be steady or pulsed with a temporal variation in the density and velocity ( see table [ tab : models ] ) .
it can be either atomic or molecular , depending on the temperature of the cfw to be assumed .
crl 618 has been recently observed in 2 1 - 0 s(1 ) at @xmath29 resolution @xcite and in co j=2 - 1 @xcite and j=6 - 5 @xcite at @xmath29 resolution ( see figs . [
fig : momobs ] and [ fig : pvobs ] ) .
it is multipolar , but here we focus only on its w1 lobe that extends @xmath29 to the west from the source .
the systemic velocity in this region is @xmath3621.5 km s@xmath32 lsr and the w1 lobe is mainly redshifted with a velocity ranging from -40 to 150 km s@xmath32 lsr .
the co and 2 emission toward the w1 lobe can be roughly separated into two components : a slow or low - velocity ( lv ) component with a velocity lower than @xmath29 20@xmath3630 km s@xmath32 from the systemic and a fast or high - velocity ( hv ) component with a velocity extending to @xmath29 170 km s@xmath32 from the systemic .
the lv component is extended . in co j=2 - 1
, it forms a limb - brightened shell structure around the optical lobe , extending to @xmath29 away from the source . in co j=6 - 5
, it also forms a shell structure but only in the southern part of the lobe , extending to only @xmath29 away from the source . as discussed in @xcite , however , it should be more extended , because most of the extended flux has been resolved out in their observations . in 2 ,
it is spatially unresolved , extending mainly from to from the source , slightly ahead of that seen in co j=2 - 1 . on the other hand ,
the hv component is more compact . in co j=2 - 1
, it extends to @xmath29 away from the source with the velocity increasing linearly with the distance from near the systemic velocity to the highest velocity . in 2 , it is seen with three localized emission peaks separated by @xmath29 : ( 1 ) a peak close to the source with a range of ( blueshifted and redshifted ) velocities , ( 2 ) a bright peak at @xmath29 , where the tip of the co hv component is , with a broad range of velocities extending from near the systemic velocity to the highest velocity , and ( 3 ) a faint peak at @xmath29 at @xmath29 80 km s@xmath32 lsr .
in the following , we present our models and the comparison with the observations . figure [ fig : models ] shows the distributions of hydrogen nuclei density and temperature with molecular fraction in our models at the age of @xmath29 160 yrs , when the outflow lobe has a length of @xmath29 6000 au , similar to the deprojected length of the w1 lobe of crl 618 .
the separation between the agb wind and the cfw is delineated by the color tracer @xmath37 , at which half is the agb wind and half is the cfw . in order to compare with the observations
, we also derive intensity maps of the lv and hv components ( fig .
[ fig : modelmoms2com ] ) and position velocity ( pv ) diagrams ( fig .
[ fig : modelpvs ] ) for the co j=2 - 1 , j=6 - 5 , and 2 1 - 0 s(1 ) emission from our models , assuming the latter to be optically thin and arising from gas in local thermal equilibrium ( lte ) .
we assume a distance of 900 pc and an inclination of 30@xmath38 , values appropriate for crl 618 @xcite .
the hv components are derived by integrating the emission with velocity higher than 50 km s@xmath32 from the systemic and the lv components by integrating the emission with velocity within 50 km s@xmath32 from the systemic . two angular resolutions , and ,
are assumed , with the latter for comparing with the current observations .
model 1 here corresponds to model 1 in @xcite .
the cfw has a temperature of 10@xmath39 k and is thus atomic .
as it blows into the agb wind , it produces a collimated outflow lobe , which is a thin shell with a cavity ( fig .
[ fig : models]a ) . as shown , the shell consists of shocked agb wind in the outer shell and shocked fast wind in the inner shell ( fig .
[ fig : models]a ) .
since the shell is already radiative and thus momentum - driven even without molecular cooling , additional molecular cooling does not change the shell dynamics , it only reduces the shell thickness as compared to that in @xcite . in the shell ,
the shock becomes stronger going from near the source toward the tip of the lobe . as a result ,
the temperature of the shock agb wind increases from tens k near the source to above 10@xmath39 k near the tip ( fig .
[ fig : models]b ) .
in addition , the shocked agb wind is mainly molecular near the source but becomes mainly atomic near the tip ( except for the newly shocked agb wind ) because of shock dissociation .
in contrast , the shocked fast wind is mainly atomic . in the simulation , a jet - like structure
is seen at the tip because of the accumulation of material there due to the shock focusing effect , as discussed in @xcite .
such accumulation might be artificially enhanced in our 2d simulations because material can not flow across the symmetry axis .
this enhancement in turn would lead to more cooling and further accumulation , and then an increase in the formation rate of molecules . therefore ,
the molecular emission from the lobe tip might be highly overestimated and should be kept in mind when comparing our models to the observations . in this model ,
the lv components of the co j=2 - 1 , j=6 - 5 , and 2 emission are seen forming limb - brightened shell structures around the cavity ( fig .
[ fig : modelmoms2com ] , model 1 ) , as in the co observations ( fig .
[ fig : momobs ] ) .
they arise from the shocked agb wind in the shell .
since the temperature in the shell increases with the distance from the source , the shell structure extends further and further away from co j=2 - 1 to co j=6 - 5 and to 2 .
the co j=2 - 1 emission traces the cold ( 20 - 100 k ) gas extending to @xmath29 from the source , the co j=6 - 5 emission traces the warm gas ( 50 - 300 k ) extending to @xmath29 , and the 2 emission traces the hot gas ( @xmath29 2000 k ) extending from to . in co j=2 - 1
, however , the shell structure in this model is significantly less extended than that seen in the observations ( fig .
[ fig : momobs ] ) , indicating that the temperature in the shell in this model must have decreased less rapidly from the tip to the source than that in the observations .
no hv component is seen in this model due to the lack of molecules at high velocity , except for the jet - like structure at the tip of the lobe .
pv diagrams of co and 2 emission cut along the outflow axis together show a v - shaped pv structure extending to @xmath29 40 km s@xmath32 from the systemic , with the co emission at the lower end and the h@xmath40 emission at the upper end ( fig .
[ fig : modelpvs ] , model 1 ) . this pv structure
is associated with the lv components , arising from the shocked agb wind in the shell , which is in the expanding lobe .
this pv structure is expected , with the left and right parts from the back and front walls of the expanding lobe , respectively . in observations ,
the lv component in co j=2 - 1 also shows a hint of a v - shaped pv structure ( fig .
[ fig : pvobs ] ) and has also been modeled with an expanding lobe by @xcite .
the expansion velocity in their model , however , is @xmath29 22 km s@xmath32 , much lower than that in our model .
the upper end of the v - shaped pv structure is also expected to be seen in 2 even at low resolutions in the observations ( fig .
[ fig : modelpvs ] , model 1 ) .
however , no such pv structure is seen in 2 observations ( fig .
[ fig : pvobs ] ) .
it is likely because the outflow lobe in crl 618 indeed has a smaller expansion velocity as found in the co j=2 - 1 observations , so that the v - shaped pv structure could have been smeared out in the observations .
model 2 here corresponds to model 4 in @xcite .
the cfw here is the same as that in model 1 but with a temporal variation in density and velocity with an amplitude @xmath41 ( i.e. , @xmath42 km s@xmath32 ) and a period @xmath43 yr ( see * ? ? ?
* ) . in this model ,
a series of internal shock pairs are formed in the cavity moving along the outflow axis at high velocity , as the faster cfw catches up with the slower cfw ( figs .
[ fig : models]c , d ) .
they are mainly atomic .
they do not affect the shell dynamics .
they only produce small disturbances ( ripples ) on the shell structure in the regions where the internal shocks interact with the shell .
thus , the emission structures in co and 2 are the same as in model 1 , except that there are faint ring - like structures seen across the cavity arising from the ripples in the shell ( fig .
[ fig : modelmoms2com ] ) .
the pv diagrams are also similar to those in model 1 , except that there are faint low - velocity 2 emission near the source arising from the ripples in the shell ( fig . [
fig : modelpvs ] ) .
no hv component is seen from the internal shocks due to the lack of molecules . as a result , although this model was found to produce optical emission in the cavity with the internal shocks @xcite , it can not produce molecular emission in the cavity .
this model is the same as model 1 but with the cfw assumed to be molecular at 1000 k , in order to have hv molecular gas inside the cavity .
note that the assumed value of the temperature is not important , because the temperature of the cfw will drop rapidly below 100 k in 200 au ( or @xmath29 ) due to radial expansion and radiative cooling ( fig .
[ fig : models]f ) .
since the shell is not pressure - driven , reducing the temperature of the cfw does not change the shell dynamics ( fig .
[ fig : models]e ) . thus
, the molecular fraction of the shocked agb wind in the shell is the same as in model 1 , and so are the emission and pv structures of the lv components ( figs .
[ fig : modelmoms2com ] and [ fig : modelpvs ] ) . on the other hand , only the newly shocked fast wind in the inner boundary of the shell is molecular ( as indicated by the contours of @xmath6 , fig . [
fig : models]c ) since the shock there is weak .
it is hot , producing two hv shell structures in 2 at the far end , one at @xmath29 around @xmath29 60 km s@xmath32 and one at @xmath29 around @xmath29 100 km s@xmath32 , with the velocity increasing with the distance from the source .
the one at @xmath29 may have a counterpart at @xmath29 in the 2 observations ( see figs .
[ fig : momobs ] and [ fig : pvobs ] ) .
since the temperature of the cfw itself drops below 100 k in 200 au , hv co emission is seen arising from the cfw itself near the source .
however , due to radial expansion of the cfw itself , this hv co emission is very faint as compared with the lv component in the pv diagrams at the resolutions of the observations ( fig .
[ fig : modelpvs ] ) , inconsistent with the observations , in which the hv co component is comparable to the lv component ( fig .
[ fig : pvobs ] ) . besides ,
no hv 2 emission is seen from the cfw itself near the source .
this model is the same as model 3 but with the cfw assumed to have a temporal variation in density and velocity with an amplitude @xmath41 ( i.e. , @xmath42 km s@xmath32 ) and a period @xmath43 yr . as in model 2 , the shell structure and dynamics are not affected much by the internal shocks ( figs .
[ fig : models]g , h ) .
thus , the emission and pv structures of the lv components , which arises from the shocked agb wind in the shell , are also similar to those in model 2 .
the internal shocks , as they propagate beyond 1000 au ( @xmath29 ) from the source , become strong enough to dissociate the molecules ( fig . [
fig : models]d ) .
therefore , only the internal shock closer to @xmath29 produces hv 2 emission ( figs .
[ fig : modelmoms2com ] & [ fig : modelpvs ] ) .
these internal shocks are so strong that the molecules in the newly shocked fast wind in the inner boundary of the shell at the end of the lobe are also dissociated .
thus , unlike model 3 , no hv 2 emission is seen from the newly shocked fast wind at the far end .
this model is the same as model 4 , but with a smaller variation amplitude with a=0.3 ( i.e. , @xmath45 km s@xmath32 ) . in this case , the internal shocks are weaker , so that molecules can survive in the internal shocks except at their tips ( figs .
[ fig : models]i , j , e , see the contours of @xmath6 ) .
therefore , hv 2 emission is seen arising from the internal shocks , with the intensity decreasing rapidly with the distance due to radial expansion ( fig .
[ fig : modelmoms2com ] ) .
it is seen arising from the first three internal shocks , forming three hv emission clumps ( or knots ) that may correspond to the three hv 2 emission peaks seen in the 2 observations ( fig .
[ fig : momobs ] ) .
the hv 2 emission seen at @xmath29 2 " away from the source can be compared to that seen at similar distance in the observations . however , its kinematics , with the velocity increasing toward the tip and an emission peak at the highest velocity ( fig .
[ fig : modelpvs ] ) , is inconsistent with the observations ( fig .
[ fig : pvobs ] ) .
hv co j=6 - 5 emission is seen from the wings of the internal shocks and may show similar pv structure to that seen in the observations . however , it is too weak ( relative to the lv co j=6 - 5 emission ) to explain the observations .
in addition , the internal shocks are too hot to have co j=2 - 1 emission .
this model is the same as model 5 , but with a smaller variation amplitude with a=0.1 ( i.e. , @xmath47 km s@xmath32 ) . in this case , the internal shocks become too weak to dissociate any molecules in the internal shocks ( figs .
[ fig : models]k , l ) .
molecules also can survive in the newly shocked fast wind in the inner boundary of the shell at the far end of the lobe , producing hv 2 emission at the far end as in model 3 .
the internal shocks are cold enough to have hv co emission in j=6 - 5 , but too cold to have hv 2 emission and too hot to have hv co emission in j=2 - 1 .
in addition , due to radial expansion , the intensity of the hv co emission in j=6 - 5 at @xmath29 2 " is still too faint to be compared with the lv component ( fig .
[ fig : modelpvs ] ) , inconsistent with the observations ( figs .
[ fig : momobs ] and [ fig : pvobs ] ) .
moreover , there will be no atomic and ionic emission from the internal shocks , inconsistent with the optical observations that show atomic and ionic emission along the body of the lobe . in summary ,
limb - brightened shell structures are seen in our models in co and 2 at low velocity arising from the shocked agb wind in the shell , and can be identified as the lv components in the observations .
however , the shell structure in co j=2 - 1 is significantly less extended than that seen in the observations .
none of our models can properly reproduce the observed hv molecular emission near the source along the body of the lobe . in our models in which the cfws are atomic
, the shell has high - velocity molecular material only at the far end of the lobe .
thus , in order to produce hv molecular emission near the source , the cfw itself has to be molecular . in our steady cfw models , although there is some hv co emission near the source from the cfw itself , it is far too weak ( relative to the lv co emission ) to explain the observations .
this is because the column densities of the hv molecular material decrease very rapidly due to radial expansion . in our pulsed cfw models ,
hv 2 emission can be seen along the outflow axis arising from the internal shocks and may correspond to that seen in the observations .
however , its kinematics is inconsistent with the observations .
hv co 6 - 5 emission can be seen arising from the internal shocks and may show similar pv structure to that seen in the observations . however , it is too weak ( relative to the lv co j=6 - 5 emission ) to explain the observations .
in addition , hv co j=2 - 1 emission from the internal shocks is far too weak .
in high - resolution optical images , crl 618 is clearly seen with multiple lobes on each side and some of these lobes are not as extended as the w1 lobe ( see fig .
[ fig : momobs ] and * ? ? ?
it is thus possible that the hv component is actually associated with a small lobe that happens to be aligned with the w1 lobe , and arises from the shell instead of the internal shocks
. this small lobe could be either a highly inclined extended lobe that appears small in projection or a younger lobe that has a smaller physical linear extent compared to the w1 lobe .
our model 3 , which has molecular emission from both the shocked agb wind and shocked fast wind in the shell , can be used to investigate this possibility . at a higher inclination of 60@xmath38
, the outflow lobe has a projected length of @xmath29 . at this higher inclination
, the emission from the shocked agb wind has a higher velocity , but still much lower than the observed hv component ( fig .
[ fig : modelpvshs ] ) .
the two hv 2 emission from the shocked fast wind at the far end are now projected to @xmath29 at @xmath29 100 km s@xmath32 and @xmath29 at @xmath29 180 km s@xmath32 , respectively .
the one at can be compared with the observed 2 component at the same distance .
however , its velocity increases with the distance , inconsistent with the observations .
in addition , no hv co emission is seen from the shocked fast wind .
only faint hv co emission is seen near the source from the cfw itself . at a younger age of 86 years
, the outflow lobe also has a projected length of @xmath29 at the inclination of 30@xmath38 .
the emission from the shocked agb wind and shocked fast wind has the same velocity structure as at older age ( fig .
[ fig : modelpvshs ] ) , because the shell is momentum - driven and thus roughly self similar . the hv 2 emission from the shocked fast wind at @xmath29 may show a similar pv structure to that seen at @xmath29 in the observations .
however , no hv co emission is seen from the shocked fast wind .
again , only faint hv co emission is seen near the source from the cfw itself . as a result , adding a small lobe into our models is still not able to reproduce the observed hv co and 2 components in crl 618 properly .
the hv molecular gas in crl 618 might have a layered structure , with different temperatures and thus different emissions in different layers .
the cfw may have a different physical structure , as concluded in @xcite when comparing optical emission along the body of the lobe in our models to the observations . here
we discuss the two possible physical structures of the cfw that have been studied in the literature .
the cfw could be in a form of a cylindrical jet , with the fast wind material confined to a small cross section and collimated to the same direction along the outflow axis . in this case
, the cfw has a constant density with the distance from the source .
the observations in co j=2 - 1 also show that the hv component is better reproduced by a cylinder with the gas flowing axially @xcite .
simulations with episodic cylindrical jets have been performed by a number of authors in order to reproduce the morphology and kinematics of protostellar outflows ( e.g. , * ? ? ?
* ; * ? ? ?
such jets can also produce a series of internal bow shocks with hv co and 2 emissions along the body of the lobe @xcite . without radial expansion , the emission of these bow shocks does not decrease as fast as that in our current models .
in addition , unlike those in our current models , the shocks are ballistic @xcite .
the cylindrical jet models have been applied to pns @xcite and may apply to ppns as well .
the jet is likely to be magnetized because the magnetic field can provide the required collimation .
in addition , a magnetized jet has also been found to better reproduce the jet emission in the young pn hen 2 - 90 than an unmagnetized jet @xcite .
the jet could be launched by magneto - centrifugal forces from a magnetized accretion disk and star system @xcite , like the protostellar jets @xcite .
the central star could have a binary companion and the accretion disk could form as the material flows to the companion @xcite . recently ,
a bullet ( i.e. , a massive clump ) model has also been proposed for ppn shaping because it can also produce a collimated outflow lobe @xcite .
the bullet could be launched by an explosive mhd mechanism ( see , e.g. , * ? ? ?
it is not clear , however , how a bullet can produce hv molecular emission near the source along the body of the lobe .
one way that we can think of is to have a chain of bullets along the body of the lobe .
note that , however , a jet model with a periodic variation in velocity has been found to be better than a model with a chain of bullets or dense clumps , in reproducing the knotty jet emission in the young pn hen 2 - 90 ( e.g. , comparing models 1 and 2 in * ? ? ?
@xcite , having compared their jet and bullet models , argued that the bow - shock heads of bullets take on a v - shaped configuration and are thus more consistent with the observations of crl 618 , whereas bow - shock heads of jets are more u - shaped .
however , the assumed density and thus the mass - loss rate of the agb wind in their models are about a factor of 1000 less than those assumed in our models , which are more appropriate for crl 618 @xcite . with a high density of the agb wind
as observed , the jet model has been found to produce v - shaped heads ( see , e.g. , * ? ? ?
* ; * ? ? ?
* ) similar to that seen in crl 618 , because of efficient cooling at high density .
the jet model in @xcite may instead apply to another ppn oh 231.8 + 4.2 , which shows a wide and more u - shaped outflow lobe @xcite . in our models ,
the cfw is assumed to be molecular in order to have hv molecular emission near the source along the body of the lobe .
it could be intrinsically molecular .
it could also be intrinsically atomic and become molecular right after launched due to its high mass - loss rate , as proposed for protostellar wind @xcite .
alternatively , the hv molecular emission could arise from the entrained agb material that was originally close to the source , as suggested by @xcite , or in the inner dense torus - like core around the source , as suggested by @xcite .
it is not clear in our simulations , however , how this entrainment can happen once the shell is formed and shields the fast wind from being interacting with the agb wind around the source .
it probably can happen if the fast wind is actually launched from around a binary companion .
as the agb wind flows to the companion , an accretion disk can form @xcite and launch the fast wind , and then the fast wind can entrain the agb wind .
we have presented simulations of cfw models including molecular cooling and time dependent chemistry of hydrogen . we have also derived from our simulations intensity maps and position velocity diagrams for co j=2 - 1 , j=6 - 5 , and 2 1 - 0 s(1 ) emission and compared them to recent observations of crl 618 . in our models ,
limb - brightened shell structures are seen in co and 2 at low velocity arising from the shocked agb wind in the shell , and can be identified as the low - velocity ( lv ) components in the observations .
however , the shell structure in co j=2 - 1 is significantly less extended than that seen in the observations .
none of our models can properly reproduce the observed high - velocity ( hv ) molecular emission near the source along the body of the lobe . in order to reproduce the hv molecular emission ,
the cfw is required to have a different structure .
one possible cfw structure is the cylindrical jet , with the fast wind material confined to a small cross section and collimated to the same direction along the outflow axis .
lee and m .- c .
hsu are financially supported by the nsc grant nsc96 - 2112-m-001 - 014-my3 .
rs thanks nasa for funding this work via an ltsa award ( nmo710840 - 102898 ) ; rs also received partial support for this work from an hst go award ( no .
go-10317.01 ) from the space telescope science institute ( operated by the association of universities for research in astronomy , inc . , under nasa
contract nas5 - 26555 ) .
some of the research described in this paper was carried out by rs at the jet propulsion laboratory , california institute of technology , under a contract with the national aeronautics and space administration .
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this paper is a follow - up to our previous study of cfw models for the well - studied ppn crl 618 .
previously , we compared our cfw models with optical observations of crl 618 in atomic and ionic lines and found that a cfw with a small opening angle can readily reproduce the highly collimated shape of the northwestern ( w1 ) lobe of crl 618 and the bow - like structure seen at its tip . in this paper
, we compare our cfw models with recent observations of crl 618 in co j=2 - 1 , j=6 - 5 , and 2 1 - 0 s(1 ) . in our models ,
limb - brightened shell structures are seen in co and 2 at low velocity arising from the shocked agb wind in the shell , and can be identified as the low - velocity ( lv ) components in the observations .
however , the shell structure in co j=2 - 1 is significantly less extended than that seen in the observations .
none of our models can properly reproduce the observed high - velocity ( hv ) molecular emission near the source along the body of the lobe . in order to reproduce the hv molecular emission in crl 618
, the cfw is required to have a different structure .
one possible cfw structure is the cylindrical jet , with the fast wind material confined to a small cross section and collimated to the same direction along the outflow axis . | <s>[INST]at the end of the evolution of low- and intermediate - mass stars , pre - planetary nebulae ( ppns ) are seen associated with post asymptotic giant branch ( post - agb ) stars .
they will turn into planetary nebulae ( pns ) in less than 1000 years as the post - agb stars become hot white dwarfs .
their shaping mechanism is still unclear and is closely related to the mass - loss processes during the end phases of the evolution .
many ppns and young pns were found to have highly aspherical shapes , with a significant fraction having highly collimated bipolar or multipolar lobes @xcite .
point symmetry , rather than axisymmetry , better characterizes the geometry of the majority of these objects [ striking examples are he2 - 115 @xcite and he3 - 1475 @xcite ] . as a result , instead of spherical fast winds as in the generalized interacting stellar winds ( gisw ) model ( see e.g. , review by * ? ? ?
* ) , collimated fast winds have been proposed to operate during the post - agb phase ( and even earlier during the late agb phase ) , and be the primary agents for the shaping of ppns and young pns @xcite . collimated fast wind ( cfw ) models have been used to account for the morphology and kinematics of a few well - studied ppns and pns , with some assuming a radial wind with a small opening angle ( lee & sahai 2003 , hereafter @xcite ; * ? ? ?
* ) , some assuming a cylindrical jet either unmagnetized @xcite or magnetized @xcite , and some assuming a bullet ( a massive clump ) along the outflow axis @xcite .
this paper is a follow - up to our previous study of cfw models for the well - studied ppn crl 618 @xcite .
crl 618 is located at a distance of 900 pc @xcite .
it shows several narrow lobes at different orientations in hst images @xcite and belongs to the multipolar " morphological classification @xcite , perhaps resulting from multiple ejections at different orientations .
the general structures of the different lobes are similar and we focus only on the northwestern ( w1 ) lobe , which seems to be better separated from other lobes . in @xcite , we compared our cfw models with optical observations of crl 618 in atomic and ionic lines and found that a cfw with a small opening angle can readily reproduce the highly collimated shape of the w1 lobe and the bow - like structure seen at its tip @xcite .
however , it may have difficulties in reproducing properly the high - velocity optical emission along the body of the lobe . in this paper
, we compare our cfw models with recent observations of crl 618 in 2 1 - 0 s(1 ) @xcite , co j=2 - 1 @xcite and j=6 - 5 @xcite .
we find that our cfw models also have difficulties in reproducing the high - velocity molecular emission in the w1 lobe and the cfw is required to have a different physical structure .
the two - dimensional hydrodynamic code , zeus 2d , is used for the simulations of our models , as in @xcite .
this code has been now modified to include molecular cooling and the time dependent chemistry of hydrogen by solving the following equations ( see also * ? ? ?
* ) : @xmath0 where @xmath1 , @xmath2 , @xmath3 , and @xmath4 are the internal energy density , thermal pressure , velocity , and temperature , respectively .
also , @xmath5 is the hydrogen nuclei density , @xmath6 is the fractional part of hydrogen molecules with @xmath7 ( i.e. , @xmath8 for atomic / ionic gas and @xmath9 for molecular gas ) , and @xmath10 is the fractional part of ionized hydrogen with @xmath11 .
helium is included as a neutral component with @xmath12 and thus @xmath13 , where @xmath14 and @xmath15 are the mass density and the mass of atomic hydrogen , respectively . here
@xmath16 and @xmath17 are dissociation and ressociation rates of molecular hydrogen , respectively ( see * ? ? ?
* and reference therein ) , @xmath18 and @xmath19 are ionization and recombination rates of atomic hydrogen , respectively .
@xmath20 is the optically thin radiative cooling from atoms and ions ( as in * ? ? ?
* ) , with the cooling at high temperature from @xcite and low temperature from @xcite .
@xmath21 is the optically thin radiative cooling from molecules , including 2 @xcite and co @xcite .
the chemistry of co is not included .
the co abundance is assumed to be constant and equal to 2@xmath22 of the number of hydrogen molecules , as in @xcite .
we believe this assumption does not significantly affect our conclusions , it only affects the small - scale structure of the co emission .
the equations of state and material coefficients are ( for similar derivation see * ? ? ?
* ) : @xmath23 where @xmath24 , @xmath25 , and @xmath26 are the boltzmann constant , mean molecular weight , and specific heat , respectively . a scalar color tracer @xmath27 is also included in the simulations to track the fast wind , it is one for the fast wind , zero for the agb wind , and a value between one and zero for a mixture of the fast wind and agb wind . as in @xcite ,
the simulations are performed in spherical coordinates but presented in cylindrical coordinates ( z , r ) , with the z - axis being the outflow axis .
our cfw models are based on models 1 and 4 in @xcite , which were found to be the best models for the w1 lobe of crl 618 as seen at optical wavelengths . in these models , a cfw with a small opening angle is assumed to emanate radially from the vicinity of the post - agb star , interacting with a spherical agb wind ( for details see * ? ? ?
* ) . in our simulations ,
the cfw is launched from the inner boundary of the simulation domain , which is at 5@xmath28 cm ( @xmath29 333 au ) away from the post - agb star .
the agb wind is assumed to be molecular with a temperature of 10 k and have a mass - loss rate of @xmath30 m@xmath31 yr@xmath32 with an expansion velocity of @xmath33 km s@xmath32 .
the cfw is assumed to have a mass - loss rate of 2.5@xmath34 m@xmath31 yr@xmath32 , a speed of 300 km s@xmath32 , and an opening angle of @xmath35 .
it can either be steady or pulsed with a temporal variation in the density and velocity ( see table [ tab : models ] ) .
it can be either atomic or molecular , depending on the temperature of the cfw to be assumed .
crl 618 has been recently observed in 2 1 - 0 s(1 ) at @xmath29 resolution @xcite and in co j=2 - 1 @xcite and j=6 - 5 @xcite at @xmath29 resolution ( see figs . [
fig : momobs ] and [ fig : pvobs ] ) .
it is multipolar , but here we focus only on its w1 lobe that extends @xmath29 to the west from the source .
the systemic velocity in this region is @xmath3621.5 km s@xmath32 lsr and the w1 lobe is mainly redshifted with a velocity ranging from -40 to 150 km s@xmath32 lsr .
the co and 2 emission toward the w1 lobe can be roughly separated into two components : a slow or low - velocity ( lv ) component with a velocity lower than @xmath29 20@xmath3630 km s@xmath32 from the systemic and a fast or high - velocity ( hv ) component with a velocity extending to @xmath29 170 km s@xmath32 from the systemic .
the lv component is extended . in co j=2 - 1
, it forms a limb - brightened shell structure around the optical lobe , extending to @xmath29 away from the source . in co j=6 - 5
, it also forms a shell structure but only in the southern part of the lobe , extending to only @xmath29 away from the source . as discussed in @xcite , however , it should be more extended , because most of the extended flux has been resolved out in their observations . in 2 ,
it is spatially unresolved , extending mainly from to from the source , slightly ahead of that seen in co j=2 - 1 . on the other hand ,
the hv component is more compact . in co j=2 - 1
, it extends to @xmath29 away from the source with the velocity increasing linearly with the distance from near the systemic velocity to the highest velocity . in 2 , it is seen with three localized emission peaks separated by @xmath29 : ( 1 ) a peak close to the source with a range of ( blueshifted and redshifted ) velocities , ( 2 ) a bright peak at @xmath29 , where the tip of the co hv component is , with a broad range of velocities extending from near the systemic velocity to the highest velocity , and ( 3 ) a faint peak at @xmath29 at @xmath29 80 km s@xmath32 lsr .
in the following , we present our models and the comparison with the observations . figure [ fig : models ] shows the distributions of hydrogen nuclei density and temperature with molecular fraction in our models at the age of @xmath29 160 yrs , when the outflow lobe has a length of @xmath29 6000 au , similar to the deprojected length of the w1 lobe of crl 618 .
the separation between the agb wind and the cfw is delineated by the color tracer @xmath37 , at which half is the agb wind and half is the cfw . in order to compare with the observations
, we also derive intensity maps of the lv and hv components ( fig .
[ fig : modelmoms2com ] ) and position velocity ( pv ) diagrams ( fig .
[ fig : modelpvs ] ) for the co j=2 - 1 , j=6 - 5 , and 2 1 - 0 s(1 ) emission from our models , assuming the latter to be optically thin and arising from gas in local thermal equilibrium ( lte ) .
we assume a distance of 900 pc and an inclination of 30@xmath38 , values appropriate for crl 618 @xcite .
the hv components are derived by integrating the emission with velocity higher than 50 km s@xmath32 from the systemic and the lv components by integrating the emission with velocity within 50 km s@xmath32 from the systemic . two angular resolutions , and ,
are assumed , with the latter for comparing with the current observations .
model 1 here corresponds to model 1 in @xcite .
the cfw has a temperature of 10@xmath39 k and is thus atomic .
as it blows into the agb wind , it produces a collimated outflow lobe , which is a thin shell with a cavity ( fig .
[ fig : models]a ) . as shown , the shell consists of shocked agb wind in the outer shell and shocked fast wind in the inner shell ( fig .
[ fig : models]a ) .
since the shell is already radiative and thus momentum - driven even without molecular cooling , additional molecular cooling does not change the shell dynamics , it only reduces the shell thickness as compared to that in @xcite . in the shell ,
the shock becomes stronger going from near the source toward the tip of the lobe . as a result ,
the temperature of the shock agb wind increases from tens k near the source to above 10@xmath39 k near the tip ( fig .
[ fig : models]b ) .
in addition , the shocked agb wind is mainly molecular near the source but becomes mainly atomic near the tip ( except for the newly shocked agb wind ) because of shock dissociation .
in contrast , the shocked fast wind is mainly atomic . in the simulation , a jet - like structure
is seen at the tip because of the accumulation of material there due to the shock focusing effect , as discussed in @xcite .
such accumulation might be artificially enhanced in our 2d simulations because material can not flow across the symmetry axis .
this enhancement in turn would lead to more cooling and further accumulation , and then an increase in the formation rate of molecules . therefore ,
the molecular emission from the lobe tip might be highly overestimated and should be kept in mind when comparing our models to the observations . in this model ,
the lv components of the co j=2 - 1 , j=6 - 5 , and 2 emission are seen forming limb - brightened shell structures around the cavity ( fig .
[ fig : modelmoms2com ] , model 1 ) , as in the co observations ( fig .
[ fig : momobs ] ) .
they arise from the shocked agb wind in the shell .
since the temperature in the shell increases with the distance from the source , the shell structure extends further and further away from co j=2 - 1 to co j=6 - 5 and to 2 .
the co j=2 - 1 emission traces the cold ( 20 - 100 k ) gas extending to @xmath29 from the source , the co j=6 - 5 emission traces the warm gas ( 50 - 300 k ) extending to @xmath29 , and the 2 emission traces the hot gas ( @xmath29 2000 k ) extending from to . in co j=2 - 1
, however , the shell structure in this model is significantly less extended than that seen in the observations ( fig .
[ fig : momobs ] ) , indicating that the temperature in the shell in this model must have decreased less rapidly from the tip to the source than that in the observations .
no hv component is seen in this model due to the lack of molecules at high velocity , except for the jet - like structure at the tip of the lobe .
pv diagrams of co and 2 emission cut along the outflow axis together show a v - shaped pv structure extending to @xmath29 40 km s@xmath32 from the systemic , with the co emission at the lower end and the h@xmath40 emission at the upper end ( fig .
[ fig : modelpvs ] , model 1 ) . this pv structure
is associated with the lv components , arising from the shocked agb wind in the shell , which is in the expanding lobe .
this pv structure is expected , with the left and right parts from the back and front walls of the expanding lobe , respectively . in observations ,
the lv component in co j=2 - 1 also shows a hint of a v - shaped pv structure ( fig .
[ fig : pvobs ] ) and has also been modeled with an expanding lobe by @xcite .
the expansion velocity in their model , however , is @xmath29 22 km s@xmath32 , much lower than that in our model .
the upper end of the v - shaped pv structure is also expected to be seen in 2 even at low resolutions in the observations ( fig .
[ fig : modelpvs ] , model 1 ) .
however , no such pv structure is seen in 2 observations ( fig .
[ fig : pvobs ] ) .
it is likely because the outflow lobe in crl 618 indeed has a smaller expansion velocity as found in the co j=2 - 1 observations , so that the v - shaped pv structure could have been smeared out in the observations .
model 2 here corresponds to model 4 in @xcite .
the cfw here is the same as that in model 1 but with a temporal variation in density and velocity with an amplitude @xmath41 ( i.e. , @xmath42 km s@xmath32 ) and a period @xmath43 yr ( see * ? ? ?
* ) . in this model ,
a series of internal shock pairs are formed in the cavity moving along the outflow axis at high velocity , as the faster cfw catches up with the slower cfw ( figs .
[ fig : models]c , d ) .
they are mainly atomic .
they do not affect the shell dynamics .
they only produce small disturbances ( ripples ) on the shell structure in the regions where the internal shocks interact with the shell .
thus , the emission structures in co and 2 are the same as in model 1 , except that there are faint ring - like structures seen across the cavity arising from the ripples in the shell ( fig .
[ fig : modelmoms2com ] ) .
the pv diagrams are also similar to those in model 1 , except that there are faint low - velocity 2 emission near the source arising from the ripples in the shell ( fig . [
fig : modelpvs ] ) .
no hv component is seen from the internal shocks due to the lack of molecules . as a result , although this model was found to produce optical emission in the cavity with the internal shocks @xcite , it can not produce molecular emission in the cavity .
this model is the same as model 1 but with the cfw assumed to be molecular at 1000 k , in order to have hv molecular gas inside the cavity .
note that the assumed value of the temperature is not important , because the temperature of the cfw will drop rapidly below 100 k in 200 au ( or @xmath29 ) due to radial expansion and radiative cooling ( fig .
[ fig : models]f ) .
since the shell is not pressure - driven , reducing the temperature of the cfw does not change the shell dynamics ( fig .
[ fig : models]e ) . thus
, the molecular fraction of the shocked agb wind in the shell is the same as in model 1 , and so are the emission and pv structures of the lv components ( figs .
[ fig : modelmoms2com ] and [ fig : modelpvs ] ) . on the other hand , only the newly shocked fast wind in the inner boundary of the shell is molecular ( as indicated by the contours of @xmath6 , fig . [
fig : models]c ) since the shock there is weak .
it is hot , producing two hv shell structures in 2 at the far end , one at @xmath29 around @xmath29 60 km s@xmath32 and one at @xmath29 around @xmath29 100 km s@xmath32 , with the velocity increasing with the distance from the source .
the one at @xmath29 may have a counterpart at @xmath29 in the 2 observations ( see figs .
[ fig : momobs ] and [ fig : pvobs ] ) .
since the temperature of the cfw itself drops below 100 k in 200 au , hv co emission is seen arising from the cfw itself near the source .
however , due to radial expansion of the cfw itself , this hv co emission is very faint as compared with the lv component in the pv diagrams at the resolutions of the observations ( fig .
[ fig : modelpvs ] ) , inconsistent with the observations , in which the hv co component is comparable to the lv component ( fig .
[ fig : pvobs ] ) . besides ,
no hv 2 emission is seen from the cfw itself near the source .
this model is the same as model 3 but with the cfw assumed to have a temporal variation in density and velocity with an amplitude @xmath41 ( i.e. , @xmath42 km s@xmath32 ) and a period @xmath43 yr . as in model 2 , the shell structure and dynamics are not affected much by the internal shocks ( figs .
[ fig : models]g , h ) .
thus , the emission and pv structures of the lv components , which arises from the shocked agb wind in the shell , are also similar to those in model 2 .
the internal shocks , as they propagate beyond 1000 au ( @xmath29 ) from the source , become strong enough to dissociate the molecules ( fig . [
fig : models]d ) .
therefore , only the internal shock closer to @xmath29 produces hv 2 emission ( figs .
[ fig : modelmoms2com ] & [ fig : modelpvs ] ) .
these internal shocks are so strong that the molecules in the newly shocked fast wind in the inner boundary of the shell at the end of the lobe are also dissociated .
thus , unlike model 3 , no hv 2 emission is seen from the newly shocked fast wind at the far end .
this model is the same as model 4 , but with a smaller variation amplitude with a=0.3 ( i.e. , @xmath45 km s@xmath32 ) . in this case , the internal shocks are weaker , so that molecules can survive in the internal shocks except at their tips ( figs .
[ fig : models]i , j , e , see the contours of @xmath6 ) .
therefore , hv 2 emission is seen arising from the internal shocks , with the intensity decreasing rapidly with the distance due to radial expansion ( fig .
[ fig : modelmoms2com ] ) .
it is seen arising from the first three internal shocks , forming three hv emission clumps ( or knots ) that may correspond to the three hv 2 emission peaks seen in the 2 observations ( fig .
[ fig : momobs ] ) .
the hv 2 emission seen at @xmath29 2 " away from the source can be compared to that seen at similar distance in the observations . however , its kinematics , with the velocity increasing toward the tip and an emission peak at the highest velocity ( fig .
[ fig : modelpvs ] ) , is inconsistent with the observations ( fig .
[ fig : pvobs ] ) .
hv co j=6 - 5 emission is seen from the wings of the internal shocks and may show similar pv structure to that seen in the observations . however , it is too weak ( relative to the lv co j=6 - 5 emission ) to explain the observations .
in addition , the internal shocks are too hot to have co j=2 - 1 emission .
this model is the same as model 5 , but with a smaller variation amplitude with a=0.1 ( i.e. , @xmath47 km s@xmath32 ) . in this case , the internal shocks become too weak to dissociate any molecules in the internal shocks ( figs .
[ fig : models]k , l ) .
molecules also can survive in the newly shocked fast wind in the inner boundary of the shell at the far end of the lobe , producing hv 2 emission at the far end as in model 3 .
the internal shocks are cold enough to have hv co emission in j=6 - 5 , but too cold to have hv 2 emission and too hot to have hv co emission in j=2 - 1 .
in addition , due to radial expansion , the intensity of the hv co emission in j=6 - 5 at @xmath29 2 " is still too faint to be compared with the lv component ( fig .
[ fig : modelpvs ] ) , inconsistent with the observations ( figs .
[ fig : momobs ] and [ fig : pvobs ] ) .
moreover , there will be no atomic and ionic emission from the internal shocks , inconsistent with the optical observations that show atomic and ionic emission along the body of the lobe . in summary ,
limb - brightened shell structures are seen in our models in co and 2 at low velocity arising from the shocked agb wind in the shell , and can be identified as the lv components in the observations .
however , the shell structure in co j=2 - 1 is significantly less extended than that seen in the observations .
none of our models can properly reproduce the observed hv molecular emission near the source along the body of the lobe . in our models in which the cfws are atomic
, the shell has high - velocity molecular material only at the far end of the lobe .
thus , in order to produce hv molecular emission near the source , the cfw itself has to be molecular . in our steady cfw models , although there is some hv co emission near the source from the cfw itself , it is far too weak ( relative to the lv co emission ) to explain the observations .
this is because the column densities of the hv molecular material decrease very rapidly due to radial expansion . in our pulsed cfw models ,
hv 2 emission can be seen along the outflow axis arising from the internal shocks and may correspond to that seen in the observations .
however , its kinematics is inconsistent with the observations .
hv co 6 - 5 emission can be seen arising from the internal shocks and may show similar pv structure to that seen in the observations . however , it is too weak ( relative to the lv co j=6 - 5 emission ) to explain the observations .
in addition , hv co j=2 - 1 emission from the internal shocks is far too weak .
in high - resolution optical images , crl 618 is clearly seen with multiple lobes on each side and some of these lobes are not as extended as the w1 lobe ( see fig .
[ fig : momobs ] and * ? ? ?
it is thus possible that the hv component is actually associated with a small lobe that happens to be aligned with the w1 lobe , and arises from the shell instead of the internal shocks
. this small lobe could be either a highly inclined extended lobe that appears small in projection or a younger lobe that has a smaller physical linear extent compared to the w1 lobe .
our model 3 , which has molecular emission from both the shocked agb wind and shocked fast wind in the shell , can be used to investigate this possibility . at a higher inclination of 60@xmath38
, the outflow lobe has a projected length of @xmath29 . at this higher inclination
, the emission from the shocked agb wind has a higher velocity , but still much lower than the observed hv component ( fig .
[ fig : modelpvshs ] ) .
the two hv 2 emission from the shocked fast wind at the far end are now projected to @xmath29 at @xmath29 100 km s@xmath32 and @xmath29 at @xmath29 180 km s@xmath32 , respectively .
the one at can be compared with the observed 2 component at the same distance .
however , its velocity increases with the distance , inconsistent with the observations .
in addition , no hv co emission is seen from the shocked fast wind .
only faint hv co emission is seen near the source from the cfw itself . at a younger age of 86 years
, the outflow lobe also has a projected length of @xmath29 at the inclination of 30@xmath38 .
the emission from the shocked agb wind and shocked fast wind has the same velocity structure as at older age ( fig .
[ fig : modelpvshs ] ) , because the shell is momentum - driven and thus roughly self similar . the hv 2 emission from the shocked fast wind at @xmath29 may show a similar pv structure to that seen at @xmath29 in the observations .
however , no hv co emission is seen from the shocked fast wind .
again , only faint hv co emission is seen near the source from the cfw itself . as a result , adding a small lobe into our models is still not able to reproduce the observed hv co and 2 components in crl 618 properly .
the hv molecular gas in crl 618 might have a layered structure , with different temperatures and thus different emissions in different layers .
the cfw may have a different physical structure , as concluded in @xcite when comparing optical emission along the body of the lobe in our models to the observations . here
we discuss the two possible physical structures of the cfw that have been studied in the literature .
the cfw could be in a form of a cylindrical jet , with the fast wind material confined to a small cross section and collimated to the same direction along the outflow axis . in this case
, the cfw has a constant density with the distance from the source .
the observations in co j=2 - 1 also show that the hv component is better reproduced by a cylinder with the gas flowing axially @xcite .
simulations with episodic cylindrical jets have been performed by a number of authors in order to reproduce the morphology and kinematics of protostellar outflows ( e.g. , * ? ? ?
* ; * ? ? ?
such jets can also produce a series of internal bow shocks with hv co and 2 emissions along the body of the lobe @xcite . without radial expansion , the emission of these bow shocks does not decrease as fast as that in our current models .
in addition , unlike those in our current models , the shocks are ballistic @xcite .
the cylindrical jet models have been applied to pns @xcite and may apply to ppns as well .
the jet is likely to be magnetized because the magnetic field can provide the required collimation .
in addition , a magnetized jet has also been found to better reproduce the jet emission in the young pn hen 2 - 90 than an unmagnetized jet @xcite .
the jet could be launched by magneto - centrifugal forces from a magnetized accretion disk and star system @xcite , like the protostellar jets @xcite .
the central star could have a binary companion and the accretion disk could form as the material flows to the companion @xcite . recently ,
a bullet ( i.e. , a massive clump ) model has also been proposed for ppn shaping because it can also produce a collimated outflow lobe @xcite .
the bullet could be launched by an explosive mhd mechanism ( see , e.g. , * ? ? ?
it is not clear , however , how a bullet can produce hv molecular emission near the source along the body of the lobe .
one way that we can think of is to have a chain of bullets along the body of the lobe .
note that , however , a jet model with a periodic variation in velocity has been found to be better than a model with a chain of bullets or dense clumps , in reproducing the knotty jet emission in the young pn hen 2 - 90 ( e.g. , comparing models 1 and 2 in * ? ? ?
@xcite , having compared their jet and bullet models , argued that the bow - shock heads of bullets take on a v - shaped configuration and are thus more consistent with the observations of crl 618 , whereas bow - shock heads of jets are more u - shaped .
however , the assumed density and thus the mass - loss rate of the agb wind in their models are about a factor of 1000 less than those assumed in our models , which are more appropriate for crl 618 @xcite . with a high density of the agb wind
as observed , the jet model has been found to produce v - shaped heads ( see , e.g. , * ? ? ?
* ; * ? ? ?
* ) similar to that seen in crl 618 , because of efficient cooling at high density .
the jet model in @xcite may instead apply to another ppn oh 231.8 + 4.2 , which shows a wide and more u - shaped outflow lobe @xcite . in our models ,
the cfw is assumed to be molecular in order to have hv molecular emission near the source along the body of the lobe .
it could be intrinsically molecular .
it could also be intrinsically atomic and become molecular right after launched due to its high mass - loss rate , as proposed for protostellar wind @xcite .
alternatively , the hv molecular emission could arise from the entrained agb material that was originally close to the source , as suggested by @xcite , or in the inner dense torus - like core around the source , as suggested by @xcite .
it is not clear in our simulations , however , how this entrainment can happen once the shell is formed and shields the fast wind from being interacting with the agb wind around the source .
it probably can happen if the fast wind is actually launched from around a binary companion .
as the agb wind flows to the companion , an accretion disk can form @xcite and launch the fast wind , and then the fast wind can entrain the agb wind .
we have presented simulations of cfw models including molecular cooling and time dependent chemistry of hydrogen . we have also derived from our simulations intensity maps and position velocity diagrams for co j=2 - 1 , j=6 - 5 , and 2 1 - 0 s(1 ) emission and compared them to recent observations of crl 618 . in our models ,
limb - brightened shell structures are seen in co and 2 at low velocity arising from the shocked agb wind in the shell , and can be identified as the low - velocity ( lv ) components in the observations .
however , the shell structure in co j=2 - 1 is significantly less extended than that seen in the observations .
none of our models can properly reproduce the observed high - velocity ( hv ) molecular emission near the source along the body of the lobe . in order to reproduce the hv molecular emission ,
the cfw is required to have a different structure .
one possible cfw structure is the cylindrical jet , with the fast wind material confined to a small cross section and collimated to the same direction along the outflow axis .
lee and m .- c .
hsu are financially supported by the nsc grant nsc96 - 2112-m-001 - 014-my3 .
rs thanks nasa for funding this work via an ltsa award ( nmo710840 - 102898 ) ; rs also received partial support for this work from an hst go award ( no .
go-10317.01 ) from the space telescope science institute ( operated by the association of universities for research in astronomy , inc . , under nasa
contract nas5 - 26555 ) .
some of the research described in this paper was carried out by rs at the jet propulsion laboratory , california institute of technology , under a contract with the national aeronautics and space administration .
akashi , m. , & soker , n. 2008 , arxiv e - prints , 805 , arxiv:0805.2332 balick , b. , & frank , a. 2002 , ara&a , 40 , 439 blackman , e. g. , frank , a. , & welch , c. 2001 , , 546 , 288 borkoski , k. j. , blondin , j. m. , & harrington , j. p. 1997
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, 2007 , aj , 134 , 2035 sahai , r. 2001 , in post - agb objects as a phase of stellar evolution , ed .
r. szczerba & s.k .
gorny ( dordrecht : kluwer),53 sahai , r. , & trauger , j.t .
1998 , aj , 116 , 1357 sahai , r. , morris , m. , snchez contreras , c. , & claussen , m. 2007 , , 134 , 2200 snchez contreras , c. , & sahai , r. & gil de paz , a 2002 , , 578 , 269 snchez contreras , c. , bujarrabal , v. , castro - carrizo , a. , alcolea , j. , & sargent , a .. 2004 , , 617 , 1142 schwarz , h. e. , aspin , c. , corradi , r. l. m. , & reipurth , b. 1997 , , 319 , 267 shu , f. , najita , j. , ostriker , e. , wilkin , f. , ruden , s. , & lizano , s. 1994 , , 429 , 781 steffen , w. , & lopez , j. a. 1998 , , 508 , 696 suttner , g. , smith , m. d. , yorke , h. w. , & zinneeker , h. 1997 , a&a , 318 , 595 trammell , s. r. , & goodrich , r. w. 2002 , , 579 , 688 lccc 1 & 10@xmath39 & atomic & steady + 2 & 10@xmath39 & atomic & pulsed with @xmath41 + 3 & 10@xmath48 & molecular & steady + 4 & 10@xmath48 & molecular & pulsed with @xmath41 + 5 & 10@xmath48 & molecular & pulsed with @xmath44 + 6 & 10@xmath48 & molecular & pulsed with @xmath46 +[/INST] collimated fast winds ( cfws ) have been proposed to operate during the post - agb evolutionary phase ( and even earlier during the late agb phase ) , responsible for the shaping of pre - planetary nebulae ( ppns ) and young planetary nebulae ( pns ) .
this paper is a follow - up to our previous study of cfw models for the well - studied ppn crl 618 .
previously , we compared our cfw models with optical observations of crl 618 in atomic and ionic lines and found that a cfw with a small opening angle can readily reproduce the highly collimated shape of the northwestern ( w1 ) lobe of crl 618 and the bow - like structure seen at its tip . in this paper
, we compare our cfw models with recent observations of crl 618 in co j=2 - 1 , j=6 - 5 , and 2 1 - 0 s(1 ) . in our models ,
limb - brightened shell structures are seen in co and 2 at low velocity arising from the shocked agb wind in the shell , and can be identified as the low - velocity ( lv ) components in the observations .
however , the shell structure in co j=2 - 1 is significantly less extended than that seen in the observations .
none of our models can properly reproduce the observed high - velocity ( hv ) molecular emission near the source along the body of the lobe . in order to reproduce the hv molecular emission in crl 618
, the cfw is required to have a different structure .
one possible cfw structure is the cylindrical jet , with the fast wind material confined to a small cross section and collimated to the same direction along the outflow axis . </s> |
massive stars ( @xmath58 m@xmath6 ) play a crucial role in the evolution of their host galaxies , but their exact formation and evolution mechanisms are still under debate @xcite .
it is not yet understood whether the formation of massive stars is only a scaled - up version of birth process of low mass stars , or is it a completely different process .
one can find more details about the current theoretical scenarios of massive star formation in the recent reviews by @xcite and @xcite .
recently , a collision between two molecular clouds followed by a strong shock compression of gas is considered as a probable formation mechanism of massive stars @xcite . @xcite
numerically found that the head - on collision between two non - identical molecular clouds can trigger the formation of massive stars , and such process could also form a broken bubble - like structure . in a detailed study of rcw 120 star - forming region using the molecular line data , @xcite reported that the collision between two nearby molecular clouds has triggered the formation of an o star in rcw 120 in a short time scale .
however , observational evidences for the formation of o stars via a collision between two molecular clouds are still very rare .
massive stars can significantly influence the surrounding interstellar medium ( ism ) through their energetics such as ionizing radiation , stellar winds , and radiation pressure .
they have an ability to help in accumulation of surrounding materials ( i.e. , positive feedback ) and/or to disperse matter into the ism .
furthermore , they can also affect the star formation positively and negatively @xcite .
the positive feedback of massive stars can trigger the birth of a new generation of stars including young massive star(s ) .
more details about the various processes of triggered star formation can be found in the review article by @xcite .
however , the feedback processes of massive stars are not yet well understood , and the direct observational proof of triggered star formation by massive stars is rare .
but the influence of massive stars on their surroundings can be studied with several other observational signatures ( like h ii region , wind - blown or radiation driven galactic bubble , etc . ) .
recently , _ spitzer _
observations have revealed thousands of ring / shell / bubble - like structures in the 8 @xmath7 m images @xcite , and many of them often enclose the hii regions .
hence , the bubbles associated with hii regions are potential targets to probe the physical processes governing the interaction and feedback effect of massive stars on their surroundings .
additionally , these sites are often grouped with the infrared dark clouds ( irdcs ) and young stellar clusters , which also allow to understand the formation and evolution of these stellar clusters . in this paper , we present a multi - wavelength study of such a mid - infrared ( mir ) bubble , n37 ( @xmath8 [email protected] , @xmath10 [email protected] ; * ? ? ?
* ) , which is associated with an hii region , g025.292 + 00.293 @xcite .
the bubble n37 is classified as a broken or incomplete ring with an average radius and thickness of 1@xmath1177 and 0@xmath1149 , respectively @xcite .
the bubble is found in the direction of the hii region rcw 173 ( sh2 - 60 ) ( see figure 9 in * ? ? ?
the velocity of the ionized gas ( @xmath1239.6 kms@xmath3 ; * ? ? ?
* ) is in agreement with the line - of - sight velocity of the molecular gas ( @xmath1241 kms@xmath3 ; * ? ? ?
* ; * ? ? ?
* ) towards the bubble
n37 , indicating the physical association of the ionized and molecular emissions . presence of several irdcs are also reported around the n37 bubble by @xcite .
@xcite analyzed the photometry and spectroscopy of stars in the direction of the hii region , rcw 173 , and found that most of the stars in the field are reddened b - type stars .
they also identified a star a805 ( g025.2465 + 00.3011 ) having spectral type of o7ii and suggested this as the main ionizing source in the area .
several kinematic distances ( 2.6 , 3.1 , 3.3 , 12.3 , and 12.6 kpc ) to the region are listed in the literature ( e.g. * ? ? ?
* ; * ? ? ?
* ; * ? ? ?
* ; * ? ? ?
* ; * ? ? ?
however , it has been pointed out by @xcite that the mir bubbles located at the galactic plane are likely to be veiled behind the foreground diffused emission if they are situated at a distance larger than @xmath128 kpc .
hence , it is unlikely for the bubble n37 to be located at a distance of about 12 kpc .
therefore , in this work , we have adopted a distance of 3.0 kpc , the average value of all available near - kinematic distance estimates .
we infer from the previous studies that the bubble is associated with an hii region and an irdc together
. however , the physical conditions inside and around the bubble n37 are not yet known , and the ionizing source(s ) of the bubble is yet to be identified .
furthermore , the impact of the energetics of massive star(s ) on its local environment is not yet explored .
the detailed multi - wavelength study of the region will allow us to study the ongoing physical processes within and around the bubble n37 . to study the physical environment and star formation mechanisms around the bubble , we employ multi - wavelength data covering from the optical , near - infrared ( nir ) to radio wavelengths .
the paper is presented in the following way . in section [ sec : observations ] , we describe the details of the multi - wavelength data .
we discuss the overall morphology of the region in section [ sec : morphology ] . in section
[ sec : result ] , we present the main results of our analysis .
the possible star formation scenarios based on the multi - wavelength outcomes are discussed in section [ sec : discussion ] .
finally , we conclude in section [ sec : conclusions ] .
in this work , we employed a multi - wavelength data to have a detailed understanding of the ongoing physical processes within and around the bubble .
we selected a large - scale region of 15@xmath015@xmath1 ( centered at @xmath8 [email protected] , @xmath10 [email protected] ) around the bubble n37 , which also contains an irdc and a pillar - like structure ( see figure [ fig1]a ) .
details of the new observations and the various archival data are described in the following sections .
to spectroscopically identify the ionizing sources of the bubble n37 , we obtained the optical spectra of two point - like sources ( v @xmath1214 mag ) using grism 7 and grism 8 of the hanle faint object spectrograph and camera ( hfosc ; with slit width of 167 @xmath13 average spectral resolution is @xmath121000 ) attached to the 2 m himalayan _ chandra _ telescope ( hct ) .
corresponding dark and flat frames were also obtained for dark - subtraction and flat - field corrections .
the reduction of these spectra was performed using a semi - automated pyraf based pipeline @xcite .
we obtained the multi - wavelength data from the various galactic plane surveys . in the following ,
we provide a brief description of these various archival data .
nir photometric @xmath14 magnitudes of point - like sources were collected from the united kingdom infrared telescope ( ukirt ) infrared deep sky survey ( ukidss ) galactic plane survey ( gps release 6.0 ; * ? ? ?
* ) catalog .
the ukidss observations were carried out using the wide field camera ( wfcam ; * ? ? ?
* ) attached to the 3.8 m ukirt telescope
. spatial resolution of the ukidss images is @xmath120@xmath158 .
only good photometric magnitudes of point sources in the selected region were obtained following the conditions given in @xcite and @xcite .
several bright sources were saturated in the ukidss frames .
hence , the ukidss sources having magnitudes brighter than j = 13.25 , h = 12.75 and k = 12.0 mag were replaced by the two micron all sky survey ( 2mass ; * ? ? ?
* ) values .
we retrieved the h@xmath16 ( 1@xmath170 ) s(1 ) 2.122 @xmath7 m continuum - subtracted image from the ukirt wide - field infrared survey for h@xmath18 ( uwish2 ; * ? ? ? * ) archive .
these observations were carried out using the wfcam @xcite on the ukirt .
the @xmath19-band linear polarization data for point sources ( resolution @xmath121@xmath155 ) are also used in this study .
the polarization observations were performed using the 1.8 m perkins telescope operated by the boston university and the corresponding data are available in the galactic plane infrared polarization survey ( gpips ; * ? ? ?
* ) archive . in our analysis , we only considered sources having good polarization measurements with p/@xmath20 2.5 ( where p is the degree of polarization and @xmath21 is the corresponding uncertainty ) and usage flag ( uf ) of 1 .
we retrieved the 3.6 , 4.5 , 5.8 and 8.0 @xmath13 images and photometric magnitudes of point sources from the _
spitzer_-galactic legacy infrared mid - plane survey extraordinaire ( glimpse ; * ? ? ?
* ) survey ( spatial resolution @xmath122@xmath22 ) .
the photometric magnitudes were obtained from the glimpse - i spring 07 highly reliable catalog .
in addition to the glimpse data , the multiband infrared photometer for spitzer ( mips ) inner galactic plane survey ( mipsgal ; * ? ? ?
* ) images at 24 @xmath7 m ( resolution @xmath126@xmath22 ) and the magnitudes of point sources at 24 @xmath13 @xcite are also used in the analysis .
some sources , which are well detected in the 24 @xmath13 image , do not have photometric magnitudes in the mipsgal 24 @xmath13 catalog of @xcite .
hence , we separately performed the photometric reduction of 24 @xmath13 image of the n37 region .
a detailed procedure of this photometric reduction can be found in @xcite . in order to construct the dust temperature and column density maps of the n37 region
, we utilized level2_5 processed _ herschel _ 70500 @xmath13 images .
the beam sizes of images at 70 , 160 , 250 , 350 , and 500 @xmath13 are 5@xmath158 , 12@xmath22 , 18@xmath22 , 25@xmath22 , and 37@xmath22 @xcite , respectively .
we have also obtained the apex telescope large area survey of galaxy ( atlasgal ; * ? ? ?
* ) 870 @xmath13 continuum image ( beam @xmath1219@xmath152 ) and the bolocam 1.1 mm @xcite image ( beam @xmath1233@xmath23 ) of the region around the bubble .
the @xmath4co ( j=10 ) line data were retrieved from the galactic ring survey ( grs ; * ? ? ? * ) .
the grs data have a velocity resolution of 0.21 kms@xmath3 , an angular resolution of 45@xmath22 with 22@xmath22 sampling , a main beam efficiency ( @xmath24 ) of @xmath120.48 , a velocity coverage of @xmath175 to 135 km s@xmath3 , and a typical rms sensitivity ( 1@xmath25 ) of @xmath26 k. the very large array ( vla ) 20 cm radio continuum map ( beam size @xmath126@xmath152@xmath275@xmath154 ) of the n37 region was obtained from the multi - array galactic plane imaging survey archive ( magpis ; * ? ? ?
a detailed understanding of the ongoing physical processes in a given star - forming region requires a thorough and careful multi - wavelength investigation of the region . in a star - forming region , the spatial distribution of the ionized , dust , and molecular emission allows us to identify the h ii regions and cold embedded condensations , which further help us to infer the physical conditions of the region .
a multi - wavelength picture of the region around the bubble is presented in figures [ fig1 ] and [ fig2 ] . in figure
[ fig1]a , on a larger scale , the 8.0 @xmath13 image shows a pillar - like structure , an irdc , an iras source ( iras 18335@xmath170646 ) , and the mir bubble n37 .
the broken or incomplete ring morphology of n37 bubble is clearly seen in the image , as previously reported by @xcite .
figure [ fig1]b shows the spatial distribution of the warm dust towards the n37 region ( rgb map : 70 @xmath13 in red ; 24 @xmath13 in green ; 5.8 @xmath13 in blue ) .
the magpis 20 cm radio continuum emission is also overlaid on the rgb map , which depicts the distribution of the ionized emission .
the periphery of the bubble is dominated by the 5.8 @xmath13 emission and encloses the warm dust as well as the ionized gas . in general ,
the polycyclic aromatic hydrocarbon ( pah ) features are seen at 3.3 , 6.2 , 7.7 , and 8.6 @xmath7 m and trace a photodissociation region ( pdr ) surrounding the ionized gas .
hence , the emission seen in the 5.8 and 8.0 @xmath7 m images might be tracing a pdr towards the n37 bubble .
a longer wavelength view ( 2501100 @xmath7 m ) of the region is presented in figure [ fig2 ] .
the images at 3.670 @xmath7 m are also shown for comparison with the submillimeter and millimeter wavelength images .
the emission at 2501100 @xmath13 traces cold dust components ( see section [ colmn_tempmap ] for quantitative estimates ) .
the cold dust emission is mainly seen towards the pillar - like structure and the iras 18335@xmath170646 .
note that the ionized emission is also detected towards the iras 18335@xmath170646 ( see figure [ fig1]b ) .
we utilized the grs @xmath4co ( j=10 ) line data to infer the physical association of different subregions seen in our selected region around the bubble n37 .
based on the velocity information of @xmath4co data , we find that there are two molecular clouds present in our selected region . the molecular cloud associated with the bubble ( i.e. n37 molecular cloud )
is traced in the velocity range of 3743 km s@xmath3 .
however , the molecular cloud associated with the iras 18335@xmath170646 ( also referred as c25.29 + 0.31 in * ? ? ?
* ) is traced in the velocity range from 43 to 48 km s@xmath3 . in the last two bottom panels ,
we show the velocity integrated @xmath4co maps of the two clouds seen in our selected region around the bubble .
the integrated @xmath4co emission map reveals an elongated morphology of the n37 molecular cloud ( i.e. velocity range @xmath123743 km s@xmath3 ) , which hosts the pillar - like structure , an irdc , and the bubble n37 . on the other hand
, the integrated @xmath4co map of the c25.29 + 0.31 cloud traces a large condensation associated with the iras 18335@xmath170646 , as seen in the longer wavelength continuum images ( see figure [ fig2 ] ) .
@xcite also reported the nh@xmath28 line parameters such as nh@xmath28(1,1 ) radial velocity @xmath1246.13 km s@xmath3 and kinematic temperature ( t@xmath29 ) @xmath1221.76 k toward the atlasgal condensation associated with the iras 18335@xmath170646 .
these results suggest that the condensation associated with the iras 18335@xmath170646 is not physically linked with the bubble n37 .
a more detailed analysis of these two molecular clouds ( i.e. n37 molecular cloud and c25.29 + 0.31 ) is discussed in the section [ sec : co ] .
in this section , we present the outcomes of our multi - wavelength analysis in the following way .
first , we present the results related to the identification of ionizing source(s ) of the region , and then the origin of the n37 bubble .
next , we present the column density and the temperature maps of the region to identify the cold condensations .
we have also identified young stellar objects ( ysos ) towards the region , and construct the surface density map of these ysos to study their spatial distribution .
finally , we examine the nir polarization data and the @xmath4co molecular line data to examine the large scale magnetic field morphology and the kinematics of co gas , respectively .
we have seen that the ionized emission is enclosed within the n37 bubble ( see figure [ fig1]b ) and two prominent peaks ( i.e. peak1 and peak2 shown in figure [ fig3 ] ) are seen in the radio continuum map . to search for possible ob type candidates located within the n37 bubble
, we performed a photometric method to identify the probable ionizing candidates of the region , following a similar procedure outlined in @xcite .
the analysis was carried out using the nir and mir photometric magnitudes of point sources from the ukidss and glimpse catalogs , respectively .
we only considered the sources located near the radio emission peaks and detected at least in five photometric bands among ukidss jhk and _ spitzer_-irac 3.6 , 4.5 and 5.8 @xmath13 bands . following this condition ,
a total of seven sources were identified , and these are marked and labeled in figure [ fig3 ] .
the extinction to these sources were estimated assuming intrinsic colors of ( j - h)@xmath30 and ( h - k)@xmath30 for o- and b - stars from @xcite and @xcite , respectively , and using the extinction law ( @xmath31 = 0.284 , @xmath32 = 0.174 , @xmath33 = 0.114 ) from @xcite .
the absolute jhk magnitudes of all these sources were calculated assuming a distance of 3.0 kpc and were compared with those listed in ( * ? ? ? * for o stars ) , and ( * ? ? ? * for b stars ) .
we found that two o - type and five b - type stars are located near the radio peaks within the n37 bubble .
all these sources with their photometric magnitudes and derived spectral types are listed in table [ table1 ] .
note that a single distance is assumed for all the sources , and the spectral types are also estimated without considering the photometric uncertainties of intrinsic colors and observed magnitudes of these sources .
spectroscopic observations will be helpful to further confirm the spectral type of these sources ( see section [ opticalspec ] ) .
llccccccccccccc 1 & 18:36:18.6 & -06:39:09 & 10.17 & 9.62 & 9.34 & 10.17 & 9.62 & 9.34 & 9.24 & 6.11 & -3.95 & -3.84 & -3.74 & o8v@xmath34 + 2 & 18:36:20.2 & -06:38:50 & 10.41 & 9.80 & 9.38 & 10.41 & 9.80 & 9.38 & 8.15 & 7.49 & -4.10 & -3.90 & -3.86 & o7v - o8v@xmath35 + 3 & 18:36:23.3 & -06:38:34 & 15.23 & 13.44 & 12.55 & 15.51 & 13.53 & 12.70 & 11.91 & 16.20 & -1.76 & -1.80 & -1.67 & b2v + 4 & 18:36:19.0 & -06:39:24 & 13.61 & 12.64 & 11.92 & 13.76 & 12.62 & 11.93 & 11.06 & 11.05 & -1.92 & -1.70 & -1.73 & b2v + 5 & 18:36:20.2 & -06:39:05 & 14.12 & 12.88 & 12.14 & 13.73 & 12.42 & 11.73 & & 12.45 & -1.80 & -1.70 & -1.66 & b2v + 6 & 18:36:23.2 & -06:39:27 & 14.52 & 12.98 & 12.20 & 14.42 & 12.71 & 11.94 & 11.38 & 14.21 & -1.90 & -1.90 & -1.81 & b2v + 7 & 18:36:17.4 & -06:39:15 & 15.29 & 13.18 & 12.08 & 15.20 & 13.04 & 11.94 & 11.18 & 19.77 & -2.71 & -2.69 & -2.56 & b1v we have carried out optical spectroscopic observations ( 4000 - 7500 ) of two brightest photometrically identified ob stars ( see asterisks in figure [ fig3 ] ) .
the remaining five sources are beyond the limit of optical spectroscopic capability of the hct ( v - limit @xmath3618-mag for spectrum having signal - to - noise ratio of about 20 with 30 min exposure ) .
the observed spectra of these two sources are shown in figure [ fig4 ] .
one of these sources ( source # 1 ) is situated near the peak1 ( @xmath1210@xmath23 ) of the 20 cm radio emission , and the other one ( # 2 ) is located @xmath1236@xmath23 away from the radio peak1 . several hydrogen and helium lines
are found in both the spectra ( figures [ fig4]a and [ fig4]b ) .
the presence of hydrogen lines is generally seen in early type sources ( o a spectral type ) , however , the existence of he i - ii lines is not found in a stars @xcite .
note that the ionization of helium requires a high temperature generally seen in o - type sources . to confirm the spectral types of these sources , we further compared our observed spectra with the available ob stars spectra @xcite . generally , spectral lines in the first part of the optical spectrum ( 4000 - 5500 ) are used to determine the spectral type of any source . however , the signal - to - noise ratio of the first part of both the spectra is not very good , possibly because of large visual extinction toward the region .
a visual comparison of the observed spectra with the available library spectra reveals that the source # 1 is likely to be a o9v star , while the other source ( # 2 ) is an b0v candidate .
it can be seen in section [ photometricionizing ] that the second source was photometrically identified as o7 - 8v star possibly because of the assumed distance of 3.0 kpc in the calculation which might not be true ( see next paragraph ) .
we have also estimated spectro - photometric distances to these two sources .
the optical bv - band magnitudes of both the sources were obtained from the american association of variable stars observers ( aavso ) photometric all - sky survey ( apass ) catalog ( dr9 ) and the nir @xmath37-band magnitudes were collected from the 2mass catalog . to estimate the distance to the o9v source , we first obtained the intrinsic color of an o9v star ( @xmath380.79 ) from @xcite .
furthermore , the color excess @xmath39 was estimated using the relation @xmath40/@xmath41 2.826 given in @xcite . though it is debatable whether the value of @xmath42 ( @xmath43/@xmath39 ) is 3.1 all over the galaxy or is it substantially different in galactic star - forming regions ( see * ? ? ? * and references therein ) ,
we considered the mean @xmath42 of 3.1 itself for the reddening correction . accordingly , the visual extinction of the source was found to be 6.3 mag .
the absolute and apparent v - band magnitudes of both the sources were obtained from @xcite and the apass catalog , respectively . with an absolute v - magnitude of -4.5 and apparent v - magnitude of 14.37
, we estimated the distance to the o9v star of 3.1 kpc . following the similar procedure for the other source ( b0v ) with the absolute and apparent magnitudes of -4.0 and 14.55 , respectively ,
the visual extinction ( @xmath43 ) was estimated to be 6.4 mag , and the corresponding distance to the source is 2.7 kpc . note that large errors ( at least 20% ) could be associated with these distance estimates due to photometric uncertainties , and the general extinction law used in the estimation . however , similar distances of these sources and the bubble suggest that they are physically associated with the n37 bubble .
the integrated radio continuum flux is used as a tool to determine the spectral type of the source responsible to develop the h ii region .
the presence of an h ii region is traced in the magpis 20 cm map ( see figure [ fig1]b ) .
the lyman continuum flux ( photons s@xmath3 ) required for the observed radio continuum emission is estimated following the equation given in @xcite : @xmath44 where @xmath45 is the frequency of observations , @xmath46 is the total observed flux density , @xmath47 is the electron temperature , and @xmath48 is the distance to the source . here , the region is assumed to be homogeneous and spherically symmetric , and a single main - sequence star is responsible for the observed free - free emission . the flux density ( @xmath46 ) and the size of the h ii region
are determined using the jmfit task of the astronomical image processing software ( aips ) .
typical value of the electron temperature , @xmath49 10000 k for a classical h ii region @xcite is adopted in the calculation .
the spectral type of the powering source is finally estimated by comparing the observed lyman continuum flux with the theoretical value for solar abundance given in @xcite . in the magpis 20 cm map ,
two radio peaks are clearly evident within the bubble ( peak1 and peak2 ; see figure [ fig3 ] ) , and we estimated the spectral type of the possible ionizing source for both the peaks separately . the lyman continuum flux for the radio peak1 ( s@xmath50 1.18 jy ; s@xmath51 10@xmath52 photons
sec@xmath3 ) corresponds to an ionizing source having spectral type of o9v , while the ionizing source corresponding to the radio peak2 ( s@xmath50 0.56 jy ; s@xmath51 10@xmath53 photons sec@xmath3 ) is a b0v star .
as mentioned before ( see sections [ photometricionizing ] and [ opticalspec ] ) , using the spectroscopy and photometry , we identified three ob stars ( o9v , b1v , and b2v ) that are located near the radio peak1 ( see figure [ fig3 ] ) .
however , the lyman continuum flux @xcite expected together from solar abundant b1v and b2v stars is about an order less compared to the o9v star , and therefore , the total flux is mainly dominated by the o9v star .
hence , it seems that an o9v star located at a distance of @xmath1210@xmath23 from the radio peak1 is the primary ionizing source of the region .
the spectral type of the ionizing source determined from the radio analysis is consistent with our spectroscopic results . toward the radio peak2
, we identified a b2v star using the photometric analysis , however the estimation from the radio continuum flux shows the ionizing source to be a b0v star .
the spectral type corresponding to the peak2 estimated using two methods is showing inconsistency because the photometric determinations of spectral types may vary substantially depending on the distance to the source and the photometric accuracy .
we have also determined the dynamical age of the h ii region using the magpis 20 cm data .
a massive source ionizes the surrounding gas , and develop an h ii region .
the ionization front of the h ii region expands until an equilibrium is achieved between the rate of ionization and recombination .
theoretical radius of the h ii region ( i.e. , strmgren radius ; * ? ? ?
* ) for a uniform density and temperature , can be written as : @xmath54 where @xmath55 is the initial ambient density , and @xmath56 is the recombination coefficient .
for a temperature of 10,000 k , the value of @xmath56 is 2.60@xmath2710@xmath57 @xmath58 s@xmath3 @xcite .
a shock front is generated because of the large temperature and pressure gradient between the ionized gas and the surrounding cold material , and the shock front is further propagated into the surroundings .
the corresponding radius of the ionized region at any given time can be written as @xcite : @xmath59 where the speed of sound in an h ii region ( c@xmath60 ) is 11@xmath2710@xmath61 cm s@xmath3 @xcite and @xmath62 is the dynamical age of the h ii region .
the size of the h ii region , i.e. , r(t ) , was estimated to be 1.4 pc by using the jmfit task of the aips .
note that the calculated dynamical age can vary substantially depending on the initial value of the ambient density .
therefore , we estimated the strmgren radius and the corresponding dynamical age for a range of ambient density starting from 1000 to 10000 @xmath63 ( e.g. classical to ultra - compact h ii regions ; * ? ? ? * ) . for the corresponding densities , the dynamical age varies from 0.210.71 myr .
however , the strmgren radius and dynamical age were calculated by assuming the region as homogeneous and spherically symmetric .
hence , the dynamical age of the h ii region should be considered as a representative value ( see section [ sec : discussion ] for more discussion ) . in figure
[ fig5]a , we present the continuum - subtracted h@xmath18 emission ( 2.122 @xmath13 ) map toward the bubble n37 , which traces the edges of the bubble .
the h@xmath18 features have similar morphology as seen in the _
spitzer_-glimpse images .
the h@xmath18 emission in a given star - forming region is originated in the shocked region developed at the interface of the ionized and cold matter . from the distribution of h@xmath16 emission ,
8.0 @xmath7 m emission and the ionized emission ( see figure [ fig2 ] ) , it is evident that the emission seen in the narrow h@xmath16-band is tracing the pdr towards the n37 region .
possibly , the h@xmath16 emission is originated in the shocked region developed due to the expansion of the ionized gas .
ratio maps of _
spitzer_-irac images have ability to provide the information about the interaction of massive star(s ) with its surrounding environment @xcite .
note that the _ spitzer_-irac bands contain several prominent characteristic atomic and molecular lines .
for example , irac ch1 contains a pah feature at 3.3 @xmath13 as well as a prominent molecular hydrogen line at 3.234 @xmath7 m ( @xmath45 = 10 @xmath64(5 ) ) .
irac ch2 also contains a molecular hydrogen emission line at 4.693 @xmath13 ( @xmath45 = 00 @xmath65(9 ) ) generally excited by outflow shocks , and a hydrogen recombination line br@xmath66 ( 4.05 @xmath7 m ) .
figure [ fig5]b shows the irac ch2/ch1 ratio map of the n37 region , which reveals the bright emission region surrounded by the dark features .
in general , the dark regions in the 4.5 @xmath7m/3.6 @xmath7 m ratio map traces the excess 3.6 @xmath7 m emission , while the bright emission region suggests the domination of 4.5 @xmath7 m emission .
the bright emission region in the ratio map is very well correlated with the radio continuum emission .
therefore , it seems that this bright emission region probably traces the br@xmath66 feature originated by the photoionized gas .
the dark features in the ratio map are also well correlated with the 2.122 @xmath7 m h@xmath16 emission , indicating that the ratio map probably traces the h@xmath16 features ( see figures [ fig5]a and [ fig5]b ) .
however , it must be noted that the ch1 also contains 3.3 @xmath13 pah emission feature which may also contribute to the dark features seen in the ratio map .
overall , we found that the irac ratio map and the continuum - subtracted h@xmath16 image trace pdr around the hii region .
massive stars can influence their parent molecular clouds via different feedback components - ( i ) pressure due to radiation ( p@xmath67 ) , ( ii ) pressure due to hii region ( p@xmath68 ) , and ( iii ) pressure due to wind ( p@xmath69 ) .
it is important to determine the strongest pressure component of massive stars in order to have a better knowledge of the feedback mechanisms .
pressure due to radiation can be formulated as p@xmath67 = @xmath70 , where @xmath71 is the bolometric luminosity and d@xmath72 is the distance from the star to the region of interest .
similarly , the pressures due to the h ii region and stellar wind can be written as p@xmath68 = @xmath73 @xmath74 and p@xmath69 = @xmath75 , respectively , where the mean molecular weight in an h ii region , @xmath7=0.678 @xcite , c@xmath60 is the sound speed in an h ii region = 11 km s@xmath3 , @xmath56 is a recombination coefficient = 2.6@xmath2710@xmath57 @xmath58 s@xmath3 , n@xmath76 is the number of uv photons , @xmath77 is the mass - loss rate of the source , @xmath78 is the terminal velocity of the stellar wind ( see * ? ? ? * for more details about these formulas ) .
all the pressure components were estimated at a distance of @xmath121 pc which is the nearest edge of the bubble from the massive o9v star .
the pressure exhibited by the h ii region with n@xmath79 10@xmath80 photons sec@xmath3 ( i.e. , total lyman continuum for both the radio continuum peaks ; see section [ sec : radio ] ) is estimated to be 2.8@xmath2710@xmath81 dyne @xmath82 . for the estimation of p@xmath67
, the bolometric luminosities of all seven ob stars within the bubble were obtained from @xcite and the total radiation pressure exhibited by all these ob stars is found to be 1.8@xmath2710@xmath81 dyne @xmath82 . to estimate the combined p@xmath69 from all the seven ob stars ,
the wind speed and the mass - loss rate for the o9v star were obtained from @xcite ( v@xmath831000 km s@xmath3 ; @xmath8410@xmath85 yr@xmath3 ) .
the corresponding values for b0v , b1v and b2v stars ( v@xmath831000 , 700 and 700 km s@xmath3 ; @xmath8410@xmath86 , 10@xmath87 ; 10@xmath88 m@xmath6 yr@xmath3 , respectively ) were obtained from @xcite .
the combined pressure due to the wind ( p@xmath69 ) from all the seven ob stars comes out to be 5.1@xmath2710@xmath89 dyne @xmath82 .
the estimation of different pressure components infers that the pressure due to the ionized gas ( i.e , h ii region ) is the predominant component . however , there is also a substantial radiation pressure contributed together by all the ob stars .
note five out of seven of these ob stars not only lack of spectroscopic confirmations , but also association of them with the n37 bubble is uncertain .
therefore , the calculated values of the pressure due to the radiation and the stellar wind should be treated as upper limits . from the overall analysis
it seems that a shock - front has been developed due to the expansion of the h ii region which excites the h@xmath18 emission as well as pah emission .
our results indicate that the n37 bubble is possibly originated due to the ionizing feedback of the massive stars .
we have constructed the column density and the temperature maps of the region using _ herschel _ images to probe the condensations and the distribution of cold matter .
a pixel - by - pixel modified blackbody fit was performed to the cold dust emission seen in the _ herschel _ 160 , 250 , 350 and 500 @xmath13 images .
the 70 @xmath13 image was not considered in our analysis because a substantial part of the 70 @xmath13 flux comes from the warm dust . before performing the fit ,
all the images were convolved to the lowest resolution of 37@xmath23 ( beam size of the 500 @xmath13 image ) and converted to the same flux unit ( jy pixel@xmath3 ) . for better estimation of the source flux
, we subtracted the corresponding background flux from each image ( see * ? ? ? * for more detail ) .
background flux was estimated in a relatively dark region ( @xmath8 [email protected] , @xmath10 [email protected] ; area : 10@xmath010@xmath1 ) away from our selected target , and corresponding fluxes are -2.202 , 1.328 , 0.693 and 0.252 jy pixel@xmath3 for 160 , 250 , 350 and 500 @xmath13 images , respectively .
finally , the pixel - by - pixel basis modified blackbody fitting was performed by using the formula @xcite : @xmath90 where optical depth can be written as : @xmath91 different symbols in the above equations are as follows - @xmath92 : observed flux density , @xmath93 : background flux density , @xmath94 : planck s function , @xmath95 : dust temperature , @xmath96 : solid angle subtended by a pixel , @xmath97 : mean molecular weight , @xmath98 : mass of hydrogen , @xmath99 : dust absorption coefficient , and @xmath100 : column density . here , we used @xmath96 = 4.612@xmath2710@xmath101 steradian ( i.e. for 14@xmath10214@xmath22 area ) , @xmath97=2.8 and @xmath99=0.1 @xmath103 @xmath104 g@xmath3 , the gas - to - dust ratio of 100 , and the dust spectral index @xmath105=2 for sources with thermal emission in the optically thick medium @xcite .
the final column density and temperature maps of the 15@xmath015@xmath1 area of the n37 region are shown in figures [ fig6]a and [ fig6]b , respectively .
several condensations are seen towards the region .
the ` clumpfind ' software @xcite has been used to identify the clumps and to measure the total column density in each clump .
the mass of a clump is estimated using the formula @xcite : @xmath106 where @xmath97=2.8 , @xmath107 is the area subtended by one pixel , and @xmath108 is the total column density of the clump obtained using the ` clumpfind ' .
a total of 17 clumps are identified toward the 15@xmath015@xmath1 area of the n37 region ( see figure [ fig6 ] ) . however , based on the integrated co maps ( see figure [ fig2 ] ) , we find only five clumps ( i.e. c25 and c10 , in figure [ fig6 ] ) associated with the n37 molecular cloud , and the remaining clumps appear to be associated with the c25.29 + 0.31 molecular cloud . in the present work ,
our analysis is focused on the n37 molecular cloud , and hence , we do not discuss the results of the c25.29 + 0.31 cloud . in the n37 molecular cloud , the five associated clumps ( i.e. c25 and c10 ; m@xmath109 from @xmath1213502150 m@xmath110 ) are having temperatures and densities in the range from @xmath122223 k and @xmath127.29.5 @xmath27 10@xmath111 @xmath82 ( corresponding a@xmath112 @xmath128.010.0 mag ) , respectively . here , to estimate the visual extinction , we use the relation @xmath113 molecules @xmath82 mag@xmath3 @xcite .
the study of ysos in a given star - forming region allows to characterize the area of the ongoing star formation .
hence , we have carried out identification of ysos using the nir and mir color - magnitude and color - color schemes . a more elaborative description of these schemes is given below . [ cols="^,^ " , ]
four different schemes are employed to identify and classify the ysos for the selected 15@xmath015@xmath1 area around the n37 region .
young sources are known to be a strong emitter at mir bands , while they are still embedded in their parent molecular clouds and can not be seen in the optical / nir bands .
hence , mir photometric criteria allow us to identify sources at a very early phase .
we cross - matched the sources that have detections in both the mipsgal 24 @xmath13 and _ spitzer_-irac / glimpse 3.6 @xmath13 bands , and constructed a color - magnitude diagram ( [ 3.6]@xmath17[24]/[3.6 ] ) to identify the ysos , following the color criteria given in @xcite and @xcite .
a total of 100 sources are found that are common in the 3.6 and 24 @xmath7 m bands .
the color - magnitude diagram of these sources is shown in figure [ fig7]a .
different classes of ysos are marked by distinct symbols and are separated by black dashed - lines .
the boundaries for other contaminants like disk - less stars and galaxies are also marked by a green dashed curve , following the criteria given in @xcite . using this scheme ,
a total of 19 class i , 12 flat - spectrum , 22 class ii , and 36 class iii sources were identified .
there are several sources that are not seen in the mipsgal 24 @xmath13 image , but detected in the _ spitzer_-irac / glimpse bands ( 3.6 , 4.5 , 5.8 , and 8.0 @xmath13 ) . hence , the color - color diagram ( [ 5.8]@xmath17[8.0])/([3.6]@xmath17[4.5 ] ) of the sources detected in all four irac bands was used to identify the additional ysos ( see figure [ fig7]b ) .
possible contaminants ( such as broad - line active galactic nuclei , pah - emitting galaxies and shock emission knots ) were removed from the sample using the criteria given in @xcite .
the selected ysos were classified into different evolutionary stages using the slopes of the _
spitzer_-irac / glimpse spectral energy distribution ( sed ) ( i.e. @xmath114 ) measured from 3.6 to 8.0 @xmath7 m ( see * ? ? ? * for more details ) .
finally , using this scheme , we identified a total of 20 class i and 99 class ii ysos .
\3 . due to prominent nebulosity seen in the irac 8.0 @xmath13 band ,
there are several sources that are not detected in the 8.0 @xmath13 image , but identified in other three glimpse - irac bands ( 3.6 , 4.5 , and 5.8 @xmath13 ) .
hence , the color - color diagram ( [ 3.6]@xmath17[4.5]/[4.5]@xmath17[5.8 ] ) was constructed to identify the additional ysos ( see figure [ fig7]c ) .
the sources that follow [ 4.5]@xmath17[5.8 ] @xmath115 0.7 mag and [ 3.6]@xmath17[4.5 ] @xmath115 0.7 mag are classified as protostars @xcite . using this scheme , a total of 17 protostars were identified in the region around the bubble .
presence of circumstellar material makes ysos to appear much redder than the nearby field stars in the nir color - magnitude diagram .
hence , we also used nir color - magnitude diagram ( h@xmath17k / k ) to identify additional ysos toward the n37 region .
the @xmath116 color cut - off of 1.8 was estimated by constructing the color - magnitude diagram ( h@xmath17k / k ) of a nearby field region ( size@xmath1215@xmath015@xmath1 area centered at @xmath8 [email protected] ; @xmath10 [email protected] ) .
this color cut - off differentiate the field stars from the sources having large nir excess .
the nir color - magnitude diagram of the sources is shown in figure [ fig7]d . using the nir scheme
, we identified a total of 1203 red sources that could be presumed as ysos
. there could be overlap of ysos identified using these four different schemes . in order to have a complete catalog ,
ysos identified using different schemes were cross - matched .
finally , a total of 29 class i , 12 flat spectrum , 99 class ii , 973 class iii ysos , and 1066 red sources are identified toward the n37 region . in order to examine
how the ysos are clustered in the region around the bubble , a nearest - neighbor ( nn ) surface density analysis of ysos was performed following the method given in @xcite and @xcite .
using monte carlo simulations , @xcite showed that the 20nn surface density is capable to detect clusters with 101500 ysos .
hence , the 20nn surface density analysis of ysos was performed using a grid size of 6@xmath159 which corresponds to 0.1 pc at a distance of 3 kpc .
figure [ fig8 ] shows the surface density contours of ysos overlaid on the _ herschel _ 500 @xmath13 image .
the contour levels are drawn at 15 , 18 , 22 , 27 , and 30 ysos pc@xmath117 .
the positions of all the clumps identified in the _ herschel _ column density map are also marked on the image .
the yso clusters are found toward the irdc , the clump c1 and the pillar - like structure , and many of these yso clusters are associated with peaks having more than 27 ysos pc@xmath117 ( see figure [ fig8 ] ) .
it is already mentioned before that the clump c1 is part of the c25.29 + 0.31 cloud and is not associated with the n37 molecular cloud . therefore , the clusters of ysos located towards the clump c1 might not have any physical association with the n37 bubble . in order to infer the physical properties of ysos ( e.g. , mass , age ) ,
the sed modeling of a few selected ysos was performed using the sed fitter tool of @xcite .
the grids of yso models were computed using the radiation transfer code of @xcite , which assumes an accretion scenario for a pre - main sequence central star , surrounded by a flared accretion disk and a rotationally flattened envelope with cavities .
the model grid has 20,000 sed models from @xcite , estimated using two - dimensional radiative transfer monte carlo simulations .
each yso model gives the output seds for 10 inclination angles with masses ranging from 0.150 m@xmath110 .
the fitter tool tries to find the best possible match of yso models for the observed multi - wavelength fluxes followed by a chi - square minimization .
the distance to the source and interstellar visual extinction ( a@xmath118 ) are used as free parameters .
we performed the sed modeling of those ysos that have fluxes at least in five filter bands ( among nir jhk and spitzer - irac bands ) , in order to constrain the diversity of the modeling parameters .
accordingly , a total of 81 ysos were selected for the sed fitting . in the models
, we used the a@xmath118 in the range from 050 mag and the distance ranging from 24 kpc . for each yso , only those models were selected which follow the criterion : @xmath119
@xmath120 @xmath121 3 , where @xmath119 is taken per data point .
note that the output parameters for each yso are not unique because several models can satisfy the observed sed .
hence , the weighted mean values were computed for all the model fitted parameters for each yso . in table
[ table2 ] , we have listed , the right ascension ( j2000 ) , declination ( j2000 ) , the weighted mean values of the stellar age , stellar mass , total luminosity , extinction and evolutionary class for a sample of 6 ysos . the complete table of 81 ysos is available online in machine readable format .
llccccl 18:35:58.8 & -06:43:18 & [email protected] & [email protected] & [email protected] & [email protected] & class ii + 18:36:17.7 & -06:45:41 & [email protected] & [email protected] & [email protected] & [email protected] & class ii + 18:36:20.0@xmath123 & -06:44:21 & [email protected] & [email protected] & [email protected] & [email protected] & class i + 18:36:24.9@xmath124 & -06:39:41 & [email protected] & [email protected] & [email protected] & [email protected] & class ii + 18:36:25.5@xmath124 & -06:39:46 & [email protected] & [email protected] & [email protected] & [email protected] & class i + 18:36:36.1@xmath125 & -06:37:51 & [email protected] & [email protected] & [email protected] & [email protected] & class ii the polarization of background starlight is often used to study the projected plane - of - the - sky magnetic field morphology .
the polarization vectors of background stars allow to trace the field direction in the plane of the sky parallel to the direction of polarization @xcite .
nir polarization data of point sources towards the n37 region were obtained from the gpips ( see * ? ? ? * for more details ) and were covered in several fields i.e. , gp0608 , gp0609 , gp0610 , gp0622 , gp0623 , gp0624 , gp0635 , gp0636 , gp0637 , gp0649 , gp0650 , gp0651 .
a total of 375 sources with reliable polarization measurements were identified in the 15@xmath12615@xmath1 area towards the n37 region using the criteria of p/@xmath127 2.5 and uf of 1 . in figure
[ fig9]a , we show a color - color diagram ( @xmath116 vs. @xmath128 ) of the selected sources and find that the majority of the sources are either reddened giants or main - sequence stars .
hence , it is evident from the nir color - color diagram that the majority of stars are located behind the n37 molecular cloud .
the histograms of the degree of polarization and the corresponding galactic position angles are also shown in figures [ fig9]b and [ fig9]c , respectively , which show that the majority of the sources have degree of polarization and position angle of about 1.5% and @xmath1260@xmath129 , respectively . if it is considered that the dust components responsible to polarize the background starlight are aligned along the magnetic field lines , then the corresponding plane - of - sky component of the magnetic field is oriented at a position angle of @xmath1260@xmath129 .
the polarization vectors overlaid on the velocity integrated @xmath4co map are shown in figure [ fig10]a . to examine the average distribution of nir @xmath19-band polarization , the mean degree of polarization vectors superimposed on the _ spitzer _ 8 @xmath13 image are shown in figure [ fig10]b . in order to study the mean polarization , our selected 15@xmath12615@xmath1 spatial area
was divided into 225 grids having 1@xmath1261@xmath1 area for each grid and the mean polarization value for each grid is computed using the average q and u stokes parameters of all the @xmath19-band sources located inside that particular grid . using the @xmath19-band polarization data
, one can not trace the morphology of the plane - of - the - sky projection of the magnetic field toward the dense clumps , where extinction is generally high enough for a background source to be detected in the nir @xmath19-band .
the grs @xmath4co ( j=10 ) line data were utilized to examine the distribution and kinematics of the molecular gas towards the n37 bubble .
additionally , the velocity information of gas inferred from the @xmath4co data is used to know the physical association of different subregions seen in the selected region around the bubble .
the integrated grs @xmath4co ( j=1@xmath170 ) velocity channel maps ( at intervals of 1 km s@xmath3 ) are shown in figure [ fig11 ] , tracing different subregions along the line of sight . as mentioned before from the @xmath4co profile that the molecular cloud associated with the bubble n37 ( i.e. , n37 molecular cloud ) is depicted in the velocity range from 3743 km s@xmath3 . in this velocity range , three condensations
( see last panel of figure [ fig11 ] for c2 , c3 , and c4 ) located towards the pillar - like structure are well detected in the channel maps .
the integrated grs @xmath4co intensity map for the c25.29 + 0.31 was previously reported by @xcite having v@xmath130 of @xmath1245.9 km s@xmath3 with a velocity range of @xmath124348 km s@xmath3 .
based on the co velocity profile and channel maps ( figure [ fig11 ] ) , we infer that two nearby but distinct molecular clouds ( i.e. n37 molecular cloud and c25.29 + 0.31 ) are present in our selected area of analysis . hence , there could be a possibility for physical interaction between these two nearby molecular clouds .
note that the position - velocity analysis of these clouds is not yet explored .
figure [ fig12]a shows an integrated velocity map ( 3743 km s@xmath3 ) of the region around the bubble n37 , which reveals the physical association of molecular condensations with the n37 molecular cloud . in general , the position - velocity plots of the molecular gas are often used to search for any expansion of gas and/or outflow activity within a given cloud ( e.g. , * ? ? ?
* ; * ? ? ?
the position - velocity diagrams of @xmath4co gas associated with the n37 cloud are shown in figures [ fig12]c and [ fig12]e .
the positions of the massive ob stars and the condensations are also marked in the position - velocity diagrams .
the velocity gradients are evident toward the condensations c2 , c3 , and c4 , which can be indicative of the outflow activities within each of them .
note that the angular resolution of the @xmath4co data ( 45@xmath23 ) is coarse therefore we can not further explore the outflow activity within these condensations .
additionally , an inverted c - like structure appears in figure [ fig12]c ( follow the marked curve ) and the massive ob stars are located near the center of the structure .
such structure is indicative of an expanding shell associated with the hii region in the bubble n37 ( e.g. , * ? ? ?
* ; * ? ? ?
the study of @xmath4co line data suggests the presence of molecular outflow(s ) and the expanding hii region with an expansion velocity of @xmath122.5 km s@xmath3 .
this expansion velocity corresponds to the half of the velocity range for the inverted c - like structure seen in the position - velocity diagram . the integrated velocity map for a larger velocity range ( 3748 km s@xmath3 ) , which covers both the n37 and c25.29 + 0.31 molecular clouds , is presented in figure [ fig12]b .
we have also constructed the position - velocity diagrams of @xmath4co gas in the corresponding velocity range ( see figures [ fig12]d and [ fig12]f ) . in figures [ fig12]d and [ fig12]f , we find that the red - shifted component ( 4348 km s@xmath3 ) and the blue - shifted component ( 3743 km s@xmath3 ) are well separated by a lower intensity intermediated velocity emission , which is referred as a broad bridge feature .
this feature in the position - velocity diagram is generally seen at the interface of the colliding molecular clouds ( see * ? ? ?
* ; * ? ? ?
* for more detail ) .
the implication of this feature is presented in the discussion section ( section [ sec : discussion ] ) .
as mentioned before , there are two molecular clouds ( i.e. n37 molecular cloud and c25.29 + 0.31 ) present in the region around the bubble .
the position - velocity analysis of the molecular gas towards these clouds reveals a broad bridge - like feature .
this bridge - like feature is indicative of a cloud - cloud collision @xcite .
these authors also suggested that the collision between two molecular clouds can be a potential mechanism to trigger the formation of massive stars .
very recently , observational evidences of the cloud - cloud collision and the formation of massive stars through this process have been reported in the galactic star - forming regions rcw120 @xcite and rcw 38 @xcite . according to @xcite and @xcite
, a collision between two non - identical clouds can produce a dense layer at the interface of these clouds and can create a cavity in the large cloud ( see figure 12 of * ? ? ?
the compressed dense layer has the ability to develop the dense cores , which can subsequently form massive stars .
after the formation of massive stars , their strong uv radiation can ionize the surrounding gas and develop an h ii region .
@xcite suggested that the cloud - cloud collision has formed an o - type star in the rcw 120 region , and made it to appear as a broken bubble .
it is mentioned before that the n37 molecular cloud hosts a pillar - like structure , irdc , and the mir bubble n37 .
the cloud also harbors ysos clusters that are associated with the irdc and pillar - like structure .
it is possible that the cloud - cloud collision has influenced the star formation within the n37 molecular cloud ( including the irdc , ob stars , and the pillar - like structure ) .
the massive ob stars might have formed due to a similar formation mechanism as it is reported for rcw 120 . with time
, the massive ob stars developed an hii region and the mir bubble morphology appears to be originated due to the expansion of the photoionized gas ( see section [ sec : ratt ] ) .
it is also possible that the collision between two molecular clouds might have developed the broken cavity and that is why the n37 bubble has appeared with a broken structure .
however , we do not have enough observational evidences to firmly conclude about the origin of the broken feature of the n37 bubble .
we calculated the dynamical age of the hii region ( t@xmath131 ) towards the n37 bubble to be @xmath1320.7 myr for an ambient density of 10000 @xmath63 ( see section [ sec : radio ] ) .
in general , the average ages of class i and class ii ysos are @xmath120.44 myr and @xmath1213 myr @xcite , respectively . considering these ages , it is unlikely that the star formation in the n37 cloud has been triggered by the expansion of the hii region . for further confirmation , we determined the average ages of ysos toward the bubble , the pillar and the clump c1 which is , however , part of c25.29 + 0.31 molecular cloud .
the distribution of class i and class ii ysos overplotted on the 8 @xmath13 image are shown in figure [ fig13]a .
a total of 13 , 7 and 10 ysos are found to be situated toward the n37 bubble , the pillar and the c1 , respectively , for which the sed modeling was performed ( see figure [ fig13]b )
. corresponding mean ages of these ysos are estimated to be 1.0 , 0.7 and 0.7 myr , respectively , which are comparable to the dynamical age of the h ii region of 0.7 myr . for a triggered star formation to occur the mean ages of ysos
should be less compared to the dynamical age of the h ii region .
however , the mean ages are associated with large standard deviations ( @xmath120.5 myr ) and hence , it is not possible to make a definite conclusion from this analysis .
we have also plotted the cumulative distribution of ages of ysos toward the bubble , c1 , and the pillar ( see figure [ fig13]c ) .
it can be seen in the cumulative distributions of the ages that the majority of the ysos ( at least @xmath1260% ) located towards the pillar are younger than the ysos towards the bubble and c1 .
hence , the formation of stars towards the pillar and c1 might have started later than the bubble .
though the ysos associated with the pillar and the c1 are younger than the ysos towards the bubble , the dynamical age of the h ii region is not consistent enough to conclude whether they have formed due to the influence of bubble / massive ob stars .
note that in this paper we do not discuss results related to the c25.29 + 0.31 cloud , which hosts the clump c1 , the iras 18335@xmath170646 , and the star a805 ( an o7ii spectral type ) ( see * ? ? ?
it should be mentioned here that the pillars are generally assumed to be potential sights of triggered star formation @xcite , and young stars are expected to appear at the tip of the pillars @xcite .
a few class i and class ii ysos are found to be associated with the pillar ( see figure [ fig13]a ) and these ysos might have formed by some other mechanisms than triggered by the ob stars or h ii region . it can be noticed in figure [ fig10]b , even though the mean polarization position angles are generally uniform at a galactic position angle of @xmath1260@xmath133 throughout the region , random changes in the polarization position angles are noticed near the interface of the n37 molecular cloud and the clump c1 which is part of the c25.29 + 0.31 molecular cloud .
we suggest that this change in the polarization position angles can be explained by a distortion of gas due to the collision between these two molecular clouds .
overall , this region correlates well with the observational signatures proposed for the cloud - cloud collision process .
in addition to the formation of ob stars , the cloud - cloud collision might have also triggered the formation of several other yso clusters in the n37 molecular cloud .
we performed a multi - wavelength analysis of the galactic mir bubble n37 and its surrounding environment .
the aim of this study is to investigate the physical environment and star formation mechanisms around the bubble .
the main conclusions of this study are the following .
\1 . in the selected @xmath134 region around the mir bubble n37 ,
two molecular clouds ( n37 molecular cloud and c25.29 + 0.31 ) are present along the line of sight .
the molecular cloud associated with the bubble ( i.e. n37 molecular cloud ) is depicted in the velocity range from 37 to 43 km s@xmath3 , while the c25.29 + 0.31 cloud is traced in the velocity range from 43 to 48 km s@xmath3 .
the n37 molecular cloud appears to be blue - shifted with respect to the c25.29 + 0.31 cloud .
\2 . using photometric criteria
, we find a total of seven ob stars within the n37 bubble , and spectroscopically confirmed two of these sources as o9v and b0v stars .
the physical association of these sources with the n37 bubble is also confirmed by estimating their spectro - photometric distances .
the o9v star is found as the primary ionizing source of the region .
this result is in agreement with the lyman continuum flux analysis using the 20 cm data .
several molecular condensations surrounding the n37 bubble are identified in the _ herschel _ column density map .
the physical association of these condensations with the n37 bubble is inferred using the molecular gas distribution as traced in the integrated @xmath4co ( j=10 ) map .
surface density analysis of the identified ysos reveals that the ysos are clustered toward these molecular condensations .
the mean ages of ysos located in different parts of the region indicate that it is unlikely that these ysos are triggered by energetics of the ob stars present within the bubble .
this interpretation is supported with the knowledge of the dynamical age of the h ii region .
the position - velocity analysis of @xmath4co data shows that two clouds ( n37 molecular cloud and c25.29 + 0.31 ) are interconnected with a lower intensity emission known as broad bridge structure .
the presence of such feature suggests the possibility of interaction between the n37 molecular cloud and the c25.29 + 0.31 cloud .
the position - velocity analysis of @xmath4co emission also reveals an inverted c - like structure , suggesting the signature of an expanding hii region .
based on the pressure calculations ( p@xmath135 , @xmath136 , and p@xmath69 ) , the photoionized gas associated with the bubble is found as the primary contributor for the feedback mechanism in the n37 cloud .
possibly the expanding hii region is responsible for the origin of the mir bubble n37 .
the collision between two clouds ( i.e. n37 molecular cloud and c25.29 + 0.31 ) might have changed the uniformity of the molecular cloud which is depicted by a slight change in the polarization position angles of background starlight .
the collision between the n37 molecular cloud and the c25.29 + 0.31 cloud might have triggered the formation of massive ob stars .
this process might also have triggered the formation of ysos clusters in the n37 molecular cloud .
we thank the anonymous referee for the constructive comments .
we are also grateful to dr .
a. luna for proving the idl - based program for the analysis of co line data .
we thank the staff of iao , hanle and crest , hosakote , that made the observations using hct possible .
the facilities at iao and crest are operated by the indian institute of astrophysics , bangalore .
we acknowledge the use of the aavso photometric all - sky survey ( apass ) , funded by the robert martin ayers sciences fund .
this work is based on data obtained as part of the ukirt infrared deep sky survey .
this publication made use of data products from the two micron all sky survey ( a joint project of the university of massachusetts and the infrared processing and analysis center/ california institute of technology , funded by nasa and nsf ) , archival data obtained with the _ spitzer _ space telescope ( operated by the jet propulsion laboratory , california institute of technology under a contract with nasa ) .
this publication makes use of molecular line data from the boston university - fcrao galactic ring survey ( grs ) .
the grs is a joint project of boston university and five college radio astronomy observatory , funded by the national science foundation ( nsf ) under grants ast-9800334 , ast-0098562 , and ast-0100793 .
this publication makes use of the galactic plane infrared polarization survey ( gpips ) .
the gpips was conducted using the _ mimir _ instrument , jointly developed at boston university and lowell observatory and supported by nasa , nsf , and the w.m .
keck foundation .
lkd is supported by the department of space , government of india .
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the selected 15@xmath015@xmath1 area around the bubble contains two molecular clouds ( n37 cloud ; v@xmath23743 km s@xmath3 , and c25.29 + 0.31 ; v@xmath24348 km s@xmath3 ) along the line of sight .
a total of seven ob stars are identified towards the bubble n37 using photometric criteria , and two of them are spectroscopically confirmed as o9v and b0v stars .
spectro - photometric distances of these two sources confirm their physical association with the bubble .
the o9v star is appeared to be the primary ionizing source of the region , which is also in agreement with the desired lyman continuum flux analysis estimated from the 20 cm data .
the presence of the expanding hii region is revealed in the n37 cloud which could be responsible for the mir bubble .
using the @xmath4co line data and photometric data , several cold molecular condensations as well as clusters of young stellar objects ( ysos ) are identified in the n37 cloud , revealing ongoing star formation ( sf ) activities .
however , the analysis of ages of ysos and the dynamical age of the hii region do not support the origin of sf due to the influence of ob stars .
the position - velocity analysis of @xmath4co data reveals that two molecular clouds are inter - connected by a bridge - like structure , favoring the onset of a cloud - cloud collision process .
the sf activities ( i.e. the formation of ysos clusters and ob stars ) in the n37 cloud are possibly influenced by the cloud - cloud collision . | <s>[INST]massive stars ( @xmath58 m@xmath6 ) play a crucial role in the evolution of their host galaxies , but their exact formation and evolution mechanisms are still under debate @xcite .
it is not yet understood whether the formation of massive stars is only a scaled - up version of birth process of low mass stars , or is it a completely different process .
one can find more details about the current theoretical scenarios of massive star formation in the recent reviews by @xcite and @xcite .
recently , a collision between two molecular clouds followed by a strong shock compression of gas is considered as a probable formation mechanism of massive stars @xcite . @xcite
numerically found that the head - on collision between two non - identical molecular clouds can trigger the formation of massive stars , and such process could also form a broken bubble - like structure . in a detailed study of rcw 120 star - forming region using the molecular line data , @xcite reported that the collision between two nearby molecular clouds has triggered the formation of an o star in rcw 120 in a short time scale .
however , observational evidences for the formation of o stars via a collision between two molecular clouds are still very rare .
massive stars can significantly influence the surrounding interstellar medium ( ism ) through their energetics such as ionizing radiation , stellar winds , and radiation pressure .
they have an ability to help in accumulation of surrounding materials ( i.e. , positive feedback ) and/or to disperse matter into the ism .
furthermore , they can also affect the star formation positively and negatively @xcite .
the positive feedback of massive stars can trigger the birth of a new generation of stars including young massive star(s ) .
more details about the various processes of triggered star formation can be found in the review article by @xcite .
however , the feedback processes of massive stars are not yet well understood , and the direct observational proof of triggered star formation by massive stars is rare .
but the influence of massive stars on their surroundings can be studied with several other observational signatures ( like h ii region , wind - blown or radiation driven galactic bubble , etc . ) .
recently , _ spitzer _
observations have revealed thousands of ring / shell / bubble - like structures in the 8 @xmath7 m images @xcite , and many of them often enclose the hii regions .
hence , the bubbles associated with hii regions are potential targets to probe the physical processes governing the interaction and feedback effect of massive stars on their surroundings .
additionally , these sites are often grouped with the infrared dark clouds ( irdcs ) and young stellar clusters , which also allow to understand the formation and evolution of these stellar clusters . in this paper , we present a multi - wavelength study of such a mid - infrared ( mir ) bubble , n37 ( @xmath8 [email protected] , @xmath10 [email protected] ; * ? ? ?
* ) , which is associated with an hii region , g025.292 + 00.293 @xcite .
the bubble n37 is classified as a broken or incomplete ring with an average radius and thickness of 1@xmath1177 and 0@xmath1149 , respectively @xcite .
the bubble is found in the direction of the hii region rcw 173 ( sh2 - 60 ) ( see figure 9 in * ? ? ?
the velocity of the ionized gas ( @xmath1239.6 kms@xmath3 ; * ? ? ?
* ) is in agreement with the line - of - sight velocity of the molecular gas ( @xmath1241 kms@xmath3 ; * ? ? ?
* ; * ? ? ?
* ) towards the bubble
n37 , indicating the physical association of the ionized and molecular emissions . presence of several irdcs are also reported around the n37 bubble by @xcite .
@xcite analyzed the photometry and spectroscopy of stars in the direction of the hii region , rcw 173 , and found that most of the stars in the field are reddened b - type stars .
they also identified a star a805 ( g025.2465 + 00.3011 ) having spectral type of o7ii and suggested this as the main ionizing source in the area .
several kinematic distances ( 2.6 , 3.1 , 3.3 , 12.3 , and 12.6 kpc ) to the region are listed in the literature ( e.g. * ? ? ?
* ; * ? ? ?
* ; * ? ? ?
* ; * ? ? ?
* ; * ? ? ?
however , it has been pointed out by @xcite that the mir bubbles located at the galactic plane are likely to be veiled behind the foreground diffused emission if they are situated at a distance larger than @xmath128 kpc .
hence , it is unlikely for the bubble n37 to be located at a distance of about 12 kpc .
therefore , in this work , we have adopted a distance of 3.0 kpc , the average value of all available near - kinematic distance estimates .
we infer from the previous studies that the bubble is associated with an hii region and an irdc together
. however , the physical conditions inside and around the bubble n37 are not yet known , and the ionizing source(s ) of the bubble is yet to be identified .
furthermore , the impact of the energetics of massive star(s ) on its local environment is not yet explored .
the detailed multi - wavelength study of the region will allow us to study the ongoing physical processes within and around the bubble n37 . to study the physical environment and star formation mechanisms around the bubble , we employ multi - wavelength data covering from the optical , near - infrared ( nir ) to radio wavelengths .
the paper is presented in the following way . in section [ sec : observations ] , we describe the details of the multi - wavelength data .
we discuss the overall morphology of the region in section [ sec : morphology ] . in section
[ sec : result ] , we present the main results of our analysis .
the possible star formation scenarios based on the multi - wavelength outcomes are discussed in section [ sec : discussion ] .
finally , we conclude in section [ sec : conclusions ] .
in this work , we employed a multi - wavelength data to have a detailed understanding of the ongoing physical processes within and around the bubble .
we selected a large - scale region of 15@xmath015@xmath1 ( centered at @xmath8 [email protected] , @xmath10 [email protected] ) around the bubble n37 , which also contains an irdc and a pillar - like structure ( see figure [ fig1]a ) .
details of the new observations and the various archival data are described in the following sections .
to spectroscopically identify the ionizing sources of the bubble n37 , we obtained the optical spectra of two point - like sources ( v @xmath1214 mag ) using grism 7 and grism 8 of the hanle faint object spectrograph and camera ( hfosc ; with slit width of 167 @xmath13 average spectral resolution is @xmath121000 ) attached to the 2 m himalayan _ chandra _ telescope ( hct ) .
corresponding dark and flat frames were also obtained for dark - subtraction and flat - field corrections .
the reduction of these spectra was performed using a semi - automated pyraf based pipeline @xcite .
we obtained the multi - wavelength data from the various galactic plane surveys . in the following ,
we provide a brief description of these various archival data .
nir photometric @xmath14 magnitudes of point - like sources were collected from the united kingdom infrared telescope ( ukirt ) infrared deep sky survey ( ukidss ) galactic plane survey ( gps release 6.0 ; * ? ? ?
* ) catalog .
the ukidss observations were carried out using the wide field camera ( wfcam ; * ? ? ?
* ) attached to the 3.8 m ukirt telescope
. spatial resolution of the ukidss images is @xmath120@xmath158 .
only good photometric magnitudes of point sources in the selected region were obtained following the conditions given in @xcite and @xcite .
several bright sources were saturated in the ukidss frames .
hence , the ukidss sources having magnitudes brighter than j = 13.25 , h = 12.75 and k = 12.0 mag were replaced by the two micron all sky survey ( 2mass ; * ? ? ?
* ) values .
we retrieved the h@xmath16 ( 1@xmath170 ) s(1 ) 2.122 @xmath7 m continuum - subtracted image from the ukirt wide - field infrared survey for h@xmath18 ( uwish2 ; * ? ? ? * ) archive .
these observations were carried out using the wfcam @xcite on the ukirt .
the @xmath19-band linear polarization data for point sources ( resolution @xmath121@xmath155 ) are also used in this study .
the polarization observations were performed using the 1.8 m perkins telescope operated by the boston university and the corresponding data are available in the galactic plane infrared polarization survey ( gpips ; * ? ? ?
* ) archive . in our analysis , we only considered sources having good polarization measurements with p/@xmath20 2.5 ( where p is the degree of polarization and @xmath21 is the corresponding uncertainty ) and usage flag ( uf ) of 1 .
we retrieved the 3.6 , 4.5 , 5.8 and 8.0 @xmath13 images and photometric magnitudes of point sources from the _
spitzer_-galactic legacy infrared mid - plane survey extraordinaire ( glimpse ; * ? ? ?
* ) survey ( spatial resolution @xmath122@xmath22 ) .
the photometric magnitudes were obtained from the glimpse - i spring 07 highly reliable catalog .
in addition to the glimpse data , the multiband infrared photometer for spitzer ( mips ) inner galactic plane survey ( mipsgal ; * ? ? ?
* ) images at 24 @xmath7 m ( resolution @xmath126@xmath22 ) and the magnitudes of point sources at 24 @xmath13 @xcite are also used in the analysis .
some sources , which are well detected in the 24 @xmath13 image , do not have photometric magnitudes in the mipsgal 24 @xmath13 catalog of @xcite .
hence , we separately performed the photometric reduction of 24 @xmath13 image of the n37 region .
a detailed procedure of this photometric reduction can be found in @xcite . in order to construct the dust temperature and column density maps of the n37 region
, we utilized level2_5 processed _ herschel _ 70500 @xmath13 images .
the beam sizes of images at 70 , 160 , 250 , 350 , and 500 @xmath13 are 5@xmath158 , 12@xmath22 , 18@xmath22 , 25@xmath22 , and 37@xmath22 @xcite , respectively .
we have also obtained the apex telescope large area survey of galaxy ( atlasgal ; * ? ? ?
* ) 870 @xmath13 continuum image ( beam @xmath1219@xmath152 ) and the bolocam 1.1 mm @xcite image ( beam @xmath1233@xmath23 ) of the region around the bubble .
the @xmath4co ( j=10 ) line data were retrieved from the galactic ring survey ( grs ; * ? ? ? * ) .
the grs data have a velocity resolution of 0.21 kms@xmath3 , an angular resolution of 45@xmath22 with 22@xmath22 sampling , a main beam efficiency ( @xmath24 ) of @xmath120.48 , a velocity coverage of @xmath175 to 135 km s@xmath3 , and a typical rms sensitivity ( 1@xmath25 ) of @xmath26 k. the very large array ( vla ) 20 cm radio continuum map ( beam size @xmath126@xmath152@xmath275@xmath154 ) of the n37 region was obtained from the multi - array galactic plane imaging survey archive ( magpis ; * ? ? ?
a detailed understanding of the ongoing physical processes in a given star - forming region requires a thorough and careful multi - wavelength investigation of the region . in a star - forming region , the spatial distribution of the ionized , dust , and molecular emission allows us to identify the h ii regions and cold embedded condensations , which further help us to infer the physical conditions of the region .
a multi - wavelength picture of the region around the bubble is presented in figures [ fig1 ] and [ fig2 ] . in figure
[ fig1]a , on a larger scale , the 8.0 @xmath13 image shows a pillar - like structure , an irdc , an iras source ( iras 18335@xmath170646 ) , and the mir bubble n37 .
the broken or incomplete ring morphology of n37 bubble is clearly seen in the image , as previously reported by @xcite .
figure [ fig1]b shows the spatial distribution of the warm dust towards the n37 region ( rgb map : 70 @xmath13 in red ; 24 @xmath13 in green ; 5.8 @xmath13 in blue ) .
the magpis 20 cm radio continuum emission is also overlaid on the rgb map , which depicts the distribution of the ionized emission .
the periphery of the bubble is dominated by the 5.8 @xmath13 emission and encloses the warm dust as well as the ionized gas . in general ,
the polycyclic aromatic hydrocarbon ( pah ) features are seen at 3.3 , 6.2 , 7.7 , and 8.6 @xmath7 m and trace a photodissociation region ( pdr ) surrounding the ionized gas .
hence , the emission seen in the 5.8 and 8.0 @xmath7 m images might be tracing a pdr towards the n37 bubble .
a longer wavelength view ( 2501100 @xmath7 m ) of the region is presented in figure [ fig2 ] .
the images at 3.670 @xmath7 m are also shown for comparison with the submillimeter and millimeter wavelength images .
the emission at 2501100 @xmath13 traces cold dust components ( see section [ colmn_tempmap ] for quantitative estimates ) .
the cold dust emission is mainly seen towards the pillar - like structure and the iras 18335@xmath170646 .
note that the ionized emission is also detected towards the iras 18335@xmath170646 ( see figure [ fig1]b ) .
we utilized the grs @xmath4co ( j=10 ) line data to infer the physical association of different subregions seen in our selected region around the bubble n37 .
based on the velocity information of @xmath4co data , we find that there are two molecular clouds present in our selected region . the molecular cloud associated with the bubble ( i.e. n37 molecular cloud )
is traced in the velocity range of 3743 km s@xmath3 .
however , the molecular cloud associated with the iras 18335@xmath170646 ( also referred as c25.29 + 0.31 in * ? ? ?
* ) is traced in the velocity range from 43 to 48 km s@xmath3 . in the last two bottom panels ,
we show the velocity integrated @xmath4co maps of the two clouds seen in our selected region around the bubble .
the integrated @xmath4co emission map reveals an elongated morphology of the n37 molecular cloud ( i.e. velocity range @xmath123743 km s@xmath3 ) , which hosts the pillar - like structure , an irdc , and the bubble n37 . on the other hand
, the integrated @xmath4co map of the c25.29 + 0.31 cloud traces a large condensation associated with the iras 18335@xmath170646 , as seen in the longer wavelength continuum images ( see figure [ fig2 ] ) .
@xcite also reported the nh@xmath28 line parameters such as nh@xmath28(1,1 ) radial velocity @xmath1246.13 km s@xmath3 and kinematic temperature ( t@xmath29 ) @xmath1221.76 k toward the atlasgal condensation associated with the iras 18335@xmath170646 .
these results suggest that the condensation associated with the iras 18335@xmath170646 is not physically linked with the bubble n37 .
a more detailed analysis of these two molecular clouds ( i.e. n37 molecular cloud and c25.29 + 0.31 ) is discussed in the section [ sec : co ] .
in this section , we present the outcomes of our multi - wavelength analysis in the following way .
first , we present the results related to the identification of ionizing source(s ) of the region , and then the origin of the n37 bubble .
next , we present the column density and the temperature maps of the region to identify the cold condensations .
we have also identified young stellar objects ( ysos ) towards the region , and construct the surface density map of these ysos to study their spatial distribution .
finally , we examine the nir polarization data and the @xmath4co molecular line data to examine the large scale magnetic field morphology and the kinematics of co gas , respectively .
we have seen that the ionized emission is enclosed within the n37 bubble ( see figure [ fig1]b ) and two prominent peaks ( i.e. peak1 and peak2 shown in figure [ fig3 ] ) are seen in the radio continuum map . to search for possible ob type candidates located within the n37 bubble
, we performed a photometric method to identify the probable ionizing candidates of the region , following a similar procedure outlined in @xcite .
the analysis was carried out using the nir and mir photometric magnitudes of point sources from the ukidss and glimpse catalogs , respectively .
we only considered the sources located near the radio emission peaks and detected at least in five photometric bands among ukidss jhk and _ spitzer_-irac 3.6 , 4.5 and 5.8 @xmath13 bands . following this condition ,
a total of seven sources were identified , and these are marked and labeled in figure [ fig3 ] .
the extinction to these sources were estimated assuming intrinsic colors of ( j - h)@xmath30 and ( h - k)@xmath30 for o- and b - stars from @xcite and @xcite , respectively , and using the extinction law ( @xmath31 = 0.284 , @xmath32 = 0.174 , @xmath33 = 0.114 ) from @xcite .
the absolute jhk magnitudes of all these sources were calculated assuming a distance of 3.0 kpc and were compared with those listed in ( * ? ? ? * for o stars ) , and ( * ? ? ? * for b stars ) .
we found that two o - type and five b - type stars are located near the radio peaks within the n37 bubble .
all these sources with their photometric magnitudes and derived spectral types are listed in table [ table1 ] .
note that a single distance is assumed for all the sources , and the spectral types are also estimated without considering the photometric uncertainties of intrinsic colors and observed magnitudes of these sources .
spectroscopic observations will be helpful to further confirm the spectral type of these sources ( see section [ opticalspec ] ) .
llccccccccccccc 1 & 18:36:18.6 & -06:39:09 & 10.17 & 9.62 & 9.34 & 10.17 & 9.62 & 9.34 & 9.24 & 6.11 & -3.95 & -3.84 & -3.74 & o8v@xmath34 + 2 & 18:36:20.2 & -06:38:50 & 10.41 & 9.80 & 9.38 & 10.41 & 9.80 & 9.38 & 8.15 & 7.49 & -4.10 & -3.90 & -3.86 & o7v - o8v@xmath35 + 3 & 18:36:23.3 & -06:38:34 & 15.23 & 13.44 & 12.55 & 15.51 & 13.53 & 12.70 & 11.91 & 16.20 & -1.76 & -1.80 & -1.67 & b2v + 4 & 18:36:19.0 & -06:39:24 & 13.61 & 12.64 & 11.92 & 13.76 & 12.62 & 11.93 & 11.06 & 11.05 & -1.92 & -1.70 & -1.73 & b2v + 5 & 18:36:20.2 & -06:39:05 & 14.12 & 12.88 & 12.14 & 13.73 & 12.42 & 11.73 & & 12.45 & -1.80 & -1.70 & -1.66 & b2v + 6 & 18:36:23.2 & -06:39:27 & 14.52 & 12.98 & 12.20 & 14.42 & 12.71 & 11.94 & 11.38 & 14.21 & -1.90 & -1.90 & -1.81 & b2v + 7 & 18:36:17.4 & -06:39:15 & 15.29 & 13.18 & 12.08 & 15.20 & 13.04 & 11.94 & 11.18 & 19.77 & -2.71 & -2.69 & -2.56 & b1v we have carried out optical spectroscopic observations ( 4000 - 7500 ) of two brightest photometrically identified ob stars ( see asterisks in figure [ fig3 ] ) .
the remaining five sources are beyond the limit of optical spectroscopic capability of the hct ( v - limit @xmath3618-mag for spectrum having signal - to - noise ratio of about 20 with 30 min exposure ) .
the observed spectra of these two sources are shown in figure [ fig4 ] .
one of these sources ( source # 1 ) is situated near the peak1 ( @xmath1210@xmath23 ) of the 20 cm radio emission , and the other one ( # 2 ) is located @xmath1236@xmath23 away from the radio peak1 . several hydrogen and helium lines
are found in both the spectra ( figures [ fig4]a and [ fig4]b ) .
the presence of hydrogen lines is generally seen in early type sources ( o a spectral type ) , however , the existence of he i - ii lines is not found in a stars @xcite .
note that the ionization of helium requires a high temperature generally seen in o - type sources . to confirm the spectral types of these sources , we further compared our observed spectra with the available ob stars spectra @xcite . generally , spectral lines in the first part of the optical spectrum ( 4000 - 5500 ) are used to determine the spectral type of any source . however , the signal - to - noise ratio of the first part of both the spectra is not very good , possibly because of large visual extinction toward the region .
a visual comparison of the observed spectra with the available library spectra reveals that the source # 1 is likely to be a o9v star , while the other source ( # 2 ) is an b0v candidate .
it can be seen in section [ photometricionizing ] that the second source was photometrically identified as o7 - 8v star possibly because of the assumed distance of 3.0 kpc in the calculation which might not be true ( see next paragraph ) .
we have also estimated spectro - photometric distances to these two sources .
the optical bv - band magnitudes of both the sources were obtained from the american association of variable stars observers ( aavso ) photometric all - sky survey ( apass ) catalog ( dr9 ) and the nir @xmath37-band magnitudes were collected from the 2mass catalog . to estimate the distance to the o9v source , we first obtained the intrinsic color of an o9v star ( @xmath380.79 ) from @xcite .
furthermore , the color excess @xmath39 was estimated using the relation @xmath40/@xmath41 2.826 given in @xcite . though it is debatable whether the value of @xmath42 ( @xmath43/@xmath39 ) is 3.1 all over the galaxy or is it substantially different in galactic star - forming regions ( see * ? ? ? * and references therein ) ,
we considered the mean @xmath42 of 3.1 itself for the reddening correction . accordingly , the visual extinction of the source was found to be 6.3 mag .
the absolute and apparent v - band magnitudes of both the sources were obtained from @xcite and the apass catalog , respectively . with an absolute v - magnitude of -4.5 and apparent v - magnitude of 14.37
, we estimated the distance to the o9v star of 3.1 kpc . following the similar procedure for the other source ( b0v ) with the absolute and apparent magnitudes of -4.0 and 14.55 , respectively ,
the visual extinction ( @xmath43 ) was estimated to be 6.4 mag , and the corresponding distance to the source is 2.7 kpc . note that large errors ( at least 20% ) could be associated with these distance estimates due to photometric uncertainties , and the general extinction law used in the estimation . however , similar distances of these sources and the bubble suggest that they are physically associated with the n37 bubble .
the integrated radio continuum flux is used as a tool to determine the spectral type of the source responsible to develop the h ii region .
the presence of an h ii region is traced in the magpis 20 cm map ( see figure [ fig1]b ) .
the lyman continuum flux ( photons s@xmath3 ) required for the observed radio continuum emission is estimated following the equation given in @xcite : @xmath44 where @xmath45 is the frequency of observations , @xmath46 is the total observed flux density , @xmath47 is the electron temperature , and @xmath48 is the distance to the source . here , the region is assumed to be homogeneous and spherically symmetric , and a single main - sequence star is responsible for the observed free - free emission . the flux density ( @xmath46 ) and the size of the h ii region
are determined using the jmfit task of the astronomical image processing software ( aips ) .
typical value of the electron temperature , @xmath49 10000 k for a classical h ii region @xcite is adopted in the calculation .
the spectral type of the powering source is finally estimated by comparing the observed lyman continuum flux with the theoretical value for solar abundance given in @xcite . in the magpis 20 cm map ,
two radio peaks are clearly evident within the bubble ( peak1 and peak2 ; see figure [ fig3 ] ) , and we estimated the spectral type of the possible ionizing source for both the peaks separately . the lyman continuum flux for the radio peak1 ( s@xmath50 1.18 jy ; s@xmath51 10@xmath52 photons
sec@xmath3 ) corresponds to an ionizing source having spectral type of o9v , while the ionizing source corresponding to the radio peak2 ( s@xmath50 0.56 jy ; s@xmath51 10@xmath53 photons sec@xmath3 ) is a b0v star .
as mentioned before ( see sections [ photometricionizing ] and [ opticalspec ] ) , using the spectroscopy and photometry , we identified three ob stars ( o9v , b1v , and b2v ) that are located near the radio peak1 ( see figure [ fig3 ] ) .
however , the lyman continuum flux @xcite expected together from solar abundant b1v and b2v stars is about an order less compared to the o9v star , and therefore , the total flux is mainly dominated by the o9v star .
hence , it seems that an o9v star located at a distance of @xmath1210@xmath23 from the radio peak1 is the primary ionizing source of the region .
the spectral type of the ionizing source determined from the radio analysis is consistent with our spectroscopic results . toward the radio peak2
, we identified a b2v star using the photometric analysis , however the estimation from the radio continuum flux shows the ionizing source to be a b0v star .
the spectral type corresponding to the peak2 estimated using two methods is showing inconsistency because the photometric determinations of spectral types may vary substantially depending on the distance to the source and the photometric accuracy .
we have also determined the dynamical age of the h ii region using the magpis 20 cm data .
a massive source ionizes the surrounding gas , and develop an h ii region .
the ionization front of the h ii region expands until an equilibrium is achieved between the rate of ionization and recombination .
theoretical radius of the h ii region ( i.e. , strmgren radius ; * ? ? ?
* ) for a uniform density and temperature , can be written as : @xmath54 where @xmath55 is the initial ambient density , and @xmath56 is the recombination coefficient .
for a temperature of 10,000 k , the value of @xmath56 is 2.60@xmath2710@xmath57 @xmath58 s@xmath3 @xcite .
a shock front is generated because of the large temperature and pressure gradient between the ionized gas and the surrounding cold material , and the shock front is further propagated into the surroundings .
the corresponding radius of the ionized region at any given time can be written as @xcite : @xmath59 where the speed of sound in an h ii region ( c@xmath60 ) is 11@xmath2710@xmath61 cm s@xmath3 @xcite and @xmath62 is the dynamical age of the h ii region .
the size of the h ii region , i.e. , r(t ) , was estimated to be 1.4 pc by using the jmfit task of the aips .
note that the calculated dynamical age can vary substantially depending on the initial value of the ambient density .
therefore , we estimated the strmgren radius and the corresponding dynamical age for a range of ambient density starting from 1000 to 10000 @xmath63 ( e.g. classical to ultra - compact h ii regions ; * ? ? ? * ) . for the corresponding densities , the dynamical age varies from 0.210.71 myr .
however , the strmgren radius and dynamical age were calculated by assuming the region as homogeneous and spherically symmetric .
hence , the dynamical age of the h ii region should be considered as a representative value ( see section [ sec : discussion ] for more discussion ) . in figure
[ fig5]a , we present the continuum - subtracted h@xmath18 emission ( 2.122 @xmath13 ) map toward the bubble n37 , which traces the edges of the bubble .
the h@xmath18 features have similar morphology as seen in the _
spitzer_-glimpse images .
the h@xmath18 emission in a given star - forming region is originated in the shocked region developed at the interface of the ionized and cold matter . from the distribution of h@xmath16 emission ,
8.0 @xmath7 m emission and the ionized emission ( see figure [ fig2 ] ) , it is evident that the emission seen in the narrow h@xmath16-band is tracing the pdr towards the n37 region .
possibly , the h@xmath16 emission is originated in the shocked region developed due to the expansion of the ionized gas .
ratio maps of _
spitzer_-irac images have ability to provide the information about the interaction of massive star(s ) with its surrounding environment @xcite .
note that the _ spitzer_-irac bands contain several prominent characteristic atomic and molecular lines .
for example , irac ch1 contains a pah feature at 3.3 @xmath13 as well as a prominent molecular hydrogen line at 3.234 @xmath7 m ( @xmath45 = 10 @xmath64(5 ) ) .
irac ch2 also contains a molecular hydrogen emission line at 4.693 @xmath13 ( @xmath45 = 00 @xmath65(9 ) ) generally excited by outflow shocks , and a hydrogen recombination line br@xmath66 ( 4.05 @xmath7 m ) .
figure [ fig5]b shows the irac ch2/ch1 ratio map of the n37 region , which reveals the bright emission region surrounded by the dark features .
in general , the dark regions in the 4.5 @xmath7m/3.6 @xmath7 m ratio map traces the excess 3.6 @xmath7 m emission , while the bright emission region suggests the domination of 4.5 @xmath7 m emission .
the bright emission region in the ratio map is very well correlated with the radio continuum emission .
therefore , it seems that this bright emission region probably traces the br@xmath66 feature originated by the photoionized gas .
the dark features in the ratio map are also well correlated with the 2.122 @xmath7 m h@xmath16 emission , indicating that the ratio map probably traces the h@xmath16 features ( see figures [ fig5]a and [ fig5]b ) .
however , it must be noted that the ch1 also contains 3.3 @xmath13 pah emission feature which may also contribute to the dark features seen in the ratio map .
overall , we found that the irac ratio map and the continuum - subtracted h@xmath16 image trace pdr around the hii region .
massive stars can influence their parent molecular clouds via different feedback components - ( i ) pressure due to radiation ( p@xmath67 ) , ( ii ) pressure due to hii region ( p@xmath68 ) , and ( iii ) pressure due to wind ( p@xmath69 ) .
it is important to determine the strongest pressure component of massive stars in order to have a better knowledge of the feedback mechanisms .
pressure due to radiation can be formulated as p@xmath67 = @xmath70 , where @xmath71 is the bolometric luminosity and d@xmath72 is the distance from the star to the region of interest .
similarly , the pressures due to the h ii region and stellar wind can be written as p@xmath68 = @xmath73 @xmath74 and p@xmath69 = @xmath75 , respectively , where the mean molecular weight in an h ii region , @xmath7=0.678 @xcite , c@xmath60 is the sound speed in an h ii region = 11 km s@xmath3 , @xmath56 is a recombination coefficient = 2.6@xmath2710@xmath57 @xmath58 s@xmath3 , n@xmath76 is the number of uv photons , @xmath77 is the mass - loss rate of the source , @xmath78 is the terminal velocity of the stellar wind ( see * ? ? ? * for more details about these formulas ) .
all the pressure components were estimated at a distance of @xmath121 pc which is the nearest edge of the bubble from the massive o9v star .
the pressure exhibited by the h ii region with n@xmath79 10@xmath80 photons sec@xmath3 ( i.e. , total lyman continuum for both the radio continuum peaks ; see section [ sec : radio ] ) is estimated to be 2.8@xmath2710@xmath81 dyne @xmath82 . for the estimation of p@xmath67
, the bolometric luminosities of all seven ob stars within the bubble were obtained from @xcite and the total radiation pressure exhibited by all these ob stars is found to be 1.8@xmath2710@xmath81 dyne @xmath82 . to estimate the combined p@xmath69 from all the seven ob stars ,
the wind speed and the mass - loss rate for the o9v star were obtained from @xcite ( v@xmath831000 km s@xmath3 ; @xmath8410@xmath85 yr@xmath3 ) .
the corresponding values for b0v , b1v and b2v stars ( v@xmath831000 , 700 and 700 km s@xmath3 ; @xmath8410@xmath86 , 10@xmath87 ; 10@xmath88 m@xmath6 yr@xmath3 , respectively ) were obtained from @xcite .
the combined pressure due to the wind ( p@xmath69 ) from all the seven ob stars comes out to be 5.1@xmath2710@xmath89 dyne @xmath82 .
the estimation of different pressure components infers that the pressure due to the ionized gas ( i.e , h ii region ) is the predominant component . however , there is also a substantial radiation pressure contributed together by all the ob stars .
note five out of seven of these ob stars not only lack of spectroscopic confirmations , but also association of them with the n37 bubble is uncertain .
therefore , the calculated values of the pressure due to the radiation and the stellar wind should be treated as upper limits . from the overall analysis
it seems that a shock - front has been developed due to the expansion of the h ii region which excites the h@xmath18 emission as well as pah emission .
our results indicate that the n37 bubble is possibly originated due to the ionizing feedback of the massive stars .
we have constructed the column density and the temperature maps of the region using _ herschel _ images to probe the condensations and the distribution of cold matter .
a pixel - by - pixel modified blackbody fit was performed to the cold dust emission seen in the _ herschel _ 160 , 250 , 350 and 500 @xmath13 images .
the 70 @xmath13 image was not considered in our analysis because a substantial part of the 70 @xmath13 flux comes from the warm dust . before performing the fit ,
all the images were convolved to the lowest resolution of 37@xmath23 ( beam size of the 500 @xmath13 image ) and converted to the same flux unit ( jy pixel@xmath3 ) . for better estimation of the source flux
, we subtracted the corresponding background flux from each image ( see * ? ? ? * for more detail ) .
background flux was estimated in a relatively dark region ( @xmath8 [email protected] , @xmath10 [email protected] ; area : 10@xmath010@xmath1 ) away from our selected target , and corresponding fluxes are -2.202 , 1.328 , 0.693 and 0.252 jy pixel@xmath3 for 160 , 250 , 350 and 500 @xmath13 images , respectively .
finally , the pixel - by - pixel basis modified blackbody fitting was performed by using the formula @xcite : @xmath90 where optical depth can be written as : @xmath91 different symbols in the above equations are as follows - @xmath92 : observed flux density , @xmath93 : background flux density , @xmath94 : planck s function , @xmath95 : dust temperature , @xmath96 : solid angle subtended by a pixel , @xmath97 : mean molecular weight , @xmath98 : mass of hydrogen , @xmath99 : dust absorption coefficient , and @xmath100 : column density . here , we used @xmath96 = 4.612@xmath2710@xmath101 steradian ( i.e. for 14@xmath10214@xmath22 area ) , @xmath97=2.8 and @xmath99=0.1 @xmath103 @xmath104 g@xmath3 , the gas - to - dust ratio of 100 , and the dust spectral index @xmath105=2 for sources with thermal emission in the optically thick medium @xcite .
the final column density and temperature maps of the 15@xmath015@xmath1 area of the n37 region are shown in figures [ fig6]a and [ fig6]b , respectively .
several condensations are seen towards the region .
the ` clumpfind ' software @xcite has been used to identify the clumps and to measure the total column density in each clump .
the mass of a clump is estimated using the formula @xcite : @xmath106 where @xmath97=2.8 , @xmath107 is the area subtended by one pixel , and @xmath108 is the total column density of the clump obtained using the ` clumpfind ' .
a total of 17 clumps are identified toward the 15@xmath015@xmath1 area of the n37 region ( see figure [ fig6 ] ) . however , based on the integrated co maps ( see figure [ fig2 ] ) , we find only five clumps ( i.e. c25 and c10 , in figure [ fig6 ] ) associated with the n37 molecular cloud , and the remaining clumps appear to be associated with the c25.29 + 0.31 molecular cloud . in the present work ,
our analysis is focused on the n37 molecular cloud , and hence , we do not discuss the results of the c25.29 + 0.31 cloud . in the n37 molecular cloud , the five associated clumps ( i.e. c25 and c10 ; m@xmath109 from @xmath1213502150 m@xmath110 ) are having temperatures and densities in the range from @xmath122223 k and @xmath127.29.5 @xmath27 10@xmath111 @xmath82 ( corresponding a@xmath112 @xmath128.010.0 mag ) , respectively . here , to estimate the visual extinction , we use the relation @xmath113 molecules @xmath82 mag@xmath3 @xcite .
the study of ysos in a given star - forming region allows to characterize the area of the ongoing star formation .
hence , we have carried out identification of ysos using the nir and mir color - magnitude and color - color schemes . a more elaborative description of these schemes is given below . [ cols="^,^ " , ]
four different schemes are employed to identify and classify the ysos for the selected 15@xmath015@xmath1 area around the n37 region .
young sources are known to be a strong emitter at mir bands , while they are still embedded in their parent molecular clouds and can not be seen in the optical / nir bands .
hence , mir photometric criteria allow us to identify sources at a very early phase .
we cross - matched the sources that have detections in both the mipsgal 24 @xmath13 and _ spitzer_-irac / glimpse 3.6 @xmath13 bands , and constructed a color - magnitude diagram ( [ 3.6]@xmath17[24]/[3.6 ] ) to identify the ysos , following the color criteria given in @xcite and @xcite .
a total of 100 sources are found that are common in the 3.6 and 24 @xmath7 m bands .
the color - magnitude diagram of these sources is shown in figure [ fig7]a .
different classes of ysos are marked by distinct symbols and are separated by black dashed - lines .
the boundaries for other contaminants like disk - less stars and galaxies are also marked by a green dashed curve , following the criteria given in @xcite . using this scheme ,
a total of 19 class i , 12 flat - spectrum , 22 class ii , and 36 class iii sources were identified .
there are several sources that are not seen in the mipsgal 24 @xmath13 image , but detected in the _ spitzer_-irac / glimpse bands ( 3.6 , 4.5 , 5.8 , and 8.0 @xmath13 ) . hence , the color - color diagram ( [ 5.8]@xmath17[8.0])/([3.6]@xmath17[4.5 ] ) of the sources detected in all four irac bands was used to identify the additional ysos ( see figure [ fig7]b ) .
possible contaminants ( such as broad - line active galactic nuclei , pah - emitting galaxies and shock emission knots ) were removed from the sample using the criteria given in @xcite .
the selected ysos were classified into different evolutionary stages using the slopes of the _
spitzer_-irac / glimpse spectral energy distribution ( sed ) ( i.e. @xmath114 ) measured from 3.6 to 8.0 @xmath7 m ( see * ? ? ? * for more details ) .
finally , using this scheme , we identified a total of 20 class i and 99 class ii ysos .
\3 . due to prominent nebulosity seen in the irac 8.0 @xmath13 band ,
there are several sources that are not detected in the 8.0 @xmath13 image , but identified in other three glimpse - irac bands ( 3.6 , 4.5 , and 5.8 @xmath13 ) .
hence , the color - color diagram ( [ 3.6]@xmath17[4.5]/[4.5]@xmath17[5.8 ] ) was constructed to identify the additional ysos ( see figure [ fig7]c ) .
the sources that follow [ 4.5]@xmath17[5.8 ] @xmath115 0.7 mag and [ 3.6]@xmath17[4.5 ] @xmath115 0.7 mag are classified as protostars @xcite . using this scheme , a total of 17 protostars were identified in the region around the bubble .
presence of circumstellar material makes ysos to appear much redder than the nearby field stars in the nir color - magnitude diagram .
hence , we also used nir color - magnitude diagram ( h@xmath17k / k ) to identify additional ysos toward the n37 region .
the @xmath116 color cut - off of 1.8 was estimated by constructing the color - magnitude diagram ( h@xmath17k / k ) of a nearby field region ( size@xmath1215@xmath015@xmath1 area centered at @xmath8 [email protected] ; @xmath10 [email protected] ) .
this color cut - off differentiate the field stars from the sources having large nir excess .
the nir color - magnitude diagram of the sources is shown in figure [ fig7]d . using the nir scheme
, we identified a total of 1203 red sources that could be presumed as ysos
. there could be overlap of ysos identified using these four different schemes . in order to have a complete catalog ,
ysos identified using different schemes were cross - matched .
finally , a total of 29 class i , 12 flat spectrum , 99 class ii , 973 class iii ysos , and 1066 red sources are identified toward the n37 region . in order to examine
how the ysos are clustered in the region around the bubble , a nearest - neighbor ( nn ) surface density analysis of ysos was performed following the method given in @xcite and @xcite .
using monte carlo simulations , @xcite showed that the 20nn surface density is capable to detect clusters with 101500 ysos .
hence , the 20nn surface density analysis of ysos was performed using a grid size of 6@xmath159 which corresponds to 0.1 pc at a distance of 3 kpc .
figure [ fig8 ] shows the surface density contours of ysos overlaid on the _ herschel _ 500 @xmath13 image .
the contour levels are drawn at 15 , 18 , 22 , 27 , and 30 ysos pc@xmath117 .
the positions of all the clumps identified in the _ herschel _ column density map are also marked on the image .
the yso clusters are found toward the irdc , the clump c1 and the pillar - like structure , and many of these yso clusters are associated with peaks having more than 27 ysos pc@xmath117 ( see figure [ fig8 ] ) .
it is already mentioned before that the clump c1 is part of the c25.29 + 0.31 cloud and is not associated with the n37 molecular cloud . therefore , the clusters of ysos located towards the clump c1 might not have any physical association with the n37 bubble . in order to infer the physical properties of ysos ( e.g. , mass , age ) ,
the sed modeling of a few selected ysos was performed using the sed fitter tool of @xcite .
the grids of yso models were computed using the radiation transfer code of @xcite , which assumes an accretion scenario for a pre - main sequence central star , surrounded by a flared accretion disk and a rotationally flattened envelope with cavities .
the model grid has 20,000 sed models from @xcite , estimated using two - dimensional radiative transfer monte carlo simulations .
each yso model gives the output seds for 10 inclination angles with masses ranging from 0.150 m@xmath110 .
the fitter tool tries to find the best possible match of yso models for the observed multi - wavelength fluxes followed by a chi - square minimization .
the distance to the source and interstellar visual extinction ( a@xmath118 ) are used as free parameters .
we performed the sed modeling of those ysos that have fluxes at least in five filter bands ( among nir jhk and spitzer - irac bands ) , in order to constrain the diversity of the modeling parameters .
accordingly , a total of 81 ysos were selected for the sed fitting . in the models
, we used the a@xmath118 in the range from 050 mag and the distance ranging from 24 kpc . for each yso , only those models were selected which follow the criterion : @xmath119
@xmath120 @xmath121 3 , where @xmath119 is taken per data point .
note that the output parameters for each yso are not unique because several models can satisfy the observed sed .
hence , the weighted mean values were computed for all the model fitted parameters for each yso . in table
[ table2 ] , we have listed , the right ascension ( j2000 ) , declination ( j2000 ) , the weighted mean values of the stellar age , stellar mass , total luminosity , extinction and evolutionary class for a sample of 6 ysos . the complete table of 81 ysos is available online in machine readable format .
llccccl 18:35:58.8 & -06:43:18 & [email protected] & [email protected] & [email protected] & [email protected] & class ii + 18:36:17.7 & -06:45:41 & [email protected] & [email protected] & [email protected] & [email protected] & class ii + 18:36:20.0@xmath123 & -06:44:21 & [email protected] & [email protected] & [email protected] & [email protected] & class i + 18:36:24.9@xmath124 & -06:39:41 & [email protected] & [email protected] & [email protected] & [email protected] & class ii + 18:36:25.5@xmath124 & -06:39:46 & [email protected] & [email protected] & [email protected] & [email protected] & class i + 18:36:36.1@xmath125 & -06:37:51 & [email protected] & [email protected] & [email protected] & [email protected] & class ii the polarization of background starlight is often used to study the projected plane - of - the - sky magnetic field morphology .
the polarization vectors of background stars allow to trace the field direction in the plane of the sky parallel to the direction of polarization @xcite .
nir polarization data of point sources towards the n37 region were obtained from the gpips ( see * ? ? ? * for more details ) and were covered in several fields i.e. , gp0608 , gp0609 , gp0610 , gp0622 , gp0623 , gp0624 , gp0635 , gp0636 , gp0637 , gp0649 , gp0650 , gp0651 .
a total of 375 sources with reliable polarization measurements were identified in the 15@xmath12615@xmath1 area towards the n37 region using the criteria of p/@xmath127 2.5 and uf of 1 . in figure
[ fig9]a , we show a color - color diagram ( @xmath116 vs. @xmath128 ) of the selected sources and find that the majority of the sources are either reddened giants or main - sequence stars .
hence , it is evident from the nir color - color diagram that the majority of stars are located behind the n37 molecular cloud .
the histograms of the degree of polarization and the corresponding galactic position angles are also shown in figures [ fig9]b and [ fig9]c , respectively , which show that the majority of the sources have degree of polarization and position angle of about 1.5% and @xmath1260@xmath129 , respectively . if it is considered that the dust components responsible to polarize the background starlight are aligned along the magnetic field lines , then the corresponding plane - of - sky component of the magnetic field is oriented at a position angle of @xmath1260@xmath129 .
the polarization vectors overlaid on the velocity integrated @xmath4co map are shown in figure [ fig10]a . to examine the average distribution of nir @xmath19-band polarization , the mean degree of polarization vectors superimposed on the _ spitzer _ 8 @xmath13 image are shown in figure [ fig10]b . in order to study the mean polarization , our selected 15@xmath12615@xmath1 spatial area
was divided into 225 grids having 1@xmath1261@xmath1 area for each grid and the mean polarization value for each grid is computed using the average q and u stokes parameters of all the @xmath19-band sources located inside that particular grid . using the @xmath19-band polarization data
, one can not trace the morphology of the plane - of - the - sky projection of the magnetic field toward the dense clumps , where extinction is generally high enough for a background source to be detected in the nir @xmath19-band .
the grs @xmath4co ( j=10 ) line data were utilized to examine the distribution and kinematics of the molecular gas towards the n37 bubble .
additionally , the velocity information of gas inferred from the @xmath4co data is used to know the physical association of different subregions seen in the selected region around the bubble .
the integrated grs @xmath4co ( j=1@xmath170 ) velocity channel maps ( at intervals of 1 km s@xmath3 ) are shown in figure [ fig11 ] , tracing different subregions along the line of sight . as mentioned before from the @xmath4co profile that the molecular cloud associated with the bubble n37 ( i.e. , n37 molecular cloud ) is depicted in the velocity range from 3743 km s@xmath3 . in this velocity range , three condensations
( see last panel of figure [ fig11 ] for c2 , c3 , and c4 ) located towards the pillar - like structure are well detected in the channel maps .
the integrated grs @xmath4co intensity map for the c25.29 + 0.31 was previously reported by @xcite having v@xmath130 of @xmath1245.9 km s@xmath3 with a velocity range of @xmath124348 km s@xmath3 .
based on the co velocity profile and channel maps ( figure [ fig11 ] ) , we infer that two nearby but distinct molecular clouds ( i.e. n37 molecular cloud and c25.29 + 0.31 ) are present in our selected area of analysis . hence , there could be a possibility for physical interaction between these two nearby molecular clouds .
note that the position - velocity analysis of these clouds is not yet explored .
figure [ fig12]a shows an integrated velocity map ( 3743 km s@xmath3 ) of the region around the bubble n37 , which reveals the physical association of molecular condensations with the n37 molecular cloud . in general , the position - velocity plots of the molecular gas are often used to search for any expansion of gas and/or outflow activity within a given cloud ( e.g. , * ? ? ?
* ; * ? ? ?
the position - velocity diagrams of @xmath4co gas associated with the n37 cloud are shown in figures [ fig12]c and [ fig12]e .
the positions of the massive ob stars and the condensations are also marked in the position - velocity diagrams .
the velocity gradients are evident toward the condensations c2 , c3 , and c4 , which can be indicative of the outflow activities within each of them .
note that the angular resolution of the @xmath4co data ( 45@xmath23 ) is coarse therefore we can not further explore the outflow activity within these condensations .
additionally , an inverted c - like structure appears in figure [ fig12]c ( follow the marked curve ) and the massive ob stars are located near the center of the structure .
such structure is indicative of an expanding shell associated with the hii region in the bubble n37 ( e.g. , * ? ? ?
* ; * ? ? ?
the study of @xmath4co line data suggests the presence of molecular outflow(s ) and the expanding hii region with an expansion velocity of @xmath122.5 km s@xmath3 .
this expansion velocity corresponds to the half of the velocity range for the inverted c - like structure seen in the position - velocity diagram . the integrated velocity map for a larger velocity range ( 3748 km s@xmath3 ) , which covers both the n37 and c25.29 + 0.31 molecular clouds , is presented in figure [ fig12]b .
we have also constructed the position - velocity diagrams of @xmath4co gas in the corresponding velocity range ( see figures [ fig12]d and [ fig12]f ) . in figures [ fig12]d and [ fig12]f , we find that the red - shifted component ( 4348 km s@xmath3 ) and the blue - shifted component ( 3743 km s@xmath3 ) are well separated by a lower intensity intermediated velocity emission , which is referred as a broad bridge feature .
this feature in the position - velocity diagram is generally seen at the interface of the colliding molecular clouds ( see * ? ? ?
* ; * ? ? ?
* for more detail ) .
the implication of this feature is presented in the discussion section ( section [ sec : discussion ] ) .
as mentioned before , there are two molecular clouds ( i.e. n37 molecular cloud and c25.29 + 0.31 ) present in the region around the bubble .
the position - velocity analysis of the molecular gas towards these clouds reveals a broad bridge - like feature .
this bridge - like feature is indicative of a cloud - cloud collision @xcite .
these authors also suggested that the collision between two molecular clouds can be a potential mechanism to trigger the formation of massive stars .
very recently , observational evidences of the cloud - cloud collision and the formation of massive stars through this process have been reported in the galactic star - forming regions rcw120 @xcite and rcw 38 @xcite . according to @xcite and @xcite
, a collision between two non - identical clouds can produce a dense layer at the interface of these clouds and can create a cavity in the large cloud ( see figure 12 of * ? ? ?
the compressed dense layer has the ability to develop the dense cores , which can subsequently form massive stars .
after the formation of massive stars , their strong uv radiation can ionize the surrounding gas and develop an h ii region .
@xcite suggested that the cloud - cloud collision has formed an o - type star in the rcw 120 region , and made it to appear as a broken bubble .
it is mentioned before that the n37 molecular cloud hosts a pillar - like structure , irdc , and the mir bubble n37 .
the cloud also harbors ysos clusters that are associated with the irdc and pillar - like structure .
it is possible that the cloud - cloud collision has influenced the star formation within the n37 molecular cloud ( including the irdc , ob stars , and the pillar - like structure ) .
the massive ob stars might have formed due to a similar formation mechanism as it is reported for rcw 120 . with time
, the massive ob stars developed an hii region and the mir bubble morphology appears to be originated due to the expansion of the photoionized gas ( see section [ sec : ratt ] ) .
it is also possible that the collision between two molecular clouds might have developed the broken cavity and that is why the n37 bubble has appeared with a broken structure .
however , we do not have enough observational evidences to firmly conclude about the origin of the broken feature of the n37 bubble .
we calculated the dynamical age of the hii region ( t@xmath131 ) towards the n37 bubble to be @xmath1320.7 myr for an ambient density of 10000 @xmath63 ( see section [ sec : radio ] ) .
in general , the average ages of class i and class ii ysos are @xmath120.44 myr and @xmath1213 myr @xcite , respectively . considering these ages , it is unlikely that the star formation in the n37 cloud has been triggered by the expansion of the hii region . for further confirmation , we determined the average ages of ysos toward the bubble , the pillar and the clump c1 which is , however , part of c25.29 + 0.31 molecular cloud .
the distribution of class i and class ii ysos overplotted on the 8 @xmath13 image are shown in figure [ fig13]a .
a total of 13 , 7 and 10 ysos are found to be situated toward the n37 bubble , the pillar and the c1 , respectively , for which the sed modeling was performed ( see figure [ fig13]b )
. corresponding mean ages of these ysos are estimated to be 1.0 , 0.7 and 0.7 myr , respectively , which are comparable to the dynamical age of the h ii region of 0.7 myr . for a triggered star formation to occur the mean ages of ysos
should be less compared to the dynamical age of the h ii region .
however , the mean ages are associated with large standard deviations ( @xmath120.5 myr ) and hence , it is not possible to make a definite conclusion from this analysis .
we have also plotted the cumulative distribution of ages of ysos toward the bubble , c1 , and the pillar ( see figure [ fig13]c ) .
it can be seen in the cumulative distributions of the ages that the majority of the ysos ( at least @xmath1260% ) located towards the pillar are younger than the ysos towards the bubble and c1 .
hence , the formation of stars towards the pillar and c1 might have started later than the bubble .
though the ysos associated with the pillar and the c1 are younger than the ysos towards the bubble , the dynamical age of the h ii region is not consistent enough to conclude whether they have formed due to the influence of bubble / massive ob stars .
note that in this paper we do not discuss results related to the c25.29 + 0.31 cloud , which hosts the clump c1 , the iras 18335@xmath170646 , and the star a805 ( an o7ii spectral type ) ( see * ? ? ?
it should be mentioned here that the pillars are generally assumed to be potential sights of triggered star formation @xcite , and young stars are expected to appear at the tip of the pillars @xcite .
a few class i and class ii ysos are found to be associated with the pillar ( see figure [ fig13]a ) and these ysos might have formed by some other mechanisms than triggered by the ob stars or h ii region . it can be noticed in figure [ fig10]b , even though the mean polarization position angles are generally uniform at a galactic position angle of @xmath1260@xmath133 throughout the region , random changes in the polarization position angles are noticed near the interface of the n37 molecular cloud and the clump c1 which is part of the c25.29 + 0.31 molecular cloud .
we suggest that this change in the polarization position angles can be explained by a distortion of gas due to the collision between these two molecular clouds .
overall , this region correlates well with the observational signatures proposed for the cloud - cloud collision process .
in addition to the formation of ob stars , the cloud - cloud collision might have also triggered the formation of several other yso clusters in the n37 molecular cloud .
we performed a multi - wavelength analysis of the galactic mir bubble n37 and its surrounding environment .
the aim of this study is to investigate the physical environment and star formation mechanisms around the bubble .
the main conclusions of this study are the following .
\1 . in the selected @xmath134 region around the mir bubble n37 ,
two molecular clouds ( n37 molecular cloud and c25.29 + 0.31 ) are present along the line of sight .
the molecular cloud associated with the bubble ( i.e. n37 molecular cloud ) is depicted in the velocity range from 37 to 43 km s@xmath3 , while the c25.29 + 0.31 cloud is traced in the velocity range from 43 to 48 km s@xmath3 .
the n37 molecular cloud appears to be blue - shifted with respect to the c25.29 + 0.31 cloud .
\2 . using photometric criteria
, we find a total of seven ob stars within the n37 bubble , and spectroscopically confirmed two of these sources as o9v and b0v stars .
the physical association of these sources with the n37 bubble is also confirmed by estimating their spectro - photometric distances .
the o9v star is found as the primary ionizing source of the region .
this result is in agreement with the lyman continuum flux analysis using the 20 cm data .
several molecular condensations surrounding the n37 bubble are identified in the _ herschel _ column density map .
the physical association of these condensations with the n37 bubble is inferred using the molecular gas distribution as traced in the integrated @xmath4co ( j=10 ) map .
surface density analysis of the identified ysos reveals that the ysos are clustered toward these molecular condensations .
the mean ages of ysos located in different parts of the region indicate that it is unlikely that these ysos are triggered by energetics of the ob stars present within the bubble .
this interpretation is supported with the knowledge of the dynamical age of the h ii region .
the position - velocity analysis of @xmath4co data shows that two clouds ( n37 molecular cloud and c25.29 + 0.31 ) are interconnected with a lower intensity emission known as broad bridge structure .
the presence of such feature suggests the possibility of interaction between the n37 molecular cloud and the c25.29 + 0.31 cloud .
the position - velocity analysis of @xmath4co emission also reveals an inverted c - like structure , suggesting the signature of an expanding hii region .
based on the pressure calculations ( p@xmath135 , @xmath136 , and p@xmath69 ) , the photoionized gas associated with the bubble is found as the primary contributor for the feedback mechanism in the n37 cloud .
possibly the expanding hii region is responsible for the origin of the mir bubble n37 .
the collision between two clouds ( i.e. n37 molecular cloud and c25.29 + 0.31 ) might have changed the uniformity of the molecular cloud which is depicted by a slight change in the polarization position angles of background starlight .
the collision between the n37 molecular cloud and the c25.29 + 0.31 cloud might have triggered the formation of massive ob stars .
this process might also have triggered the formation of ysos clusters in the n37 molecular cloud .
we thank the anonymous referee for the constructive comments .
we are also grateful to dr .
a. luna for proving the idl - based program for the analysis of co line data .
we thank the staff of iao , hanle and crest , hosakote , that made the observations using hct possible .
the facilities at iao and crest are operated by the indian institute of astrophysics , bangalore .
we acknowledge the use of the aavso photometric all - sky survey ( apass ) , funded by the robert martin ayers sciences fund .
this work is based on data obtained as part of the ukirt infrared deep sky survey .
this publication made use of data products from the two micron all sky survey ( a joint project of the university of massachusetts and the infrared processing and analysis center/ california institute of technology , funded by nasa and nsf ) , archival data obtained with the _ spitzer _ space telescope ( operated by the jet propulsion laboratory , california institute of technology under a contract with nasa ) .
this publication makes use of molecular line data from the boston university - fcrao galactic ring survey ( grs ) .
the grs is a joint project of boston university and five college radio astronomy observatory , funded by the national science foundation ( nsf ) under grants ast-9800334 , ast-0098562 , and ast-0100793 .
this publication makes use of the galactic plane infrared polarization survey ( gpips ) .
the gpips was conducted using the _ mimir _ instrument , jointly developed at boston university and lowell observatory and supported by nasa , nsf , and the w.m .
keck foundation .
lkd is supported by the department of space , government of india .
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2012 , a&a , 544 , 146 williams , j. p. , de geus , e. j. , & blitz , l. 1994 , , 428 , 693 zinnecker , h. , & yorke , h. w. 2007 , , 45 , 481[/INST] we have performed a multi - wavelength analysis of a mid - infrared ( mir ) bubble n37 and its surrounding environment .
the selected 15@xmath015@xmath1 area around the bubble contains two molecular clouds ( n37 cloud ; v@xmath23743 km s@xmath3 , and c25.29 + 0.31 ; v@xmath24348 km s@xmath3 ) along the line of sight .
a total of seven ob stars are identified towards the bubble n37 using photometric criteria , and two of them are spectroscopically confirmed as o9v and b0v stars .
spectro - photometric distances of these two sources confirm their physical association with the bubble .
the o9v star is appeared to be the primary ionizing source of the region , which is also in agreement with the desired lyman continuum flux analysis estimated from the 20 cm data .
the presence of the expanding hii region is revealed in the n37 cloud which could be responsible for the mir bubble .
using the @xmath4co line data and photometric data , several cold molecular condensations as well as clusters of young stellar objects ( ysos ) are identified in the n37 cloud , revealing ongoing star formation ( sf ) activities .
however , the analysis of ages of ysos and the dynamical age of the hii region do not support the origin of sf due to the influence of ob stars .
the position - velocity analysis of @xmath4co data reveals that two molecular clouds are inter - connected by a bridge - like structure , favoring the onset of a cloud - cloud collision process .
the sf activities ( i.e. the formation of ysos clusters and ob stars ) in the n37 cloud are possibly influenced by the cloud - cloud collision . </s> |
experiencing stress is an inevitable part of daily life that serves a critical role in shaping adaptive behavior .
brief exposure to stress can be a powerful motivating force in both the pursuit of rewards and avoidance of punishment , and can rapidly boost energy stores in times of homeostatic disruption to ensure safety and survival .
however , stress exposure and the concomitant neurophysiological response it elicits can also exert detrimental effects on brain regions that facilitate the control and regulation of behavior .
these effects are especially relevant for the regulation of fear expression , where top - down regulatory mechanisms are engaged to control emotional responses to threatening stimuli . this process broadly referred to as emotion regulationallows an individual to tailor emotional responses and behavior to a dynamic environment ( gross and thompson , 2007 ) .
the capacity to regulate fear responses to threatening cues once the value or significance of such cues change is critical to emotional resilience and health , while deficits in fear regulation capacity strongly predict vulnerability to an array of affective psychopathology , such as anxiety disorders and depression ( cisler et al .
fear responses can be flexibly changed through a broad range of processes that include learning that an aversive stimulus no longer poses a threat , or adopting a strategy to deliberately change the nature of an emotional response .
these techniques have been repeatedly shown to inhibit or alter fear expression in the service of generating more adaptive responses that are better aligned with the current state of the environment .
importantly , the adaptive benefits afforded by fear regulation are widely known to rely on intact functioning of the prefrontal cortex ( pfc ) , which supports the inhibition and flexible control of fear ( see hartley and phelps , 2010 for review ) .
the pfc , however , is also a major target of stress hormones that a growing body of research suggests can markedly impair its function ( see arnsten , 2009 or holmes and wellman , 2009 ; for reviews ) .
this suggests that the flexible control of fear responses to aversive stimuli may be compromised when accompanied or preceded by exposure to stress .
despite the significance of this possibility , stress has remained largely unexplored within the fear regulation literature . in this review ,
we examine research investigating the effects of stress and stress hormones on regulatory techniques used to flexibly control fear responses in humans . before doing so
, it is important to recognize that the constructs of fear and stress are often conflated in the literature due to their behavioral , neural and neurochemical similarities . to clearly differentiate fear expression from that of a stress response in the context of this review , we refer to fear expression as discrete emotional or behavioral responses that occur when an organism detects a threat in its environment , or when it encounters a cue that has predicted danger in the past . in rodents , fear expression
is typically measured through defensive behaviors such as freezing , whereas in humans fear is often assessed by recording transient sympathetic nervous system arousal responses ( i.e. , skin conductance , pupil dilation ) in the presence of a threatening stimulus ( critchley , 2002 , critchley et al . , 2013 ) .
in contrast , a stress response is operationalized as a more pervasive response that unfolds over a longer timescale and recruits a range of neuromodulatory systems . unlike transient fear arousal
, stressors produce more intense and prolonged response to homeostatic disruptions , eliciting both autonomic and neuroendocrine systems that can exert a broad range of effects on brain function and behavior .
fear expression can be modulated using a number of regulatory strategies , including extinction learning and retention , cognitive emotion regulation , avoidance strategies and reconsolidation .
extinction learning and retention is the most commonly explored form of fear inhibition and occurs by learning through experience that a stimulus is no longer associated with a threatening outcome .
cognitive emotion regulation refers to a broad range of regulatory strategies that can be used to deliberately alter the nature of an emotional response .
avoidance strategies entail performing certain behaviors in order to prevent the occurrence of an aversive outcome .
finally , interfering with the reconsolidation of fear memories can lead to reductions in fear expression by persistently modifying aversive associations .
the neural circuitry underlying each of these forms of fear regulation overlaps with the neural systems that orchestrate both the response to and recovery from stress exposure , rendering these techniques especially sensitive to the effects of stress . despite the pervasive use of these strategies in research and real - world settings , relatively little
understanding how stress affects these regulatory processes has broad implications both for adaptive daily functioning and for how stress - induced regulatory impairments may lead to or exacerbate affective psychopathology .
below we discuss what is known about the impact of stress on the ability to flexibly regulate fear responses that are acquired using standard pavlovian fear conditioning , a fundamental form of associative learning that imbues biologically insignificant cues with aversive value . given that our primary aim is to explore the impact of stress on fear regulation in humans , we primarily discuss techniques where stress has been linked to alterations of fear regulation in humans ( extinction and emotion regulation ) , although we also briefly mention other techniques ( avoidance and reconsolidation ) where the impact of stress or stress hormones have been mainly explored in animal models .
we begin by providing a brief overview of the neurobiological mechanisms of acute responses to stress .
our focus in this review is placed primarily on the learning and regulation of cued fear associations , which rely on the amygdala and surrounding brain regions . in the interest of space , we do not cover contextual fear learning and regulation processes , which are known to instead rely on the hippocampus .
since stress may differentially impact different phases of fear conditioning , we discuss the effects of stress and stress hormones on the phases ( i.e. , learning , consolidation , retrieval ) of fear acquisition and extinction by surveying research that has induced stress or administered stress hormones before or concurrently with these phases .
we then review the mechanisms of cognitive emotion regulation and the impact of stress in humans .
finally , we briefly review other fear regulation techniques ( avoidance and reconsolidation ) where the impact of stress and stress hormones have mainly been explored in animal models .
stress is induced when real or perceived threats are detected in the environment ( joels et al . , 2012 ) .
stressors can emerge from a number of sources that can be generally categorized as physical or psychological in nature .
physical stressors comprise threats to survival such as predatory threats that signal imminent danger , or disruptions to homeostasis such as hunger , sickness or pain .
psychogenic stressors constitute emotional or social threats that may occur through negative social evaluation or severe emotional distress ( dickerson and kemeny , 2004 ) .
irrespective of their source , stressors are typically characterized by the perception of being novel , unpredictable and , importantly , outside of one 's control ( lupien et al . , 2007 ) .
the detection of a stressor promotes a broad range of hormonal and neurotransmitter responses that can exert a powerful influence on brain function and behavior ( mcewen , 2003 ) .
acute stress exposure rapidly activates the autonomic nervous system through its sympathetic branch that triggers peripheral responses , such as increased respiration , heart rate and blood pressure and allocates metabolic resources to promote defensive behavior ( goldstein , 2003 , ulrich - lai and herman , 2009 ) .
this response also triggers catecholamine release by way of sympathetic nerves that activate noradrenergic terminals throughout the body , as well as the adrenal medulla that releases adrenaline directly into the bloodstream .
in contrast , the hypothalamic - pituitary - adrenal ( hpa ) axis elicits neuroendocrine effects that peak at a longer timescale after stress exposure .
activation of the hpa - axis triggers the systemic release of glucocorticoids ( cortisol in humans ) that can work in a synergistic manner with catecholamines to potentiate their short - lived effects ( ulrich - lai and herman , 2009 ) .
this is especially so for the effects of stress on modulating emotional learning and memory , as noradrenergic signaling is critical to the enhancing effects of glucocorticoids on memory consolidation and retrieval ( quirarte et al . , 1997 , roozendaal et al . , 2009 ) .
stressors activate the hpa - axis through the release of corticotropin - releasing hormone ( crh ) from the paraventricular nucleus ( pvn ) of the hypothalamus .
when crh reaches the anterior pituitary gland , it elicits adrenocorticotropic hormone ( acth ) release , which prompts glucocorticoid synthesis in the adrenal glands .
finally , glucocorticoids are released into the bloodstream where they travel and bind to receptors throughout the body and brain ( mcewen et al . , 1986 ,
glucocorticoid release follows a slower time course than rapidly released catecholamines , peaking 1020 min after the onset of stress exposure ( sapolsky et al . , 2000 ) .
glucocorticoids are often characterized as a recovery hormone that adapts an organism to the neurophysiological changes that occur during stress ( lupien et al . , 2007 ) .
collectively , these two systems interact and function in a complementary manner to mobilize energy and help an organism cope with stressful experiences . despite the inability of peripheral catecholamines to cross the blood
brain barrier , noradrenaline is projected throughout the brain by way of the locus coeruleus ( lc ) .
the lc serves as the brain 's primary source of noradrenaline and shares reciprocal connections with brain regions that are critical to the acquisition and regulation of conditioned fear , such as the amygdala , hippocampus and pfc ( benarroch , 2009 ) .
the high proportion of noradrenaline receptors in the amygdala and pfc render these brain regions especially sensitive to the effects of stress ( mcewen et al . , 1986 ) .
brain barrier and binding to high - affinity mineralocorticoid and low - affinity glucocorticoid receptors distributed throughout the amygdala , hippocampus and pfc ( joels et al .
the effects of glucocorticoids include dampening glucose transport within cortical neurons and glia cells , which may further influence brain function by diminishing processing and amplifying the effects of early catecholamine release by slowing their clearance from synaptic space ( grundemann et al . , 1998 , ferry et al . , 1999 , roozendaal et al . , 2002 ) .
the release of glucocorticoids is controlled through negative feedback mechanisms housed within the pfc , suggesting that this region is targeted both for glucocorticoid binding under stress and for the regulation of glucocorticoid release ( diorio et al . , 1993 ) .
consistent with this , both chronic exposure to stress and affective psychopathology have been shown to be related to deficits in hpa regulation and inhibition ( cacioppo et al .
learning to respond appropriately to cues that signal danger is critical to survival and can facilitate adaptive behavior .
pavlovian fear conditioning is often used as a laboratory paradigm to examine how biologically insignificant stimuli can acquire emotional relevance as they come to predict aversive events . in a standard cued pavlovian fear conditioning paradigm a neutral stimulus , such as a light or tone ( conditioned stimulus , or cs ) , is paired with an innately aversive stimulus , such as an electric shock or noxious odor ( unconditioned stimulus , or us ) ( pavlov , 1927 ) .
the us will automatically elicit an array of physiological , neuroendocrine and behavioral responses consistent with defensive behavior .
after a few trials a reinforced cs can come to elicit similar responses to that of the us itself .
a long tradition of research in animals and humans has provided an intricate understanding of the behavioral and neural systems underlying aversive learning and regulation .
the amygdala has been shown across species to be critical for the acquisition , storage and expression of conditioned fear ( for review , see ledoux , 2000 , maren , 2001 , davis and whalen , 2001 , phelps , 2006 ) .
the amygdala contains functionally and anatomically distinct nuclei including the lateral ( la ) , basal ( b ) and central ( ce ) nucleus that enables the acquisition and physiological expression of aversive learning .
when a cs is presented in conjunction with a us , cortical and thalamic sensory input converge in the lateral amygdala to form the cs - us association .
the ce receives this input directly from the la , or indirectly through the basal or accessory basal ( ba ) nuclei of the amygdala ( collectively referred to as the basolateral amygdala , or bla ) ( krettek and price , 1978 , ledoux , 2000 , pitkanen et al . , 1997 ) .
the ce serves as a major relay station to brainstem and hypothalamic regions that control threat responses engendered by the us alone ( ledoux , 2000 , maren , 2001 , davis and whalen , 2001 , pare et al . , 2004 ,
clusters of inhibitory gabaergic interneurons referred to as the intercalated cell masses also mediate interactions between the la and ce by gating fear expression ( millhouse , 1986 , sah et al . , 2003 ,
the amygdala contains reciprocal connections with surrounding brain regions to integrate sensory information and tailor conditioned fear responses appropriately across different circumstances .
these regions include the insula , which is thought to convey visceral sensory information that is important in pain perception and signaling the internal state of an organism ( shi and davis , 1999 , craig , 2002 ) ; the hippocampus , which is critical for the contextual modulation of fear learning and regulation ( kim and fanselow , 1992 , phillips and ledoux , 1992 , maren , 2001 , labar and phelps , 2005 ) ; the striatum , which is involved in tracking cs reinforcement and the instrumental avoidance of aversive outcomes ( ledoux and gorman , 2001 ) ; and the medial prefrontal cortex , which is partitioned into the prelimbic ( pl ) and infralimbic ( il ) cortex .
these subregions are thought to play opposing roles in the expression and regulation of fear responses ( sotres - bayon and quirk , 2010 , sierra - mercado et al . , 2011 ) .
the pl is broadly involved in conditioned fear expression and integrating sensory and affective information from somatosensory cortex ( peters et al . , 2009 ,
this brain region is thought to align in a functional manner to that of the human dorsal anterior cingulate cortex ( dacc ) , a region shown to be involved in fear responses to both conditioned ( labar et al . , 1998 , buchel et al . , 1998 ,
this region has also been shown to be both structurally and functionally associated with individual differences in fear expression in humans , such that physiological arousal responses during fear conditioning correlate positively with dacc volume and activity ( milad et al .
in contrast , the il region of the medial prefrontal cortex , ( vmpfc , in humans ) is critical to the inhibition of fear expression when circumstances become safe ( milad and quirk , 2012 ) .
once a stimulus has acquired aversive value , defensive responses can be inhibited or controlled using a number of regulatory methods . among the most
widely studied of these is extinction training , which comprises the foundation of exposure therapy , a therapeutic technique used by clinicians to treat symptoms of anxiety disorders . during extinction learning , conditioned
threat responses gradually diminish after a cs that previously signaled danger is repeatedly presented in the absence of the us ( pavlov , 1927 ) .
the development of this new , safe association relies on active learning processes , and in contrast to some early learning models ( rescorla and wagner , 1972 ) , does not constitute the elimination of the original cs - us association ( bouton , 2004 ) .
evidence that extinction is an active learning process comes from research across species that demonstrates how fear expression toward an extinguished cs can re - emerge over time ( spontaneous recovery ) , by introducing the original aversive learning context ( renewal ) or after unexpected presentations of the us ( reinstatement ) ( for review , see : bouton , 2004 ) .
converging evidence from electrophysiological , pharmacological and lesion studies in rodents suggests a critical role for the amygdala in extinction learning and consolidation .
plasticity within the la and ba is thought to facilitate extinction learning by diminishing cs - related activity when us reinforcement is omitted ( quirk et al . , 1997 , myers and davis , 2007 , hobin et al . , 2003 ) .
however , a distinct population of these neurons has been found to remain responsive during extinction learning ( repa et al . , 2001 ) , supporting the notion that the cs - us association is maintained .
recent research in rodents has also identified specific cell populations within the ba that are only responsive to the cs during extinction training and that correlate with behavioral extinction performance ( herry et al . , 2008 ) .
collectively , this suggests that the amygdala plays an active role in extinction learning by modulating fear expression in the presence of an extinguished cs by way of functionally distinct neuronal populations .
however , extinction learning also involves reciprocal interactions between the amygdala and the pl and il subregions of the vmpfc , which can differentially influence fear expression ( see herry et al .
the pl promotes fear expression through reciprocal connections with the ( bla ) amygdala , which provides signals regarding the presence of a threat .
these signals are thought to become amplified within the pl before projecting back to amygdala nuclei that then relay these signals to output regions that engender fear expression ( milad and quirk , 2012 ) .
consistent with this , firing rates of pl neurons intensify in the presence of an aversive cs in a manner related to assays of fear expression ( i.e. , freezing ) ( burgos - robles et al . , 2009 ) .
stimulation of the pl subregion enhances fear expression to css and slows extinction learning ( vidal - gonzalez et al . , 2006 ) , while inactivation the pl leads to reduced fear expression to an aversive cs ( corcoran and quirk , 2007 , sierra - mercado et al . ,
recent research in rodents has suggested that during extinction learning , these functionally distinct cell populations in the la and ba may signal the presence of a
safe cs to the il region of the vmpfc , which can then feedback to this same population of neurons ( repa et al .
, 2001 , herry et al . , 2008 , burgos - robles et al . , 2009 ) .
the il can then suppress fear expression by inhibiting the ce directly ( quirk et al . , 2003 ) or indirectly through the itcs that surround the ba and la and project heavily to the ce ( pare et al .
, 2004 , millhouse , 1986 , mcdonald , 1998 , vertes , 2004 ) .
the il can also activate local inhibitory interneurons in the la to gate fear expression ( rosenkranz et al . , 2003 ) .
finally , the hippocampus also plays an important role by providing contextual modulation of extinction learning ( milad and quirk , 2012 ) .
although extinction training serves as a useful paradigm to model safety learning , the viability of extinction training as a therapeutic option for treating affective disorders depends critically on the extent to which this learning is retained and later utilized when cues are again encountered .
research across species has demonstrated a critical role for the il of the vmpfc in the retention and retrieval of extinction learning ( akirav and maroun , 2007 , quirk and mueller , 2008 , holmes and wellman , 2009 , sotres - bayon and quirk , 2010 , milad and quirk , 2012 ) . in rodents ,
il activity correlates with levels of extinction retrieval ( milad and quirk , 2012 ) and stimulating the il inhibits fear expression and strengthens extinction retrieval ( milad et al . , 2004 ) .
in contrast , inactivation of il circuits leads to deficits in extinction retrieval ( sierra - mercado et al . ,
neuroimaging work in humans is largely consistent with these findings . during extinction learning , vmpfc activity increases ( phelps et al . , 2004 )
and correlates with the magnitude of later extinction retention ( milad et al . , 2007 ) .
, 2004 , kalisch et al . , 2006 ) and the volume of cortical tissue in this region has been shown to be positively associated with the magnitude of extinction retrieval ( hartley et al . , 2011 ) , confirming an important role across species for this region in the successful retrieval of extinction training .
although the primary focus of this review is the impact of stress on regulating fear responses to aversive stimuli , the influence of stress on the acquisition and storage of fear associations has implications for future attempts to regulate responses to these acquired fears . as outlined earlier , the acquisition and storage of pavlovian fear conditioning primarily depends on the amygdala .
the amygdala 's central role in modulating aversive learning and expression means it is also positioned to respond in a highly sensitive manner to stress and stress hormones .
specifically , noradrenergic release during acute stress enhances amygdala function ( tully et al . , 2007 , mcgaugh , 2004 ) and works in concert with circulating glucocorticoids to modulate the learning and consolidation of aversive associations ( see ledoux , 2000 , rodrigues et al . , 2009 or roozendaal et al . , 2009 for review ) .
research in animals has demonstrated that exposure to stress facilitates the acquisition of cued fear learning as measured by within - session performance ( wilson et al . , 1975 ,
noradrenaline appears to be critical to this enhancement as blocking noradrenaline in the amygdala before training impairs the acquisition of cued fear conditioning ( bush et al . ,
this does not appear to be the case for glucocorticoids since studies have found blocking their release does not affect the initial fear acquisition performance ( jin et al . , 2007 , rodrigues and sapolsky , 2009 ) .
glucocorticoids play an essential role in this process by interacting with noradrenaline in the amygdala to promote enhanced storage of aversive associations ( ferry et al . , 1999 ,
stress induced prior to training leads to enhanced consolidation of aversive learning as measured by later retrieval ( conrad et al . , 1999 ,
stress ( hui et al . , 2006 ) or glucocorticoid administration ( hui et al . , 2004 ) directly after fear conditioning enhances the consolidation of aversive associations , while blocking glucocorticoid release impairs its consolidation ( jin et al . , 2007 , rodrigues and sapolsky , 2009 ) .
interestingly , blocking noradrenergic activity after cued aversive learning training does not impair the consolidation of fear learning ( bush et al .
, 2010 , debiec and ledoux , 2004 , lee et al . , 2001 ) , suggesting that noradrenergic release during training alone is sufficient to facilitate consolidation .
however , noradrenergic activity appears to be necessary for the enhancing effects of stress - induced glucocorticoids on fear learning as blocking noradrenaline during concurrent administration of glucocorticoids into the amygdala impairs cued fear memory enhancements seen with glucocorticoid adminstration alone ( roozendaal et al . , 2006 ) .
this is consistent with the notion that noradrenergic signaling in the amygdala facilitates the acquisition ( i.e. , within - session performance ) of fear learning independently of glucocorticoids , while the consolidation of such learning relies critically on glucocorticoid activity that works synergistically with noradrenaline ( rodrigues et al . , 2009 ) .
surprisingly few studies have examined the effects of stress on cued fear learning in humans .
one study showed that stress induced an hour before fear conditioning facilitated acquisition in male participants but not females ( jackson et al . , 2006 ) .
another reported that high levels of endogenous glucocorticoids ( i.e. , cortisol ) after stress enhanced fear memory consolidation as measured by retrieval one day later ( zorawski et al . , 2006 ) .
a recent study in men ( antov et al . , 2013 ) demonstrated that stress administered prior to fear conditioning did not alter fear acquisition relative to non - stressed controls .
although group differences did not emerge , the interval of time between the stressor and fear conditioning task did influence the effects of stress hormones on conditioned responses as measured by skin conductance . specifically , stress administered 10 min before fear conditioning resulted in a positive association between conditioned responses and features of sympathetic nervous system arousal ( i.e. , blood pressure increase ) , consistent with the rapid noradrenergic effects typically reported directly after stress exposure .
in contrast , conditioning after a longer delay of 50 min led to a negative association between conditioned responses and cortisol , suggesting that hpa - axis responses at longer timescales may facilitate the recovery of a stressful experience by attenuating fear responses , as has been suggested previously ( see hermans et al . , 2014 for review ) . despite significant progress identifying the temporal and contextual factors that influence the learning and retention of extinction
, limited studies have investigated the effects of stress on this form of fear inhibition , especially in humans .
research in non - human animals , however , has provided some insight into how these processes , along with the neural circuits that support them , may be affected by acute stress .
as mentioned earlier , while pavlovian fear acquisition largely depends on the amygdala , extinction requires the interaction of the amydala and regions of the pfc , specifically the il subregion .
stress exposure is sufficient to produce neuronal alterations ( i.e. , dentritic retraction ) in il neurons ( izquierdo et al . , 2006 ) , and
impair plasticity between the mpfc and amygdala in rodents ( maroun and richter - levin , 2003 ) .
consistent with this , stress exposure prior to extinction training has been shown to impair learning ( izquierdo et al .
, 2006 , akirav and maroun , 2007 , maroun and richter - levin , 2003 ) , although reports have been mixed as some studies have showed intact extinction learning performance after stress ( miracle et al . , 2006 , garcia et al . , 2008 , knox et al . , 2012 ) .
complete blockade of noradrenaline through lesions of the locus coeruleus or its primary projection pathways impair the extinction of conditioned fear responses , suggesting optimal levels of noradrenaline play a critical role in extinction learning ( mason and fibiger , 1979 , mccormick and thompson , 1982 ) . systemic blockade of beta - adrenergic activity using propranolol has been shown to facilitate extinction learning by attenuating conditioned fear responses ( cain et al .
, 2004 , rodriguez - romaguera et al . , 2009 ) , whereas propranolol infused directly into the il does not affect within - session extinction learning performance ( mueller et al . , 2008 ) , suggesting that dampening noradrenergic responses during extinction training is most effective when it has access to beta - adrenergic receptors in the amygdala .
interestingly , enhancing noradrenergic activity systemically with yohimbine prior to extinction learning has also been shown to attenuate conditioned fear responses during extinction , however , recent research suggests these effects are variable and may be strongly modulated by genetic background , contextual variables , or how fear responses are measured ( holmes and quirk , 2010 ) .
for example , a single dose of glucocorticoids administered in rodents led to prolonged expansion of basolateral amygdala neurons that correlated with increased anxiety - like behavior ( mitra and sapolsky , 2008 ) , suggesting it might also impair or slow extinction learning .
research in rodents has shown that in the amygdala elevated levels of circulating cortisol can bind to grs within the ce leading to increased excitability ( karst et al . , 2005 ) and dendritic hypertrophy ( mitra and sapolsky , 2008 ) .
in the presence of an extinguished cs , these changes could potentially enhance fear expression by disrupting inhibitory circuits locally within the amygdala .
glucocorticoid exposure also leads to dendritic retraction and reduced plasticity in the il region of the pfc in rodents ( wellman and holmes , 2009 ) .
this work suggests that stress or glucocorticoid exposure may lead to disruptions in the vmpfc 's dense projections to inhibitory interneurons in the amygdala , which gate fear expression in the presence of an extinguished cs .
however , studies that have administered glucocorticoids alone to animals prior to extinction training have found limited effects extinction learning performance ( barrett and gonzalez - lima , 2004 , yang et al . , 2006 ) , suggesting more research is needed to fully characterize the effects of these hormones on within - session extinction training performance .
one investigation reported that using the cold - pressor task ( cpt ; a painful ice - water submersion technique ) before extinction training led to impairments in fear memory retrieval at the start of an extinction training session , a finding that was only seen in male participants ( bentz et al . , 2013 ) .
due to both the failure to retrieve the original fear association , and poor overall extinction performance , the effects of stress on extinction learning and retrieval , respectively , could not be assessed .
another study recently showed that male participants who were stressed using the cpt directly before a fear conditioning task displayed resistance to extinction training that followed ( antov et al . , 2013 ) .
in animals , repeated or chronic stress consistently has been shown to impair extinction retention even after intact training ( miracle et al . , 2006 , garcia et al .
, 2008 , knox et al . , 2012 , wilber et al . , 2011 ) .
a recent study in rats showed that a single episode of acute stress induced directly before an extinction retention test led to retrieval deficits and the re - emergence of extinguished fear ( deschaux et al . , 2013 ) .
such retrieval deficits have been linked to il dysfunction since lesioning the il region of the vmpfc in rodents has been shown to produce extinction retrieval deficits that are comparable to those seen after stress induction ( farrell et al . , 2010 ) .
impairments in extinction retention have also been documented in animal populations bred for high trait - anxiety ( muigg et al . , 2008 ) .
stress hormones play a pivotal role in facilitating the consolidation of extinction learning in both the amygdala and il .
for example , noradrenergic administration in the bla facilitates extinction memory by boosting consolidation ( berlau and mcgaugh , 2006 ) . in the il , direct infusions of propranolol before
training impairs later extinction retrieval without affecting within - session performance , supporting the critical role of the il in extinction retrieval .
in contrast , propranolol administered directly into the il after extinction training does not affect later retrieval , suggesting it leaves consolidation intact ( mueller et al . , 2008 ) .
this discrepancy is thought to be due to pre - training reductions in arousal , which may disrupt extinction learning by reducing the salience of conditioned stimuli , subsequently impairing consolidation .
conversely , intact noradrenergic signaling during extinction training itself may be enough to enable consolidation despite reductions in arousal directly after training ( mueller and cahill , 2010 ) .
administration of glucocorticoid agonists before or after initial extinction training enhances extinction retention ( cai et al .
, 2006 , yang et al . , 2006 ) , while blocking glucocorticoid activity impairs its consolidation ( barrett and gonzalez - lima , 2004 , yang et al . , 2006 ) .
repeated glucocorticoid exposure , which leads to down - regulation of glucocorticoid release , has been shown to impair the retention of extinction memory ( gourley et al . , 2008 ) , suggesting that as in other forms of memory consolidation , glucocorticoids play a critical role in the storage of extinction learning . in humans ,
a recent investigation of extinction retrieval in women at different stages of their menstrual cycles revealed that extinction recall is better when preceded by stress in mid - cycling women with high estradiol status whereas the opposite was true of early cycling woman with low estradiol status ( antov and stockhorst , 2014 ) .
this study highlights the importance of expanding investigations to assess how endogenous sex and stress hormones may interact and work synergistically or in opposition during emotional learning processes .
we have recently demonstrated that inducing acute stress using the cpt in humans impaired extinction retrieval relative to non - stressed controls 24 h after intact fear learning and extinction training , irrespective of gender ( raio et al . , 2014 ) .
interestingly , conditioned responses across the extinction retrieval session were positively correlated with cortisol in both conditions .
although speculative , these results may be related to the abundance of glucocorticoid receptors in both the amygdala and vmpfc , making these regions especially sensitive to stress . given
the vmpfc 's crucial role in extinction retrieval , dysfunction of this region or its connectivity to the amygdala is the most likely candidate by which stress might lead to extinction retrieval deficits .
consistent with this hypothesis , recent work in humans has shown that functional connectivity between the amygdala and vmpfc is disrupted after cpt stress exposure ( clewett et al . , 2013 ) .
based on the animal and human work reviewed above , stress exposure appears to influence extinction processes differently depending on the phase at which stress is induced and extinction performance is assessed .
stress can impair the acquisition of extinction learning by potentially disrupting the inhibition of conditioned fear responses . likewise , stress hormones can impair the retrieval of extinction memory after intact learning .
in contrast , stress and stress hormones can enhance the consolidation and storage of intact extinction training , leading to stronger retrieval when later tested .
these findings are generally consistent with the broader role of stress hormones in enhancing memory consolidation but impairing memory retrieval .
they also suggest that patient populations marked by anxiety or stress - related psychopathology may be most vulnerable to extinction learning and retrieval deficits but that administration of stress hormones before or after extinction training may strengthen extinction memory .
a larger body of research has examined extinction - related processes in human patient populations marked by affective and stress - related psychopathology .
those diagnosed with post - traumatic stress disorder ( ptsd ) have consistently demonstrated impairments at extinguishing conditioned fear responses ( orr et al . , 2000 , peri et al . , 2000 , blechert et al .
2011 ) . in the majority of these investigations this deficit appeared to be related to a failure to inhibit responses to a previously threatening cs + that currently signals safety ( orr et al . , 2000 , peri et al .
deficits in the retrieval of extinction after intact training have also been reported in patients with ptsd ( milad et al . , 2008 ,
furthermore , the failure to inhibit fear responses has recently been reported to be associated with higher levels of ptsd - related symptoms ( milad et al . , 2009 ,
it is thought that these impairments may arise from dysregulation in the circuitry supporting extinction processes , namely enhanced amygdala and dacc activity in combination with diminished vmpfc activity ( rauch et al .
consistent with this , neuroimaging research in healthy humans assessing the neural circuits supporting the extinction of aversive learning has shown that the integrity of reciprocal connections between the amygdala and vmpfc predict levels of trait - like anxiety ( kim and whalen , 2009 , kim et al . , 2011 ) , suggesting that dysfunction within amygdala - prefrontal circuits may contribute to stress - induced vulnerabilities to inhibit fear .
other functional neuroimaging studies assessing stress in healthy humans have reported increases in dacc activity and decreases in hippocampal and medial / orbitofrontal regions during or after stress exposure ( see dedovic et al . , 2009 , for review ) .
collectively , these studies provide a compelling marker of vulnerability to anxiety and trauma - related psychopathology under conditions of stress .
notably , the same stress hormone ( i.e. , cortisol ) that has been found in healthy humans to correlate positively with conditioned responses during extinction retrieval ( raio et al . ,
specifically , glucocorticoid administration was found to reduce trauma - related memory retrieval and symptoms in ptsd patients ( aerni et al . , 2004 ,
, 2010 ) and reduce subjective and physiological measures of fear in phobic patients who were given glucocorticoids prior to exposure therapy ( soravia et al . , 2006 , de quervain et al . , 2011 ) .
consistent with the broader role in memory enhancement , glucocorticoid administration prior to safety learning may later reduce anxiety and fear responses by bolstering initial extinction learning and consolidation within the amygdala and vmpfc . the precise mechanism underlying the immediate reduction of fear expression is less clear , but is thought to be related to glucocorticoids impairing the retrieval of previously acquired aversive associations ( de quervain and margraf , 2008 ) .
interestingly , the therapeutic effects of glucocorticoids in these reports provided benefits to anxiety patients only , indicating that glucorticoids may be most effective in patients suffering from stress - related psychopathology .
this is consistent with clinical research work showing that the hypersensitivity of glucocorticoids in ptsd patients leads to reductions in basal cortisol levels ( yehuda , 2009 ) .
therefore , anxiety populations may benefit from exogenous glucocorticoid administration because it promotes optimal glucocorticoid levels that lead to stronger inhibition of fear responses and more robust consolidation of safety learning .
when an aversive outcome is imminent , cognitive strategies can be used to assert control over emotional responses . these techniques
referred to as cognitive emotion regulation are unique to humans and denote any regulatory strategy used intentionally to generate a more adaptive emotional response ( gross , 1998 , gross and thompson , 2007 ) .
they include shifting attention away from aversive aspects of a stimulus , changing the meaning of a stimulus ( i.e. , reappraisal ) , or altering the expression of an emotional response ( for reviews , see gross and thompson , 2007 , gross , 2013 )
. recruiting cognitive strategies to deliberately change the way a stimulus is evaluated has been shown to effectively reduce the subjective ( gross , 1998 , shurick et al . , 2012 ) , physiological ( gross and thompson , 2007 , delgado et al . , 2008 ,
hartley and phelps , 2010 , schiller and delgado , 2010 ) of emotion . in humans , using cognitive control to change emotional responses is commonly used due it its unique capacity to be deployed at will in a variety of circumstances .
investigations into the neural mechanisms underlying the cognitive regulation of emotion most commonly implicate the lateral pfc , specifically the dorsolateral and ventrolateral pfc ( dlpfc and vlpfc , respectively ) , along with medial regions , such as the vmpfc and dorsomedial pfc ( dmpfc ) , as more highly active when participants utilize regulatory strategies relative to when they do not ( for reviews , see : hartley and phelps , 2010 , schiller and delgado , 2010 , ochsner et al . , 2012 ) .
this pattern of increased prefrontal activity is often coupled with decreased activity in the amygdala during the reappraisal of aversive or threatening stimuli ( delgado et al . , 2008 ,
collectively , this work has led to a provisional model of cognitive emotion regulation in which the dlpfc consistent with its broader role in executive function facilitates the online maintenance and manipulation of information needed for reappraisal to take place , while activity in the amygdala diminishes as the emotional significance of regulated stimuli dampen .
the inhibitory nature of this pfc - amygdala relationship is thought to be mediated by the vmpfc ( delgado et al . , 2008 , ochsner et al . ,
2012 ) suggesting a mechanism through which dlpfc activity could modulate amygdala activity during cognitive regulation ( hartley and phelps , 2010 , ochsner and gross , 2007 , schiller and delgado , 2010 ) .
cognitive emotion regulation relies on a number of higher - level executive functions including intact working memory , used to maintain representations of relevant information during emotion regulation ; response inhibition , which can facilitate the inhibition of automatic responses to threatening cues ; and cognitive flexibility , which enables one to adopt different strategies to foster more adaptive responses ( hofmann et al . , 2012 ) .
however , emerging work across species suggests that these processes and the prefrontal brain regions on which they depend are highly sensitive to the detrimental effects of acute stress .
specifically , these impairments are thought to arise from excessive levels of stress hormones , which have been shown in animals to disrupt neuronal activity ( i.e. , alter firing rates ) and lead to a broad range of cognitive impairments ( arnsten and goldman - rakic , 1998 , arnsten , 2009 , murphy et al . , 1996 ) .
the pfc relies on a delicate balance of catecholamines such as noradrenaline and dopamine , which each exert an inverted u - shaped influence on lateral pfc physiology and function in which optimal levels facilitate neuronal firing patters and pfc - dependent task performance , while supraoptimal levels such as those that may be reached during or after stress exposure lead to impairments .
research in humans is consistent with this : brief exposure to stress has been shown to impair executive functions including working memory capacity ( duncko et al . , 2009 ,
, 2009 , roozendaal et al . , 2004 , schoofs et al . , 2009 ) , cognitive flexibility ( alexander et al . , 2007 , plessow et al . ,
2011 ) , and goal - directed behavior ( otto et al . , 2013 ) , and leads to metabolic reduction in areas selective to emotion regulation , including the vmpfc ( kern et al . , 2008 ) and
conversely , stress enhances the functioning of a broad network of brain regions that are innervated by catecholamine and glucocorticoid inputs , such as the amygdala , hypothalamus , insula and dorsal anterior cingulate ( hermans et al . , 2014 , for review ) .
collectively , these findings suggest that under the stressful conditions when we are most likely to engage in deliberate forms of cognitive emotion regulation is precisely when the resources supporting these techniques may be compromised .
evidence for this has already been demonstrated in anxiety disorder patients that consistently show impairments using cognitive regulation strategies in the laboratory ( mennin et al . , 2005 ,
2010 ) , as well as individuals with high trait anxiety ( indovina et al . , 2011 , lissek et al . ,
this is consistent with research showing that negative affect is related to the failure to exercise self - regulatory control over thoughts and behavior ( baumeister and heatherton , 1996 , heatherton and wagner , 2011 ) .
based on this research , a recent study in our laboratory tested the hypothesis that cognitive emotion regulation would be impaired after exposure to stress ( raio et al . , 2013 ) . after a fear - conditioning task where physiological arousal was measured as an index of fear
, participants were trained to re - appraise an aversive cs and re - structure the fear - conditioning task overall in a less threatening manner .
one day later , participants either underwent a physiological stressor ( i.e. , cpt ) or a control task , before repeating the fear - conditioning task , this time with instructions to utilize their newly acquired regulation skills .
the cpt elicited greater stress responses as measured by self - report , as well as increases in salivary alpha - amylase and cortisol , markers of noradrenergic and hpa - axis activity , respectively . stressed participants exhibited marked impairments regulating both physiological and self - reported fear responses to the aversive cs and showed comparable fear responses to the previous day prior to regulation training .
in contrast , controls showed reductions in both assays of fear expression . stress may exert detrimental effects on the capacity to cognitively regulate fear responses through a number of potential mechanisms . in our study , we found a positive association between alpha - amylase and fear responses after stress , suggesting that the effects of noradrenergic activity on the brain regions that support the regulation of fear may be one possible mechanism by which cognitive fear regulation is impaired .
excessive levels of noradrenaline released after stress can target brain regions that support cognitive emotion regulation , including the amygdala , vmpfc and dorsolateral pfc ( see : arnsten , 2009 ; or , hermans et al . , 2014 , for review ) .
noradrenaline exerts regionally specific effects on the brain due to various receptor subtype availability ( berridge and waterhouse , 2003 ) .
for example , alpha-2 adrenergic receptors , which are densely distributed throughout the lateral pfc , have a high affinity for noradrenaline .
moderate levels of noradrenaline during emotional arousal therefore lead to optimal occupancy in the pfc of these high affinity alpha-2 receptors , facilitating cognitive function ( arnsten and goldman - rakic , 1985 , wang et al . , 2007 ) .
however , higher levels of noradrenaline release as seen during stress exposure is thought to engage lower affinity alpha-1 and beta - adrenergic receptor subtypes that impair prefrontal function ( birnbaum et al . , 1999 , ramos et al . , 2005 ) but strengthen activity in the amygdala ( mcgaugh , 2004 ) .
glucocorticoids can also function in a synergistic manner with noradrenaline to exacerbate its effects in pfc ( ferry et al .
, 1999 , roozendaal et al . , 2004 , grundemann et al . , 1998 ,
therefore , it is possible that both noradrenergic and glucocorticoid responses to acute stress , and the interacting influence they exert in the brain , serve as a potential mechanism for the impact of stress on the cognitive control of fear .
the observation that even a mild stressor can render cognitive emotion regulation less effective is especially striking considering that these techniques are used pervasively in clinical contexts to treat an array of psychological disorders .
cognitive reappraisal and restructuring comprise some of the primary principles underlying for cognitive - behavioral therapy ( cbt ) , a therapeutic technique often referred to as the gold - standard for treating an array of psychological dysfunction , including anxiety and trauma - related disorders ( beck and emery , 1985 , beck and dozois , 2011 , butler et al .
however , we note that our stress manipulation took place after only one session of training , whereas the majority of cbt treatment plans are instituted over an extended period of time ( e.g. , 1224 weeks ) ( butler et al .
stress likely has more limited effects of cognitive emotion regulation as training continues and is practiced over time , therefore we do not argue that cognitive regulation does not have utility in clinical settings , only that its vulnerability to acute stress in the early stages of training should be considered .
additionally , it is important to note that there are multiple components to cbt for which our study was not designed or capable of testing , such the social support garnered from therapeutic relationships , as well as a broad range of restructuring techniques inherent in cbt , which include encouraging patients to recognize and correct automatic thoughts that may be irrational or maladaptive to promote more adaptive emotional responses .
it is possible the combination of all of these components might lead to cbt being more resistant to stress even while the specific reappraisal components use in our task are notably impaired under stress .
although the majority of fear regulation techniques involve changing the value associated with an aversive stimulus , adopting a course of action or inhibiting a response in order to avoid an aversive outcome can also control fear responses .
one such method of this is referred to as active avoidance learning , which comprises a more complex learning process that involves both pavlovian and instrumental components for regulating fear . during active avoidance learning
, one must learn to first associate a cs with an aversive outcome before learning how to use a specific action to either avoid or terminate the presence of a threatening cs ( see cain et al .
importantly , it has been shown that active avoidance ( moscarello and ledoux , 2013 ) and similar active , stressor controllability paradigms ( e.g. , cain and ledoux , 2007 , baratta et al . , 2007 ) can lead to fear reduction in the presence of a cs even when the avoidance action is no longer available . in this way
, these forms of avoidance do not just regulate fear in the moment , but can be viewed as more lasting fear regulation techniques that may also change the value of the cs in future encounters .
research in rodents has revealed that the amygdala is critical to active avoidance learning ( ledoux and gorman , 2001 , gabriel et al . , 2003 ) , specifically to the initial pavlovian stage of learning . as discussed earlier
, the convergence of the cs - us association occurs through plasticity in the la and this input projects to the ce , which outputs to brainstem and hypothalamic regions that mediate fear expression and defensive responses . as
avoidance training commences , projections from the pfc are thought to inhibit conditioned fear expression , which allow the performance of instrumental avoidance responses ( see cain et al .
evidence for this comes from rodent studies showing that lesions to the il leads to excessive fear responses and impaired avoidance learning , with opposite results emerging from lesions of the ce ( moscarello and ledoux , 2013 ) .
the ba can also receive input from the la and , importantly , has direct projections to the nucleus accumbens ( na ) , which modulates goal - directed instrumental behavior , enabling avoidance behavior ( ledoux and gorman , 2001 ) .
( 2000 ) found that la lesions disrupted both the pavlovian and instrumental stage of avoidance learning .
lesions of the ce preserved avoidance learning but impaired the initial expression of conditioned responses ( i.e. freezing ) , whereas lesions to the b led to opposite results , suggesting that pathways through the b are critical to signaling striatal circuits that facilitate avoidance learning . neuroimaging
research in humans also supports a role of the striatum in learning to avoid aversive outcomes .
participants who learned to terminate the presence of a threatening cs using a button press showed reduced levels of physiological fear arousal and amygdala activation coupled with greater activation of the striatum , pointing to a role for the striatum in aversive avoidance learning ( delgado et al . , 2009 ) .
interestingly , the initial fear response to an aversive cs has been shown to impair the ability to mount an instrumental response to avoid it ( choi and ledoux , 2003 ) , suggesting higher sensitivity to acute stress may impair the ability to adopt action - related coping strategies to control fear .
choi and ledoux ( 2003 ) had rodents learn to perform an instrumental shuttling response in the presence of a cs to avoid an imminent electric shock .
a specific subset of non - learners were unable to perform this avoidance response because of high levels of conditioned fear responses ( i.e. , freezing ) .
however , after lesions to the ce , these animals were capable of adopting the avoidance strategy , indicating that excessive fear expression can impair the capacity to perform actions that promote safety and reduce fear .
this implies that higher levels of trait anxiety or acute exposure to stress may impair the capacity to acquire or retain avoidance strategies when confronted with threat .
of the limited studies that have directly assessed the effects of stress or stress hormones on avoidance learning , most have examined passive ( i.e. , inhibitory ) avoidance learning .
in contrast to active avoidance processes that require the use of an instrumental response to prevent or terminate an aversive outcome , passive avoidance requires the suppression of an innate behavior in order to successfully avoid an aversive outcome .
a common way to test passive avoidance is to measure the latency with which an animal crosses from a naturally preferred darkened chamber that has been paired with shock to a less preferred bright chamber that the animal has learned to associate with safety .
passive avoidance involves the amygdala as well as the hippocampus due to the contextual nature of the task ( ogren and stiedl , 2010 ) . as with other forms of aversive learning ,
for example , blocking noradrenaline systemically or within the la or b after avoidance training disrupts its consolidation as measured by weaker subsequent retention ( ferry et al . , 1999 ,
, 1977 , liang et al . , 1986 , quirarte et al . ,
in contrast , enhancing noradrenaline after avoidance training enhances its retention ( mcgaugh et al . , 2002 , mcintyre et al . , 2002 ) .
furthermore , infusion of glucocorticoid agonists into the la directly after training on a fear avoidance and escape task enhances subsequent retention , while gr antagonists infused prior to training impaired retention .
notably , infusions at either time point into the ce had no effect on memory retrieval ( roozendaal and mcgaugh , 1997 ) .
the effect of acute stress on passive avoidance was recently tested in rodents . before training
, animals were classified into high , medium and low anxiety based on the elevated plus - maze test ; subsequently , half of the mice in each group then underwent an acute stress manipulation .
stress altered avoidance performance in the high anxiety group only . specifically , stressed males showed enhanced avoidance as measured by longer latencies to enter a darkened chamber previously paired with shock , while stressed females showed marked impairments in avoidance learning ( navarro - francs and arenas , 2014 ) .
although more research is required to understand the effects of stress on avoidance strategies , avoidant behaviors are common among anxiety patients ( eifert and forsyth , 2007 , craske and barlow , 1988 , sprang and lajoie , 2009 ) , suggesting that stress may enhance well - practiced avoidance strategies .
it should be noted that although avoiding an aversive outcome may attenuate fear responses , the habitual avoidance of fearful situations may also prevent one from confronting aversive stimuli and engaging in extinction processes , which can be detrimental to the treatment of anxiety symptoms .
therefore , while stress may hinder the initiation of avoidance behavior during learning , overuse of avoidance strategies may lead to habitual , potentially maladaptive avoidance behaviors that are facilitated by stress .
since the fear regulation techniques discussed above can be vulnerable to the effects of acute stress , as well as other contextual and temporal factors , emerging research in animals and humans has examined the interference or blockade of fear memory reconsolidation as a putative alternative to change fear .
normative models of memory suggest that immediately after learning , there is window of time in which newly encoded information is susceptible to interference .
however , recent research suggests that memories must undergo an additional phase of consolidation each time they are reactivated , a restabilization process referred to as reconsolidation . since it is often not feasible to interfere with the initial consolidation of traumatic experiences , interfering with reconsolidation offers the possibility of altering traumatic memories in a more permanent manner . in a typical reconsolidation paradigm , after an aversive association is acquired and consolidated , a time - dependent reconsolidation window is induced by a single presentation of the cs , which is thought to reactivate the aversive memory .
a variety of behavioral or pharmacological manipulations can then be used during the presumed reconsolidation window to alter memory re - storage before later testing for the conditioned responses in the presence of the cs .
, 2014 , steinfurth et al . , 2014 ; see schiller and phelps , 2011 for review ) and animals ( nader et al . , 2000 , monfils et al . , 2009 ,
, 2013 ) has now demonstrated that disrupting or interfering with reconsolidation leads to the persistent modification of amygdala - dependent aversive associations .
recent research in rodents suggests that interfering with the reconsolidation of aversive association induces plasticity in the la ( monfils et al . , 2009
, clem and huganir , 2010 ) and in humans , reconsolidation of fear memory leads to diminished bold responses in the amygdala ( agren et al . ,
2012 ) and a failure to involve vmpfc mechanisms typically seen in standard extinction learning and retrieval process ( schiller et al . , 2014 ) , providing evidence that reconsolidation interference may target the original aversive memory trace .
the effects of stress and stress hormones on reconsolidation processes have remained relatively unexplored , however , some recent investigations have begun to characterize these effects . in animals ,
administration of propranolol directly into the amygdala after a threatening association is reactivated impairs the reconsolidation of cued ( debiec and ledoux , 2004 ) and contextual fear ( abrari et al . ,
2009 ) as well as memory of avoidance training ( przybyslawski et al . , 1999 ) , whereas increasing noradrenaline after reactivation can enhance its later retrieval ( debiec et al . ,
this is consistent with research in humans that has reported attenuated fear - related symptoms when ptsd or trauma victims are administered propranolol after the reactivation of traumatic memories ( brunet et al . , 2008 , orr et al . , 2000 ,
immediately ( but not 6 h ) after an aversive fear memory is reactivated impairs the subsequent retrieval of the aversive association but leaves within - session responses intact , an effect seen for memories that were both 1 or 10 days old ( jin et al .
similar effects were shown in an inhibitory avoidance task where systemic glucocorticoid antagonists were administered after fear memory reactivation ( taubenfeld et al . , 2009 , nikzad et al . , 2011 ) .
glucocorticoid administration directly after fear memory retrieval has also been shown to impair the subsequent retrieval of aversive associations , however , rather than impairing reconsolidation this effects appeared to be the result of enhancing extinction consolidation ( cai et al . , 2006 ) .
while the impact of acute stress on the reconsolidation process is relatively unexplored , there is evidence suggesting that the strength of the aversive us during initial fear acquisition can modulate the later susceptibility to interventions used to target reconsolidation ( suzuki et al . , 2004 , finsterwald and alberini , 2014 ) .
the effect of stress on fear memory reconsolidation has not been formally tested in humans . however , a recent study reported that across six different studies assessing how propranolol administration before or after fear memory retrieval might disrupt the reconsolidation of fear memory , individuals who reported higher levels of trait anxiety were more resistant to the effects of reconsolidation interference .
this suggests that individuals who are most vulnerable to the effects of stress may be less responsive to fear memory disruption using this technique ( soeter and kindt , 2013 ) .
from minor daily annoyances to deeply traumatic events , stressful experiences constitute an undeniable aspect of daily life .
reports on the profound impact that stress has on mental and physical health are pervasive throughout the scientific community , leading to widespread interest in understanding how to reduce stress and promote emotional control .
accordingly , empirical studies investigating emotion regulation have grown exponentially over the last two decades , reflecting mounting interest within the field ( gross , 2013 ) . despite the broad scientific interest in understanding how emotions are regulated , however ,
the notion that stress may be detrimental to emotional control has been relatively overlooked within this literature .
consequently , the effects of stress on the capacity to flexibly control emotional responses have remained largely unexplored . the studies reviewed here
offer some initial insight into understanding how acute stress exposure affects the inhibition and control of conditioned fear .
the research discussed in this review used pavlovian fear conditioning as a basis for understanding the effects of stress on the regulation of fear .
since the neural circuitry underlying fear learning is highly conserved across species , we can use animal models as a basis for understanding how stress may influence this circuitry in humans as well .
our investigation of extinction and cognitive regulation reveals robust effects of stress impairing the persistent inhibition of fear , presumably by altering prefrontal cortex function . although less is known concerning the impact of stress on the persistent fear reduction observed with avoidance and reconsolidation , it is possible these fear regulation techniques are less vulnerable to the negative consequences of stress since they rely less on the inhibitory mechanisms involved in extinction and cognitive regulation .
it is important to note that the behavioral and neural research covered in this review focused mainly on brief exposure to stress , rather than chronic exposure .
although the immediate effects of acute stress can exert detrimental effects on the brain regions critical to the regulation of fear responses , chronic exposure to stress can trigger more systemic neuroendocrine changes . for example , chronic stress can lead to dysfunctional regulation of the hpa - axis , resulting in a flattened diurnal cycle of cortisol release , such as that seen in depressives and ptsd ( young et al .
it can also lead to more profound structural and functional changes in brain regions critical to autonomic and hpa - axis related regulation ( i.e. , amygdala and hippocampus ) that can lead to suppression of synaptic plasticity and neurogenesis in these regions ( see mcewen , 2003 for review ) .
collectively , chronic stress produces what has been referred to as allostatic load , creating an overwhelming demand on the neural circuits that mediate appropriate responses and recovery from stress .
fear learning and regulation is a prominent model for describing the pathogenesis of anxiety disorders and stress - related psychopathology .
stress has been shown to play a critical role in the etiology , exacerbation and treatment of affective psychopathology suggesting close interplay between the two .
accordingly , research has shown that individuals with anxiety or depression show a broad range of abnormalities in controlling fear - related responses , suggesting that deficits in emotion regulation may be linked to neurobiological differences in response to stress .
the considerable overlap in stress and fear - related neurocircuitry is one likely explanation for why fear regulation impairments emerge in populations marked by stress .
however , it should be noted that although the interaction between stress and fear circuitry undoubtedly exist and similar mechanisms may be at play , there is likely to be a large degree of heterogeneity in terms of how acute stress may alter fear regulation in clinical populations depending on their individual diagnoses . gaining a clearer understanding of how stress affects the regulation of fear is critical to assess the efficacy of these techniques in clinical populations and inform better treatment options for populations with stress - related psychopathology . | fear learning and regulation is a prominent model for describing the pathogenesis of anxiety disorders and stress - related psychopathology .
fear expression can be modulated using a number of regulatory strategies , including extinction , cognitive emotion regulation , avoidance strategies and reconsolidation . in this review ,
we examine research investigating the effects of acute stress and stress hormones on these regulatory techniques .
we focus on what is known about the impact of stress on the ability to flexibly regulate fear responses that are acquired through pavlovian fear conditioning .
our primary aim is to explore the impact of stress on fear regulation in humans . given this , we focus on techniques where stress has been linked to alterations of fear regulation in humans ( extinction and emotion regulation ) , and briefly discuss other techniques ( avoidance and reconsolidation ) where the impact of stress or stress hormones have been mainly explored in animal models . these investigations reveal that acute stress may impair the persistent inhibition of fear , presumably by altering prefrontal cortex function . characterizing the effects of stress on fear regulation is critical for understanding the boundaries within which existing regulation strategies are viable in everyday life and can better inform treatment options for those who suffer from anxiety and stress - related psychopathology . | <s>[INST]experiencing stress is an inevitable part of daily life that serves a critical role in shaping adaptive behavior .
brief exposure to stress can be a powerful motivating force in both the pursuit of rewards and avoidance of punishment , and can rapidly boost energy stores in times of homeostatic disruption to ensure safety and survival .
however , stress exposure and the concomitant neurophysiological response it elicits can also exert detrimental effects on brain regions that facilitate the control and regulation of behavior .
these effects are especially relevant for the regulation of fear expression , where top - down regulatory mechanisms are engaged to control emotional responses to threatening stimuli . this process broadly referred to as emotion regulationallows an individual to tailor emotional responses and behavior to a dynamic environment ( gross and thompson , 2007 ) .
the capacity to regulate fear responses to threatening cues once the value or significance of such cues change is critical to emotional resilience and health , while deficits in fear regulation capacity strongly predict vulnerability to an array of affective psychopathology , such as anxiety disorders and depression ( cisler et al .
fear responses can be flexibly changed through a broad range of processes that include learning that an aversive stimulus no longer poses a threat , or adopting a strategy to deliberately change the nature of an emotional response .
these techniques have been repeatedly shown to inhibit or alter fear expression in the service of generating more adaptive responses that are better aligned with the current state of the environment .
importantly , the adaptive benefits afforded by fear regulation are widely known to rely on intact functioning of the prefrontal cortex ( pfc ) , which supports the inhibition and flexible control of fear ( see hartley and phelps , 2010 for review ) .
the pfc , however , is also a major target of stress hormones that a growing body of research suggests can markedly impair its function ( see arnsten , 2009 or holmes and wellman , 2009 ; for reviews ) .
this suggests that the flexible control of fear responses to aversive stimuli may be compromised when accompanied or preceded by exposure to stress .
despite the significance of this possibility , stress has remained largely unexplored within the fear regulation literature . in this review ,
we examine research investigating the effects of stress and stress hormones on regulatory techniques used to flexibly control fear responses in humans . before doing so
, it is important to recognize that the constructs of fear and stress are often conflated in the literature due to their behavioral , neural and neurochemical similarities . to clearly differentiate fear expression from that of a stress response in the context of this review , we refer to fear expression as discrete emotional or behavioral responses that occur when an organism detects a threat in its environment , or when it encounters a cue that has predicted danger in the past . in rodents , fear expression
is typically measured through defensive behaviors such as freezing , whereas in humans fear is often assessed by recording transient sympathetic nervous system arousal responses ( i.e. , skin conductance , pupil dilation ) in the presence of a threatening stimulus ( critchley , 2002 , critchley et al . , 2013 ) .
in contrast , a stress response is operationalized as a more pervasive response that unfolds over a longer timescale and recruits a range of neuromodulatory systems . unlike transient fear arousal
, stressors produce more intense and prolonged response to homeostatic disruptions , eliciting both autonomic and neuroendocrine systems that can exert a broad range of effects on brain function and behavior .
fear expression can be modulated using a number of regulatory strategies , including extinction learning and retention , cognitive emotion regulation , avoidance strategies and reconsolidation .
extinction learning and retention is the most commonly explored form of fear inhibition and occurs by learning through experience that a stimulus is no longer associated with a threatening outcome .
cognitive emotion regulation refers to a broad range of regulatory strategies that can be used to deliberately alter the nature of an emotional response .
avoidance strategies entail performing certain behaviors in order to prevent the occurrence of an aversive outcome .
finally , interfering with the reconsolidation of fear memories can lead to reductions in fear expression by persistently modifying aversive associations .
the neural circuitry underlying each of these forms of fear regulation overlaps with the neural systems that orchestrate both the response to and recovery from stress exposure , rendering these techniques especially sensitive to the effects of stress . despite the pervasive use of these strategies in research and real - world settings , relatively little
understanding how stress affects these regulatory processes has broad implications both for adaptive daily functioning and for how stress - induced regulatory impairments may lead to or exacerbate affective psychopathology .
below we discuss what is known about the impact of stress on the ability to flexibly regulate fear responses that are acquired using standard pavlovian fear conditioning , a fundamental form of associative learning that imbues biologically insignificant cues with aversive value . given that our primary aim is to explore the impact of stress on fear regulation in humans , we primarily discuss techniques where stress has been linked to alterations of fear regulation in humans ( extinction and emotion regulation ) , although we also briefly mention other techniques ( avoidance and reconsolidation ) where the impact of stress or stress hormones have been mainly explored in animal models .
we begin by providing a brief overview of the neurobiological mechanisms of acute responses to stress .
our focus in this review is placed primarily on the learning and regulation of cued fear associations , which rely on the amygdala and surrounding brain regions . in the interest of space , we do not cover contextual fear learning and regulation processes , which are known to instead rely on the hippocampus .
since stress may differentially impact different phases of fear conditioning , we discuss the effects of stress and stress hormones on the phases ( i.e. , learning , consolidation , retrieval ) of fear acquisition and extinction by surveying research that has induced stress or administered stress hormones before or concurrently with these phases .
we then review the mechanisms of cognitive emotion regulation and the impact of stress in humans .
finally , we briefly review other fear regulation techniques ( avoidance and reconsolidation ) where the impact of stress and stress hormones have mainly been explored in animal models .
stress is induced when real or perceived threats are detected in the environment ( joels et al . , 2012 ) .
stressors can emerge from a number of sources that can be generally categorized as physical or psychological in nature .
physical stressors comprise threats to survival such as predatory threats that signal imminent danger , or disruptions to homeostasis such as hunger , sickness or pain .
psychogenic stressors constitute emotional or social threats that may occur through negative social evaluation or severe emotional distress ( dickerson and kemeny , 2004 ) .
irrespective of their source , stressors are typically characterized by the perception of being novel , unpredictable and , importantly , outside of one 's control ( lupien et al . , 2007 ) .
the detection of a stressor promotes a broad range of hormonal and neurotransmitter responses that can exert a powerful influence on brain function and behavior ( mcewen , 2003 ) .
acute stress exposure rapidly activates the autonomic nervous system through its sympathetic branch that triggers peripheral responses , such as increased respiration , heart rate and blood pressure and allocates metabolic resources to promote defensive behavior ( goldstein , 2003 , ulrich - lai and herman , 2009 ) .
this response also triggers catecholamine release by way of sympathetic nerves that activate noradrenergic terminals throughout the body , as well as the adrenal medulla that releases adrenaline directly into the bloodstream .
in contrast , the hypothalamic - pituitary - adrenal ( hpa ) axis elicits neuroendocrine effects that peak at a longer timescale after stress exposure .
activation of the hpa - axis triggers the systemic release of glucocorticoids ( cortisol in humans ) that can work in a synergistic manner with catecholamines to potentiate their short - lived effects ( ulrich - lai and herman , 2009 ) .
this is especially so for the effects of stress on modulating emotional learning and memory , as noradrenergic signaling is critical to the enhancing effects of glucocorticoids on memory consolidation and retrieval ( quirarte et al . , 1997 , roozendaal et al . , 2009 ) .
stressors activate the hpa - axis through the release of corticotropin - releasing hormone ( crh ) from the paraventricular nucleus ( pvn ) of the hypothalamus .
when crh reaches the anterior pituitary gland , it elicits adrenocorticotropic hormone ( acth ) release , which prompts glucocorticoid synthesis in the adrenal glands .
finally , glucocorticoids are released into the bloodstream where they travel and bind to receptors throughout the body and brain ( mcewen et al . , 1986 ,
glucocorticoid release follows a slower time course than rapidly released catecholamines , peaking 1020 min after the onset of stress exposure ( sapolsky et al . , 2000 ) .
glucocorticoids are often characterized as a recovery hormone that adapts an organism to the neurophysiological changes that occur during stress ( lupien et al . , 2007 ) .
collectively , these two systems interact and function in a complementary manner to mobilize energy and help an organism cope with stressful experiences . despite the inability of peripheral catecholamines to cross the blood
brain barrier , noradrenaline is projected throughout the brain by way of the locus coeruleus ( lc ) .
the lc serves as the brain 's primary source of noradrenaline and shares reciprocal connections with brain regions that are critical to the acquisition and regulation of conditioned fear , such as the amygdala , hippocampus and pfc ( benarroch , 2009 ) .
the high proportion of noradrenaline receptors in the amygdala and pfc render these brain regions especially sensitive to the effects of stress ( mcewen et al . , 1986 ) .
brain barrier and binding to high - affinity mineralocorticoid and low - affinity glucocorticoid receptors distributed throughout the amygdala , hippocampus and pfc ( joels et al .
the effects of glucocorticoids include dampening glucose transport within cortical neurons and glia cells , which may further influence brain function by diminishing processing and amplifying the effects of early catecholamine release by slowing their clearance from synaptic space ( grundemann et al . , 1998 , ferry et al . , 1999 , roozendaal et al . , 2002 ) .
the release of glucocorticoids is controlled through negative feedback mechanisms housed within the pfc , suggesting that this region is targeted both for glucocorticoid binding under stress and for the regulation of glucocorticoid release ( diorio et al . , 1993 ) .
consistent with this , both chronic exposure to stress and affective psychopathology have been shown to be related to deficits in hpa regulation and inhibition ( cacioppo et al .
learning to respond appropriately to cues that signal danger is critical to survival and can facilitate adaptive behavior .
pavlovian fear conditioning is often used as a laboratory paradigm to examine how biologically insignificant stimuli can acquire emotional relevance as they come to predict aversive events . in a standard cued pavlovian fear conditioning paradigm a neutral stimulus , such as a light or tone ( conditioned stimulus , or cs ) , is paired with an innately aversive stimulus , such as an electric shock or noxious odor ( unconditioned stimulus , or us ) ( pavlov , 1927 ) .
the us will automatically elicit an array of physiological , neuroendocrine and behavioral responses consistent with defensive behavior .
after a few trials a reinforced cs can come to elicit similar responses to that of the us itself .
a long tradition of research in animals and humans has provided an intricate understanding of the behavioral and neural systems underlying aversive learning and regulation .
the amygdala has been shown across species to be critical for the acquisition , storage and expression of conditioned fear ( for review , see ledoux , 2000 , maren , 2001 , davis and whalen , 2001 , phelps , 2006 ) .
the amygdala contains functionally and anatomically distinct nuclei including the lateral ( la ) , basal ( b ) and central ( ce ) nucleus that enables the acquisition and physiological expression of aversive learning .
when a cs is presented in conjunction with a us , cortical and thalamic sensory input converge in the lateral amygdala to form the cs - us association .
the ce receives this input directly from the la , or indirectly through the basal or accessory basal ( ba ) nuclei of the amygdala ( collectively referred to as the basolateral amygdala , or bla ) ( krettek and price , 1978 , ledoux , 2000 , pitkanen et al . , 1997 ) .
the ce serves as a major relay station to brainstem and hypothalamic regions that control threat responses engendered by the us alone ( ledoux , 2000 , maren , 2001 , davis and whalen , 2001 , pare et al . , 2004 ,
clusters of inhibitory gabaergic interneurons referred to as the intercalated cell masses also mediate interactions between the la and ce by gating fear expression ( millhouse , 1986 , sah et al . , 2003 ,
the amygdala contains reciprocal connections with surrounding brain regions to integrate sensory information and tailor conditioned fear responses appropriately across different circumstances .
these regions include the insula , which is thought to convey visceral sensory information that is important in pain perception and signaling the internal state of an organism ( shi and davis , 1999 , craig , 2002 ) ; the hippocampus , which is critical for the contextual modulation of fear learning and regulation ( kim and fanselow , 1992 , phillips and ledoux , 1992 , maren , 2001 , labar and phelps , 2005 ) ; the striatum , which is involved in tracking cs reinforcement and the instrumental avoidance of aversive outcomes ( ledoux and gorman , 2001 ) ; and the medial prefrontal cortex , which is partitioned into the prelimbic ( pl ) and infralimbic ( il ) cortex .
these subregions are thought to play opposing roles in the expression and regulation of fear responses ( sotres - bayon and quirk , 2010 , sierra - mercado et al . , 2011 ) .
the pl is broadly involved in conditioned fear expression and integrating sensory and affective information from somatosensory cortex ( peters et al . , 2009 ,
this brain region is thought to align in a functional manner to that of the human dorsal anterior cingulate cortex ( dacc ) , a region shown to be involved in fear responses to both conditioned ( labar et al . , 1998 , buchel et al . , 1998 ,
this region has also been shown to be both structurally and functionally associated with individual differences in fear expression in humans , such that physiological arousal responses during fear conditioning correlate positively with dacc volume and activity ( milad et al .
in contrast , the il region of the medial prefrontal cortex , ( vmpfc , in humans ) is critical to the inhibition of fear expression when circumstances become safe ( milad and quirk , 2012 ) .
once a stimulus has acquired aversive value , defensive responses can be inhibited or controlled using a number of regulatory methods . among the most
widely studied of these is extinction training , which comprises the foundation of exposure therapy , a therapeutic technique used by clinicians to treat symptoms of anxiety disorders . during extinction learning , conditioned
threat responses gradually diminish after a cs that previously signaled danger is repeatedly presented in the absence of the us ( pavlov , 1927 ) .
the development of this new , safe association relies on active learning processes , and in contrast to some early learning models ( rescorla and wagner , 1972 ) , does not constitute the elimination of the original cs - us association ( bouton , 2004 ) .
evidence that extinction is an active learning process comes from research across species that demonstrates how fear expression toward an extinguished cs can re - emerge over time ( spontaneous recovery ) , by introducing the original aversive learning context ( renewal ) or after unexpected presentations of the us ( reinstatement ) ( for review , see : bouton , 2004 ) .
converging evidence from electrophysiological , pharmacological and lesion studies in rodents suggests a critical role for the amygdala in extinction learning and consolidation .
plasticity within the la and ba is thought to facilitate extinction learning by diminishing cs - related activity when us reinforcement is omitted ( quirk et al . , 1997 , myers and davis , 2007 , hobin et al . , 2003 ) .
however , a distinct population of these neurons has been found to remain responsive during extinction learning ( repa et al . , 2001 ) , supporting the notion that the cs - us association is maintained .
recent research in rodents has also identified specific cell populations within the ba that are only responsive to the cs during extinction training and that correlate with behavioral extinction performance ( herry et al . , 2008 ) .
collectively , this suggests that the amygdala plays an active role in extinction learning by modulating fear expression in the presence of an extinguished cs by way of functionally distinct neuronal populations .
however , extinction learning also involves reciprocal interactions between the amygdala and the pl and il subregions of the vmpfc , which can differentially influence fear expression ( see herry et al .
the pl promotes fear expression through reciprocal connections with the ( bla ) amygdala , which provides signals regarding the presence of a threat .
these signals are thought to become amplified within the pl before projecting back to amygdala nuclei that then relay these signals to output regions that engender fear expression ( milad and quirk , 2012 ) .
consistent with this , firing rates of pl neurons intensify in the presence of an aversive cs in a manner related to assays of fear expression ( i.e. , freezing ) ( burgos - robles et al . , 2009 ) .
stimulation of the pl subregion enhances fear expression to css and slows extinction learning ( vidal - gonzalez et al . , 2006 ) , while inactivation the pl leads to reduced fear expression to an aversive cs ( corcoran and quirk , 2007 , sierra - mercado et al . ,
recent research in rodents has suggested that during extinction learning , these functionally distinct cell populations in the la and ba may signal the presence of a
safe cs to the il region of the vmpfc , which can then feedback to this same population of neurons ( repa et al .
, 2001 , herry et al . , 2008 , burgos - robles et al . , 2009 ) .
the il can then suppress fear expression by inhibiting the ce directly ( quirk et al . , 2003 ) or indirectly through the itcs that surround the ba and la and project heavily to the ce ( pare et al .
, 2004 , millhouse , 1986 , mcdonald , 1998 , vertes , 2004 ) .
the il can also activate local inhibitory interneurons in the la to gate fear expression ( rosenkranz et al . , 2003 ) .
finally , the hippocampus also plays an important role by providing contextual modulation of extinction learning ( milad and quirk , 2012 ) .
although extinction training serves as a useful paradigm to model safety learning , the viability of extinction training as a therapeutic option for treating affective disorders depends critically on the extent to which this learning is retained and later utilized when cues are again encountered .
research across species has demonstrated a critical role for the il of the vmpfc in the retention and retrieval of extinction learning ( akirav and maroun , 2007 , quirk and mueller , 2008 , holmes and wellman , 2009 , sotres - bayon and quirk , 2010 , milad and quirk , 2012 ) . in rodents ,
il activity correlates with levels of extinction retrieval ( milad and quirk , 2012 ) and stimulating the il inhibits fear expression and strengthens extinction retrieval ( milad et al . , 2004 ) .
in contrast , inactivation of il circuits leads to deficits in extinction retrieval ( sierra - mercado et al . ,
neuroimaging work in humans is largely consistent with these findings . during extinction learning , vmpfc activity increases ( phelps et al . , 2004 )
and correlates with the magnitude of later extinction retention ( milad et al . , 2007 ) .
, 2004 , kalisch et al . , 2006 ) and the volume of cortical tissue in this region has been shown to be positively associated with the magnitude of extinction retrieval ( hartley et al . , 2011 ) , confirming an important role across species for this region in the successful retrieval of extinction training .
although the primary focus of this review is the impact of stress on regulating fear responses to aversive stimuli , the influence of stress on the acquisition and storage of fear associations has implications for future attempts to regulate responses to these acquired fears . as outlined earlier , the acquisition and storage of pavlovian fear conditioning primarily depends on the amygdala .
the amygdala 's central role in modulating aversive learning and expression means it is also positioned to respond in a highly sensitive manner to stress and stress hormones .
specifically , noradrenergic release during acute stress enhances amygdala function ( tully et al . , 2007 , mcgaugh , 2004 ) and works in concert with circulating glucocorticoids to modulate the learning and consolidation of aversive associations ( see ledoux , 2000 , rodrigues et al . , 2009 or roozendaal et al . , 2009 for review ) .
research in animals has demonstrated that exposure to stress facilitates the acquisition of cued fear learning as measured by within - session performance ( wilson et al . , 1975 ,
noradrenaline appears to be critical to this enhancement as blocking noradrenaline in the amygdala before training impairs the acquisition of cued fear conditioning ( bush et al . ,
this does not appear to be the case for glucocorticoids since studies have found blocking their release does not affect the initial fear acquisition performance ( jin et al . , 2007 , rodrigues and sapolsky , 2009 ) .
glucocorticoids play an essential role in this process by interacting with noradrenaline in the amygdala to promote enhanced storage of aversive associations ( ferry et al . , 1999 ,
stress induced prior to training leads to enhanced consolidation of aversive learning as measured by later retrieval ( conrad et al . , 1999 ,
stress ( hui et al . , 2006 ) or glucocorticoid administration ( hui et al . , 2004 ) directly after fear conditioning enhances the consolidation of aversive associations , while blocking glucocorticoid release impairs its consolidation ( jin et al . , 2007 , rodrigues and sapolsky , 2009 ) .
interestingly , blocking noradrenergic activity after cued aversive learning training does not impair the consolidation of fear learning ( bush et al .
, 2010 , debiec and ledoux , 2004 , lee et al . , 2001 ) , suggesting that noradrenergic release during training alone is sufficient to facilitate consolidation .
however , noradrenergic activity appears to be necessary for the enhancing effects of stress - induced glucocorticoids on fear learning as blocking noradrenaline during concurrent administration of glucocorticoids into the amygdala impairs cued fear memory enhancements seen with glucocorticoid adminstration alone ( roozendaal et al . , 2006 ) .
this is consistent with the notion that noradrenergic signaling in the amygdala facilitates the acquisition ( i.e. , within - session performance ) of fear learning independently of glucocorticoids , while the consolidation of such learning relies critically on glucocorticoid activity that works synergistically with noradrenaline ( rodrigues et al . , 2009 ) .
surprisingly few studies have examined the effects of stress on cued fear learning in humans .
one study showed that stress induced an hour before fear conditioning facilitated acquisition in male participants but not females ( jackson et al . , 2006 ) .
another reported that high levels of endogenous glucocorticoids ( i.e. , cortisol ) after stress enhanced fear memory consolidation as measured by retrieval one day later ( zorawski et al . , 2006 ) .
a recent study in men ( antov et al . , 2013 ) demonstrated that stress administered prior to fear conditioning did not alter fear acquisition relative to non - stressed controls .
although group differences did not emerge , the interval of time between the stressor and fear conditioning task did influence the effects of stress hormones on conditioned responses as measured by skin conductance . specifically , stress administered 10 min before fear conditioning resulted in a positive association between conditioned responses and features of sympathetic nervous system arousal ( i.e. , blood pressure increase ) , consistent with the rapid noradrenergic effects typically reported directly after stress exposure .
in contrast , conditioning after a longer delay of 50 min led to a negative association between conditioned responses and cortisol , suggesting that hpa - axis responses at longer timescales may facilitate the recovery of a stressful experience by attenuating fear responses , as has been suggested previously ( see hermans et al . , 2014 for review ) . despite significant progress identifying the temporal and contextual factors that influence the learning and retention of extinction
, limited studies have investigated the effects of stress on this form of fear inhibition , especially in humans .
research in non - human animals , however , has provided some insight into how these processes , along with the neural circuits that support them , may be affected by acute stress .
as mentioned earlier , while pavlovian fear acquisition largely depends on the amygdala , extinction requires the interaction of the amydala and regions of the pfc , specifically the il subregion .
stress exposure is sufficient to produce neuronal alterations ( i.e. , dentritic retraction ) in il neurons ( izquierdo et al . , 2006 ) , and
impair plasticity between the mpfc and amygdala in rodents ( maroun and richter - levin , 2003 ) .
consistent with this , stress exposure prior to extinction training has been shown to impair learning ( izquierdo et al .
, 2006 , akirav and maroun , 2007 , maroun and richter - levin , 2003 ) , although reports have been mixed as some studies have showed intact extinction learning performance after stress ( miracle et al . , 2006 , garcia et al . , 2008 , knox et al . , 2012 ) .
complete blockade of noradrenaline through lesions of the locus coeruleus or its primary projection pathways impair the extinction of conditioned fear responses , suggesting optimal levels of noradrenaline play a critical role in extinction learning ( mason and fibiger , 1979 , mccormick and thompson , 1982 ) . systemic blockade of beta - adrenergic activity using propranolol has been shown to facilitate extinction learning by attenuating conditioned fear responses ( cain et al .
, 2004 , rodriguez - romaguera et al . , 2009 ) , whereas propranolol infused directly into the il does not affect within - session extinction learning performance ( mueller et al . , 2008 ) , suggesting that dampening noradrenergic responses during extinction training is most effective when it has access to beta - adrenergic receptors in the amygdala .
interestingly , enhancing noradrenergic activity systemically with yohimbine prior to extinction learning has also been shown to attenuate conditioned fear responses during extinction , however , recent research suggests these effects are variable and may be strongly modulated by genetic background , contextual variables , or how fear responses are measured ( holmes and quirk , 2010 ) .
for example , a single dose of glucocorticoids administered in rodents led to prolonged expansion of basolateral amygdala neurons that correlated with increased anxiety - like behavior ( mitra and sapolsky , 2008 ) , suggesting it might also impair or slow extinction learning .
research in rodents has shown that in the amygdala elevated levels of circulating cortisol can bind to grs within the ce leading to increased excitability ( karst et al . , 2005 ) and dendritic hypertrophy ( mitra and sapolsky , 2008 ) .
in the presence of an extinguished cs , these changes could potentially enhance fear expression by disrupting inhibitory circuits locally within the amygdala .
glucocorticoid exposure also leads to dendritic retraction and reduced plasticity in the il region of the pfc in rodents ( wellman and holmes , 2009 ) .
this work suggests that stress or glucocorticoid exposure may lead to disruptions in the vmpfc 's dense projections to inhibitory interneurons in the amygdala , which gate fear expression in the presence of an extinguished cs .
however , studies that have administered glucocorticoids alone to animals prior to extinction training have found limited effects extinction learning performance ( barrett and gonzalez - lima , 2004 , yang et al . , 2006 ) , suggesting more research is needed to fully characterize the effects of these hormones on within - session extinction training performance .
one investigation reported that using the cold - pressor task ( cpt ; a painful ice - water submersion technique ) before extinction training led to impairments in fear memory retrieval at the start of an extinction training session , a finding that was only seen in male participants ( bentz et al . , 2013 ) .
due to both the failure to retrieve the original fear association , and poor overall extinction performance , the effects of stress on extinction learning and retrieval , respectively , could not be assessed .
another study recently showed that male participants who were stressed using the cpt directly before a fear conditioning task displayed resistance to extinction training that followed ( antov et al . , 2013 ) .
in animals , repeated or chronic stress consistently has been shown to impair extinction retention even after intact training ( miracle et al . , 2006 , garcia et al .
, 2008 , knox et al . , 2012 , wilber et al . , 2011 ) .
a recent study in rats showed that a single episode of acute stress induced directly before an extinction retention test led to retrieval deficits and the re - emergence of extinguished fear ( deschaux et al . , 2013 ) .
such retrieval deficits have been linked to il dysfunction since lesioning the il region of the vmpfc in rodents has been shown to produce extinction retrieval deficits that are comparable to those seen after stress induction ( farrell et al . , 2010 ) .
impairments in extinction retention have also been documented in animal populations bred for high trait - anxiety ( muigg et al . , 2008 ) .
stress hormones play a pivotal role in facilitating the consolidation of extinction learning in both the amygdala and il .
for example , noradrenergic administration in the bla facilitates extinction memory by boosting consolidation ( berlau and mcgaugh , 2006 ) . in the il , direct infusions of propranolol before
training impairs later extinction retrieval without affecting within - session performance , supporting the critical role of the il in extinction retrieval .
in contrast , propranolol administered directly into the il after extinction training does not affect later retrieval , suggesting it leaves consolidation intact ( mueller et al . , 2008 ) .
this discrepancy is thought to be due to pre - training reductions in arousal , which may disrupt extinction learning by reducing the salience of conditioned stimuli , subsequently impairing consolidation .
conversely , intact noradrenergic signaling during extinction training itself may be enough to enable consolidation despite reductions in arousal directly after training ( mueller and cahill , 2010 ) .
administration of glucocorticoid agonists before or after initial extinction training enhances extinction retention ( cai et al .
, 2006 , yang et al . , 2006 ) , while blocking glucocorticoid activity impairs its consolidation ( barrett and gonzalez - lima , 2004 , yang et al . , 2006 ) .
repeated glucocorticoid exposure , which leads to down - regulation of glucocorticoid release , has been shown to impair the retention of extinction memory ( gourley et al . , 2008 ) , suggesting that as in other forms of memory consolidation , glucocorticoids play a critical role in the storage of extinction learning . in humans ,
a recent investigation of extinction retrieval in women at different stages of their menstrual cycles revealed that extinction recall is better when preceded by stress in mid - cycling women with high estradiol status whereas the opposite was true of early cycling woman with low estradiol status ( antov and stockhorst , 2014 ) .
this study highlights the importance of expanding investigations to assess how endogenous sex and stress hormones may interact and work synergistically or in opposition during emotional learning processes .
we have recently demonstrated that inducing acute stress using the cpt in humans impaired extinction retrieval relative to non - stressed controls 24 h after intact fear learning and extinction training , irrespective of gender ( raio et al . , 2014 ) .
interestingly , conditioned responses across the extinction retrieval session were positively correlated with cortisol in both conditions .
although speculative , these results may be related to the abundance of glucocorticoid receptors in both the amygdala and vmpfc , making these regions especially sensitive to stress . given
the vmpfc 's crucial role in extinction retrieval , dysfunction of this region or its connectivity to the amygdala is the most likely candidate by which stress might lead to extinction retrieval deficits .
consistent with this hypothesis , recent work in humans has shown that functional connectivity between the amygdala and vmpfc is disrupted after cpt stress exposure ( clewett et al . , 2013 ) .
based on the animal and human work reviewed above , stress exposure appears to influence extinction processes differently depending on the phase at which stress is induced and extinction performance is assessed .
stress can impair the acquisition of extinction learning by potentially disrupting the inhibition of conditioned fear responses . likewise , stress hormones can impair the retrieval of extinction memory after intact learning .
in contrast , stress and stress hormones can enhance the consolidation and storage of intact extinction training , leading to stronger retrieval when later tested .
these findings are generally consistent with the broader role of stress hormones in enhancing memory consolidation but impairing memory retrieval .
they also suggest that patient populations marked by anxiety or stress - related psychopathology may be most vulnerable to extinction learning and retrieval deficits but that administration of stress hormones before or after extinction training may strengthen extinction memory .
a larger body of research has examined extinction - related processes in human patient populations marked by affective and stress - related psychopathology .
those diagnosed with post - traumatic stress disorder ( ptsd ) have consistently demonstrated impairments at extinguishing conditioned fear responses ( orr et al . , 2000 , peri et al . , 2000 , blechert et al .
2011 ) . in the majority of these investigations this deficit appeared to be related to a failure to inhibit responses to a previously threatening cs + that currently signals safety ( orr et al . , 2000 , peri et al .
deficits in the retrieval of extinction after intact training have also been reported in patients with ptsd ( milad et al . , 2008 ,
furthermore , the failure to inhibit fear responses has recently been reported to be associated with higher levels of ptsd - related symptoms ( milad et al . , 2009 ,
it is thought that these impairments may arise from dysregulation in the circuitry supporting extinction processes , namely enhanced amygdala and dacc activity in combination with diminished vmpfc activity ( rauch et al .
consistent with this , neuroimaging research in healthy humans assessing the neural circuits supporting the extinction of aversive learning has shown that the integrity of reciprocal connections between the amygdala and vmpfc predict levels of trait - like anxiety ( kim and whalen , 2009 , kim et al . , 2011 ) , suggesting that dysfunction within amygdala - prefrontal circuits may contribute to stress - induced vulnerabilities to inhibit fear .
other functional neuroimaging studies assessing stress in healthy humans have reported increases in dacc activity and decreases in hippocampal and medial / orbitofrontal regions during or after stress exposure ( see dedovic et al . , 2009 , for review ) .
collectively , these studies provide a compelling marker of vulnerability to anxiety and trauma - related psychopathology under conditions of stress .
notably , the same stress hormone ( i.e. , cortisol ) that has been found in healthy humans to correlate positively with conditioned responses during extinction retrieval ( raio et al . ,
specifically , glucocorticoid administration was found to reduce trauma - related memory retrieval and symptoms in ptsd patients ( aerni et al . , 2004 ,
, 2010 ) and reduce subjective and physiological measures of fear in phobic patients who were given glucocorticoids prior to exposure therapy ( soravia et al . , 2006 , de quervain et al . , 2011 ) .
consistent with the broader role in memory enhancement , glucocorticoid administration prior to safety learning may later reduce anxiety and fear responses by bolstering initial extinction learning and consolidation within the amygdala and vmpfc . the precise mechanism underlying the immediate reduction of fear expression is less clear , but is thought to be related to glucocorticoids impairing the retrieval of previously acquired aversive associations ( de quervain and margraf , 2008 ) .
interestingly , the therapeutic effects of glucocorticoids in these reports provided benefits to anxiety patients only , indicating that glucorticoids may be most effective in patients suffering from stress - related psychopathology .
this is consistent with clinical research work showing that the hypersensitivity of glucocorticoids in ptsd patients leads to reductions in basal cortisol levels ( yehuda , 2009 ) .
therefore , anxiety populations may benefit from exogenous glucocorticoid administration because it promotes optimal glucocorticoid levels that lead to stronger inhibition of fear responses and more robust consolidation of safety learning .
when an aversive outcome is imminent , cognitive strategies can be used to assert control over emotional responses . these techniques
referred to as cognitive emotion regulation are unique to humans and denote any regulatory strategy used intentionally to generate a more adaptive emotional response ( gross , 1998 , gross and thompson , 2007 ) .
they include shifting attention away from aversive aspects of a stimulus , changing the meaning of a stimulus ( i.e. , reappraisal ) , or altering the expression of an emotional response ( for reviews , see gross and thompson , 2007 , gross , 2013 )
. recruiting cognitive strategies to deliberately change the way a stimulus is evaluated has been shown to effectively reduce the subjective ( gross , 1998 , shurick et al . , 2012 ) , physiological ( gross and thompson , 2007 , delgado et al . , 2008 ,
hartley and phelps , 2010 , schiller and delgado , 2010 ) of emotion . in humans , using cognitive control to change emotional responses is commonly used due it its unique capacity to be deployed at will in a variety of circumstances .
investigations into the neural mechanisms underlying the cognitive regulation of emotion most commonly implicate the lateral pfc , specifically the dorsolateral and ventrolateral pfc ( dlpfc and vlpfc , respectively ) , along with medial regions , such as the vmpfc and dorsomedial pfc ( dmpfc ) , as more highly active when participants utilize regulatory strategies relative to when they do not ( for reviews , see : hartley and phelps , 2010 , schiller and delgado , 2010 , ochsner et al . , 2012 ) .
this pattern of increased prefrontal activity is often coupled with decreased activity in the amygdala during the reappraisal of aversive or threatening stimuli ( delgado et al . , 2008 ,
collectively , this work has led to a provisional model of cognitive emotion regulation in which the dlpfc consistent with its broader role in executive function facilitates the online maintenance and manipulation of information needed for reappraisal to take place , while activity in the amygdala diminishes as the emotional significance of regulated stimuli dampen .
the inhibitory nature of this pfc - amygdala relationship is thought to be mediated by the vmpfc ( delgado et al . , 2008 , ochsner et al . ,
2012 ) suggesting a mechanism through which dlpfc activity could modulate amygdala activity during cognitive regulation ( hartley and phelps , 2010 , ochsner and gross , 2007 , schiller and delgado , 2010 ) .
cognitive emotion regulation relies on a number of higher - level executive functions including intact working memory , used to maintain representations of relevant information during emotion regulation ; response inhibition , which can facilitate the inhibition of automatic responses to threatening cues ; and cognitive flexibility , which enables one to adopt different strategies to foster more adaptive responses ( hofmann et al . , 2012 ) .
however , emerging work across species suggests that these processes and the prefrontal brain regions on which they depend are highly sensitive to the detrimental effects of acute stress .
specifically , these impairments are thought to arise from excessive levels of stress hormones , which have been shown in animals to disrupt neuronal activity ( i.e. , alter firing rates ) and lead to a broad range of cognitive impairments ( arnsten and goldman - rakic , 1998 , arnsten , 2009 , murphy et al . , 1996 ) .
the pfc relies on a delicate balance of catecholamines such as noradrenaline and dopamine , which each exert an inverted u - shaped influence on lateral pfc physiology and function in which optimal levels facilitate neuronal firing patters and pfc - dependent task performance , while supraoptimal levels such as those that may be reached during or after stress exposure lead to impairments .
research in humans is consistent with this : brief exposure to stress has been shown to impair executive functions including working memory capacity ( duncko et al . , 2009 ,
, 2009 , roozendaal et al . , 2004 , schoofs et al . , 2009 ) , cognitive flexibility ( alexander et al . , 2007 , plessow et al . ,
2011 ) , and goal - directed behavior ( otto et al . , 2013 ) , and leads to metabolic reduction in areas selective to emotion regulation , including the vmpfc ( kern et al . , 2008 ) and
conversely , stress enhances the functioning of a broad network of brain regions that are innervated by catecholamine and glucocorticoid inputs , such as the amygdala , hypothalamus , insula and dorsal anterior cingulate ( hermans et al . , 2014 , for review ) .
collectively , these findings suggest that under the stressful conditions when we are most likely to engage in deliberate forms of cognitive emotion regulation is precisely when the resources supporting these techniques may be compromised .
evidence for this has already been demonstrated in anxiety disorder patients that consistently show impairments using cognitive regulation strategies in the laboratory ( mennin et al . , 2005 ,
2010 ) , as well as individuals with high trait anxiety ( indovina et al . , 2011 , lissek et al . ,
this is consistent with research showing that negative affect is related to the failure to exercise self - regulatory control over thoughts and behavior ( baumeister and heatherton , 1996 , heatherton and wagner , 2011 ) .
based on this research , a recent study in our laboratory tested the hypothesis that cognitive emotion regulation would be impaired after exposure to stress ( raio et al . , 2013 ) . after a fear - conditioning task where physiological arousal was measured as an index of fear
, participants were trained to re - appraise an aversive cs and re - structure the fear - conditioning task overall in a less threatening manner .
one day later , participants either underwent a physiological stressor ( i.e. , cpt ) or a control task , before repeating the fear - conditioning task , this time with instructions to utilize their newly acquired regulation skills .
the cpt elicited greater stress responses as measured by self - report , as well as increases in salivary alpha - amylase and cortisol , markers of noradrenergic and hpa - axis activity , respectively . stressed participants exhibited marked impairments regulating both physiological and self - reported fear responses to the aversive cs and showed comparable fear responses to the previous day prior to regulation training .
in contrast , controls showed reductions in both assays of fear expression . stress may exert detrimental effects on the capacity to cognitively regulate fear responses through a number of potential mechanisms . in our study , we found a positive association between alpha - amylase and fear responses after stress , suggesting that the effects of noradrenergic activity on the brain regions that support the regulation of fear may be one possible mechanism by which cognitive fear regulation is impaired .
excessive levels of noradrenaline released after stress can target brain regions that support cognitive emotion regulation , including the amygdala , vmpfc and dorsolateral pfc ( see : arnsten , 2009 ; or , hermans et al . , 2014 , for review ) .
noradrenaline exerts regionally specific effects on the brain due to various receptor subtype availability ( berridge and waterhouse , 2003 ) .
for example , alpha-2 adrenergic receptors , which are densely distributed throughout the lateral pfc , have a high affinity for noradrenaline .
moderate levels of noradrenaline during emotional arousal therefore lead to optimal occupancy in the pfc of these high affinity alpha-2 receptors , facilitating cognitive function ( arnsten and goldman - rakic , 1985 , wang et al . , 2007 ) .
however , higher levels of noradrenaline release as seen during stress exposure is thought to engage lower affinity alpha-1 and beta - adrenergic receptor subtypes that impair prefrontal function ( birnbaum et al . , 1999 , ramos et al . , 2005 ) but strengthen activity in the amygdala ( mcgaugh , 2004 ) .
glucocorticoids can also function in a synergistic manner with noradrenaline to exacerbate its effects in pfc ( ferry et al .
, 1999 , roozendaal et al . , 2004 , grundemann et al . , 1998 ,
therefore , it is possible that both noradrenergic and glucocorticoid responses to acute stress , and the interacting influence they exert in the brain , serve as a potential mechanism for the impact of stress on the cognitive control of fear .
the observation that even a mild stressor can render cognitive emotion regulation less effective is especially striking considering that these techniques are used pervasively in clinical contexts to treat an array of psychological disorders .
cognitive reappraisal and restructuring comprise some of the primary principles underlying for cognitive - behavioral therapy ( cbt ) , a therapeutic technique often referred to as the gold - standard for treating an array of psychological dysfunction , including anxiety and trauma - related disorders ( beck and emery , 1985 , beck and dozois , 2011 , butler et al .
however , we note that our stress manipulation took place after only one session of training , whereas the majority of cbt treatment plans are instituted over an extended period of time ( e.g. , 1224 weeks ) ( butler et al .
stress likely has more limited effects of cognitive emotion regulation as training continues and is practiced over time , therefore we do not argue that cognitive regulation does not have utility in clinical settings , only that its vulnerability to acute stress in the early stages of training should be considered .
additionally , it is important to note that there are multiple components to cbt for which our study was not designed or capable of testing , such the social support garnered from therapeutic relationships , as well as a broad range of restructuring techniques inherent in cbt , which include encouraging patients to recognize and correct automatic thoughts that may be irrational or maladaptive to promote more adaptive emotional responses .
it is possible the combination of all of these components might lead to cbt being more resistant to stress even while the specific reappraisal components use in our task are notably impaired under stress .
although the majority of fear regulation techniques involve changing the value associated with an aversive stimulus , adopting a course of action or inhibiting a response in order to avoid an aversive outcome can also control fear responses .
one such method of this is referred to as active avoidance learning , which comprises a more complex learning process that involves both pavlovian and instrumental components for regulating fear . during active avoidance learning
, one must learn to first associate a cs with an aversive outcome before learning how to use a specific action to either avoid or terminate the presence of a threatening cs ( see cain et al .
importantly , it has been shown that active avoidance ( moscarello and ledoux , 2013 ) and similar active , stressor controllability paradigms ( e.g. , cain and ledoux , 2007 , baratta et al . , 2007 ) can lead to fear reduction in the presence of a cs even when the avoidance action is no longer available . in this way
, these forms of avoidance do not just regulate fear in the moment , but can be viewed as more lasting fear regulation techniques that may also change the value of the cs in future encounters .
research in rodents has revealed that the amygdala is critical to active avoidance learning ( ledoux and gorman , 2001 , gabriel et al . , 2003 ) , specifically to the initial pavlovian stage of learning . as discussed earlier
, the convergence of the cs - us association occurs through plasticity in the la and this input projects to the ce , which outputs to brainstem and hypothalamic regions that mediate fear expression and defensive responses . as
avoidance training commences , projections from the pfc are thought to inhibit conditioned fear expression , which allow the performance of instrumental avoidance responses ( see cain et al .
evidence for this comes from rodent studies showing that lesions to the il leads to excessive fear responses and impaired avoidance learning , with opposite results emerging from lesions of the ce ( moscarello and ledoux , 2013 ) .
the ba can also receive input from the la and , importantly , has direct projections to the nucleus accumbens ( na ) , which modulates goal - directed instrumental behavior , enabling avoidance behavior ( ledoux and gorman , 2001 ) .
( 2000 ) found that la lesions disrupted both the pavlovian and instrumental stage of avoidance learning .
lesions of the ce preserved avoidance learning but impaired the initial expression of conditioned responses ( i.e. freezing ) , whereas lesions to the b led to opposite results , suggesting that pathways through the b are critical to signaling striatal circuits that facilitate avoidance learning . neuroimaging
research in humans also supports a role of the striatum in learning to avoid aversive outcomes .
participants who learned to terminate the presence of a threatening cs using a button press showed reduced levels of physiological fear arousal and amygdala activation coupled with greater activation of the striatum , pointing to a role for the striatum in aversive avoidance learning ( delgado et al . , 2009 ) .
interestingly , the initial fear response to an aversive cs has been shown to impair the ability to mount an instrumental response to avoid it ( choi and ledoux , 2003 ) , suggesting higher sensitivity to acute stress may impair the ability to adopt action - related coping strategies to control fear .
choi and ledoux ( 2003 ) had rodents learn to perform an instrumental shuttling response in the presence of a cs to avoid an imminent electric shock .
a specific subset of non - learners were unable to perform this avoidance response because of high levels of conditioned fear responses ( i.e. , freezing ) .
however , after lesions to the ce , these animals were capable of adopting the avoidance strategy , indicating that excessive fear expression can impair the capacity to perform actions that promote safety and reduce fear .
this implies that higher levels of trait anxiety or acute exposure to stress may impair the capacity to acquire or retain avoidance strategies when confronted with threat .
of the limited studies that have directly assessed the effects of stress or stress hormones on avoidance learning , most have examined passive ( i.e. , inhibitory ) avoidance learning .
in contrast to active avoidance processes that require the use of an instrumental response to prevent or terminate an aversive outcome , passive avoidance requires the suppression of an innate behavior in order to successfully avoid an aversive outcome .
a common way to test passive avoidance is to measure the latency with which an animal crosses from a naturally preferred darkened chamber that has been paired with shock to a less preferred bright chamber that the animal has learned to associate with safety .
passive avoidance involves the amygdala as well as the hippocampus due to the contextual nature of the task ( ogren and stiedl , 2010 ) . as with other forms of aversive learning ,
for example , blocking noradrenaline systemically or within the la or b after avoidance training disrupts its consolidation as measured by weaker subsequent retention ( ferry et al . , 1999 ,
, 1977 , liang et al . , 1986 , quirarte et al . ,
in contrast , enhancing noradrenaline after avoidance training enhances its retention ( mcgaugh et al . , 2002 , mcintyre et al . , 2002 ) .
furthermore , infusion of glucocorticoid agonists into the la directly after training on a fear avoidance and escape task enhances subsequent retention , while gr antagonists infused prior to training impaired retention .
notably , infusions at either time point into the ce had no effect on memory retrieval ( roozendaal and mcgaugh , 1997 ) .
the effect of acute stress on passive avoidance was recently tested in rodents . before training
, animals were classified into high , medium and low anxiety based on the elevated plus - maze test ; subsequently , half of the mice in each group then underwent an acute stress manipulation .
stress altered avoidance performance in the high anxiety group only . specifically , stressed males showed enhanced avoidance as measured by longer latencies to enter a darkened chamber previously paired with shock , while stressed females showed marked impairments in avoidance learning ( navarro - francs and arenas , 2014 ) .
although more research is required to understand the effects of stress on avoidance strategies , avoidant behaviors are common among anxiety patients ( eifert and forsyth , 2007 , craske and barlow , 1988 , sprang and lajoie , 2009 ) , suggesting that stress may enhance well - practiced avoidance strategies .
it should be noted that although avoiding an aversive outcome may attenuate fear responses , the habitual avoidance of fearful situations may also prevent one from confronting aversive stimuli and engaging in extinction processes , which can be detrimental to the treatment of anxiety symptoms .
therefore , while stress may hinder the initiation of avoidance behavior during learning , overuse of avoidance strategies may lead to habitual , potentially maladaptive avoidance behaviors that are facilitated by stress .
since the fear regulation techniques discussed above can be vulnerable to the effects of acute stress , as well as other contextual and temporal factors , emerging research in animals and humans has examined the interference or blockade of fear memory reconsolidation as a putative alternative to change fear .
normative models of memory suggest that immediately after learning , there is window of time in which newly encoded information is susceptible to interference .
however , recent research suggests that memories must undergo an additional phase of consolidation each time they are reactivated , a restabilization process referred to as reconsolidation . since it is often not feasible to interfere with the initial consolidation of traumatic experiences , interfering with reconsolidation offers the possibility of altering traumatic memories in a more permanent manner . in a typical reconsolidation paradigm , after an aversive association is acquired and consolidated , a time - dependent reconsolidation window is induced by a single presentation of the cs , which is thought to reactivate the aversive memory .
a variety of behavioral or pharmacological manipulations can then be used during the presumed reconsolidation window to alter memory re - storage before later testing for the conditioned responses in the presence of the cs .
, 2014 , steinfurth et al . , 2014 ; see schiller and phelps , 2011 for review ) and animals ( nader et al . , 2000 , monfils et al . , 2009 ,
, 2013 ) has now demonstrated that disrupting or interfering with reconsolidation leads to the persistent modification of amygdala - dependent aversive associations .
recent research in rodents suggests that interfering with the reconsolidation of aversive association induces plasticity in the la ( monfils et al . , 2009
, clem and huganir , 2010 ) and in humans , reconsolidation of fear memory leads to diminished bold responses in the amygdala ( agren et al . ,
2012 ) and a failure to involve vmpfc mechanisms typically seen in standard extinction learning and retrieval process ( schiller et al . , 2014 ) , providing evidence that reconsolidation interference may target the original aversive memory trace .
the effects of stress and stress hormones on reconsolidation processes have remained relatively unexplored , however , some recent investigations have begun to characterize these effects . in animals ,
administration of propranolol directly into the amygdala after a threatening association is reactivated impairs the reconsolidation of cued ( debiec and ledoux , 2004 ) and contextual fear ( abrari et al . ,
2009 ) as well as memory of avoidance training ( przybyslawski et al . , 1999 ) , whereas increasing noradrenaline after reactivation can enhance its later retrieval ( debiec et al . ,
this is consistent with research in humans that has reported attenuated fear - related symptoms when ptsd or trauma victims are administered propranolol after the reactivation of traumatic memories ( brunet et al . , 2008 , orr et al . , 2000 ,
immediately ( but not 6 h ) after an aversive fear memory is reactivated impairs the subsequent retrieval of the aversive association but leaves within - session responses intact , an effect seen for memories that were both 1 or 10 days old ( jin et al .
similar effects were shown in an inhibitory avoidance task where systemic glucocorticoid antagonists were administered after fear memory reactivation ( taubenfeld et al . , 2009 , nikzad et al . , 2011 ) .
glucocorticoid administration directly after fear memory retrieval has also been shown to impair the subsequent retrieval of aversive associations , however , rather than impairing reconsolidation this effects appeared to be the result of enhancing extinction consolidation ( cai et al . , 2006 ) .
while the impact of acute stress on the reconsolidation process is relatively unexplored , there is evidence suggesting that the strength of the aversive us during initial fear acquisition can modulate the later susceptibility to interventions used to target reconsolidation ( suzuki et al . , 2004 , finsterwald and alberini , 2014 ) .
the effect of stress on fear memory reconsolidation has not been formally tested in humans . however , a recent study reported that across six different studies assessing how propranolol administration before or after fear memory retrieval might disrupt the reconsolidation of fear memory , individuals who reported higher levels of trait anxiety were more resistant to the effects of reconsolidation interference .
this suggests that individuals who are most vulnerable to the effects of stress may be less responsive to fear memory disruption using this technique ( soeter and kindt , 2013 ) .
from minor daily annoyances to deeply traumatic events , stressful experiences constitute an undeniable aspect of daily life .
reports on the profound impact that stress has on mental and physical health are pervasive throughout the scientific community , leading to widespread interest in understanding how to reduce stress and promote emotional control .
accordingly , empirical studies investigating emotion regulation have grown exponentially over the last two decades , reflecting mounting interest within the field ( gross , 2013 ) . despite the broad scientific interest in understanding how emotions are regulated , however ,
the notion that stress may be detrimental to emotional control has been relatively overlooked within this literature .
consequently , the effects of stress on the capacity to flexibly control emotional responses have remained largely unexplored . the studies reviewed here
offer some initial insight into understanding how acute stress exposure affects the inhibition and control of conditioned fear .
the research discussed in this review used pavlovian fear conditioning as a basis for understanding the effects of stress on the regulation of fear .
since the neural circuitry underlying fear learning is highly conserved across species , we can use animal models as a basis for understanding how stress may influence this circuitry in humans as well .
our investigation of extinction and cognitive regulation reveals robust effects of stress impairing the persistent inhibition of fear , presumably by altering prefrontal cortex function . although less is known concerning the impact of stress on the persistent fear reduction observed with avoidance and reconsolidation , it is possible these fear regulation techniques are less vulnerable to the negative consequences of stress since they rely less on the inhibitory mechanisms involved in extinction and cognitive regulation .
it is important to note that the behavioral and neural research covered in this review focused mainly on brief exposure to stress , rather than chronic exposure .
although the immediate effects of acute stress can exert detrimental effects on the brain regions critical to the regulation of fear responses , chronic exposure to stress can trigger more systemic neuroendocrine changes . for example , chronic stress can lead to dysfunctional regulation of the hpa - axis , resulting in a flattened diurnal cycle of cortisol release , such as that seen in depressives and ptsd ( young et al .
it can also lead to more profound structural and functional changes in brain regions critical to autonomic and hpa - axis related regulation ( i.e. , amygdala and hippocampus ) that can lead to suppression of synaptic plasticity and neurogenesis in these regions ( see mcewen , 2003 for review ) .
collectively , chronic stress produces what has been referred to as allostatic load , creating an overwhelming demand on the neural circuits that mediate appropriate responses and recovery from stress .
fear learning and regulation is a prominent model for describing the pathogenesis of anxiety disorders and stress - related psychopathology .
stress has been shown to play a critical role in the etiology , exacerbation and treatment of affective psychopathology suggesting close interplay between the two .
accordingly , research has shown that individuals with anxiety or depression show a broad range of abnormalities in controlling fear - related responses , suggesting that deficits in emotion regulation may be linked to neurobiological differences in response to stress .
the considerable overlap in stress and fear - related neurocircuitry is one likely explanation for why fear regulation impairments emerge in populations marked by stress .
however , it should be noted that although the interaction between stress and fear circuitry undoubtedly exist and similar mechanisms may be at play , there is likely to be a large degree of heterogeneity in terms of how acute stress may alter fear regulation in clinical populations depending on their individual diagnoses . gaining a clearer understanding of how stress affects the regulation of fear is critical to assess the efficacy of these techniques in clinical populations and inform better treatment options for populations with stress - related psychopathology .[/INST]fear learning and regulation is a prominent model for describing the pathogenesis of anxiety disorders and stress - related psychopathology .
fear expression can be modulated using a number of regulatory strategies , including extinction , cognitive emotion regulation , avoidance strategies and reconsolidation . in this review ,
we examine research investigating the effects of acute stress and stress hormones on these regulatory techniques .
we focus on what is known about the impact of stress on the ability to flexibly regulate fear responses that are acquired through pavlovian fear conditioning .
our primary aim is to explore the impact of stress on fear regulation in humans . given this , we focus on techniques where stress has been linked to alterations of fear regulation in humans ( extinction and emotion regulation ) , and briefly discuss other techniques ( avoidance and reconsolidation ) where the impact of stress or stress hormones have been mainly explored in animal models . these investigations reveal that acute stress may impair the persistent inhibition of fear , presumably by altering prefrontal cortex function . characterizing the effects of stress on fear regulation is critical for understanding the boundaries within which existing regulation strategies are viable in everyday life and can better inform treatment options for those who suffer from anxiety and stress - related psychopathology .</s> |
numerous approaches
exist for the development of new drug formulations
aiming for advanced dissolution properties , including modern techniques
like the preparation of water - soluble inclusion complexes , self-(micro)emulsifying drug delivery systems , solid dispersions and solutions , nanosuspensions , and nano extrusion .
however , these
approaches frequently turn out to be highly complex and hard to control
on a large scale . on the contrary ,
there exist well - established methods
for dissolution profile variation , like polymorph control and morphology alteration . in the former , the internal structure , i.e. , the ( crystalline )
assembly , of the molecules is changed and , thus , physicochemical properties
can be significantly altered . in the latter ,
the morphology is changed ,
aiming for the formation of smaller grains , which can , in general ,
tremendously reduce the dissolution time scale by increasing the surface
area . in recent years
, extensive
theoretical work was directed toward
identifying and predicting new polymorphic forms of organic molecules ,
in particular , for compounds employed in pharmaceutical applications . in general , defined changes in the experimental
protocol , like the choice of solvent type , the concentration of the
solution , the temperature , and pressure , can promote switching between
polymorphs as different local energy minima become accessible .
the vast majority of such experiments are performed
in bulk solutions . however , the application of solid surfaces as a
nucleation or crystallization mediator is a highly promising emerging
alternative to assist the formulation of new drugs .
the presence of a substrate upon nucleation generally results
in an entropy reduction of the system , therewith facilitating initial
nucleation and subsequent bulk crystal growth .
even more importantly , organic molecules nucleating
in the proximity of a surface may assemble differently to any bulk
phase , hence forming so - called surface - induced polymorphs ( sip ) , also denoted surface - mediated polymorphs , which are not obtained
otherwise . in the field of organic
electronics , growth in various sips is
frequently observed and can alter the electronic properties of the
functional film , making polymorphism a decisive factor for the charge
transport in a device .
several experimental
pathways have been reported through which such polymorphs are experimentally
achievable .
the most prominent example
is likely the physical vapor deposition of the prototypical organic
semiconductor , pentacene , onto silicon dioxide ( sio2 ) surfaces .
extensive growth studies have been performed showing that pentacene
molecules at the very interface pack in a so - called thin - film phase .
macroscopic free - standing single crystals of
this very phase are not accessible , as surface interactions are required
for its existence ; thus , this polymorph is surface - induced .
note that ,
however , upon subsequent layer growth an increasing and independently
growing portion of the bulk phase is observed and nucleation in the
sip is limited to less than 100 nm from the substrate surface .
a more recent example showing a sip is that
of the soluble organic semiconductor , dihexyl - terthiophene , where vacuum deposition and solution processing
both revealed sip formation , thus showing that sip growth is , indeed ,
induced by the presence of the substrate and can be independent from
the preparation technique .
furthermore , it was demonstrated in this
study on dihexyl - terthiophene through well - defined drop casting and
spin coating series that the formation of the sip is kinetically driven
rather than a thermodynamic equilibrium state , i.e. , the time frame
at which crystallization takes place has a decisive impact on the
formation of a sip . in pharmaceutical science , however , scarce
data exist on the formation
of sips . although there are numerous excellent solution - based growth
studies showing , indeed , that growth alteration
occurs in the proximity of a surface , typically , only large crystals
of already known polymorphs were hitherto observed .
this is , however ,
likely brought about the fact that most of these studies lack the
experimental tools necessary to unambiguously identify the nature
of a sip , if present .
first of all , homogeneous flat samples are required
on which atomic force microscopy ( afm ) measurements can be performed
to identify morphology alteration .
such samples then further allow
for specular x - ray diffraction in order to identify the crystallographic
netplanes parallel to the substrate s surface .
frequently , such experiments reveal a single peak series
( diffraction from one set of netplanes ( hkl ) and
its higher order reflections ) , which is indicative of a unique crystalline
orientation ( texture ) in the film .
to gain knowledge regarding netplanes
that are strongly tilted or even perpendicular with respect to the
surface , grazing incidence x - ray diffraction ( gixd ) is the method
of choice , which is applicable even on layers as thin as a single
monolayer .
this technique allowed , for instance ,
three groups to solve independently the crystal structure of the pentacene thin - film
phase , almost at the same time .
in the present work , we demonstrate the applicability of these
experimental tools on a model system relevant in the field of pharmaceutical
science . as model drug , 5,5-diphenyl-2,4-imidazolidinedione ( phenytoin )
is used .
phenytoin is applicable in various fields , as it has anticonvulsive ,
antiepileptic , and antiarrhythmic effects in the human organism and
is typically applied via solid oral dosage forms , like capsules , or
in parenteral formulations . for the long - term treatment of epilepsy ,
topical routes ( e.g. , transdermal patches )
, phenytoin has been recently investigated extensively , as it
shows very promising film - forming properties . in this study , phenytoin is solution - processed onto
silicon dioxide surfaces , and the films are investigated by combining
afm with specular x - ray diffraction and gixd . by altering the preparation
parameters , we induce growth in a yet unknown sip and compare this
system to samples comprising the bulk phase of phenytoin .
finally ,
marked differences in the dissolution profiles of sip and bulk phase
samples are identified and discussed in detail .
5,5-diphenylimidazolidin-2,4-dion ( or phenytoin )
was purchased
from sigma - aldrich ( germany ) and used without any modification / purification .
spectral grade tetrahydrofuran ( thf ) ( fluka , germany ) and ethanol
( etoh ) ( aldrich , germany ) were used as solvents .
solutions of 1 mg / ml
were prepared , treated in an ultrasonic bath , and stirred until use .
conventional glass slides ( roth , germany ) cut into 1.25
1.25 cm pieces served as substrates . the surfaces were
cleaned in acetone followed by immersion into a 0.1 mol naoh solution
for 30 min , rinsed with milli - q water , and finally dried under a nitrogen
stream prior to use .
a 35 l drop of the solution was placed on the substrate ,
where special care was taken for an exact leveling of the surface
to guarantee a homogeneous drying process .
furthermore , a cover was
placed over the sample in order to reduce the solvent evaporation
rate , resulting in a drying time of about 30 min for the etoh samples
and 10 min for thf samples .
while sample preparation from etoh was
performed under ambient conditions at 22 c , the thf solution
was dropped onto glass slides within an oven held at 35 c , as
this turned out to be necessary for obtaining the sip .
specular x - ray diffraction scans were taken with an empyrean reflectometer
( panalytical , netherlands ) .
the device was equipped with a copper
sealed tube , a goebel mirror , primary and secondary slit systems ,
and a 3d - pixcel detector .
angular scans are represented in reciprocal
space as i(qz ) , where qz is the out - of - plane component of the scattering
vector . in situ
temperature - dependent specular x - ray diffraction scans
were done using the dhs900 ( anton paar gmbh , austria ) under an ambient
atmosphere .
grazing incidence x - ray diffraction ( gixd ) experiments
were performed at the id10 beamline at the esrf ( grenoble , france )
using a wavelength of 0.56 and a pilatus 300 k detector ; three
individual images were recorded and added at slightly shifted detector
positions to account for blind detector areas .
the detector images
were transferred into reciprocal space using the x - ray tool - library
xrayutilities ; for data evaluation and
figure generation , the software pygid was used .
the optical morphological investigations of the sample
were performed
using an olympus bx51 optical microscope . a flexafm atomic force microscope
with an easyscan 2 controller ( all from nanosurf , switzerland ) in
noncontact mode
the measurements were corrected for typical artifacts
like line displacement or plane inclination and are illustrated using
the software package gwyddion .
time - dependent drug release from the surface was investigated via
a nonstandard dissolution experiment .
standard dissolution tests are
typically performed following the united states pharmacopeia ( usp ) ,
which involves the usage of a proper usp apparatus , which consists
of standardized vessels and controlled flow control .
however , these setups typically require large amounts of
liquid media for the performance of controlled dissolution experiments .
because the amount of phenytoin deposited onto a single glass slide
was small ( 35 g ) , a homemade setup was applied , as this allowed
much lower quantities of the dissolution media to be used . this test
consisted of conventional sealed glass containers fixed on a horizontal
shaker ( ika yellow line rs 10 control , ika werke gmbh & co. kg ,
germany , 130 rpm at 25 c ) . as dissolution media ,
10 ml of milli - q
water was used . note that this amount of water is required to guarantee
sink conditions , meaning that the concentration gradient in the vessel
is of minor importance for the experiment .
samples of 1 ml of dissolution
media were used and placed back into the dissolution vessel after
the quantification procedure using standard quartz cuvettes ( hellma ,
mllheim , germany ) .
an absorption wavelength of 210 nm was
set at the nanophotometer ( implen , munich , germany ) .
values given
in this article are mean values of three samples ; error bars are given
as standard deviation but are , for most of the data points , smaller
than the data marker .
as is typical
in organic thin - film preparation , the resulting morphologies
are significantly altered by the choice of solvent and/or the specific
processing conditions .
for phenytoin thin films , a variety of morphologies
can be obtained , as recently shown . in these previous
studies , etoh and acetone
were used for film preparation , which , however ,
left the microstructure of the different morphologies , that is , the
crystal polymorph , unchanged .
an example of such
a morphology obtained from etoh solution is illustrated in figure 1a .
this afm height
micrograph shows the presence of extended dendrites of several hundred
micrometers in length on the glass substrate ( figure 1a ) , with adjacent branches inclined by about
45 with respect to each other .
furthermore , the dendrites are
strongly extended along their obvious growth direction but are thin
in their cross - section ; a breadth of ca . 1 m is observed for
most branches over the entire sample .
atomic force microscopy height images
of a phenytoin sample prepared
from etoh solution ( a ) or from thf solution ( b ) . a reflection mode
optical microscopy image taken under crossed polarizers of the thf
sample
the dotted lines indicate the grain boundaries
of the surface - induced phase , and arrows indicate the position of
trenches in between two common areas . in contrast
, homogeneous films also can be obtained by using
tetrahydrofuran
( thf ) as solvent ( figure 1b ) , but they have a strongly altered morphology ( compare figure 1 panel a to panels
b and c ) . in the afm image ( figure 1b ) , the structures appear to be of dendritic type ;
however , the width of the branches is now strongly increased as compared
to that of the previous example : a typical width of 15 m is
observed here for individual branches ( figure 1b , c ) . in one growth direction , a lot of vacancies
between adjacent dendrites are observed , whereas in the other direction
( 90 rotated ) , the film is nearly fully covered . as all morphologies
result from a common center and
interestingly , the
structures on a larger scale appear to be squeezed hexagons , as indicated
by dotted areas in figure 1c . at the outer borders of these hexagons , less material is
forming a trench ( indicated by arrows ) .
next to this material - depleted
area , the growth of phenytoin continues , which seems to follow the
order within these clearly present hexagons .
the color of this very
adjacent area and the morphology seem to be very similar , which typically
means that both sides of the trench have a similar extension from
the surface ( thickness ) .
however , the outer edge of these structures
has a more arbitrary shape , i.e. , it is not hexagonal .
adjacent domains
seem to interrupt the crystal formation and thus the hexagon shape
on a larger scale . to gain further insight into crystallographic
differences between
samples prepared from etoh and thf , x - ray diffraction experiments
were performed . from previous reports
, it is already known that the
preparation of phenytoin films from etoh solutions results in phenytoin
growing its known bulk structure with lattice
constants of a = 0.62 nm , b = 1.36
nm , and c = 1.55 nm .
the specular x - ray diffraction spectra of such a sample is shown
in figure 2 with peaks
located at qz = 8.07 ,
16.14 , and 24.21 nm .
a comparison with calculated
peak positions of the bulk polymorph shows that these values agree
well with the 002 bragg peak and its higher order ( 004 and 006 ) reflections .
notably , compared to an ideal ( simulated ) powder pattern , various
peaks are missing ( cf .
, a specular scan allows only reflections arising
from netplanes that are parallel to the substrate surface to be assessed .
peaks missing in specular x - ray diffraction data thus point toward
a preferential orientation of the crystallites ; e.g. , on isotropic
substrates , an orientational ( fiber ) texture occurs , as is found here for our etoh sample with a common contact
plane ( 020 ) to the substrate surface .
specular x - ray diffraction scans of phenytoin
samples prepared
from thf ( bottom ) and etoh ( center ) solutions compared to a calculated
spectra of an ideal powder of the bulk polymorph ( top ) .
samples prepared via drop casting from a thf solution
at a slightly
elevated temperature of 35 c reveal a distinct behavior in the
specular x - ray diffraction measurements ( figure 2 ) . while some small peaks still indicate
the presence of ( some ) bulk phase crystallites , significantly stronger
peaks occur at qz = 8.97 ,
17.94 , and 26.91 nm .
the positions of these new
peaks are different from those found for the etoh sample , which might
suggest a different contact plane ( texture ) .
however , the peak positions
are not explainable from any other theoretical position
of the bulk phase on the basis of the calculated powder pattern .
thus ,
this sample must contain a different phenytoin polymorph ( or pseudopolymorph ,
see below ) , i.e. , a surface - induced phase ( sip ) .
as its peak intensities
are much larger compared to the bulk phase reflections in the sample ,
the ratio of this new phase is likely much higher in the thin film .
furthermore , the absence of peaks other than higher order reflections
indicates , in analogy to the case with etoh , evidence for the presence
of defined texture also for the sip .
additional information
on the crystallographic structure of the
sip is obtained via gixd , as this technique allows information to
be assessed on netplanes that are normal ( or nearly normal ) to the
substrate surface .
the top of figure 3 shows the gixd pattern of the thf sample , revealing
two different crystallographic features .
a comparison with the known
bulk phase reveals that these rings are a result of randomly oriented
phenytoin crystallites grown in the bulk polymorph . the second
, clearly
dominating set of features is a number of high - intensity bragg spots
along qp = 10.3 , 15.4 ,
and 20.6 nm .
importantly , the separation of these
spots along qz is 4.5
nm , which is exactly half of the value of the
peak observed at 9 nm in the specular x - ray diffraction
experiment ( figure 2 ) .
this gives full confidence that the bragg spots in the gixd pattern
observed here indeed correspond to the sip .
top : experimental grazing
incidence x - ray diffraction data of the
thf sample containing randomly distributed bulk - phase crystallites
( rings ) and sharp spots originating from the sip .
bottom : corresponding
indexation of the spots on the basis of the sip unit cell parameters
derived within this work ( see text ) .
for unit cell determination , each bragg spot needs to be
described
by a certain set of miller indices ( hkl ) , which is
achieved by a proper choice of the unit cell parameters . as the spots
show clear equidistant separation in both the qz and qp directions , all unit cell angles are most likely 90.
an orthorhombic unit cell of a = 0.61 nm , b = 1.22 nm , and c = 1.395 nm can well - describe
the observed diffraction pattern . in this indexation ,
this
means that the sip film is grown in a ( 001 ) fiber texture , i.e. , this
very netplane is the contact plane to the substrate . from the
different diffraction characteristics of the two polymorphs
forming in the thf sample , the following conclusions can now be drawn .
for the bulk phase ,
the diffraction pattern yields intensity distributed
on rings , which indicates randomly oriented crystallites more or less
unaffected by the presence of the substrate surface .
this indicates
that crystallites adopting the bulk polymorph structure most likely
already form in the thf bulk solution and remain on the substrate
after solvent removal .
although both phases nucleate from the same
parent solution , the observed defined spots of the sip in the gixd
pattern show that the degree of order in this phase is high ; most
of these crystallites must be well - aligned with respect to the surface
forming a fiber texture .
therefore , it is obvious that the surface
has a decisive impact on the crystal alignment in this case and , likewise ,
on the choice of polymorph , which finally justifies our labeling of
the new phase as a sip of phenytoin . this perception is further supported
by the fact that , at this stage , there is also no evidence that the
sip can be formed in any bulk experiment despite significant experimental
efforts on this question : variations of the supersaturating degree ,
the solvent evaporation rate , the temperature , or the solvent type
did not allow the sip to be formed in the bulk .
a consideration of
the differences of both situations in terms of the hansen - solubility
parameter shows that phenytoin dissolved much better
in thf compared to that in etoh . at the
interface ,
the relative affinity of etoh to interact with the silica
surface is higher compared to that of thf .
so , from this follows that
a high solubility with a surface affinity poor solvent might be responsible
for the occurrence of this surface - induced phase .
in order to
investigate the ( meta)stability of the sip , temperature - dependent
in situ specular x - ray diffraction scans were performed . for this
experiment ,
a sample was chosen for which the sip and bulk phase are
simultaneously well - observed by their respective bragg reflections
( 002sip and 020bulk ) ; the results are shown
in figure 4 .
for the
experiment at room temperature , the peak positions are identical with
those of the previous sample ( cf .
the peaks
position start to shift toward smaller qz values ( figure 4a ) , which , in turn , means that an expansion of the
unit cell s c - axis takes place .
interestingly ,
besides the shift in peak position , an increase in intensity is also
observed ( figure 4b ) .
, the peak position is at its minimum value of 8.95 nm , which translates into a total expansion of the ( 002 ) netplanes
by 0.004 nm in real space and that of the c - axis
by 0.008 nm ( 1% larger than at room temperature ) .
comparing these
results to the concomitant expansion of the bulk phase in this temperature
range shows a very similar behavior ( 0.6% expansion ) ; the difference
is well within the error margin of the experiment . comparing
the intensity
development of the two phases shows that the sip peak intensity increases
by a factor of 2.4 while the bulk - peak intensity remains essentially
constant ( figure 4b ) .
from this
follows that during this moderate heating more diffraction
intensity of the sip into the 002sip develops , which might
be either a rearrangement of crystallites , crystal growth along the
surface normal , or defect healing , all of which might account for
such a change in intensity .
in situ temperature - dependent specular x - ray
diffraction scans
of a phenytoin sample established from thf solution ( a ) and the extracted
peak intensities of the two different phases normalized to the initial
value ( b ) . a common abscissa is used for comparability .
finally , at 118 c the intensity of the sip
starts to decrease
rapidly , with its bragg peak positions now remaining unaffected by
further increases of the temperature .
this typically means that a
solid solid phase transition has occurred ( note that the melting
point of phenytoin is 300 c ) . as the intensity of the bulk peak
slightly increases at this stage ( black curve in figure 4b ) , it is likely that a transition
into the bulk phase now takes place .
however , as the intensity increase
is low , we assume that this transition occurs either into randomly
ordered bulk phase or into another texture , which is not accessible
by specular x - ray diffraction .
as we were not able to regenerate the
sip on cooling , it is assumed that the sip is of monotropic nature ,
i.e. , it can not be reversibly transited back and forth . in the
following
, the relevance of this new polymorph of phenytoin
on future pharmaceutical applications is demonstrated by its superior
dissolution behavior .
drug dissolution testing , in general , provides
information on in vitro drug release , which is crucial for drug development .
such data are relatable to in vivo pharmacodynamics data in order
to develop an appropriate drug formulation design . for the sake of comparability ,
identical amounts of phenytoin
from both etoh and thf solutions were deposited on equally sized substrates ;
after deposition , each substrate surface contained 35 g of
phenytoin that was dissolved in the same amount of dissolution media
( 10 ml of milli - q water ) .
note that the usage of water rather than
any buffered salt solution minimizes solution / surface interactions ;
for the latter , it can be expected that ions strongly enhance dissolution
due to their surface activity .
furthermore , it should be noted that
results within this study are fully comparable , but , due to the nonstandard
methods , caution in comparing these data with literature data needs
to be advised .
nevertheless , the resulting release of phenytoin over
time for both samples is depicted in figure 5 on linear ( a ) and on double logarithmic
( b ) scales .
the etoh sample reveals a strong increase in concentration
with time ; zero is set at the first measurement point , 1 min after
the start of the experiment . a mass increase ( slope ) of 1.1
10 min , the dissolution rate decreases ,
and a second , roughly linear regime is visible , with the slope being
significantly smaller there .
the double logarithmic representation
reveals that , after about 30 min , the amount released per time interval
decreases further , until reaching a maximum of 35 g after 420
min . this last value is the maximum amount of the sample released .
phenytoin
release as a function of time for two samples represented
on a linear scale for a short time period ( a ) and the entire experimental
data on a double logarithmic scale ( b ) . inspecting the dissolution behavior of the thf sample comprising
dominantly the sip ( see above ) shows distinct behavior as compared
to that of the etoh sample .
initially , fast release is apparent , with
the slope now being steeper at 2.3 g / min .
this represents a
more than 2 times faster release after initial contact with the dissolution
media compared to that of the etoh sample . at around 5 min , the rate
at which phenytoin is released into the media reduces , and the dissolution
rate decreases continuously until all of the phenytoin is released .
this is different from etoh , which shows linear regimes instead , indicating
constant dissolution rates .
the maximum amount of 35 g is finally
reached after 240 min ( figure 5b ) , which is drastically shorter .
these results demonstrate
that the new polymorph is significantly more effective in being released
from the sample surface .
differences in dissolution profiles
typically result from various
parameters . while diffusion coefficients and concentration gradients
might be almost identical for both samples , a larger surface area
means , according to the whitney
the morphologies
present in figure 1 show that more and smaller crystallites are present in the etoh
sample .
this means that the surface area is larger compared to that
of the thf sample , where larger crystallites are present .
however ,
interestingly , the dissolution experiments show even faster dissolution
for the thf sample , suggesting that the surface area difference is
not dominant here .
another parameter that affects dissolution behavior
is the solvent boundary layer , i.e. , the capability of the solvent
to assemble in the proximity of a crystal , which thus can affect solvent crystal
interactions .
a higher dissolution rate might suggest that the sip
reduces the thickness of this boundary layer , providing the ability
to transition faster from the solid into the dissolved state . besides an explanation based on the whitney
noyes equation ,
changes in the polymorphic form can also account for dissolution differences .
the exact assembly of the phenytoin molecules in the sip unit cell
is , however , not accessible from the present data in terms of a full
structure solution . in any case ,
a slightly different molecular arrangement
can tremendously change the relative importance of h - bonding and van
der waals interaction within organic solids ; thus , the different crystal
structures of the two polymorphs might readily account for the alteration
in dissolution found here .
overall , our present set of experiments
clearly evidences the different
dissolution behavior of two types of samples . while some explanations
for this behavior can be suggested , it is likely that a combination
of various aspects is responsible for the different behavior , requiring
additional work to resolve this issues in more detail .
drop casting phenytoin on solid surfaces from a thf solution instead
of a etoh solution induces growth in a new polymorph ( sip ) with significantly
altered crystallographic and morphological properties , which translates
into changes that are beneficial for dissolution behavior .
as this
specific polymorph was hitherto impossible to achieve via different
experimental approaches in bulk solutions , we regard this form as
being mediated by the presence of the substrate , whereby the solvent
has , in addition , a decisive impact on its formation . overall , the
significant increase in dissolution rate and , therefore , improved
drug release from the surface open up a new and promising pathway
for the development of novel drug formulations . while the preparation
of thin films on model substrates allows for the fundamental identification
and characterization of such a new polymorph , future work
will now
be directed toward generating this structure also on nanoparticles
and materials suitable for patches , aiming for its use in pharmaceutical
applications . | polymorphism and morphology can represent
key factors tremendously
limiting the bioavailability of active pharmaceutical ingredients
( api ) , in particular , due to solubility issues . within this work ,
the generation of a yet unknown surface - induced polymorph ( sip ) of
the model drug , 5,5-diphenylimidazolidin-2,4-dion ( phenytoin ) ,
is
demonstrated in thin films through altering the crystallization kinetics
and the solvent type .
atomic force microscopy points toward the presence
of large single - crystalline domains of the sip , which is in contrast
to samples comprising solely the bulk phase , where extended dendritic
phenytoin networks are observed .
grazing incidence x - ray diffraction
reveals unit cell dimensions of the sip significantly different from
those of the known bulk crystal structure of phenytoin .
moreover ,
the aqueous dissolution performance of the new polymorph is benchmarked
against a pure bulk phase reference sample .
our results demonstrate
that the sip exhibits markedly advantageous drug release performance
in terms of dissolution time .
these findings suggest that thin - film
growth of pharmaceutical systems in general should be explored , where
poor aqueous dissolution represents a key limiting factor in pharmaceutical
applications , and illustrate the experimental pathway for determining
the physical properties of a pharmaceutically relevant sip . | <s>[INST]numerous approaches
exist for the development of new drug formulations
aiming for advanced dissolution properties , including modern techniques
like the preparation of water - soluble inclusion complexes , self-(micro)emulsifying drug delivery systems , solid dispersions and solutions , nanosuspensions , and nano extrusion .
however , these
approaches frequently turn out to be highly complex and hard to control
on a large scale . on the contrary ,
there exist well - established methods
for dissolution profile variation , like polymorph control and morphology alteration . in the former , the internal structure , i.e. , the ( crystalline )
assembly , of the molecules is changed and , thus , physicochemical properties
can be significantly altered . in the latter ,
the morphology is changed ,
aiming for the formation of smaller grains , which can , in general ,
tremendously reduce the dissolution time scale by increasing the surface
area . in recent years
, extensive
theoretical work was directed toward
identifying and predicting new polymorphic forms of organic molecules ,
in particular , for compounds employed in pharmaceutical applications . in general , defined changes in the experimental
protocol , like the choice of solvent type , the concentration of the
solution , the temperature , and pressure , can promote switching between
polymorphs as different local energy minima become accessible .
the vast majority of such experiments are performed
in bulk solutions . however , the application of solid surfaces as a
nucleation or crystallization mediator is a highly promising emerging
alternative to assist the formulation of new drugs .
the presence of a substrate upon nucleation generally results
in an entropy reduction of the system , therewith facilitating initial
nucleation and subsequent bulk crystal growth .
even more importantly , organic molecules nucleating
in the proximity of a surface may assemble differently to any bulk
phase , hence forming so - called surface - induced polymorphs ( sip ) , also denoted surface - mediated polymorphs , which are not obtained
otherwise . in the field of organic
electronics , growth in various sips is
frequently observed and can alter the electronic properties of the
functional film , making polymorphism a decisive factor for the charge
transport in a device .
several experimental
pathways have been reported through which such polymorphs are experimentally
achievable .
the most prominent example
is likely the physical vapor deposition of the prototypical organic
semiconductor , pentacene , onto silicon dioxide ( sio2 ) surfaces .
extensive growth studies have been performed showing that pentacene
molecules at the very interface pack in a so - called thin - film phase .
macroscopic free - standing single crystals of
this very phase are not accessible , as surface interactions are required
for its existence ; thus , this polymorph is surface - induced .
note that ,
however , upon subsequent layer growth an increasing and independently
growing portion of the bulk phase is observed and nucleation in the
sip is limited to less than 100 nm from the substrate surface .
a more recent example showing a sip is that
of the soluble organic semiconductor , dihexyl - terthiophene , where vacuum deposition and solution processing
both revealed sip formation , thus showing that sip growth is , indeed ,
induced by the presence of the substrate and can be independent from
the preparation technique .
furthermore , it was demonstrated in this
study on dihexyl - terthiophene through well - defined drop casting and
spin coating series that the formation of the sip is kinetically driven
rather than a thermodynamic equilibrium state , i.e. , the time frame
at which crystallization takes place has a decisive impact on the
formation of a sip . in pharmaceutical science , however , scarce
data exist on the formation
of sips . although there are numerous excellent solution - based growth
studies showing , indeed , that growth alteration
occurs in the proximity of a surface , typically , only large crystals
of already known polymorphs were hitherto observed .
this is , however ,
likely brought about the fact that most of these studies lack the
experimental tools necessary to unambiguously identify the nature
of a sip , if present .
first of all , homogeneous flat samples are required
on which atomic force microscopy ( afm ) measurements can be performed
to identify morphology alteration .
such samples then further allow
for specular x - ray diffraction in order to identify the crystallographic
netplanes parallel to the substrate s surface .
frequently , such experiments reveal a single peak series
( diffraction from one set of netplanes ( hkl ) and
its higher order reflections ) , which is indicative of a unique crystalline
orientation ( texture ) in the film .
to gain knowledge regarding netplanes
that are strongly tilted or even perpendicular with respect to the
surface , grazing incidence x - ray diffraction ( gixd ) is the method
of choice , which is applicable even on layers as thin as a single
monolayer .
this technique allowed , for instance ,
three groups to solve independently the crystal structure of the pentacene thin - film
phase , almost at the same time .
in the present work , we demonstrate the applicability of these
experimental tools on a model system relevant in the field of pharmaceutical
science . as model drug , 5,5-diphenyl-2,4-imidazolidinedione ( phenytoin )
is used .
phenytoin is applicable in various fields , as it has anticonvulsive ,
antiepileptic , and antiarrhythmic effects in the human organism and
is typically applied via solid oral dosage forms , like capsules , or
in parenteral formulations . for the long - term treatment of epilepsy ,
topical routes ( e.g. , transdermal patches )
, phenytoin has been recently investigated extensively , as it
shows very promising film - forming properties . in this study , phenytoin is solution - processed onto
silicon dioxide surfaces , and the films are investigated by combining
afm with specular x - ray diffraction and gixd . by altering the preparation
parameters , we induce growth in a yet unknown sip and compare this
system to samples comprising the bulk phase of phenytoin .
finally ,
marked differences in the dissolution profiles of sip and bulk phase
samples are identified and discussed in detail .
5,5-diphenylimidazolidin-2,4-dion ( or phenytoin )
was purchased
from sigma - aldrich ( germany ) and used without any modification / purification .
spectral grade tetrahydrofuran ( thf ) ( fluka , germany ) and ethanol
( etoh ) ( aldrich , germany ) were used as solvents .
solutions of 1 mg / ml
were prepared , treated in an ultrasonic bath , and stirred until use .
conventional glass slides ( roth , germany ) cut into 1.25
1.25 cm pieces served as substrates . the surfaces were
cleaned in acetone followed by immersion into a 0.1 mol naoh solution
for 30 min , rinsed with milli - q water , and finally dried under a nitrogen
stream prior to use .
a 35 l drop of the solution was placed on the substrate ,
where special care was taken for an exact leveling of the surface
to guarantee a homogeneous drying process .
furthermore , a cover was
placed over the sample in order to reduce the solvent evaporation
rate , resulting in a drying time of about 30 min for the etoh samples
and 10 min for thf samples .
while sample preparation from etoh was
performed under ambient conditions at 22 c , the thf solution
was dropped onto glass slides within an oven held at 35 c , as
this turned out to be necessary for obtaining the sip .
specular x - ray diffraction scans were taken with an empyrean reflectometer
( panalytical , netherlands ) .
the device was equipped with a copper
sealed tube , a goebel mirror , primary and secondary slit systems ,
and a 3d - pixcel detector .
angular scans are represented in reciprocal
space as i(qz ) , where qz is the out - of - plane component of the scattering
vector . in situ
temperature - dependent specular x - ray diffraction scans
were done using the dhs900 ( anton paar gmbh , austria ) under an ambient
atmosphere .
grazing incidence x - ray diffraction ( gixd ) experiments
were performed at the id10 beamline at the esrf ( grenoble , france )
using a wavelength of 0.56 and a pilatus 300 k detector ; three
individual images were recorded and added at slightly shifted detector
positions to account for blind detector areas .
the detector images
were transferred into reciprocal space using the x - ray tool - library
xrayutilities ; for data evaluation and
figure generation , the software pygid was used .
the optical morphological investigations of the sample
were performed
using an olympus bx51 optical microscope . a flexafm atomic force microscope
with an easyscan 2 controller ( all from nanosurf , switzerland ) in
noncontact mode
the measurements were corrected for typical artifacts
like line displacement or plane inclination and are illustrated using
the software package gwyddion .
time - dependent drug release from the surface was investigated via
a nonstandard dissolution experiment .
standard dissolution tests are
typically performed following the united states pharmacopeia ( usp ) ,
which involves the usage of a proper usp apparatus , which consists
of standardized vessels and controlled flow control .
however , these setups typically require large amounts of
liquid media for the performance of controlled dissolution experiments .
because the amount of phenytoin deposited onto a single glass slide
was small ( 35 g ) , a homemade setup was applied , as this allowed
much lower quantities of the dissolution media to be used . this test
consisted of conventional sealed glass containers fixed on a horizontal
shaker ( ika yellow line rs 10 control , ika werke gmbh & co. kg ,
germany , 130 rpm at 25 c ) . as dissolution media ,
10 ml of milli - q
water was used . note that this amount of water is required to guarantee
sink conditions , meaning that the concentration gradient in the vessel
is of minor importance for the experiment .
samples of 1 ml of dissolution
media were used and placed back into the dissolution vessel after
the quantification procedure using standard quartz cuvettes ( hellma ,
mllheim , germany ) .
an absorption wavelength of 210 nm was
set at the nanophotometer ( implen , munich , germany ) .
values given
in this article are mean values of three samples ; error bars are given
as standard deviation but are , for most of the data points , smaller
than the data marker .
as is typical
in organic thin - film preparation , the resulting morphologies
are significantly altered by the choice of solvent and/or the specific
processing conditions .
for phenytoin thin films , a variety of morphologies
can be obtained , as recently shown . in these previous
studies , etoh and acetone
were used for film preparation , which , however ,
left the microstructure of the different morphologies , that is , the
crystal polymorph , unchanged .
an example of such
a morphology obtained from etoh solution is illustrated in figure 1a .
this afm height
micrograph shows the presence of extended dendrites of several hundred
micrometers in length on the glass substrate ( figure 1a ) , with adjacent branches inclined by about
45 with respect to each other .
furthermore , the dendrites are
strongly extended along their obvious growth direction but are thin
in their cross - section ; a breadth of ca . 1 m is observed for
most branches over the entire sample .
atomic force microscopy height images
of a phenytoin sample prepared
from etoh solution ( a ) or from thf solution ( b ) . a reflection mode
optical microscopy image taken under crossed polarizers of the thf
sample
the dotted lines indicate the grain boundaries
of the surface - induced phase , and arrows indicate the position of
trenches in between two common areas . in contrast
, homogeneous films also can be obtained by using
tetrahydrofuran
( thf ) as solvent ( figure 1b ) , but they have a strongly altered morphology ( compare figure 1 panel a to panels
b and c ) . in the afm image ( figure 1b ) , the structures appear to be of dendritic type ;
however , the width of the branches is now strongly increased as compared
to that of the previous example : a typical width of 15 m is
observed here for individual branches ( figure 1b , c ) . in one growth direction , a lot of vacancies
between adjacent dendrites are observed , whereas in the other direction
( 90 rotated ) , the film is nearly fully covered . as all morphologies
result from a common center and
interestingly , the
structures on a larger scale appear to be squeezed hexagons , as indicated
by dotted areas in figure 1c . at the outer borders of these hexagons , less material is
forming a trench ( indicated by arrows ) .
next to this material - depleted
area , the growth of phenytoin continues , which seems to follow the
order within these clearly present hexagons .
the color of this very
adjacent area and the morphology seem to be very similar , which typically
means that both sides of the trench have a similar extension from
the surface ( thickness ) .
however , the outer edge of these structures
has a more arbitrary shape , i.e. , it is not hexagonal .
adjacent domains
seem to interrupt the crystal formation and thus the hexagon shape
on a larger scale . to gain further insight into crystallographic
differences between
samples prepared from etoh and thf , x - ray diffraction experiments
were performed . from previous reports
, it is already known that the
preparation of phenytoin films from etoh solutions results in phenytoin
growing its known bulk structure with lattice
constants of a = 0.62 nm , b = 1.36
nm , and c = 1.55 nm .
the specular x - ray diffraction spectra of such a sample is shown
in figure 2 with peaks
located at qz = 8.07 ,
16.14 , and 24.21 nm .
a comparison with calculated
peak positions of the bulk polymorph shows that these values agree
well with the 002 bragg peak and its higher order ( 004 and 006 ) reflections .
notably , compared to an ideal ( simulated ) powder pattern , various
peaks are missing ( cf .
, a specular scan allows only reflections arising
from netplanes that are parallel to the substrate surface to be assessed .
peaks missing in specular x - ray diffraction data thus point toward
a preferential orientation of the crystallites ; e.g. , on isotropic
substrates , an orientational ( fiber ) texture occurs , as is found here for our etoh sample with a common contact
plane ( 020 ) to the substrate surface .
specular x - ray diffraction scans of phenytoin
samples prepared
from thf ( bottom ) and etoh ( center ) solutions compared to a calculated
spectra of an ideal powder of the bulk polymorph ( top ) .
samples prepared via drop casting from a thf solution
at a slightly
elevated temperature of 35 c reveal a distinct behavior in the
specular x - ray diffraction measurements ( figure 2 ) . while some small peaks still indicate
the presence of ( some ) bulk phase crystallites , significantly stronger
peaks occur at qz = 8.97 ,
17.94 , and 26.91 nm .
the positions of these new
peaks are different from those found for the etoh sample , which might
suggest a different contact plane ( texture ) .
however , the peak positions
are not explainable from any other theoretical position
of the bulk phase on the basis of the calculated powder pattern .
thus ,
this sample must contain a different phenytoin polymorph ( or pseudopolymorph ,
see below ) , i.e. , a surface - induced phase ( sip ) .
as its peak intensities
are much larger compared to the bulk phase reflections in the sample ,
the ratio of this new phase is likely much higher in the thin film .
furthermore , the absence of peaks other than higher order reflections
indicates , in analogy to the case with etoh , evidence for the presence
of defined texture also for the sip .
additional information
on the crystallographic structure of the
sip is obtained via gixd , as this technique allows information to
be assessed on netplanes that are normal ( or nearly normal ) to the
substrate surface .
the top of figure 3 shows the gixd pattern of the thf sample , revealing
two different crystallographic features .
a comparison with the known
bulk phase reveals that these rings are a result of randomly oriented
phenytoin crystallites grown in the bulk polymorph . the second
, clearly
dominating set of features is a number of high - intensity bragg spots
along qp = 10.3 , 15.4 ,
and 20.6 nm .
importantly , the separation of these
spots along qz is 4.5
nm , which is exactly half of the value of the
peak observed at 9 nm in the specular x - ray diffraction
experiment ( figure 2 ) .
this gives full confidence that the bragg spots in the gixd pattern
observed here indeed correspond to the sip .
top : experimental grazing
incidence x - ray diffraction data of the
thf sample containing randomly distributed bulk - phase crystallites
( rings ) and sharp spots originating from the sip .
bottom : corresponding
indexation of the spots on the basis of the sip unit cell parameters
derived within this work ( see text ) .
for unit cell determination , each bragg spot needs to be
described
by a certain set of miller indices ( hkl ) , which is
achieved by a proper choice of the unit cell parameters . as the spots
show clear equidistant separation in both the qz and qp directions , all unit cell angles are most likely 90.
an orthorhombic unit cell of a = 0.61 nm , b = 1.22 nm , and c = 1.395 nm can well - describe
the observed diffraction pattern . in this indexation ,
this
means that the sip film is grown in a ( 001 ) fiber texture , i.e. , this
very netplane is the contact plane to the substrate . from the
different diffraction characteristics of the two polymorphs
forming in the thf sample , the following conclusions can now be drawn .
for the bulk phase ,
the diffraction pattern yields intensity distributed
on rings , which indicates randomly oriented crystallites more or less
unaffected by the presence of the substrate surface .
this indicates
that crystallites adopting the bulk polymorph structure most likely
already form in the thf bulk solution and remain on the substrate
after solvent removal .
although both phases nucleate from the same
parent solution , the observed defined spots of the sip in the gixd
pattern show that the degree of order in this phase is high ; most
of these crystallites must be well - aligned with respect to the surface
forming a fiber texture .
therefore , it is obvious that the surface
has a decisive impact on the crystal alignment in this case and , likewise ,
on the choice of polymorph , which finally justifies our labeling of
the new phase as a sip of phenytoin . this perception is further supported
by the fact that , at this stage , there is also no evidence that the
sip can be formed in any bulk experiment despite significant experimental
efforts on this question : variations of the supersaturating degree ,
the solvent evaporation rate , the temperature , or the solvent type
did not allow the sip to be formed in the bulk .
a consideration of
the differences of both situations in terms of the hansen - solubility
parameter shows that phenytoin dissolved much better
in thf compared to that in etoh . at the
interface ,
the relative affinity of etoh to interact with the silica
surface is higher compared to that of thf .
so , from this follows that
a high solubility with a surface affinity poor solvent might be responsible
for the occurrence of this surface - induced phase .
in order to
investigate the ( meta)stability of the sip , temperature - dependent
in situ specular x - ray diffraction scans were performed . for this
experiment ,
a sample was chosen for which the sip and bulk phase are
simultaneously well - observed by their respective bragg reflections
( 002sip and 020bulk ) ; the results are shown
in figure 4 .
for the
experiment at room temperature , the peak positions are identical with
those of the previous sample ( cf .
the peaks
position start to shift toward smaller qz values ( figure 4a ) , which , in turn , means that an expansion of the
unit cell s c - axis takes place .
interestingly ,
besides the shift in peak position , an increase in intensity is also
observed ( figure 4b ) .
, the peak position is at its minimum value of 8.95 nm , which translates into a total expansion of the ( 002 ) netplanes
by 0.004 nm in real space and that of the c - axis
by 0.008 nm ( 1% larger than at room temperature ) .
comparing these
results to the concomitant expansion of the bulk phase in this temperature
range shows a very similar behavior ( 0.6% expansion ) ; the difference
is well within the error margin of the experiment . comparing
the intensity
development of the two phases shows that the sip peak intensity increases
by a factor of 2.4 while the bulk - peak intensity remains essentially
constant ( figure 4b ) .
from this
follows that during this moderate heating more diffraction
intensity of the sip into the 002sip develops , which might
be either a rearrangement of crystallites , crystal growth along the
surface normal , or defect healing , all of which might account for
such a change in intensity .
in situ temperature - dependent specular x - ray
diffraction scans
of a phenytoin sample established from thf solution ( a ) and the extracted
peak intensities of the two different phases normalized to the initial
value ( b ) . a common abscissa is used for comparability .
finally , at 118 c the intensity of the sip
starts to decrease
rapidly , with its bragg peak positions now remaining unaffected by
further increases of the temperature .
this typically means that a
solid solid phase transition has occurred ( note that the melting
point of phenytoin is 300 c ) . as the intensity of the bulk peak
slightly increases at this stage ( black curve in figure 4b ) , it is likely that a transition
into the bulk phase now takes place .
however , as the intensity increase
is low , we assume that this transition occurs either into randomly
ordered bulk phase or into another texture , which is not accessible
by specular x - ray diffraction .
as we were not able to regenerate the
sip on cooling , it is assumed that the sip is of monotropic nature ,
i.e. , it can not be reversibly transited back and forth . in the
following
, the relevance of this new polymorph of phenytoin
on future pharmaceutical applications is demonstrated by its superior
dissolution behavior .
drug dissolution testing , in general , provides
information on in vitro drug release , which is crucial for drug development .
such data are relatable to in vivo pharmacodynamics data in order
to develop an appropriate drug formulation design . for the sake of comparability ,
identical amounts of phenytoin
from both etoh and thf solutions were deposited on equally sized substrates ;
after deposition , each substrate surface contained 35 g of
phenytoin that was dissolved in the same amount of dissolution media
( 10 ml of milli - q water ) .
note that the usage of water rather than
any buffered salt solution minimizes solution / surface interactions ;
for the latter , it can be expected that ions strongly enhance dissolution
due to their surface activity .
furthermore , it should be noted that
results within this study are fully comparable , but , due to the nonstandard
methods , caution in comparing these data with literature data needs
to be advised .
nevertheless , the resulting release of phenytoin over
time for both samples is depicted in figure 5 on linear ( a ) and on double logarithmic
( b ) scales .
the etoh sample reveals a strong increase in concentration
with time ; zero is set at the first measurement point , 1 min after
the start of the experiment . a mass increase ( slope ) of 1.1
10 min , the dissolution rate decreases ,
and a second , roughly linear regime is visible , with the slope being
significantly smaller there .
the double logarithmic representation
reveals that , after about 30 min , the amount released per time interval
decreases further , until reaching a maximum of 35 g after 420
min . this last value is the maximum amount of the sample released .
phenytoin
release as a function of time for two samples represented
on a linear scale for a short time period ( a ) and the entire experimental
data on a double logarithmic scale ( b ) . inspecting the dissolution behavior of the thf sample comprising
dominantly the sip ( see above ) shows distinct behavior as compared
to that of the etoh sample .
initially , fast release is apparent , with
the slope now being steeper at 2.3 g / min .
this represents a
more than 2 times faster release after initial contact with the dissolution
media compared to that of the etoh sample . at around 5 min , the rate
at which phenytoin is released into the media reduces , and the dissolution
rate decreases continuously until all of the phenytoin is released .
this is different from etoh , which shows linear regimes instead , indicating
constant dissolution rates .
the maximum amount of 35 g is finally
reached after 240 min ( figure 5b ) , which is drastically shorter .
these results demonstrate
that the new polymorph is significantly more effective in being released
from the sample surface .
differences in dissolution profiles
typically result from various
parameters . while diffusion coefficients and concentration gradients
might be almost identical for both samples , a larger surface area
means , according to the whitney
the morphologies
present in figure 1 show that more and smaller crystallites are present in the etoh
sample .
this means that the surface area is larger compared to that
of the thf sample , where larger crystallites are present .
however ,
interestingly , the dissolution experiments show even faster dissolution
for the thf sample , suggesting that the surface area difference is
not dominant here .
another parameter that affects dissolution behavior
is the solvent boundary layer , i.e. , the capability of the solvent
to assemble in the proximity of a crystal , which thus can affect solvent crystal
interactions .
a higher dissolution rate might suggest that the sip
reduces the thickness of this boundary layer , providing the ability
to transition faster from the solid into the dissolved state . besides an explanation based on the whitney
noyes equation ,
changes in the polymorphic form can also account for dissolution differences .
the exact assembly of the phenytoin molecules in the sip unit cell
is , however , not accessible from the present data in terms of a full
structure solution . in any case ,
a slightly different molecular arrangement
can tremendously change the relative importance of h - bonding and van
der waals interaction within organic solids ; thus , the different crystal
structures of the two polymorphs might readily account for the alteration
in dissolution found here .
overall , our present set of experiments
clearly evidences the different
dissolution behavior of two types of samples . while some explanations
for this behavior can be suggested , it is likely that a combination
of various aspects is responsible for the different behavior , requiring
additional work to resolve this issues in more detail .
drop casting phenytoin on solid surfaces from a thf solution instead
of a etoh solution induces growth in a new polymorph ( sip ) with significantly
altered crystallographic and morphological properties , which translates
into changes that are beneficial for dissolution behavior .
as this
specific polymorph was hitherto impossible to achieve via different
experimental approaches in bulk solutions , we regard this form as
being mediated by the presence of the substrate , whereby the solvent
has , in addition , a decisive impact on its formation . overall , the
significant increase in dissolution rate and , therefore , improved
drug release from the surface open up a new and promising pathway
for the development of novel drug formulations . while the preparation
of thin films on model substrates allows for the fundamental identification
and characterization of such a new polymorph , future work
will now
be directed toward generating this structure also on nanoparticles
and materials suitable for patches , aiming for its use in pharmaceutical
applications .[/INST]polymorphism and morphology can represent
key factors tremendously
limiting the bioavailability of active pharmaceutical ingredients
( api ) , in particular , due to solubility issues . within this work ,
the generation of a yet unknown surface - induced polymorph ( sip ) of
the model drug , 5,5-diphenylimidazolidin-2,4-dion ( phenytoin ) ,
is
demonstrated in thin films through altering the crystallization kinetics
and the solvent type .
atomic force microscopy points toward the presence
of large single - crystalline domains of the sip , which is in contrast
to samples comprising solely the bulk phase , where extended dendritic
phenytoin networks are observed .
grazing incidence x - ray diffraction
reveals unit cell dimensions of the sip significantly different from
those of the known bulk crystal structure of phenytoin .
moreover ,
the aqueous dissolution performance of the new polymorph is benchmarked
against a pure bulk phase reference sample .
our results demonstrate
that the sip exhibits markedly advantageous drug release performance
in terms of dissolution time .
these findings suggest that thin - film
growth of pharmaceutical systems in general should be explored , where
poor aqueous dissolution represents a key limiting factor in pharmaceutical
applications , and illustrate the experimental pathway for determining
the physical properties of a pharmaceutically relevant sip .</s> |
infections , caused by beta - lactam - resistant organisms , has increased due to the production of numerous enzymes in recent years ( 1 ) . extended - spectrum beta - lactamases ( esbls )
are a group of beta - lactamases that are most often derived from mutation in the older beta - lactamases that alters the amino acid configuration around the active site of these -lactamases ( 2 ) .
esbl production by organisms such as enterobacteriaceae has created challenges to clinical microbiologists and clinicians ( 3 ) .
the prevalence of antibiotic resistance among e. coli and klebsiella pneumoniae has been increased markedly in recent years by production of esbls ( 4 ) .
one of the ways of resistance in gram - negative bacteria is the production of esbls .
frequency of esbls and its variants may vary in different geographical areas , as reports indicate their spread in some certain communities .
resistance of organisms to face antibiotics has become a problem around the world with serious consequences on the treatment of infectious diseases ( 1 ) .
hence , the aim of present study was to determine the frequency of esbls in strains of klebsiella and e. coli isolated from patients hospitalized in teaching hospitals of yazd in the period 20112012 .
using total enumeration method , all samples including e. coli and klebsiella strains collected from laboratories of shahid sadoughi and shahid rahnemoun hospitals in yazd province were studied .
eosin methylene - blue ( emb ) lactose sucrose agar was used for bacteria culture .
emb is a useful differential - selective medium for isolation and identification of gram - negative intestinal bacteria .
eosin y and methylene blue are optional components added to prevent the growth of gram - positive bacteria , while allowing the gram - negative ones to grow .
lactose carbohydrates are also added to separate the isolates based on fermentation of lactose and sucrose .
e. coli is a lactose - fermenting coliform which typically creates blue - black colonies with a greenish metallic luster .
gram - negative bacilli , isolated from different clinical specimens in laboratories of shahid sadoughi and shahid rahnemoun hospitals in yazd province were collected . after filling out the questionnaire ( demographic information such as , name , age , gender , sample type , ward , and hospital and information on tests such as bacteria name , presence or absence of esbls , and antibiogram result ) , samples were transferred to the microbiology laboratory of yazd university of medical sciences .
samples were cultured in emb medium ( merck company , germany ) and kept at a temperature of 37 c for 24 hours .
the colonies which were positive in lactose emb medium ( those that created a deep pink color or metallic luster ) were identified by biochemical methods and 270 strains of klebsiella and e. coli were isolated .
lactose fermentation ( in the triple sugar iron agar ) , gas production ( in the triple sugar iron agar ) , urea hydrolysis ( in the urea agar ) , the use of citrate ( in the simon citrate ) , movement ( in the sh2-indol - motility medium ) , indole production ( in the sh2-indol - motility medium ) , methyl red test ( in the methyl red - vegesproskaure broth ) , and vp wax test ( in the methyl red - vegesproskaure broth ) .
sensitivity of e. coli and klebsiella isolates to antibiotics of gentamicin , ciprofloxacin , cotrimoxazole , clavulanate / amoxicillin , imipenem , piperacillin , cefepime , ceftazidime , and cefotaxime was measured by the disk diffusion method ( kirby - bauer ) according to clsi protocols , using bacterial suspension with a dilution equivalent to opacity of half pipe mcfarland and the solid medium of muller - hinton ( merck company , germany ) . for this purpose , a bacterial suspension with a dilution equivalent to opacity of half pipe mcfarland was prepared ( 1.510 bacteria ) .
then , the suspension was inoculated on the plates containing mller - hinton agar medium and cultured with grass method .
antibiotics disks were put on the medium using sterile forceps , as they had a distance of 20 mm from each other and 15 mm from the wall of plate .
the plates were incubated for 18 hours at a temperature of 37c . after the incubation period
, the diameter of areola related to lack of bacterial growth around the disc , was measured using a ruler ( in mm ) and compared to the table provided in clsi protocols and then sensitivity ( s ) , intermediate ( i ) , and resistant ( r ) were qualitatively reported .
all tests were performed on the standard strain of e. coli atcc25922 as the control . for this purpose , combination disk method and cefotaxime ( ctx : 30g ) , cefotaxime - clavulanic acid ( ctx 30g / clav 10g ) ,
ceftazidime ( ctx : 30g ) , and ceftazidime - clavulanic acid ( ctx 30g / clav 10g ) disks ( mast company , england ) were used .
first of all , a bacterial suspension with a dilution equivalent to opacity of half pipe mcfarland was prepared and then inoculated on the plates containing mller - hinton agar medium by a swab and cultured with grass method .
if the diameter of areola related to lack of bacterial growth around the ceftazidime - clavulanic acid or cefotaxime - clavulanic acid disks shows an increase more than 5 mm compared to the diameter of areola related to lack of growth around ceftazidime or cefotaxime , this strain is considered as a producer of eslbs .
collected data and information were analyzed using descriptive statistics such as fisher s exact test and mean in spss software , version 15 ( spss inc , chicago , illinois , usa ) , at a significant level of 0.05 .
using total enumeration method , all samples including e. coli and klebsiella strains collected from laboratories of shahid sadoughi and shahid rahnemoun hospitals in yazd province were studied .
eosin methylene - blue ( emb ) lactose sucrose agar was used for bacteria culture .
emb is a useful differential - selective medium for isolation and identification of gram - negative intestinal bacteria .
eosin y and methylene blue are optional components added to prevent the growth of gram - positive bacteria , while allowing the gram - negative ones to grow .
lactose carbohydrates are also added to separate the isolates based on fermentation of lactose and sucrose .
e. coli is a lactose - fermenting coliform which typically creates blue - black colonies with a greenish metallic luster .
gram - negative bacilli , isolated from different clinical specimens in laboratories of shahid sadoughi and shahid rahnemoun hospitals in yazd province were collected . after filling out the questionnaire ( demographic information such as , name , age , gender , sample type , ward , and hospital and information on tests such as bacteria name , presence or absence of esbls , and antibiogram result ) , samples were transferred to the microbiology laboratory of yazd university of medical sciences .
samples were cultured in emb medium ( merck company , germany ) and kept at a temperature of 37 c for 24 hours .
the colonies which were positive in lactose emb medium ( those that created a deep pink color or metallic luster ) were identified by biochemical methods and 270 strains of klebsiella and e. coli were isolated .
lactose fermentation ( in the triple sugar iron agar ) , gas production ( in the triple sugar iron agar ) , urea hydrolysis ( in the urea agar ) , the use of citrate ( in the simon citrate ) , movement ( in the sh2-indol - motility medium ) , indole production ( in the sh2-indol - motility medium ) , methyl red test ( in the methyl red - vegesproskaure broth ) , and vp wax test ( in the methyl red - vegesproskaure broth ) .
sensitivity of e. coli and klebsiella isolates to antibiotics of gentamicin , ciprofloxacin , cotrimoxazole , clavulanate / amoxicillin , imipenem , piperacillin , cefepime , ceftazidime , and cefotaxime was measured by the disk diffusion method ( kirby - bauer ) according to clsi protocols , using bacterial suspension with a dilution equivalent to opacity of half pipe mcfarland and the solid medium of muller - hinton ( merck company , germany ) . for this purpose , a bacterial suspension with a dilution equivalent to opacity of half pipe mcfarland
then , the suspension was inoculated on the plates containing mller - hinton agar medium and cultured with grass method .
antibiotics disks were put on the medium using sterile forceps , as they had a distance of 20 mm from each other and 15 mm from the wall of plate .
the plates were incubated for 18 hours at a temperature of 37c . after the incubation period ,
the diameter of areola related to lack of bacterial growth around the disc , was measured using a ruler ( in mm ) and compared to the table provided in clsi protocols and then sensitivity ( s ) , intermediate ( i ) , and resistant ( r ) were qualitatively reported .
all tests were performed on the standard strain of e. coli atcc25922 as the control .
for this purpose , combination disk method and cefotaxime ( ctx : 30g ) , cefotaxime - clavulanic acid ( ctx 30g / clav 10g ) , ceftazidime ( ctx : 30g ) , and ceftazidime - clavulanic acid ( ctx 30g / clav 10g ) disks ( mast company , england ) were used .
first of all , a bacterial suspension with a dilution equivalent to opacity of half pipe mcfarland was prepared and then inoculated on the plates containing mller - hinton agar medium by a swab and cultured with grass method .
if the diameter of areola related to lack of bacterial growth around the ceftazidime - clavulanic acid or cefotaxime - clavulanic acid disks shows an increase more than 5 mm compared to the diameter of areola related to lack of growth around ceftazidime or cefotaxime , this strain is considered as a producer of eslbs .
collected data and information were analyzed using descriptive statistics such as fisher s exact test and mean in spss software , version 15 ( spss inc , chicago , illinois , usa ) , at a significant level of 0.05 .
in this study , 270 samples were examined including 152 samples of e. coli ( 56.3% ) and 118 samples of klebsiella pneumoniae ( 43.7% ) . among the 270 studied strains , 89 strains ( 33% ) were producers of esbls and 181 strains ( 67% ) were negative in terms of esbls production . among the 152 samples of e. coli , 45 strains ( 30% ) were producers of esbls .
in addition , among the 118 samples of klebsiella pneumoniae , 44 strains ( 37.3% ) were producers of esbls ( table 1 ) . according to the studies conducted on the frequency of esbls in strains of klebsiella and e. coli in terms of gender
, the following results were obtained : among a total of 270 samples , 149 samples ( 55.1% ) male strains were cultured ( 73 strains of e. coli and 76 strains of klebsiella ) . in this group ,
21 samples of e. coli ( 28.8% ) and 28 samples of klebsiella ( 36.8% ) were producers of eslbs ( p - value=0.3 ) . among a total of 270 samples , 121 samples ( 44.9% )
female strains were cultured ( 79 strains of e. coli and 42 strains of klebsiella ) . in this group ,
24 samples of e. coli ( 30.4% ) and 16 samples of klebsiella ( 38.1% ) were producers of eslbs ( p - value=0.42 ) ( table 2 ) . to determine the frequency of esbls in strains of klebsiella and e. coli in terms of age ,
the studies samples were classified into four age groups including below 20 , 2040 , 4060 , and above 60 . among the 270 studied samples , 78 samples ( 28.8% ) were in the age group of 4060 ( 44 strains of e. coli and 34 strains of klebsiella ) . among them , 9 samples of e. coli ( 20.4% ) and 11 samples of klebsiella ( 32.3% ) were producers of eslbs ( p - value=0.29 ) . in analysis of data
on determining the frequency of esbls in strains of klebsiella and e. coli in terms of sample type ( urine , ulcer , lung secretions , sputum , blood , and csf ) , the following results were obtained : among the 270 studied samples , 35 samples ( 13% ) were obtained from culture of ulcers ( 15 strains of e. coli and 20 strains of klebsiella ) . among them , 2 samples of e. coli ( 13.3% ) and 9 samples of klebsiella ( 45% ) were positive in terms of eslbs ( p - value=0.06 ) . among the 270 studied samples , 7 samples ( 2.59% ) were obtained from culture of sputum ( 1 strain of e. coli and 7 strains of klebsiella ) . among them , only 2 samples of klebsiella ( 33.3% ) were positive , in terms of eslbs ( p - value=1 ) . among the 270
studied samples , 20 samples ( 7.4% ) were obtained from culture of blood ( 12 strains of e. coli and 8 strains of klebsiella ) . among them , 7 samples of e. coli ( 58.3% ) and 3 samples of klebsiella ( 37.5% ) were positive in terms of eslbs ( p - value=0.65 ) .
the results obtained from determining the resistance frequency of klebsiella and e. coli strains to antibiotics of gentamicin , ciprofloxacin , cotrimoxazole , clavulanate / amoxicillin , imipenem , piperacillin , cefepime , ceftazidime , and cefotaxime by the diffusion disk method are as follows : among the 89 samples producing esbls , 65 samples ( 73% ) ( 68.8% of e. coli strains and 77.2% of klebsiella strains ) were resistant and 24 samples ( 23% ) ( 31.2% of e. coli strains and 22.8% of klebsiella strains ) were sensitive to cotrimoxazole ( p - value=0.47 ) . among the 89 samples producing esbls , 52 samples ( 58.4% ) ( 71.1% of e. coli strains and 45.4% of klebsiella strains ) were resistant and 37 samples ( 41.7% ) ( 28.9% of e. coli strains and 54.6% of klebsiella strains ) were sensitive to piperacillin ( p - value=0.01 ) ( table 3 ) .
since the 1980s , a new group of antibiotics called oxyimino cephalosporins , which were resistant to hydrolytic activity of beta - lactamase , were used for treatment of infections caused by gram - negative bacteria ( 8 , 9 ) . in early 1990 ,
esbls produced by gram - negative bacteria , showed resistance to cephalosporins such as ceftazidime and cefotaxime , with higher resistance to cefotaxime than ceftazidime ( 10 ) .
esbls enzyme gene is related to plasmid and causes this enzyme to be easily transmitted among bacteria .
in addition to the gene of esbls , most of these plasmids also transmit the genes resistant to several beta lactam and non - beta - lactam antibiotics ( including aminoglycosides , cotrimoxazoles , and fluoroquinolones ) . as a result ,
most of isolated esbls are resistant to many types of antibiotics ( 11 ) . in the present study , among the 154 strains of e. coli , 45 samples ( 30% ) were producers of esbls , while this figure in strains of klebsiella was 44 out of 118 sample ( 37.3% ) .
navarro conducted a study on the frequency of e. coli producing esbls , and the results showed that production of esbls in nosocomial samples of e. coli is 30% ( 12 ) . in another study conducted by ibrahim ( 2011 ) on the frequency of esbls in e. coli samples in sudan , among the 233 samples of e. coli , 70 samples ( 30.2% ) were positive in terms of esbls ( 13 ) .
( 2007 ) studied 87 samples of e. coli of which 25 of them ( 32.1% ) showed production of esbls ( 14 ) .
the results of these studies on the frequency of esbls in e. coli strains are consistent with the findings of the present study with slight differences . in a study by romero and two other studies carried out in turkey , frequency of these enzymes in e. coli
has been reported to be 1% , 12% , and 19.5% , respectively ( 1517 ) .
these figures are less than those obtained in the present study . in studies conducted by ghafourian , korten in turkey and ozgunes , frequency of esbls in klebsiella samples
these figures are higher than the findings of the present study ( 15 , 17 , 18 ) . in addition , in studies carried out by romero , prevalence of these enzymes was found to be 2.8% which is less than the figures in this study ( 16 ) . as it can be seen in different studies , the frequency of esbls enzymes may vary in different regions , cities , and hospitals . in a study conducted in thailand on various species of enterobacteriaceae , no statistically significant association was found between age and esbls production in bacteria ( 6 ) . in another study conducted by ibrahim et al . on the frequency of esbls in e. coli samples in hospitals of khartoum ,
sudan from april to august 2011 , no significant difference was observed between samples taken from children and adults in terms of esbls production ( 13 ) . in the present study , according to the results obtained for age ranges ( below 20 , 2040 , 4060 , and above 60 ) , no significant relationship was found between age ranges and studied samples ( p - value= 1 , 0.54 , 0.29 , and 0.36 , respectively ) . in a study conducted by luvsansharav et al . on different species of enterobacteriaceae ,
e. coli was the most common species producing esbls and no statistically significant association was found between gender and esbl production in bacteria ( 6 ) .
the relationship between gender and frequency of esbls in the present study was not significant , with p - values of 0.3 for men and 0.42 for women .
as mentioned in the results , frequency of esbls in e. coli and klebsiella strains in urine , blood , ulcer , csf , lung secretions , and sputum was 27% and 31.5% , 58.3% and 37.5% , 13.3% and 45% , 40% and 0% , 50% and 46% , and 0% and 33.3% , respectively .
the highest frequency of these enzymes in e. coli and klebsiella strains was obtained in blood culture and lung secretions culture , respectively .
none of the findings for frequency of esbls in e. coli and klebsiella strains in different samples were statistically significant . in a study in three hospitals in 3 regions of iran
, 113 samples of klebsiella pneumoniae were isolated from respiratory tract infection that 67 samples ( 59.2% ) were producers of esbls ( 18 ) .
accordingly , 17 samples in a hospital in ilam ( 43.6% ) , 37 samples in milad hospital of tehran ( 74% ) , and 13 samples in imam reza hospital of mashhad ( 54.27% ) were positive in terms of esbls ( 18 ) . in the present study , frequency of esbls in klebsiella samples of lung secretions culture was more than that of the hospital in ilam but less than that of milad hospital of tehran and imam reza hospital of mashhad . in another study in hospitals of khartoum , sudan , among the 233 samples of e. coli , 70 samples ( 30.2% ) were positive in terms of esbls .
however , the highest frequency of esbls in the present study , was observed in blood culture samples . in the present study , 73.3% of e. coli and
these figures for resistance of e. coli and klebsiella strains to cotrimoxazole , ciprofloxacin , piperacillin , cefotaxime , cefepime , amoxicillin / clavulanate , ceftazidime , and imipenem were 68.8% and 77.2% , 53.3% and 54.5% , 71.1% and 45.4% , 100% and 100% , 75.5% and 79.5% , 48.8% and 50% , 97.7% and 100% , and 35.5% and 47.7% , respectively . in the present study , resistance of klebsiella to all antibiotics except piperacillin was higher than e. coli .
strains of e. coli and klebsiella both showed the highest resistance to cefotaxime , ceftazidime , and cefepime .
e. coli strains had the highest sensitivity to imipenem , amoxicillin / clavulanate , and ciprofloxacin , while klebsiella strains showed the highest sensitivity to piperacillin , imipenem , and amoxicillin / clavulanate . among antibiotics ,
only piperacillin , with a p - value of 0.01 , was statistically significant . in another study , 87 samples of e. coli and 40 samples of klebsiella .
activity of esbls was confirmed in 25 samples of e. coli ( 32.1% ) and 18 samples of klebsiella ( 45% ) .
resistance of esbls to ciprofloxacin , trimethoprim / sulfamethoxazole , gentamicin , and piperacillin / tazobactam in klebsiella and e. coli samples was 56% and 76% , 55.6% and 68% , 64% and 77.8% , and 28% and 50% , respectively ( 14 ) .
these figures indicate higher resistance of e. coli than klebsiella , while klebsiella showed higher resistance than e. coli in the present study . the highest and lowest resistance in both bacteria ,
was shown to be related to gentamicin and piperacillin , respectively . in the present study ,
both e. coli and klebsiella showed the highest resistance to gentamicin , while the lowest resistance of klebsiella and e. coli was to piperacillin and ciprofloxacin , respectively . in a study on the frequency of esbls in e. coli samples in sudan , among the 233 samples of e. coli , 70 samples ( 30.2% ) were positive in terms of esbls . according to the survey conducted on antibiotic resistance in strains producing esbls , 98.6% of them were resistant to cotrimoxazole and 81.4% showed resistance to ciprofloxacin ( 13 ) . in the present study ,
percentage of resistance to above - mentioned antibiotics ( except for cefotaxime which was completely consistent with the results of this study ) was higher , especially in terms of imipenem and gentamicin .
in addition , the highest and the lowest antibiotic resistance in the present study were related to cefotaxime and imipenem , respectively .
according to the study findings , frequency of esbls in klebsiella strains was higher than e. coli strains .
the highest frequency of esbls in e. coli and klebsiella strains was found in blood culture and lung secretions culture samples , respectively . however , the findings showed no significant difference between e. coli and klebsiella strains in terms of the frequency of esbls . in the present study , resistance of klebsiella to all antibiotics
in addition , e. coli strains showed the highest sensitivity to imipenem , amoxicillin / clavulanate , and ciprofloxacin , while the highest antibiotic sensitivity of klebsiella strains was shown to be to piperacillin , imipenem , and amoxicillin / clavulanate . | introductionfrequency of extended - spectrum beta - lactamases ( esbls ) and its variants may vary in different geographical areas , as reports indicate their spread in some certain communities .
the aim of this study was to determine the frequency of esbls in strains of klebsiella and e. coli , isolated from patients hospitalized in teaching hospitals of yazd.methodsthis cross - sectional study was carried out on samples including e. coli and klebsiella strains collected from laboratories of shahid sadoughi and shahid rahnemoun hospitals in yazd , iran in the period of 20112012 .
the colonies which were positive in lactose eosin methylene - blue ( emb ) medium were identified by biochemical methods , and 270 strains of klebsiella and e. coli were isolated .
collected data and information were analyzed using fisher s exact test and descriptive statistics such as mean in spss software , version 15 , at a significant level of 0.05.resultsin this study , 270 samples were examined , including 152 samples of e. coli ( 56.3% ) and 118 samples of klebsiella pneumonia ( 43.7% ) . among the 152 samples of e. coli , 45 strains ( 30% ) were producers of esbls .
in addition , among the 118 samples of klebsiella pneumonia , 44 strains ( 37.3% ) were producers of esbls .
e. coli strains showed the most resistance to cefotaxime ( 100% ) , ceftazidime ( 97.7% ) , and cefepime ( 75.5% ) respectively and klebsiella strains showed the most resistance to cefotaxime ( 100% ) , ceftazidime ( 100% ) and cefepime ( 79.5% ) , respectively.conclusionfrequency of esbls in klebsiella strains was higher than e. coli strains .
no significant relationship was found between frequency of esbls and age or gender .
in addition , e. coli strains showed the highest sensitivity to imipenem , amoxicillin / clavulanate , and ciprofloxacin , while the highest antibiotic sensitivity of klebsiella strains was shown to be to piperacillin , imipenem , and amoxicillin / clavulanate . | <s>[INST]infections , caused by beta - lactam - resistant organisms , has increased due to the production of numerous enzymes in recent years ( 1 ) . extended - spectrum beta - lactamases ( esbls )
are a group of beta - lactamases that are most often derived from mutation in the older beta - lactamases that alters the amino acid configuration around the active site of these -lactamases ( 2 ) .
esbl production by organisms such as enterobacteriaceae has created challenges to clinical microbiologists and clinicians ( 3 ) .
the prevalence of antibiotic resistance among e. coli and klebsiella pneumoniae has been increased markedly in recent years by production of esbls ( 4 ) .
one of the ways of resistance in gram - negative bacteria is the production of esbls .
frequency of esbls and its variants may vary in different geographical areas , as reports indicate their spread in some certain communities .
resistance of organisms to face antibiotics has become a problem around the world with serious consequences on the treatment of infectious diseases ( 1 ) .
hence , the aim of present study was to determine the frequency of esbls in strains of klebsiella and e. coli isolated from patients hospitalized in teaching hospitals of yazd in the period 20112012 .
using total enumeration method , all samples including e. coli and klebsiella strains collected from laboratories of shahid sadoughi and shahid rahnemoun hospitals in yazd province were studied .
eosin methylene - blue ( emb ) lactose sucrose agar was used for bacteria culture .
emb is a useful differential - selective medium for isolation and identification of gram - negative intestinal bacteria .
eosin y and methylene blue are optional components added to prevent the growth of gram - positive bacteria , while allowing the gram - negative ones to grow .
lactose carbohydrates are also added to separate the isolates based on fermentation of lactose and sucrose .
e. coli is a lactose - fermenting coliform which typically creates blue - black colonies with a greenish metallic luster .
gram - negative bacilli , isolated from different clinical specimens in laboratories of shahid sadoughi and shahid rahnemoun hospitals in yazd province were collected . after filling out the questionnaire ( demographic information such as , name , age , gender , sample type , ward , and hospital and information on tests such as bacteria name , presence or absence of esbls , and antibiogram result ) , samples were transferred to the microbiology laboratory of yazd university of medical sciences .
samples were cultured in emb medium ( merck company , germany ) and kept at a temperature of 37 c for 24 hours .
the colonies which were positive in lactose emb medium ( those that created a deep pink color or metallic luster ) were identified by biochemical methods and 270 strains of klebsiella and e. coli were isolated .
lactose fermentation ( in the triple sugar iron agar ) , gas production ( in the triple sugar iron agar ) , urea hydrolysis ( in the urea agar ) , the use of citrate ( in the simon citrate ) , movement ( in the sh2-indol - motility medium ) , indole production ( in the sh2-indol - motility medium ) , methyl red test ( in the methyl red - vegesproskaure broth ) , and vp wax test ( in the methyl red - vegesproskaure broth ) .
sensitivity of e. coli and klebsiella isolates to antibiotics of gentamicin , ciprofloxacin , cotrimoxazole , clavulanate / amoxicillin , imipenem , piperacillin , cefepime , ceftazidime , and cefotaxime was measured by the disk diffusion method ( kirby - bauer ) according to clsi protocols , using bacterial suspension with a dilution equivalent to opacity of half pipe mcfarland and the solid medium of muller - hinton ( merck company , germany ) . for this purpose , a bacterial suspension with a dilution equivalent to opacity of half pipe mcfarland was prepared ( 1.510 bacteria ) .
then , the suspension was inoculated on the plates containing mller - hinton agar medium and cultured with grass method .
antibiotics disks were put on the medium using sterile forceps , as they had a distance of 20 mm from each other and 15 mm from the wall of plate .
the plates were incubated for 18 hours at a temperature of 37c . after the incubation period
, the diameter of areola related to lack of bacterial growth around the disc , was measured using a ruler ( in mm ) and compared to the table provided in clsi protocols and then sensitivity ( s ) , intermediate ( i ) , and resistant ( r ) were qualitatively reported .
all tests were performed on the standard strain of e. coli atcc25922 as the control . for this purpose , combination disk method and cefotaxime ( ctx : 30g ) , cefotaxime - clavulanic acid ( ctx 30g / clav 10g ) ,
ceftazidime ( ctx : 30g ) , and ceftazidime - clavulanic acid ( ctx 30g / clav 10g ) disks ( mast company , england ) were used .
first of all , a bacterial suspension with a dilution equivalent to opacity of half pipe mcfarland was prepared and then inoculated on the plates containing mller - hinton agar medium by a swab and cultured with grass method .
if the diameter of areola related to lack of bacterial growth around the ceftazidime - clavulanic acid or cefotaxime - clavulanic acid disks shows an increase more than 5 mm compared to the diameter of areola related to lack of growth around ceftazidime or cefotaxime , this strain is considered as a producer of eslbs .
collected data and information were analyzed using descriptive statistics such as fisher s exact test and mean in spss software , version 15 ( spss inc , chicago , illinois , usa ) , at a significant level of 0.05 .
using total enumeration method , all samples including e. coli and klebsiella strains collected from laboratories of shahid sadoughi and shahid rahnemoun hospitals in yazd province were studied .
eosin methylene - blue ( emb ) lactose sucrose agar was used for bacteria culture .
emb is a useful differential - selective medium for isolation and identification of gram - negative intestinal bacteria .
eosin y and methylene blue are optional components added to prevent the growth of gram - positive bacteria , while allowing the gram - negative ones to grow .
lactose carbohydrates are also added to separate the isolates based on fermentation of lactose and sucrose .
e. coli is a lactose - fermenting coliform which typically creates blue - black colonies with a greenish metallic luster .
gram - negative bacilli , isolated from different clinical specimens in laboratories of shahid sadoughi and shahid rahnemoun hospitals in yazd province were collected . after filling out the questionnaire ( demographic information such as , name , age , gender , sample type , ward , and hospital and information on tests such as bacteria name , presence or absence of esbls , and antibiogram result ) , samples were transferred to the microbiology laboratory of yazd university of medical sciences .
samples were cultured in emb medium ( merck company , germany ) and kept at a temperature of 37 c for 24 hours .
the colonies which were positive in lactose emb medium ( those that created a deep pink color or metallic luster ) were identified by biochemical methods and 270 strains of klebsiella and e. coli were isolated .
lactose fermentation ( in the triple sugar iron agar ) , gas production ( in the triple sugar iron agar ) , urea hydrolysis ( in the urea agar ) , the use of citrate ( in the simon citrate ) , movement ( in the sh2-indol - motility medium ) , indole production ( in the sh2-indol - motility medium ) , methyl red test ( in the methyl red - vegesproskaure broth ) , and vp wax test ( in the methyl red - vegesproskaure broth ) .
sensitivity of e. coli and klebsiella isolates to antibiotics of gentamicin , ciprofloxacin , cotrimoxazole , clavulanate / amoxicillin , imipenem , piperacillin , cefepime , ceftazidime , and cefotaxime was measured by the disk diffusion method ( kirby - bauer ) according to clsi protocols , using bacterial suspension with a dilution equivalent to opacity of half pipe mcfarland and the solid medium of muller - hinton ( merck company , germany ) . for this purpose , a bacterial suspension with a dilution equivalent to opacity of half pipe mcfarland
then , the suspension was inoculated on the plates containing mller - hinton agar medium and cultured with grass method .
antibiotics disks were put on the medium using sterile forceps , as they had a distance of 20 mm from each other and 15 mm from the wall of plate .
the plates were incubated for 18 hours at a temperature of 37c . after the incubation period ,
the diameter of areola related to lack of bacterial growth around the disc , was measured using a ruler ( in mm ) and compared to the table provided in clsi protocols and then sensitivity ( s ) , intermediate ( i ) , and resistant ( r ) were qualitatively reported .
all tests were performed on the standard strain of e. coli atcc25922 as the control .
for this purpose , combination disk method and cefotaxime ( ctx : 30g ) , cefotaxime - clavulanic acid ( ctx 30g / clav 10g ) , ceftazidime ( ctx : 30g ) , and ceftazidime - clavulanic acid ( ctx 30g / clav 10g ) disks ( mast company , england ) were used .
first of all , a bacterial suspension with a dilution equivalent to opacity of half pipe mcfarland was prepared and then inoculated on the plates containing mller - hinton agar medium by a swab and cultured with grass method .
if the diameter of areola related to lack of bacterial growth around the ceftazidime - clavulanic acid or cefotaxime - clavulanic acid disks shows an increase more than 5 mm compared to the diameter of areola related to lack of growth around ceftazidime or cefotaxime , this strain is considered as a producer of eslbs .
collected data and information were analyzed using descriptive statistics such as fisher s exact test and mean in spss software , version 15 ( spss inc , chicago , illinois , usa ) , at a significant level of 0.05 .
in this study , 270 samples were examined including 152 samples of e. coli ( 56.3% ) and 118 samples of klebsiella pneumoniae ( 43.7% ) . among the 270 studied strains , 89 strains ( 33% ) were producers of esbls and 181 strains ( 67% ) were negative in terms of esbls production . among the 152 samples of e. coli , 45 strains ( 30% ) were producers of esbls .
in addition , among the 118 samples of klebsiella pneumoniae , 44 strains ( 37.3% ) were producers of esbls ( table 1 ) . according to the studies conducted on the frequency of esbls in strains of klebsiella and e. coli in terms of gender
, the following results were obtained : among a total of 270 samples , 149 samples ( 55.1% ) male strains were cultured ( 73 strains of e. coli and 76 strains of klebsiella ) . in this group ,
21 samples of e. coli ( 28.8% ) and 28 samples of klebsiella ( 36.8% ) were producers of eslbs ( p - value=0.3 ) . among a total of 270 samples , 121 samples ( 44.9% )
female strains were cultured ( 79 strains of e. coli and 42 strains of klebsiella ) . in this group ,
24 samples of e. coli ( 30.4% ) and 16 samples of klebsiella ( 38.1% ) were producers of eslbs ( p - value=0.42 ) ( table 2 ) . to determine the frequency of esbls in strains of klebsiella and e. coli in terms of age ,
the studies samples were classified into four age groups including below 20 , 2040 , 4060 , and above 60 . among the 270 studied samples , 78 samples ( 28.8% ) were in the age group of 4060 ( 44 strains of e. coli and 34 strains of klebsiella ) . among them , 9 samples of e. coli ( 20.4% ) and 11 samples of klebsiella ( 32.3% ) were producers of eslbs ( p - value=0.29 ) . in analysis of data
on determining the frequency of esbls in strains of klebsiella and e. coli in terms of sample type ( urine , ulcer , lung secretions , sputum , blood , and csf ) , the following results were obtained : among the 270 studied samples , 35 samples ( 13% ) were obtained from culture of ulcers ( 15 strains of e. coli and 20 strains of klebsiella ) . among them , 2 samples of e. coli ( 13.3% ) and 9 samples of klebsiella ( 45% ) were positive in terms of eslbs ( p - value=0.06 ) . among the 270 studied samples , 7 samples ( 2.59% ) were obtained from culture of sputum ( 1 strain of e. coli and 7 strains of klebsiella ) . among them , only 2 samples of klebsiella ( 33.3% ) were positive , in terms of eslbs ( p - value=1 ) . among the 270
studied samples , 20 samples ( 7.4% ) were obtained from culture of blood ( 12 strains of e. coli and 8 strains of klebsiella ) . among them , 7 samples of e. coli ( 58.3% ) and 3 samples of klebsiella ( 37.5% ) were positive in terms of eslbs ( p - value=0.65 ) .
the results obtained from determining the resistance frequency of klebsiella and e. coli strains to antibiotics of gentamicin , ciprofloxacin , cotrimoxazole , clavulanate / amoxicillin , imipenem , piperacillin , cefepime , ceftazidime , and cefotaxime by the diffusion disk method are as follows : among the 89 samples producing esbls , 65 samples ( 73% ) ( 68.8% of e. coli strains and 77.2% of klebsiella strains ) were resistant and 24 samples ( 23% ) ( 31.2% of e. coli strains and 22.8% of klebsiella strains ) were sensitive to cotrimoxazole ( p - value=0.47 ) . among the 89 samples producing esbls , 52 samples ( 58.4% ) ( 71.1% of e. coli strains and 45.4% of klebsiella strains ) were resistant and 37 samples ( 41.7% ) ( 28.9% of e. coli strains and 54.6% of klebsiella strains ) were sensitive to piperacillin ( p - value=0.01 ) ( table 3 ) .
since the 1980s , a new group of antibiotics called oxyimino cephalosporins , which were resistant to hydrolytic activity of beta - lactamase , were used for treatment of infections caused by gram - negative bacteria ( 8 , 9 ) . in early 1990 ,
esbls produced by gram - negative bacteria , showed resistance to cephalosporins such as ceftazidime and cefotaxime , with higher resistance to cefotaxime than ceftazidime ( 10 ) .
esbls enzyme gene is related to plasmid and causes this enzyme to be easily transmitted among bacteria .
in addition to the gene of esbls , most of these plasmids also transmit the genes resistant to several beta lactam and non - beta - lactam antibiotics ( including aminoglycosides , cotrimoxazoles , and fluoroquinolones ) . as a result ,
most of isolated esbls are resistant to many types of antibiotics ( 11 ) . in the present study , among the 154 strains of e. coli , 45 samples ( 30% ) were producers of esbls , while this figure in strains of klebsiella was 44 out of 118 sample ( 37.3% ) .
navarro conducted a study on the frequency of e. coli producing esbls , and the results showed that production of esbls in nosocomial samples of e. coli is 30% ( 12 ) . in another study conducted by ibrahim ( 2011 ) on the frequency of esbls in e. coli samples in sudan , among the 233 samples of e. coli , 70 samples ( 30.2% ) were positive in terms of esbls ( 13 ) .
( 2007 ) studied 87 samples of e. coli of which 25 of them ( 32.1% ) showed production of esbls ( 14 ) .
the results of these studies on the frequency of esbls in e. coli strains are consistent with the findings of the present study with slight differences . in a study by romero and two other studies carried out in turkey , frequency of these enzymes in e. coli
has been reported to be 1% , 12% , and 19.5% , respectively ( 1517 ) .
these figures are less than those obtained in the present study . in studies conducted by ghafourian , korten in turkey and ozgunes , frequency of esbls in klebsiella samples
these figures are higher than the findings of the present study ( 15 , 17 , 18 ) . in addition , in studies carried out by romero , prevalence of these enzymes was found to be 2.8% which is less than the figures in this study ( 16 ) . as it can be seen in different studies , the frequency of esbls enzymes may vary in different regions , cities , and hospitals . in a study conducted in thailand on various species of enterobacteriaceae , no statistically significant association was found between age and esbls production in bacteria ( 6 ) . in another study conducted by ibrahim et al . on the frequency of esbls in e. coli samples in hospitals of khartoum ,
sudan from april to august 2011 , no significant difference was observed between samples taken from children and adults in terms of esbls production ( 13 ) . in the present study , according to the results obtained for age ranges ( below 20 , 2040 , 4060 , and above 60 ) , no significant relationship was found between age ranges and studied samples ( p - value= 1 , 0.54 , 0.29 , and 0.36 , respectively ) . in a study conducted by luvsansharav et al . on different species of enterobacteriaceae ,
e. coli was the most common species producing esbls and no statistically significant association was found between gender and esbl production in bacteria ( 6 ) .
the relationship between gender and frequency of esbls in the present study was not significant , with p - values of 0.3 for men and 0.42 for women .
as mentioned in the results , frequency of esbls in e. coli and klebsiella strains in urine , blood , ulcer , csf , lung secretions , and sputum was 27% and 31.5% , 58.3% and 37.5% , 13.3% and 45% , 40% and 0% , 50% and 46% , and 0% and 33.3% , respectively .
the highest frequency of these enzymes in e. coli and klebsiella strains was obtained in blood culture and lung secretions culture , respectively .
none of the findings for frequency of esbls in e. coli and klebsiella strains in different samples were statistically significant . in a study in three hospitals in 3 regions of iran
, 113 samples of klebsiella pneumoniae were isolated from respiratory tract infection that 67 samples ( 59.2% ) were producers of esbls ( 18 ) .
accordingly , 17 samples in a hospital in ilam ( 43.6% ) , 37 samples in milad hospital of tehran ( 74% ) , and 13 samples in imam reza hospital of mashhad ( 54.27% ) were positive in terms of esbls ( 18 ) . in the present study , frequency of esbls in klebsiella samples of lung secretions culture was more than that of the hospital in ilam but less than that of milad hospital of tehran and imam reza hospital of mashhad . in another study in hospitals of khartoum , sudan , among the 233 samples of e. coli , 70 samples ( 30.2% ) were positive in terms of esbls .
however , the highest frequency of esbls in the present study , was observed in blood culture samples . in the present study , 73.3% of e. coli and
these figures for resistance of e. coli and klebsiella strains to cotrimoxazole , ciprofloxacin , piperacillin , cefotaxime , cefepime , amoxicillin / clavulanate , ceftazidime , and imipenem were 68.8% and 77.2% , 53.3% and 54.5% , 71.1% and 45.4% , 100% and 100% , 75.5% and 79.5% , 48.8% and 50% , 97.7% and 100% , and 35.5% and 47.7% , respectively . in the present study , resistance of klebsiella to all antibiotics except piperacillin was higher than e. coli .
strains of e. coli and klebsiella both showed the highest resistance to cefotaxime , ceftazidime , and cefepime .
e. coli strains had the highest sensitivity to imipenem , amoxicillin / clavulanate , and ciprofloxacin , while klebsiella strains showed the highest sensitivity to piperacillin , imipenem , and amoxicillin / clavulanate . among antibiotics ,
only piperacillin , with a p - value of 0.01 , was statistically significant . in another study , 87 samples of e. coli and 40 samples of klebsiella .
activity of esbls was confirmed in 25 samples of e. coli ( 32.1% ) and 18 samples of klebsiella ( 45% ) .
resistance of esbls to ciprofloxacin , trimethoprim / sulfamethoxazole , gentamicin , and piperacillin / tazobactam in klebsiella and e. coli samples was 56% and 76% , 55.6% and 68% , 64% and 77.8% , and 28% and 50% , respectively ( 14 ) .
these figures indicate higher resistance of e. coli than klebsiella , while klebsiella showed higher resistance than e. coli in the present study . the highest and lowest resistance in both bacteria ,
was shown to be related to gentamicin and piperacillin , respectively . in the present study ,
both e. coli and klebsiella showed the highest resistance to gentamicin , while the lowest resistance of klebsiella and e. coli was to piperacillin and ciprofloxacin , respectively . in a study on the frequency of esbls in e. coli samples in sudan , among the 233 samples of e. coli , 70 samples ( 30.2% ) were positive in terms of esbls . according to the survey conducted on antibiotic resistance in strains producing esbls , 98.6% of them were resistant to cotrimoxazole and 81.4% showed resistance to ciprofloxacin ( 13 ) . in the present study ,
percentage of resistance to above - mentioned antibiotics ( except for cefotaxime which was completely consistent with the results of this study ) was higher , especially in terms of imipenem and gentamicin .
in addition , the highest and the lowest antibiotic resistance in the present study were related to cefotaxime and imipenem , respectively .
according to the study findings , frequency of esbls in klebsiella strains was higher than e. coli strains .
the highest frequency of esbls in e. coli and klebsiella strains was found in blood culture and lung secretions culture samples , respectively . however , the findings showed no significant difference between e. coli and klebsiella strains in terms of the frequency of esbls . in the present study , resistance of klebsiella to all antibiotics
in addition , e. coli strains showed the highest sensitivity to imipenem , amoxicillin / clavulanate , and ciprofloxacin , while the highest antibiotic sensitivity of klebsiella strains was shown to be to piperacillin , imipenem , and amoxicillin / clavulanate .[/INST]introductionfrequency of extended - spectrum beta - lactamases ( esbls ) and its variants may vary in different geographical areas , as reports indicate their spread in some certain communities .
the aim of this study was to determine the frequency of esbls in strains of klebsiella and e. coli , isolated from patients hospitalized in teaching hospitals of yazd.methodsthis cross - sectional study was carried out on samples including e. coli and klebsiella strains collected from laboratories of shahid sadoughi and shahid rahnemoun hospitals in yazd , iran in the period of 20112012 .
the colonies which were positive in lactose eosin methylene - blue ( emb ) medium were identified by biochemical methods , and 270 strains of klebsiella and e. coli were isolated .
collected data and information were analyzed using fisher s exact test and descriptive statistics such as mean in spss software , version 15 , at a significant level of 0.05.resultsin this study , 270 samples were examined , including 152 samples of e. coli ( 56.3% ) and 118 samples of klebsiella pneumonia ( 43.7% ) . among the 152 samples of e. coli , 45 strains ( 30% ) were producers of esbls .
in addition , among the 118 samples of klebsiella pneumonia , 44 strains ( 37.3% ) were producers of esbls .
e. coli strains showed the most resistance to cefotaxime ( 100% ) , ceftazidime ( 97.7% ) , and cefepime ( 75.5% ) respectively and klebsiella strains showed the most resistance to cefotaxime ( 100% ) , ceftazidime ( 100% ) and cefepime ( 79.5% ) , respectively.conclusionfrequency of esbls in klebsiella strains was higher than e. coli strains .
no significant relationship was found between frequency of esbls and age or gender .
in addition , e. coli strains showed the highest sensitivity to imipenem , amoxicillin / clavulanate , and ciprofloxacin , while the highest antibiotic sensitivity of klebsiella strains was shown to be to piperacillin , imipenem , and amoxicillin / clavulanate .</s> |
four short series of i - band time - resolved photometry of henize 2428 with merope on the mercator telescope on la palma on august 28 and 30 , 2009 .
they showed a photometric variability as large as @xmath20.36 mag between series , so the system was monitored for a single , 4-hour interval on the night of september 2 , 2009 , and an orbital period was determined .
another similar 4-hour time - series was covered in the johnson b - band with the saao 1 m telescope / shoc on july 11 , 2013 , and in the sloan i - band with the int / wfc on august 2 , 2013 .
a single 20 min spectrum with vlt / fors was secured in the blue range on june 19 , 2010 , under program i d 085.d-0629(a ) , and three additional 15 min spectra with the same configuration on the night of july 8 , 2012 , with program i d 089.d-0453(a ) . the 1200 g grism with a slit width of 0.7 arcsec was used in all cases .
the spectra covered the 409 - 556 nm range .
the resulting effective resolution was 0.8 .
these 4 spectra taken at different times during an orbit clearly showed radial velocity variations from both stars and established the need for and feasibility of a systematic radial velocity study ( see fig .
this was carried out with gtc / osiris on august 11 , 2013 .
the object was monitored for 3.8 hours with a slit width of 0.6 arcsec at parallactic angle .
the r2000b grating was used , resulting in a wavelength coverage from 396 to 569.5 nm , and the effective resolution was 1.9 .
the spectra were binned once ( binning 2@xmath101 ) in the spatial direction .
the magnitude values form the int / wfc sloan i and the saao 1 m telescope / shoc johnson b light curve data were corrected for an extinction of @xmath11= [email protected] , recomputed from an available value using a different extinction law .
we performed a period analysis using schwarzenberg - czerny s analysis - of - variance ( aov ) method on the photometric data set with the greatest time coverage ( from mercator / merope covering 6.25 hours along three nights , not shown here ) .
the aov periodogram shows the strongest peak at @xmath211.379 cycles d@xmath12 , which would correspond to a period of 0.0879 day , or 2.1 hours .
the orbital period of the system is , however , twice as long , [email protected] day ( 4.2 hours ) , as indicated by the ellipsoidal modulation of the light curve , with the two minima showing similar but different depths .
the ephemerides of the light curves indicated in table 1 were computed from their respective light curve data .
due to the asymmetry in the radial velocity curves , the corresponding ephemeris of the zero phase was computed from the ephemeris of the sloan i light curve data , taken 9 nights before , and therefore the associated , accumulated error is much larger .
the orbital and physical parameters of the nucleus of henize 2428 were determined by modelling the light curves , together with the radial velocity - curves , all folded on the orbital period , 0.1758 day .
the mass ratio @xmath13 was fixed to 1 , as suggested by the amplitude of the radial velocity curves .
a systematic search of the parameter space was performed on the inclination , orbital separation , centre - of - mass velocity , temperatures and surface potential of both stars until @xmath14 was globally minimised .
given the high effective temperature of both stars , an albedo of 1.0 was used for both components .
gravity brightening and square - root limb darkening coefficients were computed according to the temperature and gravity of each component@xmath1 .
we provide a rough estimate of the distance to henize 2428 from the comparison of the model s total luminosity to the dereddened , apparent magnitudes , adopting a bolometric correction according to the stars effective temperatures .
the resulting distance is [email protected] kpc .
observations in the b - band were taken 22 nights before the data used to determine the orbital phase ; error accumulation during this time interval amounts to half an orbital period , thus preventing accurate phase determination of the b - band data .
therefore , actually two possibilities were independently considered and modelled ; one where the deepest minimum in both light curves occurs at orbital phase 0 ( model shown in the paper ) , and another one where the deepest minimum is offset by half an orbit .
the results of both models are very similar within uncertainties .
these include the inclination , which is confined to a narrow range between 62.2@xmath3 and 63.8@xmath3 , still a few degrees away from the @xmath268@xmath3-inclined equatorial ring of the nebula .
the surface potential of both stars are slightly different in this model , and the temperature of the primary is around a thousand k lower than that of the secondary .
the total mass is slightly larger but similar to the model shown in the paper , 1.84 m@xmath0 , still above the chandrasekhar limit even when considering uncertainties .
the total luminosity of the system is somewhat larger , 1200 l@xmath0 . | the planetary nebula ( pn ) stage is the ultimate fate of stars with mass 1 to 8 solar masses ( m@xmath0 ) . the origin of their complex morphologies is poorly understood , although several mechanisms involving binary interaction have been proposed@xmath1 . in close binary systems ,
the orbital separation is short enough for the primary star to overfill its roche lobe as it expands during the asymptotic giant branch ( agb ) phase .
the excess material ends up forming a common - envelope ( ce ) surrounding both stars .
drag forces would then result in the envelope being ejected into a bipolar pn whose equator is coincident with the orbital plane of the system .
systems in which both stars have ejected their envelopes and evolve towards the white dwarf ( wd ) stage are called double - degenerates . here
we report that henize 2428 has a double - degenerate core with a combined mass unambiguously above the chandrasekhar limit of 1.4 m@xmath0 . according to its short orbital period ( 4.2 hours ) and total mass ( 1.76 m@xmath0 ) ,
the system should merge in 700 million years , triggering a type ia supernova ( sn ia ) event .
this finding supports the double - degenerate , super - chandrasekhar evolutionary channel for the formation of sne ia .
observatorio astronmico nacional , ap . de correos 112 , e-28803 , alcal de henares , spain instituto de ciencia de materiales de madrid ( csic ) , e-28049 , madrid , spain instituto de astrofsica de canarias , e-38200 la laguna , tenerife , spain departamento de astrofsica , universidad de la laguna , e-38205 la laguna , tenerife , spain south african astronomical observatory , po box 9 , observatory , 7935 , south africa southern african large telescope foundation , po box 9 , observatory , 7935 , south africa
european southern observatory , alonso de crdova 3107 , 19001 casilla , santiago , chile centro de astrobiologa , csic - inta , e-28850 torrejn de ardoz , spain the hypothesis of binarity as a key to produce bipolar pne has been progressively gaining ground , particularly with the recent discovery of many new close binary pn nuclei@xmath1@xmath1@xmath1 . to this end
, we have undertaken a campaign of photometric monitoring of pn central stars that show characteristic features such as rings and/or jets highlighted as being associated with central star binarity .
one of them , henize 2428 ( pn g049.4 + 02.4 ) , shows one of the shortest orbital periods found for this class of object .
this bipolar nebula consists of two open lobes emerging from a ring - shaped waist inclined @xmath268@xmath3 to the plane of the sky ( as deduced from the elliptical shape of the ring in images of the nebula , see fig . 1 ) .
the kinematic age of the bipolar lobes and ring implies that henize 2 - 428 is an evolved pn .
however , the presence of a high density nebular core indicates that strong mass loss and/or mass transfer is occurring close to its central star , which in turn suggests that the nebula may host a binary core .
the periodic light curves of henize 2428 in the sloan i and johnson b bands ( respective effective wavelengths 0.78 and 0.44 @xmath4 m ) demonstrate its binary nature ( fig .
2 ) .
they show two broad minima indicative of ellipsoidal modulation due to tidal distortion of one or both components .
the period analysis using schwarzenberg - czerny s analysis - of - variance ( aov ) method on the photometric data set with the greatest time coverage reveals that the orbital period is [email protected] day .
spectroscopic observations with fors2 on the very large telescope ( fig .
3 ) show the absorption lines to be double and varying with the orbital phase .
the sinusoidal doppler shifts of the double he ii 541.2 nm absorption feature are finally revealed by a series of gtc / osiris spectra obtained along a full orbit ( fig .
4 ) .
gaussian fitting of the absorption - line profiles followed by sinusoidal fitting to the data folded on the orbital period indicates that both radial velocity amplitudes are identical , with values of 206@xmath58 and 206@xmath512 , respectively .
the very similar depth of the each light curve minima , of the intensity of the he ii 541.2 nm stellar absorption line , and of the velocity amplitudes indicate that the two stars have nearly identical masses and effective temperatures .
the latter can be constrained by the presence of the photoionised nebula and by the lack of he ii emission lines in the spectrum of the nebula .
the effective temperatures of the stars have therefore been kept between 20,000 and 40,000 k in our modelling . the combined analysis of the light curves and radial velocity curves@xmath1 yields the orbital parameters of the system ( table 1 ) .
the result is a double - degenerate , overcontact binary , in which both stars overfill their roche lobes .
the total luminosity of the system , 845 l@xmath0 , is compatible with the 690 l@xmath0 reported in the literature .
the inclination of the orbital plane is confined to a narrow range between 63.4@xmath3 and 66.1@xmath3 ( see table 1 ) , close to the @xmath268@xmath3-inclined equatorial ring of the nebula , further strengthening the binary hypothesis .
it is noteworthy that the nebular and orbital axes of _ every _ pn in which both are known happen to be coincident within a few degrees .
these are a41 , a63 , a65 , hatr4 , ngc 6337 , ngc 6778 , and sp1 .
this is convincing evidence for the binary scenario formation of pne outlined above .
the most striking result is the total mass of the system , which amounts to 1.76 m@xmath0 .
this is the only reported double - degenerate system whose total mass is above the chandrasekhar limit without any ambiguity , even when considering the lowest mass allowed within the confidence range ( 1.5 m@xmath0 ) .
moreover , with a mass ratio ( mass of the secondary over mass of the primary ) of 1 , both stars are quite massive compared to average post - agb stars , and their luminosity and effective temperatures do not match the theoretical post - agb cooling tracks .
the explanation must be sought in their binary evolution .
the system seems to have first undergone a phase of mass transfer via wind or stable roche lobe overflow ( rlof ) , and then a ce .
this is likely , as in order to have two oversized pre - wd stars with r=0.68 - 0.7 r@xmath0 still hot , the two events must have happened fast and consecutively .
in addition , for the system to have a current mass ratio close to 1 , the initial mass ratio must have been also very close to 1 .
such a case would lead to a stable rlof initially , given the relatively massive cores and judging by stability studies .
after the first pre - wd star was formed ( from a quite massive agb ) , the mass ratio ( agb / pre - wd ) would then be much larger than 1 , as the secondary is still a massive agb as well , and the system would undergo a ce phase . having an initial mass ratio close to 1 would also explain the final , similar luminosities and effective temperatures . an alternate model in which one or both stars are non - degenerate helium stars deserves further discussion . a 0.88 m@xmath0 helium star approaching core helium exhaustion , produced by the hydrogen shell of a massive star being stripped off during rlof , would have a compatible luminosity of 422 l@xmath0 , although its radius , 0.16 r@xmath0 is still lower than the 0.68 r@xmath0 radius found in this work , and the position of the stars of henize 2428 in log @xmath6@xmath7 diagrams does not match the locus of helium stars in binary systems in the same way as it does not match the aforementioned post - agb cooling tracks .
this alternate model is , however , very unlikely , considering that _ ( a ) _ the computed he / h and the supersolar n / o abundance values indicate a composition more typical of a processed , agb envelope than a rgb envelope ; and _ ( b ) _ gas densities in the extended equatorial ring are around 10@xmath8 @xmath9 , implying recombination times of the order of a few tens of years for h , and a few years for n+ , o+ , and o++ .
given the nebula age , of the order of a few thousand years , that excludes the possibility that the nebula has a fossil photoionization .
in any case , more robust theoretical models should help understanding the peculiarities of this intriguing system .
the stars are massive and close enough to merge in a hubble time ( @xmath2700 million years ) , thus making henize 2428 a strong sn ia candidate .
such a massive double - degenerate system may well explain supernova remnants like snr 0509 - 67.5 , in which the single - degenerate scenario can be ruled out , and confirms the plausibility of double - degenerate scenarios as sn ia progenitors .
the thermal time scale of the stars is @xmath280,000 years , much less than the merging time of the system .
if the radius of each star contracts on the thermal timescale , then the system will relatively quickly become detached and the orbital period will shrink accordingly . if this is the case , long - term monitoring of this system might reveal small changes in the orbital period over the course of the next decades .
in addition to henize 2428 , only half a dozen double - degenerate binary systems are known so far : v458 vul ; sbs 1150 + 599a , the nucleus of ts 01 ; mt ser , the nucleus of abell 41 , ngc 6026 , and fg 1 .
however , estimates indicate they could amount up to 25% of the total pne hosting a close - binary central star
. this figure could be even larger given the strong selection effects against double degenerates in photometric surveys in fact , most double - degenerate systems may only be identified via radial velocity studies .
it is clear that a larger sample of double - degenerate central stars of pne would not only help better assess their contribution to the total number of pne or sn ia progenitors , but also better understand the role of common - envelope and/or contact - binarity in the evolution and shaping of pne and in the production of sn ia events .
this work is based on observations made with the 1 m saao , 1.2 m mercator , 2.5 m int , 4.2 m wht , 8.2 , m vlt and 10.4 m gtc telescopes .
we are grateful to tom marsh for the use of pamela and molly , to todd hillwig , onno pols and javier alcolea for their valuable comments and to jorge garca - rojas and cristina zurita for the int / wfc service observations .
this work was partially supported by the spanish mineco within the grants csd200900038 , aya201235330 , ryc201005762 and aya201238700 .
msg , prg , dj , mmrd , hb and mmk conducted the observations at the various telescopes .
msg , prg , dj and mmk reduced the data .
msg performed the light and radial velocity curves modelling , and wrote the paper .
all authors discussed the results and implications and commented on the manuscript at all stages .
reprints and permissions information is available at www.nature.com/reprints . the authors declare that they have no competing financial interests .
correspondence and requests for materials should be addressed to [email protected] . | <s>[INST]four short series of i - band time - resolved photometry of henize 2428 with merope on the mercator telescope on la palma on august 28 and 30 , 2009 .
they showed a photometric variability as large as @xmath20.36 mag between series , so the system was monitored for a single , 4-hour interval on the night of september 2 , 2009 , and an orbital period was determined .
another similar 4-hour time - series was covered in the johnson b - band with the saao 1 m telescope / shoc on july 11 , 2013 , and in the sloan i - band with the int / wfc on august 2 , 2013 .
a single 20 min spectrum with vlt / fors was secured in the blue range on june 19 , 2010 , under program i d 085.d-0629(a ) , and three additional 15 min spectra with the same configuration on the night of july 8 , 2012 , with program i d 089.d-0453(a ) . the 1200 g grism with a slit width of 0.7 arcsec was used in all cases .
the spectra covered the 409 - 556 nm range .
the resulting effective resolution was 0.8 .
these 4 spectra taken at different times during an orbit clearly showed radial velocity variations from both stars and established the need for and feasibility of a systematic radial velocity study ( see fig .
this was carried out with gtc / osiris on august 11 , 2013 .
the object was monitored for 3.8 hours with a slit width of 0.6 arcsec at parallactic angle .
the r2000b grating was used , resulting in a wavelength coverage from 396 to 569.5 nm , and the effective resolution was 1.9 .
the spectra were binned once ( binning 2@xmath101 ) in the spatial direction .
the magnitude values form the int / wfc sloan i and the saao 1 m telescope / shoc johnson b light curve data were corrected for an extinction of @xmath11= [email protected] , recomputed from an available value using a different extinction law .
we performed a period analysis using schwarzenberg - czerny s analysis - of - variance ( aov ) method on the photometric data set with the greatest time coverage ( from mercator / merope covering 6.25 hours along three nights , not shown here ) .
the aov periodogram shows the strongest peak at @xmath211.379 cycles d@xmath12 , which would correspond to a period of 0.0879 day , or 2.1 hours .
the orbital period of the system is , however , twice as long , [email protected] day ( 4.2 hours ) , as indicated by the ellipsoidal modulation of the light curve , with the two minima showing similar but different depths .
the ephemerides of the light curves indicated in table 1 were computed from their respective light curve data .
due to the asymmetry in the radial velocity curves , the corresponding ephemeris of the zero phase was computed from the ephemeris of the sloan i light curve data , taken 9 nights before , and therefore the associated , accumulated error is much larger .
the orbital and physical parameters of the nucleus of henize 2428 were determined by modelling the light curves , together with the radial velocity - curves , all folded on the orbital period , 0.1758 day .
the mass ratio @xmath13 was fixed to 1 , as suggested by the amplitude of the radial velocity curves .
a systematic search of the parameter space was performed on the inclination , orbital separation , centre - of - mass velocity , temperatures and surface potential of both stars until @xmath14 was globally minimised .
given the high effective temperature of both stars , an albedo of 1.0 was used for both components .
gravity brightening and square - root limb darkening coefficients were computed according to the temperature and gravity of each component@xmath1 .
we provide a rough estimate of the distance to henize 2428 from the comparison of the model s total luminosity to the dereddened , apparent magnitudes , adopting a bolometric correction according to the stars effective temperatures .
the resulting distance is [email protected] kpc .
observations in the b - band were taken 22 nights before the data used to determine the orbital phase ; error accumulation during this time interval amounts to half an orbital period , thus preventing accurate phase determination of the b - band data .
therefore , actually two possibilities were independently considered and modelled ; one where the deepest minimum in both light curves occurs at orbital phase 0 ( model shown in the paper ) , and another one where the deepest minimum is offset by half an orbit .
the results of both models are very similar within uncertainties .
these include the inclination , which is confined to a narrow range between 62.2@xmath3 and 63.8@xmath3 , still a few degrees away from the @xmath268@xmath3-inclined equatorial ring of the nebula .
the surface potential of both stars are slightly different in this model , and the temperature of the primary is around a thousand k lower than that of the secondary .
the total mass is slightly larger but similar to the model shown in the paper , 1.84 m@xmath0 , still above the chandrasekhar limit even when considering uncertainties .
the total luminosity of the system is somewhat larger , 1200 l@xmath0 .[/INST] the planetary nebula ( pn ) stage is the ultimate fate of stars with mass 1 to 8 solar masses ( m@xmath0 ) . the origin of their complex morphologies is poorly understood , although several mechanisms involving binary interaction have been proposed@xmath1 . in close binary systems ,
the orbital separation is short enough for the primary star to overfill its roche lobe as it expands during the asymptotic giant branch ( agb ) phase .
the excess material ends up forming a common - envelope ( ce ) surrounding both stars .
drag forces would then result in the envelope being ejected into a bipolar pn whose equator is coincident with the orbital plane of the system .
systems in which both stars have ejected their envelopes and evolve towards the white dwarf ( wd ) stage are called double - degenerates . here
we report that henize 2428 has a double - degenerate core with a combined mass unambiguously above the chandrasekhar limit of 1.4 m@xmath0 . according to its short orbital period ( 4.2 hours ) and total mass ( 1.76 m@xmath0 ) ,
the system should merge in 700 million years , triggering a type ia supernova ( sn ia ) event .
this finding supports the double - degenerate , super - chandrasekhar evolutionary channel for the formation of sne ia .
observatorio astronmico nacional , ap . de correos 112 , e-28803 , alcal de henares , spain instituto de ciencia de materiales de madrid ( csic ) , e-28049 , madrid , spain instituto de astrofsica de canarias , e-38200 la laguna , tenerife , spain departamento de astrofsica , universidad de la laguna , e-38205 la laguna , tenerife , spain south african astronomical observatory , po box 9 , observatory , 7935 , south africa southern african large telescope foundation , po box 9 , observatory , 7935 , south africa
european southern observatory , alonso de crdova 3107 , 19001 casilla , santiago , chile centro de astrobiologa , csic - inta , e-28850 torrejn de ardoz , spain the hypothesis of binarity as a key to produce bipolar pne has been progressively gaining ground , particularly with the recent discovery of many new close binary pn nuclei@xmath1@xmath1@xmath1 . to this end
, we have undertaken a campaign of photometric monitoring of pn central stars that show characteristic features such as rings and/or jets highlighted as being associated with central star binarity .
one of them , henize 2428 ( pn g049.4 + 02.4 ) , shows one of the shortest orbital periods found for this class of object .
this bipolar nebula consists of two open lobes emerging from a ring - shaped waist inclined @xmath268@xmath3 to the plane of the sky ( as deduced from the elliptical shape of the ring in images of the nebula , see fig . 1 ) .
the kinematic age of the bipolar lobes and ring implies that henize 2 - 428 is an evolved pn .
however , the presence of a high density nebular core indicates that strong mass loss and/or mass transfer is occurring close to its central star , which in turn suggests that the nebula may host a binary core .
the periodic light curves of henize 2428 in the sloan i and johnson b bands ( respective effective wavelengths 0.78 and 0.44 @xmath4 m ) demonstrate its binary nature ( fig .
2 ) .
they show two broad minima indicative of ellipsoidal modulation due to tidal distortion of one or both components .
the period analysis using schwarzenberg - czerny s analysis - of - variance ( aov ) method on the photometric data set with the greatest time coverage reveals that the orbital period is [email protected] day .
spectroscopic observations with fors2 on the very large telescope ( fig .
3 ) show the absorption lines to be double and varying with the orbital phase .
the sinusoidal doppler shifts of the double he ii 541.2 nm absorption feature are finally revealed by a series of gtc / osiris spectra obtained along a full orbit ( fig .
4 ) .
gaussian fitting of the absorption - line profiles followed by sinusoidal fitting to the data folded on the orbital period indicates that both radial velocity amplitudes are identical , with values of 206@xmath58 and 206@xmath512 , respectively .
the very similar depth of the each light curve minima , of the intensity of the he ii 541.2 nm stellar absorption line , and of the velocity amplitudes indicate that the two stars have nearly identical masses and effective temperatures .
the latter can be constrained by the presence of the photoionised nebula and by the lack of he ii emission lines in the spectrum of the nebula .
the effective temperatures of the stars have therefore been kept between 20,000 and 40,000 k in our modelling . the combined analysis of the light curves and radial velocity curves@xmath1 yields the orbital parameters of the system ( table 1 ) .
the result is a double - degenerate , overcontact binary , in which both stars overfill their roche lobes .
the total luminosity of the system , 845 l@xmath0 , is compatible with the 690 l@xmath0 reported in the literature .
the inclination of the orbital plane is confined to a narrow range between 63.4@xmath3 and 66.1@xmath3 ( see table 1 ) , close to the @xmath268@xmath3-inclined equatorial ring of the nebula , further strengthening the binary hypothesis .
it is noteworthy that the nebular and orbital axes of _ every _ pn in which both are known happen to be coincident within a few degrees .
these are a41 , a63 , a65 , hatr4 , ngc 6337 , ngc 6778 , and sp1 .
this is convincing evidence for the binary scenario formation of pne outlined above .
the most striking result is the total mass of the system , which amounts to 1.76 m@xmath0 .
this is the only reported double - degenerate system whose total mass is above the chandrasekhar limit without any ambiguity , even when considering the lowest mass allowed within the confidence range ( 1.5 m@xmath0 ) .
moreover , with a mass ratio ( mass of the secondary over mass of the primary ) of 1 , both stars are quite massive compared to average post - agb stars , and their luminosity and effective temperatures do not match the theoretical post - agb cooling tracks .
the explanation must be sought in their binary evolution .
the system seems to have first undergone a phase of mass transfer via wind or stable roche lobe overflow ( rlof ) , and then a ce .
this is likely , as in order to have two oversized pre - wd stars with r=0.68 - 0.7 r@xmath0 still hot , the two events must have happened fast and consecutively .
in addition , for the system to have a current mass ratio close to 1 , the initial mass ratio must have been also very close to 1 .
such a case would lead to a stable rlof initially , given the relatively massive cores and judging by stability studies .
after the first pre - wd star was formed ( from a quite massive agb ) , the mass ratio ( agb / pre - wd ) would then be much larger than 1 , as the secondary is still a massive agb as well , and the system would undergo a ce phase . having an initial mass ratio close to 1 would also explain the final , similar luminosities and effective temperatures . an alternate model in which one or both stars are non - degenerate helium stars deserves further discussion . a 0.88 m@xmath0 helium star approaching core helium exhaustion , produced by the hydrogen shell of a massive star being stripped off during rlof , would have a compatible luminosity of 422 l@xmath0 , although its radius , 0.16 r@xmath0 is still lower than the 0.68 r@xmath0 radius found in this work , and the position of the stars of henize 2428 in log @xmath6@xmath7 diagrams does not match the locus of helium stars in binary systems in the same way as it does not match the aforementioned post - agb cooling tracks .
this alternate model is , however , very unlikely , considering that _ ( a ) _ the computed he / h and the supersolar n / o abundance values indicate a composition more typical of a processed , agb envelope than a rgb envelope ; and _ ( b ) _ gas densities in the extended equatorial ring are around 10@xmath8 @xmath9 , implying recombination times of the order of a few tens of years for h , and a few years for n+ , o+ , and o++ .
given the nebula age , of the order of a few thousand years , that excludes the possibility that the nebula has a fossil photoionization .
in any case , more robust theoretical models should help understanding the peculiarities of this intriguing system .
the stars are massive and close enough to merge in a hubble time ( @xmath2700 million years ) , thus making henize 2428 a strong sn ia candidate .
such a massive double - degenerate system may well explain supernova remnants like snr 0509 - 67.5 , in which the single - degenerate scenario can be ruled out , and confirms the plausibility of double - degenerate scenarios as sn ia progenitors .
the thermal time scale of the stars is @xmath280,000 years , much less than the merging time of the system .
if the radius of each star contracts on the thermal timescale , then the system will relatively quickly become detached and the orbital period will shrink accordingly . if this is the case , long - term monitoring of this system might reveal small changes in the orbital period over the course of the next decades .
in addition to henize 2428 , only half a dozen double - degenerate binary systems are known so far : v458 vul ; sbs 1150 + 599a , the nucleus of ts 01 ; mt ser , the nucleus of abell 41 , ngc 6026 , and fg 1 .
however , estimates indicate they could amount up to 25% of the total pne hosting a close - binary central star
. this figure could be even larger given the strong selection effects against double degenerates in photometric surveys in fact , most double - degenerate systems may only be identified via radial velocity studies .
it is clear that a larger sample of double - degenerate central stars of pne would not only help better assess their contribution to the total number of pne or sn ia progenitors , but also better understand the role of common - envelope and/or contact - binarity in the evolution and shaping of pne and in the production of sn ia events .
this work is based on observations made with the 1 m saao , 1.2 m mercator , 2.5 m int , 4.2 m wht , 8.2 , m vlt and 10.4 m gtc telescopes .
we are grateful to tom marsh for the use of pamela and molly , to todd hillwig , onno pols and javier alcolea for their valuable comments and to jorge garca - rojas and cristina zurita for the int / wfc service observations .
this work was partially supported by the spanish mineco within the grants csd200900038 , aya201235330 , ryc201005762 and aya201238700 .
msg , prg , dj , mmrd , hb and mmk conducted the observations at the various telescopes .
msg , prg , dj and mmk reduced the data .
msg performed the light and radial velocity curves modelling , and wrote the paper .
all authors discussed the results and implications and commented on the manuscript at all stages .
reprints and permissions information is available at www.nature.com/reprints . the authors declare that they have no competing financial interests .
correspondence and requests for materials should be addressed to [email protected] . </s> |
spontaneous coronary artery dissection ( scad ) and woven coronary artery anomaly ( wcaa ) are rare causes of acute coronary syndrome or sudden cardiac death .
the incidence of scad is about 0.1% for patients who are referred for coronary angiography , and many believe this to be underestimated;1)2 ) on the other hand , the incidence of wcaa is unknown .
wcaa is an extremely rare anomaly characterized by the branching of a major epicardial coronary artery into thin channels , which then merge again in a normal conduit.3 ) the clinical presentation of both diseases depend on the location and severity of coronary involvement .
a 60-year - old female was presented to the cardiology department with stable angina pectoris that she had experienced for one year .
she had been diagnosed with portal vein thrombosis due to protein c deficiency , hypertension and hyperlipidemia .
cardiac catheterization showed a spiral dissection of the proximal right coronary artery ( rca ) , extending downwards to just below the right ventricle branch ( fig .
ventriculography showed hypokinesis of the inferior wall , and the left ventricle ejection fraction ( lvef ) was 45% .
a 2.7530 mm drug - eluting stent was successfully placed along the dissection , reducing the rca to a single lumen ( fig .
the patient was administered on warfarin , clopidogrel , perindopril and beta - blocker on discharge . at 12 weeks follow - up
a 52-year - old man was presented with stable angina pectoris that lasted for two months .
we performed coronary angiography because of the positive treadmill exercise test , and the coronary angiogram surprisingly revealed diffuse dissection that originated on the proximal bed of the second obtuse marginal - ii branch and extending to its distal bed ( fig .
3 ) . we did not perform coronary angioplasty due to technical difficulties and the narrowness of the ischemia - related artery .
the patient 's history revealed a previous right carotid artery occlusion , hyperlipidemia , hypertension and severe smoking .
the patient had been on clopidogrel , aspirin , and lisinopril for the last two months .
the patient exhibited no ischemic ecg changes , but we determined an abnormal st - segment depression on exercise testing .
subsequent coronary angiogram showed a dual twisted lumen in the proximal and medial segments of all coronary arteries ( figs . 4 , 5 , and 6 ) , and ventriculography revealed normal wall motion and lvef of 65% .
the patient 's right carotid angiography showed an occlusion , and other vessels were normal on ct angiogram .
there have been no cases reported in the literature with wcaa involving all coronary arteries .
the patient was evaluated for revascularization due to ischemic findings , but thallium-201 myocardial perfusion imaging did not show ischemia .
we did not perform optical coherance tomography ( oct ) due to the probability of coronary dissection or occlusion caused by guidewire or oct catheter .
the patient was discharged receiving 81 mg of aspirin and 75 mg of clopidogrel once a day .
a 60-year - old female was presented to the cardiology department with stable angina pectoris that she had experienced for one year .
she had been diagnosed with portal vein thrombosis due to protein c deficiency , hypertension and hyperlipidemia .
cardiac catheterization showed a spiral dissection of the proximal right coronary artery ( rca ) , extending downwards to just below the right ventricle branch ( fig .
ventriculography showed hypokinesis of the inferior wall , and the left ventricle ejection fraction ( lvef ) was 45% .
a 2.7530 mm drug - eluting stent was successfully placed along the dissection , reducing the rca to a single lumen ( fig .
the patient was administered on warfarin , clopidogrel , perindopril and beta - blocker on discharge . at 12 weeks follow - up
a 52-year - old man was presented with stable angina pectoris that lasted for two months .
we performed coronary angiography because of the positive treadmill exercise test , and the coronary angiogram surprisingly revealed diffuse dissection that originated on the proximal bed of the second obtuse marginal - ii branch and extending to its distal bed ( fig .
3 ) . we did not perform coronary angioplasty due to technical difficulties and the narrowness of the ischemia - related artery .
the patient 's history revealed a previous right carotid artery occlusion , hyperlipidemia , hypertension and severe smoking .
the patient had been on clopidogrel , aspirin , and lisinopril for the last two months .
the patient exhibited no ischemic ecg changes , but we determined an abnormal st - segment depression on exercise testing .
subsequent coronary angiogram showed a dual twisted lumen in the proximal and medial segments of all coronary arteries ( figs . 4 , 5 , and 6 ) , and ventriculography revealed normal wall motion and lvef of 65% .
the patient 's right carotid angiography showed an occlusion , and other vessels were normal on ct angiogram .
there have been no cases reported in the literature with wcaa involving all coronary arteries .
the patient was evaluated for revascularization due to ischemic findings , but thallium-201 myocardial perfusion imaging did not show ischemia .
we did not perform optical coherance tomography ( oct ) due to the probability of coronary dissection or occlusion caused by guidewire or oct catheter .
the patient was discharged receiving 81 mg of aspirin and 75 mg of clopidogrel once a day .
although it is a very rare clinical event , scad is most frequently associated with pregnant women or those in the postpartum and commonly seen in middle age , but is not infrequent in older patients.1)2)4 ) the precise aetiology and the mechanism of scad during pregnancy is uncertain .
peripartum episodes suggest hemodynamic stress of pregnancy , changes in connective tissue caused by high estrogen levels , and inflammatory changes due to infiltration of eosinophils in the adventitia of the vessel.4 - 6 ) a united states population - based study7 ) on all - cause acute myocardial infarction ( ami ) in pregnancy estimated an incidence of one ami in every 16129 pregnancies , with a mortality rate reported at 5.1% .
eighty percent of reported cases of scad occur in women with no history of heart disease or cardiovascular risk factors , and typically in the left anterior descending artery ; men tend to present with rca dissections .
of the women with scad , one - third are in the peripartum period.8 - 10 ) the disease also has higher prevalance among cases with collagen disorders , cocaine abuse , severe hypertension , smoking , and oral contraceptives.11 ) coronary artery dissection can be seen spontaneously as a consequence of coronary angiography , coronary intervention , cardiac surgery or chest trauma .
the clinical presentation of scad relates to the extent and rate of dissection , as well as the degree of myocardial ischemia .
sudden cardiac death occurs in about 50% of cases , mostly in those with left main coronary artery dissection.12 ) for the diagnosis of scad , diagnostic coronary angiography is generally the standard method , as well as multidetector computerized coronary angiography .
intravascular ultrasound may also be useful , but experience with this technique is still very limited .
when the separated intimal - medial layer pushes toward the true lumen of the vessel , the insuefficient flow of the coronary artery leads to distal myocardial ischemia and its clinical consequences . in some cases
, the false lumen may also recover spontaneously and the true lumen may supply sufficient blood to the distal beds .
compression of the vessel lumen can result from haemorrhage and haematoma between the outer media and external elastic lamina . according to the national heart , lung , and blood institute grade system developed by the coronary angioplasty registry , dissections : can be classified a - f .
type a and b dissections are characterized by filling the defects on contrast injection where there is no or minimal persistence of contrast after the dye has cleared ; type c dissections present as dye staining in an extraluminal cap ; type d is seen as a spiral luminal defect ; type e is detected as persistent luminal defects ; and type f involves total luminal occlusion.13 ) treatment of scad has not been described well ; management should be decided individually for each case , and includes medical therapy , percutaneous coronary intervention ( pci ) or coronary artery bypass graft ( cabg ) surgery . at any rate ,
some authors have advised that asymptomatic patients with a non - occlusive dissection could be managed conservatively.14 ) fibrinolytics , which may provoke bleeding or dissection progression , should be avoided.15 ) although , many dissections are not amenable to catheter interventions , pci can be considered , especially for prominent major single - vessel disease with short segment involvement ; this should be performed cautiously due to the possibility of false lumen or propagating the dissection distally .
medical management includes heparin , antiplatelets , and anti - ischaemic medications , such as beta - blockers and nitrates .
multivessel or left main scad should be managed with cabg.16 ) woven coronary artery anomaly is associated with multiple and twisted thin channels along the vessel in any coronary artery with a timi iii blood flow distally ; these then merge again in order to form the main lumen , after twisting along the coronary artery axis .
the differential diagnosis between scad and wcaa may be very difficult for invasive cardiologists , especially in patients with single or two coronary artery involvement , as the occurence of wcaa is very rare . in the differential diagnosis , in case of the flow is suprisingly normal reflecting the extension of the apparent filling defects and/or there is not any ischemic event , wcaa should be taken into consideration . for better diagnosis
, angiography should be performed using multiple projections with a careful radiological examination ( digital zooming ) .
there has only been one case involving infarct - related wcaa in the literature,17 ) and no wcaa case in which pci was performed . in a case with wcaa involving circumflex artery , reported by kursaklioglu et al.18 )
wcaa have been accepted as a benign entity and no adverse coronary event occured in the long - term follow - up period , due to timi iii blood flow until now and it may demonstrate generally normal coronary reserve with a stress test because of normal blood flow distal to the anomalous segment.18 - 20 ) some authors believed that wcaa may originate from scad and the twisting of thin channels probably causes intracoronary thrombus.20 ) as distinct from the cases reported in the literature,17 - 20 ) involving the right or circumflex artery alone , we present a very interesting wcaa , involving all coronary arteries
. it would be helpful to have the examination by oct , but we could not perform due to the risk of any procedural complication .
there are conflicting opinions in the literature about how wcaa occurs and whether it complicates any coronary ischemic event .
more information is needed to increase the understanding of the nature of this malformation . in conclusion , although woven coronary artery is an exceptionally rare coronary artery anomaly , all interventional cardiologists should keep scad and wcaa in mind during daily practice in the catheterization laboratory .
angiography with multiple projections should be obtained to make a differential diagnosis between iatrogenic dissection , thrombosis , or chronic total occlusion with bridging collaterals . in patients with scad and
wcaa who present with ischemic symptoms , those unresponsive to medical management may benefit from surgical or percutaneous revascularization .
we consider that extensive understanding of the woven coronary artery can reduce the risk of unnecessary intervention , which inherently exposes the patients .
although wcaa appear to be benign coronary anomalies without any major adverse cardiovascular events , we need more data to delineate the natural history of this malformation exactly . | spontaneous coronary artery dissection ( scad ) and woven coronary artery anomaly ( wcaa ) are relatively rare .
a few of the previously reported woven coronary artery cases have involved in a single coronary artery .
we present an unusual woven case involving all coronary arteries and two patient with scad .
we have also reviewed the literature related to these disease , as they resemble one another . | <s>[INST]spontaneous coronary artery dissection ( scad ) and woven coronary artery anomaly ( wcaa ) are rare causes of acute coronary syndrome or sudden cardiac death .
the incidence of scad is about 0.1% for patients who are referred for coronary angiography , and many believe this to be underestimated;1)2 ) on the other hand , the incidence of wcaa is unknown .
wcaa is an extremely rare anomaly characterized by the branching of a major epicardial coronary artery into thin channels , which then merge again in a normal conduit.3 ) the clinical presentation of both diseases depend on the location and severity of coronary involvement .
a 60-year - old female was presented to the cardiology department with stable angina pectoris that she had experienced for one year .
she had been diagnosed with portal vein thrombosis due to protein c deficiency , hypertension and hyperlipidemia .
cardiac catheterization showed a spiral dissection of the proximal right coronary artery ( rca ) , extending downwards to just below the right ventricle branch ( fig .
ventriculography showed hypokinesis of the inferior wall , and the left ventricle ejection fraction ( lvef ) was 45% .
a 2.7530 mm drug - eluting stent was successfully placed along the dissection , reducing the rca to a single lumen ( fig .
the patient was administered on warfarin , clopidogrel , perindopril and beta - blocker on discharge . at 12 weeks follow - up
a 52-year - old man was presented with stable angina pectoris that lasted for two months .
we performed coronary angiography because of the positive treadmill exercise test , and the coronary angiogram surprisingly revealed diffuse dissection that originated on the proximal bed of the second obtuse marginal - ii branch and extending to its distal bed ( fig .
3 ) . we did not perform coronary angioplasty due to technical difficulties and the narrowness of the ischemia - related artery .
the patient 's history revealed a previous right carotid artery occlusion , hyperlipidemia , hypertension and severe smoking .
the patient had been on clopidogrel , aspirin , and lisinopril for the last two months .
the patient exhibited no ischemic ecg changes , but we determined an abnormal st - segment depression on exercise testing .
subsequent coronary angiogram showed a dual twisted lumen in the proximal and medial segments of all coronary arteries ( figs . 4 , 5 , and 6 ) , and ventriculography revealed normal wall motion and lvef of 65% .
the patient 's right carotid angiography showed an occlusion , and other vessels were normal on ct angiogram .
there have been no cases reported in the literature with wcaa involving all coronary arteries .
the patient was evaluated for revascularization due to ischemic findings , but thallium-201 myocardial perfusion imaging did not show ischemia .
we did not perform optical coherance tomography ( oct ) due to the probability of coronary dissection or occlusion caused by guidewire or oct catheter .
the patient was discharged receiving 81 mg of aspirin and 75 mg of clopidogrel once a day .
a 60-year - old female was presented to the cardiology department with stable angina pectoris that she had experienced for one year .
she had been diagnosed with portal vein thrombosis due to protein c deficiency , hypertension and hyperlipidemia .
cardiac catheterization showed a spiral dissection of the proximal right coronary artery ( rca ) , extending downwards to just below the right ventricle branch ( fig .
ventriculography showed hypokinesis of the inferior wall , and the left ventricle ejection fraction ( lvef ) was 45% .
a 2.7530 mm drug - eluting stent was successfully placed along the dissection , reducing the rca to a single lumen ( fig .
the patient was administered on warfarin , clopidogrel , perindopril and beta - blocker on discharge . at 12 weeks follow - up
a 52-year - old man was presented with stable angina pectoris that lasted for two months .
we performed coronary angiography because of the positive treadmill exercise test , and the coronary angiogram surprisingly revealed diffuse dissection that originated on the proximal bed of the second obtuse marginal - ii branch and extending to its distal bed ( fig .
3 ) . we did not perform coronary angioplasty due to technical difficulties and the narrowness of the ischemia - related artery .
the patient 's history revealed a previous right carotid artery occlusion , hyperlipidemia , hypertension and severe smoking .
the patient had been on clopidogrel , aspirin , and lisinopril for the last two months .
the patient exhibited no ischemic ecg changes , but we determined an abnormal st - segment depression on exercise testing .
subsequent coronary angiogram showed a dual twisted lumen in the proximal and medial segments of all coronary arteries ( figs . 4 , 5 , and 6 ) , and ventriculography revealed normal wall motion and lvef of 65% .
the patient 's right carotid angiography showed an occlusion , and other vessels were normal on ct angiogram .
there have been no cases reported in the literature with wcaa involving all coronary arteries .
the patient was evaluated for revascularization due to ischemic findings , but thallium-201 myocardial perfusion imaging did not show ischemia .
we did not perform optical coherance tomography ( oct ) due to the probability of coronary dissection or occlusion caused by guidewire or oct catheter .
the patient was discharged receiving 81 mg of aspirin and 75 mg of clopidogrel once a day .
although it is a very rare clinical event , scad is most frequently associated with pregnant women or those in the postpartum and commonly seen in middle age , but is not infrequent in older patients.1)2)4 ) the precise aetiology and the mechanism of scad during pregnancy is uncertain .
peripartum episodes suggest hemodynamic stress of pregnancy , changes in connective tissue caused by high estrogen levels , and inflammatory changes due to infiltration of eosinophils in the adventitia of the vessel.4 - 6 ) a united states population - based study7 ) on all - cause acute myocardial infarction ( ami ) in pregnancy estimated an incidence of one ami in every 16129 pregnancies , with a mortality rate reported at 5.1% .
eighty percent of reported cases of scad occur in women with no history of heart disease or cardiovascular risk factors , and typically in the left anterior descending artery ; men tend to present with rca dissections .
of the women with scad , one - third are in the peripartum period.8 - 10 ) the disease also has higher prevalance among cases with collagen disorders , cocaine abuse , severe hypertension , smoking , and oral contraceptives.11 ) coronary artery dissection can be seen spontaneously as a consequence of coronary angiography , coronary intervention , cardiac surgery or chest trauma .
the clinical presentation of scad relates to the extent and rate of dissection , as well as the degree of myocardial ischemia .
sudden cardiac death occurs in about 50% of cases , mostly in those with left main coronary artery dissection.12 ) for the diagnosis of scad , diagnostic coronary angiography is generally the standard method , as well as multidetector computerized coronary angiography .
intravascular ultrasound may also be useful , but experience with this technique is still very limited .
when the separated intimal - medial layer pushes toward the true lumen of the vessel , the insuefficient flow of the coronary artery leads to distal myocardial ischemia and its clinical consequences . in some cases
, the false lumen may also recover spontaneously and the true lumen may supply sufficient blood to the distal beds .
compression of the vessel lumen can result from haemorrhage and haematoma between the outer media and external elastic lamina . according to the national heart , lung , and blood institute grade system developed by the coronary angioplasty registry , dissections : can be classified a - f .
type a and b dissections are characterized by filling the defects on contrast injection where there is no or minimal persistence of contrast after the dye has cleared ; type c dissections present as dye staining in an extraluminal cap ; type d is seen as a spiral luminal defect ; type e is detected as persistent luminal defects ; and type f involves total luminal occlusion.13 ) treatment of scad has not been described well ; management should be decided individually for each case , and includes medical therapy , percutaneous coronary intervention ( pci ) or coronary artery bypass graft ( cabg ) surgery . at any rate ,
some authors have advised that asymptomatic patients with a non - occlusive dissection could be managed conservatively.14 ) fibrinolytics , which may provoke bleeding or dissection progression , should be avoided.15 ) although , many dissections are not amenable to catheter interventions , pci can be considered , especially for prominent major single - vessel disease with short segment involvement ; this should be performed cautiously due to the possibility of false lumen or propagating the dissection distally .
medical management includes heparin , antiplatelets , and anti - ischaemic medications , such as beta - blockers and nitrates .
multivessel or left main scad should be managed with cabg.16 ) woven coronary artery anomaly is associated with multiple and twisted thin channels along the vessel in any coronary artery with a timi iii blood flow distally ; these then merge again in order to form the main lumen , after twisting along the coronary artery axis .
the differential diagnosis between scad and wcaa may be very difficult for invasive cardiologists , especially in patients with single or two coronary artery involvement , as the occurence of wcaa is very rare . in the differential diagnosis , in case of the flow is suprisingly normal reflecting the extension of the apparent filling defects and/or there is not any ischemic event , wcaa should be taken into consideration . for better diagnosis
, angiography should be performed using multiple projections with a careful radiological examination ( digital zooming ) .
there has only been one case involving infarct - related wcaa in the literature,17 ) and no wcaa case in which pci was performed . in a case with wcaa involving circumflex artery , reported by kursaklioglu et al.18 )
wcaa have been accepted as a benign entity and no adverse coronary event occured in the long - term follow - up period , due to timi iii blood flow until now and it may demonstrate generally normal coronary reserve with a stress test because of normal blood flow distal to the anomalous segment.18 - 20 ) some authors believed that wcaa may originate from scad and the twisting of thin channels probably causes intracoronary thrombus.20 ) as distinct from the cases reported in the literature,17 - 20 ) involving the right or circumflex artery alone , we present a very interesting wcaa , involving all coronary arteries
. it would be helpful to have the examination by oct , but we could not perform due to the risk of any procedural complication .
there are conflicting opinions in the literature about how wcaa occurs and whether it complicates any coronary ischemic event .
more information is needed to increase the understanding of the nature of this malformation . in conclusion , although woven coronary artery is an exceptionally rare coronary artery anomaly , all interventional cardiologists should keep scad and wcaa in mind during daily practice in the catheterization laboratory .
angiography with multiple projections should be obtained to make a differential diagnosis between iatrogenic dissection , thrombosis , or chronic total occlusion with bridging collaterals . in patients with scad and
wcaa who present with ischemic symptoms , those unresponsive to medical management may benefit from surgical or percutaneous revascularization .
we consider that extensive understanding of the woven coronary artery can reduce the risk of unnecessary intervention , which inherently exposes the patients .
although wcaa appear to be benign coronary anomalies without any major adverse cardiovascular events , we need more data to delineate the natural history of this malformation exactly .[/INST]spontaneous coronary artery dissection ( scad ) and woven coronary artery anomaly ( wcaa ) are relatively rare .
a few of the previously reported woven coronary artery cases have involved in a single coronary artery .
we present an unusual woven case involving all coronary arteries and two patient with scad .
we have also reviewed the literature related to these disease , as they resemble one another .</s> |
irritable bowel syndrome ( ibs ) affects 520% of individuals worldwide , most often women < 50 years of age .
similarly , endometriosis is very common in this same population , affecting up to 15% of menstruating women .
gastrointestinal involvement in endometriosis occurs in only 37% of cases , mostly in the rectosigmoid region and only very rarely in the small intestine .
typically endometriosis patients complain of dysmenorrhea , pelvic pain , ovulation pain , dyspareunia and dyschezia , while patients with ibs complain of abdominal pain associated with a change in the frequency or consistency of stools and abdominal bloating .
alarm symptoms , which might indicate another diagnosis but are non - specific , include : fever , weight loss , blood in the stools , anemia , abnormal physical findings , abnormal blood tests , and a family history of cancer , inflammatory bowel disease or celiac disease .
we present the case of a young woman with a 4-year history of ibs on the basis of abdominal pain associated with constipation , flatus , belching and bloating without gynecological symptoms , and who was eventually discovered to have endometriosis following surgery for a distal ileal stricture .
a 44-year - old woman noted the onset of upper and lower abdominal pain associated with constipation approximately 4 years ago .
her symptoms were worse following meals , especially if they included fried foods , fatty foods , coffee or carbonated beverages .
episodes occurred every 23 days with occasional emesis but no history of hematemesis , melena or hematochezia .
her appetite remained good , but she noted a weight loss of 25 lb over the past year .
there was no history of alcohol , coffee , aspirin or non - steroidal inflammatory medication abuse .
on physical examination she appeared to be well - developed , well - nourished and in no acute distress .
rectal examination demonstrated no masses or tenderness , with brown guaiac negative stool present in the rectal ampulla .
her diagnostic work - up included normal complete blood count , liver and kidney function tests , thyroid function and c - reactive protein .
abdominal and pelvic sonography were normal except for evidence of a prior cholecystectomy , mild fatty liver and a simple right ovarian cyst .
a lactose tolerance test was positive . on the basis of her symptoms and negative diagnostic work - up , the diagnoses of ibs
treatment with antacids and an anti - cholinergic did not provide relief . due to her recurrent symptoms ,
this revealed a partial small bowel obstruction located approximately 5 cm proximal to the ileocecal valve ( fig .
1 ) . subsequent surgical resection and histology identified the cause of the partial obstruction to be endometriosis with focal submucosal hemorrhage and serosal scarring ( fig .
endometriosis most commonly presents with gynecological symptoms of intermenstrual bleeding , premenstrual exacerbation of pain and forniceal tenderness , while ibs symptoms include more upper abdominal pain , colicky pain and exacerbation of pain by food or stress , as seen in this patient .
our patient met the rome iii diagnostic criteria for ibs with onset greater than 6 months of abdominal discomfort for at least 3 days per month over the past 3 months plus a change in stool frequency ( constipation ) and appearance ( small hard stools ) , except for the alarm symptom of weight loss .
other possible alarm symptoms include older age at symptom onset , gastrointestinal bleeding , dysphagia , anemia , fever and family history of cancer .
even with the presence of an alarm symptom , most patients are clinically considered to have ibs if symptom - guided testing is negative , and our patient underwent upper endoscopy , colonoscopy , abdominal sonography , pelvic sonography and gynecological examinations , all of which failed to reveal any other diagnoses .
a large chart review of 1,434 patients with a clinical diagnosis of ibs revealed alarm features in 84% , yet only 79% of them were found to have organic disease . in a study of 200 consecutive patients with a clinical diagnosis of an ibs who were prospectively evaluated ,
70% had alarm symptoms , but significant organic disease could only be found in 5% , with another 20% having bacterial overgrowth , lactose or fructose malabsorption .
an analysis of multiple studies involving diagnostic testing in patients with a clinical diagnosis the ibs concluded that the probability of finding organic disease was < 1% ; only celiac disease was found to be markedly higher than in the general population .
the significance of weight loss , defined as at least 5% decrease in body weight over 612 months as seen in our patient , is uncertain .
one review of published studies involving 881 patients found that in older patients ( ages 5972 ) the three most common causes of unexplained weight loss were malignancy , gastrointestinal disorders and psychiatric problems , yet despite extensive evaluation and prolonged follow - up , no diagnosis could be made in 536% of patients .
another review on the evaluation of weight loss in adults of all ages found that approximately 25% of patients will not have any diagnosis after testing and follow - up for at least 6 months , and of the remaining 75% approximately one third will have a malignancy , one third hyperthyroidism , diabetes , peptic ulcer disease or cholelithiasis , and one third will have a psychiatric disorder . in a prospective study of 101 patients with unexplained weight loss presenting to a general internal medicine clinic , no etiology could be found in 28% after 9 months , and additionally 94% of patients with no baseline abnormality on standard laboratory tests , chest x - ray and abdominal sonography were not found to have an organic disease as the cause . in conclusion , both ibs and endometriosis are very common among young women of child - bearing age .
endometriosis can often be diagnosed only by laparoscopic examination of the abdomen and pelvis , often leading to a delay in diagnosis .
alarm symptoms are used to cull out patients with other organic diseases , but are often not sufficiently reliable .
furthermore weight loss , which was the only alarm symptom present in our patient , can be non - specific in many cases . yet , as our patient illustrates , the presence of any alarm symptom in a young woman considered to have ibs should lead to close continued clinical follow - up and constant vigilance for other possible unusual causes of the presenting symptoms , including endometriosis .
| both endometriosis and irritable bowel syndrome ( ibs ) are commonly found in young women and the diagnosis of either is challenging .
alarm symptoms can exclude the diagnosis of ibs , but their onset may be insidious and often no evidence of organic disease may be found .
we present a patient with a 4-year history of presumed ibs , absent gynecological symptoms , negative gastrointestinal as well as gynecological testing who developed the only alarm symptom of weight loss and was eventually found to have endometriosis of the small intestine .
this case illustrates the need for constant vigilance in patients with ibs . | <s>[INST]irritable bowel syndrome ( ibs ) affects 520% of individuals worldwide , most often women < 50 years of age .
similarly , endometriosis is very common in this same population , affecting up to 15% of menstruating women .
gastrointestinal involvement in endometriosis occurs in only 37% of cases , mostly in the rectosigmoid region and only very rarely in the small intestine .
typically endometriosis patients complain of dysmenorrhea , pelvic pain , ovulation pain , dyspareunia and dyschezia , while patients with ibs complain of abdominal pain associated with a change in the frequency or consistency of stools and abdominal bloating .
alarm symptoms , which might indicate another diagnosis but are non - specific , include : fever , weight loss , blood in the stools , anemia , abnormal physical findings , abnormal blood tests , and a family history of cancer , inflammatory bowel disease or celiac disease .
we present the case of a young woman with a 4-year history of ibs on the basis of abdominal pain associated with constipation , flatus , belching and bloating without gynecological symptoms , and who was eventually discovered to have endometriosis following surgery for a distal ileal stricture .
a 44-year - old woman noted the onset of upper and lower abdominal pain associated with constipation approximately 4 years ago .
her symptoms were worse following meals , especially if they included fried foods , fatty foods , coffee or carbonated beverages .
episodes occurred every 23 days with occasional emesis but no history of hematemesis , melena or hematochezia .
her appetite remained good , but she noted a weight loss of 25 lb over the past year .
there was no history of alcohol , coffee , aspirin or non - steroidal inflammatory medication abuse .
on physical examination she appeared to be well - developed , well - nourished and in no acute distress .
rectal examination demonstrated no masses or tenderness , with brown guaiac negative stool present in the rectal ampulla .
her diagnostic work - up included normal complete blood count , liver and kidney function tests , thyroid function and c - reactive protein .
abdominal and pelvic sonography were normal except for evidence of a prior cholecystectomy , mild fatty liver and a simple right ovarian cyst .
a lactose tolerance test was positive . on the basis of her symptoms and negative diagnostic work - up , the diagnoses of ibs
treatment with antacids and an anti - cholinergic did not provide relief . due to her recurrent symptoms ,
this revealed a partial small bowel obstruction located approximately 5 cm proximal to the ileocecal valve ( fig .
1 ) . subsequent surgical resection and histology identified the cause of the partial obstruction to be endometriosis with focal submucosal hemorrhage and serosal scarring ( fig .
endometriosis most commonly presents with gynecological symptoms of intermenstrual bleeding , premenstrual exacerbation of pain and forniceal tenderness , while ibs symptoms include more upper abdominal pain , colicky pain and exacerbation of pain by food or stress , as seen in this patient .
our patient met the rome iii diagnostic criteria for ibs with onset greater than 6 months of abdominal discomfort for at least 3 days per month over the past 3 months plus a change in stool frequency ( constipation ) and appearance ( small hard stools ) , except for the alarm symptom of weight loss .
other possible alarm symptoms include older age at symptom onset , gastrointestinal bleeding , dysphagia , anemia , fever and family history of cancer .
even with the presence of an alarm symptom , most patients are clinically considered to have ibs if symptom - guided testing is negative , and our patient underwent upper endoscopy , colonoscopy , abdominal sonography , pelvic sonography and gynecological examinations , all of which failed to reveal any other diagnoses .
a large chart review of 1,434 patients with a clinical diagnosis of ibs revealed alarm features in 84% , yet only 79% of them were found to have organic disease . in a study of 200 consecutive patients with a clinical diagnosis of an ibs who were prospectively evaluated ,
70% had alarm symptoms , but significant organic disease could only be found in 5% , with another 20% having bacterial overgrowth , lactose or fructose malabsorption .
an analysis of multiple studies involving diagnostic testing in patients with a clinical diagnosis the ibs concluded that the probability of finding organic disease was < 1% ; only celiac disease was found to be markedly higher than in the general population .
the significance of weight loss , defined as at least 5% decrease in body weight over 612 months as seen in our patient , is uncertain .
one review of published studies involving 881 patients found that in older patients ( ages 5972 ) the three most common causes of unexplained weight loss were malignancy , gastrointestinal disorders and psychiatric problems , yet despite extensive evaluation and prolonged follow - up , no diagnosis could be made in 536% of patients .
another review on the evaluation of weight loss in adults of all ages found that approximately 25% of patients will not have any diagnosis after testing and follow - up for at least 6 months , and of the remaining 75% approximately one third will have a malignancy , one third hyperthyroidism , diabetes , peptic ulcer disease or cholelithiasis , and one third will have a psychiatric disorder . in a prospective study of 101 patients with unexplained weight loss presenting to a general internal medicine clinic , no etiology could be found in 28% after 9 months , and additionally 94% of patients with no baseline abnormality on standard laboratory tests , chest x - ray and abdominal sonography were not found to have an organic disease as the cause . in conclusion , both ibs and endometriosis are very common among young women of child - bearing age .
endometriosis can often be diagnosed only by laparoscopic examination of the abdomen and pelvis , often leading to a delay in diagnosis .
alarm symptoms are used to cull out patients with other organic diseases , but are often not sufficiently reliable .
furthermore weight loss , which was the only alarm symptom present in our patient , can be non - specific in many cases . yet , as our patient illustrates , the presence of any alarm symptom in a young woman considered to have ibs should lead to close continued clinical follow - up and constant vigilance for other possible unusual causes of the presenting symptoms , including endometriosis .
[/INST]both endometriosis and irritable bowel syndrome ( ibs ) are commonly found in young women and the diagnosis of either is challenging .
alarm symptoms can exclude the diagnosis of ibs , but their onset may be insidious and often no evidence of organic disease may be found .
we present a patient with a 4-year history of presumed ibs , absent gynecological symptoms , negative gastrointestinal as well as gynecological testing who developed the only alarm symptom of weight loss and was eventually found to have endometriosis of the small intestine .
this case illustrates the need for constant vigilance in patients with ibs .</s> |
The first open enrollment season of Obamacare ended at midnight Monday, a day that saw millions of Americans click onto Obamacare sign-up portals, dial into call centers and stand in long lines at assistance sites nationwide. The huge surge made it increasingly likely that enrollment would hit 7 million, the finish line that seemed out of reach during much of the often rocky six-month period.
Shortly after 10 p.m., the Associated Press cited two sources that said sign-ups were “on track” to hit 7 million. Administration officials wouldn’t confirm the number but said that signs were pointing in that direction.
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The HealthCare.Gov website took down enrollment forms just after midnight and displayed a new message that will transition people into a “special enrollment” period.
“Don’t worry,” it said. “We’ll still help you get the coverage you need for this year.”
(CARTOONS: Matt Wuerker on Obamacare)
Federal health officials said the site would reappear in a new guise Tuesday morning with instructions for post-March 31 sign-ups. Those will be open to people who self-report that they tried to make the deadline but failed. Depending on how long special enrollment goes on, enrollment numbers could still rise significantly.
The last official day of the Obamacare coverage push was hit by a double whammy of new HealthCare.gov glitches that caused confusion and delay. The federal website was down for six hours early Monday morning. Then it was up. Then it activated its “virtual waiting room.” Then it blocked newcomers from creating accounts.
Then it was working again, with officials reporting more than 1.6 million visitors by 2 p.m. and more than 3 million by 8 p.m. State exchanges reported similar surges. The federal site queued visitors when traffic rose, offering them a chance to get an email notification when the site would be less congested. It held through the night, despite the crush of visitors.
(WATCH: Timeline of Obamacare deadlines)
State-run exchanges are also giving grace periods to people who started but didn’t finish. Some have set stricter criteria for the extensions than others.
The technical problems, a flashback to HealthCare.gov’s botched launch last October, weren’t the focus the White House wanted as it tried to spur more Americans to be part of the late enrollment momentum. The intensity and tone of the White House messaging over these last days had evoked a confident turnout push on the eve of a close election. Suddenly it was about the glitchy website once again.
But as the day wore on, the final surge kept growing — although it will be some time before it is known precisely how many of these people will finalize their enrollment by paying their premiums, how many were previously uninsured, and, perhaps most important, how many end up liking their new coverage well enough to help Democrats construct a counter narrative.
(Also on POLITICO: The Obamacare enthusiasm gap)
Numerous polls show the law remains controversial and unpopular, and the Republicans have steadily blamed the Affordable Care Act for harming the economy, raising costs, killing jobs and depriving people of access to doctors of their choice. Even some moderate Democrats, facing tough reelection fights, want to change aspects of the four-year-old law.
Administration officials again hit the road and the airwaves Monday, touting the benefits of subsidized health insurance and celebrating the historic sign-up momentum. President Barack Obama was in Italy and Saudi Arabia last week and hasn’t given enrollment an in-person nudge since his return. But the White House released humorous photos of him and first lady Michelle Obama and even the family dogs Bo and Sunny urging everyone to get covered.
Vice President Joe Biden appeared on the “Rachael Ray Show,” talking health care — and skin care. “I think everyone is going to be surprised and pleased at how this has turned out,” the ever-garrulous vice president said in pre-recorded comments that sounded discordant against the surprise headlines about website woes. Later, Biden went to a school in Washington where people were getting help with their applications and thanked everyone.
“You are going to be better off for it. The country is going to be better off for it. So thank you,” he told them.
Enrollment had surpassed the revised 6 million threshold as of last Wednesday. ||||| As the clock ticks down on open enrollment for new coverage options under the Affordable Care Act (ACA), the latest Kaiser Health Tracking Poll finds that six in ten of the uninsured are unaware of the March 31 deadline to sign up for coverage. When reminded of the deadline and the fine for not getting covered, half of those who lack coverage as of mid-March say they plan to remain uninsured. Meanwhile, four in ten of the uninsured are still unaware of the law’s subsidies to help lower-income Americans purchase coverage, and half don’t know about the law’s expansion of Medicaid. Among the public overall, general opinion of the ACA moved in a more positive direction this month for the first time since November’s post-rollout negative shift in opinion. While unfavorable views of the law continue to outpace favorable ones, the gap between negative and positive views now stands at eight percentage points, down from 16 percentage points in January. Four years after the ACA’s passage, a little over half the public says they are tired of hearing the national debate over the law and want the country to focus more on other things, while four in ten say it’s important for the debate to continue. At the same time, six in ten want Congress to keep the law in place and either leave it as is or work to improve it, while three in ten would prefer to see it either repealed and replaced with a Republican alternative or repealed and not replaced.
Most uninsured unaware of March 31 deadline, half plan to remain uninsured
In the final days of open enrollment for new health insurance options under the ACA, substantial shares of the uninsured remain unaware of the law’s individual mandate and the looming deadline to sign up for coverage. A third of those who lack coverage as of mid-March are unaware that the law requires nearly all Americans to have health insurance or pay a fine. When it comes to the specifics, four in ten of the uninsured (39 percent) are aware that the deadline to sign up for coverage is at the end of March, leaving about six in ten unaware of the March deadline.
When reminded of the mandate and the deadline, half of those without coverage as of mid-March say they think they will remain uninsured, while four in ten expect to obtain coverage and one in ten are unsure.
A third (33 percent) of the uninsured say they have tried to get insurance for themselves in the past 6 months, including 18 percent who report attempting to get coverage through a health insurance marketplace, 14 percent from Medicaid, and 13 percent directly from a private insurance company. Still, the large majority – 67 percent – say they have not attempted to get coverage.
FIGURE 2: One-Third Of Uninsured Report Trying To Get Coverage In Past 6 Months AMONG THE UNINSURED AGES 18-64: Have you tried to get insurance for yourself in the past 6 months, or not? [If yes: From which of the following sources have you tried to get health insurance?] Yes, have tried to get insurance in past 6 months 33% Through the health insurance marketplace set up under the health care law* 18 From Medicaid* 14 Directly from a private insurance company* 13 From an employer* 9 From some other source* 2 No, have not tried to get insurance 67 * Multiple responses allowed
While some report trying to get coverage from new options available under the ACA, large shares of the uninsured remain unaware of two of the law’s key provisions that could help them get coverage. About half the uninsured are unaware that the ACA gives states the option of expanding their Medicaid programs, and more than four in ten don’t know that it provides financial help to low- and moderate-income individuals to help them purchase coverage. Despite extensive campaigns in media and on the ground attempting to get them enrolled, just one in nine (11 percent) of the uninsured say they have been personally contacted by anyone about the health care law through a phone call, email, text message, or door-to-door visit.
FIGURE 3: Awareness Of Key ACA Provisions Among The Uninsured AMONG THE UNINSURED AGES 18-64: To the best of your knowledge, would you say the health reform law does or does not do each of the following? CORRECT INCORRECT Yes No Don’t Know/Refused Require nearly all Americans to have health insurance or else pay a fine 66% 24% 10% Provide financial help to low and moderate income Americans who don’t get insurance through their jobs to help them purchase coverage 57 32 11 Give states the option of expanding their existing Medicaid program to cover more low-income, uninsured adults 49 33 19
Gap between unfavorable and favorable views shrinks this month, including among uninsured
As the ACA turns four years old, overall public opinion on the law shifted in a more positive direction this month, though unfavorable views still outnumber favorable ones. In March, 46 percent say they have an unfavorable view of the law (down 4 percentage points since January), while 38 percent say they have a favorable view (up 4 percentage points since January). The gap between unfavorable and favorable views is now eight percentage points, down from a recent high of 16 points in November and January.
When those who view the law favorably are asked to say in their own words why they like the law, the most common reason by far is that it will expand access to health care and health insurance (61 percent), followed far behind by a perception that it will make health care more affordable and control costs (10 percent), and that it will be good for the country and people in general (7 percent). Open-ended reasons for unfavorable views are more widely dispersed, the most common being concerns about costs (23 percent), opposition to the individual mandate (17 percent), and concerns about government overreach (10 percent).
FIGURE 5: In Their Own Words: Reasons For Favorable Views AMONG THE 38% WHO HAVE A FAVORABLE VIEW: Could you tell me in your own words what is the main reason you have a favorable opinion of the health reform law? Category Percent Mentioning Quotes Expanding access to care and insurance 61% “Because it allows people without insurance the ability to get insurance.�? “Because a lot of people who otherwise would not have insurance will now have it.�? “Because I am able to keep my health insurance with my parents until age 26.�? Will make health care more affordable/control costs/lower costs 10 “Because it makes health insurance affordable for people without insurance.�? “Because I think the health care system was too costly and the affordable health care act will cut costs.�? Country/people will be better off generally 7 “It makes health care better for Americans.�? “it is beneficial to the general public.�?
FIGURE 6: In Their Own Words: Reasons For Unfavorable Views AMONG THE 46% WHO HAVE AN UNFAVORABLE VIEW: Could you tell me in your own words what is the main reason you have an unfavorable opinion of the health reform law? Category Percent Mentioning Quotes Cost concerns 23% “It’s too expensive for regular people.�? “it’s costing too much money. It’s supposed to help people with low incomes and it’s not.�? “Because it’s a financial hardship on the U.S.�?
Opposed to individual mandate/ Unconstitutional 17 “Don’t think it’s right to penalize people who don’t have health care.�? “It’s unconstitutional, requiring people to have health insurance.�?
Government-related issues 10 “I don’t like the government making personal decisions for me.�? “I believe the government should stay out of health care�? “There is too much government in our personal choices.�?
General opinion of the ACA among the uninsured, which had been trending negative for the past several months, also moved in a positive direction this month, returning closer to levels measured at the end of 2013. In March, 45 percent of the uninsured say they have an unfavorable view of the law (compared to 56 percent in February) and 37 percent have a favorable view (up sharply from 22 percent last month). Opinion among the uninsured in tracking polls has shown more month-to-month variation over time than among the total public, at least in part due to the relatively smaller sample size for this subgroup, but this month’s poll finds a clear change in direction, with attitudes shifting more positively towards the law after trending in a negative direction for several months. As more Americans gain coverage under the law, we can expect the group who remain uninsured to change over time, and some changes in opinion may be attributable to changes in who remains uninsured, rather than a shift in opinion among individuals.
The large majority of the public still gives both the federal government and their own state government a rating of “only fair�? or “poor�? when it comes to implementing the ACA, though ratings for both have inched up slightly since the end of 2013. Twenty-four percent now say the federal government is doing an “excellent�? or “good�? job, up 8 percentage points since December, and 28 percent now give a positive rating to their state government, up 5 percentage points in the same time frame. Positive ratings for state governments are also somewhat higher in states operating their own health care marketplace (37 percent say “excellent�? or “good�?) than in states that defaulted to the federal marketplace (24 percent).
FIGURE 8: Federal And State Governments Get Poor Ratings For ACA Implementation Regardless of whether you support or oppose the health care law, how good a job would you say (INSERT) is doing implementing the law? The federal government Your state government Total public Total public Among those in states operating their own marketplace Among those in states defaulting to the federal marketplace* NET Excellent/Good 24% 28% 37% 24% Excellent 4 5 9 3 Good 20 23 28 21 NET Only fair/Poor 72% 59% 51% 62% Only fair 33 33 32 33 Poor 39 26 19 29 Don’t know/Refused 4% 14% 12% 14% *includes states with a state-federal partnership exchange
Over half report having personal conversations about ACA, but similar share are weary of national debate
The ACA was a common topic of personal conversations this month, and the public reports that the tone of those conversations was mostly negative. Just over half the public (55 percent) say they had at least one conversation about the law with friends or family in the past month, up from 31 percent in January 2012 (the last time this question was asked). About half those who say they discussed the law with friends or family (28 percent of the public overall) report hearing mostly bad things about the law in these discussions, while a much smaller share (5 percent of the public overall) say they heard mostly good things and the remainder say it was a mix of the two.
While personal conversations may be on the rise, many Americans appear to be weary of the national debate about the law. Just over half the public (53 percent) say they’re tired of hearing about the debate over the ACA and want the country to focus more on other issues, while about four in ten (42 percent) say they think it’s important for the country to continue the debate. Democrats and those with a favorable view of the law are more likely to say they’re tired of hearing about the debate, while Republicans and those who view the law unfavorably are more evenly split between those who are tired of hearing about it and those who want the debate to continue.
Perhaps reflecting this sense that the debate has gone on long enough, more of the public would like to see Congress keep the law in place and work to improve it (49 percent) or keep it as is (10 percent) rather than repeal it and replace it with a Republican-sponsored alternative (11 percent) or repeal it outright (18 percent).
Individual provisions mostly popular, including across parties, though many are not very well-known
As previous Kaiser tracking polls have found, many of the ACA’s major provisions continue to be quite popular, including across party lines. For example, large shares of Americans – including at least seven in ten overall and at least six in ten Democrats, Republicans, and independents – have a favorable view of the fact that the law allows young adults to stay on their parents’ insurance plans up to age 26, closes the Medicare “doughnut hole�? for prescription drug coverage, provides subsidies to low- and moderate-income Americans to help them purchase coverage, eliminates cost-sharing for preventive services, gives states the option of expanding Medicaid, and prohibits insurance companies from denying coverage based on pre-existing conditions. Nearly as many (including a majority across parties) have a favorable view of the “medical loss ratio�? provision that requires insurance companies to give their customers a rebate if they spend too little money on services and too much on administration and profits. Somewhat more divisive is the law’s Medicare payroll tax on earnings for upper-income Americans, which is viewed favorably by about three-quarters of Democrats and just over half of independents, but just a third of Republicans.
The glaring exception to the popularity of individual provisions of the law is the requirement that nearly all Americans have health insurance or pay a fine, which is viewed unfavorably by roughly two-thirds of the public.
FIGURE 12: Many Elements Of ACA Continue To Be Popular Across Parties Percent who say they have a FAVORABLE opinion of each provision of the law Total Public Democrat Independent Republican Extension of dependent coverage 80% 87% 76% 76% Close Medicare “doughnut hole�? 79 89 75 73 Subsidy assistance to individuals 77 89 74 65 Eliminate out-of-pocket costs for preventive services 77 81 76 75 Medicaid expansion 74 89 69 62 Guaranteed issue 70 74 70 69 Medical loss ratio 62 68 64 54 Increase Medicare payroll tax on upper income 56 77 54 33 Individual mandate/penalty 35 56 31 16 Note: Question wording abbreviated. For full question wording, see survey topline.
At the same time that the public reports having a favorable view of many of the component parts of the ACA, large shares remain unaware that the law actually does some of these things. A few of the law’s provisions are both popular and relatively well-known – for example, 71 percent are aware that the law extends dependent coverage up to age 26, and eight in ten have a favorable view of this provision. More than half are also aware of several other popular provisions, including the law’s subsidy assistance to low and moderate income individuals (63 percent), Medicaid expansion (60 percent), and the so-called “guaranteed issue�? provision that prohibits insurance companies from denying coverage based on health status (54 percent). Yet, in each of these three cases, the share who are aware of the provision lags roughly 15 percentage points behind the share who view it favorably.
Two other popular provisions are even less well-known. Fewer than half (43 percent) are aware that the law eliminates out-of-pocket costs for preventive services, and just four in ten (40 percent, including 38 percent of seniors) know that it gradually closes the Medicare prescription drug “doughnut hole.�? At the other end of the spectrum, the law’s least popular provision – the individual mandate – is widely recognized, with nearly eight in ten (78 percent) correctly answering that the ACA requires nearly all Americans to have health insurance or else pay a fine.
Misperceptions also persist about things the ACA does not actually do. For example, nearly half the public (46 percent) think the law allows undocumented immigrants to receive financial help from the government to buy health insurance, and another two in ten (22 percent) are unsure whether it does. A third of the public (34 percent, including 32 percent of seniors) believe the law establishes a government panel to make decisions about end-of-life care for people on Medicare, with another quarter saying they are unsure (23 percent of the public, 25 percent of seniors). ||||| You incur the fine by not signing up by the Monday, March 31, deadline, but most people wouldn’t actually pay the penalty until they file their 2014 returns, which typically happens in 2015. The IRS can collect it by reducing the size of your refund. The IRS can collect it by reducing the size of your refund, but many of its other enforcement mechanisms such as levies are not available. So, it does seem to be possible to avoid the penalty by making sure you don’t have a refund due, but many of the people in the penalty demographic typically do receive refunds. A lot of people without health insurance who would be subject to a penalty benefit from tax credits that would typically give rise to a refund. These individuals could adjust their withholding to avoid a refund, but that seems unlikely in most cases. ||||| Skip in Skip x Embed x Share CLOSE Healthcare.gov saw millions of visitors in the days leading up to the deadline to enroll: midnight on March 31. But Republican critics say that's not an accurate reflection of how people feel about the Affordable Care Act.
The home screen for HealthCare.gov announces the deadline for sign-ups. (Photo: Jon Elswick, AP)
WASHINGTON — The federal government's health care enrollment website — HealthCare.gov — went down briefly early Monday for extended maintenance as heavy traffic was building on the last day of open enrollment for 2014.
At one point, the site told visitors that it was "down for maintenance" and asked people to "please try again later." At other points, visitors were told there was heavy traffic on the system and were asked to remain online in a "virtual waiting room" until they could be connected.
Administration spokesman Aaron Albright said the website undergoes "regular nightly maintenance" during off-peak hours and that period was extended Monday because of a "technical problem."
He did not say what the problem was, but a statement from the Department of Health and Human Services called it "a software bug" unrelated to the volume of prospective applicants.
Albright said the website is typically down for maintenance during the period from 1 a.m. to 5 a.m. ET, and that as a result of the technical problems the site was down for at least three additional hours Monday morning. The site was largely restored by 8 a.m. ET.
TWITTER FIGHT: Obamacare deadline brings out the tweets
The hiccup came as the Obama administration and its allies made a last-minute push to persuade Americans to enroll in health insurance under the Affordable Care Act.
Monday at midnight is the deadline for open enrollment and the last chance to avoid a penalty for not purchasing insurance in 2014, which people will pay with their federal income taxes next year.
Those who start the process — either by working on a paper application with a navigator, attempting to enroll online, or talking with a call center representative — may continue the process after the deadline passes.
Administration officials said interest was surging as the deadline neared. Sunday evening, Health and Human Services announced 2 million visits over the weekend to HealthCare.gov, the federal government's enrollment site.
In the last week alone, the call center handled a record 2.5 million calls, surpassing the 2.4 million it received during the entire month of February.
Over the weekend, HHS Secretary Kathleen Sebelius appeared at a Baptist church in Miami to urge Floridians to sign up before the deadline. She planned a fresh round of television interviews with local stations Monday to boost enrollment numbers.
An interview with Vice President Biden encouraging young people to enroll will air Monday on celebrity chef Rachael Ray's talk show.
"The traffic and energy and interest this weekend shows many more are interested in the coverage," White House spokeswoman Tara McGuinness said Sunday afternoon.
Republicans saw the situation differently.
In an op-ed appearing in Monday's editions of USA TODAY, Sen. Tom Coburn, R-Okla., said the vast majority of enrollees were previously insured. Getting Americans to "re-enroll in insurance is no great achievement," he said, "particularly when many of those customers were forced to give up plans they liked."
Sen. John Barrosso, R-Wyo., said the administration is "cooking the books" on enrollment figures. The real test "is what kind of insurance will those people actually have," he said during an appearance on Fox News Sunday.
President Obama announced Thursday that more than 6 million people had enrolled in the federal and state health exchanges, a goal projected by the Congressional Budget Office to ensure the system is sustainable.
Administration officials have not released updated numbers, but there were signs that enrollment numbers have grown since Thursday's milestone was announced.
State officials in New York said Friday that it had bumped up enrollment in private plans almost 25,000 from the previous week, and 70% of the enrollees had not had insurance before. California has already met its goal, but its executive director, Peter Lee, planned to visit several enrollment sites over the weekend. In Washington, D.C., gospel artist John Kee and songwriter Brittney Wright performed at a "gospel enrollment concert" Friday.
The government will have to wait for the insurers to release payment data, as well as information about the newly insured, to answer. However, some states, such as California, have reported payment rates as high as 85%.
White House officials Sunday released a memo that details the administration's public outreach to tout the law. One example: White House officials, Cabinet secretaries and "celebrity surrogates," including NBA standout Kobe Bryant and actress Kerry Washington, have held more than 300 radio interviews in the last six weeks, officials said.
Contributing: Associated Press
Read or Share this story: http://usat.ly/1ge2Kyl | – As the clock ticked toward ObamaCare's midnight deadline, a second round of glitches hit HealthCare.gov today, this time blocking new users from applying. The site is now back up and running, Politico reports, but its "virtual waiting room was triggered," and the Obama administration reported that as many as 100,000 users at a time were on the site. HealthCare.gov had earlier gone down for maintenance for several hours beginning around 3am ET, with Health and Human Services officials ascribing the outage to a software bug. More last-minute tidbits: We are a nation of procrastinators: Last night, HHS revealed that the site saw 2 million visits over the weekend, and that the ObamaCare call center fielded 2.5 million calls in the last week—compared to 2.4 million for all of February, reports USA Today. Joe Biden is trying to help: By appealing to America's youth via an appearance on Rachael Ray's show today. Today's deadline isn't truly a deadline: As previously reported, would-be enrollees who begin but don't complete the process by today will be granted an extension. The penalty threat: The Wall Street Journal clarifies the specifics: a $95 fine or 1% of your income, whichever is greater. It estimates a couple with two kids bringing in $100,000 a year would pony up about $800—when paying 2014 taxes, which will happen in 2015. The unaware: The Journal points out a Kaiser Health Tracking Poll that this week determined 60% of uninsured Americans aren't aware of today's deadline. | <s>[INST]The first open enrollment season of Obamacare ended at midnight Monday, a day that saw millions of Americans click onto Obamacare sign-up portals, dial into call centers and stand in long lines at assistance sites nationwide. The huge surge made it increasingly likely that enrollment would hit 7 million, the finish line that seemed out of reach during much of the often rocky six-month period.
Shortly after 10 p.m., the Associated Press cited two sources that said sign-ups were “on track” to hit 7 million. Administration officials wouldn’t confirm the number but said that signs were pointing in that direction.
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The HealthCare.Gov website took down enrollment forms just after midnight and displayed a new message that will transition people into a “special enrollment” period.
“Don’t worry,” it said. “We’ll still help you get the coverage you need for this year.”
(CARTOONS: Matt Wuerker on Obamacare)
Federal health officials said the site would reappear in a new guise Tuesday morning with instructions for post-March 31 sign-ups. Those will be open to people who self-report that they tried to make the deadline but failed. Depending on how long special enrollment goes on, enrollment numbers could still rise significantly.
The last official day of the Obamacare coverage push was hit by a double whammy of new HealthCare.gov glitches that caused confusion and delay. The federal website was down for six hours early Monday morning. Then it was up. Then it activated its “virtual waiting room.” Then it blocked newcomers from creating accounts.
Then it was working again, with officials reporting more than 1.6 million visitors by 2 p.m. and more than 3 million by 8 p.m. State exchanges reported similar surges. The federal site queued visitors when traffic rose, offering them a chance to get an email notification when the site would be less congested. It held through the night, despite the crush of visitors.
(WATCH: Timeline of Obamacare deadlines)
State-run exchanges are also giving grace periods to people who started but didn’t finish. Some have set stricter criteria for the extensions than others.
The technical problems, a flashback to HealthCare.gov’s botched launch last October, weren’t the focus the White House wanted as it tried to spur more Americans to be part of the late enrollment momentum. The intensity and tone of the White House messaging over these last days had evoked a confident turnout push on the eve of a close election. Suddenly it was about the glitchy website once again.
But as the day wore on, the final surge kept growing — although it will be some time before it is known precisely how many of these people will finalize their enrollment by paying their premiums, how many were previously uninsured, and, perhaps most important, how many end up liking their new coverage well enough to help Democrats construct a counter narrative.
(Also on POLITICO: The Obamacare enthusiasm gap)
Numerous polls show the law remains controversial and unpopular, and the Republicans have steadily blamed the Affordable Care Act for harming the economy, raising costs, killing jobs and depriving people of access to doctors of their choice. Even some moderate Democrats, facing tough reelection fights, want to change aspects of the four-year-old law.
Administration officials again hit the road and the airwaves Monday, touting the benefits of subsidized health insurance and celebrating the historic sign-up momentum. President Barack Obama was in Italy and Saudi Arabia last week and hasn’t given enrollment an in-person nudge since his return. But the White House released humorous photos of him and first lady Michelle Obama and even the family dogs Bo and Sunny urging everyone to get covered.
Vice President Joe Biden appeared on the “Rachael Ray Show,” talking health care — and skin care. “I think everyone is going to be surprised and pleased at how this has turned out,” the ever-garrulous vice president said in pre-recorded comments that sounded discordant against the surprise headlines about website woes. Later, Biden went to a school in Washington where people were getting help with their applications and thanked everyone.
“You are going to be better off for it. The country is going to be better off for it. So thank you,” he told them.
Enrollment had surpassed the revised 6 million threshold as of last Wednesday. ||||| As the clock ticks down on open enrollment for new coverage options under the Affordable Care Act (ACA), the latest Kaiser Health Tracking Poll finds that six in ten of the uninsured are unaware of the March 31 deadline to sign up for coverage. When reminded of the deadline and the fine for not getting covered, half of those who lack coverage as of mid-March say they plan to remain uninsured. Meanwhile, four in ten of the uninsured are still unaware of the law’s subsidies to help lower-income Americans purchase coverage, and half don’t know about the law’s expansion of Medicaid. Among the public overall, general opinion of the ACA moved in a more positive direction this month for the first time since November’s post-rollout negative shift in opinion. While unfavorable views of the law continue to outpace favorable ones, the gap between negative and positive views now stands at eight percentage points, down from 16 percentage points in January. Four years after the ACA’s passage, a little over half the public says they are tired of hearing the national debate over the law and want the country to focus more on other things, while four in ten say it’s important for the debate to continue. At the same time, six in ten want Congress to keep the law in place and either leave it as is or work to improve it, while three in ten would prefer to see it either repealed and replaced with a Republican alternative or repealed and not replaced.
Most uninsured unaware of March 31 deadline, half plan to remain uninsured
In the final days of open enrollment for new health insurance options under the ACA, substantial shares of the uninsured remain unaware of the law’s individual mandate and the looming deadline to sign up for coverage. A third of those who lack coverage as of mid-March are unaware that the law requires nearly all Americans to have health insurance or pay a fine. When it comes to the specifics, four in ten of the uninsured (39 percent) are aware that the deadline to sign up for coverage is at the end of March, leaving about six in ten unaware of the March deadline.
When reminded of the mandate and the deadline, half of those without coverage as of mid-March say they think they will remain uninsured, while four in ten expect to obtain coverage and one in ten are unsure.
A third (33 percent) of the uninsured say they have tried to get insurance for themselves in the past 6 months, including 18 percent who report attempting to get coverage through a health insurance marketplace, 14 percent from Medicaid, and 13 percent directly from a private insurance company. Still, the large majority – 67 percent – say they have not attempted to get coverage.
FIGURE 2: One-Third Of Uninsured Report Trying To Get Coverage In Past 6 Months AMONG THE UNINSURED AGES 18-64: Have you tried to get insurance for yourself in the past 6 months, or not? [If yes: From which of the following sources have you tried to get health insurance?] Yes, have tried to get insurance in past 6 months 33% Through the health insurance marketplace set up under the health care law* 18 From Medicaid* 14 Directly from a private insurance company* 13 From an employer* 9 From some other source* 2 No, have not tried to get insurance 67 * Multiple responses allowed
While some report trying to get coverage from new options available under the ACA, large shares of the uninsured remain unaware of two of the law’s key provisions that could help them get coverage. About half the uninsured are unaware that the ACA gives states the option of expanding their Medicaid programs, and more than four in ten don’t know that it provides financial help to low- and moderate-income individuals to help them purchase coverage. Despite extensive campaigns in media and on the ground attempting to get them enrolled, just one in nine (11 percent) of the uninsured say they have been personally contacted by anyone about the health care law through a phone call, email, text message, or door-to-door visit.
FIGURE 3: Awareness Of Key ACA Provisions Among The Uninsured AMONG THE UNINSURED AGES 18-64: To the best of your knowledge, would you say the health reform law does or does not do each of the following? CORRECT INCORRECT Yes No Don’t Know/Refused Require nearly all Americans to have health insurance or else pay a fine 66% 24% 10% Provide financial help to low and moderate income Americans who don’t get insurance through their jobs to help them purchase coverage 57 32 11 Give states the option of expanding their existing Medicaid program to cover more low-income, uninsured adults 49 33 19
Gap between unfavorable and favorable views shrinks this month, including among uninsured
As the ACA turns four years old, overall public opinion on the law shifted in a more positive direction this month, though unfavorable views still outnumber favorable ones. In March, 46 percent say they have an unfavorable view of the law (down 4 percentage points since January), while 38 percent say they have a favorable view (up 4 percentage points since January). The gap between unfavorable and favorable views is now eight percentage points, down from a recent high of 16 points in November and January.
When those who view the law favorably are asked to say in their own words why they like the law, the most common reason by far is that it will expand access to health care and health insurance (61 percent), followed far behind by a perception that it will make health care more affordable and control costs (10 percent), and that it will be good for the country and people in general (7 percent). Open-ended reasons for unfavorable views are more widely dispersed, the most common being concerns about costs (23 percent), opposition to the individual mandate (17 percent), and concerns about government overreach (10 percent).
FIGURE 5: In Their Own Words: Reasons For Favorable Views AMONG THE 38% WHO HAVE A FAVORABLE VIEW: Could you tell me in your own words what is the main reason you have a favorable opinion of the health reform law? Category Percent Mentioning Quotes Expanding access to care and insurance 61% “Because it allows people without insurance the ability to get insurance.�? “Because a lot of people who otherwise would not have insurance will now have it.�? “Because I am able to keep my health insurance with my parents until age 26.�? Will make health care more affordable/control costs/lower costs 10 “Because it makes health insurance affordable for people without insurance.�? “Because I think the health care system was too costly and the affordable health care act will cut costs.�? Country/people will be better off generally 7 “It makes health care better for Americans.�? “it is beneficial to the general public.�?
FIGURE 6: In Their Own Words: Reasons For Unfavorable Views AMONG THE 46% WHO HAVE AN UNFAVORABLE VIEW: Could you tell me in your own words what is the main reason you have an unfavorable opinion of the health reform law? Category Percent Mentioning Quotes Cost concerns 23% “It’s too expensive for regular people.�? “it’s costing too much money. It’s supposed to help people with low incomes and it’s not.�? “Because it’s a financial hardship on the U.S.�?
Opposed to individual mandate/ Unconstitutional 17 “Don’t think it’s right to penalize people who don’t have health care.�? “It’s unconstitutional, requiring people to have health insurance.�?
Government-related issues 10 “I don’t like the government making personal decisions for me.�? “I believe the government should stay out of health care�? “There is too much government in our personal choices.�?
General opinion of the ACA among the uninsured, which had been trending negative for the past several months, also moved in a positive direction this month, returning closer to levels measured at the end of 2013. In March, 45 percent of the uninsured say they have an unfavorable view of the law (compared to 56 percent in February) and 37 percent have a favorable view (up sharply from 22 percent last month). Opinion among the uninsured in tracking polls has shown more month-to-month variation over time than among the total public, at least in part due to the relatively smaller sample size for this subgroup, but this month’s poll finds a clear change in direction, with attitudes shifting more positively towards the law after trending in a negative direction for several months. As more Americans gain coverage under the law, we can expect the group who remain uninsured to change over time, and some changes in opinion may be attributable to changes in who remains uninsured, rather than a shift in opinion among individuals.
The large majority of the public still gives both the federal government and their own state government a rating of “only fair�? or “poor�? when it comes to implementing the ACA, though ratings for both have inched up slightly since the end of 2013. Twenty-four percent now say the federal government is doing an “excellent�? or “good�? job, up 8 percentage points since December, and 28 percent now give a positive rating to their state government, up 5 percentage points in the same time frame. Positive ratings for state governments are also somewhat higher in states operating their own health care marketplace (37 percent say “excellent�? or “good�?) than in states that defaulted to the federal marketplace (24 percent).
FIGURE 8: Federal And State Governments Get Poor Ratings For ACA Implementation Regardless of whether you support or oppose the health care law, how good a job would you say (INSERT) is doing implementing the law? The federal government Your state government Total public Total public Among those in states operating their own marketplace Among those in states defaulting to the federal marketplace* NET Excellent/Good 24% 28% 37% 24% Excellent 4 5 9 3 Good 20 23 28 21 NET Only fair/Poor 72% 59% 51% 62% Only fair 33 33 32 33 Poor 39 26 19 29 Don’t know/Refused 4% 14% 12% 14% *includes states with a state-federal partnership exchange
Over half report having personal conversations about ACA, but similar share are weary of national debate
The ACA was a common topic of personal conversations this month, and the public reports that the tone of those conversations was mostly negative. Just over half the public (55 percent) say they had at least one conversation about the law with friends or family in the past month, up from 31 percent in January 2012 (the last time this question was asked). About half those who say they discussed the law with friends or family (28 percent of the public overall) report hearing mostly bad things about the law in these discussions, while a much smaller share (5 percent of the public overall) say they heard mostly good things and the remainder say it was a mix of the two.
While personal conversations may be on the rise, many Americans appear to be weary of the national debate about the law. Just over half the public (53 percent) say they’re tired of hearing about the debate over the ACA and want the country to focus more on other issues, while about four in ten (42 percent) say they think it’s important for the country to continue the debate. Democrats and those with a favorable view of the law are more likely to say they’re tired of hearing about the debate, while Republicans and those who view the law unfavorably are more evenly split between those who are tired of hearing about it and those who want the debate to continue.
Perhaps reflecting this sense that the debate has gone on long enough, more of the public would like to see Congress keep the law in place and work to improve it (49 percent) or keep it as is (10 percent) rather than repeal it and replace it with a Republican-sponsored alternative (11 percent) or repeal it outright (18 percent).
Individual provisions mostly popular, including across parties, though many are not very well-known
As previous Kaiser tracking polls have found, many of the ACA’s major provisions continue to be quite popular, including across party lines. For example, large shares of Americans – including at least seven in ten overall and at least six in ten Democrats, Republicans, and independents – have a favorable view of the fact that the law allows young adults to stay on their parents’ insurance plans up to age 26, closes the Medicare “doughnut hole�? for prescription drug coverage, provides subsidies to low- and moderate-income Americans to help them purchase coverage, eliminates cost-sharing for preventive services, gives states the option of expanding Medicaid, and prohibits insurance companies from denying coverage based on pre-existing conditions. Nearly as many (including a majority across parties) have a favorable view of the “medical loss ratio�? provision that requires insurance companies to give their customers a rebate if they spend too little money on services and too much on administration and profits. Somewhat more divisive is the law’s Medicare payroll tax on earnings for upper-income Americans, which is viewed favorably by about three-quarters of Democrats and just over half of independents, but just a third of Republicans.
The glaring exception to the popularity of individual provisions of the law is the requirement that nearly all Americans have health insurance or pay a fine, which is viewed unfavorably by roughly two-thirds of the public.
FIGURE 12: Many Elements Of ACA Continue To Be Popular Across Parties Percent who say they have a FAVORABLE opinion of each provision of the law Total Public Democrat Independent Republican Extension of dependent coverage 80% 87% 76% 76% Close Medicare “doughnut hole�? 79 89 75 73 Subsidy assistance to individuals 77 89 74 65 Eliminate out-of-pocket costs for preventive services 77 81 76 75 Medicaid expansion 74 89 69 62 Guaranteed issue 70 74 70 69 Medical loss ratio 62 68 64 54 Increase Medicare payroll tax on upper income 56 77 54 33 Individual mandate/penalty 35 56 31 16 Note: Question wording abbreviated. For full question wording, see survey topline.
At the same time that the public reports having a favorable view of many of the component parts of the ACA, large shares remain unaware that the law actually does some of these things. A few of the law’s provisions are both popular and relatively well-known – for example, 71 percent are aware that the law extends dependent coverage up to age 26, and eight in ten have a favorable view of this provision. More than half are also aware of several other popular provisions, including the law’s subsidy assistance to low and moderate income individuals (63 percent), Medicaid expansion (60 percent), and the so-called “guaranteed issue�? provision that prohibits insurance companies from denying coverage based on health status (54 percent). Yet, in each of these three cases, the share who are aware of the provision lags roughly 15 percentage points behind the share who view it favorably.
Two other popular provisions are even less well-known. Fewer than half (43 percent) are aware that the law eliminates out-of-pocket costs for preventive services, and just four in ten (40 percent, including 38 percent of seniors) know that it gradually closes the Medicare prescription drug “doughnut hole.�? At the other end of the spectrum, the law’s least popular provision – the individual mandate – is widely recognized, with nearly eight in ten (78 percent) correctly answering that the ACA requires nearly all Americans to have health insurance or else pay a fine.
Misperceptions also persist about things the ACA does not actually do. For example, nearly half the public (46 percent) think the law allows undocumented immigrants to receive financial help from the government to buy health insurance, and another two in ten (22 percent) are unsure whether it does. A third of the public (34 percent, including 32 percent of seniors) believe the law establishes a government panel to make decisions about end-of-life care for people on Medicare, with another quarter saying they are unsure (23 percent of the public, 25 percent of seniors). ||||| You incur the fine by not signing up by the Monday, March 31, deadline, but most people wouldn’t actually pay the penalty until they file their 2014 returns, which typically happens in 2015. The IRS can collect it by reducing the size of your refund. The IRS can collect it by reducing the size of your refund, but many of its other enforcement mechanisms such as levies are not available. So, it does seem to be possible to avoid the penalty by making sure you don’t have a refund due, but many of the people in the penalty demographic typically do receive refunds. A lot of people without health insurance who would be subject to a penalty benefit from tax credits that would typically give rise to a refund. These individuals could adjust their withholding to avoid a refund, but that seems unlikely in most cases. ||||| Skip in Skip x Embed x Share CLOSE Healthcare.gov saw millions of visitors in the days leading up to the deadline to enroll: midnight on March 31. But Republican critics say that's not an accurate reflection of how people feel about the Affordable Care Act.
The home screen for HealthCare.gov announces the deadline for sign-ups. (Photo: Jon Elswick, AP)
WASHINGTON — The federal government's health care enrollment website — HealthCare.gov — went down briefly early Monday for extended maintenance as heavy traffic was building on the last day of open enrollment for 2014.
At one point, the site told visitors that it was "down for maintenance" and asked people to "please try again later." At other points, visitors were told there was heavy traffic on the system and were asked to remain online in a "virtual waiting room" until they could be connected.
Administration spokesman Aaron Albright said the website undergoes "regular nightly maintenance" during off-peak hours and that period was extended Monday because of a "technical problem."
He did not say what the problem was, but a statement from the Department of Health and Human Services called it "a software bug" unrelated to the volume of prospective applicants.
Albright said the website is typically down for maintenance during the period from 1 a.m. to 5 a.m. ET, and that as a result of the technical problems the site was down for at least three additional hours Monday morning. The site was largely restored by 8 a.m. ET.
TWITTER FIGHT: Obamacare deadline brings out the tweets
The hiccup came as the Obama administration and its allies made a last-minute push to persuade Americans to enroll in health insurance under the Affordable Care Act.
Monday at midnight is the deadline for open enrollment and the last chance to avoid a penalty for not purchasing insurance in 2014, which people will pay with their federal income taxes next year.
Those who start the process — either by working on a paper application with a navigator, attempting to enroll online, or talking with a call center representative — may continue the process after the deadline passes.
Administration officials said interest was surging as the deadline neared. Sunday evening, Health and Human Services announced 2 million visits over the weekend to HealthCare.gov, the federal government's enrollment site.
In the last week alone, the call center handled a record 2.5 million calls, surpassing the 2.4 million it received during the entire month of February.
Over the weekend, HHS Secretary Kathleen Sebelius appeared at a Baptist church in Miami to urge Floridians to sign up before the deadline. She planned a fresh round of television interviews with local stations Monday to boost enrollment numbers.
An interview with Vice President Biden encouraging young people to enroll will air Monday on celebrity chef Rachael Ray's talk show.
"The traffic and energy and interest this weekend shows many more are interested in the coverage," White House spokeswoman Tara McGuinness said Sunday afternoon.
Republicans saw the situation differently.
In an op-ed appearing in Monday's editions of USA TODAY, Sen. Tom Coburn, R-Okla., said the vast majority of enrollees were previously insured. Getting Americans to "re-enroll in insurance is no great achievement," he said, "particularly when many of those customers were forced to give up plans they liked."
Sen. John Barrosso, R-Wyo., said the administration is "cooking the books" on enrollment figures. The real test "is what kind of insurance will those people actually have," he said during an appearance on Fox News Sunday.
President Obama announced Thursday that more than 6 million people had enrolled in the federal and state health exchanges, a goal projected by the Congressional Budget Office to ensure the system is sustainable.
Administration officials have not released updated numbers, but there were signs that enrollment numbers have grown since Thursday's milestone was announced.
State officials in New York said Friday that it had bumped up enrollment in private plans almost 25,000 from the previous week, and 70% of the enrollees had not had insurance before. California has already met its goal, but its executive director, Peter Lee, planned to visit several enrollment sites over the weekend. In Washington, D.C., gospel artist John Kee and songwriter Brittney Wright performed at a "gospel enrollment concert" Friday.
The government will have to wait for the insurers to release payment data, as well as information about the newly insured, to answer. However, some states, such as California, have reported payment rates as high as 85%.
White House officials Sunday released a memo that details the administration's public outreach to tout the law. One example: White House officials, Cabinet secretaries and "celebrity surrogates," including NBA standout Kobe Bryant and actress Kerry Washington, have held more than 300 radio interviews in the last six weeks, officials said.
Contributing: Associated Press
Read or Share this story: http://usat.ly/1ge2Kyl[/INST]– As the clock ticked toward ObamaCare's midnight deadline, a second round of glitches hit HealthCare.gov today, this time blocking new users from applying. The site is now back up and running, Politico reports, but its "virtual waiting room was triggered," and the Obama administration reported that as many as 100,000 users at a time were on the site. HealthCare.gov had earlier gone down for maintenance for several hours beginning around 3am ET, with Health and Human Services officials ascribing the outage to a software bug. More last-minute tidbits: We are a nation of procrastinators: Last night, HHS revealed that the site saw 2 million visits over the weekend, and that the ObamaCare call center fielded 2.5 million calls in the last week—compared to 2.4 million for all of February, reports USA Today. Joe Biden is trying to help: By appealing to America's youth via an appearance on Rachael Ray's show today. Today's deadline isn't truly a deadline: As previously reported, would-be enrollees who begin but don't complete the process by today will be granted an extension. The penalty threat: The Wall Street Journal clarifies the specifics: a $95 fine or 1% of your income, whichever is greater. It estimates a couple with two kids bringing in $100,000 a year would pony up about $800—when paying 2014 taxes, which will happen in 2015. The unaware: The Journal points out a Kaiser Health Tracking Poll that this week determined 60% of uninsured Americans aren't aware of today's deadline.</s> |
the radiation from the innermost regions of active galactic nuclei ( agn ) is primarily emitted in the x - ray band , making x - ray spectroscopy a prime tool for studying this region .
moreover , the variability of the radiation can provide additional diagnostics .
flux and spectral variations in agn are usually nothing out of the ordinary .
the drivers and nature of this variability are known to depend on the timescale of the variability .
for example , changes in the accretion rate govern the longest timescales , and lead the continuum to become softer when brighter in the x - ray band @xcite .
absorption changes can drive strong variability , with timescales and spectral signatures that depend on the type of absorber .
in general , all timescales depend on the black hole mass ( see * ? ? ? * ; * ? ? ? * and references therein ) , where the timescales are longer with increasing black hole mass . in this light
, the x - ray spectral variability of fairall 9 stands out .
this luminous seyfert 1 galaxy ( @xmath0 ) , which has been well - studied throughout the years , is renowned for its lack of a warm absorber @xcite and its simple x - ray spectrum @xcite .
the spectrum is well described by a powerlaw continuum with cold and ionized reflection @xcite , possibly with an additional soft x - ray continuum component @xcite . in particular , from a multi - epoch spectral analysis including _ xmm _ data from 2009 and _ suzaku _ data from 2007 and 2010 , @xcite conclude that the spectral modeling of the soft excess is ambiguous .
both a multi - zone ionized reflection model and a model with an additional comptonization component with a single zone ionized reflector describe the data .
the accretion disk parameters are dependent on the model chosen . for example
the black hole spin is determined to be @xmath1 for a reflection - only soft excess and @xmath2 for a comptonization soft excess .
the high black hole mass of @xmath3 @xcite suggests low amplitude short - term variability , and indeed the source does not display strong intra - observation variability on hour to day timescales @xcite .
the discovery of surprisingly rapid x - ray flux dips in 10years of _ rxte _ monitoring however has put this picture of low amplitude variations on short timescales into question @xcite . during a dip the 2 - 10kev flux decreases by a factor of two or more .
these flux dips happen on a timescale of a few days , so slightly longer than the length of a typical long x - ray observation . while it was not possible to determine the reason for the flux dips from the _ rxte _ monitoring , several possibilities
have been suggested : inner disk or coronal instabilities , absorption from compton - thick clumps in the torus , or even a failed jet cycle .
the aim of this paper is to study the broad - band spectral shape and the nature of the soft x - ray excess in fairall 9 .
to do so we have obtained new high quality _ xmm _ ccd observations combined with _
nustar _ hard x - ray coverage targeted at answering these questions . in this paper
we present a spectral analysis of these data .
a future paper will discuss the variability and timing properties .
the paper is organized in the following way ; in [ reduction ] we discuss the data reduction followed by a description of the results from the spectral analysis in [ results ] . before finally discussing the results ( [ discuss ] )
, we briefly show in [ previous ] how our new insights are consistent with the spectra already presented in @xcite .
to learn more about the x - ray flux dips , we designed an observing campaign to provide a detailed spectral and temporal study of the source .
it consists of three parts , starting with a _ swift _ @xcite monitoring campaign to observe fairall 9 in the optical , uv , and x - ray bands for several months in 2013 and 2014 with an average cadence of 2-days to search for dips .
the earliest part of this monitoring which ranged from april to june 2013 was presented in @xcite . in that study we focused on the connection of the x - ray variability to the uv variability and found correlated optical / uv variability on all time scales sampled .
we reduced the newly added data in a similar fashion to that from the pilot study .
the resulting x - ray light curve is shown in fig .
[ light_f9 ] .
the dips are immediately apparent in a visual analysis of the x - ray light curve ( fig .
[ light_f9 ] ) . based on this monitoring ,
we triggered two _ xmm _ observations , one in a dip and one out of a dip constituting the second part of our campaign .
these observations are indicated as vertical red bars in the light curve .
the third part of our campaign ( indicated by the third red bar in the light curve ) corresponds to a joint _ xmm_-_nustar _ observation meant to reveal the exact broad - band spectral shape of fairall 9 .
this observation was also taken at high flux , although not as high as the non - dip observation .
the flux variability is also apparent from the unfolded _ xmm _
spectra shown in fig .
[ spectra_unfolded ] . with three observations taken at different flux states , we have a dataset that is well - suited to study possible flux - related spectral changes .
erg / s/@xmath4 indicating the flux state of the three newest _ xmm _ observations ( xmmc , xmmd , xmme ) as red bars .
it is apparent that xmmc was taken at very low flux , while xmmd and xmme were at high flux . ]
fairall 9 is a well - studied agn ; an overview of the existing data from _ xmm _ , _ suzaku _ and _ nustar _ is given in table [ nu_obs ] . throughout the paper , reference names are used for all the pointings .
this work focuses on the newest three _ xmm _ observations ( xmmc , xmmd , xmme ) and the _ nustar _ observation ( taken in the form of two immediately subsequent pointings ) simultaneous with xmme , i.e. parts two and three of our observing campaign described in the previous section .
part one will be presented together with an analysis of the temporal properties in a furthcoming paper . [ cols="^,^,^,^,^,^,^,^ " , ]
the results presented thus far are based on observations taken over a period of less than one year ( table [ nu_obs ] ) , while the observations considered in previous works spanned a period from 2000 to 2010 . changes to the geometry of the source are plausible over a several year period .
these changes might cause the flux ratios to the continuum to vary .
further , we also note the different sensitivities of the different satellites leads to a different average power law fitted to even the same band , which would affect the data / model residual plots as well .
therefore , instead of trying to make a comparable plot for the old data we simply try to fit the suza , suzb , and xmmb observations jointly in a similar fashion to the xmmc , xmmd , and xmme / nu observations to test whether the data have similar properties . for ease of fitting , we combine the two front - illuminated _ suzaku _ xis detectors .
we include the power law soft excess in our model , as it was already seen as a possibility for the soft excess when the same observations were analyzed in @xcite .
however it was already noted then that the soft x - ray energies of _ suzaku_-xis might not be very reliable because of contamination on the detector . to avoid this affecting our general conclusion about the spectra , we exclude all _ suzaku _ data below 1kev for the spectral modeling . the high energy cut - off is kept fixed at 1000kev , as it can not be determined from _ suzaku_-pin .
we find that a model similar to that described in section [ soft ] describes the old data reasonably well ( @xmath5 for 5386 dof ) , see fig .
[ residuals_previous ] .
in particular such a fit returns very similar best fit parameters ( @xmath6,@xmath7 ) to the fit to the newer data .
the spin and inclination measurements are in agreement with those found in section [ soft ] .
this implies that the source behavior remained mostly unchanged over the last 7 years
. found to fit the new _ xmm _ and _ nustar _ data .
the residuals below 1kev are consistent with the calibration uncertainity of _ xmm _ epic - pn . ]
in this paper we have studied three _ xmm _ observations of fairall 9 taken in 2013/2014 and one _ nustar _ observation in the same time period .
our main findings are : * we are able to confirm the absence of excess ionized or neutral absorption in the soft x - ray band .
we detect emission lines in the soft band , as well as a single absorption line at 21.7 that can not be associated with fairall 9 . *
we discover fractional residuals to a simple power law in the _ xmm _ band , which remain constant even as the source flux changes significantly .
this implies a constant fractional contribution from the different model components . *
we clearly detect blurred ionized reflection in the spectrum and are able to constrain the accretion disk parameters . * a soft excess additional to that due to blurred ionized reflection , described by an additional power law component is present .
in section [ rgs_data ] we noted that there is a noticeable absorption line at 21.7 , which agrees most closely with the ovii resonance line at 21.6 .
the hot phase of the interstellar medium is known to produce prominent ovii absorption lines ( see , e.g. , * ? ? ? * and references therein ) . however , assuming the line is produced by ovii absorption , it would have a velocity shift of @xmath8kms@xmath9 , which is beyond any velocity range in the galaxy , including high velocity clouds ( @xmath10kms@xmath9 ) , or uncertainties due to errors in the rgs absolute wavelength scale ( typically 0.004 or @xmath11kms@xmath9 ) .
the most likely and appealing origin of this feature is therefore the intergalactic medium lying in the line of sight towards fairall9 . assuming that the absorption feature detected at @xmath12 at 21.7 is produced by ovii
, this would correspond to @xmath13@xmath14 at @xmath15 . in general ,
the best indicator for igm absorption is the redshifted hi ly@xmath16 absorption line ( 1215.67 at rest ) , which is commonly found in fuv spectra of agn , including fairall9 ( see , e.g. , * ? ? ?
the redshift of our putative ovii feature is consistent with the hi absorption line redshifted to 1221 clearly seen in the hi ly@xmath16 profile of fairall9 ( see * ? ? ?
* fig.10 ) .
the 21.7 line is therefore most likely of intergalactic origin . from the rgs spectra ,
we confirm the absence of any significant absorption other than galactic , as noted previously by @xcite and @xcite .
in fact , we see a set of low energy emission lines including those consistent with o vii , o viii , and n vii . plotting the flux of these lines against the ionization state ( figure [ fig : xi_vs_flux ] ) indicates that the ionization state of most of the gas is around @xmath17 .
such low ionization emission lines are consistent with a warm absorber out of our line of sight . within the context of the unified agn model ,
this agrees well with our finding that the inclination of the inner accretion disk , as measured from the multi - epoch spectra , is very low and the accretion disk is almost face - on .
previous measurements of the inclination angle have found it to be more intermediate @xcite .
this discrepancy could could be due to that earlier analyses have used an angle averaged reflection model , which the analysis presented here uses the new angle - resolved ` relxill ` model @xcite .
for very low inclinations and intermediate ionization states such as found here , the differences between an angle - averaged and angle - resolved model are especially pronounced ( see figure 2 of * ? ? ?
* ) . as we showed in section[previous
] , a reanalysis of the old data with the new ` relxill ` model now also finds a low inclination .
a second complication of the inclination measurement already discussed in @xcite , is that for intermediate inclinations ( @xmath1845deg ) the cut - off of the blue wing of the iron line , which provides the best constraint on the inclination of the accretion disk , coincides with the fe k@xmath19 line , possibly leading to a false association of this energy as the end of the blue wing of the line .
the exact modeling of the highly ionized emission lines ( fe xxv , fexxvi ) adds additional complexity to this region of the spectrum .
future high - resolution observations with , for example , the microcalorimeter on board _ astro - h _ , have the potential to answer this question once and for all . in our initial exploration of the x - ray spectrum ( section [ res_ccd ] ) we discovered that the data / model residuals of an absorbed power law , with the absorption fixed at the galactic value , are very similar for all three _ xmm _ pointings ( fig . [ resid_powerlaw ] ) .
a similar observation has been made by @xcite in mrk335 where the soft excess component at 0.6kev was found to scale with the flux , yielding a constant flux ratio
. however , the persistence of the fractional flux contributions is much more apparent in fairall 9 .
this is most likely driven by the high black hole mass of fairall 9 and its aborption - free spectrum , simplifying a detection significantly .
the observed behavior has several implications for our understanding the x - ray spectra and spectral variability .
our analysis demonstrates that the relative contribution of each individual model component at a given energy remains constant .
the number and nature of the components also remains the same .
this implies that , the geometry of the x - ray emitting region can not have changed within the time spanned by the observations .
indirectly , the accretion rate must remain approximately constant as drastic changes in the accretion rate would cause changes in the geometry . to gain further insight into the geometry , we model the simultaneous observations xmme and nu above 2kev ( to avoid the complications of the soft excess ) with a lamp - post geometry and @xmath20 were kept fixed at their multi - epoch best fit values . ] , where the corona is approximated by a point source above the disk at heigh @xmath21 .
we find that the corona would be at a height of @xmath22 above the accretion disk .
the time difference ( @xmath1810days ) between the two observations xmmc and xmmd combined with the fact that we do not see a significant lag of the cold reflection flux behind the continuum flux , allows us to place an upper limit on the distance to the cold reflector of 690@xmath23 .
this indicates that the origin of the cold reflection is the outer part of the accretion disk and not a more distant structure such as the torus .
a radius of @xmath24 lies well within the dust sublimation radius of fairall 9 ( @xmath25 ) and our finding therefore agrees well the claim of @xcite that the dust sublimation radius represents an upper limit to iron emitting region .
having set out in this paper to find the driver of the relatively rapid variability seen in the x - ray monitorings of fairall 9 , the question now is : what is causing the variability we observe in the x - ray spectra of this agn ? from our results , it is clear that the variability of the individual components is driven by the variability of the continuum ( power law ) .
both the cold and the ionized reflection components respond to these changes in the continuum , as does the soft excess .
the question of the nature of the variability is therefore transferred to the question of what causes the continuum variability .
current models connect the continuum variability to changes of the accretion flow @xcite , for example through inward propagating fluctuations of the accretion rate @xcite .
but to fully understand how these accretion flow changes are connected to changes in the coronal emission will require a better understanding of the detailed physics governing the corona . our detailed spectral analysis of the multi - epoch data revealed an additional continuum - like component in the spectra above the blurred reflection . in section
[ soft ] we found that a simple , steep power law describes this component well .
this component varies together with the bulk of the continuum emission . its strength with respect to the primary continuum does not change , similar to what is seen for the reflection components .
the spectral shape and variability behavior ( it must vary on relatively fast time scales , which are shorter than the time difference between the observations ) suggest that comptonization could give rise to the observed power law .
one possibility is that the primary corona is non - uniform in its temperature or optical depth and this gives rise to two seemingly distinct but coordinated varying components . one plausible explanation for this would be in - homogeneous heating of the corona as , for example , caused by different magnetic field strengths at different radii .
another possibility is that this comptonization occurs in an area that is spatially separate from the primary comptonization , e.g. on the surface of the innermost part of the accretion disk .
the need for an additional comptonization component to model the broad - band _ xmm _ and _ nustar _ spectra has also been found in ark120 @xcite , and ngc5548 @xcite .
both analyses assume the two comptonization components are coupled , with the first corona upscattering the accretion disk photons and the second corona comptonizing the already comptonized photons leaving the first corona .
such a scenario was outlined in @xcite .
two spatially separate but connected comptonization components , however would be problematic for the case of fairall 9 . to match the observed constancy of the flux ratios , for example , a doubling in the flux output of the first corona would need to lead to a doubling of the flux output of the second corona as well .
a doubling in the seed photon flux however does usually not lead to a doubling of the coronal emission ; in fact it would lead to a significant cooling of the second corona .
the only way to ensure the flux ratios remain constant , would be a fine - tuned heating of the second / primary corona .
therefore for fairall 9 a non - uniform corona is more likely .
it is important to note here that a separate comptonization component in the soft x - ray would naturally also extend into the uv / optical bands .
this provides another means of verifying the presence of an additional component , as a single temperature comptonization component extending from the optical to the soft x - rays would predict a significant correlation of the bands at zero lag .
this is called into question by the discovery of notable lags between the x - ray emission and the uv / optical bands @xcite .
notably these lags are seen between all x - ray energies and the uv / optical emission , not just the soft x - rays , with no strong correlation seen at zero lag .
usually these lags are associated with the thermal reprocessing of x - ray coronal emission on the optical / uv emitting regions of the accretion disk .
possibly , multi - zone comptonization , for example on the outer layers of the accretion disk ( with multiple temperatures ) could mimic a similar effect . for fairall 9
previous work also suggests the presence of thermal reprocessing in uv / optical @xcite . we will discuss the timing and uv - x - ray insights from the new data in a forthcoming paper
we thank the referee for their comments that have helped to improve the clarity of the paper .
al and acf acknowledge support from erc advanced grant feedback .
csr thanks the simons foundation fellows program ( us ) and the sackler fellowship program ( cambridge ) for support .
this work made use of data from the _ nustar _ mission , a project led by the california institute of technology , managed by the jet propulsion laboratory , and funded by the national aeronautics and space administration .
this research has made use of the _ nustar _ data analysis software ( nustardas ) jointly developed by the asi science data center ( asdc , italy ) and the california institute of technology ( usa ) .
this research has made use of data obtained from the _ suzaku _ satellite , a collaborative mission between the space agencies of japan ( jaxa ) and the usa ( nasa ) . | we present a multi - epoch x - ray spectral analysis of the seyfert 1 galaxy fairall 9 .
our analysis shows that fairall 9 displays unique spectral variability in that its ratio residuals to a simple absorbed power law in the 0.5 - 10kev band remain constant with time in spite of large variations in flux .
this behavior implies an unchanging source geometry and the same emission processes continuously at work at the timescale probed . with the constraints from _
nustar _ on the broad - band spectral shape , it is clear that the soft excess in this source is a superposition of two different processes , one being blurred ionized reflection in the innermost parts of the accretion disk , and the other a continuum component such as spatially distinct comptonizing region . alternatively , a more complex primary comptonization component together with blurred ionized reflection could be responsible . | <s>[INST]the radiation from the innermost regions of active galactic nuclei ( agn ) is primarily emitted in the x - ray band , making x - ray spectroscopy a prime tool for studying this region .
moreover , the variability of the radiation can provide additional diagnostics .
flux and spectral variations in agn are usually nothing out of the ordinary .
the drivers and nature of this variability are known to depend on the timescale of the variability .
for example , changes in the accretion rate govern the longest timescales , and lead the continuum to become softer when brighter in the x - ray band @xcite .
absorption changes can drive strong variability , with timescales and spectral signatures that depend on the type of absorber .
in general , all timescales depend on the black hole mass ( see * ? ? ? * ; * ? ? ? * and references therein ) , where the timescales are longer with increasing black hole mass . in this light
, the x - ray spectral variability of fairall 9 stands out .
this luminous seyfert 1 galaxy ( @xmath0 ) , which has been well - studied throughout the years , is renowned for its lack of a warm absorber @xcite and its simple x - ray spectrum @xcite .
the spectrum is well described by a powerlaw continuum with cold and ionized reflection @xcite , possibly with an additional soft x - ray continuum component @xcite . in particular , from a multi - epoch spectral analysis including _ xmm _ data from 2009 and _ suzaku _ data from 2007 and 2010 , @xcite conclude that the spectral modeling of the soft excess is ambiguous .
both a multi - zone ionized reflection model and a model with an additional comptonization component with a single zone ionized reflector describe the data .
the accretion disk parameters are dependent on the model chosen . for example
the black hole spin is determined to be @xmath1 for a reflection - only soft excess and @xmath2 for a comptonization soft excess .
the high black hole mass of @xmath3 @xcite suggests low amplitude short - term variability , and indeed the source does not display strong intra - observation variability on hour to day timescales @xcite .
the discovery of surprisingly rapid x - ray flux dips in 10years of _ rxte _ monitoring however has put this picture of low amplitude variations on short timescales into question @xcite . during a dip the 2 - 10kev flux decreases by a factor of two or more .
these flux dips happen on a timescale of a few days , so slightly longer than the length of a typical long x - ray observation . while it was not possible to determine the reason for the flux dips from the _ rxte _ monitoring , several possibilities
have been suggested : inner disk or coronal instabilities , absorption from compton - thick clumps in the torus , or even a failed jet cycle .
the aim of this paper is to study the broad - band spectral shape and the nature of the soft x - ray excess in fairall 9 .
to do so we have obtained new high quality _ xmm _ ccd observations combined with _
nustar _ hard x - ray coverage targeted at answering these questions . in this paper
we present a spectral analysis of these data .
a future paper will discuss the variability and timing properties .
the paper is organized in the following way ; in [ reduction ] we discuss the data reduction followed by a description of the results from the spectral analysis in [ results ] . before finally discussing the results ( [ discuss ] )
, we briefly show in [ previous ] how our new insights are consistent with the spectra already presented in @xcite .
to learn more about the x - ray flux dips , we designed an observing campaign to provide a detailed spectral and temporal study of the source .
it consists of three parts , starting with a _ swift _ @xcite monitoring campaign to observe fairall 9 in the optical , uv , and x - ray bands for several months in 2013 and 2014 with an average cadence of 2-days to search for dips .
the earliest part of this monitoring which ranged from april to june 2013 was presented in @xcite . in that study we focused on the connection of the x - ray variability to the uv variability and found correlated optical / uv variability on all time scales sampled .
we reduced the newly added data in a similar fashion to that from the pilot study .
the resulting x - ray light curve is shown in fig .
[ light_f9 ] .
the dips are immediately apparent in a visual analysis of the x - ray light curve ( fig .
[ light_f9 ] ) . based on this monitoring ,
we triggered two _ xmm _ observations , one in a dip and one out of a dip constituting the second part of our campaign .
these observations are indicated as vertical red bars in the light curve .
the third part of our campaign ( indicated by the third red bar in the light curve ) corresponds to a joint _ xmm_-_nustar _ observation meant to reveal the exact broad - band spectral shape of fairall 9 .
this observation was also taken at high flux , although not as high as the non - dip observation .
the flux variability is also apparent from the unfolded _ xmm _
spectra shown in fig .
[ spectra_unfolded ] . with three observations taken at different flux states , we have a dataset that is well - suited to study possible flux - related spectral changes .
erg / s/@xmath4 indicating the flux state of the three newest _ xmm _ observations ( xmmc , xmmd , xmme ) as red bars .
it is apparent that xmmc was taken at very low flux , while xmmd and xmme were at high flux . ]
fairall 9 is a well - studied agn ; an overview of the existing data from _ xmm _ , _ suzaku _ and _ nustar _ is given in table [ nu_obs ] . throughout the paper , reference names are used for all the pointings .
this work focuses on the newest three _ xmm _ observations ( xmmc , xmmd , xmme ) and the _ nustar _ observation ( taken in the form of two immediately subsequent pointings ) simultaneous with xmme , i.e. parts two and three of our observing campaign described in the previous section .
part one will be presented together with an analysis of the temporal properties in a furthcoming paper . [ cols="^,^,^,^,^,^,^,^ " , ]
the results presented thus far are based on observations taken over a period of less than one year ( table [ nu_obs ] ) , while the observations considered in previous works spanned a period from 2000 to 2010 . changes to the geometry of the source are plausible over a several year period .
these changes might cause the flux ratios to the continuum to vary .
further , we also note the different sensitivities of the different satellites leads to a different average power law fitted to even the same band , which would affect the data / model residual plots as well .
therefore , instead of trying to make a comparable plot for the old data we simply try to fit the suza , suzb , and xmmb observations jointly in a similar fashion to the xmmc , xmmd , and xmme / nu observations to test whether the data have similar properties . for ease of fitting , we combine the two front - illuminated _ suzaku _ xis detectors .
we include the power law soft excess in our model , as it was already seen as a possibility for the soft excess when the same observations were analyzed in @xcite .
however it was already noted then that the soft x - ray energies of _ suzaku_-xis might not be very reliable because of contamination on the detector . to avoid this affecting our general conclusion about the spectra , we exclude all _ suzaku _ data below 1kev for the spectral modeling . the high energy cut - off is kept fixed at 1000kev , as it can not be determined from _ suzaku_-pin .
we find that a model similar to that described in section [ soft ] describes the old data reasonably well ( @xmath5 for 5386 dof ) , see fig .
[ residuals_previous ] .
in particular such a fit returns very similar best fit parameters ( @xmath6,@xmath7 ) to the fit to the newer data .
the spin and inclination measurements are in agreement with those found in section [ soft ] .
this implies that the source behavior remained mostly unchanged over the last 7 years
. found to fit the new _ xmm _ and _ nustar _ data .
the residuals below 1kev are consistent with the calibration uncertainity of _ xmm _ epic - pn . ]
in this paper we have studied three _ xmm _ observations of fairall 9 taken in 2013/2014 and one _ nustar _ observation in the same time period .
our main findings are : * we are able to confirm the absence of excess ionized or neutral absorption in the soft x - ray band .
we detect emission lines in the soft band , as well as a single absorption line at 21.7 that can not be associated with fairall 9 . *
we discover fractional residuals to a simple power law in the _ xmm _ band , which remain constant even as the source flux changes significantly .
this implies a constant fractional contribution from the different model components . *
we clearly detect blurred ionized reflection in the spectrum and are able to constrain the accretion disk parameters . * a soft excess additional to that due to blurred ionized reflection , described by an additional power law component is present .
in section [ rgs_data ] we noted that there is a noticeable absorption line at 21.7 , which agrees most closely with the ovii resonance line at 21.6 .
the hot phase of the interstellar medium is known to produce prominent ovii absorption lines ( see , e.g. , * ? ? ? * and references therein ) . however , assuming the line is produced by ovii absorption , it would have a velocity shift of @xmath8kms@xmath9 , which is beyond any velocity range in the galaxy , including high velocity clouds ( @xmath10kms@xmath9 ) , or uncertainties due to errors in the rgs absolute wavelength scale ( typically 0.004 or @xmath11kms@xmath9 ) .
the most likely and appealing origin of this feature is therefore the intergalactic medium lying in the line of sight towards fairall9 . assuming that the absorption feature detected at @xmath12 at 21.7 is produced by ovii
, this would correspond to @xmath13@xmath14 at @xmath15 . in general ,
the best indicator for igm absorption is the redshifted hi ly@xmath16 absorption line ( 1215.67 at rest ) , which is commonly found in fuv spectra of agn , including fairall9 ( see , e.g. , * ? ? ?
the redshift of our putative ovii feature is consistent with the hi absorption line redshifted to 1221 clearly seen in the hi ly@xmath16 profile of fairall9 ( see * ? ? ?
* fig.10 ) .
the 21.7 line is therefore most likely of intergalactic origin . from the rgs spectra ,
we confirm the absence of any significant absorption other than galactic , as noted previously by @xcite and @xcite .
in fact , we see a set of low energy emission lines including those consistent with o vii , o viii , and n vii . plotting the flux of these lines against the ionization state ( figure [ fig : xi_vs_flux ] ) indicates that the ionization state of most of the gas is around @xmath17 .
such low ionization emission lines are consistent with a warm absorber out of our line of sight . within the context of the unified agn model ,
this agrees well with our finding that the inclination of the inner accretion disk , as measured from the multi - epoch spectra , is very low and the accretion disk is almost face - on .
previous measurements of the inclination angle have found it to be more intermediate @xcite .
this discrepancy could could be due to that earlier analyses have used an angle averaged reflection model , which the analysis presented here uses the new angle - resolved ` relxill ` model @xcite .
for very low inclinations and intermediate ionization states such as found here , the differences between an angle - averaged and angle - resolved model are especially pronounced ( see figure 2 of * ? ? ?
* ) . as we showed in section[previous
] , a reanalysis of the old data with the new ` relxill ` model now also finds a low inclination .
a second complication of the inclination measurement already discussed in @xcite , is that for intermediate inclinations ( @xmath1845deg ) the cut - off of the blue wing of the iron line , which provides the best constraint on the inclination of the accretion disk , coincides with the fe k@xmath19 line , possibly leading to a false association of this energy as the end of the blue wing of the line .
the exact modeling of the highly ionized emission lines ( fe xxv , fexxvi ) adds additional complexity to this region of the spectrum .
future high - resolution observations with , for example , the microcalorimeter on board _ astro - h _ , have the potential to answer this question once and for all . in our initial exploration of the x - ray spectrum ( section [ res_ccd ] ) we discovered that the data / model residuals of an absorbed power law , with the absorption fixed at the galactic value , are very similar for all three _ xmm _ pointings ( fig . [ resid_powerlaw ] ) .
a similar observation has been made by @xcite in mrk335 where the soft excess component at 0.6kev was found to scale with the flux , yielding a constant flux ratio
. however , the persistence of the fractional flux contributions is much more apparent in fairall 9 .
this is most likely driven by the high black hole mass of fairall 9 and its aborption - free spectrum , simplifying a detection significantly .
the observed behavior has several implications for our understanding the x - ray spectra and spectral variability .
our analysis demonstrates that the relative contribution of each individual model component at a given energy remains constant .
the number and nature of the components also remains the same .
this implies that , the geometry of the x - ray emitting region can not have changed within the time spanned by the observations .
indirectly , the accretion rate must remain approximately constant as drastic changes in the accretion rate would cause changes in the geometry . to gain further insight into the geometry , we model the simultaneous observations xmme and nu above 2kev ( to avoid the complications of the soft excess ) with a lamp - post geometry and @xmath20 were kept fixed at their multi - epoch best fit values . ] , where the corona is approximated by a point source above the disk at heigh @xmath21 .
we find that the corona would be at a height of @xmath22 above the accretion disk .
the time difference ( @xmath1810days ) between the two observations xmmc and xmmd combined with the fact that we do not see a significant lag of the cold reflection flux behind the continuum flux , allows us to place an upper limit on the distance to the cold reflector of 690@xmath23 .
this indicates that the origin of the cold reflection is the outer part of the accretion disk and not a more distant structure such as the torus .
a radius of @xmath24 lies well within the dust sublimation radius of fairall 9 ( @xmath25 ) and our finding therefore agrees well the claim of @xcite that the dust sublimation radius represents an upper limit to iron emitting region .
having set out in this paper to find the driver of the relatively rapid variability seen in the x - ray monitorings of fairall 9 , the question now is : what is causing the variability we observe in the x - ray spectra of this agn ? from our results , it is clear that the variability of the individual components is driven by the variability of the continuum ( power law ) .
both the cold and the ionized reflection components respond to these changes in the continuum , as does the soft excess .
the question of the nature of the variability is therefore transferred to the question of what causes the continuum variability .
current models connect the continuum variability to changes of the accretion flow @xcite , for example through inward propagating fluctuations of the accretion rate @xcite .
but to fully understand how these accretion flow changes are connected to changes in the coronal emission will require a better understanding of the detailed physics governing the corona . our detailed spectral analysis of the multi - epoch data revealed an additional continuum - like component in the spectra above the blurred reflection . in section
[ soft ] we found that a simple , steep power law describes this component well .
this component varies together with the bulk of the continuum emission . its strength with respect to the primary continuum does not change , similar to what is seen for the reflection components .
the spectral shape and variability behavior ( it must vary on relatively fast time scales , which are shorter than the time difference between the observations ) suggest that comptonization could give rise to the observed power law .
one possibility is that the primary corona is non - uniform in its temperature or optical depth and this gives rise to two seemingly distinct but coordinated varying components . one plausible explanation for this would be in - homogeneous heating of the corona as , for example , caused by different magnetic field strengths at different radii .
another possibility is that this comptonization occurs in an area that is spatially separate from the primary comptonization , e.g. on the surface of the innermost part of the accretion disk .
the need for an additional comptonization component to model the broad - band _ xmm _ and _ nustar _ spectra has also been found in ark120 @xcite , and ngc5548 @xcite .
both analyses assume the two comptonization components are coupled , with the first corona upscattering the accretion disk photons and the second corona comptonizing the already comptonized photons leaving the first corona .
such a scenario was outlined in @xcite .
two spatially separate but connected comptonization components , however would be problematic for the case of fairall 9 . to match the observed constancy of the flux ratios , for example , a doubling in the flux output of the first corona would need to lead to a doubling of the flux output of the second corona as well .
a doubling in the seed photon flux however does usually not lead to a doubling of the coronal emission ; in fact it would lead to a significant cooling of the second corona .
the only way to ensure the flux ratios remain constant , would be a fine - tuned heating of the second / primary corona .
therefore for fairall 9 a non - uniform corona is more likely .
it is important to note here that a separate comptonization component in the soft x - ray would naturally also extend into the uv / optical bands .
this provides another means of verifying the presence of an additional component , as a single temperature comptonization component extending from the optical to the soft x - rays would predict a significant correlation of the bands at zero lag .
this is called into question by the discovery of notable lags between the x - ray emission and the uv / optical bands @xcite .
notably these lags are seen between all x - ray energies and the uv / optical emission , not just the soft x - rays , with no strong correlation seen at zero lag .
usually these lags are associated with the thermal reprocessing of x - ray coronal emission on the optical / uv emitting regions of the accretion disk .
possibly , multi - zone comptonization , for example on the outer layers of the accretion disk ( with multiple temperatures ) could mimic a similar effect . for fairall 9
previous work also suggests the presence of thermal reprocessing in uv / optical @xcite . we will discuss the timing and uv - x - ray insights from the new data in a forthcoming paper
we thank the referee for their comments that have helped to improve the clarity of the paper .
al and acf acknowledge support from erc advanced grant feedback .
csr thanks the simons foundation fellows program ( us ) and the sackler fellowship program ( cambridge ) for support .
this work made use of data from the _ nustar _ mission , a project led by the california institute of technology , managed by the jet propulsion laboratory , and funded by the national aeronautics and space administration .
this research has made use of the _ nustar _ data analysis software ( nustardas ) jointly developed by the asi science data center ( asdc , italy ) and the california institute of technology ( usa ) .
this research has made use of data obtained from the _ suzaku _ satellite , a collaborative mission between the space agencies of japan ( jaxa ) and the usa ( nasa ) .[/INST] we present a multi - epoch x - ray spectral analysis of the seyfert 1 galaxy fairall 9 .
our analysis shows that fairall 9 displays unique spectral variability in that its ratio residuals to a simple absorbed power law in the 0.5 - 10kev band remain constant with time in spite of large variations in flux .
this behavior implies an unchanging source geometry and the same emission processes continuously at work at the timescale probed . with the constraints from _
nustar _ on the broad - band spectral shape , it is clear that the soft excess in this source is a superposition of two different processes , one being blurred ionized reflection in the innermost parts of the accretion disk , and the other a continuum component such as spatially distinct comptonizing region . alternatively , a more complex primary comptonization component together with blurred ionized reflection could be responsible . </s> |
bipolar disorder ( bp ) is a severe mental illness associated with significant morbidity and mortality ( tsuang and woolson , 1977 ; coryell et al . , 1993 ) .
the lifetime prevalence of bp in epidemiological surveys using the diagnostic and statistical manual of mental disorders ( dsm ) criteria is between 0.3% and 1.5% for bipolar i disorder ( bp - i ) and between 1.0% and 2.0% for bipolar ii disorder ( bp - ii ) ( weissman et al . , 1996 ; pini et al . ,
however , increasing evidence supports the existence of a spectrum of bp that is far wider than recognized by current diagnostic nosology ( angst et al . , 2010 ) . a significant proportion of patients in the community ( 33.555% )
have less than the dsm - iv - tr criterion of a 4-day hypomanic episode and might not be diagnosed with bp - ii ( wicki and angst , 1991 ; angst et al . , 2003 ) .
these patients are now classified as other specified bp ( sbp ) in the dsm 5 .
some researchers have proposed that patients with sbp and bp - ii have indistinguishable clinical characteristics : severity , functional impairment , comorbidities , and family history of bp ( benazzi and akiskal , 2006 ; angst et al . , 2010 , 2012 ) .
patients with sbp who have major depressive disorder ( mdd ) and short - duration hypomania ( 23 days ) also have a high rate of conversion to bp in longitudinal follow - ups ( axelson et al . , 2011 ; fiedorowicz et al . ,
2011 ) , poorer response to antidepressants , and a more morbid long - term clinical course than do mdd patients without hypomanic episodes ( smith et al . , 2009 ; angst et al . ,
some researchers ( benazzi and akiskal , 2006 ; angst et al . , 2010 , 2012 )
have even proposed the validity of a brief hypomanic episode ( 1 , 2 , or 3 days ) for diagnosis of bp - ii .
most of the evidence for a spectrum of bp far wider than currently recognized comes from epidemiological studies that lack comparable biological data to explore the similarities between sbp and bp .
in addition , there are few investigations of the differences in biomarker along the bp continuum of bp - i , bp - ii , and sbp ( bai et al . , 2014 ) .
we believe studies of the possible biological differences along the bp spectrum will provide support in addition to epidemiological data for the classification of bp - ii and sbp .
neuroinflammatory interactions with disturbances related to oxidative stress ( maes et al . , 2011 ) and neurotrophic mechanisms ( monje et al . , 2003 )
have been implicated in the neurobiological background and neuroprogressive processes of bp ( berk et al .
inflammation is thus an integrating component for the pathophysiology of bp based on evidence from shared genetic polymorphisms and gene expressions in bp and inflammation and on evidence from altered cytokine levels during symptomatic and asymptomatic intervals ( goldstein et al . , 2009 ; modabbernia et al . , 2013 ; munkholm et al .
changes in tumor necrosis factor- ( tnf- ) ( modabbernia et al . , 2013 ; munkholm et al . , 2013b ) , c - reactive protein ( crp ) ( dickerson et al . , 2007 ) ,
interleukin-8 ( il-8 ) ( obrien et al . , 2006 ) , and transforming growth factor-1 ( tgf-1 ) ( kim et al . , 2004 ) levels were found in bp with different affective states and presented different immune pathways , from proinflammatory to regulatory action . in addition , cytokines are key signaling molecules that regulate both innate and adaptive immunological responses and have widespread effects on the neuroendocrine system , neurogenesis , neurocircuitry , and neurotransmitter metabolism ( haroon et al . ,
therefore , peripheral cytokine fluctuations have been proposed as biomarkers for disease activity , affective state , or the disease nature for bp ( roda et al . , 2015 ) .
most studies , however , have a mixed group of bp patients ( ie , bp - i patients and bp - ii patients ) to compare with a control group ( modabbernia et al . , 2013 ;
comparisons between all the subtypes of bp along the spectrum , especially subthreshold bipolarity , were limited . because different subtypes of bp have variable levels of clinical outcomes , severity , and functional impairments ( akiskal et al . , 2000 ;
angst et al . , 2003 , 2010 ) , a detailed investigation of the variations of inflammatory cytokines is needed .
neurotrophins , such as brain - derived neurotrophic factor ( bdnf ) , are crucial for neuronal survival , growth , plasticity , and connectivity , all of which are thought to be involved in the pathophysiology of bp ( berk et al . , 2011 ) .
postmortem brains from bp patients have showed significantly lower - than - normal range levels of bdnf , which might contribute to brain atrophy and progressive cognitive changes ( kim et al . , 2010 ) .
the reduction of serum bdnf levels is correlated with decreased bdnf levels in the brain ( pan et al . , 1998 ) .
studies also showed a decrease in bdnf levels in acute episodes of bp ( kapczinski et al . , 2008a ) and cumulative effects when the disorder progressed ( kapczinski et al . , 2008b ) .
the levels of bdnf appear to be normal in the early stages of the disorder in euthymic bp patients and to decrease in the latter stages ( kauer - santanna et al . , 2009 ) ; therefore , peripheral bdnf is a bp biomarker for both state markers during acute episodes and disease progression markers that accompany a clinical course ( berk et al . , 2011 ; fernandes et al . , 2011
) . because cytokine and bdnf are closely correlated with the underlying pathophysiological changes and clinical presentation with bp , they are candidates for the biological marker for bp . although patients with mdd also have higher - than - normal range levels of peripheral inflammatory cytokines ( miller et al . , 2009 ) and lower - than - normal range bdnf levels ( polyakova et al . , 2015 )
, studies have hypothesized that the disturbance of inflammation ( bai et al . , 2015 ) and bdnf expression ( li et al . , 2014 ) were more severe in bp than in mdd and indicated the potential differential roles of these biomarkers ( li et al . , 2014 ) .
we wanted to investigate the plasma cytokine and bdnf levels in bp - i , bp - ii , sbp , and control groups to better understand the biological differences along the continuum of bp , which might also support the similarities or differences between bp - ii and sbp .
the research protocol was approved by the institutional review board for the protection of human subjects at tri - service general hospital and national cheng kung university hospital .
the procedures were fully explained to each participant before they were asked to sign the informed consent .
patients were recruited both from outpatient and inpatient settings and initially evaluated by an attending psychiatrist .
they then underwent a more detailed interview by a clinical psychologist using the structured interview in the chinese version of the modified schedule of affective disorder and schizophrenia- life time ( sads - l ) ( endicott and spitzer , 1978 ) , which has good inter - rater reliability ( huang et al . , 2004 ) , to determine the diagnosis in dsm - iv . patients with bp - i , bp - ii , or major depressive episodes and a previous subthreshold hypomania history ( > 2 days but < 4 days ) were included .
patients with an active infectious disease , autoimmune diseases , or uncontrolled clinically significant medical condition ( eg , cardiac , hepatic , and renal failure ) were excluded .
they were then subdivided into bp - i , bp - ii ( hypomania lasting for more than 4 days ) , and sbp ( short - duration hypomania : 23 days ) groups for further analysis .
patients who could not recall the duration of hypomania were excluded from the current analysis .
the severity of mood symptoms was assessed using the young mania rating scale ( ymrs ) ( young et al . , 1978 ) and
the hamilton depression rating scale ( hdrs ) ( hamilton , 1960 ; hamilton , 1967 ) .
they were screened by telephone , and those with a sleep disorder , substance abuse disorder , mood swings , or possible symptoms of psychosis were excluded .
the psychiatric conditions of the remaining volunteers were then carefully screened in face - to - face interviews with a clinical psychologist using the chinese version of sads - l .
all controls were free of present and past major mental illness ( affective disorder , schizophrenia , anxiety disorder , personality disorder , and substance use disorders ) , and none had a family history of psychiatric disorder among their first - degree relatives .
plasma was isolated from the whole blood after it had been centrifuged at 3000 g for 15 minutes at 4c , and then it was immediately stored at -80c .
cytokine and bdnf levels were quantified using an antibody pair assay system ( flexia ; biosource intl . ,
the immunological parameters tnf- , crp , tgf-1 , il-8 , and bdnf were measured . the respective sensitivities and ranges for cytokine assays
were : tnf- ( 0.0380.191 pg / ml and not detected [ nd ] to 2.139 pg / ml ) , crp ( 0.0050.022ng / ml and 1044185ng / ml ) , tgf-1 ( 1.715.4 pg / ml and 18289 - 63416 pg / ml ) , il-8 ( 1.57.5 pg / ml and31.2 pg / ml ) , and bdnf ( < 20 pg / ml and nd to 4137 pg / ml ) .
all laboratory procedures were performed double - blinded and all assays were done in duplicate .
fisher s exact test was substituted for the test when values were smaller than expected ( < 5 ) .
we used 1-way anova and the bonferroni posthoc test to compare the differences in mean age , disease duration , and hdrs and ymrs scores in bp - i , bp - ii , sbp , and controls groups .
multivariate analysis of covariance ( mancova ) was used to compare cytokine and bdnf levels between the groups .
when analyzing the bp - i , bp - ii , sbp , and control groups , age and sex were controlled as covariates , and age , sex , disease duration , comorbidity , and severity ( hdrs and ymrs scores ) were controlled as covariates when analyzing the bp - i , bp - ii , and sbp groups .
one - way anova was then applied to clarify the significant findings identified using mancova .
linear regression models were used to determine the correlation between cytokine and bdnf levels and between bipolar spectrum disorder and other related factors .
the research protocol was approved by the institutional review board for the protection of human subjects at tri - service general hospital and national cheng kung university hospital .
the procedures were fully explained to each participant before they were asked to sign the informed consent .
patients were recruited both from outpatient and inpatient settings and initially evaluated by an attending psychiatrist .
they then underwent a more detailed interview by a clinical psychologist using the structured interview in the chinese version of the modified schedule of affective disorder and schizophrenia- life time ( sads - l ) ( endicott and spitzer , 1978 ) , which has good inter - rater reliability ( huang et al . , 2004 ) , to determine the diagnosis in dsm - iv . patients with bp - i , bp - ii , or major depressive episodes and a previous subthreshold hypomania history ( > 2 days but < 4 days ) were included .
patients with an active infectious disease , autoimmune diseases , or uncontrolled clinically significant medical condition ( eg , cardiac , hepatic , and renal failure ) were excluded .
they were then subdivided into bp - i , bp - ii ( hypomania lasting for more than 4 days ) , and sbp ( short - duration hypomania : 23 days ) groups for further analysis .
patients who could not recall the duration of hypomania were excluded from the current analysis .
the severity of mood symptoms was assessed using the young mania rating scale ( ymrs ) ( young et al . , 1978 ) and
the hamilton depression rating scale ( hdrs ) ( hamilton , 1960 ; hamilton , 1967 ) .
they were screened by telephone , and those with a sleep disorder , substance abuse disorder , mood swings , or possible symptoms of psychosis were excluded .
the psychiatric conditions of the remaining volunteers were then carefully screened in face - to - face interviews with a clinical psychologist using the chinese version of sads - l .
all controls were free of present and past major mental illness ( affective disorder , schizophrenia , anxiety disorder , personality disorder , and substance use disorders ) , and none had a family history of psychiatric disorder among their first - degree relatives .
plasma was isolated from the whole blood after it had been centrifuged at 3000 g for 15 minutes at 4c , and then it was immediately stored at -80c .
cytokine and bdnf levels were quantified using an antibody pair assay system ( flexia ; biosource intl . ,
the immunological parameters tnf- , crp , tgf-1 , il-8 , and bdnf were measured . the respective sensitivities and ranges for cytokine assays were : tnf- ( 0.0380.191 pg / ml and not detected [ nd ] to 2.139 pg / ml ) , crp ( 0.0050.022ng / ml and 1044185ng / ml ) , tgf-1 ( 1.715.4 pg / ml and 18289 - 63416 pg / ml ) , il-8 ( 1.57.5 pg / ml and31.2 pg / ml ) , and bdnf ( < 20 pg / ml and nd to 4137 pg / ml ) .
all laboratory procedures were performed double - blinded and all assays were done in duplicate .
fisher s exact test was substituted for the test when values were smaller than expected ( < 5 ) .
we used 1-way anova and the bonferroni posthoc test to compare the differences in mean age , disease duration , and hdrs and ymrs scores in bp - i , bp - ii , sbp , and controls groups .
multivariate analysis of covariance ( mancova ) was used to compare cytokine and bdnf levels between the groups .
when analyzing the bp - i , bp - ii , sbp , and control groups , age and sex were controlled as covariates , and age , sex , disease duration , comorbidity , and severity ( hdrs and ymrs scores ) were controlled as covariates when analyzing the bp - i , bp - ii , and sbp groups .
one - way anova was then applied to clarify the significant findings identified using mancova .
linear regression models were used to determine the correlation between cytokine and bdnf levels and between bipolar spectrum disorder and other related factors .
of the 877 participants in the study , 234 had bp - i , 260 had bp - ii ( hypomania : 4 days ) , 243 had sbp ( short - duration hypomania : 23 days ) , and 140 were controls .
there were no significant differences in age and sex between bipolar spectrum groups , but there was a significantly higher percentage of men in the control group ( p=.01 ) ( table 1 ) .
there were no significant differences in the disease duration and hdrs and ymrs scores between the bp - ii and sbp groups ( table1 ) , but hdrs scores were significantly lower and ymrs scores were significantly higher ( both p <
twenty - seven ( 3.7% ) of the bipolar spectrum patients did not complete the sads - l interviews , which lasted for more than 4 to 6 hours , and their comorbidity data was incomplete . although the physical comorbidity rate was not significantly different between the three bp groups , the psychiatric comorbidity rates were significantly ( p < .008 ) higher for the bp - i and sbp groups than for the bp - ii group ( table 2 ) .
the percentage of anxiety disorder comorbidity was significantly ( p < .001 ) higher in the bp - ii and sbp groups , and the percentage of substance ( including smoking ) use disorder was significantly ( p < .001 ) higher in the bp - i group ( table 2 ) .
demographic data and hdrs and ymrs scores between bp patients and controls abbreviations : a , bp - i ; b , bp - ii ; c , sbp ; d , controls .
comorbidities in bipolar spectrum disorders
table 3 shows the inflammatory cytokines and bdnf levels in the bp - i , bp - ii , sbp , and control groups . among the three patient groups and the control group , mancova showed that there was an overall multivariate effect of the diagnostic group for cytokines and bdnf levels ( pillai s f = 4.09 , df = [ 15 , 2607 ] , p < .001 ) .
significant univariate effects were found in tnf- ( p=.006 ) , tgf-1 ( p=.01 ) , and il-8 ( p<.001 ) ( table 3 ) .
post hoc comparisons showed that the bp - i group had higher levels of tnf- , tgf-1 , and il-8 than did the control group ( p < .05 ) ( table 3 ) .
bp - ii and sbp patients had higher levels of tnf- and il-8 than did the controls but lower levels of il-8 than did bp - i patients ( p<.05 ) ( table 3 ) .
no significant differences were found between tnf- , tgf-1 , and il-8 levels in bp - ii and sbp patients ( p > .05 ) ( table 3 ) .
cytokines and bdnf levels in bp - i , bp - ii , and sbp patients and controls abbreviations : a , bp - i ; b , bp - ii ; bdnf , brain - derived neurotrophic factor ; c , sbp ; crp , c - reactive protein ; d , controls ; il-8 , interleukin-8 ; tgf-1 , transforming growth factor-1 ; tnf- , tumor necrosis factor-. model 1 : mancova and bonferroni post hoc comparisons ; group : bp - i , bp - ii , sbp , and controls ; covarying for age and sex . model 2 : mancova and bonferroni post hoc comparisons ; group : bp - i , bp - ii and sbp ; covarying for age , sex , disease duration , comorbidity , and hdrs and ymrs scores . after covarying for disease duration , comorbidity , and hdrs and ymrs scores , mancova analysis still showed a main multivariate effect for all studied groups ( pillai s f = 2.18 , df = , p = .02 ) .
there was a significant univariate effect for il-8 ( p=.03 ) ( table 3 ) .
the level of il-8 was significantly higher in bp - i patients ( p<.05 ) , but there was no difference between bp - ii and sbp patients ( table 3 ) .
the linear regression model also showed that bp - i patients had significantly ( t=-2.40 , p=.02 ) higher plasma il-8 levels than did those with bp - ii and sbp patients ( figure 1 ) .
other cytokine and bdnf levels were not significantly associated with diagnosis of bipolar spectrum disorders in regression model . however , the associations between tnf- levels and hdrs ( t=-2.74 , p=.006 ) , and between tgf-1 levels and disease duration ( t=-2.47 , p=.01 ) , comorbidities ( t=-2.17 , p=.03 ) , hdrs ( t=2.11 , p=.04 ) , and ymrs ( t=-3.49 , p=.01 ) were significant .
scatter plot of plasma interleukin-8 ( il-8 ) levels with representative linear regression of plasma il-8 levels in the bipolar spectrum disorders ( covarying for age , sex , disease duration , comorbidity , hamilton depression rating scale [ hdrs ] , and young mania rating scale [ ymrs ] scores ) .
the power estimation in mancova was approximately 1.00 for global effects and 0.45 to 0.99 for specific effects in different cytokines and bdnf in comparisons between the bp - i , bp - ii , sbp , and control groups . in a comparison between the bp - i , bp - ii , and sbp groups , the study had a power of 0.92 for global effects and 0.23 to 0.65 for specific effects for different cytokine and bdnf levels . for linear regression analysis ,
the study had a power of 0.81 to detect a small effect and of 1.00 to detect a medium effect and a large effect . in this power analysis ,
( 2007 , 2009)as follows : small effect size = 0.02 , medium effect size = 0.15 , and large effect size = 0.35 for the linear regression model ( alpha = 0.05 ) .
this is the first study that compares the inflammatory cytokines and bdnf levels in bp patients with different bipolar spectrum disorders and especially in bipolar patients with short - duration hypomania .
we found that the levels of tnf- , tgf-1 , and il-8 were significantly higher in bp spectrum patients than in controls .
in addition , the plasma il-8 levels were significantly higher in bp - i than in bp - ii and sbp patients after controlling for multiple possible confounding factors .
there were no significant differences between bp - ii and sbp patients for any of our measured potential biomarkers .
epidemiological studies ( angst et al . , 2003 ; benazzi and akiskal , 2006 ; angst et al . , 2010 ) have suggested that there was a gradient distribution from the most severe group , bp - i , to the least severe group , subthreshold bp in the disease severities and functional impairment levels .
neuropsychological data ( lin et al . , 2015 ) also showed that patients with sbp performed significantly better than did patients with bp - i in set shifting and visual - spatial memory and that patients with sbp performed similarly to those with bp - ii in all of the cognitive domains .
( 2014 ) compared inflammatory cytokine levels in bp - i and - ii and reported that patients with bp - ii had significantly lower levels of soluble ( s)tnf - r1 than did patients with bp - i , but there were no data on sbp patients .
our study provided comparable evidence supporting their claim that along the bd spectrum , bp - i is strongly associated with inflammatory cytokines dysregulation and that sbp and bp - ii have no significant differences in levels of inflammatory changes , which was consistent with other studies ( angst et al . , 2003 , 2010 ;
the diagnostic boundaries for bp are controversial , especially the required duration for hypomania , because the 4-day minimum is not evidence based ( benazzi , 2001 ) , and ideas about shorter durations have changed significantly over the years ( nusslock and frank , 2011 ) .
this definition is derived from averaging the 2-day ( probable ) and 7-day ( definite ) threshold for hypomania in the research diagnostic criteria ( spitzer et al . , 1979 ) .
it is suggested that the current 4-day threshold may unnecessarily narrow the range of bipolar spectrum disorders and a cut - off of 2 days should be used instead ( akiskal et al . , 1977 , 1979 , 2000 ; cassano et al . , 1992 ;
coryell et al . , 1995 ; angst , 1998 ; benazzi , 2001 ; akiskal and benazzi , 2003 ; angst et al .
however , concerns remain for broadening the diagnostic criteria based only on clinical characteristics and symptomatology data ( zimmerman , 2012 ) , even in the dsm-5 .
the current diagnostic criteria are descriptions of syndromes and represent an underlying group of psychological , behavioral , and biological dysfunction ; they might be imperfect representation of unknown core pathophysiological changes ( zimmerman , 2012 ) .
considerations and comparisons using biological markers might provide data that are more convincing and might improve the sensitivity and specificity of diagnoses ( zimmerman , 2012 ) . the most recognized biological evidence that supports
the hypothesis that sbp and bp - ii are identical is from family studies , which report that family histories of bipolarity in individuals displaying shorter duration of hypomania are more in line with bp - ii than unipolar depression ( cassano et al . , 1992 ;
neuropsychological tests also offer evidence that patients with sbp performed similarly to patients with bp - ii in all of the cognitive domains ( lin et al . , 2015 ) .
our study , which showed no significant difference in the immunological aspects of sbp and bp - ii , might provide biological evidence that supports the notion that bp - ii and sbp are indistinguishable .
this finding might be an important addition as a biological reference that supports past studies ( angst et al . , 2012 ) , which calls for further revision of the hypomania duration criterion to improve recognition of bipolarity and the choice of appropriate treatment regimen ( angst et al . , 2011 )
the bdnf levels in our study were not significantly different between the patient and control groups or between the 3 different bipolar spectrum patients .
the results of peripheral bdnf levels in bp were mixed in past studies , partly related to different mood episodes , disease states , or the disease progression process ( fernandes et al . , 2011 ) .
although studies that compared the bdnf levels in patients with different types of mood disorders suggested that bp - i patients had lower levels of bdnf than did mdd patients ( fernandes et al . , 2009 ) , the comparisons between bdnf levels in bp - i , bp - ii , and sbp were limited .
( 2012 ) reported a significant downregulation of the bdnf gene expression and hypermethylation of the bdnf promoter region in bd - ii than controls , but not in bd - i .
however , the bdnf levels in our bp - ii patients were not significantly lower than those in bp - i patients , and only a trend suggested the possibility of lower bdnf levels in sbp patients than in bp - i , bp - ii patients , or controls .
the plasma bdnf level is sensitive to multiple confounders , such as the metabolic profile ( chaldakov et al . , 2004 ) and medications ( fernandes et al . , 2011 )
; thus , future investigations should control more possible confounders and longitudinal follow - ups , which might provide more information .
we also found a significant correlation between the tnf- level and hdrs , which is consistent with reports that tnf- levels in depressed bp patients were higher than in controls ( obrien et al . , 2006 ; ortiz - dominguez et al .
we found no association between tnf- level and ymrs ( munkholm et al . , 2013b ) ; rather , we found associations between tgf-1 levels and disease duration , comorbidities , hdrs , and ymrs , which was rarely reported before ( munkholm et al . , 2013b ) .
the tgf-1 is an important modulator of inflammatory cytokines ( letterio and roberts , 1997 ; strober et al . , 1997 ) .
lower levels of tgf-1 were found in bp patients and higher levels after treatment ( kim et al . , 2004 ) .
the high initial plasma level of tgf-1 was also associated with a better prognosis during pharmacological treatment ( li et al . ,
the negative correlations between the levels of tgf-1 and bp disease duration , comorbidities , and ymrs might partially support and explain previous findings ( kim et al .
in addition , the difference between tnf- and tgf-1 levels between the 3 bipolar spectrum disorders became nonsignificant after controlling for the associated factors of disease duration , comorbidities , and symptom severity .
the differences between our findings and those of prior studies ( modabbernia et al . , 2013 ; munkholm et al . , 2013a , 2013b ) might be because these factors were not controlled for in prior analyses .
our sample size is relative larger than those in past studies ; however , a still larger sample might provide more compelling results .
although we tried to control for factors that might affect the changes of cytokine and bdnf levels , other possible factors , such as metabolic profiles , medications , and relapsing and remitting states , might also have affected our findings and should be controlled in future research .
additionally , we included only patients with short - duration hypomania , which constituted only part of subthreshold bipolar patients . to generalize our results to all
however , it took more than 3 years to identify and enroll such a large cohort of bp .
it would have been difficult for us to recruit a large enough cohort of mdd patients in a short period .
additional analyses of cytokine and bdnf levels in mdd patients might be needed and offer more solid evidence to classify sbp patients . finally , about 7.5% of the patients diagnosed with bp - ii became manic in a 10-year follow - up study ( coryell et al . , 1995 ) .
a misdiagnosis with current subtypes is possible , and long - term follow - ups for patients with bp - ii or sbp to confirm these findings might be needed .
despite these limitations , our data show a significant immunological dysregulation in all bp spectrum patients based on analyses of their peripheral inflammatory cytokines .
the deviance was more apparent in bp - i patients than in bp - ii and sbp patients .
bp - ii and sbp patients shared similar features among several measured biological markers in our study .
the present study supports the similarity between bp - ii and sbp from the immunological aspects , which are also associated with clinical symptoms .
our findings might be a significant biological addition to current efforts that support recognizing short - duration hypomania as an important indicator for the diagnosis of bp .
s .- h.c . , and c .- h.c . managed lab work and the data analyses .
s .- y.l . , p.s.c . , i.h.l . , k .- c.c . , y.k.y . , and
the research protocol was approved by the institutional review board for the protection of human subjects at national cheng kung university hospital and tri - service general hospital . | objective : emerging evidence suggests that inflammation and neurodegeneration underlies bipolar disorder . to investigate biological markers of cytokines and brain - derived neurotrophic factor between bipolar i , bipolar ii , and other specified bipolar disorder with short duration hypomania may support the association with inflammatory dysregulation and bipolar disorder and , more specifically , provide evidence for other specified bipolar disorder with short duration hypomania patients were similar to bipolar ii disorder patients from a biological marker perspective.methods:we enrolled patients with bipolar i disorder ( n=234 ) , bipolar ii disorder ( n=260 ) , other specified bipolar disorder with short duration hypomania ( n=243 ) , and healthy controls ( n=140 ) .
their clinical symptoms were rated using the hamilton depression rating scale and young mania rating scale .
inflammatory cytokine ( tumor necrosis factor- , c - reactive protein , transforming growth factor-1 , and interleukin-8 ) and brain - derived neurotrophic factor levels were measured in each group .
multivariate analysis of covariance and linear regression controlled for possible confounders were used to compare cytokine and brain - derived neurotrophic factor levels among the groups.results:multivariate analysis of covariance adjusted for age and sex and a main effect of diagnosis was significant ( p<.001 ) .
three of the 5 measured biomarkers ( tumor necrosis factor- , transforming growth factor-1 , and interleukin-8 ) were significantly ( p=.006 , .01 , and < .001 ) higher in all bipolar disorder patients than in controls . moreover , covarying for multiple associated confounders showed that bipolar i disorder patients had significantly higher il-8 levels than did bipolar ii disorder and other specified bipolar disorder with short duration hypomania patients in multivariate analysis of covariance ( p=.03 ) and linear regression ( p=.02 ) analyses .
biomarkers differences between bipolar ii disorder and other specified bipolar disorder with short duration hypomania patients were nonsignificant.conclusion:the immunological disturbance along the bipolar spectrum was most severe in bipolar i disorder patients .
other specified bipolar disorder with short duration hypomania patients and bipolar ii disorder patients did not differ in these biological markers . | <s>[INST]bipolar disorder ( bp ) is a severe mental illness associated with significant morbidity and mortality ( tsuang and woolson , 1977 ; coryell et al . , 1993 ) .
the lifetime prevalence of bp in epidemiological surveys using the diagnostic and statistical manual of mental disorders ( dsm ) criteria is between 0.3% and 1.5% for bipolar i disorder ( bp - i ) and between 1.0% and 2.0% for bipolar ii disorder ( bp - ii ) ( weissman et al . , 1996 ; pini et al . ,
however , increasing evidence supports the existence of a spectrum of bp that is far wider than recognized by current diagnostic nosology ( angst et al . , 2010 ) . a significant proportion of patients in the community ( 33.555% )
have less than the dsm - iv - tr criterion of a 4-day hypomanic episode and might not be diagnosed with bp - ii ( wicki and angst , 1991 ; angst et al . , 2003 ) .
these patients are now classified as other specified bp ( sbp ) in the dsm 5 .
some researchers have proposed that patients with sbp and bp - ii have indistinguishable clinical characteristics : severity , functional impairment , comorbidities , and family history of bp ( benazzi and akiskal , 2006 ; angst et al . , 2010 , 2012 ) .
patients with sbp who have major depressive disorder ( mdd ) and short - duration hypomania ( 23 days ) also have a high rate of conversion to bp in longitudinal follow - ups ( axelson et al . , 2011 ; fiedorowicz et al . ,
2011 ) , poorer response to antidepressants , and a more morbid long - term clinical course than do mdd patients without hypomanic episodes ( smith et al . , 2009 ; angst et al . ,
some researchers ( benazzi and akiskal , 2006 ; angst et al . , 2010 , 2012 )
have even proposed the validity of a brief hypomanic episode ( 1 , 2 , or 3 days ) for diagnosis of bp - ii .
most of the evidence for a spectrum of bp far wider than currently recognized comes from epidemiological studies that lack comparable biological data to explore the similarities between sbp and bp .
in addition , there are few investigations of the differences in biomarker along the bp continuum of bp - i , bp - ii , and sbp ( bai et al . , 2014 ) .
we believe studies of the possible biological differences along the bp spectrum will provide support in addition to epidemiological data for the classification of bp - ii and sbp .
neuroinflammatory interactions with disturbances related to oxidative stress ( maes et al . , 2011 ) and neurotrophic mechanisms ( monje et al . , 2003 )
have been implicated in the neurobiological background and neuroprogressive processes of bp ( berk et al .
inflammation is thus an integrating component for the pathophysiology of bp based on evidence from shared genetic polymorphisms and gene expressions in bp and inflammation and on evidence from altered cytokine levels during symptomatic and asymptomatic intervals ( goldstein et al . , 2009 ; modabbernia et al . , 2013 ; munkholm et al .
changes in tumor necrosis factor- ( tnf- ) ( modabbernia et al . , 2013 ; munkholm et al . , 2013b ) , c - reactive protein ( crp ) ( dickerson et al . , 2007 ) ,
interleukin-8 ( il-8 ) ( obrien et al . , 2006 ) , and transforming growth factor-1 ( tgf-1 ) ( kim et al . , 2004 ) levels were found in bp with different affective states and presented different immune pathways , from proinflammatory to regulatory action . in addition , cytokines are key signaling molecules that regulate both innate and adaptive immunological responses and have widespread effects on the neuroendocrine system , neurogenesis , neurocircuitry , and neurotransmitter metabolism ( haroon et al . ,
therefore , peripheral cytokine fluctuations have been proposed as biomarkers for disease activity , affective state , or the disease nature for bp ( roda et al . , 2015 ) .
most studies , however , have a mixed group of bp patients ( ie , bp - i patients and bp - ii patients ) to compare with a control group ( modabbernia et al . , 2013 ;
comparisons between all the subtypes of bp along the spectrum , especially subthreshold bipolarity , were limited . because different subtypes of bp have variable levels of clinical outcomes , severity , and functional impairments ( akiskal et al . , 2000 ;
angst et al . , 2003 , 2010 ) , a detailed investigation of the variations of inflammatory cytokines is needed .
neurotrophins , such as brain - derived neurotrophic factor ( bdnf ) , are crucial for neuronal survival , growth , plasticity , and connectivity , all of which are thought to be involved in the pathophysiology of bp ( berk et al . , 2011 ) .
postmortem brains from bp patients have showed significantly lower - than - normal range levels of bdnf , which might contribute to brain atrophy and progressive cognitive changes ( kim et al . , 2010 ) .
the reduction of serum bdnf levels is correlated with decreased bdnf levels in the brain ( pan et al . , 1998 ) .
studies also showed a decrease in bdnf levels in acute episodes of bp ( kapczinski et al . , 2008a ) and cumulative effects when the disorder progressed ( kapczinski et al . , 2008b ) .
the levels of bdnf appear to be normal in the early stages of the disorder in euthymic bp patients and to decrease in the latter stages ( kauer - santanna et al . , 2009 ) ; therefore , peripheral bdnf is a bp biomarker for both state markers during acute episodes and disease progression markers that accompany a clinical course ( berk et al . , 2011 ; fernandes et al . , 2011
) . because cytokine and bdnf are closely correlated with the underlying pathophysiological changes and clinical presentation with bp , they are candidates for the biological marker for bp . although patients with mdd also have higher - than - normal range levels of peripheral inflammatory cytokines ( miller et al . , 2009 ) and lower - than - normal range bdnf levels ( polyakova et al . , 2015 )
, studies have hypothesized that the disturbance of inflammation ( bai et al . , 2015 ) and bdnf expression ( li et al . , 2014 ) were more severe in bp than in mdd and indicated the potential differential roles of these biomarkers ( li et al . , 2014 ) .
we wanted to investigate the plasma cytokine and bdnf levels in bp - i , bp - ii , sbp , and control groups to better understand the biological differences along the continuum of bp , which might also support the similarities or differences between bp - ii and sbp .
the research protocol was approved by the institutional review board for the protection of human subjects at tri - service general hospital and national cheng kung university hospital .
the procedures were fully explained to each participant before they were asked to sign the informed consent .
patients were recruited both from outpatient and inpatient settings and initially evaluated by an attending psychiatrist .
they then underwent a more detailed interview by a clinical psychologist using the structured interview in the chinese version of the modified schedule of affective disorder and schizophrenia- life time ( sads - l ) ( endicott and spitzer , 1978 ) , which has good inter - rater reliability ( huang et al . , 2004 ) , to determine the diagnosis in dsm - iv . patients with bp - i , bp - ii , or major depressive episodes and a previous subthreshold hypomania history ( > 2 days but < 4 days ) were included .
patients with an active infectious disease , autoimmune diseases , or uncontrolled clinically significant medical condition ( eg , cardiac , hepatic , and renal failure ) were excluded .
they were then subdivided into bp - i , bp - ii ( hypomania lasting for more than 4 days ) , and sbp ( short - duration hypomania : 23 days ) groups for further analysis .
patients who could not recall the duration of hypomania were excluded from the current analysis .
the severity of mood symptoms was assessed using the young mania rating scale ( ymrs ) ( young et al . , 1978 ) and
the hamilton depression rating scale ( hdrs ) ( hamilton , 1960 ; hamilton , 1967 ) .
they were screened by telephone , and those with a sleep disorder , substance abuse disorder , mood swings , or possible symptoms of psychosis were excluded .
the psychiatric conditions of the remaining volunteers were then carefully screened in face - to - face interviews with a clinical psychologist using the chinese version of sads - l .
all controls were free of present and past major mental illness ( affective disorder , schizophrenia , anxiety disorder , personality disorder , and substance use disorders ) , and none had a family history of psychiatric disorder among their first - degree relatives .
plasma was isolated from the whole blood after it had been centrifuged at 3000 g for 15 minutes at 4c , and then it was immediately stored at -80c .
cytokine and bdnf levels were quantified using an antibody pair assay system ( flexia ; biosource intl . ,
the immunological parameters tnf- , crp , tgf-1 , il-8 , and bdnf were measured . the respective sensitivities and ranges for cytokine assays
were : tnf- ( 0.0380.191 pg / ml and not detected [ nd ] to 2.139 pg / ml ) , crp ( 0.0050.022ng / ml and 1044185ng / ml ) , tgf-1 ( 1.715.4 pg / ml and 18289 - 63416 pg / ml ) , il-8 ( 1.57.5 pg / ml and31.2 pg / ml ) , and bdnf ( < 20 pg / ml and nd to 4137 pg / ml ) .
all laboratory procedures were performed double - blinded and all assays were done in duplicate .
fisher s exact test was substituted for the test when values were smaller than expected ( < 5 ) .
we used 1-way anova and the bonferroni posthoc test to compare the differences in mean age , disease duration , and hdrs and ymrs scores in bp - i , bp - ii , sbp , and controls groups .
multivariate analysis of covariance ( mancova ) was used to compare cytokine and bdnf levels between the groups .
when analyzing the bp - i , bp - ii , sbp , and control groups , age and sex were controlled as covariates , and age , sex , disease duration , comorbidity , and severity ( hdrs and ymrs scores ) were controlled as covariates when analyzing the bp - i , bp - ii , and sbp groups .
one - way anova was then applied to clarify the significant findings identified using mancova .
linear regression models were used to determine the correlation between cytokine and bdnf levels and between bipolar spectrum disorder and other related factors .
the research protocol was approved by the institutional review board for the protection of human subjects at tri - service general hospital and national cheng kung university hospital .
the procedures were fully explained to each participant before they were asked to sign the informed consent .
patients were recruited both from outpatient and inpatient settings and initially evaluated by an attending psychiatrist .
they then underwent a more detailed interview by a clinical psychologist using the structured interview in the chinese version of the modified schedule of affective disorder and schizophrenia- life time ( sads - l ) ( endicott and spitzer , 1978 ) , which has good inter - rater reliability ( huang et al . , 2004 ) , to determine the diagnosis in dsm - iv . patients with bp - i , bp - ii , or major depressive episodes and a previous subthreshold hypomania history ( > 2 days but < 4 days ) were included .
patients with an active infectious disease , autoimmune diseases , or uncontrolled clinically significant medical condition ( eg , cardiac , hepatic , and renal failure ) were excluded .
they were then subdivided into bp - i , bp - ii ( hypomania lasting for more than 4 days ) , and sbp ( short - duration hypomania : 23 days ) groups for further analysis .
patients who could not recall the duration of hypomania were excluded from the current analysis .
the severity of mood symptoms was assessed using the young mania rating scale ( ymrs ) ( young et al . , 1978 ) and
the hamilton depression rating scale ( hdrs ) ( hamilton , 1960 ; hamilton , 1967 ) .
they were screened by telephone , and those with a sleep disorder , substance abuse disorder , mood swings , or possible symptoms of psychosis were excluded .
the psychiatric conditions of the remaining volunteers were then carefully screened in face - to - face interviews with a clinical psychologist using the chinese version of sads - l .
all controls were free of present and past major mental illness ( affective disorder , schizophrenia , anxiety disorder , personality disorder , and substance use disorders ) , and none had a family history of psychiatric disorder among their first - degree relatives .
plasma was isolated from the whole blood after it had been centrifuged at 3000 g for 15 minutes at 4c , and then it was immediately stored at -80c .
cytokine and bdnf levels were quantified using an antibody pair assay system ( flexia ; biosource intl . ,
the immunological parameters tnf- , crp , tgf-1 , il-8 , and bdnf were measured . the respective sensitivities and ranges for cytokine assays were : tnf- ( 0.0380.191 pg / ml and not detected [ nd ] to 2.139 pg / ml ) , crp ( 0.0050.022ng / ml and 1044185ng / ml ) , tgf-1 ( 1.715.4 pg / ml and 18289 - 63416 pg / ml ) , il-8 ( 1.57.5 pg / ml and31.2 pg / ml ) , and bdnf ( < 20 pg / ml and nd to 4137 pg / ml ) .
all laboratory procedures were performed double - blinded and all assays were done in duplicate .
fisher s exact test was substituted for the test when values were smaller than expected ( < 5 ) .
we used 1-way anova and the bonferroni posthoc test to compare the differences in mean age , disease duration , and hdrs and ymrs scores in bp - i , bp - ii , sbp , and controls groups .
multivariate analysis of covariance ( mancova ) was used to compare cytokine and bdnf levels between the groups .
when analyzing the bp - i , bp - ii , sbp , and control groups , age and sex were controlled as covariates , and age , sex , disease duration , comorbidity , and severity ( hdrs and ymrs scores ) were controlled as covariates when analyzing the bp - i , bp - ii , and sbp groups .
one - way anova was then applied to clarify the significant findings identified using mancova .
linear regression models were used to determine the correlation between cytokine and bdnf levels and between bipolar spectrum disorder and other related factors .
of the 877 participants in the study , 234 had bp - i , 260 had bp - ii ( hypomania : 4 days ) , 243 had sbp ( short - duration hypomania : 23 days ) , and 140 were controls .
there were no significant differences in age and sex between bipolar spectrum groups , but there was a significantly higher percentage of men in the control group ( p=.01 ) ( table 1 ) .
there were no significant differences in the disease duration and hdrs and ymrs scores between the bp - ii and sbp groups ( table1 ) , but hdrs scores were significantly lower and ymrs scores were significantly higher ( both p <
twenty - seven ( 3.7% ) of the bipolar spectrum patients did not complete the sads - l interviews , which lasted for more than 4 to 6 hours , and their comorbidity data was incomplete . although the physical comorbidity rate was not significantly different between the three bp groups , the psychiatric comorbidity rates were significantly ( p < .008 ) higher for the bp - i and sbp groups than for the bp - ii group ( table 2 ) .
the percentage of anxiety disorder comorbidity was significantly ( p < .001 ) higher in the bp - ii and sbp groups , and the percentage of substance ( including smoking ) use disorder was significantly ( p < .001 ) higher in the bp - i group ( table 2 ) .
demographic data and hdrs and ymrs scores between bp patients and controls abbreviations : a , bp - i ; b , bp - ii ; c , sbp ; d , controls .
comorbidities in bipolar spectrum disorders
table 3 shows the inflammatory cytokines and bdnf levels in the bp - i , bp - ii , sbp , and control groups . among the three patient groups and the control group , mancova showed that there was an overall multivariate effect of the diagnostic group for cytokines and bdnf levels ( pillai s f = 4.09 , df = [ 15 , 2607 ] , p < .001 ) .
significant univariate effects were found in tnf- ( p=.006 ) , tgf-1 ( p=.01 ) , and il-8 ( p<.001 ) ( table 3 ) .
post hoc comparisons showed that the bp - i group had higher levels of tnf- , tgf-1 , and il-8 than did the control group ( p < .05 ) ( table 3 ) .
bp - ii and sbp patients had higher levels of tnf- and il-8 than did the controls but lower levels of il-8 than did bp - i patients ( p<.05 ) ( table 3 ) .
no significant differences were found between tnf- , tgf-1 , and il-8 levels in bp - ii and sbp patients ( p > .05 ) ( table 3 ) .
cytokines and bdnf levels in bp - i , bp - ii , and sbp patients and controls abbreviations : a , bp - i ; b , bp - ii ; bdnf , brain - derived neurotrophic factor ; c , sbp ; crp , c - reactive protein ; d , controls ; il-8 , interleukin-8 ; tgf-1 , transforming growth factor-1 ; tnf- , tumor necrosis factor-. model 1 : mancova and bonferroni post hoc comparisons ; group : bp - i , bp - ii , sbp , and controls ; covarying for age and sex . model 2 : mancova and bonferroni post hoc comparisons ; group : bp - i , bp - ii and sbp ; covarying for age , sex , disease duration , comorbidity , and hdrs and ymrs scores . after covarying for disease duration , comorbidity , and hdrs and ymrs scores , mancova analysis still showed a main multivariate effect for all studied groups ( pillai s f = 2.18 , df = , p = .02 ) .
there was a significant univariate effect for il-8 ( p=.03 ) ( table 3 ) .
the level of il-8 was significantly higher in bp - i patients ( p<.05 ) , but there was no difference between bp - ii and sbp patients ( table 3 ) .
the linear regression model also showed that bp - i patients had significantly ( t=-2.40 , p=.02 ) higher plasma il-8 levels than did those with bp - ii and sbp patients ( figure 1 ) .
other cytokine and bdnf levels were not significantly associated with diagnosis of bipolar spectrum disorders in regression model . however , the associations between tnf- levels and hdrs ( t=-2.74 , p=.006 ) , and between tgf-1 levels and disease duration ( t=-2.47 , p=.01 ) , comorbidities ( t=-2.17 , p=.03 ) , hdrs ( t=2.11 , p=.04 ) , and ymrs ( t=-3.49 , p=.01 ) were significant .
scatter plot of plasma interleukin-8 ( il-8 ) levels with representative linear regression of plasma il-8 levels in the bipolar spectrum disorders ( covarying for age , sex , disease duration , comorbidity , hamilton depression rating scale [ hdrs ] , and young mania rating scale [ ymrs ] scores ) .
the power estimation in mancova was approximately 1.00 for global effects and 0.45 to 0.99 for specific effects in different cytokines and bdnf in comparisons between the bp - i , bp - ii , sbp , and control groups . in a comparison between the bp - i , bp - ii , and sbp groups , the study had a power of 0.92 for global effects and 0.23 to 0.65 for specific effects for different cytokine and bdnf levels . for linear regression analysis ,
the study had a power of 0.81 to detect a small effect and of 1.00 to detect a medium effect and a large effect . in this power analysis ,
( 2007 , 2009)as follows : small effect size = 0.02 , medium effect size = 0.15 , and large effect size = 0.35 for the linear regression model ( alpha = 0.05 ) .
this is the first study that compares the inflammatory cytokines and bdnf levels in bp patients with different bipolar spectrum disorders and especially in bipolar patients with short - duration hypomania .
we found that the levels of tnf- , tgf-1 , and il-8 were significantly higher in bp spectrum patients than in controls .
in addition , the plasma il-8 levels were significantly higher in bp - i than in bp - ii and sbp patients after controlling for multiple possible confounding factors .
there were no significant differences between bp - ii and sbp patients for any of our measured potential biomarkers .
epidemiological studies ( angst et al . , 2003 ; benazzi and akiskal , 2006 ; angst et al . , 2010 ) have suggested that there was a gradient distribution from the most severe group , bp - i , to the least severe group , subthreshold bp in the disease severities and functional impairment levels .
neuropsychological data ( lin et al . , 2015 ) also showed that patients with sbp performed significantly better than did patients with bp - i in set shifting and visual - spatial memory and that patients with sbp performed similarly to those with bp - ii in all of the cognitive domains .
( 2014 ) compared inflammatory cytokine levels in bp - i and - ii and reported that patients with bp - ii had significantly lower levels of soluble ( s)tnf - r1 than did patients with bp - i , but there were no data on sbp patients .
our study provided comparable evidence supporting their claim that along the bd spectrum , bp - i is strongly associated with inflammatory cytokines dysregulation and that sbp and bp - ii have no significant differences in levels of inflammatory changes , which was consistent with other studies ( angst et al . , 2003 , 2010 ;
the diagnostic boundaries for bp are controversial , especially the required duration for hypomania , because the 4-day minimum is not evidence based ( benazzi , 2001 ) , and ideas about shorter durations have changed significantly over the years ( nusslock and frank , 2011 ) .
this definition is derived from averaging the 2-day ( probable ) and 7-day ( definite ) threshold for hypomania in the research diagnostic criteria ( spitzer et al . , 1979 ) .
it is suggested that the current 4-day threshold may unnecessarily narrow the range of bipolar spectrum disorders and a cut - off of 2 days should be used instead ( akiskal et al . , 1977 , 1979 , 2000 ; cassano et al . , 1992 ;
coryell et al . , 1995 ; angst , 1998 ; benazzi , 2001 ; akiskal and benazzi , 2003 ; angst et al .
however , concerns remain for broadening the diagnostic criteria based only on clinical characteristics and symptomatology data ( zimmerman , 2012 ) , even in the dsm-5 .
the current diagnostic criteria are descriptions of syndromes and represent an underlying group of psychological , behavioral , and biological dysfunction ; they might be imperfect representation of unknown core pathophysiological changes ( zimmerman , 2012 ) .
considerations and comparisons using biological markers might provide data that are more convincing and might improve the sensitivity and specificity of diagnoses ( zimmerman , 2012 ) . the most recognized biological evidence that supports
the hypothesis that sbp and bp - ii are identical is from family studies , which report that family histories of bipolarity in individuals displaying shorter duration of hypomania are more in line with bp - ii than unipolar depression ( cassano et al . , 1992 ;
neuropsychological tests also offer evidence that patients with sbp performed similarly to patients with bp - ii in all of the cognitive domains ( lin et al . , 2015 ) .
our study , which showed no significant difference in the immunological aspects of sbp and bp - ii , might provide biological evidence that supports the notion that bp - ii and sbp are indistinguishable .
this finding might be an important addition as a biological reference that supports past studies ( angst et al . , 2012 ) , which calls for further revision of the hypomania duration criterion to improve recognition of bipolarity and the choice of appropriate treatment regimen ( angst et al . , 2011 )
the bdnf levels in our study were not significantly different between the patient and control groups or between the 3 different bipolar spectrum patients .
the results of peripheral bdnf levels in bp were mixed in past studies , partly related to different mood episodes , disease states , or the disease progression process ( fernandes et al . , 2011 ) .
although studies that compared the bdnf levels in patients with different types of mood disorders suggested that bp - i patients had lower levels of bdnf than did mdd patients ( fernandes et al . , 2009 ) , the comparisons between bdnf levels in bp - i , bp - ii , and sbp were limited .
( 2012 ) reported a significant downregulation of the bdnf gene expression and hypermethylation of the bdnf promoter region in bd - ii than controls , but not in bd - i .
however , the bdnf levels in our bp - ii patients were not significantly lower than those in bp - i patients , and only a trend suggested the possibility of lower bdnf levels in sbp patients than in bp - i , bp - ii patients , or controls .
the plasma bdnf level is sensitive to multiple confounders , such as the metabolic profile ( chaldakov et al . , 2004 ) and medications ( fernandes et al . , 2011 )
; thus , future investigations should control more possible confounders and longitudinal follow - ups , which might provide more information .
we also found a significant correlation between the tnf- level and hdrs , which is consistent with reports that tnf- levels in depressed bp patients were higher than in controls ( obrien et al . , 2006 ; ortiz - dominguez et al .
we found no association between tnf- level and ymrs ( munkholm et al . , 2013b ) ; rather , we found associations between tgf-1 levels and disease duration , comorbidities , hdrs , and ymrs , which was rarely reported before ( munkholm et al . , 2013b ) .
the tgf-1 is an important modulator of inflammatory cytokines ( letterio and roberts , 1997 ; strober et al . , 1997 ) .
lower levels of tgf-1 were found in bp patients and higher levels after treatment ( kim et al . , 2004 ) .
the high initial plasma level of tgf-1 was also associated with a better prognosis during pharmacological treatment ( li et al . ,
the negative correlations between the levels of tgf-1 and bp disease duration , comorbidities , and ymrs might partially support and explain previous findings ( kim et al .
in addition , the difference between tnf- and tgf-1 levels between the 3 bipolar spectrum disorders became nonsignificant after controlling for the associated factors of disease duration , comorbidities , and symptom severity .
the differences between our findings and those of prior studies ( modabbernia et al . , 2013 ; munkholm et al . , 2013a , 2013b ) might be because these factors were not controlled for in prior analyses .
our sample size is relative larger than those in past studies ; however , a still larger sample might provide more compelling results .
although we tried to control for factors that might affect the changes of cytokine and bdnf levels , other possible factors , such as metabolic profiles , medications , and relapsing and remitting states , might also have affected our findings and should be controlled in future research .
additionally , we included only patients with short - duration hypomania , which constituted only part of subthreshold bipolar patients . to generalize our results to all
however , it took more than 3 years to identify and enroll such a large cohort of bp .
it would have been difficult for us to recruit a large enough cohort of mdd patients in a short period .
additional analyses of cytokine and bdnf levels in mdd patients might be needed and offer more solid evidence to classify sbp patients . finally , about 7.5% of the patients diagnosed with bp - ii became manic in a 10-year follow - up study ( coryell et al . , 1995 ) .
a misdiagnosis with current subtypes is possible , and long - term follow - ups for patients with bp - ii or sbp to confirm these findings might be needed .
despite these limitations , our data show a significant immunological dysregulation in all bp spectrum patients based on analyses of their peripheral inflammatory cytokines .
the deviance was more apparent in bp - i patients than in bp - ii and sbp patients .
bp - ii and sbp patients shared similar features among several measured biological markers in our study .
the present study supports the similarity between bp - ii and sbp from the immunological aspects , which are also associated with clinical symptoms .
our findings might be a significant biological addition to current efforts that support recognizing short - duration hypomania as an important indicator for the diagnosis of bp .
s .- h.c . , and c .- h.c . managed lab work and the data analyses .
s .- y.l . , p.s.c . , i.h.l . , k .- c.c . , y.k.y . , and
the research protocol was approved by the institutional review board for the protection of human subjects at national cheng kung university hospital and tri - service general hospital .[/INST]objective : emerging evidence suggests that inflammation and neurodegeneration underlies bipolar disorder . to investigate biological markers of cytokines and brain - derived neurotrophic factor between bipolar i , bipolar ii , and other specified bipolar disorder with short duration hypomania may support the association with inflammatory dysregulation and bipolar disorder and , more specifically , provide evidence for other specified bipolar disorder with short duration hypomania patients were similar to bipolar ii disorder patients from a biological marker perspective.methods:we enrolled patients with bipolar i disorder ( n=234 ) , bipolar ii disorder ( n=260 ) , other specified bipolar disorder with short duration hypomania ( n=243 ) , and healthy controls ( n=140 ) .
their clinical symptoms were rated using the hamilton depression rating scale and young mania rating scale .
inflammatory cytokine ( tumor necrosis factor- , c - reactive protein , transforming growth factor-1 , and interleukin-8 ) and brain - derived neurotrophic factor levels were measured in each group .
multivariate analysis of covariance and linear regression controlled for possible confounders were used to compare cytokine and brain - derived neurotrophic factor levels among the groups.results:multivariate analysis of covariance adjusted for age and sex and a main effect of diagnosis was significant ( p<.001 ) .
three of the 5 measured biomarkers ( tumor necrosis factor- , transforming growth factor-1 , and interleukin-8 ) were significantly ( p=.006 , .01 , and < .001 ) higher in all bipolar disorder patients than in controls . moreover , covarying for multiple associated confounders showed that bipolar i disorder patients had significantly higher il-8 levels than did bipolar ii disorder and other specified bipolar disorder with short duration hypomania patients in multivariate analysis of covariance ( p=.03 ) and linear regression ( p=.02 ) analyses .
biomarkers differences between bipolar ii disorder and other specified bipolar disorder with short duration hypomania patients were nonsignificant.conclusion:the immunological disturbance along the bipolar spectrum was most severe in bipolar i disorder patients .
other specified bipolar disorder with short duration hypomania patients and bipolar ii disorder patients did not differ in these biological markers .</s> |
how the initial mass function ( imf ) of stars originates is one of the most basic questions that a complete theory of star formation must answer .
it is also one of the most difficult ( see reviews by bonnell et al .
2007 and mckee & ostriker 2007 and references therein ) .
many ideas have been advanced to explain the imf , including zinnecker ( 1982 ) , adams & fatuzzo ( 1996 ) , elmegreen ( 1997 ) , padoan & nordlund ( 2002 ) , larson ( 2003 ) , shu et al .
( 2004 ) , hennebelle & chabrier ( 2008 ) , and kunz & mouschovias ( 2009 ) , among others .
particularly intriguing is the proposal by padoan & nordlund ( 2002 ) that the imf is essentially determined by the supersonic turbulence , which controls the density distribution in the highly inhomogeneous clouds .
they used the jeans criterion to determine analytically the mass distribution of the gravitationally unstable regions , which was taken to represent the stellar imf .
both ingredients of the theory , the turbulent structuring of cloud density and the criterion for gravitational collapse , are strongly affected , however , by a dynamically important magnetic field .
some magnetic effects on the imf , such as the magnetic cushion of turbulent compression ( padoan & nordlund 2002 ) and the additional cloud support by magnetic pressure ( hennebelle & chabrier 2008 ) , can be incorporated into the analytic theory approximately .
other equally , if not more , important magnetic effects are not captured by the theory , and will be the focus of our investigation .
our study will concentrate on the parsec - scale , cluster - forming dense clumps of molecular clouds , where the majority of stars , especially massive stars , are thought to originate ( lada & lada 2003 ) , and where magnetic fields have been observed in some cases . for example , in the nearest region of active massive star formation , omc1 , a well - ordered field is inferred from polarized dust emission ( e.g. , vaillancourt et al .
crutcher et al .
( 1999 ) obtained , from cn zeeman measurements , a line - of - sight field strength @xmath0 @xmath1 g for this region , which corresponds to a dimensionless mass - to - flux ratio @xmath2 .
the ratio is close to the median value @xmath3 obtained by falgarone et al .
( 2008 ) for a sample of dense clumps of massive star formation .
correcting for the projection effects may reduce the ratio by a factor of 2 - 3 ( shu et al .
1999 ) , yielding a median value for the intrinsic mass - to - flux ratio of 2 - 3 . a magnetic field corresponding to @xmath4a
few would not be strong enough to support the clump against gravitational collapse by itself .
it can , however , change the mass distribution of the stars formed .
this is because individual stars form out of sub - regions of the clump , which are generally more strongly magnetized ( relative to their masses ) than the clump as a whole ( i.e. , with smaller values of @xmath5 , tilley & pudritz 2007 ; dib et al .
2007 ) , because the mass of a region ( which is proportional to volume ) decreases faster with its size than the magnetic flux ( which is proportional to area ) .
in particular , sub - regions smaller than the clump by a factor comparable to @xmath5 are expected to be magnetically subcritical ( with @xmath6 ) in general .
it would be hard to directly compress such regions into collapse by turbulence in the ideal mhd limit ( see , however , nakamura & li 2005 and basu et al .
2009 for studies that include ambipolar diffusion ) .
another effect is that the magnetic forces act on the turbulent flows anisotropically , channeling matter along the field lines into dense , flattened structures that can subsequently fragment thermally . in this letter , we seek to quantify the above effects using the cluster formation simulations of wang et al .
( 2010 ) , which were carried out with an amr mhd code that includes sink particles and outflow feedback .
we find , in
[ numerical ] , that the characteristic mass of the imf is lowered by both the magnetic field and outflow feedback .
the lowering of the characteristic stellar mass by magnetic fields is somewhat counter - intuitive .
it is interpreted physically using a so - called `` magnetically critical jeans mass '' ( eq .
[ [ magneticallycriticaljeansmass ] ] ) in [ discussion ] .
in wang et al . ( 2010 ) , we simulated cluster formation in moderately condensed , isothermal ( @xmath7 k ) , clump of 2 pc in size and @xmath8 m@xmath9 in mass .
we added to the clump , one by one , an initial turbulent velocity field of rms mach number 9 ( model hd ) , an initially uniform magnetic field of @xmath10 @xmath1 g ( corresponding to a dimensionless mass - to - flux ratio of 1.4 for the clump as a whole and a larger value of 3.3 for the central , high - density part ; model mhd ) , and mechanical feedback from collimated outflows driven by accreting stellar objects ( model wind ) . for simulation details
we refer the reader to wang et al .
( 2010 ) , where we also presented results on the global star formation rate and especially the formation of the most massive object in each simulation . here
, we will concentrate on the distribution of the stellar masses , with an emphasis on low and intermediate mass objects .
figure 1 shows the stellar mass distributions for all three models .
it is a log - linear plot of the number of stars in logarithmic mass bins of @xmath11=0.2 $ ] ( where @xmath12 is the stellar mass in m@xmath9 ) .
the distributions are all evaluated at the time when @xmath13 of the total mass has been converted into stars .
it corresponds to 1.16 myr for model wind ( the last output ) , and 0.576 and 0.723 myr for model hd and mhd , respectively ; for comparison , the free - fall time is @xmath14 myr at the clump center initially and @xmath15 myr in a sphere of 1 pc in radius . before proceeding to analyze the
numerically obtained mass distributions in fig . 1 , we should caution the reader that the mass of a star can be affected by many factors that are only crudely modeled in the current generation of large - scale cluster formation simulations , including our own .
these include ( 1 ) outflow feedback , which can potentially remove a large fraction , perhaps the majority of the mass of a star - forming core ( shu et al .
1987 ; matzner & mckee 2000 ; myers 2008 ) , ( 2 ) magnetic fields , which affect not only how dense cores form but also how they collapse , and ( 3 ) radiative feedback which , once a protostellar system ( protostar plus disk ) appears , heats up the circumstellar material and suppresses fragmentation close to the central object ( e.g. , krumholz et al .
2007 ; offner et al . 2009 ; price & bate 2009 ; smith et al . 2009 ; urban et al . 2009 ) .
it is currently not feasible to treat simultaneously all these factors in detail .
our strategy is to focus on magnetic fields and outflow feedback , which are less well studied , and treat the effects of radiative feedback as simply as possible .
specifically , we crudely capture the suppression of fragmentation near a star due to radiative feedback using a sink - particle merging algorithm , following krumholz et al .
( 2004 , see also discussion in federrath et al .
it eliminates very low mass ( @xmath16 m@xmath9 ) sink particles within a distance @xmath17 au of an existing star ( with mass @xmath18 ) .
experimentation shows that increasing @xmath19 to @xmath20 m@xmath9 does not change the star formation rate or the stellar mass distribution significantly .
the adopted merging distance @xmath21 is comparable to the radius of the so - called `` sphere of thermal influence '' ( where the temperature of the radiatively heated protostellar envelope drops to the ambient value ) of an object of solar mass and luminosity ( see equation [ 14 ] and figure 2 of adams & shu 1985 ) .
we find that increasing @xmath21 from 1000 au to 2000 au has little effect on the star formation rate and stellar mass distribution .
decreasing it to @xmath22 au ( or three times the size of the finest cell ) does not change the total star formation rate , but can change the number and masses of stars significantly , by up to 50% .
we believe , however , that the smaller merging distance is less realistic , since the gas on the smaller scale is expected to be more strongly heated .
the larger merging distance prevents a collapsing core from breaking up into many small pieces , in agreement with the fact that the best observed cores in nearby star - forming regions typically harbor one , at most a few , stellar systems ( e.g. , mundy et al .
nevertheless , in view of our crude representation of radiative feedback , we elect to focus on the difference between the stellar mass distributions of the three simulations , which use the same sink particle treatment , rather than the distributions themselves .
the magnetic field is solely responsible for the difference between model hd and mhd . from fig . 1 , we see that its main effects are to reduce the number of those intermediate - mass stars with masses around @xmath23 m@xmath9 , and to increase the number of lower mass stars with masses around @xmath24 m@xmath9 .
to be more quantitative , we fit the high mass end of the distribution with a power - law , @xmath25 , as shown in fig .
[ imf_log ] . in all three cases
the mass distribution deviates sharply from the power - law fit below a characteristic mass , @xmath26 ( sometimes dubbed the `` knee '' of the imf , e.g. , bonnell et al .
the values of @xmath26 and power - law index @xmath27 are listed in table 1 .
note that the characteristic mass of @xmath28 in model hd is not far from the initial jeans mass near the clump center , @xmath29 , consistent with bonnell et al .
the power - indexes are not well determined because of the limited number of stars in the power - law regime . nevertheless , they are all comparable to the salpeter value within uncertainties .
the characteristic masses are , however , significantly different .
in particular , the magnetic field in model mhd has apparently lowered the characteristic mass by a factor of @xmath23 compared to that in model hd .
to help understand why the field hampers the formation of intermediate - mass stars , we show in figure [ excessstars ] a snapshot of the so - called `` hd excess stars , '' defined somewhat arbitrarily as those stars in hd model in figs . 1 and 2 with masses in the three mass bins between @xmath30 and @xmath31 m@xmath9 .
the majority of these stars are produced at relatively isolated regions , by localized converging flows in the initial turbulence .
such regions are largely absent in the mhd model , where a moderately strong global magnetic field is present .
the reduction in the number of intermediate - mass stars makes the stellar mass distribution significantly narrower in the mhd model than in the hd model ( see table 1 and figs . 1 and 2 ) .
the magnetic field in the mhd model interacts strongly with the turbulence .
it changes the `` texture '' of the turbulent clump , by not only resisting the cross - field turbulent compression , but also promoting mass accumulation along the field lines into flattened sheets or filaments .
[ mhd3d ] shows an example of the ( flattened ) filaments resulted from the intrinsically anisotropic magnetic forces .
it is in such magnetically - induced filaments that the majority of the stars in the mhd model form . as we discuss in [ discussion ] , the high density in the filaments favors the formation of low - mass stars , which are more numerous compared to the non - magnetic hd model . outflow feedback is responsible for the difference between model wind and mhd . from figs . 1 and 2
, it is clear that the outflows have ( 1 ) shifted the characteristic mass @xmath26 to a lower value , from @xmath32 m@xmath9 to @xmath33 m@xmath9 , and ( 2 ) nearly doubled the number of stars , from 119 to 203 ( see table 1 ) .
the lowering of the stellar mass by outflow feedback is perhaps not too surprising , because , individually , the outflow from a given star can remove part of the dense envelope that feeds the growing star ( shu et al .
1987 ; matzner & mckee 2000 ; myers 2008 ) and , collectively , the feedback from all stars can prevent the clump from rapid global collapse ( nakamura & li 2007 ; wang et al .
2010 ) , lowering the total rate of stellar mass accretion .
there is , however , a large spread in both the rate and the duration of the mass accretion in stars of similar masses .
the spread makes it difficult to develop a complete picture of how the outflows lower the characteristic stellar mass precisely .
the number of stars produced per unit time ( i.e. , the stellar production rate ) turns out to be insensitive to the outflow feedback .
it takes longer , however , to convert the same amount of gas into stars in the presence of the feedback , which is the main reason for the larger number of stars in model wind than in model mhd .
we have shown that a magnetic field of strength in the observed range changes the imf significantly , by impeding direct turbulent compression of relatively low density material into relatively massive stars and , more importantly , promoting the formation of dense , flattened structures that subsequently fragment preferentially into low - mass stars .
the basic reason for the magnetic field to impede direct turbulent fragmentation is that a sub - region of the clump that is magnetically subcritical can not be compressed into prompt collapse by turbulence . for a region of size @xmath34 in a clump of average field strength @xmath35 and mass density @xmath36 ,
the characteristic dimensionless mass - to - flux ratio is @xmath37 which indicates that regions smaller than the characteristic size @xmath38 are typically magnetically subcritical ( with @xmath6 ) .
the characteristic size is related to the clump size @xmath39 by @xmath40 ( where `` cp '' stands for `` clump '' ) , since the mass - to - flux ratio of the clump as a whole is @xmath41 according to equation ( [ locallambda ] ) . in other words , a typical region that is smaller than the clump by a factor of @xmath42
can not be compressed directly into collapse by turbulence .
the corresponding characteristic mass is @xmath43 where we have scaled the clump mass @xmath44 by @xmath45 m@xmath9 , and the clump mass - to - flux ratio by 2.5 , comparable to the ( projection - corrected ) median value inferred from cn zeeman observations ( see discussion in [ intro ] ) .
the characteristic mass @xmath46 is essentially the magnetic jeans mass at the average clump density ( see equation [ 41 ] of mckee 1999 , which gives a numerical value three times larger ) .
it is to be compared with the average thermal jeans mass @xmath47 ( e.g. , spitzer 1978 ) .
the average magnetic jeans mass @xmath46 is therefore typically larger than the average thermal jeans mass @xmath48 , indicating that the formation of those stars with masses comparable to @xmath48 or smaller by direct turbulent compression can be strongly hindered by the magnetic field .
the most massive stars are expected to be least affected by the magnetic field .
however , their formation may be governed more by the global clump collapse ( retarded by outflow feedback and magnetic fields ) than by direct turbulent compression ( wang et al .
2010 ; see also smith et al .
indeed , massive ( @xmath49 ) stars in model mhd contain more mass than those in model hd , indicating that their formation is not hampered by magnetic fields , unlike intermediate mass stars .
the magnetic field can also promote fragmentation , because of the magnetic forces are intrinsically anisotropic .
it is easier for the turbulent flows to move material along the field lines than across them .
the net result is the formation of flattened , sheet- or filament - like condensations , which are conducive to fragmentation .
larson ( 1985 ) estimated the jeans mass for a self - gravitating sheet ( thermally supported in the vertical direction ) to be @xmath50 where @xmath51 is the isothermal sound speed , and @xmath52 the column density . in order to form stars ,
the sheet must first become magnetically supercritical , with a column density greater than the critical value @xmath53 . substituting @xmath54 into equation ( [ jeanssheet ] )
, we have @xmath55 which is the mass expected for stars formed through thermal fragmentation of magnetically critical filaments . a similar , but somewhat smaller
, characteristic mass @xmath56 was defined in shu et al .
( 2004 ) in their study of the collapse of magnetized singular isothermal spheres .
the important conceptual point is that the magnetically critical jeans mass @xmath57 ( or @xmath58 ) decreases with an increasing magnetic field strength , because a stronger magnetic field can support a higher column density , which in turn leads to a higher volume density ( due to gravitational compression along the field lines ) and thus a lower thermal jeans mass .
it should be relatively insensitive to turbulence , which is expected to be weak at the relevant ( high ) densities . in any case , the magnetically critical jeans mass is typically smaller than the average thermal jeans mass , by a factor @xmath59 which is relatively insensitive to clump parameters .
it is therefore not too surprising that a moderately strong field can lower the characteristic mass of the stars formed in a cluster significantly , as we found numerically .
magnetism is another way of setting a stellar mass scale that is distinct from the one advocated by larson ( 2005 ) , based on detailed thermal physics of molecular cloud material ( e.g. , jappsen et al .
2005 and bonnell et al .
2006 ) . to summarize
, we have demonstrated through both amr mhd simulations ( [ numerical ] ) and analytic considerations ( eqs .
[ [ locallambda]]-[[ratio ] ] ) that moderately strong magnetic fields of the observed strengths ( corresponding to a dimensionless mass - to - flux ratio of a few ) are important in shaping the mass distribution of stars produced in turbulent , cluster - forming , dense clumps .
the basic reason is that the field interacts strongly with the turbulent flows , which affects how the flows create regions unstable to gravitational collapse and star formation .
the magnetic field prevents sub - regions of the clump that are magnetically subcritical ( with masses less than the average magnetic jeans mass @xmath46 ) from being compressed directly into collapse by the turbulence .
the magnetic resistance to turbulent compression has apparently reduced the number of intermediate mass stars formed in our simulations .
more importantly , the intrinsically anisotropic magnetic forces channel part of the clump material along the field lines into dense structures , where the high density promotes the formation of low - mass stars with masses comparable to the magnetically critical jeans mass @xmath60 , which lowers the characteristic stellar mass .
the mass is further reduced by outflow feedback , which affects not only the individual stars that drive the outflows , but also the dynamics of the clump as a whole .
we conclude that magnetic fields and outflow feedback are important factors that should be accounted for in a complete theory of the stellar imf .
this work was supported in part by nasa grants ( nng06gj33 g and nnx10ah30 g ) and a grant - in - aid for scientific research of japan ( 20540228 ) . | magnetic fields are generally expected to increase the characteristic mass of stars formed in stellar clusters , because they tend to increase the effective jeans mass .
we test this expectation using adaptive mesh refinement ( amr ) magnetohydrodynamic simulations of cluster formation in turbulent magnetized clumps of molecular clouds , treating stars as accreting sink particles .
we find that , contrary to the common expectation , a magnetic field of strength in the observed range decreases , rather than increases , the characteristic stellar mass .
it ( 1 ) reduces the number of intermediate - mass stars that are formed through direct turbulent compression , because sub - regions of the clump with masses comparable to those of stars are typically magnetically subcritical and can not be compressed directly into collapse , and ( 2 ) increases the number of low - mass stars that are produced from the fragmentation of dense filaments .
the filaments result from mass accumulation along the field lines . in order to become magnetically supercritical and fragment
, the filament must accumulate a large enough column density ( proportional to the field strength ) , which yields a high volume density ( and thus a small thermal jeans mass ) that is conducive to forming low - mass stars .
we find , in addition , that the characteristic stellar mass is reduced further by outflow feedback .
the conclusion is that both magnetic fields and outflow feedback are important in shaping the stellar initial mass function ( imf ) . | <s>[INST]how the initial mass function ( imf ) of stars originates is one of the most basic questions that a complete theory of star formation must answer .
it is also one of the most difficult ( see reviews by bonnell et al .
2007 and mckee & ostriker 2007 and references therein ) .
many ideas have been advanced to explain the imf , including zinnecker ( 1982 ) , adams & fatuzzo ( 1996 ) , elmegreen ( 1997 ) , padoan & nordlund ( 2002 ) , larson ( 2003 ) , shu et al .
( 2004 ) , hennebelle & chabrier ( 2008 ) , and kunz & mouschovias ( 2009 ) , among others .
particularly intriguing is the proposal by padoan & nordlund ( 2002 ) that the imf is essentially determined by the supersonic turbulence , which controls the density distribution in the highly inhomogeneous clouds .
they used the jeans criterion to determine analytically the mass distribution of the gravitationally unstable regions , which was taken to represent the stellar imf .
both ingredients of the theory , the turbulent structuring of cloud density and the criterion for gravitational collapse , are strongly affected , however , by a dynamically important magnetic field .
some magnetic effects on the imf , such as the magnetic cushion of turbulent compression ( padoan & nordlund 2002 ) and the additional cloud support by magnetic pressure ( hennebelle & chabrier 2008 ) , can be incorporated into the analytic theory approximately .
other equally , if not more , important magnetic effects are not captured by the theory , and will be the focus of our investigation .
our study will concentrate on the parsec - scale , cluster - forming dense clumps of molecular clouds , where the majority of stars , especially massive stars , are thought to originate ( lada & lada 2003 ) , and where magnetic fields have been observed in some cases . for example , in the nearest region of active massive star formation , omc1 , a well - ordered field is inferred from polarized dust emission ( e.g. , vaillancourt et al .
crutcher et al .
( 1999 ) obtained , from cn zeeman measurements , a line - of - sight field strength @xmath0 @xmath1 g for this region , which corresponds to a dimensionless mass - to - flux ratio @xmath2 .
the ratio is close to the median value @xmath3 obtained by falgarone et al .
( 2008 ) for a sample of dense clumps of massive star formation .
correcting for the projection effects may reduce the ratio by a factor of 2 - 3 ( shu et al .
1999 ) , yielding a median value for the intrinsic mass - to - flux ratio of 2 - 3 . a magnetic field corresponding to @xmath4a
few would not be strong enough to support the clump against gravitational collapse by itself .
it can , however , change the mass distribution of the stars formed .
this is because individual stars form out of sub - regions of the clump , which are generally more strongly magnetized ( relative to their masses ) than the clump as a whole ( i.e. , with smaller values of @xmath5 , tilley & pudritz 2007 ; dib et al .
2007 ) , because the mass of a region ( which is proportional to volume ) decreases faster with its size than the magnetic flux ( which is proportional to area ) .
in particular , sub - regions smaller than the clump by a factor comparable to @xmath5 are expected to be magnetically subcritical ( with @xmath6 ) in general .
it would be hard to directly compress such regions into collapse by turbulence in the ideal mhd limit ( see , however , nakamura & li 2005 and basu et al .
2009 for studies that include ambipolar diffusion ) .
another effect is that the magnetic forces act on the turbulent flows anisotropically , channeling matter along the field lines into dense , flattened structures that can subsequently fragment thermally . in this letter , we seek to quantify the above effects using the cluster formation simulations of wang et al .
( 2010 ) , which were carried out with an amr mhd code that includes sink particles and outflow feedback .
we find , in
[ numerical ] , that the characteristic mass of the imf is lowered by both the magnetic field and outflow feedback .
the lowering of the characteristic stellar mass by magnetic fields is somewhat counter - intuitive .
it is interpreted physically using a so - called `` magnetically critical jeans mass '' ( eq .
[ [ magneticallycriticaljeansmass ] ] ) in [ discussion ] .
in wang et al . ( 2010 ) , we simulated cluster formation in moderately condensed , isothermal ( @xmath7 k ) , clump of 2 pc in size and @xmath8 m@xmath9 in mass .
we added to the clump , one by one , an initial turbulent velocity field of rms mach number 9 ( model hd ) , an initially uniform magnetic field of @xmath10 @xmath1 g ( corresponding to a dimensionless mass - to - flux ratio of 1.4 for the clump as a whole and a larger value of 3.3 for the central , high - density part ; model mhd ) , and mechanical feedback from collimated outflows driven by accreting stellar objects ( model wind ) . for simulation details
we refer the reader to wang et al .
( 2010 ) , where we also presented results on the global star formation rate and especially the formation of the most massive object in each simulation . here
, we will concentrate on the distribution of the stellar masses , with an emphasis on low and intermediate mass objects .
figure 1 shows the stellar mass distributions for all three models .
it is a log - linear plot of the number of stars in logarithmic mass bins of @xmath11=0.2 $ ] ( where @xmath12 is the stellar mass in m@xmath9 ) .
the distributions are all evaluated at the time when @xmath13 of the total mass has been converted into stars .
it corresponds to 1.16 myr for model wind ( the last output ) , and 0.576 and 0.723 myr for model hd and mhd , respectively ; for comparison , the free - fall time is @xmath14 myr at the clump center initially and @xmath15 myr in a sphere of 1 pc in radius . before proceeding to analyze the
numerically obtained mass distributions in fig . 1 , we should caution the reader that the mass of a star can be affected by many factors that are only crudely modeled in the current generation of large - scale cluster formation simulations , including our own .
these include ( 1 ) outflow feedback , which can potentially remove a large fraction , perhaps the majority of the mass of a star - forming core ( shu et al .
1987 ; matzner & mckee 2000 ; myers 2008 ) , ( 2 ) magnetic fields , which affect not only how dense cores form but also how they collapse , and ( 3 ) radiative feedback which , once a protostellar system ( protostar plus disk ) appears , heats up the circumstellar material and suppresses fragmentation close to the central object ( e.g. , krumholz et al .
2007 ; offner et al . 2009 ; price & bate 2009 ; smith et al . 2009 ; urban et al . 2009 ) .
it is currently not feasible to treat simultaneously all these factors in detail .
our strategy is to focus on magnetic fields and outflow feedback , which are less well studied , and treat the effects of radiative feedback as simply as possible .
specifically , we crudely capture the suppression of fragmentation near a star due to radiative feedback using a sink - particle merging algorithm , following krumholz et al .
( 2004 , see also discussion in federrath et al .
it eliminates very low mass ( @xmath16 m@xmath9 ) sink particles within a distance @xmath17 au of an existing star ( with mass @xmath18 ) .
experimentation shows that increasing @xmath19 to @xmath20 m@xmath9 does not change the star formation rate or the stellar mass distribution significantly .
the adopted merging distance @xmath21 is comparable to the radius of the so - called `` sphere of thermal influence '' ( where the temperature of the radiatively heated protostellar envelope drops to the ambient value ) of an object of solar mass and luminosity ( see equation [ 14 ] and figure 2 of adams & shu 1985 ) .
we find that increasing @xmath21 from 1000 au to 2000 au has little effect on the star formation rate and stellar mass distribution .
decreasing it to @xmath22 au ( or three times the size of the finest cell ) does not change the total star formation rate , but can change the number and masses of stars significantly , by up to 50% .
we believe , however , that the smaller merging distance is less realistic , since the gas on the smaller scale is expected to be more strongly heated .
the larger merging distance prevents a collapsing core from breaking up into many small pieces , in agreement with the fact that the best observed cores in nearby star - forming regions typically harbor one , at most a few , stellar systems ( e.g. , mundy et al .
nevertheless , in view of our crude representation of radiative feedback , we elect to focus on the difference between the stellar mass distributions of the three simulations , which use the same sink particle treatment , rather than the distributions themselves .
the magnetic field is solely responsible for the difference between model hd and mhd . from fig . 1 , we see that its main effects are to reduce the number of those intermediate - mass stars with masses around @xmath23 m@xmath9 , and to increase the number of lower mass stars with masses around @xmath24 m@xmath9 .
to be more quantitative , we fit the high mass end of the distribution with a power - law , @xmath25 , as shown in fig .
[ imf_log ] . in all three cases
the mass distribution deviates sharply from the power - law fit below a characteristic mass , @xmath26 ( sometimes dubbed the `` knee '' of the imf , e.g. , bonnell et al .
the values of @xmath26 and power - law index @xmath27 are listed in table 1 .
note that the characteristic mass of @xmath28 in model hd is not far from the initial jeans mass near the clump center , @xmath29 , consistent with bonnell et al .
the power - indexes are not well determined because of the limited number of stars in the power - law regime . nevertheless , they are all comparable to the salpeter value within uncertainties .
the characteristic masses are , however , significantly different .
in particular , the magnetic field in model mhd has apparently lowered the characteristic mass by a factor of @xmath23 compared to that in model hd .
to help understand why the field hampers the formation of intermediate - mass stars , we show in figure [ excessstars ] a snapshot of the so - called `` hd excess stars , '' defined somewhat arbitrarily as those stars in hd model in figs . 1 and 2 with masses in the three mass bins between @xmath30 and @xmath31 m@xmath9 .
the majority of these stars are produced at relatively isolated regions , by localized converging flows in the initial turbulence .
such regions are largely absent in the mhd model , where a moderately strong global magnetic field is present .
the reduction in the number of intermediate - mass stars makes the stellar mass distribution significantly narrower in the mhd model than in the hd model ( see table 1 and figs . 1 and 2 ) .
the magnetic field in the mhd model interacts strongly with the turbulence .
it changes the `` texture '' of the turbulent clump , by not only resisting the cross - field turbulent compression , but also promoting mass accumulation along the field lines into flattened sheets or filaments .
[ mhd3d ] shows an example of the ( flattened ) filaments resulted from the intrinsically anisotropic magnetic forces .
it is in such magnetically - induced filaments that the majority of the stars in the mhd model form . as we discuss in [ discussion ] , the high density in the filaments favors the formation of low - mass stars , which are more numerous compared to the non - magnetic hd model . outflow feedback is responsible for the difference between model wind and mhd . from figs . 1 and 2
, it is clear that the outflows have ( 1 ) shifted the characteristic mass @xmath26 to a lower value , from @xmath32 m@xmath9 to @xmath33 m@xmath9 , and ( 2 ) nearly doubled the number of stars , from 119 to 203 ( see table 1 ) .
the lowering of the stellar mass by outflow feedback is perhaps not too surprising , because , individually , the outflow from a given star can remove part of the dense envelope that feeds the growing star ( shu et al .
1987 ; matzner & mckee 2000 ; myers 2008 ) and , collectively , the feedback from all stars can prevent the clump from rapid global collapse ( nakamura & li 2007 ; wang et al .
2010 ) , lowering the total rate of stellar mass accretion .
there is , however , a large spread in both the rate and the duration of the mass accretion in stars of similar masses .
the spread makes it difficult to develop a complete picture of how the outflows lower the characteristic stellar mass precisely .
the number of stars produced per unit time ( i.e. , the stellar production rate ) turns out to be insensitive to the outflow feedback .
it takes longer , however , to convert the same amount of gas into stars in the presence of the feedback , which is the main reason for the larger number of stars in model wind than in model mhd .
we have shown that a magnetic field of strength in the observed range changes the imf significantly , by impeding direct turbulent compression of relatively low density material into relatively massive stars and , more importantly , promoting the formation of dense , flattened structures that subsequently fragment preferentially into low - mass stars .
the basic reason for the magnetic field to impede direct turbulent fragmentation is that a sub - region of the clump that is magnetically subcritical can not be compressed into prompt collapse by turbulence . for a region of size @xmath34 in a clump of average field strength @xmath35 and mass density @xmath36 ,
the characteristic dimensionless mass - to - flux ratio is @xmath37 which indicates that regions smaller than the characteristic size @xmath38 are typically magnetically subcritical ( with @xmath6 ) .
the characteristic size is related to the clump size @xmath39 by @xmath40 ( where `` cp '' stands for `` clump '' ) , since the mass - to - flux ratio of the clump as a whole is @xmath41 according to equation ( [ locallambda ] ) . in other words , a typical region that is smaller than the clump by a factor of @xmath42
can not be compressed directly into collapse by turbulence .
the corresponding characteristic mass is @xmath43 where we have scaled the clump mass @xmath44 by @xmath45 m@xmath9 , and the clump mass - to - flux ratio by 2.5 , comparable to the ( projection - corrected ) median value inferred from cn zeeman observations ( see discussion in [ intro ] ) .
the characteristic mass @xmath46 is essentially the magnetic jeans mass at the average clump density ( see equation [ 41 ] of mckee 1999 , which gives a numerical value three times larger ) .
it is to be compared with the average thermal jeans mass @xmath47 ( e.g. , spitzer 1978 ) .
the average magnetic jeans mass @xmath46 is therefore typically larger than the average thermal jeans mass @xmath48 , indicating that the formation of those stars with masses comparable to @xmath48 or smaller by direct turbulent compression can be strongly hindered by the magnetic field .
the most massive stars are expected to be least affected by the magnetic field .
however , their formation may be governed more by the global clump collapse ( retarded by outflow feedback and magnetic fields ) than by direct turbulent compression ( wang et al .
2010 ; see also smith et al .
indeed , massive ( @xmath49 ) stars in model mhd contain more mass than those in model hd , indicating that their formation is not hampered by magnetic fields , unlike intermediate mass stars .
the magnetic field can also promote fragmentation , because of the magnetic forces are intrinsically anisotropic .
it is easier for the turbulent flows to move material along the field lines than across them .
the net result is the formation of flattened , sheet- or filament - like condensations , which are conducive to fragmentation .
larson ( 1985 ) estimated the jeans mass for a self - gravitating sheet ( thermally supported in the vertical direction ) to be @xmath50 where @xmath51 is the isothermal sound speed , and @xmath52 the column density . in order to form stars ,
the sheet must first become magnetically supercritical , with a column density greater than the critical value @xmath53 . substituting @xmath54 into equation ( [ jeanssheet ] )
, we have @xmath55 which is the mass expected for stars formed through thermal fragmentation of magnetically critical filaments . a similar , but somewhat smaller
, characteristic mass @xmath56 was defined in shu et al .
( 2004 ) in their study of the collapse of magnetized singular isothermal spheres .
the important conceptual point is that the magnetically critical jeans mass @xmath57 ( or @xmath58 ) decreases with an increasing magnetic field strength , because a stronger magnetic field can support a higher column density , which in turn leads to a higher volume density ( due to gravitational compression along the field lines ) and thus a lower thermal jeans mass .
it should be relatively insensitive to turbulence , which is expected to be weak at the relevant ( high ) densities . in any case , the magnetically critical jeans mass is typically smaller than the average thermal jeans mass , by a factor @xmath59 which is relatively insensitive to clump parameters .
it is therefore not too surprising that a moderately strong field can lower the characteristic mass of the stars formed in a cluster significantly , as we found numerically .
magnetism is another way of setting a stellar mass scale that is distinct from the one advocated by larson ( 2005 ) , based on detailed thermal physics of molecular cloud material ( e.g. , jappsen et al .
2005 and bonnell et al .
2006 ) . to summarize
, we have demonstrated through both amr mhd simulations ( [ numerical ] ) and analytic considerations ( eqs .
[ [ locallambda]]-[[ratio ] ] ) that moderately strong magnetic fields of the observed strengths ( corresponding to a dimensionless mass - to - flux ratio of a few ) are important in shaping the mass distribution of stars produced in turbulent , cluster - forming , dense clumps .
the basic reason is that the field interacts strongly with the turbulent flows , which affects how the flows create regions unstable to gravitational collapse and star formation .
the magnetic field prevents sub - regions of the clump that are magnetically subcritical ( with masses less than the average magnetic jeans mass @xmath46 ) from being compressed directly into collapse by the turbulence .
the magnetic resistance to turbulent compression has apparently reduced the number of intermediate mass stars formed in our simulations .
more importantly , the intrinsically anisotropic magnetic forces channel part of the clump material along the field lines into dense structures , where the high density promotes the formation of low - mass stars with masses comparable to the magnetically critical jeans mass @xmath60 , which lowers the characteristic stellar mass .
the mass is further reduced by outflow feedback , which affects not only the individual stars that drive the outflows , but also the dynamics of the clump as a whole .
we conclude that magnetic fields and outflow feedback are important factors that should be accounted for in a complete theory of the stellar imf .
this work was supported in part by nasa grants ( nng06gj33 g and nnx10ah30 g ) and a grant - in - aid for scientific research of japan ( 20540228 ) .[/INST] magnetic fields are generally expected to increase the characteristic mass of stars formed in stellar clusters , because they tend to increase the effective jeans mass .
we test this expectation using adaptive mesh refinement ( amr ) magnetohydrodynamic simulations of cluster formation in turbulent magnetized clumps of molecular clouds , treating stars as accreting sink particles .
we find that , contrary to the common expectation , a magnetic field of strength in the observed range decreases , rather than increases , the characteristic stellar mass .
it ( 1 ) reduces the number of intermediate - mass stars that are formed through direct turbulent compression , because sub - regions of the clump with masses comparable to those of stars are typically magnetically subcritical and can not be compressed directly into collapse , and ( 2 ) increases the number of low - mass stars that are produced from the fragmentation of dense filaments .
the filaments result from mass accumulation along the field lines . in order to become magnetically supercritical and fragment
, the filament must accumulate a large enough column density ( proportional to the field strength ) , which yields a high volume density ( and thus a small thermal jeans mass ) that is conducive to forming low - mass stars .
we find , in addition , that the characteristic stellar mass is reduced further by outflow feedback .
the conclusion is that both magnetic fields and outflow feedback are important in shaping the stellar initial mass function ( imf ) . </s> |
Mr. Sater said it would be “pretty cool to get a USA President elected” and said he desired to be the ambassador to the Bahamas. “That my friend is the home run I want out of this,” he wrote.
Mr. Sater — a former F.B.I. informant who is famous for having once smashed a martini glass stem into another man’s face — has maintained a relationship with Mr. Cohen over the years. The two men have spent decades operating in the world of New York commercial real estate, where the sources of funding can be murky.
Through his lawyer, Mr. Sater declined on Monday to address why he thought the deal would be a political win for Mr. Trump. He said he brought the project to Mr. Cohen in late 2015, but that he was not working for the Trump Organization and “would not have been compensated” by them.
“During the course of our communications over several months, I routinely expressed my enthusiasm regarding what a tremendous opportunity this was for the Trump Organization,” Mr. Sater said.
Mr. Sater was a broker for the Trump Organization for several years, typically paid to deliver real estate deals. A company he worked for, Bayrock, played a role in financing the Trump SoHo Hotel in New York. Mr. Sater and Mr. Cohen even worked together on a peace plan for Ukraine and Russia that they sought to get in front of Mr. Trump’s national security adviser earlier this year.
As a broker for the Trump Organization, Mr. Sater had an incentive to overstate his business-making acumen. He presents himself in his emails as so influential in Russia that he helped arrange a 2006 trip that Mr. Trump’s daughter, Ivanka, took to Moscow.
“I arranged for Ivanka to sit in Putins private chair at his desk and office in the Kremlin,” he said. ||||| While Donald Trump was running for president in late 2015 and early 2016, his company was pursuing a plan to develop a massive Trump Tower in Moscow, according to several people familiar with the proposal and new records reviewed by Trump Organization lawyers.
As part of the discussions, a Russian-born real estate developer urged Trump to come to Moscow to tout the proposal and suggested that he could get President Vladimir Putin to say “great things” about Trump, according to several people who have been briefed on his correspondence.
The developer, Felix Sater, predicted in a November 2015 email that he and Trump Organization leaders would soon be celebrating — both one of the biggest residential projects in real estate history and Donald Trump’s election as president, according to two of the people with knowledge of the exchange.
Sater wrote to Trump Organization Executive Vice President Michael Cohen “something to the effect of, ‘Can you believe two guys from Brooklyn are going to elect a president?’ ” said one person briefed on the email exchange. Sater emigrated from what was then the Soviet Union when he was 6 and grew up in Brooklyn.
Trump never went to Moscow as Sater proposed. And although investors and Trump’s company signed a letter of intent, they lacked the land and permits to proceed and the project was abandoned at the end of January 2016, just before the presidential primaries began, several people familiar with the proposal said.
Nevertheless, the details of the deal, which have not previously been disclosed, provide evidence that Trump’s business was actively pursuing significant commercial interests in Russia at the same time he was campaigning to be president — and in a position to determine U.S.-Russia relations. The new details from the emails, which are scheduled to be turned over to congressional investigators soon, also point to the likelihood of additional contacts between Russia-connected individuals and Trump associates during his presidential bid.
White House officials declined to comment for this report. Cohen, a longtime Trump legal adviser, declined to comment, but his attorney, Stephen Ryan, said his client “has been cooperating and will continue to cooperate with both the House and Senate intelligence committees, including providing them with documents and information and answering any questions they may have about the Moscow building proposal.”
In recent months, contacts between high-ranking and lower- level Trump aides and Russians have emerged. Attorney General Jeff Sessions, then a U.S. senator and campaign adviser, twice met Russian Ambassador Sergey Kislyak.
Donald Trump Jr. organized a June 2016 meeting with campaign aide Jared Kushner, campaign manager Paul Manafort and a Russian lawyer after the president’s eldest son was promised that the lawyer would bring damaging information about Hillary Clinton as part of a Russian government effort to help the campaign.
Internal emails also show campaign adviser George Papadopoulos repeatedly sought to organize meetings with campaign officials, including Trump, and Putin or other Russians. His efforts were rebuffed.
The negotiations for the Moscow project ended before Trump’s business ties to Russia had become a major issue in the campaign. Trump denied having any business connections to Russia in July 2016, tweeting, “for the record, I have ZERO investments in Russia” and then insisting at a news conference the following day, “I have nothing to do with Russia.”
While campaigning during the 2016 election, President Trump’s company was pursuing a plan to develop a massive Trump Tower in Moscow, according to several people familiar with the proposal. (Amber Ferguson/The Washington Post)
Discussions about the Moscow project began in earnest in September 2015, according to people briefed on the deal. An unidentified investor planned to build the project and, under a licensing agreement, put Trump’s name on it. Cohen acted as a lead negotiator for the Trump Organization. It is unclear how involved or aware Trump was of the negotiations.
As the talks progressed, Trump voiced numerous supportive comments about Putin, setting himself apart from his Republican rivals for the nomination.
By the end of 2015, Putin began offering praise in return.
“He says that he wants to move to another, closer level of relations. Can we really not welcome that? Of course, we welcome that,” Putin told reporters during his annual end-of-the year news conference. He called Trump a “colorful and talented” person. Trump said afterward that the compliment was an “honor.”
Though Putin’s comments came shortly after Sater suggested that the Russian president would speak favorably about Trump, there is no indication that the two are connected.
There is no public record that Trump has ever spoken about the effort to build a Trump Tower in 2015 and 2016.
Trump’s interests in building in Moscow, however, are long-standing. He had attempted to build a Trump property for three decades, starting with a failed effort in 1987 to partner with the Soviet government on a hotel project.
“Russia is one of the hottest places in the world for investment,” he said in a 2007 court deposition.
“We will be in Moscow at some point,” he promised in the deposition.
Sater was involved in at least one of those previous efforts. In 2005, the Trump Organization gave his development company, the Bayrock Group, an exclusive one-year deal to attempt to build a Moscow Trump Tower. Sater located a site for the project — an abandoned pencil factory — and worked closely with Trump on the deal, which did not come to fruition.
In an unrelated court case in 2008, Sater said in a deposition that he would personally provide Trump “verbal updates” on the deal.
“When I’d come back, pop my head into Mr. Trump’s office and tell him, you know, ‘Moving forward on the Moscow deal.’ And he would say, ‘All right,’ ” Sater said.
In the same testimony, Sater described traveling with Trump’s children, including joining Ivanka and Donald Trump Jr. on a trip to Moscow at their father’s request.
“They were on their way by themselves, and he was all concerned,” Sater said. “He asked if I wouldn’t mind joining them and looking after them while they were in Moscow.”
Alan Garten, a lawyer for the Trump Organization, told The Washington Post last year that Sater happened to be in Moscow at the same time as Trump’s two adult children. “There was no accompanying them to Moscow,” he said.
Neither Sater nor his attorney responded to requests for comment.
Trump has repeatedly tried to distance himself from Sater, who served time in jail after assaulting a man with the stem of a broken margarita glass during a 1991 bar fight and then pleaded guilty in 1998 to his role in an organized- crime-linked stock fraud. Sater’s sentencing was delayed for years while he cooperated with the federal government on a series of criminal and national security-related investigations, federal officials have said.
During that time, Sater worked as an executive with Bayrock, whose offices were in Trump Tower, and brokered deals to license Trump’s name for developments in multiple U.S. and foreign cities. In 2010, Trump allowed Sater to briefly work out of Trump Organization office space and use a business card that identified him as a “senior adviser to Donald Trump.”
Still, when asked about Sater in 2013 court deposition, Trump said: “If he were sitting in the room right now, I really wouldn’t know what he looked like.” He added that he had spoken with Sater “not many” times. | – On Monday, the Washington Post reported on the existence of emails between a business associate of Donald Trump and Trump's lawyer back in 2015 that suggested the Trump camp was exploring the idea of building a Trump Tower in Moscow. The Post presented this as a conflict of interest because it would have given Trump, then running for president, a major business interest in Russia. The deal never came to pass, but now the New York Times has a follow-up on the actual content of those emails, sent by the Russian-born Felix Sater to Trump attorney Michael Cohen. Sater, the Times explains, was a broker for the Trump Organization who earned money by delivering real estate deals. And he was pushing hard for this one, suggesting it would help Trump's chances of getting elected: Our boy: “Buddy," Sater wrote, "our boy can become president of the USA and we can engineer it. I will get all of Putins team to buy in on this, I will manage this process.” Ivanka: At another point, Sater, in an apparent attempt to boast of his connections, said he helped arrange a visit to the Kremlin by Ivanka Trump in 2006. “I arranged for Ivanka to sit in Putins private chair at his desk and office in the Kremlin," he wrote. In a statement, Ivanka Trump confirmed she visited the Kremlin but said she never met Putin. She didn't address the odd chair statement. So what does all this mean? Cohen, for his part, says not much because Sater is prone to "puffery." But the emails are now in the hands of the House Intelligence Committee as part of its investigation into Russian meddling in the 2016 election. The Trump Organization said Monday that it "has never had any real estate holdings or interests in Russia.” | <s>[INST]Mr. Sater said it would be “pretty cool to get a USA President elected” and said he desired to be the ambassador to the Bahamas. “That my friend is the home run I want out of this,” he wrote.
Mr. Sater — a former F.B.I. informant who is famous for having once smashed a martini glass stem into another man’s face — has maintained a relationship with Mr. Cohen over the years. The two men have spent decades operating in the world of New York commercial real estate, where the sources of funding can be murky.
Through his lawyer, Mr. Sater declined on Monday to address why he thought the deal would be a political win for Mr. Trump. He said he brought the project to Mr. Cohen in late 2015, but that he was not working for the Trump Organization and “would not have been compensated” by them.
“During the course of our communications over several months, I routinely expressed my enthusiasm regarding what a tremendous opportunity this was for the Trump Organization,” Mr. Sater said.
Mr. Sater was a broker for the Trump Organization for several years, typically paid to deliver real estate deals. A company he worked for, Bayrock, played a role in financing the Trump SoHo Hotel in New York. Mr. Sater and Mr. Cohen even worked together on a peace plan for Ukraine and Russia that they sought to get in front of Mr. Trump’s national security adviser earlier this year.
As a broker for the Trump Organization, Mr. Sater had an incentive to overstate his business-making acumen. He presents himself in his emails as so influential in Russia that he helped arrange a 2006 trip that Mr. Trump’s daughter, Ivanka, took to Moscow.
“I arranged for Ivanka to sit in Putins private chair at his desk and office in the Kremlin,” he said. ||||| While Donald Trump was running for president in late 2015 and early 2016, his company was pursuing a plan to develop a massive Trump Tower in Moscow, according to several people familiar with the proposal and new records reviewed by Trump Organization lawyers.
As part of the discussions, a Russian-born real estate developer urged Trump to come to Moscow to tout the proposal and suggested that he could get President Vladimir Putin to say “great things” about Trump, according to several people who have been briefed on his correspondence.
The developer, Felix Sater, predicted in a November 2015 email that he and Trump Organization leaders would soon be celebrating — both one of the biggest residential projects in real estate history and Donald Trump’s election as president, according to two of the people with knowledge of the exchange.
Sater wrote to Trump Organization Executive Vice President Michael Cohen “something to the effect of, ‘Can you believe two guys from Brooklyn are going to elect a president?’ ” said one person briefed on the email exchange. Sater emigrated from what was then the Soviet Union when he was 6 and grew up in Brooklyn.
Trump never went to Moscow as Sater proposed. And although investors and Trump’s company signed a letter of intent, they lacked the land and permits to proceed and the project was abandoned at the end of January 2016, just before the presidential primaries began, several people familiar with the proposal said.
Nevertheless, the details of the deal, which have not previously been disclosed, provide evidence that Trump’s business was actively pursuing significant commercial interests in Russia at the same time he was campaigning to be president — and in a position to determine U.S.-Russia relations. The new details from the emails, which are scheduled to be turned over to congressional investigators soon, also point to the likelihood of additional contacts between Russia-connected individuals and Trump associates during his presidential bid.
White House officials declined to comment for this report. Cohen, a longtime Trump legal adviser, declined to comment, but his attorney, Stephen Ryan, said his client “has been cooperating and will continue to cooperate with both the House and Senate intelligence committees, including providing them with documents and information and answering any questions they may have about the Moscow building proposal.”
In recent months, contacts between high-ranking and lower- level Trump aides and Russians have emerged. Attorney General Jeff Sessions, then a U.S. senator and campaign adviser, twice met Russian Ambassador Sergey Kislyak.
Donald Trump Jr. organized a June 2016 meeting with campaign aide Jared Kushner, campaign manager Paul Manafort and a Russian lawyer after the president’s eldest son was promised that the lawyer would bring damaging information about Hillary Clinton as part of a Russian government effort to help the campaign.
Internal emails also show campaign adviser George Papadopoulos repeatedly sought to organize meetings with campaign officials, including Trump, and Putin or other Russians. His efforts were rebuffed.
The negotiations for the Moscow project ended before Trump’s business ties to Russia had become a major issue in the campaign. Trump denied having any business connections to Russia in July 2016, tweeting, “for the record, I have ZERO investments in Russia” and then insisting at a news conference the following day, “I have nothing to do with Russia.”
While campaigning during the 2016 election, President Trump’s company was pursuing a plan to develop a massive Trump Tower in Moscow, according to several people familiar with the proposal. (Amber Ferguson/The Washington Post)
Discussions about the Moscow project began in earnest in September 2015, according to people briefed on the deal. An unidentified investor planned to build the project and, under a licensing agreement, put Trump’s name on it. Cohen acted as a lead negotiator for the Trump Organization. It is unclear how involved or aware Trump was of the negotiations.
As the talks progressed, Trump voiced numerous supportive comments about Putin, setting himself apart from his Republican rivals for the nomination.
By the end of 2015, Putin began offering praise in return.
“He says that he wants to move to another, closer level of relations. Can we really not welcome that? Of course, we welcome that,” Putin told reporters during his annual end-of-the year news conference. He called Trump a “colorful and talented” person. Trump said afterward that the compliment was an “honor.”
Though Putin’s comments came shortly after Sater suggested that the Russian president would speak favorably about Trump, there is no indication that the two are connected.
There is no public record that Trump has ever spoken about the effort to build a Trump Tower in 2015 and 2016.
Trump’s interests in building in Moscow, however, are long-standing. He had attempted to build a Trump property for three decades, starting with a failed effort in 1987 to partner with the Soviet government on a hotel project.
“Russia is one of the hottest places in the world for investment,” he said in a 2007 court deposition.
“We will be in Moscow at some point,” he promised in the deposition.
Sater was involved in at least one of those previous efforts. In 2005, the Trump Organization gave his development company, the Bayrock Group, an exclusive one-year deal to attempt to build a Moscow Trump Tower. Sater located a site for the project — an abandoned pencil factory — and worked closely with Trump on the deal, which did not come to fruition.
In an unrelated court case in 2008, Sater said in a deposition that he would personally provide Trump “verbal updates” on the deal.
“When I’d come back, pop my head into Mr. Trump’s office and tell him, you know, ‘Moving forward on the Moscow deal.’ And he would say, ‘All right,’ ” Sater said.
In the same testimony, Sater described traveling with Trump’s children, including joining Ivanka and Donald Trump Jr. on a trip to Moscow at their father’s request.
“They were on their way by themselves, and he was all concerned,” Sater said. “He asked if I wouldn’t mind joining them and looking after them while they were in Moscow.”
Alan Garten, a lawyer for the Trump Organization, told The Washington Post last year that Sater happened to be in Moscow at the same time as Trump’s two adult children. “There was no accompanying them to Moscow,” he said.
Neither Sater nor his attorney responded to requests for comment.
Trump has repeatedly tried to distance himself from Sater, who served time in jail after assaulting a man with the stem of a broken margarita glass during a 1991 bar fight and then pleaded guilty in 1998 to his role in an organized- crime-linked stock fraud. Sater’s sentencing was delayed for years while he cooperated with the federal government on a series of criminal and national security-related investigations, federal officials have said.
During that time, Sater worked as an executive with Bayrock, whose offices were in Trump Tower, and brokered deals to license Trump’s name for developments in multiple U.S. and foreign cities. In 2010, Trump allowed Sater to briefly work out of Trump Organization office space and use a business card that identified him as a “senior adviser to Donald Trump.”
Still, when asked about Sater in 2013 court deposition, Trump said: “If he were sitting in the room right now, I really wouldn’t know what he looked like.” He added that he had spoken with Sater “not many” times.[/INST]– On Monday, the Washington Post reported on the existence of emails between a business associate of Donald Trump and Trump's lawyer back in 2015 that suggested the Trump camp was exploring the idea of building a Trump Tower in Moscow. The Post presented this as a conflict of interest because it would have given Trump, then running for president, a major business interest in Russia. The deal never came to pass, but now the New York Times has a follow-up on the actual content of those emails, sent by the Russian-born Felix Sater to Trump attorney Michael Cohen. Sater, the Times explains, was a broker for the Trump Organization who earned money by delivering real estate deals. And he was pushing hard for this one, suggesting it would help Trump's chances of getting elected: Our boy: “Buddy," Sater wrote, "our boy can become president of the USA and we can engineer it. I will get all of Putins team to buy in on this, I will manage this process.” Ivanka: At another point, Sater, in an apparent attempt to boast of his connections, said he helped arrange a visit to the Kremlin by Ivanka Trump in 2006. “I arranged for Ivanka to sit in Putins private chair at his desk and office in the Kremlin," he wrote. In a statement, Ivanka Trump confirmed she visited the Kremlin but said she never met Putin. She didn't address the odd chair statement. So what does all this mean? Cohen, for his part, says not much because Sater is prone to "puffery." But the emails are now in the hands of the House Intelligence Committee as part of its investigation into Russian meddling in the 2016 election. The Trump Organization said Monday that it "has never had any real estate holdings or interests in Russia.”</s> |
la demande dune prise en charge dfinitive des maladies organiques terminales chez les canadiens infects par le vih est en hausse .
jusqu tout rcemment , malgr des donnes internationales faisant foi de rsultats cliniques positifs , les canadiens atteints dune maladie hpatique terminale infects par le vih ntaient pas admissibles une transplantation , sauf en colombie - britannique ( c .- b . ) , o le programme de transplantations de bc transplant les accepte en vue dun aiguillage , dune valuation , de linscription sur la liste dattente et de lexcution dune allogreffe du foie .
simpose pour dterminer les enjeux entourant la transplantation hpatique chez les patients infects par le vih .
les chercheurs ont procd ltude des dossiers des 28 patients infects par le vih qui ont t orients vers bc transplant pour subir une transplantation hpatique entre 2004 et 2013 .
ils ont collig les donnes sur ltat du vih et de la maladie hpatique , lvaluation initiale de la transplantation et les rsultats cliniques .
la majorit prsentait des charges virales indtectables du vih , prenaient des antirtroviraux et taient infects par le virus de lhpatite c ( n=16 ) .
les comorbidits les plus courantes taient lanxit et les troubles des humeurs ( n=4 ) , ainsi que lhmophilie ( n=4 ) .
parmi les patients admissibles la transplantation , quatre ont subi une transplantation conscutive une hpatite auto - immune ( 5,67 ans aprs la transplantation ) , une statose hpatique non alcoolique ( 2,33 ans ) , un virus de lhpatite c ( 2,25 ans ) et une co - infection par lhpatite b et le virus delta ( transplantation rcente ) .
un patient est dcd dune insuffisance rnale aigu alors quil tait en attente de transplantation .
dix sont dcds pendant la prvaluation et dix ntaient pas des candidats adquats pour la transplantation .
la principale raison de ne pas tre un candidat adquat tait une maladie stable ne ncessitant pas de transplantation ( n=4 ) .
jusqu prsent , les soins interdisciplinaires et une slection attentive des patients permettent dobtenir des rsultats positifs , y compris la prsence au canada du greff hpatique infect par le vih ayant vcu le plus longtemps depuis sa transplantation .
the present study was a retrospective chart review of 28 hiv - infected candidates between 2004 and 2013 .
all patients were seen by both the transplant social worker and the transplant psychologist , in addition to the transplant hepatology and surgical staff , and the transplant coordinators .
although it may appear that the candidates misled the assessment team in certain respects , there is no proof of this and , therefore , from an ethical perspective , the patients disclosures were assumed to be truthful .
the reasons for referral for transplantation were reviewed , in addition to the status of the patients and their clinical outcomes .
the present study was approved by the university of british columbia clinical research ethics board ( vancouver , bc ) . the liver transplant program s policy with regard to placement of hiv - infected patients on the transplant waiting list after successful assessment
include the following :
all candidates must meet the general criteria for transplantation that applies to all non - hiv - infected candidates ( eg , no active infection , no active malignancy , abstinence from substance abuse , etc).candidates should be on art supervised by an hiv specialist.candidates must be free from opportunistic infection.the hiv viral load should be undetectable.although there is no absolute threshold cd4 count , the minimum accepted cd4 count is approximately 150 cells / mmpatients who did not meet these criteria were assessed on an individual basis .
all candidates must meet the general criteria for transplantation that applies to all non - hiv - infected candidates ( eg , no active infection , no active malignancy , abstinence from substance abuse , etc ) .
although there is no absolute threshold cd4 count , the minimum accepted cd4 count is approximately 150 cells / mm
since 2004 , there have been 28 hiv - infected patients referred for liver transplant assessment . the majority ( 23 of 28 [ 82% ] ) of these patients
were men and most were assessed as outpatients of the pre - assessment clinic , with a small minority referred to the transplant program as inpatients ( including hospital to hospital transfer for assessment ) .
the mean age of these patients was 47 years and the mean follow - up time was 4.1 months ( table 1 ) .
the majority of these patients were bc residents ; some were from other provinces and one was from the united states .
all patients had chronic liver disease and there were no patients with acute liver failure assessed .
one patient in an out - of - province hospital was referred on an urgent basis to the liver transplant program with acute drug hepatotoxicity secondary to highly active art ( haart ) medications .
the program accepted the patient in transfer for the purposes of expedited transplant assessment but the patient died en route to bc .
there have been no other referrals of hiv - infected patients with acute liver failure .
five patients were coinfected with hbv and seven patients had nonviral causes of liver failure .
of the non - liver and non - hiv - related medical comorbidities , the majority of these patients also had hemophilia , anxiety and depression ( table 2 ) .
one patient had autoimmune hepatitis , one had nonalcoholic hepatosteatosis , one had hepatitis c , one had hbv and hepatitis delta virus coinfection , and one died waiting ( table 3 ) .
this patient was from out of province and referred to our centre specifically because of hiv infection .
the most common reason for transplant unsuitablility was stable liver disease not requiring transplantation ( n=4 ) .
the patients had undetectable hiv viral loads and were on haart at the time of transplantation .
currently , three patients with hcv are being assessed to determine whether they are suitable transplant candidates .
his immunosuppression induction consisted of low - dose tacrolimus ( ie , 0.5 mg every third day ) , mycophenolate mofetil and tapered corticosteroids because pharmacokinetic interactions with the haart medications occurred .
this patient sustained acute renal injury while on tacrolimus ; however , renal function has recovered and his graft is now receiving mycophenolate mofetil monotherapy .
this patient has not experienced any rejection episodes ; however , he has required regular endoscopic retrograde cholangiopancreatography to manage and drain biliary sludge due to recurrent biliary anastomotic stricture . as a result
, he has a persistent increase in hepatobiliary liver biochemistry ( ie , alkaline phosphatase , gammaglutamyl transferase ) .
patient 2 was transplanted at 55 years of age for nonalcoholic steatohepatitis ( nash ) .
this patient s hiv is controlled with abacavir / lamivudine ( kivexa , viiv healthcare , canada ) and raltegravir , and because there were no drug interactions , the standard induction tacrolimus , mycophenolate mofetil and tapered corticosteroid dosing was used .
this patient also has not experienced any graft rejection , but developed persistent increases in his serum alanine aminotransferase ( alt ) level , which was previously normal ( ie , alt 120 u / l to 150
this was initially attributed to recurrent nash at one year , four months post - transplant .
he was subsequently discovered to have acquired acute hcv genotype 1b infection that is now chronic .
recent elastography ( fibroscan , echosens , france ) revealed only mild fibrosis ( ie , metavir score f1 , where f4 is cirrhosis ) .
patient 3 was transplanted at 49 years of age for hcv coinfection and is two years , six months post - transplant .
this patient s hiv infection is controlled with kivexa and raltegravir , and also received standard induction dosing with tacrolimus , mycophenolate mofetil and tapered corticosteroids . at three months post - transplant ,
it was demonstrated biochemically and with a liver biopsy that there was evidence of graft hepatitis and metavir stage 2 fibrosis ( ie , f2 ) .
two years later , this patient has experienced decreasing alt and aspartate aminotransferase ( ast ) levels , with an increased serum bilitrubin level but no other evidence of decompensation . at two years , three months post - transplant ,
the patient s ascites is being managed with diuretics with the hope that he will be suitable for a non - interferon - based antiviral regimen in the future ( table 3 ) . the final transplanted patient is 50 years of age and has hbv and hepatitis delta virus coinfection , and hepatocellular carcinoma .
the immediate post - transplant complications included postoperative bleeding , acute renal dysfunction and delayed surgical biliary anastomosis .
pretransplant , the patient s hiv antiviral agents included tenofovir df / emtricitabine and raltegravir .
his hbv viral load was undetectable and locoregional therapy of his hepatocellular carcinoma included transarterial chemoembolization .
post - transplant , he has received hepatitis immunoglobulin in addition to tenofovir . despite a prolonged hospitalization for convalescence and physical rehabilitation ,
his hepatitis b surface antigen and hepatitis d nuclei acid tests have remained negative ( table 3 ) .
overall , the post - transplant quality of life in these transplant recipients has been excellent , although the recipient with pretransplant hcv infection has developed ascites more than two years post - transplant .
since 2004 , there have been 28 hiv - infected patients referred for liver transplant assessment . the majority ( 23 of 28 [ 82% ] ) of these patients
were men and most were assessed as outpatients of the pre - assessment clinic , with a small minority referred to the transplant program as inpatients ( including hospital to hospital transfer for assessment ) .
the mean age of these patients was 47 years and the mean follow - up time was 4.1 months ( table 1 ) .
the majority of these patients were bc residents ; some were from other provinces and one was from the united states .
all patients had chronic liver disease and there were no patients with acute liver failure assessed .
one patient in an out - of - province hospital was referred on an urgent basis to the liver transplant program with acute drug hepatotoxicity secondary to highly active art ( haart ) medications .
the program accepted the patient in transfer for the purposes of expedited transplant assessment but the patient died en route to bc .
there have been no other referrals of hiv - infected patients with acute liver failure .
five patients were coinfected with hbv and seven patients had nonviral causes of liver failure .
of the non - liver and non - hiv - related medical comorbidities , the majority of these patients also had hemophilia , anxiety and depression ( table 2 ) .
one patient had autoimmune hepatitis , one had nonalcoholic hepatosteatosis , one had hepatitis c , one had hbv and hepatitis delta virus coinfection , and one died waiting ( table 3 ) .
this patient was from out of province and referred to our centre specifically because of hiv infection .
the most common reason for transplant unsuitablility was stable liver disease not requiring transplantation ( n=4 ) .
the patients had undetectable hiv viral loads and were on haart at the time of transplantation .
currently , three patients with hcv are being assessed to determine whether they are suitable transplant candidates .
his immunosuppression induction consisted of low - dose tacrolimus ( ie , 0.5 mg every third day ) , mycophenolate mofetil and tapered corticosteroids because pharmacokinetic interactions with the haart medications occurred .
this patient sustained acute renal injury while on tacrolimus ; however , renal function has recovered and his graft is now receiving mycophenolate mofetil monotherapy .
this patient has not experienced any rejection episodes ; however , he has required regular endoscopic retrograde cholangiopancreatography to manage and drain biliary sludge due to recurrent biliary anastomotic stricture . as a result
, he has a persistent increase in hepatobiliary liver biochemistry ( ie , alkaline phosphatase , gammaglutamyl transferase ) .
patient 2 was transplanted at 55 years of age for nonalcoholic steatohepatitis ( nash ) .
this patient s hiv is controlled with abacavir / lamivudine ( kivexa , viiv healthcare , canada ) and raltegravir , and because there were no drug interactions , the standard induction tacrolimus , mycophenolate mofetil and tapered corticosteroid dosing was used .
this patient also has not experienced any graft rejection , but developed persistent increases in his serum alanine aminotransferase ( alt ) level , which was previously normal ( ie , alt 120 u / l to 150
this was initially attributed to recurrent nash at one year , four months post - transplant .
he was subsequently discovered to have acquired acute hcv genotype 1b infection that is now chronic .
recent elastography ( fibroscan , echosens , france ) revealed only mild fibrosis ( ie , metavir score f1 , where f4 is cirrhosis ) .
patient 3 was transplanted at 49 years of age for hcv coinfection and is two years , six months post - transplant .
this patient s hiv infection is controlled with kivexa and raltegravir , and also received standard induction dosing with tacrolimus , mycophenolate mofetil and tapered corticosteroids . at three months post - transplant ,
it was demonstrated biochemically and with a liver biopsy that there was evidence of graft hepatitis and metavir stage 2 fibrosis ( ie , f2 ) .
two years later , this patient has experienced decreasing alt and aspartate aminotransferase ( ast ) levels , with an increased serum bilitrubin level but no other evidence of decompensation . at two years , three months post - transplant ,
the patient s ascites is being managed with diuretics with the hope that he will be suitable for a non - interferon - based antiviral regimen in the future ( table 3 ) . the final transplanted patient is 50 years of age and has hbv and hepatitis delta virus coinfection , and hepatocellular carcinoma .
the immediate post - transplant complications included postoperative bleeding , acute renal dysfunction and delayed surgical biliary anastomosis .
pretransplant , the patient s hiv antiviral agents included tenofovir df / emtricitabine and raltegravir .
his hbv viral load was undetectable and locoregional therapy of his hepatocellular carcinoma included transarterial chemoembolization .
post - transplant , he has received hepatitis immunoglobulin in addition to tenofovir . despite a prolonged hospitalization for convalescence and physical rehabilitation ,
his hepatitis b surface antigen and hepatitis d nuclei acid tests have remained negative ( table 3 ) .
overall , the post - transplant quality of life in these transplant recipients has been excellent , although the recipient with pretransplant hcv infection has developed ascites more than two years post - transplant .
nearly a decade after the establishment of an hiv liver transplant program in bc , we demonstrated that successful transplantation in hiv - infected and hiv - hcv coinfected patients is possible .
the success of these candidates is due to a multidisciplinary team that includes a transplant surgical team , transplant medicine team , hiv specialty team and psychosocial support .
these patients were selected for transplantation based on their failing liver disease . there is absolutely no bias against the hiv - infected individual ; in fact , we have been their advocates . in the first year of the program , and in the time leading up to the establishment of the program , there was uncertainty as to what subgroup of hiv - infected patients would be suitable for transplantation . within a short time , however , the attitude of the liver transplant program became one of advocacy . with the realization that patients outside of bc did not have any option for transplantation within canada
, it was decided that no referred patient with hiv would be declined without assessment , both inside bc and outside of the province .
information about death during preassessment is often not accurate because if a patient dies during the preassessment , the liver transplant program is not informed immediately by the community physicians and hospitals . in general , death during the assessment is often a reflection of an untimely late referral because the patient should have been referred earlier , or is a reflection of a patient s nonadherence to clinic appointments ; however , it is not the aim of the present article to criticize the referring physician or the patient .
we note that our three long - term transplant recipients are the longest - surviving hiv - infected transplant recipients in canada and were the second , third and fourth hiv - infected patients to receive liver transplants in this country . to date
the hiv - hcv coinfected patient has experienced graft hepatitis from hcv recurrence but has not yet developed graft loss .
this patient may be a candidate for non - pegylated interferon - based direct antiviral therapy in the future .
the patient who acquired hcv post - transplant remains stable and , if advanced fibrosis develops , he would be considered a candidate for antiviral therapy .
these patients also did not experience more intraoperative nor postoperative surgical complications compared with their non - hiv - infected recipients .
our experience , as well as the experience of others , confirms that the post - transplant management of hiv - infected recipients is complex .
not only is management of coinfected patients necessary , one must also address the management and appropriate dosing of haart medications .
immunosuppressive medications , specifically the calcineurin inhibitors , tacrolimus and cyclosporine , must be dose reduced and drug trough levels followed extremely carefully because pharmacokinetic interactions may lead to toxic levels .
our first patient was on nelfinavir and required a single , small dose of tacrolimus every third day , whereas the usual dose is twice daily at higher doses .
nelfinavir is metabolized by cytochrome p450 3a4 , which also metabolizes tacrolimus and is well known to cause significant interactions ; therefore , the dose of tacrolimus must be reduced by a factor of 70 compared with normal in the setting of nelfinavir therapy ( 10 ) .
eventually , our first patient was able to have tacrolimus discontinued , with maintenance immunosuppression consisting of mycophenolate mofetil monotherapy , and remains free from acute graft rejection .
the other art medications used in our transplant recipients were abacavir / lamivudine , raltegravir and emtricitabine / tenofovir . none of these drugs are reported to have significant interactions with tacrolimus ( 1113 ) and we have not encountered any .
drug - drug interactions with art medications and immunosuppressive therapy may appear challenging a priori , but are easily overcome , and the special management issues regarding hiv and liver transplantation become routine thereafter .
we consider the multidisciplinary post - transplant approach to these patients involving allied health care professionals , including post - transplant clinic nurses and transplant pharmacists , essential to the immunosuppressive management of these patients .
currently , the management of hiv - hcv coinfection remains challenging and it is acknowledged that overall , decreased post - transplant survival is observed ( 7 ) . nonetheless , it is clearly a subgroup within the cohort of post - transplant hiv - hcv infected patients who can achieve a substantial survival benefit ( 7 ) . for patients with decompensated allograft cirrhosis , there is the potential of possible hcv viral clearance with noninterferon - based protocols , although more post - transplant clinical trials will need to be conducted to determine whether this is feasible .
therefore , we do not see any reason to restrict the liver transplant process to only hiv - infected individuals without hcv coinfection .
we note that our hiv - hbc - hcv tri - infected patient is very stable nine months post - transplant with appropriate anti - hbv prophylaxis .
it should be noted that before 1996 , hbv was a contraindication in canada for transplant ; currently , however , hbv is considered to be a prime indication for transplantation . in the time period leading up to the decision to offer liver transplantation to hiv - infected patients , there was a great deal of concern , both within and outside of the transplant program , of the risk to operating room personnel from viral transmission of hiv during an occupational injury such as a needlestick accident .
the risk for transmission of hiv is 0.3% ( 95% ci 0.2% to 0.5% ) and is lower than the risk for transmission of hcv ( 1.8% ; range 0% to 7% ) ( 14,15 ) . in the setting of hiv , as in all health care practices ,
universal precautions should be practiced routinely ; after the first liver transplant surgery was performed using standard precautions , the concerns regarding intraoperative viral transmission dissipated as the very minimal threat of inadvertent viral transmission became apparent .
the life - span of an hiv - infected individual receiving haart is now near that of their noninfected counterparts ( 15 ) .
hiv is recognized as a chronic disease controlled with haart ( 16 ) . the demand for liver transplantion as definitive management for esld will only increase . despite increasing public awareness , developing living - related - donor programs and exploring other potential donors
until better treatments for esld are developed and implemented , both in the hiv patient population and the non - hiv patient population , the demand for liver transplant for definitive management of esld will only increase .
although our single - centre experience in canada is noteworthy , we acknowledge that any single - centre experience is limited and we are hopeful that a canadian national database will be established as transplantation of hiv - infected patients becomes more common . | historically , hiv - positive individuals have not been considered to be candidates for liver transplantation due to the need for further immunosuppresion of these patients post - transplant , as well as other factors such as pharmacokinetic interactions between the necessary antiretroviral and immunosuppressant drugs
. however , hiv - positive individuals with end - stage liver disease are now eligible for liver transplantation in british columbia .
the purpose of this study was to summarize the outcomes of hiv - positive individuals referred for liver transplanation in british columbia . | <s>[INST]la demande dune prise en charge dfinitive des maladies organiques terminales chez les canadiens infects par le vih est en hausse .
jusqu tout rcemment , malgr des donnes internationales faisant foi de rsultats cliniques positifs , les canadiens atteints dune maladie hpatique terminale infects par le vih ntaient pas admissibles une transplantation , sauf en colombie - britannique ( c .- b . ) , o le programme de transplantations de bc transplant les accepte en vue dun aiguillage , dune valuation , de linscription sur la liste dattente et de lexcution dune allogreffe du foie .
simpose pour dterminer les enjeux entourant la transplantation hpatique chez les patients infects par le vih .
les chercheurs ont procd ltude des dossiers des 28 patients infects par le vih qui ont t orients vers bc transplant pour subir une transplantation hpatique entre 2004 et 2013 .
ils ont collig les donnes sur ltat du vih et de la maladie hpatique , lvaluation initiale de la transplantation et les rsultats cliniques .
la majorit prsentait des charges virales indtectables du vih , prenaient des antirtroviraux et taient infects par le virus de lhpatite c ( n=16 ) .
les comorbidits les plus courantes taient lanxit et les troubles des humeurs ( n=4 ) , ainsi que lhmophilie ( n=4 ) .
parmi les patients admissibles la transplantation , quatre ont subi une transplantation conscutive une hpatite auto - immune ( 5,67 ans aprs la transplantation ) , une statose hpatique non alcoolique ( 2,33 ans ) , un virus de lhpatite c ( 2,25 ans ) et une co - infection par lhpatite b et le virus delta ( transplantation rcente ) .
un patient est dcd dune insuffisance rnale aigu alors quil tait en attente de transplantation .
dix sont dcds pendant la prvaluation et dix ntaient pas des candidats adquats pour la transplantation .
la principale raison de ne pas tre un candidat adquat tait une maladie stable ne ncessitant pas de transplantation ( n=4 ) .
jusqu prsent , les soins interdisciplinaires et une slection attentive des patients permettent dobtenir des rsultats positifs , y compris la prsence au canada du greff hpatique infect par le vih ayant vcu le plus longtemps depuis sa transplantation .
the present study was a retrospective chart review of 28 hiv - infected candidates between 2004 and 2013 .
all patients were seen by both the transplant social worker and the transplant psychologist , in addition to the transplant hepatology and surgical staff , and the transplant coordinators .
although it may appear that the candidates misled the assessment team in certain respects , there is no proof of this and , therefore , from an ethical perspective , the patients disclosures were assumed to be truthful .
the reasons for referral for transplantation were reviewed , in addition to the status of the patients and their clinical outcomes .
the present study was approved by the university of british columbia clinical research ethics board ( vancouver , bc ) . the liver transplant program s policy with regard to placement of hiv - infected patients on the transplant waiting list after successful assessment
include the following :
all candidates must meet the general criteria for transplantation that applies to all non - hiv - infected candidates ( eg , no active infection , no active malignancy , abstinence from substance abuse , etc).candidates should be on art supervised by an hiv specialist.candidates must be free from opportunistic infection.the hiv viral load should be undetectable.although there is no absolute threshold cd4 count , the minimum accepted cd4 count is approximately 150 cells / mmpatients who did not meet these criteria were assessed on an individual basis .
all candidates must meet the general criteria for transplantation that applies to all non - hiv - infected candidates ( eg , no active infection , no active malignancy , abstinence from substance abuse , etc ) .
although there is no absolute threshold cd4 count , the minimum accepted cd4 count is approximately 150 cells / mm
since 2004 , there have been 28 hiv - infected patients referred for liver transplant assessment . the majority ( 23 of 28 [ 82% ] ) of these patients
were men and most were assessed as outpatients of the pre - assessment clinic , with a small minority referred to the transplant program as inpatients ( including hospital to hospital transfer for assessment ) .
the mean age of these patients was 47 years and the mean follow - up time was 4.1 months ( table 1 ) .
the majority of these patients were bc residents ; some were from other provinces and one was from the united states .
all patients had chronic liver disease and there were no patients with acute liver failure assessed .
one patient in an out - of - province hospital was referred on an urgent basis to the liver transplant program with acute drug hepatotoxicity secondary to highly active art ( haart ) medications .
the program accepted the patient in transfer for the purposes of expedited transplant assessment but the patient died en route to bc .
there have been no other referrals of hiv - infected patients with acute liver failure .
five patients were coinfected with hbv and seven patients had nonviral causes of liver failure .
of the non - liver and non - hiv - related medical comorbidities , the majority of these patients also had hemophilia , anxiety and depression ( table 2 ) .
one patient had autoimmune hepatitis , one had nonalcoholic hepatosteatosis , one had hepatitis c , one had hbv and hepatitis delta virus coinfection , and one died waiting ( table 3 ) .
this patient was from out of province and referred to our centre specifically because of hiv infection .
the most common reason for transplant unsuitablility was stable liver disease not requiring transplantation ( n=4 ) .
the patients had undetectable hiv viral loads and were on haart at the time of transplantation .
currently , three patients with hcv are being assessed to determine whether they are suitable transplant candidates .
his immunosuppression induction consisted of low - dose tacrolimus ( ie , 0.5 mg every third day ) , mycophenolate mofetil and tapered corticosteroids because pharmacokinetic interactions with the haart medications occurred .
this patient sustained acute renal injury while on tacrolimus ; however , renal function has recovered and his graft is now receiving mycophenolate mofetil monotherapy .
this patient has not experienced any rejection episodes ; however , he has required regular endoscopic retrograde cholangiopancreatography to manage and drain biliary sludge due to recurrent biliary anastomotic stricture . as a result
, he has a persistent increase in hepatobiliary liver biochemistry ( ie , alkaline phosphatase , gammaglutamyl transferase ) .
patient 2 was transplanted at 55 years of age for nonalcoholic steatohepatitis ( nash ) .
this patient s hiv is controlled with abacavir / lamivudine ( kivexa , viiv healthcare , canada ) and raltegravir , and because there were no drug interactions , the standard induction tacrolimus , mycophenolate mofetil and tapered corticosteroid dosing was used .
this patient also has not experienced any graft rejection , but developed persistent increases in his serum alanine aminotransferase ( alt ) level , which was previously normal ( ie , alt 120 u / l to 150
this was initially attributed to recurrent nash at one year , four months post - transplant .
he was subsequently discovered to have acquired acute hcv genotype 1b infection that is now chronic .
recent elastography ( fibroscan , echosens , france ) revealed only mild fibrosis ( ie , metavir score f1 , where f4 is cirrhosis ) .
patient 3 was transplanted at 49 years of age for hcv coinfection and is two years , six months post - transplant .
this patient s hiv infection is controlled with kivexa and raltegravir , and also received standard induction dosing with tacrolimus , mycophenolate mofetil and tapered corticosteroids . at three months post - transplant ,
it was demonstrated biochemically and with a liver biopsy that there was evidence of graft hepatitis and metavir stage 2 fibrosis ( ie , f2 ) .
two years later , this patient has experienced decreasing alt and aspartate aminotransferase ( ast ) levels , with an increased serum bilitrubin level but no other evidence of decompensation . at two years , three months post - transplant ,
the patient s ascites is being managed with diuretics with the hope that he will be suitable for a non - interferon - based antiviral regimen in the future ( table 3 ) . the final transplanted patient is 50 years of age and has hbv and hepatitis delta virus coinfection , and hepatocellular carcinoma .
the immediate post - transplant complications included postoperative bleeding , acute renal dysfunction and delayed surgical biliary anastomosis .
pretransplant , the patient s hiv antiviral agents included tenofovir df / emtricitabine and raltegravir .
his hbv viral load was undetectable and locoregional therapy of his hepatocellular carcinoma included transarterial chemoembolization .
post - transplant , he has received hepatitis immunoglobulin in addition to tenofovir . despite a prolonged hospitalization for convalescence and physical rehabilitation ,
his hepatitis b surface antigen and hepatitis d nuclei acid tests have remained negative ( table 3 ) .
overall , the post - transplant quality of life in these transplant recipients has been excellent , although the recipient with pretransplant hcv infection has developed ascites more than two years post - transplant .
since 2004 , there have been 28 hiv - infected patients referred for liver transplant assessment . the majority ( 23 of 28 [ 82% ] ) of these patients
were men and most were assessed as outpatients of the pre - assessment clinic , with a small minority referred to the transplant program as inpatients ( including hospital to hospital transfer for assessment ) .
the mean age of these patients was 47 years and the mean follow - up time was 4.1 months ( table 1 ) .
the majority of these patients were bc residents ; some were from other provinces and one was from the united states .
all patients had chronic liver disease and there were no patients with acute liver failure assessed .
one patient in an out - of - province hospital was referred on an urgent basis to the liver transplant program with acute drug hepatotoxicity secondary to highly active art ( haart ) medications .
the program accepted the patient in transfer for the purposes of expedited transplant assessment but the patient died en route to bc .
there have been no other referrals of hiv - infected patients with acute liver failure .
five patients were coinfected with hbv and seven patients had nonviral causes of liver failure .
of the non - liver and non - hiv - related medical comorbidities , the majority of these patients also had hemophilia , anxiety and depression ( table 2 ) .
one patient had autoimmune hepatitis , one had nonalcoholic hepatosteatosis , one had hepatitis c , one had hbv and hepatitis delta virus coinfection , and one died waiting ( table 3 ) .
this patient was from out of province and referred to our centre specifically because of hiv infection .
the most common reason for transplant unsuitablility was stable liver disease not requiring transplantation ( n=4 ) .
the patients had undetectable hiv viral loads and were on haart at the time of transplantation .
currently , three patients with hcv are being assessed to determine whether they are suitable transplant candidates .
his immunosuppression induction consisted of low - dose tacrolimus ( ie , 0.5 mg every third day ) , mycophenolate mofetil and tapered corticosteroids because pharmacokinetic interactions with the haart medications occurred .
this patient sustained acute renal injury while on tacrolimus ; however , renal function has recovered and his graft is now receiving mycophenolate mofetil monotherapy .
this patient has not experienced any rejection episodes ; however , he has required regular endoscopic retrograde cholangiopancreatography to manage and drain biliary sludge due to recurrent biliary anastomotic stricture . as a result
, he has a persistent increase in hepatobiliary liver biochemistry ( ie , alkaline phosphatase , gammaglutamyl transferase ) .
patient 2 was transplanted at 55 years of age for nonalcoholic steatohepatitis ( nash ) .
this patient s hiv is controlled with abacavir / lamivudine ( kivexa , viiv healthcare , canada ) and raltegravir , and because there were no drug interactions , the standard induction tacrolimus , mycophenolate mofetil and tapered corticosteroid dosing was used .
this patient also has not experienced any graft rejection , but developed persistent increases in his serum alanine aminotransferase ( alt ) level , which was previously normal ( ie , alt 120 u / l to 150
this was initially attributed to recurrent nash at one year , four months post - transplant .
he was subsequently discovered to have acquired acute hcv genotype 1b infection that is now chronic .
recent elastography ( fibroscan , echosens , france ) revealed only mild fibrosis ( ie , metavir score f1 , where f4 is cirrhosis ) .
patient 3 was transplanted at 49 years of age for hcv coinfection and is two years , six months post - transplant .
this patient s hiv infection is controlled with kivexa and raltegravir , and also received standard induction dosing with tacrolimus , mycophenolate mofetil and tapered corticosteroids . at three months post - transplant ,
it was demonstrated biochemically and with a liver biopsy that there was evidence of graft hepatitis and metavir stage 2 fibrosis ( ie , f2 ) .
two years later , this patient has experienced decreasing alt and aspartate aminotransferase ( ast ) levels , with an increased serum bilitrubin level but no other evidence of decompensation . at two years , three months post - transplant ,
the patient s ascites is being managed with diuretics with the hope that he will be suitable for a non - interferon - based antiviral regimen in the future ( table 3 ) . the final transplanted patient is 50 years of age and has hbv and hepatitis delta virus coinfection , and hepatocellular carcinoma .
the immediate post - transplant complications included postoperative bleeding , acute renal dysfunction and delayed surgical biliary anastomosis .
pretransplant , the patient s hiv antiviral agents included tenofovir df / emtricitabine and raltegravir .
his hbv viral load was undetectable and locoregional therapy of his hepatocellular carcinoma included transarterial chemoembolization .
post - transplant , he has received hepatitis immunoglobulin in addition to tenofovir . despite a prolonged hospitalization for convalescence and physical rehabilitation ,
his hepatitis b surface antigen and hepatitis d nuclei acid tests have remained negative ( table 3 ) .
overall , the post - transplant quality of life in these transplant recipients has been excellent , although the recipient with pretransplant hcv infection has developed ascites more than two years post - transplant .
nearly a decade after the establishment of an hiv liver transplant program in bc , we demonstrated that successful transplantation in hiv - infected and hiv - hcv coinfected patients is possible .
the success of these candidates is due to a multidisciplinary team that includes a transplant surgical team , transplant medicine team , hiv specialty team and psychosocial support .
these patients were selected for transplantation based on their failing liver disease . there is absolutely no bias against the hiv - infected individual ; in fact , we have been their advocates . in the first year of the program , and in the time leading up to the establishment of the program , there was uncertainty as to what subgroup of hiv - infected patients would be suitable for transplantation . within a short time , however , the attitude of the liver transplant program became one of advocacy . with the realization that patients outside of bc did not have any option for transplantation within canada
, it was decided that no referred patient with hiv would be declined without assessment , both inside bc and outside of the province .
information about death during preassessment is often not accurate because if a patient dies during the preassessment , the liver transplant program is not informed immediately by the community physicians and hospitals . in general , death during the assessment is often a reflection of an untimely late referral because the patient should have been referred earlier , or is a reflection of a patient s nonadherence to clinic appointments ; however , it is not the aim of the present article to criticize the referring physician or the patient .
we note that our three long - term transplant recipients are the longest - surviving hiv - infected transplant recipients in canada and were the second , third and fourth hiv - infected patients to receive liver transplants in this country . to date
the hiv - hcv coinfected patient has experienced graft hepatitis from hcv recurrence but has not yet developed graft loss .
this patient may be a candidate for non - pegylated interferon - based direct antiviral therapy in the future .
the patient who acquired hcv post - transplant remains stable and , if advanced fibrosis develops , he would be considered a candidate for antiviral therapy .
these patients also did not experience more intraoperative nor postoperative surgical complications compared with their non - hiv - infected recipients .
our experience , as well as the experience of others , confirms that the post - transplant management of hiv - infected recipients is complex .
not only is management of coinfected patients necessary , one must also address the management and appropriate dosing of haart medications .
immunosuppressive medications , specifically the calcineurin inhibitors , tacrolimus and cyclosporine , must be dose reduced and drug trough levels followed extremely carefully because pharmacokinetic interactions may lead to toxic levels .
our first patient was on nelfinavir and required a single , small dose of tacrolimus every third day , whereas the usual dose is twice daily at higher doses .
nelfinavir is metabolized by cytochrome p450 3a4 , which also metabolizes tacrolimus and is well known to cause significant interactions ; therefore , the dose of tacrolimus must be reduced by a factor of 70 compared with normal in the setting of nelfinavir therapy ( 10 ) .
eventually , our first patient was able to have tacrolimus discontinued , with maintenance immunosuppression consisting of mycophenolate mofetil monotherapy , and remains free from acute graft rejection .
the other art medications used in our transplant recipients were abacavir / lamivudine , raltegravir and emtricitabine / tenofovir . none of these drugs are reported to have significant interactions with tacrolimus ( 1113 ) and we have not encountered any .
drug - drug interactions with art medications and immunosuppressive therapy may appear challenging a priori , but are easily overcome , and the special management issues regarding hiv and liver transplantation become routine thereafter .
we consider the multidisciplinary post - transplant approach to these patients involving allied health care professionals , including post - transplant clinic nurses and transplant pharmacists , essential to the immunosuppressive management of these patients .
currently , the management of hiv - hcv coinfection remains challenging and it is acknowledged that overall , decreased post - transplant survival is observed ( 7 ) . nonetheless , it is clearly a subgroup within the cohort of post - transplant hiv - hcv infected patients who can achieve a substantial survival benefit ( 7 ) . for patients with decompensated allograft cirrhosis , there is the potential of possible hcv viral clearance with noninterferon - based protocols , although more post - transplant clinical trials will need to be conducted to determine whether this is feasible .
therefore , we do not see any reason to restrict the liver transplant process to only hiv - infected individuals without hcv coinfection .
we note that our hiv - hbc - hcv tri - infected patient is very stable nine months post - transplant with appropriate anti - hbv prophylaxis .
it should be noted that before 1996 , hbv was a contraindication in canada for transplant ; currently , however , hbv is considered to be a prime indication for transplantation . in the time period leading up to the decision to offer liver transplantation to hiv - infected patients , there was a great deal of concern , both within and outside of the transplant program , of the risk to operating room personnel from viral transmission of hiv during an occupational injury such as a needlestick accident .
the risk for transmission of hiv is 0.3% ( 95% ci 0.2% to 0.5% ) and is lower than the risk for transmission of hcv ( 1.8% ; range 0% to 7% ) ( 14,15 ) . in the setting of hiv , as in all health care practices ,
universal precautions should be practiced routinely ; after the first liver transplant surgery was performed using standard precautions , the concerns regarding intraoperative viral transmission dissipated as the very minimal threat of inadvertent viral transmission became apparent .
the life - span of an hiv - infected individual receiving haart is now near that of their noninfected counterparts ( 15 ) .
hiv is recognized as a chronic disease controlled with haart ( 16 ) . the demand for liver transplantion as definitive management for esld will only increase . despite increasing public awareness , developing living - related - donor programs and exploring other potential donors
until better treatments for esld are developed and implemented , both in the hiv patient population and the non - hiv patient population , the demand for liver transplant for definitive management of esld will only increase .
although our single - centre experience in canada is noteworthy , we acknowledge that any single - centre experience is limited and we are hopeful that a canadian national database will be established as transplantation of hiv - infected patients becomes more common .[/INST]historically , hiv - positive individuals have not been considered to be candidates for liver transplantation due to the need for further immunosuppresion of these patients post - transplant , as well as other factors such as pharmacokinetic interactions between the necessary antiretroviral and immunosuppressant drugs
. however , hiv - positive individuals with end - stage liver disease are now eligible for liver transplantation in british columbia .
the purpose of this study was to summarize the outcomes of hiv - positive individuals referred for liver transplanation in british columbia .</s> |
SECTION 1. SHORT TITLE.
This Act may be cited as the ``Executive Amnesty Prevention Act''.
SEC. 2. PROHIBITION ON USE OF FUNDS.
(a) In General.--No funds, resources, or fees made available to the
Secretary of Homeland Security, or to any other official of a Federal
agency, by any Act for any fiscal year, including any deposits into the
``Immigration Examinations Fee Account'' established under section
286(m) of the Immigration and Nationality Act (8 U.S.C. 1356(m)), may
be used to implement, administer, enforce, or carry out (including
through the issuance of any regulations) any of the policy changes set
forth in the following memoranda (or any substantially similar policy
changes issued or taken on or after the date of the enactment of this
Act, whether set forth in memorandum, Executive order, regulation,
directive, or by other action):
(1) The memorandum from the Director of U.S. Immigration
and Customs Enforcement entitled ``Civil Immigration
Enforcement: Priorities for the Apprehension, Detention, and
Removal of Aliens'' dated March 2, 2011.
(2) The memorandum from the Director of U.S. Immigration
and Customs Enforcement entitled ``Exercising Prosecutorial
Discretion Consistent with the Civil Immigration Enforcement
Priorities of the Agency for the Apprehension, Detention, and
Removal of Aliens'' dated June 17, 2011.
(3) The memorandum from the Principal Legal Advisor of U.S.
Immigration and Customs Enforcement entitled ``Case-by-Case
Review of Incoming and Certain Pending Cases'' dated November
17, 2011.
(4) The memorandum from the Secretary of Homeland Security
entitled ``Exercising Prosecutorial Discretion with Respect to
Individuals Who Came to the United States as Children'' dated
June 15, 2012.
(5) The memorandum from the Director of U.S. Immigration
and Customs Enforcement entitled ``Civil Immigration
Enforcement: Guidance on the Use of Detainers in the Federal,
State, Local, and Tribal Criminal Justice Systems'' dated
December 21, 2012.
(6) The memorandum from the Secretary of Homeland Security
entitled ``Southern Border and Approaches Campaign'' dated
November 20, 2014.
(7) The memorandum from the Secretary of Homeland Security
entitled ``Policies for the Apprehension, Detention and Removal
of Undocumented Immigrants'' dated November 20, 2014.
(8) The memorandum from the Secretary of Homeland Security
entitled ``Secure Communities'' dated November 20, 2014.
(9) The memorandum from the Secretary of Homeland Security
entitled ``Exercising Prosecutorial Discretion with Respect to
Individuals Who Came to the United States as Children and with
Respect to Certain Individuals Who Are the Parents of U.S.
Citizens or Permanent Residents'' dated November 20, 2014.
(10) The memorandum from the Secretary of Homeland Security
entitled ``Expansion of the Provisional Waiver Program'' dated
November 20, 2014.
(11) The memorandum from the Secretary of Homeland Security
entitled ``Policies Supporting U.S. High-Skilled Businesses and
Workers'' dated November 20, 2014.
(12) The memorandum from the Secretary of Homeland Security
entitled ``Families of U.S. Armed Forces Members and
Enlistees'' dated November 20, 2014.
(13) The memorandum from the Secretary of Homeland Security
entitled ``Directive to Provide Consistency Regarding Advance
Parole'' dated November 20, 2014.
(14) The memorandum from the Secretary of Homeland Security
entitled ``Policies to Promote and Increase Access to U.S.
Citizenship'' dated November 20, 2014.
(15) The memorandum from the President entitled
``Modernizing and Streamlining the U.S. Immigrant Visa System
for the 21st Century'' dated November 21, 2014.
(16) The memorandum from the President entitled ``Creating
Welcoming Communities and Fully Integrating Immigrants and
Refugees'' dated November 21, 2014.
(b) No Legal Effect.--The memoranda referred to in subsection (a)
(or any substantially similar policy changes issued or taken on or
after the date of the enactment of this Act, whether set forth in
memorandum, Executive order, regulation, directive, or by other action)
have no statutory or constitutional basis and therefore have no legal
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(c) Prohibition on Federal Benefits.--No funds or fees made
available to the Secretary of Homeland Security, or to any other
official of a Federal agency, by any Act for any fiscal year, including
any deposits into the ``Immigration Examinations Fee Account''
established under section 286(m) of the Immigration and Nationality Act
(8 U.S.C. 1356(m)), may be used to grant any Federal benefit to any
alien pursuant to any of the policy changes set forth in the memoranda
referred to in subsection (a) (or any substantially similar policy
changes issued or taken on or after the date of the enactment of this
Act, whether set forth in memorandum, Executive order, regulation,
directive, or by other action).
SEC. 3. ADMISSION AND LAWFUL PRESENCE REQUIRED FOR EMPLOYMENT
AUTHORIZATION.
Section 274A(h)(3) of the Immigration and Nationality Act (8 U.S.C.
1324a(h)(3)) is amended--
(1) by inserting before ``authorized to be so employed by
this Act'' the following: ``an alien otherwise admitted to and
lawfully present in the United States, and''; and
(2) by inserting at the end the following: ``An alien
without lawful status shall be considered to be an unauthorized
alien for purposes of this Act.''.
SEC. 4. CONFORMING AMENDMENTS.
Section 286(n) of the Immigration and Nationality Act (8 U.S.C.
1356(n)) is amended--
(1) by striking ``(n) All'' and inserting ``(n)(1) Except
as provided in paragraph (2), all''; and
(2) by adding at the end the following:
``(2) No deposit in the `Immigration Examinations Fee Account' may
be used to implement, administer, carry out, or enforce the policies in
any of the memoranda referred to in section 2(a) of the Executive
Amnesty Prevention Act.''. | Executive Amnesty Prevention Act This bill prohibits the use of funds to implement specified memoranda from the President, the Secretary of Homeland Security, the Director of U.S. Immigration and Customs Enforcement (ICE), or other related memoranda. No deposit in the Immigration Examinations Fee Account may be used to implement, administer, or enforce the policies in such memoranda. Such memoranda or substantially similar policy changes are declared to have no statutory or constitutional basis and therefore no legal effect. No funds or fees made available to the Secretary or to any federal official may be used to grant any federal benefit to any alien pursuant to any of such policy changes. The Immigration and Nationality Act is amended to: (1) exclude from the definition of "unauthorized alien," with respect to employment, any alien otherwise admitted to and lawfully present in the United States; and (2) consider any alien without lawful status to be an unauthorized alien whose employment is unlawful. | <s>[INST]SECTION 1. SHORT TITLE.
This Act may be cited as the ``Executive Amnesty Prevention Act''.
SEC. 2. PROHIBITION ON USE OF FUNDS.
(a) In General.--No funds, resources, or fees made available to the
Secretary of Homeland Security, or to any other official of a Federal
agency, by any Act for any fiscal year, including any deposits into the
``Immigration Examinations Fee Account'' established under section
286(m) of the Immigration and Nationality Act (8 U.S.C. 1356(m)), may
be used to implement, administer, enforce, or carry out (including
through the issuance of any regulations) any of the policy changes set
forth in the following memoranda (or any substantially similar policy
changes issued or taken on or after the date of the enactment of this
Act, whether set forth in memorandum, Executive order, regulation,
directive, or by other action):
(1) The memorandum from the Director of U.S. Immigration
and Customs Enforcement entitled ``Civil Immigration
Enforcement: Priorities for the Apprehension, Detention, and
Removal of Aliens'' dated March 2, 2011.
(2) The memorandum from the Director of U.S. Immigration
and Customs Enforcement entitled ``Exercising Prosecutorial
Discretion Consistent with the Civil Immigration Enforcement
Priorities of the Agency for the Apprehension, Detention, and
Removal of Aliens'' dated June 17, 2011.
(3) The memorandum from the Principal Legal Advisor of U.S.
Immigration and Customs Enforcement entitled ``Case-by-Case
Review of Incoming and Certain Pending Cases'' dated November
17, 2011.
(4) The memorandum from the Secretary of Homeland Security
entitled ``Exercising Prosecutorial Discretion with Respect to
Individuals Who Came to the United States as Children'' dated
June 15, 2012.
(5) The memorandum from the Director of U.S. Immigration
and Customs Enforcement entitled ``Civil Immigration
Enforcement: Guidance on the Use of Detainers in the Federal,
State, Local, and Tribal Criminal Justice Systems'' dated
December 21, 2012.
(6) The memorandum from the Secretary of Homeland Security
entitled ``Southern Border and Approaches Campaign'' dated
November 20, 2014.
(7) The memorandum from the Secretary of Homeland Security
entitled ``Policies for the Apprehension, Detention and Removal
of Undocumented Immigrants'' dated November 20, 2014.
(8) The memorandum from the Secretary of Homeland Security
entitled ``Secure Communities'' dated November 20, 2014.
(9) The memorandum from the Secretary of Homeland Security
entitled ``Exercising Prosecutorial Discretion with Respect to
Individuals Who Came to the United States as Children and with
Respect to Certain Individuals Who Are the Parents of U.S.
Citizens or Permanent Residents'' dated November 20, 2014.
(10) The memorandum from the Secretary of Homeland Security
entitled ``Expansion of the Provisional Waiver Program'' dated
November 20, 2014.
(11) The memorandum from the Secretary of Homeland Security
entitled ``Policies Supporting U.S. High-Skilled Businesses and
Workers'' dated November 20, 2014.
(12) The memorandum from the Secretary of Homeland Security
entitled ``Families of U.S. Armed Forces Members and
Enlistees'' dated November 20, 2014.
(13) The memorandum from the Secretary of Homeland Security
entitled ``Directive to Provide Consistency Regarding Advance
Parole'' dated November 20, 2014.
(14) The memorandum from the Secretary of Homeland Security
entitled ``Policies to Promote and Increase Access to U.S.
Citizenship'' dated November 20, 2014.
(15) The memorandum from the President entitled
``Modernizing and Streamlining the U.S. Immigrant Visa System
for the 21st Century'' dated November 21, 2014.
(16) The memorandum from the President entitled ``Creating
Welcoming Communities and Fully Integrating Immigrants and
Refugees'' dated November 21, 2014.
(b) No Legal Effect.--The memoranda referred to in subsection (a)
(or any substantially similar policy changes issued or taken on or
after the date of the enactment of this Act, whether set forth in
memorandum, Executive order, regulation, directive, or by other action)
have no statutory or constitutional basis and therefore have no legal
effect.
(c) Prohibition on Federal Benefits.--No funds or fees made
available to the Secretary of Homeland Security, or to any other
official of a Federal agency, by any Act for any fiscal year, including
any deposits into the ``Immigration Examinations Fee Account''
established under section 286(m) of the Immigration and Nationality Act
(8 U.S.C. 1356(m)), may be used to grant any Federal benefit to any
alien pursuant to any of the policy changes set forth in the memoranda
referred to in subsection (a) (or any substantially similar policy
changes issued or taken on or after the date of the enactment of this
Act, whether set forth in memorandum, Executive order, regulation,
directive, or by other action).
SEC. 3. ADMISSION AND LAWFUL PRESENCE REQUIRED FOR EMPLOYMENT
AUTHORIZATION.
Section 274A(h)(3) of the Immigration and Nationality Act (8 U.S.C.
1324a(h)(3)) is amended--
(1) by inserting before ``authorized to be so employed by
this Act'' the following: ``an alien otherwise admitted to and
lawfully present in the United States, and''; and
(2) by inserting at the end the following: ``An alien
without lawful status shall be considered to be an unauthorized
alien for purposes of this Act.''.
SEC. 4. CONFORMING AMENDMENTS.
Section 286(n) of the Immigration and Nationality Act (8 U.S.C.
1356(n)) is amended--
(1) by striking ``(n) All'' and inserting ``(n)(1) Except
as provided in paragraph (2), all''; and
(2) by adding at the end the following:
``(2) No deposit in the `Immigration Examinations Fee Account' may
be used to implement, administer, carry out, or enforce the policies in
any of the memoranda referred to in section 2(a) of the Executive
Amnesty Prevention Act.''.[/INST]Executive Amnesty Prevention Act This bill prohibits the use of funds to implement specified memoranda from the President, the Secretary of Homeland Security, the Director of U.S. Immigration and Customs Enforcement (ICE), or other related memoranda. No deposit in the Immigration Examinations Fee Account may be used to implement, administer, or enforce the policies in such memoranda. Such memoranda or substantially similar policy changes are declared to have no statutory or constitutional basis and therefore no legal effect. No funds or fees made available to the Secretary or to any federal official may be used to grant any federal benefit to any alien pursuant to any of such policy changes. The Immigration and Nationality Act is amended to: (1) exclude from the definition of "unauthorized alien," with respect to employment, any alien otherwise admitted to and lawfully present in the United States; and (2) consider any alien without lawful status to be an unauthorized alien whose employment is unlawful.</s> |
quantum one - dimensional ( 1d ) spin systems have been studied in various aspects , especially with interest on their strong quantum fluctuations due to the low dimensionality .
there appear a variety of quantum disordered ground states where the continuous spin rotation symmetry is not broken and the lowest spin excitation has a finite gap ( spin - gap ) .
these quantum disordered states have no analogues in classical spin systems .
typical examples are a haldane state in a spin-1 chain @xcite , a dimer state in a spin-@xmath1 chain with bond alternation @xcite , and a spin - gap state in a spin-@xmath1 ladder @xcite . in extensive research for various 1d spin systems , spin chains with side chains
have not attracted enough attention in spite of its potentially rich physics .
since a side chain is of finite length , it may enhance quantum fluctuation in the system .
actually , the 1d kondo necklace model , which has been extensively studied as a simplified version of 1d kondo lattice model @xcite , can be regarded as a spin chain with side chains . in this model ,
the main chain is a spin-@xmath1 chain and each side chain consists of a single spin with magnitude @xmath1 .
the ground state of this model is known to be in the kondo singlet phase with spin - gap @xcite , while the spin-@xmath1 chain without side chains is critical .
this means that the quasi - long range order in the main chain is destroyed by the quantum fluctuation in the side chains .
also , if the side chains bring geometrical frustration into the system , quantum fluctuation is expected to be further enhanced .
thus , it is an interesting subject how quantum fluctuation manifests itself and what kind of ground state appears in various types of spin chains with side chains . in this paper , we investigate the natures of quantum disordered ground states of one of the simplest models with frustrated side chains .
the main chain of the model consists of two species of spins in alternating order , and each side chain consists of a single spin which are alternately attached to the main chain , as will be shown in fig .
[ lattice ] of the next section .
this model incorporates the effects of mixture of different spins , bond alternation , and frustration in spite of its simplicity .
in particular , the frustration comes from triangles , each consisting of antiferromagnetically interacting three spins .
although quantum spin systems with similar geometry have been investigated by several authors @xcite , our model is physically different from them . if the side chains of our model are removed , the main chain is in a ferrimagnetic ground state .
the side chain spins introduce frustration to the system , and destroy the ferrimagnetic order leading to quantum disordered states . ,
@xmath2 , and @xmath3 are spins whose magnitudes satisfy eq .
( [ restriction ] ) .
the case that @xmath4 , @xmath5 , and @xmath6 is studied particularly in detail . ] the disordered ground states of the present model can not be understood in the conventional valence bond solid ( vbs ) picture @xcite , which successfully explains the disordered ground states of many spin models with local frustration .
instead , we will explain the present ground states in the concept of the singlet cluster solid ( scs ) picture .
a scs state is a direct product of local singlet states , or singlet clusters .
each singlet cluster consists of more than two singlet dimers , and the dimers are resonating locally within the cluster .
the scs states are realized as a result of the interplay of quantum fluctuation and local frustration , as will be explained in detail .
it is desirable that the scs state manifested in this paper is experimentally inspected in materials .
however , a material precisely described by the present model is not found so far within our knowledge . despite the lack of materials
, it is worth clarifying the concept of the scs states and verifying the existence of them in a concrete model .
further , considering the rich variety of magnetic materials synthesized by the modern chemical technology @xcite , desired materials are expected to be synthesized , since they are not necessarily complex in structure .
the details of the model are explained in the next section .
various approaches are employed to clarify the ground state phases of this model : in section [ sec : nlsm ] , a nonlinear @xmath0 model ( nlsm ) method is proposed to grasp qualitative feature of the phase diagram . since a similar nlsm method has been developed for mixed spin chains without side chains so far , we extend it to the present side - chain case .
we also employ other approaches limiting ourselves to the simplest case of spin magnitudes 1 and @xmath1 . in section [ sec : num_diagonal ] , the numerical diagonalization for finite systems is carried out to obtain the quantitatively reliable phase diagram , which confirms the qualitative correctness of the nlsm method .
some limiting cases are exactly treated to draw physical picture for each phase in section [ sec : limit ] .
after these considerations , we arrive at the scs pictures to explain the ground states in section [ sec : scs ] .
the scs pictures are also supported by variational calculations in section [ sec : variational ] .
the last section is devoted to summary and discussion .
we study an isotropic quantum spin chain with alternately arrayed side chains as is illustrated in fig .
[ lattice ] . in the @xmath7th unit cell , @xmath8 and @xmath9
are spin operators on the main chain , and @xmath10 is a spin operator on the side chain .
the quantum numbers of spin magnitudes of these spin operators are expressed as @xmath11 , @xmath12 , and @xmath13 , respectively .
exchange parameters are represented as @xmath14 , @xmath15 , @xmath16 and @xmath17 , and assumed to be all positive .
then the hamiltonian is written as @xmath18 the spacing between nearest spins is @xmath19 , and the length of a unit cell is @xmath20 .
the hamiltonian is characterized by three independent dimensionless parameters : @xmath21 here @xmath22 measures the strength of the bond alternation in the main chain , @xmath23 measures the strength of interaction between a main - chain spin and a side - chain spin , and @xmath24 measures the strength of frustration @xcite . in the present paper ,
we assume the following restriction on spin magnitudes : @xmath25 this is the condition that the corresponding classical spin chain can have a ground state with no total magnetization ( i. e. no ferrimagnetism ) , when @xmath17 is not large .
the restriction ( [ restriction ] ) serves to simplify the berry phase term in the continuum limit .
expectation values of the spin operators for a spin coherent state are written as @xmath26 where @xmath27 , @xmath28 , and @xmath29 are unit vectors . replacing the spin operators in eq .
( [ hamiltonian ] ) by them , we have the classical version of the hamiltonian : @xmath30 ^ 2 \bigr . \nonumber \\ & \ \
+ \left(1-\frac{kr}{1-r } \right ) \ , [ \v{m}_1(p ) - \v{m}_2(p ) ] ^2 \nonumber \\ & \ \ + \bigl . \frac{k}{1-r } \ , [ \v{m}_1(p ) - r\v{m}_2(p ) - ( 1-r)\v{m}_{\bot}(p ) ] ^2 \bigr\ } , \nonumber \\ \label{c_hamiltonian}\end{aligned}\ ] ] where @xmath31 and a constant term is omitted from @xmath32 . the classical antiferromagnetic configuration , @xmath33 for all @xmath7 , @xmath34 , and @xmath35 , is the ground - state solution if the pre - factors of the squares in eq .
( [ c_hamiltonian ] ) are all positive .
this gives the condition for the classical stability of the antiferromagnetism as @xmath36 in the following arguments , we will concentrate on this region .
using the spin coherent representation , the partition function of hamiltonian ( [ hamiltonian ] ) is written in a path - integral form as @xmath37 \ , \delta(\v{m}_j^2 - 1 ) e^{-a } \label{partition}\end{aligned}\ ] ] with @xmath38 , and @xmath39 .
the action @xmath40 is written as @xmath41 - s_2 w[\v{m}_2(p ) ] - \
t w[\v{m}_{\bot}(p ) ] \ } , \nonumber \\ a_h & = \int_0^{\beta } d\tau h_c , \label{action_coherent}\end{aligned}\ ] ] where @xmath42 is the inverse of temperature , and @xmath43 $ ] is the solid angle which @xmath44 forms in period @xmath42 .
the term @xmath45 in action @xmath40 is the berry phase term .
we introduce slow variable @xmath46 for each unit cell , and fluctuation variables @xmath47 , @xmath48 , and @xmath49 for each spin in a unit cell .
then the original variables are transformed as follows : @xmath50 this transformation is found by observing and extending the transformation for a simple chain without side chain @xcite . since the left hand sides in ( [ transformation ] ) are unit vectors , we have the following constraints for the new variables : @xmath51 the fluctuation variables depends on one another , and one of them , e. g. @xmath52 can be set equal to 0 .
hence the number of independent variables are conserved in the transformation . defining new fluctuation variables , @xmath53 and taking the continuum limit
, we have @xmath54 \biggr\ } \end{aligned}\ ] ] with @xmath55 . here vectors @xmath56 and @xmath57 are given as @xmath58 integrating the partition function with respect to @xmath59 and @xmath60 , we have the following nlsm action : @xmath61 the first term is the topological term and @xmath62 is the topological angle given by @xmath63 in the absence of frustration ( @xmath64 ) , the topological angle reduces to @xmath65 .
this is the same expression as that for a simple spin chain of magnitude @xmath12 with bond alternation @xcite .
this can be interpreted as follows : a spin @xmath66 is combined with the adjacent spin @xmath3 on the side chain , and a two - spin cluster with total spin magnitude @xmath67 @xmath68 is formed .
however , the coefficients of @xmath69 and @xmath70 in eq .
( [ action - nlsm ] ) do not reduce to those for the simple spin chain , even if @xmath23 is very large .
this reflects that the quantum fluctuation of spins on side chains still survive for large @xmath23 . the topological term of eq .
( [ action - nlsm ] ) determines whether or not the system has a spin - gap in the same manner as haldane s argument @xcite .
that is , the system does not have a spin - gap if and only if the topological angle @xmath62 is just @xmath71 ( mod @xmath72 ) .
this condition is written as @xmath73 where @xmath74 is any half odd integer .
this gapless condition determines phase boundaries between gapful disordered phases in the parameter space .
we notice that , for each value of @xmath74 , boundaries for all values of @xmath24 pass through the common point @xmath75 in the @xmath23-@xmath22 plane by the nlsm method for @xmath4 , @xmath5 , and @xmath6 . for each value of @xmath24 (= @xmath76 )
the region of @xmath77 is meaningful in the nlsm method . ] in the case of @xmath4 , @xmath5 and @xmath6 , only a permitted value of @xmath74 in eq .
( [ gapless_condition ] ) is @xmath1 for @xmath78 and @xmath79 .
then the phase boundaries for several values of @xmath24 are solid lines in fig .
[ phase_nlsm ] . owing to the definitions of the parameters , they are straight lines in the present approximation
. the regions of the both sides of each boundary are gapful disordered phases .
we call them gap i phase and gap ii phase as noted in the figure . for @xmath64
the phase boundary is horizontal , since the topological angle is independent of @xmath23 as mentioned below eq .
( [ t_angle ] ) .
this is understandable by considering @xmath66 as a composite of two @xmath1 spins .
in fact , when @xmath64 , @xmath3 and one of the @xmath1 spins of @xmath66 necessarily forms a valence bond irrespective of the value of @xmath23 in the ground state .
as @xmath24 increases from 0 , the slope of the boundary becomes negatively large .
the reason will be argued later . -@xmath22
plane by the nlsm method in the cases of ( a ) @xmath80 , @xmath81 , and @xmath6 , and ( b ) in the case of @xmath80 , @xmath5 , and @xmath82 . for each value of @xmath24
the region of @xmath77 is meaningful . ]
we also show phase diagrams in other cases in fig . [ other_phases ] ; the phase boundaries in ( a ) are for @xmath80 , @xmath81 , and @xmath6 , and those in ( b ) are for @xmath80 , @xmath5 , and @xmath82 .
although the equation ( [ gapless_condition ] ) determining phase boundaries are quite general , we mainly examine the case of @xmath4 , @xmath5 , and @xmath6 . this case
is expected to include the essence of the present type of spin chains with side chains .
hamiltonian ( [ hamiltonian ] ) can be numerically diagonalized for small size systems .
the numerical calculation is effective not only to analyze the system itself in detail , but also to know the preciseness of the nlsm method by comparing the results .
we performed numerical diagonalization in the case of @xmath4 , @xmath5 , and @xmath6 to obtain the phase diagram for the ground state . , @xmath5 , and @xmath6 .
each point of a boundary is determined by extrapolation for the total spin number @xmath83 12 , 18 , and 24 .
inset : phase boundaries for small @xmath23 . ]
the phase transition points are determined as follows .
the phase transitions between different spin gap phases are expected to be the gaussian transition .
hence we employ the method of twist boundary condition proposed by kitazawa @xcite and kitazawa and nomura @xcite to determine the phase boundary .
as will be examined later , the ground state phases are described by different scs configurations . under the twisted boundary condition ,
the different singlet solid configurations have different time reversal parities depending on the even - odd parity of the number of valence bonds across the twisted boundary .
hence the energy levels of the ground state and the first excited state cross at the phase boundary without level repulsion .
this ensures the precise evaluation of the phase boundary .
the size extrapolation is based on the following formula for the finite size correction@xcite : @xmath84 where @xmath85 is the finite size critical value of quantity @xmath22 , and @xmath86 and @xmath87 are fitting parameters .
we have carried out the extrapolation using numerical results for total spin number @xmath83 12 , 18 , and 24 .
resultant phase boundaries for several values of @xmath24 are plotted in fig .
[ phase_num ] . comparing figs .
[ phase_nlsm ] and [ phase_num ] , we find that the nlsm method gives qualitatively correct phase boundaries .
in particular , for small @xmath24 , or weak frustration , the nlsm method provides a quantitatively fair approximation . with the increase of @xmath24
, the gap i phase extends to the region @xmath88 for small @xmath23 , and it is suppressed to the region @xmath89 for large @xmath23 .
although this feature qualitatively coincides with that of the nlsm results , quantitative coincidence becomes worse with the increase of @xmath24 .
this is natural because the present nlsm method starts from a classical antiferromagnetic solution in the absence of frustration .
the possibility of the first order transition between different spin - gap phases has been pointed out in the frustrated ladder by hakobyan and coworkers @xcite in the appropriate parameter regime . considering the presence of frustration ,
this type of transition can not be ruled out in the present model .
however , we did not find the numerical evidence for the first order transition within the parameter regime discussed in this paper .
to further confirm the numerical phase diagram for @xmath4 , @xmath5 , and @xmath6 , we consider the effective theory in the limiting cases of @xmath90 and @xmath91 . in the limit of @xmath92 ,
the system can be regarded as a one - dimensional array of weakly coupled 3-spin units as shown in fig . [ 3spin](a ) .
one of the 3-spin units is described by the hamiltonian @xmath93 where we have dropped the common index @xmath7 representing the @xmath7th unit cell for simplicity .
the nel basis is represented as @xmath94 , where @xmath95 takes @xmath96 , 0 or @xmath97 , and @xmath98 and @xmath13 take @xmath99 or @xmath100 . by introducing the composed spin @xmath101 @xmath102 @xmath103
, we have another set of basis vectors @xmath104 , where @xmath105 and @xmath106 are quantum numbers of the magnitude and the @xmath107-component of @xmath101 respectively , and @xmath108 discriminates multiple states with the same @xmath105 and @xmath106 , if necessary .
we seek the ground state of the 3-spin unit with @xmath109 or 1 , since all the exchange interactions are antiferromagnetic . , and ( b ) those for @xmath91 and @xmath110 in the case of @xmath4 , @xmath5 , and @xmath6 .
three spins ( circles ) in a shadowed region form a 3-spin unit . ]
\(i ) for @xmath109 , we have @xmath111
. then the one - dimensional subspace consists of a single state , @xmath112 this is a singlet eigenstate of @xmath113 belonging to the eigenvalue @xmath114 ( ii ) for @xmath115 , we have @xmath106 = 1 , 0 , or @xmath116 . in this three - dimensional subspace , it is sufficient to inspect the case of @xmath117 owing to the spherical symmetry of the hamiltonian @xmath113 .
we choose the orthonormal basis of the subspace @xmath118 as @xmath119 operating @xmath113 on these bases , we have an eigenvalue equation .
then the lowest eigenvalue @xmath120 in this subspace is determined as the smaller solution of the characteristic equation : @xmath121 introducing a normalized energy difference as @xmath122 , eq .
( [ tri_ene ] ) with eq .
( [ sing_ene ] ) reduces to @xmath123\epsilon + 2k[2-\left(1+k\right)r]=0 .
\end{aligned}\ ] ] if the smaller solution for @xmath124 is negative , the ground state is a triplet ( @xmath115 ) state ; otherwise it is a singlet ( @xmath109 ) state . using ( [ ene_diff ] ) , the condition for the triplet ground state becomes @xmath125 we notice that @xmath126 in the region of @xmath127 , which we have concentrated on in this paper . in the triplet ground state
, @xmath2 tends to orient the opposite direction to @xmath66 for @xmath128 , and @xmath3 does for @xmath129 .
the composed spin @xmath101 always orients to the same direction as @xmath66 .
the composed spin @xmath130 at the @xmath7th unit cell interacts with adjacent @xmath131 by an effective exchange interaction .
we denote the effective exchange parameter by @xmath132 .
since the interaction between @xmath9 and @xmath133 is antiferromagnetic ( @xmath134 ) , the correlation between @xmath8 and @xmath133 is antiferromagnetic for @xmath135 @xmath136 and ferromagnetic for @xmath137 @xmath138 .
therefore @xmath132 has the same sign as @xmath139 , considering the signs of @xmath140 and @xmath141 are the same . for @xmath142
, we have @xmath143 , since @xmath144 for @xmath127 .
hence the original spin chain is equivalent to a spin-1 antiferromagnetic heisenberg chain consisting of effective spins , @xmath130 s .
the ground state of an uniform spin-1 chain is the haldane state @xcite , which gives a spin - gap for excitation . in the haldane state
, there is strong correlation on each adjacent spin pair , as known from the vbs picture for effective spins , @xmath130 s @xcite . in terms of the original spins ,
there is strong correlation between adjacent 3-spin units . for @xmath145 ,
on the other hand , the ground state of each 3-spin unit is already a closed singlet state .
then the ground state of the total spin chain is approximately an array of such closed local singlets , and there is almost no correlation between adjacent 3-spin units . thus there is a gaussian transition between the two characteristic ground states with spin - gap at @xmath146 .
the value of @xmath147 in this argument for @xmath92 agrees with the critical value by the numerical diagonalization , as is seen on the @xmath148 line of the phase diagram ( fig .
[ phase_num ] )
. in the limit of @xmath91 , spins @xmath133 and @xmath9 form an effective spin @xmath149 @xmath102 @xmath150 with magnitude @xmath1 , and other interactions can be treated as perturbations .
then the effective hamiltonian for @xmath149 and @xmath10 is @xmath151 the ground state of this chain is still nontrivial .
however , @xmath17 plays a secondary role in the weakly frustrated region , so that each @xmath3 antiferromagnetically interacts with the ferromagnetic chain consisting of @xmath152 s .
therefore , it is plausible that the ground state is always nonmagnetic for small @xmath24 .
numerical studies of the effective model ( [ heff ] ) suggest no phase transition for @xmath153 where no phase transition is predicted by the nlsm method for large @xmath22 . in terms of the original hamiltonian ( [ hamiltonian ] ) ,
the ground state of @xmath91 and @xmath110 is a direct product of local singlet states of 3-spin units .
a 3-spin unit consists of @xmath9 , @xmath133 , and @xmath154 , as shown in fig .
[ 3spin](b ) .
the ground state of finite @xmath23 and @xmath24 ( @xmath91 ) is adiabatically connected to the limit without phase transition as long as @xmath24 is small .
the full phase diagram of the effective model ( [ heff ] ) is investigated in a separate paper @xcite .
, @xmath5 , and @xmath6 ; the phase diagram for @xmath155 by the nlsm method is shown .
the solid line is the phase boundary between gap i phase and gap ii phase . in each phase
, the dashed line of @xmath156 means a crossover between regions with different features .
gap i phase consists of regions i - a and i - b , while gap ii phase consists of regions ii - a and ii - b .
they are explained by scs pictures . ] in this section , we propose the scs picture to explain any ground state in the phase diagram for @xmath4 , @xmath5 , and @xmath6 .
this is a generalization of the vbs picture , and is based on expressing @xmath66 with magnitude 1 as @xmath157 where @xmath158 and @xmath159 are spins with magnitude @xmath1 @xcite . for convenience of explanation ,
we divide each phase into two regions by the line of @xmath156 as schematically shown in fig .
[ regions ] : gap i phase is divided into regions i - a and i - b , and gap ii phase is divided into regions i - a and i - b . ,
@xmath5 , and @xmath6 : ( a ) vbs i represents the ground state for @xmath90 and @xmath145 , and ( b ) vbs ii does for @xmath160 .
small circles are @xmath1-spins , and bold gray lines are valence bonds .
spin @xmath161 is expressed by two @xmath1-spins as @xmath162 .
loops including two valence bonds are for correspondence to scs pictures ( see text ) . ]
the ground states of the limiting cases in the preceding section are explained by vbs pictures .
the vbs picture for @xmath90 and @xmath145 is vbs i illustrated in fig .
[ vbs](a ) @xcite .
the valence bonds on @xmath14-interactions , which we hereafter abbreviate as the @xmath14-valence - bonds , mainly contribute to the energy gain of the ground state of vbs i. on the other hand , the vbs picture for @xmath91 is vbs ii illustrated in fig .
[ vbs](b ) .
the valence bonds on @xmath15-interactions , or the @xmath15-valence - bonds , mainly contribute to the energy gain of the ground state of vbs ii .
the vbs pictures are not adequate for regimes away from the above limiting cases , although they are expected to be qualitatively valid for small-@xmath22 and large-@xmath22 regimes . as seen in fig .
[ regions ] , the energetic advantage of @xmath14-valence - bonds of vbs i on line @xmath163 ( @xmath145 ) remains within region i - a because @xmath164 .
however the advantage is lost in region i - b because @xmath165 .
similarly , the energetic advantage of @xmath15-valence - bonds of vbs ii in the limit of @xmath160 remains within region ii - a because @xmath165 .
however the advantage is lost in region ii - b because @xmath164 .
since the line of @xmath156 is not a phase boundary , we need a new picture to explain the whole gap i ( ii ) phase which reduces to vbs i ( ii ) in the limit .
the picture will be a scs picture .
a general scs picture is defined by a wave function of a tensor product form of local singlet states .
we call this wave function the scs state and each local singlet state a singlet cluster .
it is typically written as @xmath166 where @xmath167 @xmath168 is a singlet cluster and @xmath169 is the total number of singlet clusters in the scs state . here
we have considered that any spin with magnitude more than 1 is resolved into a set of spins with magnitude @xmath1 .
then a singlet cluster is a singlet state of more than two spins with magnitude @xmath1 .
a singlet cluster in a scs state is represented as a superposition of products of valence bonds . hence the valence bonds are resonating within the singlet cluster .
a vbs is a special case of the scs , where a singlet cluster is a single valence bond and no resonation occurs .
a resonating valence bond ( rvb ) state is another special case , where the whole system is the singlet cluster and all valence bonds are resonating .
usually a scs state is not the exact ground state for a given spin hamiltonian .
however if the exact ground state is continuously modified into an appropriate scs state , the scs state describes the essence of the ground state . from this viewpoint , the scs state is useful to characterize the phase which the ground state belongs to . in some quantum spin chains without side chain ,
various ground - state phases have been successfully described by corresponding scs pictures @xcite .
furthermore , a scs state can also quantitatively describe the true ground state , if the wave function of each singlet cluster is well localized . among such systems , in the spin system on a diamond chain @xcite , we have the exact tetramer - dimer - state solution , which is a kind of scs state . , @xmath5 , and @xmath6 ) .
scs i is a tensor product form of singlet clusters .
( b ) a singlet cluster @xmath170 ( the left hand side ) in scs i. it is represented as a linear combination of two valence bond states , @xmath171 and @xmath172 ( the right hand side ) .
@xmath173 is the coefficient of the linear combination . ]
we call the scs picture for the gap i phase scs i. the scs i state is constructed by assuming the following requirements : \(i ) the ground state is continuously modified to the vbs i state without global rearrangement of the valence bond configuration .
\(ii ) the ground state is invariant under the translation by a single unit cell .
\(iii ) the ground state contains a substantial amount of component with @xmath15-valence - bonds in region i - b .
assumption ( i ) is necessary , since the gap i phase involves the limiting case of @xmath90 and @xmath145 where vbs i picture holds , and there is no phase transition in gap i phase . as for assumption ( ii ) , we confirmed that there is no indication of the translational symmetry breaking in numerical ground states .
assumption ( iii ) is required to explain region i - b . under the above requirements , we take scs i wave function in the tensor product form : @xmath174 as depicted schematically in fig .
[ scs_i](a ) . here
@xmath175 is a singlet cluster of four @xmath1-spins in the @xmath7th unit cell ; this is denoted by a loop filled in grey .
each singlet cluster is a linear combination of two valence bond states written as @xmath176 where @xmath171 and @xmath172 are the valence bond states defined in the right hand side of fig .
[ scs_i](b ) .
we have abbreviated index @xmath7 of the unit cell for simplicity .
the valence bond state @xmath171 is the same as that shown within a loop in vbs i ( fig . [ vbs](a ) ) . the valence bond state @xmath172 contains a @xmath15-valence - bond .
the coefficient @xmath173 should be 0 in the limit of @xmath90 , and may be small for region i - a ( @xmath164 ) .
but it should have a substantial amplitude in region i - b ( @xmath177 ) . for finite @xmath173
, the two valence bond states locally resonate in a singlet cluster to contribute to energy gain ; this effect is examined in subsection [ subsec : boundary ] , where the phase boundary between gap i and gap ii phases is discussed energetically .
= 0.3 and @xmath23 = 0.2 calculated numerically for @xmath178 = 12 , 18 , and 24 ( @xmath178 : the number of spins ) . ]
we examined which valence bonds really contribute to the ground state by numerically calculating the short range correlation functions . for a typical case ( @xmath24 = 0.3 and @xmath23 = 0.2 ) ,
results are shown in fig .
[ cor ] . as @xmath22 increases
, @xmath179 decreases and @xmath180 increases .
this means that the contribution from the @xmath15-valence - bonds becomes large in comparison with that from the @xmath14-valence - bonds .
it is also known that @xmath181 takes the maximum and @xmath182 takes the minimum around region i - b .
hence a @xmath16-valence - bond is reduced in region i - b .
instead , a valence bond between @xmath154 and @xmath183 ( or @xmath184 ) develops , although there is no exchange interaction between @xmath154 and @xmath8 .
all these results are consistent with the scs i picture . , @xmath5 , and @xmath6 ) . scs ii is a tensor product form of singlet clusters .
( b ) a singlet cluster @xmath185 ( the left hand side ) in scs ii .
it is represented as a linear combination of two valence bond states , @xmath186 and @xmath187 ( the right hand side ) .
@xmath173 is the coefficient of the linear combination .
( c ) identity among local valence bond states .
@xmath187 ( the left hand side ) is exactly the sum of @xmath186 and @xmath188 ( the right hand side ) . ]
we call the scs picture for the gap ii phase scs ii . similarly to the case of scs i , the scs ii state is constructed by assuming the following requirements : \(i ) the ground state is continuously modified to the vbs ii state without global rearrangement of the valence bond configuration .
\(ii ) the ground state is invariant under the translation by a single unit cell .
\(iii ) the ground state contains a substantial amount of component with @xmath14-valence - bonds in region ii - b . under the above requirements , we take scs ii wave function in the tensor product form : @xmath189 as depicted schematically in fig . [ scs_ii](a ) .
here @xmath190 is a singlet cluster of four @xmath1-spins in the @xmath7th unit cell ; this is denoted by a loop filled in grey .
each singlet cluster is a linear combination of two valence bond states written as @xmath191 where @xmath186 and @xmath187 are the two valence bond states defined in the right hand side of fig .
[ scs_ii](b ) .
we have abbreviated index @xmath7 of the unit cell for simplicity .
the valence bond state @xmath186 is the same as that shown within a loop in vbs ii ( fig .
[ vbs](b ) ) . the valence bond state @xmath187 contains a @xmath14-valence - bond .
the coefficient @xmath173 should be 0 in the limit of @xmath160 , and may be small for region ii - a ( @xmath177 ) .
but it should have substantial amplitude in region ii - b ( @xmath164 ) . for finite @xmath173 ,
the two valence bond states locally resonate in a singlet cluster to contribute to energy gain ; this effect is examined in subsection [ subsec : boundary ] .
the wave function ( [ cluster_ii ] ) of the singlet cluster is also represented as @xmath192 using identity @xmath187 = @xmath186 + @xmath188 , which is shown in fig .
[ scs_ii](c ) .
@xmath188 includes the valence bond on the @xmath17-interaction and contributes to energy gain in region ii - b ( @xmath193 ) .
first , we consider the @xmath194 part of the phase boundary ; it separates regions i - b and ii - a as seen in fig . [ regions ] .
the scs ii wave function in region ii - a is close to vbs ii with @xmath15-valence - bonds , while the scs i wave function in region i - b contains @xmath15-valence - bonds only in part in the linear combination ( eq . ( [ cluster_i ] ) ) .
then , since the energy gain owing to @xmath15-valence - bonds in region ii - a is always larger than that in region i - b , one might expect that region ii - a would extend to the whole area of @xmath194 .
the reason why region i - b actually exists is attributed to the energy gain by local resonation between the two valence bond states within each singlet cluster ( eq . ( [ cluster_i ] ) ) .
when @xmath23 or @xmath22 increases , the scs i becomes less favorable and vbs ii becomes of advantage because of strong @xmath16- or @xmath15-valence - bonds .
second , we consider the @xmath195 part of the phase boundary ; it separates regions ii - b and i - a as seen in fig .
[ regions ] .
the scs i wave function in region i - a is close to vbs i with @xmath14-valence - bonds , while the scs ii wave function in region ii - b contains @xmath14-valence - bonds only in part in the linear combination ( eq .
( [ cluster_ii ] ) ) . then , since the energy gain owing to @xmath14-valence - bonds in region i - a is always larger than that in region ii - b , one might expect that region i - a would extend to the whole area of @xmath195 .
the reason why region ii - b actually exists is attributed to the energy gain by local resonation between the two valence bond states within each singlet cluster ( eq . ( [ cluster_ii ] ) ) . since the resonation is enhanced by the frustration due to @xmath17-interactions , the area of region i - b increases with increasing @xmath24 ( @xmath196 ) as really seen in fig . [ phase_nlsm ] and fig .
[ phase_num ] .
if @xmath24 is fixed , the increase of @xmath23 ( @xmath197 ) diminishes the effect of @xmath14-interactions , and makes the effect of resonation in scs ii advantageous .
this is the reason why scs ii appears for relatively large @xmath23 in the presence of frustration @xmath24 .
in the preceding section , we explained that the scs picture represents the essence of each ground - state phase .
however it does not guarantee that each scs wave function is quantitatively satisfactory . in this section ,
we perform variational calculation using the scs i and the scs ii wave functions to examine the quantitative correctness of the wave functions . the variational wave function for scs
i is eq .
( [ var_fun_i ] ) with variational parameter @xmath173 , which is the coefficient of the linear combination .
then the energy per unit cell in energy unit @xmath14 is written as @xmath198 where @xmath199 is the total hamiltonian ( [ hamiltonian ] ) , and @xmath200 is the reduced hamiltonian for a singlet cluster in scs i given as @xmath201 after straightforward calculation , we have the following formula : @xmath202 minimizing @xmath203 with respect to @xmath173 , we have the optimal value @xmath204 of the coefficient of the linear combination : @xmath205 the result is shown in fig . [ coeff_i ] , where the left axis represents @xmath206 .
it is independent of @xmath24 , since a @xmath17-interaction is between different singlet clusters . in the limit of @xmath92 ,
we have @xmath207 and the wave function reduces to vbs i. the value @xmath208 increases with increasing @xmath22 , and for @xmath209 the term of @xmath172 including @xmath15-valence - bonds becomes dominant in @xmath170 .
this behavior is consistent with the argument about scs i in the preceding section . of the linear combination in the variational wave function for scs i ( @xmath4 , @xmath5 , and @xmath6 ) . the optimal coefficient @xmath173 does not depend on @xmath24 in the wave function .
the lines are in the order of ascending @xmath23 from the top to the bottom . ]
the variational wave function for scs ii is eq .
( [ var_fun_ii ] ) with variational parameter @xmath173 , which is the coefficient of the linear combination .
then the energy per unit cell in energy unit @xmath14 is written as @xmath210 where @xmath199 is the total hamiltonian ( [ hamiltonian ] ) , and @xmath211 is the reduced hamiltonian for a singlet cluster in scs ii given as @xmath212 of the linear combination in the variational wave function for scs i in the case of @xmath155 ( @xmath4 , @xmath5 , and @xmath6 ) .
the lines are in the order of ascending @xmath23 from the top to the bottom . ] after straightforward calculation , we have the following formula : @xmath213 minimizing @xmath214 with respect to @xmath173 , we have the optimal value @xmath204 of the coefficient of the linear combination : @xmath215 with @xmath216 and @xmath217 .
the result for @xmath155 is shown in fig .
[ coeff_ii ] , where the left axis represents @xmath218 . in the limit of @xmath91 , we have @xmath219 and the wave function reduces to vbs ii .
the result depends on @xmath24 , since a @xmath17-interaction is involved in each singlet cluster . except for @xmath24
= @xmath220 , @xmath221 increases with decreasing @xmath22 , meaning that @xmath187 including @xmath14-valence - bonds becomes dominant in eq .
( [ cluster_ii ] ) .
this feature is consistent with the scs ii picture in the preceding section . in the special case of @xmath222 (= @xmath223 )
= 1 , we have @xmath224 for any values of @xmath22 , since @xmath225 = 0 in eq .
( [ c_ii ] ) .
it is explained in the following expression for @xmath185 : @xmath226 which is derived from eq .
( [ cluster_ii ] ) by identity @xmath187 = @xmath186 + @xmath188 in fig .
[ scs_ii](c ) . for @xmath14 = @xmath17 , @xmath187 including a @xmath14-valence - bond and @xmath188 including a @xmath17-valence - bond
are equally weighted in eq .
( [ cluster_iidd ] ) , as are expected . , @xmath5 , and @xmath6 ) .
] in the above subsections , we have obtained variational energy @xmath227 of scs i for gap i phase and variational energy @xmath228 of scs ii for gap ii phase .
the phase boundary is determined by the equation @xmath229 the results for various @xmath24 are shown in fig .
[ phase_var ] .
these phase boundaries qualitatively agree with the numerical ones in fig .
[ phase_num ] , and support the correctness of the scs pictures .
region i - b in the variational phase diagram is wider in @xmath23-direction and narrower in @xmath22-direction than the accurate one ( fig .
[ phase_num ] ) .
further , region ii - b is narrower than the accurate one . remembering that regions i - b and ii - b exist because of local resonation of valence bond states , inclusion of longer - range valence bonds resonating with each other is possibly effective to improve the variational wave functions in regions i - b and ii - b .
the ground states in regions i - a and ii - a are close to vbs i and vbs ii , respectively , and the effect of resonation is relatively small . hence , the inclusion of longer longer - range valence bonds does not seem to be very effective to improve the variational wave functions .
in this paper , we investigated the nonmagnetic ground states of a mixed spin chain with side chains with weak frustration .
so far , these kind of models have not been investigated in depth despite their possible rich physics .
we have chosen the present model ( [ hamiltonian ] ) ( fig . [ lattice ] ) as a simple and nontrivial one , which will be a good starting point .
we examined the system in various approaches : a nlsm method , a numerical diagonalization method , an inspection of limiting cases , an physical interpretation based on scs pictures , and a variational calculation for scs wave functions .
nlsm methods have been developed for simple spin chains without side chain . in the present work
, we formulated a nlsm method for the typical spin chain with side chains .
the nlsm method analytically provides a ground - state phase diagram in the @xmath23-@xmath22 parameter space for various values of @xmath11 , @xmath12 , and @xmath13 . in the special case of @xmath11 = 1 ,
@xmath12 = @xmath1 , and @xmath13 = @xmath1 , the phase diagram contains two quantum disordered phases , gap i and gap ii , in each of which the system has a spin - gap .
we also examined the case of @xmath11 = 1 , @xmath12 = @xmath1 and @xmath13 = @xmath1 by the numerical diagonalization for finite chains . using the method of twisted boundary condition , we have determined phase boundaries .
when frustration is not strong ( @xmath230 ) , there are two spin - gap phases in the @xmath23-@xmath22 parameter space .
the numerical results confirms the qualitative correctness of the present nlsm method .
the limiting cases of @xmath92 and @xmath91 are precisely and analytically treated . for @xmath231 ,
the hamiltonian ( [ hamiltonian ] ) describes an array of weakly coupled 3-spin units . as @xmath23 increases from 0 , the ground state of each 3-spin unit changes from singlet to triplet .
accordingly the whole spin chain undergoes a phase transition from the vbs i state to the haldane state . for @xmath232 ,
the system is described by an effective hamiltonian where no phase transition occurs with changing @xmath23 as long as @xmath24 is small . considering the continuity to the large @xmath23 limit
, the ground state is described as a state similar to the vbs ii state .
there are regimes where no vbs picture explains the ground state for @xmath11 = 1 , @xmath12 = @xmath1 and @xmath13 = @xmath1 .
to explain the whole phase diagram , we proposed two scs pictures ; scs i and scs ii for gap i and gap ii phases , respectively .
each scs is a wave function of a tensor product form of singlet clusters . a singlet cluster in both the scs s is a local linear combination of two valence - bond states of two different patterns .
the resonation contributes to the energy gain of the system , and the whole phases are consistently explained .
to quantify the scs pictures , we performed variational calculations with the wave functions representing scs i and scs ii .
the phase boundary between gap i and gap ii phases are determined by equating the energy of the minimized wave function for scs i to that for scs ii .
the resultant phase diagram approximately reproduces the phase diagram by the numerical diagonalization .
thus we have obtained three phase diagrams : fig .
[ phase_nlsm ] by the nlsm method , fig .
[ phase_num ] by the numerical diagonalization , and fig .
[ phase_var ] by the variational calculation .
the phase diagram of fig .
[ phase_num ] is accurate , since the extrapolation by finite size systems is reliable .
the other phase diagrams qualitatively agree with the accurate one , and both the methods are shown to be useful .
so far , we have examined the spin chain with side chains when the parameter @xmath24 measuring frustration is not large ( @xmath230 ) . for larger @xmath24 , wider variety of phases
are expected .
for example , we can extend the analysis in the limit of @xmath92 to the region of @xmath233 , i. e. @xmath234
. for @xmath235 , effective spins of 3-spin units with spin magnitude 1 ferromagnetically interacts with the nearest neighbors and form a ferromagnetic ground state . in terms
of the original spins , the ground state is ferrimagnetic .
further , by the numerical diagonalization , we have found various ferrimagnetic phases with different magnetization in the strongly frustrated regime .
the study of these ferrimagnetic phases is in progress and will be reported in a separate paper .
the numerical diagonalization program is based on the package titpack ver . 2 coded by h. nishimori .
the numerical computation in this work has been carried out using the facilities of the supercomputer center , institute for solid state physics , university of tokyo and information technology center , university of tokyo .
this work is partly supported by fund for project research in toyota technological institute , and by innovative research organization , saitama university .
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one of @xmath236 , @xmath237 , and @xmath52 is a dummy variable .
it turns to be absorbed by the others , and only two variables remain as seen in eq .
( [ fluctuation_variable ] ) .
hence the number of the original degrees of freedom has conserved . the wave function ( [ sing_wf ] ) for a 3-spin unit is expressed as @xmath238 = @xmath239 , where @xmath240 means the valence bond state between @xmath241 (= @xmath158 or @xmath159 ) and @xmath242 (= @xmath2 or @xmath3 ) .
this is a part of vbs i in fig .
[ vbs](a ) . | we study a frustrated mixed spin chain with side chains , where the spin species and the exchange interactions are spatially varied . a nonlinear @xmath0 model method is formulated for this model , and a phase diagram with two disordered spin - gap phases
is obtained for typical cases . among them
we examine the case with a main chain consisting of an alternating array of spin-1 and spin-@xmath1 sites and side chains each of a single spin-@xmath1 site in great detail . based on numerical , perturbational , and variational approaches ,
we propose a singlet cluster solid picture for each phase , where the ground state is expressed as a tensor product of local singlet states . | <s>[INST]quantum one - dimensional ( 1d ) spin systems have been studied in various aspects , especially with interest on their strong quantum fluctuations due to the low dimensionality .
there appear a variety of quantum disordered ground states where the continuous spin rotation symmetry is not broken and the lowest spin excitation has a finite gap ( spin - gap ) .
these quantum disordered states have no analogues in classical spin systems .
typical examples are a haldane state in a spin-1 chain @xcite , a dimer state in a spin-@xmath1 chain with bond alternation @xcite , and a spin - gap state in a spin-@xmath1 ladder @xcite . in extensive research for various 1d spin systems , spin chains with side chains
have not attracted enough attention in spite of its potentially rich physics .
since a side chain is of finite length , it may enhance quantum fluctuation in the system .
actually , the 1d kondo necklace model , which has been extensively studied as a simplified version of 1d kondo lattice model @xcite , can be regarded as a spin chain with side chains . in this model ,
the main chain is a spin-@xmath1 chain and each side chain consists of a single spin with magnitude @xmath1 .
the ground state of this model is known to be in the kondo singlet phase with spin - gap @xcite , while the spin-@xmath1 chain without side chains is critical .
this means that the quasi - long range order in the main chain is destroyed by the quantum fluctuation in the side chains .
also , if the side chains bring geometrical frustration into the system , quantum fluctuation is expected to be further enhanced .
thus , it is an interesting subject how quantum fluctuation manifests itself and what kind of ground state appears in various types of spin chains with side chains . in this paper , we investigate the natures of quantum disordered ground states of one of the simplest models with frustrated side chains .
the main chain of the model consists of two species of spins in alternating order , and each side chain consists of a single spin which are alternately attached to the main chain , as will be shown in fig .
[ lattice ] of the next section .
this model incorporates the effects of mixture of different spins , bond alternation , and frustration in spite of its simplicity .
in particular , the frustration comes from triangles , each consisting of antiferromagnetically interacting three spins .
although quantum spin systems with similar geometry have been investigated by several authors @xcite , our model is physically different from them . if the side chains of our model are removed , the main chain is in a ferrimagnetic ground state .
the side chain spins introduce frustration to the system , and destroy the ferrimagnetic order leading to quantum disordered states . ,
@xmath2 , and @xmath3 are spins whose magnitudes satisfy eq .
( [ restriction ] ) .
the case that @xmath4 , @xmath5 , and @xmath6 is studied particularly in detail . ] the disordered ground states of the present model can not be understood in the conventional valence bond solid ( vbs ) picture @xcite , which successfully explains the disordered ground states of many spin models with local frustration .
instead , we will explain the present ground states in the concept of the singlet cluster solid ( scs ) picture .
a scs state is a direct product of local singlet states , or singlet clusters .
each singlet cluster consists of more than two singlet dimers , and the dimers are resonating locally within the cluster .
the scs states are realized as a result of the interplay of quantum fluctuation and local frustration , as will be explained in detail .
it is desirable that the scs state manifested in this paper is experimentally inspected in materials .
however , a material precisely described by the present model is not found so far within our knowledge . despite the lack of materials
, it is worth clarifying the concept of the scs states and verifying the existence of them in a concrete model .
further , considering the rich variety of magnetic materials synthesized by the modern chemical technology @xcite , desired materials are expected to be synthesized , since they are not necessarily complex in structure .
the details of the model are explained in the next section .
various approaches are employed to clarify the ground state phases of this model : in section [ sec : nlsm ] , a nonlinear @xmath0 model ( nlsm ) method is proposed to grasp qualitative feature of the phase diagram . since a similar nlsm method has been developed for mixed spin chains without side chains so far , we extend it to the present side - chain case .
we also employ other approaches limiting ourselves to the simplest case of spin magnitudes 1 and @xmath1 . in section [ sec : num_diagonal ] , the numerical diagonalization for finite systems is carried out to obtain the quantitatively reliable phase diagram , which confirms the qualitative correctness of the nlsm method .
some limiting cases are exactly treated to draw physical picture for each phase in section [ sec : limit ] .
after these considerations , we arrive at the scs pictures to explain the ground states in section [ sec : scs ] .
the scs pictures are also supported by variational calculations in section [ sec : variational ] .
the last section is devoted to summary and discussion .
we study an isotropic quantum spin chain with alternately arrayed side chains as is illustrated in fig .
[ lattice ] . in the @xmath7th unit cell , @xmath8 and @xmath9
are spin operators on the main chain , and @xmath10 is a spin operator on the side chain .
the quantum numbers of spin magnitudes of these spin operators are expressed as @xmath11 , @xmath12 , and @xmath13 , respectively .
exchange parameters are represented as @xmath14 , @xmath15 , @xmath16 and @xmath17 , and assumed to be all positive .
then the hamiltonian is written as @xmath18 the spacing between nearest spins is @xmath19 , and the length of a unit cell is @xmath20 .
the hamiltonian is characterized by three independent dimensionless parameters : @xmath21 here @xmath22 measures the strength of the bond alternation in the main chain , @xmath23 measures the strength of interaction between a main - chain spin and a side - chain spin , and @xmath24 measures the strength of frustration @xcite . in the present paper ,
we assume the following restriction on spin magnitudes : @xmath25 this is the condition that the corresponding classical spin chain can have a ground state with no total magnetization ( i. e. no ferrimagnetism ) , when @xmath17 is not large .
the restriction ( [ restriction ] ) serves to simplify the berry phase term in the continuum limit .
expectation values of the spin operators for a spin coherent state are written as @xmath26 where @xmath27 , @xmath28 , and @xmath29 are unit vectors . replacing the spin operators in eq .
( [ hamiltonian ] ) by them , we have the classical version of the hamiltonian : @xmath30 ^ 2 \bigr . \nonumber \\ & \ \
+ \left(1-\frac{kr}{1-r } \right ) \ , [ \v{m}_1(p ) - \v{m}_2(p ) ] ^2 \nonumber \\ & \ \ + \bigl . \frac{k}{1-r } \ , [ \v{m}_1(p ) - r\v{m}_2(p ) - ( 1-r)\v{m}_{\bot}(p ) ] ^2 \bigr\ } , \nonumber \\ \label{c_hamiltonian}\end{aligned}\ ] ] where @xmath31 and a constant term is omitted from @xmath32 . the classical antiferromagnetic configuration , @xmath33 for all @xmath7 , @xmath34 , and @xmath35 , is the ground - state solution if the pre - factors of the squares in eq .
( [ c_hamiltonian ] ) are all positive .
this gives the condition for the classical stability of the antiferromagnetism as @xmath36 in the following arguments , we will concentrate on this region .
using the spin coherent representation , the partition function of hamiltonian ( [ hamiltonian ] ) is written in a path - integral form as @xmath37 \ , \delta(\v{m}_j^2 - 1 ) e^{-a } \label{partition}\end{aligned}\ ] ] with @xmath38 , and @xmath39 .
the action @xmath40 is written as @xmath41 - s_2 w[\v{m}_2(p ) ] - \
t w[\v{m}_{\bot}(p ) ] \ } , \nonumber \\ a_h & = \int_0^{\beta } d\tau h_c , \label{action_coherent}\end{aligned}\ ] ] where @xmath42 is the inverse of temperature , and @xmath43 $ ] is the solid angle which @xmath44 forms in period @xmath42 .
the term @xmath45 in action @xmath40 is the berry phase term .
we introduce slow variable @xmath46 for each unit cell , and fluctuation variables @xmath47 , @xmath48 , and @xmath49 for each spin in a unit cell .
then the original variables are transformed as follows : @xmath50 this transformation is found by observing and extending the transformation for a simple chain without side chain @xcite . since the left hand sides in ( [ transformation ] ) are unit vectors , we have the following constraints for the new variables : @xmath51 the fluctuation variables depends on one another , and one of them , e. g. @xmath52 can be set equal to 0 .
hence the number of independent variables are conserved in the transformation . defining new fluctuation variables , @xmath53 and taking the continuum limit
, we have @xmath54 \biggr\ } \end{aligned}\ ] ] with @xmath55 . here vectors @xmath56 and @xmath57 are given as @xmath58 integrating the partition function with respect to @xmath59 and @xmath60 , we have the following nlsm action : @xmath61 the first term is the topological term and @xmath62 is the topological angle given by @xmath63 in the absence of frustration ( @xmath64 ) , the topological angle reduces to @xmath65 .
this is the same expression as that for a simple spin chain of magnitude @xmath12 with bond alternation @xcite .
this can be interpreted as follows : a spin @xmath66 is combined with the adjacent spin @xmath3 on the side chain , and a two - spin cluster with total spin magnitude @xmath67 @xmath68 is formed .
however , the coefficients of @xmath69 and @xmath70 in eq .
( [ action - nlsm ] ) do not reduce to those for the simple spin chain , even if @xmath23 is very large .
this reflects that the quantum fluctuation of spins on side chains still survive for large @xmath23 . the topological term of eq .
( [ action - nlsm ] ) determines whether or not the system has a spin - gap in the same manner as haldane s argument @xcite .
that is , the system does not have a spin - gap if and only if the topological angle @xmath62 is just @xmath71 ( mod @xmath72 ) .
this condition is written as @xmath73 where @xmath74 is any half odd integer .
this gapless condition determines phase boundaries between gapful disordered phases in the parameter space .
we notice that , for each value of @xmath74 , boundaries for all values of @xmath24 pass through the common point @xmath75 in the @xmath23-@xmath22 plane by the nlsm method for @xmath4 , @xmath5 , and @xmath6 . for each value of @xmath24 (= @xmath76 )
the region of @xmath77 is meaningful in the nlsm method . ] in the case of @xmath4 , @xmath5 and @xmath6 , only a permitted value of @xmath74 in eq .
( [ gapless_condition ] ) is @xmath1 for @xmath78 and @xmath79 .
then the phase boundaries for several values of @xmath24 are solid lines in fig .
[ phase_nlsm ] . owing to the definitions of the parameters , they are straight lines in the present approximation
. the regions of the both sides of each boundary are gapful disordered phases .
we call them gap i phase and gap ii phase as noted in the figure . for @xmath64
the phase boundary is horizontal , since the topological angle is independent of @xmath23 as mentioned below eq .
( [ t_angle ] ) .
this is understandable by considering @xmath66 as a composite of two @xmath1 spins .
in fact , when @xmath64 , @xmath3 and one of the @xmath1 spins of @xmath66 necessarily forms a valence bond irrespective of the value of @xmath23 in the ground state .
as @xmath24 increases from 0 , the slope of the boundary becomes negatively large .
the reason will be argued later . -@xmath22
plane by the nlsm method in the cases of ( a ) @xmath80 , @xmath81 , and @xmath6 , and ( b ) in the case of @xmath80 , @xmath5 , and @xmath82 . for each value of @xmath24
the region of @xmath77 is meaningful . ]
we also show phase diagrams in other cases in fig . [ other_phases ] ; the phase boundaries in ( a ) are for @xmath80 , @xmath81 , and @xmath6 , and those in ( b ) are for @xmath80 , @xmath5 , and @xmath82 .
although the equation ( [ gapless_condition ] ) determining phase boundaries are quite general , we mainly examine the case of @xmath4 , @xmath5 , and @xmath6 . this case
is expected to include the essence of the present type of spin chains with side chains .
hamiltonian ( [ hamiltonian ] ) can be numerically diagonalized for small size systems .
the numerical calculation is effective not only to analyze the system itself in detail , but also to know the preciseness of the nlsm method by comparing the results .
we performed numerical diagonalization in the case of @xmath4 , @xmath5 , and @xmath6 to obtain the phase diagram for the ground state . , @xmath5 , and @xmath6 .
each point of a boundary is determined by extrapolation for the total spin number @xmath83 12 , 18 , and 24 .
inset : phase boundaries for small @xmath23 . ]
the phase transition points are determined as follows .
the phase transitions between different spin gap phases are expected to be the gaussian transition .
hence we employ the method of twist boundary condition proposed by kitazawa @xcite and kitazawa and nomura @xcite to determine the phase boundary .
as will be examined later , the ground state phases are described by different scs configurations . under the twisted boundary condition ,
the different singlet solid configurations have different time reversal parities depending on the even - odd parity of the number of valence bonds across the twisted boundary .
hence the energy levels of the ground state and the first excited state cross at the phase boundary without level repulsion .
this ensures the precise evaluation of the phase boundary .
the size extrapolation is based on the following formula for the finite size correction@xcite : @xmath84 where @xmath85 is the finite size critical value of quantity @xmath22 , and @xmath86 and @xmath87 are fitting parameters .
we have carried out the extrapolation using numerical results for total spin number @xmath83 12 , 18 , and 24 .
resultant phase boundaries for several values of @xmath24 are plotted in fig .
[ phase_num ] . comparing figs .
[ phase_nlsm ] and [ phase_num ] , we find that the nlsm method gives qualitatively correct phase boundaries .
in particular , for small @xmath24 , or weak frustration , the nlsm method provides a quantitatively fair approximation . with the increase of @xmath24
, the gap i phase extends to the region @xmath88 for small @xmath23 , and it is suppressed to the region @xmath89 for large @xmath23 .
although this feature qualitatively coincides with that of the nlsm results , quantitative coincidence becomes worse with the increase of @xmath24 .
this is natural because the present nlsm method starts from a classical antiferromagnetic solution in the absence of frustration .
the possibility of the first order transition between different spin - gap phases has been pointed out in the frustrated ladder by hakobyan and coworkers @xcite in the appropriate parameter regime . considering the presence of frustration ,
this type of transition can not be ruled out in the present model .
however , we did not find the numerical evidence for the first order transition within the parameter regime discussed in this paper .
to further confirm the numerical phase diagram for @xmath4 , @xmath5 , and @xmath6 , we consider the effective theory in the limiting cases of @xmath90 and @xmath91 . in the limit of @xmath92 ,
the system can be regarded as a one - dimensional array of weakly coupled 3-spin units as shown in fig . [ 3spin](a ) .
one of the 3-spin units is described by the hamiltonian @xmath93 where we have dropped the common index @xmath7 representing the @xmath7th unit cell for simplicity .
the nel basis is represented as @xmath94 , where @xmath95 takes @xmath96 , 0 or @xmath97 , and @xmath98 and @xmath13 take @xmath99 or @xmath100 . by introducing the composed spin @xmath101 @xmath102 @xmath103
, we have another set of basis vectors @xmath104 , where @xmath105 and @xmath106 are quantum numbers of the magnitude and the @xmath107-component of @xmath101 respectively , and @xmath108 discriminates multiple states with the same @xmath105 and @xmath106 , if necessary .
we seek the ground state of the 3-spin unit with @xmath109 or 1 , since all the exchange interactions are antiferromagnetic . , and ( b ) those for @xmath91 and @xmath110 in the case of @xmath4 , @xmath5 , and @xmath6 .
three spins ( circles ) in a shadowed region form a 3-spin unit . ]
\(i ) for @xmath109 , we have @xmath111
. then the one - dimensional subspace consists of a single state , @xmath112 this is a singlet eigenstate of @xmath113 belonging to the eigenvalue @xmath114 ( ii ) for @xmath115 , we have @xmath106 = 1 , 0 , or @xmath116 . in this three - dimensional subspace , it is sufficient to inspect the case of @xmath117 owing to the spherical symmetry of the hamiltonian @xmath113 .
we choose the orthonormal basis of the subspace @xmath118 as @xmath119 operating @xmath113 on these bases , we have an eigenvalue equation .
then the lowest eigenvalue @xmath120 in this subspace is determined as the smaller solution of the characteristic equation : @xmath121 introducing a normalized energy difference as @xmath122 , eq .
( [ tri_ene ] ) with eq .
( [ sing_ene ] ) reduces to @xmath123\epsilon + 2k[2-\left(1+k\right)r]=0 .
\end{aligned}\ ] ] if the smaller solution for @xmath124 is negative , the ground state is a triplet ( @xmath115 ) state ; otherwise it is a singlet ( @xmath109 ) state . using ( [ ene_diff ] ) , the condition for the triplet ground state becomes @xmath125 we notice that @xmath126 in the region of @xmath127 , which we have concentrated on in this paper . in the triplet ground state
, @xmath2 tends to orient the opposite direction to @xmath66 for @xmath128 , and @xmath3 does for @xmath129 .
the composed spin @xmath101 always orients to the same direction as @xmath66 .
the composed spin @xmath130 at the @xmath7th unit cell interacts with adjacent @xmath131 by an effective exchange interaction .
we denote the effective exchange parameter by @xmath132 .
since the interaction between @xmath9 and @xmath133 is antiferromagnetic ( @xmath134 ) , the correlation between @xmath8 and @xmath133 is antiferromagnetic for @xmath135 @xmath136 and ferromagnetic for @xmath137 @xmath138 .
therefore @xmath132 has the same sign as @xmath139 , considering the signs of @xmath140 and @xmath141 are the same . for @xmath142
, we have @xmath143 , since @xmath144 for @xmath127 .
hence the original spin chain is equivalent to a spin-1 antiferromagnetic heisenberg chain consisting of effective spins , @xmath130 s .
the ground state of an uniform spin-1 chain is the haldane state @xcite , which gives a spin - gap for excitation . in the haldane state
, there is strong correlation on each adjacent spin pair , as known from the vbs picture for effective spins , @xmath130 s @xcite . in terms of the original spins ,
there is strong correlation between adjacent 3-spin units . for @xmath145 ,
on the other hand , the ground state of each 3-spin unit is already a closed singlet state .
then the ground state of the total spin chain is approximately an array of such closed local singlets , and there is almost no correlation between adjacent 3-spin units . thus there is a gaussian transition between the two characteristic ground states with spin - gap at @xmath146 .
the value of @xmath147 in this argument for @xmath92 agrees with the critical value by the numerical diagonalization , as is seen on the @xmath148 line of the phase diagram ( fig .
[ phase_num ] )
. in the limit of @xmath91 , spins @xmath133 and @xmath9 form an effective spin @xmath149 @xmath102 @xmath150 with magnitude @xmath1 , and other interactions can be treated as perturbations .
then the effective hamiltonian for @xmath149 and @xmath10 is @xmath151 the ground state of this chain is still nontrivial .
however , @xmath17 plays a secondary role in the weakly frustrated region , so that each @xmath3 antiferromagnetically interacts with the ferromagnetic chain consisting of @xmath152 s .
therefore , it is plausible that the ground state is always nonmagnetic for small @xmath24 .
numerical studies of the effective model ( [ heff ] ) suggest no phase transition for @xmath153 where no phase transition is predicted by the nlsm method for large @xmath22 . in terms of the original hamiltonian ( [ hamiltonian ] ) ,
the ground state of @xmath91 and @xmath110 is a direct product of local singlet states of 3-spin units .
a 3-spin unit consists of @xmath9 , @xmath133 , and @xmath154 , as shown in fig .
[ 3spin](b ) .
the ground state of finite @xmath23 and @xmath24 ( @xmath91 ) is adiabatically connected to the limit without phase transition as long as @xmath24 is small .
the full phase diagram of the effective model ( [ heff ] ) is investigated in a separate paper @xcite .
, @xmath5 , and @xmath6 ; the phase diagram for @xmath155 by the nlsm method is shown .
the solid line is the phase boundary between gap i phase and gap ii phase . in each phase
, the dashed line of @xmath156 means a crossover between regions with different features .
gap i phase consists of regions i - a and i - b , while gap ii phase consists of regions ii - a and ii - b .
they are explained by scs pictures . ] in this section , we propose the scs picture to explain any ground state in the phase diagram for @xmath4 , @xmath5 , and @xmath6 .
this is a generalization of the vbs picture , and is based on expressing @xmath66 with magnitude 1 as @xmath157 where @xmath158 and @xmath159 are spins with magnitude @xmath1 @xcite . for convenience of explanation ,
we divide each phase into two regions by the line of @xmath156 as schematically shown in fig .
[ regions ] : gap i phase is divided into regions i - a and i - b , and gap ii phase is divided into regions i - a and i - b . ,
@xmath5 , and @xmath6 : ( a ) vbs i represents the ground state for @xmath90 and @xmath145 , and ( b ) vbs ii does for @xmath160 .
small circles are @xmath1-spins , and bold gray lines are valence bonds .
spin @xmath161 is expressed by two @xmath1-spins as @xmath162 .
loops including two valence bonds are for correspondence to scs pictures ( see text ) . ]
the ground states of the limiting cases in the preceding section are explained by vbs pictures .
the vbs picture for @xmath90 and @xmath145 is vbs i illustrated in fig .
[ vbs](a ) @xcite .
the valence bonds on @xmath14-interactions , which we hereafter abbreviate as the @xmath14-valence - bonds , mainly contribute to the energy gain of the ground state of vbs i. on the other hand , the vbs picture for @xmath91 is vbs ii illustrated in fig .
[ vbs](b ) .
the valence bonds on @xmath15-interactions , or the @xmath15-valence - bonds , mainly contribute to the energy gain of the ground state of vbs ii .
the vbs pictures are not adequate for regimes away from the above limiting cases , although they are expected to be qualitatively valid for small-@xmath22 and large-@xmath22 regimes . as seen in fig .
[ regions ] , the energetic advantage of @xmath14-valence - bonds of vbs i on line @xmath163 ( @xmath145 ) remains within region i - a because @xmath164 .
however the advantage is lost in region i - b because @xmath165 .
similarly , the energetic advantage of @xmath15-valence - bonds of vbs ii in the limit of @xmath160 remains within region ii - a because @xmath165 .
however the advantage is lost in region ii - b because @xmath164 .
since the line of @xmath156 is not a phase boundary , we need a new picture to explain the whole gap i ( ii ) phase which reduces to vbs i ( ii ) in the limit .
the picture will be a scs picture .
a general scs picture is defined by a wave function of a tensor product form of local singlet states .
we call this wave function the scs state and each local singlet state a singlet cluster .
it is typically written as @xmath166 where @xmath167 @xmath168 is a singlet cluster and @xmath169 is the total number of singlet clusters in the scs state . here
we have considered that any spin with magnitude more than 1 is resolved into a set of spins with magnitude @xmath1 .
then a singlet cluster is a singlet state of more than two spins with magnitude @xmath1 .
a singlet cluster in a scs state is represented as a superposition of products of valence bonds . hence the valence bonds are resonating within the singlet cluster .
a vbs is a special case of the scs , where a singlet cluster is a single valence bond and no resonation occurs .
a resonating valence bond ( rvb ) state is another special case , where the whole system is the singlet cluster and all valence bonds are resonating .
usually a scs state is not the exact ground state for a given spin hamiltonian .
however if the exact ground state is continuously modified into an appropriate scs state , the scs state describes the essence of the ground state . from this viewpoint , the scs state is useful to characterize the phase which the ground state belongs to . in some quantum spin chains without side chain ,
various ground - state phases have been successfully described by corresponding scs pictures @xcite .
furthermore , a scs state can also quantitatively describe the true ground state , if the wave function of each singlet cluster is well localized . among such systems , in the spin system on a diamond chain @xcite , we have the exact tetramer - dimer - state solution , which is a kind of scs state . , @xmath5 , and @xmath6 ) .
scs i is a tensor product form of singlet clusters .
( b ) a singlet cluster @xmath170 ( the left hand side ) in scs i. it is represented as a linear combination of two valence bond states , @xmath171 and @xmath172 ( the right hand side ) .
@xmath173 is the coefficient of the linear combination . ]
we call the scs picture for the gap i phase scs i. the scs i state is constructed by assuming the following requirements : \(i ) the ground state is continuously modified to the vbs i state without global rearrangement of the valence bond configuration .
\(ii ) the ground state is invariant under the translation by a single unit cell .
\(iii ) the ground state contains a substantial amount of component with @xmath15-valence - bonds in region i - b .
assumption ( i ) is necessary , since the gap i phase involves the limiting case of @xmath90 and @xmath145 where vbs i picture holds , and there is no phase transition in gap i phase . as for assumption ( ii ) , we confirmed that there is no indication of the translational symmetry breaking in numerical ground states .
assumption ( iii ) is required to explain region i - b . under the above requirements , we take scs i wave function in the tensor product form : @xmath174 as depicted schematically in fig .
[ scs_i](a ) . here
@xmath175 is a singlet cluster of four @xmath1-spins in the @xmath7th unit cell ; this is denoted by a loop filled in grey .
each singlet cluster is a linear combination of two valence bond states written as @xmath176 where @xmath171 and @xmath172 are the valence bond states defined in the right hand side of fig .
[ scs_i](b ) .
we have abbreviated index @xmath7 of the unit cell for simplicity .
the valence bond state @xmath171 is the same as that shown within a loop in vbs i ( fig . [ vbs](a ) ) . the valence bond state @xmath172 contains a @xmath15-valence - bond .
the coefficient @xmath173 should be 0 in the limit of @xmath90 , and may be small for region i - a ( @xmath164 ) .
but it should have a substantial amplitude in region i - b ( @xmath177 ) . for finite @xmath173
, the two valence bond states locally resonate in a singlet cluster to contribute to energy gain ; this effect is examined in subsection [ subsec : boundary ] , where the phase boundary between gap i and gap ii phases is discussed energetically .
= 0.3 and @xmath23 = 0.2 calculated numerically for @xmath178 = 12 , 18 , and 24 ( @xmath178 : the number of spins ) . ]
we examined which valence bonds really contribute to the ground state by numerically calculating the short range correlation functions . for a typical case ( @xmath24 = 0.3 and @xmath23 = 0.2 ) ,
results are shown in fig .
[ cor ] . as @xmath22 increases
, @xmath179 decreases and @xmath180 increases .
this means that the contribution from the @xmath15-valence - bonds becomes large in comparison with that from the @xmath14-valence - bonds .
it is also known that @xmath181 takes the maximum and @xmath182 takes the minimum around region i - b .
hence a @xmath16-valence - bond is reduced in region i - b .
instead , a valence bond between @xmath154 and @xmath183 ( or @xmath184 ) develops , although there is no exchange interaction between @xmath154 and @xmath8 .
all these results are consistent with the scs i picture . , @xmath5 , and @xmath6 ) . scs ii is a tensor product form of singlet clusters .
( b ) a singlet cluster @xmath185 ( the left hand side ) in scs ii .
it is represented as a linear combination of two valence bond states , @xmath186 and @xmath187 ( the right hand side ) .
@xmath173 is the coefficient of the linear combination .
( c ) identity among local valence bond states .
@xmath187 ( the left hand side ) is exactly the sum of @xmath186 and @xmath188 ( the right hand side ) . ]
we call the scs picture for the gap ii phase scs ii . similarly to the case of scs i , the scs ii state is constructed by assuming the following requirements : \(i ) the ground state is continuously modified to the vbs ii state without global rearrangement of the valence bond configuration .
\(ii ) the ground state is invariant under the translation by a single unit cell .
\(iii ) the ground state contains a substantial amount of component with @xmath14-valence - bonds in region ii - b . under the above requirements , we take scs ii wave function in the tensor product form : @xmath189 as depicted schematically in fig . [ scs_ii](a ) .
here @xmath190 is a singlet cluster of four @xmath1-spins in the @xmath7th unit cell ; this is denoted by a loop filled in grey .
each singlet cluster is a linear combination of two valence bond states written as @xmath191 where @xmath186 and @xmath187 are the two valence bond states defined in the right hand side of fig .
[ scs_ii](b ) .
we have abbreviated index @xmath7 of the unit cell for simplicity .
the valence bond state @xmath186 is the same as that shown within a loop in vbs ii ( fig .
[ vbs](b ) ) . the valence bond state @xmath187 contains a @xmath14-valence - bond .
the coefficient @xmath173 should be 0 in the limit of @xmath160 , and may be small for region ii - a ( @xmath177 ) .
but it should have substantial amplitude in region ii - b ( @xmath164 ) . for finite @xmath173 ,
the two valence bond states locally resonate in a singlet cluster to contribute to energy gain ; this effect is examined in subsection [ subsec : boundary ] .
the wave function ( [ cluster_ii ] ) of the singlet cluster is also represented as @xmath192 using identity @xmath187 = @xmath186 + @xmath188 , which is shown in fig .
[ scs_ii](c ) .
@xmath188 includes the valence bond on the @xmath17-interaction and contributes to energy gain in region ii - b ( @xmath193 ) .
first , we consider the @xmath194 part of the phase boundary ; it separates regions i - b and ii - a as seen in fig . [ regions ] .
the scs ii wave function in region ii - a is close to vbs ii with @xmath15-valence - bonds , while the scs i wave function in region i - b contains @xmath15-valence - bonds only in part in the linear combination ( eq . ( [ cluster_i ] ) ) .
then , since the energy gain owing to @xmath15-valence - bonds in region ii - a is always larger than that in region i - b , one might expect that region ii - a would extend to the whole area of @xmath194 .
the reason why region i - b actually exists is attributed to the energy gain by local resonation between the two valence bond states within each singlet cluster ( eq . ( [ cluster_i ] ) ) .
when @xmath23 or @xmath22 increases , the scs i becomes less favorable and vbs ii becomes of advantage because of strong @xmath16- or @xmath15-valence - bonds .
second , we consider the @xmath195 part of the phase boundary ; it separates regions ii - b and i - a as seen in fig .
[ regions ] .
the scs i wave function in region i - a is close to vbs i with @xmath14-valence - bonds , while the scs ii wave function in region ii - b contains @xmath14-valence - bonds only in part in the linear combination ( eq .
( [ cluster_ii ] ) ) . then , since the energy gain owing to @xmath14-valence - bonds in region i - a is always larger than that in region ii - b , one might expect that region i - a would extend to the whole area of @xmath195 .
the reason why region ii - b actually exists is attributed to the energy gain by local resonation between the two valence bond states within each singlet cluster ( eq . ( [ cluster_ii ] ) ) . since the resonation is enhanced by the frustration due to @xmath17-interactions , the area of region i - b increases with increasing @xmath24 ( @xmath196 ) as really seen in fig . [ phase_nlsm ] and fig .
[ phase_num ] .
if @xmath24 is fixed , the increase of @xmath23 ( @xmath197 ) diminishes the effect of @xmath14-interactions , and makes the effect of resonation in scs ii advantageous .
this is the reason why scs ii appears for relatively large @xmath23 in the presence of frustration @xmath24 .
in the preceding section , we explained that the scs picture represents the essence of each ground - state phase .
however it does not guarantee that each scs wave function is quantitatively satisfactory . in this section ,
we perform variational calculation using the scs i and the scs ii wave functions to examine the quantitative correctness of the wave functions . the variational wave function for scs
i is eq .
( [ var_fun_i ] ) with variational parameter @xmath173 , which is the coefficient of the linear combination .
then the energy per unit cell in energy unit @xmath14 is written as @xmath198 where @xmath199 is the total hamiltonian ( [ hamiltonian ] ) , and @xmath200 is the reduced hamiltonian for a singlet cluster in scs i given as @xmath201 after straightforward calculation , we have the following formula : @xmath202 minimizing @xmath203 with respect to @xmath173 , we have the optimal value @xmath204 of the coefficient of the linear combination : @xmath205 the result is shown in fig . [ coeff_i ] , where the left axis represents @xmath206 .
it is independent of @xmath24 , since a @xmath17-interaction is between different singlet clusters . in the limit of @xmath92 ,
we have @xmath207 and the wave function reduces to vbs i. the value @xmath208 increases with increasing @xmath22 , and for @xmath209 the term of @xmath172 including @xmath15-valence - bonds becomes dominant in @xmath170 .
this behavior is consistent with the argument about scs i in the preceding section . of the linear combination in the variational wave function for scs i ( @xmath4 , @xmath5 , and @xmath6 ) . the optimal coefficient @xmath173 does not depend on @xmath24 in the wave function .
the lines are in the order of ascending @xmath23 from the top to the bottom . ]
the variational wave function for scs ii is eq .
( [ var_fun_ii ] ) with variational parameter @xmath173 , which is the coefficient of the linear combination .
then the energy per unit cell in energy unit @xmath14 is written as @xmath210 where @xmath199 is the total hamiltonian ( [ hamiltonian ] ) , and @xmath211 is the reduced hamiltonian for a singlet cluster in scs ii given as @xmath212 of the linear combination in the variational wave function for scs i in the case of @xmath155 ( @xmath4 , @xmath5 , and @xmath6 ) .
the lines are in the order of ascending @xmath23 from the top to the bottom . ] after straightforward calculation , we have the following formula : @xmath213 minimizing @xmath214 with respect to @xmath173 , we have the optimal value @xmath204 of the coefficient of the linear combination : @xmath215 with @xmath216 and @xmath217 .
the result for @xmath155 is shown in fig .
[ coeff_ii ] , where the left axis represents @xmath218 . in the limit of @xmath91 , we have @xmath219 and the wave function reduces to vbs ii .
the result depends on @xmath24 , since a @xmath17-interaction is involved in each singlet cluster . except for @xmath24
= @xmath220 , @xmath221 increases with decreasing @xmath22 , meaning that @xmath187 including @xmath14-valence - bonds becomes dominant in eq .
( [ cluster_ii ] ) .
this feature is consistent with the scs ii picture in the preceding section . in the special case of @xmath222 (= @xmath223 )
= 1 , we have @xmath224 for any values of @xmath22 , since @xmath225 = 0 in eq .
( [ c_ii ] ) .
it is explained in the following expression for @xmath185 : @xmath226 which is derived from eq .
( [ cluster_ii ] ) by identity @xmath187 = @xmath186 + @xmath188 in fig .
[ scs_ii](c ) . for @xmath14 = @xmath17 , @xmath187 including a @xmath14-valence - bond and @xmath188 including a @xmath17-valence - bond
are equally weighted in eq .
( [ cluster_iidd ] ) , as are expected . , @xmath5 , and @xmath6 ) .
] in the above subsections , we have obtained variational energy @xmath227 of scs i for gap i phase and variational energy @xmath228 of scs ii for gap ii phase .
the phase boundary is determined by the equation @xmath229 the results for various @xmath24 are shown in fig .
[ phase_var ] .
these phase boundaries qualitatively agree with the numerical ones in fig .
[ phase_num ] , and support the correctness of the scs pictures .
region i - b in the variational phase diagram is wider in @xmath23-direction and narrower in @xmath22-direction than the accurate one ( fig .
[ phase_num ] ) .
further , region ii - b is narrower than the accurate one . remembering that regions i - b and ii - b exist because of local resonation of valence bond states , inclusion of longer - range valence bonds resonating with each other is possibly effective to improve the variational wave functions in regions i - b and ii - b .
the ground states in regions i - a and ii - a are close to vbs i and vbs ii , respectively , and the effect of resonation is relatively small . hence , the inclusion of longer longer - range valence bonds does not seem to be very effective to improve the variational wave functions .
in this paper , we investigated the nonmagnetic ground states of a mixed spin chain with side chains with weak frustration .
so far , these kind of models have not been investigated in depth despite their possible rich physics .
we have chosen the present model ( [ hamiltonian ] ) ( fig . [ lattice ] ) as a simple and nontrivial one , which will be a good starting point .
we examined the system in various approaches : a nlsm method , a numerical diagonalization method , an inspection of limiting cases , an physical interpretation based on scs pictures , and a variational calculation for scs wave functions .
nlsm methods have been developed for simple spin chains without side chain . in the present work
, we formulated a nlsm method for the typical spin chain with side chains .
the nlsm method analytically provides a ground - state phase diagram in the @xmath23-@xmath22 parameter space for various values of @xmath11 , @xmath12 , and @xmath13 . in the special case of @xmath11 = 1 ,
@xmath12 = @xmath1 , and @xmath13 = @xmath1 , the phase diagram contains two quantum disordered phases , gap i and gap ii , in each of which the system has a spin - gap .
we also examined the case of @xmath11 = 1 , @xmath12 = @xmath1 and @xmath13 = @xmath1 by the numerical diagonalization for finite chains . using the method of twisted boundary condition , we have determined phase boundaries .
when frustration is not strong ( @xmath230 ) , there are two spin - gap phases in the @xmath23-@xmath22 parameter space .
the numerical results confirms the qualitative correctness of the present nlsm method .
the limiting cases of @xmath92 and @xmath91 are precisely and analytically treated . for @xmath231 ,
the hamiltonian ( [ hamiltonian ] ) describes an array of weakly coupled 3-spin units . as @xmath23 increases from 0 , the ground state of each 3-spin unit changes from singlet to triplet .
accordingly the whole spin chain undergoes a phase transition from the vbs i state to the haldane state . for @xmath232 ,
the system is described by an effective hamiltonian where no phase transition occurs with changing @xmath23 as long as @xmath24 is small . considering the continuity to the large @xmath23 limit
, the ground state is described as a state similar to the vbs ii state .
there are regimes where no vbs picture explains the ground state for @xmath11 = 1 , @xmath12 = @xmath1 and @xmath13 = @xmath1 .
to explain the whole phase diagram , we proposed two scs pictures ; scs i and scs ii for gap i and gap ii phases , respectively .
each scs is a wave function of a tensor product form of singlet clusters . a singlet cluster in both the scs s is a local linear combination of two valence - bond states of two different patterns .
the resonation contributes to the energy gain of the system , and the whole phases are consistently explained .
to quantify the scs pictures , we performed variational calculations with the wave functions representing scs i and scs ii .
the phase boundary between gap i and gap ii phases are determined by equating the energy of the minimized wave function for scs i to that for scs ii .
the resultant phase diagram approximately reproduces the phase diagram by the numerical diagonalization .
thus we have obtained three phase diagrams : fig .
[ phase_nlsm ] by the nlsm method , fig .
[ phase_num ] by the numerical diagonalization , and fig .
[ phase_var ] by the variational calculation .
the phase diagram of fig .
[ phase_num ] is accurate , since the extrapolation by finite size systems is reliable .
the other phase diagrams qualitatively agree with the accurate one , and both the methods are shown to be useful .
so far , we have examined the spin chain with side chains when the parameter @xmath24 measuring frustration is not large ( @xmath230 ) . for larger @xmath24 , wider variety of phases
are expected .
for example , we can extend the analysis in the limit of @xmath92 to the region of @xmath233 , i. e. @xmath234
. for @xmath235 , effective spins of 3-spin units with spin magnitude 1 ferromagnetically interacts with the nearest neighbors and form a ferromagnetic ground state . in terms
of the original spins , the ground state is ferrimagnetic .
further , by the numerical diagonalization , we have found various ferrimagnetic phases with different magnetization in the strongly frustrated regime .
the study of these ferrimagnetic phases is in progress and will be reported in a separate paper .
the numerical diagonalization program is based on the package titpack ver . 2 coded by h. nishimori .
the numerical computation in this work has been carried out using the facilities of the supercomputer center , institute for solid state physics , university of tokyo and information technology center , university of tokyo .
this work is partly supported by fund for project research in toyota technological institute , and by innovative research organization , saitama university .
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one of @xmath236 , @xmath237 , and @xmath52 is a dummy variable .
it turns to be absorbed by the others , and only two variables remain as seen in eq .
( [ fluctuation_variable ] ) .
hence the number of the original degrees of freedom has conserved . the wave function ( [ sing_wf ] ) for a 3-spin unit is expressed as @xmath238 = @xmath239 , where @xmath240 means the valence bond state between @xmath241 (= @xmath158 or @xmath159 ) and @xmath242 (= @xmath2 or @xmath3 ) .
this is a part of vbs i in fig .
[ vbs](a ) .[/INST] we study a frustrated mixed spin chain with side chains , where the spin species and the exchange interactions are spatially varied . a nonlinear @xmath0 model method is formulated for this model , and a phase diagram with two disordered spin - gap phases
is obtained for typical cases . among them
we examine the case with a main chain consisting of an alternating array of spin-1 and spin-@xmath1 sites and side chains each of a single spin-@xmath1 site in great detail . based on numerical , perturbational , and variational approaches ,
we propose a singlet cluster solid picture for each phase , where the ground state is expressed as a tensor product of local singlet states . </s> |
clostridium difficile is a gram - positive spore - forming anaerobic bacillus that is the major cause of antibiotic - associated diarrhea , accounting for 1525% cases of nosocomial antibiotic - associated diarrhea.1 given the presentation of c. difficile infection ( cdi ) , loose stools are usually sought for diagnosis and are thought to harbor higher bacterial loads of the pathogen than semiformed or formed stools .
bristol stool scale was developed by lewis and heaton in order to establish a clinical tool to monitor changes in intestinal function ( fig . 1).2
the scale was significantly correlated with this parameter in terms of stool form and defecatory frequency .
the european society of clinical microbiology and infectious diseases in its latest guidelines on cdi diagnosis and treatment include bristol stool scale in the definition of diarrhea associated with this infection.3 the scale is also included as a tool for the assessment of cdi severity in the guidance on the management and treatment of cdi published by public health england.4 a study by caroff et al5 examined the positivity of c. difficile diagnostic assays , enzyme immunoassays ( eias ) for glutamate dehydrogenase , and toxin a / b followed by a nucleic acid amplification test ( naat ) , in correlation with the bristol stool scale .
they demonstrated that a correlation between bristol stool scale and results of c. difficile assays was lacking with the organism being recovered more frequently from semiformed stools ( bristol scores of 5 or 6 ) than from liquid stools ( bristol score of 7 ) with naat .
the authors questioned whether the low fecal load of the organism or its toxin concentration in semiformed stools may have been associated with false - negative results obtained with eia .
therefore , we aimed to address this issue through assessing the correlation between bristol stool scale and the quantitative fecal load of c. difficile in order to elucidate whether low bacterial loads , particularly toxin - producing vegetative cells , may be associated with false - negative results of eia testing for c. difficile toxin as well as whether semiformed stools carry sufficient amounts of the organism to be sought for cdi diagnosis .
a secondary objective of the study was to assess the correlation of stool frequency with fecal c. difficile spores and vegetative cells to find out whether the presence of correlation may support the finding of the primary objective .
this is a descriptive observational study where we used data from a randomized , open - label study that we conducted to compare the effect of fidaxomicin versus oral vancomycin on c. difficile bacterial load of both spores and vegetative cells.6 the study protocol was approved by the hartford hospital institutional review board , and all patients provided written , informed consent prior to entry into the trial . in this study ,
three stool samples were collected from enrolled patients who tested positive for c. difficile by naat .
samples were collected at baseline ( before initiation of intervention ) , at a midpoint during the therapeutic course ( days 35 ) and at the end of the therapeutic course ( days 1013 ) .
samples were cultured , depending on availability , on either chromid c. difficile plates ( biomrieux sa)or cycloserine - cefoxitin - fructose agar ( ccfa ) plates ( bd ) since no difference in c. difficile recovery and quantitative colony counts was reported between the two types of media.7 chromid and ccfa plates were incubated under anaerobic conditions in bd gaspak anaerobic chambers ( bd ) at 37c for 24 and 48 hours , respectively .
each sample was plated twice , once without treatment and once after treatment with ethanol in order to kill vegetative cells and keep spores .
thus , untreated plates contained colonies ( colony forming unit , cfu ) that represent both spores and vegetative cells , while ethanol - treated plates contained spores only .
vegetative cells cfus were counted by subtracting the number of spores cfus in the ethanol - treated plate from the total number of cfus in the untreated plate .
log10 cfu / g of stool for both spores and vegetative cells was then calculated and plotted .
the lower limit of quantification of the culturing assay is 40 cfu / g stool .
stool frequency was determined based on a number of bowel movements over the last 24 hours prior to each sample collection .
wilk test for normality , spearman correlation coefficient ( rs ) was calculated to measure the strength of the relationship between bristol stool scale and the bacterial load of c. difficile in stool at each of the three time points .
the same test was used to evaluate the correlation of stool frequency with c. difficile fecal counts
. a p value of 0.05 was considered significant , and hence , a correlation between the two variables was deemed existent .
a total of 83 stool samples were collected from 30 patients at the three sampling points over 24 months : 28 samples were collected at baseline , 30 samples at the midpoint of therapy , and 25 samples at the end of therapy .
reasons for the decline in the number of samples from the midpoint of therapy going forward were either loss to follow - up or treatment failure and subsequent exclusion from the study .
an additional sample from a patient who failed therapy was collected at the day of attrition , which was within the midpoint window . in the case of another cdi patient ,
a baseline sample failed to be delivered to our laboratory ; however , samples at subsequent sampling points were collected and analyzed .
the mean age of patients was 67.3 15.3 years ; 20 ( 66.6% ) of them acquired their infection from the community and only 7 ( 23.3% ) of the infections were because of the north american pulsed - field gel electrophoresis type 1 ( nap1 ) strain of c. difficile ( identified by ribotyping and commonly designated nap1/bi/027 ) , which is known to be more virulent and associated with more severe diseases than other strains of the organism.1 figure 2 shows scatter plots of log10 cfu / g of stool for spores and vegetative cells at the three sampling points .
bristol stool scale and log10 cfu / g of stool for c. difficile spores and vegetative cells showed rs values of 0.14 and 0.05 ( p = 0.53 and 0.77 , respectively ) , 0.14 and 0.32 ( p = 0.52 and 0.08 , respectively ) , and 0.25 and 0.26 ( p = 0.25 and 0.22 , respectively ) at baseline , at the midpoint of therapy , and at the end of therapy , respectively .
the non - significant p values of the correlations of baseline samples indicate that a correlation bet ween bristol stool scale and log10 cfu / g of stool for both spores and vegetative cells was lacking at the diagnostic phase of cdi .
likewise , no correlation was found between bristol stool scale and quantitative fecal load of c. difficile during and after completion of cdi therapy .
stool frequency showed a weak , although statistically significant , correlation with fecal load of c. difficile with rs values of 0.22 ( p = 0.04 ) and 0.24 ( p = 0.03 ) for spores and vegetative cells , respectively , which indicates the presence of higher bacterial cfus with more frequent stools ( fig .
to our knowledge , this is the first study to examine the correlation between fecal loads of c. difficile with bristol stool scale and stool frequency . in the context of clinical disease , it would appear that the quantitative cfu of c. difficile was sufficiently high to detect the pathogen , irrespective of stool consistency , when diagnosing symptomatic patients presenting with frequent bowel movements .
in addition , semiformed and formed stools can also harbor the organism at detectable quantitative levels .
both of these findings explain why naat ( a test that detects the organism , whether in vegetative or in spore form , rather than the toxin of the organism ) was more successful in detecting c. difficile in semiformed stool ( bristol scores of 5 or 6 ) as the organism may have presented in quantitative amounts in the study by caroff et al.5 moreover , c. difficile detectability by eia may not be associated with the fecal load of the organism , but rather with the concentration of its toxins since eia is a test for c. difficile toxins .
therefore , a study examining the correlation between bristol stool scale and the concentration of c. difficile toxins in stool may further aid answering the lower detectability of c. difficile by eia in semiformed stools . | decision to test for clostridium difficile infection ( cdi ) is usually made when patients have loose stools with bristol stool score of 5 .
we aimed to assess the relationship between bacterial load of c. difficile and bristol stool scale , as well as stool frequency in stool samples collected from patients infected with the organism .
samples were collected at baseline , during therapy , and at the end of therapy .
spearman correlation test was used to evaluate these relationships . no correlation between bristol stool scale and fecal load of c. difficile
was found for both spores and vegetative cells at all time points as counts were persistently high ( p = non - significant ) .
weak positive correlations were found between stool frequency and fecal load of c. difficile spores and vegetative cells ( rs = 0.22 and 0.24 , p = 0.04 and 0.03 , respectively ) .
these findings indicate that quantitative colony counts were sufficiently high to detect c. difficile , irrespective of stool consistency , and suggest that semiformed stool should be sought for the pathogen in symptomatic patients with frequent stools . | <s>[INST]clostridium difficile is a gram - positive spore - forming anaerobic bacillus that is the major cause of antibiotic - associated diarrhea , accounting for 1525% cases of nosocomial antibiotic - associated diarrhea.1 given the presentation of c. difficile infection ( cdi ) , loose stools are usually sought for diagnosis and are thought to harbor higher bacterial loads of the pathogen than semiformed or formed stools .
bristol stool scale was developed by lewis and heaton in order to establish a clinical tool to monitor changes in intestinal function ( fig . 1).2
the scale was significantly correlated with this parameter in terms of stool form and defecatory frequency .
the european society of clinical microbiology and infectious diseases in its latest guidelines on cdi diagnosis and treatment include bristol stool scale in the definition of diarrhea associated with this infection.3 the scale is also included as a tool for the assessment of cdi severity in the guidance on the management and treatment of cdi published by public health england.4 a study by caroff et al5 examined the positivity of c. difficile diagnostic assays , enzyme immunoassays ( eias ) for glutamate dehydrogenase , and toxin a / b followed by a nucleic acid amplification test ( naat ) , in correlation with the bristol stool scale .
they demonstrated that a correlation between bristol stool scale and results of c. difficile assays was lacking with the organism being recovered more frequently from semiformed stools ( bristol scores of 5 or 6 ) than from liquid stools ( bristol score of 7 ) with naat .
the authors questioned whether the low fecal load of the organism or its toxin concentration in semiformed stools may have been associated with false - negative results obtained with eia .
therefore , we aimed to address this issue through assessing the correlation between bristol stool scale and the quantitative fecal load of c. difficile in order to elucidate whether low bacterial loads , particularly toxin - producing vegetative cells , may be associated with false - negative results of eia testing for c. difficile toxin as well as whether semiformed stools carry sufficient amounts of the organism to be sought for cdi diagnosis .
a secondary objective of the study was to assess the correlation of stool frequency with fecal c. difficile spores and vegetative cells to find out whether the presence of correlation may support the finding of the primary objective .
this is a descriptive observational study where we used data from a randomized , open - label study that we conducted to compare the effect of fidaxomicin versus oral vancomycin on c. difficile bacterial load of both spores and vegetative cells.6 the study protocol was approved by the hartford hospital institutional review board , and all patients provided written , informed consent prior to entry into the trial . in this study ,
three stool samples were collected from enrolled patients who tested positive for c. difficile by naat .
samples were collected at baseline ( before initiation of intervention ) , at a midpoint during the therapeutic course ( days 35 ) and at the end of the therapeutic course ( days 1013 ) .
samples were cultured , depending on availability , on either chromid c. difficile plates ( biomrieux sa)or cycloserine - cefoxitin - fructose agar ( ccfa ) plates ( bd ) since no difference in c. difficile recovery and quantitative colony counts was reported between the two types of media.7 chromid and ccfa plates were incubated under anaerobic conditions in bd gaspak anaerobic chambers ( bd ) at 37c for 24 and 48 hours , respectively .
each sample was plated twice , once without treatment and once after treatment with ethanol in order to kill vegetative cells and keep spores .
thus , untreated plates contained colonies ( colony forming unit , cfu ) that represent both spores and vegetative cells , while ethanol - treated plates contained spores only .
vegetative cells cfus were counted by subtracting the number of spores cfus in the ethanol - treated plate from the total number of cfus in the untreated plate .
log10 cfu / g of stool for both spores and vegetative cells was then calculated and plotted .
the lower limit of quantification of the culturing assay is 40 cfu / g stool .
stool frequency was determined based on a number of bowel movements over the last 24 hours prior to each sample collection .
wilk test for normality , spearman correlation coefficient ( rs ) was calculated to measure the strength of the relationship between bristol stool scale and the bacterial load of c. difficile in stool at each of the three time points .
the same test was used to evaluate the correlation of stool frequency with c. difficile fecal counts
. a p value of 0.05 was considered significant , and hence , a correlation between the two variables was deemed existent .
a total of 83 stool samples were collected from 30 patients at the three sampling points over 24 months : 28 samples were collected at baseline , 30 samples at the midpoint of therapy , and 25 samples at the end of therapy .
reasons for the decline in the number of samples from the midpoint of therapy going forward were either loss to follow - up or treatment failure and subsequent exclusion from the study .
an additional sample from a patient who failed therapy was collected at the day of attrition , which was within the midpoint window . in the case of another cdi patient ,
a baseline sample failed to be delivered to our laboratory ; however , samples at subsequent sampling points were collected and analyzed .
the mean age of patients was 67.3 15.3 years ; 20 ( 66.6% ) of them acquired their infection from the community and only 7 ( 23.3% ) of the infections were because of the north american pulsed - field gel electrophoresis type 1 ( nap1 ) strain of c. difficile ( identified by ribotyping and commonly designated nap1/bi/027 ) , which is known to be more virulent and associated with more severe diseases than other strains of the organism.1 figure 2 shows scatter plots of log10 cfu / g of stool for spores and vegetative cells at the three sampling points .
bristol stool scale and log10 cfu / g of stool for c. difficile spores and vegetative cells showed rs values of 0.14 and 0.05 ( p = 0.53 and 0.77 , respectively ) , 0.14 and 0.32 ( p = 0.52 and 0.08 , respectively ) , and 0.25 and 0.26 ( p = 0.25 and 0.22 , respectively ) at baseline , at the midpoint of therapy , and at the end of therapy , respectively .
the non - significant p values of the correlations of baseline samples indicate that a correlation bet ween bristol stool scale and log10 cfu / g of stool for both spores and vegetative cells was lacking at the diagnostic phase of cdi .
likewise , no correlation was found between bristol stool scale and quantitative fecal load of c. difficile during and after completion of cdi therapy .
stool frequency showed a weak , although statistically significant , correlation with fecal load of c. difficile with rs values of 0.22 ( p = 0.04 ) and 0.24 ( p = 0.03 ) for spores and vegetative cells , respectively , which indicates the presence of higher bacterial cfus with more frequent stools ( fig .
to our knowledge , this is the first study to examine the correlation between fecal loads of c. difficile with bristol stool scale and stool frequency . in the context of clinical disease , it would appear that the quantitative cfu of c. difficile was sufficiently high to detect the pathogen , irrespective of stool consistency , when diagnosing symptomatic patients presenting with frequent bowel movements .
in addition , semiformed and formed stools can also harbor the organism at detectable quantitative levels .
both of these findings explain why naat ( a test that detects the organism , whether in vegetative or in spore form , rather than the toxin of the organism ) was more successful in detecting c. difficile in semiformed stool ( bristol scores of 5 or 6 ) as the organism may have presented in quantitative amounts in the study by caroff et al.5 moreover , c. difficile detectability by eia may not be associated with the fecal load of the organism , but rather with the concentration of its toxins since eia is a test for c. difficile toxins .
therefore , a study examining the correlation between bristol stool scale and the concentration of c. difficile toxins in stool may further aid answering the lower detectability of c. difficile by eia in semiformed stools .[/INST]decision to test for clostridium difficile infection ( cdi ) is usually made when patients have loose stools with bristol stool score of 5 .
we aimed to assess the relationship between bacterial load of c. difficile and bristol stool scale , as well as stool frequency in stool samples collected from patients infected with the organism .
samples were collected at baseline , during therapy , and at the end of therapy .
spearman correlation test was used to evaluate these relationships . no correlation between bristol stool scale and fecal load of c. difficile
was found for both spores and vegetative cells at all time points as counts were persistently high ( p = non - significant ) .
weak positive correlations were found between stool frequency and fecal load of c. difficile spores and vegetative cells ( rs = 0.22 and 0.24 , p = 0.04 and 0.03 , respectively ) .
these findings indicate that quantitative colony counts were sufficiently high to detect c. difficile , irrespective of stool consistency , and suggest that semiformed stool should be sought for the pathogen in symptomatic patients with frequent stools .</s> |
SECTION 1. FINDINGS AND STATEMENT OF PURPOSE.
(a) Findings.--The Congress finds as follows:
(1) The Supplemental Security Income program provides
essential income security to more than 4,000,000 working-age
adult Americans, most of whom are disabled.
(2) Eligibility for the Supplemental Security Income
program requires the applicant to have very few assets that are
available for the individual's use. However, certain necessary
assets, such as the person's primary residence, and certain
government benefits, such as the Earned Income Tax Credit, are
excluded from the asset test.
(3) The value of a traditional defined benefit plan that
will eventually provide the former worker with periodic
payments does not count against the asset limit for the
Supplemental Security Income program, allowing a person who
becomes disabled to qualify for Supplemental Security Income
and Medicaid benefits while maintaining the right to receive a
pension at retirement age.
(4) Americans are increasingly dependent on defined
contribution plans such as 401(k) and individual retirement
accounts to provide for retirement security. Assets saved in
such plans count against a person's eligibility for
Supplemental Security Income benefits.
(5) Persons with disabilities are thus discouraged from
accumulating any retirement savings during periods of time when
they are able to work, because if their medical condition
deteriorates or they otherwise lose their job, they will have
to liquidate their retirement accounts and pay penalties in
order to qualify for Supplemental Security Income and Medicaid
benefits.
(6) The current treatment of retirement assets discourages
savings and work for disabled persons.
(b) Statement of Purpose.--The purpose of this Act is to encourage
retirement savings for all and promote work and self-sufficiency for
persons with disabilities by disregarding up to $75,000 in retirement
accounts when determining eligibility for benefits under the
Supplemental Security Income program.
SEC. 2. EXCLUSION OF LIMITED VALUE OF RETIREMENT PLANS UNDER THE SSI
PROGRAM.
(a) Resourse Exclusion.--
(1) In general.--Section 1613(a) of the Social Security Act
(42 U.S.C. 1382b(a)) is amended--
(A) by striking ``and'' at the end of paragraph
(14);
(B) by striking the period at the end of paragraph
(15) and inserting ``; and''; and
(C) by inserting after paragraph (15) the
following:
``(16) the value of any plan, contract, or account,
described in section 401(a), 403(a), 403(b), 408, 408A, 457(b),
or 501(c)(18) of the Internal Revenue Code of 1986, established
for the benefit of the individual, to the extent the aggregate
value of all such plans, contracts, and accounts so established
does not exceed $75,000 (in the case of calendar years prior to
2009) and the amount determined under section 1617(d) for the
calendar year (in the case of calendar years after 2008).''.
(2) Annual cost of living adjustment.--Section 1617 of such
Act (42 U.S.C. 1382f) is amended by adding at the end the
following new subsection:
``(d)(1) The Commissioner of Social Security shall, on or before
November 1 of 2008 and every calendar year thereafter, determine and
publish in the Federal Register a dollar amount for purposes of section
1613(a)(16) for the succeeding calendar year. The amount determined
under this subsection shall be the amount in effect in the calendar
year in which the determination is made or, if larger, the product of--
``(A) $75,000, and
``(B) the ratio of--
``(i) the Consumer Price Index for the calendar
year before the calendar year in which the
determination is made to
``(ii) the Consumer Price Index for 2007,
with such product, if not a multiple of $100, being rounded to the next
higher multiple of $100 where such product is a multiple of $50 but not
of $100 and the nearest multiple of $100 in any other case.
``(2) For purposes of this subsection, the term `Consumer Price
Index' for any year means the arithmetical mean of the Consumer Price
Index for Urban Wage Earners and Clerical Workers (CPI-W) issued by the
Bureau of Labor Statistics of the Department of Labor for the 12 months
in such year.''.
(b) Income Exclusion.--Section 1612(b) of such Act (42 U.S.C.
1382a(b)) is amended--
(1) by striking ``and'' at the end of paragraph (22);
(2) by striking the period at the end of paragraph (23) and
inserting ``; and''; and
(3) by adding at the end the following:
``(24) the interest or other earnings on the resources of
the individual that are excluded by reason of section
1613(a)(16).''.
(c) No Requirement To Accelerate Retirement Payments.--Section
1611(e)(2) of such Act (42 U.S.C. 1382(e)(2)) is amended by inserting
``(except, in the case of a person who has not attained 65 years of
age, payments from a plan, contract, or account referred to in section
1613(a)(16))'' after ``1612(a)(2)(B)''.
(d) Effective Date.--The amendments made by this section shall
apply to benefits for calendar months beginning after the date of the
enactment of this Act. | Amends title XVI (Supplemental Security Income) of the Social Security Act to exclude the first $75,000 of the value of retirement plans (adjusted annually for cost of living) in determining eligibility for, and the amount of benefits under, the SSI program. | <s>[INST]SECTION 1. FINDINGS AND STATEMENT OF PURPOSE.
(a) Findings.--The Congress finds as follows:
(1) The Supplemental Security Income program provides
essential income security to more than 4,000,000 working-age
adult Americans, most of whom are disabled.
(2) Eligibility for the Supplemental Security Income
program requires the applicant to have very few assets that are
available for the individual's use. However, certain necessary
assets, such as the person's primary residence, and certain
government benefits, such as the Earned Income Tax Credit, are
excluded from the asset test.
(3) The value of a traditional defined benefit plan that
will eventually provide the former worker with periodic
payments does not count against the asset limit for the
Supplemental Security Income program, allowing a person who
becomes disabled to qualify for Supplemental Security Income
and Medicaid benefits while maintaining the right to receive a
pension at retirement age.
(4) Americans are increasingly dependent on defined
contribution plans such as 401(k) and individual retirement
accounts to provide for retirement security. Assets saved in
such plans count against a person's eligibility for
Supplemental Security Income benefits.
(5) Persons with disabilities are thus discouraged from
accumulating any retirement savings during periods of time when
they are able to work, because if their medical condition
deteriorates or they otherwise lose their job, they will have
to liquidate their retirement accounts and pay penalties in
order to qualify for Supplemental Security Income and Medicaid
benefits.
(6) The current treatment of retirement assets discourages
savings and work for disabled persons.
(b) Statement of Purpose.--The purpose of this Act is to encourage
retirement savings for all and promote work and self-sufficiency for
persons with disabilities by disregarding up to $75,000 in retirement
accounts when determining eligibility for benefits under the
Supplemental Security Income program.
SEC. 2. EXCLUSION OF LIMITED VALUE OF RETIREMENT PLANS UNDER THE SSI
PROGRAM.
(a) Resourse Exclusion.--
(1) In general.--Section 1613(a) of the Social Security Act
(42 U.S.C. 1382b(a)) is amended--
(A) by striking ``and'' at the end of paragraph
(14);
(B) by striking the period at the end of paragraph
(15) and inserting ``; and''; and
(C) by inserting after paragraph (15) the
following:
``(16) the value of any plan, contract, or account,
described in section 401(a), 403(a), 403(b), 408, 408A, 457(b),
or 501(c)(18) of the Internal Revenue Code of 1986, established
for the benefit of the individual, to the extent the aggregate
value of all such plans, contracts, and accounts so established
does not exceed $75,000 (in the case of calendar years prior to
2009) and the amount determined under section 1617(d) for the
calendar year (in the case of calendar years after 2008).''.
(2) Annual cost of living adjustment.--Section 1617 of such
Act (42 U.S.C. 1382f) is amended by adding at the end the
following new subsection:
``(d)(1) The Commissioner of Social Security shall, on or before
November 1 of 2008 and every calendar year thereafter, determine and
publish in the Federal Register a dollar amount for purposes of section
1613(a)(16) for the succeeding calendar year. The amount determined
under this subsection shall be the amount in effect in the calendar
year in which the determination is made or, if larger, the product of--
``(A) $75,000, and
``(B) the ratio of--
``(i) the Consumer Price Index for the calendar
year before the calendar year in which the
determination is made to
``(ii) the Consumer Price Index for 2007,
with such product, if not a multiple of $100, being rounded to the next
higher multiple of $100 where such product is a multiple of $50 but not
of $100 and the nearest multiple of $100 in any other case.
``(2) For purposes of this subsection, the term `Consumer Price
Index' for any year means the arithmetical mean of the Consumer Price
Index for Urban Wage Earners and Clerical Workers (CPI-W) issued by the
Bureau of Labor Statistics of the Department of Labor for the 12 months
in such year.''.
(b) Income Exclusion.--Section 1612(b) of such Act (42 U.S.C.
1382a(b)) is amended--
(1) by striking ``and'' at the end of paragraph (22);
(2) by striking the period at the end of paragraph (23) and
inserting ``; and''; and
(3) by adding at the end the following:
``(24) the interest or other earnings on the resources of
the individual that are excluded by reason of section
1613(a)(16).''.
(c) No Requirement To Accelerate Retirement Payments.--Section
1611(e)(2) of such Act (42 U.S.C. 1382(e)(2)) is amended by inserting
``(except, in the case of a person who has not attained 65 years of
age, payments from a plan, contract, or account referred to in section
1613(a)(16))'' after ``1612(a)(2)(B)''.
(d) Effective Date.--The amendments made by this section shall
apply to benefits for calendar months beginning after the date of the
enactment of this Act.[/INST]Amends title XVI (Supplemental Security Income) of the Social Security Act to exclude the first $75,000 of the value of retirement plans (adjusted annually for cost of living) in determining eligibility for, and the amount of benefits under, the SSI program.</s> |
low - energy @xmath0 scattering offers the rare possibility to test a fundamental property of the qcd vacuum , the strength of quark - antiquark condensation @xmath2@xcite .
the knowledge of this quantity is crucial to understand the mechanism of spontaneous chiral symmetry breakdown ( sb@xmath3s ) in the standard model .
the quark condensate , as every other order parameter , depends on the number of massless flavors @xmath4 , and will in general experience a paramagnetic suppression as @xmath4 increases@xcite .
it turns out that what can actually be measured from low - energy @xmath0 scattering is the quark condensate in the limit of two massless flavors , @xmath5 .
the question to be addressed is to which extent @xmath5 is close to a critical point where @xmath2 disappears and chiral symmetry is eventually broken by higher - dimensional order parameters@xcite .
the proper framework to analyze phenomenologically the issue is provided by the generalized version of chiral perturbation theory ( @xmath3pt)@xcite in the case of su(2)@xmath6su(2 ) chiral symmetry .
this is a reorganization of the standard expansion of @xmath3pt@xcite in which the quark condensate parameter @xmath7 is considered formally as a small quantity , in order to account for the possibility that the linear and quadratic terms , in the expansion of the pion mass @xmath8 in powers of quark masses @xmath9 , be of the same order .
the chiral counting is modified accordingly , @xmath10 with @xmath11 containing additional terms , relegated in higher orders by the standard counting .
the complete effective lagrangian up to @xmath12 can be found in refs.@xcite , together with its renormalization at 1 loop . at present , the low - energy @xmath0 phase - shifts are rather poorly known , but considerable improvements are expected to come soon from new high - luminosity @xmath13 decays experiments , performed at brookhaven and da@xmath14ne .
these new data , together with the recent numerical solutions of roy equations@xcite , will allow to extract the two @xmath15-wave scattering lengths or , equivalently , the two parameters @xmath16 and @xmath17 , introduced in ref.@xcite and representing respectively the amplitude and the slope at the symmetrical point @xmath18 . in this perspective , we have established the relationship between the two - flavor quark condensate , expressed through the deviation from the gell - mann oakes renner relation , @xmath19 and the parameters @xmath16 and @xmath17 , including the leading @xmath1 double logarithmic corrections to the 1-loop result of generalized @xmath3pt .
due to the smallness of the pion mass , double chiral logarithms are among the potentially most dangerous contributions at order @xmath1 .
as first pointed out in ref.@xcite they can be obtained from a 1-loop calculation , using the fact that , in the renormalization procedure , non - local divergences must cancel . setting the space - time dimension @xmath20 to regulate the theory , all the low - energy constants ( l.e.c.s ) of the generalized lagrangian with @xmath21 derivatives and @xmath22 powers of the scalar source , @xmath23 , have dimension @xmath24 , except @xmath25 which has dimension @xmath26=d-2 $ ] .
we thus replace @xmath25 with @xmath27 , making appear explicitly the scale parameter @xmath28 brought in by the regularization procedure . since each loop involves a factor @xmath29 , the chiral expansion of a generic amplitude @xmath30 , apart from an overall dimensional factor , takes the form , @xmath31 where @xmath32 are polynomials in the l.e.c.s and @xmath33 and @xmath34 are loop - functions of the kinematical variables , expressed in terms of dimensionless quantities . after writing the laurent expansions of the loop - functions and of the coupling constants , @xmath35 and imposing the cancellation of the non - local divergences @xmath36
, one finds that the double chiral logarithms are given by the residues @xmath37 of the pole in @xmath38 , and always occur in the same combination with the terms @xmath39 , @xmath40 \log \frac{m_\pi^2}{\mu^2},\ ] ] @xmath41 being the @xmath17-function coefficients of the l.e.c .
@xmath42 . notice that at order @xmath1 we never have to deal with products like @xmath43 , since all 1-loop divergences are at least @xmath12 .
we display the result for @xmath44 and @xmath45 , where all l.e.c.s , here and in the following , are renormalized at a scale @xmath28 : @xmath46 m_{\pi}^2 \left ( \frac{m_\pi^2}{16 \pi^2 f_\pi^2 } \log \frac{m_{\pi}^2}{\mu^2 } \right)^2 , \\
f_{\pi}^2 & = & f^2 \left [ 1 + 2 \xi^{(2 ) } \hat m + \left ( 2 a_1 + a_2 + 4 a_3 + 2 b_1 - 2 b_2 \right ) \hat m^2- \frac{m_{\pi}^2}{8 \pi^2 f_{\pi}^2 } \log \frac{m_{\pi}^2}{\mu^2}\right .
\nonumber \\ & & \left .
+ \frac{7}{2 } \frac{m_{\pi}^4}{f_{\pi}^4 } \left ( \frac{1}{16 \pi^2 } \log \frac{m_{\pi}^2}{\mu^2 } \right)^2 \right ] .
\end{aligned}\ ] ]
the amplitude for @xmath0 scattering up to @xmath1 has been first given in ref.@xcite , using dispersive techniques , independently of any assumption about the size of the chiral condensate .
it can be expressed in terms of 6 parameters , @xmath47 , @xmath48.\ ] ] the @xmath49 s can be determined from a set of twice subtracted fixed-@xmath50 dispersion relations ( roy equations ) , whereas @xmath16 and @xmath17 can be related to the two subtraction constants .
most of the sensitivity to @xmath2 is contained in the parameter @xmath16 , which , at tree level , varies from 1 to 4 if @xmath2 is decreased from its standard value down to zero .
the complete two - loop s@xmath3pt calculation of ref.@xcite allows in addition to express the six parameters in terms of the l.e.c.s@xcite .
it is interesting to notice that , in this standard case , the double chiral logarithms constitute by far the largest @xmath1 contribution to @xmath16 .
an explicit calculation in g@xmath3pt , along the lines described in the previous section , yields , @xmath51 \nonumber \\ & & + m_{\pi}^2 \left [ \frac{533}{72 } + \frac{18817}{30 } \frac{a \hat m^2}{m_{\pi}^2 } + \frac{61076}{15 } \left ( \frac{a \hat m ^2}{m_{\pi}^2 } \right)^2 \right .
\nonumber \\ & & \left .
+ 5808 \left ( \frac{a \hat m ^2}{m_{\pi}^2 } \right)^3 \right ] \left ( \frac{m_{\pi}^2}{16 \pi^2 f_{\pi}^2 } \log \frac{m_{\pi}^2}{\mu^2 } \right)^2 \biggr ] , \\
\beta & = & 1 + 2 \xi^{(2 ) } \hat m - 4 { \xi^{(2)}}^2 \hat m^2 + 2 \left ( 3 a_2 + 2 a_3 + 4 b_1 + 2 b_2 + 4 c_1 \right ) \hat m^2 \nonumber \\ & & - \frac{4 m_{\pi}^2}{32 \pi^2 f_{\pi}^2 } \left ( 1 + 10 \frac { a \hat m^2}{m_{\pi}^2 } \right ) \left ( \log \frac{m_{\pi}^2}{\mu^2 } + 1 \right ) \nonumber \\ & & + \left ( \frac{151}{36 } m_{\pi}^4 + \frac{400}{3 } m_{\pi}^2 a \hat m^2 + 420 a^2 \hat m^4 \right ) \left [ \frac{1}{16 \pi^2 f_{\pi}^2 } \log \frac{m_{\pi}^2}{\mu^2 } \right]^2 , \\
\lambda_1 & = & 2 l_1 - \frac{1}{48 \pi^2 } \log \frac{m_{\pi}^2}{\mu^2 } - \frac { 1 } { 36 \pi^2 } + \left ( \frac{25}{18 } + \frac{130}{9 } \frac{a \hat m^2}{m_{\pi}^2 } \right ) \left [ \frac{m_{\pi}^2}{16 \pi^2 f_{\pi}^2 } \log \frac{m_{\pi}^2}{\mu^2 } \right]^2 , \\
\lambda_2 & = & l_2 - \frac{1}{48 \pi^2 } \log \frac{m_{\pi}^2}{\mu^2 } - \frac { 5 } { 288 \pi^2 } + \left ( \frac{5}{3 } + \frac{80}{9 } \frac{a \hat m^2}{m_{\pi}^2 } \right ) \left [ \frac{m_{\pi}^2}{16 \pi^2 f_{\pi}^2 } \log \frac{m_{\pi}^2}{\mu^2 } \right]^2 , \\
\lambda_3 & = & \frac{10}{9 } \left [ \frac{1}{16 \pi^2 } \log \frac{m_{\pi}^2}{\mu^2 } \right]^2 , \hspace{1 cm } \lambda_4 = -\frac{5}{18 } \left [ \frac{1}{16 \pi^2 } \log \frac{m_{\pi}^2}{\mu^2 } \right]^2.\end{aligned}\ ] ] it is easy to check that these formulae , when restricted to the standard case , agree with the ones displayed in ref.@xcite based on the complete two - loop calculation . eliminating the constant @xmath52 in favor of @xmath16 and @xmath53 in favor of @xmath17
, one can express the gor ratio of eq .
( [ eq : gor ] ) as function of the combination @xmath54 , @xmath55 \hat m^2 \nonumber \\ & & + \frac{64}{m_{\pi}^2 } ( e_1 + 2 f_1 + 2 f_2 + 4 f_4 ) \hat m^4 + \frac{m_{\pi}^2}{288 \pi^2 f_{\pi}^2 } \left ( \alpha + 2 \beta \right ) \left [ 24 - 11 ( \alpha + 2 \beta ) \right ] \nonumber \\ & & + \left [ 6 + \frac{5}{3 } ( \alpha + 2 \beta ) - \frac{11}{9 } ( \alpha + 2 \beta)^2 \right ]
\frac{m_{\pi}^2}{32 \pi^2 f_{\pi}^2 } \log \frac{m_{\pi}^2}{\mu^2 } + \left [ \frac{11}{60 } - \frac{4169}{1080 } ( \alpha + 2 \beta ) \right .
\nonumber \\ & & \left .
+ \frac{5639}{1620 } ( \alpha + 2 \beta)^2 - \frac{121}{108 } ( \alpha + 2 \beta)^3 \right ] \left ( \frac{m_{\pi}^2}{16 \pi^2 f_{\pi}^2 } \log \frac{m_{\pi}^2}{\mu^2 } \right)^2 .
\end{aligned}\ ] ] fig .
[ fig : gor ] shows this function for @xmath56 .
the upper left corner represents the standard case , corresponding to @xmath57 , while higher values for @xmath54 would imply a significant departure from that picture .
the dashed line is the result without including the @xmath1 double logarithms .
the bands are obtained varying the @xmath3pt scale by @xmath58250 mev and treating the unknown l.e.c.s as randomly distributed around zero with magnitude according to nave dimensional analysis , @xmath59 most of the uncertainty comes from the @xmath28-dependence , which however , quite interestingly , almost cancels when including the double logarithms .
the contribution from the latters is found to be rather large , although smaller that the @xmath12 one , and tends to compensate for the 1-loop shift . an additional uncertainty ( of difficult estimation ) , from the remaining @xmath60 pieces , should be understood in fig .
[ fig : gor ] . n.h .
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* b409 * ( 1997 ) , 461 . | the two - flavor gell - mann oakes renner ratio is expressed in terms of low - energy @xmath0 observables including the @xmath1 double chiral logarithms , computed in generalized chiral perturbation theory . it is found that their contribution is important and tends to compensate the one from the single chiral logarithms .
= 14.5pt | <s>[INST]low - energy @xmath0 scattering offers the rare possibility to test a fundamental property of the qcd vacuum , the strength of quark - antiquark condensation @xmath2@xcite .
the knowledge of this quantity is crucial to understand the mechanism of spontaneous chiral symmetry breakdown ( sb@xmath3s ) in the standard model .
the quark condensate , as every other order parameter , depends on the number of massless flavors @xmath4 , and will in general experience a paramagnetic suppression as @xmath4 increases@xcite .
it turns out that what can actually be measured from low - energy @xmath0 scattering is the quark condensate in the limit of two massless flavors , @xmath5 .
the question to be addressed is to which extent @xmath5 is close to a critical point where @xmath2 disappears and chiral symmetry is eventually broken by higher - dimensional order parameters@xcite .
the proper framework to analyze phenomenologically the issue is provided by the generalized version of chiral perturbation theory ( @xmath3pt)@xcite in the case of su(2)@xmath6su(2 ) chiral symmetry .
this is a reorganization of the standard expansion of @xmath3pt@xcite in which the quark condensate parameter @xmath7 is considered formally as a small quantity , in order to account for the possibility that the linear and quadratic terms , in the expansion of the pion mass @xmath8 in powers of quark masses @xmath9 , be of the same order .
the chiral counting is modified accordingly , @xmath10 with @xmath11 containing additional terms , relegated in higher orders by the standard counting .
the complete effective lagrangian up to @xmath12 can be found in refs.@xcite , together with its renormalization at 1 loop . at present , the low - energy @xmath0 phase - shifts are rather poorly known , but considerable improvements are expected to come soon from new high - luminosity @xmath13 decays experiments , performed at brookhaven and da@xmath14ne .
these new data , together with the recent numerical solutions of roy equations@xcite , will allow to extract the two @xmath15-wave scattering lengths or , equivalently , the two parameters @xmath16 and @xmath17 , introduced in ref.@xcite and representing respectively the amplitude and the slope at the symmetrical point @xmath18 . in this perspective , we have established the relationship between the two - flavor quark condensate , expressed through the deviation from the gell - mann oakes renner relation , @xmath19 and the parameters @xmath16 and @xmath17 , including the leading @xmath1 double logarithmic corrections to the 1-loop result of generalized @xmath3pt .
due to the smallness of the pion mass , double chiral logarithms are among the potentially most dangerous contributions at order @xmath1 .
as first pointed out in ref.@xcite they can be obtained from a 1-loop calculation , using the fact that , in the renormalization procedure , non - local divergences must cancel . setting the space - time dimension @xmath20 to regulate the theory , all the low - energy constants ( l.e.c.s ) of the generalized lagrangian with @xmath21 derivatives and @xmath22 powers of the scalar source , @xmath23 , have dimension @xmath24 , except @xmath25 which has dimension @xmath26=d-2 $ ] .
we thus replace @xmath25 with @xmath27 , making appear explicitly the scale parameter @xmath28 brought in by the regularization procedure . since each loop involves a factor @xmath29 , the chiral expansion of a generic amplitude @xmath30 , apart from an overall dimensional factor , takes the form , @xmath31 where @xmath32 are polynomials in the l.e.c.s and @xmath33 and @xmath34 are loop - functions of the kinematical variables , expressed in terms of dimensionless quantities . after writing the laurent expansions of the loop - functions and of the coupling constants , @xmath35 and imposing the cancellation of the non - local divergences @xmath36
, one finds that the double chiral logarithms are given by the residues @xmath37 of the pole in @xmath38 , and always occur in the same combination with the terms @xmath39 , @xmath40 \log \frac{m_\pi^2}{\mu^2},\ ] ] @xmath41 being the @xmath17-function coefficients of the l.e.c .
@xmath42 . notice that at order @xmath1 we never have to deal with products like @xmath43 , since all 1-loop divergences are at least @xmath12 .
we display the result for @xmath44 and @xmath45 , where all l.e.c.s , here and in the following , are renormalized at a scale @xmath28 : @xmath46 m_{\pi}^2 \left ( \frac{m_\pi^2}{16 \pi^2 f_\pi^2 } \log \frac{m_{\pi}^2}{\mu^2 } \right)^2 , \\
f_{\pi}^2 & = & f^2 \left [ 1 + 2 \xi^{(2 ) } \hat m + \left ( 2 a_1 + a_2 + 4 a_3 + 2 b_1 - 2 b_2 \right ) \hat m^2- \frac{m_{\pi}^2}{8 \pi^2 f_{\pi}^2 } \log \frac{m_{\pi}^2}{\mu^2}\right .
\nonumber \\ & & \left .
+ \frac{7}{2 } \frac{m_{\pi}^4}{f_{\pi}^4 } \left ( \frac{1}{16 \pi^2 } \log \frac{m_{\pi}^2}{\mu^2 } \right)^2 \right ] .
\end{aligned}\ ] ]
the amplitude for @xmath0 scattering up to @xmath1 has been first given in ref.@xcite , using dispersive techniques , independently of any assumption about the size of the chiral condensate .
it can be expressed in terms of 6 parameters , @xmath47 , @xmath48.\ ] ] the @xmath49 s can be determined from a set of twice subtracted fixed-@xmath50 dispersion relations ( roy equations ) , whereas @xmath16 and @xmath17 can be related to the two subtraction constants .
most of the sensitivity to @xmath2 is contained in the parameter @xmath16 , which , at tree level , varies from 1 to 4 if @xmath2 is decreased from its standard value down to zero .
the complete two - loop s@xmath3pt calculation of ref.@xcite allows in addition to express the six parameters in terms of the l.e.c.s@xcite .
it is interesting to notice that , in this standard case , the double chiral logarithms constitute by far the largest @xmath1 contribution to @xmath16 .
an explicit calculation in g@xmath3pt , along the lines described in the previous section , yields , @xmath51 \nonumber \\ & & + m_{\pi}^2 \left [ \frac{533}{72 } + \frac{18817}{30 } \frac{a \hat m^2}{m_{\pi}^2 } + \frac{61076}{15 } \left ( \frac{a \hat m ^2}{m_{\pi}^2 } \right)^2 \right .
\nonumber \\ & & \left .
+ 5808 \left ( \frac{a \hat m ^2}{m_{\pi}^2 } \right)^3 \right ] \left ( \frac{m_{\pi}^2}{16 \pi^2 f_{\pi}^2 } \log \frac{m_{\pi}^2}{\mu^2 } \right)^2 \biggr ] , \\
\beta & = & 1 + 2 \xi^{(2 ) } \hat m - 4 { \xi^{(2)}}^2 \hat m^2 + 2 \left ( 3 a_2 + 2 a_3 + 4 b_1 + 2 b_2 + 4 c_1 \right ) \hat m^2 \nonumber \\ & & - \frac{4 m_{\pi}^2}{32 \pi^2 f_{\pi}^2 } \left ( 1 + 10 \frac { a \hat m^2}{m_{\pi}^2 } \right ) \left ( \log \frac{m_{\pi}^2}{\mu^2 } + 1 \right ) \nonumber \\ & & + \left ( \frac{151}{36 } m_{\pi}^4 + \frac{400}{3 } m_{\pi}^2 a \hat m^2 + 420 a^2 \hat m^4 \right ) \left [ \frac{1}{16 \pi^2 f_{\pi}^2 } \log \frac{m_{\pi}^2}{\mu^2 } \right]^2 , \\
\lambda_1 & = & 2 l_1 - \frac{1}{48 \pi^2 } \log \frac{m_{\pi}^2}{\mu^2 } - \frac { 1 } { 36 \pi^2 } + \left ( \frac{25}{18 } + \frac{130}{9 } \frac{a \hat m^2}{m_{\pi}^2 } \right ) \left [ \frac{m_{\pi}^2}{16 \pi^2 f_{\pi}^2 } \log \frac{m_{\pi}^2}{\mu^2 } \right]^2 , \\
\lambda_2 & = & l_2 - \frac{1}{48 \pi^2 } \log \frac{m_{\pi}^2}{\mu^2 } - \frac { 5 } { 288 \pi^2 } + \left ( \frac{5}{3 } + \frac{80}{9 } \frac{a \hat m^2}{m_{\pi}^2 } \right ) \left [ \frac{m_{\pi}^2}{16 \pi^2 f_{\pi}^2 } \log \frac{m_{\pi}^2}{\mu^2 } \right]^2 , \\
\lambda_3 & = & \frac{10}{9 } \left [ \frac{1}{16 \pi^2 } \log \frac{m_{\pi}^2}{\mu^2 } \right]^2 , \hspace{1 cm } \lambda_4 = -\frac{5}{18 } \left [ \frac{1}{16 \pi^2 } \log \frac{m_{\pi}^2}{\mu^2 } \right]^2.\end{aligned}\ ] ] it is easy to check that these formulae , when restricted to the standard case , agree with the ones displayed in ref.@xcite based on the complete two - loop calculation . eliminating the constant @xmath52 in favor of @xmath16 and @xmath53 in favor of @xmath17
, one can express the gor ratio of eq .
( [ eq : gor ] ) as function of the combination @xmath54 , @xmath55 \hat m^2 \nonumber \\ & & + \frac{64}{m_{\pi}^2 } ( e_1 + 2 f_1 + 2 f_2 + 4 f_4 ) \hat m^4 + \frac{m_{\pi}^2}{288 \pi^2 f_{\pi}^2 } \left ( \alpha + 2 \beta \right ) \left [ 24 - 11 ( \alpha + 2 \beta ) \right ] \nonumber \\ & & + \left [ 6 + \frac{5}{3 } ( \alpha + 2 \beta ) - \frac{11}{9 } ( \alpha + 2 \beta)^2 \right ]
\frac{m_{\pi}^2}{32 \pi^2 f_{\pi}^2 } \log \frac{m_{\pi}^2}{\mu^2 } + \left [ \frac{11}{60 } - \frac{4169}{1080 } ( \alpha + 2 \beta ) \right .
\nonumber \\ & & \left .
+ \frac{5639}{1620 } ( \alpha + 2 \beta)^2 - \frac{121}{108 } ( \alpha + 2 \beta)^3 \right ] \left ( \frac{m_{\pi}^2}{16 \pi^2 f_{\pi}^2 } \log \frac{m_{\pi}^2}{\mu^2 } \right)^2 .
\end{aligned}\ ] ] fig .
[ fig : gor ] shows this function for @xmath56 .
the upper left corner represents the standard case , corresponding to @xmath57 , while higher values for @xmath54 would imply a significant departure from that picture .
the dashed line is the result without including the @xmath1 double logarithms .
the bands are obtained varying the @xmath3pt scale by @xmath58250 mev and treating the unknown l.e.c.s as randomly distributed around zero with magnitude according to nave dimensional analysis , @xmath59 most of the uncertainty comes from the @xmath28-dependence , which however , quite interestingly , almost cancels when including the double logarithms .
the contribution from the latters is found to be rather large , although smaller that the @xmath12 one , and tends to compensate for the 1-loop shift . an additional uncertainty ( of difficult estimation ) , from the remaining @xmath60 pieces , should be understood in fig .
[ fig : gor ] . n.h .
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* b409 * ( 1997 ) , 461 .[/INST] the two - flavor gell - mann oakes renner ratio is expressed in terms of low - energy @xmath0 observables including the @xmath1 double chiral logarithms , computed in generalized chiral perturbation theory . it is found that their contribution is important and tends to compensate the one from the single chiral logarithms .
= 14.5pt </s> |
modern experiments such as nomad @xcite , nutev @xcite , and chorus @xcite made a serious step forward in studies of neutrino deep inelastic scattering .
their precision measurements made it necessary to update the accuracy level of the theoretical description of the process .
important ingredients for an advanced precision in the theoretical predictions is the calculation of the relevant radiative corrections ( rc ) .
our study is motivated by the request from the nomad experiment .
electroweak ( ew ) radiative corrections to neutrino
nucleon scattering should have been implemented into the general monte carlo system for the experimental data analysis .
certain experimental conditions of particle registration and event selection should have been taken into account . in order to make the relevant subroutine describing the corrections fast
, we had to look for an analytical answer ( without numerical integrations ) . in the present work we reproduce most of the results of unpublished communication @xcite .
contrary to the earlier calculation , we used the modern technique of automatic calculations within the sanc system @xcite developed for support of analytic and numeric calculations for experiments at colliders . besides the one - loop calculation
, we consider certain contributions of higher orders and discuss the theoretical uncertainty due to unknown electroweak ( ew ) corrections for the case of the concrete experimental study .
the paper is organized as follows . in the next section
we define the notation and present the born level distributions .
then we consider different sources of radiative corrections .
special subsections are devoted to quark and muon mass singularities .
numerical results and comparisons are presented in sect .
[ numres ] .
possible applications of our formulae are discussed in conclusions .
we will consider the process of deep inelastic scattering ( dis ) in the framework of the quark parton model , assuming that we are in the proper kinematical region @xmath0 .
here we list the born level cross sections of neutrino quark interaction weighted by the quark density functions . for the charge current ( cc ) scattering processes ( k_1 )
+ q_i(p_1 ) l^-(k_2 ) + q_f(p_2 ) | + q_i l^+ + q_f we have [ snuqcc ] & & = ^0_cc , = ^0_cc(1-y)^2 , + & & ^0_cc = |v_if|^2 f_i(x,^2 ) , where @xmath1 is the @xmath2-boson mass ; @xmath3 is the center of mass energy of the neutrino - quark system squared ; @xmath4 is the element of the cabibbo - kobayashi - maskawa quark mixing matrix ; @xmath5 is the density function of the initial quark in the given nucleon .
the kinematics metrics , @xmath6 is described by the bjorken variables : & & y= , ^2 = -(p_2-p_1)^2 , x= , + & & = ( k_1+p_1)^2 xs , s = ( k_1 + p)^2 , where @xmath7 is the initial nucleon momentum .
we will use @xmath8 @xmath9 for the masses ( charges ) of the initial quark , the final quark , and the muon . for the neutral current ( nc ) scattering processes ( k_1 )
+ q_i(p_1 ) ( k_2 ) + q_f(p_2 ) | + q_i | + q_f we have [ snuqnc ] & & = ^0_nc ( g_l^2 + g_r^2(1-y)^2 - g_l g_r ) , + & & = ^0_nc ( g_r^2 + g_l^2(1-y)^2 - g_l g_r ) , + & & ^0_nc = f_i(x,^2 ) , where g_l = - + |q_i| , g_r = |q_i| , @xmath10 is the @xmath11-boson mass ; and @xmath12 is the weak mixing angle .
the radiatively corrected neutrino dis cross section can be represented as the sum of the born distribution with the contributions due to virtual loop diagrams ( virt ) , soft photon emission ( soft ) , and hard photon emission ( hard ) : = ( 1 + _ i^ + _ i^ + _ i^ ) , where the index @xmath13 denotes the type of the process under consideration ( @xmath14 , @xmath15 and so on ) .
this formula assumes calculation of the order @xmath16 rc .
certain higher order corrections will be added below as well .
we assume also that the momentum transfer square is small compared with the @xmath2-boson mass : corrections of the order @xmath17 are omitted from the calculation . contributions due to virtual ( one loop ) ew corrections are re calculated by means of the sanc system .
all the contributing one loop diagrams were calculated in the frame of the standard model .
omitting the terms suppressed by the @xmath18 ratio allowed us to get the short analytical answer . the virtual correction to the cc neutrino
quark scattering reads ^_cc & = & \ { - + & & + + & & - + & & - ( 1 + q_1 ) } , + & & _ 2 = = , = - _ 0 ^ 1y , where @xmath19 is the auxiliary photon mass , @xmath20 .
note that in the above expression we used the explicit value @xmath21 and eliminated the final state quark charge by applying the charge conservation law , @xmath22 . for the cc antineutrino
quark scattering we get ^_| cc & = & \ { - + & & + + & & + - q_1 } . for the pure qed part of the virtual corrections to the nc neutrino ( and antineutrino ) scattering we have ^_nc & = & q_1 ^ 2\ { - ( + -2)+ ^2 + ^2 + & & + ( + ) - 2 + _ 2 } . the weak part of the virtual correction to the nc case is included in the definition of the effective electroweak couplings : g_l(r ) _
l = ( - + |q_i| ) , _ r = |q_i| , where @xmath23 and @xmath24 are the electroweak form factors , & = & \ { ( ) + + & & + 1 - 4 i^(3)_f - ( i^(3)_f-^2 c_f + 4 i^(3)_f ^4 c_f^2 ) + } , + & = & - - + 3 i^(3)_f- ^2 + ( i^(3)_f - ^2 c_f + 4 i^(3)_f ^4 c_f^2 ) + & & + 2 b_f(q^2;m_f , m_f ) -_z^fer(q^2 ) , where @xmath25 , @xmath26 , @xmath27 , @xmath28 and @xmath29 are weak isospin , color factor ( 1 for leptons , 3 for quarks ) , charge , vector coupling and mass of a fermion ; notation for @xmath30 quark masses are evident ; @xmath31 and @xmath32 are sine and cosine of weak mixing angle and @xmath33 ; @xmath34 is veltman parameter , @xmath35;\ ] ] function @xmath36 is a useful combination of the finite parts of the standard passarino veltman functions ( without uv pole @xmath37 ) @xmath38;\ ] ] and finally @xmath39 is the @xmath40 mixing operator @xmath41 note , that the three last quantities are taken at @xmath42 , with @xmath43 being the thooft scale .
more about the calculation and renormalization scheme applied here can be found in the book @xcite .
emission of a soft photon in neutrino dis can be described in the standard way by the accompanying radiation factors : & & ^_nc = - q_1 ^ 2 ( - ) ^2 , + & & ^_cc = - ( q_1 - q_2 - q_l ) ^2 .
we consider the problem in the rest reference frame of the final quark , @xmath44 , which is equivalent ( in the soft photon limit ) to the so called @xmath45-reference frame , used below in the evaluation of the hard photon contribution .
the soft photon energy , @xmath46 , is limited by the parameter @xmath47 , which is assumed to be small compared to the large energy scale : @xmath48 .
list of the relevant integrals is given in appendix a. for the charged current we get [ softcc ] & & ^_cc = \ { + & & - + & & - - q_1 ( 2 + q_1 ) ^2 y - q_1 ^2 ( 1 - y ) + & & + q_1 y ( 1 - y ) + q_1 ^ 2 y - ( 1 + q_1 + q_1 ^ 2 ) _ 2 + ( 1 + q_1 ) ^2 } , + & & ^_| cc = \ { + & & - + & & - + q_1 ( 2 - q_1 ) ^2 y + q_1 ^2 ( 1 - y ) + & & - q_1 y ( 1 - y ) + q_1 ^ 2 y - ( 1 - q_1 + q_1 ^ 2 ) _ 2 + ( 1 - q_1 ) ^2 } .
soft corrections for the nc case are given by [ softnc ] & & ^_nc = - q_1 ^ 2 \ { ( 2 - - ) + & & + ( + ) ^2 - ( + ) + _ 2 - 1}. the above formula is valid both for the neutrino quark and antineutrino quark nc scattering processes . in the case of hard photon emission , like in the process ( k_1 ) + q_i(p_1 ) l^-(k_2 ) + q_f(p_2 ) + ( k ) , we have to extend the list of kinematical variables : _ 2 = p_2 + k , ^2 = - 2p_1(p_2+k ) , ^2 = - ( p_2+k)^2 .
note , that in the case without real photon radiation @xmath49 .
therefore in what follows we can use @xmath50 instead of @xmath51 .
the calculations of the hard photon contribution were evaluated also in the environment of the sanc system .
the angular phase space of the hard photon is @xmath52 in the @xmath45-system of reference , where @xmath53 . for the charged current @xmath54 scattering we have ^_cc & = & \ { + & & - ( 1+q_1)^2 ^2 -q_1 ^ 2(-y ) + & & + ( 1+q_1)^2 + + & & - ( - q_1 - q_1 ^ 2)^2 y - ^2 ( 1 - y ) + ( -2 q_1 ) ( 1 - y)y + & & -(-y+q_1+q_1 ^ 2)y + & & + ( 1 - y + q_1 ) ( 1 - y ) - ( + 2 q_1 ) -(1+q_1)^2 _ 2 + & & -}. hard photon contribution to the @xmath55 cc scattering reads ^_| cc & = & \ { ( 1-y)^2 + & & - ( 1-q_1)^2 ( 1-y)^2 ^2 + ( 1-q_1)^2 ( 1-y)^2 + & & -q_1 ^ 2(1-y)^2(-y ) + + & & - ( 1-y)^2(1 + 2q_1 - q_1 ^ 2)^2 y - ( 1-y)^2 ^2 ( 1 - y ) + & & + ( 1-y)^2(1 + 2q_1 ) ( 1 - y)y + ( - + y + ( 1-y)^2q_1 - y^2 + & & - ( 1-y)^2q_1 ^ 2 ) y + ( - y + y^2 - ( 1-y)^2q_1 ) ( 1 - y ) + & & - ( 1-y)^2 ( 1 - 2 q_1 ) -(1-y)^2(1-q_1)^2 _ 2 - + yq_1 + & & - yq_1 ^ 2 - y + y^2q_1 ^ 2 + y^2 - q_1 + q_1 ^ 2 } .
for the neutral current scattering we have [ hardnc ] ^_nc & = & q_1 ^ 2 \ { ( + + y -2 ) + y + & - & - ^2 + + ^2y - _ 2 - y + & + & + ( ( 1-y)(g_l^2+g_r^2 ) + ( g_l^2(1-y)^2+g_r^2 ) ) } .
the corresponding correction to the nc antineutrino
quark scattering , @xmath56 , can be obtained from the above equation by the substitution @xmath57 . in the sum of the soft and hard photonic corrections ,
the auxiliary parameter @xmath47 ( soft - hard separator ) cancels out . the infrared singular terms ( with logarithm of @xmath58
cancel out in the sum of the virtual and soft contributions .
moreover in the total sum , the large logarithms ( mass singularities ) with the final state quark mass @xmath59 disappear in accordance with the kinoshita lee - nauenberg theorem @xcite .
large logarithms containing the initial quark mass , @xmath60 , remain in the sum of all contributions . but these logs have been already effectively taken into account in the parton density functions ( pdfs ) .
in fact , qed radiative corrections to the quark line are usually not taken into account in procedures of pdf extraction .
moreover , the leading log behaviors of the qed and qcd dglap evolution of pdfs in the leading order are proportional to each other .
so one gets evolution of pdfs with an effective coupling constant ^_s _
s + , where @xmath61 is the strong coupling constant , and @xmath62 is the qcd color factor . the nontrivial difference between the qed evolution and the qcd one starts to appear from higher orders , and the corresponding numerical effect is small compared to the remaining qcd uncertainties in pdfs @xcite .
see also ref .
@xcite for a discussion with respect to the process under consideration .
the best approach to the whole problem would be to re
analyze all the experimental dis data taking into account qed corrections to the quark line at least at the next to leading order .
but for the present task we can limit ourselves with application of the subtraction scheme @xcite to the qed part of the radiative corrections for the process under consideration .
this leads to a shift of the initial quark mass singularities ( with a certain constant term ) from our result into the corresponding quark density function .
the latter should be also taken in the scheme .
in fact , using the initial condition for the non singlet nlo qed quark structure function ( which coincides with the qcd one with the trivial substitution @xmath63 , see ref .
@xcite ) , we get the following expression for the terms to be subtracted from the full calculation with massive quarks : _ & = & q_1 ^ 2 _ 0 ^ 1 x x _ + + & = & q_1 ^ 2 ( - - ) . in the case of cc scattering , the large logarithms singular in the limit @xmath64 remain in the final answer .
these terms are in agreement with the prediction of the renormalization group approach .
in fact , they can be described by the electron ( muon ) fragmentation ( structure ) function approach @xcite : ^ll = _
j_j d_j(,q^2 ) , where @xmath65 is the differential cross section of neutrino dis with production of particle @xmath66 ( @xmath67 , etc . )
; @xmath68 describes the probability to find a muon with the relative energy fraction @xmath69 in particle @xmath66 ; sign @xmath70 stands for the convolution operation . for our purposes
it is enough to consider only the leading log approximation in the @xmath71 and @xmath72 orders including the contribution of electron positron pairs .
under these conditions we can write the qed fragmentation function in the form : [ dfun ] d^ns_(,q^2 ) & = & ( 1- ) + lp^(0 ) ( ) + ( l)^2 p^(0)()p^(0 ) ( ) + & + & ( l)^2 p^(0 ) ( ) + , where @xmath73 is the so called large logarithm , and @xmath74 is the lowest order non
singlet splitting function : p^(0 ) ( ) = _ + . for
the definition of the plus prescription and the convolution operation see for instance refs .
differential cross section @xmath75 ( for @xmath76 ) is the born level distributions ( [ snuqcc ] ) with a shifted value of variable @xmath77 : = , which provides the proper value of variable @xmath77 after the fragmentation stage under the adopted condition for particle registration .
convolution with the @xmath78 splitting function gives the following first order leading logarithmic corrections : & & _
cc^(1)ll = l(2y - ( 1-y ) + - y ) , + & & _
| cc^(1)ll = l ( 2(1-y)^2 + - y ) .
we will see that the above expressions reproduce the the leading log part of the complete result for the @xmath16 correction in eqs .
( [ ccrcnu],[ccrcnb ] ) . by convolution with the @xmath79 term from eq .
( [ dfun ] ) , we get the second order leading log corrections to the cc neutrino dis : & & _ cc^(2)ll = ( l)^2 + l _ cc^(1)ll , + & & _ | cc^(2)ll = ( l)^2 + l _
| cc^(1)ll .
argument of the large logarithm depends on the energy scale of the process under consideration and the muon mass .
we have two scales : @xmath80 and @xmath51 . in the actual calculations
the logarithm with the muon mass singularity arises in the form @xmath81 .
so we choose @xmath3 , while the difference between the two possibilities appears in our case only in terms of the order @xmath82 , which are omitted now in any case . using the formalism of the fragmentation function approach
@xcite we can get the next to leading corrections of the order @xmath82 .
but , as will be seen from our numerical estimates below , they are small compared with the requested precision tag .
summing up all the different rc contributions considered above , and applying the subtraction of the initial state quark mass singularity we arrive at the result for the corrections to neutrino
quark cross sections : = ( 1 + _
i + _ i^(2)ll - _ ) , where @xmath83 vanishes in the nc case . for neutrino
quark cc scattering we have [ ccrcnu ] _ cc & = & \ { - + ( - y -(1 - y ) + y ) + & + & ( 1-y)y - - ^2y - ^2(1-y ) + & + & ( 1-y)(1-y ) - y + yy + y + + 2_2 + & + & q_1 ( 3 - + _ 2 - ( 1-y)y - 2 ) + & + & q_1 ^ 2 ( - + - y + y^2 - _ 2 ) } , where we used the charge conservation law @xmath84 and the explicit value @xmath21 . for antineutrino
quark cc scattering we have [ ccrcnb ] _
| cc & = & \ { ( ( 1-y)^2 - + ) + ( 1-y)^2 ( 2_2 - + & + & ( 1-y)y - ^2y - ^2(1-y ) ) + ( - + y - y^2 ) + & - & + y + q_1 + q_1 ^ 2}. for the case of nc neutrino scattering we get [ ncrcnu ] _ nc & = & \ { q_1 ^ 2 + _ l^2 + _ r^2(1-y)^2 } - 1 . the expression for the one loop radiative correction to the antineutrino nc process
can be received from the above one using the substitution : [ ncrcnb ] _
|nc & = & _ nc ( g_l g_r , _
l _ r ) . formulae ( [ ccrcnu],[ccrcnb],[ncrcnu ] ) completely agree with the ones derived in ref .
moreover , our formulae for the cc scattering case agree with the calculations presented in ref .
@xcite , where the explicit expressions were given for @xmath85 and @xmath86 cc scattering channels . for the comparison
, one should subtract from their formulae for @xmath87 and @xmath88 the quantities @xmath89 and @xmath90 , respectively , c = + .
the subtraction reflects the choice of the renormalization scheme .
let us consider numerical results obtained for the following conditions : the fixed neutrino energy @xmath91 gev ; isoscalar nuclear target ; cut on the energy of the final state hadronic system @xmath92 gev .
we used the cteq4l set @xcite of parton density functions . in table 1
we present numerical values and the absolute shifts due to radiative corrections of the quantities @xcite , constructed from the cross sections of neutrino dis , & & r^= , + [ pw ] & & r^- = , + & & r^_nc = , r^_cc = - .
the born level values are @xmath93 and @xmath94 . in the computations we used the following values of constants and parameters taken from @xcite ( the same as the ones given by eq .
( 4.6 ) of ref .
flag isch defines the choice of the initial quark mass singularity treatment : isch=0 means no any subtraction ( as has been done in ref .
@xcite ) , and isch=1 corresponds to the subtraction scheme as discussed above .
the order of the series in the leading large logarithms with the lepton mass singularity is governed by flag illa : @xmath95 for illa=1 and @xmath96 for illa=2 .
.effect of rc on @xmath97 , @xmath98 , and @xmath99 values in different approximations . [ cols="^,^,^,^,^,^,^ " , ] first , we have observed already the electroweak scheme dependence . from the general point of view
, the @xmath100 scheme looks preferable for our problem . by trying the other ew scheme
, we get an estimate of how large can be unknown higher order electroweak corrections .
the pure qed corrections are in our case not large , and by looking at the leading second order logarithmic contribution , we can put a limit on unknown higher order qed contributions . as the main source of the theoretical uncertainty we consider the contribution of the radiative corrections of the order @xmath101 .
they can appear as in the loop insertions into the @xmath2-boson propagator as well as in amplitudes where photonic and gluonic lines appear simultaneously . in our approach , we separated the ew rc from the qcd ones .
after all , we receive a direct product of qcd effects ( see i.e. ref .
@xcite ) and ew corrections , which does nt cover the full @xmath101 answer .
moreover , as can be seen from our calculations , we always consider @xmath50 to be the argument of the partonic density function .
but in the case of hard photon radiation off lepton , @xmath50 does nt coincide with the square of the `` true '' hadronic momentum transfer .
this leads to a certain effect in @xmath101 . to estimate the corresponding uncertainty we varied the value of @xmath102 in the argument of the pdfs . as the result of our estimates we found that our result for radiative corrections can receive up to @xmath103 of a relative shift . having a unique value of uncertainty for the functions of two variables seems to be reasonable , because the functions are relatively flat , and because , in the derivation of the number we looked both at the variations at the differential level and at the ones for the integrated cross sections .
note that we estimated the uncertainties in the form of maximal variations .
a work is going on to extend our consideration to the case of other variables and to avoid the effect of improper argument in pdfs , mentioned above .
it is worth to note , that radiative corrections to the same series of processes calculated in a different set of variables can have a completely different behavior .
for example , in the variables adopted by the nutev experiment , the size of corrections to the cc scattering ( where the energy and angle of the outgoing charge lepton can be measured ) are much bigger than the corrections presented here . in the same manner , estimates of the theoretical uncertainties
should be considered taking into account the choice of variables and , may be , other relevant experimental conditions .
nevertheless we agree with the authors of ref .
@xcite , who claimed that the higher order contributions to the theoretical uncertainty seem to have been underestimated by the nutev experiment @xcite .
our analytical results are combined into a fortran code , which can be directly used for experimental data analysis . as can be seen from the numerical estimates
the effect of radiative corrections is greater than the present experimental uncertainty , see _
e.g. _ the nutev @xcite result : = 0.2277 0.0013 ( ) 0.0009(syst . ) . that makes it important to take rc into account in the proper way .
estimates of the theoretical uncertainty becomes also relevant for the derivation of the resulting error in the analysis of experimental data in the present and future precision experiments on neutrino dis .
all relevant integrals are defined in the reference frame @xmath104 .
they are : & & = 4 ( - l_1 ) , + & & = 4 ( - 1 ) , + & & = 4 ( - l_l ) , + & & = 2 ( 2l_1 - l_1 ^ 2 - 2(2 ) ) , + & & = 2(2l_l - l_l^2 - 2(2 ) ) , + & & = 2 , + & & l_1 = = + , l_l = = , + & & w = 2p_1k_2 - ^2 , ^2 = 2m_2p_1 ^ 0 , + & & = 1 - 1 . terms which are suppressed by the ratio of a quark or muon mass to a large energy scale ( beam energy or momentum transferred ) are neglected .
a. andonov , d. bardin , s. bondarenko , p. christova , l. kalinovskaya , g. nanava and g. passarino , _ project sanc ( former calcphep ) : support of analytic and numeric calculations for experiments at colliders , _ published in in proceedings of ichep , amsterdam , the netherlands , july 2002 , p.825 [ hep - ph/0209297 ] .
a. andonov , d. bardin , s. bondarenko , p. christova , l. kalinovskaya and g. nanava , phys .
* 34 * ( 2003 ) 577 .
d. bardin , g. passarino , _ the standard model in the making : precision study of electroweak interactions , _ oxford , clarendon , 1999 . | radiative corrections to neutrino deep inelastic scattering are revisited .
one loop electroweak corrections are re calculated within the automatic sanc system .
terms with mass singularities are treated including higher order leading logarithmic corrections .
scheme dependence of corrections due to weak interactions is investigated .
the results are implemented into the data analysis of the nomad experiment .
the present theoretical accuracy in description of the process is discussed . , , and neutrino , deep inelastic scattering , radiative corrections 13.15.+g neutrino interactions , 12.15.lk electroweak radiative corrections , 13.40.ks electromagnetic corrections to strong- and weak - interaction processes | <s>[INST]modern experiments such as nomad @xcite , nutev @xcite , and chorus @xcite made a serious step forward in studies of neutrino deep inelastic scattering .
their precision measurements made it necessary to update the accuracy level of the theoretical description of the process .
important ingredients for an advanced precision in the theoretical predictions is the calculation of the relevant radiative corrections ( rc ) .
our study is motivated by the request from the nomad experiment .
electroweak ( ew ) radiative corrections to neutrino
nucleon scattering should have been implemented into the general monte carlo system for the experimental data analysis .
certain experimental conditions of particle registration and event selection should have been taken into account . in order to make the relevant subroutine describing the corrections fast
, we had to look for an analytical answer ( without numerical integrations ) . in the present work we reproduce most of the results of unpublished communication @xcite .
contrary to the earlier calculation , we used the modern technique of automatic calculations within the sanc system @xcite developed for support of analytic and numeric calculations for experiments at colliders . besides the one - loop calculation
, we consider certain contributions of higher orders and discuss the theoretical uncertainty due to unknown electroweak ( ew ) corrections for the case of the concrete experimental study .
the paper is organized as follows . in the next section
we define the notation and present the born level distributions .
then we consider different sources of radiative corrections .
special subsections are devoted to quark and muon mass singularities .
numerical results and comparisons are presented in sect .
[ numres ] .
possible applications of our formulae are discussed in conclusions .
we will consider the process of deep inelastic scattering ( dis ) in the framework of the quark parton model , assuming that we are in the proper kinematical region @xmath0 .
here we list the born level cross sections of neutrino quark interaction weighted by the quark density functions . for the charge current ( cc ) scattering processes ( k_1 )
+ q_i(p_1 ) l^-(k_2 ) + q_f(p_2 ) | + q_i l^+ + q_f we have [ snuqcc ] & & = ^0_cc , = ^0_cc(1-y)^2 , + & & ^0_cc = |v_if|^2 f_i(x,^2 ) , where @xmath1 is the @xmath2-boson mass ; @xmath3 is the center of mass energy of the neutrino - quark system squared ; @xmath4 is the element of the cabibbo - kobayashi - maskawa quark mixing matrix ; @xmath5 is the density function of the initial quark in the given nucleon .
the kinematics metrics , @xmath6 is described by the bjorken variables : & & y= , ^2 = -(p_2-p_1)^2 , x= , + & & = ( k_1+p_1)^2 xs , s = ( k_1 + p)^2 , where @xmath7 is the initial nucleon momentum .
we will use @xmath8 @xmath9 for the masses ( charges ) of the initial quark , the final quark , and the muon . for the neutral current ( nc ) scattering processes ( k_1 )
+ q_i(p_1 ) ( k_2 ) + q_f(p_2 ) | + q_i | + q_f we have [ snuqnc ] & & = ^0_nc ( g_l^2 + g_r^2(1-y)^2 - g_l g_r ) , + & & = ^0_nc ( g_r^2 + g_l^2(1-y)^2 - g_l g_r ) , + & & ^0_nc = f_i(x,^2 ) , where g_l = - + |q_i| , g_r = |q_i| , @xmath10 is the @xmath11-boson mass ; and @xmath12 is the weak mixing angle .
the radiatively corrected neutrino dis cross section can be represented as the sum of the born distribution with the contributions due to virtual loop diagrams ( virt ) , soft photon emission ( soft ) , and hard photon emission ( hard ) : = ( 1 + _ i^ + _ i^ + _ i^ ) , where the index @xmath13 denotes the type of the process under consideration ( @xmath14 , @xmath15 and so on ) .
this formula assumes calculation of the order @xmath16 rc .
certain higher order corrections will be added below as well .
we assume also that the momentum transfer square is small compared with the @xmath2-boson mass : corrections of the order @xmath17 are omitted from the calculation . contributions due to virtual ( one loop ) ew corrections are re calculated by means of the sanc system .
all the contributing one loop diagrams were calculated in the frame of the standard model .
omitting the terms suppressed by the @xmath18 ratio allowed us to get the short analytical answer . the virtual correction to the cc neutrino
quark scattering reads ^_cc & = & \ { - + & & + + & & - + & & - ( 1 + q_1 ) } , + & & _ 2 = = , = - _ 0 ^ 1y , where @xmath19 is the auxiliary photon mass , @xmath20 .
note that in the above expression we used the explicit value @xmath21 and eliminated the final state quark charge by applying the charge conservation law , @xmath22 . for the cc antineutrino
quark scattering we get ^_| cc & = & \ { - + & & + + & & + - q_1 } . for the pure qed part of the virtual corrections to the nc neutrino ( and antineutrino ) scattering we have ^_nc & = & q_1 ^ 2\ { - ( + -2)+ ^2 + ^2 + & & + ( + ) - 2 + _ 2 } . the weak part of the virtual correction to the nc case is included in the definition of the effective electroweak couplings : g_l(r ) _
l = ( - + |q_i| ) , _ r = |q_i| , where @xmath23 and @xmath24 are the electroweak form factors , & = & \ { ( ) + + & & + 1 - 4 i^(3)_f - ( i^(3)_f-^2 c_f + 4 i^(3)_f ^4 c_f^2 ) + } , + & = & - - + 3 i^(3)_f- ^2 + ( i^(3)_f - ^2 c_f + 4 i^(3)_f ^4 c_f^2 ) + & & + 2 b_f(q^2;m_f , m_f ) -_z^fer(q^2 ) , where @xmath25 , @xmath26 , @xmath27 , @xmath28 and @xmath29 are weak isospin , color factor ( 1 for leptons , 3 for quarks ) , charge , vector coupling and mass of a fermion ; notation for @xmath30 quark masses are evident ; @xmath31 and @xmath32 are sine and cosine of weak mixing angle and @xmath33 ; @xmath34 is veltman parameter , @xmath35;\ ] ] function @xmath36 is a useful combination of the finite parts of the standard passarino veltman functions ( without uv pole @xmath37 ) @xmath38;\ ] ] and finally @xmath39 is the @xmath40 mixing operator @xmath41 note , that the three last quantities are taken at @xmath42 , with @xmath43 being the thooft scale .
more about the calculation and renormalization scheme applied here can be found in the book @xcite .
emission of a soft photon in neutrino dis can be described in the standard way by the accompanying radiation factors : & & ^_nc = - q_1 ^ 2 ( - ) ^2 , + & & ^_cc = - ( q_1 - q_2 - q_l ) ^2 .
we consider the problem in the rest reference frame of the final quark , @xmath44 , which is equivalent ( in the soft photon limit ) to the so called @xmath45-reference frame , used below in the evaluation of the hard photon contribution .
the soft photon energy , @xmath46 , is limited by the parameter @xmath47 , which is assumed to be small compared to the large energy scale : @xmath48 .
list of the relevant integrals is given in appendix a. for the charged current we get [ softcc ] & & ^_cc = \ { + & & - + & & - - q_1 ( 2 + q_1 ) ^2 y - q_1 ^2 ( 1 - y ) + & & + q_1 y ( 1 - y ) + q_1 ^ 2 y - ( 1 + q_1 + q_1 ^ 2 ) _ 2 + ( 1 + q_1 ) ^2 } , + & & ^_| cc = \ { + & & - + & & - + q_1 ( 2 - q_1 ) ^2 y + q_1 ^2 ( 1 - y ) + & & - q_1 y ( 1 - y ) + q_1 ^ 2 y - ( 1 - q_1 + q_1 ^ 2 ) _ 2 + ( 1 - q_1 ) ^2 } .
soft corrections for the nc case are given by [ softnc ] & & ^_nc = - q_1 ^ 2 \ { ( 2 - - ) + & & + ( + ) ^2 - ( + ) + _ 2 - 1}. the above formula is valid both for the neutrino quark and antineutrino quark nc scattering processes . in the case of hard photon emission , like in the process ( k_1 ) + q_i(p_1 ) l^-(k_2 ) + q_f(p_2 ) + ( k ) , we have to extend the list of kinematical variables : _ 2 = p_2 + k , ^2 = - 2p_1(p_2+k ) , ^2 = - ( p_2+k)^2 .
note , that in the case without real photon radiation @xmath49 .
therefore in what follows we can use @xmath50 instead of @xmath51 .
the calculations of the hard photon contribution were evaluated also in the environment of the sanc system .
the angular phase space of the hard photon is @xmath52 in the @xmath45-system of reference , where @xmath53 . for the charged current @xmath54 scattering we have ^_cc & = & \ { + & & - ( 1+q_1)^2 ^2 -q_1 ^ 2(-y ) + & & + ( 1+q_1)^2 + + & & - ( - q_1 - q_1 ^ 2)^2 y - ^2 ( 1 - y ) + ( -2 q_1 ) ( 1 - y)y + & & -(-y+q_1+q_1 ^ 2)y + & & + ( 1 - y + q_1 ) ( 1 - y ) - ( + 2 q_1 ) -(1+q_1)^2 _ 2 + & & -}. hard photon contribution to the @xmath55 cc scattering reads ^_| cc & = & \ { ( 1-y)^2 + & & - ( 1-q_1)^2 ( 1-y)^2 ^2 + ( 1-q_1)^2 ( 1-y)^2 + & & -q_1 ^ 2(1-y)^2(-y ) + + & & - ( 1-y)^2(1 + 2q_1 - q_1 ^ 2)^2 y - ( 1-y)^2 ^2 ( 1 - y ) + & & + ( 1-y)^2(1 + 2q_1 ) ( 1 - y)y + ( - + y + ( 1-y)^2q_1 - y^2 + & & - ( 1-y)^2q_1 ^ 2 ) y + ( - y + y^2 - ( 1-y)^2q_1 ) ( 1 - y ) + & & - ( 1-y)^2 ( 1 - 2 q_1 ) -(1-y)^2(1-q_1)^2 _ 2 - + yq_1 + & & - yq_1 ^ 2 - y + y^2q_1 ^ 2 + y^2 - q_1 + q_1 ^ 2 } .
for the neutral current scattering we have [ hardnc ] ^_nc & = & q_1 ^ 2 \ { ( + + y -2 ) + y + & - & - ^2 + + ^2y - _ 2 - y + & + & + ( ( 1-y)(g_l^2+g_r^2 ) + ( g_l^2(1-y)^2+g_r^2 ) ) } .
the corresponding correction to the nc antineutrino
quark scattering , @xmath56 , can be obtained from the above equation by the substitution @xmath57 . in the sum of the soft and hard photonic corrections ,
the auxiliary parameter @xmath47 ( soft - hard separator ) cancels out . the infrared singular terms ( with logarithm of @xmath58
cancel out in the sum of the virtual and soft contributions .
moreover in the total sum , the large logarithms ( mass singularities ) with the final state quark mass @xmath59 disappear in accordance with the kinoshita lee - nauenberg theorem @xcite .
large logarithms containing the initial quark mass , @xmath60 , remain in the sum of all contributions . but these logs have been already effectively taken into account in the parton density functions ( pdfs ) .
in fact , qed radiative corrections to the quark line are usually not taken into account in procedures of pdf extraction .
moreover , the leading log behaviors of the qed and qcd dglap evolution of pdfs in the leading order are proportional to each other .
so one gets evolution of pdfs with an effective coupling constant ^_s _
s + , where @xmath61 is the strong coupling constant , and @xmath62 is the qcd color factor . the nontrivial difference between the qed evolution and the qcd one starts to appear from higher orders , and the corresponding numerical effect is small compared to the remaining qcd uncertainties in pdfs @xcite .
see also ref .
@xcite for a discussion with respect to the process under consideration .
the best approach to the whole problem would be to re
analyze all the experimental dis data taking into account qed corrections to the quark line at least at the next to leading order .
but for the present task we can limit ourselves with application of the subtraction scheme @xcite to the qed part of the radiative corrections for the process under consideration .
this leads to a shift of the initial quark mass singularities ( with a certain constant term ) from our result into the corresponding quark density function .
the latter should be also taken in the scheme .
in fact , using the initial condition for the non singlet nlo qed quark structure function ( which coincides with the qcd one with the trivial substitution @xmath63 , see ref .
@xcite ) , we get the following expression for the terms to be subtracted from the full calculation with massive quarks : _ & = & q_1 ^ 2 _ 0 ^ 1 x x _ + + & = & q_1 ^ 2 ( - - ) . in the case of cc scattering , the large logarithms singular in the limit @xmath64 remain in the final answer .
these terms are in agreement with the prediction of the renormalization group approach .
in fact , they can be described by the electron ( muon ) fragmentation ( structure ) function approach @xcite : ^ll = _
j_j d_j(,q^2 ) , where @xmath65 is the differential cross section of neutrino dis with production of particle @xmath66 ( @xmath67 , etc . )
; @xmath68 describes the probability to find a muon with the relative energy fraction @xmath69 in particle @xmath66 ; sign @xmath70 stands for the convolution operation . for our purposes
it is enough to consider only the leading log approximation in the @xmath71 and @xmath72 orders including the contribution of electron positron pairs .
under these conditions we can write the qed fragmentation function in the form : [ dfun ] d^ns_(,q^2 ) & = & ( 1- ) + lp^(0 ) ( ) + ( l)^2 p^(0)()p^(0 ) ( ) + & + & ( l)^2 p^(0 ) ( ) + , where @xmath73 is the so called large logarithm , and @xmath74 is the lowest order non
singlet splitting function : p^(0 ) ( ) = _ + . for
the definition of the plus prescription and the convolution operation see for instance refs .
differential cross section @xmath75 ( for @xmath76 ) is the born level distributions ( [ snuqcc ] ) with a shifted value of variable @xmath77 : = , which provides the proper value of variable @xmath77 after the fragmentation stage under the adopted condition for particle registration .
convolution with the @xmath78 splitting function gives the following first order leading logarithmic corrections : & & _
cc^(1)ll = l(2y - ( 1-y ) + - y ) , + & & _
| cc^(1)ll = l ( 2(1-y)^2 + - y ) .
we will see that the above expressions reproduce the the leading log part of the complete result for the @xmath16 correction in eqs .
( [ ccrcnu],[ccrcnb ] ) . by convolution with the @xmath79 term from eq .
( [ dfun ] ) , we get the second order leading log corrections to the cc neutrino dis : & & _ cc^(2)ll = ( l)^2 + l _ cc^(1)ll , + & & _ | cc^(2)ll = ( l)^2 + l _
| cc^(1)ll .
argument of the large logarithm depends on the energy scale of the process under consideration and the muon mass .
we have two scales : @xmath80 and @xmath51 . in the actual calculations
the logarithm with the muon mass singularity arises in the form @xmath81 .
so we choose @xmath3 , while the difference between the two possibilities appears in our case only in terms of the order @xmath82 , which are omitted now in any case . using the formalism of the fragmentation function approach
@xcite we can get the next to leading corrections of the order @xmath82 .
but , as will be seen from our numerical estimates below , they are small compared with the requested precision tag .
summing up all the different rc contributions considered above , and applying the subtraction of the initial state quark mass singularity we arrive at the result for the corrections to neutrino
quark cross sections : = ( 1 + _
i + _ i^(2)ll - _ ) , where @xmath83 vanishes in the nc case . for neutrino
quark cc scattering we have [ ccrcnu ] _ cc & = & \ { - + ( - y -(1 - y ) + y ) + & + & ( 1-y)y - - ^2y - ^2(1-y ) + & + & ( 1-y)(1-y ) - y + yy + y + + 2_2 + & + & q_1 ( 3 - + _ 2 - ( 1-y)y - 2 ) + & + & q_1 ^ 2 ( - + - y + y^2 - _ 2 ) } , where we used the charge conservation law @xmath84 and the explicit value @xmath21 . for antineutrino
quark cc scattering we have [ ccrcnb ] _
| cc & = & \ { ( ( 1-y)^2 - + ) + ( 1-y)^2 ( 2_2 - + & + & ( 1-y)y - ^2y - ^2(1-y ) ) + ( - + y - y^2 ) + & - & + y + q_1 + q_1 ^ 2}. for the case of nc neutrino scattering we get [ ncrcnu ] _ nc & = & \ { q_1 ^ 2 + _ l^2 + _ r^2(1-y)^2 } - 1 . the expression for the one loop radiative correction to the antineutrino nc process
can be received from the above one using the substitution : [ ncrcnb ] _
|nc & = & _ nc ( g_l g_r , _
l _ r ) . formulae ( [ ccrcnu],[ccrcnb],[ncrcnu ] ) completely agree with the ones derived in ref .
moreover , our formulae for the cc scattering case agree with the calculations presented in ref .
@xcite , where the explicit expressions were given for @xmath85 and @xmath86 cc scattering channels . for the comparison
, one should subtract from their formulae for @xmath87 and @xmath88 the quantities @xmath89 and @xmath90 , respectively , c = + .
the subtraction reflects the choice of the renormalization scheme .
let us consider numerical results obtained for the following conditions : the fixed neutrino energy @xmath91 gev ; isoscalar nuclear target ; cut on the energy of the final state hadronic system @xmath92 gev .
we used the cteq4l set @xcite of parton density functions . in table 1
we present numerical values and the absolute shifts due to radiative corrections of the quantities @xcite , constructed from the cross sections of neutrino dis , & & r^= , + [ pw ] & & r^- = , + & & r^_nc = , r^_cc = - .
the born level values are @xmath93 and @xmath94 . in the computations we used the following values of constants and parameters taken from @xcite ( the same as the ones given by eq .
( 4.6 ) of ref .
flag isch defines the choice of the initial quark mass singularity treatment : isch=0 means no any subtraction ( as has been done in ref .
@xcite ) , and isch=1 corresponds to the subtraction scheme as discussed above .
the order of the series in the leading large logarithms with the lepton mass singularity is governed by flag illa : @xmath95 for illa=1 and @xmath96 for illa=2 .
.effect of rc on @xmath97 , @xmath98 , and @xmath99 values in different approximations . [ cols="^,^,^,^,^,^,^ " , ] first , we have observed already the electroweak scheme dependence . from the general point of view
, the @xmath100 scheme looks preferable for our problem . by trying the other ew scheme
, we get an estimate of how large can be unknown higher order electroweak corrections .
the pure qed corrections are in our case not large , and by looking at the leading second order logarithmic contribution , we can put a limit on unknown higher order qed contributions . as the main source of the theoretical uncertainty we consider the contribution of the radiative corrections of the order @xmath101 .
they can appear as in the loop insertions into the @xmath2-boson propagator as well as in amplitudes where photonic and gluonic lines appear simultaneously . in our approach , we separated the ew rc from the qcd ones .
after all , we receive a direct product of qcd effects ( see i.e. ref .
@xcite ) and ew corrections , which does nt cover the full @xmath101 answer .
moreover , as can be seen from our calculations , we always consider @xmath50 to be the argument of the partonic density function .
but in the case of hard photon radiation off lepton , @xmath50 does nt coincide with the square of the `` true '' hadronic momentum transfer .
this leads to a certain effect in @xmath101 . to estimate the corresponding uncertainty we varied the value of @xmath102 in the argument of the pdfs . as the result of our estimates we found that our result for radiative corrections can receive up to @xmath103 of a relative shift . having a unique value of uncertainty for the functions of two variables seems to be reasonable , because the functions are relatively flat , and because , in the derivation of the number we looked both at the variations at the differential level and at the ones for the integrated cross sections .
note that we estimated the uncertainties in the form of maximal variations .
a work is going on to extend our consideration to the case of other variables and to avoid the effect of improper argument in pdfs , mentioned above .
it is worth to note , that radiative corrections to the same series of processes calculated in a different set of variables can have a completely different behavior .
for example , in the variables adopted by the nutev experiment , the size of corrections to the cc scattering ( where the energy and angle of the outgoing charge lepton can be measured ) are much bigger than the corrections presented here . in the same manner , estimates of the theoretical uncertainties
should be considered taking into account the choice of variables and , may be , other relevant experimental conditions .
nevertheless we agree with the authors of ref .
@xcite , who claimed that the higher order contributions to the theoretical uncertainty seem to have been underestimated by the nutev experiment @xcite .
our analytical results are combined into a fortran code , which can be directly used for experimental data analysis . as can be seen from the numerical estimates
the effect of radiative corrections is greater than the present experimental uncertainty , see _
e.g. _ the nutev @xcite result : = 0.2277 0.0013 ( ) 0.0009(syst . ) . that makes it important to take rc into account in the proper way .
estimates of the theoretical uncertainty becomes also relevant for the derivation of the resulting error in the analysis of experimental data in the present and future precision experiments on neutrino dis .
all relevant integrals are defined in the reference frame @xmath104 .
they are : & & = 4 ( - l_1 ) , + & & = 4 ( - 1 ) , + & & = 4 ( - l_l ) , + & & = 2 ( 2l_1 - l_1 ^ 2 - 2(2 ) ) , + & & = 2(2l_l - l_l^2 - 2(2 ) ) , + & & = 2 , + & & l_1 = = + , l_l = = , + & & w = 2p_1k_2 - ^2 , ^2 = 2m_2p_1 ^ 0 , + & & = 1 - 1 . terms which are suppressed by the ratio of a quark or muon mass to a large energy scale ( beam energy or momentum transferred ) are neglected .
a. andonov , d. bardin , s. bondarenko , p. christova , l. kalinovskaya , g. nanava and g. passarino , _ project sanc ( former calcphep ) : support of analytic and numeric calculations for experiments at colliders , _ published in in proceedings of ichep , amsterdam , the netherlands , july 2002 , p.825 [ hep - ph/0209297 ] .
a. andonov , d. bardin , s. bondarenko , p. christova , l. kalinovskaya and g. nanava , phys .
* 34 * ( 2003 ) 577 .
d. bardin , g. passarino , _ the standard model in the making : precision study of electroweak interactions , _ oxford , clarendon , 1999 .[/INST] radiative corrections to neutrino deep inelastic scattering are revisited .
one loop electroweak corrections are re calculated within the automatic sanc system .
terms with mass singularities are treated including higher order leading logarithmic corrections .
scheme dependence of corrections due to weak interactions is investigated .
the results are implemented into the data analysis of the nomad experiment .
the present theoretical accuracy in description of the process is discussed . , , and neutrino , deep inelastic scattering , radiative corrections 13.15.+g neutrino interactions , 12.15.lk electroweak radiative corrections , 13.40.ks electromagnetic corrections to strong- and weak - interaction processes </s> |
“I’m affable!” Will McAvoy yells in the pilot of “The Newsroom,” Aaron Sorkin’s new HBO series. McAvoy (played by Jeff Daniels) is an irascible anchor whose brand is likability, and it’s a good line, delivered well. It is also a rare moment of self-mockery—and one of the last sequences I was on board for in the series. In “The Newsroom,” clever people take turns admiring one another. They sing arias of facts. They aim to remake television news: “This is a new show, and there are new rules,” a maverick executive producer announces, several times, in several ways. Their outrage is so inflamed that it amounts to a form of moral eczema—only it makes the viewer itch.
This is not to say that “The Newsroom” doesn’t score points now and then, if you share its politics. It starts effectively enough, with an homage to “Network” ’s galvanizing “I’m mad as hell” rant, as McAvoy, a blandly uncontroversial cable big shot whom everyone tauntingly calls Leno, is trapped on a journalism-school panel. When the moderator needles him into answering a question about why America is the greatest country on earth, he goes volcanic, ticking off the ways in which America is no such thing, then closing with a statement of hope, about the way things used to be. This speech goes viral, and his boss (Sam Waterston) and his producer, MacKenzie McHale (Emily Mortimer), who’s also his ex-girlfriend, encourage him to create a purer news program, purged of any obsession with ratings and buzz.
Much of McAvoy’s diatribe is bona-fide baloney—false nostalgia for an America that never existed—but it is exciting to watch. And if you enjoyed “The West Wing,” Sorkin’s helpful counterprogramming to the Bush Administration, your ears will prick up. The pilot of “The Newsroom” is full of yelling and self-righteousness, but it’s got energy, just like “The West Wing,” Sorkin’s “Sports Night,” and his hit movie “The Social Network.” The second episode is more obviously stuffed with piety and syrup, although there’s one amusing segment, when McAvoy mocks some right-wing idiots. After that, “The Newsroom” gets so bad so quickly that I found my jaw dropping. The third episode is lousy (and devolves into lectures that are chopped into montages). The fourth episode is the worst. There are six to go.
Sorkin is often presented as one of the auteurs of modern television, an innovator and an original voice. But he’s more logically placed in a school of showrunners who favor patterspeak, point-counterpoint, and dialogue-driven tributes to the era of screwball romance. Some of this banter is intelligent; just as often, however, it’s artificial intelligence, predicated on the notion that more words equals smarter. Besides Sorkin, these creators include Shonda Rhimes (whose Washington melodrama, “Scandal,” employs cast members from “The West Wing”); Amy Sherman-Palladino, of “The Gilmore Girls” (and the appealing new “Bunheads”); and David E. Kelley, who created “Ally McBeal” and “Boston Legal.” Sorkin is supposed to be on a different level from his peers: longer words, worldlier topics. And many viewers clearly buy into this idea: years after Sorkin’s terrible, fascinating “Studio 60 on the Sunset Strip” was cancelled, I still occasionally run into someone who insists that Americans were just too stupid to get it.
As Dan Rather might put it, that dog won’t hunt. Sorkin’s shows are the type that people who never watch TV are always claiming are better than anything else on TV. The shows’ air of defiant intellectual superiority is rarely backed up by what’s inside—all those Wagnerian rants, fingers poked in chests, palms slammed on desks, and so on. In fact, “The Newsroom” treats the audience as though we were extremely stupid. Characters describe events we’ve just witnessed. When a cast member gets a shtick (like an obsession with Bigfoot), he delivers it over and over. In episode four, there’s a flashback to episode three. In a recent interview, Sorkin spoke patronizingly of cop shows, but his Socratic flirtations are frequently just as formulaic, right down to the magical “Ask twice!” technique.
There’s no denying that Sorkin’s shows can be addictive: I couldn’t stop watching “Studio 60,” which was about the making of a “Saturday Night Live”-style sketch show, no matter how hard I tried. That thing was alive! It was lit up with payback, as well as with portraits of Sorkin’s exes so glowing that they were radioactive. The show’s deliriously preening heroes were so memorable that they inspired a set of fictional Twitter feeds, in which the characters live on, making remarks like “Deciding if the satire I’m about to write should be scathing or whip-smart.”
“The Newsroom” sounded more promising, journalism being a natural habitat for blowhards. But so far the series lacks the squirmy vigor of “Studio 60,” particularly since Sorkin saps the drama with an odd structural choice. Rather than invent fictional crises, he’s set the show in “the recent past,” so that the plot is literally old news: the BP oil spill, the Tea Party, the Arizona immigration law. That sounds like an innovative concept, but it turns the characters into back-seat drivers, telling us how the news should have been delivered. (Instead of “Broadcast News,” it’s like a sanctimonious “Zelig.”) Naturally, McAvoy slices through crises by “speaking truth to stupid,” in McHale’s words. But he also seizes credit for “breaking stories”—like the political shenanigans of the Koch brothers—that were broken by actual journalists, all of them working in print or online. In the fourth episode, the show injects a real-life tragedy into the mix, pouring a pop ballad over the montage, just the way “E.R.” used to do whenever a busload of massacred toddlers came crashing through the door. ||||| A note from Dan Rather: I'm aware that my musings run counter to some of the more prominent early reviews in high-profile publications such as The New Yorker and the New York Times. But with all due respect (and I have a lot of it for those reviewers), I just don't think they "get it"; they've somehow missed the breadth, depth and "got it right" qualities –- and importance — of Newsroom. Maybe it's because they are print people. Then, too, maybe they're right and I'm wrong. I never rule out the possibility of that. But I've lived in the world of television newsrooms for most of my adult life. I know the people, the venues and the challenges — the satisfactions of success and the heartbreak when things go awry. From where I sit and based on my experience, Sorkin and crew have got it amazingly right, even when they over talk it.
Any television program that has its main characters quoting Cervantes can't be all bad. And so it is with The Newsroom.
Mark well, however, that with this HBO series premiere more praise is justified. A lot more. I've only seen the first program, but if what is to follow is as good as this first show then Aaron Sorkin has a winner.
Sure, I've got my nits to pick with it; and, no, it's not perfect. But there's a lot to like in what Sorkin and his cast have done here. There is a newsroom authenticity to what's presented and much that gets to the heart of modern American journalism's problems.
There is a battle for the soul of the craft that goes on daily now in virtually every newsroom in the country. It's a fight that matters, not just for journalists but for the country. It centers on whether news reporting is to be considered and practiced—to any significant degree, even a little—as a public service, in the public interest ,or is to exsist solely as just another money-making operation for owners of news outlets.
As the Newsroom character MacKenzie (Emily Mortimer) says, in challenging the anchorman Will McAvoy (Jeff Daniels) to be a crusader for quality journalism, "There is nothing more important in a democracy than a well-informed electorate. When there is no information or, much worse, wrong information, it can lead to calamitous decisions that clobber any attempts at vigorous debate."
This is the battle being lost in almost every newsroom, in every place around the world. Ratings (or circulation), demographics, and profits rule. Any talk of the public interest or of doing quality journalism of integrity with guts is considered passé.
Sorkin and his team deserve full praise for bringing the issue to the screen and to a mass audience, and for doing it in an interesting and entertaining way. They've got the right mix of issues, relationships and humor—sometimes, oft-times, comedy. (Be advised: the dialogue is sharp and fast. You need to pay close attention and listen closely.)
The show gets close to the bone of what happens, what really happens, behind the scenes in newsrooms and the boardrooms that govern them. One small nit: What's going on in gathering news and getting it on the air all seems so seamless in the show. In the real world of television news, it isn't.
I especially liked the emphasis on the necessity of having sources and doing real reporting (maybe not enough emphasis on this to satisfy me.) Also, the depiction of when to go with a story, when and what to lead with on a newscast is good.
One thing missing, for me anyway, in this first installment is a deep enough sense that most newsrooms—television and otherwise—have a kind of "valley of broken dreams" feel to them... an echo in the interior of people who got into news because of their idealism, now struggling with the reality of compromises they're forced to make daily if not hourly. In the real world, the undertow of this is palpable but often goes unspoken. In Newsroom, it's spoken often.
Yes, it's a bit too preachy here and there: show me, don't just have monologues and long pontifications about what the problems are. And no, on average newsroom people are seldom as smart or as high-minded as most of the lead characters in this fictional drama.
But if you liked the movies Citizen Kane, Network, and Broadcast News, if you liked the television series West Wing, Mad Men, or The Good Wife, you're going to love Newsroom. At least the first installment. And if Sorkin, his writers and their excellent actors can maintain this level, you'll probably like the full run.
It has the potential to become a classic.
You can watch the entire first episode of The Newsroom on YouTube.
Dan Rather is anchor and managing editor of Dan Rather Reports. You can follow him on Facebook and Twitter. ||||| (Page 2 of 2)
Then he added, “I don’t know anything about ratings (and I’ve had the ratings to back that up) but if I were the president of CNN I would put the smartest news people I know in a room and ask, ‘What would a utopian news show look like?’ and then I’d ask ‘What’s stopping us from doing that?’ ”
Mr. Sorkin says he knows there is no collective time machine to take us back to the era of Murrow and Cronkite.
“Part of the emotion and romance of the show is being reminded of the role that great journalism’s played in our past and that the possibility exists that we could lift ourselves up by coming back to that church,” he said.
For certain, there would be a few empty pews. Much of the audience expects to be infotained when they turn on the news, so every wiggle and wobble of the Tot Mom becomes freighted with meaning. But there is also a sizable audience that tunes in for updates on actual news and sees talking heads arguing over Bristol Palin as if she were a head of state, and drug-fueled cannibalism discussed as a growing trend. There are others like me, fans of news, who feel less enlightened than implicated when we do tune in.
As viewers, we hew toward picking sides in news programming because it creates the illusion not just of import and drama, but that someone is at fault and things can be fixed. The world we live in hews much closer to “Network” than “The Newsroom.” (Even Mr. Sorkin cheats on his own premise, tilting piously left in his choice of targets: the Koch brothers, the gun lobby, the Tea Party and Wall Street bankers, even though Will McAvoy is nominally a Republican.)
Mr. Sorkin wants to believe that giving people what they need to know instead of what they want to know is a worthy way to run a news network. And as someone steeped in the world of entertainment, he knows it would probably never work.
“I think the Will McAvoy that existed the minute before the show begins would be very successful,” he said. “The Will McAvoy that starts to come into focus by the third episode wouldn’t stand a chance.”
My idea? CNN still makes $600 million a year and should be happy that it gets a premium on cable systems because its global news resources are still seen as essential. Leave the Tot Mom to others and stick to coming up with a well-cooked, nutritious news diet. Why not ride through the news cycle with some dignity and feed a loyal, reliable audience, standing by for when the world threatens to blow apart and ratings skyrocket? | – Early reviews slammed Aaron Sorkin's new HBO show The Newsroom; Emily Nussbaum at the New Yorker, for example, feels it "gets bad so quickly that I found my jaw dropping." But a bona fide TV news legend begs to differ. "The show gets close to the bone of what really happens behind the scenes in newsrooms and the boardrooms that govern them," writes Dan Rather at Gawker. He applauds the show's effort to expose mass audiences to news teams' central dilemma: Whether to focus on the public interest or pander for ratings. The show's protagonists decide to take the former approach, despite the odds against them. And that could prove a model for CNN, writes David Carr in the New York Times. The network has been "clobbered" by Fox News and MSNBC, and let's face it, entertainment sells better than solid information. Yet "there is also a sizable audience that tunes in for updates on actual news," Carr notes. CNN should "stick to coming up with a well-cooked, nutritious news diet" to "feed a loyal, reliable audience"; after all, it's still making $600 million every year. Then, when "the world threatens to blow apart," ratings will soar. Click for Rather's full piece. | <s>[INST]“I’m affable!” Will McAvoy yells in the pilot of “The Newsroom,” Aaron Sorkin’s new HBO series. McAvoy (played by Jeff Daniels) is an irascible anchor whose brand is likability, and it’s a good line, delivered well. It is also a rare moment of self-mockery—and one of the last sequences I was on board for in the series. In “The Newsroom,” clever people take turns admiring one another. They sing arias of facts. They aim to remake television news: “This is a new show, and there are new rules,” a maverick executive producer announces, several times, in several ways. Their outrage is so inflamed that it amounts to a form of moral eczema—only it makes the viewer itch.
This is not to say that “The Newsroom” doesn’t score points now and then, if you share its politics. It starts effectively enough, with an homage to “Network” ’s galvanizing “I’m mad as hell” rant, as McAvoy, a blandly uncontroversial cable big shot whom everyone tauntingly calls Leno, is trapped on a journalism-school panel. When the moderator needles him into answering a question about why America is the greatest country on earth, he goes volcanic, ticking off the ways in which America is no such thing, then closing with a statement of hope, about the way things used to be. This speech goes viral, and his boss (Sam Waterston) and his producer, MacKenzie McHale (Emily Mortimer), who’s also his ex-girlfriend, encourage him to create a purer news program, purged of any obsession with ratings and buzz.
Much of McAvoy’s diatribe is bona-fide baloney—false nostalgia for an America that never existed—but it is exciting to watch. And if you enjoyed “The West Wing,” Sorkin’s helpful counterprogramming to the Bush Administration, your ears will prick up. The pilot of “The Newsroom” is full of yelling and self-righteousness, but it’s got energy, just like “The West Wing,” Sorkin’s “Sports Night,” and his hit movie “The Social Network.” The second episode is more obviously stuffed with piety and syrup, although there’s one amusing segment, when McAvoy mocks some right-wing idiots. After that, “The Newsroom” gets so bad so quickly that I found my jaw dropping. The third episode is lousy (and devolves into lectures that are chopped into montages). The fourth episode is the worst. There are six to go.
Sorkin is often presented as one of the auteurs of modern television, an innovator and an original voice. But he’s more logically placed in a school of showrunners who favor patterspeak, point-counterpoint, and dialogue-driven tributes to the era of screwball romance. Some of this banter is intelligent; just as often, however, it’s artificial intelligence, predicated on the notion that more words equals smarter. Besides Sorkin, these creators include Shonda Rhimes (whose Washington melodrama, “Scandal,” employs cast members from “The West Wing”); Amy Sherman-Palladino, of “The Gilmore Girls” (and the appealing new “Bunheads”); and David E. Kelley, who created “Ally McBeal” and “Boston Legal.” Sorkin is supposed to be on a different level from his peers: longer words, worldlier topics. And many viewers clearly buy into this idea: years after Sorkin’s terrible, fascinating “Studio 60 on the Sunset Strip” was cancelled, I still occasionally run into someone who insists that Americans were just too stupid to get it.
As Dan Rather might put it, that dog won’t hunt. Sorkin’s shows are the type that people who never watch TV are always claiming are better than anything else on TV. The shows’ air of defiant intellectual superiority is rarely backed up by what’s inside—all those Wagnerian rants, fingers poked in chests, palms slammed on desks, and so on. In fact, “The Newsroom” treats the audience as though we were extremely stupid. Characters describe events we’ve just witnessed. When a cast member gets a shtick (like an obsession with Bigfoot), he delivers it over and over. In episode four, there’s a flashback to episode three. In a recent interview, Sorkin spoke patronizingly of cop shows, but his Socratic flirtations are frequently just as formulaic, right down to the magical “Ask twice!” technique.
There’s no denying that Sorkin’s shows can be addictive: I couldn’t stop watching “Studio 60,” which was about the making of a “Saturday Night Live”-style sketch show, no matter how hard I tried. That thing was alive! It was lit up with payback, as well as with portraits of Sorkin’s exes so glowing that they were radioactive. The show’s deliriously preening heroes were so memorable that they inspired a set of fictional Twitter feeds, in which the characters live on, making remarks like “Deciding if the satire I’m about to write should be scathing or whip-smart.”
“The Newsroom” sounded more promising, journalism being a natural habitat for blowhards. But so far the series lacks the squirmy vigor of “Studio 60,” particularly since Sorkin saps the drama with an odd structural choice. Rather than invent fictional crises, he’s set the show in “the recent past,” so that the plot is literally old news: the BP oil spill, the Tea Party, the Arizona immigration law. That sounds like an innovative concept, but it turns the characters into back-seat drivers, telling us how the news should have been delivered. (Instead of “Broadcast News,” it’s like a sanctimonious “Zelig.”) Naturally, McAvoy slices through crises by “speaking truth to stupid,” in McHale’s words. But he also seizes credit for “breaking stories”—like the political shenanigans of the Koch brothers—that were broken by actual journalists, all of them working in print or online. In the fourth episode, the show injects a real-life tragedy into the mix, pouring a pop ballad over the montage, just the way “E.R.” used to do whenever a busload of massacred toddlers came crashing through the door. ||||| A note from Dan Rather: I'm aware that my musings run counter to some of the more prominent early reviews in high-profile publications such as The New Yorker and the New York Times. But with all due respect (and I have a lot of it for those reviewers), I just don't think they "get it"; they've somehow missed the breadth, depth and "got it right" qualities –- and importance — of Newsroom. Maybe it's because they are print people. Then, too, maybe they're right and I'm wrong. I never rule out the possibility of that. But I've lived in the world of television newsrooms for most of my adult life. I know the people, the venues and the challenges — the satisfactions of success and the heartbreak when things go awry. From where I sit and based on my experience, Sorkin and crew have got it amazingly right, even when they over talk it.
Any television program that has its main characters quoting Cervantes can't be all bad. And so it is with The Newsroom.
Mark well, however, that with this HBO series premiere more praise is justified. A lot more. I've only seen the first program, but if what is to follow is as good as this first show then Aaron Sorkin has a winner.
Sure, I've got my nits to pick with it; and, no, it's not perfect. But there's a lot to like in what Sorkin and his cast have done here. There is a newsroom authenticity to what's presented and much that gets to the heart of modern American journalism's problems.
There is a battle for the soul of the craft that goes on daily now in virtually every newsroom in the country. It's a fight that matters, not just for journalists but for the country. It centers on whether news reporting is to be considered and practiced—to any significant degree, even a little—as a public service, in the public interest ,or is to exsist solely as just another money-making operation for owners of news outlets.
As the Newsroom character MacKenzie (Emily Mortimer) says, in challenging the anchorman Will McAvoy (Jeff Daniels) to be a crusader for quality journalism, "There is nothing more important in a democracy than a well-informed electorate. When there is no information or, much worse, wrong information, it can lead to calamitous decisions that clobber any attempts at vigorous debate."
This is the battle being lost in almost every newsroom, in every place around the world. Ratings (or circulation), demographics, and profits rule. Any talk of the public interest or of doing quality journalism of integrity with guts is considered passé.
Sorkin and his team deserve full praise for bringing the issue to the screen and to a mass audience, and for doing it in an interesting and entertaining way. They've got the right mix of issues, relationships and humor—sometimes, oft-times, comedy. (Be advised: the dialogue is sharp and fast. You need to pay close attention and listen closely.)
The show gets close to the bone of what happens, what really happens, behind the scenes in newsrooms and the boardrooms that govern them. One small nit: What's going on in gathering news and getting it on the air all seems so seamless in the show. In the real world of television news, it isn't.
I especially liked the emphasis on the necessity of having sources and doing real reporting (maybe not enough emphasis on this to satisfy me.) Also, the depiction of when to go with a story, when and what to lead with on a newscast is good.
One thing missing, for me anyway, in this first installment is a deep enough sense that most newsrooms—television and otherwise—have a kind of "valley of broken dreams" feel to them... an echo in the interior of people who got into news because of their idealism, now struggling with the reality of compromises they're forced to make daily if not hourly. In the real world, the undertow of this is palpable but often goes unspoken. In Newsroom, it's spoken often.
Yes, it's a bit too preachy here and there: show me, don't just have monologues and long pontifications about what the problems are. And no, on average newsroom people are seldom as smart or as high-minded as most of the lead characters in this fictional drama.
But if you liked the movies Citizen Kane, Network, and Broadcast News, if you liked the television series West Wing, Mad Men, or The Good Wife, you're going to love Newsroom. At least the first installment. And if Sorkin, his writers and their excellent actors can maintain this level, you'll probably like the full run.
It has the potential to become a classic.
You can watch the entire first episode of The Newsroom on YouTube.
Dan Rather is anchor and managing editor of Dan Rather Reports. You can follow him on Facebook and Twitter. ||||| (Page 2 of 2)
Then he added, “I don’t know anything about ratings (and I’ve had the ratings to back that up) but if I were the president of CNN I would put the smartest news people I know in a room and ask, ‘What would a utopian news show look like?’ and then I’d ask ‘What’s stopping us from doing that?’ ”
Mr. Sorkin says he knows there is no collective time machine to take us back to the era of Murrow and Cronkite.
“Part of the emotion and romance of the show is being reminded of the role that great journalism’s played in our past and that the possibility exists that we could lift ourselves up by coming back to that church,” he said.
For certain, there would be a few empty pews. Much of the audience expects to be infotained when they turn on the news, so every wiggle and wobble of the Tot Mom becomes freighted with meaning. But there is also a sizable audience that tunes in for updates on actual news and sees talking heads arguing over Bristol Palin as if she were a head of state, and drug-fueled cannibalism discussed as a growing trend. There are others like me, fans of news, who feel less enlightened than implicated when we do tune in.
As viewers, we hew toward picking sides in news programming because it creates the illusion not just of import and drama, but that someone is at fault and things can be fixed. The world we live in hews much closer to “Network” than “The Newsroom.” (Even Mr. Sorkin cheats on his own premise, tilting piously left in his choice of targets: the Koch brothers, the gun lobby, the Tea Party and Wall Street bankers, even though Will McAvoy is nominally a Republican.)
Mr. Sorkin wants to believe that giving people what they need to know instead of what they want to know is a worthy way to run a news network. And as someone steeped in the world of entertainment, he knows it would probably never work.
“I think the Will McAvoy that existed the minute before the show begins would be very successful,” he said. “The Will McAvoy that starts to come into focus by the third episode wouldn’t stand a chance.”
My idea? CNN still makes $600 million a year and should be happy that it gets a premium on cable systems because its global news resources are still seen as essential. Leave the Tot Mom to others and stick to coming up with a well-cooked, nutritious news diet. Why not ride through the news cycle with some dignity and feed a loyal, reliable audience, standing by for when the world threatens to blow apart and ratings skyrocket?[/INST]– Early reviews slammed Aaron Sorkin's new HBO show The Newsroom; Emily Nussbaum at the New Yorker, for example, feels it "gets bad so quickly that I found my jaw dropping." But a bona fide TV news legend begs to differ. "The show gets close to the bone of what really happens behind the scenes in newsrooms and the boardrooms that govern them," writes Dan Rather at Gawker. He applauds the show's effort to expose mass audiences to news teams' central dilemma: Whether to focus on the public interest or pander for ratings. The show's protagonists decide to take the former approach, despite the odds against them. And that could prove a model for CNN, writes David Carr in the New York Times. The network has been "clobbered" by Fox News and MSNBC, and let's face it, entertainment sells better than solid information. Yet "there is also a sizable audience that tunes in for updates on actual news," Carr notes. CNN should "stick to coming up with a well-cooked, nutritious news diet" to "feed a loyal, reliable audience"; after all, it's still making $600 million every year. Then, when "the world threatens to blow apart," ratings will soar. Click for Rather's full piece.</s> |
hematopoietic stem cell transplantation ( hsct ) has become the treatment of choice to cure or improve the outcomes of a wide variety of haematological malignancies and disorders.14 hsct can be performed by the transfer of hematopoietic stem cells from the donor to the recipient ( allogeneic hsct ) or by the return of previously harvested cells of the same individual ( autologous hsct ) after administration of conditioning regimens.4 myeloablative ( ma ) conditioning leads to profound pancytopenia , and also breaks down mucosal barriers , which might result in seeding of residing microorganisms of the gastrointestinal system into the bloodstream .
nonmyeloablative ( nma ) conditioning has the advantages of reduced regimen - related toxicity and transplant - related mortality .
therefore , patients being referred for hsct but not eligible to receive a myeloablative conditioning may have the opportunity to benefit from hsct .
recipients of nma allogeneic hsct experience a heterogeneous duration and degree of pancytopenia according to the administered regimen .
nma regimens with lower mucosal toxicity and myelosuppression provide a low incidence of infectious complications within the early period after transplantation .
immune recovery after nma regimens was shown to be faster than that was seen following ma regimens , and improved immune reconstitution was associated with lower incidence of life - threatening infectious complications . even though myelosuppressive potential of nma regimens seems to be milder than ma regimens ,
the severity and duration of lymphodepletion is assumed to be similar , because of the implementation of immunosuppressive treatment to prevent graft rejection.48
infectious complications are the major contributors of morbidity and mortality , especially within one year following hsct . in the early post - transplant period , presence of neutropenia and mucosal damage predispose patients to infections .
presence and severity of graft - versus - host disease ( gvhd ) and immunosuppressive treatment for it have a considerable impact on the degree of overall immunosuppression and risk of infection.4,7 the frequent use of central venous catheters brings about a substantial risk for severe , often recurrent , and potentially lethal infections.911 recipient factors such as age , comorbidities , and previous exposure to infectious agents prior to transplant , and the type of transplant , due to the distinct duration required for immune reconstitution , also influence the risk of infectious complications.4 initiating broad - spectrum empirical antibacterial therapy results in decreased mortality in febrile neutropenic hsct recipients . on the other hand ,
the use of such therapy has the risk of selection of resistant pathogens.9,1214 fluoroquinolone prophylaxis in haematology settings led emerging fluoroquinolone resistance.1520 this prophylaxis has also been associated with emerging methicillin - resistant staphylococcus aureus ( mrsa ) , multidrug - resistant ( mdr ) escherichia coli , and pseudomonas aeruginosa bacteraemia , and clostridium difficile infections.2125 consequently , empirical carbapenem use in patients receiving quinolone prophylaxis has increased , a practice may , in turn , result in increased carbapenem - resistant bacterial infections.16,26 in addition , prolonged and/or repeated hospitalisations , intensive care unit ( icu ) stay , severity of illness , healthcare - associated infections , presence of urinary catheter and older age are considered as major risk factors for resistant bacterial infections.12,2630 main risk factors for certain resistant bacterial infections are summarised in the table 1 .
the data on epidemiology of bacterial infections and their resistance patterns in hsct recipients mostly reflect isolates from bloodstream infections ( bsis ) which are the most frequent microbiologically documented bacterial infections .
the rate of bsis varies between 2030% of allogeneic and 5% of autologous hsct recipients , especially within pre - engraftment phase .
even though bacterial pneumonia and skin and soft tissue infections are also common among these patients , microbial aetiology may remain undocumented.29,31 during 1960s and 1970s , the incidence of gram - negative infections was high in haematology settings .
nevertheless , the incidence of gram - positive pathogens increased during mid-1980s and 1990s as a result of extensive use of indwelling catheters , early - generation fluoroquinolone prophylaxis and broad - spectrum empirical anti - gram - negative antibacterial therapy.12,29,3234 afterwards , coagulase - negative staphylococci were reported as the most common bacterial etiologic agents isolated from blood cultures in most centres.10,35 however , recent reports from a number of centres revealed drug - resistant gram - negative pathogens such as esbl - producing gram - negative bacteria , multidrug resistant ( mdr ) p. aeruginosa , acinetobacter baumannii , stenotrophomonas maltophilia , and carbapenemase - producing gram - negative bacteria as the causative agents of increasing numbers of infections.9,12,3644 in countries where high rates of antibiotic resistance exist , esbl - producing or mdr gram - negative bacteria contribute up to 1314% of clinical isolates.26,28,40,45 a significant increase in the prevalence of resistant gram - positive cocci such as mrsa and vancomycin - resistant enterococci ( vre ) have also been reported and stated as the overriding resistant pathogens in some centres.46,47 penicillin - resistant viridans streptococci and penicillin - resistant streptococcus pneumoniae ( prsp ) are less common , yet they may be the causative agents of severe infections.9,10,12,48 the epidemiology of bacterial infections and their resistance patterns show distinct geographic and inter - centre variability .
being aware of the current data on local epidemiology of predominant pathogens and close monitoring of their resistance patterns are of great importance , especially in empirical antibacterial treatment decisions.12,29,49,50 recent reviews on epidemiology of bsis in cancer patients , primarily with hematologic malignancies including hsct recipients , revealed that among all bsi isolates , coagulase - negative staphylococci and enterobacteriaceae ( frequently e. coli ) were the most common pathogens followed by p. aeruginosa , s. aureus , viridans streptococci , and enterococci .
the approximate rates of these commonly encountered pathogens were : 25% ( range : 560% ) for coagulase - negative staphylococci ; 25% ( range : 654% ) for enterobacteriaceae ; 10% ( range : 030% ) for p. aeruginosa ; 6% ( range : 020% ) for s. aureus ; 5% ( range : 016% ) for viridans streptococci ; and 5% ( range : 038% ) for enterococci.29,49,51 a brief information on the epidemiology of global resistance data for gram - positive and gram - negative bacteria is given below in each corresponding title .
an online website showing the current drug resistance rates and antimicrobial use worldwide is also available at
e. coli is one of the most frequent pathogens causing bacteraemia in patients with cancer and neutropenia.49,5153 production of one or more extended spectrum beta - lactamases ( esbls ) is the main resistance mechanism against broad - spectrum penicillins and cephalosporins in enteric gram - negative pathogens .
many esbl - producing e. coli are also resistant to non - beta - lactam antibiotics including aminoglycosides and quinolones with altered resistance mechanisms.5254 esbl - encoding plasmids may also encode resistance to aminoglycosides , tetracyclines , sulphonamides and trimethoprim.52,55 these plasmids frequently encode an inhibitor - resistant beta - lactamase , which confers resistance to beta - lactam - beta - lactamase inhibitor combinations including amoxicillin - clavulanate and piperacillin - tazobactam.52,55,56 aminoglycoside resistance among e. coli and other gram - negative enteric pathogens is determined by aminoglycoside - modifying enzymes which can be encoded on the same plasmid with esbls.52
e. coli was the second most frequent carbapenem - resistant enterobacteriaceae ( cre ) following klebsiella pneumoniae . in a recent us survey , the incidence of cre was determined as 2.93 per 100.000 population.52,57 one of the most significant carbapenemases described in enterobacteriaceae is new delhi metallo - beta - lactamase-1 ( ndm-1 ) .
this enzyme is prevalent in the indian subcontinent , but also frequently reported in balkans and the middle east.52,58 the bacteria harbouring this enzyme have spread worldwide and are usually only susceptible to colistin , tigecycline and fosfomycin , although susceptibility to these agents is not universal.52,59 since e. coli infections are very frequent in the outpatient settings , it is feared that a progressive increase in the prevalence of ndm-1 producing e. coli may occur.52,58 plasmid - mediated colistin resistance ( via mcr-1 colistin resistance gene ) has recently been described in e. coli isolates worldwide from mainly livestock and less frequently in human samples.52,6065 the implications of this finding may be horrendous since the offending plasmid can easily be transferred between e. coli strains and to k. pneumonia and p. aeruginosa.52,66 as a matter of fact , recent reports already noted the presence of this gene from plasmids in salmonella and k. pneumoniae.52,6770 along with esbls as the main resistance mechanism to broad - spectrum penicillins and cephalosporins in enteric gram - negative pathogens , carbapenem resistance has become the most important epidemiologic and therapeutic challenge in k. pneumoniae.52,58 there are mainly 3 classes of carbapenemases involved including kpc ( class a ) , oxa-48 ( class d ) and ndm ( class b ) for which different epidemiological reservoirs exist.52,58,59,7174 a specific kpc-2 or kpc-3-producing clone has been widely disseminated worldwide contributing the spread of resistance.52,58 carbapenem - resistant isolates usually show mdr pattern and are susceptible only to colistin , fosfomycin and tigecycline .
however , there is also emergence of resistance against these antibiotics.52,75,76 p. aeruginosa strains with high resistance rates to aminoglycosides , ceftazidime , quinolones , piperacillin - tazobactam and carbapenems are usually reported from southern and eastern part of europe.52,77 several beta - lactamases have been described for causing resistance and these include ampc , esbl ( particularly per-1 ) and metallo - beta - lactamases.52,55 carbapenem resistance in p. aeruginosa is mostly due to porin deficiencies and rarely caused by carbapenemase production.52,78 emergence of colistin resistance in p. aeruginosa has also been reported.52,79 the most frequent class a esbls found in a. baumannii are per- , ges- and veb - type enzymes .
these beta - lactamases confer resistance to extended - spectrum cephalosporins , but inhibited by tazobactam and clavulanic acid.52,78 tem- , shv- and ctx - m - type esbls are rarely found in a. baumannii .
class b beta - lactamases ( metalloenzymes ) are also reported in a. baumannii and include imp- , vim- and ndm - type enzymes .
these beta - lactamases provide activity against not only to carbapenems , but also to broad - spectrum cephalosporins and penicillins.52,80 class d , oxa - type carbapenemases are the most widespread carbapenemases in a. baumannii.52,55 these enzymes cause weak resistance to carbapenems .
thus , high - level resistance usually require other mechanisms involved such as efflux and porin loss.52,78 the arma enzyme is the most frequent methylase which is responsible for high - level resistance to all aminoglycosides in a. baumannii .
usually several of these mechanisms are present in mdr acinetobacter isolates.52 for treatment of mdr gram - negative infections , especially due to carbapenem - resistant enterobacteriaceae , pseudomonas species , and acinetobacter species , colistin ( polymyxin e ) has been increasingly used as a therapeutic option , administered as monotherapy or in combination regimens , even though limited data exist on its use in haematology patients and hsct recipients.2628,81,82 there are many reports on successful combination regimens for mdr gram - negative infections.26,8385 colistin plus rifampicin treatment has shown in vitro and in vivo synergistic activity for a. baumannii infections.86,87 however , in a multicentre , randomized clinical trial , colistin plus rifampicin revealed no difference in infection - related mortality and length of hospital stay in the treatment of serious infections due to extensively drug - resistant a. baumannii as compared to colistin alone , but a significant increase in microbiological eradication rate was determined in the colistin plus rifampicin arm.88 in a recent study , survival benefit with combination therapy ( colistin plus carbapenem or tigecycline plus carbapenem ) was demonstrated in patients with kpc - producing k. pneumoniae bacteraemia.89
methicillin resistance is the hallmark of antimicrobial resistance in s. aureus and coagulase - negative staphylococci.52 while , vancomycin has long been successfully used for treatment of mrsa infections , emergence of s. aureus strains with vancomycin mics
2 mg / l has coincided with reports of treatment failures.9,90 community - acquired mrsa ( ca - mrsa ) infections have emerged as a global problem since the beginning of the 21 century.51,9092 although ca - mrsa strains initially caused mainly skin and soft tissue infections in healthy individuals and some certain populations such as homeless and imprisoned people , increased rates of bacteraemia both in community and hospital setting ; ventilator associated pneumonia ; and surgical site infections have recently been reported.52,94,95 ca - mrsa isolates usually remain susceptible to many non - beta - lactam antibiotics including clindamycin and trimethoprim - sulfamethoxazole ( tmp - smx).52,96 coagulase - negative staphylococci are the most common cause of nosocomial bsis and are responsible almost one - third of all healthcare - associated bacteraemia .
the incidence is highest in those with cancer and neutropenia and those with catheter- and/or prosthetic device - related infections.29,52,97 multiple antibiotic resistance is highly encountered among hospital isolates and usually related with methicillin resistance.52,98 resistance to vancomycin is very rare , however a 20.8% resistance to teicoplanin was reported from uk , particularly in s. haemolyticus.98 penicillin - resistant pneumococci are more likely to show higher resistance to other classes of antimicrobials .
current figures of resistance in the us include 35% to macrolides , 10% to clindamycin , 30% to tmp - smx , 18% to doxycycline and 2% to respiratory quinolones.52,99 higher rates of macrolide resistance are reported from europe.52,100 viridans streptococci can cause infective endocarditis , especially in patients with compromised heart valves , and they can also produce bacteraemia and septic shock particularly in patients with neutropenia.51,52,101 although these bacteria are susceptible to most antimicrobials , beta - lactam resistance , due to the altered penicillin binding proteins has emerged and may cause a significant problem especially in patients with immunosuppression and bacteraemia.51,52,102 ceftriaxone and cefepime resistance has been reported up to 23 and 25% , respectively in strains isolated from hospitalised or cancer patients.52,103,104 vancomycin is highly effective on such strains.52 among all enterococci , enterococcus faecium is the most challenging one in terms of antibacterial resistance and therapy . in the us , enterococci are the second most common bacteria isolated from catheter - related ( cr)-bsis.52,105 enterococci are intrinsically resistant to many antimicrobials , but also easily acquire mutations and exogenous genes to develop further resistance.52,106 while aminopenicillin resistance is rare in e. faecalis , it is encountered around 90% of nosocomial e. faecium isolates.52,100,106 beta - lactamase production is infrequently associated with resistance and can be overcome with the use of beta - lactamase inhibitor compounds .
the production of pbp5 with low affinity to penicillins is the major culprit for beta - lactam resistance.52,106 high - level resistance to all aminoglycosides eliminates the synergistic activity of penicillins and vancomycin both of which can enhance activity of aminoglycosides in enterococci with low - to - moderate resistance . high - level aminoglycoside resistance has increased in both e. faecalis and e. faecium during the last 3 decades.52,100 glycopeptide resistance in enterococci is a much bigger problem in the us than in europe and elsewhere . by 2007 , >
80% of e. faecium isolates in the us hospitals were reported to be resistant to vancomycin whereas in europe only ireland reported a resistance rate of > 50%.52,100,106,107 similarly , mdr enterococci is much more prevalent in the us.52,106 enterococci are the third most frequent agents of bacteraemia in haematological cancer patients and hsct recipients and may affect up to 12% of all transplant patients . on these patient groups ,
a shift from e. faecalis to e. faecium has resulted in higher rates of vre infections.51,52 however , similar to the general epidemiology , vre infections constitute a less significant problem in western european transplant centres with < 5% of enterococci being resistant to vancomycin.52,104 resistance to linezolid and daptomycin is rarely reported.52,108 newer agents with activity against glycopeptide non - susceptible gram - positive pathogens , such as daptomycin , linezolid , and tigecycline are being increasingly used in various clinical settings.9,12,2729,109 one of the major drawbacks of daptomycin is the inactivation of the drug by pulmonary surfactant , which limits its use in treatment of pneumonia . moreover , treatment failure in staphylococcal central nervous system infection was noticed.26,110 even though daptomycin had not been evaluated in controlled trials in haematology patients , its efficacy on gram - positive infections in neutropenic patients has been reported.26,111,112 the clinical utility of tigecycline is limited by its low peak - serum concentrations , and increased failure and mortality rates.26,113,114 c. difficile infection ( cdi ) is among the major concerns in patients undergoing hsct .
risk factors for cdi in hsct patients are specified as exposure to broad - spectrum antimicrobial agents , receipt of chemotherapy prior to conditioning for hsct , total body irradiation , presence of acute gvhd , and vre colonisation.115118 the outcomes of cdi include increased morbidity and mortality due to increased risk of developing complications such as colitis or toxic megacolon , extended hospital stays , necessity to discontinue the required antibiotics , and increased healthcare costs.119,120 the emergence of an epidemic strain termed as north american pfge type 1 or nap1 is associated with large outbreaks in europe and the united states .
nap1 has a genetic alteration that results in enhanced toxin production and has been associated with increased severity of cdi , higher relapse and mortality rates.9,121,122 even though the studies conducted in 1980s and 1990s revealed that orally administered metronidazole and vancomycin showed equal effectiveness for treatment of cdi,9,123,124 with the emergence of the epidemic strain , reports of higher rates of treatment failure or delayed treatment responses have appeared with metronidazole as compared to oral vancomycin.125128 there are variable data on the outcomes of cdi in haematology settings , but treatment response to metronidazole and vancomycin is reported to be similar.26,129131 while initiation of treatment for cdi , age , white blood cell count , and serum creatinine level should be taken into consideration as indicators for severe or complicated course.122,132 for the initial episode of mild - to - moderate cdi , metronidazole is the drug of choice .
vancomycin should be preferred for an initial episode of severe cdi . in case of existence of ileus , megacolon , hypotension or shock , vancomycin at higher doses ( 500 mg 4 times per day ) plus
the recommendations for first recurrence are the same as for initial episode . however , in second recurrence , vancomycin ( in a tapered and/or pulsed regimen ) is the drug of choice.132 the data on alternative treatment options for cdi are limited in haematology patients and hsct recipients . with the use of fidaxomicin , clinical response and recurrence rates were found to be comparable to that of conventional therapy.133 however , fidaxomicin was associated with a lower recurrence rate of cdi associated with nap1 strains.134 in a recent post hoc analysis , fidaxomicin was found to be superior to vancomycin for treatment of cdi in patients with cancer in terms of shorter time to resolution of diarrhoea , higher cure and sustained response rates , and fewer recurrences.135
infection prevention and control measures such as hand hygiene , contact barrier precautions , isolation , and appropriate environmental cleaning are crucial to deal with the spread of mdr bacteria in haematology settings.144146 active surveillance can help to identify individuals colonised with mdr pathogens .
however , it is not clearly defined whether an active - surveillance for mdr bacteria as an additional strategy to infection control procedures is beneficial to prevent health - care - associated transmission.144,147149 colonisation may persist for months in the case of severe underlying disorders , prolonged or recurrent antimicrobial exposure , and presence of invasive devices.144,150 patient populations for targeted screening , as well as ideal screening method and timing of surveillance , are not definitely determined , but can be chosen among those considered to have risk factors for colonization with mdr pathogens , such as prolonged hospital stay , exposure to antimicrobials , icu stay or transfer from settings known to have high mdr bacteria rates . another approach is to obtain surveillance cultures from each patient admitted to the settings with high prevalence of mdr pathogens .
while some centres establish weekly surveillance cultures , others choose to obtain cultures at the time of admission and/or whenever risk factors emerge for colonisation of mdr bacteria.144,150153 screening for mrsa colonisation is not routinely performed , but can be established if mrsa rates remain to be high despite effective implementation of infection control measures . in such circumstances ,
mrsa surveillance cultures should be obtained on admission and thereafter ( e.g. weekly ) with or without concomitant decolonization.144,154156 vre surveillance cultures can be considered in case of ongoing spread of vre in an hsct unit to identify colonised patients.144,152 active surveillance cultures for mdr - gnbs can be used in units with high rates of mdr - gnb infections . a point prevalence survey is recommended if previously unnoticed cases with cre are identified by the review of microbiology reports for the preceding 612 months.144,146 in a retrospective nationwide survey from italy , documented carbapenem - resistant k. pneumoniae ( crkp ) colonization before or after hsct was determined to be followed by infection in 25.8% of autologous hsct and 39.2% of allogeneic hsct recipients ; and infection - related mortality rates were stated as 16% in autologous hsct and 64.4% in allogeneic hsct patients.44 in endemic settings , screening for crkp before transplantation prior to hospital admission and weekly after transplantation for those who remain negative in case of isolation of crkp in that unit is recommended.157,158 recent reports have revealed that decolonization with aminoglycosides or colistin could succeed in patients colonised with cre.157,159163 nevertheless , development of resistance to these agents is of concern , and patients can be recolonized after gastrointestinal decolonization.158,159,164
for empirical antibacterial treatment in febrile neutropenia , escalation or de - escalation approach can be used . in escalation strategy , initial therapy targets activity against enterobacteriaceae and p. aeruginosa , but , esbl- and carbapenemase - producing gram - negative bacilli and drug - resistant non - fermentative bacteria remain out of empirical coverage . in case of development of clinical deterioration or isolation of a resistant pathogen from clinical samples , the spectrum of antibacterial coverage must be broadened . in de - escalation strategy ,
initial regimen targets to cover drug - resistant pathogens , and once the microbiological data become available , therapy is de - escalated to an appropriate narrower spectrum .
escalation strategy may be considered for patients followed in a centre where mdr pathogens are rarely seen at the onset of febrile neutropenia and for those without any specific risk factors for resistant bacterial infections .
de - escalation strategy may be used for febrile neutropenic patients having risk factors for resistant bacterial infections , such as previous infection or known colonisation with esbl - producing gram - negative bacteria , residents of a centre where mdr pathogens are common , and also for those presenting with septic shock and pneumonia .
initial regimen in de - escalation strategy may include monotherapy with a carbapenem or combination therapy with an anti - pseudomonal beta - lactam agent and an aminoglycoside / quinolone or combination therapy with colistin and a beta - lactam agent / rifampicin .
if risk factors for resistant gram - positive infections are present , early coverage with a glycopeptide or newer agents ( linezolid , daptomycin , tigecycline ) with activity against glycopeptide non - susceptible gram - positive pathogens should be considered .
patients with suspicion of catheter - related infection , known colonisation with mrsa , vre , and prsp , hemodynamic instability , severe sepsis , septic shock , presence of skin and soft tissue infection and pneumonia are accepted as candidates for additional antibiotics against resistant gram - positive pathogens.12,2729,51
the emergence of infections with resistant bacterial pathogens is associated with trends towards poor outcomes , prolonged hospital stay , more frequent icu admissions , and increased treatment costs in haematology patients.26,45,136138 moreover , the bacterial resistance complicates the use of standard antimicrobial regimens in febrile hsct recipients .
antimicrobial treatment approach for neutropenic or chronically immunosuppressed hsct recipients with gvhd necessitates careful evaluation of patients ; detailed knowledge on local epidemiological data on antibacterial resistance ; close monitoring of the emergence of resistance in bacterial pathogens ; and use of robust treatment options in the context of a rational antimicrobial stewardship program.9,139,140 convenient infection control measures and appropriate vaccination schedules should be implemented to prevent patients from exposure to pathogens.9,30,50,141143 besides , effective attempts should be provided in the development of new antibacterial agents and immune augmentation strategies to cope with resistant bacterial pathogens.9 | recipients of hematopoietic stem cell transplantation ( hsct ) are at substantial risk of bacterial , fungal , viral , and parasitic infections depending on the time elapsed since transplantation , presence of graft - versus - host disease ( gvhd ) , and the degree of immunosuppression .
infectious complications in hsct recipients are associated with high morbidity and mortality .
bacterial infections constitute the major cause of infectious complications , especially in the early post - transplant period .
the emergence of antibacterial resistance complicates the management of bacterial infections in this patient group .
multidrug - resistant bacterial infections in this group of patients have attracted considerable interest and may lead to significant morbidity and mortality .
empirical antibacterial therapy in patients with hsct and febrile neutropenia has a critical role for survival and should be based on local epidemiology .
this review attempts to provide an overview of risk factors and epidemiology of emerging resistant bacterial infections and their management in hsct recipients . | <s>[INST]hematopoietic stem cell transplantation ( hsct ) has become the treatment of choice to cure or improve the outcomes of a wide variety of haematological malignancies and disorders.14 hsct can be performed by the transfer of hematopoietic stem cells from the donor to the recipient ( allogeneic hsct ) or by the return of previously harvested cells of the same individual ( autologous hsct ) after administration of conditioning regimens.4 myeloablative ( ma ) conditioning leads to profound pancytopenia , and also breaks down mucosal barriers , which might result in seeding of residing microorganisms of the gastrointestinal system into the bloodstream .
nonmyeloablative ( nma ) conditioning has the advantages of reduced regimen - related toxicity and transplant - related mortality .
therefore , patients being referred for hsct but not eligible to receive a myeloablative conditioning may have the opportunity to benefit from hsct .
recipients of nma allogeneic hsct experience a heterogeneous duration and degree of pancytopenia according to the administered regimen .
nma regimens with lower mucosal toxicity and myelosuppression provide a low incidence of infectious complications within the early period after transplantation .
immune recovery after nma regimens was shown to be faster than that was seen following ma regimens , and improved immune reconstitution was associated with lower incidence of life - threatening infectious complications . even though myelosuppressive potential of nma regimens seems to be milder than ma regimens ,
the severity and duration of lymphodepletion is assumed to be similar , because of the implementation of immunosuppressive treatment to prevent graft rejection.48
infectious complications are the major contributors of morbidity and mortality , especially within one year following hsct . in the early post - transplant period , presence of neutropenia and mucosal damage predispose patients to infections .
presence and severity of graft - versus - host disease ( gvhd ) and immunosuppressive treatment for it have a considerable impact on the degree of overall immunosuppression and risk of infection.4,7 the frequent use of central venous catheters brings about a substantial risk for severe , often recurrent , and potentially lethal infections.911 recipient factors such as age , comorbidities , and previous exposure to infectious agents prior to transplant , and the type of transplant , due to the distinct duration required for immune reconstitution , also influence the risk of infectious complications.4 initiating broad - spectrum empirical antibacterial therapy results in decreased mortality in febrile neutropenic hsct recipients . on the other hand ,
the use of such therapy has the risk of selection of resistant pathogens.9,1214 fluoroquinolone prophylaxis in haematology settings led emerging fluoroquinolone resistance.1520 this prophylaxis has also been associated with emerging methicillin - resistant staphylococcus aureus ( mrsa ) , multidrug - resistant ( mdr ) escherichia coli , and pseudomonas aeruginosa bacteraemia , and clostridium difficile infections.2125 consequently , empirical carbapenem use in patients receiving quinolone prophylaxis has increased , a practice may , in turn , result in increased carbapenem - resistant bacterial infections.16,26 in addition , prolonged and/or repeated hospitalisations , intensive care unit ( icu ) stay , severity of illness , healthcare - associated infections , presence of urinary catheter and older age are considered as major risk factors for resistant bacterial infections.12,2630 main risk factors for certain resistant bacterial infections are summarised in the table 1 .
the data on epidemiology of bacterial infections and their resistance patterns in hsct recipients mostly reflect isolates from bloodstream infections ( bsis ) which are the most frequent microbiologically documented bacterial infections .
the rate of bsis varies between 2030% of allogeneic and 5% of autologous hsct recipients , especially within pre - engraftment phase .
even though bacterial pneumonia and skin and soft tissue infections are also common among these patients , microbial aetiology may remain undocumented.29,31 during 1960s and 1970s , the incidence of gram - negative infections was high in haematology settings .
nevertheless , the incidence of gram - positive pathogens increased during mid-1980s and 1990s as a result of extensive use of indwelling catheters , early - generation fluoroquinolone prophylaxis and broad - spectrum empirical anti - gram - negative antibacterial therapy.12,29,3234 afterwards , coagulase - negative staphylococci were reported as the most common bacterial etiologic agents isolated from blood cultures in most centres.10,35 however , recent reports from a number of centres revealed drug - resistant gram - negative pathogens such as esbl - producing gram - negative bacteria , multidrug resistant ( mdr ) p. aeruginosa , acinetobacter baumannii , stenotrophomonas maltophilia , and carbapenemase - producing gram - negative bacteria as the causative agents of increasing numbers of infections.9,12,3644 in countries where high rates of antibiotic resistance exist , esbl - producing or mdr gram - negative bacteria contribute up to 1314% of clinical isolates.26,28,40,45 a significant increase in the prevalence of resistant gram - positive cocci such as mrsa and vancomycin - resistant enterococci ( vre ) have also been reported and stated as the overriding resistant pathogens in some centres.46,47 penicillin - resistant viridans streptococci and penicillin - resistant streptococcus pneumoniae ( prsp ) are less common , yet they may be the causative agents of severe infections.9,10,12,48 the epidemiology of bacterial infections and their resistance patterns show distinct geographic and inter - centre variability .
being aware of the current data on local epidemiology of predominant pathogens and close monitoring of their resistance patterns are of great importance , especially in empirical antibacterial treatment decisions.12,29,49,50 recent reviews on epidemiology of bsis in cancer patients , primarily with hematologic malignancies including hsct recipients , revealed that among all bsi isolates , coagulase - negative staphylococci and enterobacteriaceae ( frequently e. coli ) were the most common pathogens followed by p. aeruginosa , s. aureus , viridans streptococci , and enterococci .
the approximate rates of these commonly encountered pathogens were : 25% ( range : 560% ) for coagulase - negative staphylococci ; 25% ( range : 654% ) for enterobacteriaceae ; 10% ( range : 030% ) for p. aeruginosa ; 6% ( range : 020% ) for s. aureus ; 5% ( range : 016% ) for viridans streptococci ; and 5% ( range : 038% ) for enterococci.29,49,51 a brief information on the epidemiology of global resistance data for gram - positive and gram - negative bacteria is given below in each corresponding title .
an online website showing the current drug resistance rates and antimicrobial use worldwide is also available at
e. coli is one of the most frequent pathogens causing bacteraemia in patients with cancer and neutropenia.49,5153 production of one or more extended spectrum beta - lactamases ( esbls ) is the main resistance mechanism against broad - spectrum penicillins and cephalosporins in enteric gram - negative pathogens .
many esbl - producing e. coli are also resistant to non - beta - lactam antibiotics including aminoglycosides and quinolones with altered resistance mechanisms.5254 esbl - encoding plasmids may also encode resistance to aminoglycosides , tetracyclines , sulphonamides and trimethoprim.52,55 these plasmids frequently encode an inhibitor - resistant beta - lactamase , which confers resistance to beta - lactam - beta - lactamase inhibitor combinations including amoxicillin - clavulanate and piperacillin - tazobactam.52,55,56 aminoglycoside resistance among e. coli and other gram - negative enteric pathogens is determined by aminoglycoside - modifying enzymes which can be encoded on the same plasmid with esbls.52
e. coli was the second most frequent carbapenem - resistant enterobacteriaceae ( cre ) following klebsiella pneumoniae . in a recent us survey , the incidence of cre was determined as 2.93 per 100.000 population.52,57 one of the most significant carbapenemases described in enterobacteriaceae is new delhi metallo - beta - lactamase-1 ( ndm-1 ) .
this enzyme is prevalent in the indian subcontinent , but also frequently reported in balkans and the middle east.52,58 the bacteria harbouring this enzyme have spread worldwide and are usually only susceptible to colistin , tigecycline and fosfomycin , although susceptibility to these agents is not universal.52,59 since e. coli infections are very frequent in the outpatient settings , it is feared that a progressive increase in the prevalence of ndm-1 producing e. coli may occur.52,58 plasmid - mediated colistin resistance ( via mcr-1 colistin resistance gene ) has recently been described in e. coli isolates worldwide from mainly livestock and less frequently in human samples.52,6065 the implications of this finding may be horrendous since the offending plasmid can easily be transferred between e. coli strains and to k. pneumonia and p. aeruginosa.52,66 as a matter of fact , recent reports already noted the presence of this gene from plasmids in salmonella and k. pneumoniae.52,6770 along with esbls as the main resistance mechanism to broad - spectrum penicillins and cephalosporins in enteric gram - negative pathogens , carbapenem resistance has become the most important epidemiologic and therapeutic challenge in k. pneumoniae.52,58 there are mainly 3 classes of carbapenemases involved including kpc ( class a ) , oxa-48 ( class d ) and ndm ( class b ) for which different epidemiological reservoirs exist.52,58,59,7174 a specific kpc-2 or kpc-3-producing clone has been widely disseminated worldwide contributing the spread of resistance.52,58 carbapenem - resistant isolates usually show mdr pattern and are susceptible only to colistin , fosfomycin and tigecycline .
however , there is also emergence of resistance against these antibiotics.52,75,76 p. aeruginosa strains with high resistance rates to aminoglycosides , ceftazidime , quinolones , piperacillin - tazobactam and carbapenems are usually reported from southern and eastern part of europe.52,77 several beta - lactamases have been described for causing resistance and these include ampc , esbl ( particularly per-1 ) and metallo - beta - lactamases.52,55 carbapenem resistance in p. aeruginosa is mostly due to porin deficiencies and rarely caused by carbapenemase production.52,78 emergence of colistin resistance in p. aeruginosa has also been reported.52,79 the most frequent class a esbls found in a. baumannii are per- , ges- and veb - type enzymes .
these beta - lactamases confer resistance to extended - spectrum cephalosporins , but inhibited by tazobactam and clavulanic acid.52,78 tem- , shv- and ctx - m - type esbls are rarely found in a. baumannii .
class b beta - lactamases ( metalloenzymes ) are also reported in a. baumannii and include imp- , vim- and ndm - type enzymes .
these beta - lactamases provide activity against not only to carbapenems , but also to broad - spectrum cephalosporins and penicillins.52,80 class d , oxa - type carbapenemases are the most widespread carbapenemases in a. baumannii.52,55 these enzymes cause weak resistance to carbapenems .
thus , high - level resistance usually require other mechanisms involved such as efflux and porin loss.52,78 the arma enzyme is the most frequent methylase which is responsible for high - level resistance to all aminoglycosides in a. baumannii .
usually several of these mechanisms are present in mdr acinetobacter isolates.52 for treatment of mdr gram - negative infections , especially due to carbapenem - resistant enterobacteriaceae , pseudomonas species , and acinetobacter species , colistin ( polymyxin e ) has been increasingly used as a therapeutic option , administered as monotherapy or in combination regimens , even though limited data exist on its use in haematology patients and hsct recipients.2628,81,82 there are many reports on successful combination regimens for mdr gram - negative infections.26,8385 colistin plus rifampicin treatment has shown in vitro and in vivo synergistic activity for a. baumannii infections.86,87 however , in a multicentre , randomized clinical trial , colistin plus rifampicin revealed no difference in infection - related mortality and length of hospital stay in the treatment of serious infections due to extensively drug - resistant a. baumannii as compared to colistin alone , but a significant increase in microbiological eradication rate was determined in the colistin plus rifampicin arm.88 in a recent study , survival benefit with combination therapy ( colistin plus carbapenem or tigecycline plus carbapenem ) was demonstrated in patients with kpc - producing k. pneumoniae bacteraemia.89
methicillin resistance is the hallmark of antimicrobial resistance in s. aureus and coagulase - negative staphylococci.52 while , vancomycin has long been successfully used for treatment of mrsa infections , emergence of s. aureus strains with vancomycin mics
2 mg / l has coincided with reports of treatment failures.9,90 community - acquired mrsa ( ca - mrsa ) infections have emerged as a global problem since the beginning of the 21 century.51,9092 although ca - mrsa strains initially caused mainly skin and soft tissue infections in healthy individuals and some certain populations such as homeless and imprisoned people , increased rates of bacteraemia both in community and hospital setting ; ventilator associated pneumonia ; and surgical site infections have recently been reported.52,94,95 ca - mrsa isolates usually remain susceptible to many non - beta - lactam antibiotics including clindamycin and trimethoprim - sulfamethoxazole ( tmp - smx).52,96 coagulase - negative staphylococci are the most common cause of nosocomial bsis and are responsible almost one - third of all healthcare - associated bacteraemia .
the incidence is highest in those with cancer and neutropenia and those with catheter- and/or prosthetic device - related infections.29,52,97 multiple antibiotic resistance is highly encountered among hospital isolates and usually related with methicillin resistance.52,98 resistance to vancomycin is very rare , however a 20.8% resistance to teicoplanin was reported from uk , particularly in s. haemolyticus.98 penicillin - resistant pneumococci are more likely to show higher resistance to other classes of antimicrobials .
current figures of resistance in the us include 35% to macrolides , 10% to clindamycin , 30% to tmp - smx , 18% to doxycycline and 2% to respiratory quinolones.52,99 higher rates of macrolide resistance are reported from europe.52,100 viridans streptococci can cause infective endocarditis , especially in patients with compromised heart valves , and they can also produce bacteraemia and septic shock particularly in patients with neutropenia.51,52,101 although these bacteria are susceptible to most antimicrobials , beta - lactam resistance , due to the altered penicillin binding proteins has emerged and may cause a significant problem especially in patients with immunosuppression and bacteraemia.51,52,102 ceftriaxone and cefepime resistance has been reported up to 23 and 25% , respectively in strains isolated from hospitalised or cancer patients.52,103,104 vancomycin is highly effective on such strains.52 among all enterococci , enterococcus faecium is the most challenging one in terms of antibacterial resistance and therapy . in the us , enterococci are the second most common bacteria isolated from catheter - related ( cr)-bsis.52,105 enterococci are intrinsically resistant to many antimicrobials , but also easily acquire mutations and exogenous genes to develop further resistance.52,106 while aminopenicillin resistance is rare in e. faecalis , it is encountered around 90% of nosocomial e. faecium isolates.52,100,106 beta - lactamase production is infrequently associated with resistance and can be overcome with the use of beta - lactamase inhibitor compounds .
the production of pbp5 with low affinity to penicillins is the major culprit for beta - lactam resistance.52,106 high - level resistance to all aminoglycosides eliminates the synergistic activity of penicillins and vancomycin both of which can enhance activity of aminoglycosides in enterococci with low - to - moderate resistance . high - level aminoglycoside resistance has increased in both e. faecalis and e. faecium during the last 3 decades.52,100 glycopeptide resistance in enterococci is a much bigger problem in the us than in europe and elsewhere . by 2007 , >
80% of e. faecium isolates in the us hospitals were reported to be resistant to vancomycin whereas in europe only ireland reported a resistance rate of > 50%.52,100,106,107 similarly , mdr enterococci is much more prevalent in the us.52,106 enterococci are the third most frequent agents of bacteraemia in haematological cancer patients and hsct recipients and may affect up to 12% of all transplant patients . on these patient groups ,
a shift from e. faecalis to e. faecium has resulted in higher rates of vre infections.51,52 however , similar to the general epidemiology , vre infections constitute a less significant problem in western european transplant centres with < 5% of enterococci being resistant to vancomycin.52,104 resistance to linezolid and daptomycin is rarely reported.52,108 newer agents with activity against glycopeptide non - susceptible gram - positive pathogens , such as daptomycin , linezolid , and tigecycline are being increasingly used in various clinical settings.9,12,2729,109 one of the major drawbacks of daptomycin is the inactivation of the drug by pulmonary surfactant , which limits its use in treatment of pneumonia . moreover , treatment failure in staphylococcal central nervous system infection was noticed.26,110 even though daptomycin had not been evaluated in controlled trials in haematology patients , its efficacy on gram - positive infections in neutropenic patients has been reported.26,111,112 the clinical utility of tigecycline is limited by its low peak - serum concentrations , and increased failure and mortality rates.26,113,114 c. difficile infection ( cdi ) is among the major concerns in patients undergoing hsct .
risk factors for cdi in hsct patients are specified as exposure to broad - spectrum antimicrobial agents , receipt of chemotherapy prior to conditioning for hsct , total body irradiation , presence of acute gvhd , and vre colonisation.115118 the outcomes of cdi include increased morbidity and mortality due to increased risk of developing complications such as colitis or toxic megacolon , extended hospital stays , necessity to discontinue the required antibiotics , and increased healthcare costs.119,120 the emergence of an epidemic strain termed as north american pfge type 1 or nap1 is associated with large outbreaks in europe and the united states .
nap1 has a genetic alteration that results in enhanced toxin production and has been associated with increased severity of cdi , higher relapse and mortality rates.9,121,122 even though the studies conducted in 1980s and 1990s revealed that orally administered metronidazole and vancomycin showed equal effectiveness for treatment of cdi,9,123,124 with the emergence of the epidemic strain , reports of higher rates of treatment failure or delayed treatment responses have appeared with metronidazole as compared to oral vancomycin.125128 there are variable data on the outcomes of cdi in haematology settings , but treatment response to metronidazole and vancomycin is reported to be similar.26,129131 while initiation of treatment for cdi , age , white blood cell count , and serum creatinine level should be taken into consideration as indicators for severe or complicated course.122,132 for the initial episode of mild - to - moderate cdi , metronidazole is the drug of choice .
vancomycin should be preferred for an initial episode of severe cdi . in case of existence of ileus , megacolon , hypotension or shock , vancomycin at higher doses ( 500 mg 4 times per day ) plus
the recommendations for first recurrence are the same as for initial episode . however , in second recurrence , vancomycin ( in a tapered and/or pulsed regimen ) is the drug of choice.132 the data on alternative treatment options for cdi are limited in haematology patients and hsct recipients . with the use of fidaxomicin , clinical response and recurrence rates were found to be comparable to that of conventional therapy.133 however , fidaxomicin was associated with a lower recurrence rate of cdi associated with nap1 strains.134 in a recent post hoc analysis , fidaxomicin was found to be superior to vancomycin for treatment of cdi in patients with cancer in terms of shorter time to resolution of diarrhoea , higher cure and sustained response rates , and fewer recurrences.135
infection prevention and control measures such as hand hygiene , contact barrier precautions , isolation , and appropriate environmental cleaning are crucial to deal with the spread of mdr bacteria in haematology settings.144146 active surveillance can help to identify individuals colonised with mdr pathogens .
however , it is not clearly defined whether an active - surveillance for mdr bacteria as an additional strategy to infection control procedures is beneficial to prevent health - care - associated transmission.144,147149 colonisation may persist for months in the case of severe underlying disorders , prolonged or recurrent antimicrobial exposure , and presence of invasive devices.144,150 patient populations for targeted screening , as well as ideal screening method and timing of surveillance , are not definitely determined , but can be chosen among those considered to have risk factors for colonization with mdr pathogens , such as prolonged hospital stay , exposure to antimicrobials , icu stay or transfer from settings known to have high mdr bacteria rates . another approach is to obtain surveillance cultures from each patient admitted to the settings with high prevalence of mdr pathogens .
while some centres establish weekly surveillance cultures , others choose to obtain cultures at the time of admission and/or whenever risk factors emerge for colonisation of mdr bacteria.144,150153 screening for mrsa colonisation is not routinely performed , but can be established if mrsa rates remain to be high despite effective implementation of infection control measures . in such circumstances ,
mrsa surveillance cultures should be obtained on admission and thereafter ( e.g. weekly ) with or without concomitant decolonization.144,154156 vre surveillance cultures can be considered in case of ongoing spread of vre in an hsct unit to identify colonised patients.144,152 active surveillance cultures for mdr - gnbs can be used in units with high rates of mdr - gnb infections . a point prevalence survey is recommended if previously unnoticed cases with cre are identified by the review of microbiology reports for the preceding 612 months.144,146 in a retrospective nationwide survey from italy , documented carbapenem - resistant k. pneumoniae ( crkp ) colonization before or after hsct was determined to be followed by infection in 25.8% of autologous hsct and 39.2% of allogeneic hsct recipients ; and infection - related mortality rates were stated as 16% in autologous hsct and 64.4% in allogeneic hsct patients.44 in endemic settings , screening for crkp before transplantation prior to hospital admission and weekly after transplantation for those who remain negative in case of isolation of crkp in that unit is recommended.157,158 recent reports have revealed that decolonization with aminoglycosides or colistin could succeed in patients colonised with cre.157,159163 nevertheless , development of resistance to these agents is of concern , and patients can be recolonized after gastrointestinal decolonization.158,159,164
for empirical antibacterial treatment in febrile neutropenia , escalation or de - escalation approach can be used . in escalation strategy , initial therapy targets activity against enterobacteriaceae and p. aeruginosa , but , esbl- and carbapenemase - producing gram - negative bacilli and drug - resistant non - fermentative bacteria remain out of empirical coverage . in case of development of clinical deterioration or isolation of a resistant pathogen from clinical samples , the spectrum of antibacterial coverage must be broadened . in de - escalation strategy ,
initial regimen targets to cover drug - resistant pathogens , and once the microbiological data become available , therapy is de - escalated to an appropriate narrower spectrum .
escalation strategy may be considered for patients followed in a centre where mdr pathogens are rarely seen at the onset of febrile neutropenia and for those without any specific risk factors for resistant bacterial infections .
de - escalation strategy may be used for febrile neutropenic patients having risk factors for resistant bacterial infections , such as previous infection or known colonisation with esbl - producing gram - negative bacteria , residents of a centre where mdr pathogens are common , and also for those presenting with septic shock and pneumonia .
initial regimen in de - escalation strategy may include monotherapy with a carbapenem or combination therapy with an anti - pseudomonal beta - lactam agent and an aminoglycoside / quinolone or combination therapy with colistin and a beta - lactam agent / rifampicin .
if risk factors for resistant gram - positive infections are present , early coverage with a glycopeptide or newer agents ( linezolid , daptomycin , tigecycline ) with activity against glycopeptide non - susceptible gram - positive pathogens should be considered .
patients with suspicion of catheter - related infection , known colonisation with mrsa , vre , and prsp , hemodynamic instability , severe sepsis , septic shock , presence of skin and soft tissue infection and pneumonia are accepted as candidates for additional antibiotics against resistant gram - positive pathogens.12,2729,51
the emergence of infections with resistant bacterial pathogens is associated with trends towards poor outcomes , prolonged hospital stay , more frequent icu admissions , and increased treatment costs in haematology patients.26,45,136138 moreover , the bacterial resistance complicates the use of standard antimicrobial regimens in febrile hsct recipients .
antimicrobial treatment approach for neutropenic or chronically immunosuppressed hsct recipients with gvhd necessitates careful evaluation of patients ; detailed knowledge on local epidemiological data on antibacterial resistance ; close monitoring of the emergence of resistance in bacterial pathogens ; and use of robust treatment options in the context of a rational antimicrobial stewardship program.9,139,140 convenient infection control measures and appropriate vaccination schedules should be implemented to prevent patients from exposure to pathogens.9,30,50,141143 besides , effective attempts should be provided in the development of new antibacterial agents and immune augmentation strategies to cope with resistant bacterial pathogens.9[/INST]recipients of hematopoietic stem cell transplantation ( hsct ) are at substantial risk of bacterial , fungal , viral , and parasitic infections depending on the time elapsed since transplantation , presence of graft - versus - host disease ( gvhd ) , and the degree of immunosuppression .
infectious complications in hsct recipients are associated with high morbidity and mortality .
bacterial infections constitute the major cause of infectious complications , especially in the early post - transplant period .
the emergence of antibacterial resistance complicates the management of bacterial infections in this patient group .
multidrug - resistant bacterial infections in this group of patients have attracted considerable interest and may lead to significant morbidity and mortality .
empirical antibacterial therapy in patients with hsct and febrile neutropenia has a critical role for survival and should be based on local epidemiology .
this review attempts to provide an overview of risk factors and epidemiology of emerging resistant bacterial infections and their management in hsct recipients .</s> |
SECTION 1. SHORT TITLE.
This Act may be cited as the ``Urban Asthma Assistance Act''.
SEC. 2. FINDINGS.
The Congress finds as follows:
(1) Asthma is a serious chronic condition affecting an
estimated 14,000,000 to 15,000,000 individuals in the United
States, including almost 5,000,000 children.
(2) Asthma accounts for an estimated 3 million lost
workdays for adults and 10.1 million lost school days in
children annually. Asthma is one of the Nation's most common
and costly diseases. Over the past 20 years mortality,
morbidity and hospital discharge rates attributed to asthma
have substantially increased. Between 1979 and 1998, the age-
adjusted mortality rate increased 56 per-cent while the
prevalence rate increased by almost 22 percent in males and 97
percent in females between 1982 and 1996.
(3) Asthma is a chronic illness that is treatable with
ambulatory and specialty care, but over 43 percent of its
economic impact comes from use of emergency rooms,
hospitalization, and death.
(4) Certain pests, such as cockroaches and rodents, are
known to create public health problems and proliferate at
higher rates in urban areas. These pests may spread infectious
disease and contribute to the worsening of chronic respiratory
illnesses, including asthma.
(5) Research supported by the National Institutes of Health
demonstrated that the cockroach, rodent, house dust mite, and
mold allergens, as well as tobacco smoke and feathers, are
important environmental causes of asthma-related illness and
hospitalization among children in inner-city areas of the
United States.
(6) Morbidity and mortality related to childhood asthma are
disproportionately high in urban areas.
(7) In 1996 the prevalence rate in whites was 53.5 per
1,000 persons while the prevalence rate in blacks was 69.6 per
1,000 persons. Both of these rates represent significant
differences from the rates reported in 1982, when they were
34.6 and 39.2 for whites and blacks, respectively.
(8) In 1995, there were more than 1,800,000 emergency room
visits made for asthma-related attacks and among these, the
rate for emergency room visits was 48.8 per 10,000 visits among
whites and 228.9 per 10,000 visits among blacks. These
statistics confirm that our healthcare system encourages
emergency room and trauma care rather than prevention.
(9) Hospitalization rates were highest for individuals 4
years old and younger, and were 10.9 per 10,000 visits for
whites and 35.5 per 10,000 visits for blacks.
(10) Minority children living in urban areas are especially
vulnerable to asthma. In 1988, national prevalence rates were
26 percent higher for black children than for white children.
(11) Asthma is the most common chronic illness in
childhood, afflicting nearly 5,000,000 children under age 18,
and costing an estimated $1,900,000,000 to treat those
children. The death rate for children age 19 and younger
increased by 78 percent between 1980 and 1993.
(12) From 1979 to 1992, the hospitalization rates among
children due to asthma increased 74 percent. It is estimated
that more than 7 percent of children now have asthma.
(13) Although asthma can occur at any age, about 80 percent
of the children who will develop asthma do so before starting
school.
(14) From 1980 to 1994, the most substantial prevalence
rate increase for asthma occurred among children aged 0 to 4
years (160 percent) and persons aged 5 to 14 years (74 percent).
(15) Children aged 0 to 5 years who are exposed to maternal
smoking are 201 times more likely to develop asthma compared
with those free from exposure.
(16) According to data from the 1988 National Health
Interview Survey (NHIS), which surveyed children for their
health experiences over a 12-month period, 25 percent of those
children reported experiencing a great deal of pain or
discomfort due to asthma either often or all the time during
the previous 12 months.
(17) Asthma entails an annual economic cost to our nation
in direct health care costs of $8.1 billion; indirect costs
(lost productivity) add another $4.6 billion for a total of
$12.7 billion. Inpatient hospital services represented the
largest single direct medical expenditure, over $3.5 billion.
The value of reduced productivity due to loss of school days
represented the largest single indirect cost at $1.5 billion.
(18) According to a 1995 National Institute of Health
workshop report, missed school days accounted for an estimated
cost of lost productivity for parents of children with asthma
of almost $1,000,000,000 per year.
(19) Managing asthma requires a long-term, multifaceted
approach, including patient education, specialty care, life
skills training, nutrition counseling elimination or avoidance
of asthma triggers, pharmacologic therapy, and scheduled
medical follow-up.
(20) In recognition of the growing public health crisis in
asthma, in 1999, the Centers for Disease Control and Prevention
developed the National Asthma Control Program within the
National Center for Environmental Health to determine the
incidence, prevalence, and circumstances of asthma cases.
(21) Enhancing the available prevention, educational,
research, and treatment resources with respect to asthma in the
United States will allow our Nation to address more effectively
the problems associated with this increasing threat to the
health and well-being of our citizen.
SEC. 3. CDC'S URBAN ASTHMA PREVENTION PROGRAMS.
(a) In General.--The Secretary of Health and Human Services, acting
through the Director of the Centers for Disease Control and Prevention,
shall provide, through the National Asthma Control Program within the
National Center for Environmental Health, additional intervention
program grants to address the incidence of asthma in urban areas.
(b) Authorization of Appropriations.--For the purpose of carrying
out subsection (a), there are authorized to be appropriated $15,000,000
for fiscal year 2003, and such sums as may be necessary for each of the
fiscal years 2004 through 2007.
SEC. 4. MEDICAID MODEL TREATMENT CENTERS DEMONSTRATION PROGRAM.
Under the authority provided in section 1115 of the Social Security
Act (42 U.S.C. 1315), the Secretary of Health and Human Services shall
permit States under the medicaid program under title XIX of the Social
Security Act to develop model asthma treatment centers demonstration
programs that--
(1) are based on the scientifically validated asthma
treatment models developed by the National Cooperative Inner-
City Asthma Study supported by the National Institute of
Allergy and Infectious Diseases;
(2) include education, screening, and treatment services
for children with asthma;
(3) involve nonprofit organizations that can affect patient
beliefs, behavior, and outcomes;
(4) include specialty care and access to a full range of
available treatments to minimize unwanted side effects; and
(5) improve health outcomes while lowering overall health
care expenditures.
SEC. 5. CDC GUIDELINES REGARDING COORDINATION OF DATA.
For the purpose of facilitating the utility and comparability of
asthma data collected by State and local health departments, the
Secretary of Health and Human Services, acting through the Director of
the Centers for Disease Control and Prevention, shall develop and
disseminate to such departments guidelines on the collection and
reporting of such data.
SEC. 6. INCREASING NUMBER OF CDC HEALTH PROFESSIONALS SERVING IN ASTHMA
PROGRAMS.
For the purpose of increasing the number of full-time equivalent
employees of the Centers for Disease Control and Prevention who are
health professionals and serve in asthma programs of such Centers,
there are authorized to be appropriated $4,000,000 for fiscal year
2003, and such sums as may be necessary for each of the fiscal years
2004 through 2007. | Urban Asthma Assistance Act - Requires the Secretary of Health and Human Services, acting through the Director of the Centers for Disease Control and Prevention (CDC), to provide through the National Asthma Control Program within the National Center for Environmental Health, additional intervention program grants to address the incidence of asthma in urban areas.Requires the Secretary of Health and Human Services to permit States under the medicaid program under title XIX of the Social Security Act to develop model asthma treatment centers demonstration programs.Requires the Secretary, acting through the Director of the CDC, to develop and disseminate guidelines on the collection and reporting of asthma data.Authorizes appropriations for CDC professionals serving in asthma programs. | <s>[INST]SECTION 1. SHORT TITLE.
This Act may be cited as the ``Urban Asthma Assistance Act''.
SEC. 2. FINDINGS.
The Congress finds as follows:
(1) Asthma is a serious chronic condition affecting an
estimated 14,000,000 to 15,000,000 individuals in the United
States, including almost 5,000,000 children.
(2) Asthma accounts for an estimated 3 million lost
workdays for adults and 10.1 million lost school days in
children annually. Asthma is one of the Nation's most common
and costly diseases. Over the past 20 years mortality,
morbidity and hospital discharge rates attributed to asthma
have substantially increased. Between 1979 and 1998, the age-
adjusted mortality rate increased 56 per-cent while the
prevalence rate increased by almost 22 percent in males and 97
percent in females between 1982 and 1996.
(3) Asthma is a chronic illness that is treatable with
ambulatory and specialty care, but over 43 percent of its
economic impact comes from use of emergency rooms,
hospitalization, and death.
(4) Certain pests, such as cockroaches and rodents, are
known to create public health problems and proliferate at
higher rates in urban areas. These pests may spread infectious
disease and contribute to the worsening of chronic respiratory
illnesses, including asthma.
(5) Research supported by the National Institutes of Health
demonstrated that the cockroach, rodent, house dust mite, and
mold allergens, as well as tobacco smoke and feathers, are
important environmental causes of asthma-related illness and
hospitalization among children in inner-city areas of the
United States.
(6) Morbidity and mortality related to childhood asthma are
disproportionately high in urban areas.
(7) In 1996 the prevalence rate in whites was 53.5 per
1,000 persons while the prevalence rate in blacks was 69.6 per
1,000 persons. Both of these rates represent significant
differences from the rates reported in 1982, when they were
34.6 and 39.2 for whites and blacks, respectively.
(8) In 1995, there were more than 1,800,000 emergency room
visits made for asthma-related attacks and among these, the
rate for emergency room visits was 48.8 per 10,000 visits among
whites and 228.9 per 10,000 visits among blacks. These
statistics confirm that our healthcare system encourages
emergency room and trauma care rather than prevention.
(9) Hospitalization rates were highest for individuals 4
years old and younger, and were 10.9 per 10,000 visits for
whites and 35.5 per 10,000 visits for blacks.
(10) Minority children living in urban areas are especially
vulnerable to asthma. In 1988, national prevalence rates were
26 percent higher for black children than for white children.
(11) Asthma is the most common chronic illness in
childhood, afflicting nearly 5,000,000 children under age 18,
and costing an estimated $1,900,000,000 to treat those
children. The death rate for children age 19 and younger
increased by 78 percent between 1980 and 1993.
(12) From 1979 to 1992, the hospitalization rates among
children due to asthma increased 74 percent. It is estimated
that more than 7 percent of children now have asthma.
(13) Although asthma can occur at any age, about 80 percent
of the children who will develop asthma do so before starting
school.
(14) From 1980 to 1994, the most substantial prevalence
rate increase for asthma occurred among children aged 0 to 4
years (160 percent) and persons aged 5 to 14 years (74 percent).
(15) Children aged 0 to 5 years who are exposed to maternal
smoking are 201 times more likely to develop asthma compared
with those free from exposure.
(16) According to data from the 1988 National Health
Interview Survey (NHIS), which surveyed children for their
health experiences over a 12-month period, 25 percent of those
children reported experiencing a great deal of pain or
discomfort due to asthma either often or all the time during
the previous 12 months.
(17) Asthma entails an annual economic cost to our nation
in direct health care costs of $8.1 billion; indirect costs
(lost productivity) add another $4.6 billion for a total of
$12.7 billion. Inpatient hospital services represented the
largest single direct medical expenditure, over $3.5 billion.
The value of reduced productivity due to loss of school days
represented the largest single indirect cost at $1.5 billion.
(18) According to a 1995 National Institute of Health
workshop report, missed school days accounted for an estimated
cost of lost productivity for parents of children with asthma
of almost $1,000,000,000 per year.
(19) Managing asthma requires a long-term, multifaceted
approach, including patient education, specialty care, life
skills training, nutrition counseling elimination or avoidance
of asthma triggers, pharmacologic therapy, and scheduled
medical follow-up.
(20) In recognition of the growing public health crisis in
asthma, in 1999, the Centers for Disease Control and Prevention
developed the National Asthma Control Program within the
National Center for Environmental Health to determine the
incidence, prevalence, and circumstances of asthma cases.
(21) Enhancing the available prevention, educational,
research, and treatment resources with respect to asthma in the
United States will allow our Nation to address more effectively
the problems associated with this increasing threat to the
health and well-being of our citizen.
SEC. 3. CDC'S URBAN ASTHMA PREVENTION PROGRAMS.
(a) In General.--The Secretary of Health and Human Services, acting
through the Director of the Centers for Disease Control and Prevention,
shall provide, through the National Asthma Control Program within the
National Center for Environmental Health, additional intervention
program grants to address the incidence of asthma in urban areas.
(b) Authorization of Appropriations.--For the purpose of carrying
out subsection (a), there are authorized to be appropriated $15,000,000
for fiscal year 2003, and such sums as may be necessary for each of the
fiscal years 2004 through 2007.
SEC. 4. MEDICAID MODEL TREATMENT CENTERS DEMONSTRATION PROGRAM.
Under the authority provided in section 1115 of the Social Security
Act (42 U.S.C. 1315), the Secretary of Health and Human Services shall
permit States under the medicaid program under title XIX of the Social
Security Act to develop model asthma treatment centers demonstration
programs that--
(1) are based on the scientifically validated asthma
treatment models developed by the National Cooperative Inner-
City Asthma Study supported by the National Institute of
Allergy and Infectious Diseases;
(2) include education, screening, and treatment services
for children with asthma;
(3) involve nonprofit organizations that can affect patient
beliefs, behavior, and outcomes;
(4) include specialty care and access to a full range of
available treatments to minimize unwanted side effects; and
(5) improve health outcomes while lowering overall health
care expenditures.
SEC. 5. CDC GUIDELINES REGARDING COORDINATION OF DATA.
For the purpose of facilitating the utility and comparability of
asthma data collected by State and local health departments, the
Secretary of Health and Human Services, acting through the Director of
the Centers for Disease Control and Prevention, shall develop and
disseminate to such departments guidelines on the collection and
reporting of such data.
SEC. 6. INCREASING NUMBER OF CDC HEALTH PROFESSIONALS SERVING IN ASTHMA
PROGRAMS.
For the purpose of increasing the number of full-time equivalent
employees of the Centers for Disease Control and Prevention who are
health professionals and serve in asthma programs of such Centers,
there are authorized to be appropriated $4,000,000 for fiscal year
2003, and such sums as may be necessary for each of the fiscal years
2004 through 2007.[/INST]Urban Asthma Assistance Act - Requires the Secretary of Health and Human Services, acting through the Director of the Centers for Disease Control and Prevention (CDC), to provide through the National Asthma Control Program within the National Center for Environmental Health, additional intervention program grants to address the incidence of asthma in urban areas.Requires the Secretary of Health and Human Services to permit States under the medicaid program under title XIX of the Social Security Act to develop model asthma treatment centers demonstration programs.Requires the Secretary, acting through the Director of the CDC, to develop and disseminate guidelines on the collection and reporting of asthma data.Authorizes appropriations for CDC professionals serving in asthma programs.</s> |
the scientific application of surface electrical stimulation ( ses ) to treat dysphagia and especially voice disorders is new .
lagorio used vitalstim to treat swallowing disorder in a single individual and reported that , in conjunction with improvement in dysphagia symptoms , the voice functions improved . voice is one of the most important instruments for communication .
voice has some acoustic parameters that play an important role in its characterization as normal or abnormal , including fundamental frequency ( f0 ) , intensity , shimmer , jitter , and harmonic - to - noise ratio ( hnr ) .
nonetheless , the unknown details about the procedure and its effectiveness prompted researchers to investigate ses effects on normal subjects voice .
the existing literature , however , suffers from a dearth of published data on this topic .
in addition to ses studies , kempster applied implanted electrical stimulation in normal individuals internal laryngeal muscles , which resulted in increased f0 .
although implanted electrical stimulation evokes laryngeal muscles more specifically , it is invasive and not widely applicable .
previous studies have demonstrated that ses is ineffective in causing changes in acoustic voice parameters and also in closing the vocal folds .
flower found that ses resulted in statistically significant unfavorable effects on voice parameters in experimental participants . according to the published studies on ses in normal individuals ,
this finding may be attributed to the application of ses protocols , which are designed for dysphagia therapy and are not useful for voice and larynx specifically .
consequently , this method can not induce a remarkable effect on voice in normal subjects , although we should not discount ses as an important agent .
a possible method to impose changes on the internal laryngeal muscles and create subsequent acoustic changes may be the use of the potential capability of the internal superior laryngeal nerve ( isln ) to move the internal laryngeal muscles .
contrary to earlier studies that knew only a sensory role for the isln , some neuroanatomical studies in the last 3 decades have found that the isln in addition to its sensory role also contributes to the movements of the internal laryngeal muscles by its distributed motor branches to those muscles .
however , in awake humans , the literature contains only 2 studies that stimulated the isln with needle electrodes inserted around the isln and induced motor reactions , which were monitored via flexible laryngeal endoscopy and also electromyographic recordings .
the results indicated that isln stimulation caused movement and electromyographic responses in the internal laryngeal muscles .
although the findings asserted the motor role of the isln , the stimulus instrument used ( i.e. , needle electrodes ) are invasive and not applicable at clinics for repeated efforts .
accordingly , in this pre - experimental study , we employed ses as a noninvasive , cost - effective , and repeatable stimulus modality , to evoke the isln in awake subjects and then recorded the reaction of their internal laryngeal muscles in terms of the resultant acoustic changes . to our knowledge
, the present study is the first research to apply ses in order to evoke vocal cords through the isln in awake normal humans .
the aim of this study , as part of a larger research project , was to investigate the probability of utilizing the motor potentials of the isln on the vocal cords via ses , which can be used in future studies as an electrotherapy modality to treat patients with recurrent laryngeal damage .
the current study was performed on the students of school of rehabilitation sciences , iran university of medical sciences in 2014 . twenty - two female and 10 male individuals ( n=32 )
all the subjects were selected according to the accessible sampling method , although participation was on a completely voluntary basis .
because of the lack of a previous similar study , the sample size was defined according to the data gathered from our study s 10 pilot subjects . according to the applied formula to calculate the sample size presented below
, the sufficient number was 18 persons : n=[(z1-/2+z1- ) d]d(z1-/2)2 first , all the subjects completed a consent form approved by the ethics committee of iran university of medical sciences .
all the study participants were nonsmokers and reported a negative history of neck and head surgery and neurological , respiratory , serious cardiac , psychiatric , swallowing , hearing loss , voice , and speech disorders .
there were also no systemic diseases such as diabetes . according to the subjects negative self - reported voice complaints and the perceptual judgment of a speech - language pathology expert , who was experienced in voice disorder evaluation and treatment , all of the participants voice was diagnosed normal at the time of test . in addition , during the study ,
any subject who could not tolerate a gradual rise in ses intensity was excluded from the study .
likewise , inability to prolong the / a / vowel at least for 10 seconds without any changes in voice acoustic parameters led to the exclusion of the subject from the study .
ses was presented to the subjects via 2 self - adhesive circular active monopolar silver electrodes , 0.7 cm in diameter ( f-55 ) .
they were placed on the thyrohyoid membrane between the hyoid bone and the thyroid cartilage at the entrance location of the isln into the larynx on both sides .
additionally , one 65 cm rectangular farther dispersive electrode was used on the back of the neck .
the electrical current was generated by a commercially available electrotherapy system ( elpha ii 3000 , danmeter a / s , denmark ) .
the system was set to produce a 3-second current with 5-second rests between each 2 stimuli .
the current parameters were programmed on a 200-microsecond duration of pulses and a frequency of 100 hz .
amplitude was started from 0 ma and increased gradually according to the participant s tolerance . before electrode placement ,
additionally , in some males , the extra hair on the site of electrode placement was shaved .
controlling volume conduction ( diffusing the current to the contiguous tissues , especially the vocal cords and the laryngeal recurrent nerve ) was a challenge .
thus , after the termination of isln stimulation via electrodes , the 2 active electrodes were once again placed on the thyroid lamina ( the nearest place to the vocal cords and the recurrent nerve ) and the previous current was repeated precisely .
the objective was to define the amount of the direct conduction of the current to the vocal cords and the recurrent nerve and to exclude evoked isln effects .
as the intensity of the stimulant reached up to 10% of the subjects ultimate tolerance , they were asked to prolong the / a / vowel for 13 seconds : 5 seconds without stimulation ( rest period ) , 3 seconds with stimulation ( ses period ) , and finally another 5 seconds rest period .
the second rest period was meant to coordinate the time of phonation with the rest periods of the electrical stimulation .
hence , only 2 seconds of phonation from the mid - point of the first rest period and the ses period were compared with each other .
the subjects were free to practice during stimulation and were instructed to prolong a comfortable and consistent natural vowel .
voice recordings were obtained using a condenser microphone ( rode nt6 , australia ) , connected to a preamplifier ( m - audio , avid technology , inc . ) .
the acoustic parameters digitized comprised f0 , standard deviation of f0 ( sd f0 ) , shimmer , jitter , voice break , hnr , and intensity of voice .
the digitized acoustic parameters of rest and ses periods were analyzed using spss ( version 17 ) and were compared in terms of the induced changes across the 2 conditions of phonation .
the paired t - test was utilized to wcompare the means owf the acoustic parameters , namely mean f0 , minimum f0 , maximum f0 , sd f0 , jitter , shimmer , hnr , mean intensity , maximum intensity , and minimum intensity at rest and ses periods .
ses was presented to the subjects via 2 self - adhesive circular active monopolar silver electrodes , 0.7 cm in diameter ( f-55 ) .
they were placed on the thyrohyoid membrane between the hyoid bone and the thyroid cartilage at the entrance location of the isln into the larynx on both sides .
additionally , one 65 cm rectangular farther dispersive electrode was used on the back of the neck .
the electrical current was generated by a commercially available electrotherapy system ( elpha ii 3000 , danmeter a / s , denmark ) .
the system was set to produce a 3-second current with 5-second rests between each 2 stimuli .
the current parameters were programmed on a 200-microsecond duration of pulses and a frequency of 100 hz .
amplitude was started from 0 ma and increased gradually according to the participant s tolerance . before electrode placement ,
additionally , in some males , the extra hair on the site of electrode placement was shaved .
controlling volume conduction ( diffusing the current to the contiguous tissues , especially the vocal cords and the laryngeal recurrent nerve ) was a challenge .
thus , after the termination of isln stimulation via electrodes , the 2 active electrodes were once again placed on the thyroid lamina ( the nearest place to the vocal cords and the recurrent nerve ) and the previous current was repeated precisely .
the objective was to define the amount of the direct conduction of the current to the vocal cords and the recurrent nerve and to exclude evoked isln effects .
as the intensity of the stimulant reached up to 10% of the subjects ultimate tolerance , they were asked to prolong the / a / vowel for 13 seconds : 5 seconds without stimulation ( rest period ) , 3 seconds with stimulation ( ses period ) , and finally another 5 seconds rest period .
the second rest period was meant to coordinate the time of phonation with the rest periods of the electrical stimulation .
hence , only 2 seconds of phonation from the mid - point of the first rest period and the ses period were compared with each other .
the subjects were free to practice during stimulation and were instructed to prolong a comfortable and consistent natural vowel .
voice recordings were obtained using a condenser microphone ( rode nt6 , australia ) , connected to a preamplifier ( m - audio , avid technology , inc . ) .
the acoustic parameters digitized comprised f0 , standard deviation of f0 ( sd f0 ) , shimmer , jitter , voice break , hnr , and intensity of voice .
the digitized acoustic parameters of rest and ses periods were analyzed using spss ( version 17 ) and were compared in terms of the induced changes across the 2 conditions of phonation .
the paired t - test was utilized to wcompare the means owf the acoustic parameters , namely mean f0 , minimum f0 , maximum f0 , sd f0 , jitter , shimmer , hnr , mean intensity , maximum intensity , and minimum intensity at rest and ses periods .
figure 1 demonstrates mean f0 , maximum ( max ) f0 , and minimum ( min ) f0 for the rest and ses periods related to isln electrode placement .
the paired sample t - test showed no statistically significant effects of ses on mean ( m ) f0 .
as the figure indicates , mean f0 for rest was 198.35 ( sd=49.93 ) while it was 193.97 ( sd=50.15 ) for the ses period , which did not constitute significant statistical difference ( t=1.03 ; p=0.31 ) .
also , the means of max f0 during rest ( m=202.28 , sd=50.78 ) and ses ( m=203.93 , sd=52.64 ) were not significantly different ( t=0.35 ; p=0.72 ) .
however , the mean of min f0 for the rest time was 194.54 ( sd=49.19 ) versus 182.62 ( sd=53.39 ) for ses , duration which the difference between the 2 means was significant ( t=2.61 ; p=0.01 ) .
the figure presents mean fundamental frequency ( f0 ) , maximum f0 , and minimum f0 for the rest and surface electrical stimulation ( ses ) periods related to electrode placement on the internal superior laryngeal nerve .
the sd f0 means of the rest and ses durations related to electrode placement on the isln are shown in figure 2 .
the rest sd f0 mean was 1.54 ( sd=0.55 ) versus 4.15 ( sd=3.00 ) for ses .
the paired t - test indicated significant differences between the sd f0 means ( t=-4.95 ; p<0.001 ) .
the figure presents the means of the standard deviation of fundamental frequency ( sd f0 in hz ) at rest and surface electrical stimulation ( ses ) durations related to electrode placement on the internal superior laryngeal nerve .
table 1 demonstrates jitter , shimmer , hnr , mean intensity , maximum intensity , and minimum intensity results related to electrode placement on the isln .
as the table presents , the means of rest compared to those of the ses period for both jitter and shimmer increased : the changes in the means were 0.09 and 0.9 , respectively , which were statistically significant ( jitter : p<0.001 and shimmer : p<0.001 ) .
hnr mean during rest versus ses decreased by 2.21 db , with the change being significant according to the paired t - test ( p<0.001 ) .
. means , t - statistics ( t ) , and p values of jitter , shimmer , harmonic - to - noise ratio ( hnr ) , mean intensity , maximum intensity , and minimum intensity at rest and surface electrical stimulation ( ses ) periods related to electrode placement on the internal superior laryngeal nerve the means of the 3 token values of intensity decreased from rest to the ses phase .
the paired t - test indicated that the changes in both mean intensity and minimum intensity were statistically significant ( p<0.001 ) , whereas the changes in maximum intensity were not statistically significant ( t=0.92 ; p=0.36 ) .
table 2 demonstrates the acoustic changes created by ses when active electrodes were placed on both sides of the thyroid lamina .
as the table shows , the means of all the investigated acoustic parameters did not differ significantly between the rest and ses periods .
means , t - statistics ( t ) , and p values of mean fundamental frequency ( f0 ) , minimum f0 , maximum f0 , f0 standard deviation ( sd f0 ) , jitter , shimmer , harmonic - to - noise ratio ( hnr ) , mean intensity , maximum intensity , and minimum intensity at rest and during the surface electrical stimulation ( ses ) period related to electrode placement on the thyroid cartilage
the present study examined the possibility of imposing changes on the vocal cords via ses on isln topical location on skin .
the results showed that an evoked isln did not give rise to a significant change in mean f0 .
given that the contraction of the cricothyroid muscle heightens mean f0 , it can be concluded that there were no descending branches or anastomoses from the isln to the cricothyroid muscle , which is in agreement with the results of previous anatomical studies . also , as the stimulation did not evoke the external sln , which innervates the cricothyroid muscle , the stimulated location on skin was correct .
it is not possible to exclude the external sln from stimulation as ludlow et al .
nevertheless , in our study , as ses did not lead to an increase in mean f0 , ses effects on the external sln were too little to be taken into account .
the same result was observed for maximum f0 , which again confirms the above conclusions .
this result is in accordance with the previous studies that indicated insignificant effects of ses on mean f0 .
however , those studies reported increased f0 after ses , which may be due to their larger electrodes and consequent decreased current density distributed to the external laryngeal muscles .
this may have been due to the effects of ses on the thyroarytenoid muscle via the stimulation of the isln , lowering the frequency of voice .
reflects frequency variability for a large time segment , it can be concluded that ses plays an important role in imposing variability on muscles and thus contributes to muscular tension stability .
our findings do not chime in with the results of the previous studies performed on the effects of ses on voice parameters inasmuch as in none of those investigations sd f0 and minimum f0 changed significantly after ses .
perturbation , including jitter and shimmer , is another acoustic factor which increased during the ses phase .
the irregularity of the vibratory behavior of the vocal cords is referred to as perturbation . as a result
this finding is not in accordance with the previous studies insofar as they did not show significant differences in their subjects perturbation of voice .
therefore , it is impossible to create perturbation changes via ses directly throughout the thyroid cartilage and into the vocal cords . presumably , it is because of the lack of stimulus penetration due to incorrect electrode placement and electrical stimulation parameters .
nonetheless , our findings demonstrated that it was possible through the stimulation of the vocal cords directly via the isln .
greater aperiodicity of vibration may show up as greater noise in the spectrum and lesser hnr . in the present study ,
reported similar results regarding the change direction of jitter , shimmer , and hnr after ses , but the changes were not statistically significant .
it may be attributed to the differences in methodology between the study by gorham - rowan et al . and the present study . in spite of these reported aperiodicity and instability in the participants voice during the ses period , ses was able to cause only voice break in 2 subjects .
stimulated the isln by inserting needle electrodes around the isln for normal awake participants and reported voice break during phonation in 1 of their 3 subjects .
the authors attributed it to increased vocal fold adduction , which disrupted vibration . similarly in our research , voice breaks occurred in 2 subjects but the other 30 participants did not show any voice break during phonation at ses time .
this suggests that ses , unlike needle electrode stimulation , is not strong enough to interrupt the phonation process completely .
in addition to frequency and perturbation , the results showed that while mean and minimum intensity decreased with ses , maximum intensity decreased but it was not statistically significant .
as the average intensity is a criterion to present the strength of the vibratory behavior of the vocal cords , the effects of ses in terms of reducing vocal intensity may be due to glottal closure interruption consequent to ses presentation .
this result was in contrast to the results of a study by flower and et al .
, who did not report significant changes in voice intensity after ses in healthy individuals .
there are some reasons for reporting nonsignificant changes in acoustic parameters after using ses in the previous studies .
the most important reason relates to the electrical stimulation parameters applied in those studies compared to our own .
the previous investigations applied an electrical current with a low frequency ( 80 hz ) and long duration pulses ( 700 microseconds ) compared to our study with a high pulse frequency ( 100 hz ) and short duration pulses ( 200 microseconds ) .
it is possible to increase the intensity of pulses with short durations and high frequencies well above the motor threshold without stimulating pain endings .
stimulation of the deeply placed nerves ( such as the isln ) will , therefore , be feasible .
accordingly , the current method applied in the present research had more power to penetrate deeply and reach the isln .
the other reasons include different methods in electrode placement , different stimulated organs ( internal laryngeal muscles versus isln in our study ) , different sizes of electrodes , and dissimilar time of recording voice ( after or during ses presentation , as was the case in the present study ) . as the results of electrode placement on the thyroid lamina indicated
this finding confirms the notion that by dispossessing and excluding the isln from the ses - affected area and also by delivering the current at the nearest place to the vocal cords and the recurrent nerve , ses can not stimulate the vocal cords or the recurrent nerve .
it also shows that all the findings on delivering ses with electrodes placed on the thyrohyoid hint at the stimulation of the isln and not the direct conduction of the current to the vocal cords or the recurrent nerve .
the results of electrode placement on the thyroid lamina are in agreement with those reported by the previous studies whose method of electrode placement was aimed at stimulating the vocal cords directly .
this confirms the importance of correct electrode placement when seeking to impact voice through ses .
although the findings on perturbation and intensity suggested exacerbation of voice during ses presentation , they indicated the effectiveness of ses in impacting the internal laryngeal muscles from the isln as a gate for motor responses in the vocal cords .
the results of electrode placement on the thyroid lamina indicated the impossibility of stimulating the recurrent laryngeal nerve by ses .
therefore , the clinical application of this finding would see ses utilized to evoke the motor potential of the isln in order to treat patients suffering from recurrent laryngeal nerve damage .
the current study has some limitations , first and foremost among which were problems in fixing electrodes on a defined location , not least when the subjects sweated and the test had to be repeated after cleaning the skin .
in addition , some subjects feared the first sensation of tingling caused by ses and were , thus , excluded from the study .
the results of the present study demonstrated the significant impact of ses on voice changes in healthy participants . to the best of our knowledge ,
ours is the first study of its kind to report significant voice changes in consequence of ses application .
the reason for the dissimilarities between our results and those of the previous studies may be attributed to the methodology of stimulation and the time of recording voice .
our results indicated that the application of this method via the isln at least in healthy people could induce motor pulses in the vocal cords and cause voice changes .
the importance of this finding is that it hints at the possibility of ses application in patients who need to have the motor neurons of their vocal folds stimulated when there is no accessibility owing to damage to the recurrent nerve ( e.g. , patients with vocal paralysis ) . | background : repeated efforts by researchers to impose voice changes by laryngeal surface electrical stimulation ( ses ) have come to no avail .
this present pre - experimental study employed a novel method for ses application so as to evoke the motor potential of the internal superior laryngeal nerve ( isln ) and create voice changes.methods:thirty-two normal individuals ( 22 females and 10 males ) participated in this study .
the subjects were selected from the students of iran university of medical sciences in 2014 .
two monopolar active electrodes were placed on the thyrohyoid space at the location of the isln entrance to the larynx and 1 dispersive electrode was positioned on the back of the neck .
a current with special programmed parameters was applied to stimulate the isln via the active electrodes and simultaneously the resultant acoustic changes were evaluated .
all the means of the acoustic parameters during ses and rest periods were compared using the paired t-test.results:the findings indicated significant changes ( p=0.00 ) in most of the acoustic parameters during ses presentation compared to them at rest .
the mean of fundamental frequency standard deviation ( sd f0 ) at rest was 1.54 ( sd=0.55 ) versus 4.15 ( sd=3.00 ) for the ses period .
the other investigated parameters comprised fundamental frequency ( f0 ) , minimum f0 , jitter , shimmer , harmonic - to - noise ratio ( hnr ) , mean intensity , and minimum intensity.conclusion:these findings demonstrated significant changes in most of the important acoustic features , suggesting that the stimulation of the isln via ses could induce motor changes in the vocal folds .
the clinical applicability of the method utilized in the current study in patients with vocal fold paralysis requires further research . | <s>[INST]the scientific application of surface electrical stimulation ( ses ) to treat dysphagia and especially voice disorders is new .
lagorio used vitalstim to treat swallowing disorder in a single individual and reported that , in conjunction with improvement in dysphagia symptoms , the voice functions improved . voice is one of the most important instruments for communication .
voice has some acoustic parameters that play an important role in its characterization as normal or abnormal , including fundamental frequency ( f0 ) , intensity , shimmer , jitter , and harmonic - to - noise ratio ( hnr ) .
nonetheless , the unknown details about the procedure and its effectiveness prompted researchers to investigate ses effects on normal subjects voice .
the existing literature , however , suffers from a dearth of published data on this topic .
in addition to ses studies , kempster applied implanted electrical stimulation in normal individuals internal laryngeal muscles , which resulted in increased f0 .
although implanted electrical stimulation evokes laryngeal muscles more specifically , it is invasive and not widely applicable .
previous studies have demonstrated that ses is ineffective in causing changes in acoustic voice parameters and also in closing the vocal folds .
flower found that ses resulted in statistically significant unfavorable effects on voice parameters in experimental participants . according to the published studies on ses in normal individuals ,
this finding may be attributed to the application of ses protocols , which are designed for dysphagia therapy and are not useful for voice and larynx specifically .
consequently , this method can not induce a remarkable effect on voice in normal subjects , although we should not discount ses as an important agent .
a possible method to impose changes on the internal laryngeal muscles and create subsequent acoustic changes may be the use of the potential capability of the internal superior laryngeal nerve ( isln ) to move the internal laryngeal muscles .
contrary to earlier studies that knew only a sensory role for the isln , some neuroanatomical studies in the last 3 decades have found that the isln in addition to its sensory role also contributes to the movements of the internal laryngeal muscles by its distributed motor branches to those muscles .
however , in awake humans , the literature contains only 2 studies that stimulated the isln with needle electrodes inserted around the isln and induced motor reactions , which were monitored via flexible laryngeal endoscopy and also electromyographic recordings .
the results indicated that isln stimulation caused movement and electromyographic responses in the internal laryngeal muscles .
although the findings asserted the motor role of the isln , the stimulus instrument used ( i.e. , needle electrodes ) are invasive and not applicable at clinics for repeated efforts .
accordingly , in this pre - experimental study , we employed ses as a noninvasive , cost - effective , and repeatable stimulus modality , to evoke the isln in awake subjects and then recorded the reaction of their internal laryngeal muscles in terms of the resultant acoustic changes . to our knowledge
, the present study is the first research to apply ses in order to evoke vocal cords through the isln in awake normal humans .
the aim of this study , as part of a larger research project , was to investigate the probability of utilizing the motor potentials of the isln on the vocal cords via ses , which can be used in future studies as an electrotherapy modality to treat patients with recurrent laryngeal damage .
the current study was performed on the students of school of rehabilitation sciences , iran university of medical sciences in 2014 . twenty - two female and 10 male individuals ( n=32 )
all the subjects were selected according to the accessible sampling method , although participation was on a completely voluntary basis .
because of the lack of a previous similar study , the sample size was defined according to the data gathered from our study s 10 pilot subjects . according to the applied formula to calculate the sample size presented below
, the sufficient number was 18 persons : n=[(z1-/2+z1- ) d]d(z1-/2)2 first , all the subjects completed a consent form approved by the ethics committee of iran university of medical sciences .
all the study participants were nonsmokers and reported a negative history of neck and head surgery and neurological , respiratory , serious cardiac , psychiatric , swallowing , hearing loss , voice , and speech disorders .
there were also no systemic diseases such as diabetes . according to the subjects negative self - reported voice complaints and the perceptual judgment of a speech - language pathology expert , who was experienced in voice disorder evaluation and treatment , all of the participants voice was diagnosed normal at the time of test . in addition , during the study ,
any subject who could not tolerate a gradual rise in ses intensity was excluded from the study .
likewise , inability to prolong the / a / vowel at least for 10 seconds without any changes in voice acoustic parameters led to the exclusion of the subject from the study .
ses was presented to the subjects via 2 self - adhesive circular active monopolar silver electrodes , 0.7 cm in diameter ( f-55 ) .
they were placed on the thyrohyoid membrane between the hyoid bone and the thyroid cartilage at the entrance location of the isln into the larynx on both sides .
additionally , one 65 cm rectangular farther dispersive electrode was used on the back of the neck .
the electrical current was generated by a commercially available electrotherapy system ( elpha ii 3000 , danmeter a / s , denmark ) .
the system was set to produce a 3-second current with 5-second rests between each 2 stimuli .
the current parameters were programmed on a 200-microsecond duration of pulses and a frequency of 100 hz .
amplitude was started from 0 ma and increased gradually according to the participant s tolerance . before electrode placement ,
additionally , in some males , the extra hair on the site of electrode placement was shaved .
controlling volume conduction ( diffusing the current to the contiguous tissues , especially the vocal cords and the laryngeal recurrent nerve ) was a challenge .
thus , after the termination of isln stimulation via electrodes , the 2 active electrodes were once again placed on the thyroid lamina ( the nearest place to the vocal cords and the recurrent nerve ) and the previous current was repeated precisely .
the objective was to define the amount of the direct conduction of the current to the vocal cords and the recurrent nerve and to exclude evoked isln effects .
as the intensity of the stimulant reached up to 10% of the subjects ultimate tolerance , they were asked to prolong the / a / vowel for 13 seconds : 5 seconds without stimulation ( rest period ) , 3 seconds with stimulation ( ses period ) , and finally another 5 seconds rest period .
the second rest period was meant to coordinate the time of phonation with the rest periods of the electrical stimulation .
hence , only 2 seconds of phonation from the mid - point of the first rest period and the ses period were compared with each other .
the subjects were free to practice during stimulation and were instructed to prolong a comfortable and consistent natural vowel .
voice recordings were obtained using a condenser microphone ( rode nt6 , australia ) , connected to a preamplifier ( m - audio , avid technology , inc . ) .
the acoustic parameters digitized comprised f0 , standard deviation of f0 ( sd f0 ) , shimmer , jitter , voice break , hnr , and intensity of voice .
the digitized acoustic parameters of rest and ses periods were analyzed using spss ( version 17 ) and were compared in terms of the induced changes across the 2 conditions of phonation .
the paired t - test was utilized to wcompare the means owf the acoustic parameters , namely mean f0 , minimum f0 , maximum f0 , sd f0 , jitter , shimmer , hnr , mean intensity , maximum intensity , and minimum intensity at rest and ses periods .
ses was presented to the subjects via 2 self - adhesive circular active monopolar silver electrodes , 0.7 cm in diameter ( f-55 ) .
they were placed on the thyrohyoid membrane between the hyoid bone and the thyroid cartilage at the entrance location of the isln into the larynx on both sides .
additionally , one 65 cm rectangular farther dispersive electrode was used on the back of the neck .
the electrical current was generated by a commercially available electrotherapy system ( elpha ii 3000 , danmeter a / s , denmark ) .
the system was set to produce a 3-second current with 5-second rests between each 2 stimuli .
the current parameters were programmed on a 200-microsecond duration of pulses and a frequency of 100 hz .
amplitude was started from 0 ma and increased gradually according to the participant s tolerance . before electrode placement ,
additionally , in some males , the extra hair on the site of electrode placement was shaved .
controlling volume conduction ( diffusing the current to the contiguous tissues , especially the vocal cords and the laryngeal recurrent nerve ) was a challenge .
thus , after the termination of isln stimulation via electrodes , the 2 active electrodes were once again placed on the thyroid lamina ( the nearest place to the vocal cords and the recurrent nerve ) and the previous current was repeated precisely .
the objective was to define the amount of the direct conduction of the current to the vocal cords and the recurrent nerve and to exclude evoked isln effects .
as the intensity of the stimulant reached up to 10% of the subjects ultimate tolerance , they were asked to prolong the / a / vowel for 13 seconds : 5 seconds without stimulation ( rest period ) , 3 seconds with stimulation ( ses period ) , and finally another 5 seconds rest period .
the second rest period was meant to coordinate the time of phonation with the rest periods of the electrical stimulation .
hence , only 2 seconds of phonation from the mid - point of the first rest period and the ses period were compared with each other .
the subjects were free to practice during stimulation and were instructed to prolong a comfortable and consistent natural vowel .
voice recordings were obtained using a condenser microphone ( rode nt6 , australia ) , connected to a preamplifier ( m - audio , avid technology , inc . ) .
the acoustic parameters digitized comprised f0 , standard deviation of f0 ( sd f0 ) , shimmer , jitter , voice break , hnr , and intensity of voice .
the digitized acoustic parameters of rest and ses periods were analyzed using spss ( version 17 ) and were compared in terms of the induced changes across the 2 conditions of phonation .
the paired t - test was utilized to wcompare the means owf the acoustic parameters , namely mean f0 , minimum f0 , maximum f0 , sd f0 , jitter , shimmer , hnr , mean intensity , maximum intensity , and minimum intensity at rest and ses periods .
figure 1 demonstrates mean f0 , maximum ( max ) f0 , and minimum ( min ) f0 for the rest and ses periods related to isln electrode placement .
the paired sample t - test showed no statistically significant effects of ses on mean ( m ) f0 .
as the figure indicates , mean f0 for rest was 198.35 ( sd=49.93 ) while it was 193.97 ( sd=50.15 ) for the ses period , which did not constitute significant statistical difference ( t=1.03 ; p=0.31 ) .
also , the means of max f0 during rest ( m=202.28 , sd=50.78 ) and ses ( m=203.93 , sd=52.64 ) were not significantly different ( t=0.35 ; p=0.72 ) .
however , the mean of min f0 for the rest time was 194.54 ( sd=49.19 ) versus 182.62 ( sd=53.39 ) for ses , duration which the difference between the 2 means was significant ( t=2.61 ; p=0.01 ) .
the figure presents mean fundamental frequency ( f0 ) , maximum f0 , and minimum f0 for the rest and surface electrical stimulation ( ses ) periods related to electrode placement on the internal superior laryngeal nerve .
the sd f0 means of the rest and ses durations related to electrode placement on the isln are shown in figure 2 .
the rest sd f0 mean was 1.54 ( sd=0.55 ) versus 4.15 ( sd=3.00 ) for ses .
the paired t - test indicated significant differences between the sd f0 means ( t=-4.95 ; p<0.001 ) .
the figure presents the means of the standard deviation of fundamental frequency ( sd f0 in hz ) at rest and surface electrical stimulation ( ses ) durations related to electrode placement on the internal superior laryngeal nerve .
table 1 demonstrates jitter , shimmer , hnr , mean intensity , maximum intensity , and minimum intensity results related to electrode placement on the isln .
as the table presents , the means of rest compared to those of the ses period for both jitter and shimmer increased : the changes in the means were 0.09 and 0.9 , respectively , which were statistically significant ( jitter : p<0.001 and shimmer : p<0.001 ) .
hnr mean during rest versus ses decreased by 2.21 db , with the change being significant according to the paired t - test ( p<0.001 ) .
. means , t - statistics ( t ) , and p values of jitter , shimmer , harmonic - to - noise ratio ( hnr ) , mean intensity , maximum intensity , and minimum intensity at rest and surface electrical stimulation ( ses ) periods related to electrode placement on the internal superior laryngeal nerve the means of the 3 token values of intensity decreased from rest to the ses phase .
the paired t - test indicated that the changes in both mean intensity and minimum intensity were statistically significant ( p<0.001 ) , whereas the changes in maximum intensity were not statistically significant ( t=0.92 ; p=0.36 ) .
table 2 demonstrates the acoustic changes created by ses when active electrodes were placed on both sides of the thyroid lamina .
as the table shows , the means of all the investigated acoustic parameters did not differ significantly between the rest and ses periods .
means , t - statistics ( t ) , and p values of mean fundamental frequency ( f0 ) , minimum f0 , maximum f0 , f0 standard deviation ( sd f0 ) , jitter , shimmer , harmonic - to - noise ratio ( hnr ) , mean intensity , maximum intensity , and minimum intensity at rest and during the surface electrical stimulation ( ses ) period related to electrode placement on the thyroid cartilage
the present study examined the possibility of imposing changes on the vocal cords via ses on isln topical location on skin .
the results showed that an evoked isln did not give rise to a significant change in mean f0 .
given that the contraction of the cricothyroid muscle heightens mean f0 , it can be concluded that there were no descending branches or anastomoses from the isln to the cricothyroid muscle , which is in agreement with the results of previous anatomical studies . also , as the stimulation did not evoke the external sln , which innervates the cricothyroid muscle , the stimulated location on skin was correct .
it is not possible to exclude the external sln from stimulation as ludlow et al .
nevertheless , in our study , as ses did not lead to an increase in mean f0 , ses effects on the external sln were too little to be taken into account .
the same result was observed for maximum f0 , which again confirms the above conclusions .
this result is in accordance with the previous studies that indicated insignificant effects of ses on mean f0 .
however , those studies reported increased f0 after ses , which may be due to their larger electrodes and consequent decreased current density distributed to the external laryngeal muscles .
this may have been due to the effects of ses on the thyroarytenoid muscle via the stimulation of the isln , lowering the frequency of voice .
reflects frequency variability for a large time segment , it can be concluded that ses plays an important role in imposing variability on muscles and thus contributes to muscular tension stability .
our findings do not chime in with the results of the previous studies performed on the effects of ses on voice parameters inasmuch as in none of those investigations sd f0 and minimum f0 changed significantly after ses .
perturbation , including jitter and shimmer , is another acoustic factor which increased during the ses phase .
the irregularity of the vibratory behavior of the vocal cords is referred to as perturbation . as a result
this finding is not in accordance with the previous studies insofar as they did not show significant differences in their subjects perturbation of voice .
therefore , it is impossible to create perturbation changes via ses directly throughout the thyroid cartilage and into the vocal cords . presumably , it is because of the lack of stimulus penetration due to incorrect electrode placement and electrical stimulation parameters .
nonetheless , our findings demonstrated that it was possible through the stimulation of the vocal cords directly via the isln .
greater aperiodicity of vibration may show up as greater noise in the spectrum and lesser hnr . in the present study ,
reported similar results regarding the change direction of jitter , shimmer , and hnr after ses , but the changes were not statistically significant .
it may be attributed to the differences in methodology between the study by gorham - rowan et al . and the present study . in spite of these reported aperiodicity and instability in the participants voice during the ses period , ses was able to cause only voice break in 2 subjects .
stimulated the isln by inserting needle electrodes around the isln for normal awake participants and reported voice break during phonation in 1 of their 3 subjects .
the authors attributed it to increased vocal fold adduction , which disrupted vibration . similarly in our research , voice breaks occurred in 2 subjects but the other 30 participants did not show any voice break during phonation at ses time .
this suggests that ses , unlike needle electrode stimulation , is not strong enough to interrupt the phonation process completely .
in addition to frequency and perturbation , the results showed that while mean and minimum intensity decreased with ses , maximum intensity decreased but it was not statistically significant .
as the average intensity is a criterion to present the strength of the vibratory behavior of the vocal cords , the effects of ses in terms of reducing vocal intensity may be due to glottal closure interruption consequent to ses presentation .
this result was in contrast to the results of a study by flower and et al .
, who did not report significant changes in voice intensity after ses in healthy individuals .
there are some reasons for reporting nonsignificant changes in acoustic parameters after using ses in the previous studies .
the most important reason relates to the electrical stimulation parameters applied in those studies compared to our own .
the previous investigations applied an electrical current with a low frequency ( 80 hz ) and long duration pulses ( 700 microseconds ) compared to our study with a high pulse frequency ( 100 hz ) and short duration pulses ( 200 microseconds ) .
it is possible to increase the intensity of pulses with short durations and high frequencies well above the motor threshold without stimulating pain endings .
stimulation of the deeply placed nerves ( such as the isln ) will , therefore , be feasible .
accordingly , the current method applied in the present research had more power to penetrate deeply and reach the isln .
the other reasons include different methods in electrode placement , different stimulated organs ( internal laryngeal muscles versus isln in our study ) , different sizes of electrodes , and dissimilar time of recording voice ( after or during ses presentation , as was the case in the present study ) . as the results of electrode placement on the thyroid lamina indicated
this finding confirms the notion that by dispossessing and excluding the isln from the ses - affected area and also by delivering the current at the nearest place to the vocal cords and the recurrent nerve , ses can not stimulate the vocal cords or the recurrent nerve .
it also shows that all the findings on delivering ses with electrodes placed on the thyrohyoid hint at the stimulation of the isln and not the direct conduction of the current to the vocal cords or the recurrent nerve .
the results of electrode placement on the thyroid lamina are in agreement with those reported by the previous studies whose method of electrode placement was aimed at stimulating the vocal cords directly .
this confirms the importance of correct electrode placement when seeking to impact voice through ses .
although the findings on perturbation and intensity suggested exacerbation of voice during ses presentation , they indicated the effectiveness of ses in impacting the internal laryngeal muscles from the isln as a gate for motor responses in the vocal cords .
the results of electrode placement on the thyroid lamina indicated the impossibility of stimulating the recurrent laryngeal nerve by ses .
therefore , the clinical application of this finding would see ses utilized to evoke the motor potential of the isln in order to treat patients suffering from recurrent laryngeal nerve damage .
the current study has some limitations , first and foremost among which were problems in fixing electrodes on a defined location , not least when the subjects sweated and the test had to be repeated after cleaning the skin .
in addition , some subjects feared the first sensation of tingling caused by ses and were , thus , excluded from the study .
the results of the present study demonstrated the significant impact of ses on voice changes in healthy participants . to the best of our knowledge ,
ours is the first study of its kind to report significant voice changes in consequence of ses application .
the reason for the dissimilarities between our results and those of the previous studies may be attributed to the methodology of stimulation and the time of recording voice .
our results indicated that the application of this method via the isln at least in healthy people could induce motor pulses in the vocal cords and cause voice changes .
the importance of this finding is that it hints at the possibility of ses application in patients who need to have the motor neurons of their vocal folds stimulated when there is no accessibility owing to damage to the recurrent nerve ( e.g. , patients with vocal paralysis ) .[/INST]background : repeated efforts by researchers to impose voice changes by laryngeal surface electrical stimulation ( ses ) have come to no avail .
this present pre - experimental study employed a novel method for ses application so as to evoke the motor potential of the internal superior laryngeal nerve ( isln ) and create voice changes.methods:thirty-two normal individuals ( 22 females and 10 males ) participated in this study .
the subjects were selected from the students of iran university of medical sciences in 2014 .
two monopolar active electrodes were placed on the thyrohyoid space at the location of the isln entrance to the larynx and 1 dispersive electrode was positioned on the back of the neck .
a current with special programmed parameters was applied to stimulate the isln via the active electrodes and simultaneously the resultant acoustic changes were evaluated .
all the means of the acoustic parameters during ses and rest periods were compared using the paired t-test.results:the findings indicated significant changes ( p=0.00 ) in most of the acoustic parameters during ses presentation compared to them at rest .
the mean of fundamental frequency standard deviation ( sd f0 ) at rest was 1.54 ( sd=0.55 ) versus 4.15 ( sd=3.00 ) for the ses period .
the other investigated parameters comprised fundamental frequency ( f0 ) , minimum f0 , jitter , shimmer , harmonic - to - noise ratio ( hnr ) , mean intensity , and minimum intensity.conclusion:these findings demonstrated significant changes in most of the important acoustic features , suggesting that the stimulation of the isln via ses could induce motor changes in the vocal folds .
the clinical applicability of the method utilized in the current study in patients with vocal fold paralysis requires further research .</s> |
sudden cardiac death ( scd ) related to ventricular tachyarrhythmia in young athletes is a dramatic event that has emotional and social impact on the media and the medical community .
ventricular ectopic beats ( veb ) , even with frequent and/or complex forms , have frequently been described on 24-hour ecg in 2565% of athletes . for athletes with ventricular arrhythmias who have no evidence of underlying heart disease or who have an unsuspected cardiovascular disease , identifying subjects at risk of serious ventricular tachyarrhythmias is often problematic .
corrado et al ( 1 ) reported that , while sporting activity is not the cause of sudden cardiac death , it can trigger cardiac arrest in subjects whose cardiovascular conditions engender a risk of life - threatening arrhythmias during athletic activity .
frequent ventricular premature beats with complex morphology and couplets and non - sustained ventricular tachycardia ( nsvt ) may be detected in a competitive athlete during ambulatory clinical screening , without evidence of underlying cardiovascular disease . despite the increased availability of
non - invasive and invasive clinical diagnostic methods , such cases pose a diagnostic dilemma for physicians called upon to assess the subject s eligibility to practice sport .
it is necessary to make a precise differential diagnosis between an expression of athlete s heart , which may mimic cardiovascular disease , and
silent cardiovascular abnormalities that may progress to sustained tachyarrhythmias and/or sudden death with long - term intensive training .
systematic diagnostic methods , including ecg , holter monitoring , stress testing and echocardiography , are sometimes unable to reveal an underlying structural heart disease , and further evaluations are required in order to determine whether the arrhythmia is benign or potentially life - threatening .
many non - invasive markers of scd , such as depressed left ventricular ejection fraction , late potentials , qt dispersion , heart rate variability and baroreflex sensitivity , play a role in risk stratification , but are limited by their low specificity .
it is crucial to precisely identify athletes at increased risk for serious ventricular tachyarrhythmias in order to exclude them from competitive sport and implement an effective strategy to prevent sudden cardiac death .
specific forms of electrocardiographic alternans related to cardiac repolarization abnormalities have recently emerged as a cause of serious ventricular arrhythmias . in the 1980s ,
adam and smith ( 2 , 3 ) developed the spectral analysis method for detecting microvolt t - wave alternans in experimental animals and , subsequently , in humans ( 4 , 5 ) .
these studies showed that microvolt t - wave alternans is a reliable non - invasive risk marker of cardiac electrical vulnerability and a predictor of ventricular arrhythmias ( 413 ) .
electrical alternans is defined as beat - to - beat variation in the vector , amplitude and/or morphology of electrocardiographic signals , due to localized alternation in action potential duration .
the presence of amplitude alternans of the t - wave at a periodicity of 0.5 cycles / beat defines t - wave alternans .
t - wave alternans ( twa ) is a promising new non - invasive clinical tool for identifying patients at risk for sudden cardiac death in a diverse patient population . the usefulness of twa in predicting the risk of ventricular tachyarrhythmias has been widely reported in several clinical conditions , including coronary artery disease , non - ischemic cardiomyopathy , congestive heart failure and in patients with implantable cardiac defibrillators ( 14 ) .
recently , several authors have documented the high negative predictive value of twa in patients with heart disease and low ejection fraction ( 15 , 16 ) .
the aim of our study was to evaluate the predictive value of t - wave alternans in stratifying the risk of severe ventricular tachyarrhythmias and sudden cardiac death in athletes with ventricular arrhythmias , and to investigate the relationship between twa and the results of programmed ventricular stimulation during electrophysiologic endocavitary study .
in this prospective study , we enrolled 43 consecutive athletes ( 31 males , 12 females ) , with no history of cardiovascular disease , with age 34 11 years involved in different types of sports .
all subjects had been referred to our cardiology department following the detection of ventricular arrhythmias during eligibility screening for competitive sports .
these arrhythmias included frequent premature ventricular complexes ( pvc ) , arbitrarily defined as pvc 2,000 on 24-h ambulatory holter monitoring ( 28 athletes ) , or nsvt ( 13 athletes ) or sustained ventricular tachycardia ( svt ) ( 2 athletes ) .
all patients underwent a basic cardiological evaluation , which consisted of anamnesis , physical examination , routine blood tests ( including ft3 , ft4 , tsh ) , ecg , holter recording , echocardiogram and maximal exercise test .
furthermore , pharmacological testing , specific blood test for myocarditis , coronary angiogram , right and left ventriculogram , magnetic resonance imaging and endomyocardial biopsy were performed , depending on the basic cardiological evaluation .
all athletes then underwent electrophysiologic study ( ees ) with programmed ventricular stimulation ( pvs ) and microvolt t - wave alternans ( twa ) testing .
t - wave alternans was measured during a bicycle exercise test after careful skin preparation , including mild abrasion , and placement of high - resolution electrodes ( microvolt sensors , cambridge heart , inc . ,
electrocardiographic leads were placed in the standard 12-lead positions and in a frank orthogonal configuration ( x , y , z ) .
electrocardiographic signals were amplified and digitalized , and measurements were taken by means of the ch2000 system ( cambridge heart , inc . ,
this technique involved measuring the amplitudes of corresponding points in 128 consecutive t - waves , at the same time after the qrs complex .
the software then calculated :
the alternans voltage ( valt ) , defined as the difference in voltage between the overall mean beats and either the even - numbered or odd - numbered mean beats;the alternans ratio ( k ) , a measure of the significance of microvolt twa , defined as the ratio of alternans power divided by the standard deviation of the noise in the reference frequency band .
a k 3 was considered to be significant .
the alternans voltage ( valt ) , defined as the difference in voltage between the overall mean beats and either the even - numbered or odd - numbered mean beats ; the alternans ratio ( k ) , a measure of the significance of microvolt twa , defined as the ratio of alternans power divided by the standard deviation of the noise in the reference frequency band .
twa was classified as positive if it was sustained ( duration 1 min ) with onset at heart rate 110 bpm ,
valt 1.9 v and k 3 .
twa was considered negative if
it did not meet the positivity criteria and if at least 1 minute of artifact - free data was available at heart rate 105 bpm .
positive or indetermined t - wave alternans test were considered as an abnormal result ( 16 ) .
electrophysiologic study was performed in the non - sedated , postabsorptive state . a 6-french tetrapolar recording and stimulating catheter
a venous access was created in the right femoral vein and a venous introducer was inserted .
thereafter , a quadripolar catheter was advanced to the right ventricular apex under fluoroscopic control and ecg monitoring . programmed ventricular stimulation
was performed through an automatic stimulator ( micropace eps 320 ) with up to three extrastimuli at three drive cycle lengths ( 600 , 500 , 400 msec ) .
the same protocol was then repeated with the catheter placed in the right ventricular outflow tract .
the occurrence of serious ventricular arrhythmias ( svt or vf ) or scd was regarded as the end - point .
scd was defined as unexpected death occurring within 1 hour of the onset of symptoms or during sleep .
the data were firstly processed using a hierarchical clustering procedure , in order to highlight possible differences among groups of the main available variables ( age , sex , ejection fraction , sports activity , clinical presentation ) in relationship with the twa ( positive , negative and indeterminate ) and ees ( positive and negative ) variables . in the following we carried out a set of logistic regression analyses where the dependent dichotomous variables were respectively twa ( positive , negative and indeterminate ) and ees ( positive and negative ) , to evaluate the significance of the differences among groups pointed out by the clustering procedure .
finally , in order to establish a possible significant influence of the twa and ees variables on the time free from malignant arrhythmic events , we evaluated the follow - up data by generating kaplan - meier survival curves where the endpoint was the occurrence of a malignant ventricular arrhythmias and the grouping variables were twa ( positive , negative and indeterminate ) and ees ( positive and negative ) .
in this prospective study , we enrolled 43 consecutive athletes ( 31 males , 12 females ) , with no history of cardiovascular disease , with age 34 11 years involved in different types of sports .
all subjects had been referred to our cardiology department following the detection of ventricular arrhythmias during eligibility screening for competitive sports .
these arrhythmias included frequent premature ventricular complexes ( pvc ) , arbitrarily defined as pvc 2,000 on 24-h ambulatory holter monitoring ( 28 athletes ) , or nsvt ( 13 athletes ) or sustained ventricular tachycardia ( svt ) ( 2 athletes ) .
all patients underwent a basic cardiological evaluation , which consisted of anamnesis , physical examination , routine blood tests ( including ft3 , ft4 , tsh ) , ecg , holter recording , echocardiogram and maximal exercise test .
furthermore , pharmacological testing , specific blood test for myocarditis , coronary angiogram , right and left ventriculogram , magnetic resonance imaging and endomyocardial biopsy were performed , depending on the basic cardiological evaluation .
all athletes then underwent electrophysiologic study ( ees ) with programmed ventricular stimulation ( pvs ) and microvolt t - wave alternans ( twa ) testing .
t - wave alternans was measured during a bicycle exercise test after careful skin preparation , including mild abrasion , and placement of high - resolution electrodes ( microvolt sensors , cambridge heart , inc . ,
electrocardiographic leads were placed in the standard 12-lead positions and in a frank orthogonal configuration ( x , y , z ) .
electrocardiographic signals were amplified and digitalized , and measurements were taken by means of the ch2000 system ( cambridge heart , inc . ,
this technique involved measuring the amplitudes of corresponding points in 128 consecutive t - waves , at the same time after the qrs complex .
the software then calculated :
the alternans voltage ( valt ) , defined as the difference in voltage between the overall mean beats and either the even - numbered or odd - numbered mean beats;the alternans ratio ( k ) , a measure of the significance of microvolt twa , defined as the ratio of alternans power divided by the standard deviation of the noise in the reference frequency band .
a k 3 was considered to be significant .
the alternans voltage ( valt ) , defined as the difference in voltage between the overall mean beats and either the even - numbered or odd - numbered mean beats ; the alternans ratio ( k ) , a measure of the significance of microvolt twa , defined as the ratio of alternans power divided by the standard deviation of the noise in the reference frequency band .
twa was classified as positive if it was sustained ( duration 1 min ) with onset at heart rate 110 bpm ,
valt 1.9 v and k 3 .
twa was considered negative if
it did not meet the positivity criteria and if at least 1 minute of artifact - free data was available at heart rate 105 bpm .
positive or indetermined t - wave alternans test were considered as an abnormal result ( 16 ) .
electrophysiologic study was performed in the non - sedated , postabsorptive state . a 6-french tetrapolar recording and stimulating catheter
a venous access was created in the right femoral vein and a venous introducer was inserted .
thereafter , a quadripolar catheter was advanced to the right ventricular apex under fluoroscopic control and ecg monitoring . programmed ventricular stimulation was performed through an automatic stimulator ( micropace eps 320 ) with up to three extrastimuli at three drive cycle lengths ( 600 , 500 , 400 msec ) .
the same protocol was then repeated with the catheter placed in the right ventricular outflow tract .
the occurrence of serious ventricular arrhythmias ( svt or vf ) or scd was regarded as the end - point .
scd was defined as unexpected death occurring within 1 hour of the onset of symptoms or during sleep .
the data were firstly processed using a hierarchical clustering procedure , in order to highlight possible differences among groups of the main available variables ( age , sex , ejection fraction , sports activity , clinical presentation ) in relationship with the twa ( positive , negative and indeterminate ) and ees ( positive and negative ) variables . in the following we carried out a set of logistic regression analyses where the dependent dichotomous variables were respectively twa ( positive , negative and indeterminate ) and ees ( positive and negative ) , to evaluate the significance of the differences among groups pointed out by the clustering procedure .
finally , in order to establish a possible significant influence of the twa and ees variables on the time free from malignant arrhythmic events , we evaluated the follow - up data by generating kaplan - meier survival curves where the endpoint was the occurrence of a malignant ventricular arrhythmias and the grouping variables were twa ( positive , negative and indeterminate ) and ees ( positive and negative ) .
at the end of cardiological screening , a structural heart disease was identified in 7 patients ( 16% ) .
specifically , arrhythmogenic right ventricular dysplasia was diagnosed in 3 patients and myocarditis in 2 .
the diagnosis of myocarditis was made on the basis of magnetic resonance imaging , which showed areas of hyper - enhancement with
furthermore , in 2 patients , the echocardiographic picture was borderline for the diagnosis of early - stage dilated cardiomyopathy .
pharmacological antiarrhythmic therapy was started in 15 patients ( 35% ) : 7 ( 47% ) were affected by structural heart disease , while in 8 ( 53% ) there was no diagnosis of evident heart disease , therapy being started because
the patients were heavily symptomatic for palpitations .
antiarrhythmic therapy consisted of amiodarone in 7 patients ( 47% ) , beta blockers in 3 ( 20% ) , sotalol in 3 ( 20% ) and an association of amiodarone and beta blockers in 2 ( 13% ) .
after cardiological evaluation , an icd was implanted in 4 subjects ( 9% ) : 3 affected by arrhythmogenic right ventricular dysplasia and 1 with myocarditis ( fig .
1- results of twa test and ees and occurrence of spontaneous ventricular arrhythmias during follow - up in study population . in brackets
results of twa test and ees and occurrence of spontaneous ventricular arrhythmias during follow - up in study population . in brackets
microvolt - twa testing proved negative in 28 patients ( 65% ) , positive in 8 ( 19% ) and indeterminate because of excessive noise in 7 ( 16% ) ( fig .
there were no significant differences between patients with positive , indetermined or negative twa in terms of age , sex , ejection fraction , sports activity , and clinical presentation ( tab .
table i- comparison of clinical and demographic characteristics between patients with negative , indeterminate and positive twanegativetwaindeterminatetwapositivetwapage34 1333 1034 9p = nsmales21 ( 75%)4 ( 57%)6 ( 75%)p = nssport - soccer5 ( 18%)2 ( 28%)2 ( 25%)p = ns - running7 ( 25%)3 ( 44%)2 ( 25%)p = ns - skiing2 ( 7%)1 ( 14%)0 ( 0%)p = ns - cycling4 ( 14%)1 ( 14%)2 ( 25%)p = ns - motorcycling1 ( 4%)0 ( 0%)0 ( 0%)p = ns - volleyball4 ( 14%)0 ( 0%)1 ( 12.5%)p = ns - swimming4 ( 14%)0 ( 0%)0 ( 0%)p = ns - climbing1 ( 4%)0 ( 0%)0 ( 0%)p = ns - gymnastics0 ( 0%)0 ( 0%)1 ( 12.5%)p = nsef ( % ) 66 566 565 4p = nsarrhythmias - vebs19 ( 68%)5 ( 71%)4 ( 50%)p = ns - nsvts9 ( 32%)2 ( 29%)2 ( 25%)p = ns - svts0 ( 0%)0 ( 0%)2 ( 25%)p = ns
fig .
2- positive twa test in a 23-year - old male athlete with ventricular arrhythmias . -
malignant ventricular arrhythmias were induced through programmed ventricular stimulation in 10 patients ( 23% ) , and were not induced in 33 ( 77% ) ( fig .
3 ) . there were no significant differences between these patients in terms of age , sex , clinical presentation , ejection fraction , sports activity and clinical presentation .
3- induction of vf during programmed ventricular stimulation ( double extrastimulus ) in the same patient of figure 2 .
- induction of vf during programmed ventricular stimulation ( double extrastimulus ) in the same patient of figure 2 .
malignant ventricular arrhythmias were not inducible during electrophysiologic study in any of the subjects in whom the twa test was negative . logistic regression analysis demonstrated a significant correlation between a negative microvolt - twa test and non - inducibility of ventricular arrhythmias during electrophysiologic study ( p<0.001 ) .
in contrast , in all patients with a positive twa test , ventricular tachyarrhythmias were inducible during electrophysiologic study ( svt requiring external defibrillation in 6 patients and ventricular fibrillation in 2 patients ) .
however , logistic regression analysis did not show a significant correlation between a positive twa test and inducibility of ventricular arrhythmias during electrophysiologic study . of the patients in whom the twa test was indeterminate , 2 ( 29% ) showed inducibility of ventricular arrhythmias during electrophysiologic study ( sustained ventricular tachycardia requiring external defibrillation in all patients ) , while in 5 ( 71% ) the electrophysiologic study was negative .
logistic regression analysis did not show a significant correlation between an indeterminate twa test and inducibility or non - inducibility of ventricular arrhythmias during electrophysiologic study ( p>0.05 ) . however , logistic regression analysis showed significant correlation between abnormal twa test ( positive or indeterminate ) and inducibility of ventricular arrhythmias at electrophysiologic study ( p<0.001 ) .
our data demonstrate that the twa test has a positive predictive value ( ppv ) of 100% for positive twa test and of 67% for abnormal twa , and a negative predictive value ( npv ) of 100% in predicting the inducibility of ventricular arrhythmias during electrophysiologic study ( tab .
table ii- correlation between twa test and electrophysiologic studynegativeeespositiveeespnegative twa28 ( 100%)0 ( 0%)p<0.001indeterminate twa5 ( 71%)2 ( 29%)p = nspositive twa0 ( 0%)8 ( 100%)p = nsabnormal twa ( indeterminate + positive)5 ( 33%)10 ( 67%)p<0.001
during a mean follow - up of 25 months , 3 patients ( 7% ) experienced an arrhythmic event regarded as the end - point of the study ( vf in 1 patient , svt in 1 and both arrhythmias in 1 ) . the difference in end - point occurrence rate was significant between patients with a negative twa test ( 0% ) and those with a positive twa test ( 37.5% ) ( p<0.01 ) . the difference in end - point occurrence was significant also considering patients with negative ( 0% ) or abnormal twa test ( 20% ) ( p<0.05 ) . in our study ,
the twa test predicted the occurrence of malignant ventricular arrhythmias with an npv of 100% and a ppv of 37.5% for positive twa and 20% for abnormal twa ( fig .
4- kaplan - meier survival curves comparing end - point occurrence between patients with negative , indeterminate and positive twa . - kaplan - meier survival curves comparing end - point occurrence between patients with negative , indeterminate and positive twa .
similarly , there was a significant difference in endpoint occurrence rate between patients in whom the electrophysiologic study proved positive and those in whom it was negative ( 30% vs 0% ) ( p<0.01 ) .
the electrophysiologic study predicted the occurrence of malignant ventricular arrhythmias with an npv of 100% and a ppv of 30% ( fig .
5- kaplan - meier survival curves comparing end - point occurrence between patients with negative and positive ees . - kaplan - meier survival curves comparing end - point occurrence between patients with negative and positive ees .
microvolt - twa testing proved negative in 28 patients ( 65% ) , positive in 8 ( 19% ) and indeterminate because of excessive noise in 7 ( 16% ) ( fig .
there were no significant differences between patients with positive , indetermined or negative twa in terms of age , sex , ejection fraction , sports activity , and clinical presentation ( tab .
table i- comparison of clinical and demographic characteristics between patients with negative , indeterminate and positive twanegativetwaindeterminatetwapositivetwapage34 1333 1034 9p = nsmales21 ( 75%)4 ( 57%)6 ( 75%)p = nssport - soccer5 ( 18%)2 ( 28%)2 ( 25%)p = ns - running7 ( 25%)3 ( 44%)2 ( 25%)p = ns - skiing2 ( 7%)1 ( 14%)0 ( 0%)p = ns - cycling4 ( 14%)1 ( 14%)2 ( 25%)p = ns - motorcycling1 ( 4%)0 ( 0%)0 ( 0%)p = ns - volleyball4 ( 14%)0 ( 0%)1 ( 12.5%)p = ns - swimming4 ( 14%)0 ( 0%)0 ( 0%)p = ns - climbing1 ( 4%)0 ( 0%)0 ( 0%)p = ns - gymnastics0 ( 0%)0 ( 0%)1 ( 12.5%)p = nsef ( % ) 66 566 565 4p = nsarrhythmias - vebs19 ( 68%)5 ( 71%)4 ( 50%)p = ns - nsvts9 ( 32%)2 ( 29%)2 ( 25%)p = ns - svts0 ( 0%)0 ( 0%)2 ( 25%)p = ns
fig .
2- positive twa test in a 23-year - old male athlete with ventricular arrhythmias . -
malignant ventricular arrhythmias were induced through programmed ventricular stimulation in 10 patients ( 23% ) , and were not induced in 33 ( 77% ) ( fig .
3 ) . there were no significant differences between these patients in terms of age , sex , clinical presentation , ejection fraction , sports activity and clinical presentation .
3- induction of vf during programmed ventricular stimulation ( double extrastimulus ) in the same patient of figure 2 .
- induction of vf during programmed ventricular stimulation ( double extrastimulus ) in the same patient of figure 2 .
malignant ventricular arrhythmias were not inducible during electrophysiologic study in any of the subjects in whom the twa test was negative .
logistic regression analysis demonstrated a significant correlation between a negative microvolt - twa test and non - inducibility of ventricular arrhythmias during electrophysiologic study ( p<0.001 ) .
in contrast , in all patients with a positive twa test , ventricular tachyarrhythmias were inducible during electrophysiologic study ( svt requiring external defibrillation in 6 patients and ventricular fibrillation in 2 patients ) .
however , logistic regression analysis did not show a significant correlation between a positive twa test and inducibility of ventricular arrhythmias during electrophysiologic study . of the patients in whom the twa test was indeterminate , 2 ( 29% ) showed inducibility of ventricular arrhythmias during electrophysiologic study ( sustained ventricular tachycardia requiring external defibrillation in all patients ) , while in 5 ( 71% ) the electrophysiologic study was negative .
logistic regression analysis did not show a significant correlation between an indeterminate twa test and inducibility or non - inducibility of ventricular arrhythmias during electrophysiologic study ( p>0.05 ) . however , logistic regression analysis showed significant correlation between abnormal twa test ( positive or indeterminate ) and inducibility of ventricular arrhythmias at electrophysiologic study ( p<0.001 ) .
our data demonstrate that the twa test has a positive predictive value ( ppv ) of 100% for positive twa test and of 67% for abnormal twa , and a negative predictive value ( npv ) of 100% in predicting the inducibility of ventricular arrhythmias during electrophysiologic study ( tab .
table ii- correlation between twa test and electrophysiologic studynegativeeespositiveeespnegative twa28 ( 100%)0 ( 0%)p<0.001indeterminate twa5 ( 71%)2 ( 29%)p = nspositive twa0 ( 0%)8 ( 100%)p = nsabnormal twa ( indeterminate + positive)5 ( 33%)10 ( 67%)p<0.001
during a mean follow - up of 25 months , 3 patients ( 7% ) experienced an arrhythmic event regarded as the end - point of the study ( vf in 1 patient , svt in 1 and both arrhythmias in 1 ) .
the difference in end - point occurrence rate was significant between patients with a negative twa test ( 0% ) and those with a positive twa test ( 37.5% ) ( p<0.01 ) .
the difference in end - point occurrence was significant also considering patients with negative ( 0% ) or abnormal twa test ( 20% ) ( p<0.05 ) . in our study ,
the twa test predicted the occurrence of malignant ventricular arrhythmias with an npv of 100% and a ppv of 37.5% for positive twa and 20% for abnormal twa ( fig .
4- kaplan - meier survival curves comparing end - point occurrence between patients with negative , indeterminate and positive twa
. - kaplan - meier survival curves comparing end - point occurrence between patients with negative , indeterminate and positive twa .
similarly , there was a significant difference in endpoint occurrence rate between patients in whom the electrophysiologic study proved positive and those in whom it was negative ( 30% vs 0% ) ( p<0.01 ) .
the electrophysiologic study predicted the occurrence of malignant ventricular arrhythmias with an npv of 100% and a ppv of 30% ( fig .
5- kaplan - meier survival curves comparing end - point occurrence between patients with negative and positive ees
. - kaplan - meier survival curves comparing end - point occurrence between patients with negative and positive ees .
ventricular ectopic beats have been detected by surface electrocardiogram in 1% of the general population , and by 24-hour ambulatory ecg holter monitoring in 40% to 75% of apparently healthy subjects ( 1619 ) .
however , athletes constitute a particular population of healthy people , in that they show a high prevalence of morphological cardiac alterations ( a condition known as athlete s heart ) , electrocardiographic abnormalities ( wave voltage modification , st and t wave changes ) and frequent and/or complex ventricular beats .
consequently , it is not easy to make a differential diagnosis with heart diseases at risk of sudden death , such as , for example , hypertrophic and dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy , which are often difficult to diagnose in their initial phase .
the onset of these alterations in the athlete s heart can be due to adaptation to dynamic sports activity and the impact of training on cardiac cavity size .
several prospective studies have shown that detraining and physical deconditioning can result in cardiac reverse remodeling , with a reduction in cavity size , and in the reversibility of ventricular arrhythmias , which is complete in about 25% of subjects and partial in 50% ( 2022 ) .
biffi et al ( 23 ) reported that the presence of frequent and/or complex ventricular beats in competitive athletes did not indicate an adverse prognosis in subjects without underlying structural heart disease .
nevertheless , the detection of frequent and complex ventricular arrhythmias in a competitive athlete requires particular attention on the part of cardiologists and sports physicians in order to determine whether these arrhythmias have a good prognosis or are potentially life - threatening . in recent studies ,
several authors have reported that competitive athletes with silent arrhythmogenic heart disease have a higher risk of sudden death than sedentary subjects of the same age and with a similar latent cardiac substrate ( 2427 ) . when frequent and complex ventricular arrhythmias are diagnosed in a young athlete ,
firstly , it is mandatory to clarify whether there is an undiagnosed structural heart disease .
if diagnostic screening does not demonstrate the presence of heart disease , there are other issues to consider : the role of intense training on the arrhythmic pattern in young athletes and the potential usefulness of detraining , the criteria of eligibility for sports activity , the importance of the athlete s own wishes and the pressure exerted by family members and coaches .
the value of twa in predicting ventricular tachyarrhythmias in patients with congestive heart failure and with previous myocardial infarction has been evaluated in several clinical studies ( 7 , 13 , 28 ) .
these reports document a highly significant statistical association between positive twa and ventricular tachyarrhythmic events .
gehi et al ( 29 ) recently conducted a meta - analysis of the results of 19 studies carried out on a wide range of subjects , including those with ischemic or non - ischemic congestive heart failure , coronary artery disease , athletes and healthy individuals .
these authors found that the risk of tachyarrhythmic events was nearly four - fold higher in subjects in whom twa testing was positive than in those in whom it was negative , and that there was no difference between patients with ischemic or non - ischemic heart failure . the positive predictive value of twa varied in the meta - analysis from 0% to 51% , depending on the patient population studied , while the negative predictive value was 97% ( 29 ) .
very few data are available on the risk stratification of sudden cardiac death and severe ventricular tachyarrhythmic events in athletes with ventricular arrhythymias . in a multi - center study of 52 competitive athletes with severe arrhythymias ,
furlanello et al ( 27 ) found a high negative predictive value of twa when both programmed ventricular stimulation and follow up were used as endpoints .
unfortunately , the limited number of athletes with positive twa in this study did not allow to obtain a significant positive predictive value .
in our population of athletes undergoing twa evaluation and programmed ventricular stimulation , we documented a significant correlation between twa test negativity and non - inducibility of ventricular arrhythmias through programmed ventricular stimulation .
in contrast , our study did not show a significant correlation between positive or indeterminate twa testing and the result of electrophysiologic study , although we found a non - significant trend towards correlation with inducibility of ventricular arrhythmias .
however , this correlation become significant if we consider patients with abnormal twa ( positive and indeterminate ) .
the pathophysiological reason for this trend may be that twa testing often proves indeterminate in patients with very frequent and complex ventricular ectopic beats ; in such subjects , programmed ventricular stimulation can induce ventricular arrhythmias , and arrhythmic events may occur during follow up . in our study ,
twa testing showed a very high npv ( 100% ) and ppv ( 100% for positive twa and 67% for abnormal twa ) in predicting the result of programmed ventricular stimulation .
however , a larger study population may be needed in order to demonstrate a significant correlation between positive and indeterminate twa testing and inducibility of ventricular arrhythmias during electrophysiologic study .
review of a number of prospective studies conducted in a variety of clinical patient populations , including subjects with non - ischemic or ischemic cardiac disease , syncope , dilated cardiomyopathy and congestive heart failure , suggests that the occurrence rate of severe ventricular tachyarrhythmias in patients with positive twa is equivalent to that of ventricular tachyarrhythmias in patients with a positive result on programmed ventricular stimulation during electrophysiologic endocavitary study .
the event rate among patients with negative twa is low , and in many cases lower than the event rate in patients with a negative response to programmed ventricular stimulation ( 7 , 12 , 13 , 28 ) .
rosenbaum et al ( 4 ) evaluated t wave alternans as a predictor of severe arrhythmic events in a group of 83 patients who underwent programmed ventricular stimulation for previous tachyarrhythmic events . during a follow - up of 20 months
, kaplan - meier survival analysis showed that twa had a good predictive value , in that the rates of arrhythmia - free survival were 94% in patients with negative twa and 19% in those with positive twa . in a multi - center trial of 313 patients undergoing programmed ventricular stimulation and twa testing , gold et al ( 7 ) documented that twa was a highly significant predictor of major ventricular tachyarrhythmias . during
follow up , the presence of positive twa was associated with a relative risk of 10.9 , versus 7.1 for ees and 4.5 for signal - averaged electrocardiography ( saecg ) , for the end - point of sudden cardiac death and sustained ventricular tachycardia , ventricular fibrillation or icd implantation .
in many studies , twa has proved to be equivalent to programmed ventricular stimulation and better than saecg in the risk stratification of patients for life - threatening arrhythmias ( 4 , 7 , 11 , 3032 ) . in our study
we found a significant difference between patients with positive and negative twa tests with regard to the occurrence of sudden death , ventricular fibrillation and sustained ventricular tachycardia during an average follow - up of 25 months .
kaplan - meier survival analysis showed a 100% rate of end - point - free survival in patients with a negative twa test and a 62.5% rate in subjects with a positive twa test , suggesting that twa can also predict spontaneous malignant arrhythmic events in athletes with ventricular arrhythmias .
the difference was significant also considering patients with abnormal twa , in whom there was a 80% rate of end - point - free survival .
the npv ( 100% ) and ppv ( 37.5% for positive twa test and 20% for abnormal twa test ) obtained in our study are comparable to those reported by gehi et al ( 29 ) in different populations .
few studies have evaluated t wave alternans as a predictor of arrhythmic events in competitive athletes , and little information is available on the comparison of twa and programmed ventricular stimulation in arrhythmia risk stratification in this population ( 27 ) . in our study ,
the predictive accuracy of invasive programmed ventricular stimulation during ees was similar to that of twa .
these results , which were obtained in a single - center experience , are in line with those from a multicenter study by furlanello et al ( 27 ) on 52 competitive athletes , and suggest that twa may play an important role in the prognostic stratification of athletes with ventricular arrhythmias .
unlike electrophysiological study , which is an invasive procedure requiring hospitalization , twa testing is non - invasive , cheap , easy to perform and repeatable during follow - up .
review of a number of prospective studies conducted in a variety of clinical patient populations , including subjects with non - ischemic or ischemic cardiac disease , syncope , dilated cardiomyopathy and congestive heart failure , suggests that the occurrence rate of severe ventricular tachyarrhythmias in patients with positive twa is equivalent to that of ventricular tachyarrhythmias in patients with a positive result on programmed ventricular stimulation during electrophysiologic endocavitary study .
the event rate among patients with negative twa is low , and in many cases lower than the event rate in patients with a negative response to programmed ventricular stimulation ( 7 , 12 , 13 , 28 ) .
rosenbaum et al ( 4 ) evaluated t wave alternans as a predictor of severe arrhythmic events in a group of 83 patients who underwent programmed ventricular stimulation for previous tachyarrhythmic events . during a follow - up of 20 months
, kaplan - meier survival analysis showed that twa had a good predictive value , in that the rates of arrhythmia - free survival were 94% in patients with negative twa and 19% in those with positive twa . in a multi - center trial of 313 patients undergoing programmed ventricular stimulation and twa testing , gold et al ( 7 ) documented that twa was a highly significant predictor of major ventricular tachyarrhythmias . during
follow up , the presence of positive twa was associated with a relative risk of 10.9 , versus 7.1 for ees and 4.5 for signal - averaged electrocardiography ( saecg ) , for the end - point of sudden cardiac death and sustained ventricular tachycardia , ventricular fibrillation or icd implantation . in many studies ,
twa has proved to be equivalent to programmed ventricular stimulation and better than saecg in the risk stratification of patients for life - threatening arrhythmias ( 4 , 7 , 11 , 3032 ) . in our study
we found a significant difference between patients with positive and negative twa tests with regard to the occurrence of sudden death , ventricular fibrillation and sustained ventricular tachycardia during an average follow - up of 25 months .
kaplan - meier survival analysis showed a 100% rate of end - point - free survival in patients with a negative twa test and a 62.5% rate in subjects with a positive twa test , suggesting that twa can also predict spontaneous malignant arrhythmic events in athletes with ventricular arrhythmias .
the difference was significant also considering patients with abnormal twa , in whom there was a 80% rate of end - point - free survival .
the npv ( 100% ) and ppv ( 37.5% for positive twa test and 20% for abnormal twa test ) obtained in our study are comparable to those reported by gehi et al ( 29 ) in different populations .
few studies have evaluated t wave alternans as a predictor of arrhythmic events in competitive athletes , and little information is available on the comparison of twa and programmed ventricular stimulation in arrhythmia risk stratification in this population ( 27 ) . in our study ,
the predictive accuracy of invasive programmed ventricular stimulation during ees was similar to that of twa .
these results , which were obtained in a single - center experience , are in line with those from a multicenter study by furlanello et al ( 27 ) on 52 competitive athletes , and suggest that twa may play an important role in the prognostic stratification of athletes with ventricular arrhythmias .
unlike electrophysiological study , which is an invasive procedure requiring hospitalization , twa testing is non - invasive , cheap , easy to perform and repeatable during follow - up .
twa is an effective non - invasive predictor of the risk of severe ventricular tachyarrhythmias and sudden cardiac death in competitive athletes , its efficacy being at least comparable to that of invasive programmed ventricular stimulation . in particular , | introduction : aim of our study is to evaluate the role of twa to stratify the risk of sudden cardiac death in athletes ( ath ) with complex ventricular arrhythmias ( va ) , and to document a possible correlation between twa and electrophysiological testing ( ees ) results.methods:we studied 43 ath with va ( 31 m , mean age 34 12 years ) . in all cases a cardiological evaluation was performed , including twa and ees . the patients were evaluated during a follow - up of 25 22 months .
the end - point was the occurrence of sudden death or malignant ventricular tachyarrhythmias ( vt).results : twa was negative in 28 ath ( 65% ) , positive in 8 ( 19% ) and indeterminate in 7 ( 16% ) .
all subjects with negative twa did not show induction of vt at ees , with significant correlation between negative twa and negative ees ( p<0.001 ) .
all ath with positive twa also had vt induced by a ees , but without significant correlation between positive twa and positive ees . in 2 ath with undetermined twa ( 29% )
vt were induced at ees .
our data did not show significant correlation between indeterminate twa and positive or negative ees . however , logistic regression analysis showed significant correlation between abnormal twa test ( positive or indeterminate ) and inducibility of vt at ees ( p<0.001 ) . during follow - up
we observed a significant difference in end - point occurrence between ath with negative or positive twa and between ath with negative or positive ees.conclusion:twa confirm its role as a simple and non - invasive test , and it seems useful for prognostic stratification of ath with va . | <s>[INST]sudden cardiac death ( scd ) related to ventricular tachyarrhythmia in young athletes is a dramatic event that has emotional and social impact on the media and the medical community .
ventricular ectopic beats ( veb ) , even with frequent and/or complex forms , have frequently been described on 24-hour ecg in 2565% of athletes . for athletes with ventricular arrhythmias who have no evidence of underlying heart disease or who have an unsuspected cardiovascular disease , identifying subjects at risk of serious ventricular tachyarrhythmias is often problematic .
corrado et al ( 1 ) reported that , while sporting activity is not the cause of sudden cardiac death , it can trigger cardiac arrest in subjects whose cardiovascular conditions engender a risk of life - threatening arrhythmias during athletic activity .
frequent ventricular premature beats with complex morphology and couplets and non - sustained ventricular tachycardia ( nsvt ) may be detected in a competitive athlete during ambulatory clinical screening , without evidence of underlying cardiovascular disease . despite the increased availability of
non - invasive and invasive clinical diagnostic methods , such cases pose a diagnostic dilemma for physicians called upon to assess the subject s eligibility to practice sport .
it is necessary to make a precise differential diagnosis between an expression of athlete s heart , which may mimic cardiovascular disease , and
silent cardiovascular abnormalities that may progress to sustained tachyarrhythmias and/or sudden death with long - term intensive training .
systematic diagnostic methods , including ecg , holter monitoring , stress testing and echocardiography , are sometimes unable to reveal an underlying structural heart disease , and further evaluations are required in order to determine whether the arrhythmia is benign or potentially life - threatening .
many non - invasive markers of scd , such as depressed left ventricular ejection fraction , late potentials , qt dispersion , heart rate variability and baroreflex sensitivity , play a role in risk stratification , but are limited by their low specificity .
it is crucial to precisely identify athletes at increased risk for serious ventricular tachyarrhythmias in order to exclude them from competitive sport and implement an effective strategy to prevent sudden cardiac death .
specific forms of electrocardiographic alternans related to cardiac repolarization abnormalities have recently emerged as a cause of serious ventricular arrhythmias . in the 1980s ,
adam and smith ( 2 , 3 ) developed the spectral analysis method for detecting microvolt t - wave alternans in experimental animals and , subsequently , in humans ( 4 , 5 ) .
these studies showed that microvolt t - wave alternans is a reliable non - invasive risk marker of cardiac electrical vulnerability and a predictor of ventricular arrhythmias ( 413 ) .
electrical alternans is defined as beat - to - beat variation in the vector , amplitude and/or morphology of electrocardiographic signals , due to localized alternation in action potential duration .
the presence of amplitude alternans of the t - wave at a periodicity of 0.5 cycles / beat defines t - wave alternans .
t - wave alternans ( twa ) is a promising new non - invasive clinical tool for identifying patients at risk for sudden cardiac death in a diverse patient population . the usefulness of twa in predicting the risk of ventricular tachyarrhythmias has been widely reported in several clinical conditions , including coronary artery disease , non - ischemic cardiomyopathy , congestive heart failure and in patients with implantable cardiac defibrillators ( 14 ) .
recently , several authors have documented the high negative predictive value of twa in patients with heart disease and low ejection fraction ( 15 , 16 ) .
the aim of our study was to evaluate the predictive value of t - wave alternans in stratifying the risk of severe ventricular tachyarrhythmias and sudden cardiac death in athletes with ventricular arrhythmias , and to investigate the relationship between twa and the results of programmed ventricular stimulation during electrophysiologic endocavitary study .
in this prospective study , we enrolled 43 consecutive athletes ( 31 males , 12 females ) , with no history of cardiovascular disease , with age 34 11 years involved in different types of sports .
all subjects had been referred to our cardiology department following the detection of ventricular arrhythmias during eligibility screening for competitive sports .
these arrhythmias included frequent premature ventricular complexes ( pvc ) , arbitrarily defined as pvc 2,000 on 24-h ambulatory holter monitoring ( 28 athletes ) , or nsvt ( 13 athletes ) or sustained ventricular tachycardia ( svt ) ( 2 athletes ) .
all patients underwent a basic cardiological evaluation , which consisted of anamnesis , physical examination , routine blood tests ( including ft3 , ft4 , tsh ) , ecg , holter recording , echocardiogram and maximal exercise test .
furthermore , pharmacological testing , specific blood test for myocarditis , coronary angiogram , right and left ventriculogram , magnetic resonance imaging and endomyocardial biopsy were performed , depending on the basic cardiological evaluation .
all athletes then underwent electrophysiologic study ( ees ) with programmed ventricular stimulation ( pvs ) and microvolt t - wave alternans ( twa ) testing .
t - wave alternans was measured during a bicycle exercise test after careful skin preparation , including mild abrasion , and placement of high - resolution electrodes ( microvolt sensors , cambridge heart , inc . ,
electrocardiographic leads were placed in the standard 12-lead positions and in a frank orthogonal configuration ( x , y , z ) .
electrocardiographic signals were amplified and digitalized , and measurements were taken by means of the ch2000 system ( cambridge heart , inc . ,
this technique involved measuring the amplitudes of corresponding points in 128 consecutive t - waves , at the same time after the qrs complex .
the software then calculated :
the alternans voltage ( valt ) , defined as the difference in voltage between the overall mean beats and either the even - numbered or odd - numbered mean beats;the alternans ratio ( k ) , a measure of the significance of microvolt twa , defined as the ratio of alternans power divided by the standard deviation of the noise in the reference frequency band .
a k 3 was considered to be significant .
the alternans voltage ( valt ) , defined as the difference in voltage between the overall mean beats and either the even - numbered or odd - numbered mean beats ; the alternans ratio ( k ) , a measure of the significance of microvolt twa , defined as the ratio of alternans power divided by the standard deviation of the noise in the reference frequency band .
twa was classified as positive if it was sustained ( duration 1 min ) with onset at heart rate 110 bpm ,
valt 1.9 v and k 3 .
twa was considered negative if
it did not meet the positivity criteria and if at least 1 minute of artifact - free data was available at heart rate 105 bpm .
positive or indetermined t - wave alternans test were considered as an abnormal result ( 16 ) .
electrophysiologic study was performed in the non - sedated , postabsorptive state . a 6-french tetrapolar recording and stimulating catheter
a venous access was created in the right femoral vein and a venous introducer was inserted .
thereafter , a quadripolar catheter was advanced to the right ventricular apex under fluoroscopic control and ecg monitoring . programmed ventricular stimulation
was performed through an automatic stimulator ( micropace eps 320 ) with up to three extrastimuli at three drive cycle lengths ( 600 , 500 , 400 msec ) .
the same protocol was then repeated with the catheter placed in the right ventricular outflow tract .
the occurrence of serious ventricular arrhythmias ( svt or vf ) or scd was regarded as the end - point .
scd was defined as unexpected death occurring within 1 hour of the onset of symptoms or during sleep .
the data were firstly processed using a hierarchical clustering procedure , in order to highlight possible differences among groups of the main available variables ( age , sex , ejection fraction , sports activity , clinical presentation ) in relationship with the twa ( positive , negative and indeterminate ) and ees ( positive and negative ) variables . in the following we carried out a set of logistic regression analyses where the dependent dichotomous variables were respectively twa ( positive , negative and indeterminate ) and ees ( positive and negative ) , to evaluate the significance of the differences among groups pointed out by the clustering procedure .
finally , in order to establish a possible significant influence of the twa and ees variables on the time free from malignant arrhythmic events , we evaluated the follow - up data by generating kaplan - meier survival curves where the endpoint was the occurrence of a malignant ventricular arrhythmias and the grouping variables were twa ( positive , negative and indeterminate ) and ees ( positive and negative ) .
in this prospective study , we enrolled 43 consecutive athletes ( 31 males , 12 females ) , with no history of cardiovascular disease , with age 34 11 years involved in different types of sports .
all subjects had been referred to our cardiology department following the detection of ventricular arrhythmias during eligibility screening for competitive sports .
these arrhythmias included frequent premature ventricular complexes ( pvc ) , arbitrarily defined as pvc 2,000 on 24-h ambulatory holter monitoring ( 28 athletes ) , or nsvt ( 13 athletes ) or sustained ventricular tachycardia ( svt ) ( 2 athletes ) .
all patients underwent a basic cardiological evaluation , which consisted of anamnesis , physical examination , routine blood tests ( including ft3 , ft4 , tsh ) , ecg , holter recording , echocardiogram and maximal exercise test .
furthermore , pharmacological testing , specific blood test for myocarditis , coronary angiogram , right and left ventriculogram , magnetic resonance imaging and endomyocardial biopsy were performed , depending on the basic cardiological evaluation .
all athletes then underwent electrophysiologic study ( ees ) with programmed ventricular stimulation ( pvs ) and microvolt t - wave alternans ( twa ) testing .
t - wave alternans was measured during a bicycle exercise test after careful skin preparation , including mild abrasion , and placement of high - resolution electrodes ( microvolt sensors , cambridge heart , inc . ,
electrocardiographic leads were placed in the standard 12-lead positions and in a frank orthogonal configuration ( x , y , z ) .
electrocardiographic signals were amplified and digitalized , and measurements were taken by means of the ch2000 system ( cambridge heart , inc . ,
this technique involved measuring the amplitudes of corresponding points in 128 consecutive t - waves , at the same time after the qrs complex .
the software then calculated :
the alternans voltage ( valt ) , defined as the difference in voltage between the overall mean beats and either the even - numbered or odd - numbered mean beats;the alternans ratio ( k ) , a measure of the significance of microvolt twa , defined as the ratio of alternans power divided by the standard deviation of the noise in the reference frequency band .
a k 3 was considered to be significant .
the alternans voltage ( valt ) , defined as the difference in voltage between the overall mean beats and either the even - numbered or odd - numbered mean beats ; the alternans ratio ( k ) , a measure of the significance of microvolt twa , defined as the ratio of alternans power divided by the standard deviation of the noise in the reference frequency band .
twa was classified as positive if it was sustained ( duration 1 min ) with onset at heart rate 110 bpm ,
valt 1.9 v and k 3 .
twa was considered negative if
it did not meet the positivity criteria and if at least 1 minute of artifact - free data was available at heart rate 105 bpm .
positive or indetermined t - wave alternans test were considered as an abnormal result ( 16 ) .
electrophysiologic study was performed in the non - sedated , postabsorptive state . a 6-french tetrapolar recording and stimulating catheter
a venous access was created in the right femoral vein and a venous introducer was inserted .
thereafter , a quadripolar catheter was advanced to the right ventricular apex under fluoroscopic control and ecg monitoring . programmed ventricular stimulation was performed through an automatic stimulator ( micropace eps 320 ) with up to three extrastimuli at three drive cycle lengths ( 600 , 500 , 400 msec ) .
the same protocol was then repeated with the catheter placed in the right ventricular outflow tract .
the occurrence of serious ventricular arrhythmias ( svt or vf ) or scd was regarded as the end - point .
scd was defined as unexpected death occurring within 1 hour of the onset of symptoms or during sleep .
the data were firstly processed using a hierarchical clustering procedure , in order to highlight possible differences among groups of the main available variables ( age , sex , ejection fraction , sports activity , clinical presentation ) in relationship with the twa ( positive , negative and indeterminate ) and ees ( positive and negative ) variables . in the following we carried out a set of logistic regression analyses where the dependent dichotomous variables were respectively twa ( positive , negative and indeterminate ) and ees ( positive and negative ) , to evaluate the significance of the differences among groups pointed out by the clustering procedure .
finally , in order to establish a possible significant influence of the twa and ees variables on the time free from malignant arrhythmic events , we evaluated the follow - up data by generating kaplan - meier survival curves where the endpoint was the occurrence of a malignant ventricular arrhythmias and the grouping variables were twa ( positive , negative and indeterminate ) and ees ( positive and negative ) .
at the end of cardiological screening , a structural heart disease was identified in 7 patients ( 16% ) .
specifically , arrhythmogenic right ventricular dysplasia was diagnosed in 3 patients and myocarditis in 2 .
the diagnosis of myocarditis was made on the basis of magnetic resonance imaging , which showed areas of hyper - enhancement with
furthermore , in 2 patients , the echocardiographic picture was borderline for the diagnosis of early - stage dilated cardiomyopathy .
pharmacological antiarrhythmic therapy was started in 15 patients ( 35% ) : 7 ( 47% ) were affected by structural heart disease , while in 8 ( 53% ) there was no diagnosis of evident heart disease , therapy being started because
the patients were heavily symptomatic for palpitations .
antiarrhythmic therapy consisted of amiodarone in 7 patients ( 47% ) , beta blockers in 3 ( 20% ) , sotalol in 3 ( 20% ) and an association of amiodarone and beta blockers in 2 ( 13% ) .
after cardiological evaluation , an icd was implanted in 4 subjects ( 9% ) : 3 affected by arrhythmogenic right ventricular dysplasia and 1 with myocarditis ( fig .
1- results of twa test and ees and occurrence of spontaneous ventricular arrhythmias during follow - up in study population . in brackets
results of twa test and ees and occurrence of spontaneous ventricular arrhythmias during follow - up in study population . in brackets
microvolt - twa testing proved negative in 28 patients ( 65% ) , positive in 8 ( 19% ) and indeterminate because of excessive noise in 7 ( 16% ) ( fig .
there were no significant differences between patients with positive , indetermined or negative twa in terms of age , sex , ejection fraction , sports activity , and clinical presentation ( tab .
table i- comparison of clinical and demographic characteristics between patients with negative , indeterminate and positive twanegativetwaindeterminatetwapositivetwapage34 1333 1034 9p = nsmales21 ( 75%)4 ( 57%)6 ( 75%)p = nssport - soccer5 ( 18%)2 ( 28%)2 ( 25%)p = ns - running7 ( 25%)3 ( 44%)2 ( 25%)p = ns - skiing2 ( 7%)1 ( 14%)0 ( 0%)p = ns - cycling4 ( 14%)1 ( 14%)2 ( 25%)p = ns - motorcycling1 ( 4%)0 ( 0%)0 ( 0%)p = ns - volleyball4 ( 14%)0 ( 0%)1 ( 12.5%)p = ns - swimming4 ( 14%)0 ( 0%)0 ( 0%)p = ns - climbing1 ( 4%)0 ( 0%)0 ( 0%)p = ns - gymnastics0 ( 0%)0 ( 0%)1 ( 12.5%)p = nsef ( % ) 66 566 565 4p = nsarrhythmias - vebs19 ( 68%)5 ( 71%)4 ( 50%)p = ns - nsvts9 ( 32%)2 ( 29%)2 ( 25%)p = ns - svts0 ( 0%)0 ( 0%)2 ( 25%)p = ns
fig .
2- positive twa test in a 23-year - old male athlete with ventricular arrhythmias . -
malignant ventricular arrhythmias were induced through programmed ventricular stimulation in 10 patients ( 23% ) , and were not induced in 33 ( 77% ) ( fig .
3 ) . there were no significant differences between these patients in terms of age , sex , clinical presentation , ejection fraction , sports activity and clinical presentation .
3- induction of vf during programmed ventricular stimulation ( double extrastimulus ) in the same patient of figure 2 .
- induction of vf during programmed ventricular stimulation ( double extrastimulus ) in the same patient of figure 2 .
malignant ventricular arrhythmias were not inducible during electrophysiologic study in any of the subjects in whom the twa test was negative . logistic regression analysis demonstrated a significant correlation between a negative microvolt - twa test and non - inducibility of ventricular arrhythmias during electrophysiologic study ( p<0.001 ) .
in contrast , in all patients with a positive twa test , ventricular tachyarrhythmias were inducible during electrophysiologic study ( svt requiring external defibrillation in 6 patients and ventricular fibrillation in 2 patients ) .
however , logistic regression analysis did not show a significant correlation between a positive twa test and inducibility of ventricular arrhythmias during electrophysiologic study . of the patients in whom the twa test was indeterminate , 2 ( 29% ) showed inducibility of ventricular arrhythmias during electrophysiologic study ( sustained ventricular tachycardia requiring external defibrillation in all patients ) , while in 5 ( 71% ) the electrophysiologic study was negative .
logistic regression analysis did not show a significant correlation between an indeterminate twa test and inducibility or non - inducibility of ventricular arrhythmias during electrophysiologic study ( p>0.05 ) . however , logistic regression analysis showed significant correlation between abnormal twa test ( positive or indeterminate ) and inducibility of ventricular arrhythmias at electrophysiologic study ( p<0.001 ) .
our data demonstrate that the twa test has a positive predictive value ( ppv ) of 100% for positive twa test and of 67% for abnormal twa , and a negative predictive value ( npv ) of 100% in predicting the inducibility of ventricular arrhythmias during electrophysiologic study ( tab .
table ii- correlation between twa test and electrophysiologic studynegativeeespositiveeespnegative twa28 ( 100%)0 ( 0%)p<0.001indeterminate twa5 ( 71%)2 ( 29%)p = nspositive twa0 ( 0%)8 ( 100%)p = nsabnormal twa ( indeterminate + positive)5 ( 33%)10 ( 67%)p<0.001
during a mean follow - up of 25 months , 3 patients ( 7% ) experienced an arrhythmic event regarded as the end - point of the study ( vf in 1 patient , svt in 1 and both arrhythmias in 1 ) . the difference in end - point occurrence rate was significant between patients with a negative twa test ( 0% ) and those with a positive twa test ( 37.5% ) ( p<0.01 ) . the difference in end - point occurrence was significant also considering patients with negative ( 0% ) or abnormal twa test ( 20% ) ( p<0.05 ) . in our study ,
the twa test predicted the occurrence of malignant ventricular arrhythmias with an npv of 100% and a ppv of 37.5% for positive twa and 20% for abnormal twa ( fig .
4- kaplan - meier survival curves comparing end - point occurrence between patients with negative , indeterminate and positive twa . - kaplan - meier survival curves comparing end - point occurrence between patients with negative , indeterminate and positive twa .
similarly , there was a significant difference in endpoint occurrence rate between patients in whom the electrophysiologic study proved positive and those in whom it was negative ( 30% vs 0% ) ( p<0.01 ) .
the electrophysiologic study predicted the occurrence of malignant ventricular arrhythmias with an npv of 100% and a ppv of 30% ( fig .
5- kaplan - meier survival curves comparing end - point occurrence between patients with negative and positive ees . - kaplan - meier survival curves comparing end - point occurrence between patients with negative and positive ees .
microvolt - twa testing proved negative in 28 patients ( 65% ) , positive in 8 ( 19% ) and indeterminate because of excessive noise in 7 ( 16% ) ( fig .
there were no significant differences between patients with positive , indetermined or negative twa in terms of age , sex , ejection fraction , sports activity , and clinical presentation ( tab .
table i- comparison of clinical and demographic characteristics between patients with negative , indeterminate and positive twanegativetwaindeterminatetwapositivetwapage34 1333 1034 9p = nsmales21 ( 75%)4 ( 57%)6 ( 75%)p = nssport - soccer5 ( 18%)2 ( 28%)2 ( 25%)p = ns - running7 ( 25%)3 ( 44%)2 ( 25%)p = ns - skiing2 ( 7%)1 ( 14%)0 ( 0%)p = ns - cycling4 ( 14%)1 ( 14%)2 ( 25%)p = ns - motorcycling1 ( 4%)0 ( 0%)0 ( 0%)p = ns - volleyball4 ( 14%)0 ( 0%)1 ( 12.5%)p = ns - swimming4 ( 14%)0 ( 0%)0 ( 0%)p = ns - climbing1 ( 4%)0 ( 0%)0 ( 0%)p = ns - gymnastics0 ( 0%)0 ( 0%)1 ( 12.5%)p = nsef ( % ) 66 566 565 4p = nsarrhythmias - vebs19 ( 68%)5 ( 71%)4 ( 50%)p = ns - nsvts9 ( 32%)2 ( 29%)2 ( 25%)p = ns - svts0 ( 0%)0 ( 0%)2 ( 25%)p = ns
fig .
2- positive twa test in a 23-year - old male athlete with ventricular arrhythmias . -
malignant ventricular arrhythmias were induced through programmed ventricular stimulation in 10 patients ( 23% ) , and were not induced in 33 ( 77% ) ( fig .
3 ) . there were no significant differences between these patients in terms of age , sex , clinical presentation , ejection fraction , sports activity and clinical presentation .
3- induction of vf during programmed ventricular stimulation ( double extrastimulus ) in the same patient of figure 2 .
- induction of vf during programmed ventricular stimulation ( double extrastimulus ) in the same patient of figure 2 .
malignant ventricular arrhythmias were not inducible during electrophysiologic study in any of the subjects in whom the twa test was negative .
logistic regression analysis demonstrated a significant correlation between a negative microvolt - twa test and non - inducibility of ventricular arrhythmias during electrophysiologic study ( p<0.001 ) .
in contrast , in all patients with a positive twa test , ventricular tachyarrhythmias were inducible during electrophysiologic study ( svt requiring external defibrillation in 6 patients and ventricular fibrillation in 2 patients ) .
however , logistic regression analysis did not show a significant correlation between a positive twa test and inducibility of ventricular arrhythmias during electrophysiologic study . of the patients in whom the twa test was indeterminate , 2 ( 29% ) showed inducibility of ventricular arrhythmias during electrophysiologic study ( sustained ventricular tachycardia requiring external defibrillation in all patients ) , while in 5 ( 71% ) the electrophysiologic study was negative .
logistic regression analysis did not show a significant correlation between an indeterminate twa test and inducibility or non - inducibility of ventricular arrhythmias during electrophysiologic study ( p>0.05 ) . however , logistic regression analysis showed significant correlation between abnormal twa test ( positive or indeterminate ) and inducibility of ventricular arrhythmias at electrophysiologic study ( p<0.001 ) .
our data demonstrate that the twa test has a positive predictive value ( ppv ) of 100% for positive twa test and of 67% for abnormal twa , and a negative predictive value ( npv ) of 100% in predicting the inducibility of ventricular arrhythmias during electrophysiologic study ( tab .
table ii- correlation between twa test and electrophysiologic studynegativeeespositiveeespnegative twa28 ( 100%)0 ( 0%)p<0.001indeterminate twa5 ( 71%)2 ( 29%)p = nspositive twa0 ( 0%)8 ( 100%)p = nsabnormal twa ( indeterminate + positive)5 ( 33%)10 ( 67%)p<0.001
during a mean follow - up of 25 months , 3 patients ( 7% ) experienced an arrhythmic event regarded as the end - point of the study ( vf in 1 patient , svt in 1 and both arrhythmias in 1 ) .
the difference in end - point occurrence rate was significant between patients with a negative twa test ( 0% ) and those with a positive twa test ( 37.5% ) ( p<0.01 ) .
the difference in end - point occurrence was significant also considering patients with negative ( 0% ) or abnormal twa test ( 20% ) ( p<0.05 ) . in our study ,
the twa test predicted the occurrence of malignant ventricular arrhythmias with an npv of 100% and a ppv of 37.5% for positive twa and 20% for abnormal twa ( fig .
4- kaplan - meier survival curves comparing end - point occurrence between patients with negative , indeterminate and positive twa
. - kaplan - meier survival curves comparing end - point occurrence between patients with negative , indeterminate and positive twa .
similarly , there was a significant difference in endpoint occurrence rate between patients in whom the electrophysiologic study proved positive and those in whom it was negative ( 30% vs 0% ) ( p<0.01 ) .
the electrophysiologic study predicted the occurrence of malignant ventricular arrhythmias with an npv of 100% and a ppv of 30% ( fig .
5- kaplan - meier survival curves comparing end - point occurrence between patients with negative and positive ees
. - kaplan - meier survival curves comparing end - point occurrence between patients with negative and positive ees .
ventricular ectopic beats have been detected by surface electrocardiogram in 1% of the general population , and by 24-hour ambulatory ecg holter monitoring in 40% to 75% of apparently healthy subjects ( 1619 ) .
however , athletes constitute a particular population of healthy people , in that they show a high prevalence of morphological cardiac alterations ( a condition known as athlete s heart ) , electrocardiographic abnormalities ( wave voltage modification , st and t wave changes ) and frequent and/or complex ventricular beats .
consequently , it is not easy to make a differential diagnosis with heart diseases at risk of sudden death , such as , for example , hypertrophic and dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy , which are often difficult to diagnose in their initial phase .
the onset of these alterations in the athlete s heart can be due to adaptation to dynamic sports activity and the impact of training on cardiac cavity size .
several prospective studies have shown that detraining and physical deconditioning can result in cardiac reverse remodeling , with a reduction in cavity size , and in the reversibility of ventricular arrhythmias , which is complete in about 25% of subjects and partial in 50% ( 2022 ) .
biffi et al ( 23 ) reported that the presence of frequent and/or complex ventricular beats in competitive athletes did not indicate an adverse prognosis in subjects without underlying structural heart disease .
nevertheless , the detection of frequent and complex ventricular arrhythmias in a competitive athlete requires particular attention on the part of cardiologists and sports physicians in order to determine whether these arrhythmias have a good prognosis or are potentially life - threatening . in recent studies ,
several authors have reported that competitive athletes with silent arrhythmogenic heart disease have a higher risk of sudden death than sedentary subjects of the same age and with a similar latent cardiac substrate ( 2427 ) . when frequent and complex ventricular arrhythmias are diagnosed in a young athlete ,
firstly , it is mandatory to clarify whether there is an undiagnosed structural heart disease .
if diagnostic screening does not demonstrate the presence of heart disease , there are other issues to consider : the role of intense training on the arrhythmic pattern in young athletes and the potential usefulness of detraining , the criteria of eligibility for sports activity , the importance of the athlete s own wishes and the pressure exerted by family members and coaches .
the value of twa in predicting ventricular tachyarrhythmias in patients with congestive heart failure and with previous myocardial infarction has been evaluated in several clinical studies ( 7 , 13 , 28 ) .
these reports document a highly significant statistical association between positive twa and ventricular tachyarrhythmic events .
gehi et al ( 29 ) recently conducted a meta - analysis of the results of 19 studies carried out on a wide range of subjects , including those with ischemic or non - ischemic congestive heart failure , coronary artery disease , athletes and healthy individuals .
these authors found that the risk of tachyarrhythmic events was nearly four - fold higher in subjects in whom twa testing was positive than in those in whom it was negative , and that there was no difference between patients with ischemic or non - ischemic heart failure . the positive predictive value of twa varied in the meta - analysis from 0% to 51% , depending on the patient population studied , while the negative predictive value was 97% ( 29 ) .
very few data are available on the risk stratification of sudden cardiac death and severe ventricular tachyarrhythmic events in athletes with ventricular arrhythymias . in a multi - center study of 52 competitive athletes with severe arrhythymias ,
furlanello et al ( 27 ) found a high negative predictive value of twa when both programmed ventricular stimulation and follow up were used as endpoints .
unfortunately , the limited number of athletes with positive twa in this study did not allow to obtain a significant positive predictive value .
in our population of athletes undergoing twa evaluation and programmed ventricular stimulation , we documented a significant correlation between twa test negativity and non - inducibility of ventricular arrhythmias through programmed ventricular stimulation .
in contrast , our study did not show a significant correlation between positive or indeterminate twa testing and the result of electrophysiologic study , although we found a non - significant trend towards correlation with inducibility of ventricular arrhythmias .
however , this correlation become significant if we consider patients with abnormal twa ( positive and indeterminate ) .
the pathophysiological reason for this trend may be that twa testing often proves indeterminate in patients with very frequent and complex ventricular ectopic beats ; in such subjects , programmed ventricular stimulation can induce ventricular arrhythmias , and arrhythmic events may occur during follow up . in our study ,
twa testing showed a very high npv ( 100% ) and ppv ( 100% for positive twa and 67% for abnormal twa ) in predicting the result of programmed ventricular stimulation .
however , a larger study population may be needed in order to demonstrate a significant correlation between positive and indeterminate twa testing and inducibility of ventricular arrhythmias during electrophysiologic study .
review of a number of prospective studies conducted in a variety of clinical patient populations , including subjects with non - ischemic or ischemic cardiac disease , syncope , dilated cardiomyopathy and congestive heart failure , suggests that the occurrence rate of severe ventricular tachyarrhythmias in patients with positive twa is equivalent to that of ventricular tachyarrhythmias in patients with a positive result on programmed ventricular stimulation during electrophysiologic endocavitary study .
the event rate among patients with negative twa is low , and in many cases lower than the event rate in patients with a negative response to programmed ventricular stimulation ( 7 , 12 , 13 , 28 ) .
rosenbaum et al ( 4 ) evaluated t wave alternans as a predictor of severe arrhythmic events in a group of 83 patients who underwent programmed ventricular stimulation for previous tachyarrhythmic events . during a follow - up of 20 months
, kaplan - meier survival analysis showed that twa had a good predictive value , in that the rates of arrhythmia - free survival were 94% in patients with negative twa and 19% in those with positive twa . in a multi - center trial of 313 patients undergoing programmed ventricular stimulation and twa testing , gold et al ( 7 ) documented that twa was a highly significant predictor of major ventricular tachyarrhythmias . during
follow up , the presence of positive twa was associated with a relative risk of 10.9 , versus 7.1 for ees and 4.5 for signal - averaged electrocardiography ( saecg ) , for the end - point of sudden cardiac death and sustained ventricular tachycardia , ventricular fibrillation or icd implantation .
in many studies , twa has proved to be equivalent to programmed ventricular stimulation and better than saecg in the risk stratification of patients for life - threatening arrhythmias ( 4 , 7 , 11 , 3032 ) . in our study
we found a significant difference between patients with positive and negative twa tests with regard to the occurrence of sudden death , ventricular fibrillation and sustained ventricular tachycardia during an average follow - up of 25 months .
kaplan - meier survival analysis showed a 100% rate of end - point - free survival in patients with a negative twa test and a 62.5% rate in subjects with a positive twa test , suggesting that twa can also predict spontaneous malignant arrhythmic events in athletes with ventricular arrhythmias .
the difference was significant also considering patients with abnormal twa , in whom there was a 80% rate of end - point - free survival .
the npv ( 100% ) and ppv ( 37.5% for positive twa test and 20% for abnormal twa test ) obtained in our study are comparable to those reported by gehi et al ( 29 ) in different populations .
few studies have evaluated t wave alternans as a predictor of arrhythmic events in competitive athletes , and little information is available on the comparison of twa and programmed ventricular stimulation in arrhythmia risk stratification in this population ( 27 ) . in our study ,
the predictive accuracy of invasive programmed ventricular stimulation during ees was similar to that of twa .
these results , which were obtained in a single - center experience , are in line with those from a multicenter study by furlanello et al ( 27 ) on 52 competitive athletes , and suggest that twa may play an important role in the prognostic stratification of athletes with ventricular arrhythmias .
unlike electrophysiological study , which is an invasive procedure requiring hospitalization , twa testing is non - invasive , cheap , easy to perform and repeatable during follow - up .
review of a number of prospective studies conducted in a variety of clinical patient populations , including subjects with non - ischemic or ischemic cardiac disease , syncope , dilated cardiomyopathy and congestive heart failure , suggests that the occurrence rate of severe ventricular tachyarrhythmias in patients with positive twa is equivalent to that of ventricular tachyarrhythmias in patients with a positive result on programmed ventricular stimulation during electrophysiologic endocavitary study .
the event rate among patients with negative twa is low , and in many cases lower than the event rate in patients with a negative response to programmed ventricular stimulation ( 7 , 12 , 13 , 28 ) .
rosenbaum et al ( 4 ) evaluated t wave alternans as a predictor of severe arrhythmic events in a group of 83 patients who underwent programmed ventricular stimulation for previous tachyarrhythmic events . during a follow - up of 20 months
, kaplan - meier survival analysis showed that twa had a good predictive value , in that the rates of arrhythmia - free survival were 94% in patients with negative twa and 19% in those with positive twa . in a multi - center trial of 313 patients undergoing programmed ventricular stimulation and twa testing , gold et al ( 7 ) documented that twa was a highly significant predictor of major ventricular tachyarrhythmias . during
follow up , the presence of positive twa was associated with a relative risk of 10.9 , versus 7.1 for ees and 4.5 for signal - averaged electrocardiography ( saecg ) , for the end - point of sudden cardiac death and sustained ventricular tachycardia , ventricular fibrillation or icd implantation . in many studies ,
twa has proved to be equivalent to programmed ventricular stimulation and better than saecg in the risk stratification of patients for life - threatening arrhythmias ( 4 , 7 , 11 , 3032 ) . in our study
we found a significant difference between patients with positive and negative twa tests with regard to the occurrence of sudden death , ventricular fibrillation and sustained ventricular tachycardia during an average follow - up of 25 months .
kaplan - meier survival analysis showed a 100% rate of end - point - free survival in patients with a negative twa test and a 62.5% rate in subjects with a positive twa test , suggesting that twa can also predict spontaneous malignant arrhythmic events in athletes with ventricular arrhythmias .
the difference was significant also considering patients with abnormal twa , in whom there was a 80% rate of end - point - free survival .
the npv ( 100% ) and ppv ( 37.5% for positive twa test and 20% for abnormal twa test ) obtained in our study are comparable to those reported by gehi et al ( 29 ) in different populations .
few studies have evaluated t wave alternans as a predictor of arrhythmic events in competitive athletes , and little information is available on the comparison of twa and programmed ventricular stimulation in arrhythmia risk stratification in this population ( 27 ) . in our study ,
the predictive accuracy of invasive programmed ventricular stimulation during ees was similar to that of twa .
these results , which were obtained in a single - center experience , are in line with those from a multicenter study by furlanello et al ( 27 ) on 52 competitive athletes , and suggest that twa may play an important role in the prognostic stratification of athletes with ventricular arrhythmias .
unlike electrophysiological study , which is an invasive procedure requiring hospitalization , twa testing is non - invasive , cheap , easy to perform and repeatable during follow - up .
twa is an effective non - invasive predictor of the risk of severe ventricular tachyarrhythmias and sudden cardiac death in competitive athletes , its efficacy being at least comparable to that of invasive programmed ventricular stimulation . in particular ,[/INST]introduction : aim of our study is to evaluate the role of twa to stratify the risk of sudden cardiac death in athletes ( ath ) with complex ventricular arrhythmias ( va ) , and to document a possible correlation between twa and electrophysiological testing ( ees ) results.methods:we studied 43 ath with va ( 31 m , mean age 34 12 years ) . in all cases a cardiological evaluation was performed , including twa and ees . the patients were evaluated during a follow - up of 25 22 months .
the end - point was the occurrence of sudden death or malignant ventricular tachyarrhythmias ( vt).results : twa was negative in 28 ath ( 65% ) , positive in 8 ( 19% ) and indeterminate in 7 ( 16% ) .
all subjects with negative twa did not show induction of vt at ees , with significant correlation between negative twa and negative ees ( p<0.001 ) .
all ath with positive twa also had vt induced by a ees , but without significant correlation between positive twa and positive ees . in 2 ath with undetermined twa ( 29% )
vt were induced at ees .
our data did not show significant correlation between indeterminate twa and positive or negative ees . however , logistic regression analysis showed significant correlation between abnormal twa test ( positive or indeterminate ) and inducibility of vt at ees ( p<0.001 ) . during follow - up
we observed a significant difference in end - point occurrence between ath with negative or positive twa and between ath with negative or positive ees.conclusion:twa confirm its role as a simple and non - invasive test , and it seems useful for prognostic stratification of ath with va .</s> |
Fact Check: Those statistics are based on one analysis of preliminary crime data released by the Justice Department, and they accurately reflect what officials say is a spike in murders in some big cities. It leaves out the drop in others, like New York City, which saw a 25 percent drop in homicides in the first three months of 2016.
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• “In our nation’s capital, killings have risen by 50 percent. They are up nearly 60 percent in nearby Baltimore.”
Fact Check: Those statistics are based on an analysis performed by The Washington Post, which found no clear pattern in which cities saw increases in homicides.
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• “In the president’s hometown of Chicago, more than 2,000 have been the victims of shootings this year alone. And almost 4,000 have been killed in the Chicago area since he took office.”
Fact Check: This is largely true. The Chicago police department reports 2,242 shootings so far in 2016. And while it is unclear exactly what Mr. Trump means by “the Chicago area,” that figure appears to track with reported murders since the start of 2009.
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• “The number of police officers killed in the line of duty has risen by almost 50 percent compared to this point last year.”
Fact Check: In fact, the Officer Down Memorial Page, which tracks officer deaths, reports that 68 police officers have been killed so far this year, almost exactly the same as the 69 who were killed in the same period last year.
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• “Nearly 180,000 illegal immigrants with criminal records, ordered deported from our country, are tonight roaming free to threaten peaceful citizens.”
Fact Check: Those numbers come from a report by the Department of Homeland Security, which told Congress late last year that nearly 1 million undocumented immigrants have been ordered deported but remain in the country. Mr. Trump did not mention that most of those 180,000 are likely people charged with nonviolent crimes.
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• “The number of new illegal immigrant families who have crossed the border so far this year already exceeds the entire total from 2015.”
Fact Check: This is true, according to reports from the Border Patrol, which said that more than 51,000 families have been apprehended on the border in the first nine months of the fiscal year, compared to about 40,000 last fiscal year. But that is still less than 2014, when a surge of families across the border caused a political stir.
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• “Nearly four in 10 African-American children are living in poverty, while 58 percent of African-American youth are not employed.”
Fact Check: According to the Bureau of Labor Statistics, the unemployment rate of African Americans ages 16-19 in June was 31.2 percent (among whites of the same age, it was 14.1 percent).
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• “Household incomes are down more than $4,000 since the year 2000.”
Fact Check: This is mostly true. Median household income in 2000 was $57,724; in 2014, which has the most recent available data, it was $53,657.
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• “Our manufacturing trade deficit has reached an all-time high – nearly $800 billion in a single year.”
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Fact Check: The goods deficit — more imported goods, less exported goods — was $763 billion last year. But that includes agricultural products and raw materials like coal. Moreover, the total trade deficit last year was only $500 billion because the U.S. runs a trade surplus in services.
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• “President Obama has doubled our national debt to more than $19 trillion, and growing.”
Fact Check: The national debt was $10.6 trillion on the day Obama took office. It was $19.2 trillion in April, so not quite double, but close.
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• “Forty-three million Americans are on food stamps.”
Fact Check: As of October, this figure was largely accurate, according to the United States Department of Agriculture.
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• “In 2009, pre-Hillary, ISIS was not even on the map. Libya was cooperating. Egypt was peaceful. Iraq was seeing and, really, a big, big reduction in violence. Iran was being choked by sanctions. Syria was under control.”
Fact Check: Mr. Trump is mostly right. But Libya, Syria and Egypt were swept up in the Arab Spring, an uprising out of Mrs. Clinton’s and Mr. Obama’s control. And the sanctions on Iran were just getting ramped up at that time; they became far tougher under the Obama administration than they were during the Bush administration. That helped force Tehran to the negotiating table for last year’s deal.
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• “This was just prior to the signing of the Iran deal, which gave back to Iran $150 billion and gave us nothing — it will go down in history as one of the worst deals ever negotiated.”
Fact Check: The deal does not directly give Iran money, but by easing or terminating sanctions, it would allow Iran to have access to many billions of dollars of its own money that has been frozen in overseas accounts. And the exact value of those sanctions is debatable.
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• “My opponent has called for a radical 550 percent increase in Syrian refugees on top of existing massive refugee flows coming into our country under the leadership of President Obama.”
Fact Check: This is true, as Mrs. Clinton said in September she wanted to “move from what is a good start with 10,000 to 65,000.” But she also said she would improve the already extensive vetting process, especially from Syria. ||||| Republican Presidential Candidate Donald Trump gestures as he speaks during the final day of the Republican National Convention in Cleveland, Thursday, July 21, 2016. (AP Photo/Mark J. Terrill) (Associated Press)
Republican Presidential Candidate Donald Trump gestures as he speaks during the final day of the Republican National Convention in Cleveland, Thursday, July 21, 2016. (AP Photo/Mark J. Terrill) (Associated Press)
Republican Presidential Candidate Donald Trump gestures as he speaks during the final day of the Republican National Convention in Cleveland, Thursday, July 21, 2016. (AP Photo/Mark J. Terrill) (Associated Press) Republican Presidential Candidate Donald Trump gestures as he speaks during the final day of the Republican National Convention in Cleveland, Thursday, July 21, 2016. (AP Photo/Mark J. Terrill) (Associated Press)
WASHINGTON (AP) — Despite promising "the truth, and nothing else" in his convention speech, Donald Trump presented the nation with a series of previously debunked claims and some new ones Thursday night — about the U.S. tax burden, the perils facing police, Hillary Clinton's record and more.
A look at some of the Republican presidential candidate's claims and how they compare with the facts:
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TRUMP: "Decades of progress made in bringing down crime are now being reversed by this administration's rollback of criminal enforcement. Homicides last year increased by 17 percent in America's 50 largest cities. That's the largest increase in 25 years."
THE FACTS: A rollback? President Barack Obama has actually achieved some big increases in spending for state and local law enforcement, including billions in grants provided through the 2009 stimulus. While FBI crime statistics for 2015 are not yet available, Trump's claim about rising homicides appears to come from a Washington Post analysis published in January. While Trump accurately quotes part of the analysis, he omits that the statistical jump was so large because homicides are still very low by historical standards. In the 50 cities cited by the Post, for example, half as many people were killed last year as in 1991.
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TRUMP: "The number of new illegal immigrant families who have crossed the border so far this year already exceeds the entire total from 2015. They are being released by the tens of thousands into our communities with no regard for the impact on public safety or resources."
THE FACTS: The pace of releasing immigrants is driven not by the Obama administration, but by a court ruling. A federal judge ruled last year that the government couldn't hold parents and children in jail for more than 20 days. An appeals court partially rolled that back earlier this month, saying that parents could be detained but children must be released.
By the standard used by the government to estimate illegal border crossings - the number of arrests — Trump is right that the number in this budget year has already exceeded last year's total. But it's down from 2014.
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TRUMP: "When a secretary of state illegally stores her emails on a private server, deletes 33,000 of them so the authorities can't see her crime, puts our country at risk, lies about it in every different form and faces no consequence - I know that corruption has reached a level like never before."
THE FACTS: Clinton's use of a private server to store her emails was not illegal under federal law. Her actions were not established as a crime. The FBI investigated the matter and its role was to advise the Justice Department whether to bring charges against her based on what it found. FBI Director James Comey declined to refer the case for criminal prosecution to the Justice Department, instead accusing Clinton of extreme carelessness.
As for Trump's claim that Clinton faces no consequence, that may be true in a legal sense. But the matter has been a distraction to her campaign and fed into public perceptions that she can't be trusted. The election will test whether she has paid a price politically.
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TRUMP: "The number of police officers killed in the line of duty has risen by almost 50 percent compared to this point last year."
THE FACTS: Not according to the National Law Enforcement Officers Memorial Fund, which tracks police fatalities daily. The group found that the number of police officers who died as of July 20 is up just slightly this year, at 67, compared with 62 through the same period last year. That includes deaths in the line of duty from all causes, including traffic fatalities.
It is true that there has been a spike in police deaths from intentional shootings, 32 this year compared with 18 last year, largely attributable to the recent mass shootings in Dallas and Baton Rouge. But that was not his claim.
And overall, police are statistically safer on America's streets now than at any time in recent decades.
For example, the 109 law enforcement fatalities in 2013 were the lowest since 1956.
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TRUMP: "Two million more Latinos are in poverty today than when President Obama took his oath of office less than eight years ago. Another 14 million people have left the workforce entirely. ... President Obama has almost doubled our national debt to more than $19 trillion, and growing."
THE FACTS: Trump is playing with numbers to make the economy look worse than it actually is. The sluggish recovery over the past seven years has been frustrating. But with unemployment at 4.9 percent, the situation isn't as bleak as he suggests.
Trump's figure of 14 million who've stopped working since Obama took office comes from the Labor Department's measure of people not in the workforce. It's misleading for three reasons: The U.S. population has increased in that time; the country has aged and people have retired; and younger people are staying in school longer for college and advanced degrees, so they're not in the labor force, either.
A better figure is labor force participation — the share of people with jobs or who are searching for work. That figure has declined from 65.7 percent when Obama took office to 62.7 percent now. Part of that decrease reflects retirements, but the decline is also a long-term trend.
On national debt, economists say a more meaningful measure than dollars is the share of the overall economy taken up by the debt. By that measure, the debt rose 36 percent under Obama (rather than doubling). That's roughly the same as what occurred under Republican President George W. Bush.
The Hispanic population has risen since Obama while the poverty rate has fallen. The Pew Research Center found that 23.5 percent of the country's 55.3 million Latinos live in poverty, compared with 24.7 percent in 2010.
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Associated Press writers Josh Boak, Stephen Braun, Deb Riechmann, Jim Drinkard and Alicia A. Caldwell in Washington and Elliot Spagat in San Diego contributed to this report. ||||| Donald Trump painted a dark picture of America during his acceptance speech at the Republican National Convention, but some of his doomsday stats are rather dubious. The Post's Fact Checker examined 25 of his key claims. (Jenny Starrs/The Washington Post)
The dark portrait of America that Donald J. Trump sketched in his acceptance speech at the Republican National Convention is a compendium of doomsday stats that fall apart upon close scrutiny. Numbers are taken out of context, data is manipulated, and sometimes the facts are wrong.
When facts are inconveniently positive — such as rising incomes and an unemployment rate under 5 percent — Trump simply declines to mention them. He describes an exceedingly violent nation, flooded with murders, when in reality, the violent-crime rate has been cut in half since the crack cocaine epidemic hit its peak in 1991.
In his speech, Trump promised to present “the plain facts that have been edited out of your nightly news and your morning newspaper.” But he relies on statistics that are ripe for manipulation, citing misleading numbers on the economy, for example, through selective use of years, data and sources.
Here is a rundown of 25 of Trump’s key claims — and how they differ from reality — arranged by subject. As is our practice, we do not award Pinocchios for a roundup of claims made in convention events.
Crime
“Homicides last year increased by 17 percent in America’s 50 largest cities. That’s the largest increase in 25 years. In our nation’s capital, killings have risen by 50 percent. They are up nearly 60 percent in nearby Baltimore.”
Trump cherry-picks data to paint an alarming picture of homicide trends, when in reality, they have been declining for decades.
In 2015, there was an uptick in homicides in 36 of the 50 largest cities compared to the previous years. The rate did, indeed, increase nearly 17 percent, and it was the worst annual change since 1990. The homicide rate was up 54.3 percent in Washington, and 58.5 percent in Baltimore.
But in the first months of 2016, homicide trends were about evenly split in the major cities. Out of 63 agencies reporting to the Major Cities Chiefs Association, 32 cities saw a decrease in homicides in first quarter 2016 and 31 saw an increase.
The problem with cherry-picking such data is that crime trends are measured over decades of data. Many factors — even weather — can drive crime numbers up or down at a given short period of time. In reality, homicides and overall violent crime, in both raw number and rates per population, have been on a decades-long decline in major cities.
“The debate over the size, scope and causes of the homicide increase in 2015 has been largely free of systematic evidence,” according to a June 2016 Department of Justice report.
“The number of police officers killed in the line of duty has risen by almost 50 percent compared to this point last year.”
This is wrong.
The number of law enforcement officers killed on the job has increased 8 percent compared to this point in 2015. He may be referring to the total number of officers killed in shootings, which has increased 78 percent. This includes the recent shootings in Dallas and Baton Rouge.
The overall number of police deaths has decreased in the past two decades. For the past 10 to 15 years, traffic-related incidents (including criminal pursuit and instances where officers are intentionally struck by offenders) have been the leading cause of death among police officers.
[Update: The Trump campaign responded to our fact-check and provided more information about the data they used for the speech. The campaign picked July 2014 to July 2015, and compared it to July 2015 to July 2016, using data from the Officers Down Memorial Page. The memorial page works with the National Law Enforcement Officers Memorial Fund, whose data we cited initially for our fact-check, to update officer death data in real time.
This is not the standard way that both organizations and the FBI maintain police death data, which is by calendar year. The campaign said that it wanted to reflect the latest available data, to show police deaths have “been getting worse in recent days.”]
“Decades of progress made in bringing down crime are now being reversed by this administration’s rollback of criminal enforcement.”
It’s not clear what Trump is referring to here. Perhaps this is a reference to Obama’s clemency initiative, granting early releases to prisoners with nonviolent drug offenses who have been serving mandatory sentences. Some critics of Obama’s clemency policies have said they were concerned about the application process for clemency and whether the prisoners properly met all the criteria.
Trump also may be referring to the current efforts to overhaul the criminal justice system, specifically on sentencing policies. Legislation is making its way through Congress and has been pushed strongly by the White House. But this effort has bipartisan support and has brought together an unlikely coalition that includes Koch Industries and the American Civil Liberties Union.
Immigration
“The number of new illegal immigrant families who have crossed the border so far this year already exceeds the entire total from 2015. They are being released by the tens of thousands into our communities with no regard for the impact on public safety or resources.”
This is another cherry-picked number. In the fiscal year that began in October, 51,152 families have been apprehended at the Southwest border through June, compared to 39,838 in fiscal year 2015, according to U.S. Customs and Border Protection. (There are three months left in the fiscal year.) But overall apprehensions, including unaccompanied minors, are running slightly higher than 2015 but are far fewer than 2014, 2013 and 2012.
There are Central American families arriving at the U.S.-Mexico border who are being allowed into the country pending review of their cases in immigration court. If they are being released, it is because they have requested asylum or intend to because they are fleeing extreme violence, instability and endemic poverty in El Salvador, Guatemala and Honduras.
“Nearly 180,000 illegal immigrants with criminal records, ordered deported from our country, are tonight roaming free to threaten peaceful citizens.”
This number sounds worse than it really is. U.S. Immigration and Customs Enforcement in fiscal 2015 deported nearly 140,000 convicted criminals. ICE has estimated that there are 953,507 noncitizens with final orders who are still in the United States, of whom 182,786 have been convicted of crimes; 176,126 have not been detained.
The actual crimes committed by this group are not documented, so Trump cannot easily claim all of these illegal immigrants are threatening.
The Migration Policy Institute, using a dataset of all 3.7 million deportations that were carried out between fiscal 2003 and 2013, found that the largest category of convictions for criminal deportees was immigration crimes, accounting for 18 percent of criminal removals between FY 2003-13. The three next largest crime categories were FBI Part 1 crimes (a definition that includes homicide, aggravated assault and burglary, 15 percent of criminal removals during the period), FBI Part 2 crimes identified by MPI as violent offenses (14 percent) and FBI Part 2 crimes identified by MPI as nonviolent offenses (14 percent).
Update: The Center for Immigration Studies points to data concerning illegal immigrants released from detention. For instance, in 2015, ICE released nearly 20,000, of whom there were about 8,000 violent convictions and about 200 homicides; the most common crime was driving under the influence. Jessica Vaughan of CIS also wrote a critique of our fact check.)
“Decades of record immigration have produced lower wages and higher unemployment for our citizens, especially for African American and Latino workers.”
This claim is quite convoluted, and the impact of legal and illegal immigration on blacks and Latinos is more complicated than Trump describes it.
Trump does not discern between legal and unauthorized immigration. Legal immigration flow has increased in the past four decades, and has remained at roughly 1 million people obtaining lawful permanent resident status every year since 2001. The unauthorized immigrant population increased from about 4 million in 1990 to about 12 million in 2007. But researchers estimate net zero illegal immigration flow from 2007 to 2014, due to the number of unauthorized immigrants leaving the country after the economic recession. Preliminary research from 2015 suggests net illegal immigration may have increased.
In general, economists have found that immigration overall results in a net positive to the U.S. economy and to overall workers. There are slight negative effects, but they are felt most strongly by less-educated and low-skilled workers. Illegal immigration, in particular, tends to affect less-educated and low-skilled American workers the most, which disproportionately comprises black men and recently arrived low-educated legal immigrants.
The U.S. Commission on Civil Rights 2010 report found that illegal immigration has tended to depress wages and employment particularly for black men. But factors other than illegal immigration contribute to black unemployment, the report found, including the high school dropout rate and low job-retention rates.
The competition with other Latinos, particularly Latino immigrants, is the most intense in industries like construction, agriculture, manufacturing and service jobs, said Randy Capps, the Migration Policy Institute’s director of research of U.S. programs. But the consensus among economic research studies is that the impact of immigration is primarily a net positive.
“One such border-crosser was released and made his way to Nebraska. There, he ended the life of an innocent young girl named Sarah Root. She was 21 years old and was killed the day after graduating from college with a 4.0 grade point average. Her killer was then released a second time, and he is now a fugitive from the law.”
Sarah Root is a relatively new anecdote of Donald Trump’s, though her story has been cited often by other immigration hard-liners.
Root, 21, died in a car crash 16 hours after she graduated summa cum laude from Bellevue University in Nebraska. She was driving home and was struck by a man whose blood alcohol level was more than three times the legal limit, and who was speeding in a truck.
The man was Eswin Mejia, 19, who was in the United States illegally. He was born in Honduras and arrived in America at age 16. He was released on bail, and fled. Authorities have not been able to find him, as of July 2016.
Mejia had several run-ins with law enforcement, but officials said he was not detained because he was not an “enforcement priority” and had no prior criminal convictions, according to the Des Moines Register.
Economy
“Fifty-eight percent of African American youth are not employed.”
The official unemployment rate for black youth is about half of what Trump says it is.
According to the Bureau of Labor Statistics, the unemployment rate among blacks 16 to 19 years old was 31.2 percent in June 2016. This official unemployment rate refers to jobless people who are actively looking for jobs, as a percentage of the total available workforce of people who are working or are looking for jobs.
What Trump may be referring to, as our friends at PolitiFact Virginia noted, is the BLS employment-population ratio. This is a broad measure that refers to the ratio of the number of people employed compared to the total population, including people who are not looking for jobs. The employment-population ratio for blacks 16 to 24 years old was 42 percent in June 2016, so Trump maybe using the flip side of that — 58 percent, for the unemployment-population ratio.
“2 million more Latinos are in poverty today than when the president took his oath of office.”
Trump is being misleading here, turning a good news story into something negative by using raw numbers and using 2008 as a base, instead of 2009, when Obama took office. From March 2009 to March, 2014, the most recent year for which data is available, the number of Latinos in poverty has increased 750,000, according to the Census Bureau. But the overall number of Latinos has grown by nearly 7 million, so the percentage in poverty has declined from 25.3 percent to 23.6 percent.
“Another 14 million people have left the workforce entirely.”
This is yet another misleading figure. The number of people who have left the workforce has certainly increased since 2009, though this is usually expressed as the labor participation rate, not raw employment numbers. The labor participation rate has dropped under Obama, from 65.7 percent in 2009 to 62.7 percent, but experts say just over half of the post-1999 decline in the participation rate comes from the retirement of the baby boomers. Economists estimate that just 15 percent of the drop in the labor force stems from people who want a job and are of prime working age (25-54).
“Household incomes are down more than $4,000 since the year 2000.”
This is a stale statistic, based on 2014 Census data, which ignores the fact that incomes have risen sharply in the last two years.
A more up-to-date figure is obtained from the nonpartisan economic consulting firm Sentier Research, which produces a monthly report using data from the Census Bureau’s monthly household survey.
The most recent report, released on the day of Trump’s speech, shows median annual household income in June was $57,206, slightly below the income of $57,826 in January 2000, in 2016 dollars. So it is essentially flat, not down $4,000.
“Forty-three million Americans are on food stamps.”
Trump’s point was that America’s economy has suffered under the Obama administration. But he fails to mention that this is actually the lowest number of people receiving food stamps since it reached its peak in 2013, a sign that the economy is finally improving enough that the delayed impact of economic recovery has reached families who depend on them.
There are 43.6 million people enrolled in the Supplemental Nutrition Assistance Program (SNAP), the official name for food stamps, as of the most recent monthly data available from April 2016. It was the lowest number of monthly enrollees since November 2010, U.S. Department of Agriculture data show.
The number of people receiving SNAP benefits increased after Obama took office in part because of changes in the food stamp program under President George W. Bush, when Congress overrode his veto of the 2008 Farm Bill. That law boosted the purchasing power of food stamps by indexing key elements to inflation.
At the same time, Obama’s stimulus bill also temporarily boosted benefits even more. The Obama administration also announced that it was pushing to expand eligibility, in part on the theory that expanding the food stamp program is also good for the economy because the money is quickly spent.
Of course, the economic aftershocks of the Great Recession, which was in full force before Obama took office, has a lot to do with the increase. There often is a time lag between when economic disaster strikes and when people begin to apply for food-stamp assistance. We explored these reasons in a 2011 fact check.
“America is one of the highest-taxed nations in the world.”
As a billionaire, Trump probably personally faces high tax rates. But the statistics don’t lie — the United States isn’t anywhere near the top among industrialized nations.
In 2014, according to comparative tables of the Organization for Economic Cooperation and Development (OECD), revenue as a percentage of the gross domestic product — the broadest measure of the economy — was 26 percent for the United States.
Out of 34 countries, that put the United States in the bottom third — and well below the OECD average of 34.4 percent.
Still, it’s an advance that Trump now says the United States is one of the highest-taxed nations. He used to assert the United States was the highest-taxed nation — when that dubious honor actually belongs to Denmark, with revenue at 50.9 percent of GDP.
“Excessive regulation is costing our country as much as $2 trillion a year.”
Trump presents an unbalanced figure here.
Various organizations, such as the Small Business Administration, the National Association of Manufacturers and the Competitive Enterprise Institute have come up with similar estimates on the cost of regulations. We have in the past looked deeply at the methodological issues concerning this $2 trillion estimate, which can be found in previous fact checks from 2014 and 2011.
But there is an important element missing in the use of this somewhat sketchy figure — the benefit side of the analysis. Every regulation has costs — but also benefits.
Look at cars, for example. Seat belts are a regulation, but they also result in fewer deaths, which is presumably a benefit. Higher fuel-economy standards raise the initial cost of a car, but also result in savings on gasoline over time.
Foreign Policy
“This was just prior to the signing of the Iran deal, which gave back to Iran $150 billion and gave us absolutely nothing — it will go down in history as one of the worst deals ever made.”
Trump frequently misstates the facts about the Iran deal, making it sound like the United States simply shipped $150 billion of taxpayer’s funds to Iran.
This was always Iran’s money, frozen in banks around the world, but $150 billion is the high estimate of the money that could be received. The Treasury Department says the figure is in the range of $100 to $125 billion, but the usual liquid assets would only be about $50 billion, as the rest of the assets are either obligated in illiquid projects (such as over 50 projects with China) that cannot be monetized quickly, if at all, or are composed of outstanding loans to Iranian entities that cannot repay them.
For its part, the Central Bank of Iran said the number was actually $32 billion.
Reasonable people can disagree on the merits of the Iran deal, but it’s a stretch to say “nothing” was received. Iran’s nuclear program was certainly put on ice for at least a decade.
“In Libya, our consulate – the symbol of American prestige around the globe — was brought down in flames.”
Trump falsely calls the Benghazi facility a “consulate” and a “symbol of American prestige.” It was merely an unofficial and temporary facility that had not even been declared to the host government — which is a key reason it did not get the security that was needed.
“In 2009, pre-Hillary, ISIS was not even on the map. Libya was cooperating. Egypt was peaceful. Iraq was seeing a reduction in violence. Iran was being choked by sanctions. Syria was somewhat under control.”
This is an interesting list, but aspects are not factually correct.
The Islamic State of today is simply an outgrowth of al-Qaeda in Iraq. It was established in April 2004 by longtime Sunni extremist Abu Musab al-Zarqawi, according to the National Counterterrorism Center. Zarqawi was killed by a U.S. airstrike in 2006, and afterward his successor announced the formation of the Islamic State — more than two years before George W. Bush left office.
The Islamic State certainly gained strength and territory from the civil war in Syria, but Clinton as secretary of state had pressed to funnel arms to the rebels; she was rebuffed by the president.
Libya, Syria and Egypt were run by dictators in 2009, but it’s odd to somehow suggest the 2011 uprising in those countries against the repressive regimes had much to do with U.S. policy.
As for sanctions against Iran, they did not really begin to bite until new ones were imposed by the Obama administration under the direction of Hillary Clinton.
“Only weeks ago, in Orlando, Florida, 49 wonderful Americans were savagely murdered by an Islamic terrorist. This time, the terrorist targeted our LGBTQ community.”
The FBI has found no evidence so far that the shooter targeted Pulse night club in Orlando because it is a gay club.
The shooting rattled the LGBT community in Orlando and beyond, who felt they were targeted in a hateful attack. But there is no evidence yet that the shooter’s attack was motivated by homophobia, The Washington Post reported on July 16.
“My opponent, in Syria — think of this, think of this, this is not believable but this is what’s happening. A 550 percentage increase in Syrian refugees on top of the existing massive refugee flows coming into our country already under the leadership of President Obama. She proposes this despite the fact that there’s no way to screen these refugees in order to find out who they are or where they come from.”
Trump gets it right on the “550” percentage, but falsely claims there’s “no way to screen” refugees.
President Obama has proposed accepting 10,000 refugees in fiscal year 2016, and in September Clinton said she would like to move toward as many as 65,000. That’s where Trump gets his “550 percent.” Clinton has emphasized there would be careful screening, with an emphasis on those facing religious persecution.
The process of vetting refugees starts with the United Nations High Commissioner for Refugees and then continues with checks by U.S. intelligence and security agencies. It takes one to two years, or longer in some cases. (Our colleagues at PolitiFact described this process in detail.)
Hillary Clinton
“In fact, her single greatest accomplishment may be committing such an egregious crime and getting away with it — especially when others who have done far less have paid so dearly.”
Trump likes to say “others” have gotten punished for far less than Hillary Clinton’s private email server, but there are few known cases that are comparable to hers. But Clinton’s case lacked malicious intent and other nefarious actions that are prerequisites for criminal charges.
The example Trump usually uses is Gen. David H. Petraeus. Petraeus knowingly leaked classified information in his personal notebooks for release to the public through his biographer, then lied to the FBI when he got caught. FBI Director James B. Comey said the Petraeus case “illustrates perfectly” the type of case the Department of Justice would be willing to prosecute: a combination of obstruction of justice, intentional misconduct and vast quantities of classified information. Those elements weren’t there in Clinton’s case. (For more on Clinton’s email controversy, see our complete collection of fact checks.)
“When that same secretary of state rakes in millions of dollars trading access and favors to special interests and foreign powers, I know the time for action has come.”
Trump has criticized Clinton’s record as secretary of state and donations given to the Clinton Foundation, as outlined in Peter Schweizer’s book, “Clinton Cash: The Untold Story of How and Why Foreign Governments and Businesses Helped Make Bill and Hillary Rich.”
Schweizer raises many questions about donations to the Clinton Foundation, led by Bill Clinton, while Hillary Clinton was secretary of state. But critics, including Schweizer, have not been able to prove quid pro quo.
“My opponent dismissed the VA scandal — one more sign of how out of touch she really is.”
Hillary Clinton has said the Department of Veterans Affairs wait-time scandal was not “as widespread as it has been made out to be,” but her campaign has walked back this statement after she was criticized for downplaying the scandal.
Below is the full exchange from MSNBC’s “The Rachel Maddow Show” in October 2015. The specific claim Trump is citing is in bold.
Rachel Maddow: The reason they [Republicans] are able to propose something that radical [privatizing the Department of Veterans Affairs] is because the problems at the VA seem so intractable. If I had been running Republican campaign against President Obama last year, I would have run it entirely on the VA — a bureaucracy, a bloated big government program that can’t be fixed, and let’s do right by our veterans. Do you have any new ideas for trying to fix it? You can’t find a person in politics who doesn’t say we shouldn’t do right by our veterans. But for some reason, this can’t get fixed fast enough. Hillary Clinton: Yes, and I don’t understand that. You know, I don’t understand why we have such a problem, because there have been a number of surveys of veterans. And overall, veterans who do get treated are satisfied with their treatment. … Now, nobody would believe that from the coverage that you see, and the constant berating of the VA that comes from the Republicans, in part in pursuit of this ideological agenda that they have. Maddow: But in part because there has been real scandal. Clinton: There has been. But it’s not been as widespread as it has been made out to be.
Clinton was criticized immediately, and her campaign later clarified that Clinton does believe there is a systemic problem of delays in veterans’ access to health care and processing their disability claims. The campaign told The Fact Checker that she was “speaking with reference to Republicans who have sought to use the wait times scandal to suggest the VA is so incompetent as to be beyond fixing, such that the only fix is privatization.”
Still, we awarded her Two Pinocchios for saying that a “number of surveys” show veterans “are satisfied with their treatment.” She was referring to VA satisfaction surveys funded by the VA or a nonscientific survey of veterans’ attitudes. Independent, scientific surveys show veterans’ attitudes toward medical care at the VA are mixed.
Trade
“America has lost nearly-one third of its manufacturing jobs since 1997, following the enactment of disastrous trade deals supported by Bill and Hillary Clinton.”
Trump picks a high point for manufacturing jobs, in Clinton’s second term, and ignores that fact that nearly 1 million manufacturing jobs have been added since the low point after the Great Recession. It is simplistic to pin all of the blame on trade agreements, when efficiency and technology have also played a major role.
“Remember, it was Bill Clinton who signed NAFTA, one of the worst economic deals ever made by our country.”
Bill Clinton was certainly a supporter of NAFTA who pushed approval through Congress. But it was negotiated and signed by President George H.W. Bush. (Here’s a photo.) Moreover, more Republicans than Democrats voted for the deal, as the trade pact was vehemently opposed by labor unions. One key ally for Clinton was then-House Minority Whip (and later House speaker) Newt Gingrich (R-Ga.), now a Trump supporter.
Clinton did put his political prestige on the line to get it approved by Congress — even as two top Democrats, House Majority Leader Richard Gephardt (Mo.) and House Majority Whip David Bonior (Mich.), opposed it. In the House, NAFTA passed 234-200; 132 Republicans and 102 Democrats voted in favor of it. The Senate approved NAFTA 61-38, with the backing of 34 Republicans and 27 Democrats.
In both the House and the Senate, more Democrats voted against NAFTA than for it — a signal that the Bernie Sanders wing of the Democratic Party was strong even then. Clinton held a signing ceremony for the implementing legislation on Dec. 3, 1993, flanked by former presidents and congressional leaders of both parties. But that’s not the same as negotiating and signing the treaty with Mexico and Canada. The trade agreement went into effect on Jan. 1, 1994.
As we have noted repeatedly before, economists have not reached any firm conclusion on the impact of NAFTA, but many think that claims of massive job losses are overstated. The Congressional Research Service in 2015 concluded that the “net overall effect of NAFTA on the U.S. economy appears to have been relatively modest, primarily because trade with Canada and Mexico accounts for a small percentage of U.S. GDP [gross domestic product].”
“She [Hillary Clinton] has supported the Trans-Pacific Partnership, which will not only destroy our manufacturing, but it will make America subject to the rulings of foreign governments.”
It’s a matter of opinion that the Trans-Pacific Partnership will “destroy” manufacturing — most economists would disagree — but the other part of Trump’s statement is fantasy sometimes promoted by the far-left. TPP, like other trade deals, does establish a commission to monitor implementation. It periodically may make suggestions on changes that are needed in the agreement as the global economy modernizes, but those changes have to be carried out through domestic processes.
All TPP members are already part of the World Trade Organization. It settles trade disputes and can allow for monetary retaliation. But the dispute settlement rulings cannot force changes in U.S. laws.
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Sign up for The Fact Checker weekly newsletter | – Despite promising "the truth, and nothing else" in his convention speech, Donald Trump presented the nation with a series of previously debunked claims and some new ones Thursday night—about the US tax burden, the perils facing police, Hillary Clinton's record, and more. Here's what fact-checkers at the AP, the New York Times, and the Washington Post made of his claims, which painted a bleak portrait of the USA in 2016: "The number of police officers killed in the line of duty has risen almost 50% compared to this point last year." False: According to the National Law Enforcement Officers Memorial Fund, line-of-duty deaths are up 8% this year, from 62 at this point last year to 67 so far this year. "Homicides last year increased by 17% in America's 50 largest cities. That's the largest increase in 25 years." True, though analysts say Trump cherry-picked those figures, omitting that the statistical jump was so large because homicides are still very low by historical standards—and are down again so far in 2016. "Two million more Latinos are in poverty today than when President Obama took his oath of office less than eight years ago." True, but misleading: The Hispanic population has risen since Obama took office, while the poverty rate has fallen. The Pew Research Center found that 23.5% of the country's 55.3 million Latinos live in poverty, compared with 24.7% in 2010. "Nearly four in 10 African-American children are living in poverty, while 58% of African-American youth are not employed." False: The correct youth unemployment figure is 31%, compared to 14% for whites. "America is one of the highest-taxed nations in the world." False: The US tax burden is actually the fourth lowest among the 34 developed and large emerging-market economies that make up the Organization for Economic Cooperation and Development, below only Chile, South Korea, and Mexico. Taxes made up 26% of the total US economy in 2014, according to the OECD, far below Sweden's tax burden of 42.7% or Germany's 36.1%. "Household incomes are down more than $4,000 since the year 2000." This would have been true in 2014, when the median household income was $53,657, compared to $57,724 in 2000. The most recent report puts median household income at $57,206, almost the same as in 2000, though the figures haven't been adjusted for inflation. "President Obama has doubled our national debt to more than $19 trillion, and growing." Almost true: the debt has gone from $10.6 trillion when Obama took office to $19.2 trillion as of April. The Post notes that not only has Trump cherry-picked or inflated many figures, he has simply ignored positive ones, "such as rising incomes and an unemployment rate under 5%," as well as the fact that the violent crime rate is still around half what it was 25 years ago. | <s>[INST]Fact Check: Those statistics are based on one analysis of preliminary crime data released by the Justice Department, and they accurately reflect what officials say is a spike in murders in some big cities. It leaves out the drop in others, like New York City, which saw a 25 percent drop in homicides in the first three months of 2016.
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• “In our nation’s capital, killings have risen by 50 percent. They are up nearly 60 percent in nearby Baltimore.”
Fact Check: Those statistics are based on an analysis performed by The Washington Post, which found no clear pattern in which cities saw increases in homicides.
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• “In the president’s hometown of Chicago, more than 2,000 have been the victims of shootings this year alone. And almost 4,000 have been killed in the Chicago area since he took office.”
Fact Check: This is largely true. The Chicago police department reports 2,242 shootings so far in 2016. And while it is unclear exactly what Mr. Trump means by “the Chicago area,” that figure appears to track with reported murders since the start of 2009.
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• “The number of police officers killed in the line of duty has risen by almost 50 percent compared to this point last year.”
Fact Check: In fact, the Officer Down Memorial Page, which tracks officer deaths, reports that 68 police officers have been killed so far this year, almost exactly the same as the 69 who were killed in the same period last year.
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• “Nearly 180,000 illegal immigrants with criminal records, ordered deported from our country, are tonight roaming free to threaten peaceful citizens.”
Fact Check: Those numbers come from a report by the Department of Homeland Security, which told Congress late last year that nearly 1 million undocumented immigrants have been ordered deported but remain in the country. Mr. Trump did not mention that most of those 180,000 are likely people charged with nonviolent crimes.
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• “The number of new illegal immigrant families who have crossed the border so far this year already exceeds the entire total from 2015.”
Fact Check: This is true, according to reports from the Border Patrol, which said that more than 51,000 families have been apprehended on the border in the first nine months of the fiscal year, compared to about 40,000 last fiscal year. But that is still less than 2014, when a surge of families across the border caused a political stir.
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• “Nearly four in 10 African-American children are living in poverty, while 58 percent of African-American youth are not employed.”
Fact Check: According to the Bureau of Labor Statistics, the unemployment rate of African Americans ages 16-19 in June was 31.2 percent (among whites of the same age, it was 14.1 percent).
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• “Household incomes are down more than $4,000 since the year 2000.”
Fact Check: This is mostly true. Median household income in 2000 was $57,724; in 2014, which has the most recent available data, it was $53,657.
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• “Our manufacturing trade deficit has reached an all-time high – nearly $800 billion in a single year.”
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Fact Check: The goods deficit — more imported goods, less exported goods — was $763 billion last year. But that includes agricultural products and raw materials like coal. Moreover, the total trade deficit last year was only $500 billion because the U.S. runs a trade surplus in services.
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• “President Obama has doubled our national debt to more than $19 trillion, and growing.”
Fact Check: The national debt was $10.6 trillion on the day Obama took office. It was $19.2 trillion in April, so not quite double, but close.
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• “Forty-three million Americans are on food stamps.”
Fact Check: As of October, this figure was largely accurate, according to the United States Department of Agriculture.
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• “In 2009, pre-Hillary, ISIS was not even on the map. Libya was cooperating. Egypt was peaceful. Iraq was seeing and, really, a big, big reduction in violence. Iran was being choked by sanctions. Syria was under control.”
Fact Check: Mr. Trump is mostly right. But Libya, Syria and Egypt were swept up in the Arab Spring, an uprising out of Mrs. Clinton’s and Mr. Obama’s control. And the sanctions on Iran were just getting ramped up at that time; they became far tougher under the Obama administration than they were during the Bush administration. That helped force Tehran to the negotiating table for last year’s deal.
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• “This was just prior to the signing of the Iran deal, which gave back to Iran $150 billion and gave us nothing — it will go down in history as one of the worst deals ever negotiated.”
Fact Check: The deal does not directly give Iran money, but by easing or terminating sanctions, it would allow Iran to have access to many billions of dollars of its own money that has been frozen in overseas accounts. And the exact value of those sanctions is debatable.
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• “My opponent has called for a radical 550 percent increase in Syrian refugees on top of existing massive refugee flows coming into our country under the leadership of President Obama.”
Fact Check: This is true, as Mrs. Clinton said in September she wanted to “move from what is a good start with 10,000 to 65,000.” But she also said she would improve the already extensive vetting process, especially from Syria. ||||| Republican Presidential Candidate Donald Trump gestures as he speaks during the final day of the Republican National Convention in Cleveland, Thursday, July 21, 2016. (AP Photo/Mark J. Terrill) (Associated Press)
Republican Presidential Candidate Donald Trump gestures as he speaks during the final day of the Republican National Convention in Cleveland, Thursday, July 21, 2016. (AP Photo/Mark J. Terrill) (Associated Press)
Republican Presidential Candidate Donald Trump gestures as he speaks during the final day of the Republican National Convention in Cleveland, Thursday, July 21, 2016. (AP Photo/Mark J. Terrill) (Associated Press) Republican Presidential Candidate Donald Trump gestures as he speaks during the final day of the Republican National Convention in Cleveland, Thursday, July 21, 2016. (AP Photo/Mark J. Terrill) (Associated Press)
WASHINGTON (AP) — Despite promising "the truth, and nothing else" in his convention speech, Donald Trump presented the nation with a series of previously debunked claims and some new ones Thursday night — about the U.S. tax burden, the perils facing police, Hillary Clinton's record and more.
A look at some of the Republican presidential candidate's claims and how they compare with the facts:
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TRUMP: "Decades of progress made in bringing down crime are now being reversed by this administration's rollback of criminal enforcement. Homicides last year increased by 17 percent in America's 50 largest cities. That's the largest increase in 25 years."
THE FACTS: A rollback? President Barack Obama has actually achieved some big increases in spending for state and local law enforcement, including billions in grants provided through the 2009 stimulus. While FBI crime statistics for 2015 are not yet available, Trump's claim about rising homicides appears to come from a Washington Post analysis published in January. While Trump accurately quotes part of the analysis, he omits that the statistical jump was so large because homicides are still very low by historical standards. In the 50 cities cited by the Post, for example, half as many people were killed last year as in 1991.
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TRUMP: "The number of new illegal immigrant families who have crossed the border so far this year already exceeds the entire total from 2015. They are being released by the tens of thousands into our communities with no regard for the impact on public safety or resources."
THE FACTS: The pace of releasing immigrants is driven not by the Obama administration, but by a court ruling. A federal judge ruled last year that the government couldn't hold parents and children in jail for more than 20 days. An appeals court partially rolled that back earlier this month, saying that parents could be detained but children must be released.
By the standard used by the government to estimate illegal border crossings - the number of arrests — Trump is right that the number in this budget year has already exceeded last year's total. But it's down from 2014.
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TRUMP: "When a secretary of state illegally stores her emails on a private server, deletes 33,000 of them so the authorities can't see her crime, puts our country at risk, lies about it in every different form and faces no consequence - I know that corruption has reached a level like never before."
THE FACTS: Clinton's use of a private server to store her emails was not illegal under federal law. Her actions were not established as a crime. The FBI investigated the matter and its role was to advise the Justice Department whether to bring charges against her based on what it found. FBI Director James Comey declined to refer the case for criminal prosecution to the Justice Department, instead accusing Clinton of extreme carelessness.
As for Trump's claim that Clinton faces no consequence, that may be true in a legal sense. But the matter has been a distraction to her campaign and fed into public perceptions that she can't be trusted. The election will test whether she has paid a price politically.
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TRUMP: "The number of police officers killed in the line of duty has risen by almost 50 percent compared to this point last year."
THE FACTS: Not according to the National Law Enforcement Officers Memorial Fund, which tracks police fatalities daily. The group found that the number of police officers who died as of July 20 is up just slightly this year, at 67, compared with 62 through the same period last year. That includes deaths in the line of duty from all causes, including traffic fatalities.
It is true that there has been a spike in police deaths from intentional shootings, 32 this year compared with 18 last year, largely attributable to the recent mass shootings in Dallas and Baton Rouge. But that was not his claim.
And overall, police are statistically safer on America's streets now than at any time in recent decades.
For example, the 109 law enforcement fatalities in 2013 were the lowest since 1956.
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TRUMP: "Two million more Latinos are in poverty today than when President Obama took his oath of office less than eight years ago. Another 14 million people have left the workforce entirely. ... President Obama has almost doubled our national debt to more than $19 trillion, and growing."
THE FACTS: Trump is playing with numbers to make the economy look worse than it actually is. The sluggish recovery over the past seven years has been frustrating. But with unemployment at 4.9 percent, the situation isn't as bleak as he suggests.
Trump's figure of 14 million who've stopped working since Obama took office comes from the Labor Department's measure of people not in the workforce. It's misleading for three reasons: The U.S. population has increased in that time; the country has aged and people have retired; and younger people are staying in school longer for college and advanced degrees, so they're not in the labor force, either.
A better figure is labor force participation — the share of people with jobs or who are searching for work. That figure has declined from 65.7 percent when Obama took office to 62.7 percent now. Part of that decrease reflects retirements, but the decline is also a long-term trend.
On national debt, economists say a more meaningful measure than dollars is the share of the overall economy taken up by the debt. By that measure, the debt rose 36 percent under Obama (rather than doubling). That's roughly the same as what occurred under Republican President George W. Bush.
The Hispanic population has risen since Obama while the poverty rate has fallen. The Pew Research Center found that 23.5 percent of the country's 55.3 million Latinos live in poverty, compared with 24.7 percent in 2010.
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Associated Press writers Josh Boak, Stephen Braun, Deb Riechmann, Jim Drinkard and Alicia A. Caldwell in Washington and Elliot Spagat in San Diego contributed to this report. ||||| Donald Trump painted a dark picture of America during his acceptance speech at the Republican National Convention, but some of his doomsday stats are rather dubious. The Post's Fact Checker examined 25 of his key claims. (Jenny Starrs/The Washington Post)
The dark portrait of America that Donald J. Trump sketched in his acceptance speech at the Republican National Convention is a compendium of doomsday stats that fall apart upon close scrutiny. Numbers are taken out of context, data is manipulated, and sometimes the facts are wrong.
When facts are inconveniently positive — such as rising incomes and an unemployment rate under 5 percent — Trump simply declines to mention them. He describes an exceedingly violent nation, flooded with murders, when in reality, the violent-crime rate has been cut in half since the crack cocaine epidemic hit its peak in 1991.
In his speech, Trump promised to present “the plain facts that have been edited out of your nightly news and your morning newspaper.” But he relies on statistics that are ripe for manipulation, citing misleading numbers on the economy, for example, through selective use of years, data and sources.
Here is a rundown of 25 of Trump’s key claims — and how they differ from reality — arranged by subject. As is our practice, we do not award Pinocchios for a roundup of claims made in convention events.
Crime
“Homicides last year increased by 17 percent in America’s 50 largest cities. That’s the largest increase in 25 years. In our nation’s capital, killings have risen by 50 percent. They are up nearly 60 percent in nearby Baltimore.”
Trump cherry-picks data to paint an alarming picture of homicide trends, when in reality, they have been declining for decades.
In 2015, there was an uptick in homicides in 36 of the 50 largest cities compared to the previous years. The rate did, indeed, increase nearly 17 percent, and it was the worst annual change since 1990. The homicide rate was up 54.3 percent in Washington, and 58.5 percent in Baltimore.
But in the first months of 2016, homicide trends were about evenly split in the major cities. Out of 63 agencies reporting to the Major Cities Chiefs Association, 32 cities saw a decrease in homicides in first quarter 2016 and 31 saw an increase.
The problem with cherry-picking such data is that crime trends are measured over decades of data. Many factors — even weather — can drive crime numbers up or down at a given short period of time. In reality, homicides and overall violent crime, in both raw number and rates per population, have been on a decades-long decline in major cities.
“The debate over the size, scope and causes of the homicide increase in 2015 has been largely free of systematic evidence,” according to a June 2016 Department of Justice report.
“The number of police officers killed in the line of duty has risen by almost 50 percent compared to this point last year.”
This is wrong.
The number of law enforcement officers killed on the job has increased 8 percent compared to this point in 2015. He may be referring to the total number of officers killed in shootings, which has increased 78 percent. This includes the recent shootings in Dallas and Baton Rouge.
The overall number of police deaths has decreased in the past two decades. For the past 10 to 15 years, traffic-related incidents (including criminal pursuit and instances where officers are intentionally struck by offenders) have been the leading cause of death among police officers.
[Update: The Trump campaign responded to our fact-check and provided more information about the data they used for the speech. The campaign picked July 2014 to July 2015, and compared it to July 2015 to July 2016, using data from the Officers Down Memorial Page. The memorial page works with the National Law Enforcement Officers Memorial Fund, whose data we cited initially for our fact-check, to update officer death data in real time.
This is not the standard way that both organizations and the FBI maintain police death data, which is by calendar year. The campaign said that it wanted to reflect the latest available data, to show police deaths have “been getting worse in recent days.”]
“Decades of progress made in bringing down crime are now being reversed by this administration’s rollback of criminal enforcement.”
It’s not clear what Trump is referring to here. Perhaps this is a reference to Obama’s clemency initiative, granting early releases to prisoners with nonviolent drug offenses who have been serving mandatory sentences. Some critics of Obama’s clemency policies have said they were concerned about the application process for clemency and whether the prisoners properly met all the criteria.
Trump also may be referring to the current efforts to overhaul the criminal justice system, specifically on sentencing policies. Legislation is making its way through Congress and has been pushed strongly by the White House. But this effort has bipartisan support and has brought together an unlikely coalition that includes Koch Industries and the American Civil Liberties Union.
Immigration
“The number of new illegal immigrant families who have crossed the border so far this year already exceeds the entire total from 2015. They are being released by the tens of thousands into our communities with no regard for the impact on public safety or resources.”
This is another cherry-picked number. In the fiscal year that began in October, 51,152 families have been apprehended at the Southwest border through June, compared to 39,838 in fiscal year 2015, according to U.S. Customs and Border Protection. (There are three months left in the fiscal year.) But overall apprehensions, including unaccompanied minors, are running slightly higher than 2015 but are far fewer than 2014, 2013 and 2012.
There are Central American families arriving at the U.S.-Mexico border who are being allowed into the country pending review of their cases in immigration court. If they are being released, it is because they have requested asylum or intend to because they are fleeing extreme violence, instability and endemic poverty in El Salvador, Guatemala and Honduras.
“Nearly 180,000 illegal immigrants with criminal records, ordered deported from our country, are tonight roaming free to threaten peaceful citizens.”
This number sounds worse than it really is. U.S. Immigration and Customs Enforcement in fiscal 2015 deported nearly 140,000 convicted criminals. ICE has estimated that there are 953,507 noncitizens with final orders who are still in the United States, of whom 182,786 have been convicted of crimes; 176,126 have not been detained.
The actual crimes committed by this group are not documented, so Trump cannot easily claim all of these illegal immigrants are threatening.
The Migration Policy Institute, using a dataset of all 3.7 million deportations that were carried out between fiscal 2003 and 2013, found that the largest category of convictions for criminal deportees was immigration crimes, accounting for 18 percent of criminal removals between FY 2003-13. The three next largest crime categories were FBI Part 1 crimes (a definition that includes homicide, aggravated assault and burglary, 15 percent of criminal removals during the period), FBI Part 2 crimes identified by MPI as violent offenses (14 percent) and FBI Part 2 crimes identified by MPI as nonviolent offenses (14 percent).
Update: The Center for Immigration Studies points to data concerning illegal immigrants released from detention. For instance, in 2015, ICE released nearly 20,000, of whom there were about 8,000 violent convictions and about 200 homicides; the most common crime was driving under the influence. Jessica Vaughan of CIS also wrote a critique of our fact check.)
“Decades of record immigration have produced lower wages and higher unemployment for our citizens, especially for African American and Latino workers.”
This claim is quite convoluted, and the impact of legal and illegal immigration on blacks and Latinos is more complicated than Trump describes it.
Trump does not discern between legal and unauthorized immigration. Legal immigration flow has increased in the past four decades, and has remained at roughly 1 million people obtaining lawful permanent resident status every year since 2001. The unauthorized immigrant population increased from about 4 million in 1990 to about 12 million in 2007. But researchers estimate net zero illegal immigration flow from 2007 to 2014, due to the number of unauthorized immigrants leaving the country after the economic recession. Preliminary research from 2015 suggests net illegal immigration may have increased.
In general, economists have found that immigration overall results in a net positive to the U.S. economy and to overall workers. There are slight negative effects, but they are felt most strongly by less-educated and low-skilled workers. Illegal immigration, in particular, tends to affect less-educated and low-skilled American workers the most, which disproportionately comprises black men and recently arrived low-educated legal immigrants.
The U.S. Commission on Civil Rights 2010 report found that illegal immigration has tended to depress wages and employment particularly for black men. But factors other than illegal immigration contribute to black unemployment, the report found, including the high school dropout rate and low job-retention rates.
The competition with other Latinos, particularly Latino immigrants, is the most intense in industries like construction, agriculture, manufacturing and service jobs, said Randy Capps, the Migration Policy Institute’s director of research of U.S. programs. But the consensus among economic research studies is that the impact of immigration is primarily a net positive.
“One such border-crosser was released and made his way to Nebraska. There, he ended the life of an innocent young girl named Sarah Root. She was 21 years old and was killed the day after graduating from college with a 4.0 grade point average. Her killer was then released a second time, and he is now a fugitive from the law.”
Sarah Root is a relatively new anecdote of Donald Trump’s, though her story has been cited often by other immigration hard-liners.
Root, 21, died in a car crash 16 hours after she graduated summa cum laude from Bellevue University in Nebraska. She was driving home and was struck by a man whose blood alcohol level was more than three times the legal limit, and who was speeding in a truck.
The man was Eswin Mejia, 19, who was in the United States illegally. He was born in Honduras and arrived in America at age 16. He was released on bail, and fled. Authorities have not been able to find him, as of July 2016.
Mejia had several run-ins with law enforcement, but officials said he was not detained because he was not an “enforcement priority” and had no prior criminal convictions, according to the Des Moines Register.
Economy
“Fifty-eight percent of African American youth are not employed.”
The official unemployment rate for black youth is about half of what Trump says it is.
According to the Bureau of Labor Statistics, the unemployment rate among blacks 16 to 19 years old was 31.2 percent in June 2016. This official unemployment rate refers to jobless people who are actively looking for jobs, as a percentage of the total available workforce of people who are working or are looking for jobs.
What Trump may be referring to, as our friends at PolitiFact Virginia noted, is the BLS employment-population ratio. This is a broad measure that refers to the ratio of the number of people employed compared to the total population, including people who are not looking for jobs. The employment-population ratio for blacks 16 to 24 years old was 42 percent in June 2016, so Trump maybe using the flip side of that — 58 percent, for the unemployment-population ratio.
“2 million more Latinos are in poverty today than when the president took his oath of office.”
Trump is being misleading here, turning a good news story into something negative by using raw numbers and using 2008 as a base, instead of 2009, when Obama took office. From March 2009 to March, 2014, the most recent year for which data is available, the number of Latinos in poverty has increased 750,000, according to the Census Bureau. But the overall number of Latinos has grown by nearly 7 million, so the percentage in poverty has declined from 25.3 percent to 23.6 percent.
“Another 14 million people have left the workforce entirely.”
This is yet another misleading figure. The number of people who have left the workforce has certainly increased since 2009, though this is usually expressed as the labor participation rate, not raw employment numbers. The labor participation rate has dropped under Obama, from 65.7 percent in 2009 to 62.7 percent, but experts say just over half of the post-1999 decline in the participation rate comes from the retirement of the baby boomers. Economists estimate that just 15 percent of the drop in the labor force stems from people who want a job and are of prime working age (25-54).
“Household incomes are down more than $4,000 since the year 2000.”
This is a stale statistic, based on 2014 Census data, which ignores the fact that incomes have risen sharply in the last two years.
A more up-to-date figure is obtained from the nonpartisan economic consulting firm Sentier Research, which produces a monthly report using data from the Census Bureau’s monthly household survey.
The most recent report, released on the day of Trump’s speech, shows median annual household income in June was $57,206, slightly below the income of $57,826 in January 2000, in 2016 dollars. So it is essentially flat, not down $4,000.
“Forty-three million Americans are on food stamps.”
Trump’s point was that America’s economy has suffered under the Obama administration. But he fails to mention that this is actually the lowest number of people receiving food stamps since it reached its peak in 2013, a sign that the economy is finally improving enough that the delayed impact of economic recovery has reached families who depend on them.
There are 43.6 million people enrolled in the Supplemental Nutrition Assistance Program (SNAP), the official name for food stamps, as of the most recent monthly data available from April 2016. It was the lowest number of monthly enrollees since November 2010, U.S. Department of Agriculture data show.
The number of people receiving SNAP benefits increased after Obama took office in part because of changes in the food stamp program under President George W. Bush, when Congress overrode his veto of the 2008 Farm Bill. That law boosted the purchasing power of food stamps by indexing key elements to inflation.
At the same time, Obama’s stimulus bill also temporarily boosted benefits even more. The Obama administration also announced that it was pushing to expand eligibility, in part on the theory that expanding the food stamp program is also good for the economy because the money is quickly spent.
Of course, the economic aftershocks of the Great Recession, which was in full force before Obama took office, has a lot to do with the increase. There often is a time lag between when economic disaster strikes and when people begin to apply for food-stamp assistance. We explored these reasons in a 2011 fact check.
“America is one of the highest-taxed nations in the world.”
As a billionaire, Trump probably personally faces high tax rates. But the statistics don’t lie — the United States isn’t anywhere near the top among industrialized nations.
In 2014, according to comparative tables of the Organization for Economic Cooperation and Development (OECD), revenue as a percentage of the gross domestic product — the broadest measure of the economy — was 26 percent for the United States.
Out of 34 countries, that put the United States in the bottom third — and well below the OECD average of 34.4 percent.
Still, it’s an advance that Trump now says the United States is one of the highest-taxed nations. He used to assert the United States was the highest-taxed nation — when that dubious honor actually belongs to Denmark, with revenue at 50.9 percent of GDP.
“Excessive regulation is costing our country as much as $2 trillion a year.”
Trump presents an unbalanced figure here.
Various organizations, such as the Small Business Administration, the National Association of Manufacturers and the Competitive Enterprise Institute have come up with similar estimates on the cost of regulations. We have in the past looked deeply at the methodological issues concerning this $2 trillion estimate, which can be found in previous fact checks from 2014 and 2011.
But there is an important element missing in the use of this somewhat sketchy figure — the benefit side of the analysis. Every regulation has costs — but also benefits.
Look at cars, for example. Seat belts are a regulation, but they also result in fewer deaths, which is presumably a benefit. Higher fuel-economy standards raise the initial cost of a car, but also result in savings on gasoline over time.
Foreign Policy
“This was just prior to the signing of the Iran deal, which gave back to Iran $150 billion and gave us absolutely nothing — it will go down in history as one of the worst deals ever made.”
Trump frequently misstates the facts about the Iran deal, making it sound like the United States simply shipped $150 billion of taxpayer’s funds to Iran.
This was always Iran’s money, frozen in banks around the world, but $150 billion is the high estimate of the money that could be received. The Treasury Department says the figure is in the range of $100 to $125 billion, but the usual liquid assets would only be about $50 billion, as the rest of the assets are either obligated in illiquid projects (such as over 50 projects with China) that cannot be monetized quickly, if at all, or are composed of outstanding loans to Iranian entities that cannot repay them.
For its part, the Central Bank of Iran said the number was actually $32 billion.
Reasonable people can disagree on the merits of the Iran deal, but it’s a stretch to say “nothing” was received. Iran’s nuclear program was certainly put on ice for at least a decade.
“In Libya, our consulate – the symbol of American prestige around the globe — was brought down in flames.”
Trump falsely calls the Benghazi facility a “consulate” and a “symbol of American prestige.” It was merely an unofficial and temporary facility that had not even been declared to the host government — which is a key reason it did not get the security that was needed.
“In 2009, pre-Hillary, ISIS was not even on the map. Libya was cooperating. Egypt was peaceful. Iraq was seeing a reduction in violence. Iran was being choked by sanctions. Syria was somewhat under control.”
This is an interesting list, but aspects are not factually correct.
The Islamic State of today is simply an outgrowth of al-Qaeda in Iraq. It was established in April 2004 by longtime Sunni extremist Abu Musab al-Zarqawi, according to the National Counterterrorism Center. Zarqawi was killed by a U.S. airstrike in 2006, and afterward his successor announced the formation of the Islamic State — more than two years before George W. Bush left office.
The Islamic State certainly gained strength and territory from the civil war in Syria, but Clinton as secretary of state had pressed to funnel arms to the rebels; she was rebuffed by the president.
Libya, Syria and Egypt were run by dictators in 2009, but it’s odd to somehow suggest the 2011 uprising in those countries against the repressive regimes had much to do with U.S. policy.
As for sanctions against Iran, they did not really begin to bite until new ones were imposed by the Obama administration under the direction of Hillary Clinton.
“Only weeks ago, in Orlando, Florida, 49 wonderful Americans were savagely murdered by an Islamic terrorist. This time, the terrorist targeted our LGBTQ community.”
The FBI has found no evidence so far that the shooter targeted Pulse night club in Orlando because it is a gay club.
The shooting rattled the LGBT community in Orlando and beyond, who felt they were targeted in a hateful attack. But there is no evidence yet that the shooter’s attack was motivated by homophobia, The Washington Post reported on July 16.
“My opponent, in Syria — think of this, think of this, this is not believable but this is what’s happening. A 550 percentage increase in Syrian refugees on top of the existing massive refugee flows coming into our country already under the leadership of President Obama. She proposes this despite the fact that there’s no way to screen these refugees in order to find out who they are or where they come from.”
Trump gets it right on the “550” percentage, but falsely claims there’s “no way to screen” refugees.
President Obama has proposed accepting 10,000 refugees in fiscal year 2016, and in September Clinton said she would like to move toward as many as 65,000. That’s where Trump gets his “550 percent.” Clinton has emphasized there would be careful screening, with an emphasis on those facing religious persecution.
The process of vetting refugees starts with the United Nations High Commissioner for Refugees and then continues with checks by U.S. intelligence and security agencies. It takes one to two years, or longer in some cases. (Our colleagues at PolitiFact described this process in detail.)
Hillary Clinton
“In fact, her single greatest accomplishment may be committing such an egregious crime and getting away with it — especially when others who have done far less have paid so dearly.”
Trump likes to say “others” have gotten punished for far less than Hillary Clinton’s private email server, but there are few known cases that are comparable to hers. But Clinton’s case lacked malicious intent and other nefarious actions that are prerequisites for criminal charges.
The example Trump usually uses is Gen. David H. Petraeus. Petraeus knowingly leaked classified information in his personal notebooks for release to the public through his biographer, then lied to the FBI when he got caught. FBI Director James B. Comey said the Petraeus case “illustrates perfectly” the type of case the Department of Justice would be willing to prosecute: a combination of obstruction of justice, intentional misconduct and vast quantities of classified information. Those elements weren’t there in Clinton’s case. (For more on Clinton’s email controversy, see our complete collection of fact checks.)
“When that same secretary of state rakes in millions of dollars trading access and favors to special interests and foreign powers, I know the time for action has come.”
Trump has criticized Clinton’s record as secretary of state and donations given to the Clinton Foundation, as outlined in Peter Schweizer’s book, “Clinton Cash: The Untold Story of How and Why Foreign Governments and Businesses Helped Make Bill and Hillary Rich.”
Schweizer raises many questions about donations to the Clinton Foundation, led by Bill Clinton, while Hillary Clinton was secretary of state. But critics, including Schweizer, have not been able to prove quid pro quo.
“My opponent dismissed the VA scandal — one more sign of how out of touch she really is.”
Hillary Clinton has said the Department of Veterans Affairs wait-time scandal was not “as widespread as it has been made out to be,” but her campaign has walked back this statement after she was criticized for downplaying the scandal.
Below is the full exchange from MSNBC’s “The Rachel Maddow Show” in October 2015. The specific claim Trump is citing is in bold.
Rachel Maddow: The reason they [Republicans] are able to propose something that radical [privatizing the Department of Veterans Affairs] is because the problems at the VA seem so intractable. If I had been running Republican campaign against President Obama last year, I would have run it entirely on the VA — a bureaucracy, a bloated big government program that can’t be fixed, and let’s do right by our veterans. Do you have any new ideas for trying to fix it? You can’t find a person in politics who doesn’t say we shouldn’t do right by our veterans. But for some reason, this can’t get fixed fast enough. Hillary Clinton: Yes, and I don’t understand that. You know, I don’t understand why we have such a problem, because there have been a number of surveys of veterans. And overall, veterans who do get treated are satisfied with their treatment. … Now, nobody would believe that from the coverage that you see, and the constant berating of the VA that comes from the Republicans, in part in pursuit of this ideological agenda that they have. Maddow: But in part because there has been real scandal. Clinton: There has been. But it’s not been as widespread as it has been made out to be.
Clinton was criticized immediately, and her campaign later clarified that Clinton does believe there is a systemic problem of delays in veterans’ access to health care and processing their disability claims. The campaign told The Fact Checker that she was “speaking with reference to Republicans who have sought to use the wait times scandal to suggest the VA is so incompetent as to be beyond fixing, such that the only fix is privatization.”
Still, we awarded her Two Pinocchios for saying that a “number of surveys” show veterans “are satisfied with their treatment.” She was referring to VA satisfaction surveys funded by the VA or a nonscientific survey of veterans’ attitudes. Independent, scientific surveys show veterans’ attitudes toward medical care at the VA are mixed.
Trade
“America has lost nearly-one third of its manufacturing jobs since 1997, following the enactment of disastrous trade deals supported by Bill and Hillary Clinton.”
Trump picks a high point for manufacturing jobs, in Clinton’s second term, and ignores that fact that nearly 1 million manufacturing jobs have been added since the low point after the Great Recession. It is simplistic to pin all of the blame on trade agreements, when efficiency and technology have also played a major role.
“Remember, it was Bill Clinton who signed NAFTA, one of the worst economic deals ever made by our country.”
Bill Clinton was certainly a supporter of NAFTA who pushed approval through Congress. But it was negotiated and signed by President George H.W. Bush. (Here’s a photo.) Moreover, more Republicans than Democrats voted for the deal, as the trade pact was vehemently opposed by labor unions. One key ally for Clinton was then-House Minority Whip (and later House speaker) Newt Gingrich (R-Ga.), now a Trump supporter.
Clinton did put his political prestige on the line to get it approved by Congress — even as two top Democrats, House Majority Leader Richard Gephardt (Mo.) and House Majority Whip David Bonior (Mich.), opposed it. In the House, NAFTA passed 234-200; 132 Republicans and 102 Democrats voted in favor of it. The Senate approved NAFTA 61-38, with the backing of 34 Republicans and 27 Democrats.
In both the House and the Senate, more Democrats voted against NAFTA than for it — a signal that the Bernie Sanders wing of the Democratic Party was strong even then. Clinton held a signing ceremony for the implementing legislation on Dec. 3, 1993, flanked by former presidents and congressional leaders of both parties. But that’s not the same as negotiating and signing the treaty with Mexico and Canada. The trade agreement went into effect on Jan. 1, 1994.
As we have noted repeatedly before, economists have not reached any firm conclusion on the impact of NAFTA, but many think that claims of massive job losses are overstated. The Congressional Research Service in 2015 concluded that the “net overall effect of NAFTA on the U.S. economy appears to have been relatively modest, primarily because trade with Canada and Mexico accounts for a small percentage of U.S. GDP [gross domestic product].”
“She [Hillary Clinton] has supported the Trans-Pacific Partnership, which will not only destroy our manufacturing, but it will make America subject to the rulings of foreign governments.”
It’s a matter of opinion that the Trans-Pacific Partnership will “destroy” manufacturing — most economists would disagree — but the other part of Trump’s statement is fantasy sometimes promoted by the far-left. TPP, like other trade deals, does establish a commission to monitor implementation. It periodically may make suggestions on changes that are needed in the agreement as the global economy modernizes, but those changes have to be carried out through domestic processes.
All TPP members are already part of the World Trade Organization. It settles trade disputes and can allow for monetary retaliation. But the dispute settlement rulings cannot force changes in U.S. laws.
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Sign up for The Fact Checker weekly newsletter[/INST]– Despite promising "the truth, and nothing else" in his convention speech, Donald Trump presented the nation with a series of previously debunked claims and some new ones Thursday night—about the US tax burden, the perils facing police, Hillary Clinton's record, and more. Here's what fact-checkers at the AP, the New York Times, and the Washington Post made of his claims, which painted a bleak portrait of the USA in 2016: "The number of police officers killed in the line of duty has risen almost 50% compared to this point last year." False: According to the National Law Enforcement Officers Memorial Fund, line-of-duty deaths are up 8% this year, from 62 at this point last year to 67 so far this year. "Homicides last year increased by 17% in America's 50 largest cities. That's the largest increase in 25 years." True, though analysts say Trump cherry-picked those figures, omitting that the statistical jump was so large because homicides are still very low by historical standards—and are down again so far in 2016. "Two million more Latinos are in poverty today than when President Obama took his oath of office less than eight years ago." True, but misleading: The Hispanic population has risen since Obama took office, while the poverty rate has fallen. The Pew Research Center found that 23.5% of the country's 55.3 million Latinos live in poverty, compared with 24.7% in 2010. "Nearly four in 10 African-American children are living in poverty, while 58% of African-American youth are not employed." False: The correct youth unemployment figure is 31%, compared to 14% for whites. "America is one of the highest-taxed nations in the world." False: The US tax burden is actually the fourth lowest among the 34 developed and large emerging-market economies that make up the Organization for Economic Cooperation and Development, below only Chile, South Korea, and Mexico. Taxes made up 26% of the total US economy in 2014, according to the OECD, far below Sweden's tax burden of 42.7% or Germany's 36.1%. "Household incomes are down more than $4,000 since the year 2000." This would have been true in 2014, when the median household income was $53,657, compared to $57,724 in 2000. The most recent report puts median household income at $57,206, almost the same as in 2000, though the figures haven't been adjusted for inflation. "President Obama has doubled our national debt to more than $19 trillion, and growing." Almost true: the debt has gone from $10.6 trillion when Obama took office to $19.2 trillion as of April. The Post notes that not only has Trump cherry-picked or inflated many figures, he has simply ignored positive ones, "such as rising incomes and an unemployment rate under 5%," as well as the fact that the violent crime rate is still around half what it was 25 years ago.</s> |
SECTION 1. SHORT TITLE.
This Act may be cited as the ``Family and Medical Leave Enhancement
Act of 2005''.
SEC. 2. ELIGIBLE EMPLOYEE.
Section 101(2)(B)(ii) of the Family and Medical Leave Act of 1993
(29 U.S.C. 2611(2)(B)(ii)) is amended by striking ``less than 50'' each
place it appears and inserting ``fewer than 25''.
SEC. 3. ADDITIONAL ENTITLEMENT TO LEAVE FOR PARENTAL INVOLVEMENT.
(a) Leave Requirement.--Section 102(a) of the Family and Medical
Leave Act of 1993 (29 U.S.C. 2612(a)) is amended by adding at the end
the following new paragraph:
``(3) Entitlement to additional leave for parental
involvement.--
``(A) In general.--Subject to section 103(f), in
addition to leave available under paragraph (1), an
eligible employee shall be entitled to a total of four
hours of leave during any 30-day period, and a total of
24 hours of leave during any 12-month period to
participate in or attend an activity that--
``(i) is sponsored by a school or community
organization; and
``(ii) relates to a program of the school
or organization that is attended by a son or
daughter or a grandchild of the employee.
``(B) Definitions.--As used in this paragraph:
``(i) School.--The term `school' means an
elementary school or secondary school (as such
terms are defined in the Elementary and
Secondary Education Act of 1965 (20 U.S.C. 6301
et seq.)), a Head Start program assisted under
the Head Start Act (42 U.S.C. 9831 et seq.),
and a child care facility licensed under State
law.
``(ii) Community organization.--The term
`community organization' means a private
nonprofit organization that is representative
of a community or a significant segment of a
community and provides activities for
individuals described in subparagraph (A) or
(B) of section 101(12), such as a scouting or
sports organization.''.
(b) Schedule.--Section 102(b)(1) of such Act (29 U.S.C. 2612(b)(1))
is amended by inserting after the second sentence the following new
sentence: ``Leave under subsection (a)(3)(A) may be taken
intermittently or on a reduced leave schedule.''.
(c) Substitution of Paid Leave.--Section 102(d)(2)(A) of such Act
(29 U.S.C. 2612(d)(2)(A)) is amended by inserting after ``subsection
(a)(1)'' the following: ``or under subsection (a)(3)(A)''.
(d) Notice.--Section 102(e)(1) of such Act (29 U.S.C. 2612(e)(1))
is amended by adding at the end the following new sentence: ``In any
case in which an employee requests leave under subsection (a)(3)(A),
the employee shall provide the employer with not less than seven days'
notice, before the date the leave is to begin, of the employee's
intention to take leave under such subsection.''.
(e) Certification.--Section 103 of such Act (29 U.S.C. 2613) is
amended by adding at the end the following new subsection:
``(f) Certification for Parental Involvement Leave.--An employer
may require that a request for leave under section 102(a)(3)(A) be
supported by a certification issued at such time and in such manner as
the Secretary may by regulation prescribe.''.
SEC. 4. ENTITLEMENT TO LEAVE FOR CIVIL SERVANTS FOR PARENTAL
INVOLVEMENT.
(a) Leave Requirement.--Section 6382(a) of title 5, United States
Code, is amended by adding at the end the following new paragraph:
``(3)(A) Subject to section 6383(f), in addition to leave available
under paragraph (1), an employee shall be entitled to a total of four
hours of leave during any 30-day period, and a total of 24 hours of
leave during any 12-month period to participate in or attend an
activity that--
``(i) is sponsored by a school or community organization;
and
``(ii) relates to a program of the school or organization
that is attended by a son or daughter or a grandchild of the
employee.
``(B) For the purpose of this paragraph:
``(i) The term `school' means an elementary school or
secondary school (as such terms are defined in the Elementary
and Secondary Education Act of 1965 (20 U.S.C. 6301 et seq.)),
a Head Start program assisted under the Head Start Act (42
U.S.C. 9831 et seq.), and a child care facility licensed under
State law.
``(ii) The term `community organization' means a private
nonprofit organization that is representative of a community or
a significant segment of a community and provides activities
for individuals described in subparagraph (A) or (B) of section
6381(6), such as a scouting or sports organization.''.
(b) Schedule.--Section 6382(b)(1) of such title is amended by
inserting after the second sentence the following new sentence: ``Leave
under subsection (a)(3)(A) may be taken intermittently or on a reduced
leave schedule.''.
(c) Substitution of Paid Leave.--Section 6382(d) of such title is
amended by inserting before ``, except'' the following: ``, or for
leave provided under subsection (a)(3)(A) any of the employee's accrued
or accumulated annual leave under subchapter I for any part of the 24-
hour period of such leave under such subsection''.
(d) Notice.--Section 6382(e)(1) of such title is amended by adding
at the end the following new sentence: ``In any case in which an
employee requests leave under subsection (a)(3)(A), the employee shall
provide the employing agency with not less than seven days' notice,
before the date the leave is to begin, of the employee's intention to
take leave under such subsection.''.
(e) Certification.--Section 6383 of such title is amended by adding
at the end the following new subsection:
``(f) An employing agency may require that a request for leave
under section 6382(a)(3)(A) be supported by a certification issued at
such time and in such manner as the Office of Personnel Management may
by regulation prescribe.''.
SEC. 5. CLARIFICATION OF ENTITLEMENT TO LEAVE.
(a) In General.--Section 102(a)(1) of the Family and Medical Leave
Act of 1993 (29 U.S.C. 2612(a)(1)) and section 6382(a)(1) of title 5,
United States Code, are each amended by adding at the end the following
new subparagraphs:
``(E) In order to meet routine family medical care
needs, including transportation of a son or daughter or
a grandchild for medical and dental appointments for
annual checkups and vaccinations.
``(F) In order to meet the routine family medical
care needs of elderly individuals who are related to
the eligible employee, including visits to nursing
homes and group homes.''.
(b) Schedule.--
(1) Family and medical leave act of 1993.--The first
sentence of section 102(b)(1) of such Act (29 U.S.C.
2612(b)(1)) is amended by striking ``subparagraph (A) or (B)''
and inserting ``subparagraph (A), (B), (E), or (F)''.
(2) Title 5.--The first sentence of section 6382(b)(1) of
such title is amended by striking ``subparagraph (A) or (B)''
and inserting ``subparagraph (A), (B), (E), or (F)''.
(c) Substitution of Paid Leave.--
(1) Family and medical leave act of 1993.--Section
102(d)(2)(A) of such Act (29 U.S.C. 2612(d)(2)(A)) (as amended
by section 3(c)) is further amended by striking ``subparagraph
(A), (B), or (C)'' and inserting ``subparagraph (A), (B), (C),
(E), or (F)''.
(2) Title 5.--Section 6382(d) of such title (as amended by
section 4(c)) is further amended by striking ``subparagraph
(A), (B), (C), or (D)'' and inserting ``subparagraph (A), (B),
(C), (D), (E), or (F)''.
(d) Notice.--
(1) Family and medical leave act of 1993.--The first
sentence of section 102(e)(1) of such Act (29 U.S.C.
2612(e)(1)) (as created by the amendment made by section 3(d))
is amended by striking ``subparagraph (A) or (B)'' and
inserting ``subparagraph (A), (B), (E), or (F)''.
(2) Title 5.--The first sentence of section 6382(e)(1) of
such title (as created by the amendment made by section 4(d))
is amended by striking ``subparagraph (A) or (B)'' and
inserting ``subparagraph (A), (B), (E), or (F)''.
(e) Spouses Employed by Same Employer.--Section 102(f)(1) of the
Family and Medical Leave Act of 1993 (29 U.S.C. 2612(f)(1)) is amended
by striking ``subparagraph (A) or (B)'' and inserting ``subparagraph
(A), (B), (E), or (F)''.
(f) Certification.--
(1) Family and medical leave act of 1993.--Section 103 of
such Act (29 U.S.C. 2613) (as amended by section 3(e)) is
further amended by adding at the end the following new
subsection:
``(g) Certification for Routine Family Medical Care Needs.--An
employer may require that a request for leave under subparagraph (E) or
(F) of section 102(a)(1) be supported by a certification issued at such
time and in such manner as the Secretary may by regulation
prescribe.''.
(2) Title 5.--Section 6383 of such title (as amended by
section 4(e)) is further amended by adding at the end the
following new subsection:
``(g) An employing agency may require that a request for leave
under subparagraph (E) or (F) of section 6382(a)(1) be supported by a
certification issued at such time and in such manner as the Office of
Personnel Management may by regulation prescribe.''.
SEC. 6. DEFINITION OF GRANDCHILD.
(a) Non-Civil-Service Employees.--Section 101 of the Family and
Medical Leave Act (29 U.S.C. 2611) is amended by adding at the end the
following new paragraph:
``(14) Grandchild.--The term `grandchild' means a son or
daughter of an employee's child.''.
(b) Civil Service Employees.--Section 6381 of title 5, United
States Code, is amended--
(1) in paragraph (5)(B), by striking ``and'' at the end;
(2) in paragraph (6)(B), by striking the period at the end
and inserting ``; and''; and
(3) by adding at the end the following new paragraph:
``(7) the term `grandchild' means a son or daughter of an
employee's child.''. | Family and Medical Leave Enhancement Act of 2005 - Amends the Family and Medical Leave Act of 1993 (FMLA) to cover employees at worksites that employ fewer than 50 employees, but not fewer than 25 employees. Continues to exempt from FMLA coverage employees at worksites that employ fewer than 25 employees (currently 50), if the total number of employees employed by that employer within 75 miles of that worksite is fewer than 25 (currently 50).
Allows all employees covered by FMLA to take up to 4 hours during any 30-day period, and up to 24 hours during any 12-month period, of parental involvement leave to participate in or attend their children's or grandchildren's educational and extracurricular activities. Amends Federal civil service law to apply such parental involvement leave allowance to Federal employees.
Includes under FMLA entitlement leave for transporting children and grandchildren to medical and dental appointments and for visiting elderly relatives in nursing or group homes. | <s>[INST]SECTION 1. SHORT TITLE.
This Act may be cited as the ``Family and Medical Leave Enhancement
Act of 2005''.
SEC. 2. ELIGIBLE EMPLOYEE.
Section 101(2)(B)(ii) of the Family and Medical Leave Act of 1993
(29 U.S.C. 2611(2)(B)(ii)) is amended by striking ``less than 50'' each
place it appears and inserting ``fewer than 25''.
SEC. 3. ADDITIONAL ENTITLEMENT TO LEAVE FOR PARENTAL INVOLVEMENT.
(a) Leave Requirement.--Section 102(a) of the Family and Medical
Leave Act of 1993 (29 U.S.C. 2612(a)) is amended by adding at the end
the following new paragraph:
``(3) Entitlement to additional leave for parental
involvement.--
``(A) In general.--Subject to section 103(f), in
addition to leave available under paragraph (1), an
eligible employee shall be entitled to a total of four
hours of leave during any 30-day period, and a total of
24 hours of leave during any 12-month period to
participate in or attend an activity that--
``(i) is sponsored by a school or community
organization; and
``(ii) relates to a program of the school
or organization that is attended by a son or
daughter or a grandchild of the employee.
``(B) Definitions.--As used in this paragraph:
``(i) School.--The term `school' means an
elementary school or secondary school (as such
terms are defined in the Elementary and
Secondary Education Act of 1965 (20 U.S.C. 6301
et seq.)), a Head Start program assisted under
the Head Start Act (42 U.S.C. 9831 et seq.),
and a child care facility licensed under State
law.
``(ii) Community organization.--The term
`community organization' means a private
nonprofit organization that is representative
of a community or a significant segment of a
community and provides activities for
individuals described in subparagraph (A) or
(B) of section 101(12), such as a scouting or
sports organization.''.
(b) Schedule.--Section 102(b)(1) of such Act (29 U.S.C. 2612(b)(1))
is amended by inserting after the second sentence the following new
sentence: ``Leave under subsection (a)(3)(A) may be taken
intermittently or on a reduced leave schedule.''.
(c) Substitution of Paid Leave.--Section 102(d)(2)(A) of such Act
(29 U.S.C. 2612(d)(2)(A)) is amended by inserting after ``subsection
(a)(1)'' the following: ``or under subsection (a)(3)(A)''.
(d) Notice.--Section 102(e)(1) of such Act (29 U.S.C. 2612(e)(1))
is amended by adding at the end the following new sentence: ``In any
case in which an employee requests leave under subsection (a)(3)(A),
the employee shall provide the employer with not less than seven days'
notice, before the date the leave is to begin, of the employee's
intention to take leave under such subsection.''.
(e) Certification.--Section 103 of such Act (29 U.S.C. 2613) is
amended by adding at the end the following new subsection:
``(f) Certification for Parental Involvement Leave.--An employer
may require that a request for leave under section 102(a)(3)(A) be
supported by a certification issued at such time and in such manner as
the Secretary may by regulation prescribe.''.
SEC. 4. ENTITLEMENT TO LEAVE FOR CIVIL SERVANTS FOR PARENTAL
INVOLVEMENT.
(a) Leave Requirement.--Section 6382(a) of title 5, United States
Code, is amended by adding at the end the following new paragraph:
``(3)(A) Subject to section 6383(f), in addition to leave available
under paragraph (1), an employee shall be entitled to a total of four
hours of leave during any 30-day period, and a total of 24 hours of
leave during any 12-month period to participate in or attend an
activity that--
``(i) is sponsored by a school or community organization;
and
``(ii) relates to a program of the school or organization
that is attended by a son or daughter or a grandchild of the
employee.
``(B) For the purpose of this paragraph:
``(i) The term `school' means an elementary school or
secondary school (as such terms are defined in the Elementary
and Secondary Education Act of 1965 (20 U.S.C. 6301 et seq.)),
a Head Start program assisted under the Head Start Act (42
U.S.C. 9831 et seq.), and a child care facility licensed under
State law.
``(ii) The term `community organization' means a private
nonprofit organization that is representative of a community or
a significant segment of a community and provides activities
for individuals described in subparagraph (A) or (B) of section
6381(6), such as a scouting or sports organization.''.
(b) Schedule.--Section 6382(b)(1) of such title is amended by
inserting after the second sentence the following new sentence: ``Leave
under subsection (a)(3)(A) may be taken intermittently or on a reduced
leave schedule.''.
(c) Substitution of Paid Leave.--Section 6382(d) of such title is
amended by inserting before ``, except'' the following: ``, or for
leave provided under subsection (a)(3)(A) any of the employee's accrued
or accumulated annual leave under subchapter I for any part of the 24-
hour period of such leave under such subsection''.
(d) Notice.--Section 6382(e)(1) of such title is amended by adding
at the end the following new sentence: ``In any case in which an
employee requests leave under subsection (a)(3)(A), the employee shall
provide the employing agency with not less than seven days' notice,
before the date the leave is to begin, of the employee's intention to
take leave under such subsection.''.
(e) Certification.--Section 6383 of such title is amended by adding
at the end the following new subsection:
``(f) An employing agency may require that a request for leave
under section 6382(a)(3)(A) be supported by a certification issued at
such time and in such manner as the Office of Personnel Management may
by regulation prescribe.''.
SEC. 5. CLARIFICATION OF ENTITLEMENT TO LEAVE.
(a) In General.--Section 102(a)(1) of the Family and Medical Leave
Act of 1993 (29 U.S.C. 2612(a)(1)) and section 6382(a)(1) of title 5,
United States Code, are each amended by adding at the end the following
new subparagraphs:
``(E) In order to meet routine family medical care
needs, including transportation of a son or daughter or
a grandchild for medical and dental appointments for
annual checkups and vaccinations.
``(F) In order to meet the routine family medical
care needs of elderly individuals who are related to
the eligible employee, including visits to nursing
homes and group homes.''.
(b) Schedule.--
(1) Family and medical leave act of 1993.--The first
sentence of section 102(b)(1) of such Act (29 U.S.C.
2612(b)(1)) is amended by striking ``subparagraph (A) or (B)''
and inserting ``subparagraph (A), (B), (E), or (F)''.
(2) Title 5.--The first sentence of section 6382(b)(1) of
such title is amended by striking ``subparagraph (A) or (B)''
and inserting ``subparagraph (A), (B), (E), or (F)''.
(c) Substitution of Paid Leave.--
(1) Family and medical leave act of 1993.--Section
102(d)(2)(A) of such Act (29 U.S.C. 2612(d)(2)(A)) (as amended
by section 3(c)) is further amended by striking ``subparagraph
(A), (B), or (C)'' and inserting ``subparagraph (A), (B), (C),
(E), or (F)''.
(2) Title 5.--Section 6382(d) of such title (as amended by
section 4(c)) is further amended by striking ``subparagraph
(A), (B), (C), or (D)'' and inserting ``subparagraph (A), (B),
(C), (D), (E), or (F)''.
(d) Notice.--
(1) Family and medical leave act of 1993.--The first
sentence of section 102(e)(1) of such Act (29 U.S.C.
2612(e)(1)) (as created by the amendment made by section 3(d))
is amended by striking ``subparagraph (A) or (B)'' and
inserting ``subparagraph (A), (B), (E), or (F)''.
(2) Title 5.--The first sentence of section 6382(e)(1) of
such title (as created by the amendment made by section 4(d))
is amended by striking ``subparagraph (A) or (B)'' and
inserting ``subparagraph (A), (B), (E), or (F)''.
(e) Spouses Employed by Same Employer.--Section 102(f)(1) of the
Family and Medical Leave Act of 1993 (29 U.S.C. 2612(f)(1)) is amended
by striking ``subparagraph (A) or (B)'' and inserting ``subparagraph
(A), (B), (E), or (F)''.
(f) Certification.--
(1) Family and medical leave act of 1993.--Section 103 of
such Act (29 U.S.C. 2613) (as amended by section 3(e)) is
further amended by adding at the end the following new
subsection:
``(g) Certification for Routine Family Medical Care Needs.--An
employer may require that a request for leave under subparagraph (E) or
(F) of section 102(a)(1) be supported by a certification issued at such
time and in such manner as the Secretary may by regulation
prescribe.''.
(2) Title 5.--Section 6383 of such title (as amended by
section 4(e)) is further amended by adding at the end the
following new subsection:
``(g) An employing agency may require that a request for leave
under subparagraph (E) or (F) of section 6382(a)(1) be supported by a
certification issued at such time and in such manner as the Office of
Personnel Management may by regulation prescribe.''.
SEC. 6. DEFINITION OF GRANDCHILD.
(a) Non-Civil-Service Employees.--Section 101 of the Family and
Medical Leave Act (29 U.S.C. 2611) is amended by adding at the end the
following new paragraph:
``(14) Grandchild.--The term `grandchild' means a son or
daughter of an employee's child.''.
(b) Civil Service Employees.--Section 6381 of title 5, United
States Code, is amended--
(1) in paragraph (5)(B), by striking ``and'' at the end;
(2) in paragraph (6)(B), by striking the period at the end
and inserting ``; and''; and
(3) by adding at the end the following new paragraph:
``(7) the term `grandchild' means a son or daughter of an
employee's child.''.[/INST]Family and Medical Leave Enhancement Act of 2005 - Amends the Family and Medical Leave Act of 1993 (FMLA) to cover employees at worksites that employ fewer than 50 employees, but not fewer than 25 employees. Continues to exempt from FMLA coverage employees at worksites that employ fewer than 25 employees (currently 50), if the total number of employees employed by that employer within 75 miles of that worksite is fewer than 25 (currently 50).
Allows all employees covered by FMLA to take up to 4 hours during any 30-day period, and up to 24 hours during any 12-month period, of parental involvement leave to participate in or attend their children's or grandchildren's educational and extracurricular activities. Amends Federal civil service law to apply such parental involvement leave allowance to Federal employees.
Includes under FMLA entitlement leave for transporting children and grandchildren to medical and dental appointments and for visiting elderly relatives in nursing or group homes.</s> |
SECTION 1. SHORT TITLE.
This Act may be cited as the ``Senior Investor Protections
Enhancement Act of 2008''.
SEC. 2. DEFINITIONS.
In this Act, the following definitions shall apply:
(1) Senior.--The term ``senior'' means an individual who is
62 years of age or older.
(2) Securities laws.--The term ``securities laws'' means
the Securities Act of 1933 (15 U.S.C. 77b et seq.), the
Securities Exchange Act of 1934 (15 U.S.C. 78a et seq.), the
Investment Company Act of 1940 (15 U.S.C. 80a et seq.), and the
Investment Advisers Act of 1940 (15 U.S.C. 80b et seq.).
SEC. 3. ENHANCED PENALTIES FOR VIOLATIONS OF SECURITIES ACT OF 1933.
(a) Civil Actions.--Section 20(d)(2) of the Securities Act of 1933
(15 U.S.C. 77t(d)(2)) is amended by adding at the end the following:
``(D) Special rule for seniors.--Notwithstanding
subparagraphs (A), (B), and (C), the amount of penalty
for each violation described in paragraph (1) that may
be imposed under subparagraph (A), (B), or (C) may be
increased by not more than $50,000, if the violation is
primarily directed toward, targets, or is committed
against an individual who, at the time of the
violation, is 62 years of age or older.''.
(b) Other Violations.--Section 24 of the Securities Act of 1933 (15
U.S.C. 77x) is amended--
(1) by inserting ``(a) In General.--'' before ``Any
person''; and
(2) by adding at the end the following:
``(b) Special Rule for Seniors.--Notwithstanding subsection (a),
the amount of a fine that may be imposed under subsection (a) may be
increased by not more than $50,000, if the violation is primarily
directed toward, targets, or is committed against an individual who, at
the time of the violation, is 62 years of age or older.''.
SEC. 4. ENHANCED PENALTIES FOR VIOLATIONS OF SECURITIES ACT OF 1934.
(a) Civil Actions.--Section 21(d)(3)(B) of the Securities Exchange
Act of 1934 (15 U.S.C. 78u(d)(3)(B)) is amended by adding at the end
the following:
``(iv) Special rule for seniors.--
Notwithstanding clauses (i), (ii), and (iii),
the amount of penalty for each violation
described in subparagraph (A) that may be
imposed under clause (i), (ii), or (iii) may be
increased by not more than $50,000, if the
violation is primarily directed toward,
targets, or is committed against an individual
who, at the time of the violation, is 62 years
of age or older.''.
(b) Willful Violations.--Section 21B(b) of the Securities Exchange
Act of 1934 (15 U.S.C. 78u-2(b)) is amended by adding at the end the
following:
``(4) Special rule for seniors.--Notwithstanding paragraphs
(1), (2), and (3), the amount of penalty for each violation
described in subsection (a) that may be imposed under paragraph
(1), (2), or (3) may be increased by not more than $50,000, if
the violation is primarily directed toward, targets, or is
committed against an individual who, at the time of the
violation, is 62 years of age or older.''.
(c) Other Violations.--Section 32 of the Securities Exchange Act of
1934 (15 U.S.C. 78ff) is amended by adding at the end the following:
``(d) Special Rule for Seniors.--Notwithstanding subsection (a),
the amount of fine that may be imposed under subsection (a) may be
increased by not more than $50,000, if the violation is primarily
directed toward, targets, or is committed against an individual who, at
the time of the violation, is 62 years of age or older.''.
SEC. 5. ENHANCED PENALTIES FOR VIOLATIONS OF INVESTMENT COMPANY ACT OF
1940.
(a) Willful Violations.--Section 9(d)(2) of the Investment Company
Act of 1940 (15 U.S.C. 80a-9(d)(2)) is amended by adding at the end the
following:
``(D) Special rule for seniors.--Notwithstanding
subparagraphs (A), (B), and (C), the amount of penalty
for each violation described in paragraph (1) that may
be imposed under subparagraph (A), (B), or (C) may be
increased by not more than $50,000, if the violation is
primarily directed toward, targets, or is committed
against an individual who, at the time of the
violation, is 62 years of age or older.''.
(b) Civil Actions.--Section 42(e)(2) of the Investment Company Act
of 1940 (15 U.S.C. 80a-41(l)(2)) is amended by adding at the end the
following:
``(D) Special rule for seniors.--Notwithstanding
subparagraphs (A), (B), and (C), the amount of penalty
for each violation described in paragraph (1) that may
be imposed under subparagraph (A), (B), or (C) may be
increased by not more than $50,000, if the violation is
primarily directed toward, targets, or is committed
against an individual who, at the time of the
violation, is 62 years of age or older.''.
(c) Other Violations.--Section 49 of the Investment Company Act of
1940 (15 U.S.C. 80a-48) is amended--
(1) by inserting ``(a) In General.--'' before ``Any
person''; and
(2) by adding at the end the following:
``(b) Special Rule for Seniors.--Notwithstanding subsection (a),
the amount of fine that may be imposed under subsection (a) may be
increased by not more than $50,000, if the violation is primarily
directed toward, targets, or is committed against an individual who, at
the time of the violation, is 62 years of age or older.''.
SEC. 6. ENHANCED PENALTIES FOR VIOLATIONS OF INVESTMENT ADVISERS ACT OF
1940.
(a) Willful Violations.--Section 203(i)(2) of the Investment
Advisers Act of 1940 (15 U.S.C. 80b-3(i)(2)) is amended by adding at
the end the following:
``(D) Special rule for seniors.--Notwithstanding
subparagraphs (A), (B), and (C), the amount of penalty
for each violation described in paragraph (1) that may
be imposed under subparagraph (A), (B), or (C) may be
increased by not more than $50,000, if the violation is
primarily directed toward, targets, or is committed
against an individual who, at the time of the
violation, is 62 years of age or older.''.
(b) Civil Actions.--Section 209(e)(2) of the Investment Advisers
Act of 1940 (15 U.S.C. 80b-9(e)(2)) is amended by adding at the end the
following:
``(D) Special rule for seniors.--Notwithstanding
subparagraphs (A), (B), and (C), the amount of penalty
for each violation under this title that may be imposed
under subparagraph (A), (B), or (C) may be increased by
not more than $50,000, if the violation is primarily
directed toward, targets, or is committed against an
individual who, at the time of the violation, is 62
years of age or older.''.
(c) Other Violations.--Section 217 of the Investment Advisers Act
of 1940 (15 U.S.C. 80b-17) is amended--
(1) by inserting ``(a) In General.--'' before ``Any
person''; and
(2) by adding at the end the following:
``(b) Special Rule for Seniors.--Notwithstanding subsection (a),
the amount of fine that may be imposed under subsection (a) may be
increased by not more than $50,000, if the violation is primarily
directed toward, targets, or is committed against an individual who, at
the time of the violation, is 62 years of age or older.''.
SEC. 7. DIRECTIVE TO THE UNITED STATES SENTENCING COMMISSION.
(a) In General.--Pursuant to its authority under section 994(p) of
title 28, United States Code, and in accordance with this section, the
United States Sentencing Commission shall review and amend the Federal
sentencing guidelines and policy statements to ensure that the
guideline offense levels and enhancements appropriately punish
violations of the securities laws against seniors.
(b) Requirements.--In carrying out this section, the United States
Sentencing Commission shall--
(1) ensure that section 2B1.1 and 2C1.1 of the Federal
sentencing guidelines (and any successors thereto) apply to and
punish offenses in which the victim of a violation of the
securities laws is a senior;
(2) ensure reasonable consistency with other relevant
directives, provisions of the Federal sentencing guidelines,
and statutory provisions;
(3) make any necessary and conforming changes to the
Federal sentencing guidelines, in accordance with the
amendments made by this Act; and
(4) ensure that the Federal sentencing guidelines
adequately meet the purposes of sentencing set forth in section
3553(a)(2) of title 18, United States Code. | Senior Investor Protections Enhancement Act of 2008 - Amends the Securities Act of 1933, the Securities Exchange Act of 1934, the Investment Company Act of 1940, and the Investment Advisers Act of 1940 to increase to a maximum of $50,000 the civil penalty for a violation of the Act primarily directed toward or committed against a senior (age 62 or older).
Directs the United States Sentencing Commission to review and amend federal sentencing guidelines and policy statements to ensure that guideline offense levels and enhancements appropriately punish criminal violations of the securities laws against seniors. | <s>[INST]SECTION 1. SHORT TITLE.
This Act may be cited as the ``Senior Investor Protections
Enhancement Act of 2008''.
SEC. 2. DEFINITIONS.
In this Act, the following definitions shall apply:
(1) Senior.--The term ``senior'' means an individual who is
62 years of age or older.
(2) Securities laws.--The term ``securities laws'' means
the Securities Act of 1933 (15 U.S.C. 77b et seq.), the
Securities Exchange Act of 1934 (15 U.S.C. 78a et seq.), the
Investment Company Act of 1940 (15 U.S.C. 80a et seq.), and the
Investment Advisers Act of 1940 (15 U.S.C. 80b et seq.).
SEC. 3. ENHANCED PENALTIES FOR VIOLATIONS OF SECURITIES ACT OF 1933.
(a) Civil Actions.--Section 20(d)(2) of the Securities Act of 1933
(15 U.S.C. 77t(d)(2)) is amended by adding at the end the following:
``(D) Special rule for seniors.--Notwithstanding
subparagraphs (A), (B), and (C), the amount of penalty
for each violation described in paragraph (1) that may
be imposed under subparagraph (A), (B), or (C) may be
increased by not more than $50,000, if the violation is
primarily directed toward, targets, or is committed
against an individual who, at the time of the
violation, is 62 years of age or older.''.
(b) Other Violations.--Section 24 of the Securities Act of 1933 (15
U.S.C. 77x) is amended--
(1) by inserting ``(a) In General.--'' before ``Any
person''; and
(2) by adding at the end the following:
``(b) Special Rule for Seniors.--Notwithstanding subsection (a),
the amount of a fine that may be imposed under subsection (a) may be
increased by not more than $50,000, if the violation is primarily
directed toward, targets, or is committed against an individual who, at
the time of the violation, is 62 years of age or older.''.
SEC. 4. ENHANCED PENALTIES FOR VIOLATIONS OF SECURITIES ACT OF 1934.
(a) Civil Actions.--Section 21(d)(3)(B) of the Securities Exchange
Act of 1934 (15 U.S.C. 78u(d)(3)(B)) is amended by adding at the end
the following:
``(iv) Special rule for seniors.--
Notwithstanding clauses (i), (ii), and (iii),
the amount of penalty for each violation
described in subparagraph (A) that may be
imposed under clause (i), (ii), or (iii) may be
increased by not more than $50,000, if the
violation is primarily directed toward,
targets, or is committed against an individual
who, at the time of the violation, is 62 years
of age or older.''.
(b) Willful Violations.--Section 21B(b) of the Securities Exchange
Act of 1934 (15 U.S.C. 78u-2(b)) is amended by adding at the end the
following:
``(4) Special rule for seniors.--Notwithstanding paragraphs
(1), (2), and (3), the amount of penalty for each violation
described in subsection (a) that may be imposed under paragraph
(1), (2), or (3) may be increased by not more than $50,000, if
the violation is primarily directed toward, targets, or is
committed against an individual who, at the time of the
violation, is 62 years of age or older.''.
(c) Other Violations.--Section 32 of the Securities Exchange Act of
1934 (15 U.S.C. 78ff) is amended by adding at the end the following:
``(d) Special Rule for Seniors.--Notwithstanding subsection (a),
the amount of fine that may be imposed under subsection (a) may be
increased by not more than $50,000, if the violation is primarily
directed toward, targets, or is committed against an individual who, at
the time of the violation, is 62 years of age or older.''.
SEC. 5. ENHANCED PENALTIES FOR VIOLATIONS OF INVESTMENT COMPANY ACT OF
1940.
(a) Willful Violations.--Section 9(d)(2) of the Investment Company
Act of 1940 (15 U.S.C. 80a-9(d)(2)) is amended by adding at the end the
following:
``(D) Special rule for seniors.--Notwithstanding
subparagraphs (A), (B), and (C), the amount of penalty
for each violation described in paragraph (1) that may
be imposed under subparagraph (A), (B), or (C) may be
increased by not more than $50,000, if the violation is
primarily directed toward, targets, or is committed
against an individual who, at the time of the
violation, is 62 years of age or older.''.
(b) Civil Actions.--Section 42(e)(2) of the Investment Company Act
of 1940 (15 U.S.C. 80a-41(l)(2)) is amended by adding at the end the
following:
``(D) Special rule for seniors.--Notwithstanding
subparagraphs (A), (B), and (C), the amount of penalty
for each violation described in paragraph (1) that may
be imposed under subparagraph (A), (B), or (C) may be
increased by not more than $50,000, if the violation is
primarily directed toward, targets, or is committed
against an individual who, at the time of the
violation, is 62 years of age or older.''.
(c) Other Violations.--Section 49 of the Investment Company Act of
1940 (15 U.S.C. 80a-48) is amended--
(1) by inserting ``(a) In General.--'' before ``Any
person''; and
(2) by adding at the end the following:
``(b) Special Rule for Seniors.--Notwithstanding subsection (a),
the amount of fine that may be imposed under subsection (a) may be
increased by not more than $50,000, if the violation is primarily
directed toward, targets, or is committed against an individual who, at
the time of the violation, is 62 years of age or older.''.
SEC. 6. ENHANCED PENALTIES FOR VIOLATIONS OF INVESTMENT ADVISERS ACT OF
1940.
(a) Willful Violations.--Section 203(i)(2) of the Investment
Advisers Act of 1940 (15 U.S.C. 80b-3(i)(2)) is amended by adding at
the end the following:
``(D) Special rule for seniors.--Notwithstanding
subparagraphs (A), (B), and (C), the amount of penalty
for each violation described in paragraph (1) that may
be imposed under subparagraph (A), (B), or (C) may be
increased by not more than $50,000, if the violation is
primarily directed toward, targets, or is committed
against an individual who, at the time of the
violation, is 62 years of age or older.''.
(b) Civil Actions.--Section 209(e)(2) of the Investment Advisers
Act of 1940 (15 U.S.C. 80b-9(e)(2)) is amended by adding at the end the
following:
``(D) Special rule for seniors.--Notwithstanding
subparagraphs (A), (B), and (C), the amount of penalty
for each violation under this title that may be imposed
under subparagraph (A), (B), or (C) may be increased by
not more than $50,000, if the violation is primarily
directed toward, targets, or is committed against an
individual who, at the time of the violation, is 62
years of age or older.''.
(c) Other Violations.--Section 217 of the Investment Advisers Act
of 1940 (15 U.S.C. 80b-17) is amended--
(1) by inserting ``(a) In General.--'' before ``Any
person''; and
(2) by adding at the end the following:
``(b) Special Rule for Seniors.--Notwithstanding subsection (a),
the amount of fine that may be imposed under subsection (a) may be
increased by not more than $50,000, if the violation is primarily
directed toward, targets, or is committed against an individual who, at
the time of the violation, is 62 years of age or older.''.
SEC. 7. DIRECTIVE TO THE UNITED STATES SENTENCING COMMISSION.
(a) In General.--Pursuant to its authority under section 994(p) of
title 28, United States Code, and in accordance with this section, the
United States Sentencing Commission shall review and amend the Federal
sentencing guidelines and policy statements to ensure that the
guideline offense levels and enhancements appropriately punish
violations of the securities laws against seniors.
(b) Requirements.--In carrying out this section, the United States
Sentencing Commission shall--
(1) ensure that section 2B1.1 and 2C1.1 of the Federal
sentencing guidelines (and any successors thereto) apply to and
punish offenses in which the victim of a violation of the
securities laws is a senior;
(2) ensure reasonable consistency with other relevant
directives, provisions of the Federal sentencing guidelines,
and statutory provisions;
(3) make any necessary and conforming changes to the
Federal sentencing guidelines, in accordance with the
amendments made by this Act; and
(4) ensure that the Federal sentencing guidelines
adequately meet the purposes of sentencing set forth in section
3553(a)(2) of title 18, United States Code.[/INST]Senior Investor Protections Enhancement Act of 2008 - Amends the Securities Act of 1933, the Securities Exchange Act of 1934, the Investment Company Act of 1940, and the Investment Advisers Act of 1940 to increase to a maximum of $50,000 the civil penalty for a violation of the Act primarily directed toward or committed against a senior (age 62 or older).
Directs the United States Sentencing Commission to review and amend federal sentencing guidelines and policy statements to ensure that guideline offense levels and enhancements appropriately punish criminal violations of the securities laws against seniors.</s> |
Lamar Odom Confessed to Doing Coke Days Before 911 Emergency
EXCLUSIVE
The person who made the Lamar Odom 911 call tells TMZ, he told the dispatcher Lamar confessed to doing coke days before he lapsed into unconsciousness.
Richard Hunter, media director of Love Ranch South, tells TMZ one of the women who found Lamar Tuesday afternoon unconscious in his room came running down the hall, screaming for him. Hunter says when he saw Lamar, he immediately called 911.
The dispatcher asked if Lamar had done drugs or consumed alcohol. Hunter says one of the girls said Lamar had consumed cognac and had taken a "s***load" of an herbal substitute for Viagra. When pressed, she said he took around 10 in the 3 days he was there.
Hunter then said he pressed her to see if Lamar had done any drugs, and the woman said he admitted to having taken "a small amount of cocaine" before he arrived on Saturday. Hunter says he conveyed that information to the dispatcher.
What doesn't make a lot of sense ... why would Lamar confess to doing coke just before arriving but not doing it once he got there?
As we reported, we're told doctors have determined Lamar had coke in his system.
Hunter tells us there was no evidence of drugs in the room, but he acknowledges Lamar was by himself for hours and the people who run the place do not search people for drugs. ||||| Lamar Odom 'Distinctly Possible' He'll Be Prosecuted If Cocaine Found
Breaking News
Cops confirm TMZ's story ... that someone from the brothel told the 911 dispatcher Lamar Odom confessed to her he had used cocaine days before he lapsed into unconsciousness, and if cops determine it's cocaine it's "distinctly possible" he'll be prosecuted.
Nye County Sheriff Sharon Wehrly just said her dept. obtained a search warrant and drew blood from Lamar in the hospital Wednesday, and the blood will now be tested for drugs.
As we reported, sources tell us doctors found cocaine in Odom's system.
The sheriff said she is not ruling out a suicide attempt. ||||| Lamar Odom 911 Call There's a White Substance ... On His Face
Lamar Odom 911 Call -- There's a White Substance On His Face (AUDIO)
Breaking News
Lamar Odom was unconscious with white stuff coming out of his nose when 2 different people at the Love Ranch South dialed 911 to get him medical assistance.
The Nye County Sheriff's Office just released the recordings from 2 employees of the Nevada brothel. They both described a white/pinkish substance running out of his nose and mouth.
The male caller was Richard Hunter, media director of the ranch, and he told the operator Lamar had cocaine on him on Saturday. He also said Lamar was taking heavy doses of the herbal Viagra substitute called Reload.
TMZ broke the story ... doctors determined there was cocaine in Odom's system when he got to the hospital Tuesday afternoon.
The sheriff says there's a possibility Odom could be charged for drug possession. ||||| Lamar Odom 50/50 Chance for Survival
Lamar Odom Has A 50/50 Chance for Survival
EXCLUSIVE
Lamar Odom's survival is right on the line.
Sources at the hospital tell us doctors are now saying Lamar has a 50/50 chance of surviving after enduring multiple medical problems ... the apparent result of complications from drug use.
Our sources say doctors are saying 4 of Lamar's organs, including his kidneys, are failing. As we reported, he's had a series of strokes in the hospital and has heart problems as well.
The doctors are saying with each failing organ the chances of survival go down significantly.
We're also told doctors are having trouble determining the extent of any brain damage because the organ issues make it difficult to test and get an accurate reading on brain function.
||||| There is no shortage of love, compassion and prayer for Lamar Odom, who remains hospitalized in a Las Vegas hospital, and on Wednesday evening, Rob Kardashian shared his own tribute to the former NBA star.
Rob, brother of Odom's ex Khloe Kardashian, took to Instagram to share a heartfelt photo of himself and the 35-year-old in happier times.
WATCH: Lamar Odom's Friends and Former Teammates Offer Prayers and Support: 'He's a Fighter'
Rob, who lived with Odom and his sister for years while they were married, captioned the photo, "Praying nonstop for my Brother !!"
Odom was found unconscious at the Love Ranch brothel in Crystal, Nevada on Tuesday and has remained hospitalized at Sunrise Hospital in Las Vegas. The circumstances surrounding the incident are still being investigated.
As reported on Tuesday, despite Lamar and Khloe's split, the Kardashian-Jenner family have never stopped caring for the 35-year-old former Los Angeles Lakers star, according to an ET source, and rushed to his bedside after being informed of his condition.
WATCH: Kardashian-Jenner Family 'Still Loves' Lamar Odom, Source Says, He 'Just Has Very Bad Demons'
Earlier Wednesday, Rob’s mother Kris Jenner took to Twitter asking her followers to "Please pray for Lamar." Kendall Jenner, Khloe's half-sister, also shared an emotional tweet, writing early Wednesday morning, "Please don't go."
please don't go. — Kendall Jenner (@KendallJenner) October 14, 2015
WATCH: Lamar Odom Struggled in Las Vegas, Was 'Pretty Much Broke,' Source Says
There has been an outpouring of support and well-wishes for Odom since news of his hospitalization broke, with countless friends and former teammates sharing their love on social media. Check out the video below to see how some of Odom’s closest friends reacted to the news. | – Details of the days before Lamar Odom was found unconscious at a Nevada brothel are trickling out: Sources at Love Ranch South tell TMZ that employees from the brothel picked Odom up at his Las Vegas home, 70 miles away, and took him to the ranch. He had the VIP suite and picked two of the "working girls," and within three days he had spent $75,000. Sources previously told TMZ that doctors found cocaine in Odom's system; whoever called 911 from the brothel told the dispatcher that Odom told her he'd used cocaine before arriving at the ranch. If that's found to be true, authorities say it's "distinctly possible" he'll be charged with drug possession; the sheriff's department is testing Odom's blood for drugs. The 911 caller also said Odom had a "white/pinkish substance" coming from his nose and mouth when he was found, TMZ reports. The gossip site sounds skeptical that Odom didn't also do cocaine at the ranch, noting: "What doesn't make a lot of sense ... why would Lamar confess to doing coke just before arriving but not doing it once he got there?" As for his current condition, TMZ says he has a 50/50 chance of survival due to drug-related complications including strokes, multiple organ failure, and heart problems. Multiple members of the Kardashian family have spoken out in support of Lamar. | <s>[INST]Lamar Odom Confessed to Doing Coke Days Before 911 Emergency
EXCLUSIVE
The person who made the Lamar Odom 911 call tells TMZ, he told the dispatcher Lamar confessed to doing coke days before he lapsed into unconsciousness.
Richard Hunter, media director of Love Ranch South, tells TMZ one of the women who found Lamar Tuesday afternoon unconscious in his room came running down the hall, screaming for him. Hunter says when he saw Lamar, he immediately called 911.
The dispatcher asked if Lamar had done drugs or consumed alcohol. Hunter says one of the girls said Lamar had consumed cognac and had taken a "s***load" of an herbal substitute for Viagra. When pressed, she said he took around 10 in the 3 days he was there.
Hunter then said he pressed her to see if Lamar had done any drugs, and the woman said he admitted to having taken "a small amount of cocaine" before he arrived on Saturday. Hunter says he conveyed that information to the dispatcher.
What doesn't make a lot of sense ... why would Lamar confess to doing coke just before arriving but not doing it once he got there?
As we reported, we're told doctors have determined Lamar had coke in his system.
Hunter tells us there was no evidence of drugs in the room, but he acknowledges Lamar was by himself for hours and the people who run the place do not search people for drugs. ||||| Lamar Odom 'Distinctly Possible' He'll Be Prosecuted If Cocaine Found
Breaking News
Cops confirm TMZ's story ... that someone from the brothel told the 911 dispatcher Lamar Odom confessed to her he had used cocaine days before he lapsed into unconsciousness, and if cops determine it's cocaine it's "distinctly possible" he'll be prosecuted.
Nye County Sheriff Sharon Wehrly just said her dept. obtained a search warrant and drew blood from Lamar in the hospital Wednesday, and the blood will now be tested for drugs.
As we reported, sources tell us doctors found cocaine in Odom's system.
The sheriff said she is not ruling out a suicide attempt. ||||| Lamar Odom 911 Call There's a White Substance ... On His Face
Lamar Odom 911 Call -- There's a White Substance On His Face (AUDIO)
Breaking News
Lamar Odom was unconscious with white stuff coming out of his nose when 2 different people at the Love Ranch South dialed 911 to get him medical assistance.
The Nye County Sheriff's Office just released the recordings from 2 employees of the Nevada brothel. They both described a white/pinkish substance running out of his nose and mouth.
The male caller was Richard Hunter, media director of the ranch, and he told the operator Lamar had cocaine on him on Saturday. He also said Lamar was taking heavy doses of the herbal Viagra substitute called Reload.
TMZ broke the story ... doctors determined there was cocaine in Odom's system when he got to the hospital Tuesday afternoon.
The sheriff says there's a possibility Odom could be charged for drug possession. ||||| Lamar Odom 50/50 Chance for Survival
Lamar Odom Has A 50/50 Chance for Survival
EXCLUSIVE
Lamar Odom's survival is right on the line.
Sources at the hospital tell us doctors are now saying Lamar has a 50/50 chance of surviving after enduring multiple medical problems ... the apparent result of complications from drug use.
Our sources say doctors are saying 4 of Lamar's organs, including his kidneys, are failing. As we reported, he's had a series of strokes in the hospital and has heart problems as well.
The doctors are saying with each failing organ the chances of survival go down significantly.
We're also told doctors are having trouble determining the extent of any brain damage because the organ issues make it difficult to test and get an accurate reading on brain function.
||||| There is no shortage of love, compassion and prayer for Lamar Odom, who remains hospitalized in a Las Vegas hospital, and on Wednesday evening, Rob Kardashian shared his own tribute to the former NBA star.
Rob, brother of Odom's ex Khloe Kardashian, took to Instagram to share a heartfelt photo of himself and the 35-year-old in happier times.
WATCH: Lamar Odom's Friends and Former Teammates Offer Prayers and Support: 'He's a Fighter'
Rob, who lived with Odom and his sister for years while they were married, captioned the photo, "Praying nonstop for my Brother !!"
Odom was found unconscious at the Love Ranch brothel in Crystal, Nevada on Tuesday and has remained hospitalized at Sunrise Hospital in Las Vegas. The circumstances surrounding the incident are still being investigated.
As reported on Tuesday, despite Lamar and Khloe's split, the Kardashian-Jenner family have never stopped caring for the 35-year-old former Los Angeles Lakers star, according to an ET source, and rushed to his bedside after being informed of his condition.
WATCH: Kardashian-Jenner Family 'Still Loves' Lamar Odom, Source Says, He 'Just Has Very Bad Demons'
Earlier Wednesday, Rob’s mother Kris Jenner took to Twitter asking her followers to "Please pray for Lamar." Kendall Jenner, Khloe's half-sister, also shared an emotional tweet, writing early Wednesday morning, "Please don't go."
please don't go. — Kendall Jenner (@KendallJenner) October 14, 2015
WATCH: Lamar Odom Struggled in Las Vegas, Was 'Pretty Much Broke,' Source Says
There has been an outpouring of support and well-wishes for Odom since news of his hospitalization broke, with countless friends and former teammates sharing their love on social media. Check out the video below to see how some of Odom’s closest friends reacted to the news.[/INST]– Details of the days before Lamar Odom was found unconscious at a Nevada brothel are trickling out: Sources at Love Ranch South tell TMZ that employees from the brothel picked Odom up at his Las Vegas home, 70 miles away, and took him to the ranch. He had the VIP suite and picked two of the "working girls," and within three days he had spent $75,000. Sources previously told TMZ that doctors found cocaine in Odom's system; whoever called 911 from the brothel told the dispatcher that Odom told her he'd used cocaine before arriving at the ranch. If that's found to be true, authorities say it's "distinctly possible" he'll be charged with drug possession; the sheriff's department is testing Odom's blood for drugs. The 911 caller also said Odom had a "white/pinkish substance" coming from his nose and mouth when he was found, TMZ reports. The gossip site sounds skeptical that Odom didn't also do cocaine at the ranch, noting: "What doesn't make a lot of sense ... why would Lamar confess to doing coke just before arriving but not doing it once he got there?" As for his current condition, TMZ says he has a 50/50 chance of survival due to drug-related complications including strokes, multiple organ failure, and heart problems. Multiple members of the Kardashian family have spoken out in support of Lamar.</s> |
So I got banned as an Uber driver for tweeting "hateful statements about the company"
UPDATE: After the social media fallout, an Uber higher up called and left me a voicemail saying the local Uber office removing me as a driver was a mistake and that my driver account was reinstated. I have not reactivated my driver account.
--
And really, it wasn't even my comments.
When Uber arrived in Albuquerque, I was excited. We usually don't get cool tech-y things in the Land of Enchantment.
I was not only an early advocate for the multi-billion dollar rideshare company, I was also one of the first drivers. For two months I was a happy Uber driver. Save from one incident where a drunk passenger punched out my side mirrors, I was a happy Uber driver. I made some easy cash on the side and got to catch up on my podcasts.
I stopped driving for Uber at the end of June because I had two vacations planned and I was getting busy with my "real" job as the co-founder and editor of NewsCastic, a social platform/marketplace solution for local news.
Cut to last week. With the annual International Balloon Fiesta coming to town, I figured it would be easy money to start driving for Uber again. I logged into my driver account to find my account had been deactivated. I figured it was because of missing paperwork (like insurance), so I emailed the local Albuquerque Uber office to find out what I needed to do to get my account back to active. Well, Balloon Fiesta came and went but I finally got an email back from Uber.
UPDATE: I've suddenly been approved as a driver. Wonder why.
This is the email Uber sent me, telling my my driver account was permanently deactivated
The "hateful" statement Driving for Uber, not much safer than driving a taxi http://t.co/rEJhvYlK4G — Christopher J. Ortiz (@ChrisJOrtiz) August 25, 2014 What's funny is the "hateful statement" John from Uber was referring to wasn't even my own opinion - it was from a Pando Daily story. What's not funny is that Uber is monitoring drivers' social media accounts. So, if a driver doesn't toe the line they'll be blackballed? Not cool, Uber, not cool at all.
Since tweeting a screenshot of the Uber email, the story has gone viral. If you want to be an Uber driver, don’t say mean things about them on Twitter cc @mcarney @nathanielmott pic.twitter.com/A4GVa75A9u — Christopher J. Ortiz (@ChrisJOrtiz) October 16, 2014
Uber Fired a Driver Over a "Hateful" Tweet About the Company Earlier this afternoon, Uber driver Christopher J. Ortiz posted the email above informing him that he would be "permanently deactivated" because of a single tweet. "I think that's pretty much fired--for a 'independent contractor,'" Ortiz told Valleywag. [via Valleywag] read full story >
Uber Canceled A Driver s Account For Tweeting Negative Things About The Company "Your account has been permanently deactivated due to hateful statements regarding Uber through Social Media." .. [via Buzzfeed] read full story >
I still supported Uber even after a drunk passenger punched out my side mirrors. Thanks to @Uber_ABQ for standing behind one of their drivers. Had a very comforting conversation with support. — Christopher J. Ortiz (@ChrisJOrtiz) June 14, 2014 A very intoxicated Uber passenger punched out my side mirrors after I refused to give him a ride out of fear for my safety. Uber initially denied to compensate me for my damages and lost wages but ultimately agreed to recoup my damages.
Uber Deactivated A Driver For Tweeting A Negative Story About Uber - Forbes Uber's watching you, and if you say something bad about the company, you might get booted out. Uber told an Albuquerque UberX driver that he had been "permanently deactivated due to hateful statements regarding Uber through Social Media," according to emails. "Best of luck," the email said. "UBER on!" [via Forbes] read full story > ||||| Earlier this afternoon, Uber driver Christopher J. Ortiz posted the email above informing him that he would be "permanently deactivated" because of a single tweet. "I think that's pretty much fired—for a 'independent contractor,'" Ortiz told Valleywag.
Ortiz, a journalist and startup founder, had driven for Uber in May and June as research for his startup, Newscastic, "which is also in the marketplace space," he said. He was considering starting up again and asked how he could get his account reactivated, which is when he received the email from John Hamby, an Uber operations manager.
If you want to be an Uber driver, don’t say mean things about them on Twitter cc @mcarney @nathanielmott pic.twitter.com/A4GVa75A9u — Christopher J. Ortiz (@ChrisJOrtiz) October 16, 2014
The odd thing, given prevailing public sentiment about Uber, is that the tweet wasn't hateful, much less mean.
Driving for Uber, not much safer than driving a taxi http://t.co/rEJhvYlK4G — Christopher J. Ortiz (@ChrisJOrtiz) August 25, 2014
After getting the letter, Ortiz pulled his archive of tweets and found dozens of references to Uber. "90 percent of them are headlines of stories, not my opinions," he said. "I have a bunch of friends who drive and whenever I read a story about Uber, good or bad, I tweet them about it."
Ortiz says he communicated with Hamby before. "Near the end of June, a drunk passenger attacked my car and smashed my rear view mirrors so he knows me from that experience. I had to fight with Uber to pay for the damage and pay me for the days I was unable to drive because of the damage."
Ortiz said Uber ended up paying him about $180 for damges and $250 for time off the road after initially declining. "They made 'an exception' for me."
@mcarney what’s funny is I was an early supporter and advocate for Uber when they first moved to ABQ. — Christopher J. Ortiz (@ChrisJOrtiz) October 16, 2014
He supported Uber when they launched in Albuquerque and even now doesn't seem banged up about how they treated him. "It's more funny than anything. And I'm sure they are regretting sending that email now," he said. You can read his write-up about the incident on NewsCastic. All's well that ends startup?
I contacted Uber to verify the information and will update the post if I hear back. To contact the author of this post, please email [email protected].
[Image via @ChrisJOrtiz] | – Be careful what you tweet. When Uber driver Christopher J. Ortiz wrote "Driving for Uber, not much safer than driving a taxi," in August, he wasn't expecting the statement to cause any problems with the San Francisco startup. The journalist drove for Uber in May and June before bowing out to focus on his own startup, NewsCastic, but with the tourist-heavy International Balloon Fiesta coming to Albuquerque, the New Mexico man decided to get behind the wheel again. But he found his account was no longer active, and yesterday he was sent an email from the company's operations manager explaining why: His account had been "permanently deactivated" due to "hateful statements regarding Uber" through social media—he had, in effect, been fired, reports Valleywag. But on NewsCastic, which he describes as "a social platform/marketplace solution for local news," Ortiz writes that the comment wasn't even his—he'd tweeted someone else's opinion from a PandoDaily story. That, Ortiz writes, is the "funny" part. "What's not funny is that Uber is monitoring drivers' social media accounts," he adds. "So, if a driver doesn't toe the line they'll be blackballed? Not cool, Uber, not cool at all." The story has gone viral and Uber appears to have noticed; Ortiz has updated his post saying he's suddenly been approved as a driver. Uber reached out to Newser with the following: "This was an error by the local team and the driver’s account should have never been deactivated. ... We apologize to this highly rated driver-partner for the inconvenience." (Meanwhile, complaints are now surfacing from drivers for both Uber and Lyft of being underpaid and exploited.) | <s>[INST]So I got banned as an Uber driver for tweeting "hateful statements about the company"
UPDATE: After the social media fallout, an Uber higher up called and left me a voicemail saying the local Uber office removing me as a driver was a mistake and that my driver account was reinstated. I have not reactivated my driver account.
--
And really, it wasn't even my comments.
When Uber arrived in Albuquerque, I was excited. We usually don't get cool tech-y things in the Land of Enchantment.
I was not only an early advocate for the multi-billion dollar rideshare company, I was also one of the first drivers. For two months I was a happy Uber driver. Save from one incident where a drunk passenger punched out my side mirrors, I was a happy Uber driver. I made some easy cash on the side and got to catch up on my podcasts.
I stopped driving for Uber at the end of June because I had two vacations planned and I was getting busy with my "real" job as the co-founder and editor of NewsCastic, a social platform/marketplace solution for local news.
Cut to last week. With the annual International Balloon Fiesta coming to town, I figured it would be easy money to start driving for Uber again. I logged into my driver account to find my account had been deactivated. I figured it was because of missing paperwork (like insurance), so I emailed the local Albuquerque Uber office to find out what I needed to do to get my account back to active. Well, Balloon Fiesta came and went but I finally got an email back from Uber.
UPDATE: I've suddenly been approved as a driver. Wonder why.
This is the email Uber sent me, telling my my driver account was permanently deactivated
The "hateful" statement Driving for Uber, not much safer than driving a taxi http://t.co/rEJhvYlK4G — Christopher J. Ortiz (@ChrisJOrtiz) August 25, 2014 What's funny is the "hateful statement" John from Uber was referring to wasn't even my own opinion - it was from a Pando Daily story. What's not funny is that Uber is monitoring drivers' social media accounts. So, if a driver doesn't toe the line they'll be blackballed? Not cool, Uber, not cool at all.
Since tweeting a screenshot of the Uber email, the story has gone viral. If you want to be an Uber driver, don’t say mean things about them on Twitter cc @mcarney @nathanielmott pic.twitter.com/A4GVa75A9u — Christopher J. Ortiz (@ChrisJOrtiz) October 16, 2014
Uber Fired a Driver Over a "Hateful" Tweet About the Company Earlier this afternoon, Uber driver Christopher J. Ortiz posted the email above informing him that he would be "permanently deactivated" because of a single tweet. "I think that's pretty much fired--for a 'independent contractor,'" Ortiz told Valleywag. [via Valleywag] read full story >
Uber Canceled A Driver s Account For Tweeting Negative Things About The Company "Your account has been permanently deactivated due to hateful statements regarding Uber through Social Media." .. [via Buzzfeed] read full story >
I still supported Uber even after a drunk passenger punched out my side mirrors. Thanks to @Uber_ABQ for standing behind one of their drivers. Had a very comforting conversation with support. — Christopher J. Ortiz (@ChrisJOrtiz) June 14, 2014 A very intoxicated Uber passenger punched out my side mirrors after I refused to give him a ride out of fear for my safety. Uber initially denied to compensate me for my damages and lost wages but ultimately agreed to recoup my damages.
Uber Deactivated A Driver For Tweeting A Negative Story About Uber - Forbes Uber's watching you, and if you say something bad about the company, you might get booted out. Uber told an Albuquerque UberX driver that he had been "permanently deactivated due to hateful statements regarding Uber through Social Media," according to emails. "Best of luck," the email said. "UBER on!" [via Forbes] read full story > ||||| Earlier this afternoon, Uber driver Christopher J. Ortiz posted the email above informing him that he would be "permanently deactivated" because of a single tweet. "I think that's pretty much fired—for a 'independent contractor,'" Ortiz told Valleywag.
Ortiz, a journalist and startup founder, had driven for Uber in May and June as research for his startup, Newscastic, "which is also in the marketplace space," he said. He was considering starting up again and asked how he could get his account reactivated, which is when he received the email from John Hamby, an Uber operations manager.
If you want to be an Uber driver, don’t say mean things about them on Twitter cc @mcarney @nathanielmott pic.twitter.com/A4GVa75A9u — Christopher J. Ortiz (@ChrisJOrtiz) October 16, 2014
The odd thing, given prevailing public sentiment about Uber, is that the tweet wasn't hateful, much less mean.
Driving for Uber, not much safer than driving a taxi http://t.co/rEJhvYlK4G — Christopher J. Ortiz (@ChrisJOrtiz) August 25, 2014
After getting the letter, Ortiz pulled his archive of tweets and found dozens of references to Uber. "90 percent of them are headlines of stories, not my opinions," he said. "I have a bunch of friends who drive and whenever I read a story about Uber, good or bad, I tweet them about it."
Ortiz says he communicated with Hamby before. "Near the end of June, a drunk passenger attacked my car and smashed my rear view mirrors so he knows me from that experience. I had to fight with Uber to pay for the damage and pay me for the days I was unable to drive because of the damage."
Ortiz said Uber ended up paying him about $180 for damges and $250 for time off the road after initially declining. "They made 'an exception' for me."
@mcarney what’s funny is I was an early supporter and advocate for Uber when they first moved to ABQ. — Christopher J. Ortiz (@ChrisJOrtiz) October 16, 2014
He supported Uber when they launched in Albuquerque and even now doesn't seem banged up about how they treated him. "It's more funny than anything. And I'm sure they are regretting sending that email now," he said. You can read his write-up about the incident on NewsCastic. All's well that ends startup?
I contacted Uber to verify the information and will update the post if I hear back. To contact the author of this post, please email [email protected].
[Image via @ChrisJOrtiz][/INST]– Be careful what you tweet. When Uber driver Christopher J. Ortiz wrote "Driving for Uber, not much safer than driving a taxi," in August, he wasn't expecting the statement to cause any problems with the San Francisco startup. The journalist drove for Uber in May and June before bowing out to focus on his own startup, NewsCastic, but with the tourist-heavy International Balloon Fiesta coming to Albuquerque, the New Mexico man decided to get behind the wheel again. But he found his account was no longer active, and yesterday he was sent an email from the company's operations manager explaining why: His account had been "permanently deactivated" due to "hateful statements regarding Uber" through social media—he had, in effect, been fired, reports Valleywag. But on NewsCastic, which he describes as "a social platform/marketplace solution for local news," Ortiz writes that the comment wasn't even his—he'd tweeted someone else's opinion from a PandoDaily story. That, Ortiz writes, is the "funny" part. "What's not funny is that Uber is monitoring drivers' social media accounts," he adds. "So, if a driver doesn't toe the line they'll be blackballed? Not cool, Uber, not cool at all." The story has gone viral and Uber appears to have noticed; Ortiz has updated his post saying he's suddenly been approved as a driver. Uber reached out to Newser with the following: "This was an error by the local team and the driver’s account should have never been deactivated. ... We apologize to this highly rated driver-partner for the inconvenience." (Meanwhile, complaints are now surfacing from drivers for both Uber and Lyft of being underpaid and exploited.)</s> |
SECTION 1. SHORT TITLE.
This Act may be cited as the ``Drug Impaired Driving Research and
Prevention Act''.
SEC. 2. FINDINGS.
Congress finds that--
(1) driving under the influence of, or after having used,
illegal drugs has become a significant problem worldwide;
(2) in 2002, over 35,000,000 persons in the United States
aged 12 or older had used illegal drugs in the past year and
almost 11,000,000 of these persons (5 percent of the total
population of the United States aged 12 or older and 31 percent
of past year illicit drug users) had driven under the influence
of, or after having used, illegal drugs in the past year;
(3) research has established that abuse of a number of
drugs can impair driving performance;
(4) according to the National Highway Traffic Safety
Administration, illegal drugs (often in combination with
alcohol) are used by approximately 10 to 22 percent of drivers
involved in all motor vehicles crashes;
(5) drug impaired drivers are less frequently detected,
prosecuted, or referred to treatment than drunk drivers;
(6) there is a lack of uniformity or consistency in the way
the 50 States approach drug impaired drivers;
(7) too few police officers have been trained to detect
drug impaired drivers, and too few prosecutors have been
trained to prove drug impaired driving cases beyond a
reasonable doubt;
(8) per se drug impaired driving laws, like those used for
driving under the influence of alcohol, are feasible and
represent a sound strategy for dealing with drug impaired
drivers and can assist in the prosecution of drug impaired
driving offenders; and
(9) while it is illegal in all States to drive a motor
vehicle while under the influence of alcohol, drugs other than
alcohol, or a combination of alcohol and other drugs, there is
no consistent method across States for identifying drug
impairment and the presence of drugs in the body.
SEC. 3. PURPOSES.
The purposes of this Act are--
(1) to provide a model for States to implement and enforce
a drug impaired driving statute;
(2) to ensure drivers in need of drug education or
treatment are identified and provided with the appropriate
assistance;
(3) to advance research and development of testing
mechanisms and knowledge about drugged driving and its impact
on traffic safety; and
(4) to enhance the training of traffic safety officers and
prosecutors to detect, enforce, and prosecute drug impaired
driving laws.
SEC. 4. DEFINITIONS.
In this Act, the following definitions apply:
(1) Controlled substance.--The term ``controlled
substance'' includes substances listed in schedules I through V
of section 112(e) of the Controlled Substances Act (21 U.S.C.
812(e)).
(2) Inhalant.--The term ``inhalant'' means a household or
commercial product that can be used by inhaling for
intoxicating effect.
(3) Drug recognition expert.--The term ``drug recognition
expert'' means an individual trained in a specific evaluation
procedure that enables the person to determine whether an
individual is under the influence of drugs and then to
determine the type of drug causing the observable impairment.
SEC. 5. MODEL STATUTE.
(a) In General.--Not later than one year after the date of
enactment of this Act, the Secretary shall develop and provide to the
States a model statute relating to drug impaired driving which
incorporates the provisions described in this Act.
(b) Mandatory Provisions.--Provisions of the model statute
developed by the Secretary for recommendation to the States under this
section shall include, at a minimum, a provision that the crime of drug
impaired driving is committed when a person operates a motor vehicle--
(1) while any detectable amount of a controlled substance
is present in the person's body, as measured in the person's
blood, urine, saliva, or other bodily substance; or
(2) due to the presence of a controlled substance or a
controlled substance in combination with alcohol or an
inhalant, or both, in the person's body, the person's mental or
physical faculties are affected to a noticeable or perceptible
degree.
(c) Discretionary Provisions.--Provisions of the model statute
developed by the Secretary for recommendation to the States under this
section may include the following:
(1) Sanctions for refusing to submit to a test for the
presence of a controlled substance in a person's body which are
equivalent to sanctions for a positive test result.
(2) Lawful use of any controlled substance listed in
schedule II, III, IV, or V of section 112(c) of the Controlled
Substances Act (21 U.S.C. 812(c)) that was lawfully prescribed
by a physician licensed under State law is an affirmative
defense to a charge of drug impaired driving; except that the
affirmative defense shall not be available if it is shown that
the person's mental or physical faculties were impaired by such
use to a noticeable or perceptible degree.
(3) A graduated system of penalties for repeat offenses of
drug impaired driving, including, at a minimum, that a third or
subsequent offense within a 10-year period shall be a felony
punishable by imprisonment for more than a year.
(4) Authorization for States to suspend or revoke the
license of any driver upon receiving a record of the driver's
conviction of driving a motor vehicle while under the influence
of a controlled substance.
(5) Provisions that require a sentence of imprisonment
imposed for any drug impaired driving offense be served
consecutively, not concurrently, from a sentence imposed for
any other criminal act; except that a sentence imposed for the
same act of impaired driving may be imposed concurrently if the
additional conviction was based on an alternate theory of
culpability for the same act.
(6) An appropriate system of evaluation, counseling,
treatment (if required), and supervision for persons convicted
of drug impaired driving.
SEC. 6. RESEARCH AND DEVELOPMENT.
Section 403(b) of title 23, United States Code, is amended by
adding at the end the following:
``(5) New technology to detect drug use.
``(6) Research and development to improve testing
technology, including toxicology lab resources and field test
mechanisms to enable States to process toxicology evidence in a
more timely manner.
``(7) Determining per se impairment levels for controlled
substances and the compound effects of alcohol and controlled
substances on impairment to facilitate enforcement of per se
drug impaired driving laws. Research under this paragraph shall
be carried out in collaboration with the National Institute on
Drug Abuse of the National Institutes of Health.''.
SEC. 7. GOALS FOR TRAINING.
Section 403 of title 23, United States Code, is amended by adding
at the end the following:
``(g) Training Goals.--For the purpose of enhancing the States'
ability to detect, enforce, and prosecute drug impaired driving laws,
the Secretary shall--
``(1) establish and carry out programs to enhance police
and prosecutor training efforts for enforcement of laws
relating to drug impaired driving and for development of
programs to improve enforcement of such laws; and
``(2) ensure that drug impaired driving enforcement
training or drug recognition expert programs, or both, exist in
all 50 States and the District of Columbia by December 31,
2006.''.
SEC. 8. DUTIES.
The Administrator of the National Highway Traffic Safety
Administration shall--
(1) advise and coordinate with other Federal agencies on
how to address the problem of driving under the influence of an
illegal drug; and
(2) conduct research on the prevention, detection, and
prosecution of driving under the influence of an illegal drug.
SEC. 9. REPORTS.
(a) In General.--Not later than 18 months after the date of
enactment of this Act and annually thereafter, the Secretary shall
transmit to Congress a report on the progress being made in carrying
out this Act, including the amendments made by this Act.
(b) Contents.--The Secretary shall include in the report an
assessment of the status of drug impaired driving laws in the United
States--
(1) new research and technologies in the area of drug
impaired driving enforcement;
(2) a description of the extent of the problem of driving
under the influence of an illegal drug in each State and any
available information relating thereto, including a description
of any laws relating to the problem of driving under the
influence of an illegal drug; and
(3) recommendations for addressing the problem of driving
under the influence of an illegal drug.
SEC. 10. FUNDING.
Out of amounts appropriated to carry out section 403 of title 23,
United States Code, for fiscal years 2004 through 2009, the Secretary
shall use, at a minimum, $1,200,000 per fiscal year to carry out drug
impaired driving traffic safety programs, including the provisions of
this section and the amendments made by this section. | Drug Impaired Driving Research and Prevention Act - Directs the Secretary of Transportation to develop and provide to the States a model statute relating to drug impaired driving which incorporates certain mandatory and discretionary provisions, including, at a minimum, a provision that the crime of drug impaired driving is committed when a person operates a motor vehicle: (1) while any detectable amount of a controlled substance is present in the person's body; or (2) due to the presence of a controlled substance or a controlled substance in combination with alcohol or an inhalant, or both, the person's mental or physical faculties are affected to a noticeable degree.
Specifies discretionary provisions, including: (1) sanctions for refusing to submit to a drug test which are equivalent to sanctions for a positive test result; (2) a graduated system of penalties for repeat offenses; (3) authorization for States to suspend or revoke the license of a driver convicted of driving while under the influence of a controlled substance; and (4) a system of evaluation, counseling, treatment, and supervision for persons convicted of drug impaired driving.
Authorizes the Secretary to use certain funds for research and development in drug detection and testing technology.
Specifies certain training goals to enhance the State's ability to detect, enforce, and prosecute drug impaired driving laws.
Requires the Administrator of the National Highway Traffic Safety Administration to advise and coordinate with other Federal agencies on how to address the problem of driving under the influence of an illegal drug, and to conduct research on the prevention, detection, and prosecution of driving under the influence of an illegal drug. | <s>[INST]SECTION 1. SHORT TITLE.
This Act may be cited as the ``Drug Impaired Driving Research and
Prevention Act''.
SEC. 2. FINDINGS.
Congress finds that--
(1) driving under the influence of, or after having used,
illegal drugs has become a significant problem worldwide;
(2) in 2002, over 35,000,000 persons in the United States
aged 12 or older had used illegal drugs in the past year and
almost 11,000,000 of these persons (5 percent of the total
population of the United States aged 12 or older and 31 percent
of past year illicit drug users) had driven under the influence
of, or after having used, illegal drugs in the past year;
(3) research has established that abuse of a number of
drugs can impair driving performance;
(4) according to the National Highway Traffic Safety
Administration, illegal drugs (often in combination with
alcohol) are used by approximately 10 to 22 percent of drivers
involved in all motor vehicles crashes;
(5) drug impaired drivers are less frequently detected,
prosecuted, or referred to treatment than drunk drivers;
(6) there is a lack of uniformity or consistency in the way
the 50 States approach drug impaired drivers;
(7) too few police officers have been trained to detect
drug impaired drivers, and too few prosecutors have been
trained to prove drug impaired driving cases beyond a
reasonable doubt;
(8) per se drug impaired driving laws, like those used for
driving under the influence of alcohol, are feasible and
represent a sound strategy for dealing with drug impaired
drivers and can assist in the prosecution of drug impaired
driving offenders; and
(9) while it is illegal in all States to drive a motor
vehicle while under the influence of alcohol, drugs other than
alcohol, or a combination of alcohol and other drugs, there is
no consistent method across States for identifying drug
impairment and the presence of drugs in the body.
SEC. 3. PURPOSES.
The purposes of this Act are--
(1) to provide a model for States to implement and enforce
a drug impaired driving statute;
(2) to ensure drivers in need of drug education or
treatment are identified and provided with the appropriate
assistance;
(3) to advance research and development of testing
mechanisms and knowledge about drugged driving and its impact
on traffic safety; and
(4) to enhance the training of traffic safety officers and
prosecutors to detect, enforce, and prosecute drug impaired
driving laws.
SEC. 4. DEFINITIONS.
In this Act, the following definitions apply:
(1) Controlled substance.--The term ``controlled
substance'' includes substances listed in schedules I through V
of section 112(e) of the Controlled Substances Act (21 U.S.C.
812(e)).
(2) Inhalant.--The term ``inhalant'' means a household or
commercial product that can be used by inhaling for
intoxicating effect.
(3) Drug recognition expert.--The term ``drug recognition
expert'' means an individual trained in a specific evaluation
procedure that enables the person to determine whether an
individual is under the influence of drugs and then to
determine the type of drug causing the observable impairment.
SEC. 5. MODEL STATUTE.
(a) In General.--Not later than one year after the date of
enactment of this Act, the Secretary shall develop and provide to the
States a model statute relating to drug impaired driving which
incorporates the provisions described in this Act.
(b) Mandatory Provisions.--Provisions of the model statute
developed by the Secretary for recommendation to the States under this
section shall include, at a minimum, a provision that the crime of drug
impaired driving is committed when a person operates a motor vehicle--
(1) while any detectable amount of a controlled substance
is present in the person's body, as measured in the person's
blood, urine, saliva, or other bodily substance; or
(2) due to the presence of a controlled substance or a
controlled substance in combination with alcohol or an
inhalant, or both, in the person's body, the person's mental or
physical faculties are affected to a noticeable or perceptible
degree.
(c) Discretionary Provisions.--Provisions of the model statute
developed by the Secretary for recommendation to the States under this
section may include the following:
(1) Sanctions for refusing to submit to a test for the
presence of a controlled substance in a person's body which are
equivalent to sanctions for a positive test result.
(2) Lawful use of any controlled substance listed in
schedule II, III, IV, or V of section 112(c) of the Controlled
Substances Act (21 U.S.C. 812(c)) that was lawfully prescribed
by a physician licensed under State law is an affirmative
defense to a charge of drug impaired driving; except that the
affirmative defense shall not be available if it is shown that
the person's mental or physical faculties were impaired by such
use to a noticeable or perceptible degree.
(3) A graduated system of penalties for repeat offenses of
drug impaired driving, including, at a minimum, that a third or
subsequent offense within a 10-year period shall be a felony
punishable by imprisonment for more than a year.
(4) Authorization for States to suspend or revoke the
license of any driver upon receiving a record of the driver's
conviction of driving a motor vehicle while under the influence
of a controlled substance.
(5) Provisions that require a sentence of imprisonment
imposed for any drug impaired driving offense be served
consecutively, not concurrently, from a sentence imposed for
any other criminal act; except that a sentence imposed for the
same act of impaired driving may be imposed concurrently if the
additional conviction was based on an alternate theory of
culpability for the same act.
(6) An appropriate system of evaluation, counseling,
treatment (if required), and supervision for persons convicted
of drug impaired driving.
SEC. 6. RESEARCH AND DEVELOPMENT.
Section 403(b) of title 23, United States Code, is amended by
adding at the end the following:
``(5) New technology to detect drug use.
``(6) Research and development to improve testing
technology, including toxicology lab resources and field test
mechanisms to enable States to process toxicology evidence in a
more timely manner.
``(7) Determining per se impairment levels for controlled
substances and the compound effects of alcohol and controlled
substances on impairment to facilitate enforcement of per se
drug impaired driving laws. Research under this paragraph shall
be carried out in collaboration with the National Institute on
Drug Abuse of the National Institutes of Health.''.
SEC. 7. GOALS FOR TRAINING.
Section 403 of title 23, United States Code, is amended by adding
at the end the following:
``(g) Training Goals.--For the purpose of enhancing the States'
ability to detect, enforce, and prosecute drug impaired driving laws,
the Secretary shall--
``(1) establish and carry out programs to enhance police
and prosecutor training efforts for enforcement of laws
relating to drug impaired driving and for development of
programs to improve enforcement of such laws; and
``(2) ensure that drug impaired driving enforcement
training or drug recognition expert programs, or both, exist in
all 50 States and the District of Columbia by December 31,
2006.''.
SEC. 8. DUTIES.
The Administrator of the National Highway Traffic Safety
Administration shall--
(1) advise and coordinate with other Federal agencies on
how to address the problem of driving under the influence of an
illegal drug; and
(2) conduct research on the prevention, detection, and
prosecution of driving under the influence of an illegal drug.
SEC. 9. REPORTS.
(a) In General.--Not later than 18 months after the date of
enactment of this Act and annually thereafter, the Secretary shall
transmit to Congress a report on the progress being made in carrying
out this Act, including the amendments made by this Act.
(b) Contents.--The Secretary shall include in the report an
assessment of the status of drug impaired driving laws in the United
States--
(1) new research and technologies in the area of drug
impaired driving enforcement;
(2) a description of the extent of the problem of driving
under the influence of an illegal drug in each State and any
available information relating thereto, including a description
of any laws relating to the problem of driving under the
influence of an illegal drug; and
(3) recommendations for addressing the problem of driving
under the influence of an illegal drug.
SEC. 10. FUNDING.
Out of amounts appropriated to carry out section 403 of title 23,
United States Code, for fiscal years 2004 through 2009, the Secretary
shall use, at a minimum, $1,200,000 per fiscal year to carry out drug
impaired driving traffic safety programs, including the provisions of
this section and the amendments made by this section.[/INST]Drug Impaired Driving Research and Prevention Act - Directs the Secretary of Transportation to develop and provide to the States a model statute relating to drug impaired driving which incorporates certain mandatory and discretionary provisions, including, at a minimum, a provision that the crime of drug impaired driving is committed when a person operates a motor vehicle: (1) while any detectable amount of a controlled substance is present in the person's body; or (2) due to the presence of a controlled substance or a controlled substance in combination with alcohol or an inhalant, or both, the person's mental or physical faculties are affected to a noticeable degree.
Specifies discretionary provisions, including: (1) sanctions for refusing to submit to a drug test which are equivalent to sanctions for a positive test result; (2) a graduated system of penalties for repeat offenses; (3) authorization for States to suspend or revoke the license of a driver convicted of driving while under the influence of a controlled substance; and (4) a system of evaluation, counseling, treatment, and supervision for persons convicted of drug impaired driving.
Authorizes the Secretary to use certain funds for research and development in drug detection and testing technology.
Specifies certain training goals to enhance the State's ability to detect, enforce, and prosecute drug impaired driving laws.
Requires the Administrator of the National Highway Traffic Safety Administration to advise and coordinate with other Federal agencies on how to address the problem of driving under the influence of an illegal drug, and to conduct research on the prevention, detection, and prosecution of driving under the influence of an illegal drug.</s> |
leprosy is a chronic multisystemic disease caused by mycobacterium leprae , wherein the clinicopathological presentation is determined by the complex interaction between the invading organism and the immune status of the individual .
the most common organs involved are the skin , monocyte macrophage system and peripheral nervous system .
however , a mild to moderate degree of infiltration is seen in many other organs and organ systems like the liver , kidneys , eyes , oral mucosa , lymph nodes , bones and joints and gonads . historically , destructive changes in facial bones formed the basis for diagnosing leprosy among skeletons excavated from the site of a leprosy hospital in denmark that existed between 1250 and 1550 .
inflammatory changes of the hard palate , varying from small pits near the transverse palatal sutures to palatal perforation along with atrophy of the anterior nasal spine and alveolar process of maxilla were seen in a majority of these specimens .
involvement of the hard palate suggests that lesions of the oral mucosa occur in patients with advanced disease .
involvement of oral mucosa in leprosy is considered to be of greater epidemiological significance as this , along with nasal mucosal involvement , may constitute an important source of transmission of bacilli .
involvement of the oral cavity in leprosy is variable , seen in 1960% of the patients , with involvement being more common in multibacillary disease compared with paucibacillary leprosy .
recently , martins et al . observed that leprosy - related lesions are not present in patients undergoing treatment , probably due to response to multidrug therapy .
this to an extent explains the preferential sites involved in leprosy , i.e. the peripheral nerves and the nasal mucosa .
confirmed this hypothesis by observing that the bacterial index was much higher in skin with a mean surface temperature of 32.5c compared with skin with a mean surface temperature of 33.46c .
scheepers et al . found the hard palate to be the most frequent site of oral involvement in leprosy , followed by the soft palate , labial maxillary gingival , tongue , lips , buccal maxillary gingival , labial mandibular gingival and the buccal mucosa .
the anterior palate , which may be involved in up to 75% in cases with oral lesions , shows a mean surface temperature of 27.4c .
mouthbreathing is commonly seen in patients with lepromatous leprosy due to nasal obstruction and stuffiness .
this lowers the mean surface temperatures , especially over the dorsum of the tongue and the hard and the soft palate .
pinkerton in 1932 described the various pathological alterations seen in the nasal and oral mucous membranes following mycobacterial invasion .
initially , there is congestion of the mucosa followed by infiltration and formation of nodules , which may ulcerate . in advanced disease
, complications arise due to fibrosis , leading to deformities , gross disfiguration and functional abnormalities .
the spectrum of lesions may vary from relatively non - specific ones like enanthem of palate or uvula , which , on histopathology , may show no changes or non - specific infiltrate to more specific lesions like papules , nodules and ulcers , which may show bacillary positivity .
table 1 enumerates the various non - specific and specific lesions seen in the oral cavity in leprosy .
females tend to present at a younger age , probably because of the greater cosmetic concern .
the same authors observe the presence of family history of leprosy to be a significant factor in determining the severity of the oral lesions .
non - specific and specific oral lesions seen in leprosy leprous involvement of the lips may present as macrocheilia , presence of flat - topped nodules and microstomia .
the swollen and rigid appearance of the lips may be marked and hence cosmetically quite troublesome . in a study by handa et al .
, leprous macrochelia was seen in 10.7% of the 28 patients presenting with chronic macrocheilia .
the tongue may be involved in 1725% of the cases . commonly observed lesions include multiple superficial ulcers , mild glossitis , loss of papillae , chronic atrophic candidiasis and fissured tongue .
nodular lesions may be present over the anterior part of the tongue , giving a pavement - stone appearance and ultimately lead to scarring .
the muscles of the tongue are usually spared unlike the extensive involvement seen in other subcutaneous muscles .
in advanced cases , there may be diffuse infiltration , swellings , papulonodules and ulceration .
hard palate , as already mentioned , is the most common site of involvement and shows the most varied type of lesions .
the disease may present as erythematous or reddish papules that gradually increase in size and number and coalesce to form a generalized nodular sub - mucosal infiltrate [ figures 14 ] .
as the disease progresses , the mucosa loses its shininess and gives a matt - like appearance .
ultimately , there may be palatal ulceration and perforation leading to communication between the oral and nasal cavity . at this time
reported erythema nodosum leprosum to be an important but rare cause of destruction of the hard and soft palate .
further in the course of disease , the mucosa of the soft palate , uvula and fauces of tonsils become infiltrated with the appearance of miliary papules or nodules .
the uvula may initially appear swollen and later completely effaced or may become adherent to the soft palate .
scarring in the region of fauces may lead to a triangular deformity instead of the normal faucial arch .
erythematous infiltrated plaque on upper lip in a case of borderline tubercular leprosy with type 1 reaction induration on the tip and lateral border of the tongue superficial erosion on the hard palate nodule on the right fauci ( encircled ) in case of lepromatous leprosy involvement of gums may be in the form of gingivitis , periodontitis and periodontoclasia .
gums appear swollen with shiny and purplish mucosa and bleed easily with decreased sensitivity to pain .
miranda et al . described three different types of leprotic involvement of teeth : specific pulpitis , dental anomalies and periapical granulomas .
further concluded that leprosy patients tend to have poor dental and periodontal health , unrelated to the presence of facial destruction or the type of leprosy .
in addition , it has been postulated that oral chronic infections may be associated with the recurrence of leprosy reaction episodes .
motta et al . compared 38 patients with leprosy 19 with and 19 without oral infections and found the latter group to show clinical improvement in leprosy reactions after dental treatment .
grenz zone , which is a consistent feature in skin lesions , is rarely seen in oral lesions .
intense infiltration of macrophages , lymphocytes and plasma cells is prominently seen in oral lesions of lepromatous leprosy , with abundance of acid fast bacilli .
hyperkeratosis is observed in some cases and is believed to be analogous to desquamation of skin , as seen in reversal or downgrading reactions .
abreu et al . studied 19 patients with multibacillary leprosy between 2000 and 2002 , and concluded that clinical alterations in the oral mucosa do not imply disease involvement and should be confirmed by histopathological examination .
while concluding , it may be emphasized that examination of the oral mucosa should form an integral part of the examination of a patient with leprosy .
although the patient with leprosy will at first report to the dermatologist and rarely to the dental professional , the dental professional should be well aware of the precautions ( wearing gloves and mask , proper sterilization , etc . ) to be taken while giving any kind of treatment to this patient in a leprosy center .
appropriate treatment of dental infections will help to reduce the recurrence in leprosy reactions in addition to improving the general oral hygiene of the patient .
further , it is believed that oral lesions along with nasal lesions form an important source of bacillary dissemination in the community , and the reduced number or absence of patients exhibiting oral manifestations of leprosy can be attributed to the early diagnosis of the disease and the effectiveness of multidrug therapy . | although leprosy involves the oral cavity in up to 60% of the patients , examination of the oral cavity in leprosy clinics or oral health science clinics is often neglected . oral involvement in leprosy
can broadly be divided into non - specific and specific lesions . in this review ,
we discuss various oral manifestations in leprosy patients so as to increase the awareness about this aspect among dermatologists and dental surgeons . | <s>[INST]leprosy is a chronic multisystemic disease caused by mycobacterium leprae , wherein the clinicopathological presentation is determined by the complex interaction between the invading organism and the immune status of the individual .
the most common organs involved are the skin , monocyte macrophage system and peripheral nervous system .
however , a mild to moderate degree of infiltration is seen in many other organs and organ systems like the liver , kidneys , eyes , oral mucosa , lymph nodes , bones and joints and gonads . historically , destructive changes in facial bones formed the basis for diagnosing leprosy among skeletons excavated from the site of a leprosy hospital in denmark that existed between 1250 and 1550 .
inflammatory changes of the hard palate , varying from small pits near the transverse palatal sutures to palatal perforation along with atrophy of the anterior nasal spine and alveolar process of maxilla were seen in a majority of these specimens .
involvement of the hard palate suggests that lesions of the oral mucosa occur in patients with advanced disease .
involvement of oral mucosa in leprosy is considered to be of greater epidemiological significance as this , along with nasal mucosal involvement , may constitute an important source of transmission of bacilli .
involvement of the oral cavity in leprosy is variable , seen in 1960% of the patients , with involvement being more common in multibacillary disease compared with paucibacillary leprosy .
recently , martins et al . observed that leprosy - related lesions are not present in patients undergoing treatment , probably due to response to multidrug therapy .
this to an extent explains the preferential sites involved in leprosy , i.e. the peripheral nerves and the nasal mucosa .
confirmed this hypothesis by observing that the bacterial index was much higher in skin with a mean surface temperature of 32.5c compared with skin with a mean surface temperature of 33.46c .
scheepers et al . found the hard palate to be the most frequent site of oral involvement in leprosy , followed by the soft palate , labial maxillary gingival , tongue , lips , buccal maxillary gingival , labial mandibular gingival and the buccal mucosa .
the anterior palate , which may be involved in up to 75% in cases with oral lesions , shows a mean surface temperature of 27.4c .
mouthbreathing is commonly seen in patients with lepromatous leprosy due to nasal obstruction and stuffiness .
this lowers the mean surface temperatures , especially over the dorsum of the tongue and the hard and the soft palate .
pinkerton in 1932 described the various pathological alterations seen in the nasal and oral mucous membranes following mycobacterial invasion .
initially , there is congestion of the mucosa followed by infiltration and formation of nodules , which may ulcerate . in advanced disease
, complications arise due to fibrosis , leading to deformities , gross disfiguration and functional abnormalities .
the spectrum of lesions may vary from relatively non - specific ones like enanthem of palate or uvula , which , on histopathology , may show no changes or non - specific infiltrate to more specific lesions like papules , nodules and ulcers , which may show bacillary positivity .
table 1 enumerates the various non - specific and specific lesions seen in the oral cavity in leprosy .
females tend to present at a younger age , probably because of the greater cosmetic concern .
the same authors observe the presence of family history of leprosy to be a significant factor in determining the severity of the oral lesions .
non - specific and specific oral lesions seen in leprosy leprous involvement of the lips may present as macrocheilia , presence of flat - topped nodules and microstomia .
the swollen and rigid appearance of the lips may be marked and hence cosmetically quite troublesome . in a study by handa et al .
, leprous macrochelia was seen in 10.7% of the 28 patients presenting with chronic macrocheilia .
the tongue may be involved in 1725% of the cases . commonly observed lesions include multiple superficial ulcers , mild glossitis , loss of papillae , chronic atrophic candidiasis and fissured tongue .
nodular lesions may be present over the anterior part of the tongue , giving a pavement - stone appearance and ultimately lead to scarring .
the muscles of the tongue are usually spared unlike the extensive involvement seen in other subcutaneous muscles .
in advanced cases , there may be diffuse infiltration , swellings , papulonodules and ulceration .
hard palate , as already mentioned , is the most common site of involvement and shows the most varied type of lesions .
the disease may present as erythematous or reddish papules that gradually increase in size and number and coalesce to form a generalized nodular sub - mucosal infiltrate [ figures 14 ] .
as the disease progresses , the mucosa loses its shininess and gives a matt - like appearance .
ultimately , there may be palatal ulceration and perforation leading to communication between the oral and nasal cavity . at this time
reported erythema nodosum leprosum to be an important but rare cause of destruction of the hard and soft palate .
further in the course of disease , the mucosa of the soft palate , uvula and fauces of tonsils become infiltrated with the appearance of miliary papules or nodules .
the uvula may initially appear swollen and later completely effaced or may become adherent to the soft palate .
scarring in the region of fauces may lead to a triangular deformity instead of the normal faucial arch .
erythematous infiltrated plaque on upper lip in a case of borderline tubercular leprosy with type 1 reaction induration on the tip and lateral border of the tongue superficial erosion on the hard palate nodule on the right fauci ( encircled ) in case of lepromatous leprosy involvement of gums may be in the form of gingivitis , periodontitis and periodontoclasia .
gums appear swollen with shiny and purplish mucosa and bleed easily with decreased sensitivity to pain .
miranda et al . described three different types of leprotic involvement of teeth : specific pulpitis , dental anomalies and periapical granulomas .
further concluded that leprosy patients tend to have poor dental and periodontal health , unrelated to the presence of facial destruction or the type of leprosy .
in addition , it has been postulated that oral chronic infections may be associated with the recurrence of leprosy reaction episodes .
motta et al . compared 38 patients with leprosy 19 with and 19 without oral infections and found the latter group to show clinical improvement in leprosy reactions after dental treatment .
grenz zone , which is a consistent feature in skin lesions , is rarely seen in oral lesions .
intense infiltration of macrophages , lymphocytes and plasma cells is prominently seen in oral lesions of lepromatous leprosy , with abundance of acid fast bacilli .
hyperkeratosis is observed in some cases and is believed to be analogous to desquamation of skin , as seen in reversal or downgrading reactions .
abreu et al . studied 19 patients with multibacillary leprosy between 2000 and 2002 , and concluded that clinical alterations in the oral mucosa do not imply disease involvement and should be confirmed by histopathological examination .
while concluding , it may be emphasized that examination of the oral mucosa should form an integral part of the examination of a patient with leprosy .
although the patient with leprosy will at first report to the dermatologist and rarely to the dental professional , the dental professional should be well aware of the precautions ( wearing gloves and mask , proper sterilization , etc . ) to be taken while giving any kind of treatment to this patient in a leprosy center .
appropriate treatment of dental infections will help to reduce the recurrence in leprosy reactions in addition to improving the general oral hygiene of the patient .
further , it is believed that oral lesions along with nasal lesions form an important source of bacillary dissemination in the community , and the reduced number or absence of patients exhibiting oral manifestations of leprosy can be attributed to the early diagnosis of the disease and the effectiveness of multidrug therapy .[/INST]although leprosy involves the oral cavity in up to 60% of the patients , examination of the oral cavity in leprosy clinics or oral health science clinics is often neglected . oral involvement in leprosy
can broadly be divided into non - specific and specific lesions . in this review ,
we discuss various oral manifestations in leprosy patients so as to increase the awareness about this aspect among dermatologists and dental surgeons .</s> |
poly(amidoamine ) ( pamam ) dendrimers have
attracted significant
interest since they were first synthesized by tomalia et al . in 1985 .
the dendritic architecture has many properties
that are interesting from both materials and biological standpoints ,
including the scaling of size and number of functional groups with
generation .
the dynamics of the branches of pamam dendrimers have
also been shown to vary as a function of generation , with lower generations
( g0g5 ) being highly flexible and having the ability to fold
branches into the core region . for higher generations ( g6 ) ,
the branches are tightly packed and the dendrimer shape becomes more
like a sphere , although backfolding of terminal groups is still observed .
the primary and secondary amines of pamam dendrimer are protonated
at different ph levels , allowing for swelling and conformational changes
as a function of ph .
g5 pamam is particularly interesting for biological applications
because of its size , which is large enough to solubilize multiple
hydrophobic entities yet small enough to diffuse through tissue , making
it an excellent scaffold for a variety drug and gene delivery applications .
physical properties of pamam dendrimer such as size and diffusion
rate impact important biological properties including pharmacodynamics
and biodistribution .
several studies have shown that molecular weight ,
radius , diffusion rates , and the density profiles of pamam all scale
with generation .
for considering biological applications ,
radius of hydration ( rh ) is a parameter
of particular interest because detailed knowledge of this value is
needed for understanding both diffusion through and localization in
biological tissue .
the ph response is important as well , particularly
from the range of 7.4 to 3 , which is the range of tissue and cytosol
to that of lysosomes .
for g5 pamam , reported values for rh range from 2.2 to 3.4 for ph 7.4 with values as high as 4.8 nm reported under acidic conditions .
this gives
a reported range of hydrodynamic volume from 45 to 165 nm at ph 7.4 and a potential increase in volume up to 463 nm upon protonation in acidic media .
this is a wide range of possible
values at physiological ph with large consequences for expected biological
properties .
the dramatic volume change upon acidification has significant
implications for the behavior of these materials in endosomes and
lysosomes , where they are known to accumulate .
given the importance of these values for understanding
key issues in drug and gene delivery , it is important to understand
how the various molecular weight ( mw ) fractions making up commercial
g5 pamam dendrimer contribute to the measured volumes and volume changes
as a function of ph .
in addition , the hydrodynamic radii and volume
values for a narrow mw fraction g5 pamam dendrimer free of trailing
generations and oligomers are desired to provide data related to the
biodistribution of this fraction and for better comparison with theoretical
calculations that employ ideal dendrimer structures .
most previous
studies have employed unpurified commercial grade materials , and this
may contribute to the substantial range of values present in the literature .
indicates that as - received biomedical
grade g5 pamam dendrimer contains 35% trailing and oligomeric
material fractions by mass .
the resolution
of these components , which is improved as compared with many previous
reports , was made possible
by increased resolution of mass fractions using reverse - phase ultrahigh
performance liquid chromatography ( rp - uplc ) and a c18 column . using
these methods , the amounts of trailing generations and high oligomers
were quantified . in particular , it was possible to resolve the significant
amounts of trailing generation four and dimer from the g5 monomer
( g5 m ) pamam peak .
the presence of trailing generations one to four
( t1t4 ) and dimers , trimers , and tetramers of g5 is anticipated
to have a significant impact on previous rh measurements of commercial material , including ph response .
previous
measurements of g0g3 pamam have indicated little size response
as a function of ph , whereas materials similar in size to the oligomers ,
such as g6 and g7 pamam , are reported to have a substantially larger
ph response than g5 pamam . in the present work , semipreparative
scale reverse - phase high - performance
liquid chromatography ( rp - hplc )
was employed to separate commercial
g5 pamam ( g5c ) material into its constituent fractions including trailing
generations t1t3 , g5 m ( 2130 kdaa fraction , 93 nh2 terminated arms , pdi = 1.019 ) , and dimer , trimer , and tetramer
of g5 .
the g5 m fraction , which represents 65% of the as - received
g5c material , contains the entire distribution of branching type defects
( i.e. , missing arms and intramolecular loops ) with structurally perfect
g5 present as < 0.01% of the mixture .
although these branching defects
are so numerous as to make it impossible to isolate structurally perfect
g5 for study by these methods , this technique does allow isolation
of g5 m free of t1t4 and g5-derived oligomers .
diffusion - order
spectroscopy ( dosy ) nmr was employed to study the scaling of diffusion ,
radius , and ph response for all isolated fractions .
it was found that
the self - diffusion of the isolated dendrimer structures scaled at
a rate of r n , in good agreement with previous studies of scaling by generation .
in addition , g5 m shows little ph response with rh of 3.1(0.1 ) versus 3.2 nm for ph 7 and 3 , respectively ;
however , a substantial response is observed for the dimer fraction
with rh of 4.4 versus 5.9 nm for ph 7
and 3 , respectively .
in other words , g5 m undergoes a hydrodynamic
volume change of just 10% , whereas the dimer undergoes a hydrodynamic
volume change of 140% .
this study indicates that important physical
properties relevant to biomedical application ascribed to g5 pamam
dendrimer arise from components present as part of the mixture that
makes up commercial grade g5 pamam material .
biomedical - grade g5 pamam dendrimer was purchased from dendritech
in midland , mi , and g3 pamam dendrimer from sigma - aldrich .
g3c
( commercial g3 ) were used as received . trailing generation and oligomer
structures
were isolated from g5c using semipreparative rp - hplc according
to previously published protocols .
all
other chemicals were purchased from sigma - aldrich or fisher scientific
and used as received .
a ph
3 buffer was prepared from 51.4 mg potassium hydrogen phthalate , 58
l of 2 m deuterium chloride , and 2442 ul of deuterium oxide ,
and then a 1:2 dilution was performed .
a ph 5 buffer was prepared
using 53.2 mg of potassium hydrogen phthalate , 57 l of 2 m
sodium deuteroxide , and 944 l of deuterium oxide , and then
a 1:5 dilution was performed .
a ph 7 buffer was prepared using 32.2
mg potassium dihydrogen phosphate , 73 l of 2 m sodium deuteroxide ,
and 427 l of deuterium oxide , and then a 1:10 dilution was
performed .
a ph 9 buffer was prepared using 73.7 mg disodium hydrogen
phosphate , 11.8 l of 2 m deuterium chloride , and 2488 l
of deuterium oxide , and then a 1:2 dilution was performed .
a ph 11
buffer was prepared using 137.1 mg of disodium hydrogen phosphate ,
347 l of 0.1 m sodium deuteroxide , and 653 l of deuterium
oxide .
the dendrimer solutions were prepared at 0.032 m ( with
respect to protonatable primary amines ) , whereas the buffering capacities
ranged from 0.05 to 0.1 m. the semiprep
rp - hplc , rp - uplc ,
and gpc protocols employed here have been previously reported .
nmr samples were prepared in
deuterium oxide or a deuterated buffer at a concentration of 10 mg / ml
( within the infinite dilution range for these samples at 0.12.1
mm ) .
the temperature
was set to 30 c , and samples were allowed to equilibrate for
no fewer than 15 min .
the dosy gradient - compensated stimulated
echo with spin lock and convection compensation ( dgcstesl_cc ) pulse
sequence was employed with a diffusion gradient length of 4.0 ms and
a diffusion delay of 200 ms .
a 10 s relaxation delay was employed
with a total of 16 scans . for analysis ,
the entire spectral region
from 3.7 to 2.3 ppm was used and arbitrarily set to an integral value
of 100 for the gradient field strength ( g ) of 0 g / cm
for each sample .
six samples were obtained from the commercial material : trailing generation
2 ( t2 ) , trailing generation 3 ( t3 ) , g5 m , ( g5)2 dimer , ( g5)3 trimer , and ( g5)4 tetramer ( figure 1 ) .
sufficient resolution was not achieved to obtain an independent
fraction of t4 , which elutes as a left shoulder on the g5 m peak .
also ,
t4t4 dimers are expected to coelute with g5 m because they
have the same expected molecular weight .
the g5 dimer peak has 14%
of the area of the g5 m peak ; therefore , a t4 dimer would be expected
to have 14% area than the t4 peak .
this translates to < 1.5%
of the g5 m peak so that convolution of t4 dimer behavior with g5 m
behavior is expected to be small .
all possible defects
apart from oligomerization ( i.e. , incomplete michael s addition
and intramolecular loop formation ) lead to lower - than - theoretical
molecular weights . as such ,
the rate of structural defect formation
was estimated to be 715% . in
other words , 1 out of every 10 branching reactions result
in a defective arm , reducing the number of primary amines and molecular
weight available each generation .
the effect is small in previous
generations , with only about three defects expected for a g3 .
however ,
during the synthesis of g5c , on average 10 new defects form per dendrimer .
this effect is greater in the oligomer structures due to the compounding
of skeletal defects , as is observed by the further deviation from
the theoretical molecular weight .
uplc chromatograms of commercial ( black
trace ) and isolated fractions
( overlaid colored traces ) .
t4 appears as a left - hand shoulder to the
g5 m peak but can not be isolated without substantial g5 m also present .
each isolated fraction was then
examined using diffusion nmr to measure self - diffusion coefficients
( d ) and hydrodynamic radii ( rh ) .
larger structures diffuse more slowly , which can be observed
by the spin echo signal changes due to the distribution of
special displacements of the resonant nuclei in a magnetic field with
gradient and nuclear magnetic relaxation processes . experimentally , a change in the rate of signal decay in
a pulse field gradient nmr experiment is observed ( figure 2 ) .
the self - diffusion
coefficient can be determined from the slope of the stejskal
tanner
plot , which relates it to signal intensity by the following equationwhere g is the gradient field
strength ( in gauss / cm ) , i is the integral of the
peak area at a given value g , i0 is the integral of the peak area at g =
0 , is the magnetogyric constant of the nucleus ( 2.675
10 t s for h ) , is the diffusion gradient length parameter ( 4.0
ms ) , is the diffusion delay ( 100.0 ms ) , and d is the self - consistent diffusion coefficient . the stejskal
tanner
plots of g5c , g5 m , and all other isolated fractions are shown in figure 3 .
examples of arrayed dosy spectra of ( a ) g5c , ( b ) g5 m ,
( c ) t2 , and
( d ) g5 tetramer in d2o .
g5 m , g5c , and g3c represent an average
of five runs with standard error .
einstein equation ( with stick boundary conditions)where kb is the
boltzmann constant , t is the temperature ( in k ) ,
and is the viscosity of the solution ( 9.7 cp for d2o at 30 c ) .
the diffusion
coefficients and hydrodynamic radii obtained for the isolated dendrimer
structures are summarized in table 2 .
dendrimer radius increases
with generation ( along with molecular
weight ) , and it is expected that d should also be
a function of dendrimer generation .
employed small - angle
x - ray scattering ( saxs ) to show that the radius of gyration ( rg ) of pamam ( synthesized at michigan molecular
institute ) scaled as a function of generation ( r n for g3 , rg of g5c = 2.41 nm ) .
the results indicate that the surface
density increases with generation until at higher generations ( g6 )
the density becomes generation - independent and the dendrimers are
best modeled as densely packed .
urban et al . used molecular
modeling in addition to saxs to study g0g8 .
rg for a structurally perfect g5 monomer was calculated
to be 3.6 nm but was only 2.3 nm for g5c material , as measured by
saxs .
the authors concluded that rg is
generationally dependent , with a change from flexible to compact structures
at higher generations and also concluded that r n for g3 .
maiti and goddard et al . employed full atomistic md studies to show
that radius scaled as r n for structurally perfect g0g11 pamam , where n is the number of atoms or repeat units in the dendrimer .
the authors also report that up until at least g6 the idealized dendrimer
structures are highly flexible under the conditions studied ( gas phase ) .
canetta and maino employed molecular dynamics
on structurally perfect pamam to show that a dynamic transition occurs
from g5 to g6 and that diffusion constants vary nonlinearly with generation .
their simulations also showed that the radius of gyration scales as r n. for g5c and all of the dendrimer fractions isolated
from this mixture ,
diffusion constants and hydrodynamic radii scale with molecular weight .
the sample with the smallest molecular weight ( t2 at 4755 da or 16%
of the expected value for structurally perfect g5 monomer ) diffused
the fastest ( 1.44 10 m / s )
at almost twice the rate of the g5c .
this corresponds to the smallest
observed hydrodynamic radius ( 1.6 nm ) , just over 60% of the average
value for g5c . by way of comparison , g5 tetramer ( 74 400 da
or 250% of the theoretical value for perfect g5 ) diffused at only
half the rate and has a radius nearly 150% larger than that observed
for g5c .
overall , this leads to the conclusion that the g5c material ,
with an average hydrodynamic volume of 91 nm ,
consists of particles ranging from 17 to 408 nm .
these
are substantially different values that will result in different pharmacodynamics
and biodistribution .
the observed d and rh values of the material fractionated
from g5c scale with molecular
weight .
a similar trend was observed by jimnez et al . where
diffusion coefficients of low commercial generation dendrimer materials
were shown to scale exponentially with the number of atoms in the
dendrimerwhere n is the number of
atoms and is a solvent - dependent scaling constant . in this relationship , a good solvent
,
in which solvent dendrimer interaction is favored over self - interaction
of the branches , has a theoretical value of 0.5 .
jimnez et al . found that for low - generation commercial pamam
( g0g3 ) , scaling was ph - dependent with = 0.50
at ph 7 ( a good solvent ) and = 0.39
at ph 12 ( a poor solvent with significant backfolding
of the dendrimer arms ) .
for the isolated structures studied in this
work , an exact atomistic count is not available or reasonable , given
that branching defects are more prevalent at higher generations .
however ,
for a given material fraction it is a good approximation to assume
that the number of atoms is proportional to molecular weight .
therefore ,
each sample fraction was assigned a number of atoms based on the percentage
of atoms in a perfect g5 dendrimer .
the g5 m in this study had a molecular weight
that is 87% of this value ; it was therefore hypothesized to have 4076
atoms .
figure 4 gives the log log representation
of the d to n relationship . from
the slope of this relationship , the scaling factor = 0.35 .
this is significantly lower than that observed for neutral low - generation
dendrimers ( 0.5 in neutral ph ) and indicates a change in material
distribution related to increased backfolding of dendrimer arms .
however , the isolated samples were washed with
a ph 7.4 buffer , giving solutions of a lower ph ( 7 based on
the observed ph - dependent chemical shifts ) than solutions of commercial material dissolved directly into water
( typically ph 12 ) .
this value of is much closer to
that reported for low - generation dendrimers at high ph , where significant
backfolding is expected to occur .
this suggests that even at neutral
ph the primary amines spend a significant fraction of time folded
into the dendrimer core .
the commercial materials were excluded from
this analysis because the molecular weight does not accurately represent
the large mass distribution ( and therefore atomistic distribution )
of species in the sample . however , both g3c and g5c had self - diffusion
coefficients 16% faster than predicted by this relationship .
these commercial materials are mixtures of many generations and oligomers
of dendrimer . in nmr ,
signal intensity is a function of concentration ;
therefore , the skewing toward fast diffusion ( i.e. , smaller entities )
may be the result of relatively higher molar concentrations of trailing
generations present in the fractions .
to test this idea , an estimated
value of d for g5c was computed by taking the population
weighted average ( percentages from peak fitting of chromatogram of
g5c in figure 1 ) of the experimental values
of d measured for the individually measured t2 ( 0.8% ) ,
t3 ( 2.3% ) , g5 m ( 74.9% ) , dimer ( 11.7% ) , trimer ( 2.3% ) , and tetramer
( < 0.5% ) species and taking computed values for d for t1 ( < 0.5% ) and t4 ( 7.6% ) from the best - fit line in figure 4 .
the resulting value of 7.50 10 m / s is within 10% of the measured value of 8.21
10 m / s for g5c .
log representation
of the scaling of diffusion coefficients
versus the approximate number of atoms for each dendrimer species .
the commercial g5c and g3c mixtures are shown but not included in
the best - fit line calculation .
error bars for g3c , g5c , and g5 m were experimentally determined ,
whereas error for remaining samples was estimated by averaging the
three experimental errors .
an analogous analysis was performed to describe the scaling
of rh for the isolated samples as a function
of
numbers of atoms .
it was determined that rh n , which is very close
to the previously reported relationship of r n for dendrimers by generation .
this indicates that the trailing and oligomer material fractions
isolated from g5c behave nearly identically to lower and higher generation
dendrimers . as a result
, the g5c dendrimer may be viewed as a mixture
of g2g5 dendrimers with the dimer , trimer , and tetramer behaving
similarly in terms of scaling to monomers with the same number of
atoms ( i.e. , g5 tetramer is similar to g7 ) .
tanner analysis
is that g5 m appears to have a slightly larger rh than the g5c mixture .
interestingly , doubling
the reported hydrodynamic radius for the commercial material ( 2.8
0.1 nm ) gives a close match to the diameter reported by the
manufacturer , dendritech , of 5.4 nm . by way of contrast
, the isolated
g5 m fraction has an rh value of 3.1
0.1 nm , which is in agreement with the value reported by bnyai
et al . for a purified commercial g5 sample in deuterium oxide ( reported
to contain 90% g5 m , 8% dimer , and 2% t4 ) .
the apparent larger size arises from the fact that dissolving g5 m
in d2o results in a ph of 7 , whereas dissolving
g5c in d2o gives a solution of ph 12 .
this difference
arises from the use of ph 7.4 buffers in the preparation of g5 m . when
dosy is used to obtain the value for rh under controlled ph conditions the values are the same within error
( vida infra ) .
solvated conditions are especially important for
describing the
behavior of dendrimers . in aqueous environments ,
protonation of the
amines can influence backfolding and swelling in addition to generational
effects .
for example , maiti and goddard et al . initially demonstrated
by md that the radius of gyration of a structurally perfect g5 dendrimer
swells from 2.1 nm at ph 10 to 2.5 nm at ph 7 .
dosy nmr experiments have been employed to study
the diffusion properties of pamam in methanol and aqueous environments .
jimnez
et al . reported that both diffusion and hydrodynamic radii scale with
dendrimer generation ( from g0 to g3 commercial materials ) and that
ph - induced swelling increases at higher generations .
employed dosy nmr to study commercial
g5 pamam materials with amine and carboxylate surface groups in aqueous
environments .
amine - terminated g5c material in deuterium oxide had
a measured rh of 3.05 nm , which they interpreted
as the g5c behaving as a hard - sphere colloid with significant swelling
upon hydration .
a scaling of diffusion with solution ph ( slower diffusion
with lower ph ) was also observed .
jachimska
et al . observed a similar trend of ph induced swelling of 25%
in commercial g6 pamam by quartz crystal microbalance .
however , the relationship between ph and
dendrimer radius is far
from clear .
porcar and chen et al . used sans to study commercial g3g6
dendrimer materials at various ph values . only a small ( 5% )
increase in rg ( rg = 2.09 nm for g5 )
large
changes in internal structure were still observed ; therefore , the
authors hypothesize that counterion shielding effects minimize the
repulsion between charged terminal amines that would theoretically
lead to swelling . in subsequent studies
on commercial g4 and g5 pamam , this observation was experimentally
attributed to a ph - induced conformational change from a dense - core
structure at neutral ph to an evenly distributed structure at lower
ph , with similar rg in both environments .
liu and goddard et al . confirmed in simulation on structurally perfect
pamam models that explicitly including counterions in calculations
prevented the observed swelling previously reported by md .
interestingly , chen et al . found that at higher
generations ( g7g8 commercial materials ) , a noticeable swelling
still occurred upon protonation of the dendrimer .
the source of the
swelling was found to be the same structural rearrangement ( redistribution
of mass from the center to the periphery and intradendrimer hydration ) seen in lower generations , with a more observable
result .
the effect of counterion association
has also been studied by md and sans and has been shown to influence
observed properties such as structure rearrangement and observed radius . to gain experimental insight into the
effect of ph on the variously
sized components of g5c
, we studied the diffusion behavior of g5c ,
g5 m , and g5 dimer in ph buffers ranging from 3 to 11 .
the ph of a
solution of g5c in deuterium oxide is 12 . the isolated material ,
however , had ph values closer to 7 due to treatment with ph 7.4 buffer
in preparation . to ensure that the observed differences in hydrodynamic
radii were not due to swelling at lower ph , we collected dosy spectra
of both g5c and g5 m in deuterated buffers at ph 3 , 5 , 7 , 9 , and 11 .
figure 5 and table 3 give the resulting stejskal tanner plots . for g5c , only the
ph 11 sample fell within one standard deviation of the d2o sample .
this is expected because pamam is basic in solution ( ph
11 to 12 ) . as ph is lowered , the primary and secondary amines
become partially to fully protonated .
this causes a swelling of the
dendrimer , evidenced by the rh increasing
from 2.8 to 3.1 nm ( 10% ) .
the ph of a solution of g5 m in deuterium
oxide is 7 due to the preparation .
when comparing g5 m to g5c
at any given ph , a significant difference only appears at ph 11 , the
most basic condition used .
this implies that the larger observed radius
for g5 m as compared with g5c material stems from a lesser conformational
change due to ph . at high ph
, the amines are expected to be neutral
and the dendrimer branches spend more time folded into the core than
extended out . however , this does not appear to be the case for g5 m , which has
approximately the same radius from ph 3 to 11 with no significant
swelling .
stejskal tanner plots of ( a ) g5c and ( b ) g5 m dissolved in
various ph buffers .
chen et al . suggested
that ph response
only becomes significant for higher generation dendrimers .
experimentally ,
they found that commercial g3 and higher pamams underwent significant
swelling , whereas g2 and g1 did not .
however , the work reported here
suggests that dendrimer as large as g5 , in monomer form ( g5 m ) , does
not undergo significant swelling due to changes in ph .
it is hypothesized ,
therefore , that the observed swelling in the commercial material is
actually due to oligomer structures that make up > 15% of the commercial
sample .
, as
oligomers become more prevalent at higher generations so g3c would
be expected to have significantly more oligomers present than g2c .
g5 dimers are approximately the same size as a g6 pamam dendrimer
by molecular weight ; therefore , they would be expected to undergo
larger conformational changes upon protonation than a g5-sized dendrimer .
to test this theory
, we collected dosy spectra of isolated g5 dimer
at ph 3 , 7 , and 11 ( figure 6 , table 4 ) .
a 44% increase in hydrodynamic radius was observed
when the ph was lowered from 11 to 3 , indicating a much higher degree
of swelling for the dimer samples as compared with g5 m .
therefore ,
the small difference in ph response of the g5c material compared with
the g5 m is the result of swelling of the 14% dimer and higher
oligomer fractions present in the g5c material . it also explains why
the rh value of g5 m is larger than the
average rh value g5c at high ph when the
larger oligomer structures present in g5c are collapsed , decreasing
the average rh of the g5c mixture .
standard deviations are approximated by averaging the percent deviations
of the g3c , g5c , and g5 m at each data point .
einstein
equation in the form for stick boundary conditions
assumes the sphere surface ( i.e. , the dendrimer ) rotates with the
same velocity as the liquid surface ( i.e. , d2o ) . under the slip boundary condition
, the dendrimer
rotates independently from the solvent ( i.e. , no interaction ) , and
the stokes
einstein relation takes the formconsequently increasing the measured radii
by a factor of 1.5 .
the authors state that improper boundary conditions
may have caused some groups to measure erroneous increases in rh by diffusion .
it seems logical to assume that
the charged surface amines present at lower ph values would interact
more with the d2o than the neutral surface amines at higher
ph .
this would imply that lower ph values are closer to the stick
limit and higher ph at the slip limit .
treatment of the g5 m at high
ph in the slip limit would imply that the dendrimer actually decreases in rh as ph is lowered .
at ph 11
, the slip - limit rh of g5 m would
give a volume of 421 nm , and at ph 3 a stick - limit rh gives a volume of 138 nm .
this
would reflect a collapsing of the dendrimer structure
upon protonation of the primary amines , an extremely unlikely event
that is not supported by md computations .
a stick / slip boundary limit
transition would , in fact , account for the measured change in the
dimer case .
a ph 11 slip - limit gives an observed rh value of 6.2 nm and a ph 3 stick - limit rh value of 5.9 nm ( around the expected error of 0.1
nm ) .
however , because the g5 dimer has the same chemical components
as the g5 m , there is no reason for the solvent to interact with it
differently .
therefore , although it can not be determined from dosy
alone which limiting case is most appropriate , the observed trend
of the g5 m data indicates that a complete switching of limits is not
appropriate .
therefore , the swelling observed for the dimer is not
an artifact of a boundary condition change of the stokes
in summary , the diffusion behavior of t2 and t3 trailing generation ,
g5 m , and dimer , trimer , and tetramer oligomers isolated from commercial
pamam dendrimer material was studied by dosy nmr spectroscopy .
samples
isolated from the commercial material ranged in size from roughly
equivalent to g2 ( 4700 da ) to g5 tetramers ( 73 000 da ) .
the
self - diffusion constants of the isolated structures were found to
scale exponentially with structure size at a similar rate as those
reported as a function of dendrimer generation in poor solvents ( i.e. ,
when significant backfolding will occur ) . additionally , the radius
of hydration was found to scale exponentially with molecular weight
( approximated by number of atoms ) in good agreement with the molecular
dynamics predicted relation of r n. this result indicates that low- and high - molecular - weight
fractions present in commercial g5 pamam dendrimer material effectively
behave like trailing and higher generation pamam structures .
experimental
results from ensemble techniques such as nmr spectroscopy and x - ray
or neutron scattering on commercial g5 dendrimer materials reflect
an average of many generations of dendrimers .
this explains why a
bulk response to ph has been observed in commercial pamam material
but was not predicted by molecular models performed using structurally
perfect simulations .
the commercial g5 material had a slight ( 10% ) swelling
when the ph was lowered from 11 to 3 . however , the isolated g5 monomer
had no significant change in rh across
this range .
it was found that the large , oligomeric fractions ( dimer ,
in particular ) had changes in observed rh of 44% when ph was lowered from 11 to 3 .
we conclude that dimer
and larger fractions are the source of the change observed in the
commercial sample . | commercial generation - five poly(amidoamine )
dendrimer material
( g5c ) was fractionated into its major structural components .
monomeric
g5 ( g5 m ; 2130 kda ) was isolated to compare its functional
properties to the g5c material .
diffusion - ordered nuclear magnetic
resonance spectroscopy was employed to measure the self - diffusion
coefficients and corresponding hydrodynamic radii of g5 m and other
g5c components as a function of dendrimer size ( i.e. , molecular weight )
and tertiary structure ( i.e. , generational or oligomeric nature ) .
it was found that the hydrodynamic radius ( rh ) scales with approximate numbers of atoms in the trailing
generations , g5 m , and oligomeric material at a rate of rh n0.35 , in good
agreement with previous reports of rh scaling
for pamam dendrimer with generation .
g5c materials can be thought
of as a heterogeneous mixture of dendrimers ranging in size from trailing
generation two to tetramers of g5 , approximately the same in size
as a g7 dendrimer , with g5 m comprising 65% of the material .
the radius of hydration for g5 m was measured to be 3.1 0.1
nm at ph 7.4 .
the 10% swelling in response to a drop in ph observed
for the g5c material was not observed for isolated g5 m ; however , the
isolated g5g5 dimers had an increase of 44% in rh , indicating that the g5c ph response results from the
increase in rh of the oligomeric fraction
upon protonation .
finally , the data allow for an experimental test
of the slip and stick boundary models
of the stokes
einstein equation for pamam dendrimer in water . | <s>[INST]poly(amidoamine ) ( pamam ) dendrimers have
attracted significant
interest since they were first synthesized by tomalia et al . in 1985 .
the dendritic architecture has many properties
that are interesting from both materials and biological standpoints ,
including the scaling of size and number of functional groups with
generation .
the dynamics of the branches of pamam dendrimers have
also been shown to vary as a function of generation , with lower generations
( g0g5 ) being highly flexible and having the ability to fold
branches into the core region . for higher generations ( g6 ) ,
the branches are tightly packed and the dendrimer shape becomes more
like a sphere , although backfolding of terminal groups is still observed .
the primary and secondary amines of pamam dendrimer are protonated
at different ph levels , allowing for swelling and conformational changes
as a function of ph .
g5 pamam is particularly interesting for biological applications
because of its size , which is large enough to solubilize multiple
hydrophobic entities yet small enough to diffuse through tissue , making
it an excellent scaffold for a variety drug and gene delivery applications .
physical properties of pamam dendrimer such as size and diffusion
rate impact important biological properties including pharmacodynamics
and biodistribution .
several studies have shown that molecular weight ,
radius , diffusion rates , and the density profiles of pamam all scale
with generation .
for considering biological applications ,
radius of hydration ( rh ) is a parameter
of particular interest because detailed knowledge of this value is
needed for understanding both diffusion through and localization in
biological tissue .
the ph response is important as well , particularly
from the range of 7.4 to 3 , which is the range of tissue and cytosol
to that of lysosomes .
for g5 pamam , reported values for rh range from 2.2 to 3.4 for ph 7.4 with values as high as 4.8 nm reported under acidic conditions .
this gives
a reported range of hydrodynamic volume from 45 to 165 nm at ph 7.4 and a potential increase in volume up to 463 nm upon protonation in acidic media .
this is a wide range of possible
values at physiological ph with large consequences for expected biological
properties .
the dramatic volume change upon acidification has significant
implications for the behavior of these materials in endosomes and
lysosomes , where they are known to accumulate .
given the importance of these values for understanding
key issues in drug and gene delivery , it is important to understand
how the various molecular weight ( mw ) fractions making up commercial
g5 pamam dendrimer contribute to the measured volumes and volume changes
as a function of ph .
in addition , the hydrodynamic radii and volume
values for a narrow mw fraction g5 pamam dendrimer free of trailing
generations and oligomers are desired to provide data related to the
biodistribution of this fraction and for better comparison with theoretical
calculations that employ ideal dendrimer structures .
most previous
studies have employed unpurified commercial grade materials , and this
may contribute to the substantial range of values present in the literature .
indicates that as - received biomedical
grade g5 pamam dendrimer contains 35% trailing and oligomeric
material fractions by mass .
the resolution
of these components , which is improved as compared with many previous
reports , was made possible
by increased resolution of mass fractions using reverse - phase ultrahigh
performance liquid chromatography ( rp - uplc ) and a c18 column . using
these methods , the amounts of trailing generations and high oligomers
were quantified . in particular , it was possible to resolve the significant
amounts of trailing generation four and dimer from the g5 monomer
( g5 m ) pamam peak .
the presence of trailing generations one to four
( t1t4 ) and dimers , trimers , and tetramers of g5 is anticipated
to have a significant impact on previous rh measurements of commercial material , including ph response .
previous
measurements of g0g3 pamam have indicated little size response
as a function of ph , whereas materials similar in size to the oligomers ,
such as g6 and g7 pamam , are reported to have a substantially larger
ph response than g5 pamam . in the present work , semipreparative
scale reverse - phase high - performance
liquid chromatography ( rp - hplc )
was employed to separate commercial
g5 pamam ( g5c ) material into its constituent fractions including trailing
generations t1t3 , g5 m ( 2130 kdaa fraction , 93 nh2 terminated arms , pdi = 1.019 ) , and dimer , trimer , and tetramer
of g5 .
the g5 m fraction , which represents 65% of the as - received
g5c material , contains the entire distribution of branching type defects
( i.e. , missing arms and intramolecular loops ) with structurally perfect
g5 present as < 0.01% of the mixture .
although these branching defects
are so numerous as to make it impossible to isolate structurally perfect
g5 for study by these methods , this technique does allow isolation
of g5 m free of t1t4 and g5-derived oligomers .
diffusion - order
spectroscopy ( dosy ) nmr was employed to study the scaling of diffusion ,
radius , and ph response for all isolated fractions .
it was found that
the self - diffusion of the isolated dendrimer structures scaled at
a rate of r n , in good agreement with previous studies of scaling by generation .
in addition , g5 m shows little ph response with rh of 3.1(0.1 ) versus 3.2 nm for ph 7 and 3 , respectively ;
however , a substantial response is observed for the dimer fraction
with rh of 4.4 versus 5.9 nm for ph 7
and 3 , respectively .
in other words , g5 m undergoes a hydrodynamic
volume change of just 10% , whereas the dimer undergoes a hydrodynamic
volume change of 140% .
this study indicates that important physical
properties relevant to biomedical application ascribed to g5 pamam
dendrimer arise from components present as part of the mixture that
makes up commercial grade g5 pamam material .
biomedical - grade g5 pamam dendrimer was purchased from dendritech
in midland , mi , and g3 pamam dendrimer from sigma - aldrich .
g3c
( commercial g3 ) were used as received . trailing generation and oligomer
structures
were isolated from g5c using semipreparative rp - hplc according
to previously published protocols .
all
other chemicals were purchased from sigma - aldrich or fisher scientific
and used as received .
a ph
3 buffer was prepared from 51.4 mg potassium hydrogen phthalate , 58
l of 2 m deuterium chloride , and 2442 ul of deuterium oxide ,
and then a 1:2 dilution was performed .
a ph 5 buffer was prepared
using 53.2 mg of potassium hydrogen phthalate , 57 l of 2 m
sodium deuteroxide , and 944 l of deuterium oxide , and then
a 1:5 dilution was performed .
a ph 7 buffer was prepared using 32.2
mg potassium dihydrogen phosphate , 73 l of 2 m sodium deuteroxide ,
and 427 l of deuterium oxide , and then a 1:10 dilution was
performed .
a ph 9 buffer was prepared using 73.7 mg disodium hydrogen
phosphate , 11.8 l of 2 m deuterium chloride , and 2488 l
of deuterium oxide , and then a 1:2 dilution was performed .
a ph 11
buffer was prepared using 137.1 mg of disodium hydrogen phosphate ,
347 l of 0.1 m sodium deuteroxide , and 653 l of deuterium
oxide .
the dendrimer solutions were prepared at 0.032 m ( with
respect to protonatable primary amines ) , whereas the buffering capacities
ranged from 0.05 to 0.1 m. the semiprep
rp - hplc , rp - uplc ,
and gpc protocols employed here have been previously reported .
nmr samples were prepared in
deuterium oxide or a deuterated buffer at a concentration of 10 mg / ml
( within the infinite dilution range for these samples at 0.12.1
mm ) .
the temperature
was set to 30 c , and samples were allowed to equilibrate for
no fewer than 15 min .
the dosy gradient - compensated stimulated
echo with spin lock and convection compensation ( dgcstesl_cc ) pulse
sequence was employed with a diffusion gradient length of 4.0 ms and
a diffusion delay of 200 ms .
a 10 s relaxation delay was employed
with a total of 16 scans . for analysis ,
the entire spectral region
from 3.7 to 2.3 ppm was used and arbitrarily set to an integral value
of 100 for the gradient field strength ( g ) of 0 g / cm
for each sample .
six samples were obtained from the commercial material : trailing generation
2 ( t2 ) , trailing generation 3 ( t3 ) , g5 m , ( g5)2 dimer , ( g5)3 trimer , and ( g5)4 tetramer ( figure 1 ) .
sufficient resolution was not achieved to obtain an independent
fraction of t4 , which elutes as a left shoulder on the g5 m peak .
also ,
t4t4 dimers are expected to coelute with g5 m because they
have the same expected molecular weight .
the g5 dimer peak has 14%
of the area of the g5 m peak ; therefore , a t4 dimer would be expected
to have 14% area than the t4 peak .
this translates to < 1.5%
of the g5 m peak so that convolution of t4 dimer behavior with g5 m
behavior is expected to be small .
all possible defects
apart from oligomerization ( i.e. , incomplete michael s addition
and intramolecular loop formation ) lead to lower - than - theoretical
molecular weights . as such ,
the rate of structural defect formation
was estimated to be 715% . in
other words , 1 out of every 10 branching reactions result
in a defective arm , reducing the number of primary amines and molecular
weight available each generation .
the effect is small in previous
generations , with only about three defects expected for a g3 .
however ,
during the synthesis of g5c , on average 10 new defects form per dendrimer .
this effect is greater in the oligomer structures due to the compounding
of skeletal defects , as is observed by the further deviation from
the theoretical molecular weight .
uplc chromatograms of commercial ( black
trace ) and isolated fractions
( overlaid colored traces ) .
t4 appears as a left - hand shoulder to the
g5 m peak but can not be isolated without substantial g5 m also present .
each isolated fraction was then
examined using diffusion nmr to measure self - diffusion coefficients
( d ) and hydrodynamic radii ( rh ) .
larger structures diffuse more slowly , which can be observed
by the spin echo signal changes due to the distribution of
special displacements of the resonant nuclei in a magnetic field with
gradient and nuclear magnetic relaxation processes . experimentally , a change in the rate of signal decay in
a pulse field gradient nmr experiment is observed ( figure 2 ) .
the self - diffusion
coefficient can be determined from the slope of the stejskal
tanner
plot , which relates it to signal intensity by the following equationwhere g is the gradient field
strength ( in gauss / cm ) , i is the integral of the
peak area at a given value g , i0 is the integral of the peak area at g =
0 , is the magnetogyric constant of the nucleus ( 2.675
10 t s for h ) , is the diffusion gradient length parameter ( 4.0
ms ) , is the diffusion delay ( 100.0 ms ) , and d is the self - consistent diffusion coefficient . the stejskal
tanner
plots of g5c , g5 m , and all other isolated fractions are shown in figure 3 .
examples of arrayed dosy spectra of ( a ) g5c , ( b ) g5 m ,
( c ) t2 , and
( d ) g5 tetramer in d2o .
g5 m , g5c , and g3c represent an average
of five runs with standard error .
einstein equation ( with stick boundary conditions)where kb is the
boltzmann constant , t is the temperature ( in k ) ,
and is the viscosity of the solution ( 9.7 cp for d2o at 30 c ) .
the diffusion
coefficients and hydrodynamic radii obtained for the isolated dendrimer
structures are summarized in table 2 .
dendrimer radius increases
with generation ( along with molecular
weight ) , and it is expected that d should also be
a function of dendrimer generation .
employed small - angle
x - ray scattering ( saxs ) to show that the radius of gyration ( rg ) of pamam ( synthesized at michigan molecular
institute ) scaled as a function of generation ( r n for g3 , rg of g5c = 2.41 nm ) .
the results indicate that the surface
density increases with generation until at higher generations ( g6 )
the density becomes generation - independent and the dendrimers are
best modeled as densely packed .
urban et al . used molecular
modeling in addition to saxs to study g0g8 .
rg for a structurally perfect g5 monomer was calculated
to be 3.6 nm but was only 2.3 nm for g5c material , as measured by
saxs .
the authors concluded that rg is
generationally dependent , with a change from flexible to compact structures
at higher generations and also concluded that r n for g3 .
maiti and goddard et al . employed full atomistic md studies to show
that radius scaled as r n for structurally perfect g0g11 pamam , where n is the number of atoms or repeat units in the dendrimer .
the authors also report that up until at least g6 the idealized dendrimer
structures are highly flexible under the conditions studied ( gas phase ) .
canetta and maino employed molecular dynamics
on structurally perfect pamam to show that a dynamic transition occurs
from g5 to g6 and that diffusion constants vary nonlinearly with generation .
their simulations also showed that the radius of gyration scales as r n. for g5c and all of the dendrimer fractions isolated
from this mixture ,
diffusion constants and hydrodynamic radii scale with molecular weight .
the sample with the smallest molecular weight ( t2 at 4755 da or 16%
of the expected value for structurally perfect g5 monomer ) diffused
the fastest ( 1.44 10 m / s )
at almost twice the rate of the g5c .
this corresponds to the smallest
observed hydrodynamic radius ( 1.6 nm ) , just over 60% of the average
value for g5c . by way of comparison , g5 tetramer ( 74 400 da
or 250% of the theoretical value for perfect g5 ) diffused at only
half the rate and has a radius nearly 150% larger than that observed
for g5c .
overall , this leads to the conclusion that the g5c material ,
with an average hydrodynamic volume of 91 nm ,
consists of particles ranging from 17 to 408 nm .
these
are substantially different values that will result in different pharmacodynamics
and biodistribution .
the observed d and rh values of the material fractionated
from g5c scale with molecular
weight .
a similar trend was observed by jimnez et al . where
diffusion coefficients of low commercial generation dendrimer materials
were shown to scale exponentially with the number of atoms in the
dendrimerwhere n is the number of
atoms and is a solvent - dependent scaling constant . in this relationship , a good solvent
,
in which solvent dendrimer interaction is favored over self - interaction
of the branches , has a theoretical value of 0.5 .
jimnez et al . found that for low - generation commercial pamam
( g0g3 ) , scaling was ph - dependent with = 0.50
at ph 7 ( a good solvent ) and = 0.39
at ph 12 ( a poor solvent with significant backfolding
of the dendrimer arms ) .
for the isolated structures studied in this
work , an exact atomistic count is not available or reasonable , given
that branching defects are more prevalent at higher generations .
however ,
for a given material fraction it is a good approximation to assume
that the number of atoms is proportional to molecular weight .
therefore ,
each sample fraction was assigned a number of atoms based on the percentage
of atoms in a perfect g5 dendrimer .
the g5 m in this study had a molecular weight
that is 87% of this value ; it was therefore hypothesized to have 4076
atoms .
figure 4 gives the log log representation
of the d to n relationship . from
the slope of this relationship , the scaling factor = 0.35 .
this is significantly lower than that observed for neutral low - generation
dendrimers ( 0.5 in neutral ph ) and indicates a change in material
distribution related to increased backfolding of dendrimer arms .
however , the isolated samples were washed with
a ph 7.4 buffer , giving solutions of a lower ph ( 7 based on
the observed ph - dependent chemical shifts ) than solutions of commercial material dissolved directly into water
( typically ph 12 ) .
this value of is much closer to
that reported for low - generation dendrimers at high ph , where significant
backfolding is expected to occur .
this suggests that even at neutral
ph the primary amines spend a significant fraction of time folded
into the dendrimer core .
the commercial materials were excluded from
this analysis because the molecular weight does not accurately represent
the large mass distribution ( and therefore atomistic distribution )
of species in the sample . however , both g3c and g5c had self - diffusion
coefficients 16% faster than predicted by this relationship .
these commercial materials are mixtures of many generations and oligomers
of dendrimer . in nmr ,
signal intensity is a function of concentration ;
therefore , the skewing toward fast diffusion ( i.e. , smaller entities )
may be the result of relatively higher molar concentrations of trailing
generations present in the fractions .
to test this idea , an estimated
value of d for g5c was computed by taking the population
weighted average ( percentages from peak fitting of chromatogram of
g5c in figure 1 ) of the experimental values
of d measured for the individually measured t2 ( 0.8% ) ,
t3 ( 2.3% ) , g5 m ( 74.9% ) , dimer ( 11.7% ) , trimer ( 2.3% ) , and tetramer
( < 0.5% ) species and taking computed values for d for t1 ( < 0.5% ) and t4 ( 7.6% ) from the best - fit line in figure 4 .
the resulting value of 7.50 10 m / s is within 10% of the measured value of 8.21
10 m / s for g5c .
log representation
of the scaling of diffusion coefficients
versus the approximate number of atoms for each dendrimer species .
the commercial g5c and g3c mixtures are shown but not included in
the best - fit line calculation .
error bars for g3c , g5c , and g5 m were experimentally determined ,
whereas error for remaining samples was estimated by averaging the
three experimental errors .
an analogous analysis was performed to describe the scaling
of rh for the isolated samples as a function
of
numbers of atoms .
it was determined that rh n , which is very close
to the previously reported relationship of r n for dendrimers by generation .
this indicates that the trailing and oligomer material fractions
isolated from g5c behave nearly identically to lower and higher generation
dendrimers . as a result
, the g5c dendrimer may be viewed as a mixture
of g2g5 dendrimers with the dimer , trimer , and tetramer behaving
similarly in terms of scaling to monomers with the same number of
atoms ( i.e. , g5 tetramer is similar to g7 ) .
tanner analysis
is that g5 m appears to have a slightly larger rh than the g5c mixture .
interestingly , doubling
the reported hydrodynamic radius for the commercial material ( 2.8
0.1 nm ) gives a close match to the diameter reported by the
manufacturer , dendritech , of 5.4 nm . by way of contrast
, the isolated
g5 m fraction has an rh value of 3.1
0.1 nm , which is in agreement with the value reported by bnyai
et al . for a purified commercial g5 sample in deuterium oxide ( reported
to contain 90% g5 m , 8% dimer , and 2% t4 ) .
the apparent larger size arises from the fact that dissolving g5 m
in d2o results in a ph of 7 , whereas dissolving
g5c in d2o gives a solution of ph 12 .
this difference
arises from the use of ph 7.4 buffers in the preparation of g5 m . when
dosy is used to obtain the value for rh under controlled ph conditions the values are the same within error
( vida infra ) .
solvated conditions are especially important for
describing the
behavior of dendrimers . in aqueous environments ,
protonation of the
amines can influence backfolding and swelling in addition to generational
effects .
for example , maiti and goddard et al . initially demonstrated
by md that the radius of gyration of a structurally perfect g5 dendrimer
swells from 2.1 nm at ph 10 to 2.5 nm at ph 7 .
dosy nmr experiments have been employed to study
the diffusion properties of pamam in methanol and aqueous environments .
jimnez
et al . reported that both diffusion and hydrodynamic radii scale with
dendrimer generation ( from g0 to g3 commercial materials ) and that
ph - induced swelling increases at higher generations .
employed dosy nmr to study commercial
g5 pamam materials with amine and carboxylate surface groups in aqueous
environments .
amine - terminated g5c material in deuterium oxide had
a measured rh of 3.05 nm , which they interpreted
as the g5c behaving as a hard - sphere colloid with significant swelling
upon hydration .
a scaling of diffusion with solution ph ( slower diffusion
with lower ph ) was also observed .
jachimska
et al . observed a similar trend of ph induced swelling of 25%
in commercial g6 pamam by quartz crystal microbalance .
however , the relationship between ph and
dendrimer radius is far
from clear .
porcar and chen et al . used sans to study commercial g3g6
dendrimer materials at various ph values . only a small ( 5% )
increase in rg ( rg = 2.09 nm for g5 )
large
changes in internal structure were still observed ; therefore , the
authors hypothesize that counterion shielding effects minimize the
repulsion between charged terminal amines that would theoretically
lead to swelling . in subsequent studies
on commercial g4 and g5 pamam , this observation was experimentally
attributed to a ph - induced conformational change from a dense - core
structure at neutral ph to an evenly distributed structure at lower
ph , with similar rg in both environments .
liu and goddard et al . confirmed in simulation on structurally perfect
pamam models that explicitly including counterions in calculations
prevented the observed swelling previously reported by md .
interestingly , chen et al . found that at higher
generations ( g7g8 commercial materials ) , a noticeable swelling
still occurred upon protonation of the dendrimer .
the source of the
swelling was found to be the same structural rearrangement ( redistribution
of mass from the center to the periphery and intradendrimer hydration ) seen in lower generations , with a more observable
result .
the effect of counterion association
has also been studied by md and sans and has been shown to influence
observed properties such as structure rearrangement and observed radius . to gain experimental insight into the
effect of ph on the variously
sized components of g5c
, we studied the diffusion behavior of g5c ,
g5 m , and g5 dimer in ph buffers ranging from 3 to 11 .
the ph of a
solution of g5c in deuterium oxide is 12 . the isolated material ,
however , had ph values closer to 7 due to treatment with ph 7.4 buffer
in preparation . to ensure that the observed differences in hydrodynamic
radii were not due to swelling at lower ph , we collected dosy spectra
of both g5c and g5 m in deuterated buffers at ph 3 , 5 , 7 , 9 , and 11 .
figure 5 and table 3 give the resulting stejskal tanner plots . for g5c , only the
ph 11 sample fell within one standard deviation of the d2o sample .
this is expected because pamam is basic in solution ( ph
11 to 12 ) . as ph is lowered , the primary and secondary amines
become partially to fully protonated .
this causes a swelling of the
dendrimer , evidenced by the rh increasing
from 2.8 to 3.1 nm ( 10% ) .
the ph of a solution of g5 m in deuterium
oxide is 7 due to the preparation .
when comparing g5 m to g5c
at any given ph , a significant difference only appears at ph 11 , the
most basic condition used .
this implies that the larger observed radius
for g5 m as compared with g5c material stems from a lesser conformational
change due to ph . at high ph
, the amines are expected to be neutral
and the dendrimer branches spend more time folded into the core than
extended out . however , this does not appear to be the case for g5 m , which has
approximately the same radius from ph 3 to 11 with no significant
swelling .
stejskal tanner plots of ( a ) g5c and ( b ) g5 m dissolved in
various ph buffers .
chen et al . suggested
that ph response
only becomes significant for higher generation dendrimers .
experimentally ,
they found that commercial g3 and higher pamams underwent significant
swelling , whereas g2 and g1 did not .
however , the work reported here
suggests that dendrimer as large as g5 , in monomer form ( g5 m ) , does
not undergo significant swelling due to changes in ph .
it is hypothesized ,
therefore , that the observed swelling in the commercial material is
actually due to oligomer structures that make up > 15% of the commercial
sample .
, as
oligomers become more prevalent at higher generations so g3c would
be expected to have significantly more oligomers present than g2c .
g5 dimers are approximately the same size as a g6 pamam dendrimer
by molecular weight ; therefore , they would be expected to undergo
larger conformational changes upon protonation than a g5-sized dendrimer .
to test this theory
, we collected dosy spectra of isolated g5 dimer
at ph 3 , 7 , and 11 ( figure 6 , table 4 ) .
a 44% increase in hydrodynamic radius was observed
when the ph was lowered from 11 to 3 , indicating a much higher degree
of swelling for the dimer samples as compared with g5 m .
therefore ,
the small difference in ph response of the g5c material compared with
the g5 m is the result of swelling of the 14% dimer and higher
oligomer fractions present in the g5c material . it also explains why
the rh value of g5 m is larger than the
average rh value g5c at high ph when the
larger oligomer structures present in g5c are collapsed , decreasing
the average rh of the g5c mixture .
standard deviations are approximated by averaging the percent deviations
of the g3c , g5c , and g5 m at each data point .
einstein
equation in the form for stick boundary conditions
assumes the sphere surface ( i.e. , the dendrimer ) rotates with the
same velocity as the liquid surface ( i.e. , d2o ) . under the slip boundary condition
, the dendrimer
rotates independently from the solvent ( i.e. , no interaction ) , and
the stokes
einstein relation takes the formconsequently increasing the measured radii
by a factor of 1.5 .
the authors state that improper boundary conditions
may have caused some groups to measure erroneous increases in rh by diffusion .
it seems logical to assume that
the charged surface amines present at lower ph values would interact
more with the d2o than the neutral surface amines at higher
ph .
this would imply that lower ph values are closer to the stick
limit and higher ph at the slip limit .
treatment of the g5 m at high
ph in the slip limit would imply that the dendrimer actually decreases in rh as ph is lowered .
at ph 11
, the slip - limit rh of g5 m would
give a volume of 421 nm , and at ph 3 a stick - limit rh gives a volume of 138 nm .
this
would reflect a collapsing of the dendrimer structure
upon protonation of the primary amines , an extremely unlikely event
that is not supported by md computations .
a stick / slip boundary limit
transition would , in fact , account for the measured change in the
dimer case .
a ph 11 slip - limit gives an observed rh value of 6.2 nm and a ph 3 stick - limit rh value of 5.9 nm ( around the expected error of 0.1
nm ) .
however , because the g5 dimer has the same chemical components
as the g5 m , there is no reason for the solvent to interact with it
differently .
therefore , although it can not be determined from dosy
alone which limiting case is most appropriate , the observed trend
of the g5 m data indicates that a complete switching of limits is not
appropriate .
therefore , the swelling observed for the dimer is not
an artifact of a boundary condition change of the stokes
in summary , the diffusion behavior of t2 and t3 trailing generation ,
g5 m , and dimer , trimer , and tetramer oligomers isolated from commercial
pamam dendrimer material was studied by dosy nmr spectroscopy .
samples
isolated from the commercial material ranged in size from roughly
equivalent to g2 ( 4700 da ) to g5 tetramers ( 73 000 da ) .
the
self - diffusion constants of the isolated structures were found to
scale exponentially with structure size at a similar rate as those
reported as a function of dendrimer generation in poor solvents ( i.e. ,
when significant backfolding will occur ) . additionally , the radius
of hydration was found to scale exponentially with molecular weight
( approximated by number of atoms ) in good agreement with the molecular
dynamics predicted relation of r n. this result indicates that low- and high - molecular - weight
fractions present in commercial g5 pamam dendrimer material effectively
behave like trailing and higher generation pamam structures .
experimental
results from ensemble techniques such as nmr spectroscopy and x - ray
or neutron scattering on commercial g5 dendrimer materials reflect
an average of many generations of dendrimers .
this explains why a
bulk response to ph has been observed in commercial pamam material
but was not predicted by molecular models performed using structurally
perfect simulations .
the commercial g5 material had a slight ( 10% ) swelling
when the ph was lowered from 11 to 3 . however , the isolated g5 monomer
had no significant change in rh across
this range .
it was found that the large , oligomeric fractions ( dimer ,
in particular ) had changes in observed rh of 44% when ph was lowered from 11 to 3 .
we conclude that dimer
and larger fractions are the source of the change observed in the
commercial sample .[/INST]commercial generation - five poly(amidoamine )
dendrimer material
( g5c ) was fractionated into its major structural components .
monomeric
g5 ( g5 m ; 2130 kda ) was isolated to compare its functional
properties to the g5c material .
diffusion - ordered nuclear magnetic
resonance spectroscopy was employed to measure the self - diffusion
coefficients and corresponding hydrodynamic radii of g5 m and other
g5c components as a function of dendrimer size ( i.e. , molecular weight )
and tertiary structure ( i.e. , generational or oligomeric nature ) .
it was found that the hydrodynamic radius ( rh ) scales with approximate numbers of atoms in the trailing
generations , g5 m , and oligomeric material at a rate of rh n0.35 , in good
agreement with previous reports of rh scaling
for pamam dendrimer with generation .
g5c materials can be thought
of as a heterogeneous mixture of dendrimers ranging in size from trailing
generation two to tetramers of g5 , approximately the same in size
as a g7 dendrimer , with g5 m comprising 65% of the material .
the radius of hydration for g5 m was measured to be 3.1 0.1
nm at ph 7.4 .
the 10% swelling in response to a drop in ph observed
for the g5c material was not observed for isolated g5 m ; however , the
isolated g5g5 dimers had an increase of 44% in rh , indicating that the g5c ph response results from the
increase in rh of the oligomeric fraction
upon protonation .
finally , the data allow for an experimental test
of the slip and stick boundary models
of the stokes
einstein equation for pamam dendrimer in water .</s> |
cancer of the esophagus has been known and described for nearly two thousand years and dysphagia is the most common complaint within the earliest reported symptoms ( fig .
the first form of palliative therapy for this neoplasm was described at the end of 19 century .
this therapy was centered on the formation of an artificial feeding tube which bypassed the tumor and at the same time narrowed the lumen of the esophagus . in 20 century
some number of other surgical procedures were developed which allowed radical excision of portions in the esophagus , along with the tumor , and using the replacement of prosthetic parts .
esophageal cancer with fiberogastroscop inside unfortunately only 10 - 20% of patients with a diagnosis of esophageal neoplasm is qualified for surgical treatment . in the majority of cases
infiltrates surrounding organs what , along with the frequent involvement of the mediastinal lymphatic system , leads to disqualification from radical surgical treatment .
usually palliative radiotherapy and/or chemotherapy is offered to such patients as they belong to a group with a poor prognosis . in spite of previously applied treatments ,
patients with advanced stage of esophagus tumors die as a result of metastases as well as involvement of neighboring organs and quite often from internal bleeding .
other cause of death is the formation of bronchoesophageal fistulas resulting from the effects of radiotherapy and disintegration of the tumor , which in turn leads to inflammation of the mediastinum and lungs , causing direct threat to a patient life .
a number of methods of palliation have been used in attempt to improve patients quality of life and to provide normal swallowing till death of a patient resulting from progress of systemic disease .
these methods include : thermal ablation , photodynamic therapy , radiotherapy ( external beam or brachytherapy ) , chemotherapy , injected chemotherapy , argon beam or bipolar electrocoagulation therapy , internal feeding ( nasal - gastric intubation / percutaneous endoscopic gastrostomy ) , and intubation ( self - expanding metal stents sems or semi - rigid prosthetic tubes ) with varying success and complications rates .
endoesophageal brachytherapy allows to apply high doses of radiation to the tumor itself with concurrent protection of adjoining healthy tissues thanks to the rapid fall of the dose by the square of distance from the center of the applicator .
the above treatment is also associated with a smaller proportion of late radiation complications . in the treatment of esophageal cancers ,
occasionally brachytherapy is used along with external beam radiation therapy ( erbt ) in doses of 10 - 40 gy , which may extend the palliative effects of improved swallowing among patients .
brachytherapy used alone as a individual way of treatment , in comparison to ebrt , gives lower percentage of complications [ 4 , 5 ] , out of which the most common problems are ulcerations and bleeding and bronchoesophageal fistulas .
the aims of palliative brachytherapy are : maintenance of oral intake , minimization of hospital stay , relief of pain , elimination of reflux and regurgitation , prevention of aspiration and improvement of the patient s well - being .
the results of hdr - bt as a palliative treatment are well known [ 6 , 7 ] . in spite of all this facts , the access to this procedure on a national scale
is limited due to the need for oncology centers to possess highly specialized equipment and appropriately qualified medical staff .
in other centers , the use of other means for palliative treatment of the esophagus such as endoscopic insertion of self - expanding metal stents ( sems ) [ 8 , 9 ] is not available .
however theoretically , this type of procedure may be carried out in any regional center every single day whenever there is no need for more invasive methods , that may lead to problems associated with control of bleeding .
previous studies have confirmed that up to 95% of patients with stents application reported reduced dysphagia that resulted in improved swallowing and body mass increasing [ 10 , 11 ] .
complications after implantation procedures are infrequent but include perforation of the esophageal wall , chest pain , bleeding and migration of the stent to the stomach or fistulas .
blockage of the stent plates by growth of the tumor mass occurs in 27% of cases and requires renewed endoscopic intervention .
complications after insertion of the stent are also connected to the location of its implantation . in the proximal portion of the esophagus ,
a patient may initially experience some breathing difficulties , while in the distal and intra - diaphragmatic portions , gastro - esophageal reflux may require pharmacological treatment .
figure 2 shows the most commonly used variations of stents , while summarized indications and contraindications for the application of esophageal stents are presented in table 1 .
esophageal perforation , usually iatrogenic , from direct endoscopic trauma or following factor of dilatation .
it is suggested to have a normal coagulation profile with an international normalized ratio which is less than 1.5 and platelet count less than 50 000 .
recent large dose of chemotherapy or radiotherapy ( 3 to 6 weeks ) because of reported increase of rates of hemorrhage and perforation .
four types of esophageal stents ( from left to right ) : ultraflex ( microvasive , boston scientific , natick , massachusetts , usa ) , wallstent ( microvasive , boston scientific ) , esophacoil ( instent , minneapolis , minnesota , usa ) , z - stent ( wilson cook , winston salem , north carolina , usa ) hdr - bt is often proceeded with stent implantation which , apart from providing the insertion of the applicator itself , improves patient s swallowing . in the presented work , the clinical data and results were obtained from stent / hdr - bt palliative treatment of patients with inoperable advanced cancers of the esophagus .
effects of the treatment on patient survival in association of selected prognostic factors are presented .
fifty patients with inoperable advanced esophageal cancer were treated with the use of hdr - bt and endoesophageal stent implantation at the greater poland cancer center between june 2001 and december 2005 .
these patients were not qualified for surgical treatment or radical external beam radiotherapy because of poor general condition , clinical stage and tumor location .
palliative hdr - bt was the treatment , of choice due to limited possibility of external beam therapy and , in most of the cases , the patient s advanced clinical stage .
a rapid improvement in dysphagia was expected after brachytherapy which was performed on outpatient basis .
the combined stent / hdr - bt palliative treatment was proposed to patients in order to rapidly improve their quality of life , in relation of treating each patient by both methods separately . in all patients ,
gastroscopy , x - ray , and ct scan were performed as well as a histological diagnosis in order to evaluate the extent of the tumor .
the group consisted of 41 ( 82% ) men and 9 women ( 18% ) , aged between 44 and 79 years ( average 59.3 years ) .
pathologically , the most frequently diagnosed cancers were squamous cell carcinoma ( 40 cases 80% ) and adenocarcinoma ( 7 cases 14% ) . in majority of patients ( 61.2% )
qualified for palliative treatment , the location of the tumor was in the mid ( one third ) portion of the mediastinal esophagus .
positions in the upper and lower thirds represented 5 ( 10.2% ) and 14 ( 28.6% ) of patients respectively .
the most recurrent infiltrations were observed during gastroscopy at 5 - 10 cm ( 59.2% ) in length , while smaller than 5 cm or greater than 10 cm were noted in 10 cases ( 20.4% ) .
patients for palliative treatment were eligible on the grounds of swallowing difficulties ( dysphagia ) , generally grade i ( 26 patients 55.3% ) and grade ii ( 15 patients 31.9% ) .
grades were qualified as follows : 0 no dysphagia , i dysphagia for solids ,
, distant liver and brain metastases were discovered in 2 patients ( 4% ) , whereas malignant neoplasm s were identified in other locations in 4 cases ( 8% ) .
gastroscopy , x - rays , and ct were performed as well as a histological diagnosis to evaluate the extent of the tumor . in most of the
cases hdr - bt was applied within two weeks of the implantation of the stent .
after initial medication , the applicator was inserted , via the oral cavity , into the esophageal lumen . following the placement of a catheter with specific marker , an x - ray was taken which was later used in preparation of the treatment plan and to define volume of the tumor . in all treatment plans
the dose was prescribed at distance of 10 mm from the surface of the source .
the target volume included visualization of residues of the tumor , which has been previously evaluated during gastroscopy and 2 cm safety margin in the cranial and caudal directions .
192-ir with 10 ci nominal activity and hdr - gammamed 12i unit ( mick radio - nuclear instruments , inc . ,
80% of patients were given hdr - bt monotherapy and 20% were additionally treated with ebrt and chemotherapy .
36 of patients ( 72% ) received total dose of 22.5 gy given in three weekly fractions of 7.5 gy per week .
fourteen patients ( 28% ) received total dose of 15 gy ( 2 7.5 gy ) .
x - ray of stents inside esophagus brachytherapy applicator with metal marker visible endoesophageal self - expanding metal stents ( sems ) were inserted via working channel during gastroscopy on short term intravenous anesthesia in the gastroenterology clinics in d , pozna and wrocaw ( fig .
implantation of the stent often required earlier mechanical widening of the area of infiltration , because of implant s diameter limitation ( 15 - 20 mm ) .
this procedure is usually performed with the use of a balloon and in rare cases with the help of neodymium laser ( nd yag ) .
visible stents during gastroscopy degree of dysphagia , remission and complications arising from combined stent / brt treatment were evaluated 4 weeks after the completion of the treatment .
the degree of remission was verified on the basis of subjective tests , an interview and imaging techniques ( x - rays of the gastrointestinal tract , computerized tomography and gastroscopy ) .
the patients survival was compared with selected clinical factors such as : the grade of evaluated remission ( radiological and during gastroscopy ) in the first month after treatment , age , sex , histopathology , the zubrod score , clinical stage , grade of dysphagia , location and size of tumor .
the respective survival periods were ascertained for particular groups in relation to treatment ( remission , partial remission , no remission , progression ) . in order to statistically assess the effects of prognostic factors on survival ,
the mann - whitney test was used ( for groups included 2 patients ) and the kruskal - wallis test for groups included 3 or more patients . in turn to evaluate the relationships within the above factors , the spearman test was applied .
local reaction to the combined brachytherapy hdr and stent implantation treatment was estimated after 4 weeks .
complete remission ( cr ) was confirmed by imaging techniques and was observed in 2 cases ( 4% ) , partial remission ( pr ) in 31 patients ( 62% ) , no remission ( nr ) in 6 cases ( 12% ) and in 11 ( 22% ) patients progression was determined ( fig .
longer survival periods were noted in patients with infiltrations shorter than 5 cm ( 6.1 months ) rather than in patients with infiltrations longer than 10 cm ( 4.9 months ) .
remission after 4 weeks during first check - up : cr complete remission , pr partial remission , nr no remission , prog progression the statistical analysis revealed the effects of prognostic factors of the patients clinical stage .
the kruskal - wallis test analyzed certain aspects such as : the effects of infiltration localization ( p = 0.428 ) , histopathology results ( p = 0.408 ) , loss of body weight ( p = 0.363 ) , length of the infiltration ( p = 0.605 ) , the zubrod score ( p = 0.830 ) , grade of dysphagia ( p = 0.695 ) and pain level ( p = 0.059 ) .
the maximum clinical response after treatment was presented by the pain factor ( according to the kruskal - wallis test this aspect was not significant , though the pain relationship was shown by this test for correlation ) .
similarly , using the mann - whitney test , correlations were investigated within : treatment scheme ( p = 0.288 ) , number of brachytherapy fractions ( p = 0.580 ) , the occurrence of complications ( p = 0.165 ) , age ( p = 0.604 ) , sex ( p = 0.988 ) and clinical response .
none of these prognostic factors had any statistical effect on results of treatment obtained ( table 3 . ) .
spearman statistical correlation between prognostic factors values in bold are statistically different from 0 with a significance level alpha = 0.05 furthermore , using the spearman test , we attempted to find relationships among the above mentioned prognostic factors ( correlation testing ) .
statistically significant correlations that are worth mentioning are : reported pain levels / response to treatment ( p = 0.025 ) and pain level / localization of the infiltration ( p = 0.009 ) , localization of the infiltration / body weight loss ( p = 0.002 ) , general condition according to the zubrod score / occurrence of complications ( p = 0.025 ) , pain level / loss of body weight ( p = 0.000 ) .
the remaining correlations discovered by use of the spearman test are presented in table 4 .
statistically significant correlations between prognostic factors ( spearman test ) complications were diagnosed in 11 patients ( 22% ) .
necrosis was seen in 1 patient ( 2% ) , serious hemorrhage was observed in 1 patient .
bronchoesophageal fistulas were found in 9 patients ( 18% ) estimated in follow - up x - ray examinations or bronchoscopy .
as highlighted above , the statistically significant correlation was found between the frequency of complication occurring after combined therapy and the general state of a patient , according to the zubrod score .
the prognosis for patients with inoperable advanced esophageal cancer is still very bad despite the introduction of improved treatment modalities such as surgery , radiotherapy and chemotherapy .
the reported 2 and 5 year survival rates range from 30 - 40% and 10 - 25% , respectively , regardless of the tumor stage or treatment options [ 16 , 17 ] . moreover , the prognosis is worse for patients with tumor stage iv and for patients with inoperable advanced cancer .
the frequency of esophageal cancer in western societies is steadily rising , particularly in lower , sub - cardiac locations on the basis of barrett s metaplasia .
unfortunately , at the time of diagnosis only few patients qualify for radical treatment as a result of general condition of their health , advanced stage of disease , metastases to distant locations or cardiac and respiratory difficulties .
30 - 40% of patients may potentially be treated with radical surgery ; however , 5 year survival in this group amounts to only 20% [ 1820 ] .
the prognosis for inoperable cases is always poor and such treatment is targeted at reducing suffering of patients in addition to improve their quality of life . in our institution
we apply a combined therapy that integrates chemotherapy , radiotherapy , as well as restorative laser and endoesophageal stents .
dysphagia is the most frequent problem among patients with advanced esophagus cancer and is described in almost 90% of cases . in correlation to this symptoms , procedure must be as noninvasive as possible and should quickly lead to palliative effects with minimal risk of complications .
the above criteria are well fulfilled in combined method of implantation of a stent into the lumen of the esophagus during endoscopy procedure , followed by endoesophageal irradiation of high dose brachytherapy .
after mechanical widening of the narrowed area and positioning of the metal stent , the immediate palliative effects are usually visible .
the aim of instant application of brachytherapy is to prolong the effects acquired through prevention of renewed stenosis within the stent .
this way of treatment is quite comfortable for patients , since it does not require an extensive hospital stay and can be applied in ambulatory condition .
this gets out of giving an endoesophageal dose of ionizing radiation to the portion of the esophageal wall with great precision .
the authors have no found publications on the subject of hdr brachytherapy combined with stent placement .
physical parameters such as treated volume , specific point of dosage and the diameter of applicators are the frequent topic of scientific publications [ 21 , 22 ] .
a number of findings are available on the subject of brachytherapy results as applied as a single therapeutic method . in march 2003 , homs and
co - workers published treatment results for 149 patients treated with hdr brachytherapy of average dose 15 gy , delivered in two or three fractions .
the average survival time of patients in the group mentioned above was 160 days , with annual survival of 15% .
the most regular amount of observed complications after brachytherapy were bleeding and the formation of tracheoesophageal fistulas ( 7% ) , chest pain ( 8% ) and perioperative morbidity ( 2% ) . according to the authors of the work ,
the treatment was considered to be effective in spite of the fact that symptoms of dysphagia returned in 37% of patients after a short post - treatment time .
the frequency of complication occurrence was described as very low but often required additional treatment . in the year
2002 sur and colleagues , from the university of johannesburg , compared two brachytherapy schemes for advanced cancer of the esophagus .
232 patients were divided into two groups , depending on the dose and number of fractions used ( a-3 x 6 gy i b-2 x 8 gy ) .
patients were excluded from the study if their neoplasm involved large mediastinal vessels , was localized in the portion in the neck , the distance from the infiltration to the cardia was less than 1 cm or in the instance of bronchoesophageal fistulas .
survival time for the whole studied group was 7,9 months ( groups a and b 9.1 and 6.9 months respectively ) .
the coefficient for survival without dysphagia complications were reported as 7.8 and 6.3 months respectively .
the authors of the study sought a relationship between prognostic factors and the palliative effects of treatment .
a clear statistical correlation was found between the initial body weight of the patient , their general state , their initial degree of dysphagia , histopathologic differentiation and the coefficient for survival without dysphagia .
the age of the patients had a statistically significant effect on the survival of the whole study group .
palliative brachytherapy was shown to be a safe treatment modality with small number of complications ( fistulas 22 cases , narrowing of the lumen of the esophagus 25 cases ) .
hdr brachytherapy treatment in 3 fractions of 6 gy was barely more effective and the frequency of complications in both groups were comparable .
the next center published its scientific results of the treatment of esophageal cancer was the tata memorial hospital in mumbai , india . between 1994 and 2000
the procedure was used in therapy of 58 patients , out of which 21 cases with recurrence of neoplasm s treated earlier .
brachytherapy as a single way of treatment was used in 38 cases ( 65% ) , while the remaining number of patients received radiation treatments with the use of external sources .
furthermore , higher than formerly noted ( 10 months ) coefficient of survival without dysphagia was reported .
the occurrence of complications was seen more frequently in patients with recurrence after previous radiation ( 27% ) .
the observed complications were narrowing ( 15% ) , ulceration ( 10% ) and fistula formation ( 5% ) .
the average survival time for the whole group amounted to 7 months and was marginally higher for patients not previously treated by radiotherapy ( 7.8 yrs 6 months ) . at this point ,
results of palliative treatment for cancer of the esophagus with the use of stent implantation should be taken into consideration .
most authors that published their data on this subject noted high effectiveness of this method ( reduction of dysphagia symptoms in 95 - 100% of patients ) [ 2529 ] .
the survival period in the majority of studies was dependent on the additional treatments used among the patients .
the average ratio of patients treated with chemotherapy and radiotherapy was 318 days while patients without additional treatment survived between 77 and 168 days . among early complications , chest pain occurred in nearly 100% of cases after the procedure , even though only 13% of patients suffered for more than a week .
an additional post therapy difficulties in 10 - 20% of patients was bleeding , perforation of the wall , choking inflammation of the lungs and fistula formation . morbidity associated with implantation of the stent was 7% .
migration of the stent to the lumen of the stomach is an occasional complication of the procedure and has been observed in 3 - 6% of cases .
the occurrence of complications after implantation is largely affected by earlier treatment , particularly mechanical widening , laser therapy , radiotherapy and brachytherapy .
repeated intervention as a result of the tumor recurrence or infiltration of the lumen of the stent is more common and occurs in 8 - 35% of cases , renewed dysphagia is seen in close to 60% of these patients .
it is worth to emphasize that complications , especially life threatening conditions ( fistula formation , massive bleeding , perforations , tracheal compression ) , occur more frequently with stent localized in one third of the proximal portion , as indicated by wang and colleagues .
the treatment results for patients with advanced cancer of the esophagus presented in our work are not different in general from papers published globally .
the advantage of hdr brachytherapy in combination with stent implantation was the immediate improvement of swallowing which is so greatly desired in this disease .
most patients , after stent implantation , return to usual diet ( 75 - 90% ) .
the role of endoesophageal brachytherapy treatment appears to be significant in prolonging the palliative effects of stent implantation , despite its lack of effect in the extension of survival . from our studies we know that some patients experience a recurrence of dysphagia symptoms owing to infiltration of the lumen of the implant [ 13 , 36 ] . that requires invasive procedures which pose a direct threat to a patient s life , since they are extremely difficult and complex . in case of patient s good general condition ,
the use of hdr brachytherapy provides satisfactory reduction of post - treatment complications and perioperative morbidity . in order to extend the survival time of patients
the cost of endoesophageal implants is high , however health care centers are able to provide and apply treatment method during a single day of hospital stay .
this kind of arrangement allows important reduction of operating cost and represents serious grounds for combined therapies .
however , in many cases , the choice of treatment method is based on the experience of medical staff and the availability of therapeutic equipment .
further comparative studies are required in order to determine whether the type of stent used in palliative treatments in combination with hdr - bt is directly connected to minimum post - treatment complications .
nevertheless , in such type of scientific analysis , the extension of patients survival periods is least apparent .
hdr brachytherapy for advanced esophageal cancer allowed the improvement of dysphagia in most of the patients .
the palliative effects that were obtained from the therapy did not influence the increase of complications , in particular bronchoesophageal fistulas . | purposein the study we present the initial results of palliative treatment using combined methods of hdr - bt and stent insertion in patients with advanced esophagus cancer.material and methodsfifty patients were treated in the great poland cancer center using hdr - bt between june 2001 and december 2005 and they were enrolled into the study .
all patients underwent endoscopic insertion of self - expanding , metal , endoesophageal stents owing to blockages in the lumen of the esophagus which excluded brachytherapy .
the group included 41 men and 9 women , aged between 44 and 79 years ( average 59.3 years ) .
36 of patients received 3 fractions of hdr once a week of 7.5 gy , up to total dose of 22.5 gy , 14 patients received 2 fractions of 7.5 gy ( 15 gy).resultsthe average patient observation period was 5.4 months .
complete remission ( cr ) was observed after 4 weeks in 2 cases ( 4% ) , partial remission ( pr ) in 31 ( 62% ) , no remission ( nr ) was seen in 6 patients ( 12% ) and progression was noted in 11 cases ( 22% ) .
complications of brachytherapy for esophageal cancer were observed in 11 patients ( 22% ) , ulceration in 1 patient ( 2% ) , haemorrhage in 1 patient ( 2% ) and bronchotracheal fistulas in 9 ( 18% ) patients .
the average observation period for patients with bronchotracheal fistulas was notably shorter than in remaining patients and amounted 3.5 months.conclusions1 .
endoscopic implantation of stents to the lumen of the esophagus provides access to esophagus and , in many cases , allows application of hdr - bt .
2 .
hdr - bt for advanced esophageal cancer brought relief from dysphagia in most of patients .
3 . the combination of the two methods of treatment represents an effective choice for palliative care of this group of patients , with a complication rate similar to observed one in the instance of brachytherapy alone . | <s>[INST]cancer of the esophagus has been known and described for nearly two thousand years and dysphagia is the most common complaint within the earliest reported symptoms ( fig .
the first form of palliative therapy for this neoplasm was described at the end of 19 century .
this therapy was centered on the formation of an artificial feeding tube which bypassed the tumor and at the same time narrowed the lumen of the esophagus . in 20 century
some number of other surgical procedures were developed which allowed radical excision of portions in the esophagus , along with the tumor , and using the replacement of prosthetic parts .
esophageal cancer with fiberogastroscop inside unfortunately only 10 - 20% of patients with a diagnosis of esophageal neoplasm is qualified for surgical treatment . in the majority of cases
infiltrates surrounding organs what , along with the frequent involvement of the mediastinal lymphatic system , leads to disqualification from radical surgical treatment .
usually palliative radiotherapy and/or chemotherapy is offered to such patients as they belong to a group with a poor prognosis . in spite of previously applied treatments ,
patients with advanced stage of esophagus tumors die as a result of metastases as well as involvement of neighboring organs and quite often from internal bleeding .
other cause of death is the formation of bronchoesophageal fistulas resulting from the effects of radiotherapy and disintegration of the tumor , which in turn leads to inflammation of the mediastinum and lungs , causing direct threat to a patient life .
a number of methods of palliation have been used in attempt to improve patients quality of life and to provide normal swallowing till death of a patient resulting from progress of systemic disease .
these methods include : thermal ablation , photodynamic therapy , radiotherapy ( external beam or brachytherapy ) , chemotherapy , injected chemotherapy , argon beam or bipolar electrocoagulation therapy , internal feeding ( nasal - gastric intubation / percutaneous endoscopic gastrostomy ) , and intubation ( self - expanding metal stents sems or semi - rigid prosthetic tubes ) with varying success and complications rates .
endoesophageal brachytherapy allows to apply high doses of radiation to the tumor itself with concurrent protection of adjoining healthy tissues thanks to the rapid fall of the dose by the square of distance from the center of the applicator .
the above treatment is also associated with a smaller proportion of late radiation complications . in the treatment of esophageal cancers ,
occasionally brachytherapy is used along with external beam radiation therapy ( erbt ) in doses of 10 - 40 gy , which may extend the palliative effects of improved swallowing among patients .
brachytherapy used alone as a individual way of treatment , in comparison to ebrt , gives lower percentage of complications [ 4 , 5 ] , out of which the most common problems are ulcerations and bleeding and bronchoesophageal fistulas .
the aims of palliative brachytherapy are : maintenance of oral intake , minimization of hospital stay , relief of pain , elimination of reflux and regurgitation , prevention of aspiration and improvement of the patient s well - being .
the results of hdr - bt as a palliative treatment are well known [ 6 , 7 ] . in spite of all this facts , the access to this procedure on a national scale
is limited due to the need for oncology centers to possess highly specialized equipment and appropriately qualified medical staff .
in other centers , the use of other means for palliative treatment of the esophagus such as endoscopic insertion of self - expanding metal stents ( sems ) [ 8 , 9 ] is not available .
however theoretically , this type of procedure may be carried out in any regional center every single day whenever there is no need for more invasive methods , that may lead to problems associated with control of bleeding .
previous studies have confirmed that up to 95% of patients with stents application reported reduced dysphagia that resulted in improved swallowing and body mass increasing [ 10 , 11 ] .
complications after implantation procedures are infrequent but include perforation of the esophageal wall , chest pain , bleeding and migration of the stent to the stomach or fistulas .
blockage of the stent plates by growth of the tumor mass occurs in 27% of cases and requires renewed endoscopic intervention .
complications after insertion of the stent are also connected to the location of its implantation . in the proximal portion of the esophagus ,
a patient may initially experience some breathing difficulties , while in the distal and intra - diaphragmatic portions , gastro - esophageal reflux may require pharmacological treatment .
figure 2 shows the most commonly used variations of stents , while summarized indications and contraindications for the application of esophageal stents are presented in table 1 .
esophageal perforation , usually iatrogenic , from direct endoscopic trauma or following factor of dilatation .
it is suggested to have a normal coagulation profile with an international normalized ratio which is less than 1.5 and platelet count less than 50 000 .
recent large dose of chemotherapy or radiotherapy ( 3 to 6 weeks ) because of reported increase of rates of hemorrhage and perforation .
four types of esophageal stents ( from left to right ) : ultraflex ( microvasive , boston scientific , natick , massachusetts , usa ) , wallstent ( microvasive , boston scientific ) , esophacoil ( instent , minneapolis , minnesota , usa ) , z - stent ( wilson cook , winston salem , north carolina , usa ) hdr - bt is often proceeded with stent implantation which , apart from providing the insertion of the applicator itself , improves patient s swallowing . in the presented work , the clinical data and results were obtained from stent / hdr - bt palliative treatment of patients with inoperable advanced cancers of the esophagus .
effects of the treatment on patient survival in association of selected prognostic factors are presented .
fifty patients with inoperable advanced esophageal cancer were treated with the use of hdr - bt and endoesophageal stent implantation at the greater poland cancer center between june 2001 and december 2005 .
these patients were not qualified for surgical treatment or radical external beam radiotherapy because of poor general condition , clinical stage and tumor location .
palliative hdr - bt was the treatment , of choice due to limited possibility of external beam therapy and , in most of the cases , the patient s advanced clinical stage .
a rapid improvement in dysphagia was expected after brachytherapy which was performed on outpatient basis .
the combined stent / hdr - bt palliative treatment was proposed to patients in order to rapidly improve their quality of life , in relation of treating each patient by both methods separately . in all patients ,
gastroscopy , x - ray , and ct scan were performed as well as a histological diagnosis in order to evaluate the extent of the tumor .
the group consisted of 41 ( 82% ) men and 9 women ( 18% ) , aged between 44 and 79 years ( average 59.3 years ) .
pathologically , the most frequently diagnosed cancers were squamous cell carcinoma ( 40 cases 80% ) and adenocarcinoma ( 7 cases 14% ) . in majority of patients ( 61.2% )
qualified for palliative treatment , the location of the tumor was in the mid ( one third ) portion of the mediastinal esophagus .
positions in the upper and lower thirds represented 5 ( 10.2% ) and 14 ( 28.6% ) of patients respectively .
the most recurrent infiltrations were observed during gastroscopy at 5 - 10 cm ( 59.2% ) in length , while smaller than 5 cm or greater than 10 cm were noted in 10 cases ( 20.4% ) .
patients for palliative treatment were eligible on the grounds of swallowing difficulties ( dysphagia ) , generally grade i ( 26 patients 55.3% ) and grade ii ( 15 patients 31.9% ) .
grades were qualified as follows : 0 no dysphagia , i dysphagia for solids ,
, distant liver and brain metastases were discovered in 2 patients ( 4% ) , whereas malignant neoplasm s were identified in other locations in 4 cases ( 8% ) .
gastroscopy , x - rays , and ct were performed as well as a histological diagnosis to evaluate the extent of the tumor . in most of the
cases hdr - bt was applied within two weeks of the implantation of the stent .
after initial medication , the applicator was inserted , via the oral cavity , into the esophageal lumen . following the placement of a catheter with specific marker , an x - ray was taken which was later used in preparation of the treatment plan and to define volume of the tumor . in all treatment plans
the dose was prescribed at distance of 10 mm from the surface of the source .
the target volume included visualization of residues of the tumor , which has been previously evaluated during gastroscopy and 2 cm safety margin in the cranial and caudal directions .
192-ir with 10 ci nominal activity and hdr - gammamed 12i unit ( mick radio - nuclear instruments , inc . ,
80% of patients were given hdr - bt monotherapy and 20% were additionally treated with ebrt and chemotherapy .
36 of patients ( 72% ) received total dose of 22.5 gy given in three weekly fractions of 7.5 gy per week .
fourteen patients ( 28% ) received total dose of 15 gy ( 2 7.5 gy ) .
x - ray of stents inside esophagus brachytherapy applicator with metal marker visible endoesophageal self - expanding metal stents ( sems ) were inserted via working channel during gastroscopy on short term intravenous anesthesia in the gastroenterology clinics in d , pozna and wrocaw ( fig .
implantation of the stent often required earlier mechanical widening of the area of infiltration , because of implant s diameter limitation ( 15 - 20 mm ) .
this procedure is usually performed with the use of a balloon and in rare cases with the help of neodymium laser ( nd yag ) .
visible stents during gastroscopy degree of dysphagia , remission and complications arising from combined stent / brt treatment were evaluated 4 weeks after the completion of the treatment .
the degree of remission was verified on the basis of subjective tests , an interview and imaging techniques ( x - rays of the gastrointestinal tract , computerized tomography and gastroscopy ) .
the patients survival was compared with selected clinical factors such as : the grade of evaluated remission ( radiological and during gastroscopy ) in the first month after treatment , age , sex , histopathology , the zubrod score , clinical stage , grade of dysphagia , location and size of tumor .
the respective survival periods were ascertained for particular groups in relation to treatment ( remission , partial remission , no remission , progression ) . in order to statistically assess the effects of prognostic factors on survival ,
the mann - whitney test was used ( for groups included 2 patients ) and the kruskal - wallis test for groups included 3 or more patients . in turn to evaluate the relationships within the above factors , the spearman test was applied .
local reaction to the combined brachytherapy hdr and stent implantation treatment was estimated after 4 weeks .
complete remission ( cr ) was confirmed by imaging techniques and was observed in 2 cases ( 4% ) , partial remission ( pr ) in 31 patients ( 62% ) , no remission ( nr ) in 6 cases ( 12% ) and in 11 ( 22% ) patients progression was determined ( fig .
longer survival periods were noted in patients with infiltrations shorter than 5 cm ( 6.1 months ) rather than in patients with infiltrations longer than 10 cm ( 4.9 months ) .
remission after 4 weeks during first check - up : cr complete remission , pr partial remission , nr no remission , prog progression the statistical analysis revealed the effects of prognostic factors of the patients clinical stage .
the kruskal - wallis test analyzed certain aspects such as : the effects of infiltration localization ( p = 0.428 ) , histopathology results ( p = 0.408 ) , loss of body weight ( p = 0.363 ) , length of the infiltration ( p = 0.605 ) , the zubrod score ( p = 0.830 ) , grade of dysphagia ( p = 0.695 ) and pain level ( p = 0.059 ) .
the maximum clinical response after treatment was presented by the pain factor ( according to the kruskal - wallis test this aspect was not significant , though the pain relationship was shown by this test for correlation ) .
similarly , using the mann - whitney test , correlations were investigated within : treatment scheme ( p = 0.288 ) , number of brachytherapy fractions ( p = 0.580 ) , the occurrence of complications ( p = 0.165 ) , age ( p = 0.604 ) , sex ( p = 0.988 ) and clinical response .
none of these prognostic factors had any statistical effect on results of treatment obtained ( table 3 . ) .
spearman statistical correlation between prognostic factors values in bold are statistically different from 0 with a significance level alpha = 0.05 furthermore , using the spearman test , we attempted to find relationships among the above mentioned prognostic factors ( correlation testing ) .
statistically significant correlations that are worth mentioning are : reported pain levels / response to treatment ( p = 0.025 ) and pain level / localization of the infiltration ( p = 0.009 ) , localization of the infiltration / body weight loss ( p = 0.002 ) , general condition according to the zubrod score / occurrence of complications ( p = 0.025 ) , pain level / loss of body weight ( p = 0.000 ) .
the remaining correlations discovered by use of the spearman test are presented in table 4 .
statistically significant correlations between prognostic factors ( spearman test ) complications were diagnosed in 11 patients ( 22% ) .
necrosis was seen in 1 patient ( 2% ) , serious hemorrhage was observed in 1 patient .
bronchoesophageal fistulas were found in 9 patients ( 18% ) estimated in follow - up x - ray examinations or bronchoscopy .
as highlighted above , the statistically significant correlation was found between the frequency of complication occurring after combined therapy and the general state of a patient , according to the zubrod score .
the prognosis for patients with inoperable advanced esophageal cancer is still very bad despite the introduction of improved treatment modalities such as surgery , radiotherapy and chemotherapy .
the reported 2 and 5 year survival rates range from 30 - 40% and 10 - 25% , respectively , regardless of the tumor stage or treatment options [ 16 , 17 ] . moreover , the prognosis is worse for patients with tumor stage iv and for patients with inoperable advanced cancer .
the frequency of esophageal cancer in western societies is steadily rising , particularly in lower , sub - cardiac locations on the basis of barrett s metaplasia .
unfortunately , at the time of diagnosis only few patients qualify for radical treatment as a result of general condition of their health , advanced stage of disease , metastases to distant locations or cardiac and respiratory difficulties .
30 - 40% of patients may potentially be treated with radical surgery ; however , 5 year survival in this group amounts to only 20% [ 1820 ] .
the prognosis for inoperable cases is always poor and such treatment is targeted at reducing suffering of patients in addition to improve their quality of life . in our institution
we apply a combined therapy that integrates chemotherapy , radiotherapy , as well as restorative laser and endoesophageal stents .
dysphagia is the most frequent problem among patients with advanced esophagus cancer and is described in almost 90% of cases . in correlation to this symptoms , procedure must be as noninvasive as possible and should quickly lead to palliative effects with minimal risk of complications .
the above criteria are well fulfilled in combined method of implantation of a stent into the lumen of the esophagus during endoscopy procedure , followed by endoesophageal irradiation of high dose brachytherapy .
after mechanical widening of the narrowed area and positioning of the metal stent , the immediate palliative effects are usually visible .
the aim of instant application of brachytherapy is to prolong the effects acquired through prevention of renewed stenosis within the stent .
this way of treatment is quite comfortable for patients , since it does not require an extensive hospital stay and can be applied in ambulatory condition .
this gets out of giving an endoesophageal dose of ionizing radiation to the portion of the esophageal wall with great precision .
the authors have no found publications on the subject of hdr brachytherapy combined with stent placement .
physical parameters such as treated volume , specific point of dosage and the diameter of applicators are the frequent topic of scientific publications [ 21 , 22 ] .
a number of findings are available on the subject of brachytherapy results as applied as a single therapeutic method . in march 2003 , homs and
co - workers published treatment results for 149 patients treated with hdr brachytherapy of average dose 15 gy , delivered in two or three fractions .
the average survival time of patients in the group mentioned above was 160 days , with annual survival of 15% .
the most regular amount of observed complications after brachytherapy were bleeding and the formation of tracheoesophageal fistulas ( 7% ) , chest pain ( 8% ) and perioperative morbidity ( 2% ) . according to the authors of the work ,
the treatment was considered to be effective in spite of the fact that symptoms of dysphagia returned in 37% of patients after a short post - treatment time .
the frequency of complication occurrence was described as very low but often required additional treatment . in the year
2002 sur and colleagues , from the university of johannesburg , compared two brachytherapy schemes for advanced cancer of the esophagus .
232 patients were divided into two groups , depending on the dose and number of fractions used ( a-3 x 6 gy i b-2 x 8 gy ) .
patients were excluded from the study if their neoplasm involved large mediastinal vessels , was localized in the portion in the neck , the distance from the infiltration to the cardia was less than 1 cm or in the instance of bronchoesophageal fistulas .
survival time for the whole studied group was 7,9 months ( groups a and b 9.1 and 6.9 months respectively ) .
the coefficient for survival without dysphagia complications were reported as 7.8 and 6.3 months respectively .
the authors of the study sought a relationship between prognostic factors and the palliative effects of treatment .
a clear statistical correlation was found between the initial body weight of the patient , their general state , their initial degree of dysphagia , histopathologic differentiation and the coefficient for survival without dysphagia .
the age of the patients had a statistically significant effect on the survival of the whole study group .
palliative brachytherapy was shown to be a safe treatment modality with small number of complications ( fistulas 22 cases , narrowing of the lumen of the esophagus 25 cases ) .
hdr brachytherapy treatment in 3 fractions of 6 gy was barely more effective and the frequency of complications in both groups were comparable .
the next center published its scientific results of the treatment of esophageal cancer was the tata memorial hospital in mumbai , india . between 1994 and 2000
the procedure was used in therapy of 58 patients , out of which 21 cases with recurrence of neoplasm s treated earlier .
brachytherapy as a single way of treatment was used in 38 cases ( 65% ) , while the remaining number of patients received radiation treatments with the use of external sources .
furthermore , higher than formerly noted ( 10 months ) coefficient of survival without dysphagia was reported .
the occurrence of complications was seen more frequently in patients with recurrence after previous radiation ( 27% ) .
the observed complications were narrowing ( 15% ) , ulceration ( 10% ) and fistula formation ( 5% ) .
the average survival time for the whole group amounted to 7 months and was marginally higher for patients not previously treated by radiotherapy ( 7.8 yrs 6 months ) . at this point ,
results of palliative treatment for cancer of the esophagus with the use of stent implantation should be taken into consideration .
most authors that published their data on this subject noted high effectiveness of this method ( reduction of dysphagia symptoms in 95 - 100% of patients ) [ 2529 ] .
the survival period in the majority of studies was dependent on the additional treatments used among the patients .
the average ratio of patients treated with chemotherapy and radiotherapy was 318 days while patients without additional treatment survived between 77 and 168 days . among early complications , chest pain occurred in nearly 100% of cases after the procedure , even though only 13% of patients suffered for more than a week .
an additional post therapy difficulties in 10 - 20% of patients was bleeding , perforation of the wall , choking inflammation of the lungs and fistula formation . morbidity associated with implantation of the stent was 7% .
migration of the stent to the lumen of the stomach is an occasional complication of the procedure and has been observed in 3 - 6% of cases .
the occurrence of complications after implantation is largely affected by earlier treatment , particularly mechanical widening , laser therapy , radiotherapy and brachytherapy .
repeated intervention as a result of the tumor recurrence or infiltration of the lumen of the stent is more common and occurs in 8 - 35% of cases , renewed dysphagia is seen in close to 60% of these patients .
it is worth to emphasize that complications , especially life threatening conditions ( fistula formation , massive bleeding , perforations , tracheal compression ) , occur more frequently with stent localized in one third of the proximal portion , as indicated by wang and colleagues .
the treatment results for patients with advanced cancer of the esophagus presented in our work are not different in general from papers published globally .
the advantage of hdr brachytherapy in combination with stent implantation was the immediate improvement of swallowing which is so greatly desired in this disease .
most patients , after stent implantation , return to usual diet ( 75 - 90% ) .
the role of endoesophageal brachytherapy treatment appears to be significant in prolonging the palliative effects of stent implantation , despite its lack of effect in the extension of survival . from our studies we know that some patients experience a recurrence of dysphagia symptoms owing to infiltration of the lumen of the implant [ 13 , 36 ] . that requires invasive procedures which pose a direct threat to a patient s life , since they are extremely difficult and complex . in case of patient s good general condition ,
the use of hdr brachytherapy provides satisfactory reduction of post - treatment complications and perioperative morbidity . in order to extend the survival time of patients
the cost of endoesophageal implants is high , however health care centers are able to provide and apply treatment method during a single day of hospital stay .
this kind of arrangement allows important reduction of operating cost and represents serious grounds for combined therapies .
however , in many cases , the choice of treatment method is based on the experience of medical staff and the availability of therapeutic equipment .
further comparative studies are required in order to determine whether the type of stent used in palliative treatments in combination with hdr - bt is directly connected to minimum post - treatment complications .
nevertheless , in such type of scientific analysis , the extension of patients survival periods is least apparent .
hdr brachytherapy for advanced esophageal cancer allowed the improvement of dysphagia in most of the patients .
the palliative effects that were obtained from the therapy did not influence the increase of complications , in particular bronchoesophageal fistulas .[/INST]purposein the study we present the initial results of palliative treatment using combined methods of hdr - bt and stent insertion in patients with advanced esophagus cancer.material and methodsfifty patients were treated in the great poland cancer center using hdr - bt between june 2001 and december 2005 and they were enrolled into the study .
all patients underwent endoscopic insertion of self - expanding , metal , endoesophageal stents owing to blockages in the lumen of the esophagus which excluded brachytherapy .
the group included 41 men and 9 women , aged between 44 and 79 years ( average 59.3 years ) .
36 of patients received 3 fractions of hdr once a week of 7.5 gy , up to total dose of 22.5 gy , 14 patients received 2 fractions of 7.5 gy ( 15 gy).resultsthe average patient observation period was 5.4 months .
complete remission ( cr ) was observed after 4 weeks in 2 cases ( 4% ) , partial remission ( pr ) in 31 ( 62% ) , no remission ( nr ) was seen in 6 patients ( 12% ) and progression was noted in 11 cases ( 22% ) .
complications of brachytherapy for esophageal cancer were observed in 11 patients ( 22% ) , ulceration in 1 patient ( 2% ) , haemorrhage in 1 patient ( 2% ) and bronchotracheal fistulas in 9 ( 18% ) patients .
the average observation period for patients with bronchotracheal fistulas was notably shorter than in remaining patients and amounted 3.5 months.conclusions1 .
endoscopic implantation of stents to the lumen of the esophagus provides access to esophagus and , in many cases , allows application of hdr - bt .
2 .
hdr - bt for advanced esophageal cancer brought relief from dysphagia in most of patients .
3 . the combination of the two methods of treatment represents an effective choice for palliative care of this group of patients , with a complication rate similar to observed one in the instance of brachytherapy alone .</s> |
trypanosoma cruzi is an obligate intracellular parasite that is responsible for chagas disease , which affects 1618 million people in latin america .
this parasite has a complex biphasic life cycle in which four developmental forms alternate between the reduviid beetle vector ( epimastigotes and metacyclic trypomastigotes ) and the mammalian host ( amastigotes and bloodstream trypomastigotes ) .
transmission is initiated in the reduviid beetle vector , which becomes infected by taking up circulating trypomastigotes during a blood meal .
after trypomastigotes differentiate to epimastigotes in the insect gut lumen , the parasite divides by binary fission before migrating along the hindgut and rectum , where they transform to metacyclic trypomastigotes .
these trypomastigotes are released near the bite wound with the insect feces during the next blood meal . following its introduction into mammalian blood , the trypomastigotes penetrate nonphagocytic and phagocytic cells through a parasitophorous vacuole to start the intracellular cycle . in this stage
amastigotes develop into nondividing bloodstream trypomastigotes that can either initiate another round of infection to propagate to different organs or can be taken up by the insect vector to complete the life cycle . throughout its life cycle ,
t. cruzi survives under a wide range of environmental conditions that induce complex morphological changes among parasite stages .
in addition to the four main developmental forms , it is possible to observe intermediate forms ( ifs ) that seem to follow the same differentiation path , independent of whether they exist in a vertebrate or in an invertebrate host [ 1 , 2 ] .
intermediate forms appear transiently during the differentiation of epimastigotes into metacyclic trypomastigotes ( metacyclogenesis ) in the triatomine , the differentiation of metacyclic trypomastigotes ( primary amastigogenesis ) , and tissue - derived trypomastigotes ( secondary amastigogenesis ) into amastigotes and also into bloodstream trypomastigotes inside the mammalian host cell [ 25 ] .
adaptation of t. cruzi to diverse environments found in the different hosts undoubtedly induces a complex regulation of gene expression that apparently precedes the morphological changes observed during parasite transformation .
several researchers have studied some of the factors that represent physiological stress for the parasite and have demonstrated that temperature , nutritional conditions , and ph stimulate morphological differentiation during amastigogenesis [ 58 ] .
the vast majority of the information regarding in vivo and in vitro amastigogenesis comes from data in which tissue - derived trypomastigotes were used because it was possible to obtain higher yields of these parasites [ 3 , 5 , 815 ] .
ultra - structural and molecular analyses during the trypomastigote to amastigote transformation have shown a complex and progressive morphological rearrangement of parasite shape and flagellum that has been associated with the differential expression of stage - specific antigens [ 3 , 5 , 8 ] . a comparative morphology study showed that even when metacyclic and bloodstream trypomastigotes share similar biological and morphological properties , primary and secondary amastigogenesis apparently display different developmental processes , which suggests that their intracellular mechanisms are different .
although the basic features of the amastigogenesis transformation process are known , the molecular mechanisms involved are still unidentified .
analysis of the molecules implicated in the detonation and control of the transformation process will increase our knowledge about morphogenesis and gene expression programs that are involved not only in the differentiation between developmental forms but also during parasite transitions from the nonreplicative to the replicative stage .
the usefulness of a differentiation system for molecular research in which a population of cells is involved depends first on the synchrony of the transition , second on the availability of easily analyzable markers for monitoring the process , and third on the system efficiency for obtaining large enough amounts of analyzable sample for further biochemical , biological , and molecular analyses . to date , in vitro conditions that allow for obtaining ifs that satisfy these needs have not been reported .
therefore , in vitro conditions that induce high rates of pure ifs during the transformation of culture - derived trypomastigotes into amastigotes are described in this work .
furthermore , morphological , cellular , and molecular characterizations of the different ifs obtained are presented .
nih 3t3 fibroblasts were grown in high glucose dulbecco 's minimal essential medium ( hgdmem ) supplemented with 10% fetal bovine serum ( fbs ) , 1% glutamine , and 5 g / ml penicillin - streptomycin at 37c in a humidified atmosphere with 5% co2 in a 75 cm corning cell culture flask ( catalog number 4306 - 41 ) .
epimastigotes of t. cruzi cl - brener strain were grown in liver infusion tryptose medium ( lyt ) containing 10% fbs and hemin ( 25 g / ml ) at 28c .
fifty percent confluent fibroblasts were infected with 2 10 cl - brener mid - log - phase epimastigotes per ml of hgdmem ( 15 ml ) supplemented with 2% fbs to get a parasite - host cell ratio of 10 : 1 .
the nih 3t3 monolayers were washed every 2 days with hgdmem medium until nonadherent parasites were removed , and then fresh hgdmem plus 2% fbs was added .
the parasites released from the early infections corresponding to the first 6 days after the first liberation were harvested every day at 2000 g for 5 minutes .
the trypomastigotes were separated from amastigotes by immunoprecipitation using 500 l of hybridoma supernatant of monoclonal antibody 2c2b6 , which is specific for the ssp4 surface antigen of amastigotes , per 3 10 parasites at 37c for 1 hour .
the trypomastigotes were separated from amastigotes at 800 rpm for 10 seconds in a microcentrifuge and were washed with 1x pbs as many times as necessary to obtain pure parasites .
the amastigotes were found in the pellet , and the trypomastigotes were found in the supernatant .
purified tissue culture - derived trypomastigotes ( 5 10 ) were harvested at 500 g for 10 minutes and were transferred to 100 20 mm untreated petri dishes containing 1 ml per experiment of hgdmem at different phs ( 4 , 5 , 6 , 7 , 8 , and 9 ) without or with different fbs concentrations ( 0.5% , 1% , 1.5% , and 2% ) incubated at 37c in a 5% co2 atmosphere .
after 1 , 2 , 3 , 4 , 5 , 6 , 12 , 24 , 48 , or 72 hours , the parasites were washed , fixed with 4% paraformaldehyde in 1xpbs , washed again , and dropped ( 3 10 parasites/10 l ) over poly - l - lysine - treated slides ( silane - prep slides sigma diagnostics , catalog number s4651 ) inside circles delimited with a liquid - repellent slide marker pen ( electron microscopy sciences catalog number 71310 ) . after the slides were air dried , the parasites were stained with hema 3 according to the protocol supplied by the manufacturer ( fisher diagnostic 840021 ) , and the percentages of trypomastigotes , ifs , and amastigotes were determined for 100 cells analyzed randomly under an optic microscope .
trypomastigotes , amastigotes , epimastigotes , or ifs ( 2 10 parasites ) were incubated with 500 l of fresh human serum at 37c for 30 , 60 , and 120 minutes .
parasite lysis was determined by adding one volume of trypan blue ( 0.4% in 1x pbs , hycel 23850 ) and counting the complement - resistant parasites in a hemocytometer under a light microscope .
three independent experiments , repeated in triplicate each time , were carried out using serum from different donors .
the parasites were harvested , washed , fixed , and dropped over poly - l - lysine - treated slides as described above .
the parasites were permeabilized with 0.1% triton - x100 for 5 minutes , rinsed extensively with 1x pbs , and treated with 2% bsa ( albumin , bovine , cohn fraction v / 1x pbs ph 7 ) at 37c for 30 minutes .
these preparations were washed with pbs and incubated 1 hour at 37c with hybridoma supernatant ( 1 : 50 ) of the amastigote - specific monoclonal antibody 2c2b6 .
after rinsing , a secondary antimouse antibody tagged with alexa fluor 488 green diluted 1 : 1000 was layered on the parasites and incubated for 1 hour at 37c .
h-1000 ) , and observed under an olympus fluorescence microscope ( bx41 ) equipped with a 60x/1.25 oil iris ph3 uplanfl n objective .
the images were captured using an evolution vf fast cooled color media cybernetics camera and were analyzed using the image - pro plus v 6.0 media cybernetics program .
the parasites were processed and analyzed as per the indirect immunofluorescence protocol described above , with some specifications .
after treatment with a polyclonal antibody against the epimastigotes ( 1 : 200 ) obtained from the mouse and the antimouse antibody tagged with alexa fluor 546 red ( 1 : 1000 ) as the first and second antibodies , the parasites were stained with 10 g / ml dapi ( molecular probes ) .
as mentioned before , conditions such as temperature , nutritional environment , and ph stimulate the in vitro differentiation of trypomastigotes into amastigotes [ 58 ] . to determine the best conditions for obtaining the highest rates of transformation , in vitro experiments
were performed using tissue - derived trypomastigotes incubated at 37c in hgdmem medium at different phs ( 4 , 5 , 6 , 7 , 8 , and 9 ) , without or with 0.5% , 1% , 1.5% , or 2% fbs for different lengths of time , as described in the materials and methods .
the movement and morphology of the parasites were analyzed in fresh preparations under a light microscope , and the relative percentages of trypomastigotes , ifs , and amastigotes were determined . in all of the conditions in which parasite differentiation was achieved , the trypomastigotes showed gradual morphological changes and size reduction ; they transformed from the typical s- or c - shaped bloodstream morphology to diverse ifs that finally reached the rounded or oval shape characteristic of amastigotes after 12 hours of incubation
. a progressive reduction of parasite movement concomitant with the gradual shortening of the undulating membrane and flagellum was also observed .
although similar morphological patterns of differentiation could be seen in some of the different conditions tested , very different rates of transformation were obtained .
incubation at 37c in hgdmem at ph 5 without fbs induced the most efficient rates of differentiation . under these conditions ,
the level of tissue - derived trypomastigotes decreased concomitantly with increasing amounts of ifs , which reached 85% within 3 hours of incubation ( figure 1 ) .
subsequently , as the percentage of ifs decreased , the relative amount of amastigotes increased , and the transformation process was completed after 12 hours of incubation . a homogenous population ( 100% ) of round - shaped forms , which displayed either no flagella or very short protruding flagella and a noticeable reduction of movement , was observed at this point . on the contrary ,
when tissue - derived trypomastigotes were incubated in hgdmem at ph 4 without fbs , only 30% of the cells were transformed into amastigotes after 3 hours and 65% after 12 hours ( data not shown ) .
in addition , only 21% of the trypomastigotes differentiated into amastigotes after 24 hours of incubation at ph 6 without fbs ( data not shown ) . finally , at phs 7 , 8 , and 9 in the absence of fbs as well as those same phs with 0.5% , 1% , 1.5% , and 2%
these results indicate that the differentiation process during the in vitro secondary amastigogenesis involves several ifs as a result of the morphological change of the parasites .
in addition , the optimal conditions to induce the highest rates of transformation from tissue - derived trypomastigotes into amastigotes were ph 5 , serum - deprivation and 37c .
the different developmental forms of t. cruzi can be identified by morphological and biological parasite features , such as the size and shape of the parasite , undulating membrane and flagellum , the position of flagellum emergence , and the size , shape , and relative position of the nucleus and the kinetoplast .
the amastigote has a spherical- to oval - shaped form that is 2 to 4 m in diameter with no or very short free flagellum and a kinetoplast located in the middle of the parasite body close to the nucleus .
the trypomastigotes have a flagellum and an undulating membrane that extends the entire length of the parasite ( 1625 m long and 2 m diameter ) .
trypomastigotes found in the blood of infected mammals have a slender s- or c - shaped form , while the trypomastigotes found in infected insects usually have a straight form .
once the best conditions to induce the transformation of the parasite were determined , a detailed morphological analysis was carried out on fixed and stained preparations , and the relative amounts of trypomastigotes , amastigotes , and ifs were determined at different points of the differentiation kinetics at 37c using hgdmem at ph 5 with serum - deprivation ( figure 2 ) .
this methodology allowed us to perform a morphometrical analysis and a more precise quantification of the transformation process compared to those obtained with fresh preparations . before initiating the differentiation process
, tissue - derived trypomastigotes showed the typical morphology previously described ( figure 2a ) . during the transformation process
, the parasite progressively reduced its entire length by 22% at 1 hour , 23% at 2 hours , 39% at 3 hours , 48% at 4 hours , 50% at 5 hours , and 53% at 6 hours of transformation as shown in figure 2 and table 1 .
the quantitative analysis indicated that as little as 1 hour of transformation time was enough to induce high rates of ifs ( 80% ) in which the parasites displayed a widening and shortening of their body , flagellum , and undulating membrane ; however , this last one maintained the subterminal emergence site that is characteristic of trypomastigotes ( figure 2b and table 1 ) .
after 2 hours of transformation , no trypomastigotes were detected , which indicates that the culture contained 100% ifs .
these ifs showed size reduction , a light oval - shaped form , shortening of their flagellum , and an undulating membrane in which their emergence site was slightly displaced to the middle of the parasite body ( figure 2(c ) and table 1 ) .
after 3 hours , the morphology of the ifs was very close to the one observed at 2 hours of transformation , but their size continued to reduce and the undulating membrane was not appreciable ( figure 2(d ) and table 1 ) .
after 4 and 5 hours of transformation , the ifs showed similar size and morphology to the amastigotes and were only distinguished by the progressive shortening of their flagellum ( figures 2(e ) and 2(f ) and table 1 ) .
finally , after 6 hours of transformation , the parasites reached the spherical- to oval - shaped form with no or very short free flagellum ( figure 2(g ) ) , and their morphology was indistinguishable from the one observed in the cell culture - derived amastigotes ( figure 2(h ) and table 1 ) . to assess the reversibility of the differentiation process , the ifs were cultured again in hgdmem at ph 7.2 complemented with 2% fbs after 1 , 2 , 3 , 4 , 5 , 6 , 12 , 24 , 48 or 72 hours of differentiation at 37c using hgdmem at ph 5 with serum deprivation . in all cases ,
the ifs continued their differentiation , thus indicating that once detonated , this process can not be stopped and is not reversible ( data not shown ) .
these results showed that , under the in vitro conditions used , the trypomastigotes differentiated very efficiently into highly homogeneous and pure if populations after 2 hours of induction . to continue with the morphological analysis of the ifs , the shape and position of the nucleus and the kinetoplast at each point of the transformation kinetics were determined .
the parasites were then stained with a polyclonal antibody against epimastigote total proteins , which had been previously shown to recognize all of the developmental forms and ifs of t. cruzi .
the reactions were developed with an alexa fluor 546 red - conjugated antimouse antibody , and the kinetoplast and nucleus were counterstained with dapi . as shown in previous experiments , the same morphological transformation pattern of the parasite body
was found with this technique ( compare figures 2 and 3 ) . nucleus remodeling and a progressive and continuous displacement of the kinetoplast from the posterior to the anterior position with respect to the parasite nucleus were also observed .
as shown in table 1 , the distance between the nucleus and the kinetoplast became shorter during the transformation kinetics . at 1 hour of transformation ( figure 3(b ) ) , the distance between both organelles was reduced by 28% ( table 1 ) , even though the ifs showed a subterminal kinetoplast posterior to the nucleus , as commonly observed in trypomastigotes ( figure 3(a ) ) .
after 2 hours of transformation , the ifs showed a displacement of their kinetoplast to the middle of the parasite body and reduced the distance with respect to the nucleus ( now remodeled from the lengthened - shaped form to an oval - shaped form ) by 58% ( figure 3(c ) and table 1 ) .
after 3 hours of transformation , the kinetoplast remained located posterior to the nucleus , close to the middle part of the parasite body , with a 66% reduction in the distance between both organelles ( figure 3(d ) and table 1 ) . at 4 hours of transformation , the kinetoplast was positioned next to and parallel to the nucleus in a transversal position in the middle of the parasite body and showed 85% reduction in the organelle distance ( figure 3(e ) and table 1 ) .
after 5 hours of transformation , the kinetoplast moved to an anterior position with respect to the nucleus , in the middle part of the parasite body and showed a 90% reduction in the distance between the organelles ( figure 3(f ) and table 1 ) .
finally , at 6 hours of transformation ( figure 3(g ) and table 1 ) , the parasite morphology and the position of the kinetoplast were very similar to those observed in the tissue - derived amastigotes ( figure 3(h ) and table 1 ) .
these results showed that , concomitant with the morphological parasite shape transformation , nucleus remodeling and kinetoplast displacement are observed during the transformation kinetics under the in vitro conditions used .
the morphological analysis described above showed homogenous if populations ; nevertheless , the nucleus remodeling and kinetoplast displacement studies indicated that each point of the transformation kinetics is composed of 3 different ifs .
the percentages of trypomastigotes , amastigotes and the different ifs were then determined for each time point evaluated in the previous experiment .
as shown in figure 4 , 3 different ifs were observed at 1 , 2 , 3 , 4 and 5 hours of in vitro differentiation ( figures 4(a ) and 4(c ) ) . at 1 hour of transformation
the first if , which was arbitrarily named if1 , showed similar morphology to the immediate previous parasite stage ( trypomastigotes for the first hour and if3 for 2 , 3 , 4 , and 5 hours ) and represented 2% to 3% of the total parasites .
the second intermediary form , named if2 , showed a slightly , but clearly , more differentiated morphology than if1 and represented the most abundant parasite population ( 85% to 90% ) .
the third if , still more differentiated than if2 and named if3 ( 2% to 15% ) , displayed characteristics similar to the if1 that emerged from the next time of transformation . at 1 hour of transformation
, trypomastigotes comprised only 2% of the culture , which confirms that the transformation process is very efficient under the established conditions ( figures 4(a ) , 4(b ) and 4(c ) ) .
moreover , from 1 to 5 hours of transformation were not observed any amastigotes ( panel a ) .
finally , at 6 hours of transformation , 100% of the parasites showed a very similar morphology to that of tissue - derived amastigotes ( figures 3(g ) and 3(h ) , table 1 and figures 4(a ) , 4(b ) and 4(c ) ) .
the only forms detected after 2 , 3 , 4 and 5 hours of transformation were ifs with a gradually increasing degree of differentiation .
therefore , this experimental model could be useful for future analysis of the differential expression between the ifs and the completely differentiated forms of t. cruzi .
in addition , even when the ifs at 1 hour of transformation showed morphometric characteristics that corresponded with an if , the presence of contaminant trypomastigotes ( 2% ) rendered this population not useful for differential expression studies ( figure 4 ) .
the previous results demonstrated that different ifs , which can be identified by specific morphological characteristics , are generated during amastigogenesis . since it was necessary to know more about their biological properties , a molecular marker was evaluated for the different ifs during the transformation kinetics .
it has been reported that the morphological differentiation of the ifs implies the remodeling of parasite surface molecules [ 3 , 8 ] .
the expression of the amastigote - specific surface glycoprotein ssp4 was evaluated by indirect immunofluorescence in the diverse ifs as well as in trypomastigotes and amastigotes used as controls .
the results presented in figure 5 showed that , as expected , the trypomastigotes did not express the amastigote - specific surface glycoprotein ( figures 5(a ) and 5(b ) ) , while amastigotes displayed heterogeneous levels of ssp4 ( figures 5(o ) and 5(p ) ) .
moreover , while the ifs generated at 1 , 2 , and , 3 hours of transformation did not express ssp4 ( from figures 5(c ) to 5(h ) ) , approximately 8% and 36% of parasites at 4 ( figures 5(i ) and 5(j ) ) and 5 hours of differentiation ( figures 5(k ) and 5(l ) ) , respectively , showed low expression levels .
in addition , after 6 hours of transformation ( figures 5(m ) and 5(n ) ) , approximately 76% of the parasites showed variable and lower levels of ssp4 compared to culture - derived amastigotes ( figures 5(o ) and 5(p ) ) .
finally , after 72 hours of transformation , all parasites showed equivalent expression of ssp4 to that of culture - derived amastigotes ( data not show ) .
these results indicated that the consecutive and gradual expression of ssp4 was concomitant with the morphological transformation of trypomastigotes into amastigotes , in which the ifs with a similar morphology to amastigotes were the ones that started expressing the amastigote - specific glycoprotein .
moreover , even though the morphology of the parasites at 6 hours of transformation was similar to the tissue - derived amastigote morphology , the expression of this molecular marker indicated that these parasites were not completely transformed at the molecular level .
continuing with the biological analysis of the different ifs , their resistance to complement - mediated lysis was determined . as the ifs
are obtained during trypomastigote differentiation into amastigotes and both developmental stages are resistant to complement - mediated lysis , it would not be surprising if the ifs are also resistant . however , it was important to evaluate this phenotype because ( 1 ) the ifs are usually intracellular and therefore not exposed to the blood and extracellular space in the vertebrate host and so they would not need to be resistant to complement - mediated lysis and ( 2 ) the ifs obtained during metacyclogenesis and amastigogenesis show very similar morphological characteristics , and very little is known about biological properties that could be used to distinguish them .
however , this biological property has not been evaluated in the ifs obtained during amastigogenesis .
therefore , the complement - sensitivity of the ifs obtained was evaluated using fresh human serum as described in the materials and methods . as shown in figure 6 , the if at 3 hours of transformation , similar to trypomastigotes and amastigotes
moreover , all of the ifs obtained through the transformation kinetics were also resistant to complement - mediated lysis ( data not shown ) .
as expected , epimastigotes were sensitive to complement , thus reaching 100% lysed parasites in the first 30 minutes of treatment .
these results suggest that the ifs obtained during the in vitro amastigogenesis do not lose the ability to resist complement - mediated lysis . therefore ,
even if the ifs from metacyclogenesis and amastigogenesis are morphologically similar , they have different biological properties that can be used to distinguish them .
the lack of effective in vitro conditions to obtain high rates of synchronic and pure ifs has delayed the understanding of the molecular mechanisms that mediate the cellular remodeling and the identification of molecular markers that are important for amastigogenesis . in the present work , we established an improved method to obtain high rates of pure ifs and correlated parasite differentiation with the expression of a specific developmental marker , complement - mediated lysis sensitivity and morphometrical analysis of the nucleus , kinetoplast and parasite body throughout the complete transformation process .
the efficient transformation of cell culture - derived trypomastigotes to amastigotes was induced using an acidic ph and serum deprivation at 37c ( figure 1 ) .
the parasites showed dramatic cell restructuring with a gradual and progressive reduction of their size and the readsorption of their flagellum and undulating membrane until they reached the typical round shape of tissue - derived amastigotes ( figure 2 ) .
these results are consistent with previous reports that document the existence of several intermediate forms during the life cycle of t. cruzi , either under in vivo or in vitro conditions that showed the same gradual and progressive parasite morphometrical transformation , apparently as an obligatory step for the differentiation process [ 1 , 3 , 5 , 8 , 1822 ] . the quantitative analysis demonstrated that parasite transformation was initiated immediately after the exposure to hgdmem at ph5 and 37c , thus reaching 100% ifs after only 2 hours of incubation ( figure 4 ) ; this indicates a faster and more efficient differentiation rate than previously reported [ 5 , 8 ]
. these differences could be the result of the absence of bsa in the differentiation medium used in this study in comparison with the 0.4% bsa contained in the previously reported medium [ 5 , 8 ] .
in addition , the condition of the cell culture - derived trypomastigotes used to initiate parasite differentiation may play an important role in the process .
the parasites used in all of the experiments in this study were early released trypomastigotes that were obtained from early infections corresponding to the first 6 days after the first trypomastigote liberation , because the parasites released later showed variable , not synchronous and inefficient transformation rates .
interestingly , andrews et al , and tomlinson et al , also used only trypomastigotes early released from infected cells for their transformation experiments . even when these authors did not justify this specification
the morphological restructuring of t. cruzi during amastigogenesis has shown that the transition from the slender to the spherical or oval parasite shape comprises an extensive remodeling of cellular architecture , the flagellum and the undulating membrane , and a dramatic change in the overall parasite size , apparently as a result of the reorganization of their subpellicular microtubules .
this dramatic restructuring also affects the location and morphology of the parasite organelles during t. cruzi differentiation .
the kinetoplast of the trypomastigotes is spherical ; whereas in amastigotes , it is elongated [ 8 , 21 , 23 , 24 ] .
in contrast , the nuclei of the trypomastigotes are elongated , apparently following the parasite 's shape ; meanwhile , it is round in amastigotes .
these morphometrical characteristics of the nucleus and the kinetoplast have been reported to allow the distinction of the t. cruzi developmental stages .
therefore , this was the criteria used to initiate the characterization of the ifs obtained ( figure 3 and table 1 ) .
the results showed that the morphometrical analysis of the nucleus and the kinetoplast allows the clear identification of the different ifs .
the trypomastigotes showed a bigger distance between the nucleus and the kinetoplast than did the amastigotes .
in addition , during amastigogenesis , together with the parasite shape change , we observed nucleus remodeling and a progressive and continuous displacement of the kinetoplast from the posterior to the anterior position with respect to the parasite nucleus .
similar observations were reported by contreras and collaborators in 2002 , during primary amastigogenesis . as in the quantitative analysis conducted during the morphometrical characterization of the ifs ( figure 2 and table 1 ) , the shape and position of the nucleus and the kinetoplast ( figure 3 and table 1 ) allowed us to very precisely determine that one of these populations was highly predominant even when three different if populations were present at each time of the transformation kinetics ( from 85% to 90% ) , which confirmed a high efficiency of the homogeneity and synchronicity of the differentiation process in our in vitro conditions ( figure 4 ) .
differentiation of the diverse developmental stages of t. cruzi has been associated with changes in their biological properties and with the expression of stage - specific surface molecules .
moreover , the morphological transformation during primary amastigogenesis has been associated with changes in the glycoprotein profile related to the expression of trans - sialidase and mucin previously described in t. cruzi .
the same behavior was observed in this work during the secondary amastigogenesis : contrary to the positive expression of ssp4 observed in the amastigote surface , the trypomastigotes , epimastigotes and ifs at 1 , 2 and 3 hours of transformation did not express this amastigote - specific glycoprotein ( gp ) ( figure 5 ) . in the case of the ifs obtained at 4 , 5 and 6 hours of transformation , low and heterogeneous levels of ssp4 expression
were observed . at these times , the total number of parasites expressing ssp4 as well as the expression level of this gp on their surfaces , increased in parallel with the degree of transformation from trypomastigotes to amastigotes , which confirms that the progressive expression of ssp4 can be useful as a molecular marker of differentiation [ 3 , 8 , 21 ] . to initiate and establish infection in the mammalian host ,
t. cruzi needs to develop several strategies to avoid the immune response . to survive and disseminate in the bloodstream and in the extracellular space ,
trypomastigotes and amastigotes have developed a stage - specific capacity to resist complement - mediated lysis [ 2527 ] , apparently using stage - specific regulators [ 2830 ] .
conversely , epimastigotes found in the insect vector activate the complement cascade , but they are not able to inhibit its lytic action .
complement - mediated lysis of the ifs obtained during in vitro secondary amastigogenesis was evaluated . as expected ,
trypomastigotes and amastigotes , but not epimastigotes , were resistant to the lytic effects of complement . besides this , the ifs obtained during in vitro amastigogenesis were not sensitive to complement lysis ( figure 6 ) .
this result indicates that these ifs express the proteins that participate in the stage - specific inhibition of complement activation .
nevertheless , future studies will be necessary to elucidate which stage - specific proteins from trypomastigotes and/or amastigotes are expressed by the ifs in order to inhibit complement activation .
it has been reported that the ifs generated during the transformation from epimastigote to trypomastigote are sensitive to complement lysis .
the ifs obtained during the metacyclogenesis and amastigogenesis are morphologically indistinguishable , which is remarkable , because this biological property might be used as a criterion to distinguish both types of ifs .
moreover , this result further supports the existence of the alternative parasite life subcycle that was previously proposed and the hypothesis that this could be the result of the premature lysis of the infected cells or the extracellular parasite differentiation . in summary
, we have shown that the experimental differentiation model reported in this work provides , for the first time , a highly synchronous system that could be useful for studying the molecular mechanism of the transformation process and the identification of the regulators involved in differentiation control , with the potential to identify routes to block the cycle of t. cruzi infection . | trypanosoma cruzi undergoes a biphasic life cycle that consists of four alternate developmental stages . in vitro conditions to obtain a synchronic transformation and efficient rates of pure intermediate forms ( ifs ) , which are indispensable for further biochemical , biological , and molecular studies , have not been reported . in the present study , we established an improved method to obtain ifs from secondary amastigogenesis . during the transformation kinetics , we observed progressive decreases in the size of the parasite body , undulating membrane and flagellum that were concomitant with nucleus remodeling and kinetoplast displacement .
in addition , a gradual reduction in parasite movement and acquisition of the amastigote - specific ssp4 antigen were observed .
therefore , our results showed that the in vitro conditions used obtained large quantities of highly synchronous and pure ifs that were clearly distinguished by morphometrical and molecular analyses . obtaining
these ifs represents the first step towards an understanding of the molecular mechanisms involved in amastigogenesis . | <s>[INST]trypanosoma cruzi is an obligate intracellular parasite that is responsible for chagas disease , which affects 1618 million people in latin america .
this parasite has a complex biphasic life cycle in which four developmental forms alternate between the reduviid beetle vector ( epimastigotes and metacyclic trypomastigotes ) and the mammalian host ( amastigotes and bloodstream trypomastigotes ) .
transmission is initiated in the reduviid beetle vector , which becomes infected by taking up circulating trypomastigotes during a blood meal .
after trypomastigotes differentiate to epimastigotes in the insect gut lumen , the parasite divides by binary fission before migrating along the hindgut and rectum , where they transform to metacyclic trypomastigotes .
these trypomastigotes are released near the bite wound with the insect feces during the next blood meal . following its introduction into mammalian blood , the trypomastigotes penetrate nonphagocytic and phagocytic cells through a parasitophorous vacuole to start the intracellular cycle . in this stage
amastigotes develop into nondividing bloodstream trypomastigotes that can either initiate another round of infection to propagate to different organs or can be taken up by the insect vector to complete the life cycle . throughout its life cycle ,
t. cruzi survives under a wide range of environmental conditions that induce complex morphological changes among parasite stages .
in addition to the four main developmental forms , it is possible to observe intermediate forms ( ifs ) that seem to follow the same differentiation path , independent of whether they exist in a vertebrate or in an invertebrate host [ 1 , 2 ] .
intermediate forms appear transiently during the differentiation of epimastigotes into metacyclic trypomastigotes ( metacyclogenesis ) in the triatomine , the differentiation of metacyclic trypomastigotes ( primary amastigogenesis ) , and tissue - derived trypomastigotes ( secondary amastigogenesis ) into amastigotes and also into bloodstream trypomastigotes inside the mammalian host cell [ 25 ] .
adaptation of t. cruzi to diverse environments found in the different hosts undoubtedly induces a complex regulation of gene expression that apparently precedes the morphological changes observed during parasite transformation .
several researchers have studied some of the factors that represent physiological stress for the parasite and have demonstrated that temperature , nutritional conditions , and ph stimulate morphological differentiation during amastigogenesis [ 58 ] .
the vast majority of the information regarding in vivo and in vitro amastigogenesis comes from data in which tissue - derived trypomastigotes were used because it was possible to obtain higher yields of these parasites [ 3 , 5 , 815 ] .
ultra - structural and molecular analyses during the trypomastigote to amastigote transformation have shown a complex and progressive morphological rearrangement of parasite shape and flagellum that has been associated with the differential expression of stage - specific antigens [ 3 , 5 , 8 ] . a comparative morphology study showed that even when metacyclic and bloodstream trypomastigotes share similar biological and morphological properties , primary and secondary amastigogenesis apparently display different developmental processes , which suggests that their intracellular mechanisms are different .
although the basic features of the amastigogenesis transformation process are known , the molecular mechanisms involved are still unidentified .
analysis of the molecules implicated in the detonation and control of the transformation process will increase our knowledge about morphogenesis and gene expression programs that are involved not only in the differentiation between developmental forms but also during parasite transitions from the nonreplicative to the replicative stage .
the usefulness of a differentiation system for molecular research in which a population of cells is involved depends first on the synchrony of the transition , second on the availability of easily analyzable markers for monitoring the process , and third on the system efficiency for obtaining large enough amounts of analyzable sample for further biochemical , biological , and molecular analyses . to date , in vitro conditions that allow for obtaining ifs that satisfy these needs have not been reported .
therefore , in vitro conditions that induce high rates of pure ifs during the transformation of culture - derived trypomastigotes into amastigotes are described in this work .
furthermore , morphological , cellular , and molecular characterizations of the different ifs obtained are presented .
nih 3t3 fibroblasts were grown in high glucose dulbecco 's minimal essential medium ( hgdmem ) supplemented with 10% fetal bovine serum ( fbs ) , 1% glutamine , and 5 g / ml penicillin - streptomycin at 37c in a humidified atmosphere with 5% co2 in a 75 cm corning cell culture flask ( catalog number 4306 - 41 ) .
epimastigotes of t. cruzi cl - brener strain were grown in liver infusion tryptose medium ( lyt ) containing 10% fbs and hemin ( 25 g / ml ) at 28c .
fifty percent confluent fibroblasts were infected with 2 10 cl - brener mid - log - phase epimastigotes per ml of hgdmem ( 15 ml ) supplemented with 2% fbs to get a parasite - host cell ratio of 10 : 1 .
the nih 3t3 monolayers were washed every 2 days with hgdmem medium until nonadherent parasites were removed , and then fresh hgdmem plus 2% fbs was added .
the parasites released from the early infections corresponding to the first 6 days after the first liberation were harvested every day at 2000 g for 5 minutes .
the trypomastigotes were separated from amastigotes by immunoprecipitation using 500 l of hybridoma supernatant of monoclonal antibody 2c2b6 , which is specific for the ssp4 surface antigen of amastigotes , per 3 10 parasites at 37c for 1 hour .
the trypomastigotes were separated from amastigotes at 800 rpm for 10 seconds in a microcentrifuge and were washed with 1x pbs as many times as necessary to obtain pure parasites .
the amastigotes were found in the pellet , and the trypomastigotes were found in the supernatant .
purified tissue culture - derived trypomastigotes ( 5 10 ) were harvested at 500 g for 10 minutes and were transferred to 100 20 mm untreated petri dishes containing 1 ml per experiment of hgdmem at different phs ( 4 , 5 , 6 , 7 , 8 , and 9 ) without or with different fbs concentrations ( 0.5% , 1% , 1.5% , and 2% ) incubated at 37c in a 5% co2 atmosphere .
after 1 , 2 , 3 , 4 , 5 , 6 , 12 , 24 , 48 , or 72 hours , the parasites were washed , fixed with 4% paraformaldehyde in 1xpbs , washed again , and dropped ( 3 10 parasites/10 l ) over poly - l - lysine - treated slides ( silane - prep slides sigma diagnostics , catalog number s4651 ) inside circles delimited with a liquid - repellent slide marker pen ( electron microscopy sciences catalog number 71310 ) . after the slides were air dried , the parasites were stained with hema 3 according to the protocol supplied by the manufacturer ( fisher diagnostic 840021 ) , and the percentages of trypomastigotes , ifs , and amastigotes were determined for 100 cells analyzed randomly under an optic microscope .
trypomastigotes , amastigotes , epimastigotes , or ifs ( 2 10 parasites ) were incubated with 500 l of fresh human serum at 37c for 30 , 60 , and 120 minutes .
parasite lysis was determined by adding one volume of trypan blue ( 0.4% in 1x pbs , hycel 23850 ) and counting the complement - resistant parasites in a hemocytometer under a light microscope .
three independent experiments , repeated in triplicate each time , were carried out using serum from different donors .
the parasites were harvested , washed , fixed , and dropped over poly - l - lysine - treated slides as described above .
the parasites were permeabilized with 0.1% triton - x100 for 5 minutes , rinsed extensively with 1x pbs , and treated with 2% bsa ( albumin , bovine , cohn fraction v / 1x pbs ph 7 ) at 37c for 30 minutes .
these preparations were washed with pbs and incubated 1 hour at 37c with hybridoma supernatant ( 1 : 50 ) of the amastigote - specific monoclonal antibody 2c2b6 .
after rinsing , a secondary antimouse antibody tagged with alexa fluor 488 green diluted 1 : 1000 was layered on the parasites and incubated for 1 hour at 37c .
h-1000 ) , and observed under an olympus fluorescence microscope ( bx41 ) equipped with a 60x/1.25 oil iris ph3 uplanfl n objective .
the images were captured using an evolution vf fast cooled color media cybernetics camera and were analyzed using the image - pro plus v 6.0 media cybernetics program .
the parasites were processed and analyzed as per the indirect immunofluorescence protocol described above , with some specifications .
after treatment with a polyclonal antibody against the epimastigotes ( 1 : 200 ) obtained from the mouse and the antimouse antibody tagged with alexa fluor 546 red ( 1 : 1000 ) as the first and second antibodies , the parasites were stained with 10 g / ml dapi ( molecular probes ) .
as mentioned before , conditions such as temperature , nutritional environment , and ph stimulate the in vitro differentiation of trypomastigotes into amastigotes [ 58 ] . to determine the best conditions for obtaining the highest rates of transformation , in vitro experiments
were performed using tissue - derived trypomastigotes incubated at 37c in hgdmem medium at different phs ( 4 , 5 , 6 , 7 , 8 , and 9 ) , without or with 0.5% , 1% , 1.5% , or 2% fbs for different lengths of time , as described in the materials and methods .
the movement and morphology of the parasites were analyzed in fresh preparations under a light microscope , and the relative percentages of trypomastigotes , ifs , and amastigotes were determined . in all of the conditions in which parasite differentiation was achieved , the trypomastigotes showed gradual morphological changes and size reduction ; they transformed from the typical s- or c - shaped bloodstream morphology to diverse ifs that finally reached the rounded or oval shape characteristic of amastigotes after 12 hours of incubation
. a progressive reduction of parasite movement concomitant with the gradual shortening of the undulating membrane and flagellum was also observed .
although similar morphological patterns of differentiation could be seen in some of the different conditions tested , very different rates of transformation were obtained .
incubation at 37c in hgdmem at ph 5 without fbs induced the most efficient rates of differentiation . under these conditions ,
the level of tissue - derived trypomastigotes decreased concomitantly with increasing amounts of ifs , which reached 85% within 3 hours of incubation ( figure 1 ) .
subsequently , as the percentage of ifs decreased , the relative amount of amastigotes increased , and the transformation process was completed after 12 hours of incubation . a homogenous population ( 100% ) of round - shaped forms , which displayed either no flagella or very short protruding flagella and a noticeable reduction of movement , was observed at this point . on the contrary ,
when tissue - derived trypomastigotes were incubated in hgdmem at ph 4 without fbs , only 30% of the cells were transformed into amastigotes after 3 hours and 65% after 12 hours ( data not shown ) .
in addition , only 21% of the trypomastigotes differentiated into amastigotes after 24 hours of incubation at ph 6 without fbs ( data not shown ) . finally , at phs 7 , 8 , and 9 in the absence of fbs as well as those same phs with 0.5% , 1% , 1.5% , and 2%
these results indicate that the differentiation process during the in vitro secondary amastigogenesis involves several ifs as a result of the morphological change of the parasites .
in addition , the optimal conditions to induce the highest rates of transformation from tissue - derived trypomastigotes into amastigotes were ph 5 , serum - deprivation and 37c .
the different developmental forms of t. cruzi can be identified by morphological and biological parasite features , such as the size and shape of the parasite , undulating membrane and flagellum , the position of flagellum emergence , and the size , shape , and relative position of the nucleus and the kinetoplast .
the amastigote has a spherical- to oval - shaped form that is 2 to 4 m in diameter with no or very short free flagellum and a kinetoplast located in the middle of the parasite body close to the nucleus .
the trypomastigotes have a flagellum and an undulating membrane that extends the entire length of the parasite ( 1625 m long and 2 m diameter ) .
trypomastigotes found in the blood of infected mammals have a slender s- or c - shaped form , while the trypomastigotes found in infected insects usually have a straight form .
once the best conditions to induce the transformation of the parasite were determined , a detailed morphological analysis was carried out on fixed and stained preparations , and the relative amounts of trypomastigotes , amastigotes , and ifs were determined at different points of the differentiation kinetics at 37c using hgdmem at ph 5 with serum - deprivation ( figure 2 ) .
this methodology allowed us to perform a morphometrical analysis and a more precise quantification of the transformation process compared to those obtained with fresh preparations . before initiating the differentiation process
, tissue - derived trypomastigotes showed the typical morphology previously described ( figure 2a ) . during the transformation process
, the parasite progressively reduced its entire length by 22% at 1 hour , 23% at 2 hours , 39% at 3 hours , 48% at 4 hours , 50% at 5 hours , and 53% at 6 hours of transformation as shown in figure 2 and table 1 .
the quantitative analysis indicated that as little as 1 hour of transformation time was enough to induce high rates of ifs ( 80% ) in which the parasites displayed a widening and shortening of their body , flagellum , and undulating membrane ; however , this last one maintained the subterminal emergence site that is characteristic of trypomastigotes ( figure 2b and table 1 ) .
after 2 hours of transformation , no trypomastigotes were detected , which indicates that the culture contained 100% ifs .
these ifs showed size reduction , a light oval - shaped form , shortening of their flagellum , and an undulating membrane in which their emergence site was slightly displaced to the middle of the parasite body ( figure 2(c ) and table 1 ) .
after 3 hours , the morphology of the ifs was very close to the one observed at 2 hours of transformation , but their size continued to reduce and the undulating membrane was not appreciable ( figure 2(d ) and table 1 ) .
after 4 and 5 hours of transformation , the ifs showed similar size and morphology to the amastigotes and were only distinguished by the progressive shortening of their flagellum ( figures 2(e ) and 2(f ) and table 1 ) .
finally , after 6 hours of transformation , the parasites reached the spherical- to oval - shaped form with no or very short free flagellum ( figure 2(g ) ) , and their morphology was indistinguishable from the one observed in the cell culture - derived amastigotes ( figure 2(h ) and table 1 ) . to assess the reversibility of the differentiation process , the ifs were cultured again in hgdmem at ph 7.2 complemented with 2% fbs after 1 , 2 , 3 , 4 , 5 , 6 , 12 , 24 , 48 or 72 hours of differentiation at 37c using hgdmem at ph 5 with serum deprivation . in all cases ,
the ifs continued their differentiation , thus indicating that once detonated , this process can not be stopped and is not reversible ( data not shown ) .
these results showed that , under the in vitro conditions used , the trypomastigotes differentiated very efficiently into highly homogeneous and pure if populations after 2 hours of induction . to continue with the morphological analysis of the ifs , the shape and position of the nucleus and the kinetoplast at each point of the transformation kinetics were determined .
the parasites were then stained with a polyclonal antibody against epimastigote total proteins , which had been previously shown to recognize all of the developmental forms and ifs of t. cruzi .
the reactions were developed with an alexa fluor 546 red - conjugated antimouse antibody , and the kinetoplast and nucleus were counterstained with dapi . as shown in previous experiments , the same morphological transformation pattern of the parasite body
was found with this technique ( compare figures 2 and 3 ) . nucleus remodeling and a progressive and continuous displacement of the kinetoplast from the posterior to the anterior position with respect to the parasite nucleus were also observed .
as shown in table 1 , the distance between the nucleus and the kinetoplast became shorter during the transformation kinetics . at 1 hour of transformation ( figure 3(b ) ) , the distance between both organelles was reduced by 28% ( table 1 ) , even though the ifs showed a subterminal kinetoplast posterior to the nucleus , as commonly observed in trypomastigotes ( figure 3(a ) ) .
after 2 hours of transformation , the ifs showed a displacement of their kinetoplast to the middle of the parasite body and reduced the distance with respect to the nucleus ( now remodeled from the lengthened - shaped form to an oval - shaped form ) by 58% ( figure 3(c ) and table 1 ) .
after 3 hours of transformation , the kinetoplast remained located posterior to the nucleus , close to the middle part of the parasite body , with a 66% reduction in the distance between both organelles ( figure 3(d ) and table 1 ) . at 4 hours of transformation , the kinetoplast was positioned next to and parallel to the nucleus in a transversal position in the middle of the parasite body and showed 85% reduction in the organelle distance ( figure 3(e ) and table 1 ) .
after 5 hours of transformation , the kinetoplast moved to an anterior position with respect to the nucleus , in the middle part of the parasite body and showed a 90% reduction in the distance between the organelles ( figure 3(f ) and table 1 ) .
finally , at 6 hours of transformation ( figure 3(g ) and table 1 ) , the parasite morphology and the position of the kinetoplast were very similar to those observed in the tissue - derived amastigotes ( figure 3(h ) and table 1 ) .
these results showed that , concomitant with the morphological parasite shape transformation , nucleus remodeling and kinetoplast displacement are observed during the transformation kinetics under the in vitro conditions used .
the morphological analysis described above showed homogenous if populations ; nevertheless , the nucleus remodeling and kinetoplast displacement studies indicated that each point of the transformation kinetics is composed of 3 different ifs .
the percentages of trypomastigotes , amastigotes and the different ifs were then determined for each time point evaluated in the previous experiment .
as shown in figure 4 , 3 different ifs were observed at 1 , 2 , 3 , 4 and 5 hours of in vitro differentiation ( figures 4(a ) and 4(c ) ) . at 1 hour of transformation
the first if , which was arbitrarily named if1 , showed similar morphology to the immediate previous parasite stage ( trypomastigotes for the first hour and if3 for 2 , 3 , 4 , and 5 hours ) and represented 2% to 3% of the total parasites .
the second intermediary form , named if2 , showed a slightly , but clearly , more differentiated morphology than if1 and represented the most abundant parasite population ( 85% to 90% ) .
the third if , still more differentiated than if2 and named if3 ( 2% to 15% ) , displayed characteristics similar to the if1 that emerged from the next time of transformation . at 1 hour of transformation
, trypomastigotes comprised only 2% of the culture , which confirms that the transformation process is very efficient under the established conditions ( figures 4(a ) , 4(b ) and 4(c ) ) .
moreover , from 1 to 5 hours of transformation were not observed any amastigotes ( panel a ) .
finally , at 6 hours of transformation , 100% of the parasites showed a very similar morphology to that of tissue - derived amastigotes ( figures 3(g ) and 3(h ) , table 1 and figures 4(a ) , 4(b ) and 4(c ) ) .
the only forms detected after 2 , 3 , 4 and 5 hours of transformation were ifs with a gradually increasing degree of differentiation .
therefore , this experimental model could be useful for future analysis of the differential expression between the ifs and the completely differentiated forms of t. cruzi .
in addition , even when the ifs at 1 hour of transformation showed morphometric characteristics that corresponded with an if , the presence of contaminant trypomastigotes ( 2% ) rendered this population not useful for differential expression studies ( figure 4 ) .
the previous results demonstrated that different ifs , which can be identified by specific morphological characteristics , are generated during amastigogenesis . since it was necessary to know more about their biological properties , a molecular marker was evaluated for the different ifs during the transformation kinetics .
it has been reported that the morphological differentiation of the ifs implies the remodeling of parasite surface molecules [ 3 , 8 ] .
the expression of the amastigote - specific surface glycoprotein ssp4 was evaluated by indirect immunofluorescence in the diverse ifs as well as in trypomastigotes and amastigotes used as controls .
the results presented in figure 5 showed that , as expected , the trypomastigotes did not express the amastigote - specific surface glycoprotein ( figures 5(a ) and 5(b ) ) , while amastigotes displayed heterogeneous levels of ssp4 ( figures 5(o ) and 5(p ) ) .
moreover , while the ifs generated at 1 , 2 , and , 3 hours of transformation did not express ssp4 ( from figures 5(c ) to 5(h ) ) , approximately 8% and 36% of parasites at 4 ( figures 5(i ) and 5(j ) ) and 5 hours of differentiation ( figures 5(k ) and 5(l ) ) , respectively , showed low expression levels .
in addition , after 6 hours of transformation ( figures 5(m ) and 5(n ) ) , approximately 76% of the parasites showed variable and lower levels of ssp4 compared to culture - derived amastigotes ( figures 5(o ) and 5(p ) ) .
finally , after 72 hours of transformation , all parasites showed equivalent expression of ssp4 to that of culture - derived amastigotes ( data not show ) .
these results indicated that the consecutive and gradual expression of ssp4 was concomitant with the morphological transformation of trypomastigotes into amastigotes , in which the ifs with a similar morphology to amastigotes were the ones that started expressing the amastigote - specific glycoprotein .
moreover , even though the morphology of the parasites at 6 hours of transformation was similar to the tissue - derived amastigote morphology , the expression of this molecular marker indicated that these parasites were not completely transformed at the molecular level .
continuing with the biological analysis of the different ifs , their resistance to complement - mediated lysis was determined . as the ifs
are obtained during trypomastigote differentiation into amastigotes and both developmental stages are resistant to complement - mediated lysis , it would not be surprising if the ifs are also resistant . however , it was important to evaluate this phenotype because ( 1 ) the ifs are usually intracellular and therefore not exposed to the blood and extracellular space in the vertebrate host and so they would not need to be resistant to complement - mediated lysis and ( 2 ) the ifs obtained during metacyclogenesis and amastigogenesis show very similar morphological characteristics , and very little is known about biological properties that could be used to distinguish them .
however , this biological property has not been evaluated in the ifs obtained during amastigogenesis .
therefore , the complement - sensitivity of the ifs obtained was evaluated using fresh human serum as described in the materials and methods . as shown in figure 6 , the if at 3 hours of transformation , similar to trypomastigotes and amastigotes
moreover , all of the ifs obtained through the transformation kinetics were also resistant to complement - mediated lysis ( data not shown ) .
as expected , epimastigotes were sensitive to complement , thus reaching 100% lysed parasites in the first 30 minutes of treatment .
these results suggest that the ifs obtained during the in vitro amastigogenesis do not lose the ability to resist complement - mediated lysis . therefore ,
even if the ifs from metacyclogenesis and amastigogenesis are morphologically similar , they have different biological properties that can be used to distinguish them .
the lack of effective in vitro conditions to obtain high rates of synchronic and pure ifs has delayed the understanding of the molecular mechanisms that mediate the cellular remodeling and the identification of molecular markers that are important for amastigogenesis . in the present work , we established an improved method to obtain high rates of pure ifs and correlated parasite differentiation with the expression of a specific developmental marker , complement - mediated lysis sensitivity and morphometrical analysis of the nucleus , kinetoplast and parasite body throughout the complete transformation process .
the efficient transformation of cell culture - derived trypomastigotes to amastigotes was induced using an acidic ph and serum deprivation at 37c ( figure 1 ) .
the parasites showed dramatic cell restructuring with a gradual and progressive reduction of their size and the readsorption of their flagellum and undulating membrane until they reached the typical round shape of tissue - derived amastigotes ( figure 2 ) .
these results are consistent with previous reports that document the existence of several intermediate forms during the life cycle of t. cruzi , either under in vivo or in vitro conditions that showed the same gradual and progressive parasite morphometrical transformation , apparently as an obligatory step for the differentiation process [ 1 , 3 , 5 , 8 , 1822 ] . the quantitative analysis demonstrated that parasite transformation was initiated immediately after the exposure to hgdmem at ph5 and 37c , thus reaching 100% ifs after only 2 hours of incubation ( figure 4 ) ; this indicates a faster and more efficient differentiation rate than previously reported [ 5 , 8 ]
. these differences could be the result of the absence of bsa in the differentiation medium used in this study in comparison with the 0.4% bsa contained in the previously reported medium [ 5 , 8 ] .
in addition , the condition of the cell culture - derived trypomastigotes used to initiate parasite differentiation may play an important role in the process .
the parasites used in all of the experiments in this study were early released trypomastigotes that were obtained from early infections corresponding to the first 6 days after the first trypomastigote liberation , because the parasites released later showed variable , not synchronous and inefficient transformation rates .
interestingly , andrews et al , and tomlinson et al , also used only trypomastigotes early released from infected cells for their transformation experiments . even when these authors did not justify this specification
the morphological restructuring of t. cruzi during amastigogenesis has shown that the transition from the slender to the spherical or oval parasite shape comprises an extensive remodeling of cellular architecture , the flagellum and the undulating membrane , and a dramatic change in the overall parasite size , apparently as a result of the reorganization of their subpellicular microtubules .
this dramatic restructuring also affects the location and morphology of the parasite organelles during t. cruzi differentiation .
the kinetoplast of the trypomastigotes is spherical ; whereas in amastigotes , it is elongated [ 8 , 21 , 23 , 24 ] .
in contrast , the nuclei of the trypomastigotes are elongated , apparently following the parasite 's shape ; meanwhile , it is round in amastigotes .
these morphometrical characteristics of the nucleus and the kinetoplast have been reported to allow the distinction of the t. cruzi developmental stages .
therefore , this was the criteria used to initiate the characterization of the ifs obtained ( figure 3 and table 1 ) .
the results showed that the morphometrical analysis of the nucleus and the kinetoplast allows the clear identification of the different ifs .
the trypomastigotes showed a bigger distance between the nucleus and the kinetoplast than did the amastigotes .
in addition , during amastigogenesis , together with the parasite shape change , we observed nucleus remodeling and a progressive and continuous displacement of the kinetoplast from the posterior to the anterior position with respect to the parasite nucleus .
similar observations were reported by contreras and collaborators in 2002 , during primary amastigogenesis . as in the quantitative analysis conducted during the morphometrical characterization of the ifs ( figure 2 and table 1 ) , the shape and position of the nucleus and the kinetoplast ( figure 3 and table 1 ) allowed us to very precisely determine that one of these populations was highly predominant even when three different if populations were present at each time of the transformation kinetics ( from 85% to 90% ) , which confirmed a high efficiency of the homogeneity and synchronicity of the differentiation process in our in vitro conditions ( figure 4 ) .
differentiation of the diverse developmental stages of t. cruzi has been associated with changes in their biological properties and with the expression of stage - specific surface molecules .
moreover , the morphological transformation during primary amastigogenesis has been associated with changes in the glycoprotein profile related to the expression of trans - sialidase and mucin previously described in t. cruzi .
the same behavior was observed in this work during the secondary amastigogenesis : contrary to the positive expression of ssp4 observed in the amastigote surface , the trypomastigotes , epimastigotes and ifs at 1 , 2 and 3 hours of transformation did not express this amastigote - specific glycoprotein ( gp ) ( figure 5 ) . in the case of the ifs obtained at 4 , 5 and 6 hours of transformation , low and heterogeneous levels of ssp4 expression
were observed . at these times , the total number of parasites expressing ssp4 as well as the expression level of this gp on their surfaces , increased in parallel with the degree of transformation from trypomastigotes to amastigotes , which confirms that the progressive expression of ssp4 can be useful as a molecular marker of differentiation [ 3 , 8 , 21 ] . to initiate and establish infection in the mammalian host ,
t. cruzi needs to develop several strategies to avoid the immune response . to survive and disseminate in the bloodstream and in the extracellular space ,
trypomastigotes and amastigotes have developed a stage - specific capacity to resist complement - mediated lysis [ 2527 ] , apparently using stage - specific regulators [ 2830 ] .
conversely , epimastigotes found in the insect vector activate the complement cascade , but they are not able to inhibit its lytic action .
complement - mediated lysis of the ifs obtained during in vitro secondary amastigogenesis was evaluated . as expected ,
trypomastigotes and amastigotes , but not epimastigotes , were resistant to the lytic effects of complement . besides this , the ifs obtained during in vitro amastigogenesis were not sensitive to complement lysis ( figure 6 ) .
this result indicates that these ifs express the proteins that participate in the stage - specific inhibition of complement activation .
nevertheless , future studies will be necessary to elucidate which stage - specific proteins from trypomastigotes and/or amastigotes are expressed by the ifs in order to inhibit complement activation .
it has been reported that the ifs generated during the transformation from epimastigote to trypomastigote are sensitive to complement lysis .
the ifs obtained during the metacyclogenesis and amastigogenesis are morphologically indistinguishable , which is remarkable , because this biological property might be used as a criterion to distinguish both types of ifs .
moreover , this result further supports the existence of the alternative parasite life subcycle that was previously proposed and the hypothesis that this could be the result of the premature lysis of the infected cells or the extracellular parasite differentiation . in summary
, we have shown that the experimental differentiation model reported in this work provides , for the first time , a highly synchronous system that could be useful for studying the molecular mechanism of the transformation process and the identification of the regulators involved in differentiation control , with the potential to identify routes to block the cycle of t. cruzi infection .[/INST]trypanosoma cruzi undergoes a biphasic life cycle that consists of four alternate developmental stages . in vitro conditions to obtain a synchronic transformation and efficient rates of pure intermediate forms ( ifs ) , which are indispensable for further biochemical , biological , and molecular studies , have not been reported . in the present study , we established an improved method to obtain ifs from secondary amastigogenesis . during the transformation kinetics , we observed progressive decreases in the size of the parasite body , undulating membrane and flagellum that were concomitant with nucleus remodeling and kinetoplast displacement .
in addition , a gradual reduction in parasite movement and acquisition of the amastigote - specific ssp4 antigen were observed .
therefore , our results showed that the in vitro conditions used obtained large quantities of highly synchronous and pure ifs that were clearly distinguished by morphometrical and molecular analyses . obtaining
these ifs represents the first step towards an understanding of the molecular mechanisms involved in amastigogenesis .</s> |
The Fontana woman accused in a multi-vehicle collision on the 60 Freeway in Diamond Bar that left six people dead had a prior DUI conviction, according to reports.
The 21-year-old woman who authorities say was under the influence of alcohol when she drove the wrong way on the 60 Freeway, killing six people, had previously been convicted of drunk driving.
Olivia Carolee Culbreath was 17 when she was convicted of drunk driving in San Bernardino County, Department of Motor Vehicle officials said. State records also show that she was cited for traffic violations at least two other times. The DMV said the restrictions on her license were lifted last week.
The revelations come as authorities tried to piece together how the accident occurred.
About 4:40 a.m. Sunday, witnesses reported seeing Culbreath's red Chevrolet Camaro traveling east on the westbound 60 at about 100 mph until it struck a red Ford Explorer, which then collided with a third vehicle. Several people were ejected from the vehicles; Culbreath and Joel Cortez, the driver of the third vehicle, survived.
Culbreath is hospitalized and has been arrested on suspicion of DUI causing great bodily injury and manslaughter, authorities said.
Cortez, 57, said Monday that the crash occurred during what was a typical Sunday morning for him. He woke up before dawn, got ready to head to his job as a technician in the City of Industry and asked God to protect four things: himself, his children, his job and the road.
He left his home in Ontario, tuned into one of his favorite Spanish-language radio stations and headed west on the 60 for a 20-minute drive. He settled into a lane and trailed a Ford Explorer for about 10 minutes. Suddenly, he saw the red vehicle flying through the air. He tried to swerve.
Something slammed into the passenger side of his car, and his air bag deployed. His vehicle struck the center divider. He looked out and saw something in the road. In the morning darkness it looked like a big bag.
Then he heard a scream: "There are bodies all over."
There was twisted metal, wheels, blood. He stayed in the car and called his children. Paramedics soon arrived and flashed a light in his face. After seeing that he was alive and seemed to be OK, a paramedic asked him to wait a bit. Others were worse off, Cortez was told.
The four family members in the Explorer, who all died, have been identified as Gregorio Mejia-Martinez, 47; Leticia Ibarra, 42; Jessica Jasmine Mejia, 20; and Ester Delgado, 80.
Their family members gathered at a single-story home in Huntington Park on Monday afternoon. Some huddled near a porch and others stared at the ground, wiping away tears. A man who declined to give his name said he and other family members did not want to speak to the media.
Culbreath's sister, Maya, 24, and a friend, Kristin Melissa Young, 21, were killed.
A woman who answered the door at the Culbreath family home in Fontana choked up and said, "I'm just the grandmother, but I've more or less lost two babies."
"I can't answer anymore. I'm sorry," she said, her eyes downcast as she closed the door.
For Cynthia Schroeder, who met Young at International Polytechnic High in Pomona, the loss of the friend who complimented her necklace on the first day of school and introduced her to the music of the Smiths — felt surreal.
"It's right out of a movie," she said. "I prefer to only speak about positive things — that's the way Kristin would want it."
As Cortez reflected on the crash from his living room Monday afternoon, his neck, chest and knees ached and he was nursing a headache with painkillers. But, really, he said he was thinking about his prayer. About what he asks God for every day before he drives to work and again before he drives home each evening.
"He listened to me," Cortez said.
[email protected]
[email protected]
[email protected]
Times staff writers Matt Stevens and Marisa Gerber contributed to this report. ||||| Two days later, many questions remain about a fiery crash along Interstate 275 caused by a driver barreling down the wrong side of the highway.
The Florida High Way Patrol has not identified the driver, or where he got onto the interstate.
Another question: was the driver intentionally on the other side of the road?
The collision killed four USF students: Jobin Kuriakose, Ankeet Patel, Imtiyaz "Jim" Ilias, and Dammie Yesudhas.
The driver of a white Ford Explorer hit the car they were in head-on.
Answers to many questions about the driver of the SUV are not yet clear.
In the meantime, family and friends are dealing with the loss, and many are stepping up to help.
The shock of the crash will never leave Mohsin Hussain, the national president of the Sigma Beta Rho fraternity.
"Four young men, they were doing nothing wrong, just trying to get home," Hussain said.
He doesn't want families of the 20-somethings burdened with funeral costs.
"When it comes to losing a loved one, the last thing you want to think about is money and how you're going to arrange a funeral," Hussain said.
We spoke to him via Skype from New Jersey about the fundraising page he started on GoFundMe. He'd hoped for $40,000 for the four families.
The eyewitness video spread online and so far, 1,800 people have donated more than $65,000.
"It's been shocking to say the least, that the community was able to come together like it was," Hussain said.
FHP's investigation has been slowed by heavy damage to both vehicles. They want to know where the SUV entered the highway, where the driver was beforehand and whether drugs were involved.
Hussain was friends with 21-year-old victim Dammie Yesudhas. He last saw him three weeks ago.
"He liked to spread joy," said Hussain. "Everytime I saw him, it was always a hug and he would tell me how great it was to see me again."
Their fraternity celebrated multiculturalism. They're learning that they're not alone in their time of grief.
"It opened up people's eyes to how short life can be," he said.
At USF, hearts are heavy.
"It is not why, it is not how, it is how we remember them and that's what we've been focusing on. The other things are insignificant," said Raj Patel, the president of Sigma Beta Rho, the USF fraternity to which four of the crash victims belonged.
"I don't know them, I don't know their friends, but I feel for them," said freshman Haley Eckert.
Jimmy Kora knew Jobin Kuriakose from church and school.
"He was a great guy to talk to. My heart goes out to his brother and his family," he said.
The tragedy is felt across the state in Melbourne were two of the victims are from.
"My sister, she cry all day all day she never talks eat anything or nothing," said the uncle of Ankeet Patel.
Back here in Tampa Bay, there is a vigil planned for the four young men on Thursday at USF to remember four young men whose lives were cut short.
"Life really isn't promised," Kora said. "You don't understand that until something hits you close to home." ||||| The 21-year-old driver of a Chevrolet Camaro who is suspected of DUI and causing a three-car pileup in Diamond Bar on Sunday morning that killed six people has a previous conviction for driving under the influence, according to the Department of Motor Vehicles.
Olivia Carolee Culbreath was just 17 years old when she was convicted in a San Bernardino juvenile court on April 13, 2010, of driving drunk, DMV officials said. She was cited for traffic violations at least two more times before her license was reinstated in December 2011, state records show.
The restrictions on Culbreath's license were lifted last week, the DMV said.
PHOTOS: Wrong-way crash on 60 Freeway
Authorities say Culbreath was drunk when she drove her 2013 Camaro the wrong way on the westbound 60 Freeway and hit two other vehicles, killing two people in her car and four people in a Ford Explorer. Lt. Fred Corral of the Los Angeles County Coroner's office said investigators "believe from what they found in the vehicle that alcohol was involved."
Witnesses told California Highway Patrol officials that Culbreath may have been driving as fast as 100 mph.
After dark on Sunday at the Culbreath home in Fontana, Olivia's brother Kehtai Culbreath said the family knew little about her condition and did not want to talk about the incident.
"There's not much to say," Kehtai Culbreath said. "We're all still grieving."
Culbreath is listed in stable condition and will be arrested on suspicion of DUI causing great bodily injury and manslaughter when she’s released, the California Highway Patrol said. She suffered a broken leg and ruptured bladder in the crash. Maya Culbreath, 24, believed to be the driver's sister, and Kristin Melissa Young, 21, were in the car with her and died.
[Updated 1:30 p.m. PST, Feb. 10: Maya Culbreath also had been convicted of DUI multiple times, according to state records.
DMV records showed her driver’s license was suspended multiple times in connection with excessive blood-alcohol levels. Her license was revoked effective May 6, 2013, and it had not been reinstated at the time of the crash, DMV officials said.]
Gregorio Mejia-Martinez, 47; Leticia Ibarra, 42; Jessica Jasmine Mejia, 20; and Esther Delgado (whose age was not immediately available) were in the Explorer and were killed. All were members of the same family, authorities said.
The driver of the third car, Joel Cortez, 57, of Ontario, suffered minor injuries and is home recovering.
His daughter said her father described a movie-like scene on the 60 Freeway: twisted metal, blood and mangled bodies.
“He remembers seeing part of an engine that hit him, pushed him against a wall, completely crushing both sides of our car,” said Cortez’ daughter, 24-year-old Emma Cortez. “In shock, first thing he does is look around. There’s a freeway, two cars completely destroyed. And there’s bodies on the floor without heads…this is something you would see out of a movie.”
ALSO:
California couple's gold-coin find called greatest in U.S. history
Fight over school's American flag t-shirt ban likely to continue
Former NFL player Darren Sharper surrenders to police in New Orleans rape case
Twitter: @josephserna
[email protected] | – The driver in a wrong-way crash that killed six people early Sunday had restrictions on her driver's license from a previous drunk driving conviction and other traffic violations—restrictions that were lifted just last week, the Los Angeles Times reports. Olivia Carolee Culbreath, 21, is suspected of being drunk when she drove her Camaro 100mph the wrong way on a California freeway; she was previously convicted of drunk driving when she was 17. Sunday's crash killed Culbreath's sister Maya, 24, and friend Kristin Melissa Young, 21, as well as four members of a family traveling in the Explorer Culbreath hit: Gregorio Mejia-Martinez, 47; Leticia Ibarra, 42; Jessica Jasmine Mejia, 20; and Ester Delgado, 80. Maya Culbreath also had multiple DUI convictions; her license was revoked at the time of the crash, the Times notes. Olivia Culbreath survived and has been arrested on suspicion of DUI causing great bodily injury and manslaughter. Joel Cortez, 57, who was driving a third vehicle that the Explorer collided with, also survived with minor injuries. He tells the Times that after the crash, as he looked out his window, he heard someone scream, "There are bodies all over." In Florida, where another wrong-way crash killed five people Sunday morning, police are still searching for answers, Fox 13 reports. The wrong-way driver, who was among those killed, has not been identified publicly. Police are still investigating whether drugs were involved, where the driver got on the interstate, and whether he was intentionally on the wrong side of the road. | <s>[INST]The Fontana woman accused in a multi-vehicle collision on the 60 Freeway in Diamond Bar that left six people dead had a prior DUI conviction, according to reports.
The 21-year-old woman who authorities say was under the influence of alcohol when she drove the wrong way on the 60 Freeway, killing six people, had previously been convicted of drunk driving.
Olivia Carolee Culbreath was 17 when she was convicted of drunk driving in San Bernardino County, Department of Motor Vehicle officials said. State records also show that she was cited for traffic violations at least two other times. The DMV said the restrictions on her license were lifted last week.
The revelations come as authorities tried to piece together how the accident occurred.
About 4:40 a.m. Sunday, witnesses reported seeing Culbreath's red Chevrolet Camaro traveling east on the westbound 60 at about 100 mph until it struck a red Ford Explorer, which then collided with a third vehicle. Several people were ejected from the vehicles; Culbreath and Joel Cortez, the driver of the third vehicle, survived.
Culbreath is hospitalized and has been arrested on suspicion of DUI causing great bodily injury and manslaughter, authorities said.
Cortez, 57, said Monday that the crash occurred during what was a typical Sunday morning for him. He woke up before dawn, got ready to head to his job as a technician in the City of Industry and asked God to protect four things: himself, his children, his job and the road.
He left his home in Ontario, tuned into one of his favorite Spanish-language radio stations and headed west on the 60 for a 20-minute drive. He settled into a lane and trailed a Ford Explorer for about 10 minutes. Suddenly, he saw the red vehicle flying through the air. He tried to swerve.
Something slammed into the passenger side of his car, and his air bag deployed. His vehicle struck the center divider. He looked out and saw something in the road. In the morning darkness it looked like a big bag.
Then he heard a scream: "There are bodies all over."
There was twisted metal, wheels, blood. He stayed in the car and called his children. Paramedics soon arrived and flashed a light in his face. After seeing that he was alive and seemed to be OK, a paramedic asked him to wait a bit. Others were worse off, Cortez was told.
The four family members in the Explorer, who all died, have been identified as Gregorio Mejia-Martinez, 47; Leticia Ibarra, 42; Jessica Jasmine Mejia, 20; and Ester Delgado, 80.
Their family members gathered at a single-story home in Huntington Park on Monday afternoon. Some huddled near a porch and others stared at the ground, wiping away tears. A man who declined to give his name said he and other family members did not want to speak to the media.
Culbreath's sister, Maya, 24, and a friend, Kristin Melissa Young, 21, were killed.
A woman who answered the door at the Culbreath family home in Fontana choked up and said, "I'm just the grandmother, but I've more or less lost two babies."
"I can't answer anymore. I'm sorry," she said, her eyes downcast as she closed the door.
For Cynthia Schroeder, who met Young at International Polytechnic High in Pomona, the loss of the friend who complimented her necklace on the first day of school and introduced her to the music of the Smiths — felt surreal.
"It's right out of a movie," she said. "I prefer to only speak about positive things — that's the way Kristin would want it."
As Cortez reflected on the crash from his living room Monday afternoon, his neck, chest and knees ached and he was nursing a headache with painkillers. But, really, he said he was thinking about his prayer. About what he asks God for every day before he drives to work and again before he drives home each evening.
"He listened to me," Cortez said.
[email protected]
[email protected]
[email protected]
Times staff writers Matt Stevens and Marisa Gerber contributed to this report. ||||| Two days later, many questions remain about a fiery crash along Interstate 275 caused by a driver barreling down the wrong side of the highway.
The Florida High Way Patrol has not identified the driver, or where he got onto the interstate.
Another question: was the driver intentionally on the other side of the road?
The collision killed four USF students: Jobin Kuriakose, Ankeet Patel, Imtiyaz "Jim" Ilias, and Dammie Yesudhas.
The driver of a white Ford Explorer hit the car they were in head-on.
Answers to many questions about the driver of the SUV are not yet clear.
In the meantime, family and friends are dealing with the loss, and many are stepping up to help.
The shock of the crash will never leave Mohsin Hussain, the national president of the Sigma Beta Rho fraternity.
"Four young men, they were doing nothing wrong, just trying to get home," Hussain said.
He doesn't want families of the 20-somethings burdened with funeral costs.
"When it comes to losing a loved one, the last thing you want to think about is money and how you're going to arrange a funeral," Hussain said.
We spoke to him via Skype from New Jersey about the fundraising page he started on GoFundMe. He'd hoped for $40,000 for the four families.
The eyewitness video spread online and so far, 1,800 people have donated more than $65,000.
"It's been shocking to say the least, that the community was able to come together like it was," Hussain said.
FHP's investigation has been slowed by heavy damage to both vehicles. They want to know where the SUV entered the highway, where the driver was beforehand and whether drugs were involved.
Hussain was friends with 21-year-old victim Dammie Yesudhas. He last saw him three weeks ago.
"He liked to spread joy," said Hussain. "Everytime I saw him, it was always a hug and he would tell me how great it was to see me again."
Their fraternity celebrated multiculturalism. They're learning that they're not alone in their time of grief.
"It opened up people's eyes to how short life can be," he said.
At USF, hearts are heavy.
"It is not why, it is not how, it is how we remember them and that's what we've been focusing on. The other things are insignificant," said Raj Patel, the president of Sigma Beta Rho, the USF fraternity to which four of the crash victims belonged.
"I don't know them, I don't know their friends, but I feel for them," said freshman Haley Eckert.
Jimmy Kora knew Jobin Kuriakose from church and school.
"He was a great guy to talk to. My heart goes out to his brother and his family," he said.
The tragedy is felt across the state in Melbourne were two of the victims are from.
"My sister, she cry all day all day she never talks eat anything or nothing," said the uncle of Ankeet Patel.
Back here in Tampa Bay, there is a vigil planned for the four young men on Thursday at USF to remember four young men whose lives were cut short.
"Life really isn't promised," Kora said. "You don't understand that until something hits you close to home." ||||| The 21-year-old driver of a Chevrolet Camaro who is suspected of DUI and causing a three-car pileup in Diamond Bar on Sunday morning that killed six people has a previous conviction for driving under the influence, according to the Department of Motor Vehicles.
Olivia Carolee Culbreath was just 17 years old when she was convicted in a San Bernardino juvenile court on April 13, 2010, of driving drunk, DMV officials said. She was cited for traffic violations at least two more times before her license was reinstated in December 2011, state records show.
The restrictions on Culbreath's license were lifted last week, the DMV said.
PHOTOS: Wrong-way crash on 60 Freeway
Authorities say Culbreath was drunk when she drove her 2013 Camaro the wrong way on the westbound 60 Freeway and hit two other vehicles, killing two people in her car and four people in a Ford Explorer. Lt. Fred Corral of the Los Angeles County Coroner's office said investigators "believe from what they found in the vehicle that alcohol was involved."
Witnesses told California Highway Patrol officials that Culbreath may have been driving as fast as 100 mph.
After dark on Sunday at the Culbreath home in Fontana, Olivia's brother Kehtai Culbreath said the family knew little about her condition and did not want to talk about the incident.
"There's not much to say," Kehtai Culbreath said. "We're all still grieving."
Culbreath is listed in stable condition and will be arrested on suspicion of DUI causing great bodily injury and manslaughter when she’s released, the California Highway Patrol said. She suffered a broken leg and ruptured bladder in the crash. Maya Culbreath, 24, believed to be the driver's sister, and Kristin Melissa Young, 21, were in the car with her and died.
[Updated 1:30 p.m. PST, Feb. 10: Maya Culbreath also had been convicted of DUI multiple times, according to state records.
DMV records showed her driver’s license was suspended multiple times in connection with excessive blood-alcohol levels. Her license was revoked effective May 6, 2013, and it had not been reinstated at the time of the crash, DMV officials said.]
Gregorio Mejia-Martinez, 47; Leticia Ibarra, 42; Jessica Jasmine Mejia, 20; and Esther Delgado (whose age was not immediately available) were in the Explorer and were killed. All were members of the same family, authorities said.
The driver of the third car, Joel Cortez, 57, of Ontario, suffered minor injuries and is home recovering.
His daughter said her father described a movie-like scene on the 60 Freeway: twisted metal, blood and mangled bodies.
“He remembers seeing part of an engine that hit him, pushed him against a wall, completely crushing both sides of our car,” said Cortez’ daughter, 24-year-old Emma Cortez. “In shock, first thing he does is look around. There’s a freeway, two cars completely destroyed. And there’s bodies on the floor without heads…this is something you would see out of a movie.”
ALSO:
California couple's gold-coin find called greatest in U.S. history
Fight over school's American flag t-shirt ban likely to continue
Former NFL player Darren Sharper surrenders to police in New Orleans rape case
Twitter: @josephserna
[email protected][/INST]– The driver in a wrong-way crash that killed six people early Sunday had restrictions on her driver's license from a previous drunk driving conviction and other traffic violations—restrictions that were lifted just last week, the Los Angeles Times reports. Olivia Carolee Culbreath, 21, is suspected of being drunk when she drove her Camaro 100mph the wrong way on a California freeway; she was previously convicted of drunk driving when she was 17. Sunday's crash killed Culbreath's sister Maya, 24, and friend Kristin Melissa Young, 21, as well as four members of a family traveling in the Explorer Culbreath hit: Gregorio Mejia-Martinez, 47; Leticia Ibarra, 42; Jessica Jasmine Mejia, 20; and Ester Delgado, 80. Maya Culbreath also had multiple DUI convictions; her license was revoked at the time of the crash, the Times notes. Olivia Culbreath survived and has been arrested on suspicion of DUI causing great bodily injury and manslaughter. Joel Cortez, 57, who was driving a third vehicle that the Explorer collided with, also survived with minor injuries. He tells the Times that after the crash, as he looked out his window, he heard someone scream, "There are bodies all over." In Florida, where another wrong-way crash killed five people Sunday morning, police are still searching for answers, Fox 13 reports. The wrong-way driver, who was among those killed, has not been identified publicly. Police are still investigating whether drugs were involved, where the driver got on the interstate, and whether he was intentionally on the wrong side of the road.</s> |
(Imgur)
For the third year in a row, the world’s richest tech-billionaire-turned-nerd-philanthropist hosted an "Ask Me Anything" session on Reddit.
As in the past, Gates’s AMA session was very popular, generating more than 5,000 questions and comments and overloading Reddit’s servers at least twice.
The founder of Microsoft and current co-chair of the nonprofit Bill and Melinda Gates Foundation answered approximately 30 questions on a wide range of topics, including climate change, the future of technology, virtual currency, his pets, and what it’s like to drink water made from human waste (no different than regular water, he says — we’ll just take his word for that).
Here are some of the highlights.
1. One of the first questions Gates tackled is whether technology is making us all dumber. (The unsurprising answer? No.):
Technology is not making people less intelligent. If you just look at the complexity people like in Entertainment you can see a big change over my lifetime. Technology is letting people get their questions answered better so they stay more curious.
It turns out that Gates is a Breaking Bad fan. Well, duh.
2. You know what does make Bill Gates feel stupid? Not being able to speak a foreign language.
I took Latin and Greek in High School and got A’s and I guess it helps my vocabulary but I wish I knew French or Arabic or Chinese. I keep hoping to get time to study one of these — probably French because it is the easiest. I did Duolingo for awhile but didn’t keep it up. Mark Zuckerberg amazingly learned Mandarin and did a Q&A with Chinese students — incredible.
We’re pretty sure that just made Zuck’s day.
3. Here’s what Mr. Bill thinks technology will look like 30 years from now:
There will be more progress in the next 30 years than ever. Even in the next 10, problems like vision and speech understanding and translation will be very good. Mechanical robot tasks like picking fruit or moving a hospital patient will be solved. Once computers/robots get to a level of capability where seeing and moving is easy for them then they will be used very extensively.
One project I am working on with Microsoft is the Personal Agent which will remember everything and help you go back and find things and help you pick what things to pay attention to. The idea that you have to find applications and pick them and they each are trying to tell you what is new is just not the efficient model — the agent will help solve this. It will work across all your devices.
4. Gates also weighed in on the new holographic glasses his former company unveiled last week:
The HoloLens is pretty amazing. Microsoft has put a lot into the chips and the software. It is the start of virtual reality. Making the device so you don’t get dizzy or nauseous is really hard — the speed of the alignment has to be super super fast. It will take a few years of software applications being built to realize the full promise of this.
hololens More
(Microsoft)
He did not offer an opinion as to whether this device finally makes Microsoft ‘cool’, however.
5. The single greatest thing that has improved life in poor countries? Vaccines, says Gates.
Being able to grow up healthy is the most basic thing. So many kids get infectious diseases and don’t develop mentally and physically. I was in Berlin yesterday helping raise $7.5B for vaccines for kids in poor countries. We barely made it but we did which is so exciting to me!
Read More ||||| Hi Reddit, I’m Bill Gates and I’m back for my third AMA. Ask me anything.
I’m back for my third AMA. I’m happy to talk about anything. Philanthropy, technology, what it’s like to drink water made from human waste... (Short answer: Just like drinking any other kind of water, except that people get a little freaked out by the whole idea.)
I hope you’ll take a few minutes to look at the annual letter that Melinda and I just published (gatesletter.com). This year we make the case that in the next 15 years, life will improve faster for people in poor countries than it ever has before.
Proof: http://i.imgur.com/lBMmhsA.gif
https://twitter.com/BillGates/status/560503503274008576
UPDATE: I have to go. But thanks for all the questions. This really is a fantastic community: Thanks! http://i.imgur.com/aHGlmuI.gifv
I’d like to sign off with one last plug for the Annual Letter, www.gatesletter.com, and my blog, www.thegatesnotes.com.
FINAL UPDATE: Thanks for joining in, Reddit. I knew all that time I spent writing signs would pay off: http://youtu.be/9p4bm-RAlLA | – It's safe to say Bill Gates is no dummy. But one thing does make the Microsoft co-founder feel like one: "I feel pretty stupid that I don't know any foreign languages," he revealed in his third Reddit "Ask Me Anything." (It was again a popular one, notes Yahoo! Tech, which reports Gates answered about 30 of the 5,000 questions submitted.) "I took Latin and Greek in High School and got A's and I guess it helps my vocabulary but I wish I knew French or Arabic or Chinese. I keep hoping to get time to study one of these—probably French because it is the easiest." He also mentioned a fellow techie who outranks him in this particular arena: "Mark Zuckerberg amazingly learned Mandarin and did a Q&A with Chinese students—incredible." Gates also revealed that he believes when it comes to technology, "there will be more progress in the next 30 years than ever. Even in the next 10 problems like vision and speech understanding and translation will be very good. Mechanical robot tasks like picking fruit or moving a hospital patient will be solved." But he'd prefer any robots we develop not be all that smart. "I am in the camp that is concerned about super intelligence. First the machines will do a lot of jobs for us and not be super intelligent. That should be positive if we manage it well. A few decades after that though the intelligence is strong enough to be a concern." In less alarming quotes, when asked for a life lesson, he offered: "Don't stay up too late even if the book is really exciting. You will regret it in the morning." (Stephen Hawking is with him on the smart robot problem.) | <s>[INST](Imgur)
For the third year in a row, the world’s richest tech-billionaire-turned-nerd-philanthropist hosted an "Ask Me Anything" session on Reddit.
As in the past, Gates’s AMA session was very popular, generating more than 5,000 questions and comments and overloading Reddit’s servers at least twice.
The founder of Microsoft and current co-chair of the nonprofit Bill and Melinda Gates Foundation answered approximately 30 questions on a wide range of topics, including climate change, the future of technology, virtual currency, his pets, and what it’s like to drink water made from human waste (no different than regular water, he says — we’ll just take his word for that).
Here are some of the highlights.
1. One of the first questions Gates tackled is whether technology is making us all dumber. (The unsurprising answer? No.):
Technology is not making people less intelligent. If you just look at the complexity people like in Entertainment you can see a big change over my lifetime. Technology is letting people get their questions answered better so they stay more curious.
It turns out that Gates is a Breaking Bad fan. Well, duh.
2. You know what does make Bill Gates feel stupid? Not being able to speak a foreign language.
I took Latin and Greek in High School and got A’s and I guess it helps my vocabulary but I wish I knew French or Arabic or Chinese. I keep hoping to get time to study one of these — probably French because it is the easiest. I did Duolingo for awhile but didn’t keep it up. Mark Zuckerberg amazingly learned Mandarin and did a Q&A with Chinese students — incredible.
We’re pretty sure that just made Zuck’s day.
3. Here’s what Mr. Bill thinks technology will look like 30 years from now:
There will be more progress in the next 30 years than ever. Even in the next 10, problems like vision and speech understanding and translation will be very good. Mechanical robot tasks like picking fruit or moving a hospital patient will be solved. Once computers/robots get to a level of capability where seeing and moving is easy for them then they will be used very extensively.
One project I am working on with Microsoft is the Personal Agent which will remember everything and help you go back and find things and help you pick what things to pay attention to. The idea that you have to find applications and pick them and they each are trying to tell you what is new is just not the efficient model — the agent will help solve this. It will work across all your devices.
4. Gates also weighed in on the new holographic glasses his former company unveiled last week:
The HoloLens is pretty amazing. Microsoft has put a lot into the chips and the software. It is the start of virtual reality. Making the device so you don’t get dizzy or nauseous is really hard — the speed of the alignment has to be super super fast. It will take a few years of software applications being built to realize the full promise of this.
hololens More
(Microsoft)
He did not offer an opinion as to whether this device finally makes Microsoft ‘cool’, however.
5. The single greatest thing that has improved life in poor countries? Vaccines, says Gates.
Being able to grow up healthy is the most basic thing. So many kids get infectious diseases and don’t develop mentally and physically. I was in Berlin yesterday helping raise $7.5B for vaccines for kids in poor countries. We barely made it but we did which is so exciting to me!
Read More ||||| Hi Reddit, I’m Bill Gates and I’m back for my third AMA. Ask me anything.
I’m back for my third AMA. I’m happy to talk about anything. Philanthropy, technology, what it’s like to drink water made from human waste... (Short answer: Just like drinking any other kind of water, except that people get a little freaked out by the whole idea.)
I hope you’ll take a few minutes to look at the annual letter that Melinda and I just published (gatesletter.com). This year we make the case that in the next 15 years, life will improve faster for people in poor countries than it ever has before.
Proof: http://i.imgur.com/lBMmhsA.gif
https://twitter.com/BillGates/status/560503503274008576
UPDATE: I have to go. But thanks for all the questions. This really is a fantastic community: Thanks! http://i.imgur.com/aHGlmuI.gifv
I’d like to sign off with one last plug for the Annual Letter, www.gatesletter.com, and my blog, www.thegatesnotes.com.
FINAL UPDATE: Thanks for joining in, Reddit. I knew all that time I spent writing signs would pay off: http://youtu.be/9p4bm-RAlLA[/INST]– It's safe to say Bill Gates is no dummy. But one thing does make the Microsoft co-founder feel like one: "I feel pretty stupid that I don't know any foreign languages," he revealed in his third Reddit "Ask Me Anything." (It was again a popular one, notes Yahoo! Tech, which reports Gates answered about 30 of the 5,000 questions submitted.) "I took Latin and Greek in High School and got A's and I guess it helps my vocabulary but I wish I knew French or Arabic or Chinese. I keep hoping to get time to study one of these—probably French because it is the easiest." He also mentioned a fellow techie who outranks him in this particular arena: "Mark Zuckerberg amazingly learned Mandarin and did a Q&A with Chinese students—incredible." Gates also revealed that he believes when it comes to technology, "there will be more progress in the next 30 years than ever. Even in the next 10 problems like vision and speech understanding and translation will be very good. Mechanical robot tasks like picking fruit or moving a hospital patient will be solved." But he'd prefer any robots we develop not be all that smart. "I am in the camp that is concerned about super intelligence. First the machines will do a lot of jobs for us and not be super intelligent. That should be positive if we manage it well. A few decades after that though the intelligence is strong enough to be a concern." In less alarming quotes, when asked for a life lesson, he offered: "Don't stay up too late even if the book is really exciting. You will regret it in the morning." (Stephen Hawking is with him on the smart robot problem.)</s> |
SECTION 1. SHORT TITLE.
This Act may be cited as the ``Essential Air Service Modernization
Act of 2003''.
SEC. 2. AUTHORIZATION.
Section 41742(a)(2) is amended by striking ``$15,000,000'' and
inserting ``$75,000,000''.
SEC. 3. TERMINATION NOTICE.
Section 41733 of title 49, United States Code, is amended by adding
at the end the following--
``(f) Termination Notice.--If the Secretary decides to terminate
basic essential service to an eligible place, the Secretary shall
notify the affected community not less than 90 days before such service
is to be terminated.''.
SEC. 4. JOINT PROPOSALS.
(a) In General.--Section 41740 of title 49, United States Code, is
amended by adding at the end the following: ``The Secretary shall
facilitate and assist in establishing negotiations between major and
national air carriers and air carriers that provide essential air
service to an eligible place in order to determine equitable joint
fares.''.
(b) Report.--Not later than 12 months after enactment of this Act,
the Secretary shall transmit a report to Congress regarding the
progress and effectiveness of implementation of the amendment made by
subsection (a).
SEC. 5. COMMUNITY AND REGIONAL CHOICE PROGRAM.
(a) In General.--Subchapter II of chapter 417 of title 49, United
States Code, is amended by adding at the end the following:
``Sec. 41745. Community and regional choice program
``(a) Establishment.--The Secretary of Transportation shall
establish an alternate essential air service program in accordance with
the requirements of this section.
``(b) Compensation to Eligible Places.--In carrying out the
program, the Secretary, instead of paying compensation to an air
carrier to provide essential air service to an eligible place, may pay
compensation directly to a unit of local government having jurisdiction
over the eligible place or a State within the boundaries of which the
eligible place is located.
``(c) Use of Compensation.--A unit of local government or State
receiving compensation for an eligible place under the program shall
use the compensation for any of the following purposes:
``(1) To provide assistance to an air carrier to provide
scheduled air service to and from the eligible place, without
being subject to the requirements of 41732(b).
``(2) To provide assistance to a person to provide
scheduled or on-demand air taxi service to and from the
eligible place and a non-hub or a small, medium, or large hub.
``(3) To provide assistance to a person to provide
scheduled or on-demand surface transportation to and from the
eligible place and a non-hub or a small, medium, or large hub.
``(4) In combination with other units of local government
in the same region, to provide transportation services to and
from all the eligible places in that region at an airport or
other transportation center that can serve all the eligible
places in that region.
``(d) Applications.--
``(1) In general.--A unit of local government or State
seeking to participate in the program for an eligible place
shall submit to the Secretary an application in such form and
containing such information as the Secretary may require.
``(2) Required information.--At a minimum, the application
shall include--
``(A) a statement of the amount of compensation
required; and
``(B) a description of how the compensation will be
used.
``(e) Participation Requirements.--An eligible place for which
compensation is received under the program in a fiscal year shall not
be eligible to receive in that fiscal year the essential air service
that it would otherwise be entitled to under this subchapter.
``(f) Subsequent Participation.--A unit of local government
participating in the program under this section in a fiscal year shall
not be prohibited from participating in the basic essential air service
program under this chapter in a subsequent fiscal year if such unit is
otherwise eligible to participate in such basic program.
``(g) Funding.--Amounts appropriated or otherwise made available to
carry out the essential air service program under this subchapter shall
be available to carry out this section.
``Sec. 41746. Compensation for units of local government
``Of the amounts made available under section 41742(a) the
Secretary shall pay directly to a unit of local government having
jurisdiction over the eligible place not less than $5,000 for such
fiscal year to promote public use of the air service or transportation
for which compensation is being paid.''.
(b) Conforming Amendment.--The analysis for such chapter is amended
by inserting after the item relating to section 41744 the following:
``41745. Community and regional choice program.
``41746. Compensation for units of local government.''. | Essential Air Service Modernization Act of 2003 - Increases the authorization of appropriations to carry out the essential air service program.
Requires the Secretary to: (1) notify an affected community at least 90 days before the basic essential service to that community is terminated: (2) facilitate and assist in negotiations between major and national air carriers and carriers that provide essential air service in order to determine equitable joint fares; (3) establish an alternate essential air service program which would provide compensation directly to local governments, instead of to air carriers, to use to obtain air service, to obtain surface transportation to and from air hubs, or to participate with other local governments in providing regional transportation services to airports; and (4) pay $5,000 to local governments to promote public use of air service or transportation for which compensation is received under the program. | <s>[INST]SECTION 1. SHORT TITLE.
This Act may be cited as the ``Essential Air Service Modernization
Act of 2003''.
SEC. 2. AUTHORIZATION.
Section 41742(a)(2) is amended by striking ``$15,000,000'' and
inserting ``$75,000,000''.
SEC. 3. TERMINATION NOTICE.
Section 41733 of title 49, United States Code, is amended by adding
at the end the following--
``(f) Termination Notice.--If the Secretary decides to terminate
basic essential service to an eligible place, the Secretary shall
notify the affected community not less than 90 days before such service
is to be terminated.''.
SEC. 4. JOINT PROPOSALS.
(a) In General.--Section 41740 of title 49, United States Code, is
amended by adding at the end the following: ``The Secretary shall
facilitate and assist in establishing negotiations between major and
national air carriers and air carriers that provide essential air
service to an eligible place in order to determine equitable joint
fares.''.
(b) Report.--Not later than 12 months after enactment of this Act,
the Secretary shall transmit a report to Congress regarding the
progress and effectiveness of implementation of the amendment made by
subsection (a).
SEC. 5. COMMUNITY AND REGIONAL CHOICE PROGRAM.
(a) In General.--Subchapter II of chapter 417 of title 49, United
States Code, is amended by adding at the end the following:
``Sec. 41745. Community and regional choice program
``(a) Establishment.--The Secretary of Transportation shall
establish an alternate essential air service program in accordance with
the requirements of this section.
``(b) Compensation to Eligible Places.--In carrying out the
program, the Secretary, instead of paying compensation to an air
carrier to provide essential air service to an eligible place, may pay
compensation directly to a unit of local government having jurisdiction
over the eligible place or a State within the boundaries of which the
eligible place is located.
``(c) Use of Compensation.--A unit of local government or State
receiving compensation for an eligible place under the program shall
use the compensation for any of the following purposes:
``(1) To provide assistance to an air carrier to provide
scheduled air service to and from the eligible place, without
being subject to the requirements of 41732(b).
``(2) To provide assistance to a person to provide
scheduled or on-demand air taxi service to and from the
eligible place and a non-hub or a small, medium, or large hub.
``(3) To provide assistance to a person to provide
scheduled or on-demand surface transportation to and from the
eligible place and a non-hub or a small, medium, or large hub.
``(4) In combination with other units of local government
in the same region, to provide transportation services to and
from all the eligible places in that region at an airport or
other transportation center that can serve all the eligible
places in that region.
``(d) Applications.--
``(1) In general.--A unit of local government or State
seeking to participate in the program for an eligible place
shall submit to the Secretary an application in such form and
containing such information as the Secretary may require.
``(2) Required information.--At a minimum, the application
shall include--
``(A) a statement of the amount of compensation
required; and
``(B) a description of how the compensation will be
used.
``(e) Participation Requirements.--An eligible place for which
compensation is received under the program in a fiscal year shall not
be eligible to receive in that fiscal year the essential air service
that it would otherwise be entitled to under this subchapter.
``(f) Subsequent Participation.--A unit of local government
participating in the program under this section in a fiscal year shall
not be prohibited from participating in the basic essential air service
program under this chapter in a subsequent fiscal year if such unit is
otherwise eligible to participate in such basic program.
``(g) Funding.--Amounts appropriated or otherwise made available to
carry out the essential air service program under this subchapter shall
be available to carry out this section.
``Sec. 41746. Compensation for units of local government
``Of the amounts made available under section 41742(a) the
Secretary shall pay directly to a unit of local government having
jurisdiction over the eligible place not less than $5,000 for such
fiscal year to promote public use of the air service or transportation
for which compensation is being paid.''.
(b) Conforming Amendment.--The analysis for such chapter is amended
by inserting after the item relating to section 41744 the following:
``41745. Community and regional choice program.
``41746. Compensation for units of local government.''.[/INST]Essential Air Service Modernization Act of 2003 - Increases the authorization of appropriations to carry out the essential air service program.
Requires the Secretary to: (1) notify an affected community at least 90 days before the basic essential service to that community is terminated: (2) facilitate and assist in negotiations between major and national air carriers and carriers that provide essential air service in order to determine equitable joint fares; (3) establish an alternate essential air service program which would provide compensation directly to local governments, instead of to air carriers, to use to obtain air service, to obtain surface transportation to and from air hubs, or to participate with other local governments in providing regional transportation services to airports; and (4) pay $5,000 to local governments to promote public use of air service or transportation for which compensation is received under the program.</s> |
Yoan Valat / Pool via Reuters President Nicolas Sarkozy visits a cheese factory in Vallieres in the French Alps on Feb. 16.
It’s a matter of (spurious) debate if France’s president is a “surrender monkey,” but one thing seems clear: He is no longer cheese-eating.
Nicolas Sarkozy decided to stop savoring "le fromage" after meals, the AFP reported in an article on the kitchens at the presidential Elysee Palace. His chef said Sarkozy was trying to eat healthily, preferring "light, balanced meals and poultry to red meat," AFP added.
The term “cheese-eating surrender monkeys” was first used on "The Simpsons" and was popularized by National Review journalist Jonah Goldberg, who claimed he had made it “an accepted term in official diplomatic channels around the globe.”
Most French people would surely object to the idea of being “surrender monkeys,” but they would likely embrace the term “cheese-eating” wholeheartedly.
National pride
The variety and flavor of cheeses to be found across France is a matter of national and regional pride, a subject that can fire considerable passion.
As the U.K.’s Telegraph newspaper noted, Charles de Gaulle, leader of the Free French forces during the Second World War and later president, once declared, “How can anyone govern a nation that has 246 different kinds of cheese?”
It remains to be seen if a non-cheese-eating leader is acceptable to the French electorate, who will decide whether Sarkozy remains in the Elysee in presidential elections in just three weeks’ time.
It's been a tough reelection fight for French President Nicolas Sarkozy, who has been trailing in the polls, but the recent Toulouse terror attacks and Sarkozy's sharp swing to the right have given him at least a temporary boost. ITV's James Mates reports.
Presidential chef Bernard Vaussion, who has cooked for five French presidents, may have made an inadvertent intervention into the world of politics by declaring that cheese was “too much” for Sarkozy, as reported by the Telegraph’s Paris correspondent Henry Samuel.
Samuel also noted Sarkozy had caused a minor diplomatic incident in October last year when he remarked to another European leader that German Chancellor Angela Merkel “says she is on a diet and then helps herself to a second helping of cheese.”
An anti-cheese French president? Quelle horreur!
More from msnbc.com and NBC News:
Follow us on Twitter: @msnbc_world ||||| Upgrade to the latest Flash Player for improved playback performance. Upgrade now or more info ||||| Charles de Gaulle once famously declared: "How can anyone govern a nation that has two hundred and forty-six different kinds of cheese?"
The fitness mad Mr Sarkozy has chosen to remove the source of De Gaulle's angst from his sight, according to presidential chef Bernard Vaussion, who is cooking for his fifth French head of state.
The French were famously dubbed "cheese-eating surrender monkeys" by irate US Republicans when they failed to support the 2003 invasion of Iraq.
But Mr Sarkozy has done away with the high-fat stuff altogether after meals, his chef explained, as "it was too much" for him.
His cheese aversion even threatened to spark a diplomatic incident last October, when he offended Angela Merkel, the German Chancellor, by telling another EU leader that over dinner "she says she is on a diet and then helps herself to a second helping of cheese".
The health-conscious leader opts instead for "light, balanced meals and poultry to red meat", his chef said, in a clear break with his predecessors who were not afraid of heartier fare, even at lunchtime.
The French had already found it hard to swallow the fact that their leader drinks no wine, a source of great national pride. The latest revelation risks striking another symbolic blow to the leader's credentials as a flag-bearer of French gastronomy.
On the advice of his former supermodel wife, Carla, 13 years his junior, the one-time chocoholic president has been on a draconian fitness and nutrition programme for most of his presidency, served a frugal diet of fish, vegetables, salads and sorbets. Cottage cheese, it is believed, still makes the grade.
Some blamed the low-calorie diet on Mr Sarkozy collapsing in 2009 during one of his gruelling daily jogs
However, with presidential elections just three weeks away, Mr Sarkozy has chosen to throw his normal dietary rules out of the window if it can help him win an uphill battle to secure a second five-year term.
In a sign he is prepared to go the extra political mile, he kicked off his re-election campaign with a visit to a cheese-making factory in the Alpine city of Annecy, also stoically accepting chocolate, crepes and sausages from shopkeepers.
"I'll put on three kilos and it's only the first day," he joked before going on to enjoy a fondue lunch with a group of supporters.
He then spent four hours at Paris's annual agricultural fair accepting offerings of langoustine, chocolate and Reblochon cheese in a bid to stave off the National Front, whose leader Marine Le Pen claimed to be the "champion" of rural France.
If, as the polls predict, the Socialist François Hollande wins power next month, the Elysée chef may be asked to bring back the gooey stuff.
However, Mr Hollande has also been on a strict diet in a bid to shed his unfortunate nickname of Flanby – a wobbly caramel custard dessert.
"There is always uncertainty. We will see, it will be up to him to decide," said Mr Vaussion wistfully. ||||| PARIS (AFP) - Since President Nicolas Sarkozy embarked on his re-election campaign, the kitchens of the Elysee Palace have been quiet.
This leaves the presidential chef, Bernard Vaussion, lots of time to wonder whether he will get to cook for a sixth French head of state.
If, as the polls predict, the Socialist Francois Hollande wins power next month, will he want to bring in a new chef?
"There is always uncertainty. We will see, it will be up to him to decide," said the 58-year-old, who plans to retire in two years anyhow, as he gave AFP a guided tour of the presidential kitchens.
An enormous cast-iron range dominates the giant room lit by tall windows that look on to the Elysee courtyard.
The workforce here is 100 percent male, an unwritten rule instigated by Bernadette Chirac, the wife of Sarkozy's predecessor, Jacques Chirac.
She feared that a feminine presence in the kitchens might "disturb" the team, said Vaussion, adding that he regularly takes on women for work experience but has never hired one.
Sarkozy's term, which began in 2007, has seen "fewer state dinners and more intimate meetings", explained Vaussion, dressed in white work clothes with the French national colours -- blue, white and red -- decorating his chest.
The right-wing president personally approves the menu every morning, as his predecessors Francois Mitterrand and Valery Giscard d'Estaing did before him.
"He writes 'yes' in the margin next to the dishes I propose," said the cook, who happily notes that the incumbent has a healthy appetite.
But Sarkozy is also health conscious, preferring "light, balanced meals and poultry to red meat", in a clear break with his predecessors who were not afraid of rich fare, even at lunchtime.
Sarkozy also did away with cheese after meals, he noted.
The only president who called on the services of a nutritionist was the Socialist Mitterrand but that was only "when he was sick", said Vaussion, who arrived in the Elysee in January 1974 as a commis chef after finishing a seven-year apprenticeship.
"Chirac loved casseroles and he loved lamb in all its forms: leg of lamb, saddle of lamb, shoulder of lamb. Mitterrand adored seared foie gras, but I also used to roast it for him," he recalled with emotion.
Vaussion may have spent nearly four decades in the loyal service of the French head of state, but he says he is still awed by the prestigious guests who turn up at the Elysee palace.
"We get high society here, people who often frequent the best restaurants. We have to watch our every step," he said, noting that if a restaurant gets it wrong, the client won't come back.
"Here it's the opposite. It's us who leave," he joked. | – In an otherwise innocuous interview with AFP, the presidential chef in France let slip that that the health-conscious Nicolas Sarkozy has done away with cheese after meals. Which explains why Britain's Telegraph is trumpeting a "Sarkozy bans cheese from Elysée Palace" headline and trying to stir up an election-year kerfuffle in the cheese-loving nation. "The French had already found it hard to swallow the fact that their leader drinks no wine, a source of great national pride," it writes. Overkill? Maybe so, but the paper also notes that Sarkozy—in a close race with Socialist François Hollande—kicked off his election campaign with a tour of a cheese factory in the French Alps. All of which prompts MSNBC to weigh in with some context on the origins of the phrase "cheese-eating surrender monkeys." (Thank the Simpsons.) | <s>[INST]Yoan Valat / Pool via Reuters President Nicolas Sarkozy visits a cheese factory in Vallieres in the French Alps on Feb. 16.
It’s a matter of (spurious) debate if France’s president is a “surrender monkey,” but one thing seems clear: He is no longer cheese-eating.
Nicolas Sarkozy decided to stop savoring "le fromage" after meals, the AFP reported in an article on the kitchens at the presidential Elysee Palace. His chef said Sarkozy was trying to eat healthily, preferring "light, balanced meals and poultry to red meat," AFP added.
The term “cheese-eating surrender monkeys” was first used on "The Simpsons" and was popularized by National Review journalist Jonah Goldberg, who claimed he had made it “an accepted term in official diplomatic channels around the globe.”
Most French people would surely object to the idea of being “surrender monkeys,” but they would likely embrace the term “cheese-eating” wholeheartedly.
National pride
The variety and flavor of cheeses to be found across France is a matter of national and regional pride, a subject that can fire considerable passion.
As the U.K.’s Telegraph newspaper noted, Charles de Gaulle, leader of the Free French forces during the Second World War and later president, once declared, “How can anyone govern a nation that has 246 different kinds of cheese?”
It remains to be seen if a non-cheese-eating leader is acceptable to the French electorate, who will decide whether Sarkozy remains in the Elysee in presidential elections in just three weeks’ time.
It's been a tough reelection fight for French President Nicolas Sarkozy, who has been trailing in the polls, but the recent Toulouse terror attacks and Sarkozy's sharp swing to the right have given him at least a temporary boost. ITV's James Mates reports.
Presidential chef Bernard Vaussion, who has cooked for five French presidents, may have made an inadvertent intervention into the world of politics by declaring that cheese was “too much” for Sarkozy, as reported by the Telegraph’s Paris correspondent Henry Samuel.
Samuel also noted Sarkozy had caused a minor diplomatic incident in October last year when he remarked to another European leader that German Chancellor Angela Merkel “says she is on a diet and then helps herself to a second helping of cheese.”
An anti-cheese French president? Quelle horreur!
More from msnbc.com and NBC News:
Follow us on Twitter: @msnbc_world ||||| Upgrade to the latest Flash Player for improved playback performance. Upgrade now or more info ||||| Charles de Gaulle once famously declared: "How can anyone govern a nation that has two hundred and forty-six different kinds of cheese?"
The fitness mad Mr Sarkozy has chosen to remove the source of De Gaulle's angst from his sight, according to presidential chef Bernard Vaussion, who is cooking for his fifth French head of state.
The French were famously dubbed "cheese-eating surrender monkeys" by irate US Republicans when they failed to support the 2003 invasion of Iraq.
But Mr Sarkozy has done away with the high-fat stuff altogether after meals, his chef explained, as "it was too much" for him.
His cheese aversion even threatened to spark a diplomatic incident last October, when he offended Angela Merkel, the German Chancellor, by telling another EU leader that over dinner "she says she is on a diet and then helps herself to a second helping of cheese".
The health-conscious leader opts instead for "light, balanced meals and poultry to red meat", his chef said, in a clear break with his predecessors who were not afraid of heartier fare, even at lunchtime.
The French had already found it hard to swallow the fact that their leader drinks no wine, a source of great national pride. The latest revelation risks striking another symbolic blow to the leader's credentials as a flag-bearer of French gastronomy.
On the advice of his former supermodel wife, Carla, 13 years his junior, the one-time chocoholic president has been on a draconian fitness and nutrition programme for most of his presidency, served a frugal diet of fish, vegetables, salads and sorbets. Cottage cheese, it is believed, still makes the grade.
Some blamed the low-calorie diet on Mr Sarkozy collapsing in 2009 during one of his gruelling daily jogs
However, with presidential elections just three weeks away, Mr Sarkozy has chosen to throw his normal dietary rules out of the window if it can help him win an uphill battle to secure a second five-year term.
In a sign he is prepared to go the extra political mile, he kicked off his re-election campaign with a visit to a cheese-making factory in the Alpine city of Annecy, also stoically accepting chocolate, crepes and sausages from shopkeepers.
"I'll put on three kilos and it's only the first day," he joked before going on to enjoy a fondue lunch with a group of supporters.
He then spent four hours at Paris's annual agricultural fair accepting offerings of langoustine, chocolate and Reblochon cheese in a bid to stave off the National Front, whose leader Marine Le Pen claimed to be the "champion" of rural France.
If, as the polls predict, the Socialist François Hollande wins power next month, the Elysée chef may be asked to bring back the gooey stuff.
However, Mr Hollande has also been on a strict diet in a bid to shed his unfortunate nickname of Flanby – a wobbly caramel custard dessert.
"There is always uncertainty. We will see, it will be up to him to decide," said Mr Vaussion wistfully. ||||| PARIS (AFP) - Since President Nicolas Sarkozy embarked on his re-election campaign, the kitchens of the Elysee Palace have been quiet.
This leaves the presidential chef, Bernard Vaussion, lots of time to wonder whether he will get to cook for a sixth French head of state.
If, as the polls predict, the Socialist Francois Hollande wins power next month, will he want to bring in a new chef?
"There is always uncertainty. We will see, it will be up to him to decide," said the 58-year-old, who plans to retire in two years anyhow, as he gave AFP a guided tour of the presidential kitchens.
An enormous cast-iron range dominates the giant room lit by tall windows that look on to the Elysee courtyard.
The workforce here is 100 percent male, an unwritten rule instigated by Bernadette Chirac, the wife of Sarkozy's predecessor, Jacques Chirac.
She feared that a feminine presence in the kitchens might "disturb" the team, said Vaussion, adding that he regularly takes on women for work experience but has never hired one.
Sarkozy's term, which began in 2007, has seen "fewer state dinners and more intimate meetings", explained Vaussion, dressed in white work clothes with the French national colours -- blue, white and red -- decorating his chest.
The right-wing president personally approves the menu every morning, as his predecessors Francois Mitterrand and Valery Giscard d'Estaing did before him.
"He writes 'yes' in the margin next to the dishes I propose," said the cook, who happily notes that the incumbent has a healthy appetite.
But Sarkozy is also health conscious, preferring "light, balanced meals and poultry to red meat", in a clear break with his predecessors who were not afraid of rich fare, even at lunchtime.
Sarkozy also did away with cheese after meals, he noted.
The only president who called on the services of a nutritionist was the Socialist Mitterrand but that was only "when he was sick", said Vaussion, who arrived in the Elysee in January 1974 as a commis chef after finishing a seven-year apprenticeship.
"Chirac loved casseroles and he loved lamb in all its forms: leg of lamb, saddle of lamb, shoulder of lamb. Mitterrand adored seared foie gras, but I also used to roast it for him," he recalled with emotion.
Vaussion may have spent nearly four decades in the loyal service of the French head of state, but he says he is still awed by the prestigious guests who turn up at the Elysee palace.
"We get high society here, people who often frequent the best restaurants. We have to watch our every step," he said, noting that if a restaurant gets it wrong, the client won't come back.
"Here it's the opposite. It's us who leave," he joked.[/INST]– In an otherwise innocuous interview with AFP, the presidential chef in France let slip that that the health-conscious Nicolas Sarkozy has done away with cheese after meals. Which explains why Britain's Telegraph is trumpeting a "Sarkozy bans cheese from Elysée Palace" headline and trying to stir up an election-year kerfuffle in the cheese-loving nation. "The French had already found it hard to swallow the fact that their leader drinks no wine, a source of great national pride," it writes. Overkill? Maybe so, but the paper also notes that Sarkozy—in a close race with Socialist François Hollande—kicked off his election campaign with a tour of a cheese factory in the French Alps. All of which prompts MSNBC to weigh in with some context on the origins of the phrase "cheese-eating surrender monkeys." (Thank the Simpsons.)</s> |
granular flows are often separated into two categories dealing with ( i ) dense granular flows where the flow density is not far from the density of static packing ( for studies in 2 dimensions see @xcite or in 3 dimensions see @xcite ) and ( ii ) a rapid , very dilute ( gas ) regime @xcite , which is often analyzed in terms of a kinetic theory @xcite ) . although flow on a rough inclined plane has become a model experiment because of its simple geometry most of the available research focuses on the dense regime while less data is devoted to characterizing the gas regime and the transition between the dense and very dilute phase regimes .
a granular layer of thickness @xmath2 on a rough inclined plane starts flowing only if the plane inclination @xmath3 surpasses a critical angle @xmath4 and stops flowing when @xmath3 is decreased below an angle of repose @xmath5 ( for reviews see : @xcite ) .
experiments in 3 dimensions typically feature a storage container with an opening of height @xmath6 that influences the volume flow rate of material down the plane @xcite .
the properties of granular flows in this system have been extensively studied when @xmath3 is not much larger than the flow initiation conditions @xcite . for @xmath7 and for small volume flow rates , intermittent flows
are observed @xcite including avalanches @xcite and wave - like motion @xcite . at somewhat larger @xmath3 ,
the grains flow uniformly with a statistically steady flow velocity that depends on the layer height @xcite .
for still higher @xmath3 , the flow properties have not been well studied although an interesting stripe state has been reported @xcite .
one might expect that the layer density would decrease as @xmath3 is increased because of higher average flow velocity which creates larger shear rates and higher granular temperature . because the ratio of the down - plane force to the normal force diverges at @xmath8 , one might also ask whether a dense phase with a well defined layer thickness continues to exist at large @xmath3 .
flowing granular layers can be described by a set of macroscopic variables that depend on the system control parameters .
the two control parameters for granular flow on a rough inclined plane are the hopper opening @xmath6 and the inclination angle @xmath3 .
the hopper opening largely influences the volume flow rate from the hopper whereas @xmath3 controls the balance of tangential and normal gravitational force on the layer .
an additional parameter that is harder to vary systematically is the roughness of the inclined plane surface . for fixed surface roughness ,
the flow properties of the layer at fixed @xmath6 and @xmath3 can be characterized by the surface velocity , the height @xmath2 and the average density @xmath9 .
these quantities depend on the control parameters and on each other in a complicated manner .
part of our purpose in this paper is to understand these relationships .
one particular issue for granular flows at high inclination angles was suggested by idealized numerical simulations in which gravitational forcing can not be balanced by energy dissipation mechanisms , and the flow is predicted to accelerate @xcite .
constitutive equations recently proposed for dense granular flows suggest that the effective friction coefficient saturates to a finite value @xmath10 for high shear rates @xcite . in this case the flow is expected to accelerate for @xmath3 above @xmath11atan@xmath12 .
as we will show in the present work , in accordance with the data presented in @xcite the dense , non - accelerating regime can only be observed up to tan@xmath13tan@xmath14 . for the case of density
we show , that @xmath9 is observed to decrease substantially from its closed - packed value at plane inclinations starting from tan@xmath13tan@xmath15 ( in our case tan@xmath16tan@xmath17 ) . at very high plane inclinations where
a very dilute gas phase is observed the equation of state is certainly much different than for the dense flows and the above criterion is not relevant . for the case of velocity @xmath18 ,
our characterization of @xmath18 as a function of downstream distance demonstrates that there is a healing length of order the size of our inclined plane for moderate plane inclinations that complicates a comparison with the predictions for an acceleration threshold .
we conclude that because of the limited plane length our data are not complete enough to make a quantitative prediction of the angle up to which stationary flows exist .
as demonstrated in other experiments , air can sometimes have a profound effect on the observed behavior of the granular flow as in , for example , segregation of vertically - vibrated granular materials @xcite , discharging hourglasses @xcite , or impact studies @xcite .
thus , in order to characterize the properties of granular flow at high inclination angles , it is important to understand how air interacts with the granular flow and to determine the level of fluidization and grain velocity when the role of air drag is no longer negligible . in this paper
, we characterize the flow of relatively mono - dispersed sand particles on a rough inclined plane .
the experimental apparatus , that allows for measurements of flow conditions as a function of air pressure , and a characterization of the average terminal velocity of individual grains with different mean sizes and material composition are presented in sec .
[ sec : exp ] . in sec .
[ sec : results ] , we describe our measurements of granular layer velocity , height and density as a function of hopper opening @xmath6 .
we summarize our findings in a phase diagram that includes the transition to a gaseous phase .
finally , we conclude with some discussion of the implications and further opportunities for the system of granular flow on an inclined plane .
we start by characterizing the granular material and describing the experimental apparatus used to make quantitative measurements of the flow . for determining the flow properties of the granular layer , we used sand that was sifted with 300 and 500 @xmath19 m sieves to yield a mean diameter of @xmath20 m .
we designate this distribution as having a mean of @xmath20 m and a standard deviation of @xmath21 m .
we also used finer sand , salt and glass beads to help calibrate the air drag effects . the experimental setup used for measurements of inclined plane flows
is shown in fig .
[ setup ] .
a glass plate with dimensions 230 cm x 15 cm was set inside a 274 cm long , 20 cm diameter cast - acrylic tube .
the leftmost 40 cm of the tube ( full with sand in the image ) serves as the hopper .
the surface of the remaining part ( 190 cm ) of the glass plate was made rough by gluing one layer of grains onto it or by covering the plate with sandpaper that had a characteristic roughness of 190 @xmath19 m ( 80 grit ) . the same flow regimes were observed for both surfaces . because the surface of the sandpaper was slightly smoother , we observed a small ( about 10@xmath22 ) increase of the flow velocity compared to the case of grains glued onto the plate .
the tube was rotatable about the middle so that we could set an arbitrary inclination angle @xmath3 .
the whole system could be pumped down to @xmath23 0.5 mbar .
the flow velocity @xmath18 at the surface was determined by analyzing high speed ( 8000 frames per second ) recordings .
space time plots were created by taking one line of the recordings parallel to the main flow .
the fourier transform of such an image ( consisting of streaks as traces of particles in the flow ) yields the average velocity of surface particles .
the thickness of the flow @xmath2 was monitored by the translation of a laser spot formed by the intersection with the surface of a laser beam aligned at an angle of @xmath24 with respect to the inclined plane .
the flow properties were characterized by varying two control parameters : the plane inclination @xmath25 and the hopper opening @xmath26 cm ( _ i.e. _ @xmath27 ) . setting a constant @xmath6
, we observed a slight increase of the hopper discharge rate when increasing @xmath3 , _
e.g. _ , see fig .
[ discharge ] .
the hopper discharge rate also depended on the presence of air in the system @xcite . in a typical hourglass geometry ,
when the hopper and the main chamber are separated , the flow of sand faces a counterflow of air as the hopper discharges and a pressure difference builds up . without a connection between the two chambers in our experiment , the hopper discharge rate was significantly smaller ( by about @xmath28 ) in the presence of air when compared to the case in vacuum . by connecting the two chambers with a flexible tube ,
the counterflow was substantially reduced , and the discharge rate was about @xmath29 of the discharge rate observed in vacuum ( fig .
[ discharge ] ) .
all the measurements presented here were done for the case of reduced counterflow . to set the stage for our discussions of air effects in inclined plane flows , we introduce some results related to the interaction of granular particles with air . one way in which air can affect a granular flow is through the drag force of air acting on an isolated particle . given a spherical particle of radius @xmath30 ( diameter @xmath31 ) and density
@xmath32 falling under gravity @xmath33 in air with dynamic viscosity @xmath19 and density @xmath34 , the equation of motion is @xmath35 where the buoyancy term is ignored since @xmath36 and @xmath37 is a turbulent drag correction @xcite @xmath38 with @xmath39 .
the turbulent drag coefficient @xmath37 yields a good approximation for the range of velocities that are of interest here .
the terminal velocity @xmath40 is obtained by setting @xmath41 and solving numerically the equation @xmath42 the air drag on the individual grains is characterized by the reynolds number @xmath43 of a particle of diameter @xmath31 falling at velocity @xmath44 .
taking spherical particles with @xmath45 mm and with the density of sand @xmath46 g/@xmath47 , by solving eq .
( [ eqn : eom2 ] ) numerically we obtain @xmath48 m / s with a corresponding @xmath49 .
the values of @xmath40 were also measured by dropping particles from 2.7 m. all of the particles reached a terminal velocity where the change in their velocities was below @xmath50 over a 7 cm interrogation window .
the velocity distribution reflecting the variations in particle size and shape is presented for 100 particles in fig .
[ terminalvelo ] .
the average value of the terminal velocity for the 400 @xmath19 m sand is @xmath51 m / s .
the measurements were also done for fine sand @xmath52 m , salt @xmath53 m and glass beads @xmath54 m , yielding the the velocity distributions presented in fig .
[ terminalvelo ] .
the corresponding mean values of @xmath40 are @xmath55 m / s , @xmath56 m / s and @xmath57 m / s , respectively .
the calculated values of @xmath40 are indicated with a vertical line for each case .
the calculated values of @xmath40 are close to the measured values with deviations between data and theory presumably resulting from non - spherical shapes and/or uncertainties in the mean particle diameter .
for example , the deviations observed for the two sets of sand can be consistently explained with non - centered size distributions . having determined that our calculation of @xmath40 agrees well with the measured data , we used eq .
[ eqn : eom2 ] to estimate the air drag reduction and the resulting increase in @xmath40 as a function of air pressure .
the dynamic viscosity @xmath19 of air is almost constant as a function of air pressure @xmath58 .
using an ideal gas relationship between @xmath34 and p and eq .
[ eqn : eom2 ] , one obtains @xmath40 ( and @xmath59 ) as a function of @xmath58 .
as seen in fig .
[ vt - pressure ] , @xmath40 is expected to increase by a factor of 4 when @xmath58 decreases to 0.5 mbar .
if air drag plays a significant role in determining the granular flow state , the substantial decrease in air drag under vacuum will reveal that effect .
here we ignore the expected further increase in the terminal velocity at very low pressures when the air mean free path is comparable to the particle diameter .
another approach to estimating the effect of air drag on a flowing granular layer is to assume that the granular layer is similar to a fluid and that the air forms a boundary layer between air at large distance with zero velocity and the granular layer flowing with a `` surface velocity '' @xmath44 .
a prandtl boundary layer description yields a boundary layer thickness @xmath60 where @xmath0 is the downstream distance .
the force per unit area @xmath61 exerted on the flow by the entrained air is approximately @xmath62 .
the relevant parameters of the air are @xmath63 pa s , @xmath64 kg / m@xmath65 ( for local pressure @xmath66 ) , and @xmath67 . taking a distance @xmath68 cm and @xmath69 cm / sec , one obtains @xmath70 cm and @xmath71 n / m@xmath72 which is less than 0.1@xmath22 of the gravitational force @xmath73 a negligible effect .
the surface of a granular flow , however , is not as sharply defined as it is for liquid flows .
if there were substantial fluidization of the granular layer , the cumulative drag force experienced by the low density particles might play a role in the instabilities of the homogeneous flow .
based on qualitative observations of the flow and on quantitative measurements presented below , we can separate the granular flow into regions with certain characteristic features .
such a phase diagram identifying the different flow regimes as a function of the two control parameters @xmath6 and @xmath3 is shown in fig . [ phasediagram ] .
the ratios tan@xmath3/tan@xmath5 and @xmath74 are also shown on the top and right axes , respectively , where @xmath75 is the independently measured bulk angle of repose for the granular material used here .
the boundaries are neither precisely defined nor indicative of sharp transitions between different flow regimes .
further , this phase diagram does not capture the convective nature of the granular flow in that features or flow properties may evolve over length scales comparable to the length of the inclined plane .
nevertheless , identification of the general regimes are useful in setting the stage for more complex issues raised below . at very slow flow rates and low plane inclinations
the homogeneous flow is unstable and organizes itself into waves .
the properties of such waves have been studied extensively @xcite . by increasing the flow rate and staying in the range of not very steep plane inclinations ( up to about @xmath76 ) ,
the flow becomes homogeneous . for steeper planes an instability occurs leading to a pattern consisting of lateral stripes @xcite .
a detailed characterization of the stripe state in our system will be presented elsewhere @xcite .
the dashed line divides the diagram into two regions : accelerating and @xmath1invariant steady flows . above the dashed line the acceleration of the flow ( averaged over the range of @xmath77 cm ) was more than 5% of g sin@xmath78
this boundary depends on the distance downstream @xmath0 at which the acceleration was measured as discussed in more detail in sec .
[ subsec : velocity ] .
the phase diagram was found to be qualitatively the same for flow at ambient pressure and flow at low pressure with @xmath79 mbar . the plane of the images shown in fig .
[ laserspot ] was parallel to the inclined plane .
a laser beam projected from the left hand side of the image at an angle of @xmath24 with respect to the plane of the image produced a localized laser spot .
the first image , fig .
[ laserspot]a , shows the case of the empty chamber without flow , where the laser beam was reflected by the rough surface of the inclined plane . the other images ( b - h ) were taken in the presence of flow at a constant hopper opening @xmath80 cm and downstream distance @xmath81 cm with increasing @xmath3 as we go from ( b - h ) .
the laser beam was reflected from the particles at the surface of the flowing layer . the horizontal shift of the laser spot with respect to image ( a ) measured the thickness of the flowing layer .
this measurement is straightforward when the laser spot did not change its shape , _
i.e. _ , the surface of the flow was well defined ( figs .
[ laserspot]b - e ) .
the first sign of decreasing flow density can be seen in fig .
[ laserspot]f where the shape of the reflected laser spot changed significantly .
the spot spreading became more pronounced with increasing @xmath3 ( figs .
[ laserspot]g - h ) . to get a better measure of the flow thickness in this regime the light intensity @xmath82 detected at a height @xmath83 above
the inclined plane was integrated over 200 equally - spaced images taken over a time period of 3.3 s. the @xmath84 curves are shown in fig .
[ heightintensityprofile ] corresponding to the last four plane inclinations of fig .
[ laserspot ] . because of the increasing fluctuations in the laser spot intensity for the higher @xmath3 , averaging over many images was necessary . for the relatively dense regime ( with a compact laser spot ) , the position of the center of mass of the laser spot was taken as the flow thickness @xmath2 . in the very dilute regime
we integrate the @xmath84 curves and define @xmath2 as the height below which 80@xmath22 of the flowing grains were detected .
the flow density was measured in the following manner . a stationary flow was established and was maintained for about 4 seconds .
the flow was then `` frozen '' by rapidly decreasing the plane inclination .
the time evolution of the center of mass of the laser spot is shown in fig .
[ height - time ] for the same set of plane inclinations as in fig .
[ heightintensityprofile ] .
the flow height fluctuated in the first 4 seconds with larger fluctuations in @xmath2 for higher values of @xmath3 .
as the flow stopped , the height dropped to the height corresponding to the static ( nearly random closed packed ) material .
the height change between the stationary flow and the frozen state reflected the mean density change which became larger with increasing @xmath3 , see fig .
[ height - time ] .
the ratio of the static height and the height of the stationary flow gives the normalized depth - averaged density of the flow @xmath85 , where @xmath86 is the static density .
this measurement of height and density averages over some distance in @xmath0 because the flow does not stop instantaneously . assuming an exponential decay of the velocity and a total stopping time of about 0.5 sec from the data in fig .
[ heightintensityprofile ] , one obtains an averaging length of between 10 and 50 cm . below we describe a more local albeit less precise measure of density derived from measurements of @xmath18 and @xmath2 .
granular material exits the hopper at low velocity with height @xmath6 and a density @xmath86 that is close to that of a random close - packed state .
the material accelerates , thins and becomes less dense as the interaction of the grains with the rough bottom surface partially fluidizes the granular state . at low inclination angles
, the system reaches an an @xmath1invariant steady state after some healing length @xmath87 where layer height @xmath2 , mean velocity @xmath18 , and mean density @xmath9 do not change with downstream distance @xmath0 . for @xmath3 larger than about @xmath76 , the flow is not stationary as a function of @xmath0 and more complicated states are observed . the flow appears to become stationary on healing lengths of order the plane length @xmath88 for large values of @xmath3 as described below .
all measurements of @xmath18 and @xmath2 were repeated at six locations at a distance @xmath0 measured from the hopper in the range of @xmath89 cm @xmath90 cm .
the flow velocity @xmath18 and layer height @xmath2 are shown as functions of @xmath0 for three hopper openings @xmath91 0.8 cm , 1.6 cm and 2.4 cm in figs .
[ velo - x - theta]a - f . for higher plane inclinations the flow did not reach a stationary state over the plane length @xmath88 .
the evolution of the granular flow can be partially understood by an analysis of @xmath18 as a function of downstream distance @xmath0 for different @xmath3 .
the flow is driven by the gravitational force @xmath92 and damped by dissipation forces , _
e.g. _ , friction and/or inelastic collisions . in the simplest approach
we can assume that the flow would approach a terminal velocity @xmath93 like @xmath94 where @xmath87 corresponds to the healing length of the flow .
fitting the data in fig .
[ velo - x - theta]a - c to this form allows for the determination of @xmath87 and the velocities @xmath95 and @xmath93 for different @xmath6 and @xmath3 . in fig .
[ healing - length]a , we show data for @xmath18 and fits to the exponential form .
the data are well fit by exponential saturation .
the resulting values of @xmath87 are shown in fig .
[ healing - length]b . as a function of @xmath3 for @xmath96 cm and @xmath97 cm .
the healing lengths are of order @xmath98 for @xmath99 . because the data show little variation with @xmath0 for smaller @xmath3 , our fits almost certainly overestimate @xmath87 in that region . from information about the surface velocity @xmath18 and the layer thickness @xmath2
, additional information can be inferred about the granular layer despite the inability to directly measure the @xmath83 dependence of density and velocity . if we assume that the @xmath100 and @xmath101 profiles do not change their character along @xmath0 , then by conservation of mass one has that the mass flux per unit channel width is @xmath102 where the overbar denotes a depth average .
numerical simulations @xcite suggest that for at least some range of @xmath3 , @xmath9 is almost constant over the depth . with that assumption , we have that @xmath103 .
thus , as a first approximation , plotting @xmath104 as a function of @xmath0 provides information about the downstream evolution of the mean density @xmath105 . the degree
to which this is a good approximation depends on the details of @xmath101 and @xmath100 .
the slight difference in @xmath105 between the values estimated this way and measured by a more precise method presented sec .
[ subsec : thickness ] , can result from a nonuniform ( @xmath83 dependent density ) at faster flows . because we do not know the absolute value for @xmath106 , we normalize the resulting values of @xmath105 assuming that the flow density for the lowest plane inclination was near to the density of the static packing @xmath86 near the hopper . for the other values of @xmath3 we assumed a @xmath107 increase of the hopper flow rate between @xmath108 for all values of @xmath6 . the resulting normalized mean density @xmath85 is shown in figs .
[ velo - x - theta]g - i as a function of @xmath0 .
one sees that the density drops rapidly as a result of increasing velocity for higher plane inclinations especially for the case of lower incoming flow rates .
a more precise characterization of the density change using the method described in section [ subsec : thickness ] , made at one downstream location @xmath109 cm , will be presented below .
results of the two methods agree within the uncertainties inherent in each approach . using the @xmath110 curves the acceleration of the flow
was obtained by assuming that @xmath111 . the average value of @xmath112 over the range 60 cm @xmath113 140 cm is presented as a function of @xmath3 in fig .
[ accel - theta ] . at higher plane inclinations
, there is a significant acceleration for each value of @xmath6 whereas for the lowest value of @xmath3 the flow is @xmath1invariant for all the @xmath6 values we investigated . the value of @xmath6 corresponding to @xmath114 is indicated as a function of @xmath3 in fig .
[ phasediagram ] with a dotted line as a boundary between the accelerating and @xmath1invariant steady regimes measured at this distance from the hopper . in the following
we analyze the velocity @xmath18 , flow thickness @xmath2 and dimensionless mean flow density @xmath85 as a function of @xmath3 and @xmath6 at the location @xmath109 cm below the hopper .
parts of our data correspond to accelerating non - stationary flow .
since we are reporting averages obtained near the channel center , we need to determine the degree to which those averages depend on the lateral homogeneity of the flow .
thus , we first indicate some measure of the lateral flow structure
. lateral velocity profiles @xmath115 are presented in fig .
[ velo - profiles ] . in the homogeneous dense flow regime ,
the velocity is relatively constant over the center 12 cm of the channel corresponding to about 75% of the channel width . at the edges of the channel
there are boundary layers that arise from the friction with the sidewalls . as the sidewalls of the channel have a smooth surface , friction is significantly less important there when compared to the rough plane .
the transition to the stripe state ( see curves in fig . [ velo - profiles ] with @xmath3 values of 42.6@xmath116 and 45.8@xmath116 ) happens at around @xmath117 .
the surface flow velocity @xmath18 , the height of the flowing layer @xmath2 and its standard deviation defined as @xmath118 are shown as a function of @xmath6 in fig .
[ height - velo - spread - opening ] as measured at @xmath119 cm .
the flow velocity is a monotonically increasing function of @xmath6 for all plane inclinations . in the fluid - like regime @xmath2
is a monotonically increasing function of @xmath6 as well , whereas @xmath120 has a constant low value reflecting the constant shape of the laser spot .
the sign of the transition into the gaseous phase is the rapid increase of @xmath2 and @xmath120 with decreasing @xmath6 at higher plane inclinations .
the same set of data for @xmath18 , @xmath2 and @xmath120 is presented in fig .
[ height - velo - spread - inclination ] as a function of @xmath3 .
again @xmath18 is a monotonically increasing function of @xmath3 for each value of @xmath6 . in the fluid - like regime ( larger values of @xmath6 )
the slope of the @xmath121 curves is nearly constant . at smaller @xmath6
the slope increases considerably when entering the gaseous regime .
the flow thickness @xmath2 decreases with increasing @xmath3 in the fluid - like regime meaning that larger flow velocity results in smaller flow thickness .
this effect is actually stronger than fig .
[ height - velo - spread - inclination]b indicates , as the incoming flow rate slightly increases with increasing @xmath3 ( see fig .
[ discharge ] ) .
thus , thinning of the flow as a result of larger flow velocities is slightly counterbalanced by the growing value of the flow rate by increasing @xmath3 .
the different flow regimes can best be characterized by the flow density . as we see in fig .
[ inclination - density ] the normalized mean density @xmath85 drops continuously with increasing @xmath3 .
the density drop is more dramatic for smaller incoming flow rate than for thicker flows .
the _ first regime _ corresponds to dense flows ( slightly above the angle of repose ) and is often characterized by the pouliquen flow rule , where the depth averaged velocity @xmath122 is proportional to @xmath123 @xcite .
this regime is reported to exist for the plane inclinations @xmath124 , and the dense flow can be unstable with respect to the formation of waves @xcite . according to our measurements the mean density in this regime is slightly decreasing with @xmath3 but always stays larger than @xmath125 . according to a recent theory by jenkins @xcite the density should decrease as @xmath126tan@xmath127 .
a reasonable fit is obtained by this formula for a range of @xmath6 up to the plane inclination @xmath128 yielding @xmath129 . in the _ second regime _ falling in the range of @xmath130 , a stripe pattern can be observed with an average density of @xmath131 . the detailed characterization of the stripe structure is beyond the scope of this paper . in the _ third regime _ , the stripe structure disappears as the flow gets very fluidized with an average density of @xmath132 .
a dramatic density decrease was observed for lower incoming flow rates , typically at @xmath133 , yielding a gas - like phase where the density was less than @xmath134 of @xmath86 .
we characterize this transition in more detail below .
the surface flow velocity @xmath18 as a function of height @xmath2 is presented in fig .
[ height - velo]a for the fluid - like regime .
note that only the first curve ( at @xmath135 ) corresponds to stationary flows , the other curves ( partly ) fall already in the range of accelerating flows .
two sets of data were taken : ( i ) in the presence of air ( filled symbols ) and ( ii ) at low pressure @xmath79 mbar ( open symbols ) . in this regime
the two sets of data match implying that air drag does not become important even at the fastest flows where the grain velocity is close to the value of the terminal velocity measured in free fall . in the gaseous regime , however , ( see fig .
[ height - velo]b ) particle velocities measured at ambient pressure are slightly smaller than at low pressure .
thus , in the gas phase the average interparticle distance is considerably increased and the contribution of air drag to the dissipation becomes important .
the changing nature of the flow is visualized in fig .
[ height - velo]c where all the data points are presented for two plane inclinations for the two regimes and the transition between them .
the sharply different tendency of the @xmath136 curves in fig .
[ height - velo]a and fig .
[ height - velo]b reflects the nature of the transition between the fluid - like and gaseous phases . for @xmath137
the larger flow rates give rise to dense flows ( fig .
[ height - velo]a ) where increasing @xmath6 leads to increasing @xmath2 and faster flow . at lower values of the hopper flow rate decreasing
@xmath6 leads to increasing levels of fluidization and to a transition to the gaseous phase . in this regime , see fig .
[ height - velo]b , the density of the flow rapidly decreases with decreasing @xmath6 and the measured thickness rapidly increases .
contrary to trends for the fluid - like phase , the leftmost data points of the curves in fig .
[ height - velo]b correspond to the highest hopper flow rates and the rightmost ones to the lowest hopper flow rate .
thus , the flow is not simply determined by ( @xmath3 , @xmath2 , @xmath0 ) as is the case for dense flows . for a given @xmath2 , @xmath3 and @xmath0 , two solutions exists , one corresponding to a dense phase and the other to a very dilute one , depending on the flow rate . a recent linear stability analysis indicated , that the air drag could play a role in the development of stripe patterns in the fluid - like regime @xcite . according to our findings the density of the flow for the stripe state was in the range of @xmath131 , corresponding to the regime where the role of the air drag is minor .
the flow properties are not affected even at flow velocities near the terminal velocity in free fall . at the transition to the gaseous state
the stripes disappear and the rapid decrease of the flow density leads to visible effects of air drag . in summary , we have presented a detailed description of granular flow on a rough inclined plane - one of the most commonly used model systems for granular dynamics - concentrating on the fast flow regime .
we developed a method to measure the depth averaged normalized flow density @xmath85 and characterized the flow regimes as a function of @xmath85 .
we have characterized the transition to a very dilute gaseous phase that takes place by increasing plane inclination and decreasing incoming flow rate . by measuring the flow properties at ambient pressure and at low pressure ( @xmath138 mbar ) in a vacuum flow channel
we have shown that the dissipation by the air drag ( with respect to the other dissipational processes ) is non - negligible only in the dilute gas - like phase .
other implications of this work involves the possibility of linking changes in the flow structure ( such as the stripe state ) as a function of plane inclination to the change in the depth averaged normalized flow density @xmath85 .
this work was funded by the us department of energy ( w-7405-eng ) .
the authors benefited from discussions with i.s .
t.b . acknowledges support by the bolyai jnos scholarship of the hungarian academy of sciences and the hungarian scientific research fund ( contract no .
otka - f-060157 ) . | we report experiments on the overall phase diagram of granular flows on an incline with emphasis on high inclination angles where the mean layer velocity approaches the terminal velocity of a single particle free falling in air .
the granular flow was characterized by measurements of the surface velocity , the average layer height , and the mean density of the layer as functions of the hopper opening , the plane inclination angle and the downstream distance @xmath0 of the flow . at high
inclination angles the flow does not reach an @xmath1invariant steady state over the length of the inclined plane . for low volume flow rates ,
a transition was detected between dense and very dilute ( gas ) flow regimes .
we show using a vacuum flow channel that air did not qualitatively change the phase diagram and did not quantitatively modify mean flow velocities of the granular layer except for small changes in the very dilute gas - like phase . | <s>[INST]granular flows are often separated into two categories dealing with ( i ) dense granular flows where the flow density is not far from the density of static packing ( for studies in 2 dimensions see @xcite or in 3 dimensions see @xcite ) and ( ii ) a rapid , very dilute ( gas ) regime @xcite , which is often analyzed in terms of a kinetic theory @xcite ) . although flow on a rough inclined plane has become a model experiment because of its simple geometry most of the available research focuses on the dense regime while less data is devoted to characterizing the gas regime and the transition between the dense and very dilute phase regimes .
a granular layer of thickness @xmath2 on a rough inclined plane starts flowing only if the plane inclination @xmath3 surpasses a critical angle @xmath4 and stops flowing when @xmath3 is decreased below an angle of repose @xmath5 ( for reviews see : @xcite ) .
experiments in 3 dimensions typically feature a storage container with an opening of height @xmath6 that influences the volume flow rate of material down the plane @xcite .
the properties of granular flows in this system have been extensively studied when @xmath3 is not much larger than the flow initiation conditions @xcite . for @xmath7 and for small volume flow rates , intermittent flows
are observed @xcite including avalanches @xcite and wave - like motion @xcite . at somewhat larger @xmath3 ,
the grains flow uniformly with a statistically steady flow velocity that depends on the layer height @xcite .
for still higher @xmath3 , the flow properties have not been well studied although an interesting stripe state has been reported @xcite .
one might expect that the layer density would decrease as @xmath3 is increased because of higher average flow velocity which creates larger shear rates and higher granular temperature . because the ratio of the down - plane force to the normal force diverges at @xmath8 , one might also ask whether a dense phase with a well defined layer thickness continues to exist at large @xmath3 .
flowing granular layers can be described by a set of macroscopic variables that depend on the system control parameters .
the two control parameters for granular flow on a rough inclined plane are the hopper opening @xmath6 and the inclination angle @xmath3 .
the hopper opening largely influences the volume flow rate from the hopper whereas @xmath3 controls the balance of tangential and normal gravitational force on the layer .
an additional parameter that is harder to vary systematically is the roughness of the inclined plane surface . for fixed surface roughness ,
the flow properties of the layer at fixed @xmath6 and @xmath3 can be characterized by the surface velocity , the height @xmath2 and the average density @xmath9 .
these quantities depend on the control parameters and on each other in a complicated manner .
part of our purpose in this paper is to understand these relationships .
one particular issue for granular flows at high inclination angles was suggested by idealized numerical simulations in which gravitational forcing can not be balanced by energy dissipation mechanisms , and the flow is predicted to accelerate @xcite .
constitutive equations recently proposed for dense granular flows suggest that the effective friction coefficient saturates to a finite value @xmath10 for high shear rates @xcite . in this case the flow is expected to accelerate for @xmath3 above @xmath11atan@xmath12 .
as we will show in the present work , in accordance with the data presented in @xcite the dense , non - accelerating regime can only be observed up to tan@xmath13tan@xmath14 . for the case of density
we show , that @xmath9 is observed to decrease substantially from its closed - packed value at plane inclinations starting from tan@xmath13tan@xmath15 ( in our case tan@xmath16tan@xmath17 ) . at very high plane inclinations where
a very dilute gas phase is observed the equation of state is certainly much different than for the dense flows and the above criterion is not relevant . for the case of velocity @xmath18 ,
our characterization of @xmath18 as a function of downstream distance demonstrates that there is a healing length of order the size of our inclined plane for moderate plane inclinations that complicates a comparison with the predictions for an acceleration threshold .
we conclude that because of the limited plane length our data are not complete enough to make a quantitative prediction of the angle up to which stationary flows exist .
as demonstrated in other experiments , air can sometimes have a profound effect on the observed behavior of the granular flow as in , for example , segregation of vertically - vibrated granular materials @xcite , discharging hourglasses @xcite , or impact studies @xcite .
thus , in order to characterize the properties of granular flow at high inclination angles , it is important to understand how air interacts with the granular flow and to determine the level of fluidization and grain velocity when the role of air drag is no longer negligible . in this paper
, we characterize the flow of relatively mono - dispersed sand particles on a rough inclined plane .
the experimental apparatus , that allows for measurements of flow conditions as a function of air pressure , and a characterization of the average terminal velocity of individual grains with different mean sizes and material composition are presented in sec .
[ sec : exp ] . in sec .
[ sec : results ] , we describe our measurements of granular layer velocity , height and density as a function of hopper opening @xmath6 .
we summarize our findings in a phase diagram that includes the transition to a gaseous phase .
finally , we conclude with some discussion of the implications and further opportunities for the system of granular flow on an inclined plane .
we start by characterizing the granular material and describing the experimental apparatus used to make quantitative measurements of the flow . for determining the flow properties of the granular layer , we used sand that was sifted with 300 and 500 @xmath19 m sieves to yield a mean diameter of @xmath20 m .
we designate this distribution as having a mean of @xmath20 m and a standard deviation of @xmath21 m .
we also used finer sand , salt and glass beads to help calibrate the air drag effects . the experimental setup used for measurements of inclined plane flows
is shown in fig .
[ setup ] .
a glass plate with dimensions 230 cm x 15 cm was set inside a 274 cm long , 20 cm diameter cast - acrylic tube .
the leftmost 40 cm of the tube ( full with sand in the image ) serves as the hopper .
the surface of the remaining part ( 190 cm ) of the glass plate was made rough by gluing one layer of grains onto it or by covering the plate with sandpaper that had a characteristic roughness of 190 @xmath19 m ( 80 grit ) . the same flow regimes were observed for both surfaces . because the surface of the sandpaper was slightly smoother , we observed a small ( about 10@xmath22 ) increase of the flow velocity compared to the case of grains glued onto the plate .
the tube was rotatable about the middle so that we could set an arbitrary inclination angle @xmath3 .
the whole system could be pumped down to @xmath23 0.5 mbar .
the flow velocity @xmath18 at the surface was determined by analyzing high speed ( 8000 frames per second ) recordings .
space time plots were created by taking one line of the recordings parallel to the main flow .
the fourier transform of such an image ( consisting of streaks as traces of particles in the flow ) yields the average velocity of surface particles .
the thickness of the flow @xmath2 was monitored by the translation of a laser spot formed by the intersection with the surface of a laser beam aligned at an angle of @xmath24 with respect to the inclined plane .
the flow properties were characterized by varying two control parameters : the plane inclination @xmath25 and the hopper opening @xmath26 cm ( _ i.e. _ @xmath27 ) . setting a constant @xmath6
, we observed a slight increase of the hopper discharge rate when increasing @xmath3 , _
e.g. _ , see fig .
[ discharge ] .
the hopper discharge rate also depended on the presence of air in the system @xcite . in a typical hourglass geometry ,
when the hopper and the main chamber are separated , the flow of sand faces a counterflow of air as the hopper discharges and a pressure difference builds up . without a connection between the two chambers in our experiment , the hopper discharge rate was significantly smaller ( by about @xmath28 ) in the presence of air when compared to the case in vacuum . by connecting the two chambers with a flexible tube ,
the counterflow was substantially reduced , and the discharge rate was about @xmath29 of the discharge rate observed in vacuum ( fig .
[ discharge ] ) .
all the measurements presented here were done for the case of reduced counterflow . to set the stage for our discussions of air effects in inclined plane flows , we introduce some results related to the interaction of granular particles with air . one way in which air can affect a granular flow is through the drag force of air acting on an isolated particle . given a spherical particle of radius @xmath30 ( diameter @xmath31 ) and density
@xmath32 falling under gravity @xmath33 in air with dynamic viscosity @xmath19 and density @xmath34 , the equation of motion is @xmath35 where the buoyancy term is ignored since @xmath36 and @xmath37 is a turbulent drag correction @xcite @xmath38 with @xmath39 .
the turbulent drag coefficient @xmath37 yields a good approximation for the range of velocities that are of interest here .
the terminal velocity @xmath40 is obtained by setting @xmath41 and solving numerically the equation @xmath42 the air drag on the individual grains is characterized by the reynolds number @xmath43 of a particle of diameter @xmath31 falling at velocity @xmath44 .
taking spherical particles with @xmath45 mm and with the density of sand @xmath46 g/@xmath47 , by solving eq .
( [ eqn : eom2 ] ) numerically we obtain @xmath48 m / s with a corresponding @xmath49 .
the values of @xmath40 were also measured by dropping particles from 2.7 m. all of the particles reached a terminal velocity where the change in their velocities was below @xmath50 over a 7 cm interrogation window .
the velocity distribution reflecting the variations in particle size and shape is presented for 100 particles in fig .
[ terminalvelo ] .
the average value of the terminal velocity for the 400 @xmath19 m sand is @xmath51 m / s .
the measurements were also done for fine sand @xmath52 m , salt @xmath53 m and glass beads @xmath54 m , yielding the the velocity distributions presented in fig .
[ terminalvelo ] .
the corresponding mean values of @xmath40 are @xmath55 m / s , @xmath56 m / s and @xmath57 m / s , respectively .
the calculated values of @xmath40 are indicated with a vertical line for each case .
the calculated values of @xmath40 are close to the measured values with deviations between data and theory presumably resulting from non - spherical shapes and/or uncertainties in the mean particle diameter .
for example , the deviations observed for the two sets of sand can be consistently explained with non - centered size distributions . having determined that our calculation of @xmath40 agrees well with the measured data , we used eq .
[ eqn : eom2 ] to estimate the air drag reduction and the resulting increase in @xmath40 as a function of air pressure .
the dynamic viscosity @xmath19 of air is almost constant as a function of air pressure @xmath58 .
using an ideal gas relationship between @xmath34 and p and eq .
[ eqn : eom2 ] , one obtains @xmath40 ( and @xmath59 ) as a function of @xmath58 .
as seen in fig .
[ vt - pressure ] , @xmath40 is expected to increase by a factor of 4 when @xmath58 decreases to 0.5 mbar .
if air drag plays a significant role in determining the granular flow state , the substantial decrease in air drag under vacuum will reveal that effect .
here we ignore the expected further increase in the terminal velocity at very low pressures when the air mean free path is comparable to the particle diameter .
another approach to estimating the effect of air drag on a flowing granular layer is to assume that the granular layer is similar to a fluid and that the air forms a boundary layer between air at large distance with zero velocity and the granular layer flowing with a `` surface velocity '' @xmath44 .
a prandtl boundary layer description yields a boundary layer thickness @xmath60 where @xmath0 is the downstream distance .
the force per unit area @xmath61 exerted on the flow by the entrained air is approximately @xmath62 .
the relevant parameters of the air are @xmath63 pa s , @xmath64 kg / m@xmath65 ( for local pressure @xmath66 ) , and @xmath67 . taking a distance @xmath68 cm and @xmath69 cm / sec , one obtains @xmath70 cm and @xmath71 n / m@xmath72 which is less than 0.1@xmath22 of the gravitational force @xmath73 a negligible effect .
the surface of a granular flow , however , is not as sharply defined as it is for liquid flows .
if there were substantial fluidization of the granular layer , the cumulative drag force experienced by the low density particles might play a role in the instabilities of the homogeneous flow .
based on qualitative observations of the flow and on quantitative measurements presented below , we can separate the granular flow into regions with certain characteristic features .
such a phase diagram identifying the different flow regimes as a function of the two control parameters @xmath6 and @xmath3 is shown in fig . [ phasediagram ] .
the ratios tan@xmath3/tan@xmath5 and @xmath74 are also shown on the top and right axes , respectively , where @xmath75 is the independently measured bulk angle of repose for the granular material used here .
the boundaries are neither precisely defined nor indicative of sharp transitions between different flow regimes .
further , this phase diagram does not capture the convective nature of the granular flow in that features or flow properties may evolve over length scales comparable to the length of the inclined plane .
nevertheless , identification of the general regimes are useful in setting the stage for more complex issues raised below . at very slow flow rates and low plane inclinations
the homogeneous flow is unstable and organizes itself into waves .
the properties of such waves have been studied extensively @xcite . by increasing the flow rate and staying in the range of not very steep plane inclinations ( up to about @xmath76 ) ,
the flow becomes homogeneous . for steeper planes an instability occurs leading to a pattern consisting of lateral stripes @xcite .
a detailed characterization of the stripe state in our system will be presented elsewhere @xcite .
the dashed line divides the diagram into two regions : accelerating and @xmath1invariant steady flows . above the dashed line the acceleration of the flow ( averaged over the range of @xmath77 cm ) was more than 5% of g sin@xmath78
this boundary depends on the distance downstream @xmath0 at which the acceleration was measured as discussed in more detail in sec .
[ subsec : velocity ] .
the phase diagram was found to be qualitatively the same for flow at ambient pressure and flow at low pressure with @xmath79 mbar . the plane of the images shown in fig .
[ laserspot ] was parallel to the inclined plane .
a laser beam projected from the left hand side of the image at an angle of @xmath24 with respect to the plane of the image produced a localized laser spot .
the first image , fig .
[ laserspot]a , shows the case of the empty chamber without flow , where the laser beam was reflected by the rough surface of the inclined plane . the other images ( b - h ) were taken in the presence of flow at a constant hopper opening @xmath80 cm and downstream distance @xmath81 cm with increasing @xmath3 as we go from ( b - h ) .
the laser beam was reflected from the particles at the surface of the flowing layer . the horizontal shift of the laser spot with respect to image ( a ) measured the thickness of the flowing layer .
this measurement is straightforward when the laser spot did not change its shape , _
i.e. _ , the surface of the flow was well defined ( figs .
[ laserspot]b - e ) .
the first sign of decreasing flow density can be seen in fig .
[ laserspot]f where the shape of the reflected laser spot changed significantly .
the spot spreading became more pronounced with increasing @xmath3 ( figs .
[ laserspot]g - h ) . to get a better measure of the flow thickness in this regime the light intensity @xmath82 detected at a height @xmath83 above
the inclined plane was integrated over 200 equally - spaced images taken over a time period of 3.3 s. the @xmath84 curves are shown in fig .
[ heightintensityprofile ] corresponding to the last four plane inclinations of fig .
[ laserspot ] . because of the increasing fluctuations in the laser spot intensity for the higher @xmath3 , averaging over many images was necessary . for the relatively dense regime ( with a compact laser spot ) , the position of the center of mass of the laser spot was taken as the flow thickness @xmath2 . in the very dilute regime
we integrate the @xmath84 curves and define @xmath2 as the height below which 80@xmath22 of the flowing grains were detected .
the flow density was measured in the following manner . a stationary flow was established and was maintained for about 4 seconds .
the flow was then `` frozen '' by rapidly decreasing the plane inclination .
the time evolution of the center of mass of the laser spot is shown in fig .
[ height - time ] for the same set of plane inclinations as in fig .
[ heightintensityprofile ] .
the flow height fluctuated in the first 4 seconds with larger fluctuations in @xmath2 for higher values of @xmath3 .
as the flow stopped , the height dropped to the height corresponding to the static ( nearly random closed packed ) material .
the height change between the stationary flow and the frozen state reflected the mean density change which became larger with increasing @xmath3 , see fig .
[ height - time ] .
the ratio of the static height and the height of the stationary flow gives the normalized depth - averaged density of the flow @xmath85 , where @xmath86 is the static density .
this measurement of height and density averages over some distance in @xmath0 because the flow does not stop instantaneously . assuming an exponential decay of the velocity and a total stopping time of about 0.5 sec from the data in fig .
[ heightintensityprofile ] , one obtains an averaging length of between 10 and 50 cm . below we describe a more local albeit less precise measure of density derived from measurements of @xmath18 and @xmath2 .
granular material exits the hopper at low velocity with height @xmath6 and a density @xmath86 that is close to that of a random close - packed state .
the material accelerates , thins and becomes less dense as the interaction of the grains with the rough bottom surface partially fluidizes the granular state . at low inclination angles
, the system reaches an an @xmath1invariant steady state after some healing length @xmath87 where layer height @xmath2 , mean velocity @xmath18 , and mean density @xmath9 do not change with downstream distance @xmath0 . for @xmath3 larger than about @xmath76 , the flow is not stationary as a function of @xmath0 and more complicated states are observed . the flow appears to become stationary on healing lengths of order the plane length @xmath88 for large values of @xmath3 as described below .
all measurements of @xmath18 and @xmath2 were repeated at six locations at a distance @xmath0 measured from the hopper in the range of @xmath89 cm @xmath90 cm .
the flow velocity @xmath18 and layer height @xmath2 are shown as functions of @xmath0 for three hopper openings @xmath91 0.8 cm , 1.6 cm and 2.4 cm in figs .
[ velo - x - theta]a - f . for higher plane inclinations the flow did not reach a stationary state over the plane length @xmath88 .
the evolution of the granular flow can be partially understood by an analysis of @xmath18 as a function of downstream distance @xmath0 for different @xmath3 .
the flow is driven by the gravitational force @xmath92 and damped by dissipation forces , _
e.g. _ , friction and/or inelastic collisions . in the simplest approach
we can assume that the flow would approach a terminal velocity @xmath93 like @xmath94 where @xmath87 corresponds to the healing length of the flow .
fitting the data in fig .
[ velo - x - theta]a - c to this form allows for the determination of @xmath87 and the velocities @xmath95 and @xmath93 for different @xmath6 and @xmath3 . in fig .
[ healing - length]a , we show data for @xmath18 and fits to the exponential form .
the data are well fit by exponential saturation .
the resulting values of @xmath87 are shown in fig .
[ healing - length]b . as a function of @xmath3 for @xmath96 cm and @xmath97 cm .
the healing lengths are of order @xmath98 for @xmath99 . because the data show little variation with @xmath0 for smaller @xmath3 , our fits almost certainly overestimate @xmath87 in that region . from information about the surface velocity @xmath18 and the layer thickness @xmath2
, additional information can be inferred about the granular layer despite the inability to directly measure the @xmath83 dependence of density and velocity . if we assume that the @xmath100 and @xmath101 profiles do not change their character along @xmath0 , then by conservation of mass one has that the mass flux per unit channel width is @xmath102 where the overbar denotes a depth average .
numerical simulations @xcite suggest that for at least some range of @xmath3 , @xmath9 is almost constant over the depth . with that assumption , we have that @xmath103 .
thus , as a first approximation , plotting @xmath104 as a function of @xmath0 provides information about the downstream evolution of the mean density @xmath105 . the degree
to which this is a good approximation depends on the details of @xmath101 and @xmath100 .
the slight difference in @xmath105 between the values estimated this way and measured by a more precise method presented sec .
[ subsec : thickness ] , can result from a nonuniform ( @xmath83 dependent density ) at faster flows . because we do not know the absolute value for @xmath106 , we normalize the resulting values of @xmath105 assuming that the flow density for the lowest plane inclination was near to the density of the static packing @xmath86 near the hopper . for the other values of @xmath3 we assumed a @xmath107 increase of the hopper flow rate between @xmath108 for all values of @xmath6 . the resulting normalized mean density @xmath85 is shown in figs .
[ velo - x - theta]g - i as a function of @xmath0 .
one sees that the density drops rapidly as a result of increasing velocity for higher plane inclinations especially for the case of lower incoming flow rates .
a more precise characterization of the density change using the method described in section [ subsec : thickness ] , made at one downstream location @xmath109 cm , will be presented below .
results of the two methods agree within the uncertainties inherent in each approach . using the @xmath110 curves the acceleration of the flow
was obtained by assuming that @xmath111 . the average value of @xmath112 over the range 60 cm @xmath113 140 cm is presented as a function of @xmath3 in fig .
[ accel - theta ] . at higher plane inclinations
, there is a significant acceleration for each value of @xmath6 whereas for the lowest value of @xmath3 the flow is @xmath1invariant for all the @xmath6 values we investigated . the value of @xmath6 corresponding to @xmath114 is indicated as a function of @xmath3 in fig .
[ phasediagram ] with a dotted line as a boundary between the accelerating and @xmath1invariant steady regimes measured at this distance from the hopper . in the following
we analyze the velocity @xmath18 , flow thickness @xmath2 and dimensionless mean flow density @xmath85 as a function of @xmath3 and @xmath6 at the location @xmath109 cm below the hopper .
parts of our data correspond to accelerating non - stationary flow .
since we are reporting averages obtained near the channel center , we need to determine the degree to which those averages depend on the lateral homogeneity of the flow .
thus , we first indicate some measure of the lateral flow structure
. lateral velocity profiles @xmath115 are presented in fig .
[ velo - profiles ] . in the homogeneous dense flow regime ,
the velocity is relatively constant over the center 12 cm of the channel corresponding to about 75% of the channel width . at the edges of the channel
there are boundary layers that arise from the friction with the sidewalls . as the sidewalls of the channel have a smooth surface , friction is significantly less important there when compared to the rough plane .
the transition to the stripe state ( see curves in fig . [ velo - profiles ] with @xmath3 values of 42.6@xmath116 and 45.8@xmath116 ) happens at around @xmath117 .
the surface flow velocity @xmath18 , the height of the flowing layer @xmath2 and its standard deviation defined as @xmath118 are shown as a function of @xmath6 in fig .
[ height - velo - spread - opening ] as measured at @xmath119 cm .
the flow velocity is a monotonically increasing function of @xmath6 for all plane inclinations . in the fluid - like regime @xmath2
is a monotonically increasing function of @xmath6 as well , whereas @xmath120 has a constant low value reflecting the constant shape of the laser spot .
the sign of the transition into the gaseous phase is the rapid increase of @xmath2 and @xmath120 with decreasing @xmath6 at higher plane inclinations .
the same set of data for @xmath18 , @xmath2 and @xmath120 is presented in fig .
[ height - velo - spread - inclination ] as a function of @xmath3 .
again @xmath18 is a monotonically increasing function of @xmath3 for each value of @xmath6 . in the fluid - like regime ( larger values of @xmath6 )
the slope of the @xmath121 curves is nearly constant . at smaller @xmath6
the slope increases considerably when entering the gaseous regime .
the flow thickness @xmath2 decreases with increasing @xmath3 in the fluid - like regime meaning that larger flow velocity results in smaller flow thickness .
this effect is actually stronger than fig .
[ height - velo - spread - inclination]b indicates , as the incoming flow rate slightly increases with increasing @xmath3 ( see fig .
[ discharge ] ) .
thus , thinning of the flow as a result of larger flow velocities is slightly counterbalanced by the growing value of the flow rate by increasing @xmath3 .
the different flow regimes can best be characterized by the flow density . as we see in fig .
[ inclination - density ] the normalized mean density @xmath85 drops continuously with increasing @xmath3 .
the density drop is more dramatic for smaller incoming flow rate than for thicker flows .
the _ first regime _ corresponds to dense flows ( slightly above the angle of repose ) and is often characterized by the pouliquen flow rule , where the depth averaged velocity @xmath122 is proportional to @xmath123 @xcite .
this regime is reported to exist for the plane inclinations @xmath124 , and the dense flow can be unstable with respect to the formation of waves @xcite . according to our measurements the mean density in this regime is slightly decreasing with @xmath3 but always stays larger than @xmath125 . according to a recent theory by jenkins @xcite the density should decrease as @xmath126tan@xmath127 .
a reasonable fit is obtained by this formula for a range of @xmath6 up to the plane inclination @xmath128 yielding @xmath129 . in the _ second regime _ falling in the range of @xmath130 , a stripe pattern can be observed with an average density of @xmath131 . the detailed characterization of the stripe structure is beyond the scope of this paper . in the _ third regime _ , the stripe structure disappears as the flow gets very fluidized with an average density of @xmath132 .
a dramatic density decrease was observed for lower incoming flow rates , typically at @xmath133 , yielding a gas - like phase where the density was less than @xmath134 of @xmath86 .
we characterize this transition in more detail below .
the surface flow velocity @xmath18 as a function of height @xmath2 is presented in fig .
[ height - velo]a for the fluid - like regime .
note that only the first curve ( at @xmath135 ) corresponds to stationary flows , the other curves ( partly ) fall already in the range of accelerating flows .
two sets of data were taken : ( i ) in the presence of air ( filled symbols ) and ( ii ) at low pressure @xmath79 mbar ( open symbols ) . in this regime
the two sets of data match implying that air drag does not become important even at the fastest flows where the grain velocity is close to the value of the terminal velocity measured in free fall . in the gaseous regime , however , ( see fig .
[ height - velo]b ) particle velocities measured at ambient pressure are slightly smaller than at low pressure .
thus , in the gas phase the average interparticle distance is considerably increased and the contribution of air drag to the dissipation becomes important .
the changing nature of the flow is visualized in fig .
[ height - velo]c where all the data points are presented for two plane inclinations for the two regimes and the transition between them .
the sharply different tendency of the @xmath136 curves in fig .
[ height - velo]a and fig .
[ height - velo]b reflects the nature of the transition between the fluid - like and gaseous phases . for @xmath137
the larger flow rates give rise to dense flows ( fig .
[ height - velo]a ) where increasing @xmath6 leads to increasing @xmath2 and faster flow . at lower values of the hopper flow rate decreasing
@xmath6 leads to increasing levels of fluidization and to a transition to the gaseous phase . in this regime , see fig .
[ height - velo]b , the density of the flow rapidly decreases with decreasing @xmath6 and the measured thickness rapidly increases .
contrary to trends for the fluid - like phase , the leftmost data points of the curves in fig .
[ height - velo]b correspond to the highest hopper flow rates and the rightmost ones to the lowest hopper flow rate .
thus , the flow is not simply determined by ( @xmath3 , @xmath2 , @xmath0 ) as is the case for dense flows . for a given @xmath2 , @xmath3 and @xmath0 , two solutions exists , one corresponding to a dense phase and the other to a very dilute one , depending on the flow rate . a recent linear stability analysis indicated , that the air drag could play a role in the development of stripe patterns in the fluid - like regime @xcite . according to our findings the density of the flow for the stripe state was in the range of @xmath131 , corresponding to the regime where the role of the air drag is minor .
the flow properties are not affected even at flow velocities near the terminal velocity in free fall . at the transition to the gaseous state
the stripes disappear and the rapid decrease of the flow density leads to visible effects of air drag . in summary , we have presented a detailed description of granular flow on a rough inclined plane - one of the most commonly used model systems for granular dynamics - concentrating on the fast flow regime .
we developed a method to measure the depth averaged normalized flow density @xmath85 and characterized the flow regimes as a function of @xmath85 .
we have characterized the transition to a very dilute gaseous phase that takes place by increasing plane inclination and decreasing incoming flow rate . by measuring the flow properties at ambient pressure and at low pressure ( @xmath138 mbar ) in a vacuum flow channel
we have shown that the dissipation by the air drag ( with respect to the other dissipational processes ) is non - negligible only in the dilute gas - like phase .
other implications of this work involves the possibility of linking changes in the flow structure ( such as the stripe state ) as a function of plane inclination to the change in the depth averaged normalized flow density @xmath85 .
this work was funded by the us department of energy ( w-7405-eng ) .
the authors benefited from discussions with i.s .
t.b . acknowledges support by the bolyai jnos scholarship of the hungarian academy of sciences and the hungarian scientific research fund ( contract no .
otka - f-060157 ) .[/INST] we report experiments on the overall phase diagram of granular flows on an incline with emphasis on high inclination angles where the mean layer velocity approaches the terminal velocity of a single particle free falling in air .
the granular flow was characterized by measurements of the surface velocity , the average layer height , and the mean density of the layer as functions of the hopper opening , the plane inclination angle and the downstream distance @xmath0 of the flow . at high
inclination angles the flow does not reach an @xmath1invariant steady state over the length of the inclined plane . for low volume flow rates ,
a transition was detected between dense and very dilute ( gas ) flow regimes .
we show using a vacuum flow channel that air did not qualitatively change the phase diagram and did not quantitatively modify mean flow velocities of the granular layer except for small changes in the very dilute gas - like phase . </s> |
share tweet pin email
Admittedly, lip syncing (or for that matter, singing of any kind) rarely involves protective glasses. But Melissa McCarthy does things a little differently.
The actress and star of new movie "The Boss" joined Jimmy Fallon on "The Tonight Show" on Monday night for an epic "Lip Sync Battle," and the results truly colored our world.
"I gotta be honest, I'm a little nervous," admitted Fallon before they went head-to-head.
"I don't get nervous a lot," she fired back. "I am pretty freaked out about crushing you."
MORE: From Dwayne Johnson to Anne Hathaway: Our favorite 'Lip Sync Battle' performers
Clearly, this was not going to be just any old lip sync battle. Fallon started things off with classic "Brand New Key" (sung originally by Melanie in 1971), but McCarthy stepped up the game quickly with DMX's 2003 hard hitter "X Gon' Give It To Ya" with a performance that left The Roots either laughing or looking stunned.
For the second round Fallon bounced back with Zayn Malik's recent hit "Pillowtalk" (he even brought a pillow out on stage to back him up). But he ultimately was no match for McCarthy, who came out on stage with clear goggles, a wind machine and a nature-themed backdrop as she launched into "Colors of the Wind," which Judy Kuhn sang for 1995's "Pocahontas."
But wait, there's more: As she launched into the song, stuffed animals (an otter, a heron and a wolf) blew in from offstage ... and then came the feathers and the glitter. So much glitter.
Surprise on @fallontonight Jimmy & I get Krazzzzy A video posted by Melissa McCarthy (@melissamccarthy) on Apr 4, 2016 at 5:27pm PDT
Jimmy Fallon (and all of us at home) doubled over in laughter. It may have been the messiest, most entertaining lip sync yet!
The Tonight Show Starring Jimmy Melissa McCarthy and Jimmy Fallon made a mess of the lip sync battle, and it was perfect.
MORE: John Krasinski gets his mind blown by Anna Kendrick on 'Lip Sync Battle': 'What is happening?'
"The Tonight Show Starring Jimmy Fallon" airs weeknights at 11:35 p.m. on NBC.
Follow Randee Dawn on Twitter. ||||| “What You Missed” on NBC: Melissa McCarthy stopped by “The Tonight Show” to promote her new movie “The Boss”, and to show Jimmy Fallon how a lip sync battle is done. Melissa started with a hit DMX song and then brought the house down with an action-packed performance from the Disney classic, “Pocahontas”. ||||| Published on Apr 4, 2016
Jimmy faces off with Melissa McCarthy in a hilarious lip sync-off to songs like ZAYN's "Pillowtalk" and "Colors of the Wind" from Disney's Pocahontas.
Subscribe NOW to The Tonight Show Starring Jimmy Fallon: http://bit.ly/1nwT1aN
Watch The Tonight Show Starring Jimmy Fallon Weeknights 11:35/10:35c
Get more Jimmy Fallon:
Follow Jimmy: http://Twitter.com/JimmyFallon
Like Jimmy: https://Facebook.com/JimmyFallon
Get more The Tonight Show Starring Jimmy Fallon:
Follow The Tonight Show: http://Twitter.com/FallonTonight
Like The Tonight Show: https://Facebook.com/FallonTonight
The Tonight Show Tumblr: http://fallontonight.tumblr.com/
Get more NBC:
NBC YouTube: http://bit.ly/1dM1qBH
Like NBC: http://Facebook.com/NBC
Follow NBC: http://Twitter.com/NBC
NBC Tumblr: http://nbctv.tumblr.com/
NBC Google+: https://plus.google.com/+NBC/posts
The Tonight Show Starring Jimmy Fallon features hilarious highlights from the show including: comedy sketches, music parodies, celebrity interviews, ridiculous games, and, of course, Jimmy's Thank You Notes and hashtags! You'll also find behind the scenes videos and other great web exclusives.
Lip Sync Battle with Melissa McCarthy
http://www.youtube.com/fallontonight #FallonTonight #JimmyFallon #LipSyncBattle #FallonTonight #JimmyFallon #LipSyncBattle ||||| Who’s the new queen of the Lip Sync Battle? Melissa McCarthy, that’s who!
The 45-year-old actress shut down the house Monday on The Tonight Show during the popular segment Lip Sync Battle against host Jimmy Fallon.
Things started off slowly with Fallon lip-syncing to “Brand New Key” by Melanie as he pretended to roller-skate around the set. But McCarthy challenged him with a lip-sync of DMX’s “X Gon’ Give It to Ya,” which pretty much left everyone speechless — including Fallon.
For Round 2, Fallon brought out the goods with Zayn Malik’s hit “Pillowtalk” — but it was McCarthy that stole the show with “Colors of the Wind” from Disney’s Pocahontas.
Watch the hilarious Lip Sync Battle in the video player above | – Melissa McCarthy clearly won Monday night's Lip Sync Battle with Jimmy Fallon on The Tonight Show, with a performance that's being called "epic," "gritty," and "the messiest, most entertaining lip sync ever." But Fallon did give it his best shot, expertly miming bad rollerskating during his lip sync of Melanie's "Brand New Key" and then later writhing around on the ground with a pillow during his lip sync of Zayn Malik's "Pillowtalk." But McCarthy had him beat with her performances of DMX's "X Gon' Give It to Ya" and, brilliantly, "Colors of the Wind" from 1995's Pocahontas, which must be seen to be believed. | <s>[INST]share tweet pin email
Admittedly, lip syncing (or for that matter, singing of any kind) rarely involves protective glasses. But Melissa McCarthy does things a little differently.
The actress and star of new movie "The Boss" joined Jimmy Fallon on "The Tonight Show" on Monday night for an epic "Lip Sync Battle," and the results truly colored our world.
"I gotta be honest, I'm a little nervous," admitted Fallon before they went head-to-head.
"I don't get nervous a lot," she fired back. "I am pretty freaked out about crushing you."
MORE: From Dwayne Johnson to Anne Hathaway: Our favorite 'Lip Sync Battle' performers
Clearly, this was not going to be just any old lip sync battle. Fallon started things off with classic "Brand New Key" (sung originally by Melanie in 1971), but McCarthy stepped up the game quickly with DMX's 2003 hard hitter "X Gon' Give It To Ya" with a performance that left The Roots either laughing or looking stunned.
For the second round Fallon bounced back with Zayn Malik's recent hit "Pillowtalk" (he even brought a pillow out on stage to back him up). But he ultimately was no match for McCarthy, who came out on stage with clear goggles, a wind machine and a nature-themed backdrop as she launched into "Colors of the Wind," which Judy Kuhn sang for 1995's "Pocahontas."
But wait, there's more: As she launched into the song, stuffed animals (an otter, a heron and a wolf) blew in from offstage ... and then came the feathers and the glitter. So much glitter.
Surprise on @fallontonight Jimmy & I get Krazzzzy A video posted by Melissa McCarthy (@melissamccarthy) on Apr 4, 2016 at 5:27pm PDT
Jimmy Fallon (and all of us at home) doubled over in laughter. It may have been the messiest, most entertaining lip sync yet!
The Tonight Show Starring Jimmy Melissa McCarthy and Jimmy Fallon made a mess of the lip sync battle, and it was perfect.
MORE: John Krasinski gets his mind blown by Anna Kendrick on 'Lip Sync Battle': 'What is happening?'
"The Tonight Show Starring Jimmy Fallon" airs weeknights at 11:35 p.m. on NBC.
Follow Randee Dawn on Twitter. ||||| “What You Missed” on NBC: Melissa McCarthy stopped by “The Tonight Show” to promote her new movie “The Boss”, and to show Jimmy Fallon how a lip sync battle is done. Melissa started with a hit DMX song and then brought the house down with an action-packed performance from the Disney classic, “Pocahontas”. ||||| Published on Apr 4, 2016
Jimmy faces off with Melissa McCarthy in a hilarious lip sync-off to songs like ZAYN's "Pillowtalk" and "Colors of the Wind" from Disney's Pocahontas.
Subscribe NOW to The Tonight Show Starring Jimmy Fallon: http://bit.ly/1nwT1aN
Watch The Tonight Show Starring Jimmy Fallon Weeknights 11:35/10:35c
Get more Jimmy Fallon:
Follow Jimmy: http://Twitter.com/JimmyFallon
Like Jimmy: https://Facebook.com/JimmyFallon
Get more The Tonight Show Starring Jimmy Fallon:
Follow The Tonight Show: http://Twitter.com/FallonTonight
Like The Tonight Show: https://Facebook.com/FallonTonight
The Tonight Show Tumblr: http://fallontonight.tumblr.com/
Get more NBC:
NBC YouTube: http://bit.ly/1dM1qBH
Like NBC: http://Facebook.com/NBC
Follow NBC: http://Twitter.com/NBC
NBC Tumblr: http://nbctv.tumblr.com/
NBC Google+: https://plus.google.com/+NBC/posts
The Tonight Show Starring Jimmy Fallon features hilarious highlights from the show including: comedy sketches, music parodies, celebrity interviews, ridiculous games, and, of course, Jimmy's Thank You Notes and hashtags! You'll also find behind the scenes videos and other great web exclusives.
Lip Sync Battle with Melissa McCarthy
http://www.youtube.com/fallontonight #FallonTonight #JimmyFallon #LipSyncBattle #FallonTonight #JimmyFallon #LipSyncBattle ||||| Who’s the new queen of the Lip Sync Battle? Melissa McCarthy, that’s who!
The 45-year-old actress shut down the house Monday on The Tonight Show during the popular segment Lip Sync Battle against host Jimmy Fallon.
Things started off slowly with Fallon lip-syncing to “Brand New Key” by Melanie as he pretended to roller-skate around the set. But McCarthy challenged him with a lip-sync of DMX’s “X Gon’ Give It to Ya,” which pretty much left everyone speechless — including Fallon.
For Round 2, Fallon brought out the goods with Zayn Malik’s hit “Pillowtalk” — but it was McCarthy that stole the show with “Colors of the Wind” from Disney’s Pocahontas.
Watch the hilarious Lip Sync Battle in the video player above[/INST]– Melissa McCarthy clearly won Monday night's Lip Sync Battle with Jimmy Fallon on The Tonight Show, with a performance that's being called "epic," "gritty," and "the messiest, most entertaining lip sync ever." But Fallon did give it his best shot, expertly miming bad rollerskating during his lip sync of Melanie's "Brand New Key" and then later writhing around on the ground with a pillow during his lip sync of Zayn Malik's "Pillowtalk." But McCarthy had him beat with her performances of DMX's "X Gon' Give It to Ya" and, brilliantly, "Colors of the Wind" from 1995's Pocahontas, which must be seen to be believed.</s> |
SECTION 1. SHORT TITLE.
This Act may be cited as the ``Empowering America Act of 2006''.
SEC. 2. EXTENSION AND MODIFICATION OF CREDIT FOR RESIDENTIAL ENERGY
EFFICIENT PROPERTY.
(a) Extension.--Subsection (g) of section 25D of the Internal
Revenue Code of 1986 (relating to termination) is amended by striking
``2007'' and inserting ``2015''.
(b) Modification of Maximum Credit.--Paragraph (1) of section
25D(b) of such Code (relating to limitations) is amended to read as
follows:
``(1) Maximum credit.--The credit allowed under subsection
(a) for any taxable year shall not exceed--
``(A) $2,000 with respect to each half kilowatt of
capacity of qualified photovoltaic property for which
qualified photovoltaic property expenditures are made,
``(B) $2,000 with respect to any qualified solar
water heating property expenditures, and
``(C) $500 with respect to each half kilowatt of
capacity of qualified fuel cell property (as defined in
section 48(c)(1)) for which qualified fuel cell
property expenditures are made.''.
(c) Credit Allowed Against Alternative Minimum Tax.--
(1) In general.--Section 25D(b) of such Code (as amended by
subsection (b)) is amended by adding at the end the following
new paragraph:
``(3) Credit allowed against alternative minimum tax.--The
credit allowed under subsection (a) for the taxable year shall
not exceed the excess of--
``(A) the sum of the regular tax liability (as
defined in section 26(b)) plus the tax imposed by
section 55, over
``(B) the sum of the credits allowable under
subpart A of part IV of subchapter A and section 27 for
the taxable year.''.
(2) Conforming amendment.--Subsection (c) of section 25D of
such Code is amended to read as follows:
``(c) Carryforward of Unused Credit.--If the credit allowable under
subsection (a) for any taxable year exceeds the limitation imposed by
subsection (b)(3) for such taxable year, such excess shall be carried
to the succeeding taxable year and added to the credit allowable under
subsection (a) for such succeeding taxable year.''.
(d) Effective Date.--The amendments made by this section shall
apply to taxable years beginning after December 31, 2006.
SEC. 3. EXTENSION AND MODIFICATION OF CREDIT FOR NONBUSINESS ENERGY
PROPERTY.
(a) Extension.--Subsection (g) of section 25C of the Internal
Revenue Code of 1986 (relating to termination) is amended by striking
``2007'' and inserting ``2015''.
(b) Modification of Credit Amount.--Section 25C of such Code
(relating to nonbusiness energy property) is amended--
(1) in subsection (a)(1), by striking ``10 percent'' and
inserting ``15 percent'', and
(2) in subsection (b)--
(A) in paragraph (1), by striking ``$500'' and
inserting ``$1,000'',
(B) in paragraph (2), by striking ``$200'' and
inserting ``$500'', and
(C) in paragraph (3)--
(i) in subparagraph (A), by striking
``$50'' and inserting ``$150'',
(ii) in subparagraph (B), by striking
``$150'' and inserting ``$300'', and
(iii) in subparagraph (C), by striking
``$300'' and inserting ``$500''.
(c) Credit Allowed Against Alternative Minimum Tax.--Section 25C(b)
of such Code (as amended by subsection (b)(2)) is amended by adding at
the end the following new paragraph:
``(4) Credit allowed against alternative minimum tax.--The
credit allowed under subsection (a) for the taxable year shall
not exceed the excess of--
``(A) the sum of the regular tax liability (as
defined in section 26(b)) plus the tax imposed by
section 55, over
``(B) the sum of the credits allowable under
subpart A of part IV of subchapter A and section 27 for
the taxable year.''.
(d) Effective Date.--The amendments made by this section shall
apply to taxable years beginning after December 31, 2006.
SEC. 4. EXTENSION AND MODIFICATION OF ENERGY EFFICIENT COMMERCIAL
BUILDINGS DEDUCTION.
(a) Extension.--Subsection (h) of section 179D of the Internal
Revenue Code of 1986 (relating to termination) is amended by striking
``2007'' and inserting ``2015''.
(b) Modification of Maximum Deduction.--Subparagraph (A) of section
179D(b)(1)(A) of such Code (relating to maximum amount of deduction) is
amended by striking ``$1.80'' and inserting ``$2.00''.
(c) Modification of Partial Allowance.--Subparagraph (A) of section
179D(d)(1) of such Code (relating to partial allowance) is amended in
the flush text following clause (ii) by striking ``substituting `$.60'
for `$1.80''' and inserting ``substituting `$.75' for `$2.00'''.
(d) Effective Date.--The amendments made by this section shall
apply to taxable years beginning after December 31, 2006.
SEC. 5. EXTENSION OF ENERGY CREDIT FOR EQUIPMENT WHICH USES SOLAR
ENERGY.
(a) In General.--Subsection (a) of section 48 of the Internal
Revenue Code of 1986 (relating to energy credit) is amended--
(1) in paragraph (2)(A)(i)(II) by striking ``2008'' and
inserting ``2015'', and
(2) in paragraph (3)(A)(ii) by striking ``2008'' and
inserting ``2015''.
(b) Effective Date.--The amendments made by this section shall
apply to taxable years beginning after December 31, 2006.
SEC. 6. STUDY ON EFFECTIVENESS OF ENERGY EFFICIENCY TAX INCENTIVES.
(a) Study.--The Secretary of Energy, in collaboration with the
Secretary of the Treasury, shall conduct a study on the effectiveness
of the conservation and energy efficiency tax incentives enacted in
subtitle C of the Energy Tax Incentives Act of 2005 that includes an
analysis of the rate of participation with respect to such tax
incentives and recommendations for additional measures that could be
taken to increase the rate of participation.
(b) Report.--Not later than 1 year after the date of enactment of
this Act, the Secretary of Energy shall transmit to Congress a report
on the results of the study conducted pursuant to subsection (a).
SEC. 7. ENERGY EFFICIENT APPLIANCE REBATE PROGRAMS.
Section 124(f) of the Energy Policy Act of 2005 (42 U.S.C.
15821(f)) is amended by striking ``2010'' and inserting ``2015''.
SEC. 8. SOLAR ENERGY SYSTEMS BUILDING PERMIT REQUIREMENTS FOR RECEIPT
OF COMMUNITY DEVELOPMENT BLOCK GRANT FUNDS.
Section 104 of the Housing and Community Development Act of 1974
(42 U.S.C. 5304) is amended by adding at the end the following new
subsection:
``(n) Requirements for Building Permits Regarding Solar Energy
Systems.--
``(1) In general.--A grant under section 106 for a fiscal
year may be made only if the grantee certifies to the Secretary
that--
``(A) in the case of a grant under section 106(a)
for any Indian tribe or insular area, during such
fiscal year the cost of any permit or license, for
construction or installation of any solar energy system
for any structure, that is required by the tribe or
insular area or by any other unit of general local
government or other political subdivision of such tribe
or insular area, complies with paragraph (2);
``(B) in the case of a grant under section 106(b)
for any metropolitan city or urban county, during such
fiscal year the cost of any permit or license, for
construction or installation of any solar energy system
for any structure, that is required by the metropolitan
city or urban county, or by any other political
subdivision of such city or county, complies with
paragraph (2); and
``(C) in the case of a grant under section 106(d)
for any State, during such fiscal year the cost of any
permit or license, for construction or installation of
any solar energy system for any structure, that is
required by the State, or by any other unit of general
local government within any nonentitlement area of such
State, or other political subdivision within any
nonentitlement area of such State or such a unit of
general local government, complies with paragraph (2).
``(2) Limitation on cost.--The cost of permit or license
for construction or installation of any solar energy system
complies with this paragraph only if such cost does not exceed
the following amount:
``(A) Residential structures.--In the case of a
structure primarily for residential use, $500.
``(B) Nonresidential structures.--In the case of a
structure primarily for nonresidential use, 1.0 percent
of the total cost of the installation or construction
of the solar energy system.
``(3) Noncompliance.--If the Secretary determines that a
grantee of a grant made under section 106 is not in compliance
with a certification under paragraph (1)--
``(A) the Secretary shall notify the grantee of
such determination; and
``(B) if the grantee has not corrected such
noncompliance before the expiration of the 6-month
period beginning upon notification under subparagraph
(A), such grantee shall not be eligible for a grant
under section 106 for the first fiscal year that
commences after the expiration of such 6-month period.
``(4) Solar energy system.--For purposes of this
subsection, the term `solar energy system' means, with respect
to a structure, equipment that uses solar energy to generate
electricity for, or to heat or cool (or provide hot water for
use in), such structure.''.
SEC. 9. PROHIBITION OF RESTRICTIONS ON RESIDENTIAL INSTALLATION OF
SOLAR ENERGY SYSTEM.
(a) Regulations.--Within 180 days after the enactment of this Act,
the Secretary of Housing and Urban Development, in consultation with
the Secretary of Energy, shall issue regulations--
(1) to prohibit any private covenant, contract provision,
lease provision, homeowners' association rule or bylaw, or
similar restriction, that impairs the ability of the owner or
lessee of any residential structure designed for occupancy by
one family to install, construct, maintain, or use a solar
energy system on such residential property; and
(2) to require that whenever any such covenant, provision,
rule or bylaw, or restriction requires approval for the
installation or use of a solar energy system, the application
for approval shall be processed and approved by the appropriate
approving entity in the same manner as an application for
approval of an architectural modification to the property, and
shall not be willfully avoided or delayed.
(b) Contents.--Such regulations shall provide that--
(1) such a covenant, provision, rule or bylaw, or
restriction impairs the installation, construction,
maintenance, or use of a solar energy system if it--
(A) unreasonably delays or prevents installation,
maintenance, or use;
(B) unreasonably increases the cost of
installation, maintenance, or use; or
(C) precludes use of such a system; and
(2) any fee or cost imposed on the owner or lessee of such
a residential structure by such a covenant, provision, rule or
bylaw, or restriction shall be considered unreasonable if--
(A) such fee or cost is not reasonable in
comparison to the cost of the solar energy system or
the value of its use; or
(B) treatment of solar energy systems by the
covenant, provision, rule or bylaw, or restriction is
not reasonable in comparison with treatment of
comparable systems by the same covenant, provision,
rule or bylaw, or restriction.
(c) Solar Energy System.--For purposes of this section, the term
``solar energy system'' means, with respect to a structure, equipment
that uses solar energy to generate electricity for, or to heat or cool
(or provide hot water for use in), such structure.
SEC. 10. CENTER FOR ADVANCED SOLAR RESEARCH.
(a) Establishment.--The Secretary of Energy shall establish a
Center for Advanced Solar Research and Development within the Office of
Energy Efficiency and Renewable Energy to carry out an advanced solar
research and development program to coordinate and promote the further
development of solar technologies. This program shall include a
competitive grant program for academia and private research in solar
technologies. The Center shall serve as a clearinghouse for United
States solar research and development, supporting research,
development, and demonstration of advanced solar energy systems. The
Center shall advance--
(1) performance, reliability, environmental impact, and
cost-competiveness of solar thermal and photovoltaic
technologies;
(2) large-scale photovoltaic and solar thermal power
plants;
(3) thermal and electricity storage technologies to enhance
the dispatchability of solar energy;
(4) fuel production technologies using solar energy;
(5) innovation in manufacturing techniques and processes
for solar energy systems;
(6) materials and devices to improve photovoltaic
conversion efficiencies and reduce costs;
(7) policy analysis aimed at increasing use of solar energy
technologies, and monitoring the effectiveness of existing
policies; and
(8) comprehensive solar systems integration.
(b) Authorization of Appropriations.--There are authorized to be
appropriated to the Secretary of Energy for carrying out this section
$250,000,000 for each of the fiscal years 2007 through 2011, to remain
available until expended. | Empowering America Act of 2006 - Amends the Internal Revenue Code to increase and extend through 2015: (1) the tax credit for residential energy efficient property; (2) the tax credit for nonbusiness energy property; and (3) the tax deduction for energy efficient commercial buildings. Extends through 2015 the energy tax credit for equipment which uses solar energy.
Amends the Energy Policy Act of 2005 to extend through FY2015 funding of energy efficient appliance rebate programs.
Amends the Housing and Community Development Act of 1974 to require that states, counties, and Indian tribes which receive community development block grants limit the cost of permits or licenses for the construction or installation of solar energy systems in residential and nonresidential structures.
Directs the Secretary of Housing and Urban Development to issue regulations to prohibit restrictions on the installation, construction, maintenance, or use of a solar energy system in a single family residence.
Directs the Secretary of Energy to: (1) study the effectiveness of the conservation and energy efficiency tax incentives enacted by the Energy Tax Incentives Act of 2005 and report to Congress on such study; and (2) establish a Center for Advanced Solar Research and Development. | <s>[INST]SECTION 1. SHORT TITLE.
This Act may be cited as the ``Empowering America Act of 2006''.
SEC. 2. EXTENSION AND MODIFICATION OF CREDIT FOR RESIDENTIAL ENERGY
EFFICIENT PROPERTY.
(a) Extension.--Subsection (g) of section 25D of the Internal
Revenue Code of 1986 (relating to termination) is amended by striking
``2007'' and inserting ``2015''.
(b) Modification of Maximum Credit.--Paragraph (1) of section
25D(b) of such Code (relating to limitations) is amended to read as
follows:
``(1) Maximum credit.--The credit allowed under subsection
(a) for any taxable year shall not exceed--
``(A) $2,000 with respect to each half kilowatt of
capacity of qualified photovoltaic property for which
qualified photovoltaic property expenditures are made,
``(B) $2,000 with respect to any qualified solar
water heating property expenditures, and
``(C) $500 with respect to each half kilowatt of
capacity of qualified fuel cell property (as defined in
section 48(c)(1)) for which qualified fuel cell
property expenditures are made.''.
(c) Credit Allowed Against Alternative Minimum Tax.--
(1) In general.--Section 25D(b) of such Code (as amended by
subsection (b)) is amended by adding at the end the following
new paragraph:
``(3) Credit allowed against alternative minimum tax.--The
credit allowed under subsection (a) for the taxable year shall
not exceed the excess of--
``(A) the sum of the regular tax liability (as
defined in section 26(b)) plus the tax imposed by
section 55, over
``(B) the sum of the credits allowable under
subpart A of part IV of subchapter A and section 27 for
the taxable year.''.
(2) Conforming amendment.--Subsection (c) of section 25D of
such Code is amended to read as follows:
``(c) Carryforward of Unused Credit.--If the credit allowable under
subsection (a) for any taxable year exceeds the limitation imposed by
subsection (b)(3) for such taxable year, such excess shall be carried
to the succeeding taxable year and added to the credit allowable under
subsection (a) for such succeeding taxable year.''.
(d) Effective Date.--The amendments made by this section shall
apply to taxable years beginning after December 31, 2006.
SEC. 3. EXTENSION AND MODIFICATION OF CREDIT FOR NONBUSINESS ENERGY
PROPERTY.
(a) Extension.--Subsection (g) of section 25C of the Internal
Revenue Code of 1986 (relating to termination) is amended by striking
``2007'' and inserting ``2015''.
(b) Modification of Credit Amount.--Section 25C of such Code
(relating to nonbusiness energy property) is amended--
(1) in subsection (a)(1), by striking ``10 percent'' and
inserting ``15 percent'', and
(2) in subsection (b)--
(A) in paragraph (1), by striking ``$500'' and
inserting ``$1,000'',
(B) in paragraph (2), by striking ``$200'' and
inserting ``$500'', and
(C) in paragraph (3)--
(i) in subparagraph (A), by striking
``$50'' and inserting ``$150'',
(ii) in subparagraph (B), by striking
``$150'' and inserting ``$300'', and
(iii) in subparagraph (C), by striking
``$300'' and inserting ``$500''.
(c) Credit Allowed Against Alternative Minimum Tax.--Section 25C(b)
of such Code (as amended by subsection (b)(2)) is amended by adding at
the end the following new paragraph:
``(4) Credit allowed against alternative minimum tax.--The
credit allowed under subsection (a) for the taxable year shall
not exceed the excess of--
``(A) the sum of the regular tax liability (as
defined in section 26(b)) plus the tax imposed by
section 55, over
``(B) the sum of the credits allowable under
subpart A of part IV of subchapter A and section 27 for
the taxable year.''.
(d) Effective Date.--The amendments made by this section shall
apply to taxable years beginning after December 31, 2006.
SEC. 4. EXTENSION AND MODIFICATION OF ENERGY EFFICIENT COMMERCIAL
BUILDINGS DEDUCTION.
(a) Extension.--Subsection (h) of section 179D of the Internal
Revenue Code of 1986 (relating to termination) is amended by striking
``2007'' and inserting ``2015''.
(b) Modification of Maximum Deduction.--Subparagraph (A) of section
179D(b)(1)(A) of such Code (relating to maximum amount of deduction) is
amended by striking ``$1.80'' and inserting ``$2.00''.
(c) Modification of Partial Allowance.--Subparagraph (A) of section
179D(d)(1) of such Code (relating to partial allowance) is amended in
the flush text following clause (ii) by striking ``substituting `$.60'
for `$1.80''' and inserting ``substituting `$.75' for `$2.00'''.
(d) Effective Date.--The amendments made by this section shall
apply to taxable years beginning after December 31, 2006.
SEC. 5. EXTENSION OF ENERGY CREDIT FOR EQUIPMENT WHICH USES SOLAR
ENERGY.
(a) In General.--Subsection (a) of section 48 of the Internal
Revenue Code of 1986 (relating to energy credit) is amended--
(1) in paragraph (2)(A)(i)(II) by striking ``2008'' and
inserting ``2015'', and
(2) in paragraph (3)(A)(ii) by striking ``2008'' and
inserting ``2015''.
(b) Effective Date.--The amendments made by this section shall
apply to taxable years beginning after December 31, 2006.
SEC. 6. STUDY ON EFFECTIVENESS OF ENERGY EFFICIENCY TAX INCENTIVES.
(a) Study.--The Secretary of Energy, in collaboration with the
Secretary of the Treasury, shall conduct a study on the effectiveness
of the conservation and energy efficiency tax incentives enacted in
subtitle C of the Energy Tax Incentives Act of 2005 that includes an
analysis of the rate of participation with respect to such tax
incentives and recommendations for additional measures that could be
taken to increase the rate of participation.
(b) Report.--Not later than 1 year after the date of enactment of
this Act, the Secretary of Energy shall transmit to Congress a report
on the results of the study conducted pursuant to subsection (a).
SEC. 7. ENERGY EFFICIENT APPLIANCE REBATE PROGRAMS.
Section 124(f) of the Energy Policy Act of 2005 (42 U.S.C.
15821(f)) is amended by striking ``2010'' and inserting ``2015''.
SEC. 8. SOLAR ENERGY SYSTEMS BUILDING PERMIT REQUIREMENTS FOR RECEIPT
OF COMMUNITY DEVELOPMENT BLOCK GRANT FUNDS.
Section 104 of the Housing and Community Development Act of 1974
(42 U.S.C. 5304) is amended by adding at the end the following new
subsection:
``(n) Requirements for Building Permits Regarding Solar Energy
Systems.--
``(1) In general.--A grant under section 106 for a fiscal
year may be made only if the grantee certifies to the Secretary
that--
``(A) in the case of a grant under section 106(a)
for any Indian tribe or insular area, during such
fiscal year the cost of any permit or license, for
construction or installation of any solar energy system
for any structure, that is required by the tribe or
insular area or by any other unit of general local
government or other political subdivision of such tribe
or insular area, complies with paragraph (2);
``(B) in the case of a grant under section 106(b)
for any metropolitan city or urban county, during such
fiscal year the cost of any permit or license, for
construction or installation of any solar energy system
for any structure, that is required by the metropolitan
city or urban county, or by any other political
subdivision of such city or county, complies with
paragraph (2); and
``(C) in the case of a grant under section 106(d)
for any State, during such fiscal year the cost of any
permit or license, for construction or installation of
any solar energy system for any structure, that is
required by the State, or by any other unit of general
local government within any nonentitlement area of such
State, or other political subdivision within any
nonentitlement area of such State or such a unit of
general local government, complies with paragraph (2).
``(2) Limitation on cost.--The cost of permit or license
for construction or installation of any solar energy system
complies with this paragraph only if such cost does not exceed
the following amount:
``(A) Residential structures.--In the case of a
structure primarily for residential use, $500.
``(B) Nonresidential structures.--In the case of a
structure primarily for nonresidential use, 1.0 percent
of the total cost of the installation or construction
of the solar energy system.
``(3) Noncompliance.--If the Secretary determines that a
grantee of a grant made under section 106 is not in compliance
with a certification under paragraph (1)--
``(A) the Secretary shall notify the grantee of
such determination; and
``(B) if the grantee has not corrected such
noncompliance before the expiration of the 6-month
period beginning upon notification under subparagraph
(A), such grantee shall not be eligible for a grant
under section 106 for the first fiscal year that
commences after the expiration of such 6-month period.
``(4) Solar energy system.--For purposes of this
subsection, the term `solar energy system' means, with respect
to a structure, equipment that uses solar energy to generate
electricity for, or to heat or cool (or provide hot water for
use in), such structure.''.
SEC. 9. PROHIBITION OF RESTRICTIONS ON RESIDENTIAL INSTALLATION OF
SOLAR ENERGY SYSTEM.
(a) Regulations.--Within 180 days after the enactment of this Act,
the Secretary of Housing and Urban Development, in consultation with
the Secretary of Energy, shall issue regulations--
(1) to prohibit any private covenant, contract provision,
lease provision, homeowners' association rule or bylaw, or
similar restriction, that impairs the ability of the owner or
lessee of any residential structure designed for occupancy by
one family to install, construct, maintain, or use a solar
energy system on such residential property; and
(2) to require that whenever any such covenant, provision,
rule or bylaw, or restriction requires approval for the
installation or use of a solar energy system, the application
for approval shall be processed and approved by the appropriate
approving entity in the same manner as an application for
approval of an architectural modification to the property, and
shall not be willfully avoided or delayed.
(b) Contents.--Such regulations shall provide that--
(1) such a covenant, provision, rule or bylaw, or
restriction impairs the installation, construction,
maintenance, or use of a solar energy system if it--
(A) unreasonably delays or prevents installation,
maintenance, or use;
(B) unreasonably increases the cost of
installation, maintenance, or use; or
(C) precludes use of such a system; and
(2) any fee or cost imposed on the owner or lessee of such
a residential structure by such a covenant, provision, rule or
bylaw, or restriction shall be considered unreasonable if--
(A) such fee or cost is not reasonable in
comparison to the cost of the solar energy system or
the value of its use; or
(B) treatment of solar energy systems by the
covenant, provision, rule or bylaw, or restriction is
not reasonable in comparison with treatment of
comparable systems by the same covenant, provision,
rule or bylaw, or restriction.
(c) Solar Energy System.--For purposes of this section, the term
``solar energy system'' means, with respect to a structure, equipment
that uses solar energy to generate electricity for, or to heat or cool
(or provide hot water for use in), such structure.
SEC. 10. CENTER FOR ADVANCED SOLAR RESEARCH.
(a) Establishment.--The Secretary of Energy shall establish a
Center for Advanced Solar Research and Development within the Office of
Energy Efficiency and Renewable Energy to carry out an advanced solar
research and development program to coordinate and promote the further
development of solar technologies. This program shall include a
competitive grant program for academia and private research in solar
technologies. The Center shall serve as a clearinghouse for United
States solar research and development, supporting research,
development, and demonstration of advanced solar energy systems. The
Center shall advance--
(1) performance, reliability, environmental impact, and
cost-competiveness of solar thermal and photovoltaic
technologies;
(2) large-scale photovoltaic and solar thermal power
plants;
(3) thermal and electricity storage technologies to enhance
the dispatchability of solar energy;
(4) fuel production technologies using solar energy;
(5) innovation in manufacturing techniques and processes
for solar energy systems;
(6) materials and devices to improve photovoltaic
conversion efficiencies and reduce costs;
(7) policy analysis aimed at increasing use of solar energy
technologies, and monitoring the effectiveness of existing
policies; and
(8) comprehensive solar systems integration.
(b) Authorization of Appropriations.--There are authorized to be
appropriated to the Secretary of Energy for carrying out this section
$250,000,000 for each of the fiscal years 2007 through 2011, to remain
available until expended.[/INST]Empowering America Act of 2006 - Amends the Internal Revenue Code to increase and extend through 2015: (1) the tax credit for residential energy efficient property; (2) the tax credit for nonbusiness energy property; and (3) the tax deduction for energy efficient commercial buildings. Extends through 2015 the energy tax credit for equipment which uses solar energy.
Amends the Energy Policy Act of 2005 to extend through FY2015 funding of energy efficient appliance rebate programs.
Amends the Housing and Community Development Act of 1974 to require that states, counties, and Indian tribes which receive community development block grants limit the cost of permits or licenses for the construction or installation of solar energy systems in residential and nonresidential structures.
Directs the Secretary of Housing and Urban Development to issue regulations to prohibit restrictions on the installation, construction, maintenance, or use of a solar energy system in a single family residence.
Directs the Secretary of Energy to: (1) study the effectiveness of the conservation and energy efficiency tax incentives enacted by the Energy Tax Incentives Act of 2005 and report to Congress on such study; and (2) establish a Center for Advanced Solar Research and Development.</s> |
over the last four decades , the physics of particle scattering from different kinds of black holes was one of the most active topics of strong gravitational fields . apart from the quasinormal modes which , in principle , can be identified as the poles of the corresponding black hole scattering matrix , the behaviour of the cross section with respect to the scattering angle is one of the most interesting features in this area . the key issues around which the physics of black hole scattering centers are related to phenomena such as glory , orbiting ( or spiralling ) , rainbow and super - radiant scattering .
one should note that these features are observed experimentally and studied extensively theoretically in nucleus - nucleus scattering .
it is gratifying to see similar phenomena occurring in black hole scattering @xcite . in the pioneering papers of ford and wheeler @xcite ,
using semi - classical arguments , a connection between the classical rainbow , glory and orbiting phenomena was made with their quantum mechanical counterparts .
starting with a procedure as proposed by mott and massey @xcite which gave the classical cross section @xmath3 , the authors noticed that the classical deflection function can be written in terms of the quantum mechanical scattering phase shift as @xmath4/dl$ ] , where @xmath5 is the angular momentum and @xmath6 the impact parameter .
for particles scattered into the solid angle @xmath7 , the cross sectional area can be written as , @xmath8 , so that the differential cross section is proportional to @xmath9 .
the classical angular momentum is @xmath10 .
going over to the quantum mechanical case , if we now consider the de broglie wavelength @xmath11 of the particle to be small compared to the range of the force , we may write , @xmath12 .
in fact , while working with semi - classical approximations such as the wkb , one must replace @xmath13 . in the article of ford and wheeler
, the authors thus obtain the differential cross section proportional to @xmath14 , which is divergent when the scattering angle @xmath15 is @xmath16 or @xmath17 .
glory is characterized by @xmath18 passing with finite slope through @xmath19 etc and rainbow by the maxima or minima in @xmath18 .
if the deflection function displays a singularity at a certain critical value @xmath1 of @xmath5 , they show that @xmath18 will vary logarithmically near @xmath20 . for values of @xmath5 below and above @xmath1 the particle would have spiralling trajectories and @xmath20 would give the limit of an unstable circular orbit .
for a particle incident with energy @xmath21 and for an effective potential , @xmath22 , which is the sum of an actual interaction potential and a centrifugal term , the condition corresponding to such an orbit was shown to be @xmath23 ( which as we shall see later is @xmath24 for massless particles with @xmath25 ) , where @xmath26 is the position of the maximum of the effective potential and @xmath21 the available energy .
quantum mechanically , one does not get divergent cross sections .
one rather observes peaks in the cross sections as a function of angle in the backward directions for glory and orbiting scattering .
based on the works of ford and wheeler , the characterization of the above phenomena in black hole scattering is mostly done in literature by noting the behaviour of the real part of the scattering phase shift or by looking at the oscillating patterns in the cross sections at backward angles . in the present work , we relate the phenomenon of orbiting scattering to the imaginary part of the scattering phase shift .
to be specific we evaluate the reflection coefficient in black hole scattering from schwarzschild black holes by solving the corresponding riccati equation numerically . finding a sudden rise of the reflection coefficient
, @xmath27 plotted as a function of @xmath5 , at a certain critical value of @xmath5 for different energies and different spins ( @xmath28 ) of the massless scattering particles , we show that this critical @xmath5 is nothing but the @xmath1 corresponding to the unstable circular orbit .
we also find that the normalized @xmath0 always passes through a value of @xmath29 at the critical value @xmath1 .
the present work differs from others @xcite in view of the points mentioned above .
the reflection coefficient is evaluated exactly using the variable amplitude method as compared to approximate calculations ( third reference in @xcite ) , @xcite .
we also find a potential proportional to @xmath30 which gives remarkably good results when compared with the numerical ones .
for this potential the transmission coefficients can be found analytically .
parametrizing the @xmath31 potential to fit the regge - wheeler potential , we find semi - analytical results for black hole scattering .
even though the scattering off black holes is a widely explored area , not much attention has been paid to the orbiting phenomenon ( mostly the glory and rainbow effects have been discussed ) . here
we supplement the existing literature by a detailed study of how the existence of a classical orbit gets reflected in the quantum mechanical expressions of the scattering of a massless particle from a black hole .
this leads to a conjecture regarding quantum corrections to the classical effective potential for massless particles . in the next section
, we provide briefly the formalism for black hole scattering in general and go on to discuss the critical parameters relevant to orbiting and glory scattering . in section iii , we discuss the calculation of the reflection coefficient and present results regarding its connection to orbiting scattering .
we also present a conjecture related to these phenomena . in section
iv we discuss how the regge - wheeler potential can be re - interpreted as an effective potential plus quantum corrections proportional @xmath32 . in section
v we summarize our findings .
we start by presenting some generalities in black hole scattering . consider the propagation of a massless scalar field @xmath33 governed by the wave equation @xmath34 where @xmath35 denotes a static , spherically symmetric black hole metric whose line element is @xmath36 using the following ansatz @xmath37 it is standard @xcite to reduce the above equation to a schrdinger - like equation for the radial part @xmath38\psi_{n \ell \omega } = \omega^2\psi_{n \ell \omega } , \ ] ] where in principle @xmath39 , but we shall drop the subscript for convenience in what follows .
moreover , @xmath40 ( with the form of @xmath41 depending on the metric under consideration ) and @xmath42 here , a prime denotes differentiation with respect to @xmath43 whereas @xmath44 is a tortoise coordinate defined through @xmath45 in case of the schwarzschild metric which we shall consider in the present work , @xmath46 where @xmath47 is the mass of the black hole and the tortoise coordinate is given by @xmath48 eq .
( [ radial ] ) can also be obtained for other spins .
the corresponding regge - wheeler potential for spins @xmath28 is given as @xcite @xmath49\ ] ] where , @xmath50 .
note that as we move from @xmath51 at the event horizon to @xmath52 , the tortoise coordinate varies from @xmath53 to @xmath54 .
since the scattering problem with the radial coordinate @xmath43 in three dimensions ( 3d ) gets mapped into a one - dimensional ( 1d ) one with the @xmath55 coordinate , the schrdinger - like equation ( [ radial ] ) in black hole scattering can be solved using standard techniques for 1d tunneling in quantum mechanics .
the asymptotic solutions of the schrdinger equation ( [ radial ] ) are @xmath56 @xmath57 for waves incident on the black hole from the right ( i.e. @xmath58 ) we have @xmath59 , the reflection amplitude @xmath60 and the transmission amplitude @xmath61 , so that @xmath62 @xmath63 an anomalous large angle scattering , called alas , was observed often in nuclear reactions between @xmath64-like nuclei such as @xmath65c-@xmath66o , @xmath66o-@xmath67si etc @xcite and has been attributed to the orbiting mechanism in scattering .
the origin of this mechanism can be traced back to classical dynamics , where a particle approaching the potential center can get trapped in a circular orbit of radius @xmath68 if its energy equals the maximum of the effective potential at @xmath68 .
ford and wheeler @xcite found the connection of this phenomenon with the classical deflection function which becomes singular at a critical value of the angular momentum for which the circular orbit can exist and leads to divergent cross sections .
the analogous effect in quantum mechanical scattering corresponds to the appearance of a diffraction pattern ( or peaks ) in the scattering cross section in the backward direction .
it was shown in @xcite that as long as the classical deflection function @xmath18 remains between @xmath16 and @xmath69 , the semi - classical cross section can be entirely described by the classical cross section .
if the deflection function passes smoothly through @xmath16 or @xmath69 , it leads to the phenomenon named glory .
though classically it corresponds to a singularity in the cross section , quantum mechanically one expects only a prominent peak in the cross section .
ford and wheeler related the deflection function to the real part of the quantum mechanical scattering phase shift .
detailed discussions on the topic can be found in @xcite and @xcite . here
we directly state their conclusion , namely , @xmath70 connecting the deflection function with the real part of the phase shift . there exists a critical value @xmath71 corresponding to backward glory scattering . the deflection function at backward angles can be approximated as @xmath72 orbiting occurs when the effective potential as a function of the radial coordinate @xmath43 possesses for some angular momentum @xmath1 , a relative maximum equal to the available energy . for massive particles in classical general relativity ( gr )
this means @xmath73 .
@xmath22 enters the geodesic equation in the form @xmath74 . for massless particles ,
the same condition with @xmath22 from the geodesic equation of motion is @xmath75 with @xmath76 where @xmath77 has the dimension of angular momentum per mass which makes @xmath22 dimensionless . replacing @xmath78 by @xmath79 we return back to the quantum mechanical picture .
note that part of @xmath80 ( i.e. the first term of v(r ) in ( [ blackpot ] ) ) is proportional to @xmath22 and in the case of @xmath81 , the entire @xmath82 is proportional to @xmath22 .
we shall come back to this point later .
under such a condition , the deflection function was shown to vary logarithmically @xmath83 where @xmath84 , @xmath85 and @xmath6 are constants .
the particle is expected to spiral below or above the barrier depending on the value of @xmath5 being greater or less than @xmath1 , respectively .
if @xmath20 , the particle is trapped in a circular orbit and @xmath18 is singular . with @xmath18 being related to the real phase shift as in ( [ deflphase ] )
, one expects a steep jump down in the real part of the phase shift at the critical value of @xmath5 . in black hole scattering with @xmath86 , eq .
( [ blackpot ] ) is proportional to the classical @xmath22 from general relativity .
here one expects an unstable photon orbit at @xmath87 .
considering the potential @xmath88 with the semi - classical prescription of @xmath89 , it is easy to see that the critical value of the angular momentum @xmath5 is given by @xmath90 , where @xmath91 .
if one uses @xmath92 instead , one of course ends up with a quadratic equation for @xmath1 .
the two values of @xmath1 should however be quite close for large values of @xmath5 .
one could try to find the critical @xmath1 for the occurrence of circular orbits in the scattering of spin 0 and 2 particles in the same way too . considering @xmath93 in ( [ blackpot ] ) at @xmath94
leads to @xmath95 in the semi - classical approximation and @xmath96 quantum mechanically . in table
i we list the two sets of @xmath1 for different values of @xmath97 .
as expected , the difference between the semi - classical @xmath98 and @xmath99 is little for large values of @xmath5 .
note that for @xmath100 , there exists a critical @xmath97 below which one can not find a real @xmath1 .
.[tab1]critical values of @xmath5 obtained using @xmath101 .
the numbers outside parentheses correspond to @xmath98 and those inside to @xmath99 . [
cols="<,<,<,<",options="header " , ] the reader will notice that apart from the value of @xmath1 which can not be determined for @xmath102 ( @xmath103 ) in table i , the remaining values are quite close to those in table ii .
what appears at a first glance as a curious coincidence will be explained in the next section by analyzing the form of @xmath93 . in what follows
, we shall present an exact numerical calculation of the reflection coefficient and study its behaviour as a function of @xmath5 in context with orbiting scattering .
in this section we will compare and discuss three different methods to calculate the reflection coefficient : a semi - analytical result , numerical results using the variable amplitude method and the approximation of a rectangular barrier adjusted to the problem of black hole scattering .
we will see that the semi - analytical result gives a very good overall description of the problem .
the reflection amplitude in black hole scattering has also been calculated in literature @xcite using semi - classical approximations . before we go over to the details of the calculations of the reflection coefficient ,
let us briefly examine the nature of the potential in black hole scattering and what results one can expect .
the potential in the schwarzschild case as given in eq.([blackpot ] ) is made up of two functions , namely , @xmath104 ( see eq .
( [ blackpotur ] ) ) and @xmath41 , such that @xmath105 .
@xmath104 consists of a @xmath5 dependent term which resembles the centrifugal barrier in standard problems in quantum mechanics .
the form of @xmath41 depends on the metric under consideration . in fig . 1
, we plot the potential as a function of the coordinate @xmath43 as well as @xmath55 and note the following features + ( i ) the potential looks very different when taken as a function of @xmath43 or @xmath44 .
+ ( ii ) if we plot the function @xmath104 only , the steep rise of the centrifugal barrier is evident , however , only when plotted as a function of @xmath43 and not @xmath55 .
+ ( iii ) due to the presence of @xmath41 , the potential plotted as a function of @xmath55 resembles a gaussian barrier and the centrifugal term is not explicitly seen in the shape of the potential . however , as evident from fig.2 the height of the potential rises with @xmath5 . + the schwarzschild black hole potential for spin @xmath106 and @xmath107 . ( a ) potential plotted as a function of the dimensionless coordinate @xmath108 and ( b ) @xmath109 , where @xmath55 is the tortoise coordinate and @xmath68 the schwarzschild radius.,width=264,height=377 ] the regge - wheeler potential compared with the @xmath31 potential from equation ( [ cosh2 ] ) for different spins and angular momentum .
the discrepancy between the two cases is more prominent at smaller energies where the regge - wheeler potential displays an asymmetric tail .
notice also that increasing @xmath5 results in an increasing height.,width=340,height=302 ] new insights can be often gained by searching for analytical and semi - analytical results . to this end
we notice that the reflection coefficients for the potential @xmath110 ( or modification of the above by a shift of the argument ) can be obtained analytically ( we refer the reader for details to @xcite ) .
the relevance of this potential to our problem is its similarity to the regge - wheeler potential in the tortoise coordinate .
indeed , @xmath111 fits the regge - wheeler potential quite well for @xmath112 provided we choose @xmath113 , @xmath114 and the height @xmath115 to be the regge - wheeler potential at @xmath116 , i.e. , @xmath117 which is different for different choices of @xmath118 and @xmath5-dependent .
for instance , in the cases @xmath112 we obtain @xmath119\ , , \quad s = 0\\ \nonumber r_0 ^ 2v_0=\frac{4}{27 } 4l(l+1 ) \
, , \quad s = 1 \\
\nonumber r_0 ^ 2v_0=\frac{1}{27}\left [ 4l(l+1 ) -8\right ] \ ,
, \quad s = 2\end{aligned}\ ] ] the comparison between the regge - wheeler and the parametrized @xmath31 potential is shown in fig.2 .
evidently , one would expect some quantitative agreement in both cases for the reflection coefficient for tunneling at higher energies , i.e. , where the two potentials almost overlap .
we will see that this is indeed the case . to be able to use the analytical results from @xcite we use : @xmath120 , @xmath121 and @xmath122 .
this gives the following transmission coefficients : @xmath123 if @xmath124 and @xmath125 for @xmath126 .
the pschl - teller potential defined in equations ( [ cosh1 ] ) and ( [ cosh2 ] ) has been used to extract quasi - normal modes of black holes , either as an approximation @xcite or in obtaining exact results in the nariai spacetime @xcite for which the scalar field equation reduces to the radial equation with the pschl - teller potential . in @xcite handler and matzner used a rectangular barrier as an approximate solution to obtain the transmission coefficients corresponding to the black hole scattering problem of spin 1 particles .
their choice of the height of the barrier is @xmath115 with the same definition as explained above .
the width @xmath6 is energy and @xmath5 dependent : @xmath127 .
the standard analytical results for the rectangular barrier read for @xmath128 @xmath129 . for @xmath130
one obtains @xmath131 .
notice that with this prescription one can not calculate @xmath132 for @xmath133 which as far as the results of handler and matzner are concerned is a valid assumption as they restrained themselves to @xmath86 and therefore via @xmath50 to @xmath134 . in this section
, @xmath135 will be evaluated numerically via the variable amplitude method .
the variable amplitude method was first introduced in @xcite and has been widely used to evaluate the reflection and transmission coefficients for different potentials in literature @xcite .
this method involves writing the solution of the schrdinger equation as a superposition of the reflected and transmitted waves , namely , @xmath136 $ ] , which leads to the following equation for @xmath137 @xmath138 ^ 2 .\ ] ] the absence of reflection behind the potential at @xmath139 imposes the boundary condition @xmath140 on the above equation .
the reflection coefficient is given by @xmath141 .
when we calculate the reflection coefficient , we expect it to be large and close to unity for energies much below the height of the barrier ( where transmission is a quantum mechanical possibility and hence very small ) . since transmission increases with energy , the reflection coefficient falls and at high energies ( above the barrier ) where transmission becomes the classical phenomenon and reflection a quantum mechanical effect , the reflection coefficient is negligibly small . in fig .
3 , we show the reflection coefficient as a function of energy for black hole scattering . on the left
is shown the exact numerical result using the regge - wheeler potential and on the right the reflection coefficient evaluated from the expressions for @xmath142 discussed in the previous sections for a rectangular barrier and parametrized @xmath31 potential ( which is similar in shape to a gaussian barrier @xcite ) .
reflection coefficient as a function of energy for @xmath100 and for different values of @xmath5 in black hole scattering . on the left we plot the numerical results and on the right the reflection coefficient for an adjusted rectangular barrier ( see text ) of height @xmath115 ( dashed line ) and for the parametrized @xmath31 potential ( solid line ) . since the results for the latter almost coincide with the numerical ones we plot them in two different boxes.,width=491,height=264 ] in fig .
3 we have plotted the results in two separate boxes since the numerical results would almost overlap with the results obtained from the @xmath31 potential .
this agreement is remarkable .
in contrast to that , the results obtained via the rectangular potential differ from the exact ( numerical ) results .
reflection coefficient or the scattering amplitude squared as a function of @xmath5 for the scattering of massless scalar ( @xmath106 ) , electromagnetic ( @xmath81 ) and gravitational ( @xmath143 ) waves from a black hole .
for comparison we plot also for @xmath144 the results obtained from the parametrized @xmath31 potential .
as expected the agreement with numerical results improves with energy . for @xmath86 the same comparison
is done in the next figure . for @xmath100 , we just mention that here the agreement between the numerical and the semi - analytical results is the best among the three cases.,width=491,height=415 ] in fig .
4 , we plot the numerically evaluated reflection coefficient as function of @xmath5 for different values of @xmath97 and for different spins of the scattering particles .
it is interesting to note that @xmath0 goes through a sudden rise at the critical values of @xmath5 listed in the tables and connected to the orbiting phenomenon .
the fact that the reflection coefficient for a given energy rises as a function of @xmath5 can be understood by examining the plot of the potential for different @xmath5 values at the same energy . in fig .
2 , we see that the effect of increasing @xmath5 is to increase the height of the barrier . hence , for example , an energy close to the top of the barrier for @xmath145 will lead to little reflection but at the same energy , the barrier for @xmath146 is much higher leading to larger reflection .
for @xmath144 we made a comparison with the corresponding @xmath31 potential .
for small energies , the agreement is still not perfect , but improves rapidly with growing energies as is evident from the plots .
this behaviour is to be expected since the regge - wheeler potential differs from the fitted @xmath31 case if the energy of the particle is much below the height of the potential where the regge - wheeler displays an asymmetric tail .
this small mismatch between the the results obtained from the two potentials should be also present for the cases @xmath147 , but will not be so prominent as for @xmath144 .
the reason is that @xmath0 for @xmath147 saturates at smaller value of @xmath5 . as a result
the difference between the small energy and the height is less then in the case @xmath144 where the saturation sets in at higher @xmath5 . indeed , as one can infer from fig .
5 the agreement between the exact results for the regge - wheeler and the @xmath31 potential is remarkably good for @xmath86 even for small energies .
comparison of the reflection coefficients calculated using numerical methods , the adjusted rectangular barrier and the parametrized @xmath31 potential as a function of @xmath5 for the case @xmath81 .
evidently the rectangular barrier ( dash - dotted ) is not a good approximation whereas the @xmath31 ( dashed lines ) gives a very good agreement with exact numerical results ( solid lines).,width=491,height=415 ] an approximate calculation of the magnitude of the reflection amplitude was done in the third reference in @xcite ( article by handler and matzner ) . for the case of @xmath81 ,
the authors approximated the potential by a rectangular barrier as explained before in the text and studied the features of the corresponding reflection amplitude as a function of the angular momentum @xmath5 .
the magnitude of the reflection amplitude for the various values of @xmath97 studied here , started saturating to unity at a certain value of @xmath5 which the authors referred to as @xmath71 , the critical value for the onset of glory scattering .
it also showed a sudden rise through @xmath29 as a function of @xmath5 ( this @xmath5 value however is different for the rectangular and realistic regge - wheeler case ) .
however , no interpretation was attempted to explain this fact .
indeed , here we have clearly connected it to the orbiting effects .
the findings in @xcite are not similar to those of the present work for the case @xmath148
. a closer look at fig .
5 reveals the differences between the exact results and the results from a rectangular barrier . not only is the shape of the reflection coefficients different , but also the values at which the reflection coefficient makes a jump and at which it saturates to unity .
a possible explanation for @xmath149 as seen in figs 4 and 5 for the numerical results can be found by examining the approximate expression of the reflection coefficient as obtained in the wkb approximation @xcite . in case of barrier penetration ,
when the energy @xmath150 of the incident particle lies below the top of the barrier , the semi - classical reflection coefficient is given as @xmath151 with @xmath152 where @xmath153 and @xmath154 are the classical turning points .
for very small values of @xmath150 , @xmath0 approaches unity . however , when @xmath150 equals the maximum height of the barrier , @xmath155 , @xmath156 and @xmath157 .
thus one can relate the orbiting phenomenon with a critical @xmath5 value @xmath1 such that @xmath149 .
finally an interesting observation in connection with the orbiting is that the reflection coefficient which characterizes the critical value @xmath1 is related to the imaginary part of the scattering phase shift .
if one relates the reflection amplitude to the @xmath158 matrix in three dimensional ( 3d ) scattering , one can write @xmath159 , where @xmath160 in general , is the complex scattering phase shift .
thus , @xmath161 , where , @xmath162 is known as the inelasticity parameter which can be less than or equal to 1 . in the 1-dimensional case , the @xmath158 matrix is a @xmath163 matrix with two channels , namely , transmission and reflection such that @xmath164 .
if @xmath165 , it implies that @xmath166 and there exists complete reflection .
however , @xmath167 corresponds to the existence of the transmission channel .
the reflection coefficient @xmath168 , i.e. , @xmath169 and is related only to the imaginary part of the phase shift .
the sudden rise in @xmath170 at @xmath1 corresponds to a peak in @xmath171 , where @xmath172 this should be contrasted with the semi - classical characterization in eq .
( [ deflphase ] ) where the orbiting and glory parameters are characterized using the real part of the scattering phase shifts .
this is also due to the fact that the scattering phase shifts calculated within the semi - classical approaches such as the wkb are always real . using an exact numerical evaluation of @xmath0 here
, we find a connection of the orbiting parameters with the imaginary part of the phase shift .
for @xmath81 ( @xmath173 ) , @xmath26 obtained from ( [ veffgeo ] ) agrees with the quantum mechanical calculation via @xmath174 ( corresponding to the jump in @xmath0 ) .
the same would be true for @xmath175 if @xmath26 is computed through eq.([veffgeo ] ) , replacing therein @xmath22 by @xmath80 .
the argument for @xmath175 , namely , that @xmath1 is connected to the classical unstable circular orbit , can be now maintained if we attempt a reinterpretation of @xmath80 .
restoring @xmath32 in our expressions amounts to replacing @xmath176 by @xmath177 or equivalently @xmath178 by @xmath179 .
the schrdinger - like equation then reads @xmath180\psi_{n \ell \omega } = e^2\psi_{n \ell \omega } \ , .\ ] ] identifying @xmath181 with @xmath182 , we can write @xmath183\ , , \\ \nonumber \tilde{v}_{eff } & = & \biggl ( 1 - { 2 m \over r } \biggr ) \ , { l^2 \over r^2 } \ , .\end{aligned}\ ] ] in identifying @xmath184 by @xmath182 , we are going back from quantum mechanics to classical physics .
it is reasonable to speculate that @xmath185 represents the full effective potential , i.e. , the classical part plus @xmath186 quantum mechanical corrections .
indeed , @xmath185 would then be the correct tool to calculate a classical unstable orbit .
recently , @xmath32 corrections to the newtonian potential , have been discussed in @xcite , where it was found that the additional terms are proportional to @xmath187 ( @xmath188 is the restored newtonian constant ) .
the procedure to arrive at such a result is to consider non - relativistic amplitudes with zero and higher order loop corrections .
the difference from our case is that these corrections were calculated for massive particles where the newtonian potential exists and the non - relativistic limit makes sense . in a massless case , such a procedure is not well - defined .
therefore our conjecture is well motivated but remains open .
since the dimensions of @xmath22 from gr and @xmath189 are different , let us be more specific . to make @xmath185 dimensionless we divide it by the planck mass squared , @xmath190 and identify @xmath191 .
thus , @xmath192\ , .\ ] ] our speculation is simply to say that @xmath22 receives a small quantum correction proportional to @xmath32 in the above equation .
this explains also the coincidences found in the previous section .
indeed , calculating @xmath26 from @xmath22 or @xmath22 plus quantum corrections will give very similar results .
therefore it is not a surprise that @xmath99 comes out quite close to the @xmath1 evaluated from @xmath26 .
the behaviour of the reflection coefficient , @xmath0 , which enters the scattering cross sections is investigated for the scattering of scalar , electromagnetic and gravitational waves from a schwarzschild black hole .
we paid special attention to the issue of orbiting effects in a quantum mechanical scattering off black holes .
our investigation displays the following features : * for @xmath193 we found that @xmath0 jumps at a certain critical value @xmath1 , i.e. its second derivative with respect to @xmath5 is zero .
the regge - wheeler potential is proportional to the classical effective potential for @xmath86 only .
we find that @xmath1 is connected with the unstable circular orbit at @xmath87 for @xmath86 .
* we find the @xmath1 values for @xmath175 , too . here
also we would expect that the critical value @xmath1 is connected to an unstable circular orbit at a critical @xmath26 .
interestingly , the @xmath1 values calculated using @xmath194 lie very close to those using @xmath195 .
this can be explained if we re - interpret the regge wheeler potential as the classical effective potential with @xmath32 corrections .
notice that with the values of @xmath1 obtained via the rectangular potential , such a conclusion would be impossible as the jump occurs at a different @xmath1 and the connection to the unstable circular orbit is lost .
* for all values of @xmath97 and spins @xmath196 and @xmath197 we find that @xmath149 .
* we have shown that the transmission and reflection coefficients of the potential proportional to @xmath30 ( pschl - teller ) match very well with the exact results . since for this particular case
the transmission coefficient can be given analytically , this allows us to study the black hole scattering in a semi - analytical way and supplements the conclusion that such a potential is a good approximate tool in black hole physics @xcite .
both the semi - analytical results and the numerical ones refine approximate results obtained elsewhere and reveal some deficiencies of the approximation methods .
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n. froeman and p. o. froeman , _ jwkb approximation : contributions to the theory _ , north - holland , amsterdam ( 1965 ) . | rainbow , glory and orbiting scattering are usually described by the properties of the classical deflection function related to the real part of the quantum mechanical scattering phase shift or by the diffractive pattern of the quantum mechanical cross sections . here
we show that the case of orbiting scattering of massless spin 0 , 1 and 2 particles from schwarzschild black holes can be characterized by a sudden rise in @xmath0 at a critical angular momentum @xmath1 , which we show corresponds to the unstable circular orbits of these particles . for the cases , @xmath2 , we attempt a new interpretation of the regge - wheeler potential by identifying the quantum mechanical corrections to the effective potential of massless particles .
we probe into the black hole scattering by using numerical and semi - analytical methods which give very good agreements with the exact numerical results .
the limitations of previously used approximations as compared to the exact and semi - analytical results are discussed . | <s>[INST]over the last four decades , the physics of particle scattering from different kinds of black holes was one of the most active topics of strong gravitational fields . apart from the quasinormal modes which , in principle , can be identified as the poles of the corresponding black hole scattering matrix , the behaviour of the cross section with respect to the scattering angle is one of the most interesting features in this area . the key issues around which the physics of black hole scattering centers are related to phenomena such as glory , orbiting ( or spiralling ) , rainbow and super - radiant scattering .
one should note that these features are observed experimentally and studied extensively theoretically in nucleus - nucleus scattering .
it is gratifying to see similar phenomena occurring in black hole scattering @xcite . in the pioneering papers of ford and wheeler @xcite ,
using semi - classical arguments , a connection between the classical rainbow , glory and orbiting phenomena was made with their quantum mechanical counterparts .
starting with a procedure as proposed by mott and massey @xcite which gave the classical cross section @xmath3 , the authors noticed that the classical deflection function can be written in terms of the quantum mechanical scattering phase shift as @xmath4/dl$ ] , where @xmath5 is the angular momentum and @xmath6 the impact parameter .
for particles scattered into the solid angle @xmath7 , the cross sectional area can be written as , @xmath8 , so that the differential cross section is proportional to @xmath9 .
the classical angular momentum is @xmath10 .
going over to the quantum mechanical case , if we now consider the de broglie wavelength @xmath11 of the particle to be small compared to the range of the force , we may write , @xmath12 .
in fact , while working with semi - classical approximations such as the wkb , one must replace @xmath13 . in the article of ford and wheeler
, the authors thus obtain the differential cross section proportional to @xmath14 , which is divergent when the scattering angle @xmath15 is @xmath16 or @xmath17 .
glory is characterized by @xmath18 passing with finite slope through @xmath19 etc and rainbow by the maxima or minima in @xmath18 .
if the deflection function displays a singularity at a certain critical value @xmath1 of @xmath5 , they show that @xmath18 will vary logarithmically near @xmath20 . for values of @xmath5 below and above @xmath1 the particle would have spiralling trajectories and @xmath20 would give the limit of an unstable circular orbit .
for a particle incident with energy @xmath21 and for an effective potential , @xmath22 , which is the sum of an actual interaction potential and a centrifugal term , the condition corresponding to such an orbit was shown to be @xmath23 ( which as we shall see later is @xmath24 for massless particles with @xmath25 ) , where @xmath26 is the position of the maximum of the effective potential and @xmath21 the available energy .
quantum mechanically , one does not get divergent cross sections .
one rather observes peaks in the cross sections as a function of angle in the backward directions for glory and orbiting scattering .
based on the works of ford and wheeler , the characterization of the above phenomena in black hole scattering is mostly done in literature by noting the behaviour of the real part of the scattering phase shift or by looking at the oscillating patterns in the cross sections at backward angles . in the present work , we relate the phenomenon of orbiting scattering to the imaginary part of the scattering phase shift .
to be specific we evaluate the reflection coefficient in black hole scattering from schwarzschild black holes by solving the corresponding riccati equation numerically . finding a sudden rise of the reflection coefficient
, @xmath27 plotted as a function of @xmath5 , at a certain critical value of @xmath5 for different energies and different spins ( @xmath28 ) of the massless scattering particles , we show that this critical @xmath5 is nothing but the @xmath1 corresponding to the unstable circular orbit .
we also find that the normalized @xmath0 always passes through a value of @xmath29 at the critical value @xmath1 .
the present work differs from others @xcite in view of the points mentioned above .
the reflection coefficient is evaluated exactly using the variable amplitude method as compared to approximate calculations ( third reference in @xcite ) , @xcite .
we also find a potential proportional to @xmath30 which gives remarkably good results when compared with the numerical ones .
for this potential the transmission coefficients can be found analytically .
parametrizing the @xmath31 potential to fit the regge - wheeler potential , we find semi - analytical results for black hole scattering .
even though the scattering off black holes is a widely explored area , not much attention has been paid to the orbiting phenomenon ( mostly the glory and rainbow effects have been discussed ) . here
we supplement the existing literature by a detailed study of how the existence of a classical orbit gets reflected in the quantum mechanical expressions of the scattering of a massless particle from a black hole .
this leads to a conjecture regarding quantum corrections to the classical effective potential for massless particles . in the next section
, we provide briefly the formalism for black hole scattering in general and go on to discuss the critical parameters relevant to orbiting and glory scattering . in section iii , we discuss the calculation of the reflection coefficient and present results regarding its connection to orbiting scattering .
we also present a conjecture related to these phenomena . in section
iv we discuss how the regge - wheeler potential can be re - interpreted as an effective potential plus quantum corrections proportional @xmath32 . in section
v we summarize our findings .
we start by presenting some generalities in black hole scattering . consider the propagation of a massless scalar field @xmath33 governed by the wave equation @xmath34 where @xmath35 denotes a static , spherically symmetric black hole metric whose line element is @xmath36 using the following ansatz @xmath37 it is standard @xcite to reduce the above equation to a schrdinger - like equation for the radial part @xmath38\psi_{n \ell \omega } = \omega^2\psi_{n \ell \omega } , \ ] ] where in principle @xmath39 , but we shall drop the subscript for convenience in what follows .
moreover , @xmath40 ( with the form of @xmath41 depending on the metric under consideration ) and @xmath42 here , a prime denotes differentiation with respect to @xmath43 whereas @xmath44 is a tortoise coordinate defined through @xmath45 in case of the schwarzschild metric which we shall consider in the present work , @xmath46 where @xmath47 is the mass of the black hole and the tortoise coordinate is given by @xmath48 eq .
( [ radial ] ) can also be obtained for other spins .
the corresponding regge - wheeler potential for spins @xmath28 is given as @xcite @xmath49\ ] ] where , @xmath50 .
note that as we move from @xmath51 at the event horizon to @xmath52 , the tortoise coordinate varies from @xmath53 to @xmath54 .
since the scattering problem with the radial coordinate @xmath43 in three dimensions ( 3d ) gets mapped into a one - dimensional ( 1d ) one with the @xmath55 coordinate , the schrdinger - like equation ( [ radial ] ) in black hole scattering can be solved using standard techniques for 1d tunneling in quantum mechanics .
the asymptotic solutions of the schrdinger equation ( [ radial ] ) are @xmath56 @xmath57 for waves incident on the black hole from the right ( i.e. @xmath58 ) we have @xmath59 , the reflection amplitude @xmath60 and the transmission amplitude @xmath61 , so that @xmath62 @xmath63 an anomalous large angle scattering , called alas , was observed often in nuclear reactions between @xmath64-like nuclei such as @xmath65c-@xmath66o , @xmath66o-@xmath67si etc @xcite and has been attributed to the orbiting mechanism in scattering .
the origin of this mechanism can be traced back to classical dynamics , where a particle approaching the potential center can get trapped in a circular orbit of radius @xmath68 if its energy equals the maximum of the effective potential at @xmath68 .
ford and wheeler @xcite found the connection of this phenomenon with the classical deflection function which becomes singular at a critical value of the angular momentum for which the circular orbit can exist and leads to divergent cross sections .
the analogous effect in quantum mechanical scattering corresponds to the appearance of a diffraction pattern ( or peaks ) in the scattering cross section in the backward direction .
it was shown in @xcite that as long as the classical deflection function @xmath18 remains between @xmath16 and @xmath69 , the semi - classical cross section can be entirely described by the classical cross section .
if the deflection function passes smoothly through @xmath16 or @xmath69 , it leads to the phenomenon named glory .
though classically it corresponds to a singularity in the cross section , quantum mechanically one expects only a prominent peak in the cross section .
ford and wheeler related the deflection function to the real part of the quantum mechanical scattering phase shift .
detailed discussions on the topic can be found in @xcite and @xcite . here
we directly state their conclusion , namely , @xmath70 connecting the deflection function with the real part of the phase shift . there exists a critical value @xmath71 corresponding to backward glory scattering . the deflection function at backward angles can be approximated as @xmath72 orbiting occurs when the effective potential as a function of the radial coordinate @xmath43 possesses for some angular momentum @xmath1 , a relative maximum equal to the available energy . for massive particles in classical general relativity ( gr )
this means @xmath73 .
@xmath22 enters the geodesic equation in the form @xmath74 . for massless particles ,
the same condition with @xmath22 from the geodesic equation of motion is @xmath75 with @xmath76 where @xmath77 has the dimension of angular momentum per mass which makes @xmath22 dimensionless . replacing @xmath78 by @xmath79 we return back to the quantum mechanical picture .
note that part of @xmath80 ( i.e. the first term of v(r ) in ( [ blackpot ] ) ) is proportional to @xmath22 and in the case of @xmath81 , the entire @xmath82 is proportional to @xmath22 .
we shall come back to this point later .
under such a condition , the deflection function was shown to vary logarithmically @xmath83 where @xmath84 , @xmath85 and @xmath6 are constants .
the particle is expected to spiral below or above the barrier depending on the value of @xmath5 being greater or less than @xmath1 , respectively .
if @xmath20 , the particle is trapped in a circular orbit and @xmath18 is singular . with @xmath18 being related to the real phase shift as in ( [ deflphase ] )
, one expects a steep jump down in the real part of the phase shift at the critical value of @xmath5 . in black hole scattering with @xmath86 , eq .
( [ blackpot ] ) is proportional to the classical @xmath22 from general relativity .
here one expects an unstable photon orbit at @xmath87 .
considering the potential @xmath88 with the semi - classical prescription of @xmath89 , it is easy to see that the critical value of the angular momentum @xmath5 is given by @xmath90 , where @xmath91 .
if one uses @xmath92 instead , one of course ends up with a quadratic equation for @xmath1 .
the two values of @xmath1 should however be quite close for large values of @xmath5 .
one could try to find the critical @xmath1 for the occurrence of circular orbits in the scattering of spin 0 and 2 particles in the same way too . considering @xmath93 in ( [ blackpot ] ) at @xmath94
leads to @xmath95 in the semi - classical approximation and @xmath96 quantum mechanically . in table
i we list the two sets of @xmath1 for different values of @xmath97 .
as expected , the difference between the semi - classical @xmath98 and @xmath99 is little for large values of @xmath5 .
note that for @xmath100 , there exists a critical @xmath97 below which one can not find a real @xmath1 .
.[tab1]critical values of @xmath5 obtained using @xmath101 .
the numbers outside parentheses correspond to @xmath98 and those inside to @xmath99 . [
cols="<,<,<,<",options="header " , ] the reader will notice that apart from the value of @xmath1 which can not be determined for @xmath102 ( @xmath103 ) in table i , the remaining values are quite close to those in table ii .
what appears at a first glance as a curious coincidence will be explained in the next section by analyzing the form of @xmath93 . in what follows
, we shall present an exact numerical calculation of the reflection coefficient and study its behaviour as a function of @xmath5 in context with orbiting scattering .
in this section we will compare and discuss three different methods to calculate the reflection coefficient : a semi - analytical result , numerical results using the variable amplitude method and the approximation of a rectangular barrier adjusted to the problem of black hole scattering .
we will see that the semi - analytical result gives a very good overall description of the problem .
the reflection amplitude in black hole scattering has also been calculated in literature @xcite using semi - classical approximations . before we go over to the details of the calculations of the reflection coefficient ,
let us briefly examine the nature of the potential in black hole scattering and what results one can expect .
the potential in the schwarzschild case as given in eq.([blackpot ] ) is made up of two functions , namely , @xmath104 ( see eq .
( [ blackpotur ] ) ) and @xmath41 , such that @xmath105 .
@xmath104 consists of a @xmath5 dependent term which resembles the centrifugal barrier in standard problems in quantum mechanics .
the form of @xmath41 depends on the metric under consideration . in fig . 1
, we plot the potential as a function of the coordinate @xmath43 as well as @xmath55 and note the following features + ( i ) the potential looks very different when taken as a function of @xmath43 or @xmath44 .
+ ( ii ) if we plot the function @xmath104 only , the steep rise of the centrifugal barrier is evident , however , only when plotted as a function of @xmath43 and not @xmath55 .
+ ( iii ) due to the presence of @xmath41 , the potential plotted as a function of @xmath55 resembles a gaussian barrier and the centrifugal term is not explicitly seen in the shape of the potential . however , as evident from fig.2 the height of the potential rises with @xmath5 . + the schwarzschild black hole potential for spin @xmath106 and @xmath107 . ( a ) potential plotted as a function of the dimensionless coordinate @xmath108 and ( b ) @xmath109 , where @xmath55 is the tortoise coordinate and @xmath68 the schwarzschild radius.,width=264,height=377 ] the regge - wheeler potential compared with the @xmath31 potential from equation ( [ cosh2 ] ) for different spins and angular momentum .
the discrepancy between the two cases is more prominent at smaller energies where the regge - wheeler potential displays an asymmetric tail .
notice also that increasing @xmath5 results in an increasing height.,width=340,height=302 ] new insights can be often gained by searching for analytical and semi - analytical results . to this end
we notice that the reflection coefficients for the potential @xmath110 ( or modification of the above by a shift of the argument ) can be obtained analytically ( we refer the reader for details to @xcite ) .
the relevance of this potential to our problem is its similarity to the regge - wheeler potential in the tortoise coordinate .
indeed , @xmath111 fits the regge - wheeler potential quite well for @xmath112 provided we choose @xmath113 , @xmath114 and the height @xmath115 to be the regge - wheeler potential at @xmath116 , i.e. , @xmath117 which is different for different choices of @xmath118 and @xmath5-dependent .
for instance , in the cases @xmath112 we obtain @xmath119\ , , \quad s = 0\\ \nonumber r_0 ^ 2v_0=\frac{4}{27 } 4l(l+1 ) \
, , \quad s = 1 \\
\nonumber r_0 ^ 2v_0=\frac{1}{27}\left [ 4l(l+1 ) -8\right ] \ ,
, \quad s = 2\end{aligned}\ ] ] the comparison between the regge - wheeler and the parametrized @xmath31 potential is shown in fig.2 .
evidently , one would expect some quantitative agreement in both cases for the reflection coefficient for tunneling at higher energies , i.e. , where the two potentials almost overlap .
we will see that this is indeed the case . to be able to use the analytical results from @xcite we use : @xmath120 , @xmath121 and @xmath122 .
this gives the following transmission coefficients : @xmath123 if @xmath124 and @xmath125 for @xmath126 .
the pschl - teller potential defined in equations ( [ cosh1 ] ) and ( [ cosh2 ] ) has been used to extract quasi - normal modes of black holes , either as an approximation @xcite or in obtaining exact results in the nariai spacetime @xcite for which the scalar field equation reduces to the radial equation with the pschl - teller potential . in @xcite handler and matzner used a rectangular barrier as an approximate solution to obtain the transmission coefficients corresponding to the black hole scattering problem of spin 1 particles .
their choice of the height of the barrier is @xmath115 with the same definition as explained above .
the width @xmath6 is energy and @xmath5 dependent : @xmath127 .
the standard analytical results for the rectangular barrier read for @xmath128 @xmath129 . for @xmath130
one obtains @xmath131 .
notice that with this prescription one can not calculate @xmath132 for @xmath133 which as far as the results of handler and matzner are concerned is a valid assumption as they restrained themselves to @xmath86 and therefore via @xmath50 to @xmath134 . in this section
, @xmath135 will be evaluated numerically via the variable amplitude method .
the variable amplitude method was first introduced in @xcite and has been widely used to evaluate the reflection and transmission coefficients for different potentials in literature @xcite .
this method involves writing the solution of the schrdinger equation as a superposition of the reflected and transmitted waves , namely , @xmath136 $ ] , which leads to the following equation for @xmath137 @xmath138 ^ 2 .\ ] ] the absence of reflection behind the potential at @xmath139 imposes the boundary condition @xmath140 on the above equation .
the reflection coefficient is given by @xmath141 .
when we calculate the reflection coefficient , we expect it to be large and close to unity for energies much below the height of the barrier ( where transmission is a quantum mechanical possibility and hence very small ) . since transmission increases with energy , the reflection coefficient falls and at high energies ( above the barrier ) where transmission becomes the classical phenomenon and reflection a quantum mechanical effect , the reflection coefficient is negligibly small . in fig .
3 , we show the reflection coefficient as a function of energy for black hole scattering . on the left
is shown the exact numerical result using the regge - wheeler potential and on the right the reflection coefficient evaluated from the expressions for @xmath142 discussed in the previous sections for a rectangular barrier and parametrized @xmath31 potential ( which is similar in shape to a gaussian barrier @xcite ) .
reflection coefficient as a function of energy for @xmath100 and for different values of @xmath5 in black hole scattering . on the left we plot the numerical results and on the right the reflection coefficient for an adjusted rectangular barrier ( see text ) of height @xmath115 ( dashed line ) and for the parametrized @xmath31 potential ( solid line ) . since the results for the latter almost coincide with the numerical ones we plot them in two different boxes.,width=491,height=264 ] in fig .
3 we have plotted the results in two separate boxes since the numerical results would almost overlap with the results obtained from the @xmath31 potential .
this agreement is remarkable .
in contrast to that , the results obtained via the rectangular potential differ from the exact ( numerical ) results .
reflection coefficient or the scattering amplitude squared as a function of @xmath5 for the scattering of massless scalar ( @xmath106 ) , electromagnetic ( @xmath81 ) and gravitational ( @xmath143 ) waves from a black hole .
for comparison we plot also for @xmath144 the results obtained from the parametrized @xmath31 potential .
as expected the agreement with numerical results improves with energy . for @xmath86 the same comparison
is done in the next figure . for @xmath100 , we just mention that here the agreement between the numerical and the semi - analytical results is the best among the three cases.,width=491,height=415 ] in fig .
4 , we plot the numerically evaluated reflection coefficient as function of @xmath5 for different values of @xmath97 and for different spins of the scattering particles .
it is interesting to note that @xmath0 goes through a sudden rise at the critical values of @xmath5 listed in the tables and connected to the orbiting phenomenon .
the fact that the reflection coefficient for a given energy rises as a function of @xmath5 can be understood by examining the plot of the potential for different @xmath5 values at the same energy . in fig .
2 , we see that the effect of increasing @xmath5 is to increase the height of the barrier . hence , for example , an energy close to the top of the barrier for @xmath145 will lead to little reflection but at the same energy , the barrier for @xmath146 is much higher leading to larger reflection .
for @xmath144 we made a comparison with the corresponding @xmath31 potential .
for small energies , the agreement is still not perfect , but improves rapidly with growing energies as is evident from the plots .
this behaviour is to be expected since the regge - wheeler potential differs from the fitted @xmath31 case if the energy of the particle is much below the height of the potential where the regge - wheeler displays an asymmetric tail .
this small mismatch between the the results obtained from the two potentials should be also present for the cases @xmath147 , but will not be so prominent as for @xmath144 .
the reason is that @xmath0 for @xmath147 saturates at smaller value of @xmath5 . as a result
the difference between the small energy and the height is less then in the case @xmath144 where the saturation sets in at higher @xmath5 . indeed , as one can infer from fig .
5 the agreement between the exact results for the regge - wheeler and the @xmath31 potential is remarkably good for @xmath86 even for small energies .
comparison of the reflection coefficients calculated using numerical methods , the adjusted rectangular barrier and the parametrized @xmath31 potential as a function of @xmath5 for the case @xmath81 .
evidently the rectangular barrier ( dash - dotted ) is not a good approximation whereas the @xmath31 ( dashed lines ) gives a very good agreement with exact numerical results ( solid lines).,width=491,height=415 ] an approximate calculation of the magnitude of the reflection amplitude was done in the third reference in @xcite ( article by handler and matzner ) . for the case of @xmath81 ,
the authors approximated the potential by a rectangular barrier as explained before in the text and studied the features of the corresponding reflection amplitude as a function of the angular momentum @xmath5 .
the magnitude of the reflection amplitude for the various values of @xmath97 studied here , started saturating to unity at a certain value of @xmath5 which the authors referred to as @xmath71 , the critical value for the onset of glory scattering .
it also showed a sudden rise through @xmath29 as a function of @xmath5 ( this @xmath5 value however is different for the rectangular and realistic regge - wheeler case ) .
however , no interpretation was attempted to explain this fact .
indeed , here we have clearly connected it to the orbiting effects .
the findings in @xcite are not similar to those of the present work for the case @xmath148
. a closer look at fig .
5 reveals the differences between the exact results and the results from a rectangular barrier . not only is the shape of the reflection coefficients different , but also the values at which the reflection coefficient makes a jump and at which it saturates to unity .
a possible explanation for @xmath149 as seen in figs 4 and 5 for the numerical results can be found by examining the approximate expression of the reflection coefficient as obtained in the wkb approximation @xcite . in case of barrier penetration ,
when the energy @xmath150 of the incident particle lies below the top of the barrier , the semi - classical reflection coefficient is given as @xmath151 with @xmath152 where @xmath153 and @xmath154 are the classical turning points .
for very small values of @xmath150 , @xmath0 approaches unity . however , when @xmath150 equals the maximum height of the barrier , @xmath155 , @xmath156 and @xmath157 .
thus one can relate the orbiting phenomenon with a critical @xmath5 value @xmath1 such that @xmath149 .
finally an interesting observation in connection with the orbiting is that the reflection coefficient which characterizes the critical value @xmath1 is related to the imaginary part of the scattering phase shift .
if one relates the reflection amplitude to the @xmath158 matrix in three dimensional ( 3d ) scattering , one can write @xmath159 , where @xmath160 in general , is the complex scattering phase shift .
thus , @xmath161 , where , @xmath162 is known as the inelasticity parameter which can be less than or equal to 1 . in the 1-dimensional case , the @xmath158 matrix is a @xmath163 matrix with two channels , namely , transmission and reflection such that @xmath164 .
if @xmath165 , it implies that @xmath166 and there exists complete reflection .
however , @xmath167 corresponds to the existence of the transmission channel .
the reflection coefficient @xmath168 , i.e. , @xmath169 and is related only to the imaginary part of the phase shift .
the sudden rise in @xmath170 at @xmath1 corresponds to a peak in @xmath171 , where @xmath172 this should be contrasted with the semi - classical characterization in eq .
( [ deflphase ] ) where the orbiting and glory parameters are characterized using the real part of the scattering phase shifts .
this is also due to the fact that the scattering phase shifts calculated within the semi - classical approaches such as the wkb are always real . using an exact numerical evaluation of @xmath0 here
, we find a connection of the orbiting parameters with the imaginary part of the phase shift .
for @xmath81 ( @xmath173 ) , @xmath26 obtained from ( [ veffgeo ] ) agrees with the quantum mechanical calculation via @xmath174 ( corresponding to the jump in @xmath0 ) .
the same would be true for @xmath175 if @xmath26 is computed through eq.([veffgeo ] ) , replacing therein @xmath22 by @xmath80 .
the argument for @xmath175 , namely , that @xmath1 is connected to the classical unstable circular orbit , can be now maintained if we attempt a reinterpretation of @xmath80 .
restoring @xmath32 in our expressions amounts to replacing @xmath176 by @xmath177 or equivalently @xmath178 by @xmath179 .
the schrdinger - like equation then reads @xmath180\psi_{n \ell \omega } = e^2\psi_{n \ell \omega } \ , .\ ] ] identifying @xmath181 with @xmath182 , we can write @xmath183\ , , \\ \nonumber \tilde{v}_{eff } & = & \biggl ( 1 - { 2 m \over r } \biggr ) \ , { l^2 \over r^2 } \ , .\end{aligned}\ ] ] in identifying @xmath184 by @xmath182 , we are going back from quantum mechanics to classical physics .
it is reasonable to speculate that @xmath185 represents the full effective potential , i.e. , the classical part plus @xmath186 quantum mechanical corrections .
indeed , @xmath185 would then be the correct tool to calculate a classical unstable orbit .
recently , @xmath32 corrections to the newtonian potential , have been discussed in @xcite , where it was found that the additional terms are proportional to @xmath187 ( @xmath188 is the restored newtonian constant ) .
the procedure to arrive at such a result is to consider non - relativistic amplitudes with zero and higher order loop corrections .
the difference from our case is that these corrections were calculated for massive particles where the newtonian potential exists and the non - relativistic limit makes sense . in a massless case , such a procedure is not well - defined .
therefore our conjecture is well motivated but remains open .
since the dimensions of @xmath22 from gr and @xmath189 are different , let us be more specific . to make @xmath185 dimensionless we divide it by the planck mass squared , @xmath190 and identify @xmath191 .
thus , @xmath192\ , .\ ] ] our speculation is simply to say that @xmath22 receives a small quantum correction proportional to @xmath32 in the above equation .
this explains also the coincidences found in the previous section .
indeed , calculating @xmath26 from @xmath22 or @xmath22 plus quantum corrections will give very similar results .
therefore it is not a surprise that @xmath99 comes out quite close to the @xmath1 evaluated from @xmath26 .
the behaviour of the reflection coefficient , @xmath0 , which enters the scattering cross sections is investigated for the scattering of scalar , electromagnetic and gravitational waves from a schwarzschild black hole .
we paid special attention to the issue of orbiting effects in a quantum mechanical scattering off black holes .
our investigation displays the following features : * for @xmath193 we found that @xmath0 jumps at a certain critical value @xmath1 , i.e. its second derivative with respect to @xmath5 is zero .
the regge - wheeler potential is proportional to the classical effective potential for @xmath86 only .
we find that @xmath1 is connected with the unstable circular orbit at @xmath87 for @xmath86 .
* we find the @xmath1 values for @xmath175 , too . here
also we would expect that the critical value @xmath1 is connected to an unstable circular orbit at a critical @xmath26 .
interestingly , the @xmath1 values calculated using @xmath194 lie very close to those using @xmath195 .
this can be explained if we re - interpret the regge wheeler potential as the classical effective potential with @xmath32 corrections .
notice that with the values of @xmath1 obtained via the rectangular potential , such a conclusion would be impossible as the jump occurs at a different @xmath1 and the connection to the unstable circular orbit is lost .
* for all values of @xmath97 and spins @xmath196 and @xmath197 we find that @xmath149 .
* we have shown that the transmission and reflection coefficients of the potential proportional to @xmath30 ( pschl - teller ) match very well with the exact results . since for this particular case
the transmission coefficient can be given analytically , this allows us to study the black hole scattering in a semi - analytical way and supplements the conclusion that such a potential is a good approximate tool in black hole physics @xcite .
both the semi - analytical results and the numerical ones refine approximate results obtained elsewhere and reveal some deficiencies of the approximation methods .
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n. froeman and p. o. froeman , _ jwkb approximation : contributions to the theory _ , north - holland , amsterdam ( 1965 ) .[/INST] rainbow , glory and orbiting scattering are usually described by the properties of the classical deflection function related to the real part of the quantum mechanical scattering phase shift or by the diffractive pattern of the quantum mechanical cross sections . here
we show that the case of orbiting scattering of massless spin 0 , 1 and 2 particles from schwarzschild black holes can be characterized by a sudden rise in @xmath0 at a critical angular momentum @xmath1 , which we show corresponds to the unstable circular orbits of these particles . for the cases , @xmath2 , we attempt a new interpretation of the regge - wheeler potential by identifying the quantum mechanical corrections to the effective potential of massless particles .
we probe into the black hole scattering by using numerical and semi - analytical methods which give very good agreements with the exact numerical results .
the limitations of previously used approximations as compared to the exact and semi - analytical results are discussed . </s> |
the standard sequence - to - structure - to - function paradigm for proteins assumes that each protein first folds into a three - dimensional ( 3d ) structure and that the resulting structure enables function via the lock and key ( 1 ) or the induced fit ( 2 ) models .
enzymes and their functions , which were traditionally the focus of studies in biochemistry , provided the basis for the lock and key and induced fit models ; hence , as expected these models generally and perhaps universally explain enzymatic function .
one reflection of the intimate relationship between protein structure and catalytic function is the relatively higher coverage of enzymes in the protein data bank ( pdb ) as compared with other protein types ( 3 ) .
non - catalytic protein functions relating to signaling , regulation and control , such as protein protein interactions , protein dna interactions , protein rna interactions , post - translational modifications and linker activities to name a few , are increasingly being studied .
many of these non - catalytic functions have been suggested to depend on , or have been experimentally demonstrated to depend on , proteins that lack fixed 3d structure , with interesting publications on this topic dating up to 70 years ago ( 48 ) .
functional proteins that lack the relatively fixed structure of enzymes and other globular proteins have been called rheomormorphic ( 9 ) , natively unfolded ( 10 ) , intrinsically unstructured ( 11 ) and natively or intrinsically disordered ( 12 ) , among other terms .
these proteins or protein regions exist as interconverting , dynamic ensembles of structures instead of folding into a single structure and many of their signaling or regulatory functions depend on their highly flexible nature .
conformational flexibility facilitates a number of post - translational modifications , such as phosphorylation ( 13 ) and ubiquitination ( 1416 ) for example , possibly because similar sequence segments in different proteins can use this flexibility to conform to the active sites of the modifying enzymes .
many protein - binding interactions important for signaling and regulation involve modular binding domains that often associate with rather short linear motifs ( 1721 ) . in many cases ,
these interactions involve disorder - to - order transitions for at least one of the partners . such complex formation by coupled folding and binding ( 22 ) provides an important mechanism for achieving both high specificity and low affinity ( 8) , which is an ideal combination for signaling and regulation .
not only can individual disordered proteins and regions bind to multiple partners ( 46,23 ) , but also multiple disordered sequences can each adapt to fit one partner ( 24 ) .
these partnering abilities of disordered proteins suggest their importance and common usage in protein interaction and signaling networks .
some biological functions involve the flexibility itself , one important example being the ball and chain model for inactivation of voltage - gated ion channels ( 7 ) .
often the flexibility of disordered regions provides a linker function to enable structured ( or unstructured ) functional domains to move relative to each other , which can lead to enhanced affinity .
the experimental data describing intrinsically disordered proteins ( idps ) are growing rapidly due in part to the increasing interest in signaling , regulation and control .
the rapidly increasing number of idp examples has generated the need for a publicly accessible repository . to facilitate efficient management and annotation of idp information , the database of disordered proteins ( disprot )
, disprot contained 460 idps and 1103 disordered regions , encompassing 35 functional categories all based on published experimental data .
intrinsically disordered regions and proteins carry out a number of vital functions in the living cell . a new structure function paradigm that extends the aforementioned sequence - to - structure - to - function model by including disorder as a type of structure provides the basis for describing the functions that depend on disorder ( 11 ) .
the protein trinity hypothesis suggests that functional proteins can exist in one of three conformational states : the solid - like ordered state ( globular proteins ) , the liquid - like collapsed disordered state ( molten globule ) and the gas - like extended disordered state ( 25 ) .
one more extended disordered conformation , the pre - molten globule state , was added to complete the the protein quartet model ( 26 ) .
the pre - molten globule contains specific regions that transiently form regular secondary structure while extended disorder lacks a significant amount of such regions and behaves more like a typical random coil . because the set of natively unfolded proteins probably forms a continuum ranging from little or no transient secondary structure to significant amounts of transient secondary structure but still without the compactness of the molten globule , it is uncertain whether the unfolded realm ought to remain as one category or be partitioned into two separate regions as suggested above .
a difficulty with the partitioning is that it is unclear how to carry out this separation in a consistent manner .
so given this uncertainty , function is then proposed to arise from any of these three ( trinity model ) or four ( quartet model ) states , or from transitions between them . currently , seven idp - related high - level functional classifications have been proposed and are included in disprot ( table 1 ) .
these are chaperone , entropic chain , metal sponge , modification site , molecular assembly , molecular recognition effectors and molecular recognition scavengers .
more specific function annotations , referred to here as functional subclasses , are also provided ( table 1 ) .
only a few of the currently identified 35 functional subclasses attributed to idps are included in table 1 . as additional biological processes and functions
are continuously identified as being dependent upon protein intrinsic disorder , we anticipate that functional classes and subclasses will be expanded upon over time . indeed , a recent bioinformatics study suggested that additional functions associated with protein disorder are evident in the literature ( see discussion ) . mining
this new source of information will add to the idp functional classifications listed in disprot .
examples of idp - related functional classes and subclasses the first column contains one of each of the high - level functional classes currently included in disprot .
information in the remaining columns includes illustrative details for exemplary annotated proteins from the database with disordered regions that perform the indicated functions .
regions may be annotated with multiple subclasses ( this is not reflected in the table ) .
disprot provides users with a number of tools to carry out a variety of biological and computational analyses .
some of these tools are as follows : disordered region sequence download , homologous protein sequence retrieval , functional narratives , graphical ordered and disordered region maps , isoform display , author - verified entries and a comprehensive bibliography for disordered proteins . from every protein entry page ( figure 1 ) , the sequence of the protein and disordered region(s )
homologues included in disprot obtained using the cd - hit clustering program with a 50% identity threshold , are also accessible via links .
a manually annotated description of the protein and its functional role(s ) is provided in the functional narrative section .
information on the protein family , cellular localization , or relation to cancer or any other disease is provided in the narrative .
when a protein includes both ordered and disordered regions and when the ordered segment(s ) are in the pdb , the relevant pdb links are included .
the protein and region map provides a visual representation of the location of the ordered and disordered regions in the context of the entire protein .
author - verified protein entries are proteins in which the author(s ) of the referenced papers have reviewed and verified all disorder information available for that entry . at the time of this writing
( a ) protein display for dp000039 , non - histone chromosomal protein hmg-17 , and ( b ) bibliography query page . a searchable bibliography ( figure 1b ) that includes all the papers referenced by disprot , together with papers that have cited several key references on disordered proteins and some other papers found by keyword searches .
although not displayed , abstract text is included in keyword searches in order to increase the usefulness of this collection .
in addition , a link to the pubmed abstract is provided for every applicable paper . as of now
, the total number of papers in the bibliography is 2289 . the number of papers published per year in this field growing rapidly as evident in figure 2 .
the number of papers tallied by year referencing protein disorder that are included in the searchable bibliography of disprot . an additional feature of disprot related to individual protein entries that is not illustrated in figure 1a is that isoforms included in disprot ( produced primarily through alternative splicing ) are annotated as a sub - entry to the original protein .
for example , information about isoform 1 of calcineurin , dp00092 , is coded in dp00092_a001 . since alternatively spliced segments of pre - mrna were recently shown to code for regions of intrinsic disorder much more frequently than they code for regions of 3d structure ( 27 ) ,
although the data in disprot are based on experimental data , predictors of protein disorder have been found to be useful for the analysis of relationships among primary amino acid sequence , structure and function of proteins ( 28,29 ) .
this list is updated as new predictors become available . through display and tabulation of known disorder information of individual proteins combined with relationships among isoforms and similar proteins
, disprot can supply useful examples for crystallographers and structural biologists as an aid to solving the structures of target proteins that contain unstructured regions .
disorder can typically be characterized by x - ray crystallography , nmr spectroscopy , cd spectroscopy ( both far and near uv ) and protease sensitivity in addition to several other less frequently used experimental techniques .
a comprehensive list of all detection methods currently used to characterize idps and the descriptions of these techniques can be found using convenient links provided in the database .
each protein entry includes the method(s ) used for disorder characterization as well as the specific experimental conditions .
clicking on a detection method link brings up a list of all proteins in the database that have been characterized using that particular method .
disprot is supported by an apache web server with the web interface implemented using php and javascript .
disprot is available to the public and can be accessed at . simplified idef1x representation of the disprot database structure .
boxes with round edges represent tables with at least one foreign key . dashed lines with an oval at one end and a cross at the other represent mandatory relationships ( not null foreign keys ) , plane lines with an oval at one end and a cross at the other represent identifying relationship ( foreign keys , possibly null , for which the field names in the tables are identical ) , dashed lines with an oval at both ends represent non - identifying optional relationships ( foreign keys , possibly null , for which the field names are not identical ) .
it is also possible to query the database using amino acid sequence , keywords , protein name , organism name or accession numbers from uniprot , swissprot , ncbi and other databases .
query sequences are searched , using rps - blast , against a database containing the profiles of all the proteins in the current release .
sequence homologues within disprot are found using the cd - hit-2d program with a 50% identity threshold .
in addition , the complete disprot database is available for download in the fasta and xml format ( ) .
disprot is the central repository for structure function annotations associated with protein intrinsic disorder .
these users are involved in many branches of protein science and are from a variety of different organization types , including academic , industry and government .
the nearly 450 papers published in 2005 is about twice the number published in 2004 , and the number of papers in 2006 , although the year is not complete as of this writing , shows clear evidence of a continued rapid rise ( figure 2 ) .
because inconsistent nomenclature is used to describe these proteins , the bibliography in disprot is very useful to researchers in this rapidly growing field .
the rapid growth of disorder - related publications argues for the importance of having an organized database such as disprot .
researchers who study idps are encouraged to look over this bibliography and to send us the citations of papers that we have missed .
our initial attempt to identify disorder - function relationships led to 28 specific functions that we grouped into four classes ( 12 ) .
a different schema was proposed at about the same time that led to additional functions being added ( 30 ) .
the 7 and 35 functional classes and subclasses , respectfully , in the current disprot came mostly from these prior publications , but with a number of additions that were discovered during the process of annotating proteins .
a search of the pdb for short segments called molecular recognition features , morfs , was carried out .
morfs undergo disorder - to - order transitions upon binding to their partners , which typically have globular structure .
this search yielded 1261 morfs that were clustered into 372 sets on the basis of high - sequence identity among members of a given set ( 31 ) .
many of these morfs have experimental data supporting disorder - to - order transitions upon binding .
in addition , proteins that undergo disorder - to - order transitions upon complex formation are distinguishable from globular proteins that associate with one another .
the disorder - based complexes have larger monomer surface areas and larger interaction surface areas as compared to interacting globular proteins ( 32 ) .
all of the 372 morf - partner complexes exhibit these large surface areas for the monomers and interfaces ; furthermore , nearly all of the morfs have substantial prediction of disorder in their flanking regions as well .
both these observations support the concept that these interactions involve disorder - to - order transitions of the morfs ( 31 ) .
direct experimental evidence in support of this concept has been presented in the case of deacetylation ( 33 ) and phosphorylation sites , sh3 interaction motifs ( 34 ) and recognition elements of 14 - 3 - 3 proteins ( 24 ) , which all have been found in locally disordered regions of their parent proteins .
the possible generality of this mode of protein protein interactions has also been underlined by predicting the local structural preferences of interaction sites of idps ( 35 ) .
another approach , based on sequence comparison rather than analysis of structures in pdb , has been used to systematically identify short , linear motifs that bind to protein partners ( 20,21,36 ) .
these sequence - identified segments have been collected and are contained in the eukaryotic linear motif ( elm ) server ( ) ( 20 ) .
many of the sequence - based elms and the structure - based morfs are simply different descriptions of the same protein segments , and in these cases the elms likely undergo coupled binding and folding upon association with their partners ( fuxreiter , tompa and simon , work in progress ) .
the elms that have been experimentally verified to be unstructured in the absence of their partners and the elm - morf matches will be added to disprot with appropriate cross - references to the elm collection .
we recently carried out a bioinformatics study to determine which swiss protein keywords were associated with the prediction of long disordered regions and which keywords were associated with the absence of such predictions . of 711 function - associated keywords
for which there were enough protein examples in swiss protein to make statistical inferences , 302 keywords were strongly associated with the absence of disorder prediction and 262 were strongly associated with the prediction of disorder .
manual literature searches provided numerous confirmatory examples for which laboratory experiments verified the direct involvement of disordered regions in carrying out the identified functions ( h. xie , s. vucetic , l.m .
, we will focus our annotation efforts on finding papers that determine whether or not idps are directly responsible for carrying out the 262 functions that were indicated to be idp - associated .
this bioinformatics - directed disprot expansion will enable us to rapidly increase the number of experimentally verified disordered protein function relationships .
by expanding the number of different functions associated with experimentally characterized idps , disprot will become increasingly more useful in the field of genome annotation .
since intrinsically disordered regions often show high - sequence variability compared with structured regions in the same proteins , identifying functional homologues by sequence matching will be generally more difficult for idps than for structured proteins .
we previously showed that disordered regions could be classified based on differences in sequence properties and these disordered regions with differing sequence properties showed differences in function . a major goal in concert with
the expansion of disprot will be to refine the associations between different functions and different sequence properties , thus facilitating the use of disprot for function annotation .
given the high frequency of idps and the large number of functions carried out by these proteins , future versions of disprot and the associated tools to be developed will become essential for complete function annotation of proteomes .
another direction of the disprot future development will be the elaboration of tools for the idp sequence analyses .
. the availability of blast - like analyses using scoring matrices associated with the idp - specific sequence features would enable sequence / function relationships amongst idps to be more accurately analyzed .
although in its current configuration disprot contains links to known publicly available disorder predictors , a planned development is a disorder prediction service , in which results are obtained from multiple servers and compiled in one report ( i.e. a service resembling the predictprotein server ( 37,38 ) . rather than limiting users to the predictors
we have developed , we hope to make an array of predictors available , which can then be used in combination for more detailed analysis as described recently ( 39 ) .
another useful tool is the recently described disorder score versus sequence complexity plot ( 40 ) ; these plots appear to be extremely useful for comparing idps . in these ways | the database of protein disorder ( disprot ) links structure and function information for intrinsically disordered proteins ( idps ) .
intrinsically disordered proteins do not form a fixed three - dimensional structure under physiological conditions , either in their entireties or in segments or regions .
we define idp as a protein that contains at least one experimentally determined disordered region .
although lacking fixed structure , idps and regions carry out important biological functions , being typically involved in regulation , signaling and control .
such functions can involve high - specificity low - affinity interactions , the multiple binding of one protein to many partners and the multiple binding of many proteins to one partner .
these three features are all enabled and enhanced by protein intrinsic disorder .
one of the major hindrances in the study of idps has been the lack of organized information .
disprot was developed to enable idp research by collecting and organizing knowledge regarding the experimental characterization and the functional associations of idps .
in addition to being a unique source of biological information , disprot opens doors for a plethora of bioinformatics studies .
disprot is openly available at . | <s>[INST]the standard sequence - to - structure - to - function paradigm for proteins assumes that each protein first folds into a three - dimensional ( 3d ) structure and that the resulting structure enables function via the lock and key ( 1 ) or the induced fit ( 2 ) models .
enzymes and their functions , which were traditionally the focus of studies in biochemistry , provided the basis for the lock and key and induced fit models ; hence , as expected these models generally and perhaps universally explain enzymatic function .
one reflection of the intimate relationship between protein structure and catalytic function is the relatively higher coverage of enzymes in the protein data bank ( pdb ) as compared with other protein types ( 3 ) .
non - catalytic protein functions relating to signaling , regulation and control , such as protein protein interactions , protein dna interactions , protein rna interactions , post - translational modifications and linker activities to name a few , are increasingly being studied .
many of these non - catalytic functions have been suggested to depend on , or have been experimentally demonstrated to depend on , proteins that lack fixed 3d structure , with interesting publications on this topic dating up to 70 years ago ( 48 ) .
functional proteins that lack the relatively fixed structure of enzymes and other globular proteins have been called rheomormorphic ( 9 ) , natively unfolded ( 10 ) , intrinsically unstructured ( 11 ) and natively or intrinsically disordered ( 12 ) , among other terms .
these proteins or protein regions exist as interconverting , dynamic ensembles of structures instead of folding into a single structure and many of their signaling or regulatory functions depend on their highly flexible nature .
conformational flexibility facilitates a number of post - translational modifications , such as phosphorylation ( 13 ) and ubiquitination ( 1416 ) for example , possibly because similar sequence segments in different proteins can use this flexibility to conform to the active sites of the modifying enzymes .
many protein - binding interactions important for signaling and regulation involve modular binding domains that often associate with rather short linear motifs ( 1721 ) . in many cases ,
these interactions involve disorder - to - order transitions for at least one of the partners . such complex formation by coupled folding and binding ( 22 ) provides an important mechanism for achieving both high specificity and low affinity ( 8) , which is an ideal combination for signaling and regulation .
not only can individual disordered proteins and regions bind to multiple partners ( 46,23 ) , but also multiple disordered sequences can each adapt to fit one partner ( 24 ) .
these partnering abilities of disordered proteins suggest their importance and common usage in protein interaction and signaling networks .
some biological functions involve the flexibility itself , one important example being the ball and chain model for inactivation of voltage - gated ion channels ( 7 ) .
often the flexibility of disordered regions provides a linker function to enable structured ( or unstructured ) functional domains to move relative to each other , which can lead to enhanced affinity .
the experimental data describing intrinsically disordered proteins ( idps ) are growing rapidly due in part to the increasing interest in signaling , regulation and control .
the rapidly increasing number of idp examples has generated the need for a publicly accessible repository . to facilitate efficient management and annotation of idp information , the database of disordered proteins ( disprot )
, disprot contained 460 idps and 1103 disordered regions , encompassing 35 functional categories all based on published experimental data .
intrinsically disordered regions and proteins carry out a number of vital functions in the living cell . a new structure function paradigm that extends the aforementioned sequence - to - structure - to - function model by including disorder as a type of structure provides the basis for describing the functions that depend on disorder ( 11 ) .
the protein trinity hypothesis suggests that functional proteins can exist in one of three conformational states : the solid - like ordered state ( globular proteins ) , the liquid - like collapsed disordered state ( molten globule ) and the gas - like extended disordered state ( 25 ) .
one more extended disordered conformation , the pre - molten globule state , was added to complete the the protein quartet model ( 26 ) .
the pre - molten globule contains specific regions that transiently form regular secondary structure while extended disorder lacks a significant amount of such regions and behaves more like a typical random coil . because the set of natively unfolded proteins probably forms a continuum ranging from little or no transient secondary structure to significant amounts of transient secondary structure but still without the compactness of the molten globule , it is uncertain whether the unfolded realm ought to remain as one category or be partitioned into two separate regions as suggested above .
a difficulty with the partitioning is that it is unclear how to carry out this separation in a consistent manner .
so given this uncertainty , function is then proposed to arise from any of these three ( trinity model ) or four ( quartet model ) states , or from transitions between them . currently , seven idp - related high - level functional classifications have been proposed and are included in disprot ( table 1 ) .
these are chaperone , entropic chain , metal sponge , modification site , molecular assembly , molecular recognition effectors and molecular recognition scavengers .
more specific function annotations , referred to here as functional subclasses , are also provided ( table 1 ) .
only a few of the currently identified 35 functional subclasses attributed to idps are included in table 1 . as additional biological processes and functions
are continuously identified as being dependent upon protein intrinsic disorder , we anticipate that functional classes and subclasses will be expanded upon over time . indeed , a recent bioinformatics study suggested that additional functions associated with protein disorder are evident in the literature ( see discussion ) . mining
this new source of information will add to the idp functional classifications listed in disprot .
examples of idp - related functional classes and subclasses the first column contains one of each of the high - level functional classes currently included in disprot .
information in the remaining columns includes illustrative details for exemplary annotated proteins from the database with disordered regions that perform the indicated functions .
regions may be annotated with multiple subclasses ( this is not reflected in the table ) .
disprot provides users with a number of tools to carry out a variety of biological and computational analyses .
some of these tools are as follows : disordered region sequence download , homologous protein sequence retrieval , functional narratives , graphical ordered and disordered region maps , isoform display , author - verified entries and a comprehensive bibliography for disordered proteins . from every protein entry page ( figure 1 ) , the sequence of the protein and disordered region(s )
homologues included in disprot obtained using the cd - hit clustering program with a 50% identity threshold , are also accessible via links .
a manually annotated description of the protein and its functional role(s ) is provided in the functional narrative section .
information on the protein family , cellular localization , or relation to cancer or any other disease is provided in the narrative .
when a protein includes both ordered and disordered regions and when the ordered segment(s ) are in the pdb , the relevant pdb links are included .
the protein and region map provides a visual representation of the location of the ordered and disordered regions in the context of the entire protein .
author - verified protein entries are proteins in which the author(s ) of the referenced papers have reviewed and verified all disorder information available for that entry . at the time of this writing
( a ) protein display for dp000039 , non - histone chromosomal protein hmg-17 , and ( b ) bibliography query page . a searchable bibliography ( figure 1b ) that includes all the papers referenced by disprot , together with papers that have cited several key references on disordered proteins and some other papers found by keyword searches .
although not displayed , abstract text is included in keyword searches in order to increase the usefulness of this collection .
in addition , a link to the pubmed abstract is provided for every applicable paper . as of now
, the total number of papers in the bibliography is 2289 . the number of papers published per year in this field growing rapidly as evident in figure 2 .
the number of papers tallied by year referencing protein disorder that are included in the searchable bibliography of disprot . an additional feature of disprot related to individual protein entries that is not illustrated in figure 1a is that isoforms included in disprot ( produced primarily through alternative splicing ) are annotated as a sub - entry to the original protein .
for example , information about isoform 1 of calcineurin , dp00092 , is coded in dp00092_a001 . since alternatively spliced segments of pre - mrna were recently shown to code for regions of intrinsic disorder much more frequently than they code for regions of 3d structure ( 27 ) ,
although the data in disprot are based on experimental data , predictors of protein disorder have been found to be useful for the analysis of relationships among primary amino acid sequence , structure and function of proteins ( 28,29 ) .
this list is updated as new predictors become available . through display and tabulation of known disorder information of individual proteins combined with relationships among isoforms and similar proteins
, disprot can supply useful examples for crystallographers and structural biologists as an aid to solving the structures of target proteins that contain unstructured regions .
disorder can typically be characterized by x - ray crystallography , nmr spectroscopy , cd spectroscopy ( both far and near uv ) and protease sensitivity in addition to several other less frequently used experimental techniques .
a comprehensive list of all detection methods currently used to characterize idps and the descriptions of these techniques can be found using convenient links provided in the database .
each protein entry includes the method(s ) used for disorder characterization as well as the specific experimental conditions .
clicking on a detection method link brings up a list of all proteins in the database that have been characterized using that particular method .
disprot is supported by an apache web server with the web interface implemented using php and javascript .
disprot is available to the public and can be accessed at . simplified idef1x representation of the disprot database structure .
boxes with round edges represent tables with at least one foreign key . dashed lines with an oval at one end and a cross at the other represent mandatory relationships ( not null foreign keys ) , plane lines with an oval at one end and a cross at the other represent identifying relationship ( foreign keys , possibly null , for which the field names in the tables are identical ) , dashed lines with an oval at both ends represent non - identifying optional relationships ( foreign keys , possibly null , for which the field names are not identical ) .
it is also possible to query the database using amino acid sequence , keywords , protein name , organism name or accession numbers from uniprot , swissprot , ncbi and other databases .
query sequences are searched , using rps - blast , against a database containing the profiles of all the proteins in the current release .
sequence homologues within disprot are found using the cd - hit-2d program with a 50% identity threshold .
in addition , the complete disprot database is available for download in the fasta and xml format ( ) .
disprot is the central repository for structure function annotations associated with protein intrinsic disorder .
these users are involved in many branches of protein science and are from a variety of different organization types , including academic , industry and government .
the nearly 450 papers published in 2005 is about twice the number published in 2004 , and the number of papers in 2006 , although the year is not complete as of this writing , shows clear evidence of a continued rapid rise ( figure 2 ) .
because inconsistent nomenclature is used to describe these proteins , the bibliography in disprot is very useful to researchers in this rapidly growing field .
the rapid growth of disorder - related publications argues for the importance of having an organized database such as disprot .
researchers who study idps are encouraged to look over this bibliography and to send us the citations of papers that we have missed .
our initial attempt to identify disorder - function relationships led to 28 specific functions that we grouped into four classes ( 12 ) .
a different schema was proposed at about the same time that led to additional functions being added ( 30 ) .
the 7 and 35 functional classes and subclasses , respectfully , in the current disprot came mostly from these prior publications , but with a number of additions that were discovered during the process of annotating proteins .
a search of the pdb for short segments called molecular recognition features , morfs , was carried out .
morfs undergo disorder - to - order transitions upon binding to their partners , which typically have globular structure .
this search yielded 1261 morfs that were clustered into 372 sets on the basis of high - sequence identity among members of a given set ( 31 ) .
many of these morfs have experimental data supporting disorder - to - order transitions upon binding .
in addition , proteins that undergo disorder - to - order transitions upon complex formation are distinguishable from globular proteins that associate with one another .
the disorder - based complexes have larger monomer surface areas and larger interaction surface areas as compared to interacting globular proteins ( 32 ) .
all of the 372 morf - partner complexes exhibit these large surface areas for the monomers and interfaces ; furthermore , nearly all of the morfs have substantial prediction of disorder in their flanking regions as well .
both these observations support the concept that these interactions involve disorder - to - order transitions of the morfs ( 31 ) .
direct experimental evidence in support of this concept has been presented in the case of deacetylation ( 33 ) and phosphorylation sites , sh3 interaction motifs ( 34 ) and recognition elements of 14 - 3 - 3 proteins ( 24 ) , which all have been found in locally disordered regions of their parent proteins .
the possible generality of this mode of protein protein interactions has also been underlined by predicting the local structural preferences of interaction sites of idps ( 35 ) .
another approach , based on sequence comparison rather than analysis of structures in pdb , has been used to systematically identify short , linear motifs that bind to protein partners ( 20,21,36 ) .
these sequence - identified segments have been collected and are contained in the eukaryotic linear motif ( elm ) server ( ) ( 20 ) .
many of the sequence - based elms and the structure - based morfs are simply different descriptions of the same protein segments , and in these cases the elms likely undergo coupled binding and folding upon association with their partners ( fuxreiter , tompa and simon , work in progress ) .
the elms that have been experimentally verified to be unstructured in the absence of their partners and the elm - morf matches will be added to disprot with appropriate cross - references to the elm collection .
we recently carried out a bioinformatics study to determine which swiss protein keywords were associated with the prediction of long disordered regions and which keywords were associated with the absence of such predictions . of 711 function - associated keywords
for which there were enough protein examples in swiss protein to make statistical inferences , 302 keywords were strongly associated with the absence of disorder prediction and 262 were strongly associated with the prediction of disorder .
manual literature searches provided numerous confirmatory examples for which laboratory experiments verified the direct involvement of disordered regions in carrying out the identified functions ( h. xie , s. vucetic , l.m .
, we will focus our annotation efforts on finding papers that determine whether or not idps are directly responsible for carrying out the 262 functions that were indicated to be idp - associated .
this bioinformatics - directed disprot expansion will enable us to rapidly increase the number of experimentally verified disordered protein function relationships .
by expanding the number of different functions associated with experimentally characterized idps , disprot will become increasingly more useful in the field of genome annotation .
since intrinsically disordered regions often show high - sequence variability compared with structured regions in the same proteins , identifying functional homologues by sequence matching will be generally more difficult for idps than for structured proteins .
we previously showed that disordered regions could be classified based on differences in sequence properties and these disordered regions with differing sequence properties showed differences in function . a major goal in concert with
the expansion of disprot will be to refine the associations between different functions and different sequence properties , thus facilitating the use of disprot for function annotation .
given the high frequency of idps and the large number of functions carried out by these proteins , future versions of disprot and the associated tools to be developed will become essential for complete function annotation of proteomes .
another direction of the disprot future development will be the elaboration of tools for the idp sequence analyses .
. the availability of blast - like analyses using scoring matrices associated with the idp - specific sequence features would enable sequence / function relationships amongst idps to be more accurately analyzed .
although in its current configuration disprot contains links to known publicly available disorder predictors , a planned development is a disorder prediction service , in which results are obtained from multiple servers and compiled in one report ( i.e. a service resembling the predictprotein server ( 37,38 ) . rather than limiting users to the predictors
we have developed , we hope to make an array of predictors available , which can then be used in combination for more detailed analysis as described recently ( 39 ) .
another useful tool is the recently described disorder score versus sequence complexity plot ( 40 ) ; these plots appear to be extremely useful for comparing idps . in these ways[/INST]the database of protein disorder ( disprot ) links structure and function information for intrinsically disordered proteins ( idps ) .
intrinsically disordered proteins do not form a fixed three - dimensional structure under physiological conditions , either in their entireties or in segments or regions .
we define idp as a protein that contains at least one experimentally determined disordered region .
although lacking fixed structure , idps and regions carry out important biological functions , being typically involved in regulation , signaling and control .
such functions can involve high - specificity low - affinity interactions , the multiple binding of one protein to many partners and the multiple binding of many proteins to one partner .
these three features are all enabled and enhanced by protein intrinsic disorder .
one of the major hindrances in the study of idps has been the lack of organized information .
disprot was developed to enable idp research by collecting and organizing knowledge regarding the experimental characterization and the functional associations of idps .
in addition to being a unique source of biological information , disprot opens doors for a plethora of bioinformatics studies .
disprot is openly available at .</s> |
let @xmath11 denote an acyclic directed graph , where @xmath12 denotes the set of all the vertices ( or points ) in @xmath0 and @xmath13 denotes the set of all the edges in @xmath0 . in this paper ,
a _ path _ in @xmath0 is treated as a set of concatenated edges . for @xmath14 paths @xmath15 in @xmath11 , we say these paths _ merge _
@xcite at an edge @xmath16 if 1 .
@xmath17 , 2 .
there are at least two distinct edges @xmath18 such that @xmath19 are immediately ahead of @xmath20 on some @xmath21 , @xmath22 , respectively .
we call the maximal subpath that starts with @xmath20 and that is shared by all @xmath23 s ( i.e. , @xmath20 together with the subsequent concatenated edges shared by all @xmath23 s until some @xmath23 branches off ) _ merged subpath _ ( or simply _ merging _ ) by all @xmath23 s at @xmath20 ; see figure [ picmergings ] for a quick example .
for any two vertices @xmath24 , we call any set consisting of the maximum number of pairwise edge - disjoint directed paths from @xmath25 to @xmath26 a set of _ menger s paths _ from @xmath25 to @xmath26 . by menger
s theorem @xcite , the cardinality of menger s paths from @xmath25 to @xmath26 is equal to the min - cut between @xmath25 and @xmath26 . here , we remark that the ford - fulkerson algorithm @xcite can find the min - cut and a set of menger s paths from @xmath25 to @xmath26 in polynomial time .
assume that @xmath11 has @xmath27 sources @xmath1 and @xmath27 distinct sinks @xmath2 .
for @xmath3 , let @xmath4 denote the min - cut between @xmath5 and @xmath6 , and let @xmath28 denote a set of menger s paths from @xmath5 to @xmath6 .
we are interested in the number of mergings among paths from different @xmath29 s , denoted by @xmath30 . in this paper
we will count the number of mergings * without * multiplicity : all the mergings at the same edge @xmath20 will be counted as one merging at @xmath20 .
merge at edge @xmath31 and at merged subpath ( or merging ) @xmath32 , and paths @xmath33 merge at edge @xmath34 and at merged subpath ( or merging ) @xmath35.,scaledwidth=48.0% ] the motivation for such consideration is more or less obvious in transportation networks : mergings among different groups of transportation paths can cause congestions , which may either decrease the whole network throughput or incur unnecessary cost . the connection between the number of mergings and the encoding complexity in computer networks ,
however , is a bit more subtle , which can be best illustrated by the following three examples in network coding theory ( for a brief introduction to this theory , see @xcite ) .
the first example is the famous `` butterfly network '' @xcite . as depicted in figure [ picthreeeg](a ) , for the purpose of transmitting messages @xmath36 simultaneously from the sender @xmath37 to the receivers @xmath38 , network encoding has to be done at node @xmath39 .
another way to interpret the necessity of network coding at @xmath39 ( for the simultaneous transmission to @xmath40 and @xmath41 ) is as follows : if the transmission to @xmath41 is ignored , menger s paths @xmath42 and @xmath43 can be used to transmit messages @xmath36 from @xmath37 to @xmath40 ; if the transmission to @xmath40 is ignored , menger s paths @xmath44 and @xmath45 can be used to transmit messages @xmath36 from @xmath37 to @xmath41 . for the simultaneous transmission to @xmath40 and @xmath41 ,
merging by these two groups of menger s paths at @xmath46 becomes a `` bottle neck '' , therefore network coding at @xmath39 is required to avoid the possible congestions .
the second example is a variant of the classical butterfly network ( see example 17.2 of @xcite ; cf .
the two - way channel in page @xmath47 of @xcite ) with two senders and two receivers , where the sender @xmath48 is attached to the receiver @xmath41 to form a group and the sender @xmath49 is attached to the receiver @xmath40 to form the other group . as depicted in figure [ picthreeeg](b )
, the two groups wish to exchange messages @xmath50 and @xmath51 through the network .
similarly as in the first example , the edge @xmath31 is where the menger s paths @xmath52 and @xmath53 merge with each other , which is a bottle neck for the simultaneous transmission of messages @xmath36 .
the simultaneous transmission is achievable if upon receiving the messages @xmath50 and @xmath51 , network encoding is performed at the node @xmath54 and the newly derived message @xmath55 is sent over the channel @xmath56 .
the third example is concerned with two sessions of unicast in a network @xcite . as shown in figure [ picthreeeg](c ) , the sender @xmath48 is to transmit message @xmath50 to the receiver @xmath40 using path @xmath57 .
and the sender @xmath49 is to transmit message @xmath51 to the receiver @xmath41 using two menger s paths @xmath58 and @xmath59 .
since mergings @xmath31 , @xmath46 and @xmath60 become bottle necks for the simultaneous transmission of messages @xmath50 and @xmath51 , network coding at these bottle necks , as shown in figure [ picthreeeg](c ) , is performed to ensure the simultaneous message transmission . generally speaking , for a network with multiple groups of menger s paths , each of which is used to transmit a set of messages to a particular sink , network encoding is needed at mergings by different groups of menger s paths . as a result , the number of mergings is the number of network encoding operations required in the network .
so , we are interested in the number of mergings among different groups of menger s paths in such networks . for the case when all sources in @xmath0 are in fact identical , @xmath61 is defined as the minimum of @xmath30 over all possible menger s path sets @xmath29 s , @xmath3 , and @xmath62 is defined as the supremum of @xmath61 over all possible choices of such @xmath0 .
it is clear that @xmath61 is the least number of network encoding operations required for a given @xmath0 , and @xmath62 is the largest such number among all such @xmath0 ( with the min - cut between the @xmath63-th pair of source and sink being @xmath4 ) . as for @xmath10 ,
the authors of @xcite used the idea of `` subtree decomposition '' to first prove that @xmath64 although their idea seems to be difficult to generalize to other parameters , it does allow us to gain deeper understanding about the topological structure of the graphs achieving @xmath65 mergings for this special case .
it was first shown in @xcite that @xmath66 is finite for all @xmath67 ( see theorem @xmath68 in @xcite ) , and subsequently @xmath62 is finite for all @xmath69 . for the case
when all sources in @xmath0 are distinct , @xmath70 is defined as the minimum of @xmath30 over all possible menger s path sets @xmath29 s , @xmath71 , and @xmath72 is defined as the supremum of @xmath70 over all possible choices of such @xmath0 .
again , the encoding idea for the second example can be easily generalized to networks , where each receiver is attached to all senders except its associated one .
it is clear that the number of mergings is a tight upper bound for the number of network encoding operations required . for networks with several unicast sessions , in @xcite ,
an upper bound for the encoding complexity of a network with two unicast sessions was given , as a result of a more general treatment ( to networks with two multicast sessions ) by the authors .
it is easy to see that for networks with multiple unicast sessions ( straightforward generalizations of the third example ) , @xmath9 with appropriate parameters can serve as an upper bound on network encoding complexity .
it was first conjectured that @xmath72 is finite in @xcite .
more specifically the authors proved that ( see lemma @xmath73 in @xcite ) if @xmath74 is finite for all @xmath67 , then @xmath72 is finite as well . here
, we remark that we have rephrased the work in @xcite , since all of them are done using very different languages from ours . in @xcite
, we have shown that for any @xmath69 , @xmath62 , @xmath72 are both finite , and we further studied the behaviors of @xmath75 as functions of the min - cuts . in this paper , further continuing the work in @xcite , we compute exact values of and give tighter bounds on @xmath10 and @xmath9 for certain parameters . for a path @xmath76 in @xmath0 ,
let @xmath77 denote _ head _ ( or _ starting point _ ) and _ tail _ ( or _ ending point _ ) of path @xmath76 , respectively ; let @xmath78 $ ] denote the subpath of @xmath76 with the starting point @xmath25 and the ending point @xmath26 .
for two distinct paths @xmath79 in @xmath0 , we say @xmath80 is _ smaller _ than @xmath81 ( or , @xmath81 is _ larger _
than @xmath80 ) if there is a directed path from @xmath82 to @xmath83 ; if @xmath79 and the connecting path from @xmath82 to @xmath83 are subpaths of path @xmath76 , we say @xmath80 is _ smaller _ than @xmath81 on @xmath76 .
note that this definition also applies to the case when paths degenerate to vertices / edges ; in other words , in the definition , @xmath79 or the connecting path from @xmath82 to @xmath83 can be vertices / edges in @xmath0 , which can be viewed as degenerated paths . if @xmath84 , we use @xmath85 to denote the path obtained by concatenating @xmath80 and @xmath81 subsequently . for a set of vertices
@xmath86 in @xmath0 , define @xmath87 to be the subgraph of @xmath0 induced on the set of vertices , each of which is smaller or equal to some @xmath88 , @xmath89 .
@xmath0 is said to be a _
@xmath90-graph _ if every edge in @xmath0 belongs to some @xmath29-path , or , in loose terms , all @xmath29 s `` cover '' the whole @xmath0 . for a @xmath90-graph ,
the number of mergings is the number of vertices whose in - degree is at least @xmath91 .
it is clear that to compute @xmath72 ( @xmath62 ) , it is enough to consider all the @xmath90-graphs with distinct ( identical ) sources . for a @xmath90-graph @xmath0
, we say @xmath29 is _ reroutable _ if there exists a different set of menger s paths @xmath92 from @xmath5 to @xmath6 , and we say @xmath0 is _ reroutable _ ( or alternatively , there is a _ rerouting _ in @xmath0 ) , if some @xmath29 , @xmath3 , is reroutable .
note that for a non - reroutable @xmath0 , the choice of @xmath29 s is unique , so we often write @xmath93 as @xmath94 for notational simplicity .
now , for a fixed @xmath63 , reverse the directions of edges that only belong to @xmath29 to obtain a new graph @xmath95 . for any two mergings @xmath96 ,
if there exists a directed path in @xmath95 from the head ( or tail ) of @xmath97 to the head ( or tail ) of @xmath98 , we say the head ( or tail ) of @xmath97 _ semi - reaches _ the head ( or tail ) of @xmath98 against @xmath29 , or alternatively , @xmath97 _ semi - reaches _ against @xmath29 from head ( or tail ) to head ( or tail ) .
it is easy to check that @xmath0 is reroutable if and only if there exists @xmath63 and a merging @xmath97 such that @xmath97 semi - reaches itself against @xmath29 from head to head , which is equivalent to the condition that there exists @xmath63 and a merging @xmath81 such that @xmath81 semi - reaches itself against @xmath29 from tail to tail . for the graph depicted in figure [ picgv ]
, the source @xmath48 is connected to the sink @xmath40 by a group of menger s paths @xmath99 and the source @xmath49 is connected to the sink @xmath41 by a group of menger s paths @xmath100 then @xmath101 are mergings by @xmath102-paths and @xmath103-paths .
@xmath104 , @xmath105 are smaller than @xmath106 and @xmath107 .
@xmath108 only consists of two isolated vertices @xmath109 ; @xmath110 is the subgraph of @xmath0 induced on the set of vertices @xmath111 ; @xmath112 is the subgraph of @xmath0 induced on the set of vertices @xmath113 and @xmath114 is just @xmath0 itself .
the group of menger s paths @xmath102 is reroutable , since there exists another group of menger s paths @xmath115 from @xmath48 to @xmath40 .
similarly , @xmath103 is also reroutable .
it is easy to check , by definition , that @xmath106 semi - reaches @xmath107 against @xmath103 from head to head , @xmath104 semi - reaches @xmath107 against @xmath103 from tail to head , and @xmath107 semi - reaches itself against @xmath102 ( or alternatively @xmath103 ) from head to head .
hence , @xmath0 is reroutable .
for any @xmath116 , consider the following procedure to `` draw '' an @xmath117-graph : for `` fixed '' edge - disjoint paths @xmath118 from @xmath49 to @xmath41 , we extend edge - disjoint paths @xmath119 from @xmath48 to merge with @xmath103-paths until we reach @xmath40 . more specifically , the procedure of extending @xmath102-paths is done step by step , and for each step , we choose to extend one of @xmath120 @xmath102-paths to merge with one of @xmath121 @xmath103-paths .
thus for each step , we have @xmath122 `` strokes '' to choose from the following set @xmath123 here , by `` drawing '' the _ path pair _ @xmath124 , we mean further extending path @xmath125 to merge with path @xmath126 , while ensuring the new merged subpath is larger than any existing merged subpaths on path @xmath126 . apparently , the procedure , and thus the graph ,
is uniquely determined by the sequence of strokes ( see example [ stack - graph ] ) , which will be referred to as a _ merging sequence _ of this @xmath117-graph . it is also easy to see that any @xmath117-graph can be generated by some merging sequence .
[ stack - graph ] consider the following two graphs in figure [ picmergingsequence ] ( here and hereafter , all the mergings in this paper are represented by solid dots instead ) .
listing the elements in the merging sequence , graph ( a ) can be described by @xmath127 $ ] , or alternatively @xmath128 $ ] . when the context is clear , we often omit @xmath129 in the merging sequence for notational .
for example , graph ( b ) can be described by a merging sequence @xmath130 $ ] .
note that it can not be described by @xmath131 $ ] , since @xmath132 ( or , more precisely , the merging corresponding to @xmath132 ) is larger than @xmath133 on @xmath134 .
consider a non - reroutable @xmath117-graph @xmath0 with two sources @xmath109 , two distinct sinks @xmath38 , a set of menger s paths @xmath135 from @xmath48 to @xmath40 , and a set of menger s paths @xmath136 from @xmath49 to @xmath41 . for the case when @xmath48 and @xmath49 are distinct , consider the following procedure on @xmath0 . starting from @xmath48 , go along path @xmath125 until we reach a merged subpath ( or more precisely , the terminal vertex of a merged subpath ) , we then go against the associated @xmath103-path ( corresponding to the merged subpath just visited ) until we reach another merged subpath , we then go along the associated @xmath102-path , @xmath137 continue this procedure ( of alternately going along @xmath102-paths or going against @xmath103-paths until we reach a merged subpath ) in the same manner as above , then the fact that @xmath0 is non - reroutable and acyclic guarantees that eventually we will reach @xmath40 or @xmath49 .
by sequentially listing all the terminal vertices of any merged subpaths visited , such a procedure produces a _ @xmath125-aa - sequence_. apparently , there are @xmath120 @xmath102-aa - sequences
. similarly , consider the following procedure on @xmath0 .
starting from @xmath41 , go against path @xmath126 until we reach a merged subpath , we then go along the associated @xmath102-path ( corresponding to the merged subpath just visited ) until we reach another merged subpath , we then go against the associated @xmath103-path , @xmath137 continue this procedure in the same manner , again , eventually , we are guaranteed to reach @xmath40 or @xmath49 .
by sequentially listing all the terminal vertices of any merged subpaths visited , such a procedure produces a _ @xmath126-aa - sequence_. apparently , there are @xmath121 @xmath103-aa - sequences .
the _ length _ of an aa - sequence @xmath138 , denoted by @xmath139 , is defined to be the number of terminal vertices of merged subpaths visited during the procedure . since each such terminal vertex in an aa - sequence is associated with a path pair , equivalently , the length of an aa - sequence can be also defined as the number of the associated path pairs . for the purpose of computing @xmath140 , we can assume that each menger s path in @xmath0 merges at least once , which implies that each aa - sequence is of positive length .
for the case when @xmath48 and @xmath49 are identical , by proposition @xmath141 in @xcite , we can restrict our attention to the case when @xmath142 .
for the purpose of computing @xmath143 , by the proof of proposition @xmath141 in @xcite , we can assume that paths @xmath125 and @xmath144 share a _ starting subpath _
( a maximal shared subpath by @xmath125 and @xmath144 starting from the source ) for @xmath71 , and due to non - reroutability of @xmath0 , @xmath145 and @xmath146 do not merge with any other path .
then , @xmath103-aa - sequences and their lengths can be similarly defined as in the case when @xmath48 and @xmath49 are distinct , except that we have to replace `` merged subpath '' by `` merged subpath or starting subpath '' .
( here , let us note that the procedure of defining @xmath102-aa - sequences does not carry over .
) it can be checked that the existence of @xmath120 starting subpaths implies that any @xmath103-aa - sequence is of positive length and will always terminate at @xmath40 .
it turns out that the lengths of aa - sequences are related to the number of mergings in @xmath0 .
[ aa - to - number - of - merings ] for a non - reroutable @xmath117-graph @xmath0 with distinct sources , @xmath147 for a non - reroutable @xmath148-graph @xmath0 with identical sources and @xmath121 starting subpaths , @xmath149 where the two summations above are over the all the possible aa - sequences . [ aa - examples ]
consider the two graphs in figure [ picaasequences ] .
let `` @xmath150 '' and `` @xmath151 '' denote `` go along '' and `` go against '' , respectively . in graph ( a ) ,
sequentially listing the terminal vertices of merged subpaths visited during the procedure , two @xmath102-aa - sequences can be represented by @xmath152 and @xmath153 .
similarly , two @xmath103-aa - sequences can be represented by @xmath154 and @xmath155 .
one also checks that the number of mergings is @xmath156 , which is half of @xmath157 , the sum of lengths of all aa - sequences . in graph
( b ) , sequentially listing the terminal vertices of merged subpaths and starting subpaths visited during the procedure , three @xmath103-aa - sequences can be represented by @xmath158 , @xmath159 and @xmath160 .
one also checks the number of mergings is @xmath161 , which is half of @xmath162 .
[ lengthofaasequence ] the shortest @xmath102-aa - sequence ( @xmath103-aa - sequence ) is of length at most @xmath163 .
suppose , by contradiction , that the shortest @xmath102-aa - sequence is of length at least @xmath91 .
pick any @xmath102-path , say @xmath164 .
assume that @xmath164 first merges with @xmath165 at merged subpath @xmath166 .
since the @xmath164-aa - sequence is of length at least @xmath91 , there exists a @xmath102-path , say @xmath167 , such that @xmath167 has a merged subpath , say @xmath168 , smaller than @xmath166 on @xmath165 .
now assume that @xmath167 first merges with @xmath169 at merged subpath @xmath170 , then similarly there exists a @xmath102-path , say @xmath171 , such that @xmath171 has a merged subpath , say @xmath172 , smaller than @xmath170 on @xmath169 .
continue this procedure in the similar manner to @xmath173 apparently , there exists @xmath174 such that @xmath175 .
one then checks that @xmath176 \circ \psi_{j_{l-1}}[h(\mu_{i_l , j_{l-1 } } ) , h(\lambda_{i_{l-1},j_{l-1}})]\ \circ \phi_{i_{l-1}}[h(\lambda_{i_{l-1},j_{l-1 } } ) , h(\mu_{i_{l-1 } , j_{l-2}})]\\ \circ & \psi_{j_{l-2}}[h(\mu_{i_{l-1 } , j_{l-2 } } ) , h(\lambda_{i_{l-2 } , j_{l-2 } } ) ] \circ \cdots \circ \phi_{i_{k+1}}[h(\lambda_{i_{k+1 } , j_{k+1 } } ) , h(\mu_{i_{k+1 } , j_k } ) ] \circ \psi_{j_k}[h(\mu_{i_{k+1 } , j_k } ) , h(\lambda_{i_k , j_k})]\end{aligned}\ ] ] constitutes a cycle , which contradicts the assumption that @xmath0 is acyclic .
a parallel argument can be applied to the shortest @xmath103-aa - sequence .
[ each - path - pair - at - most - once ] for a non - reroutable graph @xmath0 , any path pair occurs at most once in any given aa - sequence . by contradiction , suppose that the same path pair occurs in an aa - sequence twice . as in the proof of lemma 2.7 in @xcite , one can prove @xmath0 is reroutable , which is a contradiction .
it then immediately follows from lemma [ each - path - pair - at - most - once ] that in a non - reroutable @xmath177-graph with distinct sources , * the longest @xmath102-aa - sequence ( @xmath103-aa - sequence ) is of length at most @xmath122 ; * any @xmath102-path ( @xmath103-path ) merges at most @xmath122 times .
and in a non - reroutable @xmath178-graph with identical sources , * the longest @xmath103-aa - sequence is of length at most @xmath179 ; * any @xmath102-path ( @xmath103-path ) merges at most @xmath179 times .
in this section , we give exact values of @xmath9 and @xmath10 for certain special parameters .
[ threeproofs ] @xmath180 we first show that @xmath181 . consider the following @xmath182-graph specified by the following merging sequence ( for a simple example , see figure [ pictwomm2](a ) ) : @xmath183 $ ] , where @xmath184_2 , 1 ) & \mathrm{if}\ k=3i-2 & \mathrm{for}\ 1\leq i\leq n , \\ ( [ i]_2 , i+1 ) & \mathrm{if}\ k=3i-1 & \mathrm{for}\ 1\leq i \leq n-1,\\ ( [ i+1]_2 , i+1 ) & \mathrm{if}\ k=3i & \mathrm{for}\ 1\leq i \leq n-1,\\ ( [ n+1]_2 , 1 ) & \mathrm{if}\ k=3n-1 . & \end{array } \right.\ ] ] where @xmath185_2=1 $ ] when @xmath186 is odd , @xmath185_2=2 $ ] when @xmath186 is even .
-graph with 8 mergings ( b ) an example of a @xmath187-graph , scaledwidth=72.0% ] one checks that the above graph is non - reroutable with @xmath188 mergings , which implies that @xmath181 .
next , we show that @xmath189 . consider a non - reroutable @xmath182-graph @xmath0 with distinct sources @xmath109 , sinks @xmath38 , a set of menger s paths @xmath190 from @xmath48 to @xmath40 , and a set of menger s paths @xmath191 from @xmath49 to @xmath41 .
define @xmath192 note that for any @xmath193 , @xmath194 must belong to different @xmath102-paths .
we say @xmath193 is of _ type i _
, if @xmath97 belongs to @xmath195 , and @xmath193 is of _ type ii _ , if @xmath97 belongs to @xmath196 .
for any two different elements @xmath197 .
we say @xmath198 if either ( they are of the same type and @xmath199 is smaller than @xmath200 ) or ( they are of different types and @xmath199 is smaller than @xmath201 ) .
one then checks that the relationship defined by @xmath202 is a strict total order . letting @xmath186
denote the number of elements in @xmath203 , we define @xmath204 to be the sequence of the ordered ( by @xmath202 ) elements in @xmath203 .
now we consecutively partition @xmath205 into @xmath206 `` _ _ medium - blocks _ _ '' @xmath207 , and further consecutively partition each @xmath208 into @xmath209 `` _ _ mini - blocks _ _ '' @xmath210 ( see example [ mediumandmini ] for an example ) such that * for any @xmath211 , the elements in @xmath212 are of the same type . * for any @xmath211 , @xmath212 is _ linked _ to @xmath213 in the following sense : let @xmath214 denote the element with the largest second component in @xmath212 and let @xmath215 denote the element with the smallest first component in @xmath213 , then @xmath216 . * for any @xmath63 , @xmath217 is not linked to @xmath218 .
a mini - block is said to be a _ singleton _ if it has only one element .
we then have the following lemma , whose proof is omitted .
[ two - singletons ] between any two `` adjacent '' singletons ( meaning there is no singleton between these two singletons ) in a medium - block , there must exist a mini - block containing at least three elements .
letting @xmath219 denote the number of mini - blocks in @xmath205 and @xmath220 denote the number of elements in medium - block @xmath208 for @xmath221 , we then have @xmath222 suppose there are @xmath14 singletons in @xmath205 , then by lemma [ two - singletons ] , we can find @xmath223 mini - blocks , each of which has at least three elements .
hence , for @xmath221 , @xmath224=2y_i-1,\ ] ] which implies @xmath225 for any two linked mini - blocks @xmath212 and @xmath213 , let @xmath214 denote the element with the largest second component in @xmath212 , and let @xmath215 denote the element with the smallest first component in @xmath213 . by the definition ( of two mini - blocks
being linked ) , we have @xmath216 , which means @xmath212 and @xmath213 share a common merging . together with the fact that each element in @xmath203 is a pair of mergings
, this further implies that the number of mergings in @xmath0 is @xmath226 belong to the same @xmath103-path , and furthermore , there exists only one @xmath102-path passing by both an element ( more precisely , passing by both its mergings ) in @xmath227 and an element in @xmath228 .
so , @xmath121 , the number of @xmath103-paths in @xmath0 can be computed as @xmath229 it then follows from ( [ eq-1 ] ) , ( [ eq-2 ] ) , ( [ eq-3 ] ) and the fact @xmath230 that @xmath231 and furthermore @xmath232 consider the graph in figure [ pictwomm2](b ) and assume the context is as in the proof of theorem [ threeproofs ] .
then we have , @xmath233 among all the elements in @xmath203 , @xmath234 , @xmath235 , @xmath236 and @xmath237 are of type i , and @xmath238 , @xmath239 are of type ii .
it is easy to check that @xmath240 which is partitioned into three mini - blocks @xmath241 , @xmath242 and @xmath243 .
the first mini - block is linked to the second one , but the second one is not linked to the third , so @xmath205 is partitioned into two medium - blocks : @xmath244 [ pell ] the result in theorem [ threeproofs ] in fact has already been proved in @xcite using a different approach . the proof in this paper , however , is more intrinsic in the sense that it reveals in greater depth the topological structure of non - reroutable @xmath182-graphs achieving @xmath188 mergings , and further helps to determine the number of such graphs .
assume a non - reroutable @xmath182-graph @xmath0 has @xmath188 mergings .
one then checks that in the proof of theorem [ threeproofs ] , equalities hold for ( [ eq-5 ] ) .
it then follows that * @xmath245 , namely , there is only one medium - block in @xmath205 ; * equalities hold necessarily for ( [ eq-4 ] ) , ( [ eq-1 ] ) and eventually ( [ eq-0 ] ) , which further implies that between two adjacent singletons , only one mini - block has three elements and any other mini - block has two elements . furthermore , one checks that * for a mini - block with two elements @xmath246 , @xmath201 is smaller than @xmath247 ; * for a mini - block with three elements @xmath248 , @xmath249 , @xmath250 , either ( @xmath201 is smaller than @xmath251 and @xmath251 is smaller than @xmath247 ) or ( @xmath251 is smaller than @xmath247 and @xmath247 is smaller than @xmath201 ) .
assume that @xmath0 is `` reduced '' in the sense that , other than @xmath252 , each vertex in @xmath0 is a terminal vertex of some merging .
the properties above allow us to count how many reduced non - reroutable @xmath182-graphs ( up to graph isomorphism ) can achieve @xmath188 mergings : suppose that there are @xmath14 ( @xmath253 ) singletons in @xmath0 , then necessarily , there are @xmath223 three - element mini - blocks and @xmath254 two - element mini - blocks in @xmath205 .
it can be checked that the number of ways for these @xmath121 mini - blocks to form @xmath205 for some @xmath182-graph is @xmath255 .
this implies that the number of @xmath182-graph , whose @xmath205 consists of @xmath14 singletons , @xmath223 three element mini - blocks and @xmath256 two element mini - blocks , is @xmath255 . through a computation summing over all feasible @xmath14 ,
the number of reduced non - reroutable @xmath182-graphs with @xmath188 mergings can be computed as @xmath257 = p_n,\ ] ] where @xmath258 is the @xmath121-th pell number @xcite .
[ mstar44 ] @xmath259 consider a non - reroutable @xmath260-graph @xmath0 with one source @xmath37 , two sinks @xmath38 , a set of menger s paths @xmath261 from @xmath37 to @xmath40 and a set of menger s paths @xmath262 from @xmath37 to @xmath41 .
as discussed in section [ aa - sequences ] , we assume that @xmath144 and @xmath125 share a starting subpath @xmath263 from @xmath37 for @xmath264 , and furthermore , we assume @xmath265 do not merge with any other paths , directly `` flowing '' to the sinks .
consider the four @xmath103-aa - sequences , which will be referred to as @xmath266 in the following .
it is easy to check that each @xmath267 , @xmath268 , will be of odd length . without loss of generality , assume that @xmath269 is the shortest such sequence , and thus by lemma [ lengthofaasequence ] , @xmath269 is of length @xmath163 ; let @xmath270 be the merging associated with @xmath269 . by lemma [ each - path - pair - at - most - once ] , each @xmath267 can only be associated with each path pair @xmath271 , @xmath272 and @xmath273 at most once .
it then follows that excluding @xmath270 , each @xmath274 , @xmath275 , can only merge with each @xmath276 , @xmath277 , at most once .
one then further checks that each @xmath267 , @xmath278 , can only be associated with @xmath271 , @xmath272 and @xmath273 for @xmath279 times in total . by lemma [ aa - to - number - of - merings ]
, we then derive @xmath280 we next prove that @xmath94 can not be @xmath73 .
suppose , by contradiction , that @xmath94 is @xmath73 .
then , necessarily , the longest @xmath103-aa - sequence , say @xmath281 , will be of length @xmath282 .
it then follows that the two pairs , @xmath283 and @xmath284 must be associated with @xmath281 .
it also follows that @xmath285 must be of length @xmath279 .
now we prove that @xmath270 belongs to @xmath195 and @xmath286 .
it suffices to prove that each of @xmath287 can not have four mergings .
suppose , by contradiction , there are four mergings in @xmath134 , say @xmath288 , in the ascending order ; here @xmath289 is necessarily @xmath270
. then , there are two mergings belonging to the same @xmath102-path , say @xmath290 , @xmath291 .
now we consider two cases : if @xmath292 , then @xmath293 must belong to different @xmath103-aa - sequences .
suppose @xmath294 , @xmath295 , @xmath296 and @xmath297 , where @xmath298 .
note that @xmath299 and @xmath300 belong to the same @xmath103-aa - sequence for @xmath301 , @xmath302 and @xmath303 belong to the same @xmath103-aa - sequence .
this implies that @xmath304 , @xmath305 and @xmath306 .
it then follows that @xmath307 can not belong to @xmath308 or @xmath309 , so it must belong to @xmath310 . on the other hand , either @xmath201 or @xmath251 must belong to @xmath196 , the same @xmath102-path to which @xmath311 belongs
. then @xmath312 occurs at least twice in @xmath310 , which violates the lemma [ each - path - pair - at - most - once ] .
if @xmath313 , then @xmath314 must belong to different @xmath103-aa - sequences .
suppose @xmath315 , @xmath316 , @xmath296 and @xmath297 , where @xmath298 .
note that @xmath299 and @xmath300 belong to the same @xmath103-aa - sequence for @xmath301 ; @xmath302 and @xmath311 belong to the same @xmath103-aa - sequence .
this implies that @xmath317 , @xmath318 and @xmath319 . in this case
@xmath251 must belong to @xmath196 , the same path to which @xmath311 belongs .
it then follows that @xmath311 can not belong to @xmath320 , so it must belong to @xmath310 .
but then we have @xmath302 , @xmath317 , which violates the lemma [ each - path - pair - at - most - once ] . combining the above two cases , we conclude that there can not be four mergings on @xmath134 . with a parallel argument applied to @xmath321 ,
we conclude that there are four mergings on @xmath286 , say @xmath322 , in the ascending order .
next , we examine all the following cases to show that @xmath94 can not be @xmath73 .
paths @xmath195 and @xmath286 merge at @xmath104 and @xmath107 . for this case
, we have the following two subcases .
@xmath195 first merges with @xmath286 . for this case
, it is easy to check that @xmath281 is of length @xmath323 , which contradicts the fact that it is of length @xmath282 ( see figure [ pic44](a ) ) .
@xmath195 first merges with @xmath134 or @xmath324 ; without loss of generality , assume that @xmath195 first merges with @xmath134 at the merging denoted by @xmath98 . then necessarily , @xmath195 immediately merges with @xmath286 at the merging @xmath104
then , we have @xmath325 , which violates lemma [ each - path - pair - at - most - once ] ( see figure [ pic44](b ) ) . paths @xmath195 and @xmath286 merge at @xmath106 and @xmath107 .. for this case , we consider the following subcases .
@xmath195 first merges with @xmath286 .
then , we have @xmath326 , which violates lemma [ each - path - pair - at - most - once ] ( see figure [ pic44](c ) ) .
@xmath195 first merges with @xmath134 or @xmath324 ; without loss of generality , assume that @xmath195 first merges with @xmath134 . then necessarily , @xmath195 will subsequently merges with @xmath286 , @xmath324 and @xmath286 .
let @xmath327 be the smallest mergings in @xmath328 , respectively .
it is clear that at least one of @xmath199 and @xmath200 belongs to @xmath195 , since otherwise @xmath329 would belong to @xmath330 , respectively , and thus @xmath199 would semi - reach itself from head to head again @xmath103 , which implies the existence of a rerouting , a contradiction .
both the first mergings on @xmath134 , @xmath324 belong to @xmath195 .
then , @xmath104 is the largest merging on either @xmath196 or @xmath331 , that is , from @xmath104 , the associated path can not go forward to merge anymore .
@xmath331 can only first merges with @xmath134 and @xmath196 can only first merges with @xmath286 at @xmath105 , which implies the existence of a rerouting ( @xmath105 semi - reaches itself against @xmath102 from head to head ) .
see figure [ pic44](d ) for an example .
the first merging @xmath199 on @xmath134 belongs to @xmath195 , and the first merging on @xmath324 belongs to @xmath196 .
if @xmath196 first merges with @xmath324 , then @xmath331 can only first merges @xmath286 at @xmath104 , one check that @xmath281 is of length @xmath332 , a contradiction ( see figure [ pic44](e ) ) ; if @xmath196 first merges with @xmath286 at @xmath105 ( if @xmath196 first merges with @xmath286 at @xmath104 , then @xmath281 is of length @xmath333 , a contradiction ) , then @xmath331 can only first merge with @xmath286 at @xmath104 , and then merges with @xmath324 , @xmath134 , which implies the existence of a rerouting ( @xmath105 semi - reaches itself against @xmath102 from head to head )
. see figure [ pic44](f ) for an example .
the first merging @xmath200 on @xmath324 belongs to @xmath195 , and
the first merging @xmath199 on @xmath134 belongs to @xmath331 .
if @xmath331 first merges with @xmath286 , then necessarily the merging is @xmath104 , and @xmath331 further merges with @xmath134 at @xmath199 . in this case
@xmath196 can not go forward to merge anymore , which contradicts the fact that @xmath196 merges with @xmath103-paths just three times ( see figure [ pic44](g ) ) ; if @xmath331 first merges @xmath134 at @xmath199 , then @xmath196 can only first merges with @xmath286 at @xmath104 , and then merge with @xmath134 . in this case
, @xmath196 can not go forward to merge anymore , which also contradicts the fact that @xmath196 merges with @xmath103-paths exactly three times ( see figure [ pic44](h ) ) .
all the above cases combined imply that @xmath94 is at most @xmath282 . on the other hand
, one can find a non - reroutable @xmath260-graph with one source , two sinks and @xmath282 mergings as in figure [ picmstar44 ] , which implies @xmath334 ( see a more general result in theorem [ lowerboundmstar ] ) .
we then have established the theorem .
[ m33 ] @xmath335 consider a non - reroutable @xmath336-graph @xmath0 with two source @xmath109 and two sinks @xmath38 .
let @xmath337 , @xmath338 denote the set of menger s paths from @xmath109 to @xmath38 , respectively . as discussed in section [ aa - sequences ] , we assume each aa - sequences is of positive length .
then , by lemma [ lengthofaasequence ] , the shortest aa - sequence is of length @xmath163 .
it can also be checked that the longest aa - sequence in @xmath0 is of length at most @xmath279 .
so , by lemma [ aa - to - number - of - merings ] , we have @xmath339 it follows from theorem [ mmnlb ] ( this is proven later in section [ bounds - section ] ) that @xmath340 .
we next show @xmath341 can not be @xmath342 or @xmath343 .
note that any non - reroutable @xmath336-graph having 15 mergings implies that @xmath344 and @xmath343 mergings implies that @xmath345 @xmath346 the idea of the proof is that we first preprocess to eliminate many cases by checking if ( [ 15-mergings ] ) and ( [ 14-mergings ] ) are satisfied , then we can exhaustively investigate all the remaining cases to prove @xmath341 can not be equal to @xmath343 or @xmath342 .
-aa - sequence , scaledwidth=83.0% ] suppose , by contradiction , that @xmath0 has @xmath343 or @xmath342 mergings .
then , as before , at least one of aa - sequences of @xmath0 is of length @xmath279 . without loss of generality
, we assume the @xmath195-aa - sequences is of length @xmath279 .
one then checks that , up to obvious symmetry , as depicted in figure [ m33iiiiii ] , we only have three possible cases for the @xmath195-aa - sequence : for case @xmath163 , the @xmath195-aa - sequence is @xmath347 ; for case @xmath91 , the @xmath195-aa - sequence is @xmath347 ; for case @xmath323 , the @xmath195-aa - sequence is @xmath348 .
note that the graphs in figure [ m33iiiiii ] only show the segments of paths @xmath349 associated with the @xmath195-aa - sequence .
next , for each of the above - mentioned cases , we will extend these segments either backward or forward in all possible ways , and we shall show that no matter how we extend , the number of mergings in @xmath0 will not exceed @xmath350 .
, subcase @xmath351,scaledwidth=80.0% ] as shown in figure [ m33iiiiii](a ) .
for this case , one checks that after @xmath195 first merge with @xmath146 at @xmath106 , it must immediately merge with @xmath324 at @xmath352 ; one also checks that for paths @xmath353 , each of them can only go backward to merge at most twice . in the following , by subcase ( @xmath354 , @xmath355 )
, we mean the case when path @xmath331 goes backward to merge @xmath354 times and path @xmath196 goes backward to merge @xmath355 times .
it suffices to check the following nine subcases : @xmath356 , @xmath357 , @xmath358 , @xmath359 , @xmath360 , @xmath361 , @xmath362 , @xmath363 , @xmath133 .
the checking procedure is rather mechanical and tedious , so we only go through subcase @xmath362 , as shown in figure [ m33i20abc ] , for illustrative purposes . for this case , we have three choices for path @xmath331 . for choice @xmath163 as shown in figure [ m33i20abc](a ) , the @xmath331-aa - sequence is of length @xmath163 , so path @xmath195 must go forward to merge further to make sure the @xmath196-aa - sequence is of length more than @xmath333 .
therefore , from @xmath364 , path @xmath331 can not go forward to merge any more and it must go to @xmath41 directly .
then one exhaustively checks that from @xmath365 and @xmath366 , paths @xmath195 and @xmath196 can not go forward to merge more than four times in total . for choice @xmath91 as shown in figure [ m33i20abc](b )
, the @xmath196-aa - sequence is of length @xmath163 , and path @xmath195 can not go forward to merge anymore .
one exhaustively checks that from @xmath366 and @xmath364 , paths @xmath196 and @xmath331 can not go forward to merge five times in total . for choice @xmath323 as shown in figure [ m33i20abc](c )
, the @xmath331-aa - sequence is of length @xmath163 , and the @xmath196-aa - sequence is of length @xmath323 .
so , ( [ 15-mergings ] ) or ( [ 14-mergings ] ) is not satisfied . as shown in figure [ m33iiiiii](b ) .
for this case , one checks that each of paths @xmath196 and @xmath331 can not go backward to merge more than three times .
one also checks that path @xmath195 , after merging with @xmath146 at @xmath106 , will immediately merge with @xmath134 at @xmath107 .
since otherwise , one verifies that the total number of mergings is strictly less than @xmath343 : path @xmath331 can go backward to merge for at most twice and path @xmath196 can not go backward to merge ; furthermore , path @xmath331 can not go forward to merge anymore from @xmath105 and paths @xmath195 and @xmath196 can not go forward to merge four times in total .
it suffices to check the following subcases : @xmath356 , @xmath359 , @xmath360 , @xmath362 , @xmath363 , @xmath133 , @xmath367 , @xmath357 , @xmath358 , @xmath361 .
as shown in figure [ m33iiiiii](c ) . for this case ,
after path @xmath195 merges with @xmath146 at @xmath105 , it has to immediately merge with @xmath134 at @xmath107 .
similarly as before , it suffices to check the following subcases : @xmath356 , @xmath359 , @xmath360 , @xmath363 , @xmath133 , @xmath357 , @xmath358 , @xmath361 .
@xmath368 it follows from @xcite that @xmath369 to prove the theorem , we will consider the following four cases : @xmath370 .
it immediately follows from theorem [ one - one - two ] that @xmath371 @xmath372 .
it can be checked that the @xmath373-graph in figure [ picm122twopic](a ) is non - reroutable , which implies that @xmath374 . since , by ( [ 4n+1 ] ) , @xmath375
, it suffices to prove that @xmath376 is not @xmath282 .
-graph with 8 mergings ( b ) the edge - labeled non - reroutable @xmath377-graph , scaledwidth=72.0% ] suppose , by contradiction , that a non - reroutable @xmath373-graph @xmath0 has @xmath282 mergings .
assume @xmath0 has distinct sources @xmath378 , sinks @xmath379 , path @xmath76 from @xmath48 to @xmath40 , a set of two menger s paths @xmath380 from @xmath49 to @xmath41 and a set of two menger s paths @xmath381 from @xmath382 to @xmath383 .
since @xmath0 is non - reroutable , path @xmath76 merges with each of paths @xmath384 at most once ( otherwise path @xmath76 is reroutable through the path with which @xmath76 merges twice ) .
this , together with the assumption that @xmath385 and the fact that @xmath386 , implies that @xmath387 , where @xmath95 denotes the subgraph of @xmath0 induced on @xmath388 , and @xmath76 must merge with each of @xmath384 exactly once . here , by remark
[ pell ] , @xmath95 has only two `` reduced '' instances : the graph in figure [ picm122twopic](b ) and its `` reversed '' version obtained by reversing all its edges ; so , we can assume @xmath95 takes the form as in figure [ picm122twopic](b ) .
moreover , since we count mergings without multiplicity , we can further assume that every merging in @xmath0 is by exactly two menger s paths .
now , we exhaustively examine all ways in which @xmath76 can merge with @xmath95 without generating any reroutings or cycles .
the following rule can be used to eliminate many cases : for any two paths @xmath389 , @xmath390 in @xmath95 , if @xmath389 is smaller than @xmath390 , then @xmath76 can not merge with them both ( since , otherwise , @xmath76 is reroutable through @xmath389 and @xmath390 ) . with the subpaths of @xmath384 labeled as in figure [ picm122twopic](b ) , we obtain the following sets of subpaths , each of which consists of ( unordered ) subpaths , where @xmath76 can merge with @xmath388 without violating the above - mentioned rule : @xmath391 , @xmath392 , @xmath393 , @xmath394 , @xmath395 , @xmath396 . in the following ,
we examine each of the above possibilities , and conclude that there is no way one can add path @xmath76 without generating reroutings or cycles , which further implies that @xmath397 .
below , expression like `` @xmath398 '' means `` if after @xmath76 merges with @xmath399 , it further immediately with @xmath195 , and further immediately with @xmath146 , then the group of menger s paths @xmath400 are reroutable '' .
1 . @xmath401 .
+ @xmath402 , @xmath403 , @xmath404 , @xmath405 , + @xmath406 , @xmath407 , @xmath408 , @xmath398 .
+ it is easy to check we can not find path @xmath76 without some of the above subpaths .
2 . @xmath409 . + for @xmath410 and @xmath196 , @xmath411 , @xmath412 .
+ for @xmath410 and @xmath146 , @xmath413 , @xmath414 .
+ for @xmath410 and @xmath399 , @xmath415 , @xmath416 .
+ hence , path @xmath76 can not merge with @xmath410 , if it merges the other three edges .
@xmath417 . + for @xmath399 and @xmath196 , @xmath418 , @xmath419 .
+ for @xmath399 and @xmath134 , @xmath420 , @xmath421 .
+ for @xmath399 and @xmath422 , @xmath423 , @xmath424 .
+ hence , path @xmath76 can not merge with @xmath399 , if it merges the other three edges .
@xmath425 . + for @xmath324 and @xmath196 , @xmath426 , @xmath427 .
+ for @xmath324 and @xmath422 , @xmath428 , @xmath429 .
+ for @xmath324 and @xmath430 , @xmath431 , @xmath432 .
+ hence , path @xmath76 can not merge with @xmath324 , if it merges the other three edges .
@xmath433 . + for @xmath331 and @xmath324 , @xmath434 , @xmath435 .
+ for @xmath331 and @xmath422 , @xmath436 , @xmath437 .
+ for @xmath331 and @xmath438 , @xmath439 , @xmath440 .
+ hence , path @xmath76 can not merge with @xmath331 , if it merges the other three edges .
+ @xmath442 , @xmath443 , @xmath444 , @xmath445 , + @xmath446 , @xmath447 , @xmath448 , @xmath449 .
+ it is easy to check we can not find path @xmath76 without some of the above subpaths . @xmath450 .
it can be checked that the @xmath451-graph as in figure [ picm123and124](a ) is non - reroutable , which implies that @xmath452 . since , by ( [ 4n+1 ] ) , @xmath453
, it suffices to prove that @xmath376 is not @xmath350 .
suppose , by contradiction , that a non - reroutable @xmath451-graph @xmath0 has @xmath350 mergings .
assume @xmath0 has distinct sources @xmath378 , sinks @xmath379 , path @xmath76 from @xmath48 to @xmath40 , a set of two menger s paths @xmath380 from @xmath49 to @xmath41 and a set of three menger s paths @xmath454 from @xmath382 to @xmath383 .
since @xmath0 is non - reroutable , path @xmath76 merges each of paths @xmath455 at most once ( otherwise path @xmath76 is reroutable through the path with which @xmath456 merges twice ) .
this , together with the fact that @xmath457 and the fact that @xmath458 , implies that @xmath76 must merge with each of @xmath455 exactly once and the number of mergings among @xmath380 and @xmath454 is @xmath332 .
similar to the proof for the case @xmath372 , we consider the subgraph @xmath95 of @xmath0 induced on paths @xmath455 .
one then checks that any @xmath459-graph must have , up to relabeling , one of five merging sequences .
we then exhaustively investigate how @xmath76 can be `` added '' to @xmath95 to form @xmath0 without generating any reroutings or cycles . through a similar discussion , we conclude that there is no way we can add such path @xmath76 to generate a non - reroutable @xmath460-graph with 13 mergings . as a result , @xmath461 .
-graph with 12 mergings
( b ) a non - reroutable @xmath462-graph with 17 mergings , scaledwidth=75.0% ] @xmath463 . by ( [ 4n+1 ] ) , we only need to construct a non - reroutable @xmath464-graph with @xmath465 mergings .
first , we consider a non - reroutable @xmath182-graph with distinct sources @xmath466 , sinks @xmath467 and the following merging sequence : @xmath468 for @xmath469 , @xmath470_2,1 ) & \mathrm{if}\ k=3i-1 & \mathrm{for}\ 3\leq i\leq n , \\ ( [ i]_2,i+1 ) & \mathrm{if}\ k=3i & \mathrm{for}\ 3\leq i\leq n-1 , \\ ( [ i+1]_2,i+1 ) & \mathrm{if}\ k=3i+1 & \mathrm{for}\ 3\leq i\leq n-1 , \end{array } \right.\ ] ] where @xmath185_2=1 $ ] when @xmath186 is odd , @xmath185_2=2 $ ] when @xmath186 is even .
one can check that this @xmath182-graph is non - reroutable .
assume that the two menger s paths from @xmath49 to @xmath41 start with the subpaths @xmath471 , respectively ; and the @xmath121 menger s paths from @xmath382 to @xmath383 start with the subpaths @xmath472 , respectively ; and there are no mergings on @xmath473 .
next , we add a path @xmath76 to construct a non - reroutable @xmath474-graph such that path @xmath76 , starting from @xmath48 , successively merges with @xmath475 ( these mergings are labeled as @xmath476 in figure [ picm123and124](b ) ) , and eventually reaches @xmath40 . it can be checked that this newly constructed @xmath464-graph is non - reroutable . through exhaustive
searching , we are able to compute exact values for @xmath477 and @xmath478 with some small parameters : @xmath479 , @xmath480 , @xmath481 , @xmath482 , @xmath483 , @xmath484 , @xmath485 , @xmath486 , @xmath487 , @xmath488 , @xmath489 , @xmath490 , @xmath491 , @xmath492 , @xmath493 .
computations show that for @xmath494 and @xmath495 , @xmath496 [ turan ] @xmath497 for the `` @xmath498 '' direction , by proposition @xmath499 of @xcite , we deduce that @xmath500 to prove the `` @xmath501 '' direction , consider a non - reroutable @xmath502-graph @xmath0 with distinct sources and sets of menger s paths @xmath503 .
it is easy to check that due to non - reroutability of @xmath0 , any two @xmath76-paths can merge with each other at most once . without loss of generality , assume that @xmath504 merges @xmath505 times with @xmath506 , @xmath507 ; and any other path @xmath23 , @xmath508 , merges at most @xmath505 times .
again , due to non - reroutability of @xmath0 , there are no non-@xmath504-involved mergings among paths @xmath506 , where we say a merging at edge @xmath20 is _ @xmath504-involved _ if @xmath20 belongs to @xmath504 .
it then follows that any non-@xmath504-involved merging in @xmath0 must be associated with one of paths from @xmath509 , each of which merges at most @xmath505 times .
we then conclude that @xmath510 [ wriggle ] for a non - reroutable @xmath502-graph @xmath0 , in order to prove @xmath511 we only need the following two conditions : 1 .
any two @xmath512 can merge at most once ; 2 .
there are at most two mergings in any subgraph of @xmath0 induced on any three @xmath513 .
so , in some sense , theorem [ turan ] is a `` dual '' version of the classical turan s theorem @xcite , which states that the number of edges in a graph is less than @xmath514 if 1 .
the graph is simple , i.e. , there is at most one edge between any two vertices ; 2 . the graph does not have triangles , i.e. , there are at most two edges among any three vertices .
[ one - one - two ] @xmath515 consider any non - reroutable @xmath516-graph @xmath0 with distinct sources @xmath517 , sinks @xmath518 , a menger s path @xmath23 from @xmath5 to @xmath6 for @xmath519 , two menger s paths @xmath520 from @xmath521 to @xmath522 .
let @xmath523 denote the set of @xmath76-paths , each of which first merges with @xmath524 and then with @xmath525 .
let @xmath526 denote the set of @xmath76-paths , each of which only merges with @xmath527 , and let @xmath39 denote the set of @xmath76-paths , each of which does not merge with @xmath146 or @xmath134 .
and we write @xmath528 consider any path @xmath504 in @xmath529 .
assume that @xmath504 merges with @xmath146 at merged subpath @xmath530 and with @xmath134 at merged subpath @xmath531 .
now , pick any path @xmath532 ( @xmath533 ) .
if , for some @xmath534 , @xmath535 overlaps ( i.e. , shares an edge ) with @xmath536 , then by the non - reroutability of @xmath0 , we have 1 .
@xmath537 ( @xmath538 ) , in which case @xmath539 does not overlap with @xmath540 ; or 2 .
@xmath541 ( @xmath533 ) , in which case @xmath542 must share * the edge on @xmath536 ( @xmath540 ) ending at @xmath543 ( @xmath544 ) , * the subpath @xmath545 $ ] ( @xmath546 $ ] ) , * and the edge on @xmath540 ( @xmath536 ) starting from @xmath547 ( @xmath548 ) + with @xmath23 . in the remainder of this proof ,
we say @xmath542 is in the same _ equivalence class _ as @xmath23 . in the following ,
we say a merging at edge @xmath20 is _ @xmath103-involved _ if @xmath20 belongs to either @xmath146 or @xmath134 .
the following properties then follow from the non - reroutability of @xmath0 : 1 .
all @xmath529-paths of the same type ( meaning all of them belong to either @xmath538 or @xmath533 ) and their equivalent classes can be ( partially ) ordered in the following sense : consider @xmath549 of the same type .
assume that @xmath23 merges with @xmath550 at @xmath551 , and @xmath542 merges with @xmath550 at @xmath552 .
if @xmath536 is smaller than @xmath535 , then @xmath540 must be smaller than @xmath539 ; in this case , we say that @xmath23 is _ smaller _ than @xmath542 , and the equivalence class of @xmath23 is _ smaller _ than that of @xmath542 . as a result , we can list the equivalence classes of all @xmath538-paths in ascending order : @xmath553 , and the equivalence classes of all @xmath533-paths in ascending order : @xmath554 .
2 . a merging by two equivalent @xmath529-paths or two @xmath529-paths of different types must be @xmath103-involved . if a merging by any two non - equivalent @xmath529-paths @xmath21 is non-@xmath103-involved , then @xmath23 and @xmath542 are of the same type .
if furthermore @xmath23 is smaller than @xmath542 , then there exists @xmath25 such that @xmath555 and @xmath556 . as a consequence , for any @xmath557 @xmath558|_{\mathcal{m } } \leq \min\{|q_u| , |q_{u+1}|\ } , \quad |g[\widehat{q}_v , \widehat{q}_{v+1}]|_{\mathcal{m } } \leq \min\{|\widehat{q}_v| , |\widehat{q}_{v+1}|\},\ ] ] where @xmath559 $ ] ( @xmath560 $ ] ) denotes the subgraph of @xmath0 induced on all the @xmath561-paths and @xmath562-paths .
3 . any @xmath54-path can merge with at most one @xmath538-path and at most one @xmath533-path .
any three @xmath76-paths can only merge with each other at most twice .
now , by the definition of @xmath54 and @xmath529 , we have the number of @xmath103-involved mergings is upper bounded by @xmath563 and by theorem [ turan ] , the number of non-@xmath103-involved mergings is upper bounded by @xmath564 .
it then follows that @xmath565 note that for any @xmath566 , @xmath567 so , from now on , we only consider the case when @xmath568 .
it can be easily checked that when @xmath569 , @xmath570 next , we show that when @xmath571 , @xmath572 if @xmath573 , by ( [ universal - upper - bound-1 ] ) , the above inequality immediately holds . if @xmath574 , we have the following cases to consider : there exists some equivalence class that has more than one element . without loss of generality ,
assume some @xmath538-class has more than one element , and let @xmath575 be the smallest such class with @xmath576 , and let @xmath577 be the largest such class with @xmath578 .
the number of non-@xmath103-involved mergings between @xmath575 and @xmath579 is strictly less than @xmath120 .
then , one checks that * @xmath580|_{\mathcal{m } } \leq m+1 $ ] , where @xmath581 $ ] denotes the subgraph of @xmath0 induced on all the @xmath575-paths and @xmath103-paths ; * the number of @xmath103-involved mergings by @xmath582-paths , @xmath534 , and @xmath103-paths is upper bounded by @xmath583 . *
the number of non-@xmath103-involved mergings by @xmath575-paths and other @xmath538-classes is upper bounded by @xmath120 .
* by theorem [ turan ] , the number of non-@xmath103-involved mergings among @xmath582-paths , @xmath534 , is upper bounded by @xmath584 . *
the number of non-@xmath103-involved mergings by @xmath575-paths and ( @xmath54-paths or @xmath39-paths ) is upper bounded by @xmath585 . combining all the bounds above ,
we have @xmath586 @xmath587 the number of non-@xmath103-involved mergings between @xmath575 and @xmath579 is equal to @xmath120 , which necessarily implies that @xmath588 .
then , for either @xmath575 or @xmath577 , the number of non-@xmath103-involved mergings with @xmath54-paths is at most @xmath589 , so we have @xmath590 @xmath591 every equivalence class has exactly one element . for this case , since the number of @xmath103-involved mergings is upper bounded by @xmath592 , it suffices to show that the number of non-@xmath103-involved mergings is upper bounded by @xmath593 there do not exist non-@xmath103-involved mergings among all equivalence classes . for this case ,
the total number of mergings by @xmath594 , any two chosen @xmath529-paths of the same type , and ( @xmath54-paths or @xmath39-paths ) is at most @xmath595 .
we then conclude that the number of non-@xmath103-involved mergings is upper bounded by @xmath596 there exists a non-@xmath103-involved merging by two adjacent equivalent classes , say @xmath597 , and these two classes merge with each other once , however they do not merge with any other @xmath538-classes . by property @xmath598 ,
both of these two classes are of the same type . moreover , by property @xmath599 , the number of mergings between these two classes and ( @xmath54-paths or @xmath39-paths ) is at most @xmath595 .
hence , we have the number of non-@xmath103-involved mergings is upper bounded by @xmath600 there exist at least three adjacent equivalent classes , say @xmath601 , @xmath602 , such that @xmath603 merges with @xmath604 , @xmath605 , however there are no mergings by @xmath606 and other @xmath538-classes . for this case
, it can be checked that at least one of @xmath607 , @xmath608 and @xmath609 merges with @xmath54-paths at most @xmath589 times .
since each of the above pair of paths merge with @xmath529-paths at most twice and merges with @xmath39-paths at most @xmath610 times , we thus have the number of non-@xmath103-involved mergings is upper bounded by @xmath611 now , combining all the cases above , we then have established the upper bound direction : @xmath612 first , consider the following @xmath516-graph @xmath0 with distinct sources @xmath517 , sinks @xmath518 , a menger s path @xmath23 from @xmath5 to @xmath6 for @xmath519 , two menger s paths @xmath520 from @xmath521 to @xmath522 such that * every merging in @xmath0 is by exactly two paths ; * for @xmath89 , @xmath23 first merges with @xmath146 at @xmath613 , and then merges with @xmath134 at @xmath614 ; * for any @xmath615 , @xmath23 is smaller than @xmath542 ; * for any @xmath616 , @xmath23 merges with @xmath617 at @xmath618 such that @xmath618 is larger than @xmath614 and smaller than @xmath619 ; * there are no other mergings
. see figure [ picm1k12twocases](a ) for an example .
it can be verified that the above @xmath0 is a non - reroutable @xmath516-graph with @xmath620 mergings , which implies that @xmath621 next , consider the following @xmath516-graph @xmath0 with distinct sources @xmath517 , sinks @xmath518 , a menger s path @xmath23 from @xmath5 to @xmath6 for @xmath519 , two menger s paths @xmath520 from @xmath521 to @xmath522 such that * every merging in @xmath0 is by exactly two paths ; * for @xmath622 , @xmath623 , @xmath23 merges with @xmath542 at @xmath624 ; * for any @xmath625 and any @xmath626 , @xmath627 is smaller than @xmath628 ; * for any @xmath629 and any @xmath630 , @xmath631 is smaller than @xmath632 ; * for @xmath623 , @xmath146 merges with @xmath542 at @xmath633 such that @xmath633 is larger than @xmath634 ; * for @xmath622 , @xmath134 merges with @xmath23 at @xmath635 such that @xmath635 is smaller than @xmath636 ; * @xmath146 merges with @xmath637 at @xmath638 such that @xmath638 is smaller than @xmath639 and @xmath640 ; * @xmath134 merges with @xmath504 at @xmath641 such that @xmath641 is larger than @xmath642 and @xmath643 ; * there are no other mergings
. see figure [ picm1k12twocases](b ) for an example .
it can be verified that the above @xmath0 is a non - reroutable @xmath516-graph with @xmath644 mergings , which implies that @xmath645 combining ( [ greater-1 ] ) and ( [ greater-2 ] ) , we then have established the lower bound direction .
@xmath646 for the `` @xmath647 '' direction , it follows from @xcite that @xmath648 next , we show that the following @xmath649-graph @xmath0 , which has distinct sources @xmath650 and sinks @xmath651 , is non - reroutable with @xmath652 mergings .
the graph @xmath0 ( see figure [ picm11113 ] for an example ) can be described as follows : * there is a path @xmath23 from @xmath5 to @xmath6 for @xmath519 and @xmath121 menger s paths @xmath653 from @xmath521 to @xmath522 ; * for any feasible @xmath654 , @xmath23 merges with @xmath126 exactly once at the merging @xmath655 ; * for any feasible @xmath654 , @xmath23 in @xmath538 or @xmath656 merges with @xmath542 in @xmath533 exactly once at the merging @xmath657 , where @xmath658 here , @xmath659 , @xmath660 , @xmath661 ; * the mergings on each path can be sequentially listed in the ascending order as follows : + for @xmath519 , @xmath662 for @xmath663 , @xmath664 for @xmath665 , @xmath666 for @xmath667 , @xmath668 it can be checked that @xmath0 is non - reroutable with @xmath669 -graph with 16 mergings , scaledwidth=54.0% ]
in this section , we will construct a non - reroutable @xmath671-graph @xmath672 with one source @xmath37 , two sinks @xmath38 , a set of menger s paths @xmath673 from @xmath37 to @xmath40 , a set of menger s paths @xmath674 from @xmath37 to @xmath41 and @xmath675 mergings for any positive integer @xmath121 , thus giving a lower bound on @xmath670 .
the graph @xmath672 can be described as follows : for each @xmath676 , paths @xmath125 and @xmath144 share a starting subpath @xmath263 .
after @xmath677 , path @xmath678 does not merge any more , directly `` flowing '' to @xmath40 ; after @xmath679 , path @xmath680 does not merge any more , directly `` flowing '' to @xmath41 .
the rest of the graph can be determined how paths @xmath681 merge with @xmath682 . in more detail , for a given @xmath121
, we define @xmath683 and @xmath684 it can be checked that all @xmath685 s , @xmath686 s are distinct and @xmath687 now we define a mapping @xmath688 by @xmath689 then the merging sequence of the rest of the graph can be defined as @xmath690.\ ] ] for example , @xmath691 , as illustrated in figure [ picmstar44 ] , is determined by the merging sequence @xmath692.\ ] ] now , we prove that with @xmath282 mergings , scaledwidth=50.0% ] [ fnn ] @xmath672 is non - reroutable .
let @xmath693 . for each @xmath694
, label each merging @xmath695 in the merging sequence as @xmath696 ( it can be easily checked that no two mergings share the same label ) .
we only prove that there is only one possible set of menger s paths from @xmath37 to @xmath40 .
the uniqueness of menger s path sets from @xmath37 to @xmath41 can be established using a parallel argument .
let @xmath697 be an arbitrary yet fixed set of menger s paths from @xmath37 to @xmath40 .
it suffices to prove that @xmath697 is non - reroutable .
note that each path in @xmath697 must end with either @xmath698 or @xmath699 , @xmath700 ( here and hereafter , slightly abusing the notations `` @xmath701 '' and `` @xmath702 '' , for paths ( or vertices ) @xmath703 , we use @xmath704 or @xmath705 to denote the path which sequentially passes through @xmath706 ; it can be checked that in this proof such an expression uniquely determines a path ) . in @xmath697 , label the menger s path ending with @xmath699 as the @xmath63-th menger s path for @xmath707 , and the menger s path ending with @xmath698 as the @xmath206-th one .
it is obvious that in @xmath708 , there is only one path ending with @xmath698 , which implies that the @xmath206-th menger s path in @xmath697 is `` fixed '' ( as @xmath709 ) ; or , more rigorously , for any set of menger s paths @xmath710 , the @xmath206-th menger s path in @xmath710 is the same as the @xmath206-th one in @xmath697 .
so , for the purpose of choosing other menger s paths , all the edges on @xmath709 are `` occupied '' .
it then follows that , in @xmath697 , @xmath711 must `` come '' from @xmath712 ; more precisely , in @xmath697 , @xmath712 is smaller than @xmath711 on the @xmath713-th path and there is no other merging between them on this path .
now , all the edges on @xmath714 are occupied .
inductively , only considering unoccupied edges , one can check that for @xmath715 , @xmath716 must come from @xmath717 ; in other words , for @xmath715 , the @xmath63-th menger s path must end with @xmath718 .
it then follows that the @xmath719-th menger s path must come from @xmath720 ; so , the @xmath719-th menger s path is fixed as @xmath721 .
we now proceed by induction on @xmath505 , @xmath722 .
suppose that , for @xmath723 , the @xmath63-th menger s path is already fixed ( and hence the edges on these paths are all occupied ) , and for @xmath724 , the @xmath63-th menger s path ends with @xmath725 ( so , the edges on these paths are all occupied ) . only considering the unoccupied edges , one checks that for @xmath726
, @xmath727 must come from @xmath728 .
it then follows that the menger s path , which ends with @xmath729 , must come from @xmath730 .
so , the @xmath505-th menger s path can now be fixed as @xmath731 .
now , for @xmath732 , the @xmath63-th menger s path is fixed , and for @xmath726 , the @xmath63-th menger s path must end with @xmath733 .
it follows from the above inductive argument that for @xmath734 , the @xmath63-th menger s path is fixed , and the @xmath713-th menger s path must end with @xmath735 @xmath736 @xmath737 @xmath738 .
one then checks that the @xmath739 must come from @xmath679 , which implies that the @xmath713-th menger s path is fixed as @xmath740 .
the proof of uniqueness of menger s path set from @xmath37 to @xmath40 is then complete .
the above lemma then immediately implies that [ lowerboundmstar ] @xmath741 the following theorem gives an upper bound on @xmath143 .
first , we remind the reader that , by proposition @xmath141 in @xcite , @xmath742 for any @xmath743 . @xmath744 consider any @xmath671-graph @xmath0 with one source @xmath37 , sinks @xmath38 , a set of menger s paths
@xmath745 from @xmath37 to @xmath40 , a set of menger s paths @xmath136 from @xmath37 to @xmath41 .
as discussed in section [ aa - sequences ] , we assume that , for @xmath746 , paths @xmath125 and @xmath144 share a starting subpath , and paths @xmath145 and @xmath680 do not merge with any other paths , directly flowing to the sinks ( then , necessarily , each @xmath103-aa - sequence is of positive length , and by lemma [ lengthofaasequence ] , the shortest @xmath103-aa - sequence is of length @xmath163 ) .
we say that the path pair @xmath747 is _ matched _ if @xmath748 , otherwise , _
unmatched_. apparently , each starting subpath corresponds to a matched path pair ; and among the set of all path pairs , each of which corresponds some merging in @xmath0 , there are at most @xmath749 matched and at most @xmath750 unmatched .
we then consider the following two cases ( note that the following two cases may not be mutually exclusive ) : there exists a shortest @xmath103-aa - sequence associated with a matched path pair . by lemma
[ each - path - pair - at - most - once ] and the fact that each starting subpath corresponds to a matched path pair , there are at most @xmath751 mergings corresponding to this path pair , at most @xmath752 corresponding to any other matched path pair , and at most @xmath751 mergings corresponding to any unmatched .
so , the number of mergings is upper bounded by @xmath753 there exists a shortest @xmath103-aa - sequence associated with an unmatched path pair .
again , by lemma [ each - path - pair - at - most - once ] and the fact that each starting subpath corresponds to a matched path pair , there are at most @xmath754 mergings corresponding to this path pair , at most @xmath751 mergings corresponding to any other unmatched path pair , and at most @xmath752 mergings corresponding to any matched .
so , the number of mergings is upper bounded by @xmath755 then @xmath756 . for odd @xmath121 , ( [ mstarbound - i ] ) is larger than ( [ mstarbound - ii ] ) , so we have @xmath757 for even @xmath121 , ( [ mstarbound - ii ] ) is larger than ( [ mstarbound - i ] ) , so we have @xmath758 the proof is then complete .
consider the following @xmath671-graph @xmath760 with distinct sources @xmath109 , sinks @xmath38 , a set of menger s paths @xmath745 from @xmath48 to @xmath40 ,
a set of menger s paths @xmath136 from @xmath49 to @xmath41 , and a merging sequence @xmath761 $ ] , where @xmath762_n , i+1 ) & \mathrm{if}\ k=2i(n-1)+j\quad \\ & \mathrm{for } \ ( 0\le i\le n-1 , 1\le j\le n-1)\ \mathrm{or}\ ( i = n-1,j = n),\\ ( n - i,[i - j+2]_n ) & \mathrm{if}\ k=(2i+1)(n-1)+j\quad \mathrm{for } \ 0\le i\le n-2 , 1\le j\le n-1 , \end{array } \right.\ ] ] where , for any integer @xmath186 , @xmath185_n$ ] denotes the least strictly positive residue of @xmath186 modulo @xmath121 . for a quick example , see @xmath763 in figure [ pic33blockwithsplitted](a ) , whose merging sequence is @xmath764.\end{aligned}\ ] ] then , similar to the proof of lemma [ fnn ] , through verifying the uniqueness of the set of menger s paths from @xmath5 to @xmath6 , we can show that @xmath760 is non - reroutable . consider a non - reroutable @xmath765-graph @xmath766 with distinct sources @xmath767 , sinks @xmath768 , a set of menger s paths @xmath769 from @xmath770 to @xmath771 , a set of menger s paths @xmath772 from @xmath773 to @xmath774 . for a fixed merging sequence of @xmath766 , assume , without loss of generality , that the first element is @xmath775 .
now , we consider the following procedure of concatenating graphs @xmath760 and @xmath776 to obtain a new graph : 1 .
split @xmath40 into @xmath121 copies @xmath777 such that path @xmath125 has the ending point @xmath778 ; split @xmath41 into @xmath121 copies @xmath779 such that path @xmath144 has the ending point @xmath780 ; 2 .
split @xmath770 into @xmath14 copies @xmath781 such that path @xmath782 has the starting point @xmath783 ; split @xmath773 into @xmath121 copies @xmath784 such that path @xmath144 has the starting point @xmath785 ; 3 .
delete all edges on @xmath195 and all edges on @xmath786 , each of which is larger than merging @xmath787 to obtain new @xmath195 and @xmath786 ; 4 .
delete all edges on @xmath788 and all edges on @xmath789 , each of which is smaller than merging @xmath790 to obtain new @xmath788 and @xmath789 ; 5 .
concatenate @xmath195 and @xmath791 to obtain @xmath792 ( so , necessarily , @xmath786 and @xmath789 are concatenated simultaneously and we obtain @xmath793 ) ; 6 .
identify @xmath794 ; identify @xmath795 ; identify @xmath780 and @xmath785 for @xmath796 . obviously , such procedure produces a @xmath797-graph with two distinct sources @xmath798 and two sinks @xmath771 and @xmath774 , a set of menger s paths
@xmath799 from @xmath48 to @xmath771 and a set of menger s paths @xmath800 from @xmath49 to @xmath774 .
for example , in figure [ picconcatenation ] , we concatenate @xmath801 and a non - reroutable @xmath377-graph to obtain a @xmath802-graph .
we have the following lemma , whose proof is similar to lemma [ fnn ] and thus omitted . with @xmath803 mergings
( b ) splitting of @xmath40 in @xmath763,scaledwidth=65.0% ] [ concatenationlemma ] the concatenated graph as above is a non - reroutable @xmath804-graph with the number of mergings equal to @xmath805 .
we are now ready for the following theorem , which gives us a lower bound on @xmath140 .
[ mmnlb ] @xmath806 without loss of generality , assume that @xmath807 . for @xmath808 and @xmath809
, we will iteratively construct a sequence of non - reroutable @xmath810-graphs with @xmath811 mergings , which immediately implies the theorem .
first , for any @xmath14 , @xmath812 , a non - reroutable @xmath813-graph can be given by specifying its mergings sequence @xmath814.\ ] ] next , consider the case @xmath815 .
assume that for any @xmath816 such that @xmath817 , @xmath818 , @xmath819 , however @xmath820 , we have constructed a non - reroutable @xmath810-graph , which is effectively a non - reroutable @xmath821-graph as well .
we obtain a new @xmath117-graph through the following procedure : 1 . if @xmath142 , concatenate @xmath822 and an already constructed non - reroutable @xmath823-graph @xmath824 ; 2 . if @xmath825 , concatenate @xmath822 and an already constructed non - reroutable @xmath826-graph .
for the first case , according to lemma [ concatenationlemma ] , the obtained graph is non - reroutable @xmath827-graph with the number of mergings @xmath828 similarly , for the second case , the obtained graph is a non - reroutable @xmath117-graph with the number of mergings @xmath829 we then have established the theorem . and a non - reroutable @xmath377-graph , scaledwidth=70.0% ] to construct a non - reroutable @xmath830-graph with @xmath831 mergings , one can concatenate @xmath832 and a non - reroutable @xmath833-graph , which can be obtained by concatenating @xmath834 and a non - reroutable @xmath459-graph .
the latter can be obtained by concatenating @xmath835 and a non - reroutable @xmath133-graph .
finally , a non - reroutable @xmath133-graph can be obtained by concatenating @xmath835 and @xmath836 .
one readily checks that the number of mergings in the eventually obtained graph is @xmath837 @xmath838 consider any @xmath117-graph @xmath0 with distinct sources @xmath109 , sinks @xmath38 , a set of menger s paths @xmath135 from @xmath48 to @xmath40 , a set of menger s paths @xmath136 from @xmath49 to @xmath41 . as discussed in section [ aa - sequences ] , we assume that all the aa - sequences are of positive lengths . by lemma [ lengthofaasequence ] ,
the shortest @xmath102-aa - sequence and @xmath103-aa - sequence are both of length @xmath163 .
we then consider the following two cases ( note that the following two cases may not be mutually exclusive ) : there exists a shortest @xmath102-aa - sequence and a shortest @xmath103-aa - sequence , which are associated with the same path pair . by lemma
[ each - path - pair - at - most - once ] , there are at most @xmath839 mergings corresponding to this path pair , and at most @xmath840 mergings corresponding to any other path pair .
so , the number of mergings is upper bounded by@xmath841 there exists a shortest @xmath102-aa - sequence and a shortest @xmath103-aa - sequence , which are associated with two distinct path pairs .
again , by lemma [ each - path - pair - at - most - once ] , there are at most @xmath842 mergings corresponding to each of these two path pairs , and at most @xmath840 mergings corresponding to any other path pair .
so , the number of mergings is upper bounded by @xmath843 then , @xmath844 .
straightforward computations then lead to the theorem .
it has been established in @xcite that @xmath845 summarizing all the four bounds we obtain , we have @xmath846 it has been shown in @xcite that for any @xmath14 , there exists @xmath848 such that @xmath849 for all @xmath121 , where @xmath848 can be rather loose .
the following result refines the above result for the case when @xmath850 .
@xmath851 consider any non - reroutable @xmath852-graph @xmath0 with distinct sources @xmath109 , sinks @xmath38 , a set of menger s paths @xmath853 from @xmath48 to @xmath40 and a set of menger s paths @xmath854 from @xmath49 to @xmath41 .
if a merging is the smallest ( the largest ) one on a @xmath855-path , we say it is an _ @xmath186-terminal _ ( _ @xmath219-terminal _ ) merging on the @xmath855-path , or simply a _
@xmath855-terminal _ merging .
consider the following iterative procedure ( figures [ pic14mergings ] , [ pic3ncase1 ] and [ pic3ncase2 ] roughly illustrate the procedure ) , where , for notational simplicity , we treat a graph as a union of its vertex set and edge set . initially set @xmath856 , and @xmath857 . now for each @xmath272 , pick a merging @xmath858 such that @xmath858 belongs to path @xmath859 and @xmath860 where one can choose @xmath858 to be @xmath48 if such merged subpath does not exist on @xmath859 .
now set @xmath861 and @xmath862 suppose that we already obtain @xmath863 and @xmath864 where @xmath865 contains exactly 14 mergings and at least two @xmath855-terminal merged subpaths .
we then continue to pick merged subpath @xmath696 on @xmath859 from @xmath866 such that @xmath867 and there are at least two @xmath855-terminal mergings in @xmath868 . if such @xmath869 s exist , set @xmath870 and if @xmath871 , set @xmath872 and terminate the iterative procedure .
so far , for any obtained `` block '' @xmath873 , either we have @xmath874 or ( @xmath875 and there are at least two @xmath855-terminal mergings in @xmath873 ) ; such block @xmath873 is said to be _
normal_. if @xmath876 , however , we can not find a normal block , we continue the procedure and define a _ singular _
@xmath873 in the following .
-graph @xmath0 into blocks , scaledwidth=55.0% ] note that @xmath877 .
let @xmath878 , where @xmath220 and @xmath209 denote the number of @xmath186-terminal and @xmath219-terminal mergings in the @xmath855-paths in @xmath865 , respectively ; then @xmath879 is the number of @xmath103-paths which can continue to merge within @xmath866 .
if a normal block does not exist after @xmath63 iterations , necessarily we will have @xmath880 ( suppose @xmath881 , by the fact that @xmath882 ( see theorem [ m33 ] ) , we would be able to obtain a normal block @xmath873 , which contains two @xmath186-terminals or ( an @xmath186-terminal and a @xmath219-terminal ) ) .
we say a merged subpath is _ critical _ within a subgraph of @xmath0 if the corresponding @xmath103-path , after merging at this merged subpath , does not merge anymore within this subgraph .
it then follows that the number of the critical merged subpaths within @xmath883 is @xmath879 .
now , let @xmath884 denote the set of all the merged subpaths within @xmath866 , each of which can semi - reach the tail of some critical merged subpath within @xmath883 against @xmath103 .
one checks at least one of those @xmath102-paths , each of which contains at least one critical merged subpath within @xmath883 , does not contain any merged subpath within @xmath884 . without loss of generality , we assume that @xmath885 .
now we consider the following two cases : @xmath886 and @xmath887 .
as shown in figure [ pic3ncase1 ] , assume that within @xmath884 , @xmath888 are the largest merged subpaths on @xmath889 , respectively .
now , set @xmath890\cup { \phi}_2[t(\gamma_{i-1,2}),t(\lambda_{i,2})].\ ] ] note that for @xmath655 , @xmath891 , the associated @xmath103-path , from @xmath655 , may merge outside @xmath892 next time . if this @xmath103-path merges within @xmath892 again after a number of mergings outside @xmath892 , we call it an _ excursive _ @xmath103-path .
one checks that there are at most one excursive @xmath103-path ( since , otherwise , we can find a cycle in @xmath0 , which is a contradiction ) . on the other hand , for any merged subpath from @xmath884 other than @xmath888 , say @xmath98 , the associated @xmath103-path , from @xmath98 ,
can only merge within @xmath892 and will not merge outside @xmath892 .
so , the number of * connected * @xmath103-paths that contain at least one merged subpath within @xmath893 is upper bounded by @xmath894 .
then , by the fact that @xmath895 ( see theorem [ threeproofs ] ) , we have latexmath:[\[\label{with - t } it is clear that all non - excursive @xmath103-paths that contain at least one merged subpath within @xmath897 must have @xmath186-terminals in @xmath873
. thus , again by the fact that @xmath895 , we have @xmath898 ) and ( [ not - with - t ] ) that @xmath899 next , we claim that @xmath900 . to see this , suppose , by contradiction , that @xmath901 . observing that @xmath902 , we then consider the following two cases : if @xmath903 , we have @xmath904 which implies that we can continue to choose a normal block ( with two @xmath855-terminal merged subpaths ) , a contradiction . if @xmath905 , we have @xmath906 , @xmath907 .
note that if there is no excursive @xmath103-path , we have @xmath908 ; if there is one excursive @xmath103-path , then @xmath909 .
this , together with @xmath910 , implies that @xmath911 and there is no excursive @xmath103-path .
consequently , we have @xmath912 but this , together with @xmath882 , implies that we can continue to choose a normal block with an @xmath186-terminal and a @xmath219-terminal merged subpaths , which is a contradiction .
@xmath886 and @xmath913 .
as shown in figure [ pic3ncase2 ] , assume that within @xmath884 , @xmath914 is the largest merged subpath on @xmath915 .
apparently , there is no excursive @xmath103-path . by the fact that @xmath916 ( see example @xmath917 of @xcite ) and @xmath918 , we have @xmath919 it then immediately follows that @xmath920 .
similarly as before , we claim that @xmath921 . to see this ,
suppose , by contradiction , that @xmath901 . from @xmath922
, we infer that @xmath923 and @xmath906 , and further @xmath924 which implies that we can in fact obtain a normal block , a contradiction . combining the above two cases , we conclude that the number of merged subpaths within the singular block @xmath873 is upper bounded by @xmath925 , where @xmath921 .
we continue these operations in an iterative fashion to further obtain normal blocks and singular blocks until there are no merged subpaths left in the graph .
suppose there are @xmath926 singular blocks @xmath927 and @xmath928 normal blocks .
note that each singular block has at least three @xmath855-terminal merged subpaths and each normal block except the last one has at least two @xmath855-terminal merged subpaths .
if the last normal block has at least two @xmath103-terminal merged subpaths , we then have @xmath929 it then follows that latexmath:[\[\label{last - one - has - more - than - one } if the last normal block has only one @xmath103-terminal merged subpath , necessarily , there are at most three mergings in the last normal block , we then have @xmath931 it then follows that @xmath932 ) and ( [ last - one - has - only - one ] ) , we then have established the theorem .
consider two non - reroutable @xmath671-graph @xmath933 .
for @xmath891 , assume that @xmath934 has one source @xmath935 , two sinks @xmath936 .
let @xmath937 denote the set of menger s paths from @xmath935 to @xmath938 and @xmath939 denote the set of menger s paths from @xmath935 to @xmath940 .
as before , we assume that , for @xmath746 , paths @xmath941 and @xmath942 share a starting subpath . 1 .
reverse the direction of each edge in @xmath944 to obtain a new graph @xmath945 ( for @xmath946 , path @xmath947 in @xmath944 becomes path @xmath948 in @xmath945 and path @xmath949 in @xmath944 becomes path @xmath950 in @xmath945 ) ; 2 .
split @xmath951 into @xmath121 copies @xmath952 in @xmath943 such that paths @xmath953 and @xmath954 have the same starting point @xmath955 ; split @xmath956 into @xmath121 copies @xmath957 in @xmath945 such that paths @xmath948 and @xmath950 have the same ending point @xmath958 ; 3 . for @xmath959 ,
identify @xmath955 and @xmath958 .
obviously , such procedure produces an @xmath671-graph with two distinct sources @xmath960 , two sinks @xmath961 , a set of menger s paths @xmath962 from @xmath963 to @xmath964 and a set of menger s paths @xmath965 from @xmath966 to @xmath967 .
see figure [ pictwomstar ] for an example where we concatenate two @xmath968-graphs .
consider a non - reroutable @xmath971-graph @xmath943 and a non - reroutable @xmath972-graph @xmath944 .
the graph @xmath943 has one source @xmath951 , two sinks @xmath973 , a set of menger s paths @xmath974 from @xmath951 to @xmath964 and a set of menger s paths @xmath975 from @xmath951 to @xmath967 . as discussed in section
[ aa - sequences ] , we assume paths @xmath125 and @xmath144 share a starting subpath @xmath263 , and paths @xmath145 , @xmath680 do not merge with any other paths in @xmath943 , directly flowing to the sinks .
the graph @xmath944 has one source @xmath956 , two sinks @xmath976 , a set of menger s paths @xmath977 from @xmath956 to @xmath963 and a set of menger s paths @xmath978 from @xmath956 to @xmath966 .
again , assume paths @xmath979 and @xmath980 share a starting subpath . 1 . reverse the direction of each edge in @xmath944 to obtain a new graph @xmath945 ( for @xmath796 , path @xmath979 in @xmath944 becomes path @xmath981 in @xmath945 and path @xmath980 in @xmath944 becomes path @xmath982 in @xmath945 ) ; 2 .
split @xmath951 into @xmath983 copies @xmath984 in @xmath943 such that paths @xmath125 and @xmath144 have the same starting point @xmath985 ; split @xmath956 into @xmath986 copies @xmath987 in @xmath945 such that paths @xmath981 and @xmath982 have the same ending point @xmath988 ; 3 . delete all edges on @xmath145 , each of which is larger than @xmath989 ; delete all edges on @xmath680 , each of which is larger than @xmath679 ; 4 .
identify @xmath963 and @xmath990 ; for @xmath796 , identify @xmath958 and @xmath955 ; identify @xmath966 and @xmath991 .
obviously , such procedure produces an @xmath671-graph with two distinct sources @xmath960 , two sinks @xmath973 , a set of menger s paths @xmath992 from @xmath963 to @xmath964 and a set of menger s paths @xmath993 from @xmath966 to @xmath967 .
for example , in figure [ picmstar4422 ] , we concatenate a @xmath377-graph and a @xmath994-graph to obtain a @xmath968-graph .
consider @xmath997 .
for @xmath998 , consider a non - reroutable @xmath999-graph @xmath934 with one source @xmath935 , two sinks @xmath1000 , a set of menger s paths @xmath1001 from @xmath935 to @xmath1002 and a set of menger s paths @xmath1003 from @xmath935 to @xmath1004 .
as before , we assume that paths @xmath1005 and @xmath1006 share a starting subpath for @xmath1007 . 1
. for @xmath1009 , split @xmath1004 into @xmath1010 copies @xmath1011 such that path @xmath1006 has the ending point @xmath1012 ; 2 . for @xmath1013 , split @xmath935 into @xmath1010 copies @xmath1014 such that paths @xmath1005 and @xmath1006 have the same starting point @xmath1015 ; 3 . for @xmath1009 and @xmath1016 ,
identify @xmath1012 and @xmath1017 .
relabel @xmath1018 as @xmath1019 , respectively .
we then have an @xmath1020-graph with one source @xmath37 , @xmath14 sinks @xmath1021 and a set of menger s paths @xmath1022 from @xmath37 to @xmath1002 for @xmath1023 , where @xmath1024 | consider an acyclic directed network @xmath0 with sources @xmath1 and distinct sinks @xmath2 . for @xmath3 , let @xmath4 denote the min - cut between @xmath5 and @xmath6 . then , by menger s theorem , there exists a group of @xmath4 edge - disjoint paths from @xmath5 to @xmath6 , which will be referred to as a group of menger s paths from @xmath5 to @xmath6 in this paper .
although within the same group they are edge - disjoint , the menger s paths from different groups may have to merge with each other .
it is known that by choosing menger s paths appropriately , the number of mergings among different groups of menger s paths is always bounded by a constant , which is independent of the size and the topology of @xmath0 .
the tightest such constant for the all the above - mentioned networks is denoted by @xmath7 when all @xmath5 s are distinct , and by @xmath8 when all @xmath5 s are in fact identical .
it turns out that @xmath9 and @xmath10 are closely related to the network encoding complexity for a variety of networks , such as multicast networks , two - way networks and networks with multiple sessions of unicast . using this connection ,
we compute in this paper some exact values and bounds in network encoding complexity using a graph theoretical approach . | <s>[INST]let @xmath11 denote an acyclic directed graph , where @xmath12 denotes the set of all the vertices ( or points ) in @xmath0 and @xmath13 denotes the set of all the edges in @xmath0 . in this paper ,
a _ path _ in @xmath0 is treated as a set of concatenated edges . for @xmath14 paths @xmath15 in @xmath11 , we say these paths _ merge _
@xcite at an edge @xmath16 if 1 .
@xmath17 , 2 .
there are at least two distinct edges @xmath18 such that @xmath19 are immediately ahead of @xmath20 on some @xmath21 , @xmath22 , respectively .
we call the maximal subpath that starts with @xmath20 and that is shared by all @xmath23 s ( i.e. , @xmath20 together with the subsequent concatenated edges shared by all @xmath23 s until some @xmath23 branches off ) _ merged subpath _ ( or simply _ merging _ ) by all @xmath23 s at @xmath20 ; see figure [ picmergings ] for a quick example .
for any two vertices @xmath24 , we call any set consisting of the maximum number of pairwise edge - disjoint directed paths from @xmath25 to @xmath26 a set of _ menger s paths _ from @xmath25 to @xmath26 . by menger
s theorem @xcite , the cardinality of menger s paths from @xmath25 to @xmath26 is equal to the min - cut between @xmath25 and @xmath26 . here , we remark that the ford - fulkerson algorithm @xcite can find the min - cut and a set of menger s paths from @xmath25 to @xmath26 in polynomial time .
assume that @xmath11 has @xmath27 sources @xmath1 and @xmath27 distinct sinks @xmath2 .
for @xmath3 , let @xmath4 denote the min - cut between @xmath5 and @xmath6 , and let @xmath28 denote a set of menger s paths from @xmath5 to @xmath6 .
we are interested in the number of mergings among paths from different @xmath29 s , denoted by @xmath30 . in this paper
we will count the number of mergings * without * multiplicity : all the mergings at the same edge @xmath20 will be counted as one merging at @xmath20 .
merge at edge @xmath31 and at merged subpath ( or merging ) @xmath32 , and paths @xmath33 merge at edge @xmath34 and at merged subpath ( or merging ) @xmath35.,scaledwidth=48.0% ] the motivation for such consideration is more or less obvious in transportation networks : mergings among different groups of transportation paths can cause congestions , which may either decrease the whole network throughput or incur unnecessary cost . the connection between the number of mergings and the encoding complexity in computer networks ,
however , is a bit more subtle , which can be best illustrated by the following three examples in network coding theory ( for a brief introduction to this theory , see @xcite ) .
the first example is the famous `` butterfly network '' @xcite . as depicted in figure [ picthreeeg](a ) , for the purpose of transmitting messages @xmath36 simultaneously from the sender @xmath37 to the receivers @xmath38 , network encoding has to be done at node @xmath39 .
another way to interpret the necessity of network coding at @xmath39 ( for the simultaneous transmission to @xmath40 and @xmath41 ) is as follows : if the transmission to @xmath41 is ignored , menger s paths @xmath42 and @xmath43 can be used to transmit messages @xmath36 from @xmath37 to @xmath40 ; if the transmission to @xmath40 is ignored , menger s paths @xmath44 and @xmath45 can be used to transmit messages @xmath36 from @xmath37 to @xmath41 . for the simultaneous transmission to @xmath40 and @xmath41 ,
merging by these two groups of menger s paths at @xmath46 becomes a `` bottle neck '' , therefore network coding at @xmath39 is required to avoid the possible congestions .
the second example is a variant of the classical butterfly network ( see example 17.2 of @xcite ; cf .
the two - way channel in page @xmath47 of @xcite ) with two senders and two receivers , where the sender @xmath48 is attached to the receiver @xmath41 to form a group and the sender @xmath49 is attached to the receiver @xmath40 to form the other group . as depicted in figure [ picthreeeg](b )
, the two groups wish to exchange messages @xmath50 and @xmath51 through the network .
similarly as in the first example , the edge @xmath31 is where the menger s paths @xmath52 and @xmath53 merge with each other , which is a bottle neck for the simultaneous transmission of messages @xmath36 .
the simultaneous transmission is achievable if upon receiving the messages @xmath50 and @xmath51 , network encoding is performed at the node @xmath54 and the newly derived message @xmath55 is sent over the channel @xmath56 .
the third example is concerned with two sessions of unicast in a network @xcite . as shown in figure [ picthreeeg](c ) , the sender @xmath48 is to transmit message @xmath50 to the receiver @xmath40 using path @xmath57 .
and the sender @xmath49 is to transmit message @xmath51 to the receiver @xmath41 using two menger s paths @xmath58 and @xmath59 .
since mergings @xmath31 , @xmath46 and @xmath60 become bottle necks for the simultaneous transmission of messages @xmath50 and @xmath51 , network coding at these bottle necks , as shown in figure [ picthreeeg](c ) , is performed to ensure the simultaneous message transmission . generally speaking , for a network with multiple groups of menger s paths , each of which is used to transmit a set of messages to a particular sink , network encoding is needed at mergings by different groups of menger s paths . as a result , the number of mergings is the number of network encoding operations required in the network .
so , we are interested in the number of mergings among different groups of menger s paths in such networks . for the case when all sources in @xmath0 are in fact identical , @xmath61 is defined as the minimum of @xmath30 over all possible menger s path sets @xmath29 s , @xmath3 , and @xmath62 is defined as the supremum of @xmath61 over all possible choices of such @xmath0 .
it is clear that @xmath61 is the least number of network encoding operations required for a given @xmath0 , and @xmath62 is the largest such number among all such @xmath0 ( with the min - cut between the @xmath63-th pair of source and sink being @xmath4 ) . as for @xmath10 ,
the authors of @xcite used the idea of `` subtree decomposition '' to first prove that @xmath64 although their idea seems to be difficult to generalize to other parameters , it does allow us to gain deeper understanding about the topological structure of the graphs achieving @xmath65 mergings for this special case .
it was first shown in @xcite that @xmath66 is finite for all @xmath67 ( see theorem @xmath68 in @xcite ) , and subsequently @xmath62 is finite for all @xmath69 . for the case
when all sources in @xmath0 are distinct , @xmath70 is defined as the minimum of @xmath30 over all possible menger s path sets @xmath29 s , @xmath71 , and @xmath72 is defined as the supremum of @xmath70 over all possible choices of such @xmath0 .
again , the encoding idea for the second example can be easily generalized to networks , where each receiver is attached to all senders except its associated one .
it is clear that the number of mergings is a tight upper bound for the number of network encoding operations required . for networks with several unicast sessions , in @xcite ,
an upper bound for the encoding complexity of a network with two unicast sessions was given , as a result of a more general treatment ( to networks with two multicast sessions ) by the authors .
it is easy to see that for networks with multiple unicast sessions ( straightforward generalizations of the third example ) , @xmath9 with appropriate parameters can serve as an upper bound on network encoding complexity .
it was first conjectured that @xmath72 is finite in @xcite .
more specifically the authors proved that ( see lemma @xmath73 in @xcite ) if @xmath74 is finite for all @xmath67 , then @xmath72 is finite as well . here
, we remark that we have rephrased the work in @xcite , since all of them are done using very different languages from ours . in @xcite
, we have shown that for any @xmath69 , @xmath62 , @xmath72 are both finite , and we further studied the behaviors of @xmath75 as functions of the min - cuts . in this paper , further continuing the work in @xcite , we compute exact values of and give tighter bounds on @xmath10 and @xmath9 for certain parameters . for a path @xmath76 in @xmath0 ,
let @xmath77 denote _ head _ ( or _ starting point _ ) and _ tail _ ( or _ ending point _ ) of path @xmath76 , respectively ; let @xmath78 $ ] denote the subpath of @xmath76 with the starting point @xmath25 and the ending point @xmath26 .
for two distinct paths @xmath79 in @xmath0 , we say @xmath80 is _ smaller _ than @xmath81 ( or , @xmath81 is _ larger _
than @xmath80 ) if there is a directed path from @xmath82 to @xmath83 ; if @xmath79 and the connecting path from @xmath82 to @xmath83 are subpaths of path @xmath76 , we say @xmath80 is _ smaller _ than @xmath81 on @xmath76 .
note that this definition also applies to the case when paths degenerate to vertices / edges ; in other words , in the definition , @xmath79 or the connecting path from @xmath82 to @xmath83 can be vertices / edges in @xmath0 , which can be viewed as degenerated paths . if @xmath84 , we use @xmath85 to denote the path obtained by concatenating @xmath80 and @xmath81 subsequently . for a set of vertices
@xmath86 in @xmath0 , define @xmath87 to be the subgraph of @xmath0 induced on the set of vertices , each of which is smaller or equal to some @xmath88 , @xmath89 .
@xmath0 is said to be a _
@xmath90-graph _ if every edge in @xmath0 belongs to some @xmath29-path , or , in loose terms , all @xmath29 s `` cover '' the whole @xmath0 . for a @xmath90-graph ,
the number of mergings is the number of vertices whose in - degree is at least @xmath91 .
it is clear that to compute @xmath72 ( @xmath62 ) , it is enough to consider all the @xmath90-graphs with distinct ( identical ) sources . for a @xmath90-graph @xmath0
, we say @xmath29 is _ reroutable _ if there exists a different set of menger s paths @xmath92 from @xmath5 to @xmath6 , and we say @xmath0 is _ reroutable _ ( or alternatively , there is a _ rerouting _ in @xmath0 ) , if some @xmath29 , @xmath3 , is reroutable .
note that for a non - reroutable @xmath0 , the choice of @xmath29 s is unique , so we often write @xmath93 as @xmath94 for notational simplicity .
now , for a fixed @xmath63 , reverse the directions of edges that only belong to @xmath29 to obtain a new graph @xmath95 . for any two mergings @xmath96 ,
if there exists a directed path in @xmath95 from the head ( or tail ) of @xmath97 to the head ( or tail ) of @xmath98 , we say the head ( or tail ) of @xmath97 _ semi - reaches _ the head ( or tail ) of @xmath98 against @xmath29 , or alternatively , @xmath97 _ semi - reaches _ against @xmath29 from head ( or tail ) to head ( or tail ) .
it is easy to check that @xmath0 is reroutable if and only if there exists @xmath63 and a merging @xmath97 such that @xmath97 semi - reaches itself against @xmath29 from head to head , which is equivalent to the condition that there exists @xmath63 and a merging @xmath81 such that @xmath81 semi - reaches itself against @xmath29 from tail to tail . for the graph depicted in figure [ picgv ]
, the source @xmath48 is connected to the sink @xmath40 by a group of menger s paths @xmath99 and the source @xmath49 is connected to the sink @xmath41 by a group of menger s paths @xmath100 then @xmath101 are mergings by @xmath102-paths and @xmath103-paths .
@xmath104 , @xmath105 are smaller than @xmath106 and @xmath107 .
@xmath108 only consists of two isolated vertices @xmath109 ; @xmath110 is the subgraph of @xmath0 induced on the set of vertices @xmath111 ; @xmath112 is the subgraph of @xmath0 induced on the set of vertices @xmath113 and @xmath114 is just @xmath0 itself .
the group of menger s paths @xmath102 is reroutable , since there exists another group of menger s paths @xmath115 from @xmath48 to @xmath40 .
similarly , @xmath103 is also reroutable .
it is easy to check , by definition , that @xmath106 semi - reaches @xmath107 against @xmath103 from head to head , @xmath104 semi - reaches @xmath107 against @xmath103 from tail to head , and @xmath107 semi - reaches itself against @xmath102 ( or alternatively @xmath103 ) from head to head .
hence , @xmath0 is reroutable .
for any @xmath116 , consider the following procedure to `` draw '' an @xmath117-graph : for `` fixed '' edge - disjoint paths @xmath118 from @xmath49 to @xmath41 , we extend edge - disjoint paths @xmath119 from @xmath48 to merge with @xmath103-paths until we reach @xmath40 . more specifically , the procedure of extending @xmath102-paths is done step by step , and for each step , we choose to extend one of @xmath120 @xmath102-paths to merge with one of @xmath121 @xmath103-paths .
thus for each step , we have @xmath122 `` strokes '' to choose from the following set @xmath123 here , by `` drawing '' the _ path pair _ @xmath124 , we mean further extending path @xmath125 to merge with path @xmath126 , while ensuring the new merged subpath is larger than any existing merged subpaths on path @xmath126 . apparently , the procedure , and thus the graph ,
is uniquely determined by the sequence of strokes ( see example [ stack - graph ] ) , which will be referred to as a _ merging sequence _ of this @xmath117-graph . it is also easy to see that any @xmath117-graph can be generated by some merging sequence .
[ stack - graph ] consider the following two graphs in figure [ picmergingsequence ] ( here and hereafter , all the mergings in this paper are represented by solid dots instead ) .
listing the elements in the merging sequence , graph ( a ) can be described by @xmath127 $ ] , or alternatively @xmath128 $ ] . when the context is clear , we often omit @xmath129 in the merging sequence for notational .
for example , graph ( b ) can be described by a merging sequence @xmath130 $ ] .
note that it can not be described by @xmath131 $ ] , since @xmath132 ( or , more precisely , the merging corresponding to @xmath132 ) is larger than @xmath133 on @xmath134 .
consider a non - reroutable @xmath117-graph @xmath0 with two sources @xmath109 , two distinct sinks @xmath38 , a set of menger s paths @xmath135 from @xmath48 to @xmath40 , and a set of menger s paths @xmath136 from @xmath49 to @xmath41 . for the case when @xmath48 and @xmath49 are distinct , consider the following procedure on @xmath0 . starting from @xmath48 , go along path @xmath125 until we reach a merged subpath ( or more precisely , the terminal vertex of a merged subpath ) , we then go against the associated @xmath103-path ( corresponding to the merged subpath just visited ) until we reach another merged subpath , we then go along the associated @xmath102-path , @xmath137 continue this procedure ( of alternately going along @xmath102-paths or going against @xmath103-paths until we reach a merged subpath ) in the same manner as above , then the fact that @xmath0 is non - reroutable and acyclic guarantees that eventually we will reach @xmath40 or @xmath49 .
by sequentially listing all the terminal vertices of any merged subpaths visited , such a procedure produces a _ @xmath125-aa - sequence_. apparently , there are @xmath120 @xmath102-aa - sequences
. similarly , consider the following procedure on @xmath0 .
starting from @xmath41 , go against path @xmath126 until we reach a merged subpath , we then go along the associated @xmath102-path ( corresponding to the merged subpath just visited ) until we reach another merged subpath , we then go against the associated @xmath103-path , @xmath137 continue this procedure in the same manner , again , eventually , we are guaranteed to reach @xmath40 or @xmath49 .
by sequentially listing all the terminal vertices of any merged subpaths visited , such a procedure produces a _ @xmath126-aa - sequence_. apparently , there are @xmath121 @xmath103-aa - sequences .
the _ length _ of an aa - sequence @xmath138 , denoted by @xmath139 , is defined to be the number of terminal vertices of merged subpaths visited during the procedure . since each such terminal vertex in an aa - sequence is associated with a path pair , equivalently , the length of an aa - sequence can be also defined as the number of the associated path pairs . for the purpose of computing @xmath140 , we can assume that each menger s path in @xmath0 merges at least once , which implies that each aa - sequence is of positive length .
for the case when @xmath48 and @xmath49 are identical , by proposition @xmath141 in @xcite , we can restrict our attention to the case when @xmath142 .
for the purpose of computing @xmath143 , by the proof of proposition @xmath141 in @xcite , we can assume that paths @xmath125 and @xmath144 share a _ starting subpath _
( a maximal shared subpath by @xmath125 and @xmath144 starting from the source ) for @xmath71 , and due to non - reroutability of @xmath0 , @xmath145 and @xmath146 do not merge with any other path .
then , @xmath103-aa - sequences and their lengths can be similarly defined as in the case when @xmath48 and @xmath49 are distinct , except that we have to replace `` merged subpath '' by `` merged subpath or starting subpath '' .
( here , let us note that the procedure of defining @xmath102-aa - sequences does not carry over .
) it can be checked that the existence of @xmath120 starting subpaths implies that any @xmath103-aa - sequence is of positive length and will always terminate at @xmath40 .
it turns out that the lengths of aa - sequences are related to the number of mergings in @xmath0 .
[ aa - to - number - of - merings ] for a non - reroutable @xmath117-graph @xmath0 with distinct sources , @xmath147 for a non - reroutable @xmath148-graph @xmath0 with identical sources and @xmath121 starting subpaths , @xmath149 where the two summations above are over the all the possible aa - sequences . [ aa - examples ]
consider the two graphs in figure [ picaasequences ] .
let `` @xmath150 '' and `` @xmath151 '' denote `` go along '' and `` go against '' , respectively . in graph ( a ) ,
sequentially listing the terminal vertices of merged subpaths visited during the procedure , two @xmath102-aa - sequences can be represented by @xmath152 and @xmath153 .
similarly , two @xmath103-aa - sequences can be represented by @xmath154 and @xmath155 .
one also checks that the number of mergings is @xmath156 , which is half of @xmath157 , the sum of lengths of all aa - sequences . in graph
( b ) , sequentially listing the terminal vertices of merged subpaths and starting subpaths visited during the procedure , three @xmath103-aa - sequences can be represented by @xmath158 , @xmath159 and @xmath160 .
one also checks the number of mergings is @xmath161 , which is half of @xmath162 .
[ lengthofaasequence ] the shortest @xmath102-aa - sequence ( @xmath103-aa - sequence ) is of length at most @xmath163 .
suppose , by contradiction , that the shortest @xmath102-aa - sequence is of length at least @xmath91 .
pick any @xmath102-path , say @xmath164 .
assume that @xmath164 first merges with @xmath165 at merged subpath @xmath166 .
since the @xmath164-aa - sequence is of length at least @xmath91 , there exists a @xmath102-path , say @xmath167 , such that @xmath167 has a merged subpath , say @xmath168 , smaller than @xmath166 on @xmath165 .
now assume that @xmath167 first merges with @xmath169 at merged subpath @xmath170 , then similarly there exists a @xmath102-path , say @xmath171 , such that @xmath171 has a merged subpath , say @xmath172 , smaller than @xmath170 on @xmath169 .
continue this procedure in the similar manner to @xmath173 apparently , there exists @xmath174 such that @xmath175 .
one then checks that @xmath176 \circ \psi_{j_{l-1}}[h(\mu_{i_l , j_{l-1 } } ) , h(\lambda_{i_{l-1},j_{l-1}})]\ \circ \phi_{i_{l-1}}[h(\lambda_{i_{l-1},j_{l-1 } } ) , h(\mu_{i_{l-1 } , j_{l-2}})]\\ \circ & \psi_{j_{l-2}}[h(\mu_{i_{l-1 } , j_{l-2 } } ) , h(\lambda_{i_{l-2 } , j_{l-2 } } ) ] \circ \cdots \circ \phi_{i_{k+1}}[h(\lambda_{i_{k+1 } , j_{k+1 } } ) , h(\mu_{i_{k+1 } , j_k } ) ] \circ \psi_{j_k}[h(\mu_{i_{k+1 } , j_k } ) , h(\lambda_{i_k , j_k})]\end{aligned}\ ] ] constitutes a cycle , which contradicts the assumption that @xmath0 is acyclic .
a parallel argument can be applied to the shortest @xmath103-aa - sequence .
[ each - path - pair - at - most - once ] for a non - reroutable graph @xmath0 , any path pair occurs at most once in any given aa - sequence . by contradiction , suppose that the same path pair occurs in an aa - sequence twice . as in the proof of lemma 2.7 in @xcite , one can prove @xmath0 is reroutable , which is a contradiction .
it then immediately follows from lemma [ each - path - pair - at - most - once ] that in a non - reroutable @xmath177-graph with distinct sources , * the longest @xmath102-aa - sequence ( @xmath103-aa - sequence ) is of length at most @xmath122 ; * any @xmath102-path ( @xmath103-path ) merges at most @xmath122 times .
and in a non - reroutable @xmath178-graph with identical sources , * the longest @xmath103-aa - sequence is of length at most @xmath179 ; * any @xmath102-path ( @xmath103-path ) merges at most @xmath179 times .
in this section , we give exact values of @xmath9 and @xmath10 for certain special parameters .
[ threeproofs ] @xmath180 we first show that @xmath181 . consider the following @xmath182-graph specified by the following merging sequence ( for a simple example , see figure [ pictwomm2](a ) ) : @xmath183 $ ] , where @xmath184_2 , 1 ) & \mathrm{if}\ k=3i-2 & \mathrm{for}\ 1\leq i\leq n , \\ ( [ i]_2 , i+1 ) & \mathrm{if}\ k=3i-1 & \mathrm{for}\ 1\leq i \leq n-1,\\ ( [ i+1]_2 , i+1 ) & \mathrm{if}\ k=3i & \mathrm{for}\ 1\leq i \leq n-1,\\ ( [ n+1]_2 , 1 ) & \mathrm{if}\ k=3n-1 . & \end{array } \right.\ ] ] where @xmath185_2=1 $ ] when @xmath186 is odd , @xmath185_2=2 $ ] when @xmath186 is even .
-graph with 8 mergings ( b ) an example of a @xmath187-graph , scaledwidth=72.0% ] one checks that the above graph is non - reroutable with @xmath188 mergings , which implies that @xmath181 .
next , we show that @xmath189 . consider a non - reroutable @xmath182-graph @xmath0 with distinct sources @xmath109 , sinks @xmath38 , a set of menger s paths @xmath190 from @xmath48 to @xmath40 , and a set of menger s paths @xmath191 from @xmath49 to @xmath41 .
define @xmath192 note that for any @xmath193 , @xmath194 must belong to different @xmath102-paths .
we say @xmath193 is of _ type i _
, if @xmath97 belongs to @xmath195 , and @xmath193 is of _ type ii _ , if @xmath97 belongs to @xmath196 .
for any two different elements @xmath197 .
we say @xmath198 if either ( they are of the same type and @xmath199 is smaller than @xmath200 ) or ( they are of different types and @xmath199 is smaller than @xmath201 ) .
one then checks that the relationship defined by @xmath202 is a strict total order . letting @xmath186
denote the number of elements in @xmath203 , we define @xmath204 to be the sequence of the ordered ( by @xmath202 ) elements in @xmath203 .
now we consecutively partition @xmath205 into @xmath206 `` _ _ medium - blocks _ _ '' @xmath207 , and further consecutively partition each @xmath208 into @xmath209 `` _ _ mini - blocks _ _ '' @xmath210 ( see example [ mediumandmini ] for an example ) such that * for any @xmath211 , the elements in @xmath212 are of the same type . * for any @xmath211 , @xmath212 is _ linked _ to @xmath213 in the following sense : let @xmath214 denote the element with the largest second component in @xmath212 and let @xmath215 denote the element with the smallest first component in @xmath213 , then @xmath216 . * for any @xmath63 , @xmath217 is not linked to @xmath218 .
a mini - block is said to be a _ singleton _ if it has only one element .
we then have the following lemma , whose proof is omitted .
[ two - singletons ] between any two `` adjacent '' singletons ( meaning there is no singleton between these two singletons ) in a medium - block , there must exist a mini - block containing at least three elements .
letting @xmath219 denote the number of mini - blocks in @xmath205 and @xmath220 denote the number of elements in medium - block @xmath208 for @xmath221 , we then have @xmath222 suppose there are @xmath14 singletons in @xmath205 , then by lemma [ two - singletons ] , we can find @xmath223 mini - blocks , each of which has at least three elements .
hence , for @xmath221 , @xmath224=2y_i-1,\ ] ] which implies @xmath225 for any two linked mini - blocks @xmath212 and @xmath213 , let @xmath214 denote the element with the largest second component in @xmath212 , and let @xmath215 denote the element with the smallest first component in @xmath213 . by the definition ( of two mini - blocks
being linked ) , we have @xmath216 , which means @xmath212 and @xmath213 share a common merging . together with the fact that each element in @xmath203 is a pair of mergings
, this further implies that the number of mergings in @xmath0 is @xmath226 belong to the same @xmath103-path , and furthermore , there exists only one @xmath102-path passing by both an element ( more precisely , passing by both its mergings ) in @xmath227 and an element in @xmath228 .
so , @xmath121 , the number of @xmath103-paths in @xmath0 can be computed as @xmath229 it then follows from ( [ eq-1 ] ) , ( [ eq-2 ] ) , ( [ eq-3 ] ) and the fact @xmath230 that @xmath231 and furthermore @xmath232 consider the graph in figure [ pictwomm2](b ) and assume the context is as in the proof of theorem [ threeproofs ] .
then we have , @xmath233 among all the elements in @xmath203 , @xmath234 , @xmath235 , @xmath236 and @xmath237 are of type i , and @xmath238 , @xmath239 are of type ii .
it is easy to check that @xmath240 which is partitioned into three mini - blocks @xmath241 , @xmath242 and @xmath243 .
the first mini - block is linked to the second one , but the second one is not linked to the third , so @xmath205 is partitioned into two medium - blocks : @xmath244 [ pell ] the result in theorem [ threeproofs ] in fact has already been proved in @xcite using a different approach . the proof in this paper , however , is more intrinsic in the sense that it reveals in greater depth the topological structure of non - reroutable @xmath182-graphs achieving @xmath188 mergings , and further helps to determine the number of such graphs .
assume a non - reroutable @xmath182-graph @xmath0 has @xmath188 mergings .
one then checks that in the proof of theorem [ threeproofs ] , equalities hold for ( [ eq-5 ] ) .
it then follows that * @xmath245 , namely , there is only one medium - block in @xmath205 ; * equalities hold necessarily for ( [ eq-4 ] ) , ( [ eq-1 ] ) and eventually ( [ eq-0 ] ) , which further implies that between two adjacent singletons , only one mini - block has three elements and any other mini - block has two elements . furthermore , one checks that * for a mini - block with two elements @xmath246 , @xmath201 is smaller than @xmath247 ; * for a mini - block with three elements @xmath248 , @xmath249 , @xmath250 , either ( @xmath201 is smaller than @xmath251 and @xmath251 is smaller than @xmath247 ) or ( @xmath251 is smaller than @xmath247 and @xmath247 is smaller than @xmath201 ) .
assume that @xmath0 is `` reduced '' in the sense that , other than @xmath252 , each vertex in @xmath0 is a terminal vertex of some merging .
the properties above allow us to count how many reduced non - reroutable @xmath182-graphs ( up to graph isomorphism ) can achieve @xmath188 mergings : suppose that there are @xmath14 ( @xmath253 ) singletons in @xmath0 , then necessarily , there are @xmath223 three - element mini - blocks and @xmath254 two - element mini - blocks in @xmath205 .
it can be checked that the number of ways for these @xmath121 mini - blocks to form @xmath205 for some @xmath182-graph is @xmath255 .
this implies that the number of @xmath182-graph , whose @xmath205 consists of @xmath14 singletons , @xmath223 three element mini - blocks and @xmath256 two element mini - blocks , is @xmath255 . through a computation summing over all feasible @xmath14 ,
the number of reduced non - reroutable @xmath182-graphs with @xmath188 mergings can be computed as @xmath257 = p_n,\ ] ] where @xmath258 is the @xmath121-th pell number @xcite .
[ mstar44 ] @xmath259 consider a non - reroutable @xmath260-graph @xmath0 with one source @xmath37 , two sinks @xmath38 , a set of menger s paths @xmath261 from @xmath37 to @xmath40 and a set of menger s paths @xmath262 from @xmath37 to @xmath41 .
as discussed in section [ aa - sequences ] , we assume that @xmath144 and @xmath125 share a starting subpath @xmath263 from @xmath37 for @xmath264 , and furthermore , we assume @xmath265 do not merge with any other paths , directly `` flowing '' to the sinks .
consider the four @xmath103-aa - sequences , which will be referred to as @xmath266 in the following .
it is easy to check that each @xmath267 , @xmath268 , will be of odd length . without loss of generality , assume that @xmath269 is the shortest such sequence , and thus by lemma [ lengthofaasequence ] , @xmath269 is of length @xmath163 ; let @xmath270 be the merging associated with @xmath269 . by lemma [ each - path - pair - at - most - once ] , each @xmath267 can only be associated with each path pair @xmath271 , @xmath272 and @xmath273 at most once .
it then follows that excluding @xmath270 , each @xmath274 , @xmath275 , can only merge with each @xmath276 , @xmath277 , at most once .
one then further checks that each @xmath267 , @xmath278 , can only be associated with @xmath271 , @xmath272 and @xmath273 for @xmath279 times in total . by lemma [ aa - to - number - of - merings ]
, we then derive @xmath280 we next prove that @xmath94 can not be @xmath73 .
suppose , by contradiction , that @xmath94 is @xmath73 .
then , necessarily , the longest @xmath103-aa - sequence , say @xmath281 , will be of length @xmath282 .
it then follows that the two pairs , @xmath283 and @xmath284 must be associated with @xmath281 .
it also follows that @xmath285 must be of length @xmath279 .
now we prove that @xmath270 belongs to @xmath195 and @xmath286 .
it suffices to prove that each of @xmath287 can not have four mergings .
suppose , by contradiction , there are four mergings in @xmath134 , say @xmath288 , in the ascending order ; here @xmath289 is necessarily @xmath270
. then , there are two mergings belonging to the same @xmath102-path , say @xmath290 , @xmath291 .
now we consider two cases : if @xmath292 , then @xmath293 must belong to different @xmath103-aa - sequences .
suppose @xmath294 , @xmath295 , @xmath296 and @xmath297 , where @xmath298 .
note that @xmath299 and @xmath300 belong to the same @xmath103-aa - sequence for @xmath301 , @xmath302 and @xmath303 belong to the same @xmath103-aa - sequence .
this implies that @xmath304 , @xmath305 and @xmath306 .
it then follows that @xmath307 can not belong to @xmath308 or @xmath309 , so it must belong to @xmath310 . on the other hand , either @xmath201 or @xmath251 must belong to @xmath196 , the same @xmath102-path to which @xmath311 belongs
. then @xmath312 occurs at least twice in @xmath310 , which violates the lemma [ each - path - pair - at - most - once ] .
if @xmath313 , then @xmath314 must belong to different @xmath103-aa - sequences .
suppose @xmath315 , @xmath316 , @xmath296 and @xmath297 , where @xmath298 .
note that @xmath299 and @xmath300 belong to the same @xmath103-aa - sequence for @xmath301 ; @xmath302 and @xmath311 belong to the same @xmath103-aa - sequence .
this implies that @xmath317 , @xmath318 and @xmath319 . in this case
@xmath251 must belong to @xmath196 , the same path to which @xmath311 belongs .
it then follows that @xmath311 can not belong to @xmath320 , so it must belong to @xmath310 .
but then we have @xmath302 , @xmath317 , which violates the lemma [ each - path - pair - at - most - once ] . combining the above two cases , we conclude that there can not be four mergings on @xmath134 . with a parallel argument applied to @xmath321 ,
we conclude that there are four mergings on @xmath286 , say @xmath322 , in the ascending order .
next , we examine all the following cases to show that @xmath94 can not be @xmath73 .
paths @xmath195 and @xmath286 merge at @xmath104 and @xmath107 . for this case
, we have the following two subcases .
@xmath195 first merges with @xmath286 . for this case
, it is easy to check that @xmath281 is of length @xmath323 , which contradicts the fact that it is of length @xmath282 ( see figure [ pic44](a ) ) .
@xmath195 first merges with @xmath134 or @xmath324 ; without loss of generality , assume that @xmath195 first merges with @xmath134 at the merging denoted by @xmath98 . then necessarily , @xmath195 immediately merges with @xmath286 at the merging @xmath104
then , we have @xmath325 , which violates lemma [ each - path - pair - at - most - once ] ( see figure [ pic44](b ) ) . paths @xmath195 and @xmath286 merge at @xmath106 and @xmath107 .. for this case , we consider the following subcases .
@xmath195 first merges with @xmath286 .
then , we have @xmath326 , which violates lemma [ each - path - pair - at - most - once ] ( see figure [ pic44](c ) ) .
@xmath195 first merges with @xmath134 or @xmath324 ; without loss of generality , assume that @xmath195 first merges with @xmath134 . then necessarily , @xmath195 will subsequently merges with @xmath286 , @xmath324 and @xmath286 .
let @xmath327 be the smallest mergings in @xmath328 , respectively .
it is clear that at least one of @xmath199 and @xmath200 belongs to @xmath195 , since otherwise @xmath329 would belong to @xmath330 , respectively , and thus @xmath199 would semi - reach itself from head to head again @xmath103 , which implies the existence of a rerouting , a contradiction .
both the first mergings on @xmath134 , @xmath324 belong to @xmath195 .
then , @xmath104 is the largest merging on either @xmath196 or @xmath331 , that is , from @xmath104 , the associated path can not go forward to merge anymore .
@xmath331 can only first merges with @xmath134 and @xmath196 can only first merges with @xmath286 at @xmath105 , which implies the existence of a rerouting ( @xmath105 semi - reaches itself against @xmath102 from head to head ) .
see figure [ pic44](d ) for an example .
the first merging @xmath199 on @xmath134 belongs to @xmath195 , and the first merging on @xmath324 belongs to @xmath196 .
if @xmath196 first merges with @xmath324 , then @xmath331 can only first merges @xmath286 at @xmath104 , one check that @xmath281 is of length @xmath332 , a contradiction ( see figure [ pic44](e ) ) ; if @xmath196 first merges with @xmath286 at @xmath105 ( if @xmath196 first merges with @xmath286 at @xmath104 , then @xmath281 is of length @xmath333 , a contradiction ) , then @xmath331 can only first merge with @xmath286 at @xmath104 , and then merges with @xmath324 , @xmath134 , which implies the existence of a rerouting ( @xmath105 semi - reaches itself against @xmath102 from head to head )
. see figure [ pic44](f ) for an example .
the first merging @xmath200 on @xmath324 belongs to @xmath195 , and
the first merging @xmath199 on @xmath134 belongs to @xmath331 .
if @xmath331 first merges with @xmath286 , then necessarily the merging is @xmath104 , and @xmath331 further merges with @xmath134 at @xmath199 . in this case
@xmath196 can not go forward to merge anymore , which contradicts the fact that @xmath196 merges with @xmath103-paths just three times ( see figure [ pic44](g ) ) ; if @xmath331 first merges @xmath134 at @xmath199 , then @xmath196 can only first merges with @xmath286 at @xmath104 , and then merge with @xmath134 . in this case
, @xmath196 can not go forward to merge anymore , which also contradicts the fact that @xmath196 merges with @xmath103-paths exactly three times ( see figure [ pic44](h ) ) .
all the above cases combined imply that @xmath94 is at most @xmath282 . on the other hand
, one can find a non - reroutable @xmath260-graph with one source , two sinks and @xmath282 mergings as in figure [ picmstar44 ] , which implies @xmath334 ( see a more general result in theorem [ lowerboundmstar ] ) .
we then have established the theorem .
[ m33 ] @xmath335 consider a non - reroutable @xmath336-graph @xmath0 with two source @xmath109 and two sinks @xmath38 .
let @xmath337 , @xmath338 denote the set of menger s paths from @xmath109 to @xmath38 , respectively . as discussed in section [ aa - sequences ] , we assume each aa - sequences is of positive length .
then , by lemma [ lengthofaasequence ] , the shortest aa - sequence is of length @xmath163 .
it can also be checked that the longest aa - sequence in @xmath0 is of length at most @xmath279 .
so , by lemma [ aa - to - number - of - merings ] , we have @xmath339 it follows from theorem [ mmnlb ] ( this is proven later in section [ bounds - section ] ) that @xmath340 .
we next show @xmath341 can not be @xmath342 or @xmath343 .
note that any non - reroutable @xmath336-graph having 15 mergings implies that @xmath344 and @xmath343 mergings implies that @xmath345 @xmath346 the idea of the proof is that we first preprocess to eliminate many cases by checking if ( [ 15-mergings ] ) and ( [ 14-mergings ] ) are satisfied , then we can exhaustively investigate all the remaining cases to prove @xmath341 can not be equal to @xmath343 or @xmath342 .
-aa - sequence , scaledwidth=83.0% ] suppose , by contradiction , that @xmath0 has @xmath343 or @xmath342 mergings .
then , as before , at least one of aa - sequences of @xmath0 is of length @xmath279 . without loss of generality
, we assume the @xmath195-aa - sequences is of length @xmath279 .
one then checks that , up to obvious symmetry , as depicted in figure [ m33iiiiii ] , we only have three possible cases for the @xmath195-aa - sequence : for case @xmath163 , the @xmath195-aa - sequence is @xmath347 ; for case @xmath91 , the @xmath195-aa - sequence is @xmath347 ; for case @xmath323 , the @xmath195-aa - sequence is @xmath348 .
note that the graphs in figure [ m33iiiiii ] only show the segments of paths @xmath349 associated with the @xmath195-aa - sequence .
next , for each of the above - mentioned cases , we will extend these segments either backward or forward in all possible ways , and we shall show that no matter how we extend , the number of mergings in @xmath0 will not exceed @xmath350 .
, subcase @xmath351,scaledwidth=80.0% ] as shown in figure [ m33iiiiii](a ) .
for this case , one checks that after @xmath195 first merge with @xmath146 at @xmath106 , it must immediately merge with @xmath324 at @xmath352 ; one also checks that for paths @xmath353 , each of them can only go backward to merge at most twice . in the following , by subcase ( @xmath354 , @xmath355 )
, we mean the case when path @xmath331 goes backward to merge @xmath354 times and path @xmath196 goes backward to merge @xmath355 times .
it suffices to check the following nine subcases : @xmath356 , @xmath357 , @xmath358 , @xmath359 , @xmath360 , @xmath361 , @xmath362 , @xmath363 , @xmath133 .
the checking procedure is rather mechanical and tedious , so we only go through subcase @xmath362 , as shown in figure [ m33i20abc ] , for illustrative purposes . for this case , we have three choices for path @xmath331 . for choice @xmath163 as shown in figure [ m33i20abc](a ) , the @xmath331-aa - sequence is of length @xmath163 , so path @xmath195 must go forward to merge further to make sure the @xmath196-aa - sequence is of length more than @xmath333 .
therefore , from @xmath364 , path @xmath331 can not go forward to merge any more and it must go to @xmath41 directly .
then one exhaustively checks that from @xmath365 and @xmath366 , paths @xmath195 and @xmath196 can not go forward to merge more than four times in total . for choice @xmath91 as shown in figure [ m33i20abc](b )
, the @xmath196-aa - sequence is of length @xmath163 , and path @xmath195 can not go forward to merge anymore .
one exhaustively checks that from @xmath366 and @xmath364 , paths @xmath196 and @xmath331 can not go forward to merge five times in total . for choice @xmath323 as shown in figure [ m33i20abc](c )
, the @xmath331-aa - sequence is of length @xmath163 , and the @xmath196-aa - sequence is of length @xmath323 .
so , ( [ 15-mergings ] ) or ( [ 14-mergings ] ) is not satisfied . as shown in figure [ m33iiiiii](b ) .
for this case , one checks that each of paths @xmath196 and @xmath331 can not go backward to merge more than three times .
one also checks that path @xmath195 , after merging with @xmath146 at @xmath106 , will immediately merge with @xmath134 at @xmath107 .
since otherwise , one verifies that the total number of mergings is strictly less than @xmath343 : path @xmath331 can go backward to merge for at most twice and path @xmath196 can not go backward to merge ; furthermore , path @xmath331 can not go forward to merge anymore from @xmath105 and paths @xmath195 and @xmath196 can not go forward to merge four times in total .
it suffices to check the following subcases : @xmath356 , @xmath359 , @xmath360 , @xmath362 , @xmath363 , @xmath133 , @xmath367 , @xmath357 , @xmath358 , @xmath361 .
as shown in figure [ m33iiiiii](c ) . for this case ,
after path @xmath195 merges with @xmath146 at @xmath105 , it has to immediately merge with @xmath134 at @xmath107 .
similarly as before , it suffices to check the following subcases : @xmath356 , @xmath359 , @xmath360 , @xmath363 , @xmath133 , @xmath357 , @xmath358 , @xmath361 .
@xmath368 it follows from @xcite that @xmath369 to prove the theorem , we will consider the following four cases : @xmath370 .
it immediately follows from theorem [ one - one - two ] that @xmath371 @xmath372 .
it can be checked that the @xmath373-graph in figure [ picm122twopic](a ) is non - reroutable , which implies that @xmath374 . since , by ( [ 4n+1 ] ) , @xmath375
, it suffices to prove that @xmath376 is not @xmath282 .
-graph with 8 mergings ( b ) the edge - labeled non - reroutable @xmath377-graph , scaledwidth=72.0% ] suppose , by contradiction , that a non - reroutable @xmath373-graph @xmath0 has @xmath282 mergings .
assume @xmath0 has distinct sources @xmath378 , sinks @xmath379 , path @xmath76 from @xmath48 to @xmath40 , a set of two menger s paths @xmath380 from @xmath49 to @xmath41 and a set of two menger s paths @xmath381 from @xmath382 to @xmath383 .
since @xmath0 is non - reroutable , path @xmath76 merges with each of paths @xmath384 at most once ( otherwise path @xmath76 is reroutable through the path with which @xmath76 merges twice ) .
this , together with the assumption that @xmath385 and the fact that @xmath386 , implies that @xmath387 , where @xmath95 denotes the subgraph of @xmath0 induced on @xmath388 , and @xmath76 must merge with each of @xmath384 exactly once . here , by remark
[ pell ] , @xmath95 has only two `` reduced '' instances : the graph in figure [ picm122twopic](b ) and its `` reversed '' version obtained by reversing all its edges ; so , we can assume @xmath95 takes the form as in figure [ picm122twopic](b ) .
moreover , since we count mergings without multiplicity , we can further assume that every merging in @xmath0 is by exactly two menger s paths .
now , we exhaustively examine all ways in which @xmath76 can merge with @xmath95 without generating any reroutings or cycles .
the following rule can be used to eliminate many cases : for any two paths @xmath389 , @xmath390 in @xmath95 , if @xmath389 is smaller than @xmath390 , then @xmath76 can not merge with them both ( since , otherwise , @xmath76 is reroutable through @xmath389 and @xmath390 ) . with the subpaths of @xmath384 labeled as in figure [ picm122twopic](b ) , we obtain the following sets of subpaths , each of which consists of ( unordered ) subpaths , where @xmath76 can merge with @xmath388 without violating the above - mentioned rule : @xmath391 , @xmath392 , @xmath393 , @xmath394 , @xmath395 , @xmath396 . in the following ,
we examine each of the above possibilities , and conclude that there is no way one can add path @xmath76 without generating reroutings or cycles , which further implies that @xmath397 .
below , expression like `` @xmath398 '' means `` if after @xmath76 merges with @xmath399 , it further immediately with @xmath195 , and further immediately with @xmath146 , then the group of menger s paths @xmath400 are reroutable '' .
1 . @xmath401 .
+ @xmath402 , @xmath403 , @xmath404 , @xmath405 , + @xmath406 , @xmath407 , @xmath408 , @xmath398 .
+ it is easy to check we can not find path @xmath76 without some of the above subpaths .
2 . @xmath409 . + for @xmath410 and @xmath196 , @xmath411 , @xmath412 .
+ for @xmath410 and @xmath146 , @xmath413 , @xmath414 .
+ for @xmath410 and @xmath399 , @xmath415 , @xmath416 .
+ hence , path @xmath76 can not merge with @xmath410 , if it merges the other three edges .
@xmath417 . + for @xmath399 and @xmath196 , @xmath418 , @xmath419 .
+ for @xmath399 and @xmath134 , @xmath420 , @xmath421 .
+ for @xmath399 and @xmath422 , @xmath423 , @xmath424 .
+ hence , path @xmath76 can not merge with @xmath399 , if it merges the other three edges .
@xmath425 . + for @xmath324 and @xmath196 , @xmath426 , @xmath427 .
+ for @xmath324 and @xmath422 , @xmath428 , @xmath429 .
+ for @xmath324 and @xmath430 , @xmath431 , @xmath432 .
+ hence , path @xmath76 can not merge with @xmath324 , if it merges the other three edges .
@xmath433 . + for @xmath331 and @xmath324 , @xmath434 , @xmath435 .
+ for @xmath331 and @xmath422 , @xmath436 , @xmath437 .
+ for @xmath331 and @xmath438 , @xmath439 , @xmath440 .
+ hence , path @xmath76 can not merge with @xmath331 , if it merges the other three edges .
+ @xmath442 , @xmath443 , @xmath444 , @xmath445 , + @xmath446 , @xmath447 , @xmath448 , @xmath449 .
+ it is easy to check we can not find path @xmath76 without some of the above subpaths . @xmath450 .
it can be checked that the @xmath451-graph as in figure [ picm123and124](a ) is non - reroutable , which implies that @xmath452 . since , by ( [ 4n+1 ] ) , @xmath453
, it suffices to prove that @xmath376 is not @xmath350 .
suppose , by contradiction , that a non - reroutable @xmath451-graph @xmath0 has @xmath350 mergings .
assume @xmath0 has distinct sources @xmath378 , sinks @xmath379 , path @xmath76 from @xmath48 to @xmath40 , a set of two menger s paths @xmath380 from @xmath49 to @xmath41 and a set of three menger s paths @xmath454 from @xmath382 to @xmath383 .
since @xmath0 is non - reroutable , path @xmath76 merges each of paths @xmath455 at most once ( otherwise path @xmath76 is reroutable through the path with which @xmath456 merges twice ) .
this , together with the fact that @xmath457 and the fact that @xmath458 , implies that @xmath76 must merge with each of @xmath455 exactly once and the number of mergings among @xmath380 and @xmath454 is @xmath332 .
similar to the proof for the case @xmath372 , we consider the subgraph @xmath95 of @xmath0 induced on paths @xmath455 .
one then checks that any @xmath459-graph must have , up to relabeling , one of five merging sequences .
we then exhaustively investigate how @xmath76 can be `` added '' to @xmath95 to form @xmath0 without generating any reroutings or cycles . through a similar discussion , we conclude that there is no way we can add such path @xmath76 to generate a non - reroutable @xmath460-graph with 13 mergings . as a result , @xmath461 .
-graph with 12 mergings
( b ) a non - reroutable @xmath462-graph with 17 mergings , scaledwidth=75.0% ] @xmath463 . by ( [ 4n+1 ] ) , we only need to construct a non - reroutable @xmath464-graph with @xmath465 mergings .
first , we consider a non - reroutable @xmath182-graph with distinct sources @xmath466 , sinks @xmath467 and the following merging sequence : @xmath468 for @xmath469 , @xmath470_2,1 ) & \mathrm{if}\ k=3i-1 & \mathrm{for}\ 3\leq i\leq n , \\ ( [ i]_2,i+1 ) & \mathrm{if}\ k=3i & \mathrm{for}\ 3\leq i\leq n-1 , \\ ( [ i+1]_2,i+1 ) & \mathrm{if}\ k=3i+1 & \mathrm{for}\ 3\leq i\leq n-1 , \end{array } \right.\ ] ] where @xmath185_2=1 $ ] when @xmath186 is odd , @xmath185_2=2 $ ] when @xmath186 is even .
one can check that this @xmath182-graph is non - reroutable .
assume that the two menger s paths from @xmath49 to @xmath41 start with the subpaths @xmath471 , respectively ; and the @xmath121 menger s paths from @xmath382 to @xmath383 start with the subpaths @xmath472 , respectively ; and there are no mergings on @xmath473 .
next , we add a path @xmath76 to construct a non - reroutable @xmath474-graph such that path @xmath76 , starting from @xmath48 , successively merges with @xmath475 ( these mergings are labeled as @xmath476 in figure [ picm123and124](b ) ) , and eventually reaches @xmath40 . it can be checked that this newly constructed @xmath464-graph is non - reroutable . through exhaustive
searching , we are able to compute exact values for @xmath477 and @xmath478 with some small parameters : @xmath479 , @xmath480 , @xmath481 , @xmath482 , @xmath483 , @xmath484 , @xmath485 , @xmath486 , @xmath487 , @xmath488 , @xmath489 , @xmath490 , @xmath491 , @xmath492 , @xmath493 .
computations show that for @xmath494 and @xmath495 , @xmath496 [ turan ] @xmath497 for the `` @xmath498 '' direction , by proposition @xmath499 of @xcite , we deduce that @xmath500 to prove the `` @xmath501 '' direction , consider a non - reroutable @xmath502-graph @xmath0 with distinct sources and sets of menger s paths @xmath503 .
it is easy to check that due to non - reroutability of @xmath0 , any two @xmath76-paths can merge with each other at most once . without loss of generality , assume that @xmath504 merges @xmath505 times with @xmath506 , @xmath507 ; and any other path @xmath23 , @xmath508 , merges at most @xmath505 times .
again , due to non - reroutability of @xmath0 , there are no non-@xmath504-involved mergings among paths @xmath506 , where we say a merging at edge @xmath20 is _ @xmath504-involved _ if @xmath20 belongs to @xmath504 .
it then follows that any non-@xmath504-involved merging in @xmath0 must be associated with one of paths from @xmath509 , each of which merges at most @xmath505 times .
we then conclude that @xmath510 [ wriggle ] for a non - reroutable @xmath502-graph @xmath0 , in order to prove @xmath511 we only need the following two conditions : 1 .
any two @xmath512 can merge at most once ; 2 .
there are at most two mergings in any subgraph of @xmath0 induced on any three @xmath513 .
so , in some sense , theorem [ turan ] is a `` dual '' version of the classical turan s theorem @xcite , which states that the number of edges in a graph is less than @xmath514 if 1 .
the graph is simple , i.e. , there is at most one edge between any two vertices ; 2 . the graph does not have triangles , i.e. , there are at most two edges among any three vertices .
[ one - one - two ] @xmath515 consider any non - reroutable @xmath516-graph @xmath0 with distinct sources @xmath517 , sinks @xmath518 , a menger s path @xmath23 from @xmath5 to @xmath6 for @xmath519 , two menger s paths @xmath520 from @xmath521 to @xmath522 .
let @xmath523 denote the set of @xmath76-paths , each of which first merges with @xmath524 and then with @xmath525 .
let @xmath526 denote the set of @xmath76-paths , each of which only merges with @xmath527 , and let @xmath39 denote the set of @xmath76-paths , each of which does not merge with @xmath146 or @xmath134 .
and we write @xmath528 consider any path @xmath504 in @xmath529 .
assume that @xmath504 merges with @xmath146 at merged subpath @xmath530 and with @xmath134 at merged subpath @xmath531 .
now , pick any path @xmath532 ( @xmath533 ) .
if , for some @xmath534 , @xmath535 overlaps ( i.e. , shares an edge ) with @xmath536 , then by the non - reroutability of @xmath0 , we have 1 .
@xmath537 ( @xmath538 ) , in which case @xmath539 does not overlap with @xmath540 ; or 2 .
@xmath541 ( @xmath533 ) , in which case @xmath542 must share * the edge on @xmath536 ( @xmath540 ) ending at @xmath543 ( @xmath544 ) , * the subpath @xmath545 $ ] ( @xmath546 $ ] ) , * and the edge on @xmath540 ( @xmath536 ) starting from @xmath547 ( @xmath548 ) + with @xmath23 . in the remainder of this proof ,
we say @xmath542 is in the same _ equivalence class _ as @xmath23 . in the following ,
we say a merging at edge @xmath20 is _ @xmath103-involved _ if @xmath20 belongs to either @xmath146 or @xmath134 .
the following properties then follow from the non - reroutability of @xmath0 : 1 .
all @xmath529-paths of the same type ( meaning all of them belong to either @xmath538 or @xmath533 ) and their equivalent classes can be ( partially ) ordered in the following sense : consider @xmath549 of the same type .
assume that @xmath23 merges with @xmath550 at @xmath551 , and @xmath542 merges with @xmath550 at @xmath552 .
if @xmath536 is smaller than @xmath535 , then @xmath540 must be smaller than @xmath539 ; in this case , we say that @xmath23 is _ smaller _ than @xmath542 , and the equivalence class of @xmath23 is _ smaller _ than that of @xmath542 . as a result , we can list the equivalence classes of all @xmath538-paths in ascending order : @xmath553 , and the equivalence classes of all @xmath533-paths in ascending order : @xmath554 .
2 . a merging by two equivalent @xmath529-paths or two @xmath529-paths of different types must be @xmath103-involved . if a merging by any two non - equivalent @xmath529-paths @xmath21 is non-@xmath103-involved , then @xmath23 and @xmath542 are of the same type .
if furthermore @xmath23 is smaller than @xmath542 , then there exists @xmath25 such that @xmath555 and @xmath556 . as a consequence , for any @xmath557 @xmath558|_{\mathcal{m } } \leq \min\{|q_u| , |q_{u+1}|\ } , \quad |g[\widehat{q}_v , \widehat{q}_{v+1}]|_{\mathcal{m } } \leq \min\{|\widehat{q}_v| , |\widehat{q}_{v+1}|\},\ ] ] where @xmath559 $ ] ( @xmath560 $ ] ) denotes the subgraph of @xmath0 induced on all the @xmath561-paths and @xmath562-paths .
3 . any @xmath54-path can merge with at most one @xmath538-path and at most one @xmath533-path .
any three @xmath76-paths can only merge with each other at most twice .
now , by the definition of @xmath54 and @xmath529 , we have the number of @xmath103-involved mergings is upper bounded by @xmath563 and by theorem [ turan ] , the number of non-@xmath103-involved mergings is upper bounded by @xmath564 .
it then follows that @xmath565 note that for any @xmath566 , @xmath567 so , from now on , we only consider the case when @xmath568 .
it can be easily checked that when @xmath569 , @xmath570 next , we show that when @xmath571 , @xmath572 if @xmath573 , by ( [ universal - upper - bound-1 ] ) , the above inequality immediately holds . if @xmath574 , we have the following cases to consider : there exists some equivalence class that has more than one element . without loss of generality ,
assume some @xmath538-class has more than one element , and let @xmath575 be the smallest such class with @xmath576 , and let @xmath577 be the largest such class with @xmath578 .
the number of non-@xmath103-involved mergings between @xmath575 and @xmath579 is strictly less than @xmath120 .
then , one checks that * @xmath580|_{\mathcal{m } } \leq m+1 $ ] , where @xmath581 $ ] denotes the subgraph of @xmath0 induced on all the @xmath575-paths and @xmath103-paths ; * the number of @xmath103-involved mergings by @xmath582-paths , @xmath534 , and @xmath103-paths is upper bounded by @xmath583 . *
the number of non-@xmath103-involved mergings by @xmath575-paths and other @xmath538-classes is upper bounded by @xmath120 .
* by theorem [ turan ] , the number of non-@xmath103-involved mergings among @xmath582-paths , @xmath534 , is upper bounded by @xmath584 . *
the number of non-@xmath103-involved mergings by @xmath575-paths and ( @xmath54-paths or @xmath39-paths ) is upper bounded by @xmath585 . combining all the bounds above ,
we have @xmath586 @xmath587 the number of non-@xmath103-involved mergings between @xmath575 and @xmath579 is equal to @xmath120 , which necessarily implies that @xmath588 .
then , for either @xmath575 or @xmath577 , the number of non-@xmath103-involved mergings with @xmath54-paths is at most @xmath589 , so we have @xmath590 @xmath591 every equivalence class has exactly one element . for this case , since the number of @xmath103-involved mergings is upper bounded by @xmath592 , it suffices to show that the number of non-@xmath103-involved mergings is upper bounded by @xmath593 there do not exist non-@xmath103-involved mergings among all equivalence classes . for this case ,
the total number of mergings by @xmath594 , any two chosen @xmath529-paths of the same type , and ( @xmath54-paths or @xmath39-paths ) is at most @xmath595 .
we then conclude that the number of non-@xmath103-involved mergings is upper bounded by @xmath596 there exists a non-@xmath103-involved merging by two adjacent equivalent classes , say @xmath597 , and these two classes merge with each other once , however they do not merge with any other @xmath538-classes . by property @xmath598 ,
both of these two classes are of the same type . moreover , by property @xmath599 , the number of mergings between these two classes and ( @xmath54-paths or @xmath39-paths ) is at most @xmath595 .
hence , we have the number of non-@xmath103-involved mergings is upper bounded by @xmath600 there exist at least three adjacent equivalent classes , say @xmath601 , @xmath602 , such that @xmath603 merges with @xmath604 , @xmath605 , however there are no mergings by @xmath606 and other @xmath538-classes . for this case
, it can be checked that at least one of @xmath607 , @xmath608 and @xmath609 merges with @xmath54-paths at most @xmath589 times .
since each of the above pair of paths merge with @xmath529-paths at most twice and merges with @xmath39-paths at most @xmath610 times , we thus have the number of non-@xmath103-involved mergings is upper bounded by @xmath611 now , combining all the cases above , we then have established the upper bound direction : @xmath612 first , consider the following @xmath516-graph @xmath0 with distinct sources @xmath517 , sinks @xmath518 , a menger s path @xmath23 from @xmath5 to @xmath6 for @xmath519 , two menger s paths @xmath520 from @xmath521 to @xmath522 such that * every merging in @xmath0 is by exactly two paths ; * for @xmath89 , @xmath23 first merges with @xmath146 at @xmath613 , and then merges with @xmath134 at @xmath614 ; * for any @xmath615 , @xmath23 is smaller than @xmath542 ; * for any @xmath616 , @xmath23 merges with @xmath617 at @xmath618 such that @xmath618 is larger than @xmath614 and smaller than @xmath619 ; * there are no other mergings
. see figure [ picm1k12twocases](a ) for an example .
it can be verified that the above @xmath0 is a non - reroutable @xmath516-graph with @xmath620 mergings , which implies that @xmath621 next , consider the following @xmath516-graph @xmath0 with distinct sources @xmath517 , sinks @xmath518 , a menger s path @xmath23 from @xmath5 to @xmath6 for @xmath519 , two menger s paths @xmath520 from @xmath521 to @xmath522 such that * every merging in @xmath0 is by exactly two paths ; * for @xmath622 , @xmath623 , @xmath23 merges with @xmath542 at @xmath624 ; * for any @xmath625 and any @xmath626 , @xmath627 is smaller than @xmath628 ; * for any @xmath629 and any @xmath630 , @xmath631 is smaller than @xmath632 ; * for @xmath623 , @xmath146 merges with @xmath542 at @xmath633 such that @xmath633 is larger than @xmath634 ; * for @xmath622 , @xmath134 merges with @xmath23 at @xmath635 such that @xmath635 is smaller than @xmath636 ; * @xmath146 merges with @xmath637 at @xmath638 such that @xmath638 is smaller than @xmath639 and @xmath640 ; * @xmath134 merges with @xmath504 at @xmath641 such that @xmath641 is larger than @xmath642 and @xmath643 ; * there are no other mergings
. see figure [ picm1k12twocases](b ) for an example .
it can be verified that the above @xmath0 is a non - reroutable @xmath516-graph with @xmath644 mergings , which implies that @xmath645 combining ( [ greater-1 ] ) and ( [ greater-2 ] ) , we then have established the lower bound direction .
@xmath646 for the `` @xmath647 '' direction , it follows from @xcite that @xmath648 next , we show that the following @xmath649-graph @xmath0 , which has distinct sources @xmath650 and sinks @xmath651 , is non - reroutable with @xmath652 mergings .
the graph @xmath0 ( see figure [ picm11113 ] for an example ) can be described as follows : * there is a path @xmath23 from @xmath5 to @xmath6 for @xmath519 and @xmath121 menger s paths @xmath653 from @xmath521 to @xmath522 ; * for any feasible @xmath654 , @xmath23 merges with @xmath126 exactly once at the merging @xmath655 ; * for any feasible @xmath654 , @xmath23 in @xmath538 or @xmath656 merges with @xmath542 in @xmath533 exactly once at the merging @xmath657 , where @xmath658 here , @xmath659 , @xmath660 , @xmath661 ; * the mergings on each path can be sequentially listed in the ascending order as follows : + for @xmath519 , @xmath662 for @xmath663 , @xmath664 for @xmath665 , @xmath666 for @xmath667 , @xmath668 it can be checked that @xmath0 is non - reroutable with @xmath669 -graph with 16 mergings , scaledwidth=54.0% ]
in this section , we will construct a non - reroutable @xmath671-graph @xmath672 with one source @xmath37 , two sinks @xmath38 , a set of menger s paths @xmath673 from @xmath37 to @xmath40 , a set of menger s paths @xmath674 from @xmath37 to @xmath41 and @xmath675 mergings for any positive integer @xmath121 , thus giving a lower bound on @xmath670 .
the graph @xmath672 can be described as follows : for each @xmath676 , paths @xmath125 and @xmath144 share a starting subpath @xmath263 .
after @xmath677 , path @xmath678 does not merge any more , directly `` flowing '' to @xmath40 ; after @xmath679 , path @xmath680 does not merge any more , directly `` flowing '' to @xmath41 .
the rest of the graph can be determined how paths @xmath681 merge with @xmath682 . in more detail , for a given @xmath121
, we define @xmath683 and @xmath684 it can be checked that all @xmath685 s , @xmath686 s are distinct and @xmath687 now we define a mapping @xmath688 by @xmath689 then the merging sequence of the rest of the graph can be defined as @xmath690.\ ] ] for example , @xmath691 , as illustrated in figure [ picmstar44 ] , is determined by the merging sequence @xmath692.\ ] ] now , we prove that with @xmath282 mergings , scaledwidth=50.0% ] [ fnn ] @xmath672 is non - reroutable .
let @xmath693 . for each @xmath694
, label each merging @xmath695 in the merging sequence as @xmath696 ( it can be easily checked that no two mergings share the same label ) .
we only prove that there is only one possible set of menger s paths from @xmath37 to @xmath40 .
the uniqueness of menger s path sets from @xmath37 to @xmath41 can be established using a parallel argument .
let @xmath697 be an arbitrary yet fixed set of menger s paths from @xmath37 to @xmath40 .
it suffices to prove that @xmath697 is non - reroutable .
note that each path in @xmath697 must end with either @xmath698 or @xmath699 , @xmath700 ( here and hereafter , slightly abusing the notations `` @xmath701 '' and `` @xmath702 '' , for paths ( or vertices ) @xmath703 , we use @xmath704 or @xmath705 to denote the path which sequentially passes through @xmath706 ; it can be checked that in this proof such an expression uniquely determines a path ) . in @xmath697 , label the menger s path ending with @xmath699 as the @xmath63-th menger s path for @xmath707 , and the menger s path ending with @xmath698 as the @xmath206-th one .
it is obvious that in @xmath708 , there is only one path ending with @xmath698 , which implies that the @xmath206-th menger s path in @xmath697 is `` fixed '' ( as @xmath709 ) ; or , more rigorously , for any set of menger s paths @xmath710 , the @xmath206-th menger s path in @xmath710 is the same as the @xmath206-th one in @xmath697 .
so , for the purpose of choosing other menger s paths , all the edges on @xmath709 are `` occupied '' .
it then follows that , in @xmath697 , @xmath711 must `` come '' from @xmath712 ; more precisely , in @xmath697 , @xmath712 is smaller than @xmath711 on the @xmath713-th path and there is no other merging between them on this path .
now , all the edges on @xmath714 are occupied .
inductively , only considering unoccupied edges , one can check that for @xmath715 , @xmath716 must come from @xmath717 ; in other words , for @xmath715 , the @xmath63-th menger s path must end with @xmath718 .
it then follows that the @xmath719-th menger s path must come from @xmath720 ; so , the @xmath719-th menger s path is fixed as @xmath721 .
we now proceed by induction on @xmath505 , @xmath722 .
suppose that , for @xmath723 , the @xmath63-th menger s path is already fixed ( and hence the edges on these paths are all occupied ) , and for @xmath724 , the @xmath63-th menger s path ends with @xmath725 ( so , the edges on these paths are all occupied ) . only considering the unoccupied edges , one checks that for @xmath726
, @xmath727 must come from @xmath728 .
it then follows that the menger s path , which ends with @xmath729 , must come from @xmath730 .
so , the @xmath505-th menger s path can now be fixed as @xmath731 .
now , for @xmath732 , the @xmath63-th menger s path is fixed , and for @xmath726 , the @xmath63-th menger s path must end with @xmath733 .
it follows from the above inductive argument that for @xmath734 , the @xmath63-th menger s path is fixed , and the @xmath713-th menger s path must end with @xmath735 @xmath736 @xmath737 @xmath738 .
one then checks that the @xmath739 must come from @xmath679 , which implies that the @xmath713-th menger s path is fixed as @xmath740 .
the proof of uniqueness of menger s path set from @xmath37 to @xmath40 is then complete .
the above lemma then immediately implies that [ lowerboundmstar ] @xmath741 the following theorem gives an upper bound on @xmath143 .
first , we remind the reader that , by proposition @xmath141 in @xcite , @xmath742 for any @xmath743 . @xmath744 consider any @xmath671-graph @xmath0 with one source @xmath37 , sinks @xmath38 , a set of menger s paths
@xmath745 from @xmath37 to @xmath40 , a set of menger s paths @xmath136 from @xmath37 to @xmath41 .
as discussed in section [ aa - sequences ] , we assume that , for @xmath746 , paths @xmath125 and @xmath144 share a starting subpath , and paths @xmath145 and @xmath680 do not merge with any other paths , directly flowing to the sinks ( then , necessarily , each @xmath103-aa - sequence is of positive length , and by lemma [ lengthofaasequence ] , the shortest @xmath103-aa - sequence is of length @xmath163 ) .
we say that the path pair @xmath747 is _ matched _ if @xmath748 , otherwise , _
unmatched_. apparently , each starting subpath corresponds to a matched path pair ; and among the set of all path pairs , each of which corresponds some merging in @xmath0 , there are at most @xmath749 matched and at most @xmath750 unmatched .
we then consider the following two cases ( note that the following two cases may not be mutually exclusive ) : there exists a shortest @xmath103-aa - sequence associated with a matched path pair . by lemma
[ each - path - pair - at - most - once ] and the fact that each starting subpath corresponds to a matched path pair , there are at most @xmath751 mergings corresponding to this path pair , at most @xmath752 corresponding to any other matched path pair , and at most @xmath751 mergings corresponding to any unmatched .
so , the number of mergings is upper bounded by @xmath753 there exists a shortest @xmath103-aa - sequence associated with an unmatched path pair .
again , by lemma [ each - path - pair - at - most - once ] and the fact that each starting subpath corresponds to a matched path pair , there are at most @xmath754 mergings corresponding to this path pair , at most @xmath751 mergings corresponding to any other unmatched path pair , and at most @xmath752 mergings corresponding to any matched .
so , the number of mergings is upper bounded by @xmath755 then @xmath756 . for odd @xmath121 , ( [ mstarbound - i ] ) is larger than ( [ mstarbound - ii ] ) , so we have @xmath757 for even @xmath121 , ( [ mstarbound - ii ] ) is larger than ( [ mstarbound - i ] ) , so we have @xmath758 the proof is then complete .
consider the following @xmath671-graph @xmath760 with distinct sources @xmath109 , sinks @xmath38 , a set of menger s paths @xmath745 from @xmath48 to @xmath40 ,
a set of menger s paths @xmath136 from @xmath49 to @xmath41 , and a merging sequence @xmath761 $ ] , where @xmath762_n , i+1 ) & \mathrm{if}\ k=2i(n-1)+j\quad \\ & \mathrm{for } \ ( 0\le i\le n-1 , 1\le j\le n-1)\ \mathrm{or}\ ( i = n-1,j = n),\\ ( n - i,[i - j+2]_n ) & \mathrm{if}\ k=(2i+1)(n-1)+j\quad \mathrm{for } \ 0\le i\le n-2 , 1\le j\le n-1 , \end{array } \right.\ ] ] where , for any integer @xmath186 , @xmath185_n$ ] denotes the least strictly positive residue of @xmath186 modulo @xmath121 . for a quick example , see @xmath763 in figure [ pic33blockwithsplitted](a ) , whose merging sequence is @xmath764.\end{aligned}\ ] ] then , similar to the proof of lemma [ fnn ] , through verifying the uniqueness of the set of menger s paths from @xmath5 to @xmath6 , we can show that @xmath760 is non - reroutable . consider a non - reroutable @xmath765-graph @xmath766 with distinct sources @xmath767 , sinks @xmath768 , a set of menger s paths @xmath769 from @xmath770 to @xmath771 , a set of menger s paths @xmath772 from @xmath773 to @xmath774 . for a fixed merging sequence of @xmath766 , assume , without loss of generality , that the first element is @xmath775 .
now , we consider the following procedure of concatenating graphs @xmath760 and @xmath776 to obtain a new graph : 1 .
split @xmath40 into @xmath121 copies @xmath777 such that path @xmath125 has the ending point @xmath778 ; split @xmath41 into @xmath121 copies @xmath779 such that path @xmath144 has the ending point @xmath780 ; 2 .
split @xmath770 into @xmath14 copies @xmath781 such that path @xmath782 has the starting point @xmath783 ; split @xmath773 into @xmath121 copies @xmath784 such that path @xmath144 has the starting point @xmath785 ; 3 .
delete all edges on @xmath195 and all edges on @xmath786 , each of which is larger than merging @xmath787 to obtain new @xmath195 and @xmath786 ; 4 .
delete all edges on @xmath788 and all edges on @xmath789 , each of which is smaller than merging @xmath790 to obtain new @xmath788 and @xmath789 ; 5 .
concatenate @xmath195 and @xmath791 to obtain @xmath792 ( so , necessarily , @xmath786 and @xmath789 are concatenated simultaneously and we obtain @xmath793 ) ; 6 .
identify @xmath794 ; identify @xmath795 ; identify @xmath780 and @xmath785 for @xmath796 . obviously , such procedure produces a @xmath797-graph with two distinct sources @xmath798 and two sinks @xmath771 and @xmath774 , a set of menger s paths
@xmath799 from @xmath48 to @xmath771 and a set of menger s paths @xmath800 from @xmath49 to @xmath774 .
for example , in figure [ picconcatenation ] , we concatenate @xmath801 and a non - reroutable @xmath377-graph to obtain a @xmath802-graph .
we have the following lemma , whose proof is similar to lemma [ fnn ] and thus omitted . with @xmath803 mergings
( b ) splitting of @xmath40 in @xmath763,scaledwidth=65.0% ] [ concatenationlemma ] the concatenated graph as above is a non - reroutable @xmath804-graph with the number of mergings equal to @xmath805 .
we are now ready for the following theorem , which gives us a lower bound on @xmath140 .
[ mmnlb ] @xmath806 without loss of generality , assume that @xmath807 . for @xmath808 and @xmath809
, we will iteratively construct a sequence of non - reroutable @xmath810-graphs with @xmath811 mergings , which immediately implies the theorem .
first , for any @xmath14 , @xmath812 , a non - reroutable @xmath813-graph can be given by specifying its mergings sequence @xmath814.\ ] ] next , consider the case @xmath815 .
assume that for any @xmath816 such that @xmath817 , @xmath818 , @xmath819 , however @xmath820 , we have constructed a non - reroutable @xmath810-graph , which is effectively a non - reroutable @xmath821-graph as well .
we obtain a new @xmath117-graph through the following procedure : 1 . if @xmath142 , concatenate @xmath822 and an already constructed non - reroutable @xmath823-graph @xmath824 ; 2 . if @xmath825 , concatenate @xmath822 and an already constructed non - reroutable @xmath826-graph .
for the first case , according to lemma [ concatenationlemma ] , the obtained graph is non - reroutable @xmath827-graph with the number of mergings @xmath828 similarly , for the second case , the obtained graph is a non - reroutable @xmath117-graph with the number of mergings @xmath829 we then have established the theorem . and a non - reroutable @xmath377-graph , scaledwidth=70.0% ] to construct a non - reroutable @xmath830-graph with @xmath831 mergings , one can concatenate @xmath832 and a non - reroutable @xmath833-graph , which can be obtained by concatenating @xmath834 and a non - reroutable @xmath459-graph .
the latter can be obtained by concatenating @xmath835 and a non - reroutable @xmath133-graph .
finally , a non - reroutable @xmath133-graph can be obtained by concatenating @xmath835 and @xmath836 .
one readily checks that the number of mergings in the eventually obtained graph is @xmath837 @xmath838 consider any @xmath117-graph @xmath0 with distinct sources @xmath109 , sinks @xmath38 , a set of menger s paths @xmath135 from @xmath48 to @xmath40 , a set of menger s paths @xmath136 from @xmath49 to @xmath41 . as discussed in section [ aa - sequences ] , we assume that all the aa - sequences are of positive lengths . by lemma [ lengthofaasequence ] ,
the shortest @xmath102-aa - sequence and @xmath103-aa - sequence are both of length @xmath163 .
we then consider the following two cases ( note that the following two cases may not be mutually exclusive ) : there exists a shortest @xmath102-aa - sequence and a shortest @xmath103-aa - sequence , which are associated with the same path pair . by lemma
[ each - path - pair - at - most - once ] , there are at most @xmath839 mergings corresponding to this path pair , and at most @xmath840 mergings corresponding to any other path pair .
so , the number of mergings is upper bounded by@xmath841 there exists a shortest @xmath102-aa - sequence and a shortest @xmath103-aa - sequence , which are associated with two distinct path pairs .
again , by lemma [ each - path - pair - at - most - once ] , there are at most @xmath842 mergings corresponding to each of these two path pairs , and at most @xmath840 mergings corresponding to any other path pair .
so , the number of mergings is upper bounded by @xmath843 then , @xmath844 .
straightforward computations then lead to the theorem .
it has been established in @xcite that @xmath845 summarizing all the four bounds we obtain , we have @xmath846 it has been shown in @xcite that for any @xmath14 , there exists @xmath848 such that @xmath849 for all @xmath121 , where @xmath848 can be rather loose .
the following result refines the above result for the case when @xmath850 .
@xmath851 consider any non - reroutable @xmath852-graph @xmath0 with distinct sources @xmath109 , sinks @xmath38 , a set of menger s paths @xmath853 from @xmath48 to @xmath40 and a set of menger s paths @xmath854 from @xmath49 to @xmath41 .
if a merging is the smallest ( the largest ) one on a @xmath855-path , we say it is an _ @xmath186-terminal _ ( _ @xmath219-terminal _ ) merging on the @xmath855-path , or simply a _
@xmath855-terminal _ merging .
consider the following iterative procedure ( figures [ pic14mergings ] , [ pic3ncase1 ] and [ pic3ncase2 ] roughly illustrate the procedure ) , where , for notational simplicity , we treat a graph as a union of its vertex set and edge set . initially set @xmath856 , and @xmath857 . now for each @xmath272 , pick a merging @xmath858 such that @xmath858 belongs to path @xmath859 and @xmath860 where one can choose @xmath858 to be @xmath48 if such merged subpath does not exist on @xmath859 .
now set @xmath861 and @xmath862 suppose that we already obtain @xmath863 and @xmath864 where @xmath865 contains exactly 14 mergings and at least two @xmath855-terminal merged subpaths .
we then continue to pick merged subpath @xmath696 on @xmath859 from @xmath866 such that @xmath867 and there are at least two @xmath855-terminal mergings in @xmath868 . if such @xmath869 s exist , set @xmath870 and if @xmath871 , set @xmath872 and terminate the iterative procedure .
so far , for any obtained `` block '' @xmath873 , either we have @xmath874 or ( @xmath875 and there are at least two @xmath855-terminal mergings in @xmath873 ) ; such block @xmath873 is said to be _
normal_. if @xmath876 , however , we can not find a normal block , we continue the procedure and define a _ singular _
@xmath873 in the following .
-graph @xmath0 into blocks , scaledwidth=55.0% ] note that @xmath877 .
let @xmath878 , where @xmath220 and @xmath209 denote the number of @xmath186-terminal and @xmath219-terminal mergings in the @xmath855-paths in @xmath865 , respectively ; then @xmath879 is the number of @xmath103-paths which can continue to merge within @xmath866 .
if a normal block does not exist after @xmath63 iterations , necessarily we will have @xmath880 ( suppose @xmath881 , by the fact that @xmath882 ( see theorem [ m33 ] ) , we would be able to obtain a normal block @xmath873 , which contains two @xmath186-terminals or ( an @xmath186-terminal and a @xmath219-terminal ) ) .
we say a merged subpath is _ critical _ within a subgraph of @xmath0 if the corresponding @xmath103-path , after merging at this merged subpath , does not merge anymore within this subgraph .
it then follows that the number of the critical merged subpaths within @xmath883 is @xmath879 .
now , let @xmath884 denote the set of all the merged subpaths within @xmath866 , each of which can semi - reach the tail of some critical merged subpath within @xmath883 against @xmath103 .
one checks at least one of those @xmath102-paths , each of which contains at least one critical merged subpath within @xmath883 , does not contain any merged subpath within @xmath884 . without loss of generality , we assume that @xmath885 .
now we consider the following two cases : @xmath886 and @xmath887 .
as shown in figure [ pic3ncase1 ] , assume that within @xmath884 , @xmath888 are the largest merged subpaths on @xmath889 , respectively .
now , set @xmath890\cup { \phi}_2[t(\gamma_{i-1,2}),t(\lambda_{i,2})].\ ] ] note that for @xmath655 , @xmath891 , the associated @xmath103-path , from @xmath655 , may merge outside @xmath892 next time . if this @xmath103-path merges within @xmath892 again after a number of mergings outside @xmath892 , we call it an _ excursive _ @xmath103-path .
one checks that there are at most one excursive @xmath103-path ( since , otherwise , we can find a cycle in @xmath0 , which is a contradiction ) . on the other hand , for any merged subpath from @xmath884 other than @xmath888 , say @xmath98 , the associated @xmath103-path , from @xmath98 ,
can only merge within @xmath892 and will not merge outside @xmath892 .
so , the number of * connected * @xmath103-paths that contain at least one merged subpath within @xmath893 is upper bounded by @xmath894 .
then , by the fact that @xmath895 ( see theorem [ threeproofs ] ) , we have latexmath:[\[\label{with - t } it is clear that all non - excursive @xmath103-paths that contain at least one merged subpath within @xmath897 must have @xmath186-terminals in @xmath873
. thus , again by the fact that @xmath895 , we have @xmath898 ) and ( [ not - with - t ] ) that @xmath899 next , we claim that @xmath900 . to see this , suppose , by contradiction , that @xmath901 . observing that @xmath902 , we then consider the following two cases : if @xmath903 , we have @xmath904 which implies that we can continue to choose a normal block ( with two @xmath855-terminal merged subpaths ) , a contradiction . if @xmath905 , we have @xmath906 , @xmath907 .
note that if there is no excursive @xmath103-path , we have @xmath908 ; if there is one excursive @xmath103-path , then @xmath909 .
this , together with @xmath910 , implies that @xmath911 and there is no excursive @xmath103-path .
consequently , we have @xmath912 but this , together with @xmath882 , implies that we can continue to choose a normal block with an @xmath186-terminal and a @xmath219-terminal merged subpaths , which is a contradiction .
@xmath886 and @xmath913 .
as shown in figure [ pic3ncase2 ] , assume that within @xmath884 , @xmath914 is the largest merged subpath on @xmath915 .
apparently , there is no excursive @xmath103-path . by the fact that @xmath916 ( see example @xmath917 of @xcite ) and @xmath918 , we have @xmath919 it then immediately follows that @xmath920 .
similarly as before , we claim that @xmath921 . to see this ,
suppose , by contradiction , that @xmath901 . from @xmath922
, we infer that @xmath923 and @xmath906 , and further @xmath924 which implies that we can in fact obtain a normal block , a contradiction . combining the above two cases , we conclude that the number of merged subpaths within the singular block @xmath873 is upper bounded by @xmath925 , where @xmath921 .
we continue these operations in an iterative fashion to further obtain normal blocks and singular blocks until there are no merged subpaths left in the graph .
suppose there are @xmath926 singular blocks @xmath927 and @xmath928 normal blocks .
note that each singular block has at least three @xmath855-terminal merged subpaths and each normal block except the last one has at least two @xmath855-terminal merged subpaths .
if the last normal block has at least two @xmath103-terminal merged subpaths , we then have @xmath929 it then follows that latexmath:[\[\label{last - one - has - more - than - one } if the last normal block has only one @xmath103-terminal merged subpath , necessarily , there are at most three mergings in the last normal block , we then have @xmath931 it then follows that @xmath932 ) and ( [ last - one - has - only - one ] ) , we then have established the theorem .
consider two non - reroutable @xmath671-graph @xmath933 .
for @xmath891 , assume that @xmath934 has one source @xmath935 , two sinks @xmath936 .
let @xmath937 denote the set of menger s paths from @xmath935 to @xmath938 and @xmath939 denote the set of menger s paths from @xmath935 to @xmath940 .
as before , we assume that , for @xmath746 , paths @xmath941 and @xmath942 share a starting subpath . 1 .
reverse the direction of each edge in @xmath944 to obtain a new graph @xmath945 ( for @xmath946 , path @xmath947 in @xmath944 becomes path @xmath948 in @xmath945 and path @xmath949 in @xmath944 becomes path @xmath950 in @xmath945 ) ; 2 .
split @xmath951 into @xmath121 copies @xmath952 in @xmath943 such that paths @xmath953 and @xmath954 have the same starting point @xmath955 ; split @xmath956 into @xmath121 copies @xmath957 in @xmath945 such that paths @xmath948 and @xmath950 have the same ending point @xmath958 ; 3 . for @xmath959 ,
identify @xmath955 and @xmath958 .
obviously , such procedure produces an @xmath671-graph with two distinct sources @xmath960 , two sinks @xmath961 , a set of menger s paths @xmath962 from @xmath963 to @xmath964 and a set of menger s paths @xmath965 from @xmath966 to @xmath967 .
see figure [ pictwomstar ] for an example where we concatenate two @xmath968-graphs .
consider a non - reroutable @xmath971-graph @xmath943 and a non - reroutable @xmath972-graph @xmath944 .
the graph @xmath943 has one source @xmath951 , two sinks @xmath973 , a set of menger s paths @xmath974 from @xmath951 to @xmath964 and a set of menger s paths @xmath975 from @xmath951 to @xmath967 . as discussed in section
[ aa - sequences ] , we assume paths @xmath125 and @xmath144 share a starting subpath @xmath263 , and paths @xmath145 , @xmath680 do not merge with any other paths in @xmath943 , directly flowing to the sinks .
the graph @xmath944 has one source @xmath956 , two sinks @xmath976 , a set of menger s paths @xmath977 from @xmath956 to @xmath963 and a set of menger s paths @xmath978 from @xmath956 to @xmath966 .
again , assume paths @xmath979 and @xmath980 share a starting subpath . 1 . reverse the direction of each edge in @xmath944 to obtain a new graph @xmath945 ( for @xmath796 , path @xmath979 in @xmath944 becomes path @xmath981 in @xmath945 and path @xmath980 in @xmath944 becomes path @xmath982 in @xmath945 ) ; 2 .
split @xmath951 into @xmath983 copies @xmath984 in @xmath943 such that paths @xmath125 and @xmath144 have the same starting point @xmath985 ; split @xmath956 into @xmath986 copies @xmath987 in @xmath945 such that paths @xmath981 and @xmath982 have the same ending point @xmath988 ; 3 . delete all edges on @xmath145 , each of which is larger than @xmath989 ; delete all edges on @xmath680 , each of which is larger than @xmath679 ; 4 .
identify @xmath963 and @xmath990 ; for @xmath796 , identify @xmath958 and @xmath955 ; identify @xmath966 and @xmath991 .
obviously , such procedure produces an @xmath671-graph with two distinct sources @xmath960 , two sinks @xmath973 , a set of menger s paths @xmath992 from @xmath963 to @xmath964 and a set of menger s paths @xmath993 from @xmath966 to @xmath967 .
for example , in figure [ picmstar4422 ] , we concatenate a @xmath377-graph and a @xmath994-graph to obtain a @xmath968-graph .
consider @xmath997 .
for @xmath998 , consider a non - reroutable @xmath999-graph @xmath934 with one source @xmath935 , two sinks @xmath1000 , a set of menger s paths @xmath1001 from @xmath935 to @xmath1002 and a set of menger s paths @xmath1003 from @xmath935 to @xmath1004 .
as before , we assume that paths @xmath1005 and @xmath1006 share a starting subpath for @xmath1007 . 1
. for @xmath1009 , split @xmath1004 into @xmath1010 copies @xmath1011 such that path @xmath1006 has the ending point @xmath1012 ; 2 . for @xmath1013 , split @xmath935 into @xmath1010 copies @xmath1014 such that paths @xmath1005 and @xmath1006 have the same starting point @xmath1015 ; 3 . for @xmath1009 and @xmath1016 ,
identify @xmath1012 and @xmath1017 .
relabel @xmath1018 as @xmath1019 , respectively .
we then have an @xmath1020-graph with one source @xmath37 , @xmath14 sinks @xmath1021 and a set of menger s paths @xmath1022 from @xmath37 to @xmath1002 for @xmath1023 , where @xmath1024[/INST] consider an acyclic directed network @xmath0 with sources @xmath1 and distinct sinks @xmath2 . for @xmath3 , let @xmath4 denote the min - cut between @xmath5 and @xmath6 . then , by menger s theorem , there exists a group of @xmath4 edge - disjoint paths from @xmath5 to @xmath6 , which will be referred to as a group of menger s paths from @xmath5 to @xmath6 in this paper .
although within the same group they are edge - disjoint , the menger s paths from different groups may have to merge with each other .
it is known that by choosing menger s paths appropriately , the number of mergings among different groups of menger s paths is always bounded by a constant , which is independent of the size and the topology of @xmath0 .
the tightest such constant for the all the above - mentioned networks is denoted by @xmath7 when all @xmath5 s are distinct , and by @xmath8 when all @xmath5 s are in fact identical .
it turns out that @xmath9 and @xmath10 are closely related to the network encoding complexity for a variety of networks , such as multicast networks , two - way networks and networks with multiple sessions of unicast . using this connection ,
we compute in this paper some exact values and bounds in network encoding complexity using a graph theoretical approach . </s> |
trauma patients are shown to have a high incidence of admission hypokalemia , which predicts the seriousness of trauma itself .
serum potassium decrease is particularly frequent in young patients with blunt head trauma or spinal cord trauma and has a worsening prognostic implication in terms of morbidity and mortality . concerning blunt abdominal trauma , significant
, no hypokalemia has been described in patients with other abdominal visceral injuries ( e.g. , spleen , mesentery ) [ 35 ] . besides elevation of serum aspartate and alanine aminotransferases ( ast and alt ) [ 6 , 7 ]
, there is evidence of a few - day - lasting hypokalemia [ 4 , 5 ] , despite the normal values of other serum electrolytes ( na , cl ) , daily urinary potassium and blood acid - base balance .
the aim of the present study is to investigate the evidence of hypokalemia as a suitable parameter for therapeutic decision making after severe blunt liver trauma .
we reviewed a personal series of 11 patients ( 9 m , 2 f , mean age 32 years ) admitted to san matteo hospital of pavia between 20072009 .
all of them were victims of road accidents and hospitalized for blunt liver injury ( iii - v grade according to moore organ injury scaling ) without any other abdominal visceral lesions associated ( table 1 ) . within the first 1224 hours from admission ,
they were all submitted to surgery for shock due to hemoperitoneum ( 9 cases ) or peritonitis due to choleperitoneum ( 2 cases ) , not curable otherwise . by perihepatic packing ( 8 cases ) or total vascular hepatic exclusion ( tvhe ) with an overall length of 50 minutes ( 1 case )
bleeding was controlled . in all cases to complete haemostasis and to stop bile leakage hepatic parenchymal or vascular lacerations were sutured .
one patient underwent hepatic resection of segment ii ; in two patients cholecystectomy was mandatory .
the postoperative course was uneventful in most cases ; four patients ( 36.4% ) had respiratory complications ( pleural effusion ) .
all patients recovered and were discharged after an average hospitalization of 12 days . with reference to pre- and postoperative serum potassium levels , hypokalemia was observed in 7 out of 11 ( 63.6% ) patients during the preoperative period ( mean value 2.91 meq / l ) . despite the proper serum electrolytes replacement ( na ,
k , cl , ca ) and the appropriate correction of the blood acid - base balance , hypokalemia was still observed in 8/11 ( 72.7% ) patients at the 1st postoperative day ( mean value 3.22 meq / l ) and in 3/11 ( 27.3% ) patients at the 3rd postoperative day ( mean value 3.3 meq / l ) . for all patients potassium levels returned to normal ( 3.55.3
moreover , the standard deviation values seem to indicate a convergent path to kalemia normalization after 1 week ( table 2 ) .
table 2 reports the sample statistics of kalemia at different frequencies for 11 patients affected by severe blunt liver injury . before surgical treatment the average level of serum potassium ( 3.36
meq / l ) is below the minimum threshold ( 3.55.3 meq / l ) . even if the mean value of kalemia ( 3.88
meq / l ) is normal after the 3rd operative day , the minimal value is still below the normal threshold .
moreover , after a week , kalemia variability ( 4.83.7 meq / l = 1.1 meq / l ) among patients is drastically reduced to half of the corresponding variability ( 4.32.1 meq / l = 2.2 meq / l ) before surgical treatment .
this suggests convergence of kalemia to normal values already after three days for the majority of patients .
these preliminary results require a formal investigation in order to assess their statistical significance . with this purpose , tests on the difference between the sample mean of kalemia
are then implemented to evaluate if the convergence to normal values , respectively , after one , three , and seven days , is statistically significant .
to realize this purpose , t - test and a nonparametric test , the wilcoxon signed rank test , that relaxes the gaussianity hypothesis of the observations , have been computed .
both tests strongly support the hypothesis that the level of potassium converges to the normal values after a week from surgery ( p values are close to 0.01 in both cases ) .
moreover , there is a significant improvement already after 3 days ( p values are close to 0.05 in both cases ) , while kalemia does not increase significantly , on average , after one day , remaining below the minimum threshold of the normality region .
meq / l ) and the maximum ( say 4.3 meq / l ) levels of potassium before surgical treatment .
the results , in terms of tests significance , are close to those obtained with the whole sample .
liver is a particularly vulnerable organ because of its size , the fixed position in the right hypochondrium , and the strict anatomical relationships with duodenum and pancreas .
patients must be carefully monitored in the intensive care unit , well equipped for rapid laboratory , radiologic ( ultrasound , computed tomography , arteriography ) and laparoscopic investigations in order to diagnose sudden risky complications , needing a prompt treatment [ 10 , 1214 ] .
emergency surgery is contemplate in case of complications , such as shock due to hemoperitoneum and peritonitis due to choleperitoneum or to other associated abdominal visceral lesions [ 15 , 16 ] .
after trauma implying hepatic parenchymal injury , the consequent cytolysis should cause hyperkalemia . on the contrary ,
this evidence could not be ascribed neither to a reduced intake nor to an abnormal potassium depletion .
it was rather assumed the hypothesis of an enhanced potassium transfer into the intracellular compartment , particularly into the hepatic one .
indeed , liver is provided with rich intraparenchymal adrenergic endings . in case of hepatic trauma ,
the stimulation of intrahepatic adrenergic fibres would cause ( nor)epinephrine release with consequent
2-adrenergic receptors stimulation .
this would lead to an increased cellular potassium uptake from the liver ( and muscles ) through a direct and an indirect mechanism ( hepatic glycogenolysis hyperglycemia insulin hyperincretion increased cellular uptake of glucose and potassium by way of membrane - bound na / k atpase stimulation ) [ 1 , 2 , 5 , 18 , 19 ] . the persistence of hypokalemia even after 2448 hours from hepatic trauma could be related to a temporary secondary hyperaldosteronism and to a slow reduction of ( nor)epinephrine levels . with reference to eleven patients belonging to our personal series (
table 1 ) , suffering from blunt liver trauma and being submitted to surgery because of complications due to parenchymal injury , in the preoperative period hypokalemia was severe ( mean value 2.91 meq / l ) in seven cases ( 63.6% ) . despite the adequate serum electrolyte replacement ( na , k , cl
, ca ) and the proper correction of the blood acid - base balance , hypokalemia was still moderate in eight patients ( 72.7% ) on the 1st postoperative day ( mean value 3.22 meq / l ) and in three patients on the 3rd postoperative day ( mean value 3.3 meq / l ) . only on the 7th postoperative day serum potassium level had completely normalized in all patients .
pre- and postoperative kalemia variations ( already after 3 days and after a week from surgery ) were statistically significant , with a p value close to 0.05 and 0.01 , respectively . according to literature results , our observations ,
although preliminary and numerically limited , seem to confirm that , after a severe blunt liver trauma , a reduction of serum potassium levels occurs as a plausible expression of the parenchymal damage seriousness . moreover , a serum potassium level increase is observed after seven days from surgery .
. this evidence should encourage further clinical research in this field in order to increase the sample size and to obtain definitive results .
finally , in case of surgical treatment , in contrast with some other extra - abdominal trauma ( blunt head trauma , spinal cord trauma ) [ 1 , 2 ] , hypokalemia , if adequately handled , does not play any worsening prognostic implication in terms of morbidity and mortality .
it remains of primary importance to remember that blunt liver injury can cause a statistically significant hypokalemia , even severe , whose normalization , despite appropriate treatment , could need up to one week .
therefore , it is important to monitor kalemia in patients with blunt liver trauma in order to prevent serious cardiac complications ( arrhythmia , heart failure ) [ 4 , 20 ] .
this recommendation seems to be useful not only in case of a surgical approach , but also when , according to clinical ( hemodynamic stability ; absence of peritonitis ) and radiological data , a nonoperative treatment is established [ 10 , 12 , 13 , 21 ] . | background .
the aim of this study is to investigate the evidence of hypokalemia as a suitable parameter for therapeutic decision making after severe blunt liver trauma . methods .
we reviewed the medical records of 11 patients ( 9 m , 2 f , mean age 32 years ) admitted to san matteo hospital of pavia between 20072009 .
all of them were victims of road accidents hospitalized for blunt liver injury and submitted to surgery .
results .
hypokalemia was observed in 7/11 ( 63.6% ) patients during the preoperative period ( mean value 2.91 meq / l ) .
serum potassium concentration normalized in all patients at the 7th postoperative day only ( p < 0.01 ) . conclusions . according to literature results
, our study confirms that after blunt hepatic injury serum potassium levels may decrease significantly .
therefore , kalemia must be carefully monitored in order to establish appropriate treatment and avoid any complications . | <s>[INST]trauma patients are shown to have a high incidence of admission hypokalemia , which predicts the seriousness of trauma itself .
serum potassium decrease is particularly frequent in young patients with blunt head trauma or spinal cord trauma and has a worsening prognostic implication in terms of morbidity and mortality . concerning blunt abdominal trauma , significant
, no hypokalemia has been described in patients with other abdominal visceral injuries ( e.g. , spleen , mesentery ) [ 35 ] . besides elevation of serum aspartate and alanine aminotransferases ( ast and alt ) [ 6 , 7 ]
, there is evidence of a few - day - lasting hypokalemia [ 4 , 5 ] , despite the normal values of other serum electrolytes ( na , cl ) , daily urinary potassium and blood acid - base balance .
the aim of the present study is to investigate the evidence of hypokalemia as a suitable parameter for therapeutic decision making after severe blunt liver trauma .
we reviewed a personal series of 11 patients ( 9 m , 2 f , mean age 32 years ) admitted to san matteo hospital of pavia between 20072009 .
all of them were victims of road accidents and hospitalized for blunt liver injury ( iii - v grade according to moore organ injury scaling ) without any other abdominal visceral lesions associated ( table 1 ) . within the first 1224 hours from admission ,
they were all submitted to surgery for shock due to hemoperitoneum ( 9 cases ) or peritonitis due to choleperitoneum ( 2 cases ) , not curable otherwise . by perihepatic packing ( 8 cases ) or total vascular hepatic exclusion ( tvhe ) with an overall length of 50 minutes ( 1 case )
bleeding was controlled . in all cases to complete haemostasis and to stop bile leakage hepatic parenchymal or vascular lacerations were sutured .
one patient underwent hepatic resection of segment ii ; in two patients cholecystectomy was mandatory .
the postoperative course was uneventful in most cases ; four patients ( 36.4% ) had respiratory complications ( pleural effusion ) .
all patients recovered and were discharged after an average hospitalization of 12 days . with reference to pre- and postoperative serum potassium levels , hypokalemia was observed in 7 out of 11 ( 63.6% ) patients during the preoperative period ( mean value 2.91 meq / l ) . despite the proper serum electrolytes replacement ( na ,
k , cl , ca ) and the appropriate correction of the blood acid - base balance , hypokalemia was still observed in 8/11 ( 72.7% ) patients at the 1st postoperative day ( mean value 3.22 meq / l ) and in 3/11 ( 27.3% ) patients at the 3rd postoperative day ( mean value 3.3 meq / l ) . for all patients potassium levels returned to normal ( 3.55.3
moreover , the standard deviation values seem to indicate a convergent path to kalemia normalization after 1 week ( table 2 ) .
table 2 reports the sample statistics of kalemia at different frequencies for 11 patients affected by severe blunt liver injury . before surgical treatment the average level of serum potassium ( 3.36
meq / l ) is below the minimum threshold ( 3.55.3 meq / l ) . even if the mean value of kalemia ( 3.88
meq / l ) is normal after the 3rd operative day , the minimal value is still below the normal threshold .
moreover , after a week , kalemia variability ( 4.83.7 meq / l = 1.1 meq / l ) among patients is drastically reduced to half of the corresponding variability ( 4.32.1 meq / l = 2.2 meq / l ) before surgical treatment .
this suggests convergence of kalemia to normal values already after three days for the majority of patients .
these preliminary results require a formal investigation in order to assess their statistical significance . with this purpose , tests on the difference between the sample mean of kalemia
are then implemented to evaluate if the convergence to normal values , respectively , after one , three , and seven days , is statistically significant .
to realize this purpose , t - test and a nonparametric test , the wilcoxon signed rank test , that relaxes the gaussianity hypothesis of the observations , have been computed .
both tests strongly support the hypothesis that the level of potassium converges to the normal values after a week from surgery ( p values are close to 0.01 in both cases ) .
moreover , there is a significant improvement already after 3 days ( p values are close to 0.05 in both cases ) , while kalemia does not increase significantly , on average , after one day , remaining below the minimum threshold of the normality region .
meq / l ) and the maximum ( say 4.3 meq / l ) levels of potassium before surgical treatment .
the results , in terms of tests significance , are close to those obtained with the whole sample .
liver is a particularly vulnerable organ because of its size , the fixed position in the right hypochondrium , and the strict anatomical relationships with duodenum and pancreas .
patients must be carefully monitored in the intensive care unit , well equipped for rapid laboratory , radiologic ( ultrasound , computed tomography , arteriography ) and laparoscopic investigations in order to diagnose sudden risky complications , needing a prompt treatment [ 10 , 1214 ] .
emergency surgery is contemplate in case of complications , such as shock due to hemoperitoneum and peritonitis due to choleperitoneum or to other associated abdominal visceral lesions [ 15 , 16 ] .
after trauma implying hepatic parenchymal injury , the consequent cytolysis should cause hyperkalemia . on the contrary ,
this evidence could not be ascribed neither to a reduced intake nor to an abnormal potassium depletion .
it was rather assumed the hypothesis of an enhanced potassium transfer into the intracellular compartment , particularly into the hepatic one .
indeed , liver is provided with rich intraparenchymal adrenergic endings . in case of hepatic trauma ,
the stimulation of intrahepatic adrenergic fibres would cause ( nor)epinephrine release with consequent
2-adrenergic receptors stimulation .
this would lead to an increased cellular potassium uptake from the liver ( and muscles ) through a direct and an indirect mechanism ( hepatic glycogenolysis hyperglycemia insulin hyperincretion increased cellular uptake of glucose and potassium by way of membrane - bound na / k atpase stimulation ) [ 1 , 2 , 5 , 18 , 19 ] . the persistence of hypokalemia even after 2448 hours from hepatic trauma could be related to a temporary secondary hyperaldosteronism and to a slow reduction of ( nor)epinephrine levels . with reference to eleven patients belonging to our personal series (
table 1 ) , suffering from blunt liver trauma and being submitted to surgery because of complications due to parenchymal injury , in the preoperative period hypokalemia was severe ( mean value 2.91 meq / l ) in seven cases ( 63.6% ) . despite the adequate serum electrolyte replacement ( na , k , cl
, ca ) and the proper correction of the blood acid - base balance , hypokalemia was still moderate in eight patients ( 72.7% ) on the 1st postoperative day ( mean value 3.22 meq / l ) and in three patients on the 3rd postoperative day ( mean value 3.3 meq / l ) . only on the 7th postoperative day serum potassium level had completely normalized in all patients .
pre- and postoperative kalemia variations ( already after 3 days and after a week from surgery ) were statistically significant , with a p value close to 0.05 and 0.01 , respectively . according to literature results , our observations ,
although preliminary and numerically limited , seem to confirm that , after a severe blunt liver trauma , a reduction of serum potassium levels occurs as a plausible expression of the parenchymal damage seriousness . moreover , a serum potassium level increase is observed after seven days from surgery .
. this evidence should encourage further clinical research in this field in order to increase the sample size and to obtain definitive results .
finally , in case of surgical treatment , in contrast with some other extra - abdominal trauma ( blunt head trauma , spinal cord trauma ) [ 1 , 2 ] , hypokalemia , if adequately handled , does not play any worsening prognostic implication in terms of morbidity and mortality .
it remains of primary importance to remember that blunt liver injury can cause a statistically significant hypokalemia , even severe , whose normalization , despite appropriate treatment , could need up to one week .
therefore , it is important to monitor kalemia in patients with blunt liver trauma in order to prevent serious cardiac complications ( arrhythmia , heart failure ) [ 4 , 20 ] .
this recommendation seems to be useful not only in case of a surgical approach , but also when , according to clinical ( hemodynamic stability ; absence of peritonitis ) and radiological data , a nonoperative treatment is established [ 10 , 12 , 13 , 21 ] .[/INST]background .
the aim of this study is to investigate the evidence of hypokalemia as a suitable parameter for therapeutic decision making after severe blunt liver trauma . methods .
we reviewed the medical records of 11 patients ( 9 m , 2 f , mean age 32 years ) admitted to san matteo hospital of pavia between 20072009 .
all of them were victims of road accidents hospitalized for blunt liver injury and submitted to surgery .
results .
hypokalemia was observed in 7/11 ( 63.6% ) patients during the preoperative period ( mean value 2.91 meq / l ) .
serum potassium concentration normalized in all patients at the 7th postoperative day only ( p < 0.01 ) . conclusions . according to literature results
, our study confirms that after blunt hepatic injury serum potassium levels may decrease significantly .
therefore , kalemia must be carefully monitored in order to establish appropriate treatment and avoid any complications .</s> |
null | alphavirus - based replicon systems are frequently used as preclinical vectors and as antigen discovery tools , and they have recently been assessed in clinical vaccine trials . typically , alphavirus replicon rnas are delivered within virus - like replicon particles ( vrp ) that are produced following transfection of replicon rna and two helper rnas into permissive cells in vitro .
the non - structural proteins expressed from the replicon rna amplify the replicon rna in cis and the helper rnas in trans , the latter providing the viral structural proteins necessary to package the replicon rna into vrp .
current helper rna designs incorporate the alphavirus 26s promoter to direct the transcription of high levels of structural gene mrnas .
we demonstrate here that the 26s promoter is not required on helper rnas to produce vrp and propose that such promoterless helper rnas , by design , reduce the probability of generating replication - competent virus that may otherwise result from rna recombination . | <s>[INST]None[/INST]alphavirus - based replicon systems are frequently used as preclinical vectors and as antigen discovery tools , and they have recently been assessed in clinical vaccine trials . typically , alphavirus replicon rnas are delivered within virus - like replicon particles ( vrp ) that are produced following transfection of replicon rna and two helper rnas into permissive cells in vitro .
the non - structural proteins expressed from the replicon rna amplify the replicon rna in cis and the helper rnas in trans , the latter providing the viral structural proteins necessary to package the replicon rna into vrp .
current helper rna designs incorporate the alphavirus 26s promoter to direct the transcription of high levels of structural gene mrnas .
we demonstrate here that the 26s promoter is not required on helper rnas to produce vrp and propose that such promoterless helper rnas , by design , reduce the probability of generating replication - competent virus that may otherwise result from rna recombination .</s> |
polyomavirus bk was first isolated 1971 from the urine of an asymptomatic renal transplant patient who was hospitalized with acute renal injury and with initials bk .
it is a deoxyribonucleic acid ( dna ) virus with circular double - stranded dna genome and a nonenveloped icosahedral capsid .
after primary infection , bk virus entered a latent state and resided in uroepitel cells .
in immunocompromised hosts , such as renal transplant patients , bk virus may reactivate and cause hemorrhagic cystitis and severe allograft dysfunction with acute tubulointerstitial nephritis [ 4 , 5 ] .
bk viruria has been associated with a variety of clinical manifestations , mostly with hemorrhagic cystitis , being associated with significant morbidity and mortality [ 6 , 7 ] .
importantly , bk virus infection could escalate from viruria to viremia to nephropathy . bk nephropathy began as a localized viral presence in the tubular epithelial cells of the kidney and progressed to a diffuse and destructive t - cell - mediated interstitial nephritis . about
50% of patients after hematopoietic bone marrow transplantation presented with bk viruria , usually within 2 months of transplantation [ 10 , 11 ] , with similar incidence in both autologous and allogenic recipients ( 3954% ) .
a 18-year - old patient with a history of matched - unrelated - donor peripheral blood stem cell transplantation ( mud - pbsct ) was admitted to the hospital because of renal failure . in november 2007
the patient was first diagnosed with acute lymphoblastic leukemia of t cells ( t - all ) at another institution , where he was treated with induction therapy according to hyper - cvad protocol ( cyclophosphamide 300 mg / m intravenously ( iv ) over 3 hours every 12 hours for six doses on days 1 through 3 , with mesna given by continuous infusion , vincristine 2 mg iv days 4 and 11 , doxorubicin 50 mg / m iv day 4 , and dexamethasone 40 mg daily on days 1 through 4 and 11 through 14 ) and was refractory when he presented in our department of hematology / oncology . the diagnosis of t - all has been confirmed , immunophenotype precursor t - all ( cd7 , cd3 , cd2 , cd4 , and cd8 pos ) , cytogenetic 46 , xy , fluorescein in sito hybridisation ( fish ) analysis 87% deletion of p16 on the chromosome 9 region p21 .
he was then treated with induction therapy according to the german multicenter all protocol ( gmall ) achieving only reduction of blasts after induction ii .
briefly , the induction in gmall protocol was composed of eight cytotoxic drugs administered sequentially in two phases over an 8-week period . during the first 4 weeks
( phase i ) , the patient received 60 mg / m prednisolone po daily ( days 1 through 28 ) plus 45 mg / m daunorubicin and 2 mg vincristine iv weekly ( days 1 , 8 , 15 , and 22 ) .
u / m ) was administered iv daily ( days 15 through 28 ) . in the second 4 weeks ( phase ii ) , the patient received two doses of 650 mg / m cyclophosphamide iv ( days 29 , 43 , and 57 ) together with 60 mg / m 6-mercaptopurine po daily ( days 29 through 57 ) and four courses of 75 mg / m cytarabine iv ( days 31 through 34 , 38 through 41 , 45 through 48 , and 52 through 55 ) .
he was then treated with nelarabine and achieved complete remission ( cr1 ) following mud - pbsct .
the conditioning consisted of total body irradiation ( tbi ) , 12 gy , given fractionated 2 times daily for three days , from day 6 to day 4 , and cyclophosphamide 60 mg / kg once daily i.v . on days 3 and 2 ( total dose 120 mg / kg b.w . ) . a human leukocyte antigen ( hla ) identical unrelated donor peripheral blood stem cells
graft - versus - host disease ( gvhd ) prophylaxis consisted of thymoglobulin ( 2 mg / kg b.w .
daily , from day 3 to 1 , total dose of 6 mg / kg b.w . )
, cyclosporine 5 mg / kg starting on day 1 , and methotrexate at days + 1 , + 3 , + 6 , and + 11 intravenously 15 mg absolute .
the bone marrow puncture on day + 28 showed a complete hematological remission with 100% donor chimerism .
along with the regeneration of white blood cells the patient developed a methylprednisolone - dependent gvhd of the skin and gastrointestinal , grade ii . after 10 days the therapy with corticosteroids
could be discontinued by rapid improvement of the gvhd - related symptoms . under the therapy with corticosteroids the patient developed a herpes simplex related oesophagitis on day 21 post transplant which was treated with 30 g daily over 5 days i.v .
the patient developed a hemorrhagic cystitis with high urine titers of bk polyoma virus and cmv infection .
a therapy with ganciclovir was initiated for ten days . under treatment with ganciclovir , cmv infection improved , and the treatment with cidofovir was started ( 1 mg / kg b.w . for two weeks ) .
the bk virus viruria and viremia improved , and the patient received ganciclovir treatment for additional two weeks ( figure 1 ) .
the cyclosporine level was from 200 to 150 from day 0 to day 30 , followed with level of 100 from day 30 to day 40 post transplant , and level of 50 from day 40 to day 50 .
the cyclosporine has been discontinued on day + 70 after mud - pbsct in absence of acute gvhd and as recommended in gmall protocol . on day
+ 48 after pbsct a cystoscopy with a continuous intravesical saline irrigation was started and discontinued 2 weeks later .
he was discharged from hospital ; his medications at the time of discharge included ciprofloxacin ( 250 mg twice daily ) , valacyclovir ( 500 mg twice daily ) , fluconazole ( 200 mg daily ) , folate , and cotrimoxazole twice weekly for prophylaxis of pneumocystis carinii infection .
over the next year the levels of urea nitrogen and creatinine gradually rose ( table 1 ) , which was attributed to drug toxicity .
blood pressure was 130/80 mmhg with 90 heart beats per minute , a temperature of 36.4c , and an oxygen saturation of 99% when the patient was breathing ambient air .
the lungs were clear , the results of the remainder of the examination were normal .
the complete blood count and levels of serum electrolytes , liver function tests , and levels of total protein and albumin were normal .
the urine sediment was not nephritic but contained a small amount of leukocytes indicating an inflammatory process such as cystitis .
ultrasonographic examination of the kidneys showed bilateral hydronephrosis stage iii - iv ( figure 2(a ) ) .
the hydronephrosis of the left kidney improved immediately and improved to grade ii in the right kidney . for histological examination tissues
the pathohistology of the specimen showed a chronic cystical urocystitis with bleedings ( figure 3(a ) ) .
tissue probes of both ureters were stained for sv40 large t antigen ( clone pab416 , oncogene science , boston , mass , usa ; dilution 1 : 100 , antigen retrieval and amplification with catalyzed system amplification , dako , carpinteria , ca ) .
the reactions were detected by means of the streptavidin - biotin method and were revealed using diaminobenzidine as a chromogen [ 15 , 16 ] . in
all tissue probes immunohistochemistry for large t antigen was negative ( figure 3(b ) ) .
the patient has undergone double - j catheter controls and changes every two months and is doing well 2 years after pbsct and 1 year after operative extirpation of tumours .
two different regions of the bkv genome were amplified by pcr , vp2 in serum and urine , and large t antigen from tissue biopsies .
nucleic acids were extracted from 200 microliter blood or urine using magnetic beads ( magna pure lc total na isolation kit , roche , mannheim , germany ) according to the manufacturer 's instructions while from formalin - fixed , paraffin - embedded material nucleic acids were extracted using the qiaamp dna ffpe tissue kit ( qiagen , hilden , germany ) .
pcr reaction was carried out in 20 microliter capillaries containing master mix ( 6 mm mgcl2 , 0.1 mg / ml bsa ( sigma , st .
louis , usa ) ) and 10 picom of each primer ( metabion , martinsried , germany ) , 3 picom of each hybridization probe ( 5-ggctgctgctgccacaggattttc - fl ( probe 1 ) and 5lc red640-gtagctgaaattgctgctggagag - ph ( probe 2 ) , 0.25 mm dntp 's ( roche ) ) , and 1u platinum taq polymerase ( invitrogen , karlsruhe , germany ) . target dna was added in a volume of 5 microliters .
two negative and 4 positive controls in different concentrations were included into each run performed on a lightcycler 1.0 instrument ( roche , mannheim , germany ) under the following conditions : initial denaturation and activation of hot - start enzyme at 95c for 30 s , followed by 45 cycles of denaturation at 95c for 0 s , annealing of primers at 58c for 10 s , and primer extension at 72c for 20 s. fluorescence was monitored by single acquisition during the annealing phase of each pcr cycle and channel setting f2/f1 ( 640 nm/530 nm ) .
differentiation of bk virus amplicons from jc virus depends on the binding of the probe 2 , which perfectly matches jc virus but differs at the two underlined positions from bk virus . thus binding to bk virus results in a shifted melting curve ( 61.5c for bk versus 63.8c for jc ) . for detection of the viral large t - antigen , a 128 bp
long fragment was amplified using modified primers from that match bkv genotypes 1 to 4 , forward primer 5-caggcaagggttctattactaaat-3 , reverse primer 5-gcaacagcagattcycaaca-3 , probe 5-6fam - aaactggtgtagatcagarggaaagtctttagggtctt - bbq .
pcr conditions were identical to the one described above except taqman probe that was used at 4 pico molar , primer annealing was 56c for 10 s , and fluorescence acquisition was at the end of each primer extension phase at 530 nm .
we described a young patient with precursor t - all who had received an unrelated matched donor pbsct and one year later presented with increase creatinine levels and bilateral hydronephrosis .
nephrological and urological examination showed an epithelial proliferation of bladder on both ostii being responsible for bilateral hydronephrosis .
we speculate that the endothelial cell injury led to capillary injury , oedema , and tumorous proliferation on both ostii .
this case demonstrated a very late ( one year after mud - hsct ) proliferative endothelial infection by a virus related to severe viral load and hemorrhagic cystitis 4 weeks after unrelated pbsct . although the tumour mass could not be unambiguously attributed to bkv since the staining of large t antigen was negative in immunohistochemical analysis , large t - cell antigen and bk virus were positive by pcr , thus supporting the view that bk virus may indeed play a role in the development of this tumour .
the oncogenic potential of bk virus has been well recognized [ 2 , 3 ] ; geetha et al .
reported the case of a simultaneous pancreas and kidney transplant recipient who developed bkv interstitial nephritis and carcinoma of the bladder with widespread metastasis .
for both the primary tumour and the metastasis , immunohistochemical staining for the large t - cell antigen showed strong nuclear positivity .
however , the diagnosis of the role of bk virus infection as a transient hit and run
agent is according to hirsch difficult to prove with the current diagnostic tools .
bk virus is an important pathogen and cause of nephropathy in renal transplant recipients , but its significance following pbsct is less well described .
recently , o'donnell et al . have shown in 124 allogeneic pbsct patients that bk viruria was manifest in 65% of the patients ; 17% of the patients developed viremia .
the median time from transplantation to bk viremia development was 128 days and was longer for viruria ( 24 days ) . among clinical factors such as sex , disease , transplant type , alemtuzumab use ,
cytomegalovirus viremia , graft - versus - host disease , and donor hla c7 allele , only cmv viremia was more common in patients with bk virus infection .
in addition , bk virus infection was analysed with other clinical factors related to the development of post - pbsct renal impairment .
on multivariate analysis , only bk viremia and alternative donor transplantation were independent predictors of development of post - hsct renal impairment .
there are numerous papers showing that there is no association between cmv and bkv reactivation .
one of the best examples is by hirsch et al . , 2002 nejm , where no cmv prophylaxis was given and only cmv seropositive and bkv seropositive kidney recipients were examined .
published the results on the incidence of bk virus in 102 children who underwent allogeneic hsct .
bk virus dna was detected in the urine of 47% children ; the only significant factor for hemorrhagic cystitis was high - dose chemotherapy .
the treatment included the use of cidofovir , which was feasible and without significant toxicity .
the evidence - based guidelines for clinical management include in addition to virus - specific therapy the use of estrogen or bladder instillation with alum salts or prostaglandin , as recently reviewed [ 2426 ] .
the transforming potential of bk virus infection has been noted early both in vitro culture models and in vivo .
one of the patients with bk virus - associated nephropathy after kidney transplantation reported by vats et al . presented with an echogenic renal mass that resolved with immunosuppression reduction and treatment with cidofovir .
contributing factors included drug toxicity around pbsct ( cyclosporine in particular ) , polyoma bk viruria , although it was not proven whether the kidneys were involved , and chronic hydronephrosis along with an inflammatory process due to the urine congestion . in summary , we could show an unusual case of late onset of bilateral hydronephrosis probably due to bk virus - induced tumorous bladder proliferation on both ostii in a young patient after mud - pbsct , successfully treated with operative incision and dj catheter . | we report here a case of acute lymphoblastic leukemia in remission presenting a late - onset bilateral hydronephrosis probably due to polyoma bk virus - induced proliferation of bladder endothelium on both ostii .
the diagnosis was made virologically by bk virus polymerase chain reaction ( pcr ) detection in the absence of any other bladder disease .
awareness of this late complication is necessary not only in patients after renal transplantation but also in patients after hematopoietic stem cell transplantation from matched unrelated donor . | <s>[INST]polyomavirus bk was first isolated 1971 from the urine of an asymptomatic renal transplant patient who was hospitalized with acute renal injury and with initials bk .
it is a deoxyribonucleic acid ( dna ) virus with circular double - stranded dna genome and a nonenveloped icosahedral capsid .
after primary infection , bk virus entered a latent state and resided in uroepitel cells .
in immunocompromised hosts , such as renal transplant patients , bk virus may reactivate and cause hemorrhagic cystitis and severe allograft dysfunction with acute tubulointerstitial nephritis [ 4 , 5 ] .
bk viruria has been associated with a variety of clinical manifestations , mostly with hemorrhagic cystitis , being associated with significant morbidity and mortality [ 6 , 7 ] .
importantly , bk virus infection could escalate from viruria to viremia to nephropathy . bk nephropathy began as a localized viral presence in the tubular epithelial cells of the kidney and progressed to a diffuse and destructive t - cell - mediated interstitial nephritis . about
50% of patients after hematopoietic bone marrow transplantation presented with bk viruria , usually within 2 months of transplantation [ 10 , 11 ] , with similar incidence in both autologous and allogenic recipients ( 3954% ) .
a 18-year - old patient with a history of matched - unrelated - donor peripheral blood stem cell transplantation ( mud - pbsct ) was admitted to the hospital because of renal failure . in november 2007
the patient was first diagnosed with acute lymphoblastic leukemia of t cells ( t - all ) at another institution , where he was treated with induction therapy according to hyper - cvad protocol ( cyclophosphamide 300 mg / m intravenously ( iv ) over 3 hours every 12 hours for six doses on days 1 through 3 , with mesna given by continuous infusion , vincristine 2 mg iv days 4 and 11 , doxorubicin 50 mg / m iv day 4 , and dexamethasone 40 mg daily on days 1 through 4 and 11 through 14 ) and was refractory when he presented in our department of hematology / oncology . the diagnosis of t - all has been confirmed , immunophenotype precursor t - all ( cd7 , cd3 , cd2 , cd4 , and cd8 pos ) , cytogenetic 46 , xy , fluorescein in sito hybridisation ( fish ) analysis 87% deletion of p16 on the chromosome 9 region p21 .
he was then treated with induction therapy according to the german multicenter all protocol ( gmall ) achieving only reduction of blasts after induction ii .
briefly , the induction in gmall protocol was composed of eight cytotoxic drugs administered sequentially in two phases over an 8-week period . during the first 4 weeks
( phase i ) , the patient received 60 mg / m prednisolone po daily ( days 1 through 28 ) plus 45 mg / m daunorubicin and 2 mg vincristine iv weekly ( days 1 , 8 , 15 , and 22 ) .
u / m ) was administered iv daily ( days 15 through 28 ) . in the second 4 weeks ( phase ii ) , the patient received two doses of 650 mg / m cyclophosphamide iv ( days 29 , 43 , and 57 ) together with 60 mg / m 6-mercaptopurine po daily ( days 29 through 57 ) and four courses of 75 mg / m cytarabine iv ( days 31 through 34 , 38 through 41 , 45 through 48 , and 52 through 55 ) .
he was then treated with nelarabine and achieved complete remission ( cr1 ) following mud - pbsct .
the conditioning consisted of total body irradiation ( tbi ) , 12 gy , given fractionated 2 times daily for three days , from day 6 to day 4 , and cyclophosphamide 60 mg / kg once daily i.v . on days 3 and 2 ( total dose 120 mg / kg b.w . ) . a human leukocyte antigen ( hla ) identical unrelated donor peripheral blood stem cells
graft - versus - host disease ( gvhd ) prophylaxis consisted of thymoglobulin ( 2 mg / kg b.w .
daily , from day 3 to 1 , total dose of 6 mg / kg b.w . )
, cyclosporine 5 mg / kg starting on day 1 , and methotrexate at days + 1 , + 3 , + 6 , and + 11 intravenously 15 mg absolute .
the bone marrow puncture on day + 28 showed a complete hematological remission with 100% donor chimerism .
along with the regeneration of white blood cells the patient developed a methylprednisolone - dependent gvhd of the skin and gastrointestinal , grade ii . after 10 days the therapy with corticosteroids
could be discontinued by rapid improvement of the gvhd - related symptoms . under the therapy with corticosteroids the patient developed a herpes simplex related oesophagitis on day 21 post transplant which was treated with 30 g daily over 5 days i.v .
the patient developed a hemorrhagic cystitis with high urine titers of bk polyoma virus and cmv infection .
a therapy with ganciclovir was initiated for ten days . under treatment with ganciclovir , cmv infection improved , and the treatment with cidofovir was started ( 1 mg / kg b.w . for two weeks ) .
the bk virus viruria and viremia improved , and the patient received ganciclovir treatment for additional two weeks ( figure 1 ) .
the cyclosporine level was from 200 to 150 from day 0 to day 30 , followed with level of 100 from day 30 to day 40 post transplant , and level of 50 from day 40 to day 50 .
the cyclosporine has been discontinued on day + 70 after mud - pbsct in absence of acute gvhd and as recommended in gmall protocol . on day
+ 48 after pbsct a cystoscopy with a continuous intravesical saline irrigation was started and discontinued 2 weeks later .
he was discharged from hospital ; his medications at the time of discharge included ciprofloxacin ( 250 mg twice daily ) , valacyclovir ( 500 mg twice daily ) , fluconazole ( 200 mg daily ) , folate , and cotrimoxazole twice weekly for prophylaxis of pneumocystis carinii infection .
over the next year the levels of urea nitrogen and creatinine gradually rose ( table 1 ) , which was attributed to drug toxicity .
blood pressure was 130/80 mmhg with 90 heart beats per minute , a temperature of 36.4c , and an oxygen saturation of 99% when the patient was breathing ambient air .
the lungs were clear , the results of the remainder of the examination were normal .
the complete blood count and levels of serum electrolytes , liver function tests , and levels of total protein and albumin were normal .
the urine sediment was not nephritic but contained a small amount of leukocytes indicating an inflammatory process such as cystitis .
ultrasonographic examination of the kidneys showed bilateral hydronephrosis stage iii - iv ( figure 2(a ) ) .
the hydronephrosis of the left kidney improved immediately and improved to grade ii in the right kidney . for histological examination tissues
the pathohistology of the specimen showed a chronic cystical urocystitis with bleedings ( figure 3(a ) ) .
tissue probes of both ureters were stained for sv40 large t antigen ( clone pab416 , oncogene science , boston , mass , usa ; dilution 1 : 100 , antigen retrieval and amplification with catalyzed system amplification , dako , carpinteria , ca ) .
the reactions were detected by means of the streptavidin - biotin method and were revealed using diaminobenzidine as a chromogen [ 15 , 16 ] . in
all tissue probes immunohistochemistry for large t antigen was negative ( figure 3(b ) ) .
the patient has undergone double - j catheter controls and changes every two months and is doing well 2 years after pbsct and 1 year after operative extirpation of tumours .
two different regions of the bkv genome were amplified by pcr , vp2 in serum and urine , and large t antigen from tissue biopsies .
nucleic acids were extracted from 200 microliter blood or urine using magnetic beads ( magna pure lc total na isolation kit , roche , mannheim , germany ) according to the manufacturer 's instructions while from formalin - fixed , paraffin - embedded material nucleic acids were extracted using the qiaamp dna ffpe tissue kit ( qiagen , hilden , germany ) .
pcr reaction was carried out in 20 microliter capillaries containing master mix ( 6 mm mgcl2 , 0.1 mg / ml bsa ( sigma , st .
louis , usa ) ) and 10 picom of each primer ( metabion , martinsried , germany ) , 3 picom of each hybridization probe ( 5-ggctgctgctgccacaggattttc - fl ( probe 1 ) and 5lc red640-gtagctgaaattgctgctggagag - ph ( probe 2 ) , 0.25 mm dntp 's ( roche ) ) , and 1u platinum taq polymerase ( invitrogen , karlsruhe , germany ) . target dna was added in a volume of 5 microliters .
two negative and 4 positive controls in different concentrations were included into each run performed on a lightcycler 1.0 instrument ( roche , mannheim , germany ) under the following conditions : initial denaturation and activation of hot - start enzyme at 95c for 30 s , followed by 45 cycles of denaturation at 95c for 0 s , annealing of primers at 58c for 10 s , and primer extension at 72c for 20 s. fluorescence was monitored by single acquisition during the annealing phase of each pcr cycle and channel setting f2/f1 ( 640 nm/530 nm ) .
differentiation of bk virus amplicons from jc virus depends on the binding of the probe 2 , which perfectly matches jc virus but differs at the two underlined positions from bk virus . thus binding to bk virus results in a shifted melting curve ( 61.5c for bk versus 63.8c for jc ) . for detection of the viral large t - antigen , a 128 bp
long fragment was amplified using modified primers from that match bkv genotypes 1 to 4 , forward primer 5-caggcaagggttctattactaaat-3 , reverse primer 5-gcaacagcagattcycaaca-3 , probe 5-6fam - aaactggtgtagatcagarggaaagtctttagggtctt - bbq .
pcr conditions were identical to the one described above except taqman probe that was used at 4 pico molar , primer annealing was 56c for 10 s , and fluorescence acquisition was at the end of each primer extension phase at 530 nm .
we described a young patient with precursor t - all who had received an unrelated matched donor pbsct and one year later presented with increase creatinine levels and bilateral hydronephrosis .
nephrological and urological examination showed an epithelial proliferation of bladder on both ostii being responsible for bilateral hydronephrosis .
we speculate that the endothelial cell injury led to capillary injury , oedema , and tumorous proliferation on both ostii .
this case demonstrated a very late ( one year after mud - hsct ) proliferative endothelial infection by a virus related to severe viral load and hemorrhagic cystitis 4 weeks after unrelated pbsct . although the tumour mass could not be unambiguously attributed to bkv since the staining of large t antigen was negative in immunohistochemical analysis , large t - cell antigen and bk virus were positive by pcr , thus supporting the view that bk virus may indeed play a role in the development of this tumour .
the oncogenic potential of bk virus has been well recognized [ 2 , 3 ] ; geetha et al .
reported the case of a simultaneous pancreas and kidney transplant recipient who developed bkv interstitial nephritis and carcinoma of the bladder with widespread metastasis .
for both the primary tumour and the metastasis , immunohistochemical staining for the large t - cell antigen showed strong nuclear positivity .
however , the diagnosis of the role of bk virus infection as a transient hit and run
agent is according to hirsch difficult to prove with the current diagnostic tools .
bk virus is an important pathogen and cause of nephropathy in renal transplant recipients , but its significance following pbsct is less well described .
recently , o'donnell et al . have shown in 124 allogeneic pbsct patients that bk viruria was manifest in 65% of the patients ; 17% of the patients developed viremia .
the median time from transplantation to bk viremia development was 128 days and was longer for viruria ( 24 days ) . among clinical factors such as sex , disease , transplant type , alemtuzumab use ,
cytomegalovirus viremia , graft - versus - host disease , and donor hla c7 allele , only cmv viremia was more common in patients with bk virus infection .
in addition , bk virus infection was analysed with other clinical factors related to the development of post - pbsct renal impairment .
on multivariate analysis , only bk viremia and alternative donor transplantation were independent predictors of development of post - hsct renal impairment .
there are numerous papers showing that there is no association between cmv and bkv reactivation .
one of the best examples is by hirsch et al . , 2002 nejm , where no cmv prophylaxis was given and only cmv seropositive and bkv seropositive kidney recipients were examined .
published the results on the incidence of bk virus in 102 children who underwent allogeneic hsct .
bk virus dna was detected in the urine of 47% children ; the only significant factor for hemorrhagic cystitis was high - dose chemotherapy .
the treatment included the use of cidofovir , which was feasible and without significant toxicity .
the evidence - based guidelines for clinical management include in addition to virus - specific therapy the use of estrogen or bladder instillation with alum salts or prostaglandin , as recently reviewed [ 2426 ] .
the transforming potential of bk virus infection has been noted early both in vitro culture models and in vivo .
one of the patients with bk virus - associated nephropathy after kidney transplantation reported by vats et al . presented with an echogenic renal mass that resolved with immunosuppression reduction and treatment with cidofovir .
contributing factors included drug toxicity around pbsct ( cyclosporine in particular ) , polyoma bk viruria , although it was not proven whether the kidneys were involved , and chronic hydronephrosis along with an inflammatory process due to the urine congestion . in summary , we could show an unusual case of late onset of bilateral hydronephrosis probably due to bk virus - induced tumorous bladder proliferation on both ostii in a young patient after mud - pbsct , successfully treated with operative incision and dj catheter .[/INST]we report here a case of acute lymphoblastic leukemia in remission presenting a late - onset bilateral hydronephrosis probably due to polyoma bk virus - induced proliferation of bladder endothelium on both ostii .
the diagnosis was made virologically by bk virus polymerase chain reaction ( pcr ) detection in the absence of any other bladder disease .
awareness of this late complication is necessary not only in patients after renal transplantation but also in patients after hematopoietic stem cell transplantation from matched unrelated donor .</s> |
the low - energy supersymmetry ( susy ) is one of the leading candidates for the physics beyond the standard model ( sm ) , and provides attractive features .
the higgs potential is stabilized against quadratic divergences .
three sm gauge couplings unify at around @xmath3gev in the minimal extension , so - called the minimal supersymmetric standard model ( mssm ) .
this fact suggests the existence of the grand unified theory ( gut ) , leading to a natural explanation of the charge quantization . with a discovery of the higgs boson with a mass of 125gev @xcite
, it tours out that a rather large radiative correction from scalar tops ( stops ) to the higgs boson mass is required @xcite , since its mass is predicted to be smaller than @xmath4 boson mass at the tree level in the mssm . in the absence of a larger trilinear coupling of the stops , the stop mass
is expected to be as large as @xmath5tev .
this is not very encouraging since it seems difficult to be consistent with another important motivation for the low - energy susy : the observed anomaly of the muon anomalous magnetic moment ( muon @xmath2 ) .
the muon @xmath2 , @xmath6 , is measured very precisely at the brookhaven e821 experiment @xcite , which is deviated from the sm prediction at the level more than 3@xmath7 @xcite . in order to resolve the discrepancy ,
the additional contribution to @xmath8 of @xmath9 is required . in the mssm ,
if the smuons and chargino / neutralino are as light as @xmath1(100)gev for @xmath10 , the susy contribution to the muon @xmath2 is large enough and the anomaly is explained @xcite .
however , this clearly implies a tension : the observed higgs boson mass suggests the heavy susy particles while the muon @xmath2 anomaly suggests the light susy particles , which arouses us to construct a non - trivial model .
in fact , there are ways suggested to resolve the tension : * new contributions to the higgs boson mass : if there is an additional contribution to the higgs boson mass , the susy particles are not necessarily heavy . in this case , the anomaly of the muon @xmath2 is explained by the contributions from the fairly light susy particles .
for instance , susy models with vector - like matter multiplets @xcite , the large trilinear coupling of the stop @xcite , or an extra gauge interaction @xcite can accommodate both the observed higgs boson mass and muon @xmath2 anomaly .
region once taking into account radiative corrections .
this is favored by the muon @xmath2 explanation . ] * splitting masses for weakly interacting susy particles and strongly interacting ones : with gut breaking effects , it is possible to obtain light masses for the weakly interacting susy particles and heavy masses for the strongly interacting ones .
this can be done for example in gauge mediation models with light colored and heavy non - colored messengers @xcite , or with the slepton multiplets embedded in extended susy multiplets at the messenger scale @xcite .
* splitting masses for the first two and third generation sfermions : instead of the splitting mass spectra for the strongly and weakly interacting susy particles , the sfermion masses can be split as in the case of sm fermions . with small masses for the first two generation sfermions of @xmath11tev and the large masses for the third generation sfermions of @xmath5tev , the tension between the higgs boson mass of 125gev and the muon @xmath2 anomaly is resolved @xcite . in this paper , we proposed a scenario with the splitting mass spectra corresponding to the case ( c ) .
the splitting masses among the first two and third generation sfermions are naturally obtained by renormalization group ( rg ) running effects from higgs soft masses @xcite , if the squared values of the higgs soft masses are negative . on the other hand ,
gaugino masses are generated by anomaly mediation @xcite with the gravitino mass of @xmath0tev . in our setup , the third generation sfermions have masses of @xmath5tev , while the first / second generation sfermions have masses of @xmath12tev without inducing the flavor changing neutral current ( fcnc ) problem .
the rest of the paper is organized as follows . in sec .
2 , we explain the setup of our model , based on the anomaly mediation . only higgs multiples couple to a susy breaking sector , which does not introduce the flavor changing neutral current problem . in sec 3 .
we describe the mechanism for splitting mass spectra of first two generation and the third generation .
then , we show the consistent regions with the muon @xmath2 and the stop mass of @xmath5tev . the unification of yukawa couplings is also discussed .
finally , section 4 is devoted to the conclusion and discussions .
we first explain the setup of our model . in our model ,
only the higgs multiplets have direct couplings to a susy breaking field at the tree level .
the other sparticle masses are generated radiatively via anomaly mediation effects and rg running effects from the higgs soft masses .
the klher potential is given by @xmath13 , \end{aligned}\ ] ] where @xmath14 is the reduced planck mass , @xmath4 is a susy breaking field , and @xmath15 is a mssm chiral superfield .
it is assumed that the vacuum expectation value ( vev ) of @xmath4 is much smaller than @xmath14 .
the susy is broken by the @xmath16-term of @xmath4 , @xmath17 , where @xmath18 is the gravitino mass . here
, @xmath19 contains direct couplings of the higgs multiplets to the susy breaking field @xmath4 : @xmath20 where @xmath21 and @xmath22 are the up - type and down - type higgs , respectively ; @xmath23 is a coefficient of @xmath24 , which is taken as a free parameter but is assumed to be positive . for simplicity , we assume @xmath21 and @xmath22 have the common coupling to @xmath4 . gauge interactions . ] this may be justified if @xmath21 and @xmath22 are embedded into a same gut multiplet of @xmath25 . in the case
@xmath26 , the above khler potential takes a sequestered form @xcite , i.e. , the mssm fields do not have direct couplings to @xmath4 at the tree level . in this case
a sfermion mass is @xmath27 where @xmath28 is an anomalous dimension defined by @xmath29 ; @xmath30 ( @xmath31 ) is a gauge ( yukawa ) coupling ; @xmath32 ( @xmath33 ) is a beta - function of @xmath30 ( @xmath31 ) ; @xmath34 is a renormalization scale .
notice that the masses of the first and second generation sleptons are inevitably tachyonic , since the beta - functions for the @xmath35 and @xmath36 gauge couplings are positive and yukawa couplings are negligibly small @xcite .
this problem is called the tachyonic slepton problem .
however , in our setup , the higgs multiplets have soft masses of @xmath5tev from @xmath19 for @xmath37tev , which play significant roles in low - energy susy mass spectra via the rg running : the tachyonic slepton problem is avoided and the masses of the third generation sfermions including the stops become @xmath5tev if the higgs soft mass squared is negative and @xmath38 is large . it is also assumed that there are no direct couplings between gauge field strength superfields and the susy breaking field , which may originate from the fact that @xmath4 is charged under a symmetry in the hidden sector .
gaugino masses vanish at the tree level and are generated radiatively from anomaly mediation @xcite : @xmath39 where @xmath40 , @xmath41 and @xmath42 are the bino , wino and gluino , respectively ; and @xmath43 , @xmath44 and @xmath45 are the gauge coupling constants of @xmath36 , @xmath35 and @xmath46 .
is taken to be consistent with @xmath47 gut . ]
these masses are expected to be @xmath11tev .
so far , the parameters of our model are summarized as @xmath48 where the boundary condition of the soft susy breaking parameters is set at @xmath49gev @xmath50 ; @xmath51 , where @xmath52 and @xmath53 are the soft masses for the up - type higgs and down - type higgs , respectively .
we fix sign(@xmath54 ) to be positive in the following discussions since we are interested in regions consistent with the muon @xmath2 experiment . in the parameter space of our interest , the typical values for @xmath18 and @xmath55 are @xmath56tev and @xmath5tev , respectively , with @xmath57 .
next , we explain how the mass hierarchy between the first / second and third generation sfermions are obtained .
as noted in @xcite , the hierarchical mass spectrum is realized when @xmath58 are negative and large .
contributions from one - loop renormalization group equations ( rges ) raise the third generation sfermion masses via terms proportional to the squared of the yukawa couplings : @xmath59 where @xmath60 and @xmath61 are the @xmath62 doublet squark and slepton of the third generation ; @xmath63 , @xmath64 and @xmath65 are the right - handed stop , sbottom and stau , respectively ; @xmath66 is the top yukawa coupling ; and @xmath67 . the contributions from eq .
( [ eq : rge_3rd ] ) dominate those from anomaly mediation . after solving rges ,
the third generation sfermions obtain masses of @xmath68tev at the low energy scale for @xmath69tev .
in addition to the contributions from anomaly mediation , the sfermions of the first two generations also obtain masses from @xmath70 and @xmath71 via the rg running , though they are suppressed , compared to those of the third generation sfermions .
this is because one - loop terms in rges are proportional to the squared of the first / second generation yukawa couplings , and gauge interaction terms are at the two - loop level . as a consequence ,
the sfermion mass spectrum at the low energy scale becomes automatically hierarchical .
note that the tachyonic slepton masses are avoided due to negative terms involving @xmath72 and terms involving the yukawa coupling squares and @xmath73 in beta - functions at the two - loop level : @xmath74 , \nonumber \\
\beta_{m_{\bar e_i}^2 } & \ni & \frac{1}{(16\pi^2)^2 } \left[\left ( \frac{36}{25 } g_1 ^ 4 \right ) ( m_{h_u}^2 + m_{h_d}^2 ) + \frac{12}{5 } g_1 ^ 2 s ' \right]\,,\end{aligned}\ ] ] where @xmath75 and @xmath76 .
the runnings of the first generation sfermion masses are shown in the left panel , and those of the third generation sfermion masses and higgs soft masses are shown in the right panel .
we take @xmath77tev , @xmath78 , and @xmath79gev@xmath80 . here , @xmath81 and @xmath82gev .
, title="fig : " ] .
the runnings of the first generation sfermion masses are shown in the left panel , and those of the third generation sfermion masses and higgs soft masses are shown in the right panel .
we take @xmath77tev , @xmath78 , and @xmath79gev@xmath80 . here , @xmath81 and @xmath82gev .
, title="fig : " ] in fig.[fig : rge ] , we show the rg running of soft mass parameters for @xmath83 and @xmath78 . here and hereafter , we take @xmath84 @xcite and @xmath85gev @xcite . in the left panel ,
the runnings of the first generation sfermion masses are shown .
the runnings of the third generation sfermion masses and the higgs soft masses are shown in the right panel .
one can see that the masses of the first generation sfermions at the low energy scale are @xmath86 - 1)tev , avoiding the tachyonic masses for the sleptons ( @xmath87 and @xmath88 ) . on the other hand , the masses for the third generation sfermions including the stop masses grow rapidly as @xmath34 decreases , and they reach to @xmath68tev at the low energy scale . in our setup , for the successful electroweak symmetry breaking ( ewsb ) with @xmath89
, the @xmath54-term has to be large as @xmath5tev and @xmath90 , which is required to avoid the tachyonic mass for the cp - odd higgs .
the latter condition can be satisfied only when the bottom- and tau- yukawa couplings , @xmath91 and @xmath92 , are large enough , which enters beta - functions for @xmath70 and @xmath71 as @xmath93 the absolute value of the negative @xmath71 decreases more than that of @xmath70 for large @xmath91 and @xmath94 , if @xmath95 is larger than @xmath96 . in our model , this is achieved with a large @xmath97 , since the bottom yukawa coupling gets larger with threshold corrections @xcite , @xmath98 where @xmath99 is a bottom quark mass ; @xmath100 is a vev of the down - type higgs ; @xmath101 ( @xmath102 ) is the mass of the lighter ( heavier ) sbottom ; @xmath103 is a loop function , @xmath104 notice that the bottom yukawa is enhanced when @xmath105 is negative for the fixed @xmath106 , while the susy contribution to the muon @xmath2 is positive when @xmath107 is positive . in our case , both @xmath108 and @xmath109 can be satisfied since the anomaly induced gaugino masses are proportional to the @xmath110 functions of the corresponding gauge couplings .
note that the threshold correction to @xmath91 , @xmath111 , improves the unification of the yukawa couplings . on @xmath106-@xmath112 plane for @xmath113100 ( top - left ) , 120 ( top - right ) , 140 ( bottom - left ) , 160 tev ( bottom - right ) . in the red ( green ) region ,
the muon @xmath2 is explained at 1@xmath7 ( 2@xmath7 ) level .
, title="fig : " ] on @xmath106-@xmath112 plane for @xmath113100 ( top - left ) , 120 ( top - right ) , 140 ( bottom - left ) , 160 tev ( bottom - right ) . in the red ( green ) region , the muon @xmath2 is explained at 1@xmath7 ( 2@xmath7 ) level .
, title="fig : " ] on @xmath106-@xmath112 plane for @xmath113100 ( top - left ) , 120 ( top - right ) , 140 ( bottom - left ) , 160 tev ( bottom - right ) . in the red ( green ) region , the muon @xmath2 is explained at 1@xmath7 ( 2@xmath7 ) level .
, title="fig : " ] on @xmath106-@xmath112 plane for @xmath113100 ( top - left ) , 120 ( top - right ) , 140 ( bottom - left ) , 160 tev ( bottom - right ) . in the red ( green ) region , the muon @xmath2 is explained at 1@xmath7 ( 2@xmath7 ) level .
, title="fig : " ] -@xmath112 plane for @xmath113100 ( top - left ) , 120 ( top - right ) , 140 ( bottom - left ) , 160tev ( bottom - right ) .
, title="fig : " ] -@xmath112 plane for @xmath113100 ( top - left ) , 120 ( top - right ) , 140 ( bottom - left ) , 160tev ( bottom - right ) .
, title="fig : " ] -@xmath112 plane for @xmath113100 ( top - left ) , 120 ( top - right ) , 140 ( bottom - left ) , 160tev ( bottom - right ) .
, title="fig : " ] -@xmath112 plane for @xmath113100 ( top - left ) , 120 ( top - right ) , 140 ( bottom - left ) , 160tev ( bottom - right ) .
, title="fig : " ] -@xmath112 plane . in the left panel ( right panel )
, the contours of @xmath114 ( @xmath115 ) are shown .
we take @xmath116tev . , title="fig : " ] -@xmath112 plane . in the left panel ( right panel ) , the contours of @xmath114 ( @xmath115 ) are shown .
we take @xmath116tev . , title="fig : " ] [ [ muon - g-2 ] ] muon @xmath2 + + + + + + + + + + + + + + + + + + + + + + in the typical parameter space of our model , the susy contribution to the muon @xmath2 , @xmath117 , is dominated by the bino-(l - smuon)-(r - smuon ) , where l and r represent the left - handed and right - handed , respectively .
this contribution is given by @xcite @xmath118 where @xmath119 is the muon mass ; @xmath120 @xmath121 is the mass of the l - smuon ( r - smuon ) ; @xmath122 is a loop function with @xmath123 .
here , @xmath124 and @xmath125 are two - loop corrections : @xmath124 is the correction to the muon yukawa coupling @xcite , @xmath126 which is positive and can become as large as @xmath127 , and @xmath128 is a leading logarithmic correction from qed @xcite , where @xmath129 is the fine - structure constant and @xmath130 is a smuon mass scale .
the susy contribution to @xmath6 is enhanced with the large @xmath131 and light smuons , which is the character of our model . in fig .
[ fig : stop_gm2 ] , we show the contours of the stop mass defined by @xmath132 and the regions consistent with the muon @xmath2 . the horizontal ( vertical ) axis shows @xmath106 @xmath133 , where @xmath134 .
the susy mass spectra and @xmath117 are calculated using suspect2.43 @xcite with modifications to include @xmath124 in eq.([eq : gm2 ] ) and the effects of the muon yukawa coupling on rg equations . in the red ( green ) regions , the muon @xmath2 is explained at 1@xmath7 @xmath135 level . as a reference value , we quote @xcite @xmath136 where @xmath137 is the experimental value @xcite and @xmath138 is a sm prediction . in those regions ,
the stop mass is as large as 11 - 17tev . in the shaded regions ,
the l - selectron ( @xmath139 ) or r - selectron ( @xmath140 ) is the lightest susy particle ( lsp ) , and these regions are considered to be excluded .
the regions with @xmath141gev , @xmath142gev gev and @xmath142gev , are chosen for the convenience of the numerical calculations . ] or the unsuccessful ewsb are dropped . in fig .
[ fig : msq_gm2 ] , we show the contours of the up - type squark mass ( @xmath143 ) , which is the lightest squark in most of the parameter space .
the mass of the up - type squark lies in the range of 1000 - 2500gev in the region consistent the muon @xmath2 at 1@xmath7 level , depending on the gravitino mass .
the gaugino masses at the susy mass scale of @xmath144tev are @xmath145 for @xmath146 . in most of the parameter space ,
the lightest susy particle ( lsp ) is the wino - like neutralino , whose mass is almost degenerate with that of the lightest chargino due to large @xmath54-term of @xmath5tev .
the mass difference dominantly comes from w / z boson loops , which tours out to be about @xmath147 @xcite .
this chargino is searched at the lhc using a disappearing - track , which leads to a constraint on the mass to be larger than 270gev with the cross section estimated assuming the direct production @xcite .- ray is severe @xcite . ] in the regions where the l / r selectron is the lsp , even if the selectron is unstable with an @xmath148-parity violation , a lhc constraint of multi - lepton final states @xcite is severe ; therefore , these regions are probably excluded .
[ [ yukawa - unification ] ] yukawa unification + + + + + + + + + + + + + + + + + + in our model , @xmath91 and @xmath92 are nearly degenerated at @xmath49gev in some regions of the parameter space .
furthermore , one can find a region where even the three yukawa couplings , @xmath91 , @xmath92 and @xmath66 , are nearly degenerated .
the unification of the yukawa couplings at @xmath149 is demonstrated in fig .
[ fig : yukawa_gut ] . motivated by the @xmath47 gut , the contours of @xmath150 is shown in the left panel , while @xmath151 in the right panel motivated by the @xmath25 gut . here ,
@xmath152 and @xmath115 are evaluated at @xmath149 .
the unification can be achieved at @xmath153% level with the help of @xmath111 in eq .
( [ eq : yb_cor ] ) . [ cols="^,^,^,^,^",options="header " , ] [ [ fcnc ] ] fcnc + + + + one might worry about the flavor violating sfermion masses induced by the yukawa couplings and large @xmath58 . in fact , the generated flavor violating masses are not so large but not negligibly small . using the leading log approximation , an off - diagonal element of the sfermion mass matrix
is estimated as @xmath154 in the super - ckm basis with @xmath155 . here
, @xmath156 is a typical squark mass .
thus , @xmath157 \approx -0.015 \left ( \frac{2 \ , { \rm tev}}{m_{\tilde q } } \right)^2 \left ( \frac{-m_{h_u}^2}{10 ^ 9 { \rm gev}^2 } \right),\end{aligned}\ ] ] which is consistent with the constraint from @xmath158 @xcite . [
[ mass - spectra ] ] mass spectra + + + + + + + + + + + + finally we show some mass spectra in our model parameter space ( table [ tab : sample ] ) , where @xmath159 ( mass eigenstate ) is the wino - like neutralino , @xmath160 is the bino - like neutralino and @xmath161 is the gluino . the higgs boson mass is computed using feynhiggs2.12.0
@xcite . in these points ,
the stop mass is large as 12 - 13tev while the first / second generation sfermions and gauginos are light as @xmath1(0.1 - 1)tev .
the higgsino mass parameter , @xmath54 , is as large as @xmath162tev , leading to the fine - tuning of the ewsb scale as @xmath163 . with the smuons of @xmath164 gev and large @xmath106 of @xmath165 ,
the muon @xmath2 is explained at the 1@xmath7 level .
we have proposed a scenario where only the higgs multiplets have direct couplings to the susy breaking sector .
the standard model matter multiplets as well as the gauge multiples do not have direct couplings to the susy breaking field at the classical level , and their masses are generated radiatively by anomaly mediation and higgs loops .
due to rg running effects from the higgs soft masses of @xmath1(10)tev , the third generation sfermions have masses of @xmath1(10)tev while the first and second generation sfermions have masses of @xmath1(0.1 - 1)tev , avoiding the tachyonic slepton problem of anomaly mediation .
the hierarchy of the masses originates from the structure of the yukawa couplings , i.e. , the yukawa couplings of the third generation are much larger than those of the first and second generations . in this case , there is no susy fcnc problem .
the hierarchical mass spectrum allows us to explain the higgs boson mass of @xmath166125gev and the observed value of the muon @xmath2 , simultaneously . in the whole region explaining the muon @xmath2 anomaly , the masses of the light squarks and gluino lies in the range smaller than 3tev ; therefore , it is expected to be checked at the lhc run-2 or the high luminosity lhc .
since the gravitino is heavier than about 100tev , the cosmological gravitino problem is relaxed @xcite . moreover , in our setup , the susy breaking field is not necessarily a gauge singlet of a hidden sector symmetry ; therefore , the cosmological moduli problem or polonyi problem @xcite can be avoided .
the possible drawback of our setup is the origin of the higgs @xmath167-term of @xmath153tev with the @xmath54-term of @xmath5tev .
this may be due to the fine - tuning of an ultraviolet model .
alternatively , the @xmath54-term and @xmath168-term may be generated by the vacuum expectation values of a @xmath169-term and @xmath16-term of a singlet chiral superfield _ a la _ the next - to minimal supersymmetric standard model .
we would like to thank yutaro shoji for collaboration at an early stage of this work .
this work is supported by jsps kakenhi grant numbers jp15h05889 ( n.y . ) and jp15k21733 ( n.y . ) .
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14 , 141801 ( 2014 ) [ arxiv:1312.4937 [ hep - ph ] ] . | we propose a scenario where only the higgs multiplets have direct couplings to a supersymmetry ( susy ) breaking sector .
the standard model matter multiplets as well as the gauge multiples are sequestered from the susy breaking sector ; therefore , their masses arise via anomaly mediation at the high energy scale with a gravitino mass of @xmath0tev .
due to renormalization group running effects from the higgs soft masses , the masses of the third generation sfermions become @xmath1(10)tev at the low energy scale , while the first and second generation sfermion masses are @xmath1(0.1 - 1)tev , avoiding the tachyonic slepton problem and flavor changing neutral current problem . with the splitting mass spectrum ,
the muon @xmath2 anomaly is explained consistently with the observed higgs boson mass of 125gev .
moreover , the third generation yukawa couplings are expected to be unified in some regions . | <s>[INST]the low - energy supersymmetry ( susy ) is one of the leading candidates for the physics beyond the standard model ( sm ) , and provides attractive features .
the higgs potential is stabilized against quadratic divergences .
three sm gauge couplings unify at around @xmath3gev in the minimal extension , so - called the minimal supersymmetric standard model ( mssm ) .
this fact suggests the existence of the grand unified theory ( gut ) , leading to a natural explanation of the charge quantization . with a discovery of the higgs boson with a mass of 125gev @xcite
, it tours out that a rather large radiative correction from scalar tops ( stops ) to the higgs boson mass is required @xcite , since its mass is predicted to be smaller than @xmath4 boson mass at the tree level in the mssm . in the absence of a larger trilinear coupling of the stops , the stop mass
is expected to be as large as @xmath5tev .
this is not very encouraging since it seems difficult to be consistent with another important motivation for the low - energy susy : the observed anomaly of the muon anomalous magnetic moment ( muon @xmath2 ) .
the muon @xmath2 , @xmath6 , is measured very precisely at the brookhaven e821 experiment @xcite , which is deviated from the sm prediction at the level more than 3@xmath7 @xcite . in order to resolve the discrepancy ,
the additional contribution to @xmath8 of @xmath9 is required . in the mssm ,
if the smuons and chargino / neutralino are as light as @xmath1(100)gev for @xmath10 , the susy contribution to the muon @xmath2 is large enough and the anomaly is explained @xcite .
however , this clearly implies a tension : the observed higgs boson mass suggests the heavy susy particles while the muon @xmath2 anomaly suggests the light susy particles , which arouses us to construct a non - trivial model .
in fact , there are ways suggested to resolve the tension : * new contributions to the higgs boson mass : if there is an additional contribution to the higgs boson mass , the susy particles are not necessarily heavy . in this case , the anomaly of the muon @xmath2 is explained by the contributions from the fairly light susy particles .
for instance , susy models with vector - like matter multiplets @xcite , the large trilinear coupling of the stop @xcite , or an extra gauge interaction @xcite can accommodate both the observed higgs boson mass and muon @xmath2 anomaly .
region once taking into account radiative corrections .
this is favored by the muon @xmath2 explanation . ] * splitting masses for weakly interacting susy particles and strongly interacting ones : with gut breaking effects , it is possible to obtain light masses for the weakly interacting susy particles and heavy masses for the strongly interacting ones .
this can be done for example in gauge mediation models with light colored and heavy non - colored messengers @xcite , or with the slepton multiplets embedded in extended susy multiplets at the messenger scale @xcite .
* splitting masses for the first two and third generation sfermions : instead of the splitting mass spectra for the strongly and weakly interacting susy particles , the sfermion masses can be split as in the case of sm fermions . with small masses for the first two generation sfermions of @xmath11tev and the large masses for the third generation sfermions of @xmath5tev , the tension between the higgs boson mass of 125gev and the muon @xmath2 anomaly is resolved @xcite . in this paper , we proposed a scenario with the splitting mass spectra corresponding to the case ( c ) .
the splitting masses among the first two and third generation sfermions are naturally obtained by renormalization group ( rg ) running effects from higgs soft masses @xcite , if the squared values of the higgs soft masses are negative . on the other hand ,
gaugino masses are generated by anomaly mediation @xcite with the gravitino mass of @xmath0tev . in our setup , the third generation sfermions have masses of @xmath5tev , while the first / second generation sfermions have masses of @xmath12tev without inducing the flavor changing neutral current ( fcnc ) problem .
the rest of the paper is organized as follows . in sec .
2 , we explain the setup of our model , based on the anomaly mediation . only higgs multiples couple to a susy breaking sector , which does not introduce the flavor changing neutral current problem . in sec 3 .
we describe the mechanism for splitting mass spectra of first two generation and the third generation .
then , we show the consistent regions with the muon @xmath2 and the stop mass of @xmath5tev . the unification of yukawa couplings is also discussed .
finally , section 4 is devoted to the conclusion and discussions .
we first explain the setup of our model . in our model ,
only the higgs multiplets have direct couplings to a susy breaking field at the tree level .
the other sparticle masses are generated radiatively via anomaly mediation effects and rg running effects from the higgs soft masses .
the klher potential is given by @xmath13 , \end{aligned}\ ] ] where @xmath14 is the reduced planck mass , @xmath4 is a susy breaking field , and @xmath15 is a mssm chiral superfield .
it is assumed that the vacuum expectation value ( vev ) of @xmath4 is much smaller than @xmath14 .
the susy is broken by the @xmath16-term of @xmath4 , @xmath17 , where @xmath18 is the gravitino mass . here
, @xmath19 contains direct couplings of the higgs multiplets to the susy breaking field @xmath4 : @xmath20 where @xmath21 and @xmath22 are the up - type and down - type higgs , respectively ; @xmath23 is a coefficient of @xmath24 , which is taken as a free parameter but is assumed to be positive . for simplicity , we assume @xmath21 and @xmath22 have the common coupling to @xmath4 . gauge interactions . ] this may be justified if @xmath21 and @xmath22 are embedded into a same gut multiplet of @xmath25 . in the case
@xmath26 , the above khler potential takes a sequestered form @xcite , i.e. , the mssm fields do not have direct couplings to @xmath4 at the tree level . in this case
a sfermion mass is @xmath27 where @xmath28 is an anomalous dimension defined by @xmath29 ; @xmath30 ( @xmath31 ) is a gauge ( yukawa ) coupling ; @xmath32 ( @xmath33 ) is a beta - function of @xmath30 ( @xmath31 ) ; @xmath34 is a renormalization scale .
notice that the masses of the first and second generation sleptons are inevitably tachyonic , since the beta - functions for the @xmath35 and @xmath36 gauge couplings are positive and yukawa couplings are negligibly small @xcite .
this problem is called the tachyonic slepton problem .
however , in our setup , the higgs multiplets have soft masses of @xmath5tev from @xmath19 for @xmath37tev , which play significant roles in low - energy susy mass spectra via the rg running : the tachyonic slepton problem is avoided and the masses of the third generation sfermions including the stops become @xmath5tev if the higgs soft mass squared is negative and @xmath38 is large . it is also assumed that there are no direct couplings between gauge field strength superfields and the susy breaking field , which may originate from the fact that @xmath4 is charged under a symmetry in the hidden sector .
gaugino masses vanish at the tree level and are generated radiatively from anomaly mediation @xcite : @xmath39 where @xmath40 , @xmath41 and @xmath42 are the bino , wino and gluino , respectively ; and @xmath43 , @xmath44 and @xmath45 are the gauge coupling constants of @xmath36 , @xmath35 and @xmath46 .
is taken to be consistent with @xmath47 gut . ]
these masses are expected to be @xmath11tev .
so far , the parameters of our model are summarized as @xmath48 where the boundary condition of the soft susy breaking parameters is set at @xmath49gev @xmath50 ; @xmath51 , where @xmath52 and @xmath53 are the soft masses for the up - type higgs and down - type higgs , respectively .
we fix sign(@xmath54 ) to be positive in the following discussions since we are interested in regions consistent with the muon @xmath2 experiment . in the parameter space of our interest , the typical values for @xmath18 and @xmath55 are @xmath56tev and @xmath5tev , respectively , with @xmath57 .
next , we explain how the mass hierarchy between the first / second and third generation sfermions are obtained .
as noted in @xcite , the hierarchical mass spectrum is realized when @xmath58 are negative and large .
contributions from one - loop renormalization group equations ( rges ) raise the third generation sfermion masses via terms proportional to the squared of the yukawa couplings : @xmath59 where @xmath60 and @xmath61 are the @xmath62 doublet squark and slepton of the third generation ; @xmath63 , @xmath64 and @xmath65 are the right - handed stop , sbottom and stau , respectively ; @xmath66 is the top yukawa coupling ; and @xmath67 . the contributions from eq .
( [ eq : rge_3rd ] ) dominate those from anomaly mediation . after solving rges ,
the third generation sfermions obtain masses of @xmath68tev at the low energy scale for @xmath69tev .
in addition to the contributions from anomaly mediation , the sfermions of the first two generations also obtain masses from @xmath70 and @xmath71 via the rg running , though they are suppressed , compared to those of the third generation sfermions .
this is because one - loop terms in rges are proportional to the squared of the first / second generation yukawa couplings , and gauge interaction terms are at the two - loop level . as a consequence ,
the sfermion mass spectrum at the low energy scale becomes automatically hierarchical .
note that the tachyonic slepton masses are avoided due to negative terms involving @xmath72 and terms involving the yukawa coupling squares and @xmath73 in beta - functions at the two - loop level : @xmath74 , \nonumber \\
\beta_{m_{\bar e_i}^2 } & \ni & \frac{1}{(16\pi^2)^2 } \left[\left ( \frac{36}{25 } g_1 ^ 4 \right ) ( m_{h_u}^2 + m_{h_d}^2 ) + \frac{12}{5 } g_1 ^ 2 s ' \right]\,,\end{aligned}\ ] ] where @xmath75 and @xmath76 .
the runnings of the first generation sfermion masses are shown in the left panel , and those of the third generation sfermion masses and higgs soft masses are shown in the right panel .
we take @xmath77tev , @xmath78 , and @xmath79gev@xmath80 . here , @xmath81 and @xmath82gev .
, title="fig : " ] .
the runnings of the first generation sfermion masses are shown in the left panel , and those of the third generation sfermion masses and higgs soft masses are shown in the right panel .
we take @xmath77tev , @xmath78 , and @xmath79gev@xmath80 . here , @xmath81 and @xmath82gev .
, title="fig : " ] in fig.[fig : rge ] , we show the rg running of soft mass parameters for @xmath83 and @xmath78 . here and hereafter , we take @xmath84 @xcite and @xmath85gev @xcite . in the left panel ,
the runnings of the first generation sfermion masses are shown .
the runnings of the third generation sfermion masses and the higgs soft masses are shown in the right panel .
one can see that the masses of the first generation sfermions at the low energy scale are @xmath86 - 1)tev , avoiding the tachyonic masses for the sleptons ( @xmath87 and @xmath88 ) . on the other hand , the masses for the third generation sfermions including the stop masses grow rapidly as @xmath34 decreases , and they reach to @xmath68tev at the low energy scale . in our setup , for the successful electroweak symmetry breaking ( ewsb ) with @xmath89
, the @xmath54-term has to be large as @xmath5tev and @xmath90 , which is required to avoid the tachyonic mass for the cp - odd higgs .
the latter condition can be satisfied only when the bottom- and tau- yukawa couplings , @xmath91 and @xmath92 , are large enough , which enters beta - functions for @xmath70 and @xmath71 as @xmath93 the absolute value of the negative @xmath71 decreases more than that of @xmath70 for large @xmath91 and @xmath94 , if @xmath95 is larger than @xmath96 . in our model , this is achieved with a large @xmath97 , since the bottom yukawa coupling gets larger with threshold corrections @xcite , @xmath98 where @xmath99 is a bottom quark mass ; @xmath100 is a vev of the down - type higgs ; @xmath101 ( @xmath102 ) is the mass of the lighter ( heavier ) sbottom ; @xmath103 is a loop function , @xmath104 notice that the bottom yukawa is enhanced when @xmath105 is negative for the fixed @xmath106 , while the susy contribution to the muon @xmath2 is positive when @xmath107 is positive . in our case , both @xmath108 and @xmath109 can be satisfied since the anomaly induced gaugino masses are proportional to the @xmath110 functions of the corresponding gauge couplings .
note that the threshold correction to @xmath91 , @xmath111 , improves the unification of the yukawa couplings . on @xmath106-@xmath112 plane for @xmath113100 ( top - left ) , 120 ( top - right ) , 140 ( bottom - left ) , 160 tev ( bottom - right ) . in the red ( green ) region ,
the muon @xmath2 is explained at 1@xmath7 ( 2@xmath7 ) level .
, title="fig : " ] on @xmath106-@xmath112 plane for @xmath113100 ( top - left ) , 120 ( top - right ) , 140 ( bottom - left ) , 160 tev ( bottom - right ) . in the red ( green ) region , the muon @xmath2 is explained at 1@xmath7 ( 2@xmath7 ) level .
, title="fig : " ] on @xmath106-@xmath112 plane for @xmath113100 ( top - left ) , 120 ( top - right ) , 140 ( bottom - left ) , 160 tev ( bottom - right ) . in the red ( green ) region , the muon @xmath2 is explained at 1@xmath7 ( 2@xmath7 ) level .
, title="fig : " ] on @xmath106-@xmath112 plane for @xmath113100 ( top - left ) , 120 ( top - right ) , 140 ( bottom - left ) , 160 tev ( bottom - right ) . in the red ( green ) region , the muon @xmath2 is explained at 1@xmath7 ( 2@xmath7 ) level .
, title="fig : " ] -@xmath112 plane for @xmath113100 ( top - left ) , 120 ( top - right ) , 140 ( bottom - left ) , 160tev ( bottom - right ) .
, title="fig : " ] -@xmath112 plane for @xmath113100 ( top - left ) , 120 ( top - right ) , 140 ( bottom - left ) , 160tev ( bottom - right ) .
, title="fig : " ] -@xmath112 plane for @xmath113100 ( top - left ) , 120 ( top - right ) , 140 ( bottom - left ) , 160tev ( bottom - right ) .
, title="fig : " ] -@xmath112 plane for @xmath113100 ( top - left ) , 120 ( top - right ) , 140 ( bottom - left ) , 160tev ( bottom - right ) .
, title="fig : " ] -@xmath112 plane . in the left panel ( right panel )
, the contours of @xmath114 ( @xmath115 ) are shown .
we take @xmath116tev . , title="fig : " ] -@xmath112 plane . in the left panel ( right panel ) , the contours of @xmath114 ( @xmath115 ) are shown .
we take @xmath116tev . , title="fig : " ] [ [ muon - g-2 ] ] muon @xmath2 + + + + + + + + + + + + + + + + + + + + + + in the typical parameter space of our model , the susy contribution to the muon @xmath2 , @xmath117 , is dominated by the bino-(l - smuon)-(r - smuon ) , where l and r represent the left - handed and right - handed , respectively .
this contribution is given by @xcite @xmath118 where @xmath119 is the muon mass ; @xmath120 @xmath121 is the mass of the l - smuon ( r - smuon ) ; @xmath122 is a loop function with @xmath123 .
here , @xmath124 and @xmath125 are two - loop corrections : @xmath124 is the correction to the muon yukawa coupling @xcite , @xmath126 which is positive and can become as large as @xmath127 , and @xmath128 is a leading logarithmic correction from qed @xcite , where @xmath129 is the fine - structure constant and @xmath130 is a smuon mass scale .
the susy contribution to @xmath6 is enhanced with the large @xmath131 and light smuons , which is the character of our model . in fig .
[ fig : stop_gm2 ] , we show the contours of the stop mass defined by @xmath132 and the regions consistent with the muon @xmath2 . the horizontal ( vertical ) axis shows @xmath106 @xmath133 , where @xmath134 .
the susy mass spectra and @xmath117 are calculated using suspect2.43 @xcite with modifications to include @xmath124 in eq.([eq : gm2 ] ) and the effects of the muon yukawa coupling on rg equations . in the red ( green ) regions , the muon @xmath2 is explained at 1@xmath7 @xmath135 level . as a reference value , we quote @xcite @xmath136 where @xmath137 is the experimental value @xcite and @xmath138 is a sm prediction . in those regions ,
the stop mass is as large as 11 - 17tev . in the shaded regions ,
the l - selectron ( @xmath139 ) or r - selectron ( @xmath140 ) is the lightest susy particle ( lsp ) , and these regions are considered to be excluded .
the regions with @xmath141gev , @xmath142gev gev and @xmath142gev , are chosen for the convenience of the numerical calculations . ] or the unsuccessful ewsb are dropped . in fig .
[ fig : msq_gm2 ] , we show the contours of the up - type squark mass ( @xmath143 ) , which is the lightest squark in most of the parameter space .
the mass of the up - type squark lies in the range of 1000 - 2500gev in the region consistent the muon @xmath2 at 1@xmath7 level , depending on the gravitino mass .
the gaugino masses at the susy mass scale of @xmath144tev are @xmath145 for @xmath146 . in most of the parameter space ,
the lightest susy particle ( lsp ) is the wino - like neutralino , whose mass is almost degenerate with that of the lightest chargino due to large @xmath54-term of @xmath5tev .
the mass difference dominantly comes from w / z boson loops , which tours out to be about @xmath147 @xcite .
this chargino is searched at the lhc using a disappearing - track , which leads to a constraint on the mass to be larger than 270gev with the cross section estimated assuming the direct production @xcite .- ray is severe @xcite . ] in the regions where the l / r selectron is the lsp , even if the selectron is unstable with an @xmath148-parity violation , a lhc constraint of multi - lepton final states @xcite is severe ; therefore , these regions are probably excluded .
[ [ yukawa - unification ] ] yukawa unification + + + + + + + + + + + + + + + + + + in our model , @xmath91 and @xmath92 are nearly degenerated at @xmath49gev in some regions of the parameter space .
furthermore , one can find a region where even the three yukawa couplings , @xmath91 , @xmath92 and @xmath66 , are nearly degenerated .
the unification of the yukawa couplings at @xmath149 is demonstrated in fig .
[ fig : yukawa_gut ] . motivated by the @xmath47 gut , the contours of @xmath150 is shown in the left panel , while @xmath151 in the right panel motivated by the @xmath25 gut . here ,
@xmath152 and @xmath115 are evaluated at @xmath149 .
the unification can be achieved at @xmath153% level with the help of @xmath111 in eq .
( [ eq : yb_cor ] ) . [ cols="^,^,^,^,^",options="header " , ] [ [ fcnc ] ] fcnc + + + + one might worry about the flavor violating sfermion masses induced by the yukawa couplings and large @xmath58 . in fact , the generated flavor violating masses are not so large but not negligibly small . using the leading log approximation , an off - diagonal element of the sfermion mass matrix
is estimated as @xmath154 in the super - ckm basis with @xmath155 . here
, @xmath156 is a typical squark mass .
thus , @xmath157 \approx -0.015 \left ( \frac{2 \ , { \rm tev}}{m_{\tilde q } } \right)^2 \left ( \frac{-m_{h_u}^2}{10 ^ 9 { \rm gev}^2 } \right),\end{aligned}\ ] ] which is consistent with the constraint from @xmath158 @xcite . [
[ mass - spectra ] ] mass spectra + + + + + + + + + + + + finally we show some mass spectra in our model parameter space ( table [ tab : sample ] ) , where @xmath159 ( mass eigenstate ) is the wino - like neutralino , @xmath160 is the bino - like neutralino and @xmath161 is the gluino . the higgs boson mass is computed using feynhiggs2.12.0
@xcite . in these points ,
the stop mass is large as 12 - 13tev while the first / second generation sfermions and gauginos are light as @xmath1(0.1 - 1)tev .
the higgsino mass parameter , @xmath54 , is as large as @xmath162tev , leading to the fine - tuning of the ewsb scale as @xmath163 . with the smuons of @xmath164 gev and large @xmath106 of @xmath165 ,
the muon @xmath2 is explained at the 1@xmath7 level .
we have proposed a scenario where only the higgs multiplets have direct couplings to the susy breaking sector .
the standard model matter multiplets as well as the gauge multiples do not have direct couplings to the susy breaking field at the classical level , and their masses are generated radiatively by anomaly mediation and higgs loops .
due to rg running effects from the higgs soft masses of @xmath1(10)tev , the third generation sfermions have masses of @xmath1(10)tev while the first and second generation sfermions have masses of @xmath1(0.1 - 1)tev , avoiding the tachyonic slepton problem of anomaly mediation .
the hierarchy of the masses originates from the structure of the yukawa couplings , i.e. , the yukawa couplings of the third generation are much larger than those of the first and second generations . in this case , there is no susy fcnc problem .
the hierarchical mass spectrum allows us to explain the higgs boson mass of @xmath166125gev and the observed value of the muon @xmath2 , simultaneously . in the whole region explaining the muon @xmath2 anomaly , the masses of the light squarks and gluino lies in the range smaller than 3tev ; therefore , it is expected to be checked at the lhc run-2 or the high luminosity lhc .
since the gravitino is heavier than about 100tev , the cosmological gravitino problem is relaxed @xcite . moreover , in our setup , the susy breaking field is not necessarily a gauge singlet of a hidden sector symmetry ; therefore , the cosmological moduli problem or polonyi problem @xcite can be avoided .
the possible drawback of our setup is the origin of the higgs @xmath167-term of @xmath153tev with the @xmath54-term of @xmath5tev .
this may be due to the fine - tuning of an ultraviolet model .
alternatively , the @xmath54-term and @xmath168-term may be generated by the vacuum expectation values of a @xmath169-term and @xmath16-term of a singlet chiral superfield _ a la _ the next - to minimal supersymmetric standard model .
we would like to thank yutaro shoji for collaboration at an early stage of this work .
this work is supported by jsps kakenhi grant numbers jp15h05889 ( n.y . ) and jp15k21733 ( n.y . ) .
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14 , 141801 ( 2014 ) [ arxiv:1312.4937 [ hep - ph ] ] .[/INST] we propose a scenario where only the higgs multiplets have direct couplings to a supersymmetry ( susy ) breaking sector .
the standard model matter multiplets as well as the gauge multiples are sequestered from the susy breaking sector ; therefore , their masses arise via anomaly mediation at the high energy scale with a gravitino mass of @xmath0tev .
due to renormalization group running effects from the higgs soft masses , the masses of the third generation sfermions become @xmath1(10)tev at the low energy scale , while the first and second generation sfermion masses are @xmath1(0.1 - 1)tev , avoiding the tachyonic slepton problem and flavor changing neutral current problem . with the splitting mass spectrum ,
the muon @xmath2 anomaly is explained consistently with the observed higgs boson mass of 125gev .
moreover , the third generation yukawa couplings are expected to be unified in some regions . </s> |
the solution of quantum chromodynamics _ on _ the light cone is still an unsolved theoretical task the present status of which is reviewed in ref . @xcite . in a recent paper @xcite a formulation of qcd in coordinates _ near _
the light cone has been proposed which has the advantage of keeping a direct link @xcite to equal time theories .
the cauchy problem is well defined in near light cone coordinates , since the initial data are given on a space like surface .
this formulation avoids the solution of constraint equations which , on the quantum field theoretic level , may be very complicated .
the problem of a nontrivial vacuum appears in a solvable form related to the transverse dynamics .
this is physically very appealing , since in high energy reactions the incoming particles propagate near the light cone and interact mainly exchanging particles with transverse momenta .
we would like to connect successful models for the soft transverse nonperturbative dynamics of high energy reactions ( refs .
@xcite ) to the underlying qcd hamiltonian . in diffractive reactions ,
fast lorentz contracted hadrons experience the confining forces of qcd in their transverse extensions and interact with other fast moving hadrons via soft interactions . in a theory of total cross sections
the nonperturbative infrared dynamics in the transverse plane is essential .
the objective of this paper is to investigate the effective transverse hamiltonian in qcd near the light cone for small light cone momenta . near light cone qcd
has a nontrivial vacuum which we claim can not be neglected even in the light cone limit .
we will demonstrate the existence of massless excitations in the zero mode theory .
these excitations do not decouple in the light cone limit .
genuine nonperturbative techniques must be used to investigate the behavior of this limit . in principle the additional parameter which labels the coordinate system can be chosen arbitrarily .
we will show that the zero mode hamiltonian depends on an effective coupling constant containing this parameter and evolves towards an infrared fixed point .
therefore , we propose a sophisticated choice of the frame dependence which facilitates calculations in the near light cone frame .
we use the infrared fixed point of the zero mode hamiltonian to follow a trajectory in the space of couplings , where high resolution is synchronized with the light cone limit .
note , we consider the parameter associated with the frame dependence as yet another coupling constant . as shown in ref .
@xcite the zero mode sector is also relevant to the definition of m - theory in light cone coordinates . we choose the following near light cone coordinates which smoothly interpolate between the lorentz and light front coordinates : x^t = x^+ & = & 12 \ { ( 1 + ) x^0 + ( 1 - ) x^3 } , + x^- & = & 12 ( x^0-x^3 ) .
[ coor ] the transverse coordinates @xmath0 , @xmath1 are unchanged ; @xmath2 is the new time coordinate , @xmath3 is a spatial coordinate . as finite quantization volume
we will take a torus and its extension in `` - '' , as well as in `` 1 , 2 '' direction is @xmath4 .
the scalar product of two 4-vectors @xmath5 and @xmath6 is given with @xmath7 as x_y^ & = & x^- y^+ + x^+ y^- - ^2 x^- y^- - _ _ + & = & x_- y_+ + x_+ y_- + ^2 x_+ y_+ - _ _ . [ scalpr ] obviously , the light - cone is approached as the parameter @xmath8 goes to zero . for non - zero @xmath8 , the transition to the coordinates introduced above can be formally identified as a lorentz - boost combined with a linear transformation , which avoids time dependent boundary conditions @xcite . the boost parameter @xmath9 is given by = , [ beta ] indicating that for @xmath10 the relative velocity @xmath11 .
of course , this is connected to the well - known interpretation of the tilted light - cone frame in terms of the infinite momentum frame .
the choice of near light cone coordinates allows to quantize the theory on a space - like finite interval of length @xmath4 in @xmath12 at equal times , _
i.e. _ @xmath13 .
the invariant length squared of this interval for @xmath14 is related to the length of the compact @xmath12 dimension .
s^2 & = & x^- x^+ + x^+ x^- - ^2 ( x^-)^2 - x_^2 + & = & -^2 l^2 . for simplicity
we consider also the transverse dimensions periodic in @xmath4 .
previous work of the st .
petersburg and erlangen groups @xcite assumed a fixed tilted coordinate system with fixed transverse ultraviolet cut off .
our main purpose in this paper is to consider the zero mode fields on a transverse lattice with _ varying _ transverse lattice spacing @xmath15 .
we propose to approach light - cone dynamics by synchronizing the continuum limit @xmath16 with the light - cone limit @xmath17 .
the vacuum fluctuations in the transverse directions induce a second order phase transition which allows to have a continuum limit of the lattice theory .
thereby we can eliminate the cut off in a controlled way , preserving the nontrivial vacuum structure .
the gauge fixing procedure in the modified light - cone gauge @xmath18 involves zero modes dependent on the transverse coordinates .
these zero mode fields carry zero linear momentum @xmath19 in near light cone coordinates , but finite amount of @xmath20 .
they correspond to `` wee '' partons in the language of the original parton model of feynman . in @xmath21
the zero mode fields @xmath22 are proportional to @xmath23 , i.e. they can be chosen color diagonal .
the use of an axial gauge is very natural for the light - cone hamiltonian even more so than in the equal - time hamiltonian .
the asymmetry of the background zero mode naturally coincides with the asymmetry of the space coordinates on the light cone .
the zero mode fields describe disorder fields . depending on the effective coupling
the zero mode transverse system will be in the massive or massless phase .
its second order phase transition allows to perform the continuum limit in the zero mode hamiltonian .
our main conjecture is that the continuum limit and light cone limit can be realized simultaneously at this critical point .
the evolution of the coupling determines the approach to the light cone with transverse resolution approaching zero .
the resulting relation is reminiscent of the simple behavior one gets from considering naive scaling relations and dynamics in the infinite momentum frame .
we will also calculate the contribution of the two dimensional zero modes to the ground state energy and show that it scales with the three dimensional volume .
this estimate demonstrates very simply the relevance of modes with lower dimensionality to the full problem in the case of critical second order behavior . the naive considerations for a simultaneous light cone and continuum limit go as follows .
we characterize the infinite momentum frame by giving the momenta of the proton and photon in usual coordinates .
the fast moving proton carries @xmath24 and the photon @xmath25 , where @xmath26 is the energy transfer in the laboratory .
the dominant contribution comes from energy conserving transitions , where the energy of the quark in the final state equals the sum of initial quark and photon energies . for collinear quarks with momentum @xmath27 , where @xmath28 denotes
the momentum fraction , one explicitly finds = x_b p+ , which yields the `` scaling variable '' @xmath29 as long as @xmath30 , i.e. the `` infinite '' momentum has to be large enough : m = p q = 1/a . at the same time , the photon has a wavelength @xmath31 which resolves transverse details of size @xmath15 in the hadronic wavefunction . by eq . , the @xmath32 factor of the `` infinite '' momentum is related to @xmath8 .
therefore we expect that the parameter @xmath8 approaches zero with the transverse cutoff @xmath33 = 1 am 0 .
one of the objectives of this paper is to derive the precise relation between @xmath8 and @xmath15 .
we will simulate the zero mode dynamics on a @xmath34 dimensional lattice to find the fixed point of the effective coupling .
the light - like limit is governed by an infrared fixed point ( ref .
most previous discussions of the zero mode problem have been on the classical equations of motion level , here we will work on the fully nonperturbative quantum level .
our work is not directly related to m - theory , but some of the consequences may be relevant for other studies with light like compactification .
@xcite the near light cone hamiltonian has been derived .
a similar hamiltonian has been obtained in equal time coordinates @xcite . here
we will sketch the derivation .
we restrict ourselves to the color gauge group @xmath21 and dynamical gluons ; only an external ( fermionic ) charge density @xmath35 is considered here .
since the @xmath36 coordinates have no momenta conjugate to them , the weyl gauge @xmath37 is the starting point for a canonical formulation .
the canonical momenta of the dynamical fields @xmath38 are given by ^a_- & = & = f^a_+- , + ^a_i & = & = f^a_-i + ^2 f^a_+i .
> from this , we get the weyl gauge hamiltonian density [ hweyl ] h_w = ^a_- ^a_- + f^a_12f^a_12 + _ i=1,2(^a_i - f^a_-i)^2 .
the hamiltonian has to be supplemented by the original euler lagrange equation for @xmath39 as constraints on the physical states ( gauss law constraints ) [ gauss ] g^a(x_,x^- ) | & = & ( d_-^ab ^b_- + d_^ab^b _ + g _
m^a ) | + & = & ( d_-^ab^b_- + g_^a ) |= 0 . in order to obtain a hamiltonian formulated in terms of unconstrained variables
, one has to resolve the gauss law constraint . via unitary gauge fixing transformations [ 9,10 ] a solution of gauss law with respect to components of the chromo
electric field @xmath40 can be accomplished .
this gives a hamiltonian independent of the conjugate gauge fields @xmath41 , _
i.e. _ the latter become cyclic variables .
classically this would correspond to the light front gauge @xmath42 .
however , this choice is not legitimate if we want to consider the theory in a finite box . instead
, the ( classical ) coulomb light front gauge @xmath43 is compatible with gauge invariance and periodic boundary conditions .
the reason is that @xmath41 carries information on the ( gauge invariant ) eigenvalues of the spatial polyakov line matrix [ polyakov ] ( x_)=p , which can be written in terms of a diagonal matrix with the zero mode field @xmath44 ( x _ ) = v v^ .
obviously we have to keep these ` zero modes ' @xmath45 as dynamical variables , while the other components of @xmath41 are eliminated .
the zero mode degrees of freedom are independent of @xmath3 and , therefore , correspond to quantities with zero longitudinal momentum @xmath46 . in order to eliminate the momentum @xmath47 , conjugate to @xmath48 , by means of gauss law
, one needs to ` invert ' the covariant derivative @xmath49 which simplifies to @xmath50 $ ] . on the space of physical states one
can simply make the replacement can be explicitly performed in terms of its eigenfunctions , . ] _
-(x_,x_- ) p_-(x_)-(d_-^-1 ) g_(x_,y^- ) .
the operator @xmath51 is also diagonal and @xmath52 is the momentum conjugate to the zero mode @xmath53 .
it has eigenvalue zero with respect to @xmath54 , _
i.e. _ @xmath55 , and is therefore not constrained .
the appearance of the zero modes implies a residual gauss law , which arises from the @xmath56 integration over eq . for the @xmath57 component using periodic boundary conditions in the @xmath56 direction
this constraint on two dimensional fields can be handled in full analogy to qed , since it concerns the diagonal part of color space .
a further coulomb gauge fixing in the @xmath21 3direction eliminates the color neutral , @xmath12independent , two dimensional longitudinal gauge field in favor of a neutral chromo electric field e_(x _ ) = g _ dy^- dy _
d(x_- y _ ) \ { f^3ab a^a_(y _ , y^- ) ^b_(y _ , y^- ) + ^3_m(y _ , y^- ) }
here we use the periodic greens function of the two dimensional laplace operator [ green2 ] d(z _ ) = - 1l^2 _ 0 1p_n^2 e^i p_n z _ , p_n = , where @xmath58 and @xmath59 are integers . as a remnant of the local gauss law constraints , a global condition [ gaussgl ] q^3 |
= dy^- dy _ \ { f^3ab a^a_(y_,y^- ) ^b_(y _ , y^- ) + ^3_m(y _ , y^- ) } | = 0 emerges .
the physical meaning of this equation is that the neutral component of the total color charge , including external matter as well as gluonic contributions , must vanish in the sector of physical states .
it can be shown ( see @xcite ) that there must be @xmath60 everywhere in transverse space in order to avoid an infinite coulomb energy .
the two conditions together suggest that physical states have to be color singlets .
the final hamiltonian density in the physical sector explicitly reads ( in terms of unconstrained @xmath61 and @xmath62 obtained after a shift is made by subtracting averages ) @xcite [ hamil ] h & = & ^2 + 1 ^ 2 ^2 + & + & 1 ^ 2 ^2 + 12 l^2 p_-^3(x _ ) p^3_-(x _ ) + & + & 1l^2 _
0^l dz^- _ 0^l dy^- _ p , q , n^ e^i 2n(z^- - y^-)/l , where @xmath63 and @xmath64 are matrix labels for rows and columns , @xmath65 and the prime indicates that the summation is restricted to @xmath66 if @xmath67 . the operator @xmath68 is defined as g_= [ gop ] _ _ + gf^abc a^b _ ( ^c _ - 1l e^c _ ) + g_m .
the last two terms of the weyl gauge hamiltonian come from the original term @xmath69 with squared electric field strengths in @xmath12 direction . after elimination of @xmath47 the zero mode part and the light cone coulomb energy in the axial gauge
remain . in the coulomb term
one sees the role of the zero mode fields as infrared regulators of the spatial momenta @xmath70 which are quantized due to the compact interval @xmath4 .
since the two dimensional theory has been coulomb gauge fixed , the electric field @xmath71 replaces the canonical momentum of the longitudinal , neutral gauge field which has been eliminated .
we note that the terms containing @xmath71 and the momentum @xmath72 , have the pre - factor @xmath73 .
physically this pre - factor signals the increase of transverse electric energies with the boost factor @xmath74 .
the boost also couples transverse electric fields with transverse magnetic fields . in the light - cone limit
the pre - factor diverges and the adjacent brackets become constraint equations .
this reflects the corresponding reduction of the number of degrees of freedom if one goes exactly on the light cone .
we do not follow this procedure , but keep a finite @xmath8 as a kind of lagrange parameter .
a characteristic feature of an exact light - cone formulation is the triviality of the ground state .
this may simplify explicit calculations , _
e.g. _ of the hadron spectrum . however , the light cone vacuum is definitely not trivial in the zero mode sector .
in fact , already in ref @xcite we have shown strong and weak coupling solutions of the zero mode hamiltonian .
massless modes influence the dynamics in the light cone limit , whereas massive modes decouple when @xmath75 .
in contrast to earlier work , we solve the zero mode hamiltonian in this paper numerically showing the transition from the massive phase to the massless phase .
the zero mode degrees of freedom @xmath76 couple to the transverse three dimensional gluon fields @xmath77 via the second magnetic term in @xmath78 , the coulomb term and directly via the electric field @xmath71 .
we remark that the transverse electric fields @xmath79 and @xmath80 are dual to the magnetic fields @xmath81 and @xmath82 .
this duality is typical for the light cone and is absent in the equal time case .
since duality plays an important role in supersymmetric qcd its role in light cone theories should deserves to be investigated in greater detail . in the following we neglect the couplings between the three and two dimensional fields and
consider the pure zero mode hamiltonian [ hamil3 ] h = d^2x .
the global constraint , eq .
, does not contain @xmath76 and @xmath19 and , consequently , is irrelevant for the time being .
even at this level of severe approximations the zero mode hamiltonian differs from the corresponding one in qed .
the reason is the hermiticity defect of the canonical momentum @xmath83 . in the schrdinger representation eq .
[ hamil4 ] h = d^2x , contains the jacobian @xmath84 which equals the haar measure of @xmath21 [ jacob ] j(a_-^3 ( _ ) ) = ^2 ( a_-^3 ( _ ) ) .
it stems from the gauge fixing procedure , effectively introducing curvilinear coordinates
. it also appears in the functional integration volume element for calculating matrix elements .
it is convenient to introduce dimensionless variables ( _ ) = , which vary in a compact domain @xmath85 .
we regularize the above hamiltonian @xmath86 by introducing a lattice spacing @xmath15 between transversal lattice points @xmath87 .
next we appeal to the physics of the infinite momentum frame and factorize the reduced true energy from the lorentz boost factor @xmath88 and the cut off by defining @xmath89 [ hdef ] h = 12a h_red in the continuum limit of the transverse lattice theory we let @xmath15 go to zero . for small lattice spacing we obtain the reduced hamiltonian h_red = _ \ { -g^2_eff 1j j + 1g^2_eff _ i=1,2 ( ( ) -(+_i))^2 } . with the effective coupling constant -5 mm [ g2eff ] g^2_eff
= the first part of the hamiltonian contains the kinetic ( electric ) energy of the @xmath21 rotators on a half circle at each lattice point and the second part gives the potential ( magnetic ) energy of these rotators due to the differences of angles at nearest neighbor sites . for further discussion
we define these electric and magnetic parts as : h_red & = & h_e + h_m + h_e & = & _ h^e _ + h_m & = & _ _
i=1,2 h^m_,+_i in the strong coupling domain where we have analytical solutions of the zero mode hamiltonian , the numerical hamiltonian lattice theory agrees with the analytical solutions for the mass gap .
the real question concerns the continuum limit of the zero mode system which occurs outside of the strong coupling region . for this purpose
we have to find the region of vanishing mass gap for the lattice hamiltonian .
we solve the equivalent lattice theory in a euclidean formulation .
the zero mode hamiltonian represents a @xmath90 dimensional theory in two spatial and one time direction .
the lattice has @xmath91 extensions in transverse space and @xmath92 extension in near light cone time . to set up the density matrix one has to write down the trotter formula for the given hamiltonian .
using @xmath93 we have ( -t h_red ) = _
n_t ^n_t , where each time evolution step @xmath94 can be separately done for the electric and magnetic part of the hamiltonian . for definiteness
, we choose @xmath95 in all the following . in the appendix
we show that this choice of @xmath94 optimizes the updating procedure since it generates approximately equal widths for the weight functions resulting from the kinetic and potential energies .
the different time slices will labeled with the index @xmath96 .
the electric hamiltonian can be evaluated by inserting products of complete set single site eigenfunctions @xmath97 ( @xcite ) .
practically a maximal number @xmath98 of eigenfunctions is fully sufficient to reach convergence in the interval of couplings we need .
[ sum_over_states ]
_ l+1 | h^e | _
n_l+1,n_l _ l+1 | n_l+1 n_l+1 | h^e | n_l n_l | _ l _ n_l=0^n_max c_n_l(_l+1 ) g_eff^2 n_l(n_l+2 ) c_n_l(_l ) with the ( single site ) eigenfunctions and eigenvalues given as : [ basis ] c_n_l(_l ) & = & \ { } , + h^e c_n_l(_l ) & = & g^2_eff n_l ( n_l+2 ) c_n_l(_l ) .
the eigenfunctions form an orthonormal set with respect to a scalar product which contains the jacobian in the measure .
the jacobian @xmath99 has been defined above .
the magnetic part is diagonal in @xmath100 _
i.e. _ local in time : \{_l()}|h_m|\{_l ( ) } = h_m(\{_l ( ) } ) = _ _ i=1,2 h^m_,+_i ( _ l()-_l(+_i ) ) .
the full partition function is given by an integral over all time slices z & = & = _ ( j ( ( ) ) d ( ) ) \ { ( ) } | | \ { ( ) } + & = & _ , l ( j ( ( ) ) d ( ) _ n_l=0^n_max c_n_l(_l+1 ( ) ) c_n_l(_l ( ) ) ) + & & _
because of the jacobian the dominant contributions to the partition function come from @xmath101 values around @xmath102 .
the hamiltonian is invariant under reflections @xmath103 . in the strong coupling limit , where @xmath104 is large , the half rotators act almost independently on each lattice site producing a large mass gap . the system is disordered . for decreasing coupling constant
@xmath104 the movement of the individual rotators becomes locked from one site to the next .
long range correlations develop . the order parameter ( or `` magnetization '' ) of the system is the expectation value of the trace of the polyakov line , which on the lattice has the form p = = 1n^3_b , ( b , ) .
[ orderpar ] the order parameter is odd under the above symmetry operation .
operator expectation values are evaluated with the density matrix defined by @xmath89 and @xmath105 : o = 1zo . at each particular @xmath106 _
g 1/g_eff^2 we simulate lattice sizes with equal number of sites in all directions @xmath107 and @xmath108 .
a metropolis algorithm is used for updating with the steps size and the number of hits adapted to @xmath106 . in order to tabulate the boltzmann weights related to the timelike links we also discretized the continuous angle variables to a system of @xmath109 orientations : @xmath110 ,
@xmath111 $ ] . in this explorative investigation we generated between @xmath112 and @xmath113 uncorrelated configurations depending on the @xmath106 and lattice size .
all our calculations were done on a cluster of alphastations with the single site metropolis updating algorithm sketched above , so the accuracy can be improved using a more powerful algorithms and/or more computing resources .
we calculate the @xmath106 dependence of the following quantities : average electric energy @xmath114 and magnetic energy @xmath115 per site , the average of the absolute value of the order parameter @xmath116 , the susceptibility @xmath117 and the normalized fourth cumulant @xmath118 ( which gives the deviation of the moments of the polyakov expectation value from a pure gaussian behavior ) : -7 mm _ e , m & = & 1n^2 h_e , m + & = & n^3 ( p^2 - p ^2 ) [ chidef ] + g_r & = & - 3 .
firstly we calculated the ground state energy for strong couplings @xmath119 and compared with the exact calculation @xcite .
the obtained results from the lattice agree with the analytical result . for higher values of @xmath106
the lattice calculation agrees within @xmath120 with the previous effective double site calculation for the energy per site@xcite . the ultraviolet regularization with @xmath94 influences the final lattice result .
the energies are measured with high accuracy and practically do not depend on the infrared cutoff , i.e. on the total lattice size for @xmath121 .
the situation for other variables is different . in order to see the emergence of a massless phase , we investigated the ( connected ) time correlation functions of the ( trace of the ) polyakov line operators : k(0 , ) = 1n^4 _ , ( ( b,0 ) ) ( ( b , ) ) - |p| ^2 .
the correlation masses are obtained from a fit of the time correlation functions @xmath122 to a parameterization taking the periodicity in time into account [ mcorr ] k(0,n ) = c . the obtained masses for different lattice sizes are shown in fig.[figmasses]a . for each fixed @xmath106 we extrapolated the mass to the limit @xmath123 using a linear @xmath124 parameterization [ mnfit ] m(_g , n ) = m_0(_g ) + . our data for @xmath125 can be fitted with this linear form for @xmath126 .
the resulting dependence of @xmath127 on @xmath106 is presented in fig.[figmasses]b .
the mass vanishes in the infinite volume limit near @xmath128 , which is a first guess for the critical coupling @xmath129 . in order to extract more exact information on the critical behavior [ mbeta ]
m(_g ) ( 1_g-1_g^*)^ . from our data on small systems
we have done a finite size scaling ( fss ) @xcite analysis of the variables @xmath116 , @xmath117 and @xmath118 , searching for the critical coupling @xmath130 in the interval @xmath131 .
we could determine the critical indices @xmath132 , @xmath32 and @xmath26 using an approach employed for @xmath21 gauge theory at the finite temperature transition by engels et al . @xcite . the general form of the scaling relations for a variable @xmath133 ( @xmath133 = @xmath116 , @xmath117 , @xmath118 ) is [ fssgen ] v(t , n ) = n^/ f_v(t
n^1/ , g_i n^y_i ) , where @xmath134 is the corresponding critical index ( @xmath132 , @xmath32 , 0 ) for the respective quantities and @xmath135 is the reduced inverse coupling @xmath106 : [ fsst ] t = . in practice eq
. is computed near @xmath136 .
expanding up to first order in @xmath135 and taking into account only the largest irrelevant exponent @xmath137 one obtains [ fssone ] v(t , n ) = n^/ . .
[ tabres ] critical parameters for the transverse qcd near the light cone .
the ising indices are from ref.@xcite . [
cols="^,^,^,^ " , ] with this parameterization we analyze our data for lattice sizes @xmath138 .
the @xmath106 dependence in eq .
is valid near the critical point .
the quality of the fit to the data in different intervals on @xmath106 can serve as a guide to localize the critical point @xmath130 @xcite .
we find that in our case this parameterization can be applied for @xmath116 and @xmath117 only for @xmath139 : for smaller @xmath106 the @xmath140 becomes too large .
finally we use the parameterization of eq . in the interval @xmath141 ( see fig.[figfss ] ) where @xmath142 and an expansion of first order in @xmath135 still is applicable . in this @xmath106 interval the fits for @xmath116 and @xmath117 yield a @xmath143 . to have a reliable error estimate for the extracted parameters we use the jackknife method . the results for @xmath144 and critical indices @xmath132 , @xmath32 and @xmath26 are presented in table 1 .
we use @xmath145 , but in fact the results do not depend on @xmath146 in the interval @xmath147 .
it should be noticed that the system frequently flips between the two ordered states on a finite lattice .
therefore the expectation value @xmath148 in equation vanishes with good accuracy .
analogously to the treatment of the magnetization in the 3-dimensional ising model , we should - instead of the expression for @xmath117 in eq .
- define the susceptibility in the broken phase as @xmath149 . for the ising case this susceptibility
is supposed to converge towards the correct infinite volume limit . due to lack of statistics , however , we did not use separate expressions for @xmath117 in the two phases .
our data for @xmath118 are even much less accurate which excludes the possibility to use them in the fss analysis .
the values found for the critical indices @xmath132 , @xmath32 and @xmath26 are not far from those of the ising model ( @xmath150 ) ( see table 1 ) .
they are much less accurate but also in agreement with a high statistics analysis @xcite of the @xmath21 deconfinement transition at finite temperature .
we interprete the behavior of the light cone zero mode theory as a consequence of the underlying @xmath151 symmetry of the hamiltonian .
@xmath151 transformations correspond to reflections of the angle variables @xmath152 around @xmath102 .
the hamiltonian and the measure of eq .
( 17 ) are invariant under these transformations .
the resulting critical behavior is common to ising like models .
the critical coupling itself is a nonuniversal quantity and we have found a rough value .
more extended work with the lattice hamiltonian near the light cone is needed to clarify the continuous transition further .
the scaling analysis gives indications that there is a second order transition between a phase with massive excitations at strong coupling and a phase with massless excitations in weak coupling . to reach a higher accuracy large scale simulations of the hamiltonian zero mode system
are needed . in this context
it is advisable to treat the coupled system of three and two dimensional modes together .
a calculation in the epsilon expansion @xcite gives the zero of the @xmath132-function as an infrared stable fixed point .
this shows that the limit of large longitudinal dimensions @xmath4 is well defined . using the running coupling constant @xmath104 of the zero mode system we have ( ) ma = ( g^2_eff - g^*2_eff)^with @xmath153 and @xmath154 from our lattice calculations ( table [ tabres ] ) .
the mass can be interpreted as an inverse correlation length @xmath155 .
when the correlation length @xmath156 approaches the temporal size of the lattice @xmath157 in the infrared limit we can identify @xmath158 with @xmath159 , where @xmath4 is our infrared length scale .
therefore the effective coupling @xmath160 ( ) runs with @xmath159 in the following way [ gevol ] g^2_eff = g^*2_eff + ( _ 0 g^*2_eff)^1/ ( ) ^1/ . the coupling to the three dimensional modes produces the usual evolution of @xmath161 in @xmath21 qcd , where the coupling @xmath162 at the lattice scale @xmath15 is related to the coupling @xmath163 defined at the infrared scale @xmath164 as follows [ gevola ] g^2(a)= . combining the eqs .
and we can synchronize the approach to the light cone , _ i.e. _ the limit @xmath165 with the continuum limit @xmath166 .
the condition that the three - dimensional evolution of @xmath161 has to be compatible with the two - dimensional evolution of @xmath104 towards @xmath167 yields that for @xmath168 the light cone parameter @xmath8 approaches zero as ( a ) ~ .
this relation is similar to the naive scaling result deduced in section @xmath169 from physics arguments besides logarithmic modification .
although at the outset we had as parameters @xmath170 and @xmath8 in the hamiltonian we reduce this multiparameter problem to a problem with one single coupling constant which can be chosen as @xmath171 .
we can use the energy and the critical behavior of the euclidean @xmath90 dimensional system to obtain its contribution to the ground state energy of the system in @xmath172 dimensions . in our calculations the energy of the zero mode hamiltonian @xmath173 near the critical coupling is proportional to @xmath174 . using the scaling of @xmath8 determined from the compatibility of 2-dimensional and 3-dimensional dynamics , we can eliminate @xmath8 in favor of @xmath175 and get a zero mode energy which grows linearly with the 3-dimensional volume .
that means the zero mode dynamics becomes relevant for the full problem , _
i.e. _ h a ~n_l n^2 _ .
[ meanha ] in reality the zero mode system is coupled to the @xmath172 dimensional system the extension of which is large .
so we expect that the couplings of the @xmath90 dimensional system can get modified . because of the universal dynamics near the infrared fixed point this will not change the qualitative form of the volume dependence obtained in eq . .
the behavior of the zero mode hamiltonian has to be taken into account when we try to solve for the infinite momentum frame solutions of the complete hamiltonian .
the discussion @xcite until now often centers on the order of limits . in order to guarantee a meaningful limit of the near light cone theory ,
one first has to take @xmath176 and then one can take @xmath177 .
this is a workable procedure in solvable @xmath178 dimensional models . in qcd in @xmath172 dimensions
it hardly can serve as a prescription .
numerical solutions have to be obtained with a finite cutoff and the continuum limit can only be reached approximately via scaling relations .
it is in this case that the role of zero mass excitations will crucially enter the physics .
as one sees above the synchronization of the continuum limit with the light cone limit leads to results which are independent of the near light cone parameter @xmath8 .
the independence of the ground state energy near the critical coupling gives us back lorentz invariance which states that the physics should not depend on the reference frame .
the vacuum energy is not allowed to depend on @xmath8 .
there are dynamical zero modes in near light cone qcd which contain the physics of the nonperturbative qcd vacuum , the physics of the gluon and quark condensates .
the nontrivial structure of the nonabelian gauge theory enters in our calculation through the kinetic operator of the rotators which at finite resolution have a finite mass gap vanishing only in the continuum limit .
the near light cone description of qcd based on a modified axial gauge @xmath179 yields a very natural formulation of high energy scattering .
polyakov variables near the light cone have already entered the calculations of high energy cross sections in two different ways : for the geometrical size of cross sections in ref.@xcite the correlations between polyakov lines along the projectile and target directions are important .
for this situation an interpolating gauge may be useful .
for the energy dependence of cross sections an evolution equation of polyakov line correlators approaching the light cone has been discussed in ref .
@xcite which generalizes the bfkl- equation .
this situation is close to the treatment in this paper .
now the decisive step is to back up our theoretical work on effective transverse qcd dynamics near the light cone with phenomenological consequences for high energy scattering .
a choice of @xmath94 is proposed by comparing monte - carlo weights @xmath180 and @xmath181 which link nearest neighbors in time and space respectively w_t(_1,_2 ) & = & _ 1(x , y,+1 ) e^-h^e _ 2(x , y , ) , + w_s(_1,_2 ) & = & _ 1(x+1,y , ) e^-h^m _ 2(x , y , ) . the probability distribution for the update of the field @xmath182 is given by the product of weights for all links connecting it to neighbors in time and space .
so the updating procedure for @xmath152 is more effective when @xmath180 and @xmath181 have similar distributions near the angle @xmath183 where the jacobian has its maximum . for @xmath184 ( fig .
[ figwlinks]a ) the spatial weights @xmath181 have a much wider distribution than the timelike weights @xmath180 , whereas for @xmath185 ( fig .
[ figwlinks]c ) the situation is reverse .
for the intermediate case @xmath95 ( fig .
[ figwlinks]b ) the widths of the distributions are very similar , therefore the updating procedure is optimal .
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a. harindranath , l. martinovic and j. p. vary , hep - th/9912085 . i. i. balitsky , hep - ph/9706411 . | starting from the qcd hamiltonian in near - light cone coordinates , we study the dynamics of the gluonic zero modes .
euclidean 2 + 1 dimensional lattice simulations show that the gap at strong coupling vanishes at intermediate coupling .
this result opens the possibility to synchronize the continuum limit with the approach to the light cone . | <s>[INST]the solution of quantum chromodynamics _ on _ the light cone is still an unsolved theoretical task the present status of which is reviewed in ref . @xcite . in a recent paper @xcite a formulation of qcd in coordinates _ near _
the light cone has been proposed which has the advantage of keeping a direct link @xcite to equal time theories .
the cauchy problem is well defined in near light cone coordinates , since the initial data are given on a space like surface .
this formulation avoids the solution of constraint equations which , on the quantum field theoretic level , may be very complicated .
the problem of a nontrivial vacuum appears in a solvable form related to the transverse dynamics .
this is physically very appealing , since in high energy reactions the incoming particles propagate near the light cone and interact mainly exchanging particles with transverse momenta .
we would like to connect successful models for the soft transverse nonperturbative dynamics of high energy reactions ( refs .
@xcite ) to the underlying qcd hamiltonian . in diffractive reactions ,
fast lorentz contracted hadrons experience the confining forces of qcd in their transverse extensions and interact with other fast moving hadrons via soft interactions . in a theory of total cross sections
the nonperturbative infrared dynamics in the transverse plane is essential .
the objective of this paper is to investigate the effective transverse hamiltonian in qcd near the light cone for small light cone momenta . near light cone qcd
has a nontrivial vacuum which we claim can not be neglected even in the light cone limit .
we will demonstrate the existence of massless excitations in the zero mode theory .
these excitations do not decouple in the light cone limit .
genuine nonperturbative techniques must be used to investigate the behavior of this limit . in principle the additional parameter which labels the coordinate system can be chosen arbitrarily .
we will show that the zero mode hamiltonian depends on an effective coupling constant containing this parameter and evolves towards an infrared fixed point .
therefore , we propose a sophisticated choice of the frame dependence which facilitates calculations in the near light cone frame .
we use the infrared fixed point of the zero mode hamiltonian to follow a trajectory in the space of couplings , where high resolution is synchronized with the light cone limit .
note , we consider the parameter associated with the frame dependence as yet another coupling constant . as shown in ref .
@xcite the zero mode sector is also relevant to the definition of m - theory in light cone coordinates . we choose the following near light cone coordinates which smoothly interpolate between the lorentz and light front coordinates : x^t = x^+ & = & 12 \ { ( 1 + ) x^0 + ( 1 - ) x^3 } , + x^- & = & 12 ( x^0-x^3 ) .
[ coor ] the transverse coordinates @xmath0 , @xmath1 are unchanged ; @xmath2 is the new time coordinate , @xmath3 is a spatial coordinate . as finite quantization volume
we will take a torus and its extension in `` - '' , as well as in `` 1 , 2 '' direction is @xmath4 .
the scalar product of two 4-vectors @xmath5 and @xmath6 is given with @xmath7 as x_y^ & = & x^- y^+ + x^+ y^- - ^2 x^- y^- - _ _ + & = & x_- y_+ + x_+ y_- + ^2 x_+ y_+ - _ _ . [ scalpr ] obviously , the light - cone is approached as the parameter @xmath8 goes to zero . for non - zero @xmath8 , the transition to the coordinates introduced above can be formally identified as a lorentz - boost combined with a linear transformation , which avoids time dependent boundary conditions @xcite . the boost parameter @xmath9 is given by = , [ beta ] indicating that for @xmath10 the relative velocity @xmath11 .
of course , this is connected to the well - known interpretation of the tilted light - cone frame in terms of the infinite momentum frame .
the choice of near light cone coordinates allows to quantize the theory on a space - like finite interval of length @xmath4 in @xmath12 at equal times , _
i.e. _ @xmath13 .
the invariant length squared of this interval for @xmath14 is related to the length of the compact @xmath12 dimension .
s^2 & = & x^- x^+ + x^+ x^- - ^2 ( x^-)^2 - x_^2 + & = & -^2 l^2 . for simplicity
we consider also the transverse dimensions periodic in @xmath4 .
previous work of the st .
petersburg and erlangen groups @xcite assumed a fixed tilted coordinate system with fixed transverse ultraviolet cut off .
our main purpose in this paper is to consider the zero mode fields on a transverse lattice with _ varying _ transverse lattice spacing @xmath15 .
we propose to approach light - cone dynamics by synchronizing the continuum limit @xmath16 with the light - cone limit @xmath17 .
the vacuum fluctuations in the transverse directions induce a second order phase transition which allows to have a continuum limit of the lattice theory .
thereby we can eliminate the cut off in a controlled way , preserving the nontrivial vacuum structure .
the gauge fixing procedure in the modified light - cone gauge @xmath18 involves zero modes dependent on the transverse coordinates .
these zero mode fields carry zero linear momentum @xmath19 in near light cone coordinates , but finite amount of @xmath20 .
they correspond to `` wee '' partons in the language of the original parton model of feynman . in @xmath21
the zero mode fields @xmath22 are proportional to @xmath23 , i.e. they can be chosen color diagonal .
the use of an axial gauge is very natural for the light - cone hamiltonian even more so than in the equal - time hamiltonian .
the asymmetry of the background zero mode naturally coincides with the asymmetry of the space coordinates on the light cone .
the zero mode fields describe disorder fields . depending on the effective coupling
the zero mode transverse system will be in the massive or massless phase .
its second order phase transition allows to perform the continuum limit in the zero mode hamiltonian .
our main conjecture is that the continuum limit and light cone limit can be realized simultaneously at this critical point .
the evolution of the coupling determines the approach to the light cone with transverse resolution approaching zero .
the resulting relation is reminiscent of the simple behavior one gets from considering naive scaling relations and dynamics in the infinite momentum frame .
we will also calculate the contribution of the two dimensional zero modes to the ground state energy and show that it scales with the three dimensional volume .
this estimate demonstrates very simply the relevance of modes with lower dimensionality to the full problem in the case of critical second order behavior . the naive considerations for a simultaneous light cone and continuum limit go as follows .
we characterize the infinite momentum frame by giving the momenta of the proton and photon in usual coordinates .
the fast moving proton carries @xmath24 and the photon @xmath25 , where @xmath26 is the energy transfer in the laboratory .
the dominant contribution comes from energy conserving transitions , where the energy of the quark in the final state equals the sum of initial quark and photon energies . for collinear quarks with momentum @xmath27 , where @xmath28 denotes
the momentum fraction , one explicitly finds = x_b p+ , which yields the `` scaling variable '' @xmath29 as long as @xmath30 , i.e. the `` infinite '' momentum has to be large enough : m = p q = 1/a . at the same time , the photon has a wavelength @xmath31 which resolves transverse details of size @xmath15 in the hadronic wavefunction . by eq . , the @xmath32 factor of the `` infinite '' momentum is related to @xmath8 .
therefore we expect that the parameter @xmath8 approaches zero with the transverse cutoff @xmath33 = 1 am 0 .
one of the objectives of this paper is to derive the precise relation between @xmath8 and @xmath15 .
we will simulate the zero mode dynamics on a @xmath34 dimensional lattice to find the fixed point of the effective coupling .
the light - like limit is governed by an infrared fixed point ( ref .
most previous discussions of the zero mode problem have been on the classical equations of motion level , here we will work on the fully nonperturbative quantum level .
our work is not directly related to m - theory , but some of the consequences may be relevant for other studies with light like compactification .
@xcite the near light cone hamiltonian has been derived .
a similar hamiltonian has been obtained in equal time coordinates @xcite . here
we will sketch the derivation .
we restrict ourselves to the color gauge group @xmath21 and dynamical gluons ; only an external ( fermionic ) charge density @xmath35 is considered here .
since the @xmath36 coordinates have no momenta conjugate to them , the weyl gauge @xmath37 is the starting point for a canonical formulation .
the canonical momenta of the dynamical fields @xmath38 are given by ^a_- & = & = f^a_+- , + ^a_i & = & = f^a_-i + ^2 f^a_+i .
> from this , we get the weyl gauge hamiltonian density [ hweyl ] h_w = ^a_- ^a_- + f^a_12f^a_12 + _ i=1,2(^a_i - f^a_-i)^2 .
the hamiltonian has to be supplemented by the original euler lagrange equation for @xmath39 as constraints on the physical states ( gauss law constraints ) [ gauss ] g^a(x_,x^- ) | & = & ( d_-^ab ^b_- + d_^ab^b _ + g _
m^a ) | + & = & ( d_-^ab^b_- + g_^a ) |= 0 . in order to obtain a hamiltonian formulated in terms of unconstrained variables
, one has to resolve the gauss law constraint . via unitary gauge fixing transformations [ 9,10 ] a solution of gauss law with respect to components of the chromo
electric field @xmath40 can be accomplished .
this gives a hamiltonian independent of the conjugate gauge fields @xmath41 , _
i.e. _ the latter become cyclic variables .
classically this would correspond to the light front gauge @xmath42 .
however , this choice is not legitimate if we want to consider the theory in a finite box . instead
, the ( classical ) coulomb light front gauge @xmath43 is compatible with gauge invariance and periodic boundary conditions .
the reason is that @xmath41 carries information on the ( gauge invariant ) eigenvalues of the spatial polyakov line matrix [ polyakov ] ( x_)=p , which can be written in terms of a diagonal matrix with the zero mode field @xmath44 ( x _ ) = v v^ .
obviously we have to keep these ` zero modes ' @xmath45 as dynamical variables , while the other components of @xmath41 are eliminated .
the zero mode degrees of freedom are independent of @xmath3 and , therefore , correspond to quantities with zero longitudinal momentum @xmath46 . in order to eliminate the momentum @xmath47 , conjugate to @xmath48 , by means of gauss law
, one needs to ` invert ' the covariant derivative @xmath49 which simplifies to @xmath50 $ ] . on the space of physical states one
can simply make the replacement can be explicitly performed in terms of its eigenfunctions , . ] _
-(x_,x_- ) p_-(x_)-(d_-^-1 ) g_(x_,y^- ) .
the operator @xmath51 is also diagonal and @xmath52 is the momentum conjugate to the zero mode @xmath53 .
it has eigenvalue zero with respect to @xmath54 , _
i.e. _ @xmath55 , and is therefore not constrained .
the appearance of the zero modes implies a residual gauss law , which arises from the @xmath56 integration over eq . for the @xmath57 component using periodic boundary conditions in the @xmath56 direction
this constraint on two dimensional fields can be handled in full analogy to qed , since it concerns the diagonal part of color space .
a further coulomb gauge fixing in the @xmath21 3direction eliminates the color neutral , @xmath12independent , two dimensional longitudinal gauge field in favor of a neutral chromo electric field e_(x _ ) = g _ dy^- dy _
d(x_- y _ ) \ { f^3ab a^a_(y _ , y^- ) ^b_(y _ , y^- ) + ^3_m(y _ , y^- ) }
here we use the periodic greens function of the two dimensional laplace operator [ green2 ] d(z _ ) = - 1l^2 _ 0 1p_n^2 e^i p_n z _ , p_n = , where @xmath58 and @xmath59 are integers . as a remnant of the local gauss law constraints , a global condition [ gaussgl ] q^3 |
= dy^- dy _ \ { f^3ab a^a_(y_,y^- ) ^b_(y _ , y^- ) + ^3_m(y _ , y^- ) } | = 0 emerges .
the physical meaning of this equation is that the neutral component of the total color charge , including external matter as well as gluonic contributions , must vanish in the sector of physical states .
it can be shown ( see @xcite ) that there must be @xmath60 everywhere in transverse space in order to avoid an infinite coulomb energy .
the two conditions together suggest that physical states have to be color singlets .
the final hamiltonian density in the physical sector explicitly reads ( in terms of unconstrained @xmath61 and @xmath62 obtained after a shift is made by subtracting averages ) @xcite [ hamil ] h & = & ^2 + 1 ^ 2 ^2 + & + & 1 ^ 2 ^2 + 12 l^2 p_-^3(x _ ) p^3_-(x _ ) + & + & 1l^2 _
0^l dz^- _ 0^l dy^- _ p , q , n^ e^i 2n(z^- - y^-)/l , where @xmath63 and @xmath64 are matrix labels for rows and columns , @xmath65 and the prime indicates that the summation is restricted to @xmath66 if @xmath67 . the operator @xmath68 is defined as g_= [ gop ] _ _ + gf^abc a^b _ ( ^c _ - 1l e^c _ ) + g_m .
the last two terms of the weyl gauge hamiltonian come from the original term @xmath69 with squared electric field strengths in @xmath12 direction . after elimination of @xmath47 the zero mode part and the light cone coulomb energy in the axial gauge
remain . in the coulomb term
one sees the role of the zero mode fields as infrared regulators of the spatial momenta @xmath70 which are quantized due to the compact interval @xmath4 .
since the two dimensional theory has been coulomb gauge fixed , the electric field @xmath71 replaces the canonical momentum of the longitudinal , neutral gauge field which has been eliminated .
we note that the terms containing @xmath71 and the momentum @xmath72 , have the pre - factor @xmath73 .
physically this pre - factor signals the increase of transverse electric energies with the boost factor @xmath74 .
the boost also couples transverse electric fields with transverse magnetic fields . in the light - cone limit
the pre - factor diverges and the adjacent brackets become constraint equations .
this reflects the corresponding reduction of the number of degrees of freedom if one goes exactly on the light cone .
we do not follow this procedure , but keep a finite @xmath8 as a kind of lagrange parameter .
a characteristic feature of an exact light - cone formulation is the triviality of the ground state .
this may simplify explicit calculations , _
e.g. _ of the hadron spectrum . however , the light cone vacuum is definitely not trivial in the zero mode sector .
in fact , already in ref @xcite we have shown strong and weak coupling solutions of the zero mode hamiltonian .
massless modes influence the dynamics in the light cone limit , whereas massive modes decouple when @xmath75 .
in contrast to earlier work , we solve the zero mode hamiltonian in this paper numerically showing the transition from the massive phase to the massless phase .
the zero mode degrees of freedom @xmath76 couple to the transverse three dimensional gluon fields @xmath77 via the second magnetic term in @xmath78 , the coulomb term and directly via the electric field @xmath71 .
we remark that the transverse electric fields @xmath79 and @xmath80 are dual to the magnetic fields @xmath81 and @xmath82 .
this duality is typical for the light cone and is absent in the equal time case .
since duality plays an important role in supersymmetric qcd its role in light cone theories should deserves to be investigated in greater detail . in the following we neglect the couplings between the three and two dimensional fields and
consider the pure zero mode hamiltonian [ hamil3 ] h = d^2x .
the global constraint , eq .
, does not contain @xmath76 and @xmath19 and , consequently , is irrelevant for the time being .
even at this level of severe approximations the zero mode hamiltonian differs from the corresponding one in qed .
the reason is the hermiticity defect of the canonical momentum @xmath83 . in the schrdinger representation eq .
[ hamil4 ] h = d^2x , contains the jacobian @xmath84 which equals the haar measure of @xmath21 [ jacob ] j(a_-^3 ( _ ) ) = ^2 ( a_-^3 ( _ ) ) .
it stems from the gauge fixing procedure , effectively introducing curvilinear coordinates
. it also appears in the functional integration volume element for calculating matrix elements .
it is convenient to introduce dimensionless variables ( _ ) = , which vary in a compact domain @xmath85 .
we regularize the above hamiltonian @xmath86 by introducing a lattice spacing @xmath15 between transversal lattice points @xmath87 .
next we appeal to the physics of the infinite momentum frame and factorize the reduced true energy from the lorentz boost factor @xmath88 and the cut off by defining @xmath89 [ hdef ] h = 12a h_red in the continuum limit of the transverse lattice theory we let @xmath15 go to zero . for small lattice spacing we obtain the reduced hamiltonian h_red = _ \ { -g^2_eff 1j j + 1g^2_eff _ i=1,2 ( ( ) -(+_i))^2 } . with the effective coupling constant -5 mm [ g2eff ] g^2_eff
= the first part of the hamiltonian contains the kinetic ( electric ) energy of the @xmath21 rotators on a half circle at each lattice point and the second part gives the potential ( magnetic ) energy of these rotators due to the differences of angles at nearest neighbor sites . for further discussion
we define these electric and magnetic parts as : h_red & = & h_e + h_m + h_e & = & _ h^e _ + h_m & = & _ _
i=1,2 h^m_,+_i in the strong coupling domain where we have analytical solutions of the zero mode hamiltonian , the numerical hamiltonian lattice theory agrees with the analytical solutions for the mass gap .
the real question concerns the continuum limit of the zero mode system which occurs outside of the strong coupling region . for this purpose
we have to find the region of vanishing mass gap for the lattice hamiltonian .
we solve the equivalent lattice theory in a euclidean formulation .
the zero mode hamiltonian represents a @xmath90 dimensional theory in two spatial and one time direction .
the lattice has @xmath91 extensions in transverse space and @xmath92 extension in near light cone time . to set up the density matrix one has to write down the trotter formula for the given hamiltonian .
using @xmath93 we have ( -t h_red ) = _
n_t ^n_t , where each time evolution step @xmath94 can be separately done for the electric and magnetic part of the hamiltonian . for definiteness
, we choose @xmath95 in all the following . in the appendix
we show that this choice of @xmath94 optimizes the updating procedure since it generates approximately equal widths for the weight functions resulting from the kinetic and potential energies .
the different time slices will labeled with the index @xmath96 .
the electric hamiltonian can be evaluated by inserting products of complete set single site eigenfunctions @xmath97 ( @xcite ) .
practically a maximal number @xmath98 of eigenfunctions is fully sufficient to reach convergence in the interval of couplings we need .
[ sum_over_states ]
_ l+1 | h^e | _
n_l+1,n_l _ l+1 | n_l+1 n_l+1 | h^e | n_l n_l | _ l _ n_l=0^n_max c_n_l(_l+1 ) g_eff^2 n_l(n_l+2 ) c_n_l(_l ) with the ( single site ) eigenfunctions and eigenvalues given as : [ basis ] c_n_l(_l ) & = & \ { } , + h^e c_n_l(_l ) & = & g^2_eff n_l ( n_l+2 ) c_n_l(_l ) .
the eigenfunctions form an orthonormal set with respect to a scalar product which contains the jacobian in the measure .
the jacobian @xmath99 has been defined above .
the magnetic part is diagonal in @xmath100 _
i.e. _ local in time : \{_l()}|h_m|\{_l ( ) } = h_m(\{_l ( ) } ) = _ _ i=1,2 h^m_,+_i ( _ l()-_l(+_i ) ) .
the full partition function is given by an integral over all time slices z & = & = _ ( j ( ( ) ) d ( ) ) \ { ( ) } | | \ { ( ) } + & = & _ , l ( j ( ( ) ) d ( ) _ n_l=0^n_max c_n_l(_l+1 ( ) ) c_n_l(_l ( ) ) ) + & & _
because of the jacobian the dominant contributions to the partition function come from @xmath101 values around @xmath102 .
the hamiltonian is invariant under reflections @xmath103 . in the strong coupling limit , where @xmath104 is large , the half rotators act almost independently on each lattice site producing a large mass gap . the system is disordered . for decreasing coupling constant
@xmath104 the movement of the individual rotators becomes locked from one site to the next .
long range correlations develop . the order parameter ( or `` magnetization '' ) of the system is the expectation value of the trace of the polyakov line , which on the lattice has the form p = = 1n^3_b , ( b , ) .
[ orderpar ] the order parameter is odd under the above symmetry operation .
operator expectation values are evaluated with the density matrix defined by @xmath89 and @xmath105 : o = 1zo . at each particular @xmath106 _
g 1/g_eff^2 we simulate lattice sizes with equal number of sites in all directions @xmath107 and @xmath108 .
a metropolis algorithm is used for updating with the steps size and the number of hits adapted to @xmath106 . in order to tabulate the boltzmann weights related to the timelike links we also discretized the continuous angle variables to a system of @xmath109 orientations : @xmath110 ,
@xmath111 $ ] . in this explorative investigation we generated between @xmath112 and @xmath113 uncorrelated configurations depending on the @xmath106 and lattice size .
all our calculations were done on a cluster of alphastations with the single site metropolis updating algorithm sketched above , so the accuracy can be improved using a more powerful algorithms and/or more computing resources .
we calculate the @xmath106 dependence of the following quantities : average electric energy @xmath114 and magnetic energy @xmath115 per site , the average of the absolute value of the order parameter @xmath116 , the susceptibility @xmath117 and the normalized fourth cumulant @xmath118 ( which gives the deviation of the moments of the polyakov expectation value from a pure gaussian behavior ) : -7 mm _ e , m & = & 1n^2 h_e , m + & = & n^3 ( p^2 - p ^2 ) [ chidef ] + g_r & = & - 3 .
firstly we calculated the ground state energy for strong couplings @xmath119 and compared with the exact calculation @xcite .
the obtained results from the lattice agree with the analytical result . for higher values of @xmath106
the lattice calculation agrees within @xmath120 with the previous effective double site calculation for the energy per site@xcite . the ultraviolet regularization with @xmath94 influences the final lattice result .
the energies are measured with high accuracy and practically do not depend on the infrared cutoff , i.e. on the total lattice size for @xmath121 .
the situation for other variables is different . in order to see the emergence of a massless phase , we investigated the ( connected ) time correlation functions of the ( trace of the ) polyakov line operators : k(0 , ) = 1n^4 _ , ( ( b,0 ) ) ( ( b , ) ) - |p| ^2 .
the correlation masses are obtained from a fit of the time correlation functions @xmath122 to a parameterization taking the periodicity in time into account [ mcorr ] k(0,n ) = c . the obtained masses for different lattice sizes are shown in fig.[figmasses]a . for each fixed @xmath106 we extrapolated the mass to the limit @xmath123 using a linear @xmath124 parameterization [ mnfit ] m(_g , n ) = m_0(_g ) + . our data for @xmath125 can be fitted with this linear form for @xmath126 .
the resulting dependence of @xmath127 on @xmath106 is presented in fig.[figmasses]b .
the mass vanishes in the infinite volume limit near @xmath128 , which is a first guess for the critical coupling @xmath129 . in order to extract more exact information on the critical behavior [ mbeta ]
m(_g ) ( 1_g-1_g^*)^ . from our data on small systems
we have done a finite size scaling ( fss ) @xcite analysis of the variables @xmath116 , @xmath117 and @xmath118 , searching for the critical coupling @xmath130 in the interval @xmath131 .
we could determine the critical indices @xmath132 , @xmath32 and @xmath26 using an approach employed for @xmath21 gauge theory at the finite temperature transition by engels et al . @xcite . the general form of the scaling relations for a variable @xmath133 ( @xmath133 = @xmath116 , @xmath117 , @xmath118 ) is [ fssgen ] v(t , n ) = n^/ f_v(t
n^1/ , g_i n^y_i ) , where @xmath134 is the corresponding critical index ( @xmath132 , @xmath32 , 0 ) for the respective quantities and @xmath135 is the reduced inverse coupling @xmath106 : [ fsst ] t = . in practice eq
. is computed near @xmath136 .
expanding up to first order in @xmath135 and taking into account only the largest irrelevant exponent @xmath137 one obtains [ fssone ] v(t , n ) = n^/ . .
[ tabres ] critical parameters for the transverse qcd near the light cone .
the ising indices are from ref.@xcite . [
cols="^,^,^,^ " , ] with this parameterization we analyze our data for lattice sizes @xmath138 .
the @xmath106 dependence in eq .
is valid near the critical point .
the quality of the fit to the data in different intervals on @xmath106 can serve as a guide to localize the critical point @xmath130 @xcite .
we find that in our case this parameterization can be applied for @xmath116 and @xmath117 only for @xmath139 : for smaller @xmath106 the @xmath140 becomes too large .
finally we use the parameterization of eq . in the interval @xmath141 ( see fig.[figfss ] ) where @xmath142 and an expansion of first order in @xmath135 still is applicable . in this @xmath106 interval the fits for @xmath116 and @xmath117 yield a @xmath143 . to have a reliable error estimate for the extracted parameters we use the jackknife method . the results for @xmath144 and critical indices @xmath132 , @xmath32 and @xmath26 are presented in table 1 .
we use @xmath145 , but in fact the results do not depend on @xmath146 in the interval @xmath147 .
it should be noticed that the system frequently flips between the two ordered states on a finite lattice .
therefore the expectation value @xmath148 in equation vanishes with good accuracy .
analogously to the treatment of the magnetization in the 3-dimensional ising model , we should - instead of the expression for @xmath117 in eq .
- define the susceptibility in the broken phase as @xmath149 . for the ising case this susceptibility
is supposed to converge towards the correct infinite volume limit . due to lack of statistics , however , we did not use separate expressions for @xmath117 in the two phases .
our data for @xmath118 are even much less accurate which excludes the possibility to use them in the fss analysis .
the values found for the critical indices @xmath132 , @xmath32 and @xmath26 are not far from those of the ising model ( @xmath150 ) ( see table 1 ) .
they are much less accurate but also in agreement with a high statistics analysis @xcite of the @xmath21 deconfinement transition at finite temperature .
we interprete the behavior of the light cone zero mode theory as a consequence of the underlying @xmath151 symmetry of the hamiltonian .
@xmath151 transformations correspond to reflections of the angle variables @xmath152 around @xmath102 .
the hamiltonian and the measure of eq .
( 17 ) are invariant under these transformations .
the resulting critical behavior is common to ising like models .
the critical coupling itself is a nonuniversal quantity and we have found a rough value .
more extended work with the lattice hamiltonian near the light cone is needed to clarify the continuous transition further .
the scaling analysis gives indications that there is a second order transition between a phase with massive excitations at strong coupling and a phase with massless excitations in weak coupling . to reach a higher accuracy large scale simulations of the hamiltonian zero mode system
are needed . in this context
it is advisable to treat the coupled system of three and two dimensional modes together .
a calculation in the epsilon expansion @xcite gives the zero of the @xmath132-function as an infrared stable fixed point .
this shows that the limit of large longitudinal dimensions @xmath4 is well defined . using the running coupling constant @xmath104 of the zero mode system we have ( ) ma = ( g^2_eff - g^*2_eff)^with @xmath153 and @xmath154 from our lattice calculations ( table [ tabres ] ) .
the mass can be interpreted as an inverse correlation length @xmath155 .
when the correlation length @xmath156 approaches the temporal size of the lattice @xmath157 in the infrared limit we can identify @xmath158 with @xmath159 , where @xmath4 is our infrared length scale .
therefore the effective coupling @xmath160 ( ) runs with @xmath159 in the following way [ gevol ] g^2_eff = g^*2_eff + ( _ 0 g^*2_eff)^1/ ( ) ^1/ . the coupling to the three dimensional modes produces the usual evolution of @xmath161 in @xmath21 qcd , where the coupling @xmath162 at the lattice scale @xmath15 is related to the coupling @xmath163 defined at the infrared scale @xmath164 as follows [ gevola ] g^2(a)= . combining the eqs .
and we can synchronize the approach to the light cone , _ i.e. _ the limit @xmath165 with the continuum limit @xmath166 .
the condition that the three - dimensional evolution of @xmath161 has to be compatible with the two - dimensional evolution of @xmath104 towards @xmath167 yields that for @xmath168 the light cone parameter @xmath8 approaches zero as ( a ) ~ .
this relation is similar to the naive scaling result deduced in section @xmath169 from physics arguments besides logarithmic modification .
although at the outset we had as parameters @xmath170 and @xmath8 in the hamiltonian we reduce this multiparameter problem to a problem with one single coupling constant which can be chosen as @xmath171 .
we can use the energy and the critical behavior of the euclidean @xmath90 dimensional system to obtain its contribution to the ground state energy of the system in @xmath172 dimensions . in our calculations the energy of the zero mode hamiltonian @xmath173 near the critical coupling is proportional to @xmath174 . using the scaling of @xmath8 determined from the compatibility of 2-dimensional and 3-dimensional dynamics , we can eliminate @xmath8 in favor of @xmath175 and get a zero mode energy which grows linearly with the 3-dimensional volume .
that means the zero mode dynamics becomes relevant for the full problem , _
i.e. _ h a ~n_l n^2 _ .
[ meanha ] in reality the zero mode system is coupled to the @xmath172 dimensional system the extension of which is large .
so we expect that the couplings of the @xmath90 dimensional system can get modified . because of the universal dynamics near the infrared fixed point this will not change the qualitative form of the volume dependence obtained in eq . .
the behavior of the zero mode hamiltonian has to be taken into account when we try to solve for the infinite momentum frame solutions of the complete hamiltonian .
the discussion @xcite until now often centers on the order of limits . in order to guarantee a meaningful limit of the near light cone theory ,
one first has to take @xmath176 and then one can take @xmath177 .
this is a workable procedure in solvable @xmath178 dimensional models . in qcd in @xmath172 dimensions
it hardly can serve as a prescription .
numerical solutions have to be obtained with a finite cutoff and the continuum limit can only be reached approximately via scaling relations .
it is in this case that the role of zero mass excitations will crucially enter the physics .
as one sees above the synchronization of the continuum limit with the light cone limit leads to results which are independent of the near light cone parameter @xmath8 .
the independence of the ground state energy near the critical coupling gives us back lorentz invariance which states that the physics should not depend on the reference frame .
the vacuum energy is not allowed to depend on @xmath8 .
there are dynamical zero modes in near light cone qcd which contain the physics of the nonperturbative qcd vacuum , the physics of the gluon and quark condensates .
the nontrivial structure of the nonabelian gauge theory enters in our calculation through the kinetic operator of the rotators which at finite resolution have a finite mass gap vanishing only in the continuum limit .
the near light cone description of qcd based on a modified axial gauge @xmath179 yields a very natural formulation of high energy scattering .
polyakov variables near the light cone have already entered the calculations of high energy cross sections in two different ways : for the geometrical size of cross sections in ref.@xcite the correlations between polyakov lines along the projectile and target directions are important .
for this situation an interpolating gauge may be useful .
for the energy dependence of cross sections an evolution equation of polyakov line correlators approaching the light cone has been discussed in ref .
@xcite which generalizes the bfkl- equation .
this situation is close to the treatment in this paper .
now the decisive step is to back up our theoretical work on effective transverse qcd dynamics near the light cone with phenomenological consequences for high energy scattering .
a choice of @xmath94 is proposed by comparing monte - carlo weights @xmath180 and @xmath181 which link nearest neighbors in time and space respectively w_t(_1,_2 ) & = & _ 1(x , y,+1 ) e^-h^e _ 2(x , y , ) , + w_s(_1,_2 ) & = & _ 1(x+1,y , ) e^-h^m _ 2(x , y , ) . the probability distribution for the update of the field @xmath182 is given by the product of weights for all links connecting it to neighbors in time and space .
so the updating procedure for @xmath152 is more effective when @xmath180 and @xmath181 have similar distributions near the angle @xmath183 where the jacobian has its maximum . for @xmath184 ( fig .
[ figwlinks]a ) the spatial weights @xmath181 have a much wider distribution than the timelike weights @xmath180 , whereas for @xmath185 ( fig .
[ figwlinks]c ) the situation is reverse .
for the intermediate case @xmath95 ( fig .
[ figwlinks]b ) the widths of the distributions are very similar , therefore the updating procedure is optimal .
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a. harindranath , l. martinovic and j. p. vary , hep - th/9912085 . i. i. balitsky , hep - ph/9706411 .[/INST] starting from the qcd hamiltonian in near - light cone coordinates , we study the dynamics of the gluonic zero modes .
euclidean 2 + 1 dimensional lattice simulations show that the gap at strong coupling vanishes at intermediate coupling .
this result opens the possibility to synchronize the continuum limit with the approach to the light cone . </s> |
SECTION 1. SHORT TITLE.
This Act may be cited as the ``Biomass Thermal Utilization Act of
2017'' or the ``BTU Act of 2017''.
SEC. 2. RESIDENTIAL ENERGY-EFFICIENT PROPERTY CREDIT FOR BIOMASS FUEL
PROPERTY EXPENDITURES.
(a) Allowance of Credit.--Subsection (a) of section 25D of the
Internal Revenue Code of 1986 is amended--
(1) by striking ``and'' at the end of paragraph (4);
(2) by striking the period at the end of paragraph (5) and
inserting ``, and''; and
(3) by adding at the end the following new paragraph:
``(6) 30 percent of the qualified biomass fuel property
expenditures made by the taxpayer during such year.''.
(b) Qualified Biomass Fuel Property Expenditures.--Subsection (d)
of section 25D of the Internal Revenue Code of 1986 is amended by
adding at the end the following new paragraph:
``(6) Qualified biomass fuel property expenditure.--
``(A) In general.--The term `qualified biomass fuel
property expenditure' means an expenditure for
property--
``(i) which uses the burning of biomass
fuel to heat a dwelling unit located in the
United States and used as a residence by the
taxpayer, or to heat water for use in such a
dwelling unit, and
``(ii) which has a thermal efficiency
rating of at least 75 percent (measured by the
higher heating value of the fuel).
``(B) Biomass fuel.--For purposes of this section,
the term `biomass fuel' means any plant-derived fuel
available on a renewable or recurring basis, including
agricultural crops and trees, wood and wood waste and
residues, plants (including aquatic plants), grasses,
residues, and fibers. Such term includes densified
biomass fuels such as wood pellets.''.
(c) Application of Termination Date.--Subsection (h) of section 25D
of the Internal Revenue Code of 1986 is amended by striking ``and
qualified solar water heating property expenditures'' and inserting ``,
qualified solar water heating property expenditures, and qualified
biomass fuel property expenditures''.
(d) Effective Date.--The amendments made by this section shall
apply to expenditures paid or incurred in taxable years beginning after
December 31, 2016.
SEC. 3. INVESTMENT TAX CREDIT FOR BIOMASS HEATING PROPERTY.
(a) In General.--Subparagraph (A) of section 48(a)(3) of the
Internal Revenue Code of 1986 is amended--
(1) at the end of clause (vi) by striking ``or'';
(2) at the end of clause (vii) by inserting ``or''; and
(3) by inserting after clause (vii) the following new
clause:
``(viii) open-loop biomass (within the
meaning of section 45(c)(3)) heating property,
including boilers or furnaces that operate at
thermal output efficiencies of not less than 65
percent (measured by the higher heating value
of the fuel) and that provide thermal energy in
the form of heat, hot water, or steam for space
heating, air conditioning, domestic hot water,
or industrial process heat,''.
(b) 30-Percent and 15-Percent Credits.--
(1) Energy percentage.--
(A) In general.--Subparagraph (A) of section
48(a)(2) of the Internal Revenue Code of 1986 is
amended by redesignating clause (ii) as clause (iii)
and by inserting after clause (i) the following new
clause:
``(ii) except as provided in clause (i)(V),
15 percent in the case of energy property
described in paragraph (3)(A)(viii), but only
with respect to property the construction of
which begins before January 1, 2022, and''.
(B) Conforming amendment.--Clause (iii) of section
48(a)(2)(A) of such Code, as so redesignated, is
amended by inserting ``or (ii)'' after ``clause (i)''.
(2) Increased credit for greater efficiency.--Clause (i) of
section 48(a)(2)(A) of such Code is amended by striking ``and''
at the end of subclause (III) and by inserting after subclause
(IV) the following new subclause:
``(V) energy property described in
paragraph (3)(A)(viii) which operates
at a thermal output efficiency of not
less than 80 percent (measured by the
higher heating value of the fuel), but
only with respect to property the
construction of which begins before
January 1, 2022,''.
(c) Effective Date.--The amendments made by this section shall
apply to periods after December 31, 2016, in taxable years ending after
such date, under rules similar to the rules of section 48(m) of the
Internal Revenue Code of 1986 (as in effect on the day before the date
of the enactment of the Revenue Reconciliation Act of 1990). | Biomass Thermal Utilization Act of 2017 or the BTU Act of 2017 This bill amends the Internal Revenue Code to include 30% of qualified biomass fuel property expenditures for property placed in service before 2022 in the residential energy efficient property tax credit. A "qualified biomass fuel property expenditure" is an expenditure for property which uses the burning of biomass fuel (a plant-derived fuel available on a renewable or recurring basis) to heat a dwelling used as a residence, or to heat water for use in such dwelling, and which has a thermal efficiency rating of at least 75%. The bill also allows: (1) a 15% energy tax credit until 2022 for investment in open-loop biomass heating property, including boilers or furnaces that operate at thermal output efficiencies of at least 65% and provide thermal energy in the form of heat, hot water, or steam for space heating, air conditioning, domestic hot water, or industrial process heat; and (2) a 30% credit until 2022 for investment in such property that operates at a thermal output efficiency of at least 80%. | <s>[INST]SECTION 1. SHORT TITLE.
This Act may be cited as the ``Biomass Thermal Utilization Act of
2017'' or the ``BTU Act of 2017''.
SEC. 2. RESIDENTIAL ENERGY-EFFICIENT PROPERTY CREDIT FOR BIOMASS FUEL
PROPERTY EXPENDITURES.
(a) Allowance of Credit.--Subsection (a) of section 25D of the
Internal Revenue Code of 1986 is amended--
(1) by striking ``and'' at the end of paragraph (4);
(2) by striking the period at the end of paragraph (5) and
inserting ``, and''; and
(3) by adding at the end the following new paragraph:
``(6) 30 percent of the qualified biomass fuel property
expenditures made by the taxpayer during such year.''.
(b) Qualified Biomass Fuel Property Expenditures.--Subsection (d)
of section 25D of the Internal Revenue Code of 1986 is amended by
adding at the end the following new paragraph:
``(6) Qualified biomass fuel property expenditure.--
``(A) In general.--The term `qualified biomass fuel
property expenditure' means an expenditure for
property--
``(i) which uses the burning of biomass
fuel to heat a dwelling unit located in the
United States and used as a residence by the
taxpayer, or to heat water for use in such a
dwelling unit, and
``(ii) which has a thermal efficiency
rating of at least 75 percent (measured by the
higher heating value of the fuel).
``(B) Biomass fuel.--For purposes of this section,
the term `biomass fuel' means any plant-derived fuel
available on a renewable or recurring basis, including
agricultural crops and trees, wood and wood waste and
residues, plants (including aquatic plants), grasses,
residues, and fibers. Such term includes densified
biomass fuels such as wood pellets.''.
(c) Application of Termination Date.--Subsection (h) of section 25D
of the Internal Revenue Code of 1986 is amended by striking ``and
qualified solar water heating property expenditures'' and inserting ``,
qualified solar water heating property expenditures, and qualified
biomass fuel property expenditures''.
(d) Effective Date.--The amendments made by this section shall
apply to expenditures paid or incurred in taxable years beginning after
December 31, 2016.
SEC. 3. INVESTMENT TAX CREDIT FOR BIOMASS HEATING PROPERTY.
(a) In General.--Subparagraph (A) of section 48(a)(3) of the
Internal Revenue Code of 1986 is amended--
(1) at the end of clause (vi) by striking ``or'';
(2) at the end of clause (vii) by inserting ``or''; and
(3) by inserting after clause (vii) the following new
clause:
``(viii) open-loop biomass (within the
meaning of section 45(c)(3)) heating property,
including boilers or furnaces that operate at
thermal output efficiencies of not less than 65
percent (measured by the higher heating value
of the fuel) and that provide thermal energy in
the form of heat, hot water, or steam for space
heating, air conditioning, domestic hot water,
or industrial process heat,''.
(b) 30-Percent and 15-Percent Credits.--
(1) Energy percentage.--
(A) In general.--Subparagraph (A) of section
48(a)(2) of the Internal Revenue Code of 1986 is
amended by redesignating clause (ii) as clause (iii)
and by inserting after clause (i) the following new
clause:
``(ii) except as provided in clause (i)(V),
15 percent in the case of energy property
described in paragraph (3)(A)(viii), but only
with respect to property the construction of
which begins before January 1, 2022, and''.
(B) Conforming amendment.--Clause (iii) of section
48(a)(2)(A) of such Code, as so redesignated, is
amended by inserting ``or (ii)'' after ``clause (i)''.
(2) Increased credit for greater efficiency.--Clause (i) of
section 48(a)(2)(A) of such Code is amended by striking ``and''
at the end of subclause (III) and by inserting after subclause
(IV) the following new subclause:
``(V) energy property described in
paragraph (3)(A)(viii) which operates
at a thermal output efficiency of not
less than 80 percent (measured by the
higher heating value of the fuel), but
only with respect to property the
construction of which begins before
January 1, 2022,''.
(c) Effective Date.--The amendments made by this section shall
apply to periods after December 31, 2016, in taxable years ending after
such date, under rules similar to the rules of section 48(m) of the
Internal Revenue Code of 1986 (as in effect on the day before the date
of the enactment of the Revenue Reconciliation Act of 1990).[/INST]Biomass Thermal Utilization Act of 2017 or the BTU Act of 2017 This bill amends the Internal Revenue Code to include 30% of qualified biomass fuel property expenditures for property placed in service before 2022 in the residential energy efficient property tax credit. A "qualified biomass fuel property expenditure" is an expenditure for property which uses the burning of biomass fuel (a plant-derived fuel available on a renewable or recurring basis) to heat a dwelling used as a residence, or to heat water for use in such dwelling, and which has a thermal efficiency rating of at least 75%. The bill also allows: (1) a 15% energy tax credit until 2022 for investment in open-loop biomass heating property, including boilers or furnaces that operate at thermal output efficiencies of at least 65% and provide thermal energy in the form of heat, hot water, or steam for space heating, air conditioning, domestic hot water, or industrial process heat; and (2) a 30% credit until 2022 for investment in such property that operates at a thermal output efficiency of at least 80%. </s> |
gravitational - wave interferometers like laser interferometric gravitational - wave observatory ( ligo ) in the united states of america @xcite , virgo @xcite in europe , and their smaller counterparts geo600 in germany @xcite and tama in japan @xcite , are using super - precise opto - mechanical measurements to search for astrophysical gravitational waves .
after several years of taking scientific data , ligo and virgo are currently being upgraded with improved instrumentation and should again become operational in 2015 @xcite , @xcite .
ligo science collaboration ( lsc ) and the virgo community are projecting @xcite that with the upgraded technology , both interferometers will soon be measuring multiple coalescences of relativistic compact objects ( neutron stars and black holes ) .
these projections are based in part on the theoretical predictions for spectral density of the interferometers noise .
it is thought that the random processes that contribute most of the noise , i.e. the seismic shaking of the suspensions @xcite , the thermo - mechanical and thermo - refractive fluctuations of the mirror surface @xcite , and the quantum - mechanical fluctuations of the light - field coupled to the test - mass motion @xcite , @xcite are well understood @xcite .
one of the dangerous unknowns for the advanced gravitational - wave interferometers is a non - gaussian noise from a superposition of transient events in the instrument . in this paper
i concentrate on the creep noise , which is caused by a superposition of the sudden localized tension stress releases ( creep events ) in suspension fibers and their end attachments .
it has been thought that a creep event would couple to the interferometer s readout via lengthening of the fiber @xcite .
specifically , it was argued that because of the earth curvature , the laser beam was not strictly perpendicular to the suspension fiber , and thus the fiber s lengthening would result in some test - mass displacement along the beam . in this paper
i show that this coupling , while present , is not dominant , at least for a simple model where the fiber is represented by a cylinder with constant radius . instead , a creep event couples to the interferometer s output predominantly through excitation of the pendulum and violin modes of the suspension ; this coupling is explicitly calculated in this work .
the fact that creep events couple to the transverse vibrational modes of the system is in agreement with the experiment of @xcite who find a substantial excess noise in the transverse motion of a tungsten wire stretched to 20% of the break - up stress .
similar excess noise in steel wires was observed by @xcite .
however , the results in @xcite were not confirmed by @xcite who did not observe any excess noise in the motion of the stressed tungsten wire . moreover ,
it is far from obvious that the processes responsible for the creep events in metallic fibers @xcite will be operating in the fused silica suspension fibers such as the ones that are currently used in geo600 and that will be used in the advanced ligo , virgo , and kagra suspensions @xcite .
two experiments with fused silica fibers have been performed by @xcite and @xcite ; in both experiments no excess noise was discovered near violin resonant frequency of the fiber . in a more recent work @xcite ,
the motion of a test mass was monitored in geo600 , where the fused silica suspension fibers were used .
the motion near the violin - mode frequency was entirely consistent with that of the thermally excited violin mode .
therefore , currently there is no experimental evidence that the creep excess noise in the future advanced gravitational - wave interferometers will pose a serious problem .
however , there are at least two reasons to keep investigating the creep noise : ( 1 ) the measurements in @xcite , @xcite , and @xcite have all been performed at frequencies from several hundreds to thousands of hz , where the noise of ground - based interferometers is strongly dominated by the quantum shot noise , while the danger from creep noise exists at much lower frequencies , in the same region of tens of hz where the shot noise is unimportant , and ( 2 ) the main source of creep noise may well be not inside the fused silica suspension fibers , but inside other carrying parts of the system like the bond between the test masses and the ears " that are supporting them ( riccardo desalvo and norna robertson , private communications ) .
it is thus important to understand how a creep event inside the suspension couples to the horizontal motion of the test - mass , as well as the frequency dependence of the noise generated by a multitude of the creep events .
this paper lays a theoretical foundation for addressing these issues .
the plan of the paper is as follows . in section 2 ,
i present a convenient reciprocity relationship for linear elasto - dynamic systems . in section 3
, i use this relationship to derive the interferometer s response to a creep event , as a function of location of the stress release in the fiber . in section 4 ,
i derive the functional form of the creep noise spectral density , in the limit where the creep noise can be treated as a stationary gaussian random process .
a brief discussion of the future work is presented in section 5 .
during the creep event , the stress changes suddenly in some small volume of the fiber . but how does this affect the motion of the test mass ? at first glance , this seems like a formidable problem in elastodynamics .
however , it turns out that solving the reciprocal problem is sufficient .
namely , one should in a mental experiment apply a sudden force to the test mass and compute the motion of the fiber at the location where the creep event originated .
the solution of the reciprocal problem leads directly to the solution of the original problem .
reciprocity relations have been thoroughly studied in elastodynamics ; see e.g. @xcite for a comprehensive review . here
i will use the following formulation of the reciprocity theorem : consider an elastodynamic system initially at rest , that is being driven by a distributed force , with the force - per - volume given by @xmath0 where @xmath1 is some function that is non - zero only for @xmath2 . consider also a readout variable @xmath3 where @xmath4 is the displacement from rest at location @xmath5 and time @xmath6 .
both the applied forces and displacement are assumed to be small , so that a linear approximation of elastodynamics holds .
the reciprocity theorem states that if in the pair of equations ( [ force1 ] ) and ( [ displacement ] ) the form - factors @xmath7 and @xmath8 are interchanged then the readout variable @xmath9 remains the same .
in other words , the input - output dynamical system is invariant with respect to @xmath10 and @xmath11 interchange , with @xmath1 being the input and @xmath12 being the output .
the proof of the theorem is as follows .
let @xmath13 be the normal modes of the system , with proper angular frequencies @xmath14 .
a displacement field @xmath15 can then be decomposed into a series @xmath16 the mode amplitudes @xmath17 are the new dynamical coordinates .
the lagrangian of the unforced system is given by @xmath18 , \label{lfree}\ ] ] where @xmath19 is the effective mass of the @xmath20th mode .
external forcing of eq .
( [ force1 ] ) is introduced via an additional interaction langangian term @xmath21 which , in terms of the coordinates @xmath22 can be rewritten as @xmath23 here @xmath24 are constants given by @xmath25 the full langrangian allows us to immediately obtain the equations of motion : @xmath26 therefore , @xmath27 where @xmath28 is the solution to the forced harmonic oscillator problem @xmath29 with the initial condition @xmath30 .
the readout variable in eq .
( [ displacement ] ) can then be written as @xmath31 where @xmath32 is defined similarly to @xmath24 : @xmath33 the readout variable @xmath12 is invariant with respect to the interchange of @xmath10 and @xmath11 .
q. e. d.
a creep event happens when a minute section of the suspension fiber refuses to support its full share of the tension stress .
what exactly happens microscopically is poorly known , but a simple model will suffice for modelling of the elastodynamical behavior .
let us assume that a small fiber element of volume @xmath34 suddenly does not support any elastic stress @xmath35 .
i now consider a slightly - reduced elastic system , namely the original one with the small volume element @xmath34 taken out .
this slightly - reduced system experiences a sudden force applied to the boundary of the volume element @xmath34 , so that the boundary surface element @xmath36 , assumed to be directed outside of the volume , experiences the force @xmath37 where @xmath38 are the unit vectors along the coordinate axes , and the summation over the dummy indices is assumed .
i would like to evaluate the test - mass displacement @xmath12 under the action of the force in eq .
( [ compensator ] ) that is switched on at @xmath39 ( this situations is somewhat similar physically to the excitation of magnetar motion as a result of sudden reconfiguration of the magnetosphere during a giant magnetar flare ; see @xcite ) . by the reciprocity theorem from the previous section ,
this is equivalent to acting with the suddenly switched on force on the test mass , directed along the laser beam : @xmath40 where @xmath41 is the heavyside function @xcite .
one then has to find the response of the slightly - reduced elastic subsystem to this force , and in particular that of the reciprocal readout variable @xmath42 that is dictated by the functional form of the force in eq .
( [ compensator ] ) @xmath43 where the integration domain is the boundary of the volume @xmath34 .
it is obvious that for sufficiently small @xcite volume @xmath34 the response of the slightly - reduced system is the same as that of the full system , and from hereon i shall make no distinction between the two . by gauss theorem , for small @xmath34
the above equation can be written as @xmath44 where the strain @xmath45 is evaluated at the location of the creep event . to sum up : by finding the response of @xmath46 from eq .
( [ xreadout ] ) to the force @xmath47 applied at the test mass along the direction of the laser beam , one finds the test - mass displacement in response to the creep event .
it is convenient and instructive to work in the fourier domain @xmath48 for the force given by eq .
( [ ftheta ] ) , the force fourier component is given by @xmath49 where positive @xmath50 serves to avoid the singularity in eq .
( [ fourier1 ] ) ; the limit @xmath51 would give @xmath52 .
the test mass horizontal displacement @xmath53 under the action of the applied force is given by @xmath54 , \label{testmassresponse}\ ] ] where the mechanical impedance @xmath55 , as derived in the appendix , is given by @xcite @xmath56={1\over \pi{\omega\over \omega_s}\cot\left[\pi{\omega\over \omega_s}\right]\omega_p^2-\omega^2}. \label{impedance}\ ] ] here , @xmath57 is the mass of the test mass , @xmath58 is the pendulum angular frequency of the test mass , @xmath59 is the fundamental violin mode angular frequency measured when the test - mass is fixed in space , and @xmath60 , @xmath61 , and @xmath62 are the length , the mass , and the number of the strings on which the test mass is suspended . the small positive @xmath63 inserted into eq .
( [ testmassresponse ] ) represent damping .
mathematically , this displaces the poles of @xmath55 into the upper half of the complex @xmath64-plane @xcite .
these poles represent the frequencies of normal modes of the suspension ; their imaginary parts equal the rate of exponential decay of their amplitudes .
the actual values of @xmath65 are only important near the normal - mode frequencies and can be measured experimentally .
if no damping is present , the poles of @xmath66 $ ] , i.e. the normal - mode frequencies , are given approximately by @xmath67 for the pendulum mode , and @xmath68 \label{violin}\ ] ] for the @xmath69 violin modes .
let us introduce non - zero @xmath70 and @xmath71 which are the damping rates of the pendulum and violin modes , respectively .
the impedance can be expanded as follows : @xmath72 substituting eqs ( [ impedance ] ) and ( [ fourierforce ] ) into eq .
( [ testmassresponse ] ) , and evaluating the inverse fourier transform , i get @xmath73+\label{xtestmass1}\\ & & \sigma_{j=1}^{\infty}{2\omega_p^2\over m\omega_{vj}^4}\left[1-\cos(\omega_{vj}t)e^{-\gamma_{vj } t}\right].\nonumber\end{aligned}\ ] ] as expected , the system s response to a sudden force is a constant displacement added to damped oscillations due to excited pendulum and violin modes .
lets take stock , and sum up what has been done so far . in a reciprocal problem , one has to find out the induced shear at the location of the creep - event source when a sudden force @xmath74 is applied to the test mass . in this subsection
i have done part of the problem , i.e. i found the test - mass displacement under the action of the said force . to make further progress , i need to choose a particular model for the suspension fiber itself . in the next subsection
i consider one of the particular cases that can be dealt with analytically .
the treatment of complicated geometries is left for future work .
let us consider in detail the case where the creep events occur inside a cyllindrical fiber of constant crossection that is rigidly attached at the top to a suspension isolation plate and at the bottom to the test mass .
it is assumed here that the allowed test - mass motion is a parallel translation but not rotation , as is the case when four suspension fibers are used .
the dominant part of the stress in the fiber is @xmath75 where @xmath62 is the number of suspension fibers and @xmath76 is the radius of the fibers horizontal crossection . the readout variable in eq .
( [ xreadout ] ) is given by @xmath77 where @xmath78 is the vertical coordinate along the fiber .
i choose @xmath79 at the fiber s top and @xmath80 at the fiber s bottom .
let @xmath81 be the spatial coordinates of the source of a creep event , where @xmath82 corresponds to the location of fiber s axis at @xmath78 , and @xmath83 is measured along the laser beam direction .
the vertical strain induced by the fiber s motion is given by ( see , e.g. , chapter 11 of @xcite ) @xmath84 where @xmath85 be horizontal displacement of the fiber .
therefore , the readout variable is @xmath86 let us now find the fiber motion @xmath87 .
its dynamical equation of motion is given by ( see , e.g. , chapter 12 of @xcite or @xcite ) @xmath88 . \label{fibermotion}\ ] ] here @xmath89 is the velocity of the tension wave in a fiber , and @xmath90 is the characteristic bending length given by @xmath91 here @xmath76 is the radius of the fiber , @xmath92 is the young modulus , and @xmath93 is the intitial stretch factor of the fiber under the loading force @xmath94 of the test mass .
advanced ligo will use the fused - silica fibers with the following parameters : @xmath95 , @xmath96 kg , @xmath97gpa , @xmath98 m , and @xmath99 fibers per test mass .
this parameters produce the bending length @xmath100 .
the periodic solutions of the homogenious equation ( [ fibermotion ] ) can be written as @xmath101 where @xmath102 for frequencies of interest , @xmath103 , and thus the solutions feature two physically distinct branches , @xmath104 and @xmath105 .
the former branch represents evanescent quasi - static bending perturbations that will be large near the fiber s attachment points , while the latter represent tension waves in a fiber .
the boundary conditions @xmath106 and @xmath107 , together with @xmath108 , determine the full solution for the fiber : @xmath109 , \label{yzt1}\ ] ] where @xmath110e^{z - l\over\lambda}\right\ } , \label{ybend}\ ] ] and @xmath111 here @xmath112 , and the amplitude @xmath113 is given by @xmath114 therefore , in the fourier domain the readout variable is given by @xmath115\omega_p^2-\omega^2\sin\left[\pi{\omega\over \omega_s}\right]}\times\nonumber\\ & & \left[\lambda^{-2 } \eta_{\rm bend}(z,\omega)-k^2\eta_{\rm wave}(z,\omega)\right],\label{readout}\end{aligned}\ ] ] where @xmath116 and @xmath117 are given by eqs .
( [ ybend ] ) and ( [ ywave ] ) , respectively . in the time - domain , putting in all the damping terms , i get @xmath118+\label{xreadout}\\ & & \sigma_{j=1}^{\infty}c_{vj}(x_c , z)\left[1-\cos(\omega_{vj } t)e^{-\gamma_{vj}t}\right ] \nonumber\end{aligned}\ ] ] where @xmath119 and @xmath120-\right.\label{cvjz}\\ & & \left.\left({\pi j\over l}\right)^2 \sin\left(\pi j z / l\right)\right\}.\nonumber\end{aligned}\ ] ] in the expressions above i used @xmath108 and @xmath121 .
i remind the reader that @xmath122 are the coordinates of the location of the creep event with the effective volume @xmath34 , and that eq .
( [ xreadout ] ) gives the test - mass response to such an event .
the geometric nature of the prefactors in eqs ( [ cpz ] ) and ( [ cvjz ] ) is apparent once one recalls @xmath123 , and @xmath124(\pi j)^{-2 } l$ ] .
it is instructive to compute a numerical example . in the expression ( [ xreadout ] ) above , consider values @xmath125 , @xmath126 , and @xmath79 ( i.e. , a formation of a nanometer - size hole at the top edge of the fiber ) .
the displacement that one then gets at a pendulum frequency is or order @xmath127 m .
it is worthwhile to have another look at the right - hand side of eq .
( [ readout ] ) .
the part of the equation in square brackets , @xmath128 determines the @xmath78-dependence of the coupling of the creep event to the horizontal motion of the test mass .
the function @xmath129 is plotted in fig . 1 , for @xmath130 ( i.e. , the fundamental violin mode ) .
fiducial parameters that were used in making the plot are specified in the figure s header .
the function peaks very strongly within @xmath90 from the attachment ends of the fiber ; there @xmath131 is dominated by the @xmath132 . away from the attachment points ,
the coupling is dominated by the @xmath133 part of the solution and @xmath134 . in this subsection s model the creep events
are assumed to be triggered homogeneously in the suspension fibers @xcite .
thus the creep events have only @xmath135 chance to be triggered within @xmath90 from the attachment points .
however , they have individually much larger impact [ by a factor of @xmath136 on the test - mass motion then those ones originating away from the attachments .
it follows that the creep events originating within the bending regions near attachment points contribute most of the creep noise ; their contribution is greater by a factor of @xmath137 than that of the creep events away from the attachment points .
this is studied in section 4 .
let us now consider the case where a laser beam is inclined by a small angle @xmath138 with respect to the horizontal direction .
this is an inevitable effect because of the spherical shape of the equipotential surface on which the test masses in the same arm are located ; for @xmath139 km arm @xmath140 radians .
it is this misalignment that was previously thought to be the major source of the creep noise @xcite ; we treat this mechanism within the formalism developed in the previous section . the reciprocal force applied at the test mass
has now a vertical component @xmath141 that causes the vertical test - mass motion @xmath142 , \label{xvert}\ ] ] where the negative sign corresponds to the upward motion .
here we take into account only one vertical suspension mode with the angular frequency @xmath143 and the damping rate @xmath144 ; the higher - order vertical modes are at much higher frequency and have a much weaker coupling to the sudden force .
the readout variable from eq .
( [ xreadout2 ] ) is given by @xmath145 .
\label{xvertreadout}\ ] ] in the fourier domain , @xmath146}. \label{xverfourrier}\ ] ] it is instructive to compare the amplitude of the vertical mode to the amplitude of the pendulum mode excited by the creep even near the attachment point , as inferred from eq .
( [ xreadout ] ) .
their ratio is approximately given by @xmath147 it is the smallness of this ratio that makes the contribution to the creep noise from the creep - induced fiber - lengthening be subdominant relative to the direct horizontal coupling , in most of the ligo band .
consider now a situation where multiple creep events are triggered in sequence , .
according to the central limit theorem , if the events occur sufficiently frequently , their superposition produces a random gaussian noise in the test - mass motion .
the response of the test - mass to a single creep event can be written as @xmath148 where @xmath149 is the time when the creep event is triggered , and @xmath150 is the set of parameters characterizing the event ( location in the fiber , effective volume , etc . ) . in what follows
we assume that the creep events are statistically independent from each other and that the creep - event parameters sample some well - defined probability - distribution function .
this assumption is known not to hold in some systems that exhibit so - called crackle noise " @xcite , and will be relaxed in future work . if the probability density distribution @xmath151 is time - invariant , then the creep noise is stationary and has a spectral density given by @xmath152 where @xmath153 is the rate of the creep events .
the @xmath154 implies a multi - dimensional integral over the parameter space of @xmath150 . evaluating this expression for the model of the cylindrical fiber , we get @xmath155 where @xmath156 and @xmath157+k\lambda[2\sin(2kl)+kl]\right\}. \label{g}\ ] ] here @xmath158 is the ensemble average of the @xmath159 of the creep events in the system . naturally , this quantity is meaningful only in our simple model for the creep events , however a term like this , representing the mean of the squared intensity of the creep events , is expected in any generic model for the localised creep events .
the first term in square brakets on the right - hand side of the above equations is due to creep events generated near the attachment points , while the second term is that due to creep events generated in the fiber s bulk ; in both of these the terms of order @xmath160 have been neglected .
it is clear that the noise is strongly dominated by the creep events near the attachment point .
the spectral sensity of noise due to the vertical lengthening of the fibers is given by @xmath161 where @xmath162 the plots for @xmath163 and @xmath164 are shown in fig .
2 . while the scale on the vertical axis of these plots is arbitrary
, since @xmath165 is unknown , the spectral density shape and the relative contribution of the two noises are fixed .
we observe that the direct horizontal coupling induces greater creep noise than the vertical motion , at all frequencies except at a narrow band around @xmath166 .
in this paper i have provided an elastodynamic calculation of the interferometer s response to a creep event , and found the functional form of the creep noise in the stationary limit .
a simple model where the fiber was modeled as a cylinder of constant radius was considered in detail , since this allowed me to obtain analytical expressions for the test - mass response .
two interrelated qualitative features of this model are worth noting : ( 1 ) creep events near the fiber s ends receive a much stronger test - mass response in the ligo band than those at the center of the fiber , and contribute the majority of the creep noise , and ( 2 ) the dominant coupling to the inteferometer s readout is via excitation of the violin and pendulum modes of the suspension , and not via the lenthening of the fiber .
i should caution though that these conclusions may not hold in a fiber with a more complex dependence of the cross - sectional radius @xmath76 on the height @xmath78 .
in particular , the fibers in advanced ligo suspensions are made significantly thicker near the end points , in order to minimize the suspension thermal noise .
this thickening will reduce the local tension stress , thus reducing both the coupling of a creep event to the test mass motion and the likelyhood of a creep event to occur . in a simple model for the creep noise
, i have assumed that the creep events are triggered homogeneously in the suspention fiber .
this may not be the case .
the creep events may be triggered preferentially ( 1 ) at the locations where the fiber is welded to the test mass or the upper suspension plate , although this is not very likely since at the weld the fiber is much thicker than in its center ( @xmath167 m ) , so the tension is small ( norna robertson , private communications ) , or ( 2 ) near the locations where the ears that support the test mass are bonded to it . the bonding material is non - metallic and non - glassy and is a potential source of problems ( riccardo desalvo , private communications ) . in future work
i plan to explore the spatial distribution of the expected creep events , as well as relax the assumption of their statistical independence .
i plan to also deal with the issues of non - gaussianity of the creep - event triggers ; it can presumably can be mitigated by considering the output of several independent interferometers .
some comfort for the advanced interferometers can be derived from the fact that experiments @xcite , @xcite , and @xcite have not observed any influence of the creep noise on the violin - mode motion .
we note , however , that all of the measurements in question have searched for the creep noise at high frequencies corresponding to the resonant frequencies of violin modes , from several hundred to several thousand hz .
if the creep events are statistically independent from each other , then the expected creep noise is red , with @xmath168 except near resonances ; see eqs .
( [ sdensity ] ) and ( [ q ] ) .
this is the same scaling as that for the suspension thermal noise in the case where damping of the fiber s motion is structural ( see , e.g. , @xcite ) .
therefore , one may argue that since no creep noise that exceeds the suspension thermal noise is observed at high frequencies , none is expected to exceed the suspension thermal noise at low frequencies as well .
this argument , however , relies on a very simple model for the creep noise that was developed in section 4 , and in particular it relies on the creep events being statistically independent
. this assumption does not hold in many systems that release their free energy via spontaneous acoustic emission events ( known as the crackle noise " ) , see @xcite and references therein .
thus further experimental and theoretical work is warranted for the low - freqyency domain .
i thank vladimir braginsky for impressing on me the importance of non - stationary noise in many a conversation that we ve had from the first time we met in september of 1994 .
i thank misha gorodetsky for his insightful comments given as part of the internal lsc review for this article .
i thank riccardo desalvo , eric gustafson , jan harms , norna robertson , and peter saulson for comments on the earlier version of this manuscript .
i thank rana adhikari , yanbei chen , kip thorne , and sergei vyatchanin for useful discussions .
finally , i thank sarah levin for proofreading parts of the manuscript before submission .
the calculations in this paper were completed during a visit to ligo laboratory at caltech .
the research was supported by the australian research council future fellowship .
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naturally , other time - dependencies may also be considered within this formalism .
more precisely , for frequencies such that the corresponding sound waves have a much larger wavelength than the size of @xmath34 , which is an excellent approximation in our situation . strictly speaking , this expression is valid only to zeroth order in @xmath169 at low frequencies , where @xmath61 and @xmath57 are the masses of the string and the test mass , respectively .
this is of order of @xmath170 for ligo .
this enforces causality of the test - mass response . in case
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here we provide a quick derivation ; similar derivations for more complicated situations when the test - mass tilt is allowed is given in e.g. appendix a of @xcite .
suppose a periodic force @xmath171 is acting on the test mass and induces its periodic motion @xmath172 the fiber s motion is given by @xmath173 here @xmath174 is the tension - wave vector .
the horizontal component of back - reaction tension force acting on the test - mass is @xmath175 the second newton s law gives @xmath176 substituting the eq .
( [ a4 ] ) above we get @xmath177 which is equivalent to eq .
( [ impedance ] ) in the text . | in gravitational - wave interferometers , test masses are suspended on thin fibers which experience considerable tension stress .
sudden microscopic stress release in a suspension fiber , which i call a creep event , would excite motion of the test mass that would be coupled to the interferometer s readout . the random test - mass motion due to a time - sequence of creep events is referred to as creep noise. in this paper i present an elasto - dynamic calculation for the test - mass motion due to a creep event .
i show that within a simple suspension model , the main coupling to the optical readout occurs via a combination of a dc " horizontal displacement of the test mass , and excitation of the violin and pendulum modes , and not , as was thought previously , via lengthening of the fiber .
when the creep events occur sufficiently frequently and their statistics is time - independent , the creep noise can be well - approximated by a stationary gaussian random process .
i derive the functional form of the creep noise spectral density in this limit , with the restrictive assumption that the creep events are statistically independent from each other . | <s>[INST]gravitational - wave interferometers like laser interferometric gravitational - wave observatory ( ligo ) in the united states of america @xcite , virgo @xcite in europe , and their smaller counterparts geo600 in germany @xcite and tama in japan @xcite , are using super - precise opto - mechanical measurements to search for astrophysical gravitational waves .
after several years of taking scientific data , ligo and virgo are currently being upgraded with improved instrumentation and should again become operational in 2015 @xcite , @xcite .
ligo science collaboration ( lsc ) and the virgo community are projecting @xcite that with the upgraded technology , both interferometers will soon be measuring multiple coalescences of relativistic compact objects ( neutron stars and black holes ) .
these projections are based in part on the theoretical predictions for spectral density of the interferometers noise .
it is thought that the random processes that contribute most of the noise , i.e. the seismic shaking of the suspensions @xcite , the thermo - mechanical and thermo - refractive fluctuations of the mirror surface @xcite , and the quantum - mechanical fluctuations of the light - field coupled to the test - mass motion @xcite , @xcite are well understood @xcite .
one of the dangerous unknowns for the advanced gravitational - wave interferometers is a non - gaussian noise from a superposition of transient events in the instrument . in this paper
i concentrate on the creep noise , which is caused by a superposition of the sudden localized tension stress releases ( creep events ) in suspension fibers and their end attachments .
it has been thought that a creep event would couple to the interferometer s readout via lengthening of the fiber @xcite .
specifically , it was argued that because of the earth curvature , the laser beam was not strictly perpendicular to the suspension fiber , and thus the fiber s lengthening would result in some test - mass displacement along the beam . in this paper
i show that this coupling , while present , is not dominant , at least for a simple model where the fiber is represented by a cylinder with constant radius . instead , a creep event couples to the interferometer s output predominantly through excitation of the pendulum and violin modes of the suspension ; this coupling is explicitly calculated in this work .
the fact that creep events couple to the transverse vibrational modes of the system is in agreement with the experiment of @xcite who find a substantial excess noise in the transverse motion of a tungsten wire stretched to 20% of the break - up stress .
similar excess noise in steel wires was observed by @xcite .
however , the results in @xcite were not confirmed by @xcite who did not observe any excess noise in the motion of the stressed tungsten wire . moreover ,
it is far from obvious that the processes responsible for the creep events in metallic fibers @xcite will be operating in the fused silica suspension fibers such as the ones that are currently used in geo600 and that will be used in the advanced ligo , virgo , and kagra suspensions @xcite .
two experiments with fused silica fibers have been performed by @xcite and @xcite ; in both experiments no excess noise was discovered near violin resonant frequency of the fiber . in a more recent work @xcite ,
the motion of a test mass was monitored in geo600 , where the fused silica suspension fibers were used .
the motion near the violin - mode frequency was entirely consistent with that of the thermally excited violin mode .
therefore , currently there is no experimental evidence that the creep excess noise in the future advanced gravitational - wave interferometers will pose a serious problem .
however , there are at least two reasons to keep investigating the creep noise : ( 1 ) the measurements in @xcite , @xcite , and @xcite have all been performed at frequencies from several hundreds to thousands of hz , where the noise of ground - based interferometers is strongly dominated by the quantum shot noise , while the danger from creep noise exists at much lower frequencies , in the same region of tens of hz where the shot noise is unimportant , and ( 2 ) the main source of creep noise may well be not inside the fused silica suspension fibers , but inside other carrying parts of the system like the bond between the test masses and the ears " that are supporting them ( riccardo desalvo and norna robertson , private communications ) .
it is thus important to understand how a creep event inside the suspension couples to the horizontal motion of the test - mass , as well as the frequency dependence of the noise generated by a multitude of the creep events .
this paper lays a theoretical foundation for addressing these issues .
the plan of the paper is as follows . in section 2 ,
i present a convenient reciprocity relationship for linear elasto - dynamic systems . in section 3
, i use this relationship to derive the interferometer s response to a creep event , as a function of location of the stress release in the fiber . in section 4 ,
i derive the functional form of the creep noise spectral density , in the limit where the creep noise can be treated as a stationary gaussian random process .
a brief discussion of the future work is presented in section 5 .
during the creep event , the stress changes suddenly in some small volume of the fiber . but how does this affect the motion of the test mass ? at first glance , this seems like a formidable problem in elastodynamics .
however , it turns out that solving the reciprocal problem is sufficient .
namely , one should in a mental experiment apply a sudden force to the test mass and compute the motion of the fiber at the location where the creep event originated .
the solution of the reciprocal problem leads directly to the solution of the original problem .
reciprocity relations have been thoroughly studied in elastodynamics ; see e.g. @xcite for a comprehensive review . here
i will use the following formulation of the reciprocity theorem : consider an elastodynamic system initially at rest , that is being driven by a distributed force , with the force - per - volume given by @xmath0 where @xmath1 is some function that is non - zero only for @xmath2 . consider also a readout variable @xmath3 where @xmath4 is the displacement from rest at location @xmath5 and time @xmath6 .
both the applied forces and displacement are assumed to be small , so that a linear approximation of elastodynamics holds .
the reciprocity theorem states that if in the pair of equations ( [ force1 ] ) and ( [ displacement ] ) the form - factors @xmath7 and @xmath8 are interchanged then the readout variable @xmath9 remains the same .
in other words , the input - output dynamical system is invariant with respect to @xmath10 and @xmath11 interchange , with @xmath1 being the input and @xmath12 being the output .
the proof of the theorem is as follows .
let @xmath13 be the normal modes of the system , with proper angular frequencies @xmath14 .
a displacement field @xmath15 can then be decomposed into a series @xmath16 the mode amplitudes @xmath17 are the new dynamical coordinates .
the lagrangian of the unforced system is given by @xmath18 , \label{lfree}\ ] ] where @xmath19 is the effective mass of the @xmath20th mode .
external forcing of eq .
( [ force1 ] ) is introduced via an additional interaction langangian term @xmath21 which , in terms of the coordinates @xmath22 can be rewritten as @xmath23 here @xmath24 are constants given by @xmath25 the full langrangian allows us to immediately obtain the equations of motion : @xmath26 therefore , @xmath27 where @xmath28 is the solution to the forced harmonic oscillator problem @xmath29 with the initial condition @xmath30 .
the readout variable in eq .
( [ displacement ] ) can then be written as @xmath31 where @xmath32 is defined similarly to @xmath24 : @xmath33 the readout variable @xmath12 is invariant with respect to the interchange of @xmath10 and @xmath11 .
q. e. d.
a creep event happens when a minute section of the suspension fiber refuses to support its full share of the tension stress .
what exactly happens microscopically is poorly known , but a simple model will suffice for modelling of the elastodynamical behavior .
let us assume that a small fiber element of volume @xmath34 suddenly does not support any elastic stress @xmath35 .
i now consider a slightly - reduced elastic system , namely the original one with the small volume element @xmath34 taken out .
this slightly - reduced system experiences a sudden force applied to the boundary of the volume element @xmath34 , so that the boundary surface element @xmath36 , assumed to be directed outside of the volume , experiences the force @xmath37 where @xmath38 are the unit vectors along the coordinate axes , and the summation over the dummy indices is assumed .
i would like to evaluate the test - mass displacement @xmath12 under the action of the force in eq .
( [ compensator ] ) that is switched on at @xmath39 ( this situations is somewhat similar physically to the excitation of magnetar motion as a result of sudden reconfiguration of the magnetosphere during a giant magnetar flare ; see @xcite ) . by the reciprocity theorem from the previous section ,
this is equivalent to acting with the suddenly switched on force on the test mass , directed along the laser beam : @xmath40 where @xmath41 is the heavyside function @xcite .
one then has to find the response of the slightly - reduced elastic subsystem to this force , and in particular that of the reciprocal readout variable @xmath42 that is dictated by the functional form of the force in eq .
( [ compensator ] ) @xmath43 where the integration domain is the boundary of the volume @xmath34 .
it is obvious that for sufficiently small @xcite volume @xmath34 the response of the slightly - reduced system is the same as that of the full system , and from hereon i shall make no distinction between the two . by gauss theorem , for small @xmath34
the above equation can be written as @xmath44 where the strain @xmath45 is evaluated at the location of the creep event . to sum up : by finding the response of @xmath46 from eq .
( [ xreadout ] ) to the force @xmath47 applied at the test mass along the direction of the laser beam , one finds the test - mass displacement in response to the creep event .
it is convenient and instructive to work in the fourier domain @xmath48 for the force given by eq .
( [ ftheta ] ) , the force fourier component is given by @xmath49 where positive @xmath50 serves to avoid the singularity in eq .
( [ fourier1 ] ) ; the limit @xmath51 would give @xmath52 .
the test mass horizontal displacement @xmath53 under the action of the applied force is given by @xmath54 , \label{testmassresponse}\ ] ] where the mechanical impedance @xmath55 , as derived in the appendix , is given by @xcite @xmath56={1\over \pi{\omega\over \omega_s}\cot\left[\pi{\omega\over \omega_s}\right]\omega_p^2-\omega^2}. \label{impedance}\ ] ] here , @xmath57 is the mass of the test mass , @xmath58 is the pendulum angular frequency of the test mass , @xmath59 is the fundamental violin mode angular frequency measured when the test - mass is fixed in space , and @xmath60 , @xmath61 , and @xmath62 are the length , the mass , and the number of the strings on which the test mass is suspended . the small positive @xmath63 inserted into eq .
( [ testmassresponse ] ) represent damping .
mathematically , this displaces the poles of @xmath55 into the upper half of the complex @xmath64-plane @xcite .
these poles represent the frequencies of normal modes of the suspension ; their imaginary parts equal the rate of exponential decay of their amplitudes .
the actual values of @xmath65 are only important near the normal - mode frequencies and can be measured experimentally .
if no damping is present , the poles of @xmath66 $ ] , i.e. the normal - mode frequencies , are given approximately by @xmath67 for the pendulum mode , and @xmath68 \label{violin}\ ] ] for the @xmath69 violin modes .
let us introduce non - zero @xmath70 and @xmath71 which are the damping rates of the pendulum and violin modes , respectively .
the impedance can be expanded as follows : @xmath72 substituting eqs ( [ impedance ] ) and ( [ fourierforce ] ) into eq .
( [ testmassresponse ] ) , and evaluating the inverse fourier transform , i get @xmath73+\label{xtestmass1}\\ & & \sigma_{j=1}^{\infty}{2\omega_p^2\over m\omega_{vj}^4}\left[1-\cos(\omega_{vj}t)e^{-\gamma_{vj } t}\right].\nonumber\end{aligned}\ ] ] as expected , the system s response to a sudden force is a constant displacement added to damped oscillations due to excited pendulum and violin modes .
lets take stock , and sum up what has been done so far . in a reciprocal problem , one has to find out the induced shear at the location of the creep - event source when a sudden force @xmath74 is applied to the test mass . in this subsection
i have done part of the problem , i.e. i found the test - mass displacement under the action of the said force . to make further progress , i need to choose a particular model for the suspension fiber itself . in the next subsection
i consider one of the particular cases that can be dealt with analytically .
the treatment of complicated geometries is left for future work .
let us consider in detail the case where the creep events occur inside a cyllindrical fiber of constant crossection that is rigidly attached at the top to a suspension isolation plate and at the bottom to the test mass .
it is assumed here that the allowed test - mass motion is a parallel translation but not rotation , as is the case when four suspension fibers are used .
the dominant part of the stress in the fiber is @xmath75 where @xmath62 is the number of suspension fibers and @xmath76 is the radius of the fibers horizontal crossection . the readout variable in eq .
( [ xreadout ] ) is given by @xmath77 where @xmath78 is the vertical coordinate along the fiber .
i choose @xmath79 at the fiber s top and @xmath80 at the fiber s bottom .
let @xmath81 be the spatial coordinates of the source of a creep event , where @xmath82 corresponds to the location of fiber s axis at @xmath78 , and @xmath83 is measured along the laser beam direction .
the vertical strain induced by the fiber s motion is given by ( see , e.g. , chapter 11 of @xcite ) @xmath84 where @xmath85 be horizontal displacement of the fiber .
therefore , the readout variable is @xmath86 let us now find the fiber motion @xmath87 .
its dynamical equation of motion is given by ( see , e.g. , chapter 12 of @xcite or @xcite ) @xmath88 . \label{fibermotion}\ ] ] here @xmath89 is the velocity of the tension wave in a fiber , and @xmath90 is the characteristic bending length given by @xmath91 here @xmath76 is the radius of the fiber , @xmath92 is the young modulus , and @xmath93 is the intitial stretch factor of the fiber under the loading force @xmath94 of the test mass .
advanced ligo will use the fused - silica fibers with the following parameters : @xmath95 , @xmath96 kg , @xmath97gpa , @xmath98 m , and @xmath99 fibers per test mass .
this parameters produce the bending length @xmath100 .
the periodic solutions of the homogenious equation ( [ fibermotion ] ) can be written as @xmath101 where @xmath102 for frequencies of interest , @xmath103 , and thus the solutions feature two physically distinct branches , @xmath104 and @xmath105 .
the former branch represents evanescent quasi - static bending perturbations that will be large near the fiber s attachment points , while the latter represent tension waves in a fiber .
the boundary conditions @xmath106 and @xmath107 , together with @xmath108 , determine the full solution for the fiber : @xmath109 , \label{yzt1}\ ] ] where @xmath110e^{z - l\over\lambda}\right\ } , \label{ybend}\ ] ] and @xmath111 here @xmath112 , and the amplitude @xmath113 is given by @xmath114 therefore , in the fourier domain the readout variable is given by @xmath115\omega_p^2-\omega^2\sin\left[\pi{\omega\over \omega_s}\right]}\times\nonumber\\ & & \left[\lambda^{-2 } \eta_{\rm bend}(z,\omega)-k^2\eta_{\rm wave}(z,\omega)\right],\label{readout}\end{aligned}\ ] ] where @xmath116 and @xmath117 are given by eqs .
( [ ybend ] ) and ( [ ywave ] ) , respectively . in the time - domain , putting in all the damping terms , i get @xmath118+\label{xreadout}\\ & & \sigma_{j=1}^{\infty}c_{vj}(x_c , z)\left[1-\cos(\omega_{vj } t)e^{-\gamma_{vj}t}\right ] \nonumber\end{aligned}\ ] ] where @xmath119 and @xmath120-\right.\label{cvjz}\\ & & \left.\left({\pi j\over l}\right)^2 \sin\left(\pi j z / l\right)\right\}.\nonumber\end{aligned}\ ] ] in the expressions above i used @xmath108 and @xmath121 .
i remind the reader that @xmath122 are the coordinates of the location of the creep event with the effective volume @xmath34 , and that eq .
( [ xreadout ] ) gives the test - mass response to such an event .
the geometric nature of the prefactors in eqs ( [ cpz ] ) and ( [ cvjz ] ) is apparent once one recalls @xmath123 , and @xmath124(\pi j)^{-2 } l$ ] .
it is instructive to compute a numerical example . in the expression ( [ xreadout ] ) above , consider values @xmath125 , @xmath126 , and @xmath79 ( i.e. , a formation of a nanometer - size hole at the top edge of the fiber ) .
the displacement that one then gets at a pendulum frequency is or order @xmath127 m .
it is worthwhile to have another look at the right - hand side of eq .
( [ readout ] ) .
the part of the equation in square brackets , @xmath128 determines the @xmath78-dependence of the coupling of the creep event to the horizontal motion of the test mass .
the function @xmath129 is plotted in fig . 1 , for @xmath130 ( i.e. , the fundamental violin mode ) .
fiducial parameters that were used in making the plot are specified in the figure s header .
the function peaks very strongly within @xmath90 from the attachment ends of the fiber ; there @xmath131 is dominated by the @xmath132 . away from the attachment points ,
the coupling is dominated by the @xmath133 part of the solution and @xmath134 . in this subsection s model the creep events
are assumed to be triggered homogeneously in the suspension fibers @xcite .
thus the creep events have only @xmath135 chance to be triggered within @xmath90 from the attachment points .
however , they have individually much larger impact [ by a factor of @xmath136 on the test - mass motion then those ones originating away from the attachments .
it follows that the creep events originating within the bending regions near attachment points contribute most of the creep noise ; their contribution is greater by a factor of @xmath137 than that of the creep events away from the attachment points .
this is studied in section 4 .
let us now consider the case where a laser beam is inclined by a small angle @xmath138 with respect to the horizontal direction .
this is an inevitable effect because of the spherical shape of the equipotential surface on which the test masses in the same arm are located ; for @xmath139 km arm @xmath140 radians .
it is this misalignment that was previously thought to be the major source of the creep noise @xcite ; we treat this mechanism within the formalism developed in the previous section . the reciprocal force applied at the test mass
has now a vertical component @xmath141 that causes the vertical test - mass motion @xmath142 , \label{xvert}\ ] ] where the negative sign corresponds to the upward motion .
here we take into account only one vertical suspension mode with the angular frequency @xmath143 and the damping rate @xmath144 ; the higher - order vertical modes are at much higher frequency and have a much weaker coupling to the sudden force .
the readout variable from eq .
( [ xreadout2 ] ) is given by @xmath145 .
\label{xvertreadout}\ ] ] in the fourier domain , @xmath146}. \label{xverfourrier}\ ] ] it is instructive to compare the amplitude of the vertical mode to the amplitude of the pendulum mode excited by the creep even near the attachment point , as inferred from eq .
( [ xreadout ] ) .
their ratio is approximately given by @xmath147 it is the smallness of this ratio that makes the contribution to the creep noise from the creep - induced fiber - lengthening be subdominant relative to the direct horizontal coupling , in most of the ligo band .
consider now a situation where multiple creep events are triggered in sequence , .
according to the central limit theorem , if the events occur sufficiently frequently , their superposition produces a random gaussian noise in the test - mass motion .
the response of the test - mass to a single creep event can be written as @xmath148 where @xmath149 is the time when the creep event is triggered , and @xmath150 is the set of parameters characterizing the event ( location in the fiber , effective volume , etc . ) . in what follows
we assume that the creep events are statistically independent from each other and that the creep - event parameters sample some well - defined probability - distribution function .
this assumption is known not to hold in some systems that exhibit so - called crackle noise " @xcite , and will be relaxed in future work . if the probability density distribution @xmath151 is time - invariant , then the creep noise is stationary and has a spectral density given by @xmath152 where @xmath153 is the rate of the creep events .
the @xmath154 implies a multi - dimensional integral over the parameter space of @xmath150 . evaluating this expression for the model of the cylindrical fiber , we get @xmath155 where @xmath156 and @xmath157+k\lambda[2\sin(2kl)+kl]\right\}. \label{g}\ ] ] here @xmath158 is the ensemble average of the @xmath159 of the creep events in the system . naturally , this quantity is meaningful only in our simple model for the creep events , however a term like this , representing the mean of the squared intensity of the creep events , is expected in any generic model for the localised creep events .
the first term in square brakets on the right - hand side of the above equations is due to creep events generated near the attachment points , while the second term is that due to creep events generated in the fiber s bulk ; in both of these the terms of order @xmath160 have been neglected .
it is clear that the noise is strongly dominated by the creep events near the attachment point .
the spectral sensity of noise due to the vertical lengthening of the fibers is given by @xmath161 where @xmath162 the plots for @xmath163 and @xmath164 are shown in fig .
2 . while the scale on the vertical axis of these plots is arbitrary
, since @xmath165 is unknown , the spectral density shape and the relative contribution of the two noises are fixed .
we observe that the direct horizontal coupling induces greater creep noise than the vertical motion , at all frequencies except at a narrow band around @xmath166 .
in this paper i have provided an elastodynamic calculation of the interferometer s response to a creep event , and found the functional form of the creep noise in the stationary limit .
a simple model where the fiber was modeled as a cylinder of constant radius was considered in detail , since this allowed me to obtain analytical expressions for the test - mass response .
two interrelated qualitative features of this model are worth noting : ( 1 ) creep events near the fiber s ends receive a much stronger test - mass response in the ligo band than those at the center of the fiber , and contribute the majority of the creep noise , and ( 2 ) the dominant coupling to the inteferometer s readout is via excitation of the violin and pendulum modes of the suspension , and not via the lenthening of the fiber .
i should caution though that these conclusions may not hold in a fiber with a more complex dependence of the cross - sectional radius @xmath76 on the height @xmath78 .
in particular , the fibers in advanced ligo suspensions are made significantly thicker near the end points , in order to minimize the suspension thermal noise .
this thickening will reduce the local tension stress , thus reducing both the coupling of a creep event to the test mass motion and the likelyhood of a creep event to occur . in a simple model for the creep noise
, i have assumed that the creep events are triggered homogeneously in the suspention fiber .
this may not be the case .
the creep events may be triggered preferentially ( 1 ) at the locations where the fiber is welded to the test mass or the upper suspension plate , although this is not very likely since at the weld the fiber is much thicker than in its center ( @xmath167 m ) , so the tension is small ( norna robertson , private communications ) , or ( 2 ) near the locations where the ears that support the test mass are bonded to it . the bonding material is non - metallic and non - glassy and is a potential source of problems ( riccardo desalvo , private communications ) . in future work
i plan to explore the spatial distribution of the expected creep events , as well as relax the assumption of their statistical independence .
i plan to also deal with the issues of non - gaussianity of the creep - event triggers ; it can presumably can be mitigated by considering the output of several independent interferometers .
some comfort for the advanced interferometers can be derived from the fact that experiments @xcite , @xcite , and @xcite have not observed any influence of the creep noise on the violin - mode motion .
we note , however , that all of the measurements in question have searched for the creep noise at high frequencies corresponding to the resonant frequencies of violin modes , from several hundred to several thousand hz .
if the creep events are statistically independent from each other , then the expected creep noise is red , with @xmath168 except near resonances ; see eqs .
( [ sdensity ] ) and ( [ q ] ) .
this is the same scaling as that for the suspension thermal noise in the case where damping of the fiber s motion is structural ( see , e.g. , @xcite ) .
therefore , one may argue that since no creep noise that exceeds the suspension thermal noise is observed at high frequencies , none is expected to exceed the suspension thermal noise at low frequencies as well .
this argument , however , relies on a very simple model for the creep noise that was developed in section 4 , and in particular it relies on the creep events being statistically independent
. this assumption does not hold in many systems that release their free energy via spontaneous acoustic emission events ( known as the crackle noise " ) , see @xcite and references therein .
thus further experimental and theoretical work is warranted for the low - freqyency domain .
i thank vladimir braginsky for impressing on me the importance of non - stationary noise in many a conversation that we ve had from the first time we met in september of 1994 .
i thank misha gorodetsky for his insightful comments given as part of the internal lsc review for this article .
i thank riccardo desalvo , eric gustafson , jan harms , norna robertson , and peter saulson for comments on the earlier version of this manuscript .
i thank rana adhikari , yanbei chen , kip thorne , and sergei vyatchanin for useful discussions .
finally , i thank sarah levin for proofreading parts of the manuscript before submission .
the calculations in this paper were completed during a visit to ligo laboratory at caltech .
the research was supported by the australian research council future fellowship .
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naturally , other time - dependencies may also be considered within this formalism .
more precisely , for frequencies such that the corresponding sound waves have a much larger wavelength than the size of @xmath34 , which is an excellent approximation in our situation . strictly speaking , this expression is valid only to zeroth order in @xmath169 at low frequencies , where @xmath61 and @xmath57 are the masses of the string and the test mass , respectively .
this is of order of @xmath170 for ligo .
this enforces causality of the test - mass response . in case
there is no damping , one needs to use the landau rule when evaluating the inverse fourier transform : the integration contour should pass under every pole .
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, this may not be so .
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here we provide a quick derivation ; similar derivations for more complicated situations when the test - mass tilt is allowed is given in e.g. appendix a of @xcite .
suppose a periodic force @xmath171 is acting on the test mass and induces its periodic motion @xmath172 the fiber s motion is given by @xmath173 here @xmath174 is the tension - wave vector .
the horizontal component of back - reaction tension force acting on the test - mass is @xmath175 the second newton s law gives @xmath176 substituting the eq .
( [ a4 ] ) above we get @xmath177 which is equivalent to eq .
( [ impedance ] ) in the text .[/INST] in gravitational - wave interferometers , test masses are suspended on thin fibers which experience considerable tension stress .
sudden microscopic stress release in a suspension fiber , which i call a creep event , would excite motion of the test mass that would be coupled to the interferometer s readout . the random test - mass motion due to a time - sequence of creep events is referred to as creep noise. in this paper i present an elasto - dynamic calculation for the test - mass motion due to a creep event .
i show that within a simple suspension model , the main coupling to the optical readout occurs via a combination of a dc " horizontal displacement of the test mass , and excitation of the violin and pendulum modes , and not , as was thought previously , via lengthening of the fiber .
when the creep events occur sufficiently frequently and their statistics is time - independent , the creep noise can be well - approximated by a stationary gaussian random process .
i derive the functional form of the creep noise spectral density in this limit , with the restrictive assumption that the creep events are statistically independent from each other . </s> |
SECTION 1. SHORT TITLE.
This Act may be cited as the ``Lesser Prairie Chicken National
Habitat Preservation Area Act of 2008''.
SEC. 2. DEFINITIONS.
In this Act:
(1) State land.--The term ``State land'' means the
approximately 13,236 acres of State land, as depicted on the
map.
(2) Map.--The term ``map'' means the map titled ``Lesser
Prairie Chicken National Habitat Preservation Area and Land
Exchange'' and dated April 30, 2008.
(3) Federal land.--The term ``Federal land'' means the land
administered by the Secretary consisting of approximately 7,718
acres as depicted on the map.
(4) Secretary.--The term ``Secretary'' means the Secretary
of the Interior.
(5) State.--The term ``State'' means the State of New
Mexico.
(6) County.--The term ``County'' means the County of
Chaves.
(7) Preservation area.--The term ``Preservation Area''
means the Lesser Prairie Chicken National Habitat Preservation
Area.
SEC. 3. LAND EXCHANGE.
(a) In General.--The Secretary may convey to the State all right,
title, and interest of the United States in and to the Federal land.
(b) Consideration.--As consideration for the conveyance of the
Federal land under subsection (a), the State shall convey to the United
States all right, title, and interest of the State in and to the State
land.
(c) Interests Included in Exchange.--Subject to valid existing
rights, the land exchange under this Act shall include the conveyance
of all surface, subsurface, mineral, and water rights to the Federal
land and State land.
(d) Compliance With Federal Land Policy and Management Act.--The
Secretary shall carry out the land exchange under this Act in
accordance with section 206 of the Federal Land Policy and Management
Act of 1976 (43 U.S.C. 1716) and other applicable laws.
(e) No Amendment to Management Plan Required.--The exchange of
Federal land and State land shall not require an amendment to the
Mimbres Resource Management Plan.
(f) Additional Terms and Conditions.--The Secretary may require
such additional terms and conditions for the land exchange as the
Secretary considers to be appropriate to protect the interests of the
United States.
SEC. 4. LESSER PRAIRIE CHICKEN NATIONAL HABITAT PRESERVATION AREA.
(a) Establishment; Purposes.--There is established in the County
the Lesser Prairie Chicken National Habitat Preservation Area to
protect, conserve, and enhance habitat for the Lesser Prairie Chicken.
(b) Boundaries.--The Preservation Area shall consist of
approximately 28,168 acres of public land and 9,402 acres of land
acquired under section 3 of this Act, as generally depicted on the map.
(c) Maps and Legal Description.--
(1) In general.--Not later than 30 days after the date of
the enactment of this Act, the Secretary shall submit to
Congress a map and legal description of the Preservation Area.
(2) Force and effect.--The map and legal description
submitted under paragraph (1) shall have the same force and
effect as if included in this Act, except that the Secretary
may correct clerical and typographical errors in the map and
legal description.
(3) Public availability.--Copies of the map and legal
description submitted under paragraph (1) shall be on file and
available for public inspection in--
(A) the Office of the Director of the Bureau of
Land Management;
(B) the Office of the State Director;
(C) the Office of the Pecos District Manager of the
Bureau of Land Management; and
(D) the Office of the County Clerk in Roswell, New
Mexico.
SEC. 5. MANAGEMENT OF THE PRESERVATION AREA.
(a) In General.--The Secretary shall manage the Preservation Area--
(1) in a manner that protects, conserves, and enhances the
habitat for the Lesser Prairie Chicken; and
(2) in accordance with--
(A) this Act;
(B) the Federal Land Policy and Management Act of
1976 (43 U.S.C. 1701 et seq.); and
(C) any other applicable laws.
(b) Uses.--
(1) In general.--The Secretary shall allow only uses of the
Preservation Area that the Secretary determines will further
the purposes for which the Preservation Area is established.
(2) Use of motorized vehicles.--Except as needed for
administrative purposes or to respond to an emergency, the use
of motorized vehicles or mechanized transport in the
Preservation Area shall be allowed only on roads and trails
designated for vehicular use under the management plan so long
as such use is in conformance with the purposes of this Act.
(c) Withdrawals.--Subject to valid existing rights, all land
managed by the Bureau of Land Management within the Preservation Area
and any land and interests in land acquired for the Preservation Area
by the United States after the date of the enactment of this Act are
withdrawn from--
(1) all forms of entry, appropriation, or disposal under
the public land laws;
(2) location, entry, and patent under the mining laws; and
(3) disposal under the mineral leasing, mineral materials,
and geothermal leasing laws.
(d) Hunting and Trapping.--
(1) In general.--Subject to paragraph (2), hunting and
trapping shall be allowed in the Preservation Area to the
extent consistent with the protection and conservation of the
Lesser Prairie Chicken.
(2) Limitations.--
(A) Regulations.--The Secretary may designate by
regulation areas in which, and establish periods during
which, for reasons of public safety, administration, or
compliance with applicable laws, no hunting or trapping
will be permitted in the Preservation Area.
(B) Consultation.--Except in emergencies, the
Secretary shall consult with the appropriate State
agency before promulgating regulations under
subparagraph (A) that close a portion of the
Preservation Area to hunting and trapping.
(e) Grazing.--The Secretary may allow grazing solely for the
purpose of vegetative management to enhance Lesser Prairie Chicken
habitat.
(f) Activities Outside Preservation Area.--The fact that an
activity or use of land is not permitted on land within the
Preservation Area shall not preclude the activity or use outside the
boundary of the Preservation Area or on private land within the
Preservation Area, consistent with other applicable law.
(g) Acquisition of Land.--
(1) In general.--The Secretary may acquire land in the
Preservation Area only--
(A) from a willing seller; and
(B) through purchase, exchange, or donation.
(2) Management.--Land acquired under paragraph (1) shall be
managed as part of the Preservation Area in accordance with
this Act.
(h) Interpretative Sites.--The Secretary may establish sites in the
Preservation Area to permit the interpretation of the historical,
cultural, scientific, archaeological, natural, and education resources
of the Preservation Area.
SEC. 6. MANAGEMENT PLAN.
(a) In General.--Not later than 1 year after the date of the
enactment of this Act, the Secretary shall develop a comprehensive plan
for the long-range protection and management of the Preservation Area.
(b) Contents.--The management plan shall--
(1) describe the appropriate uses and management of the
Preservation Area in accordance with--
(A) this Act;
(B) the Federal Land Policy and Management Act of
1976 (43 U.S.C. 1701 et seq.); and
(C) other applicable laws;
(2) incorporate, as appropriate, decisions in any other
management or activity plan for the land within or adjacent to
the Preservation Area; and
(3) take into consideration--
(A) any information developed in studies of the
land within or adjacent to the Preservation Area; and
(B) the historical involvement of the local
community in the interpretation and protection of the
resources of the Preservation Area.
Amend the title so as to read: ``A bill to provide for a
land exchange involving State land and Bureau of Land
Management land in Chaves and Dona Ana Counties, New Mexico,
and to establish the Lesser Prairie Chicken National Habitat
Preservation Area, and for other purposes.''. | Lesser Prairie Chicken National Habitat Preservation Area Act of 2008 - Authorizes the exchange of certain federal and state lands in New Mexico concerning the establishment under this Act of the Lesser Prairie Chicken Habitat Preservation Area in the County of Chaves, New Mexico.
Requires that such land exchange include the conveyance of all surface, subsurface, mineral, and water rights to the federal and state land.
Provides that the exchange of the federal and state land shall not require an amendment to the Mimbres Resource Management Plan.
Establishes the Preservation Area for the protection, conservation, and enhancement of habitat for the lesser prairie chicken.
Authorizes the Secretary of the Interior to only allow uses of the Preservation Area that will further the purposes for which it is established.
Permits the use of motorized vehicles or mechanized transport in the Preservation Area, only on roads and trails designated for vehicular use under the management plan, except as needed for administrative purposes or to respond to an emergency.
Withdraws all Bureau of Land Management (BLM) managed land within the Preservation Area and any land and interests in land acquired by the United States for the Preservation Area from: (1) all forms of entry, appropriation, or disposal under the public land laws; (2) location, entry, and patent under the mining laws; and (3) disposal under the mineral leasing, mineral materials, and geothermal leasing laws.
Allows hunting and trapping in the Preservation Area to the extent consistent with the protection and conservation of the lesser prairie chicken. Authorizes the Secretary to designate by regulation areas in which, and establish periods during which, for reasons of public safety, administration, or compliance with applicable laws, no hunting or trapping will be permitted. Instructs the Secretary, except in emergencies, to consult with the appropriate state agency before promulgating regulations that close a portion of the Preservation Area to hunting and trapping.
Authorizes the Secretary to allow grazing only for the purpose of vegetative management to enhance lesser prairie chicken habitat.
Declares that the fact that an activity or use of land is not permitted on land within the Preservation Area shall not preclude the activity or use outside the boundary of the Preservation Area or on private land within it, consistent with other applicable law.
Authorizes the Secretary to acquire land in the Preservation Area only from a willing seller or through purchase, exchange, or donation.
Authorizes the Secretary to establish sites in the Preservation Area to permit the interpretation of the Preservation Area's historical, cultural, scientific, archeological, natural, and educational resources.
Requires the Secretary to develop a plan for the long-range protection and management of the Preservation Area. | <s>[INST]SECTION 1. SHORT TITLE.
This Act may be cited as the ``Lesser Prairie Chicken National
Habitat Preservation Area Act of 2008''.
SEC. 2. DEFINITIONS.
In this Act:
(1) State land.--The term ``State land'' means the
approximately 13,236 acres of State land, as depicted on the
map.
(2) Map.--The term ``map'' means the map titled ``Lesser
Prairie Chicken National Habitat Preservation Area and Land
Exchange'' and dated April 30, 2008.
(3) Federal land.--The term ``Federal land'' means the land
administered by the Secretary consisting of approximately 7,718
acres as depicted on the map.
(4) Secretary.--The term ``Secretary'' means the Secretary
of the Interior.
(5) State.--The term ``State'' means the State of New
Mexico.
(6) County.--The term ``County'' means the County of
Chaves.
(7) Preservation area.--The term ``Preservation Area''
means the Lesser Prairie Chicken National Habitat Preservation
Area.
SEC. 3. LAND EXCHANGE.
(a) In General.--The Secretary may convey to the State all right,
title, and interest of the United States in and to the Federal land.
(b) Consideration.--As consideration for the conveyance of the
Federal land under subsection (a), the State shall convey to the United
States all right, title, and interest of the State in and to the State
land.
(c) Interests Included in Exchange.--Subject to valid existing
rights, the land exchange under this Act shall include the conveyance
of all surface, subsurface, mineral, and water rights to the Federal
land and State land.
(d) Compliance With Federal Land Policy and Management Act.--The
Secretary shall carry out the land exchange under this Act in
accordance with section 206 of the Federal Land Policy and Management
Act of 1976 (43 U.S.C. 1716) and other applicable laws.
(e) No Amendment to Management Plan Required.--The exchange of
Federal land and State land shall not require an amendment to the
Mimbres Resource Management Plan.
(f) Additional Terms and Conditions.--The Secretary may require
such additional terms and conditions for the land exchange as the
Secretary considers to be appropriate to protect the interests of the
United States.
SEC. 4. LESSER PRAIRIE CHICKEN NATIONAL HABITAT PRESERVATION AREA.
(a) Establishment; Purposes.--There is established in the County
the Lesser Prairie Chicken National Habitat Preservation Area to
protect, conserve, and enhance habitat for the Lesser Prairie Chicken.
(b) Boundaries.--The Preservation Area shall consist of
approximately 28,168 acres of public land and 9,402 acres of land
acquired under section 3 of this Act, as generally depicted on the map.
(c) Maps and Legal Description.--
(1) In general.--Not later than 30 days after the date of
the enactment of this Act, the Secretary shall submit to
Congress a map and legal description of the Preservation Area.
(2) Force and effect.--The map and legal description
submitted under paragraph (1) shall have the same force and
effect as if included in this Act, except that the Secretary
may correct clerical and typographical errors in the map and
legal description.
(3) Public availability.--Copies of the map and legal
description submitted under paragraph (1) shall be on file and
available for public inspection in--
(A) the Office of the Director of the Bureau of
Land Management;
(B) the Office of the State Director;
(C) the Office of the Pecos District Manager of the
Bureau of Land Management; and
(D) the Office of the County Clerk in Roswell, New
Mexico.
SEC. 5. MANAGEMENT OF THE PRESERVATION AREA.
(a) In General.--The Secretary shall manage the Preservation Area--
(1) in a manner that protects, conserves, and enhances the
habitat for the Lesser Prairie Chicken; and
(2) in accordance with--
(A) this Act;
(B) the Federal Land Policy and Management Act of
1976 (43 U.S.C. 1701 et seq.); and
(C) any other applicable laws.
(b) Uses.--
(1) In general.--The Secretary shall allow only uses of the
Preservation Area that the Secretary determines will further
the purposes for which the Preservation Area is established.
(2) Use of motorized vehicles.--Except as needed for
administrative purposes or to respond to an emergency, the use
of motorized vehicles or mechanized transport in the
Preservation Area shall be allowed only on roads and trails
designated for vehicular use under the management plan so long
as such use is in conformance with the purposes of this Act.
(c) Withdrawals.--Subject to valid existing rights, all land
managed by the Bureau of Land Management within the Preservation Area
and any land and interests in land acquired for the Preservation Area
by the United States after the date of the enactment of this Act are
withdrawn from--
(1) all forms of entry, appropriation, or disposal under
the public land laws;
(2) location, entry, and patent under the mining laws; and
(3) disposal under the mineral leasing, mineral materials,
and geothermal leasing laws.
(d) Hunting and Trapping.--
(1) In general.--Subject to paragraph (2), hunting and
trapping shall be allowed in the Preservation Area to the
extent consistent with the protection and conservation of the
Lesser Prairie Chicken.
(2) Limitations.--
(A) Regulations.--The Secretary may designate by
regulation areas in which, and establish periods during
which, for reasons of public safety, administration, or
compliance with applicable laws, no hunting or trapping
will be permitted in the Preservation Area.
(B) Consultation.--Except in emergencies, the
Secretary shall consult with the appropriate State
agency before promulgating regulations under
subparagraph (A) that close a portion of the
Preservation Area to hunting and trapping.
(e) Grazing.--The Secretary may allow grazing solely for the
purpose of vegetative management to enhance Lesser Prairie Chicken
habitat.
(f) Activities Outside Preservation Area.--The fact that an
activity or use of land is not permitted on land within the
Preservation Area shall not preclude the activity or use outside the
boundary of the Preservation Area or on private land within the
Preservation Area, consistent with other applicable law.
(g) Acquisition of Land.--
(1) In general.--The Secretary may acquire land in the
Preservation Area only--
(A) from a willing seller; and
(B) through purchase, exchange, or donation.
(2) Management.--Land acquired under paragraph (1) shall be
managed as part of the Preservation Area in accordance with
this Act.
(h) Interpretative Sites.--The Secretary may establish sites in the
Preservation Area to permit the interpretation of the historical,
cultural, scientific, archaeological, natural, and education resources
of the Preservation Area.
SEC. 6. MANAGEMENT PLAN.
(a) In General.--Not later than 1 year after the date of the
enactment of this Act, the Secretary shall develop a comprehensive plan
for the long-range protection and management of the Preservation Area.
(b) Contents.--The management plan shall--
(1) describe the appropriate uses and management of the
Preservation Area in accordance with--
(A) this Act;
(B) the Federal Land Policy and Management Act of
1976 (43 U.S.C. 1701 et seq.); and
(C) other applicable laws;
(2) incorporate, as appropriate, decisions in any other
management or activity plan for the land within or adjacent to
the Preservation Area; and
(3) take into consideration--
(A) any information developed in studies of the
land within or adjacent to the Preservation Area; and
(B) the historical involvement of the local
community in the interpretation and protection of the
resources of the Preservation Area.
Amend the title so as to read: ``A bill to provide for a
land exchange involving State land and Bureau of Land
Management land in Chaves and Dona Ana Counties, New Mexico,
and to establish the Lesser Prairie Chicken National Habitat
Preservation Area, and for other purposes.''.[/INST]Lesser Prairie Chicken National Habitat Preservation Area Act of 2008 - Authorizes the exchange of certain federal and state lands in New Mexico concerning the establishment under this Act of the Lesser Prairie Chicken Habitat Preservation Area in the County of Chaves, New Mexico.
Requires that such land exchange include the conveyance of all surface, subsurface, mineral, and water rights to the federal and state land.
Provides that the exchange of the federal and state land shall not require an amendment to the Mimbres Resource Management Plan.
Establishes the Preservation Area for the protection, conservation, and enhancement of habitat for the lesser prairie chicken.
Authorizes the Secretary of the Interior to only allow uses of the Preservation Area that will further the purposes for which it is established.
Permits the use of motorized vehicles or mechanized transport in the Preservation Area, only on roads and trails designated for vehicular use under the management plan, except as needed for administrative purposes or to respond to an emergency.
Withdraws all Bureau of Land Management (BLM) managed land within the Preservation Area and any land and interests in land acquired by the United States for the Preservation Area from: (1) all forms of entry, appropriation, or disposal under the public land laws; (2) location, entry, and patent under the mining laws; and (3) disposal under the mineral leasing, mineral materials, and geothermal leasing laws.
Allows hunting and trapping in the Preservation Area to the extent consistent with the protection and conservation of the lesser prairie chicken. Authorizes the Secretary to designate by regulation areas in which, and establish periods during which, for reasons of public safety, administration, or compliance with applicable laws, no hunting or trapping will be permitted. Instructs the Secretary, except in emergencies, to consult with the appropriate state agency before promulgating regulations that close a portion of the Preservation Area to hunting and trapping.
Authorizes the Secretary to allow grazing only for the purpose of vegetative management to enhance lesser prairie chicken habitat.
Declares that the fact that an activity or use of land is not permitted on land within the Preservation Area shall not preclude the activity or use outside the boundary of the Preservation Area or on private land within it, consistent with other applicable law.
Authorizes the Secretary to acquire land in the Preservation Area only from a willing seller or through purchase, exchange, or donation.
Authorizes the Secretary to establish sites in the Preservation Area to permit the interpretation of the Preservation Area's historical, cultural, scientific, archeological, natural, and educational resources.
Requires the Secretary to develop a plan for the long-range protection and management of the Preservation Area.</s> |
most of galaxies contain smbhs at their centers . if a galaxy collides with another galaxy , the merging remnant hosts two smbhs and they form a binary system .
@xcite discussed the possibility of the formation of smbh binaries and their evolutions .
they concluded that the evolution of the semi - major axis stalls after they ejected out all the nearby stars ( loss cone depletion ) and the binary is unlikely to merge within the hubble time , as far as we consider the stellar dynamical effects and the gravitational wave radiation only .
this problem is called as `` last parsec problem '' since the typical separation of a stalled binary is around one parsec .
many researchers studied this problem and confirmed that the separation of the binary stall @xcite .
most of previous works on the evolution of the smbh binary focused on the evolution of the semi - major axis .
recently , @xcite performed @xmath0-body simulations of smbh - imbh binaries with the mass ratio of 1000:1 , and found that the eccentricity of the binary grows toward unity after the loss cone depletion .
because of this increase of eccentricity , the merging timescale through the gravitational radiation goes below @xmath1 years even if the loss cone is depleted .
similar result was obtained by @xcite , and it has been reported that under certain circumstance smbh binaries of mass ratios close to 1:1 show similar increase of the eccentricity @xcite . however , this increase of the eccentricity is difficult to understand , because the measured differential cross sections of interaction between an smbh binary and field stars indicated that eccentricity of a smbh binary would not increase through interaction with field stars @xcite .
recently , @xcite pointed out that the bound stars around smbh binary play important role in the evolution of the eccentricity but did not give the explanation about the mechanism of the eccentricity growth .
if the increase of eccentricity actually occurs in real smbh binaries , it naturally explains the orbit of the binary in the quasar oj287 @xcite .
the central smbh of the quasar oj287 has the mass of @xmath2 , and the secondary black hole has the mass @xmath3 , orbital period of 12 yrs , and eccentricity of 0.66 .
currently , this smbh binary is in the process of circularization due to the gravitational wave radiation .
thus , one would expect that oj287 had much larger semi - major axis and eccentricity very close to unity in the past . in this letter
, we describe the mechanism which drives the increase of the eccentricity . in section 2
, we describe the numerical experiment we performed . in section 3 ,
we present the interpretation of the numerical result .
we give the discussion and summary in section 4 .
in order to clarify the mechanism which drives the growth of the eccentricity of unequal - mass smbh binaries , we performed @xmath0-body simulations and investigated the change in orbital property of field stars due to interaction with the smbh binary .
our initial model is similar to that of @xcite .
galaxy density profile is given by where @xmath4 is the scale length and @xmath5 is the total mass of field particles , and we set @xmath6 and @xmath7 . from observations ,
the slope of central density of a giant elliptical galaxy is shallower than @xmath8 @xcite .
this feature is well understood by numerical simulations and theory @xcite . in our simulation ,
the density is @xmath9 cusp .
the velocity profile is isotropic and consistent with the density profile .
the number of field stars @xmath0 are 16384 and 32768 .
we performed five runs for each @xmath0 .
the heavier smbh particle whose mass is @xmath10 is placed at the center of the galaxy , and the lighter one whose mass is @xmath11 is placed in an eccentric orbit with eccentricity @xmath12 of 0.2 and semi - major axis @xmath13 of 20pc . at this radius
the enclosed stellar mass is comparable to that of the secondary mass and the stall of the evolution of semi - major axis takes place quickly .
the mass of field particles @xmath14 in the case of @xmath15 .
our simulation roughly mimics the oj287 system .
the time integration scheme we used is the fourth - order hermite scheme @xcite for interactions between the field - field particles and the secondary smbh - field particles .
the forces from the primary smbh are integrated with the sixth - order hermite scheme @xcite to reduce the integration error . to save the calculation time , we used grape - dr @xcite for calculating interactions between the field - field particles .
figure 1 shows the evolution of the semi - major axis @xmath13 , the eccentricity @xmath12 and the merging timescale due to the gravitational wave radiation @xmath16 of a smbh binary using @xcite formula , for an @xmath15 run .
the evolution of the semi - major axis slows down and deviates from the theoretical prediction . at the same time , the eccentricity starts to grow , and reaches @xmath17 by @xmath18 myrs .
this increase of eccentricity causes the drastic decrease of the merger timescale through gravitational wave radiation . in this case , at @xmath19 myrs , the merger timescale is 10 gyrs , but by @xmath20 myrs the timescale shrinks to 10 myrs .
we did not include the effect of the gravitational wave radiation , but if we did , the smbh binary would have merged very quickly .
figure 2 shows the evolutions of the eccentricity for all runs .
the evolutions in all runs inferred from figure 2 are basically similar .
the variation of the results of @xmath15 runs is smaller than that of @xmath21 runs .
these appear to be no statistically significant difference between the results for @xmath21 and @xmath22 .
we have carefully analyzed the behavior of the stars around the smbh binary in our numerical simulation , and found that the following three - stage mechanism drives the increase in the eccentricity of the secondary . 1 .
the presence of the secondary gives small , non - axisymmetric perturbation to the orbits of the field stars , which would be purely keplerian otherwise . because of this perturbation the orbital motions of the stars become chaotic , and their angular momenta change chaotically .
2 . since the orbital angular momenta of stars are not conserved , they can experience close encounters with the secondary , some of which result in the ejection of stars .
when a star is on a prograde orbit relative to the orbit of the secondary , it has a much larger chance of being ejected than when it is on a retrograde orbit .
3 . since the secondary tends to scatter stars on prograde orbits , there will be more stars on retrograde orbits than on prograde orbits around the binary .
however , the chaotic changes of angular momenta of stars reduce the difference between the number of stars on prograde and retrograde orbits .
this means the angular momentum of the secondary is transferred to field stars and the eccentricity of the secondary increases .
note that in this process the transfer of angular momentum occurs between the binary and field stars , while field stars are bound to the system , through secular perturbation .
this secular perturbation is neglected in previous theoretical models on the behavior of smbh binaries @xcite or models based on scattering experiment @xcite , and can give the reasonable interpretation of the results of @xcite .
figure 3 shows the time evolution of the specific angular momentum of a star that comes close to the secondary smbh .
the orbital plane of the secondary smbh is the @xmath23 plane .
one can see that none of the three components of the angular momentum are conserved and the changes are complicated .
these changes are due to the secular perturbation of the secondary smbh .
if the secondary smbh had a circular orbit , the secular perturbation would not have any non - axisymmetric term , and therefore @xmath24 would be conserved @xcite . however , since the secondary smbh has non - zero eccentricity , the perturbation has non - axisymmetric term , resulting in a triaxial potential field .
thus , the orbits of many stars become chaotic @xcite . this chaotic change of the orbits of field stars means that they approach the secondary smbh when their total angular momentum becomes small enough .
one can assume that stars on both prograde and retrograde orbits will approach the secondary smbh in roughly equal chances .
the cross section of the large change of the binding energy , which would result in the ejection of a star , is larger for prograde orbits , because the typical relative velocity is smaller for prograde orbits and the effect of gravitational focusing is larger .
figure 4 shows the cumulative mass of ejected stars in units of the mass of secondary smbh .
we can see that prograde stars are more likely to be ejected . in this calculation , the difference between the cumulative mass of ejected stars on prograde and retrograde orbits was comparable to the mass of the secondary smbh . for @xmath25 , the ejection rates of prograde and retrograde stars are rather similar , but that is simply because the eccentricity of the secondary smbh has become large enough and therefore the relative difference in the cross section terms has become small .
figure 5 shows the evolution of the average value of @xmath24 of stars which are bound to the primary smbh at @xmath26 and are ejected by @xmath27 . the net change of @xmath24 of stars which were initially in prograde orbit is small , while that of stars in retrograde orbits is large .
thus the primary mechanism of angular momentum transfer is the transfer of angular momentum to retrograde stars through secular perturbation and removal of them through ejection .
to summarize , we found a quite efficient mechanism that causes the increase of the eccentricity of unequal - mass smbh binaries .
it is the combination of the non - axisymmetric potential field of the secondary smbh , which randomizes the angular momentum of field stars , and the selective ejection of stars with prograde orbits through close encounters with the secondary smbh .
since either effects depends on masses of field particles , our proposed mechanism does not depend on @xmath0 .
this mechanism is effective at least for smbh binaries with fairly large mass ratios ( larger than 10:1 ) .
there is no other known mechanism that can make the eccentricity of a smbh binary close to unity .
both the gravitational wave radiation and gas dynamical effect reduce the eccentricity , and interaction with field stars , if we neglect the mechanism we described in this paper , would not change the eccentricity @xcite . if the parent galaxy is globally nonspherical , the smbh binary could become eccentric because of the kozai mechanism , but it would be hard to reach very high eccentricity values since the @xmath28-component would be conserved if the parent galaxy is axisymmetric . if the parent galaxy is triaxial , we could expect to see a significant effect on the evolution of the semi - major axis @xcite , but its effect on eccentricity is currently unknown . furthermore , it is difficult to maintain triaxiality given the presence of the central smbh @xcite .
if the mass ratio between the secondary smbh and the field stars is infinite , in other words , in the continuous limit , we can expect that the eccentricity of the smbh binary reaches unity . in practice , since the mass and the number of field stars are both finite , they give random perturbations to the angular momentum of smbh binary .
if we assume that there is thermal equilibrium between tangential velocity of the secondary smbh and random velocity of stars around the secondary , we can estimate the specific angular momentum @xmath29 and the eccentricity @xmath12 of the secondary smbh as and where @xmath30 is the mean value of the specific angular momentum of the field star around the secondary smbh and @xmath31 and @xmath32 are masses of the secondary and the field star , respectively .
the timescale of the change in the angular momentum of the field stars is proportional to @xmath34 , where @xmath35 and @xmath36 are the masses of the primary and secondary smbhs , respectively .
the rate at which angular momentum is removed through ejection of stars is @xmath37 , since it is proportional to the interaction cross section . therefore ,
if @xmath34 is large , the timescale of the change in the angular momentum is shorter than that of the removal of the field stars .
thus @xmath38 is determined by the removal timescale .
the loss rate of the angular momentum of the secondary smbh is proportional to @xmath39 , where @xmath40 is the density at the radius of the secondary , @xmath41 and @xmath42 are a kepler velocity and cross section of the secondary .
thus , @xmath38 is proportional to @xmath43 . from our numerical result
, we can estimate the timescale as where @xmath44 is a semi - major axis of a stalled binary and assumed @xmath45 .
since the majority of galaxy - galaxy merger events are minor mergers with mass ratios of around 10:1 or more , the typical mass ratio of the smbh binary is also around 10:1 , if we assume the linear relationship between the smbh mass and the mass of the stellar spheroid @xcite .
therefore , we can conclude that our mechanism is effective for most of smbh binaries , and they can merge through interactions with field stars and gravitational wave radiation . our result finally has given a definite solution to the `` last - parsec problem '' @xcite .
the mechanism we found naturally explains why the oj287 system is eccentric .
most likely , this mechanism resulted in the orbit of secondary with the periastron distance similar to the present value , but with much larger semi - major axis and eccentricity , and gravitational wave radiation have driven the semi - major axis to its present value .
the state of a recently found candidate smbh binary @xcite might also be explained by our mechanism .
this system is a binary with the mass ratio of around 30:1 .
interaction with field stars can not drive its semi - major axis to the value suggested by the observed relative velocity of @xmath46 , if we assume a circular orbit .
however , our mechanism implies that all unequal - mass smbh binaries with mass ratio larger than 10:1 become highly eccentric .
thus , they all have very large relative velocities at the pericenter .
therefore the observed relative velocity is only weakly coupled to the semi - major axis .
the frequency @xmath47 is given by where @xmath48 and @xmath49 are the pericenter distance of the secondary smbh from the primary and the distance of the binary from us .
unfortunately , the frequency is too low to be observed even with space missions like lisa .
however , since the amplitude is very large , other techniques such as doppler tracking of interplanetary spacecraft or pulsar timing could be used . in this letter
, we present a stellar - dynamical mechanism that drives the increase of the eccentricity of an smbh binary .
there are two key processes involved .
the first one is the kozai mechanism under non - axisymmetric potential , which effectively randomizes the angular momenta of surrounding stars .
the other is the selective ejection of stars with prograde orbits . through these two mechanisms ,
field stars extract the orbital angular momentum of the smbh binary .
our proposed mechanism causes the increase of the eccentricity of most of smbh binaries , resulting in the rapid merger through gravitational wave radiation .
this research is partially supported by the special coordination fund for promoting science and technology ( grape - dr project ) , ministry of education , culture , sports , science and technology , japan .
part of calculations were done using the grape system at the center for computational astrophysics ( cfca ) of the national astronomical observatory of japan . | in recent numerical simulations @xcite , it has been found that the eccentricity of supermassive black hole(smbh ) - intermediate black hole(imbh ) binaries grows toward unity through interactions with stellar background .
this increase of eccentricity reduces the merging timescale of the binary through the gravitational radiation to the value well below the hubble time .
it also gives the theoretical explanation of the existence of eccentric binary such as that in oj287 @xcite . in self - consistent n - body simulations , this increase of eccentricity is always observed . on the other hand ,
the result of scattering experiment between smbh binaries and field stars @xcite indicated no increase of eccentricity .
this discrepancy leaves the high eccentricity of the smbh binaries in @xmath0-body simulations unexplained . here
we present a stellar - dynamical mechanism that drives the increase of the eccentricity of an smbh binary with large mass ratio .
there are two key processes involved .
the first one is the kozai mechanism under non - axisymmetric potential , which effectively randomizes the angular momenta of surrounding stars .
the other is the selective ejection of stars with prograde orbits . through these two mechanisms ,
field stars extract the orbital angular momentum of the smbh binary .
our proposed mechanism causes the increase in the eccentricity of most of smbh binaries , resulting in the rapid merger through gravitational wave radiation .
our result has given a definite solution to the `` last - parsec problem '' | <s>[INST]most of galaxies contain smbhs at their centers . if a galaxy collides with another galaxy , the merging remnant hosts two smbhs and they form a binary system .
@xcite discussed the possibility of the formation of smbh binaries and their evolutions .
they concluded that the evolution of the semi - major axis stalls after they ejected out all the nearby stars ( loss cone depletion ) and the binary is unlikely to merge within the hubble time , as far as we consider the stellar dynamical effects and the gravitational wave radiation only .
this problem is called as `` last parsec problem '' since the typical separation of a stalled binary is around one parsec .
many researchers studied this problem and confirmed that the separation of the binary stall @xcite .
most of previous works on the evolution of the smbh binary focused on the evolution of the semi - major axis .
recently , @xcite performed @xmath0-body simulations of smbh - imbh binaries with the mass ratio of 1000:1 , and found that the eccentricity of the binary grows toward unity after the loss cone depletion .
because of this increase of eccentricity , the merging timescale through the gravitational radiation goes below @xmath1 years even if the loss cone is depleted .
similar result was obtained by @xcite , and it has been reported that under certain circumstance smbh binaries of mass ratios close to 1:1 show similar increase of the eccentricity @xcite . however , this increase of the eccentricity is difficult to understand , because the measured differential cross sections of interaction between an smbh binary and field stars indicated that eccentricity of a smbh binary would not increase through interaction with field stars @xcite .
recently , @xcite pointed out that the bound stars around smbh binary play important role in the evolution of the eccentricity but did not give the explanation about the mechanism of the eccentricity growth .
if the increase of eccentricity actually occurs in real smbh binaries , it naturally explains the orbit of the binary in the quasar oj287 @xcite .
the central smbh of the quasar oj287 has the mass of @xmath2 , and the secondary black hole has the mass @xmath3 , orbital period of 12 yrs , and eccentricity of 0.66 .
currently , this smbh binary is in the process of circularization due to the gravitational wave radiation .
thus , one would expect that oj287 had much larger semi - major axis and eccentricity very close to unity in the past . in this letter
, we describe the mechanism which drives the increase of the eccentricity . in section 2
, we describe the numerical experiment we performed . in section 3 ,
we present the interpretation of the numerical result .
we give the discussion and summary in section 4 .
in order to clarify the mechanism which drives the growth of the eccentricity of unequal - mass smbh binaries , we performed @xmath0-body simulations and investigated the change in orbital property of field stars due to interaction with the smbh binary .
our initial model is similar to that of @xcite .
galaxy density profile is given by where @xmath4 is the scale length and @xmath5 is the total mass of field particles , and we set @xmath6 and @xmath7 . from observations ,
the slope of central density of a giant elliptical galaxy is shallower than @xmath8 @xcite .
this feature is well understood by numerical simulations and theory @xcite . in our simulation ,
the density is @xmath9 cusp .
the velocity profile is isotropic and consistent with the density profile .
the number of field stars @xmath0 are 16384 and 32768 .
we performed five runs for each @xmath0 .
the heavier smbh particle whose mass is @xmath10 is placed at the center of the galaxy , and the lighter one whose mass is @xmath11 is placed in an eccentric orbit with eccentricity @xmath12 of 0.2 and semi - major axis @xmath13 of 20pc . at this radius
the enclosed stellar mass is comparable to that of the secondary mass and the stall of the evolution of semi - major axis takes place quickly .
the mass of field particles @xmath14 in the case of @xmath15 .
our simulation roughly mimics the oj287 system .
the time integration scheme we used is the fourth - order hermite scheme @xcite for interactions between the field - field particles and the secondary smbh - field particles .
the forces from the primary smbh are integrated with the sixth - order hermite scheme @xcite to reduce the integration error . to save the calculation time , we used grape - dr @xcite for calculating interactions between the field - field particles .
figure 1 shows the evolution of the semi - major axis @xmath13 , the eccentricity @xmath12 and the merging timescale due to the gravitational wave radiation @xmath16 of a smbh binary using @xcite formula , for an @xmath15 run .
the evolution of the semi - major axis slows down and deviates from the theoretical prediction . at the same time , the eccentricity starts to grow , and reaches @xmath17 by @xmath18 myrs .
this increase of eccentricity causes the drastic decrease of the merger timescale through gravitational wave radiation . in this case , at @xmath19 myrs , the merger timescale is 10 gyrs , but by @xmath20 myrs the timescale shrinks to 10 myrs .
we did not include the effect of the gravitational wave radiation , but if we did , the smbh binary would have merged very quickly .
figure 2 shows the evolutions of the eccentricity for all runs .
the evolutions in all runs inferred from figure 2 are basically similar .
the variation of the results of @xmath15 runs is smaller than that of @xmath21 runs .
these appear to be no statistically significant difference between the results for @xmath21 and @xmath22 .
we have carefully analyzed the behavior of the stars around the smbh binary in our numerical simulation , and found that the following three - stage mechanism drives the increase in the eccentricity of the secondary . 1 .
the presence of the secondary gives small , non - axisymmetric perturbation to the orbits of the field stars , which would be purely keplerian otherwise . because of this perturbation the orbital motions of the stars become chaotic , and their angular momenta change chaotically .
2 . since the orbital angular momenta of stars are not conserved , they can experience close encounters with the secondary , some of which result in the ejection of stars .
when a star is on a prograde orbit relative to the orbit of the secondary , it has a much larger chance of being ejected than when it is on a retrograde orbit .
3 . since the secondary tends to scatter stars on prograde orbits , there will be more stars on retrograde orbits than on prograde orbits around the binary .
however , the chaotic changes of angular momenta of stars reduce the difference between the number of stars on prograde and retrograde orbits .
this means the angular momentum of the secondary is transferred to field stars and the eccentricity of the secondary increases .
note that in this process the transfer of angular momentum occurs between the binary and field stars , while field stars are bound to the system , through secular perturbation .
this secular perturbation is neglected in previous theoretical models on the behavior of smbh binaries @xcite or models based on scattering experiment @xcite , and can give the reasonable interpretation of the results of @xcite .
figure 3 shows the time evolution of the specific angular momentum of a star that comes close to the secondary smbh .
the orbital plane of the secondary smbh is the @xmath23 plane .
one can see that none of the three components of the angular momentum are conserved and the changes are complicated .
these changes are due to the secular perturbation of the secondary smbh .
if the secondary smbh had a circular orbit , the secular perturbation would not have any non - axisymmetric term , and therefore @xmath24 would be conserved @xcite . however , since the secondary smbh has non - zero eccentricity , the perturbation has non - axisymmetric term , resulting in a triaxial potential field .
thus , the orbits of many stars become chaotic @xcite . this chaotic change of the orbits of field stars means that they approach the secondary smbh when their total angular momentum becomes small enough .
one can assume that stars on both prograde and retrograde orbits will approach the secondary smbh in roughly equal chances .
the cross section of the large change of the binding energy , which would result in the ejection of a star , is larger for prograde orbits , because the typical relative velocity is smaller for prograde orbits and the effect of gravitational focusing is larger .
figure 4 shows the cumulative mass of ejected stars in units of the mass of secondary smbh .
we can see that prograde stars are more likely to be ejected . in this calculation , the difference between the cumulative mass of ejected stars on prograde and retrograde orbits was comparable to the mass of the secondary smbh . for @xmath25 , the ejection rates of prograde and retrograde stars are rather similar , but that is simply because the eccentricity of the secondary smbh has become large enough and therefore the relative difference in the cross section terms has become small .
figure 5 shows the evolution of the average value of @xmath24 of stars which are bound to the primary smbh at @xmath26 and are ejected by @xmath27 . the net change of @xmath24 of stars which were initially in prograde orbit is small , while that of stars in retrograde orbits is large .
thus the primary mechanism of angular momentum transfer is the transfer of angular momentum to retrograde stars through secular perturbation and removal of them through ejection .
to summarize , we found a quite efficient mechanism that causes the increase of the eccentricity of unequal - mass smbh binaries .
it is the combination of the non - axisymmetric potential field of the secondary smbh , which randomizes the angular momentum of field stars , and the selective ejection of stars with prograde orbits through close encounters with the secondary smbh .
since either effects depends on masses of field particles , our proposed mechanism does not depend on @xmath0 .
this mechanism is effective at least for smbh binaries with fairly large mass ratios ( larger than 10:1 ) .
there is no other known mechanism that can make the eccentricity of a smbh binary close to unity .
both the gravitational wave radiation and gas dynamical effect reduce the eccentricity , and interaction with field stars , if we neglect the mechanism we described in this paper , would not change the eccentricity @xcite . if the parent galaxy is globally nonspherical , the smbh binary could become eccentric because of the kozai mechanism , but it would be hard to reach very high eccentricity values since the @xmath28-component would be conserved if the parent galaxy is axisymmetric . if the parent galaxy is triaxial , we could expect to see a significant effect on the evolution of the semi - major axis @xcite , but its effect on eccentricity is currently unknown . furthermore , it is difficult to maintain triaxiality given the presence of the central smbh @xcite .
if the mass ratio between the secondary smbh and the field stars is infinite , in other words , in the continuous limit , we can expect that the eccentricity of the smbh binary reaches unity . in practice , since the mass and the number of field stars are both finite , they give random perturbations to the angular momentum of smbh binary .
if we assume that there is thermal equilibrium between tangential velocity of the secondary smbh and random velocity of stars around the secondary , we can estimate the specific angular momentum @xmath29 and the eccentricity @xmath12 of the secondary smbh as and where @xmath30 is the mean value of the specific angular momentum of the field star around the secondary smbh and @xmath31 and @xmath32 are masses of the secondary and the field star , respectively .
the timescale of the change in the angular momentum of the field stars is proportional to @xmath34 , where @xmath35 and @xmath36 are the masses of the primary and secondary smbhs , respectively .
the rate at which angular momentum is removed through ejection of stars is @xmath37 , since it is proportional to the interaction cross section . therefore ,
if @xmath34 is large , the timescale of the change in the angular momentum is shorter than that of the removal of the field stars .
thus @xmath38 is determined by the removal timescale .
the loss rate of the angular momentum of the secondary smbh is proportional to @xmath39 , where @xmath40 is the density at the radius of the secondary , @xmath41 and @xmath42 are a kepler velocity and cross section of the secondary .
thus , @xmath38 is proportional to @xmath43 . from our numerical result
, we can estimate the timescale as where @xmath44 is a semi - major axis of a stalled binary and assumed @xmath45 .
since the majority of galaxy - galaxy merger events are minor mergers with mass ratios of around 10:1 or more , the typical mass ratio of the smbh binary is also around 10:1 , if we assume the linear relationship between the smbh mass and the mass of the stellar spheroid @xcite .
therefore , we can conclude that our mechanism is effective for most of smbh binaries , and they can merge through interactions with field stars and gravitational wave radiation . our result finally has given a definite solution to the `` last - parsec problem '' @xcite .
the mechanism we found naturally explains why the oj287 system is eccentric .
most likely , this mechanism resulted in the orbit of secondary with the periastron distance similar to the present value , but with much larger semi - major axis and eccentricity , and gravitational wave radiation have driven the semi - major axis to its present value .
the state of a recently found candidate smbh binary @xcite might also be explained by our mechanism .
this system is a binary with the mass ratio of around 30:1 .
interaction with field stars can not drive its semi - major axis to the value suggested by the observed relative velocity of @xmath46 , if we assume a circular orbit .
however , our mechanism implies that all unequal - mass smbh binaries with mass ratio larger than 10:1 become highly eccentric .
thus , they all have very large relative velocities at the pericenter .
therefore the observed relative velocity is only weakly coupled to the semi - major axis .
the frequency @xmath47 is given by where @xmath48 and @xmath49 are the pericenter distance of the secondary smbh from the primary and the distance of the binary from us .
unfortunately , the frequency is too low to be observed even with space missions like lisa .
however , since the amplitude is very large , other techniques such as doppler tracking of interplanetary spacecraft or pulsar timing could be used . in this letter
, we present a stellar - dynamical mechanism that drives the increase of the eccentricity of an smbh binary .
there are two key processes involved .
the first one is the kozai mechanism under non - axisymmetric potential , which effectively randomizes the angular momenta of surrounding stars .
the other is the selective ejection of stars with prograde orbits . through these two mechanisms ,
field stars extract the orbital angular momentum of the smbh binary .
our proposed mechanism causes the increase of the eccentricity of most of smbh binaries , resulting in the rapid merger through gravitational wave radiation .
this research is partially supported by the special coordination fund for promoting science and technology ( grape - dr project ) , ministry of education , culture , sports , science and technology , japan .
part of calculations were done using the grape system at the center for computational astrophysics ( cfca ) of the national astronomical observatory of japan .[/INST] in recent numerical simulations @xcite , it has been found that the eccentricity of supermassive black hole(smbh ) - intermediate black hole(imbh ) binaries grows toward unity through interactions with stellar background .
this increase of eccentricity reduces the merging timescale of the binary through the gravitational radiation to the value well below the hubble time .
it also gives the theoretical explanation of the existence of eccentric binary such as that in oj287 @xcite . in self - consistent n - body simulations , this increase of eccentricity is always observed . on the other hand ,
the result of scattering experiment between smbh binaries and field stars @xcite indicated no increase of eccentricity .
this discrepancy leaves the high eccentricity of the smbh binaries in @xmath0-body simulations unexplained . here
we present a stellar - dynamical mechanism that drives the increase of the eccentricity of an smbh binary with large mass ratio .
there are two key processes involved .
the first one is the kozai mechanism under non - axisymmetric potential , which effectively randomizes the angular momenta of surrounding stars .
the other is the selective ejection of stars with prograde orbits . through these two mechanisms ,
field stars extract the orbital angular momentum of the smbh binary .
our proposed mechanism causes the increase in the eccentricity of most of smbh binaries , resulting in the rapid merger through gravitational wave radiation .
our result has given a definite solution to the `` last - parsec problem '' </s> |
About a third of all tumors discovered in routine mammography screenings are unlikely to result in illness, according to a new study that says 30 years of the breast cancer exams have resulted in the overdiagnosis of 1.3 million American women.The report, published Thursday in the New England Journal of Medicine, argues that the increase in breast cancer survival rates over the last few decades is due mostly to improved therapies and not screenings, which are intended to flag tumors when they are small and most susceptible to treatment. Instead, the widespread use of mammograms now results in the overdiagnosis of breast cancer in roughly 70,000 patients each year, needlessly exposing those women to the cost and trauma of treatment, the authors wrote."Our study raises serious questions about the value of screening mammography," wrote Dr. H. Gilbert Welch, an epidemiology and biostatistics professor at Dartmouth College 's Geisel School of Medicine. "It clarifies that the benefit of mortality reduction is probably smaller, and the harm of overdiagnosis probably larger, than has been previously recognized."The study adds to a long-running controversy over screening mammography. Its conclusions are based upon an increasing recognition that sophisticated screening can detect ever-smaller groups of cancer-like cells that would never become dangerous if left alone.Some radiologists and other proponents of routine annual screenings denounced the study as harmful to women and said it was part of a coordinated campaign to cut back on the tests to reduce healthcare expenses."This is simply malicious nonsense," said Dr. Daniel B. Kopans, a senior breast imager at Massachusetts General Hospital in Boston . "It is time to stop blaming mammography screening for 'overdiagnosis' and 'overtreatment' in an effort to deny women access to screening."Welch and Dr. Archie Bleyer, an oncologist in Bend, Ore., analyzed screening data collected by the National Cancer Institute and the Centers for Disease Control and Prevention . They found that between 1976 and 2008, diagnosis of early-stage cancers had more than doubled from 112 to 234 cases per 100,000 women. Meanwhile, the number of late-stage cancers fell 8%, from 102 cases to 94 cases per 100,000 women.The authors reasoned that if screening were to help patients, it must not only find more early-stage cancers — which it has — it must also reduce the incidence of late-stage cancers, because the tumors would have been eliminated when they were small.But the data found that this was not the case. For every 122 additional breast cancers detected early, the number of late-stage cancers fell by only eight. To the authors, this suggested something other than screening was largely responsible for the drop in breast cancer deaths.Welch said the gap was even more apparent when they factored in data for women under the age of 40, who are generally too young to get regular mammograms and therefore served as a control group of sorts. The rate of breast cancer deaths for women 40 and over declined by 28% over the 32 years, while deaths for younger women fell by 42%."There was a larger relative reduction in mortality among women who were not exposed to screening mammography than among those who were exposed," the authors wrote. "We are left to conclude, as others have, that the good news in breast cancer — decreasing mortality — must largely be the result of improved treatment, not screening."Welch, an expert on screening and overdiagnosis for many forms of cancer, said the disparity between early- and late-stage diagnosis trends was probably the result of tumors being detected that were too small to ever cause clinical symptoms. He said it was likely that many of the suspicious cells revealed by screening mammography would have regressed, or never progressed to malignancy.The idea that breast tumors may resolve on their own has been advanced by European doctors for several years. Welch and others suspect that screening technology has allowed doctors to find cells that may resemble cancer, but whose true nature is only beginning to be understood."We hear the word 'cancer' and we all assume the definition that's in my medical dictionary — it's a tumor that, left untreated, will inexorably grow and cause death," Welch said. "But now, as we look for really early forms of the disease, we realize the pathologic definition of cancer includes abnormalities that may come and go."Such growths are so small that in the past they would never have been detected by a doctor or reported by a patient. That is no longer the case, Welch said."Our ability to detect things is far ahead of our wisdom of knowing what they really mean," he said.What's more, cancers can now be treated successfully even after they grow large enough to cause symptoms, thereby reducing the benefit of catching them at the earliest stages. He compared screening for breast cancer to screening for pneumonia : "Since pneumonia can be treated successfully, no one would suggest that we screen for it."The study was roundly criticized by radiologists who specialize in breast imaging, who questioned its methodology and the suggestion that some cancer-like growths should be ignored."It's kind of unbelievable that they're telling us we're finding too many early-stage cancers," said Dr. Stamatia Destounis, a breast imager in Rochester, N.Y. "Isn't that the point?"She acknowledged that screening mammography was not perfect and that some growths would be discovered that were benign. However, the notion that cancer-like masses should not be treated was difficult to accept."There is no way for us to know which early-stage breast cancer would not progress and which one would progress to an invasive, aggressive breast cancer," Destounis said. "How would we tell a patient, 'Chances are this is early and it's probably not going to progress for a long time, if ever, so I don't think you need to do much here'? There's just no way for us to say that."Dr. Stephen Feig, a radiologist at UC Irvine and president of the American Society of Breast Disease, called the study scientifically weak and worried that it would dissuade women from undergoing screening. "This is actually harming women," he said.Most medical organizations, including the American Cancer Society , advise healthy women to get screened every one or two years beginning at age 40.In 2009, however, the U.S. Preventive Services Task Force came to the controversial conclusion that this level of testing exacted an unnecessary toll on patients in the form of financial cost, anxiety, radiation exposure, false positives and overtreatment. The government advisory panel now recommends that women between the ages of 50 and 74 with no risk factors for breast cancer be screened every other year. Women who are at increased risk — because of family history or certain genetic characteristics — may begin screening at age 40 and have mammograms more often, the panel says.Welch said he was not advising women to stop being screened, only that they should be aware of mammography's shortcomings. Instead of conducting annual screenings on the basis of age, he said, the test should be based on risk: "It's women at the highest risk of dying from breast cancer that stand to benefit the most from screening, and they're the least likely to be overdiagnosed."He also emphasized that women who develop symptoms, such as a lump in the breast, should not hesitate to get a mammogram."No one argues about the value of diagnostic mammography," he said. "The question is whether we should invite women, coerce them, threaten them, scare them to come get checked when nothing's wrong." ||||| The growing use of routine mammograms over the past 30 years has done little to lower the death rate from breast cancer but has sharply increased the number of women who are wrongly diagnosed with the disease, a new study reported. (Rui Vieira/ASSOCIATED PRESS)
The routine use of mammograms has led to more than 1 million women being unnecessarily treated for breast cancer over the past three decades, according to the latest scientific report to cast skepticism on the effectiveness of the test.
The study, published Wednesday in the New England Journal of Medicine, concluded that nearly one-third of women diagnosed with breast cancer would never have developed the full-blown disease if left untreated.
Nevertheless, in such cases patients typically undergo invasive procedures such as surgery, radiation therapy, hormonal therapy and chemotherapy, said H. Gilbert Welch, a coauthor of the study and a professor at the Geisel School of Medicine at Dartmouth College. “These are major medical interventions and they’re certainly not something you would want to undergo if you didn’t need to,” he said.
The researchers also concluded that today’s sharply lower death rate for breast cancer is mainly due to factors such as improved treatments rather than early detection through mammograms.
The new study immediately fueled the already fierce debate over how often women should get mammograms, a controversy that has embroiled policymakers, politicians and physicians, as well as their female patients.
The American Cancer Society warned that the study “must be viewed with caution.” The American College of Radiology attacked the validity of the study, charging that it was spreading “misinformation” and “the cost may be lost lives.”
The report is the latest study to undermine the once-strong consensus that regular screenings are crucial to safeguarding women’s health. Just in the past two years, a major study of Norwegian breast cancer patients found that routine mammograms reduced the risk of dying from breast cancer by less than 10 percent. Another study found no effect on death rates when comparing European nations where screening became prevalent in the 1990s with those where it became widespread in the 2000s.
Even before those findings, in November 2009, a key federal panel revised its guidelines on mammograms to say that women should begin regular screenings at age 50 rather than age 40, and then get the exam every other year rather than annually.
However, that revision by the U.S. Preventive Services Task Force, made as Congress was crafting the new health-care law, was assailed not only by groups such as the American Cancer Society and the American College of Radiology but also by the Obama administration.
In 2010, lawmakers tweaked a mandate in the health-care law requiring insurers to cover preventive services recommended by the task force free of charge. The law specifies that when it comes to mammograms, insurers must follow the task force’s old guidelines.
Wednesday’s study analyzed changes in the rates of early- and late-stage breast cancer in the United States over time.
The authors’ premise was that if screening were effective, its growing use would result in greater detection of early-stage breast cancers and a corresponding drop in the prevalence of late-stage cancers.
Instead, they found that while the number of early-stage cancers doubled over the past three decades, the rate at which women were found to have late-stage cancer dropped by only 8 percent.
Welch speculated that as mammography technology has become more advanced, doctors are discovering breast lesions in such an early state of development it is virtually impossible to distinguish them from benign cell clusters.
Yet even as the screenings produce false positives, they fail to catch forms of breast cancer that develop rapidly, explaining why the more widespread use of screenings has done so little to curb the rate at which late-stage breast cancer is found.
“The sad fact is that there’s a subset of women who develop such an aggressive form of cancer it literally can’t be caught early,” said Welch.
Debra L. Monticciolo, a physician who chairs the American College of Radiology’s Quality and Safety Commission, questioned many of the study’s methods, including the data used to account for fluctuations in the underlying incidence of breast cancer due to factors like the use of hormones.
“It stuns me that this got through peer review,” said Monticciolo.
She added that as a physician, she found it hard to believe that such a large share of screenings produce false positives. If that were the case, there would be countless tales of miraculous recoveries by women who refuse traditional treatment after being diagnosed with early-stage breast cancer.
“I’ve never seen such a case. And there’s nothing like that in the literature,” said Monticciolo.
Most important, she said, new studies continue to confirm the benefits of screenings.
“Mammograms clearly save lives,” she said.
Archie Bleyer, a professor at the Knight Cancer Institute at Oregon Health & Science University who is the study’s other coauthor, said he wouldn’t dream of suggesting that women cease getting mammograms altogether.
“There are clearly women who are benefiting from doing this,” he said.
But he and Welch said their findings suggest that the message to women about mammograms needs to be more nuanced.
“We need to start telling the truth,” said Welch. “We’ve promoted this as if it’s the most important thing a woman can do for her health. . . . And the truth is that it’s a really close call.”
Women in their 40s who feel comfortable getting annual mammograms should not be dissuaded from doing so, he said. “But women who have never felt good about it, who felt coerced into the procedure, should feel equally good about not having it.”
Similarly, Welch said, women who do get screening mammograms and are found to have a tumor in a very early stage may want to consider alternatives to aggressive treatment — engaging in watchful waiting, for instance, or signing up for a clinical trial of drugs that may halt or slow the progression of cancer. Men have faced similar issues in deciding what to do about screening and treatment of prostate cancer, he said.
“We should tell women about the trade-offs and we should allow them to make their own decision,” he said. | – Add this to the ever-going debate over mammograms: A new study in the New England Journal of Medicine says 1.3 million women have been incorrectly diagnosed—or "overdiagnosed"—with breast cancer over the past 30 years because of them, reports the Los Angeles Times. That means about 70,000 women a year undergo unnecessary treatment, say the researchers, who assert that about one-third of all tumors discovered in mammograms will never result in cancer. The findings will do little to settle the issue, based on the early reaction from proponents of the tests, notes the Washington Post. Two competing quotes: "Our study raises serious questions about the value of screening mammography," says Dr. H. Gilbert Welch of Dartmouth. "It clarifies that the benefit of mortality reduction reduction is probably smaller, and the harm of overdiagnosis probably larger, than has been previously recognized." "This is simply malicious nonsense," said Dr. Daniel Kopans of Boston's Mass General. "It is time to stop blaming mammography screening for 'overdiagnosis' and 'overtreatment' in an effort to deny women access to screening." | <s>[INST]About a third of all tumors discovered in routine mammography screenings are unlikely to result in illness, according to a new study that says 30 years of the breast cancer exams have resulted in the overdiagnosis of 1.3 million American women.The report, published Thursday in the New England Journal of Medicine, argues that the increase in breast cancer survival rates over the last few decades is due mostly to improved therapies and not screenings, which are intended to flag tumors when they are small and most susceptible to treatment. Instead, the widespread use of mammograms now results in the overdiagnosis of breast cancer in roughly 70,000 patients each year, needlessly exposing those women to the cost and trauma of treatment, the authors wrote."Our study raises serious questions about the value of screening mammography," wrote Dr. H. Gilbert Welch, an epidemiology and biostatistics professor at Dartmouth College 's Geisel School of Medicine. "It clarifies that the benefit of mortality reduction is probably smaller, and the harm of overdiagnosis probably larger, than has been previously recognized."The study adds to a long-running controversy over screening mammography. Its conclusions are based upon an increasing recognition that sophisticated screening can detect ever-smaller groups of cancer-like cells that would never become dangerous if left alone.Some radiologists and other proponents of routine annual screenings denounced the study as harmful to women and said it was part of a coordinated campaign to cut back on the tests to reduce healthcare expenses."This is simply malicious nonsense," said Dr. Daniel B. Kopans, a senior breast imager at Massachusetts General Hospital in Boston . "It is time to stop blaming mammography screening for 'overdiagnosis' and 'overtreatment' in an effort to deny women access to screening."Welch and Dr. Archie Bleyer, an oncologist in Bend, Ore., analyzed screening data collected by the National Cancer Institute and the Centers for Disease Control and Prevention . They found that between 1976 and 2008, diagnosis of early-stage cancers had more than doubled from 112 to 234 cases per 100,000 women. Meanwhile, the number of late-stage cancers fell 8%, from 102 cases to 94 cases per 100,000 women.The authors reasoned that if screening were to help patients, it must not only find more early-stage cancers — which it has — it must also reduce the incidence of late-stage cancers, because the tumors would have been eliminated when they were small.But the data found that this was not the case. For every 122 additional breast cancers detected early, the number of late-stage cancers fell by only eight. To the authors, this suggested something other than screening was largely responsible for the drop in breast cancer deaths.Welch said the gap was even more apparent when they factored in data for women under the age of 40, who are generally too young to get regular mammograms and therefore served as a control group of sorts. The rate of breast cancer deaths for women 40 and over declined by 28% over the 32 years, while deaths for younger women fell by 42%."There was a larger relative reduction in mortality among women who were not exposed to screening mammography than among those who were exposed," the authors wrote. "We are left to conclude, as others have, that the good news in breast cancer — decreasing mortality — must largely be the result of improved treatment, not screening."Welch, an expert on screening and overdiagnosis for many forms of cancer, said the disparity between early- and late-stage diagnosis trends was probably the result of tumors being detected that were too small to ever cause clinical symptoms. He said it was likely that many of the suspicious cells revealed by screening mammography would have regressed, or never progressed to malignancy.The idea that breast tumors may resolve on their own has been advanced by European doctors for several years. Welch and others suspect that screening technology has allowed doctors to find cells that may resemble cancer, but whose true nature is only beginning to be understood."We hear the word 'cancer' and we all assume the definition that's in my medical dictionary — it's a tumor that, left untreated, will inexorably grow and cause death," Welch said. "But now, as we look for really early forms of the disease, we realize the pathologic definition of cancer includes abnormalities that may come and go."Such growths are so small that in the past they would never have been detected by a doctor or reported by a patient. That is no longer the case, Welch said."Our ability to detect things is far ahead of our wisdom of knowing what they really mean," he said.What's more, cancers can now be treated successfully even after they grow large enough to cause symptoms, thereby reducing the benefit of catching them at the earliest stages. He compared screening for breast cancer to screening for pneumonia : "Since pneumonia can be treated successfully, no one would suggest that we screen for it."The study was roundly criticized by radiologists who specialize in breast imaging, who questioned its methodology and the suggestion that some cancer-like growths should be ignored."It's kind of unbelievable that they're telling us we're finding too many early-stage cancers," said Dr. Stamatia Destounis, a breast imager in Rochester, N.Y. "Isn't that the point?"She acknowledged that screening mammography was not perfect and that some growths would be discovered that were benign. However, the notion that cancer-like masses should not be treated was difficult to accept."There is no way for us to know which early-stage breast cancer would not progress and which one would progress to an invasive, aggressive breast cancer," Destounis said. "How would we tell a patient, 'Chances are this is early and it's probably not going to progress for a long time, if ever, so I don't think you need to do much here'? There's just no way for us to say that."Dr. Stephen Feig, a radiologist at UC Irvine and president of the American Society of Breast Disease, called the study scientifically weak and worried that it would dissuade women from undergoing screening. "This is actually harming women," he said.Most medical organizations, including the American Cancer Society , advise healthy women to get screened every one or two years beginning at age 40.In 2009, however, the U.S. Preventive Services Task Force came to the controversial conclusion that this level of testing exacted an unnecessary toll on patients in the form of financial cost, anxiety, radiation exposure, false positives and overtreatment. The government advisory panel now recommends that women between the ages of 50 and 74 with no risk factors for breast cancer be screened every other year. Women who are at increased risk — because of family history or certain genetic characteristics — may begin screening at age 40 and have mammograms more often, the panel says.Welch said he was not advising women to stop being screened, only that they should be aware of mammography's shortcomings. Instead of conducting annual screenings on the basis of age, he said, the test should be based on risk: "It's women at the highest risk of dying from breast cancer that stand to benefit the most from screening, and they're the least likely to be overdiagnosed."He also emphasized that women who develop symptoms, such as a lump in the breast, should not hesitate to get a mammogram."No one argues about the value of diagnostic mammography," he said. "The question is whether we should invite women, coerce them, threaten them, scare them to come get checked when nothing's wrong." ||||| The growing use of routine mammograms over the past 30 years has done little to lower the death rate from breast cancer but has sharply increased the number of women who are wrongly diagnosed with the disease, a new study reported. (Rui Vieira/ASSOCIATED PRESS)
The routine use of mammograms has led to more than 1 million women being unnecessarily treated for breast cancer over the past three decades, according to the latest scientific report to cast skepticism on the effectiveness of the test.
The study, published Wednesday in the New England Journal of Medicine, concluded that nearly one-third of women diagnosed with breast cancer would never have developed the full-blown disease if left untreated.
Nevertheless, in such cases patients typically undergo invasive procedures such as surgery, radiation therapy, hormonal therapy and chemotherapy, said H. Gilbert Welch, a coauthor of the study and a professor at the Geisel School of Medicine at Dartmouth College. “These are major medical interventions and they’re certainly not something you would want to undergo if you didn’t need to,” he said.
The researchers also concluded that today’s sharply lower death rate for breast cancer is mainly due to factors such as improved treatments rather than early detection through mammograms.
The new study immediately fueled the already fierce debate over how often women should get mammograms, a controversy that has embroiled policymakers, politicians and physicians, as well as their female patients.
The American Cancer Society warned that the study “must be viewed with caution.” The American College of Radiology attacked the validity of the study, charging that it was spreading “misinformation” and “the cost may be lost lives.”
The report is the latest study to undermine the once-strong consensus that regular screenings are crucial to safeguarding women’s health. Just in the past two years, a major study of Norwegian breast cancer patients found that routine mammograms reduced the risk of dying from breast cancer by less than 10 percent. Another study found no effect on death rates when comparing European nations where screening became prevalent in the 1990s with those where it became widespread in the 2000s.
Even before those findings, in November 2009, a key federal panel revised its guidelines on mammograms to say that women should begin regular screenings at age 50 rather than age 40, and then get the exam every other year rather than annually.
However, that revision by the U.S. Preventive Services Task Force, made as Congress was crafting the new health-care law, was assailed not only by groups such as the American Cancer Society and the American College of Radiology but also by the Obama administration.
In 2010, lawmakers tweaked a mandate in the health-care law requiring insurers to cover preventive services recommended by the task force free of charge. The law specifies that when it comes to mammograms, insurers must follow the task force’s old guidelines.
Wednesday’s study analyzed changes in the rates of early- and late-stage breast cancer in the United States over time.
The authors’ premise was that if screening were effective, its growing use would result in greater detection of early-stage breast cancers and a corresponding drop in the prevalence of late-stage cancers.
Instead, they found that while the number of early-stage cancers doubled over the past three decades, the rate at which women were found to have late-stage cancer dropped by only 8 percent.
Welch speculated that as mammography technology has become more advanced, doctors are discovering breast lesions in such an early state of development it is virtually impossible to distinguish them from benign cell clusters.
Yet even as the screenings produce false positives, they fail to catch forms of breast cancer that develop rapidly, explaining why the more widespread use of screenings has done so little to curb the rate at which late-stage breast cancer is found.
“The sad fact is that there’s a subset of women who develop such an aggressive form of cancer it literally can’t be caught early,” said Welch.
Debra L. Monticciolo, a physician who chairs the American College of Radiology’s Quality and Safety Commission, questioned many of the study’s methods, including the data used to account for fluctuations in the underlying incidence of breast cancer due to factors like the use of hormones.
“It stuns me that this got through peer review,” said Monticciolo.
She added that as a physician, she found it hard to believe that such a large share of screenings produce false positives. If that were the case, there would be countless tales of miraculous recoveries by women who refuse traditional treatment after being diagnosed with early-stage breast cancer.
“I’ve never seen such a case. And there’s nothing like that in the literature,” said Monticciolo.
Most important, she said, new studies continue to confirm the benefits of screenings.
“Mammograms clearly save lives,” she said.
Archie Bleyer, a professor at the Knight Cancer Institute at Oregon Health & Science University who is the study’s other coauthor, said he wouldn’t dream of suggesting that women cease getting mammograms altogether.
“There are clearly women who are benefiting from doing this,” he said.
But he and Welch said their findings suggest that the message to women about mammograms needs to be more nuanced.
“We need to start telling the truth,” said Welch. “We’ve promoted this as if it’s the most important thing a woman can do for her health. . . . And the truth is that it’s a really close call.”
Women in their 40s who feel comfortable getting annual mammograms should not be dissuaded from doing so, he said. “But women who have never felt good about it, who felt coerced into the procedure, should feel equally good about not having it.”
Similarly, Welch said, women who do get screening mammograms and are found to have a tumor in a very early stage may want to consider alternatives to aggressive treatment — engaging in watchful waiting, for instance, or signing up for a clinical trial of drugs that may halt or slow the progression of cancer. Men have faced similar issues in deciding what to do about screening and treatment of prostate cancer, he said.
“We should tell women about the trade-offs and we should allow them to make their own decision,” he said.[/INST]– Add this to the ever-going debate over mammograms: A new study in the New England Journal of Medicine says 1.3 million women have been incorrectly diagnosed—or "overdiagnosed"—with breast cancer over the past 30 years because of them, reports the Los Angeles Times. That means about 70,000 women a year undergo unnecessary treatment, say the researchers, who assert that about one-third of all tumors discovered in mammograms will never result in cancer. The findings will do little to settle the issue, based on the early reaction from proponents of the tests, notes the Washington Post. Two competing quotes: "Our study raises serious questions about the value of screening mammography," says Dr. H. Gilbert Welch of Dartmouth. "It clarifies that the benefit of mortality reduction reduction is probably smaller, and the harm of overdiagnosis probably larger, than has been previously recognized." "This is simply malicious nonsense," said Dr. Daniel Kopans of Boston's Mass General. "It is time to stop blaming mammography screening for 'overdiagnosis' and 'overtreatment' in an effort to deny women access to screening."</s> |
SECTION 1. SHORT TITLE.
This Act may be cited as the ``Child Gun Safety and Gun Access
Prevention Act of 2000''.
SEC. 2. INCREASING YOUTH GUN SAFETY BY RAISING THE AGE OF HANDGUN
ELIGIBILITY AND PROHIBITING YOUTH FROM POSSESSING
SEMIAUTOMATIC ASSAULT WEAPONS.
Section 922(x) of title 18, United States Code, is amended--
(1) in paragraph (1)--
(A) by striking ``juvenile'' and inserting ``person
who is less than 21 years of age'';
(B) by striking ``or'' at the end of subparagraph
(A);
(C) by striking the period at the end of
subparagraph (B) and inserting a semicolon; and
(D) by adding at the end the following:
``(C) a semiautomatic assault weapon; or
``(D) a large capacity ammunition feeding device.'';
(2) in paragraph (2)--
(A) by striking ``a juvenile'' and inserting ``less
than 21 years of age'';
(B) by striking ``or'' at the end of subparagraph
(A);
(C) by striking the period at the end of
subparagraph (B) and inserting a semicolon; and
(D) by inserting at the end the following:
``(C) a semiautomatic assault weapon; or
``(D) a large capacity ammunition feeding
device.'';
(3) in paragraph (3)(A), by inserting ``temporary'' before
``possession'';
(4) in paragraph (3)(B), by striking ``juvenile'' and
inserting ``person who is less than 21 years of age'';
(5) in paragraph (3)(C), by striking ``juvenile; or'' and
inserting ``person who is less than 21 years of age;'';
(6) by striking subparagraph (D) of paragraph (3) and
inserting the following:
``(D) the possession of a handgun or ammunition by a person
who is less than 21 years of age taken in defense of that
person or other persons against an intruder into the residence
of that person or a residence in which that person is an
invited guest; or'';
(7) by adding at the end of paragraph (3) the following:
``(E) a temporary transfer of a handgun or ammunition to a
person who is at least 18 years of age and less than 21 years
of age, or the temporary use or possession of a handgun or
ammunition by a person who is at least 18 years of age and less
than 21 years of age, if the handgun and ammunition are
possessed and used by the person--
``(i) in the course of employment, in the course of
ranching or farming related to activities at the
residence of the person (or on property used for
ranching or farming at which the person, with the
permission of the property owner or lessee, is
performing activities related to the operation of the
farm or ranch), target practice, hunting, or a course
of instruction in the safe and lawful use of a handgun;
and
``(ii) in accordance with State and local
law.''; and
(8) by amending paragraph (4) to strike ``juvenile''
wherever it appears and insert ``person who is less than 21
years of age''.
SEC. 3. ENHANCED PENALTY FOR YOUTH POSSESSION OF HANDGUNS AND
SEMIAUTOMATIC ASSAULT WEAPONS AND FOR THE TRANSFER OF
SUCH WEAPONS TO YOUTH.
Section 924(a)(6) of title 18, United States Code, is amended to
read as follows:
``(6)(A) A juvenile who violates section 922(x) shall be fined
under this title, imprisoned not more than one year, or both, and for a
second or subsequent violation, or for a first violation committed
after an adjudication of delinquency or after a State or Federal
conviction for an act that, if committed by an adult, would be a
serious violent felony (as defined in section 3559(c) of this title),
shall be fined under this title, imprisoned not more than five years,
or both.
``(B) A person other than a juvenile who knowingly violates section
922(x)--
``(i) shall be fined under this title, imprisoned not more
than five years, or both; and
``(ii) if the person sold, delivered, or otherwise
transferred a handgun, ammunition, semiautomatic assault
weapon, or large capacity ammunition feeding device to a person
who is less than 21 years of age knowing or having reasonable
cause to know that such person intended to carry or otherwise
possess or discharge or otherwise use the handgun, ammunition,
semiautomatic assault weapon, or large capacity ammunition
feeding device in the commission of a crime of violence, shall
be fined under this title, imprisoned for not more than 10
years, or both.''.
SEC. 4. GUN STORAGE AND SAFETY DEVICES FOR ALL FIREARMS.
(a) Secure Gun Storage or Safety Devices by Federal Firearms
Licensees.--Section 922 of title 18, United States Code, is amended by
adding at the end the following:
``(z) It shall be unlawful for any licensed importer, licensed
manufacturer, or licensed dealer to sell, transfer, or deliver any
firearm to any person (other than a licensed importer, licensed
manufacturer, or licensed dealer) unless the transferee is provided
with a secure gun storage or safety device.''.
(b) Penalties.--Section 924 of such title is amended--
(1) in subsection (a)(1) by inserting ``, or (p)'' before
``of this section''; and
(2) by adding at the end the following:
``(p) The Secretary may, after notice and opportunity for hearing,
suspend or revoke any license issued under this chapter or may subject
the licensee to a civil penalty of not more than $10,000 if the holder
of such license has knowingly violated section 922(z) of this chapter.
The Secretary's actions under this subsection may be reviewed only as
provided in section 923(f).''.
(c) Repeal of Inconsistent Provisions.--
(1) Section 923(d)(1) of such title is amended--
(A) in subparagraph (E) by adding at the end
``and'';
(B) in subparagraph (F) by striking ``; and'' and
inserting a period; and
(C) by striking subparagraph (G).
(2) Section 923(e) of such title is amended by striking
``or fails to have secure gun storage or safety devices
available at any place in which firearms are sold under the
license to persons who are not licensees (except that in any
case in which a secure gun storage or safety device is
temporarily unavailable because of theft, casualty loss,
consumer sales, backorders from a manufacturer, or any other
similar reason beyond the control of the licensee, shall not be
considered to be in violation of the requirement to make
available such a device)''.
(3) Section 119 of the Departments of Commerce, Justice,
and State, the Judiciary, and Related Agencies Appropriations
Act, 1999 (as contained in section 101(b) of division A of the
Omnibus Consolidated and Emergency Supplemental Appropriations
Act, 1999; Public Law 105-277) is amended by striking
subsection (d).
(d) Effective Date.--The amendments made by this section shall be
effective 180 days after the date of enactment of this Act.
SEC. 5. RESPONSIBILITY OF ADULTS FOR DEATH AND INJURY CAUSED BY CHILD
ACCESS TO FIREARMS.
Section 922 of title 18, United States Code, is further amended by
adding at the end the following:
``(aa)(1) In this subsection, the term `child' means an individual
who has not attained the age of 18 years.
``(2) Except as provided in paragraph (3), any person who--
``(A) keeps a loaded firearm, or an unloaded firearm and
ammunition for the firearm, any one of which has been shipped
or transported in interstate or foreign commerce, within any
premises that is under the custody or control of that person;
and
``(B) knows, or recklessly disregards the risk, that a
child is capable of gaining access to the firearm; and
``(C)(i) knows, or recklessly disregards the risk, that a
child will use the firearm to cause death or serious bodily
injury (as defined in section 1365 of this title) to the child
or any other person; or
``(ii) knows, or recklessly disregards the risk, that
possession of the firearm by the child is unlawful under
Federal or State law,
if the child uses the firearm to cause death or serious bodily injury
to the child or any other person, shall be imprisoned not more than 3
years, fined under this title, or both.
``(3) Paragraph (2) shall not apply if--
``(A) at the time the child obtained access, the firearm
was secured with a secure gun storage or safety device;
``(B) the person is a peace officer, a member of the Armed
Forces, or a member of the National Guard, and the child
obtains the firearm during, or incidental to, the performance
of the official duties of the person in that capacity;
``(C) the child uses the firearm in a lawful act of self-
defense or defense of 1 or more other persons; or
``(D) the person has no reasonable expectation, based on
objective facts and circumstances, that a child is likely to be
present on the premises on which the firearm is kept.''.
SEC. 6. REQUIREMENT THAT CHILD BE ACCOMPANIED BY AN ADULT DURING A GUN
SHOW.
(a) Prohibitions.--Section 922 of title 18, United States Code, is
further amended by adding at the end the following:
``(bb)(1) The parent or legal guardian of a child shall ensure
that, while the child is attending a gun show, the child is accompanied
by an adult.
``(2) It shall be unlawful for a person to conduct a gun show to
which there is admitted a child who is not accompanied by an adult.
``(3) In this subsection:
``(A) The term `child' means an individual who has not
attained 18 years of age.
``(B) The term `adult' means an individual who has attained
18 years of age.''.
(b) Penalties.--Section 924(a) of such title is amended by adding
at the end the following:
``(7) Whoever violates section 922(bb) in a State shall be punished
in accordance with the laws of the State that apply to persons
convicted of child abandonment.''.
SEC. 7. GRANTS FOR GUN SAFETY EDUCATION PROGRAMS.
(a) Program Authority.--The Attorney General is authorized to
provide grants to units of local government to enable law enforcement
agencies to develop and sponsor gun safety classes for parents and
their children.
(b) Application.--
(1) In general.--Any unit of local government that desires
to receive a grant award under this section shall submit an
application to the Attorney General at such time, in such
manner and containing such information as the Attorney General
may reasonably require.
(2) Contents.--Each application referred to in paragraph
(1) shall include an assurance that--
(A) funds received under this section shall be used
only to provide funds to law enforcement agencies to
provide gun safety classes; and
(B) gun safety classes will be offered at times
convenient to parents, including evenings and weekends.
(c) Regulations.--The Attorney General shall issue any regulations
necessary to carry out this section.
SEC. 8. EDUCATION: NATIONWIDE FIREARMS SAFETY PROGRAMS.
It is the sense of Congress that--
(1) each school district should provide or participate in a
firearms safety program for students in grades kindergarten
through 12 and should consult with a certified firearms
instructor before establishing the curriculum for the program;
and
(2) participation by students in a firearms safety program
should not be mandatory if the district receives written notice
from a parent of the student to exempt the student from the
program. | (Sec. 3) Increases penalties imposed upon: (1) a juvenile who violates Brady Act provisions for a second or subsequent violation, or for a first violation committed after an adjudication of delinquency or after a State or Federal conviction for an act that, if committed by an adult, would be a serious violent felony; and (2) a person other than a juvenile who knowingly violates such provisions if the person sold, delivered, or otherwise transferred a handgun, ammunition, semiautomatic assault weapon, or large capacity ammunition feeding device to a person who is under age 21, knowing or having reasonable cause to know that such person intended to carry, otherwise possess, discharge, or otherwise use it in the commission of a crime of violence.
(Sec. 4) Prohibits any licensed importer, manufacturer, or dealer from selling, transferring, or delivering a firearm to any person (other than a licensed importer, manufacturer, or dealer) unless the transferee is provided with a secure gun storage or safety device. Authorizes the Secretary of the Treasury, after notice and opportunity for hearing, to suspend or revoke any license issued under the Act, or to subject the licensee to a civil penalty of up to $10,000 if the holder of such license has knowingly violated this section.
(Sec. 5) Imposes penalties (with exceptions) upon any person who: (1) keeps a loaded firearm, or an unloaded firearm and ammunition for it, any one of which has been shipped or transported in interstate or foreign commerce, within any premises that is under the custody or control of that person; (2) knows, or recklessly disregards the risk, that a child is capable of gaining access to the firearm; and (3) knows, or recklessly disregards the risk, that a child will use the firearm to cause death or serious bodily injury to the child or any other person, or that possession of the firearm by the child is unlawful under Federal or State law, if the child uses the firearm to cause death or serious bodily injury.
(Sec. 6) Requires the parent or legal guardian of a child to ensure that, while the child is attending a gun show, the child is accompanied by an adult. Prohibits a person from conducting a gun show to which there is admitted a child who is not accompanied by an adult. Sets penalties for violations.
(Sec. 7) Authorizes the Attorney General to provide grants to units of local government to enable law enforcement agencies to develop and sponsor gun safety classes for parents and their children.
(Sec. 8) Expresses the sense of Congress that: (1) each school district should provide or participate in a firearms safety program for students in grades kindergarten through 12 and should consult with a certified firearms instructor before establishing the curriculum for the program; and (2) participation by students in a firearms safety program should not be mandatory if the district receives written notice from a parent of the student to exempt the student from the program. | <s>[INST]SECTION 1. SHORT TITLE.
This Act may be cited as the ``Child Gun Safety and Gun Access
Prevention Act of 2000''.
SEC. 2. INCREASING YOUTH GUN SAFETY BY RAISING THE AGE OF HANDGUN
ELIGIBILITY AND PROHIBITING YOUTH FROM POSSESSING
SEMIAUTOMATIC ASSAULT WEAPONS.
Section 922(x) of title 18, United States Code, is amended--
(1) in paragraph (1)--
(A) by striking ``juvenile'' and inserting ``person
who is less than 21 years of age'';
(B) by striking ``or'' at the end of subparagraph
(A);
(C) by striking the period at the end of
subparagraph (B) and inserting a semicolon; and
(D) by adding at the end the following:
``(C) a semiautomatic assault weapon; or
``(D) a large capacity ammunition feeding device.'';
(2) in paragraph (2)--
(A) by striking ``a juvenile'' and inserting ``less
than 21 years of age'';
(B) by striking ``or'' at the end of subparagraph
(A);
(C) by striking the period at the end of
subparagraph (B) and inserting a semicolon; and
(D) by inserting at the end the following:
``(C) a semiautomatic assault weapon; or
``(D) a large capacity ammunition feeding
device.'';
(3) in paragraph (3)(A), by inserting ``temporary'' before
``possession'';
(4) in paragraph (3)(B), by striking ``juvenile'' and
inserting ``person who is less than 21 years of age'';
(5) in paragraph (3)(C), by striking ``juvenile; or'' and
inserting ``person who is less than 21 years of age;'';
(6) by striking subparagraph (D) of paragraph (3) and
inserting the following:
``(D) the possession of a handgun or ammunition by a person
who is less than 21 years of age taken in defense of that
person or other persons against an intruder into the residence
of that person or a residence in which that person is an
invited guest; or'';
(7) by adding at the end of paragraph (3) the following:
``(E) a temporary transfer of a handgun or ammunition to a
person who is at least 18 years of age and less than 21 years
of age, or the temporary use or possession of a handgun or
ammunition by a person who is at least 18 years of age and less
than 21 years of age, if the handgun and ammunition are
possessed and used by the person--
``(i) in the course of employment, in the course of
ranching or farming related to activities at the
residence of the person (or on property used for
ranching or farming at which the person, with the
permission of the property owner or lessee, is
performing activities related to the operation of the
farm or ranch), target practice, hunting, or a course
of instruction in the safe and lawful use of a handgun;
and
``(ii) in accordance with State and local
law.''; and
(8) by amending paragraph (4) to strike ``juvenile''
wherever it appears and insert ``person who is less than 21
years of age''.
SEC. 3. ENHANCED PENALTY FOR YOUTH POSSESSION OF HANDGUNS AND
SEMIAUTOMATIC ASSAULT WEAPONS AND FOR THE TRANSFER OF
SUCH WEAPONS TO YOUTH.
Section 924(a)(6) of title 18, United States Code, is amended to
read as follows:
``(6)(A) A juvenile who violates section 922(x) shall be fined
under this title, imprisoned not more than one year, or both, and for a
second or subsequent violation, or for a first violation committed
after an adjudication of delinquency or after a State or Federal
conviction for an act that, if committed by an adult, would be a
serious violent felony (as defined in section 3559(c) of this title),
shall be fined under this title, imprisoned not more than five years,
or both.
``(B) A person other than a juvenile who knowingly violates section
922(x)--
``(i) shall be fined under this title, imprisoned not more
than five years, or both; and
``(ii) if the person sold, delivered, or otherwise
transferred a handgun, ammunition, semiautomatic assault
weapon, or large capacity ammunition feeding device to a person
who is less than 21 years of age knowing or having reasonable
cause to know that such person intended to carry or otherwise
possess or discharge or otherwise use the handgun, ammunition,
semiautomatic assault weapon, or large capacity ammunition
feeding device in the commission of a crime of violence, shall
be fined under this title, imprisoned for not more than 10
years, or both.''.
SEC. 4. GUN STORAGE AND SAFETY DEVICES FOR ALL FIREARMS.
(a) Secure Gun Storage or Safety Devices by Federal Firearms
Licensees.--Section 922 of title 18, United States Code, is amended by
adding at the end the following:
``(z) It shall be unlawful for any licensed importer, licensed
manufacturer, or licensed dealer to sell, transfer, or deliver any
firearm to any person (other than a licensed importer, licensed
manufacturer, or licensed dealer) unless the transferee is provided
with a secure gun storage or safety device.''.
(b) Penalties.--Section 924 of such title is amended--
(1) in subsection (a)(1) by inserting ``, or (p)'' before
``of this section''; and
(2) by adding at the end the following:
``(p) The Secretary may, after notice and opportunity for hearing,
suspend or revoke any license issued under this chapter or may subject
the licensee to a civil penalty of not more than $10,000 if the holder
of such license has knowingly violated section 922(z) of this chapter.
The Secretary's actions under this subsection may be reviewed only as
provided in section 923(f).''.
(c) Repeal of Inconsistent Provisions.--
(1) Section 923(d)(1) of such title is amended--
(A) in subparagraph (E) by adding at the end
``and'';
(B) in subparagraph (F) by striking ``; and'' and
inserting a period; and
(C) by striking subparagraph (G).
(2) Section 923(e) of such title is amended by striking
``or fails to have secure gun storage or safety devices
available at any place in which firearms are sold under the
license to persons who are not licensees (except that in any
case in which a secure gun storage or safety device is
temporarily unavailable because of theft, casualty loss,
consumer sales, backorders from a manufacturer, or any other
similar reason beyond the control of the licensee, shall not be
considered to be in violation of the requirement to make
available such a device)''.
(3) Section 119 of the Departments of Commerce, Justice,
and State, the Judiciary, and Related Agencies Appropriations
Act, 1999 (as contained in section 101(b) of division A of the
Omnibus Consolidated and Emergency Supplemental Appropriations
Act, 1999; Public Law 105-277) is amended by striking
subsection (d).
(d) Effective Date.--The amendments made by this section shall be
effective 180 days after the date of enactment of this Act.
SEC. 5. RESPONSIBILITY OF ADULTS FOR DEATH AND INJURY CAUSED BY CHILD
ACCESS TO FIREARMS.
Section 922 of title 18, United States Code, is further amended by
adding at the end the following:
``(aa)(1) In this subsection, the term `child' means an individual
who has not attained the age of 18 years.
``(2) Except as provided in paragraph (3), any person who--
``(A) keeps a loaded firearm, or an unloaded firearm and
ammunition for the firearm, any one of which has been shipped
or transported in interstate or foreign commerce, within any
premises that is under the custody or control of that person;
and
``(B) knows, or recklessly disregards the risk, that a
child is capable of gaining access to the firearm; and
``(C)(i) knows, or recklessly disregards the risk, that a
child will use the firearm to cause death or serious bodily
injury (as defined in section 1365 of this title) to the child
or any other person; or
``(ii) knows, or recklessly disregards the risk, that
possession of the firearm by the child is unlawful under
Federal or State law,
if the child uses the firearm to cause death or serious bodily injury
to the child or any other person, shall be imprisoned not more than 3
years, fined under this title, or both.
``(3) Paragraph (2) shall not apply if--
``(A) at the time the child obtained access, the firearm
was secured with a secure gun storage or safety device;
``(B) the person is a peace officer, a member of the Armed
Forces, or a member of the National Guard, and the child
obtains the firearm during, or incidental to, the performance
of the official duties of the person in that capacity;
``(C) the child uses the firearm in a lawful act of self-
defense or defense of 1 or more other persons; or
``(D) the person has no reasonable expectation, based on
objective facts and circumstances, that a child is likely to be
present on the premises on which the firearm is kept.''.
SEC. 6. REQUIREMENT THAT CHILD BE ACCOMPANIED BY AN ADULT DURING A GUN
SHOW.
(a) Prohibitions.--Section 922 of title 18, United States Code, is
further amended by adding at the end the following:
``(bb)(1) The parent or legal guardian of a child shall ensure
that, while the child is attending a gun show, the child is accompanied
by an adult.
``(2) It shall be unlawful for a person to conduct a gun show to
which there is admitted a child who is not accompanied by an adult.
``(3) In this subsection:
``(A) The term `child' means an individual who has not
attained 18 years of age.
``(B) The term `adult' means an individual who has attained
18 years of age.''.
(b) Penalties.--Section 924(a) of such title is amended by adding
at the end the following:
``(7) Whoever violates section 922(bb) in a State shall be punished
in accordance with the laws of the State that apply to persons
convicted of child abandonment.''.
SEC. 7. GRANTS FOR GUN SAFETY EDUCATION PROGRAMS.
(a) Program Authority.--The Attorney General is authorized to
provide grants to units of local government to enable law enforcement
agencies to develop and sponsor gun safety classes for parents and
their children.
(b) Application.--
(1) In general.--Any unit of local government that desires
to receive a grant award under this section shall submit an
application to the Attorney General at such time, in such
manner and containing such information as the Attorney General
may reasonably require.
(2) Contents.--Each application referred to in paragraph
(1) shall include an assurance that--
(A) funds received under this section shall be used
only to provide funds to law enforcement agencies to
provide gun safety classes; and
(B) gun safety classes will be offered at times
convenient to parents, including evenings and weekends.
(c) Regulations.--The Attorney General shall issue any regulations
necessary to carry out this section.
SEC. 8. EDUCATION: NATIONWIDE FIREARMS SAFETY PROGRAMS.
It is the sense of Congress that--
(1) each school district should provide or participate in a
firearms safety program for students in grades kindergarten
through 12 and should consult with a certified firearms
instructor before establishing the curriculum for the program;
and
(2) participation by students in a firearms safety program
should not be mandatory if the district receives written notice
from a parent of the student to exempt the student from the
program.[/INST](Sec. 3) Increases penalties imposed upon: (1) a juvenile who violates Brady Act provisions for a second or subsequent violation, or for a first violation committed after an adjudication of delinquency or after a State or Federal conviction for an act that, if committed by an adult, would be a serious violent felony; and (2) a person other than a juvenile who knowingly violates such provisions if the person sold, delivered, or otherwise transferred a handgun, ammunition, semiautomatic assault weapon, or large capacity ammunition feeding device to a person who is under age 21, knowing or having reasonable cause to know that such person intended to carry, otherwise possess, discharge, or otherwise use it in the commission of a crime of violence.
(Sec. 4) Prohibits any licensed importer, manufacturer, or dealer from selling, transferring, or delivering a firearm to any person (other than a licensed importer, manufacturer, or dealer) unless the transferee is provided with a secure gun storage or safety device. Authorizes the Secretary of the Treasury, after notice and opportunity for hearing, to suspend or revoke any license issued under the Act, or to subject the licensee to a civil penalty of up to $10,000 if the holder of such license has knowingly violated this section.
(Sec. 5) Imposes penalties (with exceptions) upon any person who: (1) keeps a loaded firearm, or an unloaded firearm and ammunition for it, any one of which has been shipped or transported in interstate or foreign commerce, within any premises that is under the custody or control of that person; (2) knows, or recklessly disregards the risk, that a child is capable of gaining access to the firearm; and (3) knows, or recklessly disregards the risk, that a child will use the firearm to cause death or serious bodily injury to the child or any other person, or that possession of the firearm by the child is unlawful under Federal or State law, if the child uses the firearm to cause death or serious bodily injury.
(Sec. 6) Requires the parent or legal guardian of a child to ensure that, while the child is attending a gun show, the child is accompanied by an adult. Prohibits a person from conducting a gun show to which there is admitted a child who is not accompanied by an adult. Sets penalties for violations.
(Sec. 7) Authorizes the Attorney General to provide grants to units of local government to enable law enforcement agencies to develop and sponsor gun safety classes for parents and their children.
(Sec. 8) Expresses the sense of Congress that: (1) each school district should provide or participate in a firearms safety program for students in grades kindergarten through 12 and should consult with a certified firearms instructor before establishing the curriculum for the program; and (2) participation by students in a firearms safety program should not be mandatory if the district receives written notice from a parent of the student to exempt the student from the program.</s> |
SECTION 1. SHORT TITLE.
This Act may be cited as the ``Timber Sale Financial Accountability
Act of 1995''.
SEC. 2. RELIANCE ON FOREST SERVICE TIMBER SALE RECEIPTS TO FUND TIMBER
SALES.
(a) Timber Receipts To Cover Costs.--Section 14 of the National
Forest Management Act of 1976 (16 U.S.C. 472a) is amended by adding at
the end the following new subsection:
``(j) Use of Timber Receipts To Cover Sale Costs.--
``(1) Timber receipts fund.--There is hereby established in
the Treasury of the United States a fund to be known as the
`National Forest System Timber Receipts Fund' and consisting of
receipts from the sale of trees, portions of trees, and forest
products located on National Forest System lands. The Fund
shall consist of two accounts, one account for units of the
National Forest System located east of the Mississippi River
and the other account for units located west of the Mississippi
River and in Alaska. Amounts in the two accounts may not be
commingled. Amounts in the Fund are to be available until
expended.
``(2) Use of fund.--Amounts in an account of the Fund shall
be available, in such amounts as are provided in advance in
appropriation Acts, to the Secretary of Agriculture for the
purpose of covering the cost to the United States--
``(A) for design, engineering, and supervision of
the construction of roads needed in connection with
timber sales conducted under this section in units of
the National Forest System covered by the account; and
``(B) for Forest Service preparation,
advertisement, offering, awarding, and supervision of
the operation of such timber sales.
``(3) Reliance on fund.--The Fund shall be the sole source
of amounts for the activities specified in paragraph (2), and
amounts otherwise appropriated or made available to the
Secretary or the Forest Service in appropriation Acts may not
be obligated or expended for such activities.
``(4) Effect on other laws.--Except as provided in
paragraph (5), the following provisions of law shall not apply
to receipts from the sale of trees, portions of trees, and
forest products located on National Forest System lands:
``(A) The fifth paragraph under the heading
``FOREST SERVICE'' in the Act of March 4, 1907 (34
Stat. 1270; 16 U.S.C. 499).
``(B) The fourth sentence in section 9 of the Act
of June 7, 1924 (43 Stat. 655; 16 U.S.C. 499; commonly
known as the Clarke-McNary Act).
``(C) The sixth paragraph under the heading
``FOREST SERVICE'' in the Act of May 23, 1908 (35 Stat.
260; 16 U.S.C. 500).
``(D) Section 13 of the Act of March 1, 1911 (36
Stat. 963; 16 U.S.C. 500; commonly known as the Weeks
Act).
``(E) The sixth paragraph under the heading
``administrative provisions, forest service'' in title
II of the Department of the Interior and Related
Agencies Appropriations Act, 1993 (Public Law 102-381;
106 Stat. 1400; 16 U.S.C. 500 note).
``(F) The fourteenth paragraph under the heading
``FOREST SERVICE'' of the Act of March 4, 1913 (37
Stat. 843; 16 U.S.C. 501).
``(5) Excess amounts.--Amounts in the Fund determined by
the Secretary to be in excess of the cost of accomplishing the
activities specified in paragraph (2) shall be transferred to
miscellaneous receipts in the Treasury of the United States.
Amounts transferred shall be considered as moneys received from
the national forests within the meaning of the sixth paragraph
under the heading ``FOREST SERVICE'' in the Act of May 23, 1908
(35 Stat. 260; 16 U.S.C. 500), section 13 of the Act of March
1, 1911 (36 Stat. 963; 16 U.S.C. 500; commonly known as the
Weeks Act), and the fourteenth paragraph under the heading
``FOREST SERVICE'' of the Act of March 4, 1913 (37 Stat. 843;
16 U.S.C. 501).''.
(b) Conforming Amendments.--Such section is further amended--
(1) in subsection (h)--
(A) by striking ``in a designated fund'' in the
third sentence and inserting ``in the National Forest
System Timber Receipts Fund established under
subsection (j),''; and
(B) by striking the last sentence, including the
provisos; and
(2) in subsection (i)(2), by striking ``, and such
additional sums as may be appropriated for the construction of
roads''. | Timber Sale Financial Accountability Act of 1995 - Amends the National Forest Management Act of 1976 to establish in the Treasury the National Forest System Timber Receipts Fund which shall be the sole funding source for the Forest System timber sale program. | <s>[INST]SECTION 1. SHORT TITLE.
This Act may be cited as the ``Timber Sale Financial Accountability
Act of 1995''.
SEC. 2. RELIANCE ON FOREST SERVICE TIMBER SALE RECEIPTS TO FUND TIMBER
SALES.
(a) Timber Receipts To Cover Costs.--Section 14 of the National
Forest Management Act of 1976 (16 U.S.C. 472a) is amended by adding at
the end the following new subsection:
``(j) Use of Timber Receipts To Cover Sale Costs.--
``(1) Timber receipts fund.--There is hereby established in
the Treasury of the United States a fund to be known as the
`National Forest System Timber Receipts Fund' and consisting of
receipts from the sale of trees, portions of trees, and forest
products located on National Forest System lands. The Fund
shall consist of two accounts, one account for units of the
National Forest System located east of the Mississippi River
and the other account for units located west of the Mississippi
River and in Alaska. Amounts in the two accounts may not be
commingled. Amounts in the Fund are to be available until
expended.
``(2) Use of fund.--Amounts in an account of the Fund shall
be available, in such amounts as are provided in advance in
appropriation Acts, to the Secretary of Agriculture for the
purpose of covering the cost to the United States--
``(A) for design, engineering, and supervision of
the construction of roads needed in connection with
timber sales conducted under this section in units of
the National Forest System covered by the account; and
``(B) for Forest Service preparation,
advertisement, offering, awarding, and supervision of
the operation of such timber sales.
``(3) Reliance on fund.--The Fund shall be the sole source
of amounts for the activities specified in paragraph (2), and
amounts otherwise appropriated or made available to the
Secretary or the Forest Service in appropriation Acts may not
be obligated or expended for such activities.
``(4) Effect on other laws.--Except as provided in
paragraph (5), the following provisions of law shall not apply
to receipts from the sale of trees, portions of trees, and
forest products located on National Forest System lands:
``(A) The fifth paragraph under the heading
``FOREST SERVICE'' in the Act of March 4, 1907 (34
Stat. 1270; 16 U.S.C. 499).
``(B) The fourth sentence in section 9 of the Act
of June 7, 1924 (43 Stat. 655; 16 U.S.C. 499; commonly
known as the Clarke-McNary Act).
``(C) The sixth paragraph under the heading
``FOREST SERVICE'' in the Act of May 23, 1908 (35 Stat.
260; 16 U.S.C. 500).
``(D) Section 13 of the Act of March 1, 1911 (36
Stat. 963; 16 U.S.C. 500; commonly known as the Weeks
Act).
``(E) The sixth paragraph under the heading
``administrative provisions, forest service'' in title
II of the Department of the Interior and Related
Agencies Appropriations Act, 1993 (Public Law 102-381;
106 Stat. 1400; 16 U.S.C. 500 note).
``(F) The fourteenth paragraph under the heading
``FOREST SERVICE'' of the Act of March 4, 1913 (37
Stat. 843; 16 U.S.C. 501).
``(5) Excess amounts.--Amounts in the Fund determined by
the Secretary to be in excess of the cost of accomplishing the
activities specified in paragraph (2) shall be transferred to
miscellaneous receipts in the Treasury of the United States.
Amounts transferred shall be considered as moneys received from
the national forests within the meaning of the sixth paragraph
under the heading ``FOREST SERVICE'' in the Act of May 23, 1908
(35 Stat. 260; 16 U.S.C. 500), section 13 of the Act of March
1, 1911 (36 Stat. 963; 16 U.S.C. 500; commonly known as the
Weeks Act), and the fourteenth paragraph under the heading
``FOREST SERVICE'' of the Act of March 4, 1913 (37 Stat. 843;
16 U.S.C. 501).''.
(b) Conforming Amendments.--Such section is further amended--
(1) in subsection (h)--
(A) by striking ``in a designated fund'' in the
third sentence and inserting ``in the National Forest
System Timber Receipts Fund established under
subsection (j),''; and
(B) by striking the last sentence, including the
provisos; and
(2) in subsection (i)(2), by striking ``, and such
additional sums as may be appropriated for the construction of
roads''.[/INST]Timber Sale Financial Accountability Act of 1995 - Amends the National Forest Management Act of 1976 to establish in the Treasury the National Forest System Timber Receipts Fund which shall be the sole funding source for the Forest System timber sale program.</s> |
A new study published in the latest issue of Biological Psychiatry reports the successful and instant reduction of fear in spider-fearful participants following a 2-minute exposure combined with a single dose of a regular pharmacological treatment.
Typical behavioral therapies for phobia take many sessions to produce the desired effect. If recovery could be accelerated, it would reduce distress and save time and money.
Drs. Marieke Soeter and Merel Kindt, Department of Clinical Psychology, University of Amsterdam, sought to build on the notion of "reconsolidation", identified 15 years ago by Dr. Joseph LeDoux. He and his team discovered that when memories are activated, they may be modified in fundamental ways to strengthen or weaken them.
This neuroscience breakthrough resulted from their findings that administration of a drug upon activation of a fearful memory induced amnesia for that learned fear. However, pharmacologically induced amnesia has only been convincingly demonstrated for fears created in the laboratory in animals and in healthy participants.
In this study, Soeter and Kindt recruited 45 volunteers with spider fear. The participants were randomized to receive a single dose of either propranolol, a beta blocker used to treat high blood pressure and heart conditions, or placebo following brief exposure to a tarantula.
Those who received propranolol displayed drastically reduced avoidance behavior and increased approach behavior, an effect that persisted for one year..
"Here we show for the first time that an amnesic drug given in conjunction with memory reactivation transformed avoidance behavior to approach behavior in people with a real-life spider fear. The new treatment is more like surgery than therapy," said Kindt.
"Currently patients with anxiety disorders and PTSD receive multiple sessions of cognitive behavioral treatment or daily drug intake with a gradual (and often temporary) decline of symptoms," added Kindt. "The proposed revolutionary intervention involves one single, brief intervention that leads to a sudden, substantial and lasting loss of fear."
More research is necessary, to extend these findings to patient populations and more severe phobias, in addition to testing the outcome with other variables. However, as Dr. John Krystal, Editor of Biological Psychiatry, commented, "This elegant study may suggest a strategy for accelerating the recovery from anxiety disorders."
Indeed, these promising findings may ultimately lead to a new treatment strategy that erases the emotional impact of intensely fearful memories, which would signify a true paradigm shift in the practice of psychotherapy.
Explore further: Blocking a single molecule defeats chronic fear
More information: Marieke Soeter et al. An Abrupt Transformation of Phobic Behavior After a Post-Retrieval Amnesic Agent, Biological Psychiatry (2015). DOI: 10.1016/j.biopsych.2015.04.006
||||| A new study reports the successful and "instant" reduction of terror in arachnophobic participants.
“This won’t hurt a bit. Just play with a giant tarantula for a few minutes and then we give you a shot. Voila, spider terror vanquished.“
Could it really be that simple? I mean, it’s a bit sci-fi … and anytime you start giving people pharmacological injections to induce psychological change it does feel like a slippery slope into dystopian evil. But while tried-and-true behavioral therapies to treat phobias can take repeated sessions, this new approach could lessen stress and save both time and money. For those requiring medication to treat chronic fear-based anxiety, a one-shot deal could actually be more holistic.
In their exploration of phobias, Dr. Marieke Soeter and Dr Merel Kindt from the Department of Clinical Psychology, University of Amsterdam, wanted to elaborate on the concept of "reconsolidation,” a process in which when memories are activated, they may be modified to strengthen or weaken them.
The researchers gathered 45 participants who were afraid of spiders. The volunteers were exposed to a tarantula for two minutes and then randomly given a single dose of either propranolol (a beta blocker used for high blood pressure and heart conditions) or placebo.
Those who got the real propranolol experienced drastically reduced avoidance behavior and increased approach behavior, and not just for a few hours, but for a whole year.
"Here we show for the first time that an amnesic drug given in conjunction with memory reactivation transformed avoidance behavior to approach behavior in people with a real-life spider fear. The new treatment is more like surgery than therapy," says Kindt.
"Currently patients with anxiety disorders and PTSD receive multiple sessions of cognitive behavioral treatment or daily drug intake with a gradual (and often temporary) decline of symptoms," adds Kindt. "The proposed revolutionary intervention involves one single, brief intervention that leads to a sudden, substantial and lasting loss of fear."
The researchers say that more work is necessary to further test the treatment and to extend the findings to patient populations and more severe phobias. For those of us dedicated to natural remedies, the red flag may wave high. But for people suffering from debilitating fears, the research really could signal new possibilities. As Dr. John Krystal, Editor of Biological Psychiatry, says, "This elegant study may suggest a strategy for accelerating the recovery from anxiety disorders." ||||| (Photo: tmorkemo/Flickr)
Every autumn, the turning of the leaves heralds the emergence of the spiders. This is the time of year when arachnids, like many humans, wander in search of warmth and companionship.
This year, however, things are particularly spidery in the United Kingdom, where a wet summer has resulted in an increase in eight-legged guests in people’s homes. And it’s not just houses that are receiving visits—in early November, two London schools were closed for a week following the discovery of false widow spiders creeping around the classrooms.
None of this is good news for the UK’s arachnophobics, which number around a million, according to London Zoo’s Head of Invertebrate Conservation Dave Clarke. But there is a way for those who are petrified of spiders to overcome their fears: the Zoological Society of London’s Friendly Spider Programme.
The four-hour program, run by Clarke and hypnotist John Clifford, has been operating for the last 20 years. Over an afternoon, up to 40 participants engage in discussions on arachnids and phobias before being guided through a group hypnosis. During the day, they are encouraged to find a “spider buddy”: a fellow arachnophobic with whom they can swap stories and talk through their fears. This helps them feel supported during the afternoon’s many physical and psychological challenges, and normalizes feelings of dread. Following a tea break, they face the ultimate challenge: a look-and-touch encounter with real, live spiders—including a big, furry Mexican red-kneed spider—at the London Zoo.
Though the Friendly Spider Programme can benefit anyone who has a distaste for arachnids, it is designed for those whose fear of spiders is having a significant negative impact on their life. Clarke cites examples of people who have bought a home, discovered a spider there, then had to sell the property. Others come to the course having crashed their car after seeing a spider in it while driving.
“We have people who come on our course who don’t like the word spider, or anything associated with spiders,” says Clarke. For some of these participants, feelings of fear or revulsion can come from spiderwebs or even the spider-like vine atop a tomato. A peek at a photo of a spider, such as the one below, can induce a fight-or-flight response.
Agatha, a Mexican red-kneed spider. (Photo: Zoological Society of London)
But Clarke rejects the idea that arachnophobia is based on an inherent human fear. “That’s rubbish,” he says. “People put all their negative assumptions on spiders,” regarding them as dangerous even though, in the UK, no species is capable of killing a human. Arachnophobics often develop their fear during childhood, after observing spider aversion in someone close to them—like a parent, sibling or school friend.
Clarke says even he had a fear of spiders at one stage, but his desire to become a zookeeper forced him to confront the issue. He chose the “flooding” method—a type of exposure therapy in which he forced himself to hold spiders despite wanting to do the exact opposite.
Though Clarke acknowledges the Friendly Spider Programme can’t cure every arachnophobic, he says that 97 percent of course participants choose to hold a spider in their hand at the end of the day. “Very occasionally, people lapse after coming on the course,” he says, “but it’s such a tiny proportion. We do follow up with those people as much as we can and can often still get them back to being able to deal with spiders.”
The main shift that takes place during the afternoon is in people’s perceptions of arachnids, which Clarke and hypnotist Clifford address by comparing them to other dangerous animals and highlighting spiders’ positive contributions to the ecosystem—such as their control of flies and mosquitoes.
“Spiders are quite cuddly, too, once you get to know them,” say Clarke. “We should be shouting from the rooftops how fantastic it is to have spiders around.” | – Arachnophobes, rejoice! A new study suggests a cure to your fear of spiders is just two minutes away. The only problem is that it involves being near a tarantula. Reporting in Biological Psychiatry, University of Amsterdam scientists say they built an experiment out of the idea of reconsolidation—that memories can be strengthened or weakened when activated, reports Treehugger. Previous research showed a fearful memory could be forgotten if a drug was administered when that memory was activated, per a release. So researchers exposed 45 arachnophobes to a tarantula for two minutes, then gave each a dose of beta blocker propranolol, used to treat high blood pressure and heart conditions, or a placebo. Those given propranolol saw drastically reduced "avoidance behavior" and increased "approach behavior" over the next year. In other words, they were less likely to dodge spiders and more likely to go near one. "Here we show for the first time that an amnesic drug given in conjunction with memory reactivation transformed avoidance behavior to approach behavior in people with a real-life spider fear," says study author Merel Kindt. Though more research is needed, the scientist suggests the same technique could be used on patients suffering from anxiety disorders and PTSD. These individuals "receive multiple sessions of cognitive behavioral treatment or daily drug intake with a gradual (and often temporary) decline of symptoms," Kindt says. "The proposed revolutionary intervention involves one single, brief intervention that leads to a sudden, substantial and lasting loss of fear." Not interested in hanging around a tarantula? Atlas Obscura reports the London Zoo is helping people overcome their fear of spiders with group hypnosis. An official says 97% choose to hold a spider after the meeting. (Just not one as big as a puppy.) | <s>[INST]A new study published in the latest issue of Biological Psychiatry reports the successful and instant reduction of fear in spider-fearful participants following a 2-minute exposure combined with a single dose of a regular pharmacological treatment.
Typical behavioral therapies for phobia take many sessions to produce the desired effect. If recovery could be accelerated, it would reduce distress and save time and money.
Drs. Marieke Soeter and Merel Kindt, Department of Clinical Psychology, University of Amsterdam, sought to build on the notion of "reconsolidation", identified 15 years ago by Dr. Joseph LeDoux. He and his team discovered that when memories are activated, they may be modified in fundamental ways to strengthen or weaken them.
This neuroscience breakthrough resulted from their findings that administration of a drug upon activation of a fearful memory induced amnesia for that learned fear. However, pharmacologically induced amnesia has only been convincingly demonstrated for fears created in the laboratory in animals and in healthy participants.
In this study, Soeter and Kindt recruited 45 volunteers with spider fear. The participants were randomized to receive a single dose of either propranolol, a beta blocker used to treat high blood pressure and heart conditions, or placebo following brief exposure to a tarantula.
Those who received propranolol displayed drastically reduced avoidance behavior and increased approach behavior, an effect that persisted for one year..
"Here we show for the first time that an amnesic drug given in conjunction with memory reactivation transformed avoidance behavior to approach behavior in people with a real-life spider fear. The new treatment is more like surgery than therapy," said Kindt.
"Currently patients with anxiety disorders and PTSD receive multiple sessions of cognitive behavioral treatment or daily drug intake with a gradual (and often temporary) decline of symptoms," added Kindt. "The proposed revolutionary intervention involves one single, brief intervention that leads to a sudden, substantial and lasting loss of fear."
More research is necessary, to extend these findings to patient populations and more severe phobias, in addition to testing the outcome with other variables. However, as Dr. John Krystal, Editor of Biological Psychiatry, commented, "This elegant study may suggest a strategy for accelerating the recovery from anxiety disorders."
Indeed, these promising findings may ultimately lead to a new treatment strategy that erases the emotional impact of intensely fearful memories, which would signify a true paradigm shift in the practice of psychotherapy.
Explore further: Blocking a single molecule defeats chronic fear
More information: Marieke Soeter et al. An Abrupt Transformation of Phobic Behavior After a Post-Retrieval Amnesic Agent, Biological Psychiatry (2015). DOI: 10.1016/j.biopsych.2015.04.006
||||| A new study reports the successful and "instant" reduction of terror in arachnophobic participants.
“This won’t hurt a bit. Just play with a giant tarantula for a few minutes and then we give you a shot. Voila, spider terror vanquished.“
Could it really be that simple? I mean, it’s a bit sci-fi … and anytime you start giving people pharmacological injections to induce psychological change it does feel like a slippery slope into dystopian evil. But while tried-and-true behavioral therapies to treat phobias can take repeated sessions, this new approach could lessen stress and save both time and money. For those requiring medication to treat chronic fear-based anxiety, a one-shot deal could actually be more holistic.
In their exploration of phobias, Dr. Marieke Soeter and Dr Merel Kindt from the Department of Clinical Psychology, University of Amsterdam, wanted to elaborate on the concept of "reconsolidation,” a process in which when memories are activated, they may be modified to strengthen or weaken them.
The researchers gathered 45 participants who were afraid of spiders. The volunteers were exposed to a tarantula for two minutes and then randomly given a single dose of either propranolol (a beta blocker used for high blood pressure and heart conditions) or placebo.
Those who got the real propranolol experienced drastically reduced avoidance behavior and increased approach behavior, and not just for a few hours, but for a whole year.
"Here we show for the first time that an amnesic drug given in conjunction with memory reactivation transformed avoidance behavior to approach behavior in people with a real-life spider fear. The new treatment is more like surgery than therapy," says Kindt.
"Currently patients with anxiety disorders and PTSD receive multiple sessions of cognitive behavioral treatment or daily drug intake with a gradual (and often temporary) decline of symptoms," adds Kindt. "The proposed revolutionary intervention involves one single, brief intervention that leads to a sudden, substantial and lasting loss of fear."
The researchers say that more work is necessary to further test the treatment and to extend the findings to patient populations and more severe phobias. For those of us dedicated to natural remedies, the red flag may wave high. But for people suffering from debilitating fears, the research really could signal new possibilities. As Dr. John Krystal, Editor of Biological Psychiatry, says, "This elegant study may suggest a strategy for accelerating the recovery from anxiety disorders." ||||| (Photo: tmorkemo/Flickr)
Every autumn, the turning of the leaves heralds the emergence of the spiders. This is the time of year when arachnids, like many humans, wander in search of warmth and companionship.
This year, however, things are particularly spidery in the United Kingdom, where a wet summer has resulted in an increase in eight-legged guests in people’s homes. And it’s not just houses that are receiving visits—in early November, two London schools were closed for a week following the discovery of false widow spiders creeping around the classrooms.
None of this is good news for the UK’s arachnophobics, which number around a million, according to London Zoo’s Head of Invertebrate Conservation Dave Clarke. But there is a way for those who are petrified of spiders to overcome their fears: the Zoological Society of London’s Friendly Spider Programme.
The four-hour program, run by Clarke and hypnotist John Clifford, has been operating for the last 20 years. Over an afternoon, up to 40 participants engage in discussions on arachnids and phobias before being guided through a group hypnosis. During the day, they are encouraged to find a “spider buddy”: a fellow arachnophobic with whom they can swap stories and talk through their fears. This helps them feel supported during the afternoon’s many physical and psychological challenges, and normalizes feelings of dread. Following a tea break, they face the ultimate challenge: a look-and-touch encounter with real, live spiders—including a big, furry Mexican red-kneed spider—at the London Zoo.
Though the Friendly Spider Programme can benefit anyone who has a distaste for arachnids, it is designed for those whose fear of spiders is having a significant negative impact on their life. Clarke cites examples of people who have bought a home, discovered a spider there, then had to sell the property. Others come to the course having crashed their car after seeing a spider in it while driving.
“We have people who come on our course who don’t like the word spider, or anything associated with spiders,” says Clarke. For some of these participants, feelings of fear or revulsion can come from spiderwebs or even the spider-like vine atop a tomato. A peek at a photo of a spider, such as the one below, can induce a fight-or-flight response.
Agatha, a Mexican red-kneed spider. (Photo: Zoological Society of London)
But Clarke rejects the idea that arachnophobia is based on an inherent human fear. “That’s rubbish,” he says. “People put all their negative assumptions on spiders,” regarding them as dangerous even though, in the UK, no species is capable of killing a human. Arachnophobics often develop their fear during childhood, after observing spider aversion in someone close to them—like a parent, sibling or school friend.
Clarke says even he had a fear of spiders at one stage, but his desire to become a zookeeper forced him to confront the issue. He chose the “flooding” method—a type of exposure therapy in which he forced himself to hold spiders despite wanting to do the exact opposite.
Though Clarke acknowledges the Friendly Spider Programme can’t cure every arachnophobic, he says that 97 percent of course participants choose to hold a spider in their hand at the end of the day. “Very occasionally, people lapse after coming on the course,” he says, “but it’s such a tiny proportion. We do follow up with those people as much as we can and can often still get them back to being able to deal with spiders.”
The main shift that takes place during the afternoon is in people’s perceptions of arachnids, which Clarke and hypnotist Clifford address by comparing them to other dangerous animals and highlighting spiders’ positive contributions to the ecosystem—such as their control of flies and mosquitoes.
“Spiders are quite cuddly, too, once you get to know them,” say Clarke. “We should be shouting from the rooftops how fantastic it is to have spiders around.”[/INST]– Arachnophobes, rejoice! A new study suggests a cure to your fear of spiders is just two minutes away. The only problem is that it involves being near a tarantula. Reporting in Biological Psychiatry, University of Amsterdam scientists say they built an experiment out of the idea of reconsolidation—that memories can be strengthened or weakened when activated, reports Treehugger. Previous research showed a fearful memory could be forgotten if a drug was administered when that memory was activated, per a release. So researchers exposed 45 arachnophobes to a tarantula for two minutes, then gave each a dose of beta blocker propranolol, used to treat high blood pressure and heart conditions, or a placebo. Those given propranolol saw drastically reduced "avoidance behavior" and increased "approach behavior" over the next year. In other words, they were less likely to dodge spiders and more likely to go near one. "Here we show for the first time that an amnesic drug given in conjunction with memory reactivation transformed avoidance behavior to approach behavior in people with a real-life spider fear," says study author Merel Kindt. Though more research is needed, the scientist suggests the same technique could be used on patients suffering from anxiety disorders and PTSD. These individuals "receive multiple sessions of cognitive behavioral treatment or daily drug intake with a gradual (and often temporary) decline of symptoms," Kindt says. "The proposed revolutionary intervention involves one single, brief intervention that leads to a sudden, substantial and lasting loss of fear." Not interested in hanging around a tarantula? Atlas Obscura reports the London Zoo is helping people overcome their fear of spiders with group hypnosis. An official says 97% choose to hold a spider after the meeting. (Just not one as big as a puppy.)</s> |
SECTION 1. CREDIT TO HOLDERS OF QUALIFIED BROWNFIELDS CLEANUP BONDS.
(a) In General.--Subpart B of part IV of subchapter A of chapter 1
of the Internal Revenue Code of 1986 is amended by adding at the end
the following new section:
``SEC. 30B. CREDIT TO HOLDERS OF QUALIFIED BROWNFIELDS CLEANUP BONDS.
``(a) Allowance of Credit.--In the case of a taxpayer who holds a
qualified brownfields cleanup bond on a credit allowance date of such
bond which occurs during the taxable year, there shall be allowed as a
credit against the tax imposed by this chapter for such taxable year an
amount equal to the sum of the credits determined under subsection (b)
with respect to credit allowance dates during such year on which the
taxpayer holds such bond.
``(b) Amount of Credit.--
``(1) In general.--The amount of the credit determined
under this subsection with respect to any credit allowance date
for a qualified brownfields cleanup bond is 25 percent of the
annual credit determined with respect to such bond.
``(2) Annual credit.--The annual credit determined with
respect to any qualified brownfields cleanup bond is the
product of--
``(A) the applicable credit rate, multiplied by
``(B) the outstanding face amount of the bond.
``(3) Applicable credit rate.--For purposes of paragraph
(1), the applicable credit rate with respect to an issue is the
rate equal to an average market yield (as of the day before the
date of issuance of the issue) on outstanding long-term
corporate debt obligations (determined under regulations
prescribed by the Secretary).
``(4) Special rule for issuance and redemption.--In the
case of a bond which is issued during the 3-month period ending
on a credit allowance date, the amount of the credit determined
under this subsection with respect to such credit allowance
date shall be a ratable portion of the credit otherwise
determined based on the portion of the 3-month period during
which the bond is outstanding. A similar rule shall apply when
the bond is redeemed.
``(c) Qualified Brownfields Cleanup Bond.--For purposes of this
section--
``(1) In general.--The term `qualified brownfields cleanup
bond' means any bond issued as part of an issue if--
``(A) 95 percent or more of the proceeds of such
issue are to be used for the abatement or control of
hazardous substances at a qualified contaminated site,
``(B) the bond is issued by a State or local
government within the jurisdiction of which such site
is located,
``(C) the issuer designates such bond for purposes
of this section, and
``(D) the term of each bond which is part of such
issue does not exceed 15 years.
``(2) Limitation on amount of bonds designated.--The
maximum aggregate face amount of bonds issued during any
calendar year which may be designated under paragraph (1) by
any issuer shall not exceed the limitation amount allocated
under paragraph (3) for such calendar year to such issuer.
``(3) National limitation on amount of bonds designated.--
There is a national qualified brownfields cleanup bond
limitation for each calendar year. Such limitation is--
``(A) $100,000,000 for 2002, and
``(B) $150,000,000 for 2003.
``(4) Allocation of limitation among states.--The
limitation applicable under paragraph (3) for any calendar year
shall be allocated among the States by the Secretary of the
Treasury.
``(5) Carryover of unused limitation.--If for any calendar
year--
``(A) the amount allocated under paragraph (4) to
any State, exceeds
``(B) the amount of bonds issued during such year
which are designated under paragraph (1) pursuant to
such allocation,
the limitation amount under paragraph (4) for such State for
the following calendar year shall be increased by the amount of
such excess.
``(6) Bond to be paid back from any tax revenue increase.--
A bond shall not be treated as a qualified brownfields cleanup
bond unless any increase in real property tax revenues
(attributable to increases in assessed value) by reason of the
carrying out of the purposes described in paragraph (1)(A) is
reserved exclusively for debt service on the issue referred to
in paragraph (1) (and similar issues) to the extent such
increase does not exceed such debt service.
``(d) Limitation Based on Amount of Tax.--
``(1) In general.--The credit allowed under subsection (a)
for any taxable year shall not exceed the excess of--
``(A) the sum of the regular tax liability (as
defined in section 26(b)) plus the tax imposed by
section 55, over
``(B) the sum of the credits allowable under part
IV of subchapter A (other than subpart C thereof,
relating to refundable credits).
``(2) Carryover of unused credit.--If the credit allowable
under subsection (a) exceeds the limitation imposed by
paragraph (1) for such taxable year, such excess shall be
carried to the succeeding taxable year and added to the credit
allowable under subsection (a) for such taxable year.
``(e) Other Definitions.--For purposes of this section--
``(1) Credit allowance date.--The term `credit allowance
date' means--
``(A) March 15,
``(B) June 15,
``(C) September 15, and
``(D) December 15.
Such term includes the last day on which the bond is
outstanding.
``(2) Bond.--The term `bond' includes any obligation.
``(3) State.--The term `State' includes the District of
Columbia and any possession of the United States.
``(4) Qualified contaminated site.--The term `qualified
contaminated site' means a brownfield site designated by the
Administrator of the Environmental Protection Agency.
``(5) Hazardous substance.--The term `hazardous substance'
has the meaning provided by section 198(d).
``(f) Credit Included in Gross Income.--Gross income includes the
amount of the credit allowed to the taxpayer under this section
(determined without regard to subsection (d)) and the amount so
included shall be treated as interest income.
``(g) Bonds Held by Regulated Investment Companies.--If any
qualified brownfields cleanup bond is held by a regulated investment
company, the credit determined under subsection (a) shall be allowed to
shareholders of such company under procedures prescribed by the
Secretary.
``(h) Credits May Be Stripped.--Under regulations prescribed by the
Secretary--
``(1) In general.--There may be a separation (including at
issuance) of the ownership of a qualified brownfields cleanup
bond and the entitlement to the credit under this section with
respect to such bond. In case of any such separation, the
credit under this section shall be allowed to the person who on
the credit allowance date holds the instrument evidencing the
entitlement to the credit and not to the holder of the bond.
``(2) Certain rules to apply.--In the case of a separation
described in paragraph (1), the rules of section 1286 shall
apply to the qualified brownfields cleanup bond as if it were a
stripped bond and to the credit under this section as if it
were a stripped coupon.
``(i) Treatment for Estimated Tax Purposes.--Solely for purposes of
sections 6654 and 6655, the credit allowed by this section to a
taxpayer by reason of holding a qualified brownfields cleanup bond on a
credit allowance date shall be treated as if it were a payment of
estimated tax made by the taxpayer on such date.
``(j) Credit May Be Transferred.--Nothing in any law or rule of law
shall be construed to limit the transferability of the credit allowed
by this section through sale and repurchase agreements.
``(k) Reporting.--Issuers of qualified brownfields cleanup bonds
shall submit reports similar to the reports required under section
149(e).''
(b) Reporting.--Subsection (d) of section 6049 of such Code
(relating to returns regarding payments of interest) is amended by
adding at the end the following new paragraph:
``(8) Reporting of credit on qualified brownfields cleanup
bonds.--
``(A) In general.--For purposes of subsection (a),
the term `interest' includes amounts includible in
gross income under section 30B(f) and such amounts
shall be treated as paid on the credit allowance date
(as defined in section 30B(e)(1)).
``(B) Reporting to corporations, etc.--Except as
otherwise provided in regulations, in the case of any
interest described in subparagraph (A) of this
paragraph, subsection (b)(4) of this section shall be
applied without regard to subparagraphs (A), (H), (I),
(J), (K), and (L)(i).
``(C) Regulatory authority.--The Secretary may
prescribe such regulations as are necessary or
appropriate to carry out the purposes of this
paragraph, including regulations which require more
frequent or more detailed reporting.''
(c) Conforming Amendment.--The table of sections for subpart B of
part IV of subchapter A of chapter 1 of such Code is amended by adding
at the end the following new item:
``Sec. 30B. Credit to holders of
qualified public brownfields
cleanup bonds.''
(d) Effective Date.--The amendments made by this section shall
apply to obligations issued after December 31, 2001. | Amends the Internal Revenue Code to allow a limited credit to holders of qualified brownfields cleanup bonds. Sets a national limit on the amount of such bonds and provides for allocation among the States. | <s>[INST]SECTION 1. CREDIT TO HOLDERS OF QUALIFIED BROWNFIELDS CLEANUP BONDS.
(a) In General.--Subpart B of part IV of subchapter A of chapter 1
of the Internal Revenue Code of 1986 is amended by adding at the end
the following new section:
``SEC. 30B. CREDIT TO HOLDERS OF QUALIFIED BROWNFIELDS CLEANUP BONDS.
``(a) Allowance of Credit.--In the case of a taxpayer who holds a
qualified brownfields cleanup bond on a credit allowance date of such
bond which occurs during the taxable year, there shall be allowed as a
credit against the tax imposed by this chapter for such taxable year an
amount equal to the sum of the credits determined under subsection (b)
with respect to credit allowance dates during such year on which the
taxpayer holds such bond.
``(b) Amount of Credit.--
``(1) In general.--The amount of the credit determined
under this subsection with respect to any credit allowance date
for a qualified brownfields cleanup bond is 25 percent of the
annual credit determined with respect to such bond.
``(2) Annual credit.--The annual credit determined with
respect to any qualified brownfields cleanup bond is the
product of--
``(A) the applicable credit rate, multiplied by
``(B) the outstanding face amount of the bond.
``(3) Applicable credit rate.--For purposes of paragraph
(1), the applicable credit rate with respect to an issue is the
rate equal to an average market yield (as of the day before the
date of issuance of the issue) on outstanding long-term
corporate debt obligations (determined under regulations
prescribed by the Secretary).
``(4) Special rule for issuance and redemption.--In the
case of a bond which is issued during the 3-month period ending
on a credit allowance date, the amount of the credit determined
under this subsection with respect to such credit allowance
date shall be a ratable portion of the credit otherwise
determined based on the portion of the 3-month period during
which the bond is outstanding. A similar rule shall apply when
the bond is redeemed.
``(c) Qualified Brownfields Cleanup Bond.--For purposes of this
section--
``(1) In general.--The term `qualified brownfields cleanup
bond' means any bond issued as part of an issue if--
``(A) 95 percent or more of the proceeds of such
issue are to be used for the abatement or control of
hazardous substances at a qualified contaminated site,
``(B) the bond is issued by a State or local
government within the jurisdiction of which such site
is located,
``(C) the issuer designates such bond for purposes
of this section, and
``(D) the term of each bond which is part of such
issue does not exceed 15 years.
``(2) Limitation on amount of bonds designated.--The
maximum aggregate face amount of bonds issued during any
calendar year which may be designated under paragraph (1) by
any issuer shall not exceed the limitation amount allocated
under paragraph (3) for such calendar year to such issuer.
``(3) National limitation on amount of bonds designated.--
There is a national qualified brownfields cleanup bond
limitation for each calendar year. Such limitation is--
``(A) $100,000,000 for 2002, and
``(B) $150,000,000 for 2003.
``(4) Allocation of limitation among states.--The
limitation applicable under paragraph (3) for any calendar year
shall be allocated among the States by the Secretary of the
Treasury.
``(5) Carryover of unused limitation.--If for any calendar
year--
``(A) the amount allocated under paragraph (4) to
any State, exceeds
``(B) the amount of bonds issued during such year
which are designated under paragraph (1) pursuant to
such allocation,
the limitation amount under paragraph (4) for such State for
the following calendar year shall be increased by the amount of
such excess.
``(6) Bond to be paid back from any tax revenue increase.--
A bond shall not be treated as a qualified brownfields cleanup
bond unless any increase in real property tax revenues
(attributable to increases in assessed value) by reason of the
carrying out of the purposes described in paragraph (1)(A) is
reserved exclusively for debt service on the issue referred to
in paragraph (1) (and similar issues) to the extent such
increase does not exceed such debt service.
``(d) Limitation Based on Amount of Tax.--
``(1) In general.--The credit allowed under subsection (a)
for any taxable year shall not exceed the excess of--
``(A) the sum of the regular tax liability (as
defined in section 26(b)) plus the tax imposed by
section 55, over
``(B) the sum of the credits allowable under part
IV of subchapter A (other than subpart C thereof,
relating to refundable credits).
``(2) Carryover of unused credit.--If the credit allowable
under subsection (a) exceeds the limitation imposed by
paragraph (1) for such taxable year, such excess shall be
carried to the succeeding taxable year and added to the credit
allowable under subsection (a) for such taxable year.
``(e) Other Definitions.--For purposes of this section--
``(1) Credit allowance date.--The term `credit allowance
date' means--
``(A) March 15,
``(B) June 15,
``(C) September 15, and
``(D) December 15.
Such term includes the last day on which the bond is
outstanding.
``(2) Bond.--The term `bond' includes any obligation.
``(3) State.--The term `State' includes the District of
Columbia and any possession of the United States.
``(4) Qualified contaminated site.--The term `qualified
contaminated site' means a brownfield site designated by the
Administrator of the Environmental Protection Agency.
``(5) Hazardous substance.--The term `hazardous substance'
has the meaning provided by section 198(d).
``(f) Credit Included in Gross Income.--Gross income includes the
amount of the credit allowed to the taxpayer under this section
(determined without regard to subsection (d)) and the amount so
included shall be treated as interest income.
``(g) Bonds Held by Regulated Investment Companies.--If any
qualified brownfields cleanup bond is held by a regulated investment
company, the credit determined under subsection (a) shall be allowed to
shareholders of such company under procedures prescribed by the
Secretary.
``(h) Credits May Be Stripped.--Under regulations prescribed by the
Secretary--
``(1) In general.--There may be a separation (including at
issuance) of the ownership of a qualified brownfields cleanup
bond and the entitlement to the credit under this section with
respect to such bond. In case of any such separation, the
credit under this section shall be allowed to the person who on
the credit allowance date holds the instrument evidencing the
entitlement to the credit and not to the holder of the bond.
``(2) Certain rules to apply.--In the case of a separation
described in paragraph (1), the rules of section 1286 shall
apply to the qualified brownfields cleanup bond as if it were a
stripped bond and to the credit under this section as if it
were a stripped coupon.
``(i) Treatment for Estimated Tax Purposes.--Solely for purposes of
sections 6654 and 6655, the credit allowed by this section to a
taxpayer by reason of holding a qualified brownfields cleanup bond on a
credit allowance date shall be treated as if it were a payment of
estimated tax made by the taxpayer on such date.
``(j) Credit May Be Transferred.--Nothing in any law or rule of law
shall be construed to limit the transferability of the credit allowed
by this section through sale and repurchase agreements.
``(k) Reporting.--Issuers of qualified brownfields cleanup bonds
shall submit reports similar to the reports required under section
149(e).''
(b) Reporting.--Subsection (d) of section 6049 of such Code
(relating to returns regarding payments of interest) is amended by
adding at the end the following new paragraph:
``(8) Reporting of credit on qualified brownfields cleanup
bonds.--
``(A) In general.--For purposes of subsection (a),
the term `interest' includes amounts includible in
gross income under section 30B(f) and such amounts
shall be treated as paid on the credit allowance date
(as defined in section 30B(e)(1)).
``(B) Reporting to corporations, etc.--Except as
otherwise provided in regulations, in the case of any
interest described in subparagraph (A) of this
paragraph, subsection (b)(4) of this section shall be
applied without regard to subparagraphs (A), (H), (I),
(J), (K), and (L)(i).
``(C) Regulatory authority.--The Secretary may
prescribe such regulations as are necessary or
appropriate to carry out the purposes of this
paragraph, including regulations which require more
frequent or more detailed reporting.''
(c) Conforming Amendment.--The table of sections for subpart B of
part IV of subchapter A of chapter 1 of such Code is amended by adding
at the end the following new item:
``Sec. 30B. Credit to holders of
qualified public brownfields
cleanup bonds.''
(d) Effective Date.--The amendments made by this section shall
apply to obligations issued after December 31, 2001.[/INST]Amends the Internal Revenue Code to allow a limited credit to holders of qualified brownfields cleanup bonds. Sets a national limit on the amount of such bonds and provides for allocation among the States.</s> |
cleft lip , cleft palate ( clp ) , or both are the most frequently occurring congenital facial deformities , with an incidence rate of 0.65% in newborns , influenced by ethnic and geographic variations.[1 - 2 ] the nasopharyngeal region is impacted by complex interactions of bony compartments , muscular functionality , and soft tissues .
this region also influences aesthetic facial harmony and provides the anatomical basis of speech and hearing .
the size of pharyngeal space size is determined principally by relative growth and size of the soft tissues surrounding the dental and facial skeleton .
comprehensive orthodontic diagnoses and treatment plans and orthognathic surgery treatment planning require an understanding of all functional variables , including the upper airway . volumetric imaging might be useful for planning surgical intervention in cleft patients to improve the patency of the upper airway.[6 - 8 ] clefts of the lip and palate frequently produce nasal deformities that tend to reduce the size of the nasal airway .
approximately 70% of the cleft patients have nasal airway impairment and about 80% have mouth - breathing to some extent .
craniofacial anomalies , including mandibular or maxillary retrognathism , short mandibular body , and backward and downward rotation of the mandible , may lead to reduction of the pharyngeal airway passage . the oral , nasal , and pharyngeal structures that are affected by cleft lip and palate during breathing are often compromised for speech .
the nasal airway plays a significant role in controlling speech pressures when velopharyngeal function is impaired .
the findings of the pilot study show that more variability exists in airway volume than in airway area .
this observation strengthens the viewpoint of montgomery that reported single plane cephalometric radiographs do not reflect the airway volume in a reliable manner .
cone beam computed tomography ( cbct ) is a new method which uses the reciprocal rotation of a two - dimensional receptor and a cone - shaped x - ray beam to gain volume data.the development of cbct and computer simulation in treatment planning provide the opportunity for a more precisely evaluating of cases compared with the conventional radiographs with less radiation , shorter acquisition scan times , easier imaging than a medical ct scan at a lower cost.[14 - 16 ] recent publications have demonstrated the ability of cbct to accurately image the airway to provide minimum cross section and total airway volume in obstructive sleep apnea patients and controls .
previous studies have shown that 3d imaging using cbct is a simple and effective method to accurately analyze the airway.[18 - 20 ] currently , there are a few 3d studies to measure airway volume in individuals with clp and those studies used different methods.[21 - 23 ] cheung and oberoi suggested that there was no significant difference in pharyngeal airway volume and smallest cross sectional area between cleft and normal patients , while the airway length was significantly longer in clp children when compared to non - clp group .
celikoglu demonstrated that patients affected by clp had decreased volumetric scores of nasopharyngeal , oropharyngeal , and total airways ; however , the oropharyngeal airway volume difference between the unilateral clp and the control groups was statistically significant .
however , the study of xu et al . showed an enlarged nasopharynx in isolated clp in the sagittal plane and increased nasopharyngeal airway volume mainly around the palatal plane because of the increase in the sagittal diameter of the pharyngeal airway at this plane .
the goal of this study was to find 3d differences of the pharyngeal airway using cbct in individuals with non - syndromic clp versus normal individuals .
regarding the differences in the musculoskeletal and anthropometric proportions of individuals in different ethnics and concerning the current controversies over this subject , we planned to reconstruct another study to investigate this issue over a sample of iranian population .
the research committee of the medical ethics group of shiraz medical science university approved this study ( reference code ec - p-9365 - 6385 ) .
thirty cleft patients ( 19 men , 11 women ; 17 - 45 years ) were selected from the department of orthodontics ; dental university ( shiraz , iran ) who had cbct scans of the head for other reasons ( such as evaluating impacted teeth , missing teeth , or to assess the bone level ) .
the control group included 30 individuals from the same center with class i angle occlusion who were matched for gender and age variables with the experimental group .
the control group had already cbct scans from for orthodontic treatment purpose or assessment of impacted third molars or evaluating sinusitis .
the exclusion criteria were diagnosis of a syndrome , craniofacial anomalies , previous orthognathic surgery or tonsillectomy or adenoidectomy , and detectable pathology along the upper airway through inspection of the images .
all the cbct images have been made with similar unit and technique , by newtom vgi cone beam ct machine ( qr srl company ; verona , italy ) with the aid of a guide light . since the volume of the pharyngeal airway is influenced by head posture , all subjects were seated in the upright position and maximum intercuspation and the heads of patients were then centered and fixed in the cbct system .
the midline laser beam of the cbct system was adjusted to the midsagittal plane of the skull .
the horizontal laser beam was parallel to the frankfort plane ( fhp ) of the skull .
the maxillofacial regions were scanned by using tube voltage of 110 kvp , tube current of 6.35 mas , and scan time of 18s .
all images had a full field of view [ 15 12 ] that allowed visualization of the cranial base .
this method was previously used in normal individuals by grauer et al . to assess the relationship of the pharyngeal airway volume with facial morphology and
study to analyze the airway volume .
to reconstruct the 3d models of the airways for the subjects ,
the anonymous cbct data in dicom format were transferred to itk - snap 2.4.0 ( kitware , new york , usa ) pc software for semiautomatic segmentation that is used for medical image processing .
the images were oriented as a line 6 down from sellanasion as the horizontal axis .
the interactive steps of the segmentation are selection of an initial thre - shold ( which consist of the anterior border , a vertical plane through posterior nasal spine perpendicular to the sagittal plane ; posterior border , the posterior wall of the pharynx ; lateral border , the lateral walls of the pharynx ; lower border , a horizontal plane from the most caudal medial projection of the third cervical vertebra ) ( figure 1 ) and then placement of references points ( figure 2 ) . following the edge detection ,
the growth of the reference points in the single intensity value , fill up the airway structure ( figure 3 ) .
it uses the contrast differences between the airway and surroundings structures on the grey scale images .
after segmentation , the airway was subdivided into superior and inferior compartments by a plane from the posterior nasal spine to the lower border of the first cervical vertebra ( figure 4 ) .
subsequent to the segmentation , a 3d graphical model of the volumetric object was generated by the software and the volume in mm3 of the segmented 3d model was obtained .
landmark identification and segmentation were measured by the same investigator and measurement was repeated two times with one month interval by the same investigator to scrutinize intra - observer error .
superior and inferior border of pharynx placement of references points
growth of the reference points to fill up the airway structure
segmentation to superior and inferior compartments
the databases were collected .
pearson s correlation coefficient was used to assess the relationship between the superior airway volume and inferior airway volume .
thirty patients with unrepaired clp ( 19 men , 11 women ) and 30 normal controls ( 20 male and 10 female ) were enrolled in this study .
the average volume of the pharyngeal airway of normal adult was 23.4 cm ( sd , 8.7 cm ) , with mean volumes of 9.7 cm ( sd , 2.3 cm ) for the superior component and 13.7 cm ( sd , 7.2 cm ) for the inferior component .
the average volume of the pharyngeal airway of cleft group was 18.6 cm ( sd , 9.9 cm ) , with mean volumes of 6.8 cm ( sd , 3.5 cm ) for the superior component and 11.3 cm ( sd , 5.8 cm ) for the inferior component .
the total and superior airway volume of cleft group were significantly lower than non - cleft groups ( p= 0.008 , p=0.00 , respectively ) but the inferior airway volumes were not significantly different between the cleft and non - cleft groups ( p= 0.2 ) .
data of the measured and adjusted volumes are summarized in table 1and figure 5 .
the airway volumes ( mm3 ) in cleft patients and normal individuals in 3d cbct and p - value according to mann - whitney test graph depicting airway volume ( mm3 ) in clp ( cleft palate ) vs. non - clp * sup pharynx vol = superior pharyngeal airway volume * inf pharynx vol= inferior pharyngeal airway volume there was a significant and positive correlation between superior airway volume and inferior airway volume in clp patients ( r=+0.786 , p < 0.001 ) and control group ( r=+0.575 , p= 0.001 ) . figure 6 shows the scatter diagram as well as regression line for the relationship between superior airway volume in clp patients ( figure 6a ) and control ( figure 6b ) . in assessing the intra - observer errors ,
correlations between the first and second measurements ranged from 0.965 to 0.989 ( p < 0.005 ) .
a : scatter diagram of the relationship between superior airway volume and inferior airway volume in clp ( cleft palate ) group , b : scatter diagram of the relationship between superior airway volume and inferior airway volume in control group
regarding the differences in the musculoskeletal and anthropometric proportions of individuals in different ethnics and concerning the current controversies over this subject , our study investigated this issue over a sample of iranian population .
in the study of grauer et al .
, using the same method as the current study , the measurement of the average volume of the pharyngeal airway with the same method was 20.3 cm in normal individuals .
close to their results , in our study the mean airway volume was 23.4 cm for the normal group .
the 3d study of cheung and oberoi demonstrated the mean airway volume of 18.1 cm for the cleft group similar to our result ( 18.6 cm ) , however , they reported a 15.1 cm for the non - cleft group which significantly differ from the results yielded by the current study ( 23.4 cm ) .
moreover , they stated that there was no significant difference in pharyngeal airway volume between cleft and normal patients .
the differences might be attributed to their different method or different referenced points or fewer sample size of the two compared studies .
the results of diwakar et al.s study showed that the volume of the nasopharyngeal airway was significantly reduced in the clp group when compared with the non - cleft group which is in agreement with the results yielded by current study .
that showed the patients affected by unilateral cleft lip and palate had decreased volumes of oropharyngeal and total airways compared with the well - matched control group without unilateral cleft lip and palate .
the 2d study of imamura et al . showed that there was no significant difference between the adenoidal tissue of adults with clp and control groups .
moreover , the upper airway of adults in the clp group was significantly smaller than that in the control group .
they concluded that the size of adenoid tissue may not affect airway size of cleft patients .
xu y et al . demonstrated that volumetric analysis of the total volume , volume above the palatal plane , and volume between the palatal plane and c2 plane were larger in patients with isolated clp , but there was no significant difference below the c2 plane . in their 3d imaging study ,
the most posterior points of the palatal process was selected to define the posterior nasal spine ( pns ) , resulting in a pns that was anatomically more anterior to the pterygomaxillary palatinum which may influence the result .
yoshihara et al . who used cbct for the evaluation of airways in 15 unilateral clp girl patients reported that the mandible and the oropharyngeal airway were larger in the adolescent controls than in the juvenile controls without cleft lip and palate , but there were no significant differences between the adolescent and juvenile patients with cleft lip and palate .
the small size and retrognathic position of the mandible in the cleft group compared to the control group might be expected to narrow and reduce the volume of the pharyngeal airway .
the evaluation of the nasopharyngeal airways of unilateral cleft lip and palate patients who was previously reported by aras et al . using 3d and 2d methods in which significant difference was detected between the cleft and non - cleft patients in nasal volume .
this study also concluded that the upper and middle pharyngeal airway areas were found to display significant larger areas in the non - cleft group on cephalometric images .
hence it seems that the 2d data can be insufficient and therefore might be deceiving .
consequently , they showed that even though the radiation dose of 3d imaging systems was greater ; they have benefited from the advantage of superior diagnostic outputs .
there are several methods to calculate the 3d airway volume which may affect the accuracy of the pharyngeal analysis .
our segmentation method has been described , validated , and tested for accuracy , and according to study of weissheimer et al .
, itk - snap showed less than 2% errors in volumes compared with the gold standard .
it is claimed to be more accurate than the conventional manual tracing method and other 3d analysis methods .
shi et al . also demonstrated that automatic segmentation of the airway imaged using cbctwas feasible and could be employed to assess airway cross - section and volume similar to measurements yielded by manual segmentation .
this selection was in accordance with the study enrolled by grauer et al . which reported that in skeletal class ii patients , inferior compartment airway volume was smaller than class i and class iii patients , but there were no significant differences in airway volume among the long , normal and short face - height groups .
imamura et al . suggested that adenoidal tissues in the clp have similar size compared with normal adults so we didnot consider adenoid size as an affective factor on airway volume .
reiser et al . found no correlations between the size of the initial cleft in infancy and size of the nasal airway in adulthood .
so in adult patients who were born with uclp , the size of the cleft in infancy does not seem to affect the size and function of the nasal airway in adulthood .
our analysis included only patients who underwent cbct for orthodontic planning , and no cbcts were performed solely for the purpose of studying airway volume .
3d imaging using cbct is a reliable diagnostic imaging tool to provide accurate data regarding airway size to allow clinicians to assess and screen the airway structures in clp patients . through this 3d analysis
the measurement of the pharyngeal airway volume showed that the nasal and total airway is restricted in individuals with clp but the inferior airway is not compromised in these individuals . | statement of the problem : individuals with cleft lip and cleft palate mostly have airway problems .
introduction of cone beam computed tomography ( cbct ) and imaging software has provided the opportunity for a more precisely evaluating 3d volume of the airway .
purpose : the purpose of this study was to analyze and compare 3d the pharyngeal airway volumes of cleft palate patients with normal individuals using cbct .
materials and method:30 complete cleft palate patients were selected from the department of orthodontics ; dental university ( shiraz , iran ) who had cbct scans of the head .
the control group included 30 individuals with class i angle occlusion who were matched for age and gender with the experimental group .
itk - snap 2.4.0 pc software was used to build 3d models of the airways for the subjects and measuring airway volumes .
the statistical analyses were performed using spss software ( version 19 ) .
mann - whitney test was adopted with p < 0.05 as statistical significance .
results : the average volume of the pharyngeal airway of cleft group was 18.6 cm3 , with mean volumes of 6.8 cm3 for the superior component and 11.3 cm3 for the inferior component .
the total and superior airway volume of cleft group were significantly lower than non - cleft groups ( p= 0.008 , p= 0.00 , respectively ) but the inferior airway volumes were not significantly different between the cleft and non - cleft groups .
there was a significant and positive correlation between superior airway volume and inferior airway volume in cleft palate patients ( r=+0.786 , p < 0.001 ) and control group ( r=+0.575 , p= 0.001 ) .
conclusion:3d analysis showed that the nasal and total airway was restricted in individuals with cleft palate but the inferior airway was not compromised in these individuals .
this would be a crucial data to be considered for surgeons during surgical planning . | <s>[INST]cleft lip , cleft palate ( clp ) , or both are the most frequently occurring congenital facial deformities , with an incidence rate of 0.65% in newborns , influenced by ethnic and geographic variations.[1 - 2 ] the nasopharyngeal region is impacted by complex interactions of bony compartments , muscular functionality , and soft tissues .
this region also influences aesthetic facial harmony and provides the anatomical basis of speech and hearing .
the size of pharyngeal space size is determined principally by relative growth and size of the soft tissues surrounding the dental and facial skeleton .
comprehensive orthodontic diagnoses and treatment plans and orthognathic surgery treatment planning require an understanding of all functional variables , including the upper airway . volumetric imaging might be useful for planning surgical intervention in cleft patients to improve the patency of the upper airway.[6 - 8 ] clefts of the lip and palate frequently produce nasal deformities that tend to reduce the size of the nasal airway .
approximately 70% of the cleft patients have nasal airway impairment and about 80% have mouth - breathing to some extent .
craniofacial anomalies , including mandibular or maxillary retrognathism , short mandibular body , and backward and downward rotation of the mandible , may lead to reduction of the pharyngeal airway passage . the oral , nasal , and pharyngeal structures that are affected by cleft lip and palate during breathing are often compromised for speech .
the nasal airway plays a significant role in controlling speech pressures when velopharyngeal function is impaired .
the findings of the pilot study show that more variability exists in airway volume than in airway area .
this observation strengthens the viewpoint of montgomery that reported single plane cephalometric radiographs do not reflect the airway volume in a reliable manner .
cone beam computed tomography ( cbct ) is a new method which uses the reciprocal rotation of a two - dimensional receptor and a cone - shaped x - ray beam to gain volume data.the development of cbct and computer simulation in treatment planning provide the opportunity for a more precisely evaluating of cases compared with the conventional radiographs with less radiation , shorter acquisition scan times , easier imaging than a medical ct scan at a lower cost.[14 - 16 ] recent publications have demonstrated the ability of cbct to accurately image the airway to provide minimum cross section and total airway volume in obstructive sleep apnea patients and controls .
previous studies have shown that 3d imaging using cbct is a simple and effective method to accurately analyze the airway.[18 - 20 ] currently , there are a few 3d studies to measure airway volume in individuals with clp and those studies used different methods.[21 - 23 ] cheung and oberoi suggested that there was no significant difference in pharyngeal airway volume and smallest cross sectional area between cleft and normal patients , while the airway length was significantly longer in clp children when compared to non - clp group .
celikoglu demonstrated that patients affected by clp had decreased volumetric scores of nasopharyngeal , oropharyngeal , and total airways ; however , the oropharyngeal airway volume difference between the unilateral clp and the control groups was statistically significant .
however , the study of xu et al . showed an enlarged nasopharynx in isolated clp in the sagittal plane and increased nasopharyngeal airway volume mainly around the palatal plane because of the increase in the sagittal diameter of the pharyngeal airway at this plane .
the goal of this study was to find 3d differences of the pharyngeal airway using cbct in individuals with non - syndromic clp versus normal individuals .
regarding the differences in the musculoskeletal and anthropometric proportions of individuals in different ethnics and concerning the current controversies over this subject , we planned to reconstruct another study to investigate this issue over a sample of iranian population .
the research committee of the medical ethics group of shiraz medical science university approved this study ( reference code ec - p-9365 - 6385 ) .
thirty cleft patients ( 19 men , 11 women ; 17 - 45 years ) were selected from the department of orthodontics ; dental university ( shiraz , iran ) who had cbct scans of the head for other reasons ( such as evaluating impacted teeth , missing teeth , or to assess the bone level ) .
the control group included 30 individuals from the same center with class i angle occlusion who were matched for gender and age variables with the experimental group .
the control group had already cbct scans from for orthodontic treatment purpose or assessment of impacted third molars or evaluating sinusitis .
the exclusion criteria were diagnosis of a syndrome , craniofacial anomalies , previous orthognathic surgery or tonsillectomy or adenoidectomy , and detectable pathology along the upper airway through inspection of the images .
all the cbct images have been made with similar unit and technique , by newtom vgi cone beam ct machine ( qr srl company ; verona , italy ) with the aid of a guide light . since the volume of the pharyngeal airway is influenced by head posture , all subjects were seated in the upright position and maximum intercuspation and the heads of patients were then centered and fixed in the cbct system .
the midline laser beam of the cbct system was adjusted to the midsagittal plane of the skull .
the horizontal laser beam was parallel to the frankfort plane ( fhp ) of the skull .
the maxillofacial regions were scanned by using tube voltage of 110 kvp , tube current of 6.35 mas , and scan time of 18s .
all images had a full field of view [ 15 12 ] that allowed visualization of the cranial base .
this method was previously used in normal individuals by grauer et al . to assess the relationship of the pharyngeal airway volume with facial morphology and
study to analyze the airway volume .
to reconstruct the 3d models of the airways for the subjects ,
the anonymous cbct data in dicom format were transferred to itk - snap 2.4.0 ( kitware , new york , usa ) pc software for semiautomatic segmentation that is used for medical image processing .
the images were oriented as a line 6 down from sellanasion as the horizontal axis .
the interactive steps of the segmentation are selection of an initial thre - shold ( which consist of the anterior border , a vertical plane through posterior nasal spine perpendicular to the sagittal plane ; posterior border , the posterior wall of the pharynx ; lateral border , the lateral walls of the pharynx ; lower border , a horizontal plane from the most caudal medial projection of the third cervical vertebra ) ( figure 1 ) and then placement of references points ( figure 2 ) . following the edge detection ,
the growth of the reference points in the single intensity value , fill up the airway structure ( figure 3 ) .
it uses the contrast differences between the airway and surroundings structures on the grey scale images .
after segmentation , the airway was subdivided into superior and inferior compartments by a plane from the posterior nasal spine to the lower border of the first cervical vertebra ( figure 4 ) .
subsequent to the segmentation , a 3d graphical model of the volumetric object was generated by the software and the volume in mm3 of the segmented 3d model was obtained .
landmark identification and segmentation were measured by the same investigator and measurement was repeated two times with one month interval by the same investigator to scrutinize intra - observer error .
superior and inferior border of pharynx placement of references points
growth of the reference points to fill up the airway structure
segmentation to superior and inferior compartments
the databases were collected .
pearson s correlation coefficient was used to assess the relationship between the superior airway volume and inferior airway volume .
thirty patients with unrepaired clp ( 19 men , 11 women ) and 30 normal controls ( 20 male and 10 female ) were enrolled in this study .
the average volume of the pharyngeal airway of normal adult was 23.4 cm ( sd , 8.7 cm ) , with mean volumes of 9.7 cm ( sd , 2.3 cm ) for the superior component and 13.7 cm ( sd , 7.2 cm ) for the inferior component .
the average volume of the pharyngeal airway of cleft group was 18.6 cm ( sd , 9.9 cm ) , with mean volumes of 6.8 cm ( sd , 3.5 cm ) for the superior component and 11.3 cm ( sd , 5.8 cm ) for the inferior component .
the total and superior airway volume of cleft group were significantly lower than non - cleft groups ( p= 0.008 , p=0.00 , respectively ) but the inferior airway volumes were not significantly different between the cleft and non - cleft groups ( p= 0.2 ) .
data of the measured and adjusted volumes are summarized in table 1and figure 5 .
the airway volumes ( mm3 ) in cleft patients and normal individuals in 3d cbct and p - value according to mann - whitney test graph depicting airway volume ( mm3 ) in clp ( cleft palate ) vs. non - clp * sup pharynx vol = superior pharyngeal airway volume * inf pharynx vol= inferior pharyngeal airway volume there was a significant and positive correlation between superior airway volume and inferior airway volume in clp patients ( r=+0.786 , p < 0.001 ) and control group ( r=+0.575 , p= 0.001 ) . figure 6 shows the scatter diagram as well as regression line for the relationship between superior airway volume in clp patients ( figure 6a ) and control ( figure 6b ) . in assessing the intra - observer errors ,
correlations between the first and second measurements ranged from 0.965 to 0.989 ( p < 0.005 ) .
a : scatter diagram of the relationship between superior airway volume and inferior airway volume in clp ( cleft palate ) group , b : scatter diagram of the relationship between superior airway volume and inferior airway volume in control group
regarding the differences in the musculoskeletal and anthropometric proportions of individuals in different ethnics and concerning the current controversies over this subject , our study investigated this issue over a sample of iranian population .
in the study of grauer et al .
, using the same method as the current study , the measurement of the average volume of the pharyngeal airway with the same method was 20.3 cm in normal individuals .
close to their results , in our study the mean airway volume was 23.4 cm for the normal group .
the 3d study of cheung and oberoi demonstrated the mean airway volume of 18.1 cm for the cleft group similar to our result ( 18.6 cm ) , however , they reported a 15.1 cm for the non - cleft group which significantly differ from the results yielded by the current study ( 23.4 cm ) .
moreover , they stated that there was no significant difference in pharyngeal airway volume between cleft and normal patients .
the differences might be attributed to their different method or different referenced points or fewer sample size of the two compared studies .
the results of diwakar et al.s study showed that the volume of the nasopharyngeal airway was significantly reduced in the clp group when compared with the non - cleft group which is in agreement with the results yielded by current study .
that showed the patients affected by unilateral cleft lip and palate had decreased volumes of oropharyngeal and total airways compared with the well - matched control group without unilateral cleft lip and palate .
the 2d study of imamura et al . showed that there was no significant difference between the adenoidal tissue of adults with clp and control groups .
moreover , the upper airway of adults in the clp group was significantly smaller than that in the control group .
they concluded that the size of adenoid tissue may not affect airway size of cleft patients .
xu y et al . demonstrated that volumetric analysis of the total volume , volume above the palatal plane , and volume between the palatal plane and c2 plane were larger in patients with isolated clp , but there was no significant difference below the c2 plane . in their 3d imaging study ,
the most posterior points of the palatal process was selected to define the posterior nasal spine ( pns ) , resulting in a pns that was anatomically more anterior to the pterygomaxillary palatinum which may influence the result .
yoshihara et al . who used cbct for the evaluation of airways in 15 unilateral clp girl patients reported that the mandible and the oropharyngeal airway were larger in the adolescent controls than in the juvenile controls without cleft lip and palate , but there were no significant differences between the adolescent and juvenile patients with cleft lip and palate .
the small size and retrognathic position of the mandible in the cleft group compared to the control group might be expected to narrow and reduce the volume of the pharyngeal airway .
the evaluation of the nasopharyngeal airways of unilateral cleft lip and palate patients who was previously reported by aras et al . using 3d and 2d methods in which significant difference was detected between the cleft and non - cleft patients in nasal volume .
this study also concluded that the upper and middle pharyngeal airway areas were found to display significant larger areas in the non - cleft group on cephalometric images .
hence it seems that the 2d data can be insufficient and therefore might be deceiving .
consequently , they showed that even though the radiation dose of 3d imaging systems was greater ; they have benefited from the advantage of superior diagnostic outputs .
there are several methods to calculate the 3d airway volume which may affect the accuracy of the pharyngeal analysis .
our segmentation method has been described , validated , and tested for accuracy , and according to study of weissheimer et al .
, itk - snap showed less than 2% errors in volumes compared with the gold standard .
it is claimed to be more accurate than the conventional manual tracing method and other 3d analysis methods .
shi et al . also demonstrated that automatic segmentation of the airway imaged using cbctwas feasible and could be employed to assess airway cross - section and volume similar to measurements yielded by manual segmentation .
this selection was in accordance with the study enrolled by grauer et al . which reported that in skeletal class ii patients , inferior compartment airway volume was smaller than class i and class iii patients , but there were no significant differences in airway volume among the long , normal and short face - height groups .
imamura et al . suggested that adenoidal tissues in the clp have similar size compared with normal adults so we didnot consider adenoid size as an affective factor on airway volume .
reiser et al . found no correlations between the size of the initial cleft in infancy and size of the nasal airway in adulthood .
so in adult patients who were born with uclp , the size of the cleft in infancy does not seem to affect the size and function of the nasal airway in adulthood .
our analysis included only patients who underwent cbct for orthodontic planning , and no cbcts were performed solely for the purpose of studying airway volume .
3d imaging using cbct is a reliable diagnostic imaging tool to provide accurate data regarding airway size to allow clinicians to assess and screen the airway structures in clp patients . through this 3d analysis
the measurement of the pharyngeal airway volume showed that the nasal and total airway is restricted in individuals with clp but the inferior airway is not compromised in these individuals .[/INST]statement of the problem : individuals with cleft lip and cleft palate mostly have airway problems .
introduction of cone beam computed tomography ( cbct ) and imaging software has provided the opportunity for a more precisely evaluating 3d volume of the airway .
purpose : the purpose of this study was to analyze and compare 3d the pharyngeal airway volumes of cleft palate patients with normal individuals using cbct .
materials and method:30 complete cleft palate patients were selected from the department of orthodontics ; dental university ( shiraz , iran ) who had cbct scans of the head .
the control group included 30 individuals with class i angle occlusion who were matched for age and gender with the experimental group .
itk - snap 2.4.0 pc software was used to build 3d models of the airways for the subjects and measuring airway volumes .
the statistical analyses were performed using spss software ( version 19 ) .
mann - whitney test was adopted with p < 0.05 as statistical significance .
results : the average volume of the pharyngeal airway of cleft group was 18.6 cm3 , with mean volumes of 6.8 cm3 for the superior component and 11.3 cm3 for the inferior component .
the total and superior airway volume of cleft group were significantly lower than non - cleft groups ( p= 0.008 , p= 0.00 , respectively ) but the inferior airway volumes were not significantly different between the cleft and non - cleft groups .
there was a significant and positive correlation between superior airway volume and inferior airway volume in cleft palate patients ( r=+0.786 , p < 0.001 ) and control group ( r=+0.575 , p= 0.001 ) .
conclusion:3d analysis showed that the nasal and total airway was restricted in individuals with cleft palate but the inferior airway was not compromised in these individuals .
this would be a crucial data to be considered for surgeons during surgical planning .</s> |
despite breathtaking advances in science and technology , breast cancer still remains mankind 's one of the most dreaded maladies .
timely diagnosis and well planned , and executed treatment strategy are the cornerstones of successful management of this entity .
self - breast examination or a clinical breast examination alone may not be sufficient in identifying potentially malignant breast lesions .
on such occasions x - ray mammography or sonomammography can demonstrate such lesions , which can then be subjected to fine needle aspiration cytology ( fnac ) for pathological confirmation as fnac has stood the test of time as a safe , reliable and time saving outdoor procedure with little discomfort to the patient .
x - ray mammographic screening was introduced as a means to detect small , nonpalpable , asymptomatic breast carcinomas .
principal x - ray mammographic signs of breast carcinoma are densities and calcifications . in about 10% of cases ,
the principal causes of these failures are the presence of surrounding radio dense tissue that obscures the tumor , the absence of calcification , small size , diffuse infiltrative pattern with little or no desmoplastic response , or a location close to chest wall or in periphery of breast .
sonomammography distinguishes between solid and cystic lesions and can define more precisely the borders of solid lesions .
most palpable masses that are not imaged at all by mammography are detectable by ultrasound . while traditional diagnostic approach to palpable breast masses mostly involved direct fnac of the referred case without much attention to the clinical or mammography diagnosis , the possibility that the diagnostic efficacy could further be enhanced when physical breast examination , mammography and fnac ( the triple test [ tt ] ) are jointly taken into consideration as reported in other studies .
various studies have found nearly 100% diagnostic accuracy of the tt for palpable breast masses when all three elements ( i.e. , physical examination , mammogram and fnac ) are concordant .
a clinician can proceed directly with definitive therapy without an interventional open biopsy if all the components of tt are malignant . if all the components are found to be benign , the patient can then be safely observed . in september , 1996 ,
national cancer institute sponsored conference was held for the purpose of defining a uniform approach to breast fine needle aspiration ( fna ) biopsy , and to address some of the controversies related to breast fna , including the use of core biopsies .
tt , that is , the combination of physical examination , imaging findings , and cytological examination in the reliable diagnosis of breast cancer .
consequently , it was suggested that a recommendation be included in the cytopathology reports of breast fnas to support the clinical application of the tt . considering these facts the current study was carried out with an aim of evaluating the role of tt score ( tts ) in palpable breast masses by calculating the tts in fnac cases ; classifying in to benign , malignant and nonconcordant cases according to tts , correlation with histopathology and finding the effectiveness of tts in comparison to fnac alone .
the subjects concerned included all the female patients , which were referred to the department of pathology for fnac of the breast mass .
patients with hemorrhagic diathesis , breast mass associated with pregnancy , associated localized skin infection and patients on oral anticoagulants were excluded .
one smear was fixed with 95% alcohol for a period of 30 min before drying .
lesion was classified in to inadequate , benign , atypical , suspicious , and malignant .
it included three main diagnostic features of the procedure namely physical examination , mammography and fnac .
each component of tt was assigned 1 , 2 or 3 points for a benign , suspicious or malignant result respectively .
tts has a minimum score of 3 ( concordant benign ) and a maximum score of 9 ( concordant malignant ) .
all lesions with tts 4 are considered benign ; all lesions with tts 6 are considered malignant .
the statistical analyses were done to find the ability of tts and fnac to detect the presence of malignancy in the breast in comparison to histopathology . for this sensitivity ,
specificity , positive predictive value ( ppv ) , negative predictive value ( npv ) and accuracy / efficiency were calculated .
in the study period of the present study from may 2010 to april 2012 , 225 fnac 's of breasts were done .
of the 124 benign lesions on cytology , a tts score of 3 - 4 was seen in 117 cases , out of the total 62 cases labeled as malignant , 61 cases had a tts score of 6 .
triple test score in spectrum of lesions on cytology the table 2 correlates tts with histopathology . in the present study
though tt was applied to 200 odd cases , its impact could be evaluated in 70 out of 200 as histopathological correlation was possible in only 70 patients . out of these 70 , 28 were from the benign category and 42 were from the malignant category . in the present study , out of the 28 benign cases 24 cases had the tts of 3 - 4 and only four had a tts of 5 .
out of the 42 malignant cases , 38 cases had the tts of 6 , three had a tts of 5 and only one had a tts of 3 - 4 .
correlation of tts with histopathology the correlation of the benign histopathological lesions with the tts pointed that out of the 12 cases of fibroadenoma , 11 cases ( 91.66% ) had the tts of 3 - 4 and only 1 ( 8.33% ) had a tts of 5 .
all 9 cases of fibrocystic disease that had a tts showed it to be 3 - 4 .
single case of duct ectasia and atrophic breast tissue showed a tts of 5 each .
out of 5 cases of mastitis , four had tts of 3 - 4 and one case had tts of 5 .
the correlation of the malignant histopathological lesions with the tts as seen in present study shows that out of the 35 cases of infiltrating ductal carcinoma ( idc ) that had a tts , 31 cases ( 88.57% ) had the tts of 6 , 3 ( 8.57% ) had a tts of 5 and only 1 ( 2.85% ) had a tts of 3 - 4 .
both cases of lobular carcinoma , and single case of lymphoma , medullary carcinoma , angiosarcoma and mucinous carcinoma showed a tts of 6 each .
the statistical analyses showed that a tts was 100% sensitive and 97.43% specific in diagnosing benign lesions .
it had a ppv of 96% and a npv of 97.44% in diagnosing benign lesions .
furthermore , it had ppv of 100% and a npv of 96% in diagnosing malignant lesion . in the present study ,
the statistical analyses of fnac as a diagnostic test to detect the presence of malignancy in the breast was done .
also , fnac had ppv of 97.43% and a npv of 84.37% in diagnosing malignant lesion . in the present study
the tt , was initially described in the mid-1970s , by johansen c. as the evaluation of palpable breast masses by physical examination , mammography , and fnac .
the tt has proved a reliable tool for the accurate diagnosis of palpable breast masses , due to its technical simplicity , and resulted in substantially reduced expense and morbidity compared with open surgical biopsy . due to the reduced sensitivity and specificity of lesion detection by mammography in young women under 40 and
the usefulness of sonography in this group of patients , researchers dealing with women under 40 combined sonography with mammography to the scoring system and the modified tts was introduced which is an integration of clinical breast examination , sonography and fna .
confirmatory biopsy is required only for the lesions that receive a tts of 5 . in the present study ,
tts of 5 indicates suspicious lesions , and they are to be evaluated by biopsy .
all malignant cases on cytology showed tts of 6 , except one case where tts was 5 .
this indicates discordance and is possibly due to differences in appearance of different parts of the lesion on different modalities . as per present study , all cytological malignant cases showed tts 6 , except one case of idc , where tts was 5 .
histological correlation with tts showed that in the present study , out of 28 histological benign cases 24 ( 85.71% ) had concordant tts ( 3 - 4 ) which correlates with studies by ghafouri et al .
none of the benign cases in the present study showed discordant tts which correlates with studies by morris et al . and hermansen et al .
showed 2 ( 2.24% ) discordant cases with a tts of 6 . in the present study , 4 cases ( 14.28% ) had a tts of 5 , which correlates with ghafouri et al . 3 ( 3.37% ) ,
present study suggests that tts is a very good and reliable tool for diagnosis of fibrocystic disease .
fibroadenoma , mastitis and duct ectasia can give tts of 5 , if atypical cells are seen or clinical examination / mammography suggests suspicious lesions .
table 3 indicates various studies showing tts in malignant lesions on histopathology . in the present study ,
one histological malignant case had discordant tts ( 3 - 4 ) which is in contrast to other studies who had no case in the tts of 3 - 4 .
the only discordant case was benign cytologically , may be because of the sampling error of the sample , not from the representative area .
these results suggest that tts is a reliable tool for diagnosis of malignant lesions - idc and its variants as well as tumors like angiosarcoma and lymphoma .
comparison of tts in malignant lesions on histopathology table 4 indicates statistical analysis of tts as a diagnostic tool in various studies .
table 5 shows statistical analyses of fnac as a diagnostic test in various studies and indicates good sensitivity , specificity , ppv and npv .
statistical analyses of tts as a diagnostic tool in various studies statistical analyses of fnac as a diagnostic test in various studies although histological correlation has indicated fnac to be a good diagnostic tool , statistical analysis in the present study also indicates tts to be a better tool than fnac alone .
benign breast lesions are common than malignant lesions , fibroadenoma and fibrocystic disease are more common in benign disease , whereas idc accounts for the highest number of malignant lesions . | introduction : fine - needle aspiration cytology ( fnac ) method is safe , reliable and time saving outdoor procedure with little discomfort to the patient for detecting carcinoma breast .
the efficacy can further be enhanced when physical breast examination , mammography and fnac ( the triple test [ tt ] ) are jointly taken into consideration.aims and objectives : the aim was to evaluate the role of tt score ( tts ) in palpable breast masses.materials and methods : this prospective study was carried out from may 2010 to april 2012 . in the subjects referred to the department of pathology for fnac of the breast mass ,
the tts was calculated , and histopathological findings were noted.results:in the study period tts score was calculated in 200 cases out of 225 fnac 's of breast .
of 124 benign cases on cytology , only three showed discordant tts . out of 62 malignant cases ,
61 showed concordant tts and one case of mastitis on histopathology showed tts of five .
out of all the benign lesions , two cases of fibrocystic disease and a single case of phylloides tumor gave a tts 6 .
these cases were diagnosed as infiltrating ductal carcinoma and angiosarcoma respectively on histopathology .
histopathological correlation was possible in only 70 patients .
of these 70 , 28 were from the benign category and 42 were from the malignant category .
tts of 6 has a sensitivity of 97.44% , specificity of 100% .
fnac has a sensitivity of 88.37% , specificity of 96.42%.conclusions : tt reliably guides evaluation of palpable breast masses .
histological correlation indicated tts to be better diagnostic tool than fnac alone . | <s>[INST]despite breathtaking advances in science and technology , breast cancer still remains mankind 's one of the most dreaded maladies .
timely diagnosis and well planned , and executed treatment strategy are the cornerstones of successful management of this entity .
self - breast examination or a clinical breast examination alone may not be sufficient in identifying potentially malignant breast lesions .
on such occasions x - ray mammography or sonomammography can demonstrate such lesions , which can then be subjected to fine needle aspiration cytology ( fnac ) for pathological confirmation as fnac has stood the test of time as a safe , reliable and time saving outdoor procedure with little discomfort to the patient .
x - ray mammographic screening was introduced as a means to detect small , nonpalpable , asymptomatic breast carcinomas .
principal x - ray mammographic signs of breast carcinoma are densities and calcifications . in about 10% of cases ,
the principal causes of these failures are the presence of surrounding radio dense tissue that obscures the tumor , the absence of calcification , small size , diffuse infiltrative pattern with little or no desmoplastic response , or a location close to chest wall or in periphery of breast .
sonomammography distinguishes between solid and cystic lesions and can define more precisely the borders of solid lesions .
most palpable masses that are not imaged at all by mammography are detectable by ultrasound . while traditional diagnostic approach to palpable breast masses mostly involved direct fnac of the referred case without much attention to the clinical or mammography diagnosis , the possibility that the diagnostic efficacy could further be enhanced when physical breast examination , mammography and fnac ( the triple test [ tt ] ) are jointly taken into consideration as reported in other studies .
various studies have found nearly 100% diagnostic accuracy of the tt for palpable breast masses when all three elements ( i.e. , physical examination , mammogram and fnac ) are concordant .
a clinician can proceed directly with definitive therapy without an interventional open biopsy if all the components of tt are malignant . if all the components are found to be benign , the patient can then be safely observed . in september , 1996 ,
national cancer institute sponsored conference was held for the purpose of defining a uniform approach to breast fine needle aspiration ( fna ) biopsy , and to address some of the controversies related to breast fna , including the use of core biopsies .
tt , that is , the combination of physical examination , imaging findings , and cytological examination in the reliable diagnosis of breast cancer .
consequently , it was suggested that a recommendation be included in the cytopathology reports of breast fnas to support the clinical application of the tt . considering these facts the current study was carried out with an aim of evaluating the role of tt score ( tts ) in palpable breast masses by calculating the tts in fnac cases ; classifying in to benign , malignant and nonconcordant cases according to tts , correlation with histopathology and finding the effectiveness of tts in comparison to fnac alone .
the subjects concerned included all the female patients , which were referred to the department of pathology for fnac of the breast mass .
patients with hemorrhagic diathesis , breast mass associated with pregnancy , associated localized skin infection and patients on oral anticoagulants were excluded .
one smear was fixed with 95% alcohol for a period of 30 min before drying .
lesion was classified in to inadequate , benign , atypical , suspicious , and malignant .
it included three main diagnostic features of the procedure namely physical examination , mammography and fnac .
each component of tt was assigned 1 , 2 or 3 points for a benign , suspicious or malignant result respectively .
tts has a minimum score of 3 ( concordant benign ) and a maximum score of 9 ( concordant malignant ) .
all lesions with tts 4 are considered benign ; all lesions with tts 6 are considered malignant .
the statistical analyses were done to find the ability of tts and fnac to detect the presence of malignancy in the breast in comparison to histopathology . for this sensitivity ,
specificity , positive predictive value ( ppv ) , negative predictive value ( npv ) and accuracy / efficiency were calculated .
in the study period of the present study from may 2010 to april 2012 , 225 fnac 's of breasts were done .
of the 124 benign lesions on cytology , a tts score of 3 - 4 was seen in 117 cases , out of the total 62 cases labeled as malignant , 61 cases had a tts score of 6 .
triple test score in spectrum of lesions on cytology the table 2 correlates tts with histopathology . in the present study
though tt was applied to 200 odd cases , its impact could be evaluated in 70 out of 200 as histopathological correlation was possible in only 70 patients . out of these 70 , 28 were from the benign category and 42 were from the malignant category . in the present study , out of the 28 benign cases 24 cases had the tts of 3 - 4 and only four had a tts of 5 .
out of the 42 malignant cases , 38 cases had the tts of 6 , three had a tts of 5 and only one had a tts of 3 - 4 .
correlation of tts with histopathology the correlation of the benign histopathological lesions with the tts pointed that out of the 12 cases of fibroadenoma , 11 cases ( 91.66% ) had the tts of 3 - 4 and only 1 ( 8.33% ) had a tts of 5 .
all 9 cases of fibrocystic disease that had a tts showed it to be 3 - 4 .
single case of duct ectasia and atrophic breast tissue showed a tts of 5 each .
out of 5 cases of mastitis , four had tts of 3 - 4 and one case had tts of 5 .
the correlation of the malignant histopathological lesions with the tts as seen in present study shows that out of the 35 cases of infiltrating ductal carcinoma ( idc ) that had a tts , 31 cases ( 88.57% ) had the tts of 6 , 3 ( 8.57% ) had a tts of 5 and only 1 ( 2.85% ) had a tts of 3 - 4 .
both cases of lobular carcinoma , and single case of lymphoma , medullary carcinoma , angiosarcoma and mucinous carcinoma showed a tts of 6 each .
the statistical analyses showed that a tts was 100% sensitive and 97.43% specific in diagnosing benign lesions .
it had a ppv of 96% and a npv of 97.44% in diagnosing benign lesions .
furthermore , it had ppv of 100% and a npv of 96% in diagnosing malignant lesion . in the present study ,
the statistical analyses of fnac as a diagnostic test to detect the presence of malignancy in the breast was done .
also , fnac had ppv of 97.43% and a npv of 84.37% in diagnosing malignant lesion . in the present study
the tt , was initially described in the mid-1970s , by johansen c. as the evaluation of palpable breast masses by physical examination , mammography , and fnac .
the tt has proved a reliable tool for the accurate diagnosis of palpable breast masses , due to its technical simplicity , and resulted in substantially reduced expense and morbidity compared with open surgical biopsy . due to the reduced sensitivity and specificity of lesion detection by mammography in young women under 40 and
the usefulness of sonography in this group of patients , researchers dealing with women under 40 combined sonography with mammography to the scoring system and the modified tts was introduced which is an integration of clinical breast examination , sonography and fna .
confirmatory biopsy is required only for the lesions that receive a tts of 5 . in the present study ,
tts of 5 indicates suspicious lesions , and they are to be evaluated by biopsy .
all malignant cases on cytology showed tts of 6 , except one case where tts was 5 .
this indicates discordance and is possibly due to differences in appearance of different parts of the lesion on different modalities . as per present study , all cytological malignant cases showed tts 6 , except one case of idc , where tts was 5 .
histological correlation with tts showed that in the present study , out of 28 histological benign cases 24 ( 85.71% ) had concordant tts ( 3 - 4 ) which correlates with studies by ghafouri et al .
none of the benign cases in the present study showed discordant tts which correlates with studies by morris et al . and hermansen et al .
showed 2 ( 2.24% ) discordant cases with a tts of 6 . in the present study , 4 cases ( 14.28% ) had a tts of 5 , which correlates with ghafouri et al . 3 ( 3.37% ) ,
present study suggests that tts is a very good and reliable tool for diagnosis of fibrocystic disease .
fibroadenoma , mastitis and duct ectasia can give tts of 5 , if atypical cells are seen or clinical examination / mammography suggests suspicious lesions .
table 3 indicates various studies showing tts in malignant lesions on histopathology . in the present study ,
one histological malignant case had discordant tts ( 3 - 4 ) which is in contrast to other studies who had no case in the tts of 3 - 4 .
the only discordant case was benign cytologically , may be because of the sampling error of the sample , not from the representative area .
these results suggest that tts is a reliable tool for diagnosis of malignant lesions - idc and its variants as well as tumors like angiosarcoma and lymphoma .
comparison of tts in malignant lesions on histopathology table 4 indicates statistical analysis of tts as a diagnostic tool in various studies .
table 5 shows statistical analyses of fnac as a diagnostic test in various studies and indicates good sensitivity , specificity , ppv and npv .
statistical analyses of tts as a diagnostic tool in various studies statistical analyses of fnac as a diagnostic test in various studies although histological correlation has indicated fnac to be a good diagnostic tool , statistical analysis in the present study also indicates tts to be a better tool than fnac alone .
benign breast lesions are common than malignant lesions , fibroadenoma and fibrocystic disease are more common in benign disease , whereas idc accounts for the highest number of malignant lesions .[/INST]introduction : fine - needle aspiration cytology ( fnac ) method is safe , reliable and time saving outdoor procedure with little discomfort to the patient for detecting carcinoma breast .
the efficacy can further be enhanced when physical breast examination , mammography and fnac ( the triple test [ tt ] ) are jointly taken into consideration.aims and objectives : the aim was to evaluate the role of tt score ( tts ) in palpable breast masses.materials and methods : this prospective study was carried out from may 2010 to april 2012 . in the subjects referred to the department of pathology for fnac of the breast mass ,
the tts was calculated , and histopathological findings were noted.results:in the study period tts score was calculated in 200 cases out of 225 fnac 's of breast .
of 124 benign cases on cytology , only three showed discordant tts . out of 62 malignant cases ,
61 showed concordant tts and one case of mastitis on histopathology showed tts of five .
out of all the benign lesions , two cases of fibrocystic disease and a single case of phylloides tumor gave a tts 6 .
these cases were diagnosed as infiltrating ductal carcinoma and angiosarcoma respectively on histopathology .
histopathological correlation was possible in only 70 patients .
of these 70 , 28 were from the benign category and 42 were from the malignant category .
tts of 6 has a sensitivity of 97.44% , specificity of 100% .
fnac has a sensitivity of 88.37% , specificity of 96.42%.conclusions : tt reliably guides evaluation of palpable breast masses .
histological correlation indicated tts to be better diagnostic tool than fnac alone .</s> |
in the absence of curative treatment options , patients with crohn 's disease require continuous therapeutic management and monitoring by a physician .
therapeutic choices depend on location of inflammatory lesions , severity of disease , and complications .
treatment goals for crohn 's disease , like those for many other chronic diseases , include eradication of disease - related symptoms and restoration of the patient 's quality of life while minimizing complications or therapy - related toxicities .
success depends in part on patient adherence to the therapeutic regimen , which is influenced by many factors including the physician - patient relationship , disease awareness , effectiveness of the prescribed regimen , and adverse events associated with treatment .
patients often doubt the severity of their crohn 's disease and , therefore , empirical evidence of their disease and an objective measurement of disease severity can be a powerful tool to motivate adherence , especially after symptoms improve .
the case presented here was chosen to illustrate the importance of ongoing therapy to a positive outcome based on objective diagnostic findings and patient education .
a 21-year - old man was admitted to the emergency department of a hospital in december 2007 complaining of nausea / vomiting and periumbilical pain . computed tomography of the abdomen / pelvis revealed ileal thickening and a small bowel obstruction .
the patient was admitted to the hospital and treated with nasogastric suction , intravenous fluids , and antibiotics .
he subsequently improved and was discharged . soon after , the patient presented at our office with complaints of recurrent abdominal pain , new - onset diarrhea , and rectal bleeding .
a colonoscopy in april 2008 demonstrated ulcerations of the ileum and colon consistent with crohn 's disease ; the ileum was notably stenotic , and only the distal few centimeters could be visualized ( fig .
a small bowel follow - through study with barium contrast showed the stenoses and ulcerations extending over the distal 30 cm of the ileum and confirmed a diagnosis of crohn 's disease .
treatment with mesalamine 4 g / day and a 14-day course of metronidazole relieved the abdominal pain and bleeding , but the diarrhea persisted . over the next 2 weeks , the patient developed epigastric pain and nausea and was admitted to the hospital for severe pain .
a diagnosis of pancreatitis likely due to the mesalamine prompted discontinuation of the drug and initiation of budesonide 9 mg / day .
symptoms of pancreatitis subsequently improved , and the patient was discharged from the hospital after a short stay . over the next 3 weeks , the diarrhea , bleeding , and pain resolved .
however , by the end of august 2008 , the diarrhea and cramping periumbilical pain recurred , and an immunomodulator was added to the therapeutic regimen .
ten days later , the patient was admitted to the hospital with a high fever ( 103f ) associated with elevated liver enzymes and lymphopenia .
the immunomodulator was discontinued as it was presumed that the lymphopenia had made the patient susceptible to the infection . in november 2008 ,
at the follow - up appointment in the physician 's office , a lengthy discussion with the patient included the care of crohn 's disease and the risks and benefits of biologic therapy .
a decision was made to initiate induction therapy with the anti - tumor necrosis factor ( tnf ) agent adalimumab 160 mg s.c .
2 weeks later , followed by maintenance therapy at a dose of 40 mg s.c .
a follow - up colonoscopy demonstrated complete healing of the colonic mucosa and significant ileal healing as well ( fig .
he preferred to stop the medication because he was feeling well and because he was concerned about the potential for adverse effects .
a prometheus ibd serology 7 test was ordered to help assess the need for ongoing therapy based on serologic markers .
results revealed elevations of the following biomarkers for crohn 's disease : asca ( both iga and igg ) , anti - ompc iga , anti - cbir1 , and inflammatory bowel disease ( ibd)-specific panca ( table 1 ) . after additional discussion about the prognostic value of elevations of multiple markers and the high risk for disease progression , the patient agreed that continued anti -
several studies have examined nonadherence to treatment for ibd . in one such prospective study , cerveny et al . found that 38.9% of patients were intentionally nonadherent to their ibd regimen during the 2 weeks prior to being interviewed and that patients ' disease awareness and medication knowledge are important influences on adherence .
serologic testing such as with the prometheus ibd serology 7 panel has evolved over time from its initial use in helping differentiate ulcerative colitis from crohn 's disease to further evaluating indeterminate colitis , stratifying disease , predicting the potential course of ibd , determining more severe disease phenotypes , and guiding treatment based on the prognosis of the patient .
serologic testing can determine the level of immune reactivity to various markers of disease and , therefore , can be used to predict an increased risk of complicated disease requiring ongoing treatment .
the serologic results for our 21-year - old patient were communicated clearly to him , improving his disease awareness and ability to make informed decisions during treatment .
the results facilitated an extensive discussion that strengthened his knowledge of the medication and increased his appreciation of the importance of adherence .
were the first investigative group to associate increased levels of immune response with complications of crohn 's disease .
specifically , these investigators showed that specific serologic markers are present in patients with a more aggressive disease phenotype , in whom both the number and level of antibody responses were significantly associated with an increased likelihood of fibrostenosis , internal perforating disease , and the need for small bowel surgery .
. also found an association between immune responses to asca , anti - i2 , anti - ompc , and panca in patients with a more severe crohn 's disease phenotype that included small bowel disease , longer duration of disease , a higher risk for progression , and the need for intestinal surgery .
similar correlations between the number and level of immune response and more severe disease phenotype have been observed in the pediatric population as well .
the ibd serology 7 results obtained in this case served as a valuable tool for overall disease management and facilitated physician - patient communication on disease prognosis and a continued need for therapy .
| patients with crohn 's disease require long - term therapy and physician follow - up to treat symptoms , minimize complications of the disease , and address side effects that may occur due to therapeutic interventions
. once stabilized , it is not unusual for patients to question the need for continued therapy .
this may be related to various factors including poor disease awareness , lack of adequate communication between the physician and the patient , not wanting to take medications chronically , and/or financial issues among a host of other possibilities .
however , nonadherence can have a serious impact on morbidity and mortality in patients with crohn 's disease .
this case illustrates the management and stabilization of a patient with active crohn 's disease and the use of diagnostic serological testing to aid in disease risk assessment and treatment guidance . | <s>[INST]in the absence of curative treatment options , patients with crohn 's disease require continuous therapeutic management and monitoring by a physician .
therapeutic choices depend on location of inflammatory lesions , severity of disease , and complications .
treatment goals for crohn 's disease , like those for many other chronic diseases , include eradication of disease - related symptoms and restoration of the patient 's quality of life while minimizing complications or therapy - related toxicities .
success depends in part on patient adherence to the therapeutic regimen , which is influenced by many factors including the physician - patient relationship , disease awareness , effectiveness of the prescribed regimen , and adverse events associated with treatment .
patients often doubt the severity of their crohn 's disease and , therefore , empirical evidence of their disease and an objective measurement of disease severity can be a powerful tool to motivate adherence , especially after symptoms improve .
the case presented here was chosen to illustrate the importance of ongoing therapy to a positive outcome based on objective diagnostic findings and patient education .
a 21-year - old man was admitted to the emergency department of a hospital in december 2007 complaining of nausea / vomiting and periumbilical pain . computed tomography of the abdomen / pelvis revealed ileal thickening and a small bowel obstruction .
the patient was admitted to the hospital and treated with nasogastric suction , intravenous fluids , and antibiotics .
he subsequently improved and was discharged . soon after , the patient presented at our office with complaints of recurrent abdominal pain , new - onset diarrhea , and rectal bleeding .
a colonoscopy in april 2008 demonstrated ulcerations of the ileum and colon consistent with crohn 's disease ; the ileum was notably stenotic , and only the distal few centimeters could be visualized ( fig .
a small bowel follow - through study with barium contrast showed the stenoses and ulcerations extending over the distal 30 cm of the ileum and confirmed a diagnosis of crohn 's disease .
treatment with mesalamine 4 g / day and a 14-day course of metronidazole relieved the abdominal pain and bleeding , but the diarrhea persisted . over the next 2 weeks , the patient developed epigastric pain and nausea and was admitted to the hospital for severe pain .
a diagnosis of pancreatitis likely due to the mesalamine prompted discontinuation of the drug and initiation of budesonide 9 mg / day .
symptoms of pancreatitis subsequently improved , and the patient was discharged from the hospital after a short stay . over the next 3 weeks , the diarrhea , bleeding , and pain resolved .
however , by the end of august 2008 , the diarrhea and cramping periumbilical pain recurred , and an immunomodulator was added to the therapeutic regimen .
ten days later , the patient was admitted to the hospital with a high fever ( 103f ) associated with elevated liver enzymes and lymphopenia .
the immunomodulator was discontinued as it was presumed that the lymphopenia had made the patient susceptible to the infection . in november 2008 ,
at the follow - up appointment in the physician 's office , a lengthy discussion with the patient included the care of crohn 's disease and the risks and benefits of biologic therapy .
a decision was made to initiate induction therapy with the anti - tumor necrosis factor ( tnf ) agent adalimumab 160 mg s.c .
2 weeks later , followed by maintenance therapy at a dose of 40 mg s.c .
a follow - up colonoscopy demonstrated complete healing of the colonic mucosa and significant ileal healing as well ( fig .
he preferred to stop the medication because he was feeling well and because he was concerned about the potential for adverse effects .
a prometheus ibd serology 7 test was ordered to help assess the need for ongoing therapy based on serologic markers .
results revealed elevations of the following biomarkers for crohn 's disease : asca ( both iga and igg ) , anti - ompc iga , anti - cbir1 , and inflammatory bowel disease ( ibd)-specific panca ( table 1 ) . after additional discussion about the prognostic value of elevations of multiple markers and the high risk for disease progression , the patient agreed that continued anti -
several studies have examined nonadherence to treatment for ibd . in one such prospective study , cerveny et al . found that 38.9% of patients were intentionally nonadherent to their ibd regimen during the 2 weeks prior to being interviewed and that patients ' disease awareness and medication knowledge are important influences on adherence .
serologic testing such as with the prometheus ibd serology 7 panel has evolved over time from its initial use in helping differentiate ulcerative colitis from crohn 's disease to further evaluating indeterminate colitis , stratifying disease , predicting the potential course of ibd , determining more severe disease phenotypes , and guiding treatment based on the prognosis of the patient .
serologic testing can determine the level of immune reactivity to various markers of disease and , therefore , can be used to predict an increased risk of complicated disease requiring ongoing treatment .
the serologic results for our 21-year - old patient were communicated clearly to him , improving his disease awareness and ability to make informed decisions during treatment .
the results facilitated an extensive discussion that strengthened his knowledge of the medication and increased his appreciation of the importance of adherence .
were the first investigative group to associate increased levels of immune response with complications of crohn 's disease .
specifically , these investigators showed that specific serologic markers are present in patients with a more aggressive disease phenotype , in whom both the number and level of antibody responses were significantly associated with an increased likelihood of fibrostenosis , internal perforating disease , and the need for small bowel surgery .
. also found an association between immune responses to asca , anti - i2 , anti - ompc , and panca in patients with a more severe crohn 's disease phenotype that included small bowel disease , longer duration of disease , a higher risk for progression , and the need for intestinal surgery .
similar correlations between the number and level of immune response and more severe disease phenotype have been observed in the pediatric population as well .
the ibd serology 7 results obtained in this case served as a valuable tool for overall disease management and facilitated physician - patient communication on disease prognosis and a continued need for therapy .
[/INST]patients with crohn 's disease require long - term therapy and physician follow - up to treat symptoms , minimize complications of the disease , and address side effects that may occur due to therapeutic interventions
. once stabilized , it is not unusual for patients to question the need for continued therapy .
this may be related to various factors including poor disease awareness , lack of adequate communication between the physician and the patient , not wanting to take medications chronically , and/or financial issues among a host of other possibilities .
however , nonadherence can have a serious impact on morbidity and mortality in patients with crohn 's disease .
this case illustrates the management and stabilization of a patient with active crohn 's disease and the use of diagnostic serological testing to aid in disease risk assessment and treatment guidance .</s> |
SECTION 1. SHORT TITLE.
This Act may be cited as the ``Home Building Lending Improvement
Act of 2012''.
SEC. 2. PURPOSE.
It is the purpose of this Act to--
(1) immediately provide authority and guidance that Federal
and State bank regulators can use to ensure that Federal and
State chartered banks and thrifts that provide financing to
America's home builders are permitted to make loans, provide
ongoing liquidity, and ensure stable financing; and
(2) enable Federal and State chartered banks and thrifts to
provide initial and ongoing credit in a sound manner to
America's home builders to aid in restoring liquidity and
vitality to the housing market.
SEC. 3. COORDINATED RULEMAKING.
(a) Initiation of Proceedings.--Not later than 3 months after the
date of enactment of this Act, the appropriate Federal banking agencies
shall each initiate guidance or rulemaking with respect to financial
institutions under their respective jurisdictions that make real estate
loans to home builders. Such guidance or rulemaking shall provide for
the following:
(1) Adjustment of the 100 percent of bank capital
measurement.--
(A) Loan origination.--Notwithstanding any other
provision of law, the measurement of construction loans
that triggers additional scrutiny on real estate loans
in the lending portfolio of any qualified financial
institution shall be 125 percent of bank capital. The
Federal banking agencies shall not treat the 125
percent measurement as a hard cap beyond which loans
cannot be made, but shall consider other relevant
factors besides the concentration of such loans, such
as whether the financial institution has in place
effective risk management practices that are
appropriate for the level and nature of the risk of
such loans.
(B) Lending decisions.--The appropriate Federal
banking agency shall not prevent a qualified financial
institution from making a real estate loan to a home
builder in good standing that is secured by a viable
project, unless there is a legitimate supervisory or
accounting reason to do so.
(2) Prohibition on compelling lenders to call loans in good
standing.--
(A) Home builders in good standing.--The
appropriate Federal banking agency shall not compel a
financial institution to call a real estate loan of a
home builder that is in good standing.
(B) Workout activities.--
(i) In general.--In any case in which a
home builder is in good standing on a real
estate loan, but the collateral of the home
builder with respect to that loan has decreased
in value, based on a projected valuation of a
project as completed, the appropriate Federal
banking agency shall permit a financial
institution to engage in workout activities
with such home builder to improve the prospects
for repayment of principal and interest in a
manner that is consistent with safe and sound
banking principles and the need for credit for
home building.
(ii) Period of workout activities.--Workout
activities authorized under clause (i) may be
utilized during the 24-month period following
the date of issuance of final guidance or
regulations under subsection (c).
(iii) Effects.--No real estate loan may be
required to be charged off during the period
established in clause (ii) until the
appropriate Federal banking agency has
determined that--
(I) the financial institution
holding such loan has worked in good
faith to consider reasonable workout
activities and has adequately provided
for any impairment in such loan; or
(II) the financial institution has
not considered reasonable workout
activities in a timely manner.
(C) Reclassification of loans.--The appropriate
Federal banking agency shall not require a financial
institution to reclassify any real estate loan to a
homebuilder in good standing on the balance sheet of
such institution, unless there is a legitimate
supervisory or accounting reason to do so.
(3) No waiting period.--If the provisions of paragraph (2)
help to improve the CAMEL composite rating of a financial
institution under the Uniform Financial Institutions Rating
System from 3, 4, or 5 to 1 or 2 in the next occurring
examination of such institution that begins after the date on
which final guidance or regulations are issued pursuant to
subsection (c), such improved rating shall take effect
immediately after the date on which such rating was received.
(b) Coordination, Consistency, and Comparability.--Each Federal
banking agency shall consult and coordinate with the other Federal
banking agencies for the purpose of assuring, to the extent possible,
that the guidance or regulations by each such agency and such
authorities are consistent and comparable with those prescribed by the
other such agencies and authorities.
(c) Deadline.--Each Federal banking agency shall issue final
guidance or regulations to implement this Act not later than the
earlier of--
(1) 6 months after the date of enactment of this Act; or
(2) 3 months after such guidance or regulations are
proposed.
(d) Agency Authority.--The guidance and regulations issued under
this Act shall be enforced by the appropriate Federal banking agencies.
(e) Effect on State Law.--The guidance and regulations issued under
this Act shall not supersede the law of any State, except to the extent
that such law is inconsistent with such rule, and then only to the
extent of the inconsistency.
SEC. 4. DEFINITIONS.
In this Act, the following definitions shall apply:
(1) Appropriate federal banking agency; federal banking
agency.--The terms ``appropriate Federal banking agency'' and
``Federal banking agency'' have the same meanings as in section
3 of the Federal Deposit Insurance Act (12 U.S.C. 1813).
(2) Financial institution.--The term ``financial
institution'' means an entity regulated by, and under the
supervision of, any Federal banking agency.
(3) Good standing.--The term ``good standing'' means the
borrower has made all payments on a real estate loan and any
other extensions of credit to the borrower or any affiliated
entities in accordance with the agreements for such loans.
(4) Real estate loan.--The term ``real estate loan'' means
any indebtedness secured by a mortgage, deed of trust, or other
equivalent consensual security interest on real property, for--
(A) land acquisition for residential construction
projects;
(B) land development for residential construction
projects; or
(C) residential construction projects.
(5) Total capital.--The term ``total capital'' means the
total risk-based capital of a financial institution as reported
periodically by such institution in the Call Report or Thrift
Financial Reports of the Federal Financial Institutions
Examination Council, as applicable.
(6) Viable project.--The term ``viable project'' means a
real estate project that continues to have a reasonable
prospect of reaching completion and sale within a reasonable
timeframe, and at a market price that provides for the orderly
and timely repayment of the real estate loan.
(7) Workout activities.--The term ``workout activities''
means techniques to prevent default on a real estate loan,
including a renewal or extension of loan terms, extension of
additional credit, restructuring, loan write downs, or
flexibility on using reappraisal methods that still provide
credible value conclusions.
(8) Qualified financial institution defined.--For purposes
of this paragraph, the term ``qualified financial institution''
means a financial institution that received, in the most recent
examination of the institution, a CAMEL composite rating of 1
or 2 under the Uniform Financial Institutions Rating System. | Home Building Lending Improvement Act of 2012 - Directs each of the appropriate federal banking agencies to initiate guidance or rulemaking with respect to financial institutions under their respective jurisdictions that make real estate loans to home builders.
Requires such rulemaking to provide for: (1) adjustment from 100% to 125% of bank capital the measurement that triggers additional scrutiny on real estate loans in the lending portfolio of any qualified financial institution, (2) a prohibition against compelling lenders to call loans in good standing, and (3) improved composite ratings of a financial institution to take effect immediately.
Prohibits a federal banking agency also from preventing a qualified financial institution from making a real estate loan to a home builder in good standing that is secured by a viable project, unless there is a legitimate supervisory or accounting reason to do so.
Prohibits such banking agencies from requiring a financial institution to reclassify any real estate loan to a homebuilder in good standing on the balance sheet of such institution, unless there is a legitimate supervisory or accounting reason to do so.
Prohibits such agency guidance and regulations from superseding state law, except to the extent of state law inconsistency. | <s>[INST]SECTION 1. SHORT TITLE.
This Act may be cited as the ``Home Building Lending Improvement
Act of 2012''.
SEC. 2. PURPOSE.
It is the purpose of this Act to--
(1) immediately provide authority and guidance that Federal
and State bank regulators can use to ensure that Federal and
State chartered banks and thrifts that provide financing to
America's home builders are permitted to make loans, provide
ongoing liquidity, and ensure stable financing; and
(2) enable Federal and State chartered banks and thrifts to
provide initial and ongoing credit in a sound manner to
America's home builders to aid in restoring liquidity and
vitality to the housing market.
SEC. 3. COORDINATED RULEMAKING.
(a) Initiation of Proceedings.--Not later than 3 months after the
date of enactment of this Act, the appropriate Federal banking agencies
shall each initiate guidance or rulemaking with respect to financial
institutions under their respective jurisdictions that make real estate
loans to home builders. Such guidance or rulemaking shall provide for
the following:
(1) Adjustment of the 100 percent of bank capital
measurement.--
(A) Loan origination.--Notwithstanding any other
provision of law, the measurement of construction loans
that triggers additional scrutiny on real estate loans
in the lending portfolio of any qualified financial
institution shall be 125 percent of bank capital. The
Federal banking agencies shall not treat the 125
percent measurement as a hard cap beyond which loans
cannot be made, but shall consider other relevant
factors besides the concentration of such loans, such
as whether the financial institution has in place
effective risk management practices that are
appropriate for the level and nature of the risk of
such loans.
(B) Lending decisions.--The appropriate Federal
banking agency shall not prevent a qualified financial
institution from making a real estate loan to a home
builder in good standing that is secured by a viable
project, unless there is a legitimate supervisory or
accounting reason to do so.
(2) Prohibition on compelling lenders to call loans in good
standing.--
(A) Home builders in good standing.--The
appropriate Federal banking agency shall not compel a
financial institution to call a real estate loan of a
home builder that is in good standing.
(B) Workout activities.--
(i) In general.--In any case in which a
home builder is in good standing on a real
estate loan, but the collateral of the home
builder with respect to that loan has decreased
in value, based on a projected valuation of a
project as completed, the appropriate Federal
banking agency shall permit a financial
institution to engage in workout activities
with such home builder to improve the prospects
for repayment of principal and interest in a
manner that is consistent with safe and sound
banking principles and the need for credit for
home building.
(ii) Period of workout activities.--Workout
activities authorized under clause (i) may be
utilized during the 24-month period following
the date of issuance of final guidance or
regulations under subsection (c).
(iii) Effects.--No real estate loan may be
required to be charged off during the period
established in clause (ii) until the
appropriate Federal banking agency has
determined that--
(I) the financial institution
holding such loan has worked in good
faith to consider reasonable workout
activities and has adequately provided
for any impairment in such loan; or
(II) the financial institution has
not considered reasonable workout
activities in a timely manner.
(C) Reclassification of loans.--The appropriate
Federal banking agency shall not require a financial
institution to reclassify any real estate loan to a
homebuilder in good standing on the balance sheet of
such institution, unless there is a legitimate
supervisory or accounting reason to do so.
(3) No waiting period.--If the provisions of paragraph (2)
help to improve the CAMEL composite rating of a financial
institution under the Uniform Financial Institutions Rating
System from 3, 4, or 5 to 1 or 2 in the next occurring
examination of such institution that begins after the date on
which final guidance or regulations are issued pursuant to
subsection (c), such improved rating shall take effect
immediately after the date on which such rating was received.
(b) Coordination, Consistency, and Comparability.--Each Federal
banking agency shall consult and coordinate with the other Federal
banking agencies for the purpose of assuring, to the extent possible,
that the guidance or regulations by each such agency and such
authorities are consistent and comparable with those prescribed by the
other such agencies and authorities.
(c) Deadline.--Each Federal banking agency shall issue final
guidance or regulations to implement this Act not later than the
earlier of--
(1) 6 months after the date of enactment of this Act; or
(2) 3 months after such guidance or regulations are
proposed.
(d) Agency Authority.--The guidance and regulations issued under
this Act shall be enforced by the appropriate Federal banking agencies.
(e) Effect on State Law.--The guidance and regulations issued under
this Act shall not supersede the law of any State, except to the extent
that such law is inconsistent with such rule, and then only to the
extent of the inconsistency.
SEC. 4. DEFINITIONS.
In this Act, the following definitions shall apply:
(1) Appropriate federal banking agency; federal banking
agency.--The terms ``appropriate Federal banking agency'' and
``Federal banking agency'' have the same meanings as in section
3 of the Federal Deposit Insurance Act (12 U.S.C. 1813).
(2) Financial institution.--The term ``financial
institution'' means an entity regulated by, and under the
supervision of, any Federal banking agency.
(3) Good standing.--The term ``good standing'' means the
borrower has made all payments on a real estate loan and any
other extensions of credit to the borrower or any affiliated
entities in accordance with the agreements for such loans.
(4) Real estate loan.--The term ``real estate loan'' means
any indebtedness secured by a mortgage, deed of trust, or other
equivalent consensual security interest on real property, for--
(A) land acquisition for residential construction
projects;
(B) land development for residential construction
projects; or
(C) residential construction projects.
(5) Total capital.--The term ``total capital'' means the
total risk-based capital of a financial institution as reported
periodically by such institution in the Call Report or Thrift
Financial Reports of the Federal Financial Institutions
Examination Council, as applicable.
(6) Viable project.--The term ``viable project'' means a
real estate project that continues to have a reasonable
prospect of reaching completion and sale within a reasonable
timeframe, and at a market price that provides for the orderly
and timely repayment of the real estate loan.
(7) Workout activities.--The term ``workout activities''
means techniques to prevent default on a real estate loan,
including a renewal or extension of loan terms, extension of
additional credit, restructuring, loan write downs, or
flexibility on using reappraisal methods that still provide
credible value conclusions.
(8) Qualified financial institution defined.--For purposes
of this paragraph, the term ``qualified financial institution''
means a financial institution that received, in the most recent
examination of the institution, a CAMEL composite rating of 1
or 2 under the Uniform Financial Institutions Rating System.[/INST]Home Building Lending Improvement Act of 2012 - Directs each of the appropriate federal banking agencies to initiate guidance or rulemaking with respect to financial institutions under their respective jurisdictions that make real estate loans to home builders.
Requires such rulemaking to provide for: (1) adjustment from 100% to 125% of bank capital the measurement that triggers additional scrutiny on real estate loans in the lending portfolio of any qualified financial institution, (2) a prohibition against compelling lenders to call loans in good standing, and (3) improved composite ratings of a financial institution to take effect immediately.
Prohibits a federal banking agency also from preventing a qualified financial institution from making a real estate loan to a home builder in good standing that is secured by a viable project, unless there is a legitimate supervisory or accounting reason to do so.
Prohibits such banking agencies from requiring a financial institution to reclassify any real estate loan to a homebuilder in good standing on the balance sheet of such institution, unless there is a legitimate supervisory or accounting reason to do so.
Prohibits such agency guidance and regulations from superseding state law, except to the extent of state law inconsistency.</s> |
from the pioneering work by weinberg [ 1 ] on phenomenological lagrangians , a lot of work has been devoted to this field .
specially remarkable was the work by gasser and leutwyler [ 2 ] where this technique was applied , at the one - loop level , to the description of the low - energy behavior of the nambu - goldstone bosons ( pions ) corresponding to the spontaneous breaking of the chiral symmetry of hadron interactions , i.e. the so - called chiral perturbation theory ( @xmath3pt ) .
more recently , the phenomenological lagrangian approach has also been used in the context of the symmetry breaking sector of standard model and , in particular , it was applied to the scattering of the longitudinal components of the weak gauge bosons [ 3 ] . in spite of the great phenomenological success of @xmath3pt , some problems still must be solved .
typically @xmath3pt computations are done to the one - loop level .
this fact puts strong limitations to the region of applicability of @xmath3pt which is restricted to the very low - energy regime since , at higher energies , conflicts with unitarity appear [ 4 ] .
several methods have been proposed in the literature to improve the unitarity behavior of @xmath3pt like the introduction of new fields corresponding to resonances [ 5 ] , the pad approximants [ 4 ] , the inverse amplitude method [ 6 ] etc .
more recently it was suggested that it is possible to define a sensible large @xmath0 approach to @xmath3pt ( @xmath0 being the number of nambu - goldstone bosons ) which is consistent in principle at any energy . in particular ,
it was shown in [ 7 ] how this approach can be used to compute and renormalize the pion scattering amplitude and in [ 8 ] it was used to study the @xmath4 reaction .
more recently , some of the results of [ 7 ] were reobtained in [ 9 ] by using a different method . in this work we pursuit this issue further as follows
: first we show a functional computation of the effective action for pions in the model @xmath1 to the order of @xmath5 which is non - local . from this effective action
we obtain the elastic scattering amplitude for pions .
we use this result to make a one parameter fit of the experimental data corresponding to the @xmath2 channel .
then we obtain the mass functional for the skyrmion from the large @xmath0 effective action .
we arrive to the conclusion that the skyrmion is not stable in the many pion approximation considered here and we finish by discussing which could be the reasons for that and giving the main conclusions of our work .
to define the large @xmath0 limit of @xmath3pt we start from the two - flavor chiral symmetry group @xmath6 .
then we use the equivalence of the coset spaces @xmath7 to extend this symmetry pattern to @xmath8 so that @xmath0 can be understood as the number of nambu - goldstone bosons ( ngb ) or pions .
the fields describing these ngb can be chosen as arbitrary coordinates on the coset manifold @xmath9 .
the most general @xmath10 invariant lagrangian can be obtained as a derivative expansion which is covariant respect to both , the space - time and the @xmath9 coordinates .
the lowest order is the well known non - linear sigma model lagrangian given by : @xmath11 in our computations we will select the standard coordinates @xmath12 where @xmath13 being @xmath14 the squared sphere radius and @xmath15 .
the above lagrangian gives rise not only to the kinetic term but also to interacting terms with arbitrary even number of pions .
these two - derivative interactions produce some difficulties in the quantum theory which have been largely discussed in the literature [ 10 ] . from the path integral point of view
, the proper quantization prescription is obtained by defining the path integral measure as @xmath16 $ ] which is @xmath10 invariant provided @xmath17 is the @xmath9 metric determinant .
this factor gives an extra contribution to the non - linear sigma model lagrangian proportional to @xmath18 .
as it is well known , one can deal with this new term by using dimensional regularization [ 11 ] . in this case
one work in a @xmath19 dimensional space - time so that the regularized classical lagrangian still is @xmath10 invariant and , in addition , the measure term can be ignored as a consequence of the rule @xmath20 or equivalently @xmath21 . in the following
we will work always in this regularization scheme and hence we will neglect completely the measure term ( for a recent discussion about regularization methods in @xmath22pt see [ 12 ] ) . in order to derive the regularized large @xmath0 effective action from the above non - linear sigma model
we will extend a technique that has already been used in the case of the linear theory [ 13 ] .
first we introduce an auxiliary vector field @xmath23 ( in contrast with the @xmath24 case where an auxiliary scalar field has to be introduced ) .
then we consider the new modified lagrangian for the non - linear sigma model : @xmath25 as there is not any kinetic term for the @xmath26 field in this lagrangian and it is quadratic in this field , a simple gaussian integration makes possible to integrate out this auxiliary field in such a way that the original lagrangian is recovered so that , the pion green functions obtained from the lagrangians in eq.1 and eq.2 are the same . however , the new lagrangian symplifies the computation of the @xmath0 factors for any given feynman diagram .
this is a consequence of the fact that the lagrangian in eq.2 does not produce pion self - interactions but @xmath26 mediated pion interactions .
the @xmath26 propagator is just a constant of the order @xmath5 and we have a @xmath27 vertex of the order one , a @xmath28 vertex of the order @xmath5 , a @xmath29 vertex of the order @xmath30 etc .
therefore , the most general pion green function can be obtained by attaching the external pions in all possible ways to the @xmath26 legs of the most general @xmath26 green function ( see fig 1.a for an example ) .
the most general connected @xmath26 green function ( represented in fig.1 by a black blob ) will contain loops both of pions and @xmath26 s and in general can be written in terms of @xmath26 green functions containing only pions loops ( represented in fig.1 by a dashed blob ) attached to @xmath26 lines forming loops ( see fig.1b ) .
in addition , it is not difficult to realize that the dashed @xmath26 functions are as much of the order of @xmath0 ( see fig.1c ) .
therefore , taking into account that the @xmath26 propagators are of the order of @xmath5 we conclude that , to leading order in the @xmath5 expansion , black @xmath26 green functions are equal to the dashed @xmath26 green functions or , in other words , to leading order we do not have to consider diagrams with @xmath26 loops ( see fig.1d ) . thus in the large @xmath0 limit we just need to compute the generating functional for the 1pi @xmath26 green functions and then couple the pions to the external @xmath26 legs at the tree level
. moreover , we are interested only in the two point and the four point pion green functions which are of the order of @xmath31 and @xmath5 respectively .
this means that we need to consider only one point and two point @xmath26 functions . in this case
it is not difficult to see that the only vertex that must be considered is @xmath27 since the others necessarily produce pion loops with only one vertex .
however this kind of loop vanishes because our pions are massless and we are using dimensional regularization . in principle , there could be also a contribution of the order of @xmath5 to the two - pion function coming from the one leg @xmath26 diagram with one @xmath26 loop inside .
nevertheless , this diagram is proportional to the external @xmath26 momentum so that it does not contribute to the two - pion function .
thus , the @xmath26 1pi generating functional ( or @xmath26 effective action ) that we have to compute can be written as : @xmath32=i\int d^nx(-\frac{1}{2}nf^2b^2)+\log \int[d\pi]\exp{i\tilde s[\pi , b]}\ ] ] where : @xmath33= \int d^nx ( -\frac{1}{2}\pi_a\box \pi^a+b_{\mu}\pi_a \partial^{\mu}\pi^a)\ ] ] as the functional integral is quadratic in the pion field it can be computed exactly by the use of standard methods .
we introduce the operator : @xmath34 where @xmath35 is the solution of the equation of motion @xmath36 and therefore we can write : @xmath37=\int d^nx(-\frac{1}{2}nf^2b^2)+ \tilde s[\bar \pi , b]+\frac{i}{2}tr\log k\ ] ] as usual the trace of the @xmath38 operator is expanded as : @xmath39 as it was mentioned before , we only need to compute the first two terms of this sum corresponding to the one and two points @xmath26 functions respectively .
in addition , the one point function vanishes since it is proportional to a tadpole integral .
therefore , the only contribution to the @xmath26 effective action is : @xmath40 so that , by neglecting the no @xmath26-leg contribution and terms with more than two legs we find : @xmath41=-\frac{1}{2}\int d^nxd^nyb_{\mu}(x ) \gamma^{\mu\nu}(x , y)b_{\nu}(y)\ ] ] where : @xmath42 and as usual @xmath43 and @xmath44 is an arbitrary dimensional scale .
next we add to this action the coupling with the external pions @xmath45 : @xmath46=\int d^4x b_{\mu}\pi_a\partial^{\mu}\pi^a+\gamma_{eff}[b]\ ] ] now we use this action to obtain the @xmath26 field as a functional of the @xmath47 field through the corresponding equation of motion : @xmath48 the solution to this equation can be written as : @xmath49 the effective action for pions can be written as : @xmath50=\int d^4x(\frac{1}{2}\partial_{\mu}\pi_a\partial^{\mu}\pi^a + \pi_a\partial^{\mu}\pi^a\bar b_{\mu } -\frac{1}{2}\int d^4y\bar b_{\mu}(x)\gamma^{\mu\nu}(x , y)\bar b_{\nu}(y ) ) \ ] ] by computing the inverse of the @xmath51 operator appearing in eq.10 we finally obtain : @xmath52&=&\int d^4x \frac{1}{2}\partial_{\mu}\pi_a\partial^{\mu}\pi^a \\ \nonumber & + & \frac{1}{8nf^2}\int d^4x d^4y \pi^2(x)\pi^2(y ) \int % % following line can not be broken before 80 char \frac{d^4q}{(2\pi)^4}e^{-iq(x - y)}\frac{q^2}{1-\frac{q^2}{2(4\pi)^2f^2}(n_{\epsilon } + 2+\log\frac{\mu^2}{-q^2 } ) } \\
\nonumber & + & o(1/n^2)\end{aligned}\ ] ] here the denominator must be understood as the corresponding formal geometric series .
once the regularized effective action for pions has been obtained in the large @xmath0 limit we have to deal with the renormalization of this result .
as the kinetic term of this effective action is just the classical one , no renormalization of the pion wave function is needed i.e. @xmath53 . however , in the effective action we find four pion interaction terms which are divergent and proportional to arbitrary high even powers of the momenta .
this of course reveals the well known fact that the non - linear sigma model is not renormalizable in the standard sense .
nevertheless , we can absorb all the divergences by adding to the original lagrangian in eq.1 an infinite set of new counter terms that can be chosen for example as : @xmath54 apart from these , on could also in priciple to introduce many other terms .
however , here we will adopt the philosophy of introducing only a minimal set of terms just to absorb the divergences appearing in the non - linear sigma model to leading order in the @xmath5 expansion .
now , following similar steps as in [ 7 ] , it is straightforward to obtain the renormalized pion effective action : @xmath52 & = & \int d^4x \frac{1}{2 } \partial_{\mu}\pi_a\partial^{\mu}\pi^a \\
\nonumber & + & \frac{1}{8nf^2}\int d^4x d^4y \pi^2(x)\pi^2(y ) \int \frac{d^4q}{(2\pi)^4}e^{-iq(x - y)}\frac{q^2g^r(q^2;\mu)}{1-\frac{q^2 } { 2(4\pi)^2f^2}g^r(q^2;\mu ) \log\frac{\mu^2}{-q^2 } } \\
\nonumber & + & o(1/n^2)\end{aligned}\ ] ] where @xmath55 is the generating function for the renormalized coupling constants @xmath56 at the scale @xmath44 : @xmath57 where by definition @xmath58 for every @xmath44 .
since @xmath53 , the renormalization group equation followed by the pion effective action is : @xmath59=0\ ] ] where @xmath60 . from this equation
we can obtain very easily the renormalization group equation for @xmath55 which can be integrated to give the evolution equation : @xmath61 by using this equation and eq.18 it is very easy to get the evolution equations for all the renormalized coupling constants @xmath56 . again because @xmath53 and the fact that pions continue being massless we can read very easily the elastic pion scattering amplitude from eq.17 recovering the result of [ 7 ] ( one missing factor @xmath62 in this reference has been corrected here ) : @xmath63 where : @xmath64 note that at low energies this @xmath65 function behaves as @xmath66 and this fact is important for two reasons .
first , we realize that it is compatible with the low energy theorems which state that it must go in this limit as @xmath67 ( in the chiral limit that we are considering here ) .
second we can use this low - energy theorems to set the constant @xmath68 in terms of the pion decay constant @xmath69 as @xmath70 with @xmath71 .
in addition to this scattering amplitude , there is another important object that can be obtained from the effective action in eq.17 . for static pion field configurations @xmath72
the energy density is given by minus the effective lagrangian i.e. @xmath73 which can be read off from eq.17 .
therefore , the mass functional or , equivalently , the total energy of the configuration can be written as : @xmath74=\int d\vec x(\frac{1}{2}\partial_i \pi_a \partial^i \pi^a + \frac{1}{8nf^2}\pi^2[\frac{-g^r(\nabla ; \mu)\nabla } { 1-\frac{1}{2(4\pi)^2f^2}g^r(\nabla;\mu ) \log(\frac{\mu^2}{-\nabla})\nabla}](\pi^2)\end{aligned}\ ] ] where the meaning of this non - local mass functional is given by the appropriate fourier transform . in order to use eq.22 or eq.23 to do phenomenology
we need to define the generating function @xmath55 or , in other words , the infinite number of renormalized couplings constants @xmath56 .
a typical example is the linear sigma model . in this case
, the appropriate choice is : @xmath75 where @xmath76 is the renormalized coupling constant of the linear sigma model computed in the large @xmath0 limit [ 14 ] . with this definition , eq.22 and
eq.20 provide the corresponding well known scattering amplitude and evolution equation for @xmath77 .
in addition , the amplitude in eq.22 has a pole in the second riemann sheet that has to be understood as the physical scalar resonance appearing in the linear sigma model i.e. the higgs resonance .
( see [ 14 ] and [ 15 ] for a discussion on this point ) .
however , the @xmath10 linear sigma model is not the theory that reproduces the hadron interactions at low energies . in principle
, there are two possible approaches for the determination of the renormalized coupling constants appearing in the pion effective action of eq.17 . from the theoretical point of view one could try to compute these parameters from a more fundamental theory of strong interactions like qcd . from the phenomenological point of view
, one can try to fit these constants from the experiment , for example the low - energy pion scattering data .
as the theoretical computation seems to be quite involved , it is worth to make the phenomenological determination of the couplings first in order to test the quality of the whole @xmath0 approach to this case .
using eq.22 to fit the experimental pion scattering data requires to face the fact of having an infinite number of parameters i.e. the scale @xmath44 and the values of the renormalized coupling constants @xmath56 at the scale @xmath44 .
however one can solve this problem in a easy way just by considering only particular cases where all the coupling constants but a finite set @xmath78 , @xmath79 vanish at some scale @xmath44 .
these models are defined just by a finite number of parameters ( @xmath44 and the @xmath80 coupling constants renormalized at this scale ) and therefore can be used to fit the experimental data . in particular
, one can consider the extremal case of having all the renormalized couplings equal to zero at some scale @xmath44 i.e. @xmath81 for all @xmath82 .
the model so obtained has only one parameter ( the @xmath44 scale ) and it can be considered in some sense as the non - linear sigma model renormalized at the leading order of the @xmath5 expansion . of course
, it could happen that the underlying theory ( say qcd ) were not of this type .
however this would not be a serious problem at very low energies because , for natural values of the renormalized coupling constants and the renormalization scale @xmath44 , only the very first terms of the generating function @xmath55 series in eq.18 contribute to the effective action and the scattering amplitude .
however , at higher energies the effect of the infinite set of couplings constants , when different from zero , could be important .
for example , they can conspire to give rise to resonances which appear as poles in the second riemann sheet of the partial waves amplitudes as it happens in the linear sigma model .
of course , in this case the value of the couplings can also be obtained from the underlying theory or by making extra assumptions on the behavior of the amplitudes . for comparison with the experiment
we need also to compute the phase shifts for the different channels .
these are obtained from the corresponding partial waves amplitudes .
the proper generalization of the standard @xmath83 isospin projections to the @xmath84 case is given by [ 9 ] : @xmath85 and the partial waves are given by : @xmath86 then , the @xmath87 amplitude is of the order of one but , for instance , the @xmath88 and the @xmath89 amplitudes are of the order of @xmath5 . thus at the leading order of the large @xmath0 expansion @xmath90 , @xmath91 and @xmath92 ( remind that @xmath65 is of the order of @xmath5 ) .
now it is easy to show that in this approximation the partial waves have the proper cut structure and also are elastic unitary i.e. @xmath93 just above the unitarity cut as they must be . in fig.2
we show the result of our fit of the @xmath94 phase shift channel for elastic pion scattering .
this fit has been done with only one parameter , or in other words , by using the very particular model where all the renormalized coupling constants are zero at some scale @xmath44 . as discussed above ,
the only parameter in this specially simple case is the scale @xmath44 .
the fit in fig.2 corresponds to a value of @xmath95 . for other channels like @xmath96 or @xmath97 the prediction of the leading order of the large @xmath0 expansion
is that there is no interaction .
this could appear as a rather poor prediction but it is not the case . by looking at the experimental data one can realize that the phase shifts in these channels grow very slowly with energy , for instance , at @xmath98 of center of mass energy we have @xmath99 degrees and @xmath100 degrees whilst @xmath101 degrees at the same energy .
the conclusion is that for energies below , let say , @xmath98 our simple one parameter fit gives rise to errors in the phase shifts which are lesser than @xmath102 per cent ( refered to the @xmath2 channel ) for the three channels considered . of course , for larger energies things become completely different particularly in the @xmath96 channel where the onset of the @xmath103 resonance makes this channel to be strongly interacting .
one is then tempted to make an interpretation of the scale @xmath44 as some kind of cutoff signaling the range of applicability of our approach and , in fact , this interpretation was discussed in [ 7 ] . from this point of view , it is quite interesting to realize how close is the @xmath44 fitted value @xmath104 to the @xmath103 mass . in some way , by fitting the @xmath2 channel , the model is telling us where new things can appear in other channels like the @xmath96 ( the @xmath103 resonance ) and thus setting the limits of applicability of the model .
however , we would like to stress that our renormalization method is completely consistent and our results are formally valid at any energy independently of the goodness of the fits we can obtain with them .
as it was mentioned above , the second phenomenological application of the large @xmath0 expansion that will be considered here is the description of the nucleon in the context of the so - called skyrmion model . as it is well known , the skyrmion [ 21 ] is a topological soliton of the @xmath105 chiral model
. finite energy and static pion field configurations are continous maps from the compactified space @xmath106 to the coset space @xmath106 .
these applications can be classified in homotopically non - equivalent classes since @xmath107 . therefore every map can be labeled by an integer number . in the skyrmion model of the nucleon
this topological number is interpreted as the baryonic number of the field .
the skyrmion model has proved to give a qualitative description of many of the nucleon properties [ 22 ] including ( in an highly non - trivial way ) the spin [ 23 ] .
the standard ansatz for the skyrmion field is @xmath108 with @xmath109 and @xmath110 being the right boundary conditions for the chiral angle @xmath111 in order to have baryonic number equal to one . in this description of the skyrmion
the chiral field is taken to be an element of @xmath83 which is equivalent to our coset space @xmath106 . in terms of the coordinates used here ,
the skyrmion ansatz is given by @xmath112 . in order to obtain the mass of the skyrmion in the approximation considered in this work we have to introduce this anzatz in the mass functional in eq.22 with the renormalized coupling constants obtained from the fit of the elastic pion scattering described in the previous section .
then , it is not very difficult to find : @xmath113&=&nf^22\pi\int_0^{\infty}dr r^2 ( 2 \frac{\sin^2f(r ) } { r^2}+\cos^2 f(r ) f'(r)^2 ) \\ \nonumber & + & nf^2\int_0^{\infty}dr r \sin ^2f(r)\int_0^{\infty}dr ' r ' \sin ^2f(r ' ) \int_0^{\infty}dk\sin(kr)\sin(kr ' ) \\ \nonumber & & \frac{k^2g^r(-k^2;\mu)}{1+\frac{k^2}{2(4\pi)^2f^2 } g^r(-k^2;\mu)\log\frac{\mu^2}{k^2}}\end{aligned}\ ] ] now the mass functional depends only on the chiral angle @xmath111 . by minimizing this functional
we can find in principle the mass and the shape of the skyrmion in this large @xmath0 approximation . in order to make this task easier we can use some reasonable parametrization of the chiral angle such as the one by atiyah and manton [ 24 ] : @xmath114 where the parameter @xmath115 is a measure of the size of the skyrmion . in fig.3
we show the results obtained when this parametrization is inserted in eq.26 with the @xmath116 obtained in the previous section i. e. we follow the philosophy of [ 25 ] where the authors use the skyrmion model to predict the mass of the proton from the pion scattering data .
the first and obvious conclusion from fig.3 is that , at least for this parametrization , the mass functional has not any minimum but the trivial one at @xmath117 so that the skyrmion tends to shrink to zero size in this approximation .
in fact we have checked that this is also the case when other parametrizations of the chiral angle are used . therefore , everything seems to indicate that in the large @xmath0 limit considered here , the skyrmion is not stable i.e. we are in a similar situation to the one found when one works with the two derivatives term in eq.1 .
this is a bit disappointing since one of the most appealing properties of the large @xmath0 approximation is that it includes the effect of higher derivative terms and the corresponding higher loops contributions .
this fact improves the unitarity behavior of the amplitudes and one could think that it could also improve the skyrmion description .
however , this is not the case , at least in the leading order considered here .
a simple way to understand why this is not so is the following . in the standard approach to the skyrmion one typically adds to the two derivatives term in the lagrangian one four derivative term called the skyrme term .
this term produce an stable skyrmion in such a way that the contribution to the total energy of the skyrmion coming from the two terms is exactly the same .
it is also possible to add another four derivative term called the non - skyrme term but its contribution can turn the skyrmion unstable .
one - loop effects can also be included in the mass functional [ 26 ] .
one possible interpretation of the origin of the skyrmion and the non - skyrmion terms is to understand them as the low energy remnant of the tail of one vector @xmath118 and one scalar @xmath119 resonance respectively .
in fact it is not difficult to relate the skyrme and the non - skyrme parameters with the masses of the corresponding resonances ( see for instance [ 4 ] ) .
then , the consequence of this picture is that the existence of one vector resonance like the @xmath103 produces an stable skyrmion ( and in fact it is possible to relate the @xmath103 and the nucleon masses ) but one scalar resonance do not produce an stable skyrmion by itself and even it can make unstable the skyrmion when the vector resonance is also present .
if this simple picture were correct ( as it seems to be ) the @xmath103 resonance would be the responsible of the stability of the nucleon in the skyrmion model ( or at least of the pion cloud )
. then it would be possible to understand why the skyrmion is not stable in the large @xmath0 limit approximation considered in this paper .
as we saw in the previous section this approach can describe well the elastic pion scattering in the @xmath2 channel but it does not reproduce the @xmath103 resonance ( yet in some way it predicts its existence ) and therefore it does not contain the piece that seems to keep the skyrmion stable in other much more simple approach that do not include higher derivatives neither higher loops effects .
we have computed the effective action of the @xmath1 non - linear sigma model to leading order on the @xmath5 expansion .
this action is divergent but it can be properly renormalized by introducing an infinite set of counter terms in a systematically way . the energy dependence of the corresponding renomalized couplings can be obtained thus providing a very nice example of how @xmath120 can work beyond the one - loop approximation . with an appropriate choice of these renormalized couplings we can reproduce particular models with the same symmetry breaking pattern as , for example , the linear sigma model .
we can consider also models with a finite number of couplings which can be used to fit the elastic pion scattering experimental data since the partial waves amplitudes have a very good unitarity behavior .
then , with only one parameter it is possible to reproduce well the phase shifts for energies below @xmath98 .
this parameter can be also interpreted as some kind of cutoff setting the limits of the model and , in fact , the fitted value is basically the @xmath103 mass which in principle can not be reproduced since , at leading order in the @xmath5 expansion , the @xmath96 channel is not interacting .
we have also studied the mass functional of the skyrmion solutions and we arrived to the conclusion that the skyrmion solution is not stable at the leading order in the @xmath5 expansion .
this fact is probably related with the above mentioned absence of interaction in the @xmath96 since in other approaches the @xmath103 resonance stabilizes the skyrmion . in any case
, we consider the @xmath5 expansion of @xmath120 as a very interesting alternative complementary to the standard one - loop computations .
of course , much more work is needed like including pion mass effects , going to the next to leading order in @xmath5 , considering other ways to take the limit like the one based in the @xmath121 non - linear sigma model and finally ( and this was our original motivation ) the applications to the description of the symmetry breaking sector of the standard model as a way to parametrize the future large hadron collider ( lhc ) data .
work is in progress in all these directions .
this work has been supported in part by the ministerio de educacin y ciencia ( spain ) ( cicyt aen90 - 0034 ) and colciencias ( colombia ) .
a. d. thanks also the gregorio del amo foundation for support and s. dimopoulos and the department of physics of stanford university for their kind hospitality .
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unpublished ; p. estabrooks and a.d.martin , _ nucl.phys._*b79 * ( 1974)301 * figure 1:*a ) a typical eight pion legs feynman diagram where the three @xmath26 legs function appears ( pion lines are narrow and @xmath26 lines are broader ) b ) the complete connected three @xmath26 legs function ( black blob ) in terms of the @xmath26 functions containing only pion loops ( dashed blobs ) c ) some diagrams contributing to the @xmath26 functions containing only pion loops d ) relation between the complete @xmath26 functions and the @xmath26 functions containing only pion loops at the leading order in the @xmath5 expansion . * figure 2 : * phase shifts of the elastic pion scattering for the @xmath2 channel .
the continuous line represents the one parameter fit described in the text .
the experimental data corresponds to : @xmath122 ref.[16 ] , @xmath123 ref.[17],@xmath124 ref.[18],@xmath125 ref.[19 ] , @xmath126 ref.[20 ] .
* figure 3 : * mass of the skyrmion in the large @xmath0 limit for the atiyah and manton parametrization in terms of the @xmath115 parameter .
dotted line is the contribution of the kinetic term , dashed line is the interaction energy and the full line is the total mass of the skyrmion . | the large @xmath0 effective action of the non - linear sigma model based in the coset @xmath1 is obtained .
the renormalization of this effective action requires the introduction of an infinite set of counter terms .
however , there exist particular cases where , at some scale , only a finite number of non - zero coupling constants are present .
this fact make possible a one parameter fit of the @xmath2 low - energy pion scattering .
the corresponding non - local effective action is used to study the properties of the skyrmion which is shown to be unstable in this approximation .
ft / ucm/14/93 , su - itp-93 - 32 + on leave of absence from departamento de fsica terica , universidad complutense de madrid , 28040 madrid , spain 0.83 true cm 20 true cm | <s>[INST]from the pioneering work by weinberg [ 1 ] on phenomenological lagrangians , a lot of work has been devoted to this field .
specially remarkable was the work by gasser and leutwyler [ 2 ] where this technique was applied , at the one - loop level , to the description of the low - energy behavior of the nambu - goldstone bosons ( pions ) corresponding to the spontaneous breaking of the chiral symmetry of hadron interactions , i.e. the so - called chiral perturbation theory ( @xmath3pt ) .
more recently , the phenomenological lagrangian approach has also been used in the context of the symmetry breaking sector of standard model and , in particular , it was applied to the scattering of the longitudinal components of the weak gauge bosons [ 3 ] . in spite of the great phenomenological success of @xmath3pt , some problems still must be solved .
typically @xmath3pt computations are done to the one - loop level .
this fact puts strong limitations to the region of applicability of @xmath3pt which is restricted to the very low - energy regime since , at higher energies , conflicts with unitarity appear [ 4 ] .
several methods have been proposed in the literature to improve the unitarity behavior of @xmath3pt like the introduction of new fields corresponding to resonances [ 5 ] , the pad approximants [ 4 ] , the inverse amplitude method [ 6 ] etc .
more recently it was suggested that it is possible to define a sensible large @xmath0 approach to @xmath3pt ( @xmath0 being the number of nambu - goldstone bosons ) which is consistent in principle at any energy . in particular ,
it was shown in [ 7 ] how this approach can be used to compute and renormalize the pion scattering amplitude and in [ 8 ] it was used to study the @xmath4 reaction .
more recently , some of the results of [ 7 ] were reobtained in [ 9 ] by using a different method . in this work we pursuit this issue further as follows
: first we show a functional computation of the effective action for pions in the model @xmath1 to the order of @xmath5 which is non - local . from this effective action
we obtain the elastic scattering amplitude for pions .
we use this result to make a one parameter fit of the experimental data corresponding to the @xmath2 channel .
then we obtain the mass functional for the skyrmion from the large @xmath0 effective action .
we arrive to the conclusion that the skyrmion is not stable in the many pion approximation considered here and we finish by discussing which could be the reasons for that and giving the main conclusions of our work .
to define the large @xmath0 limit of @xmath3pt we start from the two - flavor chiral symmetry group @xmath6 .
then we use the equivalence of the coset spaces @xmath7 to extend this symmetry pattern to @xmath8 so that @xmath0 can be understood as the number of nambu - goldstone bosons ( ngb ) or pions .
the fields describing these ngb can be chosen as arbitrary coordinates on the coset manifold @xmath9 .
the most general @xmath10 invariant lagrangian can be obtained as a derivative expansion which is covariant respect to both , the space - time and the @xmath9 coordinates .
the lowest order is the well known non - linear sigma model lagrangian given by : @xmath11 in our computations we will select the standard coordinates @xmath12 where @xmath13 being @xmath14 the squared sphere radius and @xmath15 .
the above lagrangian gives rise not only to the kinetic term but also to interacting terms with arbitrary even number of pions .
these two - derivative interactions produce some difficulties in the quantum theory which have been largely discussed in the literature [ 10 ] . from the path integral point of view
, the proper quantization prescription is obtained by defining the path integral measure as @xmath16 $ ] which is @xmath10 invariant provided @xmath17 is the @xmath9 metric determinant .
this factor gives an extra contribution to the non - linear sigma model lagrangian proportional to @xmath18 .
as it is well known , one can deal with this new term by using dimensional regularization [ 11 ] . in this case
one work in a @xmath19 dimensional space - time so that the regularized classical lagrangian still is @xmath10 invariant and , in addition , the measure term can be ignored as a consequence of the rule @xmath20 or equivalently @xmath21 . in the following
we will work always in this regularization scheme and hence we will neglect completely the measure term ( for a recent discussion about regularization methods in @xmath22pt see [ 12 ] ) . in order to derive the regularized large @xmath0 effective action from the above non - linear sigma model
we will extend a technique that has already been used in the case of the linear theory [ 13 ] .
first we introduce an auxiliary vector field @xmath23 ( in contrast with the @xmath24 case where an auxiliary scalar field has to be introduced ) .
then we consider the new modified lagrangian for the non - linear sigma model : @xmath25 as there is not any kinetic term for the @xmath26 field in this lagrangian and it is quadratic in this field , a simple gaussian integration makes possible to integrate out this auxiliary field in such a way that the original lagrangian is recovered so that , the pion green functions obtained from the lagrangians in eq.1 and eq.2 are the same . however , the new lagrangian symplifies the computation of the @xmath0 factors for any given feynman diagram .
this is a consequence of the fact that the lagrangian in eq.2 does not produce pion self - interactions but @xmath26 mediated pion interactions .
the @xmath26 propagator is just a constant of the order @xmath5 and we have a @xmath27 vertex of the order one , a @xmath28 vertex of the order @xmath5 , a @xmath29 vertex of the order @xmath30 etc .
therefore , the most general pion green function can be obtained by attaching the external pions in all possible ways to the @xmath26 legs of the most general @xmath26 green function ( see fig 1.a for an example ) .
the most general connected @xmath26 green function ( represented in fig.1 by a black blob ) will contain loops both of pions and @xmath26 s and in general can be written in terms of @xmath26 green functions containing only pions loops ( represented in fig.1 by a dashed blob ) attached to @xmath26 lines forming loops ( see fig.1b ) .
in addition , it is not difficult to realize that the dashed @xmath26 functions are as much of the order of @xmath0 ( see fig.1c ) .
therefore , taking into account that the @xmath26 propagators are of the order of @xmath5 we conclude that , to leading order in the @xmath5 expansion , black @xmath26 green functions are equal to the dashed @xmath26 green functions or , in other words , to leading order we do not have to consider diagrams with @xmath26 loops ( see fig.1d ) . thus in the large @xmath0 limit we just need to compute the generating functional for the 1pi @xmath26 green functions and then couple the pions to the external @xmath26 legs at the tree level
. moreover , we are interested only in the two point and the four point pion green functions which are of the order of @xmath31 and @xmath5 respectively .
this means that we need to consider only one point and two point @xmath26 functions . in this case
it is not difficult to see that the only vertex that must be considered is @xmath27 since the others necessarily produce pion loops with only one vertex .
however this kind of loop vanishes because our pions are massless and we are using dimensional regularization . in principle , there could be also a contribution of the order of @xmath5 to the two - pion function coming from the one leg @xmath26 diagram with one @xmath26 loop inside .
nevertheless , this diagram is proportional to the external @xmath26 momentum so that it does not contribute to the two - pion function .
thus , the @xmath26 1pi generating functional ( or @xmath26 effective action ) that we have to compute can be written as : @xmath32=i\int d^nx(-\frac{1}{2}nf^2b^2)+\log \int[d\pi]\exp{i\tilde s[\pi , b]}\ ] ] where : @xmath33= \int d^nx ( -\frac{1}{2}\pi_a\box \pi^a+b_{\mu}\pi_a \partial^{\mu}\pi^a)\ ] ] as the functional integral is quadratic in the pion field it can be computed exactly by the use of standard methods .
we introduce the operator : @xmath34 where @xmath35 is the solution of the equation of motion @xmath36 and therefore we can write : @xmath37=\int d^nx(-\frac{1}{2}nf^2b^2)+ \tilde s[\bar \pi , b]+\frac{i}{2}tr\log k\ ] ] as usual the trace of the @xmath38 operator is expanded as : @xmath39 as it was mentioned before , we only need to compute the first two terms of this sum corresponding to the one and two points @xmath26 functions respectively .
in addition , the one point function vanishes since it is proportional to a tadpole integral .
therefore , the only contribution to the @xmath26 effective action is : @xmath40 so that , by neglecting the no @xmath26-leg contribution and terms with more than two legs we find : @xmath41=-\frac{1}{2}\int d^nxd^nyb_{\mu}(x ) \gamma^{\mu\nu}(x , y)b_{\nu}(y)\ ] ] where : @xmath42 and as usual @xmath43 and @xmath44 is an arbitrary dimensional scale .
next we add to this action the coupling with the external pions @xmath45 : @xmath46=\int d^4x b_{\mu}\pi_a\partial^{\mu}\pi^a+\gamma_{eff}[b]\ ] ] now we use this action to obtain the @xmath26 field as a functional of the @xmath47 field through the corresponding equation of motion : @xmath48 the solution to this equation can be written as : @xmath49 the effective action for pions can be written as : @xmath50=\int d^4x(\frac{1}{2}\partial_{\mu}\pi_a\partial^{\mu}\pi^a + \pi_a\partial^{\mu}\pi^a\bar b_{\mu } -\frac{1}{2}\int d^4y\bar b_{\mu}(x)\gamma^{\mu\nu}(x , y)\bar b_{\nu}(y ) ) \ ] ] by computing the inverse of the @xmath51 operator appearing in eq.10 we finally obtain : @xmath52&=&\int d^4x \frac{1}{2}\partial_{\mu}\pi_a\partial^{\mu}\pi^a \\ \nonumber & + & \frac{1}{8nf^2}\int d^4x d^4y \pi^2(x)\pi^2(y ) \int % % following line can not be broken before 80 char \frac{d^4q}{(2\pi)^4}e^{-iq(x - y)}\frac{q^2}{1-\frac{q^2}{2(4\pi)^2f^2}(n_{\epsilon } + 2+\log\frac{\mu^2}{-q^2 } ) } \\
\nonumber & + & o(1/n^2)\end{aligned}\ ] ] here the denominator must be understood as the corresponding formal geometric series .
once the regularized effective action for pions has been obtained in the large @xmath0 limit we have to deal with the renormalization of this result .
as the kinetic term of this effective action is just the classical one , no renormalization of the pion wave function is needed i.e. @xmath53 . however , in the effective action we find four pion interaction terms which are divergent and proportional to arbitrary high even powers of the momenta .
this of course reveals the well known fact that the non - linear sigma model is not renormalizable in the standard sense .
nevertheless , we can absorb all the divergences by adding to the original lagrangian in eq.1 an infinite set of new counter terms that can be chosen for example as : @xmath54 apart from these , on could also in priciple to introduce many other terms .
however , here we will adopt the philosophy of introducing only a minimal set of terms just to absorb the divergences appearing in the non - linear sigma model to leading order in the @xmath5 expansion .
now , following similar steps as in [ 7 ] , it is straightforward to obtain the renormalized pion effective action : @xmath52 & = & \int d^4x \frac{1}{2 } \partial_{\mu}\pi_a\partial^{\mu}\pi^a \\
\nonumber & + & \frac{1}{8nf^2}\int d^4x d^4y \pi^2(x)\pi^2(y ) \int \frac{d^4q}{(2\pi)^4}e^{-iq(x - y)}\frac{q^2g^r(q^2;\mu)}{1-\frac{q^2 } { 2(4\pi)^2f^2}g^r(q^2;\mu ) \log\frac{\mu^2}{-q^2 } } \\
\nonumber & + & o(1/n^2)\end{aligned}\ ] ] where @xmath55 is the generating function for the renormalized coupling constants @xmath56 at the scale @xmath44 : @xmath57 where by definition @xmath58 for every @xmath44 .
since @xmath53 , the renormalization group equation followed by the pion effective action is : @xmath59=0\ ] ] where @xmath60 . from this equation
we can obtain very easily the renormalization group equation for @xmath55 which can be integrated to give the evolution equation : @xmath61 by using this equation and eq.18 it is very easy to get the evolution equations for all the renormalized coupling constants @xmath56 . again because @xmath53 and the fact that pions continue being massless we can read very easily the elastic pion scattering amplitude from eq.17 recovering the result of [ 7 ] ( one missing factor @xmath62 in this reference has been corrected here ) : @xmath63 where : @xmath64 note that at low energies this @xmath65 function behaves as @xmath66 and this fact is important for two reasons .
first , we realize that it is compatible with the low energy theorems which state that it must go in this limit as @xmath67 ( in the chiral limit that we are considering here ) .
second we can use this low - energy theorems to set the constant @xmath68 in terms of the pion decay constant @xmath69 as @xmath70 with @xmath71 .
in addition to this scattering amplitude , there is another important object that can be obtained from the effective action in eq.17 . for static pion field configurations @xmath72
the energy density is given by minus the effective lagrangian i.e. @xmath73 which can be read off from eq.17 .
therefore , the mass functional or , equivalently , the total energy of the configuration can be written as : @xmath74=\int d\vec x(\frac{1}{2}\partial_i \pi_a \partial^i \pi^a + \frac{1}{8nf^2}\pi^2[\frac{-g^r(\nabla ; \mu)\nabla } { 1-\frac{1}{2(4\pi)^2f^2}g^r(\nabla;\mu ) \log(\frac{\mu^2}{-\nabla})\nabla}](\pi^2)\end{aligned}\ ] ] where the meaning of this non - local mass functional is given by the appropriate fourier transform . in order to use eq.22 or eq.23 to do phenomenology
we need to define the generating function @xmath55 or , in other words , the infinite number of renormalized couplings constants @xmath56 .
a typical example is the linear sigma model . in this case
, the appropriate choice is : @xmath75 where @xmath76 is the renormalized coupling constant of the linear sigma model computed in the large @xmath0 limit [ 14 ] . with this definition , eq.22 and
eq.20 provide the corresponding well known scattering amplitude and evolution equation for @xmath77 .
in addition , the amplitude in eq.22 has a pole in the second riemann sheet that has to be understood as the physical scalar resonance appearing in the linear sigma model i.e. the higgs resonance .
( see [ 14 ] and [ 15 ] for a discussion on this point ) .
however , the @xmath10 linear sigma model is not the theory that reproduces the hadron interactions at low energies . in principle
, there are two possible approaches for the determination of the renormalized coupling constants appearing in the pion effective action of eq.17 . from the theoretical point of view one could try to compute these parameters from a more fundamental theory of strong interactions like qcd . from the phenomenological point of view
, one can try to fit these constants from the experiment , for example the low - energy pion scattering data .
as the theoretical computation seems to be quite involved , it is worth to make the phenomenological determination of the couplings first in order to test the quality of the whole @xmath0 approach to this case .
using eq.22 to fit the experimental pion scattering data requires to face the fact of having an infinite number of parameters i.e. the scale @xmath44 and the values of the renormalized coupling constants @xmath56 at the scale @xmath44 .
however one can solve this problem in a easy way just by considering only particular cases where all the coupling constants but a finite set @xmath78 , @xmath79 vanish at some scale @xmath44 .
these models are defined just by a finite number of parameters ( @xmath44 and the @xmath80 coupling constants renormalized at this scale ) and therefore can be used to fit the experimental data . in particular
, one can consider the extremal case of having all the renormalized couplings equal to zero at some scale @xmath44 i.e. @xmath81 for all @xmath82 .
the model so obtained has only one parameter ( the @xmath44 scale ) and it can be considered in some sense as the non - linear sigma model renormalized at the leading order of the @xmath5 expansion . of course
, it could happen that the underlying theory ( say qcd ) were not of this type .
however this would not be a serious problem at very low energies because , for natural values of the renormalized coupling constants and the renormalization scale @xmath44 , only the very first terms of the generating function @xmath55 series in eq.18 contribute to the effective action and the scattering amplitude .
however , at higher energies the effect of the infinite set of couplings constants , when different from zero , could be important .
for example , they can conspire to give rise to resonances which appear as poles in the second riemann sheet of the partial waves amplitudes as it happens in the linear sigma model .
of course , in this case the value of the couplings can also be obtained from the underlying theory or by making extra assumptions on the behavior of the amplitudes . for comparison with the experiment
we need also to compute the phase shifts for the different channels .
these are obtained from the corresponding partial waves amplitudes .
the proper generalization of the standard @xmath83 isospin projections to the @xmath84 case is given by [ 9 ] : @xmath85 and the partial waves are given by : @xmath86 then , the @xmath87 amplitude is of the order of one but , for instance , the @xmath88 and the @xmath89 amplitudes are of the order of @xmath5 . thus at the leading order of the large @xmath0 expansion @xmath90 , @xmath91 and @xmath92 ( remind that @xmath65 is of the order of @xmath5 ) .
now it is easy to show that in this approximation the partial waves have the proper cut structure and also are elastic unitary i.e. @xmath93 just above the unitarity cut as they must be . in fig.2
we show the result of our fit of the @xmath94 phase shift channel for elastic pion scattering .
this fit has been done with only one parameter , or in other words , by using the very particular model where all the renormalized coupling constants are zero at some scale @xmath44 . as discussed above ,
the only parameter in this specially simple case is the scale @xmath44 .
the fit in fig.2 corresponds to a value of @xmath95 . for other channels like @xmath96 or @xmath97 the prediction of the leading order of the large @xmath0 expansion
is that there is no interaction .
this could appear as a rather poor prediction but it is not the case . by looking at the experimental data one can realize that the phase shifts in these channels grow very slowly with energy , for instance , at @xmath98 of center of mass energy we have @xmath99 degrees and @xmath100 degrees whilst @xmath101 degrees at the same energy .
the conclusion is that for energies below , let say , @xmath98 our simple one parameter fit gives rise to errors in the phase shifts which are lesser than @xmath102 per cent ( refered to the @xmath2 channel ) for the three channels considered . of course , for larger energies things become completely different particularly in the @xmath96 channel where the onset of the @xmath103 resonance makes this channel to be strongly interacting .
one is then tempted to make an interpretation of the scale @xmath44 as some kind of cutoff signaling the range of applicability of our approach and , in fact , this interpretation was discussed in [ 7 ] . from this point of view , it is quite interesting to realize how close is the @xmath44 fitted value @xmath104 to the @xmath103 mass . in some way , by fitting the @xmath2 channel , the model is telling us where new things can appear in other channels like the @xmath96 ( the @xmath103 resonance ) and thus setting the limits of applicability of the model .
however , we would like to stress that our renormalization method is completely consistent and our results are formally valid at any energy independently of the goodness of the fits we can obtain with them .
as it was mentioned above , the second phenomenological application of the large @xmath0 expansion that will be considered here is the description of the nucleon in the context of the so - called skyrmion model . as it is well known , the skyrmion [ 21 ] is a topological soliton of the @xmath105 chiral model
. finite energy and static pion field configurations are continous maps from the compactified space @xmath106 to the coset space @xmath106 .
these applications can be classified in homotopically non - equivalent classes since @xmath107 . therefore every map can be labeled by an integer number . in the skyrmion model of the nucleon
this topological number is interpreted as the baryonic number of the field .
the skyrmion model has proved to give a qualitative description of many of the nucleon properties [ 22 ] including ( in an highly non - trivial way ) the spin [ 23 ] .
the standard ansatz for the skyrmion field is @xmath108 with @xmath109 and @xmath110 being the right boundary conditions for the chiral angle @xmath111 in order to have baryonic number equal to one . in this description of the skyrmion
the chiral field is taken to be an element of @xmath83 which is equivalent to our coset space @xmath106 . in terms of the coordinates used here ,
the skyrmion ansatz is given by @xmath112 . in order to obtain the mass of the skyrmion in the approximation considered in this work we have to introduce this anzatz in the mass functional in eq.22 with the renormalized coupling constants obtained from the fit of the elastic pion scattering described in the previous section .
then , it is not very difficult to find : @xmath113&=&nf^22\pi\int_0^{\infty}dr r^2 ( 2 \frac{\sin^2f(r ) } { r^2}+\cos^2 f(r ) f'(r)^2 ) \\ \nonumber & + & nf^2\int_0^{\infty}dr r \sin ^2f(r)\int_0^{\infty}dr ' r ' \sin ^2f(r ' ) \int_0^{\infty}dk\sin(kr)\sin(kr ' ) \\ \nonumber & & \frac{k^2g^r(-k^2;\mu)}{1+\frac{k^2}{2(4\pi)^2f^2 } g^r(-k^2;\mu)\log\frac{\mu^2}{k^2}}\end{aligned}\ ] ] now the mass functional depends only on the chiral angle @xmath111 . by minimizing this functional
we can find in principle the mass and the shape of the skyrmion in this large @xmath0 approximation . in order to make this task easier we can use some reasonable parametrization of the chiral angle such as the one by atiyah and manton [ 24 ] : @xmath114 where the parameter @xmath115 is a measure of the size of the skyrmion . in fig.3
we show the results obtained when this parametrization is inserted in eq.26 with the @xmath116 obtained in the previous section i. e. we follow the philosophy of [ 25 ] where the authors use the skyrmion model to predict the mass of the proton from the pion scattering data .
the first and obvious conclusion from fig.3 is that , at least for this parametrization , the mass functional has not any minimum but the trivial one at @xmath117 so that the skyrmion tends to shrink to zero size in this approximation .
in fact we have checked that this is also the case when other parametrizations of the chiral angle are used . therefore , everything seems to indicate that in the large @xmath0 limit considered here , the skyrmion is not stable i.e. we are in a similar situation to the one found when one works with the two derivatives term in eq.1 .
this is a bit disappointing since one of the most appealing properties of the large @xmath0 approximation is that it includes the effect of higher derivative terms and the corresponding higher loops contributions .
this fact improves the unitarity behavior of the amplitudes and one could think that it could also improve the skyrmion description .
however , this is not the case , at least in the leading order considered here .
a simple way to understand why this is not so is the following . in the standard approach to the skyrmion one typically adds to the two derivatives term in the lagrangian one four derivative term called the skyrme term .
this term produce an stable skyrmion in such a way that the contribution to the total energy of the skyrmion coming from the two terms is exactly the same .
it is also possible to add another four derivative term called the non - skyrme term but its contribution can turn the skyrmion unstable .
one - loop effects can also be included in the mass functional [ 26 ] .
one possible interpretation of the origin of the skyrmion and the non - skyrmion terms is to understand them as the low energy remnant of the tail of one vector @xmath118 and one scalar @xmath119 resonance respectively .
in fact it is not difficult to relate the skyrme and the non - skyrme parameters with the masses of the corresponding resonances ( see for instance [ 4 ] ) .
then , the consequence of this picture is that the existence of one vector resonance like the @xmath103 produces an stable skyrmion ( and in fact it is possible to relate the @xmath103 and the nucleon masses ) but one scalar resonance do not produce an stable skyrmion by itself and even it can make unstable the skyrmion when the vector resonance is also present .
if this simple picture were correct ( as it seems to be ) the @xmath103 resonance would be the responsible of the stability of the nucleon in the skyrmion model ( or at least of the pion cloud )
. then it would be possible to understand why the skyrmion is not stable in the large @xmath0 limit approximation considered in this paper .
as we saw in the previous section this approach can describe well the elastic pion scattering in the @xmath2 channel but it does not reproduce the @xmath103 resonance ( yet in some way it predicts its existence ) and therefore it does not contain the piece that seems to keep the skyrmion stable in other much more simple approach that do not include higher derivatives neither higher loops effects .
we have computed the effective action of the @xmath1 non - linear sigma model to leading order on the @xmath5 expansion .
this action is divergent but it can be properly renormalized by introducing an infinite set of counter terms in a systematically way . the energy dependence of the corresponding renomalized couplings can be obtained thus providing a very nice example of how @xmath120 can work beyond the one - loop approximation . with an appropriate choice of these renormalized couplings we can reproduce particular models with the same symmetry breaking pattern as , for example , the linear sigma model .
we can consider also models with a finite number of couplings which can be used to fit the elastic pion scattering experimental data since the partial waves amplitudes have a very good unitarity behavior .
then , with only one parameter it is possible to reproduce well the phase shifts for energies below @xmath98 .
this parameter can be also interpreted as some kind of cutoff setting the limits of the model and , in fact , the fitted value is basically the @xmath103 mass which in principle can not be reproduced since , at leading order in the @xmath5 expansion , the @xmath96 channel is not interacting .
we have also studied the mass functional of the skyrmion solutions and we arrived to the conclusion that the skyrmion solution is not stable at the leading order in the @xmath5 expansion .
this fact is probably related with the above mentioned absence of interaction in the @xmath96 since in other approaches the @xmath103 resonance stabilizes the skyrmion . in any case
, we consider the @xmath5 expansion of @xmath120 as a very interesting alternative complementary to the standard one - loop computations .
of course , much more work is needed like including pion mass effects , going to the next to leading order in @xmath5 , considering other ways to take the limit like the one based in the @xmath121 non - linear sigma model and finally ( and this was our original motivation ) the applications to the description of the symmetry breaking sector of the standard model as a way to parametrize the future large hadron collider ( lhc ) data .
work is in progress in all these directions .
this work has been supported in part by the ministerio de educacin y ciencia ( spain ) ( cicyt aen90 - 0034 ) and colciencias ( colombia ) .
a. d. thanks also the gregorio del amo foundation for support and s. dimopoulos and the department of physics of stanford university for their kind hospitality .
g. ecker , j. gasser , a. pich and e. de rafael , _ nuc .
* b321 * ( 1989)311 + g. ecker , j. gasser , h. leutwyler , a. pich and e. de rafael , _ phys .
_ * b223 * ( 1989)425 + j.f .
donoghue , c. ramirez and g. valencia , _ phys .
* d39*(1989)1947 + v. bernard , n. kaiser and u.g .
meissner , _ nucl .
_ * b364 * ( 1991)283 l. tararu , _ phy . rev . _
* d12 * ( 1975)3351 + t. appelquist and c. bernard , _ phys .
* d * ( 1981 ) 425 + j. zinn - justin , _ quantum field theory and critical phenomena _
, oxford university press , new york , ( 1989 ) .
l. rosselet et al.,_phys.rev .
_ * d15 * ( 1977 ) 574 .
w.mnner , in experimental meson spectroscopy , 1974 proc .
boson conference , ed .
garelich ( aip , new york,1974 ) v.srinivasan et al.,_phys.rev _ * d12*(1975 ) 681 m. david et al.,unpublished ; g. villet et al . ,
unpublished ; p. estabrooks and a.d.martin , _ nucl.phys._*b79 * ( 1974)301 * figure 1:*a ) a typical eight pion legs feynman diagram where the three @xmath26 legs function appears ( pion lines are narrow and @xmath26 lines are broader ) b ) the complete connected three @xmath26 legs function ( black blob ) in terms of the @xmath26 functions containing only pion loops ( dashed blobs ) c ) some diagrams contributing to the @xmath26 functions containing only pion loops d ) relation between the complete @xmath26 functions and the @xmath26 functions containing only pion loops at the leading order in the @xmath5 expansion . * figure 2 : * phase shifts of the elastic pion scattering for the @xmath2 channel .
the continuous line represents the one parameter fit described in the text .
the experimental data corresponds to : @xmath122 ref.[16 ] , @xmath123 ref.[17],@xmath124 ref.[18],@xmath125 ref.[19 ] , @xmath126 ref.[20 ] .
* figure 3 : * mass of the skyrmion in the large @xmath0 limit for the atiyah and manton parametrization in terms of the @xmath115 parameter .
dotted line is the contribution of the kinetic term , dashed line is the interaction energy and the full line is the total mass of the skyrmion .[/INST] the large @xmath0 effective action of the non - linear sigma model based in the coset @xmath1 is obtained .
the renormalization of this effective action requires the introduction of an infinite set of counter terms .
however , there exist particular cases where , at some scale , only a finite number of non - zero coupling constants are present .
this fact make possible a one parameter fit of the @xmath2 low - energy pion scattering .
the corresponding non - local effective action is used to study the properties of the skyrmion which is shown to be unstable in this approximation .
ft / ucm/14/93 , su - itp-93 - 32 + on leave of absence from departamento de fsica terica , universidad complutense de madrid , 28040 madrid , spain 0.83 true cm 20 true cm </s> |
usually , extensive investigation to identify the cause of bronchiectasis is not done in routine clinical practice as it is perceived to have little influence on its management .
conventionally , in absence of an obvious cause , bronchiectasis is often considered as post - infective or idiopathic . however , establishing a specific etiological diagnosis of bronchiectasis may be significant for guiding appropriately tailored therapy in some patients with a favorable outcome .
primary humoral immunodeficiency ( phi ) , an underdiagnosed entity , comprises of heterogeneous group of disorders .
common variable immunodeficiency disorder ( cvid ) represents the most commonly diagnosed form of phi .
i present here a case of 34-year - old male diagnosed as cvid who presented with bronchiectasis and multisystem involvement .
a 34-year - old male presented with fever , cough with purulent expectoration , and increased breathlessness for a week .
he received empirical antitubercular therapy twice in the past in the year 1994 and 2007 for suspected smear negative pulmonary tuberculosis and empyema thoracis , respectively .
his vitals were as follows : pulse rate = 96 beats / min , blood pressure = 90/60 mmhg , respiratory rate = 32/min , and spo2 = 95% in room air .
chest radiograph showed patchy opacities in right lower and left upper zones [ figure 1 ] .
high resolution computed tomography ( hrct ) chest confirmed bilateral diffuse bronchiectasis [ figure 2a and b ] . in view of multisystem involvement and recurrent respiratory infections , serum immunoglobulin ( ig ) estimation was done to rule out primary immunodeficiency .
all ig levels were significantly reduced ( igg < 1.37 g / l , iga < 0.231 g / l , igm < 0.17
considering the constellation of symptoms like recurrent respiratory infections / bronchiectasis , previous empyema , chronic diarrhea , suppurative otitis media , inflammatory arthritis , and low ig levels ; the diagnosis of cvid was made .
he received intravenous ceftriaxone and ceftazidime for 2 weeks and recovered from the present infective exacerbation .
intravenous ig ( ivig ) therapy could not be administered as the cost was prohibitive for the patient .
chest x - ray showing nonhomogenous opacity in right lower and left upper zones ( a ) high resolution computed tomography ( hrct ) chest showing bilateral diffuse bronchiectasis with lower lobes predominance .
phi is a broad terminology comprising of several disorders that share defective antibody production as common abnormality .
broadly phi is divided into two groups : one having a defined genetic linkage ( e.g. x - linked agammaglobulinemia and autosomal recessive agammaglobulinemia ) and one of unknown genetic base .
the latter group constitutes the largest one and includes cvid , igg subclass deficiencies , iga deficiency , and selective antibody deficiency .
the first group of diseases appear mainly during childhood and the second group appears later on .
secondary immunodeficiency usually results from neoplasms like lymphoma , chronic lymphatic leukemia and myeloma , protein energy malnutrition , protein loosing enteropathy , severe trauma , corticosteroid , and cytotoxic drugs therapy and infections like human immunodeficiency virus and cytomegalovirus .
phi usually manifests as recurrent respiratory infections like sinusitis , bronchitis , pneumonia , and bronchiectasis .
the reported incidence of cvid varies from 1 in 10,000 to 1 in 50,000 and equal in both sexes .
majority present in their 2 or 3 decade . the average delay from the onset of symptoms to diagnosis ranges from 6 to 8 years .
this delay is mainly due to two reasons : ( i ) primary immunodeficiency is not suspected or considered in adults and ( ii ) the initial symptoms are usually considered to be nonspecific . for most patients , the early symptoms of cvid are recurrent sinusitis or bronchitis .
unfortunately , serum ig levels are not measured routinely in such cases . the fundamental immunological defect in cvid
is reduced number of switch memory b cells with a failure to produce significant antibody response to specific antigens .
the diagnosis of cvid is made mostly by exclusion of secondary causes of immunodeficiency and other primary immunodeficiency disorders .
though there is no consensus definition of cvid , the most agreed one as proposed by european society for immunodeficiencies is reduced ( below 2 standard deviations of the mean ) levels of igg with reduced iga and/or igm , together with failure to mount a significant antibody response to vaccination , in the absence of a known cause .
functional ig deficiency should be considered in patients who have recurrent respiratory infections and normal ig and complement levels .
bronchiectasis is a late manifestation in cvid and signatory to repeated infective insults in the past .
bronchiectasis remains the most common pulmonary pathology detected in cvid patients with a reported prevalence varying from 17 to 76% .
hrct scan is the single best imaging tool for the diagnosis and monitoring of bronchiectasis in cvid .
it affects mostly the middle or lower lobes , and less commonly the upper lobes .
the other pulmonary manifestations are emphysema , fibrosis , granulomatous disease mimicking sarcoidosis , and interstitial lung disease .
extrapulmonary manifestations of cvid include recurrent diarrhea and malabsorption , autoimmune disorders like idiopathic thrombocytopenic purpura and autoimmune hemolytic anemia , and malignancy like lymphoma and gastric cancer .
presence of bronchiectasis and liver disease at diagnosis carries a poor prognosis in cvid patients .
bronchiectasis is not a feature in isolated iga or igm deficiencies but more likely if these occur in association with selective igg subclass deficiencies .
the differential diagnoses those closely mimic cvid include primary ciliary dyskinesia ( pcd ) , adult - onset cystic fibrosis ( cf ) , alpha-1 antitrypsin deficiency , and non - tuberculous mycobacterial ( ntm ) infection .
however , presence of rhinitis since neonatal period and a classic triad of sinusitis , situs inversus , and bronchiectasis if present ( in 50% cases ) will differentiate pcd from adult - onset cf , the later may present with recurrent pancreatitis .
the diagnosis of pcd is established by ultrastructural study of cilia , whereas sweat chloride estimation and/or genetic analysis is required in adult - onset cf .
is usually associated with concomitant emphysema and affects the lower lobes , whereas ntm infection has a predilection for middle lobe and lingula with nodular bronchiectasis and tree - in - bud appearance . subjecting every patient of bronchiectasis to an array of exhaustive investigations may not be justified .
however , such an approach may be rewarding in well - selected group of patients .
in a recent study , a cause for bronchiectasis was identified in 74% ( 122/165 ) of patients that influenced the management in 61 ( 37% ) .
another study involving 150 patients of bronchiectasis showed etiological diagnosis in 47% cases and this altered the management in 15% .
patients with immune deficiency are younger than those with idiopathic or post - infective bronchiectasis .
the standard recommendation for ivig is 400 - 600 mg / kg body weight every 3 - 4 weeks .
an igg trough level ( the igg level before the next infusion ) of at least 5
patients with bronchiectasis or diarrhea may require higher ivig doses ( 500 - 600 mg / kg ) to reach the mandatory trough level .
the dose , frequency and route of administration of ivig should be individualized to achieve maximum success .
antimicrobial therapy is the other main component of cvid therapy , because ig replacement alone may not adequately prevent or treat local and/or persistent infections .
intravenous antibiotic for a longer duration ( 10 - 14 days ) is recommended for control of acute infective exacerbation of bronchiectasis in cvid patients to prevent relapse .
those with recurrent infections despite ivig therapy may benefit from suppressive antibiotic therapy especially azithromycin given three times a week . other usual therapy for bronchiectasis like bronchodilators , inhaled corticosteroids , and airway clearance techniques should be optimized for maximum benefit .
in addition , the accompanying diseases and sequel of cvid require adequate treatment . corticosteroids and cyclosporine
a are effective for granulomatous manifestations and autoimmune diseases , although long - term treatment efficacy may be limited due to side effects .
newer agents like infliximab or etanercept have been successfully used in few cases . in conclusion
, primary immunodeficiency should be considered as a possibility for bronchiectasis in young patients who have recurrent respiratory infections and multisystem involvement . | bronchiectasis continues to be a common respiratory problem of varied etiology .
common variable immunodeficiency disorder ( cvid ) is an uncommon cause for bronchiectasis .
however , the prevalence of bronchiectasis remains very high in patients with cvid .
this remains largely an underdiagnosed entity as primary immunodeficiency is not suspected in adults as a cause of bronchiectasis and hence , serum immunoglobulin ( ig ) levels are not measured routinely .
in addition to bronchiectasis , patients with cvid usually present with various extrapulmonary symptoms .
i report here a case of young man who presented with bronchiectasis and multisystem complains who was diagnosed as cvid . | <s>[INST]usually , extensive investigation to identify the cause of bronchiectasis is not done in routine clinical practice as it is perceived to have little influence on its management .
conventionally , in absence of an obvious cause , bronchiectasis is often considered as post - infective or idiopathic . however , establishing a specific etiological diagnosis of bronchiectasis may be significant for guiding appropriately tailored therapy in some patients with a favorable outcome .
primary humoral immunodeficiency ( phi ) , an underdiagnosed entity , comprises of heterogeneous group of disorders .
common variable immunodeficiency disorder ( cvid ) represents the most commonly diagnosed form of phi .
i present here a case of 34-year - old male diagnosed as cvid who presented with bronchiectasis and multisystem involvement .
a 34-year - old male presented with fever , cough with purulent expectoration , and increased breathlessness for a week .
he received empirical antitubercular therapy twice in the past in the year 1994 and 2007 for suspected smear negative pulmonary tuberculosis and empyema thoracis , respectively .
his vitals were as follows : pulse rate = 96 beats / min , blood pressure = 90/60 mmhg , respiratory rate = 32/min , and spo2 = 95% in room air .
chest radiograph showed patchy opacities in right lower and left upper zones [ figure 1 ] .
high resolution computed tomography ( hrct ) chest confirmed bilateral diffuse bronchiectasis [ figure 2a and b ] . in view of multisystem involvement and recurrent respiratory infections , serum immunoglobulin ( ig ) estimation was done to rule out primary immunodeficiency .
all ig levels were significantly reduced ( igg < 1.37 g / l , iga < 0.231 g / l , igm < 0.17
considering the constellation of symptoms like recurrent respiratory infections / bronchiectasis , previous empyema , chronic diarrhea , suppurative otitis media , inflammatory arthritis , and low ig levels ; the diagnosis of cvid was made .
he received intravenous ceftriaxone and ceftazidime for 2 weeks and recovered from the present infective exacerbation .
intravenous ig ( ivig ) therapy could not be administered as the cost was prohibitive for the patient .
chest x - ray showing nonhomogenous opacity in right lower and left upper zones ( a ) high resolution computed tomography ( hrct ) chest showing bilateral diffuse bronchiectasis with lower lobes predominance .
phi is a broad terminology comprising of several disorders that share defective antibody production as common abnormality .
broadly phi is divided into two groups : one having a defined genetic linkage ( e.g. x - linked agammaglobulinemia and autosomal recessive agammaglobulinemia ) and one of unknown genetic base .
the latter group constitutes the largest one and includes cvid , igg subclass deficiencies , iga deficiency , and selective antibody deficiency .
the first group of diseases appear mainly during childhood and the second group appears later on .
secondary immunodeficiency usually results from neoplasms like lymphoma , chronic lymphatic leukemia and myeloma , protein energy malnutrition , protein loosing enteropathy , severe trauma , corticosteroid , and cytotoxic drugs therapy and infections like human immunodeficiency virus and cytomegalovirus .
phi usually manifests as recurrent respiratory infections like sinusitis , bronchitis , pneumonia , and bronchiectasis .
the reported incidence of cvid varies from 1 in 10,000 to 1 in 50,000 and equal in both sexes .
majority present in their 2 or 3 decade . the average delay from the onset of symptoms to diagnosis ranges from 6 to 8 years .
this delay is mainly due to two reasons : ( i ) primary immunodeficiency is not suspected or considered in adults and ( ii ) the initial symptoms are usually considered to be nonspecific . for most patients , the early symptoms of cvid are recurrent sinusitis or bronchitis .
unfortunately , serum ig levels are not measured routinely in such cases . the fundamental immunological defect in cvid
is reduced number of switch memory b cells with a failure to produce significant antibody response to specific antigens .
the diagnosis of cvid is made mostly by exclusion of secondary causes of immunodeficiency and other primary immunodeficiency disorders .
though there is no consensus definition of cvid , the most agreed one as proposed by european society for immunodeficiencies is reduced ( below 2 standard deviations of the mean ) levels of igg with reduced iga and/or igm , together with failure to mount a significant antibody response to vaccination , in the absence of a known cause .
functional ig deficiency should be considered in patients who have recurrent respiratory infections and normal ig and complement levels .
bronchiectasis is a late manifestation in cvid and signatory to repeated infective insults in the past .
bronchiectasis remains the most common pulmonary pathology detected in cvid patients with a reported prevalence varying from 17 to 76% .
hrct scan is the single best imaging tool for the diagnosis and monitoring of bronchiectasis in cvid .
it affects mostly the middle or lower lobes , and less commonly the upper lobes .
the other pulmonary manifestations are emphysema , fibrosis , granulomatous disease mimicking sarcoidosis , and interstitial lung disease .
extrapulmonary manifestations of cvid include recurrent diarrhea and malabsorption , autoimmune disorders like idiopathic thrombocytopenic purpura and autoimmune hemolytic anemia , and malignancy like lymphoma and gastric cancer .
presence of bronchiectasis and liver disease at diagnosis carries a poor prognosis in cvid patients .
bronchiectasis is not a feature in isolated iga or igm deficiencies but more likely if these occur in association with selective igg subclass deficiencies .
the differential diagnoses those closely mimic cvid include primary ciliary dyskinesia ( pcd ) , adult - onset cystic fibrosis ( cf ) , alpha-1 antitrypsin deficiency , and non - tuberculous mycobacterial ( ntm ) infection .
however , presence of rhinitis since neonatal period and a classic triad of sinusitis , situs inversus , and bronchiectasis if present ( in 50% cases ) will differentiate pcd from adult - onset cf , the later may present with recurrent pancreatitis .
the diagnosis of pcd is established by ultrastructural study of cilia , whereas sweat chloride estimation and/or genetic analysis is required in adult - onset cf .
is usually associated with concomitant emphysema and affects the lower lobes , whereas ntm infection has a predilection for middle lobe and lingula with nodular bronchiectasis and tree - in - bud appearance . subjecting every patient of bronchiectasis to an array of exhaustive investigations may not be justified .
however , such an approach may be rewarding in well - selected group of patients .
in a recent study , a cause for bronchiectasis was identified in 74% ( 122/165 ) of patients that influenced the management in 61 ( 37% ) .
another study involving 150 patients of bronchiectasis showed etiological diagnosis in 47% cases and this altered the management in 15% .
patients with immune deficiency are younger than those with idiopathic or post - infective bronchiectasis .
the standard recommendation for ivig is 400 - 600 mg / kg body weight every 3 - 4 weeks .
an igg trough level ( the igg level before the next infusion ) of at least 5
patients with bronchiectasis or diarrhea may require higher ivig doses ( 500 - 600 mg / kg ) to reach the mandatory trough level .
the dose , frequency and route of administration of ivig should be individualized to achieve maximum success .
antimicrobial therapy is the other main component of cvid therapy , because ig replacement alone may not adequately prevent or treat local and/or persistent infections .
intravenous antibiotic for a longer duration ( 10 - 14 days ) is recommended for control of acute infective exacerbation of bronchiectasis in cvid patients to prevent relapse .
those with recurrent infections despite ivig therapy may benefit from suppressive antibiotic therapy especially azithromycin given three times a week . other usual therapy for bronchiectasis like bronchodilators , inhaled corticosteroids , and airway clearance techniques should be optimized for maximum benefit .
in addition , the accompanying diseases and sequel of cvid require adequate treatment . corticosteroids and cyclosporine
a are effective for granulomatous manifestations and autoimmune diseases , although long - term treatment efficacy may be limited due to side effects .
newer agents like infliximab or etanercept have been successfully used in few cases . in conclusion
, primary immunodeficiency should be considered as a possibility for bronchiectasis in young patients who have recurrent respiratory infections and multisystem involvement .[/INST]bronchiectasis continues to be a common respiratory problem of varied etiology .
common variable immunodeficiency disorder ( cvid ) is an uncommon cause for bronchiectasis .
however , the prevalence of bronchiectasis remains very high in patients with cvid .
this remains largely an underdiagnosed entity as primary immunodeficiency is not suspected in adults as a cause of bronchiectasis and hence , serum immunoglobulin ( ig ) levels are not measured routinely .
in addition to bronchiectasis , patients with cvid usually present with various extrapulmonary symptoms .
i report here a case of young man who presented with bronchiectasis and multisystem complains who was diagnosed as cvid .</s> |
benedict was a double - blind , randomized , placebo - controlled study aimed to assess whether ace inhibitors and nondihydropyridine calcium - channel blockers , alone or in combination , prevent microalbuminuria in subjects with type 2 diabetes , hypertension , and normal urinary albumin excretion at baseline ( 13 ) .
patients ( n = 1,204 ) were randomly allocated to at least 3-year treatment with the ace inhibitor trandolapril , the nondihydropyridine calcium - channel blocker verapamil , the combination of verapamil plus trandolapril , or placebo , added on background non ace - inhibiting therapy targeting systolic / diastolic blood pressure < 120/80 mmhg ( 13 ) .
primary end point was new - onset persistent microalbuminuria ( urinary albumin excretion 20 g and < 200 g / min in at least two of three consecutive overnight urine collections on two consecutive visits 2 months apart ) .
urinary albumin excretion was measured on fresh urines at the coordinating center by nephelometry ( beckman array system ; beckman coulter ) at randomization and every 6 months thereafter .
trandolapril plus verapamil and trandolapril alone significantly delayed the onset of microalbuminuria by factors of 2.6 and 2.1 , respectively , compared with placebo ( p < 0.01 for both ) .
the incidence of microalbuminuria was reduced to a similar extent by both treatments , whereas verapamil had an effect on the incidence of microalbuminuria that was similar to that of placebo ( 12,13 ) .
thus , patients were pooled in two cohorts according to their original allocation to ace or non - ace inhibitor therapy regardless of concomitant therapy with verapamil or placebo .
gene - by - treatment interactions were tested according to ace inhibitor therapy ( yes or no ) .
the study protocol was approved by the local ethics committees , and only samples from patients who provided written informed consent according to the helsinki declaration guidelines were considered for genetic analyses .
genotyping for pro12ala single nucleotide polymorphism ( snp ; rs1801282 ) was performed using taqman pre - designed snp genotyping assay from applied biosystems ( assay c_1129864_10 ; abi , foster city , ca ) .
genotypes were scored by analyzing data on both real - time as well as allele discrimination assay platforms using sds software provided by abi .
as a quality - control procedure , we double - genotyped a subset of 200 individuals ( 18% of the whole sample ) using a different genotyping method on the lightcycler 480 system ( roche diagnostics , http://www.roche-applied-science.com ) .
this was a melting curve - based genotyping method using fluorescence - labeled hybridization probes ( 32 ) .
primers and probes for genotyping pro12ala snp on lightcycler 480 system were designed , synthesized , and validated by tib molbiol ( genoa , italy , http://www.tib-molbiol.com ) using the genomic sequence available from ncbi dbsnp for the rs1801282 .
04 707 524 001 ; roche applied science ) , 10 pmol of each primer ( forward 5gcc cag tcc ttt ctg tgt t 3 and reverse 5 gtc ccc aat agc cgt atc tg 3 , melting temperature 55c ) , 4 pmol of each probe ( sensor hybprobe lc red 640-cct tca ctg ata cac tgt ctg caa aca tat cac - phosphate and anchor hybprobe tct cct att gac cca gaa agc gat - fluorescein , melting temperature 60c and 64c , respectively ) , and 50 ng of genomic dna in a final volume of 20 l according to manufacturer 's instructions .
patients ' baseline characteristics according to ppar-2 pro12ala polymorphism are reported as means sd or frequencies and percentages .
p values refer to mann - whitney u test and pearson for continuous and categorical variables , respectively .
time to onset of microalbuminuria was considered as the main end point . for patients who did not reach the main end point ,
cox proportional hazards regression models were used , and results are expressed as hazard ratios ( hrs ) and 95% cis . to test the effect of pro12ala polymorphism on outcome , three different statistical models have been designed : the first was a model adjusted only for ace inhibitor therapy ( i.e. , yes or no = 0 or 1 ) ; in the second model , variables that predicted microalbuminuria onset in the whole cohort , such as sex , smoking status , and a1c , were added to ace inhibitor therapy ; in the third model , baseline aer levels , which were slightly lower at study entry in ala carriers , were taken into account in addition to ace inhibitor therapy and baseline covariates . between - groups comparison of aer at final visit was carried out by ancova , adjusting for baseline measurement .
nonnormally distributed covariates ( namely , aer and triglycerides ) were log transformed before analysis .
all the analyses were performed using sas statistical package release 9.1 ( sas institute , cary , nc ) .
genotyping for pro12ala single nucleotide polymorphism ( snp ; rs1801282 ) was performed using taqman pre - designed snp genotyping assay from applied biosystems ( assay c_1129864_10 ; abi , foster city , ca ) .
genotypes were scored by analyzing data on both real - time as well as allele discrimination assay platforms using sds software provided by abi .
as a quality - control procedure , we double - genotyped a subset of 200 individuals ( 18% of the whole sample ) using a different genotyping method on the lightcycler 480 system ( roche diagnostics , http://www.roche-applied-science.com ) .
this was a melting curve - based genotyping method using fluorescence - labeled hybridization probes ( 32 ) .
primers and probes for genotyping pro12ala snp on lightcycler 480 system were designed , synthesized , and validated by tib molbiol ( genoa , italy , http://www.tib-molbiol.com ) using the genomic sequence available from ncbi dbsnp for the rs1801282 .
04 707 524 001 ; roche applied science ) , 10 pmol of each primer ( forward 5gcc cag tcc ttt ctg tgt t 3 and reverse 5 gtc ccc aat agc cgt atc tg 3 , melting temperature 55c ) , 4 pmol of each probe ( sensor hybprobe lc red 640-cct tca ctg ata cac tgt ctg caa aca tat cac - phosphate and anchor hybprobe tct cct att gac cca gaa agc gat - fluorescein , melting temperature 60c and 64c , respectively ) , and 50 ng of genomic dna in a final volume of 20 l according to manufacturer 's instructions .
patients ' baseline characteristics according to ppar-2 pro12ala polymorphism are reported as means sd or frequencies and percentages .
p values refer to mann - whitney u test and pearson for continuous and categorical variables , respectively .
time to onset of microalbuminuria was considered as the main end point . for patients who did not reach the main end point , time
cox proportional hazards regression models were used , and results are expressed as hazard ratios ( hrs ) and 95% cis . to test the effect of pro12ala polymorphism on outcome , three different statistical models have been designed : the first was a model adjusted only for ace inhibitor therapy ( i.e. , yes or no = 0 or 1 ) ; in the second model , variables that predicted microalbuminuria onset in the whole cohort , such as sex , smoking status , and a1c , were added to ace inhibitor therapy ; in the third model , baseline aer levels , which were slightly lower at study entry in ala carriers , were taken into account in addition to ace inhibitor therapy and baseline covariates . between - groups comparison of aer at final visit
nonnormally distributed covariates ( namely , aer and triglycerides ) were log transformed before analysis .
all the analyses were performed using sas statistical package release 9.1 ( sas institute , cary , nc ) .
of these patients , 7 ( 0.6% ) and 170 ( 15.2% ) were homozygous and heterozygous for the ala12 allele , respectively , from now ala carriers , and 942 ( 84.2% ) were homozygous for the pro12 allele , from now pro / pro homozygotes ( fig .
1 ) . frequency of ala carriers was comparable with that previously reported in other white populations ( 25 ) .
the proportion of the pro12ala genotypes did not significantly deviate from hardy - weinberg equilibrium ( = 0.05 ; p = 0.82 ) .
data from homozygous and heterozygous ala carriers were pooled and considered together for comparative analyses with pro / pro homozygotes .
baseline characteristics of the two groups were similar ( tables 1 and 2 ) , with a trend to lower albuminuria at inclusion in ala carriers ( table 1 ) , as well as the proportion of patients allocated to ace inhibitor therapy ( yes or no ) within each group ( table 1 ) .
baseline characteristics of patients who had been randomized to ace inhibitor therapy ( yes or no ) within the two genotype groups were similar ( table 1 ) .
baseline clinical features of patients with type 2 diabetes data are means sd , n ( % ) , or geometric means ( 95% cis ) .
differences between ala carriers and pro / pro homozygotes ( overall ) as well as between acei yes and acei no ( within each genotype group ) were not significant .
acei , ace inhibitor therapy ; dbp , diastolic blood pressure ; and sbp , systolic blood pressure .
concomitant treatments in patients with type 2 diabetes at baseline and on follow - up * * all differences between the two genotype groups ( ala vs. pro / pro ) were not significant .
acei , ace inhibitor therapy . over a median ( interquartile range ) of 44 ( 17.151.9 )
months of follow - up , 7 ala carriers ( 4% ) compared with 86 pro / pro homozygotes ( 9.1% ) developed persistent microalbuminuria ( = 4.35 ; p = 0.037 ) .
the unadjusted hr for microalbuminuria in ala carriers compared with pro / pro homozygotes was 0.45 ( 95% ci 0.210.97 ) ( p = 0.042 ) ( fig .
kaplan - meier curves for the percentages of ala carriers or pro / pro homozygotes in subjects who developed persistent microalbuminuria throughout the study period .
blood pressure and a1c levels at baseline as well as throughout the whole study period were similar in the two genotype groups ( table 1 and fig .
conversely , in ala carriers compared with pro / pro homozygotes urinary aer increased less during the observation period and was significantly lower at final visit even after adjustment for baseline albuminuria ( ancova , p = 0.048 ) ( fig .
upper panels : trough systolic and diastolic blood pressure throughout the study period in ala carriers or pro / pro homozygotes ( left ) , in ala carriers according to ace inhibitor therapy ( acei ) ( yes or no ) ( middle ) , and in pro / pro homozygotes according to ace inhibitor therapy ( yes or no ) . * p < 0.05 ( ace inhibitor therapy yes vs. ace inhibitor therapy no , without bonferroni correction for multiple comparisons ) .
lower panels : a1c throughout the study period in ala carriers or pro / pro homozygotes ( left ) , in ala carriers according to ace inhibitor therapy ( yes or no ) ( middle ) , and in pro / pro homozygotes according to ace inhibitor therapy ( yes or no ) . p < 0.05 ( pro / pro homozygotes vs. ala carriers , without bonferroni correction for multiple comparisons ) .
urinary aer ( geometric mean and 95% ci ) at basal and final visits in ala carriers or pro / pro homozygotes .
the difference in urinary aer between the two genotype groups at final visit was significant after adjustment for baseline albumin excretion .
in multivariable analyses , sex , smoking status , baseline albuminuria , baseline and follow - up a1c , and follow - up mean arterial pressure significantly predicted incident microalbuminuria in the whole benedict sample ( p < 0.001 for all considered covariates ) .
ala carriers compared with pro / pro homozygotes showed a trend with lower incidence of microalbuminuria even after adjusting for sex , smoking status , and baseline a1c ( hr 0.48 [ 95% ci 0.221.05 ] ; p = 0.065 ) , but not after adjusting also for baseline albuminuria ( hr 0.64 [ 0.291.40 ] ; p = 0.263 ) . the difference in the cumulative incidence of events between the two genotype groups was constant throughout the whole observation period , and new cases of microalbuminuria were approximately 50% less in ala compared with pro / pro homozygotes at each considered time point of the follow - up ( proportionality test , p = 0.85 ) . to assess whether the difference in the development of microalbuminuria by pro12ala genotype was due to difference in blood pressure or glucose control , we evaluated interactions between baseline / follow - up mean arterial pressure or a1c and genotype on incidence of microalbuminuria .
furthermore , the distribution of concomitant treatments with glucose- , blood pressure , and lipid - lowering agents as well as of antiplatelet agents at baseline and on follow - up was similar in the two genotype groups ( table 2 ) .
the proportion of patients on two or more antihypertensive medications was also similar in the two groups .
however , there were numerically more patients on diet alone and fewer patients on insulin alone among ala carriers than among pro / pro homozygotes at baseline as well as throughout the follow - up period ( table 2 ) .
4 of the 91 patients on ace inhibitor compared with 3 of the 86 on non - ace inhibitor therapy developed microalbuminuria .
thus , in the two treatment groups the incidence of microalbuminuria ( 4.4 vs. 3.5% , respectively ) was similar ( hr 1.21 [ 95% ci 0.275.40 ] ; p = 0.805 ) .
concomitant medications , systolic / diastolic blood pressure , and a1c at baseline and on follow - up were similar in the two treatment groups ( table 1 and fig .
3 , ala carriers : upper and lower panel , respectively ) . among pro / pro homozygotes ,
29 of the 464 patients on ace inhibitor and 57 of the 478 on non - ace inhibitor therapy developed microalbuminuria ( = 9.14 ; p = 0.003 ) .
thus , the incidence of microalbuminuria ( 6.3 vs. 11.9% , respectively ) was significantly lower in those on ace than in those on non - ace inhibitor therapy ( unadjusted hr 0.46 [ 95% ci 0.290.72 ] , p < 0.001 ; adjusted for baseline characteristics including or not including albuminuria 0.44 [ 0.280.69 ] , p < 0.001 ) .
systolic / diastolic blood pressure was similar at baseline , but tended to be lower in patients on ace inhibitor therapy in the follow - up period ( table 1 and fig .
3 , pro / pro homozygotes : upper panel ) . on follow - up ,
a similar proportion of patients was on concomitant treatment with antidiabetic , lipid - lowering , and antiplatelet agents and blood pressure lowering medications , with the exception of sympatholytic agents that were more frequently prescribed in the non - ace inhibitor treatment arm ( table 2 ) .
the incidence of microalbuminuria was significantly lower in ala carriers than in pro / pro homozygotes among subjects on non - ace inhibitor therapy ( unadjusted hr 0.30 [ 0.090.95 ] ; p = 0.041 ) .
the difference was marginally significant after adjusting for sex , smoking status , and baseline a1c ( hr 0.33 [ 0.101.05 ] ; p = 0.061 ) but failed to achieve the statistical significance after adjusting also for baseline albuminuria ( hr 0.56 [ 0.171.82 ] ; p = 0.333 ) . among subjects on ace inhibitor therapy ,
the incidence of microalbuminuria was similar in the two genotype groups ( unadjusted hr 0.75 [ 0.262.12 ] ; p = 0.582 ) .
altogether , the rate of microalbuminuria in ace inhibitor treated pro / pro homozygotes was similar to that of ala carriers considered as a whole regardless of therapy ( fig . 5 ) .
kaplan - meier curves for the percentages of pro / pro homozygotes considered according to concomitant ace inhibitor therapy ( acei ) ( yes or no ) and of ala carriers considered as a whole in subjects who developed persistent microalbuminuria throughout the study period .
the interaction between baseline a1c and genotype on development of microalbuminuria was significant ( p = 0.035 ) in pro / pro homozygotes without ace inhibitor therapy , but not in those on ace inhibition ( p = 0.64 ) .
baseline a1c was higher in pro / pro homozygotes progressing to microalbuminuria compared with those with stable urinary albumin excretion among patients without ace inhibitor therapy ( p < 0.0001 ) , but not in those on ace inhibition .
there was no significant interaction between follow - up a1c or mean blood pressure and genotype on development of microalbuminuria in any considered group .
of these patients , 7 ( 0.6% ) and 170 ( 15.2% ) were homozygous and heterozygous for the ala12 allele , respectively , from now ala carriers , and 942 ( 84.2% ) were homozygous for the pro12 allele , from now pro / pro homozygotes ( fig .
1 ) . frequency of ala carriers was comparable with that previously reported in other white populations ( 25 ) .
the proportion of the pro12ala genotypes did not significantly deviate from hardy - weinberg equilibrium ( = 0.05 ; p = 0.82 ) .
data from homozygous and heterozygous ala carriers were pooled and considered together for comparative analyses with pro / pro homozygotes .
baseline characteristics of the two groups were similar ( tables 1 and 2 ) , with a trend to lower albuminuria at inclusion in ala carriers ( table 1 ) , as well as the proportion of patients allocated to ace inhibitor therapy ( yes or no ) within each group ( table 1 ) .
baseline characteristics of patients who had been randomized to ace inhibitor therapy ( yes or no ) within the two genotype groups were similar ( table 1 ) .
baseline clinical features of patients with type 2 diabetes data are means sd , n ( % ) , or geometric means ( 95% cis ) .
differences between ala carriers and pro / pro homozygotes ( overall ) as well as between acei yes and acei no ( within each genotype group ) were not significant .
acei , ace inhibitor therapy ; dbp , diastolic blood pressure ; and sbp , systolic blood pressure .
concomitant treatments in patients with type 2 diabetes at baseline and on follow - up * * all differences between the two genotype groups ( ala vs. pro / pro ) were not significant .
over a median ( interquartile range ) of 44 ( 17.151.9 ) months of follow - up , 7 ala carriers ( 4% ) compared with 86 pro / pro homozygotes ( 9.1% ) developed persistent microalbuminuria ( = 4.35 ; p = 0.037 ) .
the unadjusted hr for microalbuminuria in ala carriers compared with pro / pro homozygotes was 0.45 ( 95% ci 0.210.97 ) ( p = 0.042 ) ( fig .
kaplan - meier curves for the percentages of ala carriers or pro / pro homozygotes in subjects who developed persistent microalbuminuria throughout the study period .
blood pressure and a1c levels at baseline as well as throughout the whole study period were similar in the two genotype groups ( table 1 and fig .
conversely , in ala carriers compared with pro / pro homozygotes urinary aer increased less during the observation period and was significantly lower at final visit even after adjustment for baseline albuminuria ( ancova , p = 0.048 ) ( fig .
upper panels : trough systolic and diastolic blood pressure throughout the study period in ala carriers or pro / pro homozygotes ( left ) , in ala carriers according to ace inhibitor therapy ( acei ) ( yes or no ) ( middle ) , and in pro / pro homozygotes according to ace inhibitor therapy ( yes or no ) .
* p < 0.05 ( ace inhibitor therapy yes vs. ace inhibitor therapy no , without bonferroni correction for multiple comparisons ) .
lower panels : a1c throughout the study period in ala carriers or pro / pro homozygotes ( left ) , in ala carriers according to ace inhibitor therapy ( yes or no ) ( middle ) , and in pro / pro homozygotes according to ace inhibitor therapy ( yes or no ) . p < 0.05 ( pro / pro homozygotes vs. ala carriers , without bonferroni correction for multiple comparisons ) .
urinary aer ( geometric mean and 95% ci ) at basal and final visits in ala carriers or pro / pro homozygotes .
the difference in urinary aer between the two genotype groups at final visit was significant after adjustment for baseline albumin excretion .
in multivariable analyses , sex , smoking status , baseline albuminuria , baseline and follow - up a1c , and follow - up mean arterial pressure significantly predicted incident microalbuminuria in the whole benedict sample ( p < 0.001 for all considered covariates ) .
ala carriers compared with pro / pro homozygotes showed a trend with lower incidence of microalbuminuria even after adjusting for sex , smoking status , and baseline a1c ( hr 0.48 [ 95% ci 0.221.05 ] ; p = 0.065 ) , but not after adjusting also for baseline albuminuria ( hr 0.64 [ 0.291.40 ] ; p = 0.263 ) .
the difference in the cumulative incidence of events between the two genotype groups was constant throughout the whole observation period , and new cases of microalbuminuria were approximately 50% less in ala compared with pro / pro homozygotes at each considered time point of the follow - up ( proportionality test , p = 0.85 ) . to assess whether the difference in the development of microalbuminuria by pro12ala genotype was due to difference in blood pressure or glucose control , we evaluated interactions between baseline / follow - up mean arterial pressure or a1c and genotype on incidence of microalbuminuria .
furthermore , the distribution of concomitant treatments with glucose- , blood pressure , and lipid - lowering agents as well as of antiplatelet agents at baseline and on follow - up was similar in the two genotype groups ( table 2 ) .
the proportion of patients on two or more antihypertensive medications was also similar in the two groups .
however , there were numerically more patients on diet alone and fewer patients on insulin alone among ala carriers than among pro / pro homozygotes at baseline as well as throughout the follow - up period ( table 2 ) .
among ala carriers , 4 of the 91 patients on ace inhibitor compared with 3 of the 86 on non - ace inhibitor therapy developed microalbuminuria .
thus , in the two treatment groups the incidence of microalbuminuria ( 4.4 vs. 3.5% , respectively ) was similar ( hr 1.21 [ 95% ci 0.275.40 ] ; p = 0.805 ) .
concomitant medications , systolic / diastolic blood pressure , and a1c at baseline and on follow - up were similar in the two treatment groups ( table 1 and fig .
3 , ala carriers : upper and lower panel , respectively ) . among pro / pro homozygotes ,
29 of the 464 patients on ace inhibitor and 57 of the 478 on non - ace inhibitor therapy developed microalbuminuria ( = 9.14 ; p = 0.003 ) .
thus , the incidence of microalbuminuria ( 6.3 vs. 11.9% , respectively ) was significantly lower in those on ace than in those on non - ace inhibitor therapy ( unadjusted hr 0.46 [ 95% ci 0.290.72 ] , p < 0.001 ; adjusted for baseline characteristics including or not including albuminuria 0.44 [ 0.280.69 ] , p
systolic / diastolic blood pressure was similar at baseline , but tended to be lower in patients on ace inhibitor therapy in the follow - up period ( table 1 and fig .
3 , pro / pro homozygotes : upper panel ) . on follow - up ,
a similar proportion of patients was on concomitant treatment with antidiabetic , lipid - lowering , and antiplatelet agents and blood pressure lowering medications , with the exception of sympatholytic agents that were more frequently prescribed in the non - ace inhibitor treatment arm ( table 2 ) .
the incidence of microalbuminuria was significantly lower in ala carriers than in pro / pro homozygotes among subjects on non - ace inhibitor therapy ( unadjusted hr 0.30 [ 0.090.95 ] ; p = 0.041 ) .
the difference was marginally significant after adjusting for sex , smoking status , and baseline a1c ( hr 0.33 [ 0.101.05 ] ; p = 0.061 ) but failed to achieve the statistical significance after adjusting also for baseline albuminuria ( hr 0.56 [ 0.171.82 ] ; p = 0.333 ) . among subjects on ace inhibitor therapy , the incidence of microalbuminuria was similar in the two genotype groups ( unadjusted hr 0.75 [ 0.262.12 ] ; p = 0.582 ) .
altogether , the rate of microalbuminuria in ace inhibitor treated pro / pro homozygotes was similar to that of ala carriers considered as a whole regardless of therapy ( fig .
kaplan - meier curves for the percentages of pro / pro homozygotes considered according to concomitant ace inhibitor therapy ( acei ) ( yes or no ) and of ala carriers considered as a whole in subjects who developed persistent microalbuminuria throughout the study period .
the interaction between baseline a1c and genotype on development of microalbuminuria was significant ( p = 0.035 ) in pro / pro homozygotes without ace inhibitor therapy , but not in those on ace inhibition ( p = 0.64 ) .
baseline a1c was higher in pro / pro homozygotes progressing to microalbuminuria compared with those with stable urinary albumin excretion among patients without ace inhibitor therapy ( p < 0.0001 ) , but not in those on ace inhibition .
there was no significant interaction between follow - up a1c or mean blood pressure and genotype on development of microalbuminuria in any considered group .
the main finding of our present study is that in a large and homogeneous cohort of hypertensive patients with type 2 diabetes and normal aer prospectively followed in the setting of a randomized clinical trial , those who carried the ala12 allele of the pro12ala ppar-2 polymorphism had a significantly lower incidence of persistent microalbuminuria compared with carriers of the wild - type pro / pro genotype .
consistently , ala carriers compared with pro / pro homozygotes showed a slower increase in albuminuria over time that eventually translated into a significantly lower urinary albumin excretion at final visit .
the two genotype groups were very similar for all considered parameters , including prevalence of well - recognized risk factors for microalbuminuria such as male sex and smoking habit .
even more important , a1c and blood pressure control were similar at inclusion as well as throughout the whole study period , ruling out any confounding effect of different metabolic or blood pressure control on considered outcomes .
the comparable distribution to ace or non - ace inhibitor therapy within each group also excluded the possibility that time - dependent changes in albuminuria could be affected by an unbalanced inhibition of the renin - angiotensin system . altogether , the above findings can be taken to suggest that the ala12 allele is associated with an inborn protective effect against time - associated worsening of albuminuria that explained the trend to less albuminuria at inclusion as well as the significantly reduced incidence of microalbuminuria observed throughout the approximately 4 years of follow - up .
consistently , the cumulative incidence of microalbuminuria was 50% lower in ala carriers than in pro / pro homozygotes at any considered time point of the follow - up , and the difference between the two genotype groups was not appreciably affected by censoring all events observed in the first 6 months after inclusion .
these findings provide consistent evidence that the reduced incidence of microalbuminuria in ala carriers was only partially explained by less albuminuria at baseline and rather reflected a genuine protective effect of the ala allele against progression to microalbuminuria that was sustained throughout the whole observation period . to the best of our knowledge ,
this is the first longitudinal evidence of a ( conceivably ) causal association between the ppar-2 pro12ala polymorphism and microalbuminuria .
all previous studies exploring such association were cross - sectional in nature ( 27,28,31 ) and could not describe time - dependent changes in albuminuria according to different genotypes . among the strengths of our present study
was the rigorous definition of the entry criteria ( including the diagnosis of normoalbuminuria that was established on the basis of a urinary aer < 20 g / min in at least two of three consecutive overnight urine collections ) , which allowed to identify a homogeneous population of patients with type 2 diabetes , and the standardized monitoring and treatment of included patients that was based on the guidelines of the benedict study protocol ( 13 ) .
in particular , the diagnosis of new - onset persistent microalbuminuria was established on the basis of a urinary aer between 20 and 200 g / min in at least two of three consecutive overnight urine collections confirmed in two consecutive visits 2 months apart , which allowed to avoid the confounding effect of random fluctuations of albuminuria and intermittent microalbuminuria .
the reliability of urine collections was evaluated by measuring urinary creatinine excretion , and when the creatinine excretion was out of the expected ranges the sample was discarded and the patient was invited to repeat the collection . addressing the mechanisms explaining the reduced risk of microalbuminuria in carriers of the ppar2 ala12 allele was beyond the purposes of the present study . however , more insulin sensitivity in ala carriers might explain why , at comparable metabolic control , these patients tended to need less hypoglycemic agents or insulin than pro / pro homozygotes at baseline as well as throughout the whole observation period . whether less insulin resistance might have a role in the reduced risk of developing microalbuminuria in this population
failure to detect a significant interaction of follow - up a1c ( or mean blood pressure ) and genotype on microalbuminuria was likely explained by the optimized metabolic and blood pressure control achieved during the study in all considered groups . conceivably , this leveled out the independent effect of blood glucose and arterial pressure on progression to the end point .
this increased the study power to detect a specific predictive value for the pro12ala polymorphism in this population .
an additional finding of our present study was that ace compared with non - ace inhibitor therapy halved the incidence of microalbuminuria in pro / pro homozygotes that had their rate of microalbuminuria decreased to the rates observed in ala12 carriers considered as a whole . on the other hand , the incidence of events was so low in ala carriers that the analyses were not sufficiently powered to test the treatment effect in this population .
the significant interaction we found between baseline a1c and risk of microalbuminuria in pro / pro homozygotes without ace inhibitor therapy might indicate that less effective metabolic control might increase the rate of progression to microalbuminuria in those subjects who are at increased risk because of their genetic background .
this interaction was lost in pro / pro homozygotes on ace inhibitor therapy most likely because treatment reduced the incidence of microalbuminuria in particular in those at increased risk because of higher a1c at inclusion .
thus , the pro / pro genotype might be associated with a genetic predisposition to microalbuminuria that manifests in those with less effective metabolic control and is prevented by ace inhibitor therapy .
different outcomes in considered groups are not likely explained by differences in metabolic or blood pressure control on follow - up because multivariable analyses failed to detect any significant interaction between follow - up a1c ( or mean blood pressure ) and treatment arm on microalbuminuria .
more frequent use of sympatholytic agents in patients on non - ace inhibitor treatment did not likely affect progression to microalbuminuria in this population because these agents have not been reported to worsen insulin sensitivity or albuminuria in people with diabetes ( 33 ) . whether amelioration of insulin resistance through inhibited angiotensin ii production might have contributed to limit microalbuminuria in pro
/ pro homozygotes on ace inhibitor therapy independently of glycemia ( 34 ) is worth investigating .
our present data on treatment effect according to different genotypes can not be taken to conclude that ace inhibitor therapy is not effective in ala carriers and that response to treatment is different in the two genotype groups .
indeed , the genotype - by - treatment interaction failed to achieve statistical significance ( p = 0.222)a finding most likely explained by the small number of events in ala carriers that limited the power of comparative analyses between patients on ace or non - ace inhibitor therapy in this subgroup .
moreover , data should be taken with caution because they were generated from exploratory analyses of a study that was not originally powered to test the hypotheses under evaluation here .
on the other hand , the protective effect of ace inhibitor therapy against the development of microalbuminuria in pro / pro homozygotes was clinically relevant and statistically significant .
these data were obtained from carefully monitored patients in the setting of a prospective , controlled clinical trial and were in harmony with previous findings from cross - sectional studies in similar patient populations ( 27,28 ) .
thus , they appear to be sufficiently robust and reliable even if they were not verified in an independent external test set . of note , baseline characteristics of study patients were similar to those of patients referred to the diabetology units of the benedict network who had been screened for study participation but had not been included in the trial .
this provides the evidence that our findings can be generalized to the average population of patients with type 2 diabetes , in particular to those with arterial hypertension but still no evidence of renal involvement . in conclusion
, our prospective study found that among normoalbuminuric hypertensive patients with type 2 diabetes , ppar-2 ala carriers had a reduced rate of persistent microalbuminuria .
pro / pro homozygotes were at increased risk of developing microalbuminuria but their risk was appreciably reduced by ace inhibitor therapy . thus , screening for the pro12ala ppar-2 polymorphism may help to identify patients at increased risk who may benefit the most from early ace inhibitor therapy .
further studies are needed to unravel whether protection from microalbuminuria may translate into a reduced long - term risk of renal and cardiovascular events in this population .
our present data on treatment effect according to different genotypes can not be taken to conclude that ace inhibitor therapy is not effective in ala carriers and that response to treatment is different in the two genotype groups .
indeed , the genotype - by - treatment interaction failed to achieve statistical significance ( p = 0.222)a finding most likely explained by the small number of events in ala carriers that limited the power of comparative analyses between patients on ace or non - ace inhibitor therapy in this subgroup .
moreover , data should be taken with caution because they were generated from exploratory analyses of a study that was not originally powered to test the hypotheses under evaluation here .
on the other hand , the protective effect of ace inhibitor therapy against the development of microalbuminuria in pro / pro homozygotes was clinically relevant and statistically significant .
these data were obtained from carefully monitored patients in the setting of a prospective , controlled clinical trial and were in harmony with previous findings from cross - sectional studies in similar patient populations ( 27,28 ) .
thus , they appear to be sufficiently robust and reliable even if they were not verified in an independent external test set . of note ,
baseline characteristics of study patients were similar to those of patients referred to the diabetology units of the benedict network who had been screened for study participation but had not been included in the trial .
this provides the evidence that our findings can be generalized to the average population of patients with type 2 diabetes , in particular to those with arterial hypertension but still no evidence of renal involvement . in conclusion
, our prospective study found that among normoalbuminuric hypertensive patients with type 2 diabetes , ppar-2 ala carriers had a reduced rate of persistent microalbuminuria .
pro / pro homozygotes were at increased risk of developing microalbuminuria but their risk was appreciably reduced by ace inhibitor therapy .
thus , screening for the pro12ala ppar-2 polymorphism may help to identify patients at increased risk who may benefit the most from early ace inhibitor therapy .
further studies are needed to unravel whether protection from microalbuminuria may translate into a reduced long - term risk of renal and cardiovascular events in this population . | objectivecross - sectional studies found less microalbuminuria in type 2 diabetic patients with the ala12 allele of the peroxisome proliferator activated receptor-2 ( ppar-2 ) pro12ala polymorphism .
we prospectively evaluated the association between pro12ala polymorphism ( rs1801282 ) and new - onset microalbuminuria.research design and methodspro12ala polymorphism was genotyped by taqman - based assay in genomic dna of 1,119 consenting patients from bergamo nephrologic diabetic complications trial ( benedict)a prospective , randomized trial evaluating ace inhibition effect on new - onset microalbuminuria ( albuminuria 20200 g / min in at least two of three consecutive overnight urine collections in two consecutive visits ) in hypertensive type 2 diabetes with albuminuria < 20 g / min at inclusion.resultsbaseline characteristics of ala ( ala / ala or ala / pro ) carriers and pro / pro homozygotes were similar , with a nonsignificant trend to lower albuminuria ( p = 0.1107 ) in the 177 ala carriers . over a median ( interquartile range ) of 44.0 ( 17.151.9 ) months , 7 ( 4% ) ala carriers and 86 ( 9.1% ) pro / pro homozygotes developed microalbuminuria ( hazard ratio [ hr ] 0.45 [ 95% ci 0.210.97 ] ; p = 0.042 ) .
final albuminuria was significantly lower in ala carriers than pro / pro homozygotes ( 7.3 9.1 vs. 10.5 24.9 g / min , respectively ) , even after adjustment for baseline albuminuria ( p = 0.048 ) .
baseline and follow - up blood pressure and metabolic control were similar in both groups .
incidence of microalbuminuria was significantly decreased by ace versus non - ace inhibitor therapy in pro / pro homozygotes ( 6.3 vs. 11.9% , respectively , hr 0.46 [ 0.290.72 ] ; p < 0.001).conclusionsin type 2 diabetes , the ala allele protects from worsening albuminuria and new - onset microalbuminuria , and ace inhibition blunts the excess risk of microalbuminuria associated with the pro / pro genotype .
evaluating pro12ala polymorphism may help identifying patients at risk who may benefit the most from early renoprotective therapy . | <s>[INST]benedict was a double - blind , randomized , placebo - controlled study aimed to assess whether ace inhibitors and nondihydropyridine calcium - channel blockers , alone or in combination , prevent microalbuminuria in subjects with type 2 diabetes , hypertension , and normal urinary albumin excretion at baseline ( 13 ) .
patients ( n = 1,204 ) were randomly allocated to at least 3-year treatment with the ace inhibitor trandolapril , the nondihydropyridine calcium - channel blocker verapamil , the combination of verapamil plus trandolapril , or placebo , added on background non ace - inhibiting therapy targeting systolic / diastolic blood pressure < 120/80 mmhg ( 13 ) .
primary end point was new - onset persistent microalbuminuria ( urinary albumin excretion 20 g and < 200 g / min in at least two of three consecutive overnight urine collections on two consecutive visits 2 months apart ) .
urinary albumin excretion was measured on fresh urines at the coordinating center by nephelometry ( beckman array system ; beckman coulter ) at randomization and every 6 months thereafter .
trandolapril plus verapamil and trandolapril alone significantly delayed the onset of microalbuminuria by factors of 2.6 and 2.1 , respectively , compared with placebo ( p < 0.01 for both ) .
the incidence of microalbuminuria was reduced to a similar extent by both treatments , whereas verapamil had an effect on the incidence of microalbuminuria that was similar to that of placebo ( 12,13 ) .
thus , patients were pooled in two cohorts according to their original allocation to ace or non - ace inhibitor therapy regardless of concomitant therapy with verapamil or placebo .
gene - by - treatment interactions were tested according to ace inhibitor therapy ( yes or no ) .
the study protocol was approved by the local ethics committees , and only samples from patients who provided written informed consent according to the helsinki declaration guidelines were considered for genetic analyses .
genotyping for pro12ala single nucleotide polymorphism ( snp ; rs1801282 ) was performed using taqman pre - designed snp genotyping assay from applied biosystems ( assay c_1129864_10 ; abi , foster city , ca ) .
genotypes were scored by analyzing data on both real - time as well as allele discrimination assay platforms using sds software provided by abi .
as a quality - control procedure , we double - genotyped a subset of 200 individuals ( 18% of the whole sample ) using a different genotyping method on the lightcycler 480 system ( roche diagnostics , http://www.roche-applied-science.com ) .
this was a melting curve - based genotyping method using fluorescence - labeled hybridization probes ( 32 ) .
primers and probes for genotyping pro12ala snp on lightcycler 480 system were designed , synthesized , and validated by tib molbiol ( genoa , italy , http://www.tib-molbiol.com ) using the genomic sequence available from ncbi dbsnp for the rs1801282 .
04 707 524 001 ; roche applied science ) , 10 pmol of each primer ( forward 5gcc cag tcc ttt ctg tgt t 3 and reverse 5 gtc ccc aat agc cgt atc tg 3 , melting temperature 55c ) , 4 pmol of each probe ( sensor hybprobe lc red 640-cct tca ctg ata cac tgt ctg caa aca tat cac - phosphate and anchor hybprobe tct cct att gac cca gaa agc gat - fluorescein , melting temperature 60c and 64c , respectively ) , and 50 ng of genomic dna in a final volume of 20 l according to manufacturer 's instructions .
patients ' baseline characteristics according to ppar-2 pro12ala polymorphism are reported as means sd or frequencies and percentages .
p values refer to mann - whitney u test and pearson for continuous and categorical variables , respectively .
time to onset of microalbuminuria was considered as the main end point . for patients who did not reach the main end point ,
cox proportional hazards regression models were used , and results are expressed as hazard ratios ( hrs ) and 95% cis . to test the effect of pro12ala polymorphism on outcome , three different statistical models have been designed : the first was a model adjusted only for ace inhibitor therapy ( i.e. , yes or no = 0 or 1 ) ; in the second model , variables that predicted microalbuminuria onset in the whole cohort , such as sex , smoking status , and a1c , were added to ace inhibitor therapy ; in the third model , baseline aer levels , which were slightly lower at study entry in ala carriers , were taken into account in addition to ace inhibitor therapy and baseline covariates . between - groups comparison of aer at final visit was carried out by ancova , adjusting for baseline measurement .
nonnormally distributed covariates ( namely , aer and triglycerides ) were log transformed before analysis .
all the analyses were performed using sas statistical package release 9.1 ( sas institute , cary , nc ) .
genotyping for pro12ala single nucleotide polymorphism ( snp ; rs1801282 ) was performed using taqman pre - designed snp genotyping assay from applied biosystems ( assay c_1129864_10 ; abi , foster city , ca ) .
genotypes were scored by analyzing data on both real - time as well as allele discrimination assay platforms using sds software provided by abi .
as a quality - control procedure , we double - genotyped a subset of 200 individuals ( 18% of the whole sample ) using a different genotyping method on the lightcycler 480 system ( roche diagnostics , http://www.roche-applied-science.com ) .
this was a melting curve - based genotyping method using fluorescence - labeled hybridization probes ( 32 ) .
primers and probes for genotyping pro12ala snp on lightcycler 480 system were designed , synthesized , and validated by tib molbiol ( genoa , italy , http://www.tib-molbiol.com ) using the genomic sequence available from ncbi dbsnp for the rs1801282 .
04 707 524 001 ; roche applied science ) , 10 pmol of each primer ( forward 5gcc cag tcc ttt ctg tgt t 3 and reverse 5 gtc ccc aat agc cgt atc tg 3 , melting temperature 55c ) , 4 pmol of each probe ( sensor hybprobe lc red 640-cct tca ctg ata cac tgt ctg caa aca tat cac - phosphate and anchor hybprobe tct cct att gac cca gaa agc gat - fluorescein , melting temperature 60c and 64c , respectively ) , and 50 ng of genomic dna in a final volume of 20 l according to manufacturer 's instructions .
patients ' baseline characteristics according to ppar-2 pro12ala polymorphism are reported as means sd or frequencies and percentages .
p values refer to mann - whitney u test and pearson for continuous and categorical variables , respectively .
time to onset of microalbuminuria was considered as the main end point . for patients who did not reach the main end point , time
cox proportional hazards regression models were used , and results are expressed as hazard ratios ( hrs ) and 95% cis . to test the effect of pro12ala polymorphism on outcome , three different statistical models have been designed : the first was a model adjusted only for ace inhibitor therapy ( i.e. , yes or no = 0 or 1 ) ; in the second model , variables that predicted microalbuminuria onset in the whole cohort , such as sex , smoking status , and a1c , were added to ace inhibitor therapy ; in the third model , baseline aer levels , which were slightly lower at study entry in ala carriers , were taken into account in addition to ace inhibitor therapy and baseline covariates . between - groups comparison of aer at final visit
nonnormally distributed covariates ( namely , aer and triglycerides ) were log transformed before analysis .
all the analyses were performed using sas statistical package release 9.1 ( sas institute , cary , nc ) .
of these patients , 7 ( 0.6% ) and 170 ( 15.2% ) were homozygous and heterozygous for the ala12 allele , respectively , from now ala carriers , and 942 ( 84.2% ) were homozygous for the pro12 allele , from now pro / pro homozygotes ( fig .
1 ) . frequency of ala carriers was comparable with that previously reported in other white populations ( 25 ) .
the proportion of the pro12ala genotypes did not significantly deviate from hardy - weinberg equilibrium ( = 0.05 ; p = 0.82 ) .
data from homozygous and heterozygous ala carriers were pooled and considered together for comparative analyses with pro / pro homozygotes .
baseline characteristics of the two groups were similar ( tables 1 and 2 ) , with a trend to lower albuminuria at inclusion in ala carriers ( table 1 ) , as well as the proportion of patients allocated to ace inhibitor therapy ( yes or no ) within each group ( table 1 ) .
baseline characteristics of patients who had been randomized to ace inhibitor therapy ( yes or no ) within the two genotype groups were similar ( table 1 ) .
baseline clinical features of patients with type 2 diabetes data are means sd , n ( % ) , or geometric means ( 95% cis ) .
differences between ala carriers and pro / pro homozygotes ( overall ) as well as between acei yes and acei no ( within each genotype group ) were not significant .
acei , ace inhibitor therapy ; dbp , diastolic blood pressure ; and sbp , systolic blood pressure .
concomitant treatments in patients with type 2 diabetes at baseline and on follow - up * * all differences between the two genotype groups ( ala vs. pro / pro ) were not significant .
acei , ace inhibitor therapy . over a median ( interquartile range ) of 44 ( 17.151.9 )
months of follow - up , 7 ala carriers ( 4% ) compared with 86 pro / pro homozygotes ( 9.1% ) developed persistent microalbuminuria ( = 4.35 ; p = 0.037 ) .
the unadjusted hr for microalbuminuria in ala carriers compared with pro / pro homozygotes was 0.45 ( 95% ci 0.210.97 ) ( p = 0.042 ) ( fig .
kaplan - meier curves for the percentages of ala carriers or pro / pro homozygotes in subjects who developed persistent microalbuminuria throughout the study period .
blood pressure and a1c levels at baseline as well as throughout the whole study period were similar in the two genotype groups ( table 1 and fig .
conversely , in ala carriers compared with pro / pro homozygotes urinary aer increased less during the observation period and was significantly lower at final visit even after adjustment for baseline albuminuria ( ancova , p = 0.048 ) ( fig .
upper panels : trough systolic and diastolic blood pressure throughout the study period in ala carriers or pro / pro homozygotes ( left ) , in ala carriers according to ace inhibitor therapy ( acei ) ( yes or no ) ( middle ) , and in pro / pro homozygotes according to ace inhibitor therapy ( yes or no ) . * p < 0.05 ( ace inhibitor therapy yes vs. ace inhibitor therapy no , without bonferroni correction for multiple comparisons ) .
lower panels : a1c throughout the study period in ala carriers or pro / pro homozygotes ( left ) , in ala carriers according to ace inhibitor therapy ( yes or no ) ( middle ) , and in pro / pro homozygotes according to ace inhibitor therapy ( yes or no ) . p < 0.05 ( pro / pro homozygotes vs. ala carriers , without bonferroni correction for multiple comparisons ) .
urinary aer ( geometric mean and 95% ci ) at basal and final visits in ala carriers or pro / pro homozygotes .
the difference in urinary aer between the two genotype groups at final visit was significant after adjustment for baseline albumin excretion .
in multivariable analyses , sex , smoking status , baseline albuminuria , baseline and follow - up a1c , and follow - up mean arterial pressure significantly predicted incident microalbuminuria in the whole benedict sample ( p < 0.001 for all considered covariates ) .
ala carriers compared with pro / pro homozygotes showed a trend with lower incidence of microalbuminuria even after adjusting for sex , smoking status , and baseline a1c ( hr 0.48 [ 95% ci 0.221.05 ] ; p = 0.065 ) , but not after adjusting also for baseline albuminuria ( hr 0.64 [ 0.291.40 ] ; p = 0.263 ) . the difference in the cumulative incidence of events between the two genotype groups was constant throughout the whole observation period , and new cases of microalbuminuria were approximately 50% less in ala compared with pro / pro homozygotes at each considered time point of the follow - up ( proportionality test , p = 0.85 ) . to assess whether the difference in the development of microalbuminuria by pro12ala genotype was due to difference in blood pressure or glucose control , we evaluated interactions between baseline / follow - up mean arterial pressure or a1c and genotype on incidence of microalbuminuria .
furthermore , the distribution of concomitant treatments with glucose- , blood pressure , and lipid - lowering agents as well as of antiplatelet agents at baseline and on follow - up was similar in the two genotype groups ( table 2 ) .
the proportion of patients on two or more antihypertensive medications was also similar in the two groups .
however , there were numerically more patients on diet alone and fewer patients on insulin alone among ala carriers than among pro / pro homozygotes at baseline as well as throughout the follow - up period ( table 2 ) .
4 of the 91 patients on ace inhibitor compared with 3 of the 86 on non - ace inhibitor therapy developed microalbuminuria .
thus , in the two treatment groups the incidence of microalbuminuria ( 4.4 vs. 3.5% , respectively ) was similar ( hr 1.21 [ 95% ci 0.275.40 ] ; p = 0.805 ) .
concomitant medications , systolic / diastolic blood pressure , and a1c at baseline and on follow - up were similar in the two treatment groups ( table 1 and fig .
3 , ala carriers : upper and lower panel , respectively ) . among pro / pro homozygotes ,
29 of the 464 patients on ace inhibitor and 57 of the 478 on non - ace inhibitor therapy developed microalbuminuria ( = 9.14 ; p = 0.003 ) .
thus , the incidence of microalbuminuria ( 6.3 vs. 11.9% , respectively ) was significantly lower in those on ace than in those on non - ace inhibitor therapy ( unadjusted hr 0.46 [ 95% ci 0.290.72 ] , p < 0.001 ; adjusted for baseline characteristics including or not including albuminuria 0.44 [ 0.280.69 ] , p < 0.001 ) .
systolic / diastolic blood pressure was similar at baseline , but tended to be lower in patients on ace inhibitor therapy in the follow - up period ( table 1 and fig .
3 , pro / pro homozygotes : upper panel ) . on follow - up ,
a similar proportion of patients was on concomitant treatment with antidiabetic , lipid - lowering , and antiplatelet agents and blood pressure lowering medications , with the exception of sympatholytic agents that were more frequently prescribed in the non - ace inhibitor treatment arm ( table 2 ) .
the incidence of microalbuminuria was significantly lower in ala carriers than in pro / pro homozygotes among subjects on non - ace inhibitor therapy ( unadjusted hr 0.30 [ 0.090.95 ] ; p = 0.041 ) .
the difference was marginally significant after adjusting for sex , smoking status , and baseline a1c ( hr 0.33 [ 0.101.05 ] ; p = 0.061 ) but failed to achieve the statistical significance after adjusting also for baseline albuminuria ( hr 0.56 [ 0.171.82 ] ; p = 0.333 ) . among subjects on ace inhibitor therapy ,
the incidence of microalbuminuria was similar in the two genotype groups ( unadjusted hr 0.75 [ 0.262.12 ] ; p = 0.582 ) .
altogether , the rate of microalbuminuria in ace inhibitor treated pro / pro homozygotes was similar to that of ala carriers considered as a whole regardless of therapy ( fig . 5 ) .
kaplan - meier curves for the percentages of pro / pro homozygotes considered according to concomitant ace inhibitor therapy ( acei ) ( yes or no ) and of ala carriers considered as a whole in subjects who developed persistent microalbuminuria throughout the study period .
the interaction between baseline a1c and genotype on development of microalbuminuria was significant ( p = 0.035 ) in pro / pro homozygotes without ace inhibitor therapy , but not in those on ace inhibition ( p = 0.64 ) .
baseline a1c was higher in pro / pro homozygotes progressing to microalbuminuria compared with those with stable urinary albumin excretion among patients without ace inhibitor therapy ( p < 0.0001 ) , but not in those on ace inhibition .
there was no significant interaction between follow - up a1c or mean blood pressure and genotype on development of microalbuminuria in any considered group .
of these patients , 7 ( 0.6% ) and 170 ( 15.2% ) were homozygous and heterozygous for the ala12 allele , respectively , from now ala carriers , and 942 ( 84.2% ) were homozygous for the pro12 allele , from now pro / pro homozygotes ( fig .
1 ) . frequency of ala carriers was comparable with that previously reported in other white populations ( 25 ) .
the proportion of the pro12ala genotypes did not significantly deviate from hardy - weinberg equilibrium ( = 0.05 ; p = 0.82 ) .
data from homozygous and heterozygous ala carriers were pooled and considered together for comparative analyses with pro / pro homozygotes .
baseline characteristics of the two groups were similar ( tables 1 and 2 ) , with a trend to lower albuminuria at inclusion in ala carriers ( table 1 ) , as well as the proportion of patients allocated to ace inhibitor therapy ( yes or no ) within each group ( table 1 ) .
baseline characteristics of patients who had been randomized to ace inhibitor therapy ( yes or no ) within the two genotype groups were similar ( table 1 ) .
baseline clinical features of patients with type 2 diabetes data are means sd , n ( % ) , or geometric means ( 95% cis ) .
differences between ala carriers and pro / pro homozygotes ( overall ) as well as between acei yes and acei no ( within each genotype group ) were not significant .
acei , ace inhibitor therapy ; dbp , diastolic blood pressure ; and sbp , systolic blood pressure .
concomitant treatments in patients with type 2 diabetes at baseline and on follow - up * * all differences between the two genotype groups ( ala vs. pro / pro ) were not significant .
over a median ( interquartile range ) of 44 ( 17.151.9 ) months of follow - up , 7 ala carriers ( 4% ) compared with 86 pro / pro homozygotes ( 9.1% ) developed persistent microalbuminuria ( = 4.35 ; p = 0.037 ) .
the unadjusted hr for microalbuminuria in ala carriers compared with pro / pro homozygotes was 0.45 ( 95% ci 0.210.97 ) ( p = 0.042 ) ( fig .
kaplan - meier curves for the percentages of ala carriers or pro / pro homozygotes in subjects who developed persistent microalbuminuria throughout the study period .
blood pressure and a1c levels at baseline as well as throughout the whole study period were similar in the two genotype groups ( table 1 and fig .
conversely , in ala carriers compared with pro / pro homozygotes urinary aer increased less during the observation period and was significantly lower at final visit even after adjustment for baseline albuminuria ( ancova , p = 0.048 ) ( fig .
upper panels : trough systolic and diastolic blood pressure throughout the study period in ala carriers or pro / pro homozygotes ( left ) , in ala carriers according to ace inhibitor therapy ( acei ) ( yes or no ) ( middle ) , and in pro / pro homozygotes according to ace inhibitor therapy ( yes or no ) .
* p < 0.05 ( ace inhibitor therapy yes vs. ace inhibitor therapy no , without bonferroni correction for multiple comparisons ) .
lower panels : a1c throughout the study period in ala carriers or pro / pro homozygotes ( left ) , in ala carriers according to ace inhibitor therapy ( yes or no ) ( middle ) , and in pro / pro homozygotes according to ace inhibitor therapy ( yes or no ) . p < 0.05 ( pro / pro homozygotes vs. ala carriers , without bonferroni correction for multiple comparisons ) .
urinary aer ( geometric mean and 95% ci ) at basal and final visits in ala carriers or pro / pro homozygotes .
the difference in urinary aer between the two genotype groups at final visit was significant after adjustment for baseline albumin excretion .
in multivariable analyses , sex , smoking status , baseline albuminuria , baseline and follow - up a1c , and follow - up mean arterial pressure significantly predicted incident microalbuminuria in the whole benedict sample ( p < 0.001 for all considered covariates ) .
ala carriers compared with pro / pro homozygotes showed a trend with lower incidence of microalbuminuria even after adjusting for sex , smoking status , and baseline a1c ( hr 0.48 [ 95% ci 0.221.05 ] ; p = 0.065 ) , but not after adjusting also for baseline albuminuria ( hr 0.64 [ 0.291.40 ] ; p = 0.263 ) .
the difference in the cumulative incidence of events between the two genotype groups was constant throughout the whole observation period , and new cases of microalbuminuria were approximately 50% less in ala compared with pro / pro homozygotes at each considered time point of the follow - up ( proportionality test , p = 0.85 ) . to assess whether the difference in the development of microalbuminuria by pro12ala genotype was due to difference in blood pressure or glucose control , we evaluated interactions between baseline / follow - up mean arterial pressure or a1c and genotype on incidence of microalbuminuria .
furthermore , the distribution of concomitant treatments with glucose- , blood pressure , and lipid - lowering agents as well as of antiplatelet agents at baseline and on follow - up was similar in the two genotype groups ( table 2 ) .
the proportion of patients on two or more antihypertensive medications was also similar in the two groups .
however , there were numerically more patients on diet alone and fewer patients on insulin alone among ala carriers than among pro / pro homozygotes at baseline as well as throughout the follow - up period ( table 2 ) .
among ala carriers , 4 of the 91 patients on ace inhibitor compared with 3 of the 86 on non - ace inhibitor therapy developed microalbuminuria .
thus , in the two treatment groups the incidence of microalbuminuria ( 4.4 vs. 3.5% , respectively ) was similar ( hr 1.21 [ 95% ci 0.275.40 ] ; p = 0.805 ) .
concomitant medications , systolic / diastolic blood pressure , and a1c at baseline and on follow - up were similar in the two treatment groups ( table 1 and fig .
3 , ala carriers : upper and lower panel , respectively ) . among pro / pro homozygotes ,
29 of the 464 patients on ace inhibitor and 57 of the 478 on non - ace inhibitor therapy developed microalbuminuria ( = 9.14 ; p = 0.003 ) .
thus , the incidence of microalbuminuria ( 6.3 vs. 11.9% , respectively ) was significantly lower in those on ace than in those on non - ace inhibitor therapy ( unadjusted hr 0.46 [ 95% ci 0.290.72 ] , p < 0.001 ; adjusted for baseline characteristics including or not including albuminuria 0.44 [ 0.280.69 ] , p
systolic / diastolic blood pressure was similar at baseline , but tended to be lower in patients on ace inhibitor therapy in the follow - up period ( table 1 and fig .
3 , pro / pro homozygotes : upper panel ) . on follow - up ,
a similar proportion of patients was on concomitant treatment with antidiabetic , lipid - lowering , and antiplatelet agents and blood pressure lowering medications , with the exception of sympatholytic agents that were more frequently prescribed in the non - ace inhibitor treatment arm ( table 2 ) .
the incidence of microalbuminuria was significantly lower in ala carriers than in pro / pro homozygotes among subjects on non - ace inhibitor therapy ( unadjusted hr 0.30 [ 0.090.95 ] ; p = 0.041 ) .
the difference was marginally significant after adjusting for sex , smoking status , and baseline a1c ( hr 0.33 [ 0.101.05 ] ; p = 0.061 ) but failed to achieve the statistical significance after adjusting also for baseline albuminuria ( hr 0.56 [ 0.171.82 ] ; p = 0.333 ) . among subjects on ace inhibitor therapy , the incidence of microalbuminuria was similar in the two genotype groups ( unadjusted hr 0.75 [ 0.262.12 ] ; p = 0.582 ) .
altogether , the rate of microalbuminuria in ace inhibitor treated pro / pro homozygotes was similar to that of ala carriers considered as a whole regardless of therapy ( fig .
kaplan - meier curves for the percentages of pro / pro homozygotes considered according to concomitant ace inhibitor therapy ( acei ) ( yes or no ) and of ala carriers considered as a whole in subjects who developed persistent microalbuminuria throughout the study period .
the interaction between baseline a1c and genotype on development of microalbuminuria was significant ( p = 0.035 ) in pro / pro homozygotes without ace inhibitor therapy , but not in those on ace inhibition ( p = 0.64 ) .
baseline a1c was higher in pro / pro homozygotes progressing to microalbuminuria compared with those with stable urinary albumin excretion among patients without ace inhibitor therapy ( p < 0.0001 ) , but not in those on ace inhibition .
there was no significant interaction between follow - up a1c or mean blood pressure and genotype on development of microalbuminuria in any considered group .
the main finding of our present study is that in a large and homogeneous cohort of hypertensive patients with type 2 diabetes and normal aer prospectively followed in the setting of a randomized clinical trial , those who carried the ala12 allele of the pro12ala ppar-2 polymorphism had a significantly lower incidence of persistent microalbuminuria compared with carriers of the wild - type pro / pro genotype .
consistently , ala carriers compared with pro / pro homozygotes showed a slower increase in albuminuria over time that eventually translated into a significantly lower urinary albumin excretion at final visit .
the two genotype groups were very similar for all considered parameters , including prevalence of well - recognized risk factors for microalbuminuria such as male sex and smoking habit .
even more important , a1c and blood pressure control were similar at inclusion as well as throughout the whole study period , ruling out any confounding effect of different metabolic or blood pressure control on considered outcomes .
the comparable distribution to ace or non - ace inhibitor therapy within each group also excluded the possibility that time - dependent changes in albuminuria could be affected by an unbalanced inhibition of the renin - angiotensin system . altogether , the above findings can be taken to suggest that the ala12 allele is associated with an inborn protective effect against time - associated worsening of albuminuria that explained the trend to less albuminuria at inclusion as well as the significantly reduced incidence of microalbuminuria observed throughout the approximately 4 years of follow - up .
consistently , the cumulative incidence of microalbuminuria was 50% lower in ala carriers than in pro / pro homozygotes at any considered time point of the follow - up , and the difference between the two genotype groups was not appreciably affected by censoring all events observed in the first 6 months after inclusion .
these findings provide consistent evidence that the reduced incidence of microalbuminuria in ala carriers was only partially explained by less albuminuria at baseline and rather reflected a genuine protective effect of the ala allele against progression to microalbuminuria that was sustained throughout the whole observation period . to the best of our knowledge ,
this is the first longitudinal evidence of a ( conceivably ) causal association between the ppar-2 pro12ala polymorphism and microalbuminuria .
all previous studies exploring such association were cross - sectional in nature ( 27,28,31 ) and could not describe time - dependent changes in albuminuria according to different genotypes . among the strengths of our present study
was the rigorous definition of the entry criteria ( including the diagnosis of normoalbuminuria that was established on the basis of a urinary aer < 20 g / min in at least two of three consecutive overnight urine collections ) , which allowed to identify a homogeneous population of patients with type 2 diabetes , and the standardized monitoring and treatment of included patients that was based on the guidelines of the benedict study protocol ( 13 ) .
in particular , the diagnosis of new - onset persistent microalbuminuria was established on the basis of a urinary aer between 20 and 200 g / min in at least two of three consecutive overnight urine collections confirmed in two consecutive visits 2 months apart , which allowed to avoid the confounding effect of random fluctuations of albuminuria and intermittent microalbuminuria .
the reliability of urine collections was evaluated by measuring urinary creatinine excretion , and when the creatinine excretion was out of the expected ranges the sample was discarded and the patient was invited to repeat the collection . addressing the mechanisms explaining the reduced risk of microalbuminuria in carriers of the ppar2 ala12 allele was beyond the purposes of the present study . however , more insulin sensitivity in ala carriers might explain why , at comparable metabolic control , these patients tended to need less hypoglycemic agents or insulin than pro / pro homozygotes at baseline as well as throughout the whole observation period . whether less insulin resistance might have a role in the reduced risk of developing microalbuminuria in this population
failure to detect a significant interaction of follow - up a1c ( or mean blood pressure ) and genotype on microalbuminuria was likely explained by the optimized metabolic and blood pressure control achieved during the study in all considered groups . conceivably , this leveled out the independent effect of blood glucose and arterial pressure on progression to the end point .
this increased the study power to detect a specific predictive value for the pro12ala polymorphism in this population .
an additional finding of our present study was that ace compared with non - ace inhibitor therapy halved the incidence of microalbuminuria in pro / pro homozygotes that had their rate of microalbuminuria decreased to the rates observed in ala12 carriers considered as a whole . on the other hand , the incidence of events was so low in ala carriers that the analyses were not sufficiently powered to test the treatment effect in this population .
the significant interaction we found between baseline a1c and risk of microalbuminuria in pro / pro homozygotes without ace inhibitor therapy might indicate that less effective metabolic control might increase the rate of progression to microalbuminuria in those subjects who are at increased risk because of their genetic background .
this interaction was lost in pro / pro homozygotes on ace inhibitor therapy most likely because treatment reduced the incidence of microalbuminuria in particular in those at increased risk because of higher a1c at inclusion .
thus , the pro / pro genotype might be associated with a genetic predisposition to microalbuminuria that manifests in those with less effective metabolic control and is prevented by ace inhibitor therapy .
different outcomes in considered groups are not likely explained by differences in metabolic or blood pressure control on follow - up because multivariable analyses failed to detect any significant interaction between follow - up a1c ( or mean blood pressure ) and treatment arm on microalbuminuria .
more frequent use of sympatholytic agents in patients on non - ace inhibitor treatment did not likely affect progression to microalbuminuria in this population because these agents have not been reported to worsen insulin sensitivity or albuminuria in people with diabetes ( 33 ) . whether amelioration of insulin resistance through inhibited angiotensin ii production might have contributed to limit microalbuminuria in pro
/ pro homozygotes on ace inhibitor therapy independently of glycemia ( 34 ) is worth investigating .
our present data on treatment effect according to different genotypes can not be taken to conclude that ace inhibitor therapy is not effective in ala carriers and that response to treatment is different in the two genotype groups .
indeed , the genotype - by - treatment interaction failed to achieve statistical significance ( p = 0.222)a finding most likely explained by the small number of events in ala carriers that limited the power of comparative analyses between patients on ace or non - ace inhibitor therapy in this subgroup .
moreover , data should be taken with caution because they were generated from exploratory analyses of a study that was not originally powered to test the hypotheses under evaluation here .
on the other hand , the protective effect of ace inhibitor therapy against the development of microalbuminuria in pro / pro homozygotes was clinically relevant and statistically significant .
these data were obtained from carefully monitored patients in the setting of a prospective , controlled clinical trial and were in harmony with previous findings from cross - sectional studies in similar patient populations ( 27,28 ) .
thus , they appear to be sufficiently robust and reliable even if they were not verified in an independent external test set . of note , baseline characteristics of study patients were similar to those of patients referred to the diabetology units of the benedict network who had been screened for study participation but had not been included in the trial .
this provides the evidence that our findings can be generalized to the average population of patients with type 2 diabetes , in particular to those with arterial hypertension but still no evidence of renal involvement . in conclusion
, our prospective study found that among normoalbuminuric hypertensive patients with type 2 diabetes , ppar-2 ala carriers had a reduced rate of persistent microalbuminuria .
pro / pro homozygotes were at increased risk of developing microalbuminuria but their risk was appreciably reduced by ace inhibitor therapy . thus , screening for the pro12ala ppar-2 polymorphism may help to identify patients at increased risk who may benefit the most from early ace inhibitor therapy .
further studies are needed to unravel whether protection from microalbuminuria may translate into a reduced long - term risk of renal and cardiovascular events in this population .
our present data on treatment effect according to different genotypes can not be taken to conclude that ace inhibitor therapy is not effective in ala carriers and that response to treatment is different in the two genotype groups .
indeed , the genotype - by - treatment interaction failed to achieve statistical significance ( p = 0.222)a finding most likely explained by the small number of events in ala carriers that limited the power of comparative analyses between patients on ace or non - ace inhibitor therapy in this subgroup .
moreover , data should be taken with caution because they were generated from exploratory analyses of a study that was not originally powered to test the hypotheses under evaluation here .
on the other hand , the protective effect of ace inhibitor therapy against the development of microalbuminuria in pro / pro homozygotes was clinically relevant and statistically significant .
these data were obtained from carefully monitored patients in the setting of a prospective , controlled clinical trial and were in harmony with previous findings from cross - sectional studies in similar patient populations ( 27,28 ) .
thus , they appear to be sufficiently robust and reliable even if they were not verified in an independent external test set . of note ,
baseline characteristics of study patients were similar to those of patients referred to the diabetology units of the benedict network who had been screened for study participation but had not been included in the trial .
this provides the evidence that our findings can be generalized to the average population of patients with type 2 diabetes , in particular to those with arterial hypertension but still no evidence of renal involvement . in conclusion
, our prospective study found that among normoalbuminuric hypertensive patients with type 2 diabetes , ppar-2 ala carriers had a reduced rate of persistent microalbuminuria .
pro / pro homozygotes were at increased risk of developing microalbuminuria but their risk was appreciably reduced by ace inhibitor therapy .
thus , screening for the pro12ala ppar-2 polymorphism may help to identify patients at increased risk who may benefit the most from early ace inhibitor therapy .
further studies are needed to unravel whether protection from microalbuminuria may translate into a reduced long - term risk of renal and cardiovascular events in this population .[/INST]objectivecross - sectional studies found less microalbuminuria in type 2 diabetic patients with the ala12 allele of the peroxisome proliferator activated receptor-2 ( ppar-2 ) pro12ala polymorphism .
we prospectively evaluated the association between pro12ala polymorphism ( rs1801282 ) and new - onset microalbuminuria.research design and methodspro12ala polymorphism was genotyped by taqman - based assay in genomic dna of 1,119 consenting patients from bergamo nephrologic diabetic complications trial ( benedict)a prospective , randomized trial evaluating ace inhibition effect on new - onset microalbuminuria ( albuminuria 20200 g / min in at least two of three consecutive overnight urine collections in two consecutive visits ) in hypertensive type 2 diabetes with albuminuria < 20 g / min at inclusion.resultsbaseline characteristics of ala ( ala / ala or ala / pro ) carriers and pro / pro homozygotes were similar , with a nonsignificant trend to lower albuminuria ( p = 0.1107 ) in the 177 ala carriers . over a median ( interquartile range ) of 44.0 ( 17.151.9 ) months , 7 ( 4% ) ala carriers and 86 ( 9.1% ) pro / pro homozygotes developed microalbuminuria ( hazard ratio [ hr ] 0.45 [ 95% ci 0.210.97 ] ; p = 0.042 ) .
final albuminuria was significantly lower in ala carriers than pro / pro homozygotes ( 7.3 9.1 vs. 10.5 24.9 g / min , respectively ) , even after adjustment for baseline albuminuria ( p = 0.048 ) .
baseline and follow - up blood pressure and metabolic control were similar in both groups .
incidence of microalbuminuria was significantly decreased by ace versus non - ace inhibitor therapy in pro / pro homozygotes ( 6.3 vs. 11.9% , respectively , hr 0.46 [ 0.290.72 ] ; p < 0.001).conclusionsin type 2 diabetes , the ala allele protects from worsening albuminuria and new - onset microalbuminuria , and ace inhibition blunts the excess risk of microalbuminuria associated with the pro / pro genotype .
evaluating pro12ala polymorphism may help identifying patients at risk who may benefit the most from early renoprotective therapy .</s> |
dermatophytoses are localized fungal infections of the skin , interdigital space , groin and hair ; they are very common in the general population and do not usually cause serious clinical diseases . the prevalence of dermatophytoses in hiv - infected patients is poorly documented and may be underestimated in those living in developed countries , due to the early start of antiretroviral therapy in recent years and to the frequent use of azoles , both for prophylaxis and therapy of other fungal diseases .
tinea incognito is a peculiar dermatophytosis with altered , polymorphic manifestations , lacking most of the typical morphological features that characterize tinea corporis , including round or oval presentation , sharp edges , vesicles , and scaling .
tinea incognito is frequently misdiagnosed as psoriasis , contact dermatitis and other types of eczema , rosacea , and lupus erythematosus .
cultures from tinea incognito usually yield the same dermatophytes isolated from typical dermatophytoses , the most frequently reported in europe being trichophyton rubrum , trichophyton mentagrophytes , microsporum canis , epidermophyton floccosum , and microsporum gypseum [ 3 , 4 ] . in the present study ,
we report a case of diffuse and persistent tinea incognito caused by m. gypseum in a patient with advanced hiv disease experiencing clinical progression and an isolated brain lesion .
a 37-year - old male drug addict was diagnosed with hiv and hcv infection in 1996 .
antiretroviral therapy was started in 1997 , when his cd4 t - cell counts were 236/mm and his viral load was 23,104 copies / ml . his adherence to antiretrovirals was suboptimal until 2005 .
he carried on a dual therapy with zidovudine and didanosine at standard doses until 1998 , when he was switched to his first highly active antiretroviral therapy ( haart ) regimen including stavudine , lamivudine , nevirapine and nelfinavir .
he remained on this haart regimen with poor adherence until clinical progression late in 2005 .
his hiv viral load never exceeded 30,000 copies / ml ; cd4 t - cell counts ranged from 30 to 120/mm , with liver function tests always in the normal range . during this period ,
he worked as a floor - cleaning assistant . in absence of any signs of clinical progression ,
the patient came to our institution in may 2005 , due to dermatological lesions confined to his face and neck .
lesions consisted of annular erythematous scaly plaques with inflammatory advancing borders located on the upper lip , nose and side of the neck ( fig .
the patient missed a few programmed checks . in january 2006 , he came again to our institution because of a relapse of his facial disease .
lesions consisted of ill - defined , confluent , poorly inflammatory erythematous scaly patches , diffusely involving the face and neck ( fig .
itraconazole at the same dosage ( 400 mg daily ) was started again , without benefit . a second dermatologist prescribed biotin and topical steroids after a clinical diagnosis of seborrheic dermatitis .
after a few days , the patient was hospitalized on emergency due a generalized convulsive episode .
mri contrast imaging documented an isolated , superficial brain lesion , 1 cm in size , involving the central circumvolution of his right parietal lobe , causing remarkable perilesional edema .
a few days later , a contrast ct scan of the brain revealed a hypodense cortical and subcortical lesion at the same site as detected by mri , with normal appearance of the remaining brain parenchyma .
sampling of csf documented a mild increase in csf proteins , whereas pcr and cultural assays for herpes viruses , toxoplasma gondii and mycobacterium tuberculosis were negative .
cultural assays , both on sabouraud dextrose agar and cycloheximide - added sabouraud dextrose agar , yielded fungal isolates after a few days of incubation .
intravenous cotrimoxazole , 70 mg / kg daily , as well as liposomal amphotericin b , 3 mg / kg daily , were started suspecting neurotoxoplasmosis and/or cerebral mycosis .
a few days later , after evaluation of a grt for hiv resistance mutations , a salvage haart regimen was initiated , including enfuvirtide , tipranavir / r , zidovudine , tenofovir and lamivudine . at the ninth week of therapy , when 3 mg / kg liposomal amphotericin b was still administered 3 times weekly for maintenance , lower limb edemas ensued .
renal function tests revealed serum creatinine at 6.4 mg / dl , total serum nitrogen at 88 mg / dl , and severe proteinuria ( 1,600 mg / l ) .
cd4 t - cell counts were 122/mm , hiv viremia was undetectable ( < 50 copies / ml ) . at this time
, the cutaneous lesions had cleared , and his cerebral lesion was still detectable on a control ct scan , although much reduced in size .
tenofovir and liposomal amphotericin b were interrupted , whereas the remaining haart regimen was continued .
renal function normalized 40 days after modification of the antiretroviral regimen , and a renal sequential scintigram showed a normal perfusion pattern at the same time ; full reversion of proteinuria and peripheral edemas ensued .
as of january 2011 , approximately 4 years after the acute renal toxicity episode , cd4 t - cell counts were 389/mm and hiv viremia was persistently suppressed .
we report a case of tinea incognito involving the face and neck in a patient working as a floor - cleaning assistant , with long - lasting hiv infection and severe hiv - related immune depression .
first - line systemic treatment with itraconazole was temporarily successful . at relapse of the cutaneous lesions ,
however , an unsuccessful second - line regimen with topical steroids was administered , based on the eczematous - like appearance of the patient 's diffuse facial lesions , in absence of a microbiological characterization .
finally , m. gypseum was isolated from culture of progressed lesions . to our knowledge , this geophilic dermatophyte has been reported in only a few cases of hiv patients so far , and always in resource - poor settings [ 5 , 6 , 7 , 8 ] .
our case , therefore , is the first case of diffuse tinea incognito due to m. gypseum reported in western countries in a patient with prolonged professional exposure to soil and dust and severe immune suppression . in our case , tinea incognito , commonly originating from topical corticosteroid treatment , was likely related to the severe and long - lasting depletion and consequent loss of function of cd4 t - lymphocytes .
it thus adds to the evidence that dermatological diagnosis should never be based upon the sole appearance of lesions in hiv patients with advanced disease , the contribution of laboratory examination being essential .
misdiagnosis often leads to an inappropriate use of drugs as topical or systemic corticosteroids , possibly causing further spread of tinea incognito [ 4 , 10 ] . in our patient ,
skin involvement due to m. gypseum was diagnosed together with a lesion of the right parietal cortex brain causing seizures .
brain ct scan findings , however , were atypical for neurotoxoplasmosis , showing no involvement of the basal ganglia and normal ventricular appearance .
in addition , the search for t. gondii dna in csf by pcr was negative .
a broad - spectrum antimicrobial regimen based on cotrimoxazole and liposomal amphotericin b , together with a rescue haart regimen , led to a reversal of the patient 's severe immune suppression and to the clearance of both skin and brain lesions .
consequently , we can not exclude that the observed isolated brain lesion might have been caused by m. gypseum itself , being responsive to systemic liposomal amphotericin b and immune rescue .
our patient had never shown adequate adherence to antiretroviral treatment since he was diagnosed with hiv infection .
interestingly , the occurrence of a state of severe clinical impairment , characterized by combined skin and brain lesions , led to a remarkable and long - lasting increase in adherence to therapy , even during coadministration of a complex antibiotic and antifungal regimen , as well as when severe renal toxicity might have easily discouraged full adherence [ 11 , 12 ] . in conclusion ,
our case report may represent the first evidence of tinea incognito in a patient with advanced hiv infection and a concomitant reversible cns lesion , possibly related to the relapse of his cutaneous lesion .
microbiological characterization of skin lesions in advanced hiv patients may play a clinically relevant adjuvant role .
e.p . was funded by a grant from the fondazione camillo de lellis per l'innovazione e la ricerca in medicina , pescara , italy . | the prevalence and the clinical relevance of dermatophytoses in hiv - infected patients are poorly documented , particularly for those caused by tinea incognito . here , we report a case of widespread facial tinea incognito occurring in an italian patient with advanced hiv infection , showing both skin and brain lesions .
second - line treatment with liposomal amphotericin b and cotrimoxazole , administered after a microbiological characterization of the skin scrapings , led to complete clearance of all lesions . | <s>[INST]dermatophytoses are localized fungal infections of the skin , interdigital space , groin and hair ; they are very common in the general population and do not usually cause serious clinical diseases . the prevalence of dermatophytoses in hiv - infected patients is poorly documented and may be underestimated in those living in developed countries , due to the early start of antiretroviral therapy in recent years and to the frequent use of azoles , both for prophylaxis and therapy of other fungal diseases .
tinea incognito is a peculiar dermatophytosis with altered , polymorphic manifestations , lacking most of the typical morphological features that characterize tinea corporis , including round or oval presentation , sharp edges , vesicles , and scaling .
tinea incognito is frequently misdiagnosed as psoriasis , contact dermatitis and other types of eczema , rosacea , and lupus erythematosus .
cultures from tinea incognito usually yield the same dermatophytes isolated from typical dermatophytoses , the most frequently reported in europe being trichophyton rubrum , trichophyton mentagrophytes , microsporum canis , epidermophyton floccosum , and microsporum gypseum [ 3 , 4 ] . in the present study ,
we report a case of diffuse and persistent tinea incognito caused by m. gypseum in a patient with advanced hiv disease experiencing clinical progression and an isolated brain lesion .
a 37-year - old male drug addict was diagnosed with hiv and hcv infection in 1996 .
antiretroviral therapy was started in 1997 , when his cd4 t - cell counts were 236/mm and his viral load was 23,104 copies / ml . his adherence to antiretrovirals was suboptimal until 2005 .
he carried on a dual therapy with zidovudine and didanosine at standard doses until 1998 , when he was switched to his first highly active antiretroviral therapy ( haart ) regimen including stavudine , lamivudine , nevirapine and nelfinavir .
he remained on this haart regimen with poor adherence until clinical progression late in 2005 .
his hiv viral load never exceeded 30,000 copies / ml ; cd4 t - cell counts ranged from 30 to 120/mm , with liver function tests always in the normal range . during this period ,
he worked as a floor - cleaning assistant . in absence of any signs of clinical progression ,
the patient came to our institution in may 2005 , due to dermatological lesions confined to his face and neck .
lesions consisted of annular erythematous scaly plaques with inflammatory advancing borders located on the upper lip , nose and side of the neck ( fig .
the patient missed a few programmed checks . in january 2006 , he came again to our institution because of a relapse of his facial disease .
lesions consisted of ill - defined , confluent , poorly inflammatory erythematous scaly patches , diffusely involving the face and neck ( fig .
itraconazole at the same dosage ( 400 mg daily ) was started again , without benefit . a second dermatologist prescribed biotin and topical steroids after a clinical diagnosis of seborrheic dermatitis .
after a few days , the patient was hospitalized on emergency due a generalized convulsive episode .
mri contrast imaging documented an isolated , superficial brain lesion , 1 cm in size , involving the central circumvolution of his right parietal lobe , causing remarkable perilesional edema .
a few days later , a contrast ct scan of the brain revealed a hypodense cortical and subcortical lesion at the same site as detected by mri , with normal appearance of the remaining brain parenchyma .
sampling of csf documented a mild increase in csf proteins , whereas pcr and cultural assays for herpes viruses , toxoplasma gondii and mycobacterium tuberculosis were negative .
cultural assays , both on sabouraud dextrose agar and cycloheximide - added sabouraud dextrose agar , yielded fungal isolates after a few days of incubation .
intravenous cotrimoxazole , 70 mg / kg daily , as well as liposomal amphotericin b , 3 mg / kg daily , were started suspecting neurotoxoplasmosis and/or cerebral mycosis .
a few days later , after evaluation of a grt for hiv resistance mutations , a salvage haart regimen was initiated , including enfuvirtide , tipranavir / r , zidovudine , tenofovir and lamivudine . at the ninth week of therapy , when 3 mg / kg liposomal amphotericin b was still administered 3 times weekly for maintenance , lower limb edemas ensued .
renal function tests revealed serum creatinine at 6.4 mg / dl , total serum nitrogen at 88 mg / dl , and severe proteinuria ( 1,600 mg / l ) .
cd4 t - cell counts were 122/mm , hiv viremia was undetectable ( < 50 copies / ml ) . at this time
, the cutaneous lesions had cleared , and his cerebral lesion was still detectable on a control ct scan , although much reduced in size .
tenofovir and liposomal amphotericin b were interrupted , whereas the remaining haart regimen was continued .
renal function normalized 40 days after modification of the antiretroviral regimen , and a renal sequential scintigram showed a normal perfusion pattern at the same time ; full reversion of proteinuria and peripheral edemas ensued .
as of january 2011 , approximately 4 years after the acute renal toxicity episode , cd4 t - cell counts were 389/mm and hiv viremia was persistently suppressed .
we report a case of tinea incognito involving the face and neck in a patient working as a floor - cleaning assistant , with long - lasting hiv infection and severe hiv - related immune depression .
first - line systemic treatment with itraconazole was temporarily successful . at relapse of the cutaneous lesions ,
however , an unsuccessful second - line regimen with topical steroids was administered , based on the eczematous - like appearance of the patient 's diffuse facial lesions , in absence of a microbiological characterization .
finally , m. gypseum was isolated from culture of progressed lesions . to our knowledge , this geophilic dermatophyte has been reported in only a few cases of hiv patients so far , and always in resource - poor settings [ 5 , 6 , 7 , 8 ] .
our case , therefore , is the first case of diffuse tinea incognito due to m. gypseum reported in western countries in a patient with prolonged professional exposure to soil and dust and severe immune suppression . in our case , tinea incognito , commonly originating from topical corticosteroid treatment , was likely related to the severe and long - lasting depletion and consequent loss of function of cd4 t - lymphocytes .
it thus adds to the evidence that dermatological diagnosis should never be based upon the sole appearance of lesions in hiv patients with advanced disease , the contribution of laboratory examination being essential .
misdiagnosis often leads to an inappropriate use of drugs as topical or systemic corticosteroids , possibly causing further spread of tinea incognito [ 4 , 10 ] . in our patient ,
skin involvement due to m. gypseum was diagnosed together with a lesion of the right parietal cortex brain causing seizures .
brain ct scan findings , however , were atypical for neurotoxoplasmosis , showing no involvement of the basal ganglia and normal ventricular appearance .
in addition , the search for t. gondii dna in csf by pcr was negative .
a broad - spectrum antimicrobial regimen based on cotrimoxazole and liposomal amphotericin b , together with a rescue haart regimen , led to a reversal of the patient 's severe immune suppression and to the clearance of both skin and brain lesions .
consequently , we can not exclude that the observed isolated brain lesion might have been caused by m. gypseum itself , being responsive to systemic liposomal amphotericin b and immune rescue .
our patient had never shown adequate adherence to antiretroviral treatment since he was diagnosed with hiv infection .
interestingly , the occurrence of a state of severe clinical impairment , characterized by combined skin and brain lesions , led to a remarkable and long - lasting increase in adherence to therapy , even during coadministration of a complex antibiotic and antifungal regimen , as well as when severe renal toxicity might have easily discouraged full adherence [ 11 , 12 ] . in conclusion ,
our case report may represent the first evidence of tinea incognito in a patient with advanced hiv infection and a concomitant reversible cns lesion , possibly related to the relapse of his cutaneous lesion .
microbiological characterization of skin lesions in advanced hiv patients may play a clinically relevant adjuvant role .
e.p . was funded by a grant from the fondazione camillo de lellis per l'innovazione e la ricerca in medicina , pescara , italy .[/INST]the prevalence and the clinical relevance of dermatophytoses in hiv - infected patients are poorly documented , particularly for those caused by tinea incognito . here , we report a case of widespread facial tinea incognito occurring in an italian patient with advanced hiv infection , showing both skin and brain lesions .
second - line treatment with liposomal amphotericin b and cotrimoxazole , administered after a microbiological characterization of the skin scrapings , led to complete clearance of all lesions .</s> |
long - duration gamma - ray bursts ( grbs ) at sufficiently close distances ( @xmath6 ) have been found to be accompanied by luminous and energetic type ic supernovae ( sne ic ) called hypernovae ( hne ; grb 980425/sn 1998bw : @xcite ; grb 030329/sn 2003dh : @xcite , @xcite ; grb 031203/sn 2003lw : @xcite ) .
these grb - associated hne ( grb - hne ) are suggested to be the outcome of very energetic black hole ( bh ) forming explosions of massive stars ( e.g. , @xcite ) .
the ejected @xmath0ni mass is estimated to be @xmath7 ( e.g. , @xcite ) which is @xmath8 times larger than typical sne ic [ @xmath9 ; @xcite ] . for recently discovered nearby
long - duration grb 060505 ( @xmath10 , @xcite ) and grb 060614 ( @xmath11 , @xcite ) , no sn was detected .
upper limits to brightness of the possible sne are about 100 times fainter than sn 1998bw [ i.e. , @xmath12 . a small amount of @xmath0ni ejection has been indicated in the faintness of several type ii sne ( sne ii , e.g. , sn 1994w , @xcite ; and sn 1997d , @xcite ) .
the estimated explosion energies , @xmath13 , of these faint sne ii are very small ( @xmath14ergs , @xcite ) .
these properties are well - reproduced by the _
spherical _ explosion models that undergo significant fallback if @xmath13 is sufficiently small @xcite .
thus these faint sn explosions with low @xmath13 seem to be superficially irreconcilable to the formation of energetic grbs @xcite . however , nomoto et al .
( 2006a ; see also @xcite ) has predicted the existence of `` dark hypernovae '' ( i.e. , long grbs with no sne ) based on the argument in the next paragraph .
in this letter , we present actual hydrodynamical models in which a high - energy narrow jet produces a grb _ and _ a faint / dark sn with little @xmath0ni ejection .
an indication that some faint sne produce high - energy jets is seen in the abundance patterns of the extremely metal - poor ( emp ) stars with [ fe / h ] @xmath15 .
it has been suggested that the abundance patterns of these emp stars show the nucleosynthesis yields of a single core - collapse sn ( e.g. , @xcite ) . in particular , the c - enhanced type of the emp stars have been well explained by the faint sne @xcite , except for their large co / fe and zn / fe ratios ( e.g. , @xcite ) .
the enhancement of co and zn in low metallicity stars requires explosive nucleosynthesis under high entropy . in a `` spherical '' model
, a high - entropy explosion corresponds to a high - energy explosion that inevitably synthesizes a large amount of @xmath0ni .
one possible solution to this incompatibility is that some faint sne are associated with a narrow jet within which a high - entropy region is confined @xcite . if this would be a realistic model for the emp stars , some faint sne would accompany sufficiently energetic jets to produce grbs . in this letter
, we present hydrodynamical and nucleosynthetic models of the 40 @xmath2 star explosions with relativistic jets .
we show that these models can explain the existence of grb - hne and grbs without bright sne in a unified manner .
we suggest that both grb - hne and grbs without bright sne are bh - forming sne involving relativistic jets and that these explosions are responsible for the formation of the emp stars .
we investigate the jet - induced explosions ( e.g. , @xcite ) of the @xmath16 population iii stars @xcite using a multi - dimensional special relativistic eulerian hydrodynamic code ( @xcite ; n. tominaga , 2007 , phd thesis , in preparation ) .
we assume that the explosions of the @xmath16 population iii stars involve relativistic jets in analogy with the @xmath16 pop i grb - hne , since the fe core masses of population iii and population i stars are similar .
we inject the jets at a radius @xmath17 km , corresponding to an enclosed mass of @xmath18 , and follow the jet propagation . since the explosion mechanism of grb - hne is still under debate ,
the jets are treated parametrically with the following five parameters : energy deposition rate ( @xmath19 ) , total deposited energy ( @xmath20 ) , initial half angle of the jets ( @xmath21 ) , initial lorentz factor ( @xmath22 ) , and the ratio of thermal to total deposited energies ( @xmath23 ) . in this letter
, we investigate the dependence of nucleosynthesis outcome on @xmath19 for a range of @xmath24 .
the diversity of @xmath19 is consistent with the wide range of the observed isotropic equivalent @xmath25-ray energies and timescales of grbs ( @xcite and references therein ) .
variations of activities of the central engines , possibly corresponding to different rotational velocities or magnetic fields , may well produce the variation of @xmath19 .
we expediently fix the other parameters as @xmath26ergs , @xmath27 , @xmath28 , and @xmath29 in all models .
the thermodynamic history is traced with marker particles representing individual lagrangian elements ( e.g. , @xcite ) .
the nucleosynthesis calculation is performed as post - processing and includes 280 species up to @xmath30br ( see @xcite , table 1 ) . because recent studies ( e.g. , @xcite ) suggest that the electron fraction ( @xmath31 ) is affected by neutrino processes , we assume @xmath32 in the fe core to maximize the co / fe ratio @xcite .
the thermodynamic history of the jet is also traced by the marker particles . in computing the jet composition ,
we assume that the jet expands adiabatically from the schwartzshild radius to the inner boundary of the computational domain , and that the jet initially has the composition of the accreted stellar materials .
the details will be presented in future work .
in order to inject the jet , the ram pressure of the jet ( @xmath33 ) should overcome that of the infalling material ( @xmath34 ) .
@xmath33 is determined by @xmath35 , @xmath19 , @xmath21 , @xmath22 , and @xmath23 , thus being constant in time in the present models . on the other hand ,
@xmath34 decreases with time , since the density of the outer materials decreases following the gravitational collapse ( e.g. , @xcite ) . for lower @xmath19
, @xmath33 is lower , so that the jet injection ( @xmath36 ) is realized at a later time when the central remnant becomes more massive due to more infall .
after the jet injection is initiated , the shock fronts between the jets and the infalling material proceed outward in the stellar mantle .
figure [ fig : fallback ] is a snapshot of the model with @xmath37 at 1 s after the start of jet injection .
when the jet injection ends , the jets have been decelerated by collisions with the dense stellar mantle and the shock has become more spherical .
the inner material is ejected along the jet - axis but not along the equatorial plane . on the other hand ,
the outer material is ejected even along the equatorial plane because the infall along the equatorial plane is terminated as the shock reaches the equatorial plane ( e.g. , @xcite ) .
the top panel of figure [ fig : edotni ] shows the dependence of the ejected @xmath38 on the energy deposition rate @xmath19 . for lower @xmath19 , smaller @xmath38
is synthesized in explosive nucleosynthesis because of lower post - shock densities and temperatures ( e.g. , @xcite ; maeda & tominaga 2007 , hereafter @xcite ) .
while the materials in the c+o layer fall through the inner boundary , @xmath34 decreases only moderately , being almost constant ( @xmath39 @xmath40 ) during this phase because of the relatively shallow pre - sn density gradient in the c+o layer ( e.g. , @xcite ) . if @xmath41 , @xmath42 so that the jet injection is initiated below the bottom of the c+o layer , leading to the synthesis of @xmath43 . if @xmath44 , on the other hand , @xmath45 so that the jet injection is delayed until @xmath34 decreases below @xmath33 and initiated near the surface of the c+o core ; then the ejected @xmath0ni is as small as @xmath46 . @xmath0ni contained in the relativistic jets is only @xmath47 to @xmath48 because the total mass of the jets is @xmath49 in our model with @xmath50 and @xmath26ergs .
the @xmath0ni production in the jets is predominant only for @xmath51 in the present model ( fig . [ fig : edotni ] ) .
the models can not synthesize @xmath0ni explosively and eject very little @xmath38 ( @xmath52 ) . for high energy deposition rates ( @xmath53 ) , the explosions synthesize large @xmath38 ( @xmath54 ) being consistent with grb - hne .
the remnant mass was @xmath55 when the jet injection was started , but it grows as material is accreted from the equatorial plane .
the final bh masses range from @xmath56 for @xmath57 to @xmath58 for @xmath59 , which are consistent with the masses of stellar - mass bhs @xcite .
the model with @xmath60 synthesizes @xmath61 and results in @xmath62 .
since the jet injection with large @xmath19 is in short timescale and terminated before the jets reach the surface of the c+o core , the asphericity of the ejecta inside the c+o core for @xmath53 is probably consistent with a relatively oval explosion as indicated by the light curve and spectra of grb - hne @xcite .
neutrino annihilation has been estimated to provide only a small energy deposition rate ( e.g. , @xmath63 ; @xcite ) , leading to the synthesis of smaller @xmath38 than is required for grb - hne . in order to synthesize a sufficient amount of @xmath0ni
, large @xmath19 should be produced via some mechanism , e.g. , magneto - rotation ( @xcite ; another possibility , @xmath0ni production in the disk wind , is discussed in @xcite ) . for low energy deposition rates ( @xmath44 ) ,
the ejected @xmath0ni masses [ @xmath46 ] are smaller than the upper limits for grbs 060505 and 060614 .
the final bh masses range from @xmath65 for @xmath66 to @xmath67 for @xmath68 .
while the material ejected along the jet direction involves those from the c+o core , the material along the equatorial plane is ejected only from the outer part of the h envelope .
thus @xmath69 exceeds the c+o core mass @xmath70 for the @xmath16 star .
if the star lost the h and he envelopes before its core collapsed , and if the explosion is viewed from the jet direction , we would observe grb without sn re - brightening .
this may be the situation for grbs 060505 and 060614 . for intermediate energy deposition rates ( @xmath71 ) ,
the explosions eject @xmath72 and the final bh masses are @xmath73 .
the resulting sn is faint [ @xmath74 or sub - luminous [ @xmath75 .
nearby grbs with faint or sub - luminous sne have not been observed .
possible reasons may be that ( 1 ) they do not occur intrinsically , i.e. , the energy deposition rate is bimodally distributed , or that ( 2 ) the number of observed nearby grbs is still too small . for case 1
, the grb progenitors may be divided into two groups , e.g. , with rapid or slow rotation and/or with strong or weak magnetic fields . for case 2
, future observations will detect grbs associated with a faint or sub - luminous sn .
the bottom panel of figure [ fig : edotni ] shows the dependence of the abundance ratio [ c / fe ] on @xmath19 .
lower @xmath19 yields larger @xmath69 and thus larger [ c / fe ] , because the infall decreases the amount of inner core material ( fe ) relative to that of outer material ( c ) ( see also @xcite ) . as in the case of @xmath38 ( 3.1 )
, [ c / fe ] changes dramatically at @xmath76 .
the abundance patterns of the emp stars are good indicators of nucleosynthesis in a single sn because the galaxy was effectively unmixed at [ fe / h ] @xmath77 ( e.g. , @xcite ) .
they are classified into three groups according to [ c / fe ] : ( 1 ) [ c / fe ] @xmath78 , normal emp stars ( @xmath79 [ fe / h ] @xmath77 , e.g. , @xcite ) ; ( 2 ) [ c / fe ] @xmath80 , carbon - enhanced emp ( cemp ) stars ( @xmath79 [ fe / h ] @xmath77 , e.g. , cs 22949 - 37 ; @xcite ) ; ( 3 ) [ c / fe ] @xmath81 , hyper metal - poor ( hmp ) stars ( [ fe / h ] @xmath82 , e.g. , he 01075240 ; @xcite ; @xcite ; he 13272326 , @xcite ) .
figure 3 shows that the general abundance patterns of the normal emp stars , the cemp star cs 22949 - 37 , and the hmp stars he 01075240 and he 13272326 are reproduced by models with @xmath83 , 3.0 , 1.5 , and 0.5 , respectively ( see table 1 for model parameters ) . the model for the normal emp stars
ejects @xmath84 , i.e. a factor of 2 less than sn 1998bw . on the other hand , the models for the cemp and the hmp stars eject @xmath85 and @xmath86 , respectively , which are always smaller than the upper limits for grbs 060505 and 060614 .
the lack of the metal - poor stars at @xmath87 [ fe / h ] @xmath88 is explained by the narrow range of @xmath89 . the n / c ratio in the models for cs 22949 - 37 and he 13272326 is enhanced by partial mixing between the he and h layers during pre - sn evolution ( @xcite ) .
we have computed hydrodynamics and nucleosynthesis for the explosions induced by relativistic jets .
we have shown that ( 1 ) the explosions with large @xmath19 are observed as grb - hne and their yields explain the abundances of normal emp stars , and ( 2 ) the explosions with small @xmath19 are observed as grbs without bright sne and are responsible for the formation of the cemp and the hmp stars .
we thus propose that grb - hne and grbs without bright sne belong to a continuous series of bh - forming sne with the relativistic jets of different @xmath19 .
presently , the number fraction of grbs without bright sne relative to the known nearby grbs is @xmath90% ( e.g. , @xcite ) . on the other hand , among the emp stars with [ fe / h ] @xmath15 , the fractions of the cemp and the hmp stars relative to the emp stars are @xmath91 and @xmath92 , respectively ( @xcite ) .
although the numbers of observed grbs and the emp stars with [ fe / h ] @xmath15 are still too small to discuss statistics , the fraction of grbs without bright sne is consistent with the sum of the fractions of the cemp and the hmp stars . thus grbs 060505 and 060614 are likely related to the cemp stars ejecting @xmath3 to @xmath4 or hmp stars ejecting @xmath93 . a short grb , probably the result of the merger of two compact objects ( e.g. , @xcite ) , synthesizes
virtually no @xmath0nibecause the ejecta must be too neutron - rich .
in contrast , our model suggests that grbs 060505 and 060614 produced @xmath94 or @xmath5 .
if such a grb without a bright sn occurs in a very faint and nearby galaxy , our model predicts that some re - brightening due to the @xmath0nidecay can be observed .
nomoto , k. , tominaga , n. , tanaka , m. , maeda , k. , suzuki , t. , deng , j.s .
, mazzali , p.a .
2006a , in _ swift _ and grbs : unveiling the relativistic universe , ed .
g. chincarini et al .
( balogna : italian pysical society ) , in press ( astro - ph/0702472 ) | long - duration gamma - ray bursts ( grbs ) are thought to be connected to luminous and energetic supernovae ( sne ) , called hypernovae ( hne ) , resulting from the black - hole ( bh ) forming collapse of massive stars . for recent nearby grbs 060505 and 060614 ,
however , the expected sne have not been detected .
the upper limits to the sn brightness are about 100 times fainter than grb - associated hne ( grb - hne ) , corresponding to the upper limits to the ejected @xmath0ni masses of @xmath1 .
sne with a small amount of @xmath0ni ejection are observed as faint type ii sne .
hne and faint sne are thought to be responsible for the formation of extremely metal - poor ( emp ) stars . in this letter , a relativistic jet - induced bh forming explosion of
the 40 @xmath2 star is investigated and hydrodynamic and nucleosynthetic models are presented .
these models can explain both grb - hne and grbs without bright sne in a unified manner .
their connection to emp stars is also discussed .
we suggest that grbs without bright sne are likely to synthesize @xmath3 to @xmath4 or @xmath5 . | <s>[INST]long - duration gamma - ray bursts ( grbs ) at sufficiently close distances ( @xmath6 ) have been found to be accompanied by luminous and energetic type ic supernovae ( sne ic ) called hypernovae ( hne ; grb 980425/sn 1998bw : @xcite ; grb 030329/sn 2003dh : @xcite , @xcite ; grb 031203/sn 2003lw : @xcite ) .
these grb - associated hne ( grb - hne ) are suggested to be the outcome of very energetic black hole ( bh ) forming explosions of massive stars ( e.g. , @xcite ) .
the ejected @xmath0ni mass is estimated to be @xmath7 ( e.g. , @xcite ) which is @xmath8 times larger than typical sne ic [ @xmath9 ; @xcite ] . for recently discovered nearby
long - duration grb 060505 ( @xmath10 , @xcite ) and grb 060614 ( @xmath11 , @xcite ) , no sn was detected .
upper limits to brightness of the possible sne are about 100 times fainter than sn 1998bw [ i.e. , @xmath12 . a small amount of @xmath0ni ejection has been indicated in the faintness of several type ii sne ( sne ii , e.g. , sn 1994w , @xcite ; and sn 1997d , @xcite ) .
the estimated explosion energies , @xmath13 , of these faint sne ii are very small ( @xmath14ergs , @xcite ) .
these properties are well - reproduced by the _
spherical _ explosion models that undergo significant fallback if @xmath13 is sufficiently small @xcite .
thus these faint sn explosions with low @xmath13 seem to be superficially irreconcilable to the formation of energetic grbs @xcite . however , nomoto et al .
( 2006a ; see also @xcite ) has predicted the existence of `` dark hypernovae '' ( i.e. , long grbs with no sne ) based on the argument in the next paragraph .
in this letter , we present actual hydrodynamical models in which a high - energy narrow jet produces a grb _ and _ a faint / dark sn with little @xmath0ni ejection .
an indication that some faint sne produce high - energy jets is seen in the abundance patterns of the extremely metal - poor ( emp ) stars with [ fe / h ] @xmath15 .
it has been suggested that the abundance patterns of these emp stars show the nucleosynthesis yields of a single core - collapse sn ( e.g. , @xcite ) . in particular , the c - enhanced type of the emp stars have been well explained by the faint sne @xcite , except for their large co / fe and zn / fe ratios ( e.g. , @xcite ) .
the enhancement of co and zn in low metallicity stars requires explosive nucleosynthesis under high entropy . in a `` spherical '' model
, a high - entropy explosion corresponds to a high - energy explosion that inevitably synthesizes a large amount of @xmath0ni .
one possible solution to this incompatibility is that some faint sne are associated with a narrow jet within which a high - entropy region is confined @xcite . if this would be a realistic model for the emp stars , some faint sne would accompany sufficiently energetic jets to produce grbs . in this letter
, we present hydrodynamical and nucleosynthetic models of the 40 @xmath2 star explosions with relativistic jets .
we show that these models can explain the existence of grb - hne and grbs without bright sne in a unified manner .
we suggest that both grb - hne and grbs without bright sne are bh - forming sne involving relativistic jets and that these explosions are responsible for the formation of the emp stars .
we investigate the jet - induced explosions ( e.g. , @xcite ) of the @xmath16 population iii stars @xcite using a multi - dimensional special relativistic eulerian hydrodynamic code ( @xcite ; n. tominaga , 2007 , phd thesis , in preparation ) .
we assume that the explosions of the @xmath16 population iii stars involve relativistic jets in analogy with the @xmath16 pop i grb - hne , since the fe core masses of population iii and population i stars are similar .
we inject the jets at a radius @xmath17 km , corresponding to an enclosed mass of @xmath18 , and follow the jet propagation . since the explosion mechanism of grb - hne is still under debate ,
the jets are treated parametrically with the following five parameters : energy deposition rate ( @xmath19 ) , total deposited energy ( @xmath20 ) , initial half angle of the jets ( @xmath21 ) , initial lorentz factor ( @xmath22 ) , and the ratio of thermal to total deposited energies ( @xmath23 ) . in this letter
, we investigate the dependence of nucleosynthesis outcome on @xmath19 for a range of @xmath24 .
the diversity of @xmath19 is consistent with the wide range of the observed isotropic equivalent @xmath25-ray energies and timescales of grbs ( @xcite and references therein ) .
variations of activities of the central engines , possibly corresponding to different rotational velocities or magnetic fields , may well produce the variation of @xmath19 .
we expediently fix the other parameters as @xmath26ergs , @xmath27 , @xmath28 , and @xmath29 in all models .
the thermodynamic history is traced with marker particles representing individual lagrangian elements ( e.g. , @xcite ) .
the nucleosynthesis calculation is performed as post - processing and includes 280 species up to @xmath30br ( see @xcite , table 1 ) . because recent studies ( e.g. , @xcite ) suggest that the electron fraction ( @xmath31 ) is affected by neutrino processes , we assume @xmath32 in the fe core to maximize the co / fe ratio @xcite .
the thermodynamic history of the jet is also traced by the marker particles . in computing the jet composition ,
we assume that the jet expands adiabatically from the schwartzshild radius to the inner boundary of the computational domain , and that the jet initially has the composition of the accreted stellar materials .
the details will be presented in future work .
in order to inject the jet , the ram pressure of the jet ( @xmath33 ) should overcome that of the infalling material ( @xmath34 ) .
@xmath33 is determined by @xmath35 , @xmath19 , @xmath21 , @xmath22 , and @xmath23 , thus being constant in time in the present models . on the other hand ,
@xmath34 decreases with time , since the density of the outer materials decreases following the gravitational collapse ( e.g. , @xcite ) . for lower @xmath19
, @xmath33 is lower , so that the jet injection ( @xmath36 ) is realized at a later time when the central remnant becomes more massive due to more infall .
after the jet injection is initiated , the shock fronts between the jets and the infalling material proceed outward in the stellar mantle .
figure [ fig : fallback ] is a snapshot of the model with @xmath37 at 1 s after the start of jet injection .
when the jet injection ends , the jets have been decelerated by collisions with the dense stellar mantle and the shock has become more spherical .
the inner material is ejected along the jet - axis but not along the equatorial plane . on the other hand ,
the outer material is ejected even along the equatorial plane because the infall along the equatorial plane is terminated as the shock reaches the equatorial plane ( e.g. , @xcite ) .
the top panel of figure [ fig : edotni ] shows the dependence of the ejected @xmath38 on the energy deposition rate @xmath19 . for lower @xmath19 , smaller @xmath38
is synthesized in explosive nucleosynthesis because of lower post - shock densities and temperatures ( e.g. , @xcite ; maeda & tominaga 2007 , hereafter @xcite ) .
while the materials in the c+o layer fall through the inner boundary , @xmath34 decreases only moderately , being almost constant ( @xmath39 @xmath40 ) during this phase because of the relatively shallow pre - sn density gradient in the c+o layer ( e.g. , @xcite ) . if @xmath41 , @xmath42 so that the jet injection is initiated below the bottom of the c+o layer , leading to the synthesis of @xmath43 . if @xmath44 , on the other hand , @xmath45 so that the jet injection is delayed until @xmath34 decreases below @xmath33 and initiated near the surface of the c+o core ; then the ejected @xmath0ni is as small as @xmath46 . @xmath0ni contained in the relativistic jets is only @xmath47 to @xmath48 because the total mass of the jets is @xmath49 in our model with @xmath50 and @xmath26ergs .
the @xmath0ni production in the jets is predominant only for @xmath51 in the present model ( fig . [ fig : edotni ] ) .
the models can not synthesize @xmath0ni explosively and eject very little @xmath38 ( @xmath52 ) . for high energy deposition rates ( @xmath53 ) , the explosions synthesize large @xmath38 ( @xmath54 ) being consistent with grb - hne .
the remnant mass was @xmath55 when the jet injection was started , but it grows as material is accreted from the equatorial plane .
the final bh masses range from @xmath56 for @xmath57 to @xmath58 for @xmath59 , which are consistent with the masses of stellar - mass bhs @xcite .
the model with @xmath60 synthesizes @xmath61 and results in @xmath62 .
since the jet injection with large @xmath19 is in short timescale and terminated before the jets reach the surface of the c+o core , the asphericity of the ejecta inside the c+o core for @xmath53 is probably consistent with a relatively oval explosion as indicated by the light curve and spectra of grb - hne @xcite .
neutrino annihilation has been estimated to provide only a small energy deposition rate ( e.g. , @xmath63 ; @xcite ) , leading to the synthesis of smaller @xmath38 than is required for grb - hne . in order to synthesize a sufficient amount of @xmath0ni
, large @xmath19 should be produced via some mechanism , e.g. , magneto - rotation ( @xcite ; another possibility , @xmath0ni production in the disk wind , is discussed in @xcite ) . for low energy deposition rates ( @xmath44 ) ,
the ejected @xmath0ni masses [ @xmath46 ] are smaller than the upper limits for grbs 060505 and 060614 .
the final bh masses range from @xmath65 for @xmath66 to @xmath67 for @xmath68 .
while the material ejected along the jet direction involves those from the c+o core , the material along the equatorial plane is ejected only from the outer part of the h envelope .
thus @xmath69 exceeds the c+o core mass @xmath70 for the @xmath16 star .
if the star lost the h and he envelopes before its core collapsed , and if the explosion is viewed from the jet direction , we would observe grb without sn re - brightening .
this may be the situation for grbs 060505 and 060614 . for intermediate energy deposition rates ( @xmath71 ) ,
the explosions eject @xmath72 and the final bh masses are @xmath73 .
the resulting sn is faint [ @xmath74 or sub - luminous [ @xmath75 .
nearby grbs with faint or sub - luminous sne have not been observed .
possible reasons may be that ( 1 ) they do not occur intrinsically , i.e. , the energy deposition rate is bimodally distributed , or that ( 2 ) the number of observed nearby grbs is still too small . for case 1
, the grb progenitors may be divided into two groups , e.g. , with rapid or slow rotation and/or with strong or weak magnetic fields . for case 2
, future observations will detect grbs associated with a faint or sub - luminous sn .
the bottom panel of figure [ fig : edotni ] shows the dependence of the abundance ratio [ c / fe ] on @xmath19 .
lower @xmath19 yields larger @xmath69 and thus larger [ c / fe ] , because the infall decreases the amount of inner core material ( fe ) relative to that of outer material ( c ) ( see also @xcite ) . as in the case of @xmath38 ( 3.1 )
, [ c / fe ] changes dramatically at @xmath76 .
the abundance patterns of the emp stars are good indicators of nucleosynthesis in a single sn because the galaxy was effectively unmixed at [ fe / h ] @xmath77 ( e.g. , @xcite ) .
they are classified into three groups according to [ c / fe ] : ( 1 ) [ c / fe ] @xmath78 , normal emp stars ( @xmath79 [ fe / h ] @xmath77 , e.g. , @xcite ) ; ( 2 ) [ c / fe ] @xmath80 , carbon - enhanced emp ( cemp ) stars ( @xmath79 [ fe / h ] @xmath77 , e.g. , cs 22949 - 37 ; @xcite ) ; ( 3 ) [ c / fe ] @xmath81 , hyper metal - poor ( hmp ) stars ( [ fe / h ] @xmath82 , e.g. , he 01075240 ; @xcite ; @xcite ; he 13272326 , @xcite ) .
figure 3 shows that the general abundance patterns of the normal emp stars , the cemp star cs 22949 - 37 , and the hmp stars he 01075240 and he 13272326 are reproduced by models with @xmath83 , 3.0 , 1.5 , and 0.5 , respectively ( see table 1 for model parameters ) . the model for the normal emp stars
ejects @xmath84 , i.e. a factor of 2 less than sn 1998bw . on the other hand , the models for the cemp and the hmp stars eject @xmath85 and @xmath86 , respectively , which are always smaller than the upper limits for grbs 060505 and 060614 .
the lack of the metal - poor stars at @xmath87 [ fe / h ] @xmath88 is explained by the narrow range of @xmath89 . the n / c ratio in the models for cs 22949 - 37 and he 13272326 is enhanced by partial mixing between the he and h layers during pre - sn evolution ( @xcite ) .
we have computed hydrodynamics and nucleosynthesis for the explosions induced by relativistic jets .
we have shown that ( 1 ) the explosions with large @xmath19 are observed as grb - hne and their yields explain the abundances of normal emp stars , and ( 2 ) the explosions with small @xmath19 are observed as grbs without bright sne and are responsible for the formation of the cemp and the hmp stars .
we thus propose that grb - hne and grbs without bright sne belong to a continuous series of bh - forming sne with the relativistic jets of different @xmath19 .
presently , the number fraction of grbs without bright sne relative to the known nearby grbs is @xmath90% ( e.g. , @xcite ) . on the other hand , among the emp stars with [ fe / h ] @xmath15 , the fractions of the cemp and the hmp stars relative to the emp stars are @xmath91 and @xmath92 , respectively ( @xcite ) .
although the numbers of observed grbs and the emp stars with [ fe / h ] @xmath15 are still too small to discuss statistics , the fraction of grbs without bright sne is consistent with the sum of the fractions of the cemp and the hmp stars . thus grbs 060505 and 060614 are likely related to the cemp stars ejecting @xmath3 to @xmath4 or hmp stars ejecting @xmath93 . a short grb , probably the result of the merger of two compact objects ( e.g. , @xcite ) , synthesizes
virtually no @xmath0nibecause the ejecta must be too neutron - rich .
in contrast , our model suggests that grbs 060505 and 060614 produced @xmath94 or @xmath5 .
if such a grb without a bright sn occurs in a very faint and nearby galaxy , our model predicts that some re - brightening due to the @xmath0nidecay can be observed .
nomoto , k. , tominaga , n. , tanaka , m. , maeda , k. , suzuki , t. , deng , j.s .
, mazzali , p.a .
2006a , in _ swift _ and grbs : unveiling the relativistic universe , ed .
g. chincarini et al .
( balogna : italian pysical society ) , in press ( astro - ph/0702472 )[/INST] long - duration gamma - ray bursts ( grbs ) are thought to be connected to luminous and energetic supernovae ( sne ) , called hypernovae ( hne ) , resulting from the black - hole ( bh ) forming collapse of massive stars . for recent nearby grbs 060505 and 060614 ,
however , the expected sne have not been detected .
the upper limits to the sn brightness are about 100 times fainter than grb - associated hne ( grb - hne ) , corresponding to the upper limits to the ejected @xmath0ni masses of @xmath1 .
sne with a small amount of @xmath0ni ejection are observed as faint type ii sne .
hne and faint sne are thought to be responsible for the formation of extremely metal - poor ( emp ) stars . in this letter , a relativistic jet - induced bh forming explosion of
the 40 @xmath2 star is investigated and hydrodynamic and nucleosynthetic models are presented .
these models can explain both grb - hne and grbs without bright sne in a unified manner .
their connection to emp stars is also discussed .
we suggest that grbs without bright sne are likely to synthesize @xmath3 to @xmath4 or @xmath5 . </s> |
percutaneous coronary intervention ( pci ) has emerged as an important modality to treat coronary artery disease ( cad ) . as research improves pharmacology and clinical approaches for patient treatment ,
more complex cads are being successfully treated with pci and clinical outcomes are consistently improving .
pci can now be performed in most patients that require revascularization and it is also offered to subjects that have a high operative risk.1 ) guideline - based strategies and monitoring of pci procedures are strongly recommended to improve in - hospital and long - term clinical outcomes of patients that undergo pci.2)3)4)5 ) specifically , performance measures for pci and st - elevation myocardial infarction ( stemi)/non - st - elevation myocardial infarction ( nstemi ) were established to guide physicians with approaches for these interventions.6)7)8 ) although several multicenter registries have evaluated pci procedures in korea,9)10)11)12)13 ) no nationwide contemporary pci registries have been collected with standardized collection forms and unified reporting methods .
the korean society of cardiology ( ksc ) and korean society of interventional cardiology ( ksic ) established the korean percutaneous coronary intervention ( k - pci ) registry to collect and report results in a standardized database for pci case analysis throughout the country .
the purpose of this study was to construct baseline data standards to set - up treatment guidelines that reflect relevant clinical situations and to facilitate clinical research for cardiologists that treat cad in korea .
the k - pci registry final protocol was created in the task force team meeting and the k - pci registry governing committee conference , it was designed for enrolling participants with respect to clinical diagnosis information , procedural data , and by considering major complications after pci procedures performed to treat ischemic heart disease .
the hospitals that could perform pci were asked to participate and 92 hospitals voluntarily took part in this registry .
demographic characteristics , clinical history , procedural information and pci complications that occurred before hospital discharge were collected retrospectively using case report forms ( crfs ) comprised of a standard set of 54 data elements . when multiple interventions were performed in a subject ,
all variables corresponded with written definitions in the crf dictionary ( k - pci registry 2014 crf v1.4 . , supplementary table 1 ) in the online - only data supplement )
to standardize the data , and were provided by using common specifications with question and answer cases for participants .
this study was approved by the local institutional review board ( irb ) at each participating site .
the written consent document was waived in participating centers , because of the retrospective nature of the study , with no clinical follow - up .
this report represents pci data of the participating hospitals from january 1 , 2014 , through december 31 , 2014 .
the k - pci registry governing committee centrally managed the web - based registered study data .
after the k - pci registry was approved by the irbs , demographic , procedural , and in - hospital outcomes data for 44967 pci cases from 92 hospitals were collected .
about half ( 45.7% ) of the pci centers were located in the capital area and high - volume facilities that performed more than 781 pci procedures annually were concentrated in metropolitan areas , including seoul ( fig .
the k - pci data management and inspection program determined whether collected data were accurate and complete and the crf variables were refined based on the program results .
the k - pci registry governing committee periodically monitored the enrollment status and shared the results with participating hospitals via newsletters , the committee also performed data management quality verification through the query process .
discrete data for demographic , clinical , procedural and outcome variables were presented as numbers and percentages and compared using chi - square tests .
continuous variables are presented as medians with interquartile ranges ( iqrs ) unless otherwise specified , and were compared using the student 's t - test , analysis of variance ( anova ) or the wilcoxon rank - sum test , where applicable .
all analyses were conducted using r version 3.3.2 ( r foundation for statistical computing , vienna , austria ) .
the k - pci registry final protocol was created in the task force team meeting and the k - pci registry governing committee conference , it was designed for enrolling participants with respect to clinical diagnosis information , procedural data , and by considering major complications after pci procedures performed to treat ischemic heart disease .
the hospitals that could perform pci were asked to participate and 92 hospitals voluntarily took part in this registry .
demographic characteristics , clinical history , procedural information and pci complications that occurred before hospital discharge were collected retrospectively using case report forms ( crfs ) comprised of a standard set of 54 data elements . when multiple interventions were performed in a subject ,
all variables corresponded with written definitions in the crf dictionary ( k - pci registry 2014 crf v1.4 . , supplementary table 1 ) in the online - only data supplement )
to standardize the data , and were provided by using common specifications with question and answer cases for participants .
this study was approved by the local institutional review board ( irb ) at each participating site .
the written consent document was waived in participating centers , because of the retrospective nature of the study , with no clinical follow - up .
this report represents pci data of the participating hospitals from january 1 , 2014 , through december 31 , 2014 .
the k - pci registry governing committee centrally managed the web - based registered study data .
after the k - pci registry was approved by the irbs , demographic , procedural , and in - hospital outcomes data for 44967 pci cases from 92 hospitals were collected .
about half ( 45.7% ) of the pci centers were located in the capital area and high - volume facilities that performed more than 781 pci procedures annually were concentrated in metropolitan areas , including seoul ( fig .
the k - pci data management and inspection program determined whether collected data were accurate and complete and the crf variables were refined based on the program results .
the k - pci registry governing committee periodically monitored the enrollment status and shared the results with participating hospitals via newsletters , the committee also performed data management quality verification through the query process .
discrete data for demographic , clinical , procedural and outcome variables were presented as numbers and percentages and compared using chi - square tests .
continuous variables are presented as medians with interquartile ranges ( iqrs ) unless otherwise specified , and were compared using the student 's t - test , analysis of variance ( anova ) or the wilcoxon rank - sum test , where applicable .
all analyses were conducted using r version 3.3.2 ( r foundation for statistical computing , vienna , austria ) .
a total of 92 hospitals submitted data on 44967 pci procedures performed from january through december 2014 .
the data presented in this report provide a contemporary assessment of pci , as performed in korea during the collection period , and represent important aspects of coronary interventions , including use of diagnostic support tools and procedural devices , as well as clinical outcomes before hospital discharge . among the hospitals included in the k - pci registry , 62% performed 500 or fewer pci procedures and 11% performed more than 1000 pcis during the collection period .
twelve hospitals ( 13% ) performed 200 or fewer pcis for one year and these hospitals accounted for 3.2% of all pci procedures ( fig .
median age was 66.0 [ iqr 57.0 - 74.0 ] years and the proportion of male patients was 70.3% ( fig .
3 ) . among patients undergoing pci , 35.9% had diabetes mellitus , 9.2% had history of prior myocardial infarction , 24% had history of pci , 1.3% had prior coronary artery bypass surgery ,
6.4% had renal failure , 8.8% had prior history of cerebrovascular disease , and 2.7% had peripheral vascular disease .
unstable angina was the most common initial presentation ( 35.9% ) that was a clinical indication for pci , followed by stable angina ( 22.6% ) , nstemi ( 19.7% ) , stemi ( 18.4% ) , and silent ischemia ( 3.5% ) ( fig .
patients that were between 60 - 80 years , were more likely to present with stable angina compared with other age groups , whereas patients in younger groups and elderly groups were more likely to present with acute coronary syndrome ( acs ) ( fig 5a ) . however , when this age - diagnosis interaction was sorted by gender , there was a trend toward a higher incidence of acs in young male patients and elderly female patients ( fig .
cardiogenic shock was identified in 3.1% and cardiac arrest was present in 2.3% of patients in the 24 hours prior to admission .
beta blocking agents were the most frequently prescribed antianginal medication ( 53.5% ) within 2 weeks of the procedure , followed by calcium channel blockers ( 36.5% ) , nicorandil ( 24.1% ) , long - acting nitrates ( 17.6% ) , and trimetazidine ( 15.2% ) . from the total number of patients undergoing pci , only 13.9% ( 9.8% in acs patients , 25.8% in non - acs patients ) underwent certain types of non - invasive tests before the pci ( table 1 ) .
the treadmill test ( tmt ) was the dominant stress test ( 6.7% in acs patients , 19.5% in non - acs patients ) .
of the non - acs patients who underwent different types of non - invasive stress tests , 13.3% demonstrated positive tmt and 5.1% demonstrated positive thallium single - photon emission computed tomography .
stress echocardiography and stress magnetic resonance imaging studies were done in less than 1% of patients in this registry .
coronary computed tomography ( ct ) angiography was performed in 13.7% ( 10.0% in acs , 24.1% in non - acs ) of patients and 42.7% of those patients had one vessel involved .
pre - pci evaluation of left ventricular function was performed in 67.6% of patients and the mean left ventricular ejection fraction was 60.0% .
more than half of the patients had multi - vessel cad , whereas 42.7% of patients had single vessel involvement .
the left anterior descending artery was the most frequently involved vessel ( 70.1% ) , followed by the right coronary artery ( 35.4% ) , left circumflex artery ( 27.3% ) , and left main coronary artery ( 4.9% ) . among patients that underwent pci , a chronic total occlusion lesion was present in 10.5% and an in - stent restenosis lesion was present in 7.6% .
two - thirds of the pci procedures were performed in an elective setting . in this registry
the trans - radial approach was more frequently ( 56.1% ) used for pci procedures , compared to the trans - femoral approach ( 45.4% ) .
even among acs patients , more than half ( 52.7% ) of procedures were performed via the trans - radial approach .
mechanical support devices , such as an intra - aortic balloon pump or emergency bypass system , were used in 2.2% of all pci procedures .
at least one drug - eluting stent ( des ) was placed in 91.3% of procedures , plain old balloon angioplasty ( poba ) without stent implantation was done in 19.1% , and drug - eluting balloon ( deb ) was used in 5.9% of patients .
intravascular ultrasound ( ivus ) was used in 28.6% of patients ( 27.1% in acs patients , 32.7% in non - acs patients ) as an adjunctive pci support tool , whereas fractional flow reserve ( ffr ) was only performed in 3.7% of patients ( 2.5% in acs patients , 7.2% in non - acs patients ) .
the in - hospital , all - cause mortality for the entire cohort was 2.3% ( 1023 patients ) , of which 68.8% ( 704 patients ) experienced cardiac - related deaths ( table 3 ) . in - hospital
other in - hospital event rates were low including , non - fatal mi 1.6% , stroke 0.2% , urgent repeat revascularization 0.3% , and stent thrombosis in 0.4% ( 172 patients ) .
there were significantly higher rates of all - cause mortality ( 3.0 vs. 2.0 ; p<0.001 ) and cardiac mortality ( 2.0 vs. 1.4% ; p<0.001 ) in women undergoing pci .
the rates for transfusion during hospitalization were 2.2% , which was higher in women ( 2.9 vs. 1.9% ; p<0.001 ) .
although the number of pci procedures peaked in march and december , the incidence of in - hospital events was evenly distributed throughout the year . however ,
the rates of in - hospital cardiac events were significantly higher when pci cases were performed during weekends than for procedures performed during weekdays ( 9.4 vs. 3.8% ; p<0.001 ; fig .
6 ) , this is likely because most cases performed over the weekend were in emergency settings . to understand differences in demographics , procedural characteristics and clinical outcomes between high vs. low pci volume centers
, we divided all pci centers into three tertiles based on the number of pcis performed during the collection period ( 1st tertile : 41 - 493 ; 2nd tertile : 494 - 780 ; 3rd tertile : 781 - 1794 ) .
patients in high - volume centers were more likely to have a history of hypertension , dyslipidemia , renal failure , peripheral vascular disease , prior pci , and coronary artery bypass graft than patients from lower volume centers ( table 4 ) .
high volume centers had more stable patients , used non - invasive pre - tests more frequently , and more frequently performed elective pci with a trans - radial approach using ivus / ffr ( table 5 ) . in contrast , low volume centers had higher incidences of acute myocardial infarction , cardiogenic shock or cardiac arrest .
thus , these centers performed emergency pci more frequently ( 24.4 vs. 14.9% ; p<0.001 ) without ivus / ffr and were less likely to conduct non - invasive pre - tests . consequently , low volume centers showed higher in - hospital mortality ( 2.7 vs. 2.3 vs. 1.8% ; p<0.001 ) ( table 6 ) .
a total of 92 hospitals submitted data on 44967 pci procedures performed from january through december 2014 .
the data presented in this report provide a contemporary assessment of pci , as performed in korea during the collection period , and represent important aspects of coronary interventions , including use of diagnostic support tools and procedural devices , as well as clinical outcomes before hospital discharge . among the hospitals included in the k - pci registry , 62% performed 500 or fewer pci procedures and 11% performed more than 1000 pcis during the collection period .
twelve hospitals ( 13% ) performed 200 or fewer pcis for one year and these hospitals accounted for 3.2% of all pci procedures ( fig .
median age was 66.0 [ iqr 57.0 - 74.0 ] years and the proportion of male patients was 70.3% ( fig .
3 ) . among patients undergoing pci , 35.9% had diabetes mellitus , 9.2% had history of prior myocardial infarction , 24% had history of pci , 1.3% had prior coronary artery bypass surgery , 6.4% had renal failure , 8.8% had prior history of cerebrovascular disease , and 2.7% had peripheral vascular disease .
unstable angina was the most common initial presentation ( 35.9% ) that was a clinical indication for pci , followed by stable angina ( 22.6% ) , nstemi ( 19.7% ) , stemi ( 18.4% ) , and silent ischemia ( 3.5% ) ( fig .
patients that were between 60 - 80 years , were more likely to present with stable angina compared with other age groups , whereas patients in younger groups and elderly groups were more likely to present with acute coronary syndrome ( acs ) ( fig 5a ) . however , when this age - diagnosis interaction was sorted by gender , there was a trend toward a higher incidence of acs in young male patients and elderly female patients ( fig .
cardiogenic shock was identified in 3.1% and cardiac arrest was present in 2.3% of patients in the 24 hours prior to admission .
beta blocking agents were the most frequently prescribed antianginal medication ( 53.5% ) within 2 weeks of the procedure , followed by calcium channel blockers ( 36.5% ) , nicorandil ( 24.1% ) , long - acting nitrates ( 17.6% ) , and trimetazidine ( 15.2% ) .
from the total number of patients undergoing pci , only 13.9% ( 9.8% in acs patients , 25.8% in non - acs patients ) underwent certain types of non - invasive tests before the pci ( table 1 ) .
the treadmill test ( tmt ) was the dominant stress test ( 6.7% in acs patients , 19.5% in non - acs patients ) .
of the non - acs patients who underwent different types of non - invasive stress tests , 13.3% demonstrated positive tmt and 5.1% demonstrated positive thallium single - photon emission computed tomography .
stress echocardiography and stress magnetic resonance imaging studies were done in less than 1% of patients in this registry .
coronary computed tomography ( ct ) angiography was performed in 13.7% ( 10.0% in acs , 24.1% in non - acs ) of patients and 42.7% of those patients had one vessel involved .
pre - pci evaluation of left ventricular function was performed in 67.6% of patients and the mean left ventricular ejection fraction was 60.0% .
more than half of the patients had multi - vessel cad , whereas 42.7% of patients had single vessel involvement .
the left anterior descending artery was the most frequently involved vessel ( 70.1% ) , followed by the right coronary artery ( 35.4% ) , left circumflex artery ( 27.3% ) , and left main coronary artery ( 4.9% ) . among patients that underwent pci , a chronic total occlusion lesion was present in 10.5% and an in - stent restenosis lesion was present in 7.6% .
two - thirds of the pci procedures were performed in an elective setting . in this registry
the trans - radial approach was more frequently ( 56.1% ) used for pci procedures , compared to the trans - femoral approach ( 45.4% ) . even among acs patients , more than half ( 52.7% ) of procedures
mechanical support devices , such as an intra - aortic balloon pump or emergency bypass system , were used in 2.2% of all pci procedures .
at least one drug - eluting stent ( des ) was placed in 91.3% of procedures , plain old balloon angioplasty ( poba ) without stent implantation was done in 19.1% , and drug - eluting balloon ( deb ) was used in 5.9% of patients .
intravascular ultrasound ( ivus ) was used in 28.6% of patients ( 27.1% in acs patients , 32.7% in non - acs patients ) as an adjunctive pci support tool , whereas fractional flow reserve ( ffr ) was only performed in 3.7% of patients ( 2.5% in acs patients , 7.2% in non - acs patients ) .
the in - hospital , all - cause mortality for the entire cohort was 2.3% ( 1023 patients ) , of which 68.8% ( 704 patients ) experienced cardiac - related deaths ( table 3 ) . in - hospital
other in - hospital event rates were low including , non - fatal mi 1.6% , stroke 0.2% , urgent repeat revascularization 0.3% , and stent thrombosis in 0.4% ( 172 patients ) .
there were significantly higher rates of all - cause mortality ( 3.0 vs. 2.0 ; p<0.001 ) and cardiac mortality ( 2.0 vs. 1.4% ; p<0.001 ) in women undergoing pci .
the rates for transfusion during hospitalization were 2.2% , which was higher in women ( 2.9 vs. 1.9% ; p<0.001 ) .
although the number of pci procedures peaked in march and december , the incidence of in - hospital events was evenly distributed throughout the year . however , the rates of in - hospital cardiac events were significantly higher when pci cases were performed during weekends than for procedures performed during weekdays ( 9.4 vs. 3.8% ; p<0.001 ; fig .
6 ) , this is likely because most cases performed over the weekend were in emergency settings .
to understand differences in demographics , procedural characteristics and clinical outcomes between high vs. low pci volume centers , we divided all pci centers into three tertiles based on the number of pcis performed during the collection period ( 1st tertile : 41 - 493 ; 2nd tertile : 494 - 780 ; 3rd tertile : 781 - 1794 ) .
patients in high - volume centers were more likely to have a history of hypertension , dyslipidemia , renal failure , peripheral vascular disease , prior pci , and coronary artery bypass graft than patients from lower volume centers ( table 4 ) .
high volume centers had more stable patients , used non - invasive pre - tests more frequently , and more frequently performed elective pci with a trans - radial approach using ivus / ffr ( table 5 ) .
in contrast , low volume centers had higher incidences of acute myocardial infarction , cardiogenic shock or cardiac arrest .
thus , these centers performed emergency pci more frequently ( 24.4 vs. 14.9% ; p<0.001 ) without ivus / ffr and were less likely to conduct non - invasive pre - tests . consequently , low volume centers showed higher in - hospital mortality ( 2.7 vs. 2.3 vs. 1.8% ; p<0.001 ) ( table 6 ) .
this study represents the first nationwide database for pci in korea that was collected and analyzed by the ksc / ksic k - pci registry .
key findings were as follows : 1 ) thirty - eight percent of patients presented with acute myocardial infarction and one - third of all pci procedures were performed in urgent or emergency settings , 2 ) non - invasive stress tests were performed in 13.9% of cases , while coronary ct angiography was used in 13.7% of cases before pci , 3 ) radial artery access was used in 56.1% of all pci procedures , 4 ) devices used in pci included des , poba , deb , and bms ( 91.3% , 19.1% , 5.9% , and 1.1% of all procedures , respectively ) , 5 ) the incidences of in - hospital death , non - fatal myocardial infarction , and stroke were 2.3% , 1.6% , and 0.2% , respectively , 6 ) depending on the case volume of each center , there were differences in the baseline demographics , clinical characteristics , and in - hospital clinical outcomes after pci .
the national cardiovascular data registry ( ncdr ) of the american college of cardiology foundation ( accf ) is a representative database that was developed to assist healthcare providers document their processes and quality of care in the cardiac catheterization laboratory.14)15 ) this registry records data on patient and hospital characteristics , clinical presentation , length of hospital stay , treatment information , and in - hospital outcomes for pci procedures from > 1000 sites across the united states .
several european countries are now conducting nationwide interventional registries that are organized either by a scientific society or the government.16)17)18)19)20 ) however , patterns for korean pci practice have differed , compared to western countries , therefore a korean database that reflects relevant situations in korea is needed .
after fda approval , the use of des rapidly increased by up to 89% of all stents that were implanted in 2005 . however , after research presented in 2006 suggested that there was an increase in adverse events in patients that received des , use declined to 66% of all stents and was recorded as 73% in 2011.21 ) in the us , physicians were less likely to use des for patients that presented with myocardial infarction and were at high risk for stent thrombosis compared to unstable angina . in this cohort ,
dess were used in 91.3% of all procedures , whereas only 1.1% of patients received bare - metal stents .
moreover , physicians consistently used des across clinical diagnoses at initial presentation . even in stemi patients that underwent primary pci , 92.2% received des .
although the position of des during primary pci was not extensively established and increased risk of late stent thrombosis was indicated,22 ) the practice pattern of des use might reflect a gap in knowledge between actual and alleged benefits of des , thus representing a possibility to improve clinical outcomes and quality of care for patients with different clinical presentations . in this cohort , ivus was used in 32.7% and ffr was used in 7.2% of non - acs cases as adjunct pci support tools in patients undergoing pci .
these rates are higher than reported in us patterns of ivus and ffr use.23 ) however , there was a significant increase in the use of ffr and ivus , according to the nationwide inpatient sample ( nis ) database of patients undergoing left heart catheterization between 2009 and 2011 in the us .
specifically , the number of in - hospital ffr utilization in us increased from 1173 cases in 2008 to 21365 cases in 2012 , representing an 18-fold rise.24 ) further research studies are needed to elucidate the implementation of adjunct pci support tools in lesions with different locations and different severities in our cohort .
the overall in - hospital mortality rate for pci patients in this report was somewhat higher than previous registries.25)26 ) in - hospital mortality among 181775 pci procedures performed from january 2004 through march 2006 in us ncdr was 1.27% , ranging from 0.65% in elective pci to 4.81% in stemi patients.25 ) in our registry , in - hospital mortality ranged from 0.2% in patients with stable angina to 6.9% in stemi patients .
higher overall in - hospital mortality in our registry can be partly explained by older age , more female patients , higher proportion of diabetes mellitus , and greater likelihood of undergoing emergency pci in subjects included in our registry .
although the exact mechanism of higher mortality in the k - pci registry has not been fully elucidated , additional mortality risk model assessment is needed to accurately measure patient risks in order to improve quality of care and shared decision making.27 ) we found significant variations between high vs. low pci volume centers in terms of baseline demographic , clinical characteristics and in - hospital clinical outcomes .
for example , the frequency of non - invasive tests before pci was 12% in low - tertile volume centers while 17% in high - tertile volume centers .
the frequency of ivus / ffr use during pci was 27% in low - volume centers while 40% in high - volume centers .
these actual differences , particularly the lower utilization of ivus or ffr during procedures in low - tertile volume centers , suggest an important opportunity to improve the consistency of care for patients undergoing pci because evidence indicates that adjunct pci support tools can reduce repeat revascularization and stent thrombosis rates after pci with des implantation.28)29)30 ) the lower utilization of ivus / ffr during pci or non - invasive tests before pci in low - volume centers could be related to critical care or patient emergencies .
the low - volume centers had fewer patients with stable angina ( 20 vs. 35% in high - volume ) and that underwent less elective pci ( 60 vs. 75% in high - volume centers ) than high - volume centers .
in other words , low - volume centers more frequently performed urgent / emergency pci for patients with acs than high - volume centers
. this could affect the ability of centers to use non - invasive tests before pci or ivus / ffr during pci , which is possible in more stable patients or in pci situations .
this analysis was not designed to formulate definite conclusions from this observation . therefore , additional research efforts are needed to elucidate how the differences in quality of care have affected clinical outcomes in high- vs. low - volume centers .
performance measures and outcome implementation information from the k - pci registry could provide data for creating and developing korean guidelines for pci , acute myocardial infarction , and unstable angina / non - st - elevation myocardial infarction .
the k - pci registry will support improvements in catheterization laboratory performance around the country and assist in the acquiring and maintaining individual physician certification for ksic .
the k - pci registry committee is currently planning to capture catheterization data in 2016 and this report will be the most comprehensive database for pci in korea .
there were some limitations to this study that should be considered when interpreting the results .
first , patients and hospitals participating in the k - pci registry may not have been representative of all korean pci procedures . however , the k - pci registry represents 92 pci - capable hospitals across korea and captures the majority of pci procedures performed nationally .
second , several factors may have influenced the decision - making of the interventional cardiologists represented in different region or different hospitals , in regards to procedural features , such as use of adjunct pci tools and pre - pci non - invasive test selection .
third , the k - pci registry dataset only records clinical outcomes that occurred before hospital discharge prior to pci .
moreover , given that our data were analyzed retrospectively , clinical outcomes associated with the clinical or procedural characteristics of patients or catheterization laboratories are observational and causality can not be established .
fourth , data collection and reports lagged behind pci procedures by 1 year , thus limiting rapid feedback of contemporary practices to implement quality improvement processes for the participating centers .
this study presents the first korean pci data collected and analyzed by the ksc / ksic k - pci registry .
these data may provide an opportunity to understand current pci practices and in - hospital outcomes in korea and could be used as a foundation for developing treatment guidelines and nationwide clinical research .
there were some limitations to this study that should be considered when interpreting the results .
first , patients and hospitals participating in the k - pci registry may not have been representative of all korean pci procedures .
however , the k - pci registry represents 92 pci - capable hospitals across korea and captures the majority of pci procedures performed nationally .
second , several factors may have influenced the decision - making of the interventional cardiologists represented in different region or different hospitals , in regards to procedural features , such as use of adjunct pci tools and pre - pci non - invasive test selection .
third , the k - pci registry dataset only records clinical outcomes that occurred before hospital discharge prior to pci .
moreover , given that our data were analyzed retrospectively , clinical outcomes associated with the clinical or procedural characteristics of patients or catheterization laboratories are observational and causality can not be established .
fourth , data collection and reports lagged behind pci procedures by 1 year , thus limiting rapid feedback of contemporary practices to implement quality improvement processes for the participating centers .
this study presents the first korean pci data collected and analyzed by the ksc / ksic k - pci registry .
these data may provide an opportunity to understand current pci practices and in - hospital outcomes in korea and could be used as a foundation for developing treatment guidelines and nationwide clinical research .
| background and objectivesalthough several multicenter registries have evaluated percutaneous coronary intervention ( pci ) procedures in korea , those databases have been limited by non - standardized data collection and lack of uniform reporting methods .
we aimed to collect and report data from a standardized database to analyze pci procedures throughout the country.materials and methods both clinical and procedural data , as well as clinical outcomes data during hospital stay , were collected based on case report forms that used a standard set of 54 data elements .
this report is based on 2014 korean pci registry cohort data.resultsa total of 92 hospitals offered data on 44967 pci procedures .
the median age was 66.0 interquartile range 57.0 - 74.0 years , and 70.3% were men .
thirty - eight percent of patients presented with acute myocardial infarction and one - third of all pci procedures were performed in an urgent or emergency setting .
non - invasive stress tests were performed in 13.9% of cases , while coronary computed tomography angiography was used in 13.7% of cases prior to pci .
radial artery access was used in 56.1% of all pci procedures .
devices that used pci included drug - eluting stent , plain old balloon angioplasty , drug - eluting balloon , and bare - metal stent ( around 91% , 19% , 6% , and 1% of all procedures , respectively ) .
the incidences of in - hospital death , non - fatal myocardial infarction , and stroke were 2.3% , 1.6% , and 0.2% , respectively.conclusionthese data may provide an overview of the current pci practices and in - hospital outcomes in korea and could be used as a foundation for developing treatment guidelines and nationwide clinical research . | <s>[INST]percutaneous coronary intervention ( pci ) has emerged as an important modality to treat coronary artery disease ( cad ) . as research improves pharmacology and clinical approaches for patient treatment ,
more complex cads are being successfully treated with pci and clinical outcomes are consistently improving .
pci can now be performed in most patients that require revascularization and it is also offered to subjects that have a high operative risk.1 ) guideline - based strategies and monitoring of pci procedures are strongly recommended to improve in - hospital and long - term clinical outcomes of patients that undergo pci.2)3)4)5 ) specifically , performance measures for pci and st - elevation myocardial infarction ( stemi)/non - st - elevation myocardial infarction ( nstemi ) were established to guide physicians with approaches for these interventions.6)7)8 ) although several multicenter registries have evaluated pci procedures in korea,9)10)11)12)13 ) no nationwide contemporary pci registries have been collected with standardized collection forms and unified reporting methods .
the korean society of cardiology ( ksc ) and korean society of interventional cardiology ( ksic ) established the korean percutaneous coronary intervention ( k - pci ) registry to collect and report results in a standardized database for pci case analysis throughout the country .
the purpose of this study was to construct baseline data standards to set - up treatment guidelines that reflect relevant clinical situations and to facilitate clinical research for cardiologists that treat cad in korea .
the k - pci registry final protocol was created in the task force team meeting and the k - pci registry governing committee conference , it was designed for enrolling participants with respect to clinical diagnosis information , procedural data , and by considering major complications after pci procedures performed to treat ischemic heart disease .
the hospitals that could perform pci were asked to participate and 92 hospitals voluntarily took part in this registry .
demographic characteristics , clinical history , procedural information and pci complications that occurred before hospital discharge were collected retrospectively using case report forms ( crfs ) comprised of a standard set of 54 data elements . when multiple interventions were performed in a subject ,
all variables corresponded with written definitions in the crf dictionary ( k - pci registry 2014 crf v1.4 . , supplementary table 1 ) in the online - only data supplement )
to standardize the data , and were provided by using common specifications with question and answer cases for participants .
this study was approved by the local institutional review board ( irb ) at each participating site .
the written consent document was waived in participating centers , because of the retrospective nature of the study , with no clinical follow - up .
this report represents pci data of the participating hospitals from january 1 , 2014 , through december 31 , 2014 .
the k - pci registry governing committee centrally managed the web - based registered study data .
after the k - pci registry was approved by the irbs , demographic , procedural , and in - hospital outcomes data for 44967 pci cases from 92 hospitals were collected .
about half ( 45.7% ) of the pci centers were located in the capital area and high - volume facilities that performed more than 781 pci procedures annually were concentrated in metropolitan areas , including seoul ( fig .
the k - pci data management and inspection program determined whether collected data were accurate and complete and the crf variables were refined based on the program results .
the k - pci registry governing committee periodically monitored the enrollment status and shared the results with participating hospitals via newsletters , the committee also performed data management quality verification through the query process .
discrete data for demographic , clinical , procedural and outcome variables were presented as numbers and percentages and compared using chi - square tests .
continuous variables are presented as medians with interquartile ranges ( iqrs ) unless otherwise specified , and were compared using the student 's t - test , analysis of variance ( anova ) or the wilcoxon rank - sum test , where applicable .
all analyses were conducted using r version 3.3.2 ( r foundation for statistical computing , vienna , austria ) .
the k - pci registry final protocol was created in the task force team meeting and the k - pci registry governing committee conference , it was designed for enrolling participants with respect to clinical diagnosis information , procedural data , and by considering major complications after pci procedures performed to treat ischemic heart disease .
the hospitals that could perform pci were asked to participate and 92 hospitals voluntarily took part in this registry .
demographic characteristics , clinical history , procedural information and pci complications that occurred before hospital discharge were collected retrospectively using case report forms ( crfs ) comprised of a standard set of 54 data elements . when multiple interventions were performed in a subject ,
all variables corresponded with written definitions in the crf dictionary ( k - pci registry 2014 crf v1.4 . , supplementary table 1 ) in the online - only data supplement )
to standardize the data , and were provided by using common specifications with question and answer cases for participants .
this study was approved by the local institutional review board ( irb ) at each participating site .
the written consent document was waived in participating centers , because of the retrospective nature of the study , with no clinical follow - up .
this report represents pci data of the participating hospitals from january 1 , 2014 , through december 31 , 2014 .
the k - pci registry governing committee centrally managed the web - based registered study data .
after the k - pci registry was approved by the irbs , demographic , procedural , and in - hospital outcomes data for 44967 pci cases from 92 hospitals were collected .
about half ( 45.7% ) of the pci centers were located in the capital area and high - volume facilities that performed more than 781 pci procedures annually were concentrated in metropolitan areas , including seoul ( fig .
the k - pci data management and inspection program determined whether collected data were accurate and complete and the crf variables were refined based on the program results .
the k - pci registry governing committee periodically monitored the enrollment status and shared the results with participating hospitals via newsletters , the committee also performed data management quality verification through the query process .
discrete data for demographic , clinical , procedural and outcome variables were presented as numbers and percentages and compared using chi - square tests .
continuous variables are presented as medians with interquartile ranges ( iqrs ) unless otherwise specified , and were compared using the student 's t - test , analysis of variance ( anova ) or the wilcoxon rank - sum test , where applicable .
all analyses were conducted using r version 3.3.2 ( r foundation for statistical computing , vienna , austria ) .
a total of 92 hospitals submitted data on 44967 pci procedures performed from january through december 2014 .
the data presented in this report provide a contemporary assessment of pci , as performed in korea during the collection period , and represent important aspects of coronary interventions , including use of diagnostic support tools and procedural devices , as well as clinical outcomes before hospital discharge . among the hospitals included in the k - pci registry , 62% performed 500 or fewer pci procedures and 11% performed more than 1000 pcis during the collection period .
twelve hospitals ( 13% ) performed 200 or fewer pcis for one year and these hospitals accounted for 3.2% of all pci procedures ( fig .
median age was 66.0 [ iqr 57.0 - 74.0 ] years and the proportion of male patients was 70.3% ( fig .
3 ) . among patients undergoing pci , 35.9% had diabetes mellitus , 9.2% had history of prior myocardial infarction , 24% had history of pci , 1.3% had prior coronary artery bypass surgery ,
6.4% had renal failure , 8.8% had prior history of cerebrovascular disease , and 2.7% had peripheral vascular disease .
unstable angina was the most common initial presentation ( 35.9% ) that was a clinical indication for pci , followed by stable angina ( 22.6% ) , nstemi ( 19.7% ) , stemi ( 18.4% ) , and silent ischemia ( 3.5% ) ( fig .
patients that were between 60 - 80 years , were more likely to present with stable angina compared with other age groups , whereas patients in younger groups and elderly groups were more likely to present with acute coronary syndrome ( acs ) ( fig 5a ) . however , when this age - diagnosis interaction was sorted by gender , there was a trend toward a higher incidence of acs in young male patients and elderly female patients ( fig .
cardiogenic shock was identified in 3.1% and cardiac arrest was present in 2.3% of patients in the 24 hours prior to admission .
beta blocking agents were the most frequently prescribed antianginal medication ( 53.5% ) within 2 weeks of the procedure , followed by calcium channel blockers ( 36.5% ) , nicorandil ( 24.1% ) , long - acting nitrates ( 17.6% ) , and trimetazidine ( 15.2% ) . from the total number of patients undergoing pci , only 13.9% ( 9.8% in acs patients , 25.8% in non - acs patients ) underwent certain types of non - invasive tests before the pci ( table 1 ) .
the treadmill test ( tmt ) was the dominant stress test ( 6.7% in acs patients , 19.5% in non - acs patients ) .
of the non - acs patients who underwent different types of non - invasive stress tests , 13.3% demonstrated positive tmt and 5.1% demonstrated positive thallium single - photon emission computed tomography .
stress echocardiography and stress magnetic resonance imaging studies were done in less than 1% of patients in this registry .
coronary computed tomography ( ct ) angiography was performed in 13.7% ( 10.0% in acs , 24.1% in non - acs ) of patients and 42.7% of those patients had one vessel involved .
pre - pci evaluation of left ventricular function was performed in 67.6% of patients and the mean left ventricular ejection fraction was 60.0% .
more than half of the patients had multi - vessel cad , whereas 42.7% of patients had single vessel involvement .
the left anterior descending artery was the most frequently involved vessel ( 70.1% ) , followed by the right coronary artery ( 35.4% ) , left circumflex artery ( 27.3% ) , and left main coronary artery ( 4.9% ) . among patients that underwent pci , a chronic total occlusion lesion was present in 10.5% and an in - stent restenosis lesion was present in 7.6% .
two - thirds of the pci procedures were performed in an elective setting . in this registry
the trans - radial approach was more frequently ( 56.1% ) used for pci procedures , compared to the trans - femoral approach ( 45.4% ) .
even among acs patients , more than half ( 52.7% ) of procedures were performed via the trans - radial approach .
mechanical support devices , such as an intra - aortic balloon pump or emergency bypass system , were used in 2.2% of all pci procedures .
at least one drug - eluting stent ( des ) was placed in 91.3% of procedures , plain old balloon angioplasty ( poba ) without stent implantation was done in 19.1% , and drug - eluting balloon ( deb ) was used in 5.9% of patients .
intravascular ultrasound ( ivus ) was used in 28.6% of patients ( 27.1% in acs patients , 32.7% in non - acs patients ) as an adjunctive pci support tool , whereas fractional flow reserve ( ffr ) was only performed in 3.7% of patients ( 2.5% in acs patients , 7.2% in non - acs patients ) .
the in - hospital , all - cause mortality for the entire cohort was 2.3% ( 1023 patients ) , of which 68.8% ( 704 patients ) experienced cardiac - related deaths ( table 3 ) . in - hospital
other in - hospital event rates were low including , non - fatal mi 1.6% , stroke 0.2% , urgent repeat revascularization 0.3% , and stent thrombosis in 0.4% ( 172 patients ) .
there were significantly higher rates of all - cause mortality ( 3.0 vs. 2.0 ; p<0.001 ) and cardiac mortality ( 2.0 vs. 1.4% ; p<0.001 ) in women undergoing pci .
the rates for transfusion during hospitalization were 2.2% , which was higher in women ( 2.9 vs. 1.9% ; p<0.001 ) .
although the number of pci procedures peaked in march and december , the incidence of in - hospital events was evenly distributed throughout the year . however ,
the rates of in - hospital cardiac events were significantly higher when pci cases were performed during weekends than for procedures performed during weekdays ( 9.4 vs. 3.8% ; p<0.001 ; fig .
6 ) , this is likely because most cases performed over the weekend were in emergency settings . to understand differences in demographics , procedural characteristics and clinical outcomes between high vs. low pci volume centers
, we divided all pci centers into three tertiles based on the number of pcis performed during the collection period ( 1st tertile : 41 - 493 ; 2nd tertile : 494 - 780 ; 3rd tertile : 781 - 1794 ) .
patients in high - volume centers were more likely to have a history of hypertension , dyslipidemia , renal failure , peripheral vascular disease , prior pci , and coronary artery bypass graft than patients from lower volume centers ( table 4 ) .
high volume centers had more stable patients , used non - invasive pre - tests more frequently , and more frequently performed elective pci with a trans - radial approach using ivus / ffr ( table 5 ) . in contrast , low volume centers had higher incidences of acute myocardial infarction , cardiogenic shock or cardiac arrest .
thus , these centers performed emergency pci more frequently ( 24.4 vs. 14.9% ; p<0.001 ) without ivus / ffr and were less likely to conduct non - invasive pre - tests . consequently , low volume centers showed higher in - hospital mortality ( 2.7 vs. 2.3 vs. 1.8% ; p<0.001 ) ( table 6 ) .
a total of 92 hospitals submitted data on 44967 pci procedures performed from january through december 2014 .
the data presented in this report provide a contemporary assessment of pci , as performed in korea during the collection period , and represent important aspects of coronary interventions , including use of diagnostic support tools and procedural devices , as well as clinical outcomes before hospital discharge . among the hospitals included in the k - pci registry , 62% performed 500 or fewer pci procedures and 11% performed more than 1000 pcis during the collection period .
twelve hospitals ( 13% ) performed 200 or fewer pcis for one year and these hospitals accounted for 3.2% of all pci procedures ( fig .
median age was 66.0 [ iqr 57.0 - 74.0 ] years and the proportion of male patients was 70.3% ( fig .
3 ) . among patients undergoing pci , 35.9% had diabetes mellitus , 9.2% had history of prior myocardial infarction , 24% had history of pci , 1.3% had prior coronary artery bypass surgery , 6.4% had renal failure , 8.8% had prior history of cerebrovascular disease , and 2.7% had peripheral vascular disease .
unstable angina was the most common initial presentation ( 35.9% ) that was a clinical indication for pci , followed by stable angina ( 22.6% ) , nstemi ( 19.7% ) , stemi ( 18.4% ) , and silent ischemia ( 3.5% ) ( fig .
patients that were between 60 - 80 years , were more likely to present with stable angina compared with other age groups , whereas patients in younger groups and elderly groups were more likely to present with acute coronary syndrome ( acs ) ( fig 5a ) . however , when this age - diagnosis interaction was sorted by gender , there was a trend toward a higher incidence of acs in young male patients and elderly female patients ( fig .
cardiogenic shock was identified in 3.1% and cardiac arrest was present in 2.3% of patients in the 24 hours prior to admission .
beta blocking agents were the most frequently prescribed antianginal medication ( 53.5% ) within 2 weeks of the procedure , followed by calcium channel blockers ( 36.5% ) , nicorandil ( 24.1% ) , long - acting nitrates ( 17.6% ) , and trimetazidine ( 15.2% ) .
from the total number of patients undergoing pci , only 13.9% ( 9.8% in acs patients , 25.8% in non - acs patients ) underwent certain types of non - invasive tests before the pci ( table 1 ) .
the treadmill test ( tmt ) was the dominant stress test ( 6.7% in acs patients , 19.5% in non - acs patients ) .
of the non - acs patients who underwent different types of non - invasive stress tests , 13.3% demonstrated positive tmt and 5.1% demonstrated positive thallium single - photon emission computed tomography .
stress echocardiography and stress magnetic resonance imaging studies were done in less than 1% of patients in this registry .
coronary computed tomography ( ct ) angiography was performed in 13.7% ( 10.0% in acs , 24.1% in non - acs ) of patients and 42.7% of those patients had one vessel involved .
pre - pci evaluation of left ventricular function was performed in 67.6% of patients and the mean left ventricular ejection fraction was 60.0% .
more than half of the patients had multi - vessel cad , whereas 42.7% of patients had single vessel involvement .
the left anterior descending artery was the most frequently involved vessel ( 70.1% ) , followed by the right coronary artery ( 35.4% ) , left circumflex artery ( 27.3% ) , and left main coronary artery ( 4.9% ) . among patients that underwent pci , a chronic total occlusion lesion was present in 10.5% and an in - stent restenosis lesion was present in 7.6% .
two - thirds of the pci procedures were performed in an elective setting . in this registry
the trans - radial approach was more frequently ( 56.1% ) used for pci procedures , compared to the trans - femoral approach ( 45.4% ) . even among acs patients , more than half ( 52.7% ) of procedures
mechanical support devices , such as an intra - aortic balloon pump or emergency bypass system , were used in 2.2% of all pci procedures .
at least one drug - eluting stent ( des ) was placed in 91.3% of procedures , plain old balloon angioplasty ( poba ) without stent implantation was done in 19.1% , and drug - eluting balloon ( deb ) was used in 5.9% of patients .
intravascular ultrasound ( ivus ) was used in 28.6% of patients ( 27.1% in acs patients , 32.7% in non - acs patients ) as an adjunctive pci support tool , whereas fractional flow reserve ( ffr ) was only performed in 3.7% of patients ( 2.5% in acs patients , 7.2% in non - acs patients ) .
the in - hospital , all - cause mortality for the entire cohort was 2.3% ( 1023 patients ) , of which 68.8% ( 704 patients ) experienced cardiac - related deaths ( table 3 ) . in - hospital
other in - hospital event rates were low including , non - fatal mi 1.6% , stroke 0.2% , urgent repeat revascularization 0.3% , and stent thrombosis in 0.4% ( 172 patients ) .
there were significantly higher rates of all - cause mortality ( 3.0 vs. 2.0 ; p<0.001 ) and cardiac mortality ( 2.0 vs. 1.4% ; p<0.001 ) in women undergoing pci .
the rates for transfusion during hospitalization were 2.2% , which was higher in women ( 2.9 vs. 1.9% ; p<0.001 ) .
although the number of pci procedures peaked in march and december , the incidence of in - hospital events was evenly distributed throughout the year . however , the rates of in - hospital cardiac events were significantly higher when pci cases were performed during weekends than for procedures performed during weekdays ( 9.4 vs. 3.8% ; p<0.001 ; fig .
6 ) , this is likely because most cases performed over the weekend were in emergency settings .
to understand differences in demographics , procedural characteristics and clinical outcomes between high vs. low pci volume centers , we divided all pci centers into three tertiles based on the number of pcis performed during the collection period ( 1st tertile : 41 - 493 ; 2nd tertile : 494 - 780 ; 3rd tertile : 781 - 1794 ) .
patients in high - volume centers were more likely to have a history of hypertension , dyslipidemia , renal failure , peripheral vascular disease , prior pci , and coronary artery bypass graft than patients from lower volume centers ( table 4 ) .
high volume centers had more stable patients , used non - invasive pre - tests more frequently , and more frequently performed elective pci with a trans - radial approach using ivus / ffr ( table 5 ) .
in contrast , low volume centers had higher incidences of acute myocardial infarction , cardiogenic shock or cardiac arrest .
thus , these centers performed emergency pci more frequently ( 24.4 vs. 14.9% ; p<0.001 ) without ivus / ffr and were less likely to conduct non - invasive pre - tests . consequently , low volume centers showed higher in - hospital mortality ( 2.7 vs. 2.3 vs. 1.8% ; p<0.001 ) ( table 6 ) .
this study represents the first nationwide database for pci in korea that was collected and analyzed by the ksc / ksic k - pci registry .
key findings were as follows : 1 ) thirty - eight percent of patients presented with acute myocardial infarction and one - third of all pci procedures were performed in urgent or emergency settings , 2 ) non - invasive stress tests were performed in 13.9% of cases , while coronary ct angiography was used in 13.7% of cases before pci , 3 ) radial artery access was used in 56.1% of all pci procedures , 4 ) devices used in pci included des , poba , deb , and bms ( 91.3% , 19.1% , 5.9% , and 1.1% of all procedures , respectively ) , 5 ) the incidences of in - hospital death , non - fatal myocardial infarction , and stroke were 2.3% , 1.6% , and 0.2% , respectively , 6 ) depending on the case volume of each center , there were differences in the baseline demographics , clinical characteristics , and in - hospital clinical outcomes after pci .
the national cardiovascular data registry ( ncdr ) of the american college of cardiology foundation ( accf ) is a representative database that was developed to assist healthcare providers document their processes and quality of care in the cardiac catheterization laboratory.14)15 ) this registry records data on patient and hospital characteristics , clinical presentation , length of hospital stay , treatment information , and in - hospital outcomes for pci procedures from > 1000 sites across the united states .
several european countries are now conducting nationwide interventional registries that are organized either by a scientific society or the government.16)17)18)19)20 ) however , patterns for korean pci practice have differed , compared to western countries , therefore a korean database that reflects relevant situations in korea is needed .
after fda approval , the use of des rapidly increased by up to 89% of all stents that were implanted in 2005 . however , after research presented in 2006 suggested that there was an increase in adverse events in patients that received des , use declined to 66% of all stents and was recorded as 73% in 2011.21 ) in the us , physicians were less likely to use des for patients that presented with myocardial infarction and were at high risk for stent thrombosis compared to unstable angina . in this cohort ,
dess were used in 91.3% of all procedures , whereas only 1.1% of patients received bare - metal stents .
moreover , physicians consistently used des across clinical diagnoses at initial presentation . even in stemi patients that underwent primary pci , 92.2% received des .
although the position of des during primary pci was not extensively established and increased risk of late stent thrombosis was indicated,22 ) the practice pattern of des use might reflect a gap in knowledge between actual and alleged benefits of des , thus representing a possibility to improve clinical outcomes and quality of care for patients with different clinical presentations . in this cohort , ivus was used in 32.7% and ffr was used in 7.2% of non - acs cases as adjunct pci support tools in patients undergoing pci .
these rates are higher than reported in us patterns of ivus and ffr use.23 ) however , there was a significant increase in the use of ffr and ivus , according to the nationwide inpatient sample ( nis ) database of patients undergoing left heart catheterization between 2009 and 2011 in the us .
specifically , the number of in - hospital ffr utilization in us increased from 1173 cases in 2008 to 21365 cases in 2012 , representing an 18-fold rise.24 ) further research studies are needed to elucidate the implementation of adjunct pci support tools in lesions with different locations and different severities in our cohort .
the overall in - hospital mortality rate for pci patients in this report was somewhat higher than previous registries.25)26 ) in - hospital mortality among 181775 pci procedures performed from january 2004 through march 2006 in us ncdr was 1.27% , ranging from 0.65% in elective pci to 4.81% in stemi patients.25 ) in our registry , in - hospital mortality ranged from 0.2% in patients with stable angina to 6.9% in stemi patients .
higher overall in - hospital mortality in our registry can be partly explained by older age , more female patients , higher proportion of diabetes mellitus , and greater likelihood of undergoing emergency pci in subjects included in our registry .
although the exact mechanism of higher mortality in the k - pci registry has not been fully elucidated , additional mortality risk model assessment is needed to accurately measure patient risks in order to improve quality of care and shared decision making.27 ) we found significant variations between high vs. low pci volume centers in terms of baseline demographic , clinical characteristics and in - hospital clinical outcomes .
for example , the frequency of non - invasive tests before pci was 12% in low - tertile volume centers while 17% in high - tertile volume centers .
the frequency of ivus / ffr use during pci was 27% in low - volume centers while 40% in high - volume centers .
these actual differences , particularly the lower utilization of ivus or ffr during procedures in low - tertile volume centers , suggest an important opportunity to improve the consistency of care for patients undergoing pci because evidence indicates that adjunct pci support tools can reduce repeat revascularization and stent thrombosis rates after pci with des implantation.28)29)30 ) the lower utilization of ivus / ffr during pci or non - invasive tests before pci in low - volume centers could be related to critical care or patient emergencies .
the low - volume centers had fewer patients with stable angina ( 20 vs. 35% in high - volume ) and that underwent less elective pci ( 60 vs. 75% in high - volume centers ) than high - volume centers .
in other words , low - volume centers more frequently performed urgent / emergency pci for patients with acs than high - volume centers
. this could affect the ability of centers to use non - invasive tests before pci or ivus / ffr during pci , which is possible in more stable patients or in pci situations .
this analysis was not designed to formulate definite conclusions from this observation . therefore , additional research efforts are needed to elucidate how the differences in quality of care have affected clinical outcomes in high- vs. low - volume centers .
performance measures and outcome implementation information from the k - pci registry could provide data for creating and developing korean guidelines for pci , acute myocardial infarction , and unstable angina / non - st - elevation myocardial infarction .
the k - pci registry will support improvements in catheterization laboratory performance around the country and assist in the acquiring and maintaining individual physician certification for ksic .
the k - pci registry committee is currently planning to capture catheterization data in 2016 and this report will be the most comprehensive database for pci in korea .
there were some limitations to this study that should be considered when interpreting the results .
first , patients and hospitals participating in the k - pci registry may not have been representative of all korean pci procedures . however , the k - pci registry represents 92 pci - capable hospitals across korea and captures the majority of pci procedures performed nationally .
second , several factors may have influenced the decision - making of the interventional cardiologists represented in different region or different hospitals , in regards to procedural features , such as use of adjunct pci tools and pre - pci non - invasive test selection .
third , the k - pci registry dataset only records clinical outcomes that occurred before hospital discharge prior to pci .
moreover , given that our data were analyzed retrospectively , clinical outcomes associated with the clinical or procedural characteristics of patients or catheterization laboratories are observational and causality can not be established .
fourth , data collection and reports lagged behind pci procedures by 1 year , thus limiting rapid feedback of contemporary practices to implement quality improvement processes for the participating centers .
this study presents the first korean pci data collected and analyzed by the ksc / ksic k - pci registry .
these data may provide an opportunity to understand current pci practices and in - hospital outcomes in korea and could be used as a foundation for developing treatment guidelines and nationwide clinical research .
there were some limitations to this study that should be considered when interpreting the results .
first , patients and hospitals participating in the k - pci registry may not have been representative of all korean pci procedures .
however , the k - pci registry represents 92 pci - capable hospitals across korea and captures the majority of pci procedures performed nationally .
second , several factors may have influenced the decision - making of the interventional cardiologists represented in different region or different hospitals , in regards to procedural features , such as use of adjunct pci tools and pre - pci non - invasive test selection .
third , the k - pci registry dataset only records clinical outcomes that occurred before hospital discharge prior to pci .
moreover , given that our data were analyzed retrospectively , clinical outcomes associated with the clinical or procedural characteristics of patients or catheterization laboratories are observational and causality can not be established .
fourth , data collection and reports lagged behind pci procedures by 1 year , thus limiting rapid feedback of contemporary practices to implement quality improvement processes for the participating centers .
this study presents the first korean pci data collected and analyzed by the ksc / ksic k - pci registry .
these data may provide an opportunity to understand current pci practices and in - hospital outcomes in korea and could be used as a foundation for developing treatment guidelines and nationwide clinical research .
[/INST]background and objectivesalthough several multicenter registries have evaluated percutaneous coronary intervention ( pci ) procedures in korea , those databases have been limited by non - standardized data collection and lack of uniform reporting methods .
we aimed to collect and report data from a standardized database to analyze pci procedures throughout the country.materials and methods both clinical and procedural data , as well as clinical outcomes data during hospital stay , were collected based on case report forms that used a standard set of 54 data elements .
this report is based on 2014 korean pci registry cohort data.resultsa total of 92 hospitals offered data on 44967 pci procedures .
the median age was 66.0 interquartile range 57.0 - 74.0 years , and 70.3% were men .
thirty - eight percent of patients presented with acute myocardial infarction and one - third of all pci procedures were performed in an urgent or emergency setting .
non - invasive stress tests were performed in 13.9% of cases , while coronary computed tomography angiography was used in 13.7% of cases prior to pci .
radial artery access was used in 56.1% of all pci procedures .
devices that used pci included drug - eluting stent , plain old balloon angioplasty , drug - eluting balloon , and bare - metal stent ( around 91% , 19% , 6% , and 1% of all procedures , respectively ) .
the incidences of in - hospital death , non - fatal myocardial infarction , and stroke were 2.3% , 1.6% , and 0.2% , respectively.conclusionthese data may provide an overview of the current pci practices and in - hospital outcomes in korea and could be used as a foundation for developing treatment guidelines and nationwide clinical research .</s> |
the last decade has witnessed a surge of interest in wireless local area networks ( wlan ) , where mobile stations share a common wireless medium through contention - based medium access control ( mac ) . in wlans ,
collision of packets occurs when more than one station transmits at the same time , causing a waste of bandwidth .
recent advances in multiuser detection ( mud ) techniques @xcite open up new opportunities for resolving collisions in the physical ( phy ) layer . for example , in cdma @xcite or multiple - antenna @xcite systems , multiple packets can be received simultaneously using mud techniques without collisions .
it is expected that , with improved multipacket reception ( mpr ) capability from the phy layer , the mac layer will behave differently from what is commonly believed . in particular , to fully utilize the mpr capability for capacity enhancement in wlan ,
it is essential to understand the fundamental impact of mpr on the mac - layer design . as such
, this paper is an attempt to study the mac - layer throughput performance and the collision resolution schemes for wlans with mpr .
the key contributions of this paper are as follows : * to demonstrate mpr as a powerful capacity - enhancement technique at the system level , we analyze the mac - layer throughput of wlans with mpr capability under both finite - node and infinite - node assumptions .
our model is sufficiently general to cover both carrier - sensing and non - carrier - sensing networks .
we prove that in random - access wlans , network throughput increases super - linearly with the mpr capability of the channel .
that is , throughput divided by _
m _ increases as _ m _ increases , where _ m _ is the number of packets that can be resolved simultaneously .
the super - linear throughput scaling implies that the achievable throughput per unit cost increases with mpr capability of the channel .
this provides a strong incentive to deploy mpr in next - generation wireless networks . * we study the effect of mpr on the mac - layer collision resolution scheme , namely exponential backoff ( eb ) .
when packets collide in wlans , an eb scheme is used to schedule the retransmissions , in which the waiting time of the next retransmission will get multiplicatively longer for each collision incurred . in the commonly adopted binary exponential backoff ( beb ) scheme ( e.g. , used in ethernet @xcite , wifi @xcite , etc . ) ,
the multiplicative ( a backoff factor ) is equal to 2 .
we show in this paper that the widely used beb does not necessarily yield the close - to - optimal network throughput with the improved mpr capability from the phy layer . as a matter of fact
, beb is far from optimum for both non - carrier - sensing networks and carrier - sensing networks operated in basic access mode .
the optimal backoff factor increases with the mpr capability . meanwhile , beb is close to optimum for carrier - sensing networks when rts / cts access mode is adopted . *
built on the theoretical underpinnings established above , we propose a practical protocol to fully exploit the mpr capability in ieee 802.11-like wlans .
in contrast to @xcite-@xcite , we consider not only the mac layer protocol design , but also the phy - layer signal processing to enable mpr in distributed random - access wlans . as a result , the proposed protocol can be implemented in a fully distributed manner with marginal modification of current ieee 802.11 mac .
the first attempt to model a general mpr channel in random - access wireless networks was made by ghez , verdu , and schwartz in @xcite-@xcite in 1988 an 1989 , respectively , in which stability properties of conventional slotted aloha with mpr were studied under a simple infinite - user and single - buffer assumption .
no collision resolution scheme ( such as eb ) was considered therein .
this work was extended to csma systems by chan et al in @xcite and to finite user aloha systems by naware et al in @xcite .
it has been shown in @xcite-@xcite that mpr improves the stable throughput of aloha only when the mpr capability is comparable to the number of users in the system . in practical networks where the mpr capability is much smaller than the number of users , the stable throughput of conventional aloha is equal to 0 , same as the case without mpr . to date , little
work has been done to investigate the throughput enhancing capability of mpr in practical wlans with collision resolution schemes .
our paper here is an attempt along this direction .
protocols that exploit the mpr capability of networks have been studied by zhao and tong in @xcite-@xcite . in @xcite ,
a multi - queue service room ( mqsr ) mac protocol was proposed for networks with heterogeneous users .
the drawback of the mqsr protocol is its high computational cost due to updates of the joint distribution of all users states . to reduce complexity ,
a suboptimal dynamic queue protocol was proposed in @xcite . in both protocols ,
access to the common wireless channel is controlled by a central controller , which grants access to the channel to an appropriate subset of users at the beginning of each slot . in @xcite ,
chan et al proposed to add a mud layer to facilitate mpr in ieee 802.11 wlan . to implement the mud techniques mentioned as examples in @xcite , the ap
is assumed to have perfect knowledge of the number of concurrent transmissions , the identities of the transmitting stations , and the channel coefficients .
these information , while easy to get in a network with centralized scheduling ( e.g. , cellular systems ) , is unkown to the ap a priori in random access networks .
moreover , the preambles of concurrent packets overlap , and hence it is difficult for the ap to have a good estimation of the channel coefficients with the current protocol .
by contrast , our paper provides a solution to this issue by incorporating blind signal processing in the proposed protocol .
exponential backoff ( eb ) as a collision resolution technique has been extensively studied in different contexts @xcite-@xcite .
stability upper bound of beb has been given by goodman under a finite - node model in @xcite and recently improved by al - ammal in @xcite .
the throughput and delay characteristics of a slightly modified eb scheme have been studied in @xcite in the context of slotted aloha .
the characteristics of eb in steady state is further investigated in @xcite in time slotted wireless networks with equal slot length .
all the existing work on eb has assumed that the wireless channel can only accommodate one ongoing transmission at a time .
this paper is a first attempt to look at eb for an mpr system .
the remainder of this paper is organized as follows . in section
ii , we describe the system model and introduce the background knowledge on mud and eb . in section iii , we prove that the maximum achievable throughput of mpr wlan scales super - linearly with the mpr capability of the channel . in section iv , the effect of mpr on eb is investigated .
we show that the widely used beb scheme is no longer close - to - optimal in mpr networks . to realize mpr in ieee 802.11 wlans ,
a mac - phy protocol is presented in section v. in section vi , we discuss some practical issues related to mpr . finally , section vii concludes this paper .
we consider a fully conected infrastructure wlan where _
n _ infinitely backlogged mobile stations communicate with an access point ( ap ) .
we assume that the time axis is divided into slots and packet transmissions start only at the beginning of a slot .
in addition , after each transmission , the transmitting stations have a means to discover the result of the transmission , i.e. , success or failure .
if the transmission fails due to collision , the colliding stations will schedule retransmissions according to a collision resolution scheme ( e.g. , eb ) .
we assume that the channel has the capability to accommodate up to _ m _ simultaneous transmissions .
in other words , packets can be received correctly whenever the number of simultaneous transmissions is no larger than _ m_. when more than _ m _ stations contend for the channel at the same time , collision occurs and no packet can be decoded .
we refer to _ m _ as mpr capability . in our model , the length of a time slot is not necessarily fixed and may vary under different contexts @xcite .
we refer to this variable - length slot as backoff slot hereafter . in wlans
, the length of a backoff slot depends on the contention outcome ( hereafter referred to as channel status ) .
let @xmath0 denote the length of an idle time slot when nobody transmits ; @xmath1 denote the length of a collision time slot when more than _ m _ stations contend for the channel ; and @xmath2 denote the length of a time slot due to successful transmission when the number of transmitting stations is anywhere from 1 to _
m_. the durations of @xmath0 , @xmath1 , and @xmath2 depend on the underlying wlan configuration . for non - carrier - sensing networks such as slotted aloha ,
the stations are not aware of the channel status and the duration of all backoff slots are equal to the transmission time of a packet .
that is , @xmath3 where _ l _ is the packet size and _ r _ is the data transmission rate of a station . on the other hand , for carrier - sensing networks
, stations can distinguish between various types of channel status and the durations of different types of slots may not be the same .
for example , in ieee 802.11 dcf basic access mode , @xmath4 where @xmath5 is the time needed for a station to detect the packet transmission from any other station and is typically much smaller than @xmath1 and @xmath2 ; @xmath6 is the transmission time of phy header and mac header ; ack is the transmission time of an ack packet ; @xmath7 is the propagation delay ; and sifs and difs are the inter - frame space durations @xcite .
similarly , in ieee 802.11 dcf request - to - send / clear - to - send ( rts / cts ) access scheme , the slot durations are given by @xmath8 where @xmath9 and @xmath10 denote the transmission time of rts and cts packets , respectively . by allowing the durations of @xmath0 , @xmath1 , and @xmath2 to vary according to the underlying system , the analysis of this paper applies to a wide spectrum of various wlans , including both non - carrier - sensing and carrier - sensing networks .
this subsection briefly introduces the phy layer mud techniques used to decode multiple packets at the receiver .
let @xmath11 denote the data symbol transmitted by user _
k _ in symbol duration _
n_. if there are _ k _ stations transmitting together , then the received signal at a receiver is given by @xmath12 where @xmath13 denotes the additive noise , @xmath14 $ ] , and @xmath15^t$ ] . in multiple antenna systems
, @xmath16 is the channel vector , with the @xmath17 element being the channel coefficient from user _ k _ to the @xmath17 receive antenna .
in cdma systems , vector @xmath16 is multiplication of the spreading sequence of user _ k _ and the channel coefficient from user _ k _ to the ap .
the receiver attempts to obtain an estimate of the transmitted symbols @xmath18 from the received vector @xmath19 . to this end , various mud techniques have been proposed in the literature .
for example , the zero - forcing ( zf ) receiver is one of the most popular linear detectors .
it multiplies the received vector by the pseudo - inverse of matrix @xmath20 , denoted by @xmath21 , and the decision statistics become @xmath22 the minimum - mean - square - error ( mmse ) receiver is the optimal linear detector in the sense of maximizing the signal - to - interference - and - noise ratio ( sinr ) .
the decision statistics is calculated as @xmath23 where @xmath24 is the identity matrix , and @xmath25 is the variance of the additive noise .
given the decision statistics , an estimate of @xmath11 can be obtained by feeding the @xmath26 element of @xmath27 or @xmath28 into a quantizer .
other mud techniques include maximum - likelihood ( ml ) , parallel interference cancellation ( pic ) , successive interference cancellation ( sic ) , etc .
interested readers are referred to @xcite for more details .
eb adaptively tunes the transmission probability of a station according to the traffic intensity of the network .
it works as follows . a backlogged station sets its backoff timer by randomly choosing an integer within the range @xmath29 $ ] , where _ w _ denote the size of the contention window .
the backoff timer is decreased by one following each backoff slot .
the station transmits a packet in its queue once the backoff timer reaches zero . at the first transmission attempt of a packet , @xmath30 , referred to as the minimum contention window .
each time the transmission is unsuccessful , the _ w _ is multiplied by a backoff factor _
r_. that is , the contention window size @xmath31 after _ i _ successive transmission failures .
this section investigates the impact of mpr on the throughput of random - access wlans . in particular ,
we prove that the maximum achievable throughput scales super - linearly with the mpr capability @xmath32 . in practical systems , @xmath32 is directly related to the cost ( e.g. , bandwidth in cdma systems or antenna in multi - antenna systems ) .
super - linear scaling of throughput implies that the achievable throughput _ per unit cost _ increases with @xmath32 .
this provides a strong incentive to consider mpr in next - generation wireless networks .
as mentioned earlier , the transmission of stations is dictated by the underlying eb scheme . to capture the fundamentally achievable throughput of the system
, the following analysis assumes that each station transmits with probability @xmath33 in an arbitrary slot , without caring how @xmath33 is achieved .
the assumption will be made more rigorous in section iv , which relates @xmath33 to eb parameters such as @xmath34 and @xmath35 .
define throughput to be the average number of information bits transmitted successfully per second .
let @xmath36 denote the throughput of a wlan with @xmath37 stations when each station transmits at probability @xmath33 and the mpr capability is @xmath32 .
then , @xmath36 can be calculated as the ratio between the average payload information bits transmitted per backoff slot to the average length of a backoff slot as follows .
@xmath38 in the above , _ x _ is a random variable denoting the number of attempts in a slot .
@xmath39 let @xmath40 be the probability that a backoff slot is idle ; @xmath41 be the probability that a backoff slot is busy due to successful packet transmissions ; and @xmath42 be the probability that a backoff slot is busy due to collision of packets .
the throughput of non - carrier - sensing networks such as slotted aloha can be obtained by substituting ( [ eqn:1 ] ) into ( [ eqn:7 ] ) , which leads to following expression : @xmath43 similarly , the throughput of carrier - sensing networks , such as ieee 802.11 dcf basic - access mode and rts / cts access mode , can be obtained by substituting ( [ eqn:2 ] ) and ( [ eqn:3 ] ) into ( [ eqn:7 ] ) respectively .
we now derive the asymptotic throughput when the population size _
n _ approaches infinity . in this case
, we assume that ( i ) the system has a non - zero asymptotic throughput ; and ( ii ) the number of attempts in a backoff slot is approximated by a poisson distribution with an average attempt rate @xmath44 @xcite
. both of these assumptions are valid under an appropriate eb scheme , which will be elaborated in section iv .
let @xmath45 be the asymptotic throughput when mpr capability is _ m _ and average attempt rate is @xmath46 .
then , we derive from ( [ eqn:7 ] ) that @xmath47 where the third equality is due to the poisson approximation .
in particular , when @xmath48 , @xmath49 having derived the throughput expressions for both finite - population and infinite - population models , we now address the question : how does throughput scale as _ m _ increases . in particular , we are interested in the behavior of the maximum throughput when the channel has a mpr capability of _ m_. this directly relates to the channel - access efficiency that is achievable in mpr networks . given _
m _ , the maximum throughput can be achieved by optimizing the transmission probability @xmath33 ( or equivalently @xmath46 in the infinite - population model ) .
the optimal transmission probability can in turn be obtained by adjusting the backoff factor _
r _ in practical wlans , as will be discussed in section iv .
let @xmath50 and @xmath51 denote the maximum achievable throughputs , where @xmath52 and @xmath53 denote the optimal @xmath33 and @xmath46 when the mpr capability is _ m _ , respectively .
in theorem 1 , we prove that the throughput scales super - linearly with _
m _ in non - carrier - sensing network with infinite population .
in other words , @xmath54 is an increasing function of _
m_. in theorem 2 , we further prove that @xmath55 approaches 1 when @xmath56 .
this implies that the throughput penalty due to distributed random access diminishes when _ m _ is very large . in theorem 3 in appendix
i , we prove that the same super - linearity holds for wlans with finite population .
[ theorem:1 ] _ ( super - linearity ) _
@xmath54 is an increasing function of _
it is obvious that at the optimal @xmath53 @xmath57 consequently , @xmath58 or @xmath59 to prove theorem 1 , we show that @xmath60 for all _ m _ in the following .
@xmath61 where the last equality is due to ( [ eqn:14 ] ) and ( [ eqn:17 ] ) .
therefore , we have @xmath62 @xmath63 it is obvious that in a wlan with mpr capability of @xmath32 , the maximum possible throughput is @xmath64 when there exists a perfect scheduling . in practical random - access wlans , the actual throughput is always smaller than @xmath64 , due to the throughput penalty resulting from packet collisions and idle slots .
for example , the maximum throughput is well known to be @xmath65 when @xmath66 .
theorem 2 proves that the throughput penalty diminishes as @xmath32 becomes large .
that is , the maximum throughput approaches @xmath64 even though the channel access is based on random contentions .
[ theorem:2 ] _ ( asymptotic channel - access efficiency ) _ @xmath67 . before proving theorem 2 , we present the following two lemmas .
\(a ) @xmath68 for any attempt rate @xmath69 ; ( b ) @xmath70 for any attempt rate @xmath71 ; ( c ) @xmath72 for attempt rate @xmath73 .
_ proof of lemma 1(a ) : _
@xmath74 let @xmath75 be the lower bound of @xmath76 . by solving @xmath77
it can be easily found that @xmath78 maximizes @xmath79 and @xmath80 since @xmath81 , @xmath69 .
let @xmath82 where @xmath83 .
( [ eqn:21 ] ) can be written as @xmath84 it is obvious that @xmath85 therefore , @xmath86 on the other hand , the first equality of ( [ eqn:19 ] ) implies @xmath87 combining ( [ eqn:24 ] ) and ( [ eqn:25 ] ) , we have @xmath88 and lemma 1(a ) follows .
@xmath89 _ proof of lemma 1(b ) _ : @xmath90 let @xmath91 be the upper bound of @xmath92 . by solving @xmath93 it can be easily found that @xmath94 minimizes @xmath95 and @xmath96 since @xmath97 , @xmath71 .
let @xmath82 where @xmath98 .
( [ eqn : b3 ] ) can be written as @xmath99 due to eqn .
( [ eqn:23 ] ) @xmath100 on the other hand , it is obvious that @xmath101 combining ( [ eqn : b5 ] ) and ( [ eqn : b6 ] ) , we have @xmath102 and lemma 1(b ) follows .
_ proof of lemma 1(c ) _ : to prove lemma 1(c ) , we note that the median of poisson distribution is bounded as follows @xcite-@xcite : @xmath103 when @xmath73 and @xmath56 , the median approaches @xmath32 . according to the first equality of ( [ eqn:14 ] ) , @xmath104 @xmath89 the optimal attempt rate @xmath105 and @xmath106 .
_ proof of lemma 2 : _ the mode of poisson distribution is equal to @xmath107 , where @xmath108 denotes the largest integer that is smaller than or equal to the argument . when @xmath109 , @xmath110 which conflicts with eqn .
( [ eqn:17 ] ) .
therefore , the optimal attempt rate @xmath111 combining ( [ eqn:14 ] ) , ( [ eqn:17 ] ) , ( [ eqn:28 ] ) and lemma 1 , we have @xmath112 let @xmath113 where @xmath83 . eqn .
( [ eqn:29 ] ) can be written as @xmath114 and @xmath115 where the last equality is due to the stirling s formula @xcite .
solving eqn .
( [ eqn:31 ] ) , we have @xmath116 @xmath89 _ proof of theorem 2 _ : from lemma 1 and lemma 2 , it is obvious that @xmath67 . @xmath89 the above results are illustrated in fig .
[ fig:1 ] , where @xmath117 is plotted as a function of @xmath32 in non - carrier - sensing slotted aloha systems . _
( super - linearity with finite population ) _
@xmath118 for all @xmath119 .
_ proof of theorem 3 _ : see appendix i. in theorem 1 - 3 , super - linearity is proved assuming the network is non - carrier - sensing . in fig .
[ fig:2 ] and fig .
[ fig:3 ] , the optimal throughput @xmath120 and @xmath121 are plotted for carrier - sensing networks , respectively , with system parameters listed in table i. the figures show that system throughput is greatly enhanced due to the mpr enhancement in the phy layer .
moreover , the super - linear throughput scaling holds for carrier - sensing networks when _ m _ is relatively large .
.system parameters used in carrier - sensing networks ( adopted from ieee 802.11 g ) [ cols="^,^",options="header " , ]
in this section , we study the characteristic behavior of wlan mac and eb when the channel has mpr capability .
we first establish the relationship between transmission probability @xmath33 ( or @xmath46 ) and eb parameters including backoff factor _
r _ and minimum contention window @xmath35 . based on the analysis
, we will then study how the optimal backoff strategy changes with the mpr capability @xmath32 .
we use an infinite - state markov chain , as shown in fig .
[ fig:4 ] , to model of operation of eb with no retry limit .
the reason for the lack of a retry limit is that it is theoretically more interesting to look at the limiting case when the retry limit is infinitely large .
having said this , we note that the analysis in our paper can be easily extended to the case where there is a retry limit .
the state in the markov chain in fig .
[ fig:4 ] is the backoff stage , which is also equal to the number of retransmissions experienced by the station .
as mentioned in section ii , the contention window size is @xmath31 when a station is in state @xmath122 . in the figure
, @xmath123 denotes the conditional collision probability , which is the probability of a collision seen by a packet being transmitted on the channel .
note that @xmath123 depends on the transmission probabilities of stations other than the transmitting one . in our model
, @xmath123 is assumed to be independent of the backoff stage of the transmitting station . in our numerical results , we show that the analytical results obtained under this assumption are very accurate when @xmath37 is reasonably large . with eb , transmission probability @xmath33 is equal to the probability that the backoff timer of a station reaches zero in a slot .
note that the markov process of mpr networks is similar to the ones in @xcite , @xcite , except that the conditional collision probability @xmath123 is different for @xmath124 .
therefore , eqn .
( [ eqn:32 ] ) can be derived in a similar way as @xcite , @xcite : @xmath125 where @xmath126 is a necessary condition for the steady state to be reachable .
the detailed derivation of ( [ eqn:32 ] ) is omitted due to page limit .
interested readers are referred to @xcite , @xcite .
likewise , the conditional collision probability @xmath123 is equal to the probability that there are @xmath32 or more stations out of the remaining @xmath127 stations contending for the channel .
we thus have the following relationship : @xmath128 it can be easily shown that @xmath33 is a decreasing function of @xmath123 for any @xmath129 in ( [ eqn:32 ] ) .
meanwhile , @xmath123 is an increasing function of @xmath33 in ( [ eqn:33 ] ) .
therefore , the curves determined by ( [ eqn:32 ] ) and ( [ eqn:33 ] ) have a unique intersection corresponding to the root of the nonlinear system . by solving the nonlinear system ( [ eqn:32])-([eqn:33 ] )
numerically for different @xmath37 , we plot the analytical results of @xmath130 in fig .
[ fig:5 ] . in the figures ,
beb is adopted .
that is , @xmath131 .
the minimum contention window size @xmath132 or 32 . to validate the analysis , the simulation results are plotted as markers in the figures . in the simulation ,
the data are collected by running 5,000,000 rounds after 1,000,000 rounds of warm up . versus @xmath37 when @xmath131 ; lines are analytical results calculated from ( [ eqn:2 ] ) and ( [ eqn:3 ] ) , markers are simulation results.,scaledwidth=50.0% ] from the figures , we can see that the analytical results match the simulations very well .
moreover , it shows that @xmath130 converges to a constant quantity when @xmath37 becomes large .
this is a basic assumption in the previous section when we calculated the asymptotic throughput .
the constant quantity that @xmath130 converges to can be calculated as follows . for large @xmath37
, the number of attempts in a slot can be modeled as a poisson process @xcite .
that is , @xmath133 where @xmath134 the conditional collision probability in this limiting case is given by @xmath135 when the system is steady , the total attempt rate @xmath136 should be finite .
therefore , @xmath137 which implies @xmath138
combining ( [ eqn:36 ] ) and ( [ eqn:38 ] ) , we get the following equation @xmath139 @xmath46 can be calculated numerically from ( [ eqn:39 ] ) given @xmath32 and @xmath34 .
[ fig:5 ] shows that @xmath130 calculated from ( [ eqn:32 ] ) and ( [ eqn:33 ] ) does converge to @xmath46 when @xmath37 is large .
note that the relationship between @xmath33 , @xmath46 , and eb established above do not depend on the duration of the underlying backoff slots , and therefore can be applied in both non - carrier - sensing and carrier - sensing networks . before leaving this sub - section
, we validate another assumption adopted in section iii .
that is , eb guarantees a non - zero throughput when @xmath37 approaches infinity . to this end , the throughput of slotted aloha is plotted as a function of @xmath37 in fig .
[ fig:6 ] when beb is adopted .
it can be seen that the throughputs with the same @xmath32 converge to the same constant as @xmath37 increases , regardless of the minimum contention window @xmath35 .
similar phenomenon can also be observed in carrier - sensing networks , as illustrated in fig .
[ fig:7 ] , where the throughput of ieee 802.11 wlan with basic access mode is plotted with detailed system parameters listed in table i. the asymptotic throughput when @xmath37 is very large depends only on the mpr capability @xmath32 and the backoff factor @xmath34 . ,
scaledwidth=50.0% ] , scaledwidth=50.0% ] in section iii , we have investigated the maximum network throughput that is achieved by optimal transmission probability @xmath52 and @xmath53 .
the previous sub - section shows that transmission probability is a function of backoff factor @xmath34 .
mathematically , the optimal @xmath34 that maximizes throughput can be obtained by solving the equation @xmath140 . in this section ,
we investigate how the optimal backoff factor @xmath34 changes with the mpr capability @xmath32 . in fig .
[ fig:8 ] and fig .
[ fig:9 ] , we plot the throughput as a function of @xmath34 for both non - carrier sensing networks and carrier - sensing networks in basic - access mode . from the figure , we can see that the optimal @xmath34 that maximizes throughput increases with @xmath32 for moderate to large @xmath32 .
this observation can be intuitively explained for non - carrier - sensing networks by ( [ eqn:14 ] ) , ( [ eqn:39 ] ) , and lemma 1 as follows
( [ eqn:14 ] ) and ( [ eqn:39 ] ) indicate that @xmath141 as lemma 1 indicates , when @xmath32 is large , @xmath142 increases with @xmath32 and eventually approaches 1 .
consequently , @xmath34 increases with @xmath32 .
for non - carrier - sensing slotted aloha networks , scaledwidth=50.0% ] for carrier - sensing networks with basic - access mode , scaledwidth=50.0% ] as the figures show , the throughput decreases sharply when @xmath34 moves from the optimal @xmath143 to 1 . on the other hand , it is much less sensitive to @xmath34 when @xmath34 is larger than the @xmath143 .
therefore , in order to avoid dramatic throughput degradation , it is not wise to operate @xmath34 in the region between 1 and @xmath143 .
note that when @xmath32 is large , @xmath143 is larger than 2 .
this implies that the widely used beb might be far from optimal in mpr wlans . to further see how well beb works
, we plot the ratio of the throughput obtained by beb to the maximum achievable throughput in fig .
[ fig:10 ] .
the optimal @xmath34 that achieves the maximum throughput is plotted versus @xmath32 in fig .
[ fig:11 ] . in the figures
, we can see that beb only achieves a small fraction of the maximum achievable throughput when @xmath32 is large in non - carrier - sensing and ieee 802.11 basic - access mode .
for example , when @xmath144 beb only achieves about 80 percent of the maximum throughput in non - carrier - sensing networks .
in rts / cts mode , in contrast , the performance of beb is close to optimal for a large range of @xmath32 .
therefore , we argue from an engineering point of view that beb ( i.e. , @xmath131 ) is a good choice for rts / cts access scheme , while on the other hand tuning @xmath34 to the optimal is important for non - carrier - sensing and basic - access schemes . ,
scaledwidth=50.0% ] versus @xmath32,scaledwidth=50.0% ] having demonstrated the significant capacity improvement that mpr brings to wlans , we are highly motivated to present practical protocols to implement mpr in the widely used ieee 802.11 wifi
. in particular , we will propose protocols that consist of both mac - layer mechanisms and phy - layer signal processing schemes in the next section .
in this section , we present a mpr protocol for ieee 802.11 wlan with rts / cts mechanism .
the proposed protocol requires minimum amendment at mobile stations , and hence will be easy to implement in practical systems . throughout this section , we assume that the mpr capability is brought by the multiple antennas mounted at the access point ( ap ) .
this assumption complies with the hardware request of the latest mimo - based wlan standards .
however , the proposed mac - phy protocol can be easily extended to cdma networks , as the received signal structures in multi - antenna and cdma systems are almost the same ( refer to section ii - c ) .
the mac protocol closely follows the ieee 802.11 rts / cts access mechanism , as illustrated in fig .
[ fig:12 ] . a station with a packet to transmit first sends an rts frame to the ap . in our mpr mac model ,
when multiple stations transmit rts frames at the same time , the ap can successfully detect all the rts frames if and only if the number of rtss is no larger than @xmath32 .
when the number of transmitting stations exceeds @xmath32 , collisions occur and the ap can not decode any of the rtss . the stations will retransmit their rts frames after a backoff time period according to the original ieee 802.11 protocol . when the ap detects the rtss successfully , it responds , after a sifs period , with a cts frame that grants transmission permissions to all the requesting stations
. then the transmitting stations will start transmitting data frames after a sifs , and the ap will acknowledge the reception of the data frames by an ack frame .
the formats of the rts and data frames are the same as those defined in 802.11 , while the cts and ack frames have been modified to accommodate multiple transmitting stations for mpr .
in particular , there are @xmath32 receiver address fields in the cts and ack frames to identify up to @xmath32 intended recipients .
as described above , our mpr mac is very similar to the original ieee 802.11 mac .
in fact , to maintain this similarity in the mac layer , the challenge is pushed down to the physical layer .
for example , in the proposed mpr mac , the ap is responsible to decode all the rtss transmitted simultaneously .
however , due to the random - access nature wlan , the ap has no priori knowledge of who the senders are and the channel state information ( csi ) on the corresponding links .
this imposes a major challenge on the phy layer , as the mud techniques introduced in section ii , such as zf and mmse can not be directly applied . to tackle these problems
, we introduce the physical layer techniques in next subsection . in this subsection
, we propose a phy mechanism to implement mpr in ieee 802.11 .
the basic idea is as follows .
rts packets are typically transmitted at a lower data rate than the data packets in ieee 802.11 .
this setting is particularly suitable for blind detection schemes which can separate the rts packets without knowing the prior knowledge of the senders identities and csi @xcite-@xcite . upon successfully decoding the rts packets , the ap
can then identify the senders of the packets .
training sequences , to be transmitted in the preamble of the data packets , are then allocated to these users to facilitate channel estimation during the data transmission phase .
since the multiple stations transmit their data packets at the same time , their training sequences should be mutually orthogonal . in our system ,
no more than @xmath32 simultaneous transmissions are allowed .
therefore , a total of @xmath32 orthogonal sequences are required to be predefined and made known to all stations . the sequence allocation decision is sent to the users via the cts packet . during the data transmission phase
, csi is estimated from the orthogonal training sequences that are transmitted in the preamble of the data packets . with the estimated csi
, various mud techniques can be applied to separate the multiple data packets at the ap . using coherent detection ,
data packets can be transmitted at a much higher rate than the rts packets without involving excessive computational complexity . as mud techniques have been introduced in section ii , we focus on the blind separation of rts packets in this subsection .
assume that there are @xmath145 stations transmitting rts packets together .
then , the received signal in symbol duration @xmath146 is given by ( [ eqn:4 ] ) , where the @xmath147 element of @xmath148 denotes the channel coefficient from user @xmath149 to the @xmath17 antenna at the ap .
assuming that the channel is constant over an rts packet , which is composed of @xmath37 symbol periods , we obtain the following block formulation of the data @xmath150 where @xmath151 $ ] , @xmath152 $ ] , and @xmath153.$ ] the problem to be addressed here is the estimation of the number of sources @xmath145 , the channel matrix @xmath148 , and the symbol matrix @xmath154 , given the array output @xmath155 . for an easy start , we ignore the white noise for the moment and have @xmath156 .
the rank of @xmath148 is equal to @xmath145 if @xmath157 .
likewise , @xmath154 is full - row - rank when @xmath37 is much larger than @xmath145 .
consequently , we have @xmath158 and @xmath145 is equal to the number of nonzero singular values of @xmath155 . with white noise
added to the data , @xmath145 can be estimated from the number of singular values of @xmath155 that are significantly larger than zero . in this paper
, we adopt the finite alphabet ( fa ) based blind detection algorithm to estimate @xmath154 and @xmath148 , assuming @xmath145 is known .
the maximum - likelihood estimator yields the following separable least - squares minimization problem @xcite @xmath159 where @xmath160 is the finite alphabet to which the elements of @xmath154 belong , and @xmath161 is the frobenius norm .
the minimization of ( [ eqn:42 ] ) can be carried out in two steps .
first , we minimize ( [ eqn:42 ] ) with respect to @xmath148 and obtain @xmath162 where @xmath163 is the pseudo - inverse of a matrix .
substituting @xmath164 back into ( [ eqn:42 ] ) , we obtain a new criterion , which is a function of @xmath154 only : @xmath165 where @xmath166 , and @xmath24 is the identity matrix .
the global minimum of ( [ eqn:44 ] ) can be obtained by enumerating over all possible choices of @xmath154 .
reduced - complexity iterative algorithms that solve ( [ eqn:44 ] ) iteratively such as ilsp and ilse were introduced in @xcite .
not being one of the foci of this paper , the details of ilsp and ilse are not covered here .
interested readers are referred to @xcite and the references therein .
note that the scheme proposed in this section is only one way of implementing mpr in wlans .
it ensures that the orthogonal training sequences are transmitted in the preambles of data packets .
this leads to highly reliable channel estimation that facilitates the user of mud techniques . moreover , the modification to the original protocol is mainly restrained within the ap .
minimum amendment is needed at mobile stations .
in our analysis so far , we have assumed that packet error rate due to random fading effect is negligible when the number of simultaneous transmission is smaller than _ m _ and is close to 1 otherwise .
this assumption is quite accurate when data packets are well protected by error correction codes ( e.g. , convolutional codes in ieee 802.11 protocol ) and linear mud is deployed at the receiver .
the simplification allows us to focus on the effect of mpr on wlan without the need to consider signal processing details such as coding and detection schemes . in this section
, we relax the assumption and investigate how random channel errors would affect our analysis .
fortunately , we can prove that super - linear throughput scaling still holds even when random channel error is taken into account , as detailed in the following .
denote by @xmath167 the packet error rate due to wireless channel fading when _
k _ packets are transmitted at the same time in a network with mpr capability @xmath32 . then , @xmath168 is the packet success rate , which is the probability that a packet _ survives _ random channel fading @xcite .
typically , @xmath169 for @xmath170 and @xmath171 for @xmath172 .
assuming linear detectors , we have @xmath173 if @xmath174 and @xmath175 for @xmath176 @xcite . for simplicity ,
assume @xmath177 .
then , asymptotic throughput is given by @xmath178 at the optimal @xmath53 , @xmath179 .
consequently , @xmath180 we are now ready to prove super - linear throughput scaling @xmath181 in the following .
@xmath182 where the last inequality is due to ( [ eqn56 ] ) .
one implicit assumption in our analysis is that each station transmits at the same data rate @xmath183 . in practice ,
stations experience different channel attenuation to the ap due to their random locations .
if stations transmit at the same power level , then the data rate sustainable on each link would differ . in this case , the airtime occupied by a busy period is dominated the lowest data rate involved . hence , the effective throughput enjoyed by high - rate stations would degenerate to the level of the lowest rate .
such problem , known as performance anomaly " , is not unique to mpr .
it exists in all multi - rate ieee 802.11 networks .
fortunately , performance anomaly only causes the data rate @xmath183 in our throughput expression to degrade to @xmath184 , where @xmath184 is the lowest possible data rate .
therefore , it will not affect the scaling law of throughput in mpr networks . in this paper
, we have demonstrated the drastic increase in spectrum efficiency brought by mpr . to implement mpr ,
modification is needed in both mac and phy layers , as discussed in section v. with the same hardware enhancement ( e.g. , having @xmath32 antennas at the ap ) , an alternative is to let each link transmit at a higher data rate , but keep the single - packet - reception restriction unchanged .
this essentially becomes a traditional wlan with simo ( single - input - multiple - output ) links .
the capacity of a simo link increases logarithmically with the number of antennas at the receiver @xcite .
that is , @xmath185 where @xmath186 is the data rate of a siso ( single - input - single - output ) link .
in contrast , the data rate @xmath183 of each link in mpr wlan is set to @xmath186 , for antenna diversity is used to separate multiple data streams instead of increasing the rate of one stream therein . with ( [ eqn59 ] ) ,
the throughput of wlan with simo links is @xmath187 where the expressions for @xmath188 , @xmath189 , and @xmath190 are the same as ( [ eqn:9 ] ) , ( [ eqn:10 ] ) , and ( [ eqn:11 ] ) with @xmath66 , respectively .
likewise , @xmath191 , @xmath192 , and @xmath193 are the same as ( [ eqn:1 ] ) , ( [ eqn:2 ] ) , or ( [ eqn:3 ] ) except that @xmath183 is replaced by @xmath194 .
specifically , throughput in the aloha case becomes @xmath195 and the optimal @xmath33 that maximizes the throughput is equal to @xmath196 . in particular , the maximum achievable throughput when @xmath37 is large is @xmath197 it is obvious that the normalized throughput @xmath198 decreases with @xmath32 in simo networks .
this , in contrast to the super - linear throughput scaling in mpr networks , suggests that multiple antennas at the ap should be used to resolve simultaneous transmissions instead of increasing per - link data rate in random access wlans .
with the recent advances in phy - layer mud techniques , it is no longer a physical constraint for the wlan channel to accommodate only one packet transmission at one time . to fully utilize the mpr capability of the phy channel , it is essential to understand the fundamental impact of mpr on the mac - layer .
this paper has studied the characteristic behavior of random - access wlans with mpr .
our analysis provides a theoretical foundation for the performance evaluation of wlans with mpr , and it is useful for system design in terms of setting operating parameters of mac protocols .
our analytical framework is general and applies to various wlans including non - carrier - sensing and carrier - sensing networks . in theorems 1 and 3
, we have proved that the throughput increases super - linearly with @xmath32 for both finite and infinite population cases .
this is the case in non - carrier - sensing networks for all @xmath32 , and in carrier - sensing networks for moderate to large @xmath32 .
moreover , theorem 2 shows that the throughput penalty due to distributed random access diminishes when @xmath32 approaches infinity .
such scalability provides strong incentives for further investigations on engineering and implementation details of mpr systems .
based on the analysis , we found that the commonly deployed beb scheme is far from optimum in most systems except the carrier - sensing systems with rts / cts four - way handshake . in particular
, the optimum backoff factor @xmath34 increases with @xmath32 for large @xmath32 .
we further note that the throughput degrades sharply when @xmath34 is smaller than the optimum value , while it is much less sensitive to @xmath34 when @xmath34 exceeds the optimum .
having understood the fundamental behavior of mpr , we propose practical protocols to exploit the advantage of mpr in ieee 802.11-like wlans . by incorporating advanced phy - layer blind detection and mud techniques ,
the protocol can implement mpr in a fully distributed manner with marginal modification of mac layer .
( super - linearity with finite population ) @xmath199 for all @xmath119 at the optimal @xmath52 , the derivative @xmath204 . thus , @xmath205 combining ( [ eqn : a4 ] ) and ( [ eqn : a5 ] ) , @xmath206 it is obvious that @xmath207 substituting ( [ eqn : a6 ] ) to ( [ eqn : a7 ] ) , we have @xmath208 hence , @xmath199 for all @xmath119 .
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d. s. chan , t. berger and l. tong , on the stability and optimal decentralized throughput of csma with multipacket reception capability , " _ prof .
allerton conference on communication , control , and computing _ , sept - oct 2004 .
d. s. chan , p. suksompong , j. chen and t. berger , improving ieee 802.11 performance with cross - layer design and multipacket reception via multiuser iterative decoding , " ieee 802.11 - 05/0946r0 , sept 2005 .
ying jun ( angela ) zhang ( s00 , m05 ) received her beng degree with honors in electronic engineering from fudan university , shanghai , china , and the phd degree in electrical and electronic engineering from the hong kong university of science and technology , hong kong . since jan .
2005 , she has been with the department of information engineering in the chinese university of hong kong , where she is currently an assistant professor .
zhang is on the editorial boards of ieee transactions of wireless communications and willey security and communications networks journal .
she has served as a tpc co - chair of communication theory symposium of ieee icc 2009 , track chair of icccn 2007 , and publicity chair of ieee mass 2007 .
she has been serving as a technical program committee member for leading conferences including ieee icc , ieee globecom , ieee wcnc , ieee icccas , iwcmc , ieee ccnc , ieee itw , ieee mass , msn , chinacom , etc .
zhang is an ieee technical activity board gold representative , 2008 ieee gold technical conference program leader , ieee communication society gold coordinator , and a member of ieee communication society member relations council .
her research interests include wireless communications and mobile networks , adaptive resource allocation , optimization in wireless networks , wireless lan / man , broadband ofdm and multicarrier techniques , mimo signal processing . as the only winner from engineering science , dr .
zhang has won the hong kong young scientist award 2006 , conferred by the hong kong institution of science .
soung chang liew ( s84-m87-sm92 ) received his s.b .
, e.e . , and
degrees from the massachusetts institute of technology . from 1984
to 1988 , he was at the mit laboratory for information and decision systems , where he investigated fiber - optic communications networks . from march 1988 to july 1993
, soung was at bellcore ( now telcordia ) , new jersey , where he engaged in broadband network research .
soung is currently professor and chairman of the department of information engineering , the chinese university of hong kong .
he is adjunct professor at southeast university , china .
soung s current research interests include wireless networks , internet protocols , multimedia communications , and packet switch design .
soung and his student won the best paper awards in the 1st ieee international conference on mobile ad - hoc and sensor systems ( ieee mass 2004 ) the 4th ieee international workshop on wireless local network ( ieee wln 2004 ) . separately ,
tcp veno , a version of tcp to improve its performance over wireless networks proposed by soung and his student , has been incorporated into a recent release of linux os .
in addition , soung initiated and built the first inter - university atm network testbed in hong kong in 1993 .
besides academic activities , soung is also active in the industry .
he co - founded two technology start - ups in internet software and has been serving as consultant to many companies and industrial organizations .
he is currently consultant for the hong kong applied science and technology research institute ( astri ) , providing technical advice as well as helping to formulate r&d directions and strategies in the areas of wireless internetworking , applications , and services .
soung is the holder of four u.s .
patents and fellow of iee and hkie .
he is listed in marquis who s who in science and engineering .
he is the recipient of the first vice - chancellor exemplary teaching award at the chinese university of hong kong .
publications of soung can be found in www.ie.cuhk.edu.hk/soung .
pengxuan zheng ( s06 ) received his b.eng .
degree in computer science and engineering from zhejiang university , hangzhou , china , in 2004 , and m.phil .
degree in information engineering from the chinese university of hong kong , hong kong , china , in 2007 .
he is currently working towards the ph.d .
degree at purdue university .
his research interests include mobile ad hoc networks and wireless sensor networks . | thanks to its simplicity and cost efficiency , wireless local area network ( wlan ) enjoys unique advantages in providing high - speed and low - cost wireless services in hot spots and indoor environments .
traditional wlan medium - access - control ( mac ) protocols assume that only one station can transmit at a time : simultaneous transmissions of more than one station cause the destruction of all packets involved . by exploiting recent advances in phy - layer multiuser detection ( mud ) techniques ,
it is possible for a receiver to receive multiple packets simultaneously .
this paper argues that such multipacket reception ( mpr ) capability can greatly enhance the capacity of future wlans .
in addition , the paper provides the mac - layer and phy - layer designs needed to achieve the improved capacity .
first , to demonstrate mpr as a powerful capacity - enhancement technique , we prove a super - linearity " result , which states that the system throughput per unit cost increases as the mpr capability increases .
second , we show that the commonly deployed binary exponential backoff ( beb ) algorithm in today s wlan mac may not be optimal in an mpr system , and that the optimal backoff factor increases with the mpr capability , the number of packets that can be received simultaneously .
third , based on the above insights , we design a joint mac - phy layer protocol for an ieee 802.11-like wlan that incorporates advanced phy - layer signal processing techniques to implement mpr . wireless local area network , exponential backoff , multipacket reception . | <s>[INST]the last decade has witnessed a surge of interest in wireless local area networks ( wlan ) , where mobile stations share a common wireless medium through contention - based medium access control ( mac ) . in wlans ,
collision of packets occurs when more than one station transmits at the same time , causing a waste of bandwidth .
recent advances in multiuser detection ( mud ) techniques @xcite open up new opportunities for resolving collisions in the physical ( phy ) layer . for example , in cdma @xcite or multiple - antenna @xcite systems , multiple packets can be received simultaneously using mud techniques without collisions .
it is expected that , with improved multipacket reception ( mpr ) capability from the phy layer , the mac layer will behave differently from what is commonly believed . in particular , to fully utilize the mpr capability for capacity enhancement in wlan ,
it is essential to understand the fundamental impact of mpr on the mac - layer design . as such
, this paper is an attempt to study the mac - layer throughput performance and the collision resolution schemes for wlans with mpr .
the key contributions of this paper are as follows : * to demonstrate mpr as a powerful capacity - enhancement technique at the system level , we analyze the mac - layer throughput of wlans with mpr capability under both finite - node and infinite - node assumptions .
our model is sufficiently general to cover both carrier - sensing and non - carrier - sensing networks .
we prove that in random - access wlans , network throughput increases super - linearly with the mpr capability of the channel .
that is , throughput divided by _
m _ increases as _ m _ increases , where _ m _ is the number of packets that can be resolved simultaneously .
the super - linear throughput scaling implies that the achievable throughput per unit cost increases with mpr capability of the channel .
this provides a strong incentive to deploy mpr in next - generation wireless networks . * we study the effect of mpr on the mac - layer collision resolution scheme , namely exponential backoff ( eb ) .
when packets collide in wlans , an eb scheme is used to schedule the retransmissions , in which the waiting time of the next retransmission will get multiplicatively longer for each collision incurred . in the commonly adopted binary exponential backoff ( beb ) scheme ( e.g. , used in ethernet @xcite , wifi @xcite , etc . ) ,
the multiplicative ( a backoff factor ) is equal to 2 .
we show in this paper that the widely used beb does not necessarily yield the close - to - optimal network throughput with the improved mpr capability from the phy layer . as a matter of fact
, beb is far from optimum for both non - carrier - sensing networks and carrier - sensing networks operated in basic access mode .
the optimal backoff factor increases with the mpr capability . meanwhile , beb is close to optimum for carrier - sensing networks when rts / cts access mode is adopted . *
built on the theoretical underpinnings established above , we propose a practical protocol to fully exploit the mpr capability in ieee 802.11-like wlans .
in contrast to @xcite-@xcite , we consider not only the mac layer protocol design , but also the phy - layer signal processing to enable mpr in distributed random - access wlans . as a result , the proposed protocol can be implemented in a fully distributed manner with marginal modification of current ieee 802.11 mac .
the first attempt to model a general mpr channel in random - access wireless networks was made by ghez , verdu , and schwartz in @xcite-@xcite in 1988 an 1989 , respectively , in which stability properties of conventional slotted aloha with mpr were studied under a simple infinite - user and single - buffer assumption .
no collision resolution scheme ( such as eb ) was considered therein .
this work was extended to csma systems by chan et al in @xcite and to finite user aloha systems by naware et al in @xcite .
it has been shown in @xcite-@xcite that mpr improves the stable throughput of aloha only when the mpr capability is comparable to the number of users in the system . in practical networks where the mpr capability is much smaller than the number of users , the stable throughput of conventional aloha is equal to 0 , same as the case without mpr . to date , little
work has been done to investigate the throughput enhancing capability of mpr in practical wlans with collision resolution schemes .
our paper here is an attempt along this direction .
protocols that exploit the mpr capability of networks have been studied by zhao and tong in @xcite-@xcite . in @xcite ,
a multi - queue service room ( mqsr ) mac protocol was proposed for networks with heterogeneous users .
the drawback of the mqsr protocol is its high computational cost due to updates of the joint distribution of all users states . to reduce complexity ,
a suboptimal dynamic queue protocol was proposed in @xcite . in both protocols ,
access to the common wireless channel is controlled by a central controller , which grants access to the channel to an appropriate subset of users at the beginning of each slot . in @xcite ,
chan et al proposed to add a mud layer to facilitate mpr in ieee 802.11 wlan . to implement the mud techniques mentioned as examples in @xcite , the ap
is assumed to have perfect knowledge of the number of concurrent transmissions , the identities of the transmitting stations , and the channel coefficients .
these information , while easy to get in a network with centralized scheduling ( e.g. , cellular systems ) , is unkown to the ap a priori in random access networks .
moreover , the preambles of concurrent packets overlap , and hence it is difficult for the ap to have a good estimation of the channel coefficients with the current protocol .
by contrast , our paper provides a solution to this issue by incorporating blind signal processing in the proposed protocol .
exponential backoff ( eb ) as a collision resolution technique has been extensively studied in different contexts @xcite-@xcite .
stability upper bound of beb has been given by goodman under a finite - node model in @xcite and recently improved by al - ammal in @xcite .
the throughput and delay characteristics of a slightly modified eb scheme have been studied in @xcite in the context of slotted aloha .
the characteristics of eb in steady state is further investigated in @xcite in time slotted wireless networks with equal slot length .
all the existing work on eb has assumed that the wireless channel can only accommodate one ongoing transmission at a time .
this paper is a first attempt to look at eb for an mpr system .
the remainder of this paper is organized as follows . in section
ii , we describe the system model and introduce the background knowledge on mud and eb . in section iii , we prove that the maximum achievable throughput of mpr wlan scales super - linearly with the mpr capability of the channel . in section iv , the effect of mpr on eb is investigated .
we show that the widely used beb scheme is no longer close - to - optimal in mpr networks . to realize mpr in ieee 802.11 wlans ,
a mac - phy protocol is presented in section v. in section vi , we discuss some practical issues related to mpr . finally , section vii concludes this paper .
we consider a fully conected infrastructure wlan where _
n _ infinitely backlogged mobile stations communicate with an access point ( ap ) .
we assume that the time axis is divided into slots and packet transmissions start only at the beginning of a slot .
in addition , after each transmission , the transmitting stations have a means to discover the result of the transmission , i.e. , success or failure .
if the transmission fails due to collision , the colliding stations will schedule retransmissions according to a collision resolution scheme ( e.g. , eb ) .
we assume that the channel has the capability to accommodate up to _ m _ simultaneous transmissions .
in other words , packets can be received correctly whenever the number of simultaneous transmissions is no larger than _ m_. when more than _ m _ stations contend for the channel at the same time , collision occurs and no packet can be decoded .
we refer to _ m _ as mpr capability . in our model , the length of a time slot is not necessarily fixed and may vary under different contexts @xcite .
we refer to this variable - length slot as backoff slot hereafter . in wlans
, the length of a backoff slot depends on the contention outcome ( hereafter referred to as channel status ) .
let @xmath0 denote the length of an idle time slot when nobody transmits ; @xmath1 denote the length of a collision time slot when more than _ m _ stations contend for the channel ; and @xmath2 denote the length of a time slot due to successful transmission when the number of transmitting stations is anywhere from 1 to _
m_. the durations of @xmath0 , @xmath1 , and @xmath2 depend on the underlying wlan configuration . for non - carrier - sensing networks such as slotted aloha ,
the stations are not aware of the channel status and the duration of all backoff slots are equal to the transmission time of a packet .
that is , @xmath3 where _ l _ is the packet size and _ r _ is the data transmission rate of a station . on the other hand , for carrier - sensing networks
, stations can distinguish between various types of channel status and the durations of different types of slots may not be the same .
for example , in ieee 802.11 dcf basic access mode , @xmath4 where @xmath5 is the time needed for a station to detect the packet transmission from any other station and is typically much smaller than @xmath1 and @xmath2 ; @xmath6 is the transmission time of phy header and mac header ; ack is the transmission time of an ack packet ; @xmath7 is the propagation delay ; and sifs and difs are the inter - frame space durations @xcite .
similarly , in ieee 802.11 dcf request - to - send / clear - to - send ( rts / cts ) access scheme , the slot durations are given by @xmath8 where @xmath9 and @xmath10 denote the transmission time of rts and cts packets , respectively . by allowing the durations of @xmath0 , @xmath1 , and @xmath2 to vary according to the underlying system , the analysis of this paper applies to a wide spectrum of various wlans , including both non - carrier - sensing and carrier - sensing networks .
this subsection briefly introduces the phy layer mud techniques used to decode multiple packets at the receiver .
let @xmath11 denote the data symbol transmitted by user _
k _ in symbol duration _
n_. if there are _ k _ stations transmitting together , then the received signal at a receiver is given by @xmath12 where @xmath13 denotes the additive noise , @xmath14 $ ] , and @xmath15^t$ ] . in multiple antenna systems
, @xmath16 is the channel vector , with the @xmath17 element being the channel coefficient from user _ k _ to the @xmath17 receive antenna .
in cdma systems , vector @xmath16 is multiplication of the spreading sequence of user _ k _ and the channel coefficient from user _ k _ to the ap .
the receiver attempts to obtain an estimate of the transmitted symbols @xmath18 from the received vector @xmath19 . to this end , various mud techniques have been proposed in the literature .
for example , the zero - forcing ( zf ) receiver is one of the most popular linear detectors .
it multiplies the received vector by the pseudo - inverse of matrix @xmath20 , denoted by @xmath21 , and the decision statistics become @xmath22 the minimum - mean - square - error ( mmse ) receiver is the optimal linear detector in the sense of maximizing the signal - to - interference - and - noise ratio ( sinr ) .
the decision statistics is calculated as @xmath23 where @xmath24 is the identity matrix , and @xmath25 is the variance of the additive noise .
given the decision statistics , an estimate of @xmath11 can be obtained by feeding the @xmath26 element of @xmath27 or @xmath28 into a quantizer .
other mud techniques include maximum - likelihood ( ml ) , parallel interference cancellation ( pic ) , successive interference cancellation ( sic ) , etc .
interested readers are referred to @xcite for more details .
eb adaptively tunes the transmission probability of a station according to the traffic intensity of the network .
it works as follows . a backlogged station sets its backoff timer by randomly choosing an integer within the range @xmath29 $ ] , where _ w _ denote the size of the contention window .
the backoff timer is decreased by one following each backoff slot .
the station transmits a packet in its queue once the backoff timer reaches zero . at the first transmission attempt of a packet , @xmath30 , referred to as the minimum contention window .
each time the transmission is unsuccessful , the _ w _ is multiplied by a backoff factor _
r_. that is , the contention window size @xmath31 after _ i _ successive transmission failures .
this section investigates the impact of mpr on the throughput of random - access wlans . in particular ,
we prove that the maximum achievable throughput scales super - linearly with the mpr capability @xmath32 . in practical systems , @xmath32 is directly related to the cost ( e.g. , bandwidth in cdma systems or antenna in multi - antenna systems ) .
super - linear scaling of throughput implies that the achievable throughput _ per unit cost _ increases with @xmath32 .
this provides a strong incentive to consider mpr in next - generation wireless networks .
as mentioned earlier , the transmission of stations is dictated by the underlying eb scheme . to capture the fundamentally achievable throughput of the system
, the following analysis assumes that each station transmits with probability @xmath33 in an arbitrary slot , without caring how @xmath33 is achieved .
the assumption will be made more rigorous in section iv , which relates @xmath33 to eb parameters such as @xmath34 and @xmath35 .
define throughput to be the average number of information bits transmitted successfully per second .
let @xmath36 denote the throughput of a wlan with @xmath37 stations when each station transmits at probability @xmath33 and the mpr capability is @xmath32 .
then , @xmath36 can be calculated as the ratio between the average payload information bits transmitted per backoff slot to the average length of a backoff slot as follows .
@xmath38 in the above , _ x _ is a random variable denoting the number of attempts in a slot .
@xmath39 let @xmath40 be the probability that a backoff slot is idle ; @xmath41 be the probability that a backoff slot is busy due to successful packet transmissions ; and @xmath42 be the probability that a backoff slot is busy due to collision of packets .
the throughput of non - carrier - sensing networks such as slotted aloha can be obtained by substituting ( [ eqn:1 ] ) into ( [ eqn:7 ] ) , which leads to following expression : @xmath43 similarly , the throughput of carrier - sensing networks , such as ieee 802.11 dcf basic - access mode and rts / cts access mode , can be obtained by substituting ( [ eqn:2 ] ) and ( [ eqn:3 ] ) into ( [ eqn:7 ] ) respectively .
we now derive the asymptotic throughput when the population size _
n _ approaches infinity . in this case
, we assume that ( i ) the system has a non - zero asymptotic throughput ; and ( ii ) the number of attempts in a backoff slot is approximated by a poisson distribution with an average attempt rate @xmath44 @xcite
. both of these assumptions are valid under an appropriate eb scheme , which will be elaborated in section iv .
let @xmath45 be the asymptotic throughput when mpr capability is _ m _ and average attempt rate is @xmath46 .
then , we derive from ( [ eqn:7 ] ) that @xmath47 where the third equality is due to the poisson approximation .
in particular , when @xmath48 , @xmath49 having derived the throughput expressions for both finite - population and infinite - population models , we now address the question : how does throughput scale as _ m _ increases . in particular , we are interested in the behavior of the maximum throughput when the channel has a mpr capability of _ m_. this directly relates to the channel - access efficiency that is achievable in mpr networks . given _
m _ , the maximum throughput can be achieved by optimizing the transmission probability @xmath33 ( or equivalently @xmath46 in the infinite - population model ) .
the optimal transmission probability can in turn be obtained by adjusting the backoff factor _
r _ in practical wlans , as will be discussed in section iv .
let @xmath50 and @xmath51 denote the maximum achievable throughputs , where @xmath52 and @xmath53 denote the optimal @xmath33 and @xmath46 when the mpr capability is _ m _ , respectively .
in theorem 1 , we prove that the throughput scales super - linearly with _
m _ in non - carrier - sensing network with infinite population .
in other words , @xmath54 is an increasing function of _
m_. in theorem 2 , we further prove that @xmath55 approaches 1 when @xmath56 .
this implies that the throughput penalty due to distributed random access diminishes when _ m _ is very large . in theorem 3 in appendix
i , we prove that the same super - linearity holds for wlans with finite population .
[ theorem:1 ] _ ( super - linearity ) _
@xmath54 is an increasing function of _
it is obvious that at the optimal @xmath53 @xmath57 consequently , @xmath58 or @xmath59 to prove theorem 1 , we show that @xmath60 for all _ m _ in the following .
@xmath61 where the last equality is due to ( [ eqn:14 ] ) and ( [ eqn:17 ] ) .
therefore , we have @xmath62 @xmath63 it is obvious that in a wlan with mpr capability of @xmath32 , the maximum possible throughput is @xmath64 when there exists a perfect scheduling . in practical random - access wlans , the actual throughput is always smaller than @xmath64 , due to the throughput penalty resulting from packet collisions and idle slots .
for example , the maximum throughput is well known to be @xmath65 when @xmath66 .
theorem 2 proves that the throughput penalty diminishes as @xmath32 becomes large .
that is , the maximum throughput approaches @xmath64 even though the channel access is based on random contentions .
[ theorem:2 ] _ ( asymptotic channel - access efficiency ) _ @xmath67 . before proving theorem 2 , we present the following two lemmas .
\(a ) @xmath68 for any attempt rate @xmath69 ; ( b ) @xmath70 for any attempt rate @xmath71 ; ( c ) @xmath72 for attempt rate @xmath73 .
_ proof of lemma 1(a ) : _
@xmath74 let @xmath75 be the lower bound of @xmath76 . by solving @xmath77
it can be easily found that @xmath78 maximizes @xmath79 and @xmath80 since @xmath81 , @xmath69 .
let @xmath82 where @xmath83 .
( [ eqn:21 ] ) can be written as @xmath84 it is obvious that @xmath85 therefore , @xmath86 on the other hand , the first equality of ( [ eqn:19 ] ) implies @xmath87 combining ( [ eqn:24 ] ) and ( [ eqn:25 ] ) , we have @xmath88 and lemma 1(a ) follows .
@xmath89 _ proof of lemma 1(b ) _ : @xmath90 let @xmath91 be the upper bound of @xmath92 . by solving @xmath93 it can be easily found that @xmath94 minimizes @xmath95 and @xmath96 since @xmath97 , @xmath71 .
let @xmath82 where @xmath98 .
( [ eqn : b3 ] ) can be written as @xmath99 due to eqn .
( [ eqn:23 ] ) @xmath100 on the other hand , it is obvious that @xmath101 combining ( [ eqn : b5 ] ) and ( [ eqn : b6 ] ) , we have @xmath102 and lemma 1(b ) follows .
_ proof of lemma 1(c ) _ : to prove lemma 1(c ) , we note that the median of poisson distribution is bounded as follows @xcite-@xcite : @xmath103 when @xmath73 and @xmath56 , the median approaches @xmath32 . according to the first equality of ( [ eqn:14 ] ) , @xmath104 @xmath89 the optimal attempt rate @xmath105 and @xmath106 .
_ proof of lemma 2 : _ the mode of poisson distribution is equal to @xmath107 , where @xmath108 denotes the largest integer that is smaller than or equal to the argument . when @xmath109 , @xmath110 which conflicts with eqn .
( [ eqn:17 ] ) .
therefore , the optimal attempt rate @xmath111 combining ( [ eqn:14 ] ) , ( [ eqn:17 ] ) , ( [ eqn:28 ] ) and lemma 1 , we have @xmath112 let @xmath113 where @xmath83 . eqn .
( [ eqn:29 ] ) can be written as @xmath114 and @xmath115 where the last equality is due to the stirling s formula @xcite .
solving eqn .
( [ eqn:31 ] ) , we have @xmath116 @xmath89 _ proof of theorem 2 _ : from lemma 1 and lemma 2 , it is obvious that @xmath67 . @xmath89 the above results are illustrated in fig .
[ fig:1 ] , where @xmath117 is plotted as a function of @xmath32 in non - carrier - sensing slotted aloha systems . _
( super - linearity with finite population ) _
@xmath118 for all @xmath119 .
_ proof of theorem 3 _ : see appendix i. in theorem 1 - 3 , super - linearity is proved assuming the network is non - carrier - sensing . in fig .
[ fig:2 ] and fig .
[ fig:3 ] , the optimal throughput @xmath120 and @xmath121 are plotted for carrier - sensing networks , respectively , with system parameters listed in table i. the figures show that system throughput is greatly enhanced due to the mpr enhancement in the phy layer .
moreover , the super - linear throughput scaling holds for carrier - sensing networks when _ m _ is relatively large .
.system parameters used in carrier - sensing networks ( adopted from ieee 802.11 g ) [ cols="^,^",options="header " , ]
in this section , we study the characteristic behavior of wlan mac and eb when the channel has mpr capability .
we first establish the relationship between transmission probability @xmath33 ( or @xmath46 ) and eb parameters including backoff factor _
r _ and minimum contention window @xmath35 . based on the analysis
, we will then study how the optimal backoff strategy changes with the mpr capability @xmath32 .
we use an infinite - state markov chain , as shown in fig .
[ fig:4 ] , to model of operation of eb with no retry limit .
the reason for the lack of a retry limit is that it is theoretically more interesting to look at the limiting case when the retry limit is infinitely large .
having said this , we note that the analysis in our paper can be easily extended to the case where there is a retry limit .
the state in the markov chain in fig .
[ fig:4 ] is the backoff stage , which is also equal to the number of retransmissions experienced by the station .
as mentioned in section ii , the contention window size is @xmath31 when a station is in state @xmath122 . in the figure
, @xmath123 denotes the conditional collision probability , which is the probability of a collision seen by a packet being transmitted on the channel .
note that @xmath123 depends on the transmission probabilities of stations other than the transmitting one . in our model
, @xmath123 is assumed to be independent of the backoff stage of the transmitting station . in our numerical results , we show that the analytical results obtained under this assumption are very accurate when @xmath37 is reasonably large . with eb , transmission probability @xmath33 is equal to the probability that the backoff timer of a station reaches zero in a slot .
note that the markov process of mpr networks is similar to the ones in @xcite , @xcite , except that the conditional collision probability @xmath123 is different for @xmath124 .
therefore , eqn .
( [ eqn:32 ] ) can be derived in a similar way as @xcite , @xcite : @xmath125 where @xmath126 is a necessary condition for the steady state to be reachable .
the detailed derivation of ( [ eqn:32 ] ) is omitted due to page limit .
interested readers are referred to @xcite , @xcite .
likewise , the conditional collision probability @xmath123 is equal to the probability that there are @xmath32 or more stations out of the remaining @xmath127 stations contending for the channel .
we thus have the following relationship : @xmath128 it can be easily shown that @xmath33 is a decreasing function of @xmath123 for any @xmath129 in ( [ eqn:32 ] ) .
meanwhile , @xmath123 is an increasing function of @xmath33 in ( [ eqn:33 ] ) .
therefore , the curves determined by ( [ eqn:32 ] ) and ( [ eqn:33 ] ) have a unique intersection corresponding to the root of the nonlinear system . by solving the nonlinear system ( [ eqn:32])-([eqn:33 ] )
numerically for different @xmath37 , we plot the analytical results of @xmath130 in fig .
[ fig:5 ] . in the figures ,
beb is adopted .
that is , @xmath131 .
the minimum contention window size @xmath132 or 32 . to validate the analysis , the simulation results are plotted as markers in the figures . in the simulation ,
the data are collected by running 5,000,000 rounds after 1,000,000 rounds of warm up . versus @xmath37 when @xmath131 ; lines are analytical results calculated from ( [ eqn:2 ] ) and ( [ eqn:3 ] ) , markers are simulation results.,scaledwidth=50.0% ] from the figures , we can see that the analytical results match the simulations very well .
moreover , it shows that @xmath130 converges to a constant quantity when @xmath37 becomes large .
this is a basic assumption in the previous section when we calculated the asymptotic throughput .
the constant quantity that @xmath130 converges to can be calculated as follows . for large @xmath37
, the number of attempts in a slot can be modeled as a poisson process @xcite .
that is , @xmath133 where @xmath134 the conditional collision probability in this limiting case is given by @xmath135 when the system is steady , the total attempt rate @xmath136 should be finite .
therefore , @xmath137 which implies @xmath138
combining ( [ eqn:36 ] ) and ( [ eqn:38 ] ) , we get the following equation @xmath139 @xmath46 can be calculated numerically from ( [ eqn:39 ] ) given @xmath32 and @xmath34 .
[ fig:5 ] shows that @xmath130 calculated from ( [ eqn:32 ] ) and ( [ eqn:33 ] ) does converge to @xmath46 when @xmath37 is large .
note that the relationship between @xmath33 , @xmath46 , and eb established above do not depend on the duration of the underlying backoff slots , and therefore can be applied in both non - carrier - sensing and carrier - sensing networks . before leaving this sub - section
, we validate another assumption adopted in section iii .
that is , eb guarantees a non - zero throughput when @xmath37 approaches infinity . to this end , the throughput of slotted aloha is plotted as a function of @xmath37 in fig .
[ fig:6 ] when beb is adopted .
it can be seen that the throughputs with the same @xmath32 converge to the same constant as @xmath37 increases , regardless of the minimum contention window @xmath35 .
similar phenomenon can also be observed in carrier - sensing networks , as illustrated in fig .
[ fig:7 ] , where the throughput of ieee 802.11 wlan with basic access mode is plotted with detailed system parameters listed in table i. the asymptotic throughput when @xmath37 is very large depends only on the mpr capability @xmath32 and the backoff factor @xmath34 . ,
scaledwidth=50.0% ] , scaledwidth=50.0% ] in section iii , we have investigated the maximum network throughput that is achieved by optimal transmission probability @xmath52 and @xmath53 .
the previous sub - section shows that transmission probability is a function of backoff factor @xmath34 .
mathematically , the optimal @xmath34 that maximizes throughput can be obtained by solving the equation @xmath140 . in this section ,
we investigate how the optimal backoff factor @xmath34 changes with the mpr capability @xmath32 . in fig .
[ fig:8 ] and fig .
[ fig:9 ] , we plot the throughput as a function of @xmath34 for both non - carrier sensing networks and carrier - sensing networks in basic - access mode . from the figure , we can see that the optimal @xmath34 that maximizes throughput increases with @xmath32 for moderate to large @xmath32 .
this observation can be intuitively explained for non - carrier - sensing networks by ( [ eqn:14 ] ) , ( [ eqn:39 ] ) , and lemma 1 as follows
( [ eqn:14 ] ) and ( [ eqn:39 ] ) indicate that @xmath141 as lemma 1 indicates , when @xmath32 is large , @xmath142 increases with @xmath32 and eventually approaches 1 .
consequently , @xmath34 increases with @xmath32 .
for non - carrier - sensing slotted aloha networks , scaledwidth=50.0% ] for carrier - sensing networks with basic - access mode , scaledwidth=50.0% ] as the figures show , the throughput decreases sharply when @xmath34 moves from the optimal @xmath143 to 1 . on the other hand , it is much less sensitive to @xmath34 when @xmath34 is larger than the @xmath143 .
therefore , in order to avoid dramatic throughput degradation , it is not wise to operate @xmath34 in the region between 1 and @xmath143 .
note that when @xmath32 is large , @xmath143 is larger than 2 .
this implies that the widely used beb might be far from optimal in mpr wlans . to further see how well beb works
, we plot the ratio of the throughput obtained by beb to the maximum achievable throughput in fig .
[ fig:10 ] .
the optimal @xmath34 that achieves the maximum throughput is plotted versus @xmath32 in fig .
[ fig:11 ] . in the figures
, we can see that beb only achieves a small fraction of the maximum achievable throughput when @xmath32 is large in non - carrier - sensing and ieee 802.11 basic - access mode .
for example , when @xmath144 beb only achieves about 80 percent of the maximum throughput in non - carrier - sensing networks .
in rts / cts mode , in contrast , the performance of beb is close to optimal for a large range of @xmath32 .
therefore , we argue from an engineering point of view that beb ( i.e. , @xmath131 ) is a good choice for rts / cts access scheme , while on the other hand tuning @xmath34 to the optimal is important for non - carrier - sensing and basic - access schemes . ,
scaledwidth=50.0% ] versus @xmath32,scaledwidth=50.0% ] having demonstrated the significant capacity improvement that mpr brings to wlans , we are highly motivated to present practical protocols to implement mpr in the widely used ieee 802.11 wifi
. in particular , we will propose protocols that consist of both mac - layer mechanisms and phy - layer signal processing schemes in the next section .
in this section , we present a mpr protocol for ieee 802.11 wlan with rts / cts mechanism .
the proposed protocol requires minimum amendment at mobile stations , and hence will be easy to implement in practical systems . throughout this section , we assume that the mpr capability is brought by the multiple antennas mounted at the access point ( ap ) .
this assumption complies with the hardware request of the latest mimo - based wlan standards .
however , the proposed mac - phy protocol can be easily extended to cdma networks , as the received signal structures in multi - antenna and cdma systems are almost the same ( refer to section ii - c ) .
the mac protocol closely follows the ieee 802.11 rts / cts access mechanism , as illustrated in fig .
[ fig:12 ] . a station with a packet to transmit first sends an rts frame to the ap . in our mpr mac model ,
when multiple stations transmit rts frames at the same time , the ap can successfully detect all the rts frames if and only if the number of rtss is no larger than @xmath32 .
when the number of transmitting stations exceeds @xmath32 , collisions occur and the ap can not decode any of the rtss . the stations will retransmit their rts frames after a backoff time period according to the original ieee 802.11 protocol . when the ap detects the rtss successfully , it responds , after a sifs period , with a cts frame that grants transmission permissions to all the requesting stations
. then the transmitting stations will start transmitting data frames after a sifs , and the ap will acknowledge the reception of the data frames by an ack frame .
the formats of the rts and data frames are the same as those defined in 802.11 , while the cts and ack frames have been modified to accommodate multiple transmitting stations for mpr .
in particular , there are @xmath32 receiver address fields in the cts and ack frames to identify up to @xmath32 intended recipients .
as described above , our mpr mac is very similar to the original ieee 802.11 mac .
in fact , to maintain this similarity in the mac layer , the challenge is pushed down to the physical layer .
for example , in the proposed mpr mac , the ap is responsible to decode all the rtss transmitted simultaneously .
however , due to the random - access nature wlan , the ap has no priori knowledge of who the senders are and the channel state information ( csi ) on the corresponding links .
this imposes a major challenge on the phy layer , as the mud techniques introduced in section ii , such as zf and mmse can not be directly applied . to tackle these problems
, we introduce the physical layer techniques in next subsection . in this subsection
, we propose a phy mechanism to implement mpr in ieee 802.11 .
the basic idea is as follows .
rts packets are typically transmitted at a lower data rate than the data packets in ieee 802.11 .
this setting is particularly suitable for blind detection schemes which can separate the rts packets without knowing the prior knowledge of the senders identities and csi @xcite-@xcite . upon successfully decoding the rts packets , the ap
can then identify the senders of the packets .
training sequences , to be transmitted in the preamble of the data packets , are then allocated to these users to facilitate channel estimation during the data transmission phase .
since the multiple stations transmit their data packets at the same time , their training sequences should be mutually orthogonal . in our system ,
no more than @xmath32 simultaneous transmissions are allowed .
therefore , a total of @xmath32 orthogonal sequences are required to be predefined and made known to all stations . the sequence allocation decision is sent to the users via the cts packet . during the data transmission phase
, csi is estimated from the orthogonal training sequences that are transmitted in the preamble of the data packets . with the estimated csi
, various mud techniques can be applied to separate the multiple data packets at the ap . using coherent detection ,
data packets can be transmitted at a much higher rate than the rts packets without involving excessive computational complexity . as mud techniques have been introduced in section ii , we focus on the blind separation of rts packets in this subsection .
assume that there are @xmath145 stations transmitting rts packets together .
then , the received signal in symbol duration @xmath146 is given by ( [ eqn:4 ] ) , where the @xmath147 element of @xmath148 denotes the channel coefficient from user @xmath149 to the @xmath17 antenna at the ap .
assuming that the channel is constant over an rts packet , which is composed of @xmath37 symbol periods , we obtain the following block formulation of the data @xmath150 where @xmath151 $ ] , @xmath152 $ ] , and @xmath153.$ ] the problem to be addressed here is the estimation of the number of sources @xmath145 , the channel matrix @xmath148 , and the symbol matrix @xmath154 , given the array output @xmath155 . for an easy start , we ignore the white noise for the moment and have @xmath156 .
the rank of @xmath148 is equal to @xmath145 if @xmath157 .
likewise , @xmath154 is full - row - rank when @xmath37 is much larger than @xmath145 .
consequently , we have @xmath158 and @xmath145 is equal to the number of nonzero singular values of @xmath155 . with white noise
added to the data , @xmath145 can be estimated from the number of singular values of @xmath155 that are significantly larger than zero . in this paper
, we adopt the finite alphabet ( fa ) based blind detection algorithm to estimate @xmath154 and @xmath148 , assuming @xmath145 is known .
the maximum - likelihood estimator yields the following separable least - squares minimization problem @xcite @xmath159 where @xmath160 is the finite alphabet to which the elements of @xmath154 belong , and @xmath161 is the frobenius norm .
the minimization of ( [ eqn:42 ] ) can be carried out in two steps .
first , we minimize ( [ eqn:42 ] ) with respect to @xmath148 and obtain @xmath162 where @xmath163 is the pseudo - inverse of a matrix .
substituting @xmath164 back into ( [ eqn:42 ] ) , we obtain a new criterion , which is a function of @xmath154 only : @xmath165 where @xmath166 , and @xmath24 is the identity matrix .
the global minimum of ( [ eqn:44 ] ) can be obtained by enumerating over all possible choices of @xmath154 .
reduced - complexity iterative algorithms that solve ( [ eqn:44 ] ) iteratively such as ilsp and ilse were introduced in @xcite .
not being one of the foci of this paper , the details of ilsp and ilse are not covered here .
interested readers are referred to @xcite and the references therein .
note that the scheme proposed in this section is only one way of implementing mpr in wlans .
it ensures that the orthogonal training sequences are transmitted in the preambles of data packets .
this leads to highly reliable channel estimation that facilitates the user of mud techniques . moreover , the modification to the original protocol is mainly restrained within the ap .
minimum amendment is needed at mobile stations .
in our analysis so far , we have assumed that packet error rate due to random fading effect is negligible when the number of simultaneous transmission is smaller than _ m _ and is close to 1 otherwise .
this assumption is quite accurate when data packets are well protected by error correction codes ( e.g. , convolutional codes in ieee 802.11 protocol ) and linear mud is deployed at the receiver .
the simplification allows us to focus on the effect of mpr on wlan without the need to consider signal processing details such as coding and detection schemes . in this section
, we relax the assumption and investigate how random channel errors would affect our analysis .
fortunately , we can prove that super - linear throughput scaling still holds even when random channel error is taken into account , as detailed in the following .
denote by @xmath167 the packet error rate due to wireless channel fading when _
k _ packets are transmitted at the same time in a network with mpr capability @xmath32 . then , @xmath168 is the packet success rate , which is the probability that a packet _ survives _ random channel fading @xcite .
typically , @xmath169 for @xmath170 and @xmath171 for @xmath172 .
assuming linear detectors , we have @xmath173 if @xmath174 and @xmath175 for @xmath176 @xcite . for simplicity ,
assume @xmath177 .
then , asymptotic throughput is given by @xmath178 at the optimal @xmath53 , @xmath179 .
consequently , @xmath180 we are now ready to prove super - linear throughput scaling @xmath181 in the following .
@xmath182 where the last inequality is due to ( [ eqn56 ] ) .
one implicit assumption in our analysis is that each station transmits at the same data rate @xmath183 . in practice ,
stations experience different channel attenuation to the ap due to their random locations .
if stations transmit at the same power level , then the data rate sustainable on each link would differ . in this case , the airtime occupied by a busy period is dominated the lowest data rate involved . hence , the effective throughput enjoyed by high - rate stations would degenerate to the level of the lowest rate .
such problem , known as performance anomaly " , is not unique to mpr .
it exists in all multi - rate ieee 802.11 networks .
fortunately , performance anomaly only causes the data rate @xmath183 in our throughput expression to degrade to @xmath184 , where @xmath184 is the lowest possible data rate .
therefore , it will not affect the scaling law of throughput in mpr networks . in this paper
, we have demonstrated the drastic increase in spectrum efficiency brought by mpr . to implement mpr ,
modification is needed in both mac and phy layers , as discussed in section v. with the same hardware enhancement ( e.g. , having @xmath32 antennas at the ap ) , an alternative is to let each link transmit at a higher data rate , but keep the single - packet - reception restriction unchanged .
this essentially becomes a traditional wlan with simo ( single - input - multiple - output ) links .
the capacity of a simo link increases logarithmically with the number of antennas at the receiver @xcite .
that is , @xmath185 where @xmath186 is the data rate of a siso ( single - input - single - output ) link .
in contrast , the data rate @xmath183 of each link in mpr wlan is set to @xmath186 , for antenna diversity is used to separate multiple data streams instead of increasing the rate of one stream therein . with ( [ eqn59 ] ) ,
the throughput of wlan with simo links is @xmath187 where the expressions for @xmath188 , @xmath189 , and @xmath190 are the same as ( [ eqn:9 ] ) , ( [ eqn:10 ] ) , and ( [ eqn:11 ] ) with @xmath66 , respectively .
likewise , @xmath191 , @xmath192 , and @xmath193 are the same as ( [ eqn:1 ] ) , ( [ eqn:2 ] ) , or ( [ eqn:3 ] ) except that @xmath183 is replaced by @xmath194 .
specifically , throughput in the aloha case becomes @xmath195 and the optimal @xmath33 that maximizes the throughput is equal to @xmath196 . in particular , the maximum achievable throughput when @xmath37 is large is @xmath197 it is obvious that the normalized throughput @xmath198 decreases with @xmath32 in simo networks .
this , in contrast to the super - linear throughput scaling in mpr networks , suggests that multiple antennas at the ap should be used to resolve simultaneous transmissions instead of increasing per - link data rate in random access wlans .
with the recent advances in phy - layer mud techniques , it is no longer a physical constraint for the wlan channel to accommodate only one packet transmission at one time . to fully utilize the mpr capability of the phy channel , it is essential to understand the fundamental impact of mpr on the mac - layer .
this paper has studied the characteristic behavior of random - access wlans with mpr .
our analysis provides a theoretical foundation for the performance evaluation of wlans with mpr , and it is useful for system design in terms of setting operating parameters of mac protocols .
our analytical framework is general and applies to various wlans including non - carrier - sensing and carrier - sensing networks . in theorems 1 and 3
, we have proved that the throughput increases super - linearly with @xmath32 for both finite and infinite population cases .
this is the case in non - carrier - sensing networks for all @xmath32 , and in carrier - sensing networks for moderate to large @xmath32 .
moreover , theorem 2 shows that the throughput penalty due to distributed random access diminishes when @xmath32 approaches infinity .
such scalability provides strong incentives for further investigations on engineering and implementation details of mpr systems .
based on the analysis , we found that the commonly deployed beb scheme is far from optimum in most systems except the carrier - sensing systems with rts / cts four - way handshake . in particular
, the optimum backoff factor @xmath34 increases with @xmath32 for large @xmath32 .
we further note that the throughput degrades sharply when @xmath34 is smaller than the optimum value , while it is much less sensitive to @xmath34 when @xmath34 exceeds the optimum .
having understood the fundamental behavior of mpr , we propose practical protocols to exploit the advantage of mpr in ieee 802.11-like wlans . by incorporating advanced phy - layer blind detection and mud techniques ,
the protocol can implement mpr in a fully distributed manner with marginal modification of mac layer .
( super - linearity with finite population ) @xmath199 for all @xmath119 at the optimal @xmath52 , the derivative @xmath204 . thus , @xmath205 combining ( [ eqn : a4 ] ) and ( [ eqn : a5 ] ) , @xmath206 it is obvious that @xmath207 substituting ( [ eqn : a6 ] ) to ( [ eqn : a7 ] ) , we have @xmath208 hence , @xmath199 for all @xmath119 .
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d. s. chan , t. berger and l. tong , on the stability and optimal decentralized throughput of csma with multipacket reception capability , " _ prof .
allerton conference on communication , control , and computing _ , sept - oct 2004 .
d. s. chan , p. suksompong , j. chen and t. berger , improving ieee 802.11 performance with cross - layer design and multipacket reception via multiuser iterative decoding , " ieee 802.11 - 05/0946r0 , sept 2005 .
ying jun ( angela ) zhang ( s00 , m05 ) received her beng degree with honors in electronic engineering from fudan university , shanghai , china , and the phd degree in electrical and electronic engineering from the hong kong university of science and technology , hong kong . since jan .
2005 , she has been with the department of information engineering in the chinese university of hong kong , where she is currently an assistant professor .
zhang is on the editorial boards of ieee transactions of wireless communications and willey security and communications networks journal .
she has served as a tpc co - chair of communication theory symposium of ieee icc 2009 , track chair of icccn 2007 , and publicity chair of ieee mass 2007 .
she has been serving as a technical program committee member for leading conferences including ieee icc , ieee globecom , ieee wcnc , ieee icccas , iwcmc , ieee ccnc , ieee itw , ieee mass , msn , chinacom , etc .
zhang is an ieee technical activity board gold representative , 2008 ieee gold technical conference program leader , ieee communication society gold coordinator , and a member of ieee communication society member relations council .
her research interests include wireless communications and mobile networks , adaptive resource allocation , optimization in wireless networks , wireless lan / man , broadband ofdm and multicarrier techniques , mimo signal processing . as the only winner from engineering science , dr .
zhang has won the hong kong young scientist award 2006 , conferred by the hong kong institution of science .
soung chang liew ( s84-m87-sm92 ) received his s.b .
, e.e . , and
degrees from the massachusetts institute of technology . from 1984
to 1988 , he was at the mit laboratory for information and decision systems , where he investigated fiber - optic communications networks . from march 1988 to july 1993
, soung was at bellcore ( now telcordia ) , new jersey , where he engaged in broadband network research .
soung is currently professor and chairman of the department of information engineering , the chinese university of hong kong .
he is adjunct professor at southeast university , china .
soung s current research interests include wireless networks , internet protocols , multimedia communications , and packet switch design .
soung and his student won the best paper awards in the 1st ieee international conference on mobile ad - hoc and sensor systems ( ieee mass 2004 ) the 4th ieee international workshop on wireless local network ( ieee wln 2004 ) . separately ,
tcp veno , a version of tcp to improve its performance over wireless networks proposed by soung and his student , has been incorporated into a recent release of linux os .
in addition , soung initiated and built the first inter - university atm network testbed in hong kong in 1993 .
besides academic activities , soung is also active in the industry .
he co - founded two technology start - ups in internet software and has been serving as consultant to many companies and industrial organizations .
he is currently consultant for the hong kong applied science and technology research institute ( astri ) , providing technical advice as well as helping to formulate r&d directions and strategies in the areas of wireless internetworking , applications , and services .
soung is the holder of four u.s .
patents and fellow of iee and hkie .
he is listed in marquis who s who in science and engineering .
he is the recipient of the first vice - chancellor exemplary teaching award at the chinese university of hong kong .
publications of soung can be found in www.ie.cuhk.edu.hk/soung .
pengxuan zheng ( s06 ) received his b.eng .
degree in computer science and engineering from zhejiang university , hangzhou , china , in 2004 , and m.phil .
degree in information engineering from the chinese university of hong kong , hong kong , china , in 2007 .
he is currently working towards the ph.d .
degree at purdue university .
his research interests include mobile ad hoc networks and wireless sensor networks .[/INST] thanks to its simplicity and cost efficiency , wireless local area network ( wlan ) enjoys unique advantages in providing high - speed and low - cost wireless services in hot spots and indoor environments .
traditional wlan medium - access - control ( mac ) protocols assume that only one station can transmit at a time : simultaneous transmissions of more than one station cause the destruction of all packets involved . by exploiting recent advances in phy - layer multiuser detection ( mud ) techniques ,
it is possible for a receiver to receive multiple packets simultaneously .
this paper argues that such multipacket reception ( mpr ) capability can greatly enhance the capacity of future wlans .
in addition , the paper provides the mac - layer and phy - layer designs needed to achieve the improved capacity .
first , to demonstrate mpr as a powerful capacity - enhancement technique , we prove a super - linearity " result , which states that the system throughput per unit cost increases as the mpr capability increases .
second , we show that the commonly deployed binary exponential backoff ( beb ) algorithm in today s wlan mac may not be optimal in an mpr system , and that the optimal backoff factor increases with the mpr capability , the number of packets that can be received simultaneously .
third , based on the above insights , we design a joint mac - phy layer protocol for an ieee 802.11-like wlan that incorporates advanced phy - layer signal processing techniques to implement mpr . wireless local area network , exponential backoff , multipacket reception . </s> |
two - level systems are ubiquitous in quantum physics and have been the subject of theoretical studies for almost a century @xcite .
they constitute the fundamental building blocks for quantum information processing @xcite and time keeping with atomic clocks @xcite . for such quantum enabled technologies , physical systems that display a high degree of immunity with respect to the surrounding environment are invariably sought .
a prominent example is optical lattice clocks @xcite , where magnetically insensitive `` clock - state '' atoms are confined by `` magic '' wavelength optical fields .
the addition of coupling terms ( interaction with the environment ) to the free evolution hamiltonian for a two - level system can , however , be turned to an advantage and exploited in metrology applications . in this case
, a field induced level shift is encountered , which may be measured spectroscopically .
this may form the basis of atomic magnetometers @xcite and magnetic field imaging @xcite .
two - level atoms are typically manipulated with quasi - resonant radiation fields , giving rise to dynamics equivalent to a magnetic spin-1/2 particle in a b - field @xcite .
the physics of a two - level atom in a steady field is captured by the well - known rabi solution describing the oscillation of population between the two states , which for an atom initially in its lower energy state takes the following form for the ( single atom ) population inversion @xcite @xmath3 ^ 2\sin^2\left[\omega(\delta)t/2\right],\ ] ] where @xmath4 is the on - resonance rabi frequency and @xmath5 is the generalized rabi frequency for a field detuned by @xmath6 from the transition frequency .
the on - resonance rabi frequency is the product of the driving field amplitude and the matrix element between the two states for the atom - field interaction , and may hence display spatial variation according to the intensity distribution of the electromagnetic field .
this was recently exploited to map out the magnetic microwave near - field of a coplanar waveguide by means of ultracold @xcite and hot @xcite atomic clouds .
similarly , in the far field of a horn antenna , the effect of a spatially inhomogeneous microwave drive field has also been observed for extended atomic clouds @xcite .
the dynamics of the inversion @xmath7 may also acquire a position dependence through a spatial variation of the detuning @xmath6 .
this could , for example , arise from a position dependent differential ac stark shift imposed by a laser beam @xcite or via a nonuniform magnetic field ( zeeman shift ) @xcite . in this paper
we report on dispersive probing of microwave driven rabi oscillations between two zeeman tunable hyperfine states in a prolate sample of ultracold @xmath8rb atoms .
we organize our presentation as follows . in sec .
[ section : background ] we briefly review dispersive probing schemes and their applications , and discuss approaches for imprinting magnetic order in inhomogeneously broadened samples .
section [ section : setup ] describes our experimental setup and the acquisition and processing of data . for our atomic system , a magnetic field gradient over an elongated ( prolate )
cloud leads to an inhomogeneous shift in the resonance .
this in turn gives rise to a decay in rabi oscillations when probed dispersively along its axis .
section [ section : interplay ] presents examples of such decaying waveforms , which are interpreted in a simple dephasing model and compared to complementary data acquired by means of spatially resolved state - selective absorption imaging .
here we also discuss the small but observable effect the dispersive probe beam has on the atomic sample in terms of a differential light shift , breaking the symmetry for the resulting spin texture .
we finally summarize our findings and outline potential future directions in sec .
[ section : conclusion ] .
when a beam of light of well - defined frequency passes through a gas of atoms it may be attenuated as a result of absorption , as well as shifted in phase .
dispersive detection techniques make use of the latter effect and are a very suitable tool for tracking dynamical processes in `` real time '' for cold and ultracold atomic systems . for example
, dispersive probing has been used to follow breathing @xcite and center - of - mass oscillations @xcite , and the process of forced evaporative cooling @xcite for trapped atomic clouds . moreover , coherent phenomena such as rabi oscillations between hyperfine states @xcite , larmor precession @xcite and phase space dynamics of spinor condensates @xcite have been recorded and studied dispersively .
the phase shift measurement is obtained by comparing the phase - shifted beam to a reference beam in either homodyne or heterodyne detection schemes .
for example , the former is achieved in mach - zehnder interferometers @xcite , while the latter is achieved in frequency modulation ( fm ) spectroscopy @xcite .
furthermore , dispersive probing may also take the form of polarization spectroscopy for gases in birefringent states @xcite .
the implementations listed in the preceding paragraph all make use of non - imaging photodetectors , which are generally both faster and less expensive than low noise ccd cameras @xcite , but do , of course , imply that direct spatial information imprinted on the probe light is integrated out .
spatially resolved dispersive imaging techniques for ultracold atoms have been in play since right after the achievement of bose - einstein condensates ( becs ) @xcite , with variants thereof developing subsequently @xcite .
systems with magnetic order are of fundamental importance in condensed - matter physics and an area of substantial interest .
trapped ultracold atomic gases provide a clean and highly flexible experimental test bed where to simulate such systems and have been utilized in many studies over the last 15 years or so to investigate spatial magnetic order by using atomic spin degrees of freedom . the starting point for many such experimental studies in a continuous geometry
is to expose the gas to a spatially varying coupling field , inhomogeneously driving dynamics between spin states .
for example , matthews _
et al . _
@xcite used a spatially varying rabi drive to wind up the phase of the order parameter of a two - component @xmath9 condensate and observed the subsequent unwinding owing to its kinetic energy .
the spatial variation of the coupling resulted as a combined effect of the presence of a magnetic field gradient and the accompanying variation of the two - photon rabi frequency .
similar methods were used later to excite dipole topological modes in condensates @xcite , to create spin waves in an ultracold gas above the bec transition @xcite , to observe spatial segregation in both ultracold bose gases @xcite and fermi gases @xcite . very recently , phase - winding in an elongated two - component bec was used to generate dark - bright solitons @xcite .
the phenomenon of spin waves has direct relevance to spintronics and spin caloritronics @xcite , and studies have demonstrated universal spin transport in fermi gases near the hydrodynamic regime @xcite and engineered high - quantum number spin waves @xcite .
spatially inhomogeneous coupling has been employed in @xcite to induce spin waves and study the resulting shift of the clock frequency in an atom chip experiment . in relation to this ,
there has also been substantial interest in studying two - component becs , where spatio - temporal variation of rabi coupling was employed in association with controlling the atomic interactions to study spatial mixing - demixing dynamics @xcite , spin textures following a quench @xcite and non - equilibrium dynamics @xcite . in the present paper
, we apply a phase - winding technique similar to @xcite for imprinting magnetic order in an elongated sample of ultracold atoms .
the overall magnetization @xmath10 of the ensemble exhibits itself as a density weighted integral of the local magnetization , the latter containing information about the local coupling strength .
the temporal evolution of @xmath10 has a characteristic non - exponential profile , which we map out using both dispersive and absorptive probing . from this
, the variation in local coupling strength can be inferred , making the system a prospect tool for high bandwidth magnetic and microwave field gradiometry .
our experimental setup is shown schematically in fig . [ fig : setup ] .
the ultracold atomic samples used in our experiments typically consist of @xmath11 @xmath8rb atoms in the @xmath12 ground hyperfine state , confined in a single beam far - off - resonant dipole trap @xcite .
samples are produced using a standard bec apparatus @xcite .
atoms are initially magnetically confined in a ioffe pritchard ( ip ) trap , where they are rf evaporatively cooled to temperatures @xmath13@xmath14 , close to the bec transition . the sample is then transferred to the dipole trapping potential , produced by a 1064 nm ytterbium fiber laser with typical optical power @xmath15w and a beam waist of @xmath16@xmath17 .
the confining beam propagates along the axial ( @xmath18 ) direction of the cloud , and gives rise to radial and axial trapping frequencies of @xmath19 .
the initial peak atomic density in the dipole trap is @xmath20@xmath21 . a magnetic bias field ( @xmath22 ) pointing in the @xmath18-direction lifts the degeneracy between the zeeman states and defines a quantization axis .
the field is generated with a coil pair symmetrically placed around the cloud in an approximate helmholtz configuration . the axial field produced by
the geometry is well - approximated near the center to be linear with position with a gradient @xmath23 50 mga@xmath24cm@xmath24 . while the bias field is present , a microwave coupling field , near - resonant with the @xmath26 @xmath8rb hyperfine transition , is applied to the sample for a variable duration @xmath27 .
this microwave field is generated by mixing of signals from a waveform generator ( 6.532 ghz ) and a direct digital synthesizer ( dds ) board ( @xmath28 ) using a double - balanced frequency mixer .
the mixer output is high - pass filtered to give the up - shifted ( sum ) component , which is amplified to a power of 6.5 w. a helical end - fire antenna @xcite emits circularly polarized microwave radiation towards the atomic cloud .
the antenna is positioned @xmath29 from the atoms and , due to space constraints , at an angle of @xmath30 with the @xmath18-axis .
this configuration results in a predominantly circularly polarized microwave radiation . and @xmath31 transitions spectroscopically to be @xmath32 for this antenna orientation ( taking into account the magnetic dipole matrix elements ) . ]
the variation of microwave power over the extent of the atomic cloud is less than 2% , negligible for the purposes of the studies presented below .
the emitted microwave field induces rabi oscillations between the @xmath33 and @xmath34 states with a characteristic on - resonance rabi frequency of @xmath35 khz .
we monitor the evolution of the atomic @xmath1 population of the sample during the microwave pulse dispersively , using fm spectroscopy @xcite .
to produce an optical frequency triplet for probing , a central carrier ( c ) , far from any optical transitions in @xmath8rb , is derived from an external cavity diode laser ( ecdl ) , which is locked to the @xmath36-@xmath37 crossover peak of the @xmath38 d2 transition of the @xmath39rb isotope by means of a saturated absorption spectroscopy ( sas ) setup ( see inset panel of fig . [
fig : setup ] ) .
an acousto - optic modulator ( aom ) , used to pulse the probe beam on and off , shifts the carrier up by 80mhz , such that it is blue - detuned by 1097mhz from the @xmath8rb @xmath40 transition .
the carrier is then passed through a fiber electro - optic modulator ( eom , bandwidth 10 ghz ) , which imprints a red ( r ) and a blue ( b ) sideband shifted by @xmath41 mhz from the carrier frequency , such that the red sideband is blue - detuned by 212 mhz from the @xmath8rb @xmath40 transition .
the three frequency components have approximately equal optical power ( @xmath42 each ) . a switching routine
is administered by the aom , in which a sequence @xmath43 ( with @xmath44 typically 50 300 ) of 500 ns long probe light pulses is produced at a repetition rate of 100khz .
the probe beam is focused to a waist of 65@xmath45 m onto the atoms such that the frequency triplet propagates along the axis of our atomic sample .
the probe beam is linearly polarized , and can be decomposed into right and left circularly polarized components of equal intensity , which address the @xmath46 and @xmath47 transitions , respectively .
atom - light interactions cause each frequency ( @xmath48 ) and polarization ( @xmath49 ) component to acquire a phase shift @xmath50 . for the probe beam parameters and maximum atomic column densities in the @xmath51 state specified above , we estimate @xmath52 , @xmath53 , @xmath54 , @xmath55 , @xmath56 , and @xmath57 .
the resulting optical beat signal is detected on a fast , fiber - coupled photodiode ( finisar hdf3180 - 203 , bandwidth 4.2 ghz ) and is demodulated to baseband with a local oscillator ( lo ) at @xmath58 using an iq mixer . in this way
, components both in - phase ( i ) and in - quadrature ( q ) with the lo are obtained , so the signal can be reconstructed irrespective of the lo phase .
the signals from the two mixer output ports are simultaneously sampled at 20 ms / s by a 16-bit digitizer in @xmath59 segments centered on each pulse .
the single - pulse signal - to - noise ratio of the dispersive signal for the maximum atomic numbers we use is about 20 .
our experimental sequence is ( crucially ) triggered from the rising edge of a square wave signal synchronous to the 50 hz power line frequency .
a suitable delay is chosen to ensure that the rabi drive and dispersive probing happen around a zero crossing for the residual ac magnetic field originating from power line currents @xcite .
the timing of the microwave and the dispersive probe pulses is controlled by digital delay generators , such that similar experimental conditions are realized in every experimental run
. the cloud may be additionally ( or alternatively ) probed using conventional absorption imaging at the end of the experimental sequence , after switching off the dipole trap confinement .
atoms falling under gravity are spatially separated in the vertical direction based on their magnetic moment by a stern - gerlach gradient of @xmath60 , applied for @xmath61 .
atoms are then exposed to an optical `` repumping '' pulse , which transfers @xmath0 atoms to @xmath62 via the @xmath63 ( @xmath64 ) excited state , and finally imaged with probe light resonant with the @xmath40 transition .
this procedure produces an absorption image in which the spatial distributions of the two hyperfine states originally present are clearly distinguishable ( see fig . [ fig : setup ] ) . .
the dotted black lines indicate the integration window for each sample ( note the broken axis ) .
the lower panel shows the resulting phase shift data for this data set.,title="fig : " ] + the raw data for probe pulse @xmath65 acquired by the digitizer consists of @xmath66 and @xmath67 the voltages obtained from the i and q ports of the mixer , respectively . within each data segment
we define an integration window and numerically extract the area under the probe pulse to give the processed data sets @xmath68 .
this integration is shown schematically in fig .
[ fig : pulseanalysis](a ) and fig .
[ fig : pulseanalysis](b ) , for the first three points of a typical data set showing rabi oscillations .
the phase shift @xmath69 incurred by the red probe sideband , assumed to have a low spontaneous scattering probability , can be shown to be proportional to @xmath70 for @xmath71 , which is true under our conditions .
the resulting dispersive signal , which is proportional to population of atoms in the @xmath1 state , is plotted in fig .
[ fig : pulseanalysis](c ) , with the values corresponding to the raw data shown above indicted with yellow stars .
as described in section [ section : setupa ] , our starting point for the coherent state manipulation is an ultracold sample polarized in state @xmath72 , loaded in a focused single - beam gaussian dipole trap .
the depth of the dipole trap is @xmath73@xmath45k , such that we achieve a loading efficiency close to unity .
the small atomic sample expands along the direction of the dipole trap beam .
after 40 ms expansion , for example , the cloud has a fwhm size of 1.3 mm in the axial direction and about 60 @xmath45 m along the radial direction , such that we have a quasi-1d prolate cloud of atoms .
the typical shot - to - shot number and temperature stability of the preparation of the initial atomic sample is better than 5% . ) .
the plot is an average of five consecutive experimental runs .
the atomic sample was allowed to expand for 40 ms in the horizontal trap before applying the rabi drive and the dispersive pulses .
the line is a fit of the model described in sec .
[ section : gradient_magnetimetry ] to our data.,title="fig : " ] + in fig .
[ fig : disprecord ] , we show a typical record of the dispersive interrogation of rabi oscillations of atoms driven by microwave for 2 ms .
the expansion time of the atoms in dipole trap was 40 ms prior to microwave exposure , and the data points are averages of 5 consecutive experimental runs .
the decay of the oscillation is predominantly a result of magnetic dephasing of the zeeman - sensitive states ( which leads to the formation of spin domains , as discussed in sec .
[ section : spinwave ] ) . ) absorption images acquired at times @xmath74 during the coherent microwave manipulation .
( b ) the precession of the bloch vector at the three positions of the atomic cloud shown in ( a ) . the left- and the right - hand side cases are off - resonant , and precess at faster rates .
( c ) time evolution of the sample - integrated relative population of atoms in the @xmath1 state from absorption images ( @xmath75 ) .
the line is a fit of the model described in section [ section : gradient_magnetimetry ] to our data .
the destructive measurements based on absorption imaging are time - consuming , so we limit ourselves to recording up to 1 ms of microwave manipulation . ]
we complement our dispersive data presented in section [ section : disprabi ] with spatially resolved absorption images acquired at the end of the microwave pulse .
we chose the microwave frequency to be resonant with the atoms approximately at the location of the maximum atomic density .
figure [ fig : bloch1](a ) shows state - resolved absorption images taken after projective measurements taken at times @xmath76 , where @xmath77 is one full on - resonance rabi cycle .
the emergence of `` spin domains '' is evident , and is due to the spatial variation of rabi frequency in the presence of a small field gradient . to elucidate the time evolution of the system
, we use a bloch sphere representation of the two - level system @xcite . each point on the @xmath18-axis
is described by an effective pseudo - spin vector @xmath78 precessing in a plane perpendicular to a torque vector @xmath79 , where @xmath80 and @xmath81 are the ( local ) transverse coherences and @xmath82 is the ( local ) population difference between the two states , all defined in a frame rotating at the transition frequency .
the equation of motion of the local bloch vector is @xmath83 .
figure [ fig : bloch1](b ) illustrates the time evolution of bloch vectors at three different axial locations in the cloud . at the center of the cloud , where the microwave is resonant with the atoms ,
the torque vector is along the @xmath84 axis , and the bloch vector precesses on a great circle at a rate @xmath4 , whereas away from the center , the bloch vectors precess on minor circles at a faster rate given by eq .
( [ eqrabifreq ] ) .
since the phase advance per unit time increases monotonically away from the center of the cloud , this poses a winding mechanism by which alternating domains of the spin projection @xmath82 are formed . as an illustration of this dynamics
, @xcite shows the development of the pseudo - spin projection @xmath82 across the atomic cloud obtained by subtracting the @xmath0 part from the @xmath1 part in a series of state - selective absorption images .
figure [ fig : bloch1](c ) shows the evolution of the ensemble - integrated population of atoms in the @xmath72 state from the absorption data , which exhibits a non - exponential damping of rabi oscillations mirroring our dispersive observation [ fig .
[ fig : disprecord ] ] .
we note that the time required for the absorptive data acquisition amounted to several hours , in contrast to the dispersive measurements , which only took a few minutes . of the pseudo - spin on the bloch sphere , where @xmath85 corresponds to an atom in @xmath86 ( @xmath87 ) state .
( a ) shows the theoretical plots for the cases with @xmath88mm@xmath24 shown from top to bottom .
( b ) shows the map obtained in the experimental sequence .
( c ) zooms the theoretical map corresponding to @xmath89mm@xmath24 for easy comparison with the experimental map ( see text).,title="fig : " ] + as noted in section [ section : setupa ] , the bias magnetic field in our set up is a linear function of @xmath18 at the atomic cloud , implying that ( via the zeeman effect ) the frequency detuning of the microwave field is of the form @xmath90 . since the extent of the cloud is radially small ( @xmath91 @xmath45 m ) , we assume @xmath6 to be constant in the radial direction
furthermore , the effect of mean - field interactions are considered negligible for our experimental conditions as we are in a relatively low density regime and the s - wave scattering lengths for the various spin - states involved are similar to within a few percent .
we also neglect any identical spin rotation effect @xcite in our system , as the time scale for the exchange collision @xcite at the densities involved in our experiments is @xmath92ms , which is much longer the than the time scale of the observations made in this paper . in order to gain quantitative understanding of the ensemble - integrated evolutions presented in fig .
[ fig : disprecord ] and fig .
[ fig : bloch1 ] , we numerically solved the equation of motion for @xmath93 across the cloud assuming that a linear field gradient along @xmath18-direction is present and that the center of the cloud is resonant with the microwave field .
the maps in fig .
[ fig : bloch2](a ) show the @xmath18-dependent time evolution of the `` longitudinal angle '' [ i.e. , the bloch vector polar angle @xmath94 computed for field gradients @xmath95 .
figure [ fig : bloch2](b ) shows a corresponding map based on experimentally acquired data . as is evident , the essential features of the phase - winding in our experiments are well - captured by the model based on the presence of a linear field gradient , which suggests a field gradient of around @xmath96 ( fig . [
fig : disprecord](c ) ) . figure [ fig : bloch2](b ) shows that after about @xmath97 , the temporal evolution of the atomic pseudo - spin at positions away from the center of the cloud exhibits the emergence of spurious oscillations .
the phenomenon can not be linked to detection noises or fluctuations of magnetic fields , as the center part of the cloud remains unaffected for much longer . at the current stage
we have not been able to trace out the underlying mechanism causing this . in the analysis of _ local _ rabi frequencies in sec .
[ section : ex_local_rabi ] , we therefore only make use of the first four rabi cycles . the damping of rabi oscillations in the ensemble - integrated data obtained through absorption imaging , as shown in fig .
[ fig : bloch1](c ) , and the dispersively acquired data of fig . [
fig : disprecord ] are both non - exponential and are characterized by a rapid decay in the beginning and a much slower one at later times .
such non - exponential decays are characteristic of spatial non - uniformities , and the two obvious spatially non - uniform features of our system are the local magnetic field and the atomic density .
the full model then accounts for the overall pseudo - spin vector of the ensemble as a density - weighted integral of local spins subject to local torque vectors .
in particular the population in the @xmath12 state at time @xmath98 is described by , @xmath99 where @xmath100 is the initial normalized line density of atoms , which can be inferred from an absorption image taken at @xmath101 . ) to the dispersively obtained data .
the errorbars show the 2@xmath102 confidence intervals .
insets compare the values obtained using the dispersively ( @xmath103 ) and absorptively ( ) measured time evolution.,title="fig : " ] + when fitting the model eq .
( [ model2 ] ) to the absorptive data in fig .
[ fig : bloch1](c ) , we obtain excellent agreement . from the fit
we extract an on - resonance rabi frequency of @xmath104khz and a field gradient of @xmath105khz / mm , where the numbers in brackets are the @xmath106 confidence intervals . since the model eq .
( [ model2 ] ) does not make any assumptions on how the population measurements are made , we can also apply it to the dispersive data presented in fig . [
fig : disprecord ] .
again , we obtain excellent agreement , as in the case for absorptive data .
the fitted @xmath4 and @xmath107 parameters of the model are plotted in fig .
[ figxy1](a ) and fig .
[ figxy1](b ) , respectively , for five different spatial extents of the cloud in dipole trap .
the values of the field gradient obtained in each case are in very close proximity to that obtained from the ( time - consuming ) destructive measurements ( shown in the insets along with the corresponding values obtained dispersively).(b ) ( which corresponds to a 10ms expansion time in the dipole trap after the ip trap switch - off ) results from the instability of the field due to decaying eddy currents from the ip trap switch - off . ]
there are two important mechanisms through which the dispersive probe beam perturbs the coherent evolution of the system : the spontaneous photon scattering , and the differential light shift of the spin states involved .
in contrast , the spontaneous photon scattering and the differential light shift caused by the dipole trapping beam are small and can be completely neglected for our beam parameters . the spontaneous photon scattering results from off - resonantly populating excited atomic states during the probe pulse @xcite . for our experimental parameters
, we estimate the mean number of spontaneously scattered photons from a probe pulse ( frequency triplet ) to be about @xmath108 per atom .
this amounts to less than 0.1% of the atoms scattering a photon over 100 dispersive pulses . in our experiment
, we have about @xmath109 probe photons per pulse ( about one photon per atom ) in the red sideband of the probing triplet , and the time scale over which the decay due to spontaneously scattered photons becomes important is @xmath110 ms or longer . in the absence of light ) . without light , the bloch vectors precess about @xmath111 as encountered in fig .
[ fig : bloch1](b ) . with light pulses applied periodically , precession about @xmath112
is interleaved into this evolution , effectively decrease the cycle time for @xmath113 ( @xmath114 ) and a negative ( positive ) gradient .
( c ) the effective local rabi frequency versus @xmath18 for the cases of a negative and a positive linear field gradient and a homogeneous light shift .
also shown is the hyperbola eq .
( [ eqrabifreq ] ) symmetric about @xmath115 that describes _ both _ negative and positive field gradients in the absence of a light shift.,title="fig : " ] + we quantify the differential light shift induced by the probe beam by the ( local ) dimensionless quantity @xmath116 , where @xmath117 is the ( local ) differential light shift caused by the probe and @xmath118 is the duration of each probe pulse . for the parameters used in our experiments , the maximum differential light shift is @xmath119khz , and the corresponding @xmath120 . due to the gaussian intensity profile of the probe beam ,
the differential light shift varies across the atomic sample .
the rayleigh range is @xmath121 cm for the probe beam , which is an order of magnitude higher the axial size of the atomic sample .
this means that the light shift along this direction is essentially homogeneous . in order to gain insight into the physical process
, we again make use of the bloch sphere picture .
locally , the dispersive atom - light interaction during a probe pulse causes a rotation of the bloch vector with respect to the @xmath122-axis by an angle @xmath123 . for blue - detuned probe light ( as in our case )
, @xmath123 is positive .
when applied during the coherent microwave evolution , a series of probe pulses effectively shifts the bloch vector away from the circle on which its tip would otherwise lie , as illustrated in fig .
[ fig : dephasing2](a ) and in fig .
[ fig : dephasing2](b ) , in the presence of negative and positive field gradients , respectively .
consequently , for a positive ( negative ) field gradient , the resonance moves to the left ( right ) along the cloud .
this notion is reasserted in fig .
[ fig : dephasing2](c ) which shows the calculated local rabi frequencies along the @xmath18-direction in the presence of light pulses for both positive and negative field gradients , obtained by numerically solving the bloch equation , and assuming @xmath124 and @xmath125 khz .
-axis ( axial direction of the atomic sample ) in the presence of a positive magnetic field gradient .
the symmetry encountered in the absence of a perturbing light shift ( @xmath126 ) is broken when a _ radially _ inhomogeneous light field of increasing strength @xmath127 is applied .
in addition to a translation of the minimum also found in the homogenous case fig .
[ fig : dephasing2](c ) , the inhomogeneity leads to a `` tilt '' .
( b ) characteristic dephasing decay time @xmath128 versus position .
, title="fig : " ] + the radial size of our atomic cloud ( @xmath91@xmath45 m ) is comparable to the waist of the dispersive beam ( @xmath129@xmath45 m ) , which means that the considerations from sec .
[ section : dephasing_homogeneous ] need to be extended to include the effect of inhomogeneous light shift in the radial direction . for a given axial position @xmath18 ,
atoms at various radial distances experience different light shifts @xmath117 , which results in radially dependent azimuthal phase shifts on the bloch sphere during a probe pulse .
this leads to _ local _ dephasing at a given axial position .
the time evolution of the collective pseudospin vector @xmath130 for each point @xmath18 is the sum of the time evolution of the bloch vector for each radial position @xmath131 weighted by @xmath132 , the ( normalized ) local radial atomic density , @xmath133 .
we numerically solved this equation for @xmath130 for different values of the peak differential light shift @xmath134 while assuming a positive magnetic field gradient .
we summarize the results in terms of the distributions of local effective rabi frequency and the dephasing decay time in fig .
[ fig : dephasing3 ] . as is evident from fig .
[ fig : dephasing3](a ) , the radially inhomogeneous light shift leads to a breaking of symmetry of the local rabi frequency about the minimum point ( a `` tilt '' ) .
it also shows that the collective pseudospin vector on the right ( left ) side of the cloud precesses faster ( slower ) in the presence of dispersive pulses causing faster ( slower ) spin dynamics on the right ( left ) side of the elongated atomic sample with respect to the unperturbed case .
figure [ fig : dephasing3](b ) shows that for the probe pulse parameters used in our experiments ( @xmath124 ) , the expected characteristic decay time @xmath128 owing to the dephasing caused by the inhomogeneous light shift is much longer than the time scale of the coherent manipulation and dispersive interrogation in our experiment ( within the relevant length scale ) .
finally , we make a local analysis on the series of state resolved absorption images taken after various microwave exposure times in the absence and presence of dispersive probe pulses . figure [ figxy2](a ) and fig .
[ figxy2](b ) show the absorption images taken at @xmath135 in the two cases , respectively , revealing a clear breaking of symmetry for the latter case .
we divide the time series of absorption images in the two cases into equal sized bins and count the number of atoms in each state residing in a bin . from this the time evolution of the population in each bin is constructed and we extract the local ( effective ) rabi frequency for each bin .
the results are presented in fig .
[ figxy2](c ) for the case of a @xmath136 m bin size . evidently , dispersive probe pulses cause a small shift of the minima and break the symmetry of the curve , a result of the accompanying differential light shift of the transition , as discussed in sec .
[ section : dephasing_homogeneous ] and sec .
[ section : dephasing_inhomogeneous ] .
in particular , a behavior akin to that predicted by fig .
[ fig : dephasing3](a ) is encountered .
the inset of fig .
[ figxy2](c ) shows the corresponding local detuning @xmath137^{1/2}$ ] , where @xmath4 is the minimum of @xmath138 for the two cases .
the sign of the slope of @xmath138 is determined to be _ positive _ based on the directions of the `` shift '' and the `` tilt '' of the hyperbolic shape of fig .
[ figxy2](c ) for the dispersively probed case following the reasoning of sec .
[ section : dephasing_inhomogeneous ] .
the values of @xmath107 obtained from the corresponding linear fits [ @xmath139 khz / mm for the unperturbed case and @xmath140 khz / mm for the dispersively probed case ] are in very good agreement with each other and with the values obtained in the two sample - integrated procedures ( dispersive and absorptive ) presented in sec .
[ section : gradient_magnetimetry ] .
in this paper we have investigated a heterodyne , dispersive optical probing scheme applied to elongated ultracold rubidium clouds residing in an inhomogeneous magnetic field .
a zeeman shift gives rise to axial dephasing when driving near - resonant rabi oscillations between two hyperfine states . with the dispersive probe , the resulting decay in net polarization / magnetization of the sample
could be followed in `` real time '' . in particular , the dispersively
observed non - exponential washing out of rabi oscillations was described well by a simple model from which a value of the magnetic field gradient could be extracted .
this value for the magnetic field gradient was in excellent correspondence with complementary measurements based on absorption images . for our demonstration
we applied a field gradient of about 500 nt / mm , leading to a center - to - edge change in rabi frequency of @xmath141 from the @xmath142 khz central and on - resonance rabi frequency .
fitting our model function over a time interval @xmath143 ms ( yielding more than 10 cycles ) allows us to determine this gradient to within 25 nt .
this underscores the potential to perform gradient magnetometry to this accuracy with a @xmath144kilohertz bandwidth using the dispersive probing approach based on a single experimental run .
the absorption images of prolate clouds at the end of the rabi drive revealed the formation of ( continuous ) magnetic order along the sample similar to previously reported findings @xcite , but also how the small but finite light shift from the dispersive probe breaks the symmetry of the spin patterns .
we used this to the effect of determining the sign of the applied magnetic field gradient .
as outlined in sec .
[ section : backgroundb ] there is significant interest in spin dynamics of ultracold atomic systems , and we speculate if this mechanism can be employed for spin wave engineering similar to @xcite .
we finally point towards possible future applications of the experimental scheme outlined in this paper , in the context of probing microscopic structures .
for example , atoms have recently been used as a scanning `` soft '' probe for measuring the height and position of free - standing carbon nanotubes @xcite .
experiments of this kind have so far relied on absorption imaging for measuring the atomic loss constituting the meter variable .
dispersive probing strategies hold the promise of vastly improving the data acquisition rate over such destructive detection schemes .
furthermore , atomic clouds have been envisaged for sensing the magnetic field from oscillating micro - mechanical wires carrying a current @xcite .
we believe a rabi driven , dispersively probed , prolate atomic cloud would form an interesting interface to such systems .
we thank ana rakonjac and sascha hoinka for their contribution to the construction of the trap setup and thomas mckellar for his role in developing the dispersive probing scheme .
we are grateful to peter engels , who made results of his group on phase winding in a field gradient available to us , and to andrea bertoldi for generously surrendering some spare high speed photo diodes to us . finally , nk acknowledges motivating discussions on spin waves and spinor systems with blair blakie .
65ifxundefined [ 1 ] ifx#1 ifnum [ 1 ]
# 1firstoftwo secondoftwo ifx [ 1 ] # 1firstoftwo secondoftwo `` `` # 1''''@noop [ 0]secondoftwosanitize@url [ 0 ] + 12$12 & 12#1212_12%12@startlink[1]@endlink[0]@bib@innerbibempty link:\doibase 10.1098/rspa.1932.0165 [ * * , ( ) ] link:\doibase 10.1103/physrev.51.652 [ * * , ( ) ] link:\doibase 10.1103/physrevlett.109.060401 [ * * , ( ) ] link:\doibase 10.1140/epjd / e2005 - 00251 - 1 [ * * , ( ) ] @noop _ _ ( , ) @noop _ _ ( , ) link:\doibase 10.1103/revmodphys.83.331 [ * * , ( ) ] link:\doibase 10.1016/0375 - 9601(69)90480 - 0 [ * * , ( ) ] link:\doibase 10.1038/nature01484 [ * * , ( ) ] link:\doibase 10.1364/oe.18.002190 [ * * , ( ) ] link:\doibase 10.1364/oe.16.013062 [ * * , ( ) ] link:\doibase 10.1063/1.1722572 [ * * , ( ) ] @noop _ _ ( , ) link:\doibase 10.1063/1.3470591 [ * * , ( ) ] link:\doibase 10.1063/1.4760267 [ * * , ( ) ] link:\doibase 10.1103/physreva.87.063402 [ * * , ( ) ] http://stacks.iop.org/1367-2630/10/i=5/a=053032 [ * * , ( ) ] link:\doibase 10.1103/physreva.75.033803 [ * * , ( ) ] link:\doibase 10.1088/1367 - 2630/13/8/085006 [ * * , ( ) ] link:\doibase 10.1103/physreva.86.065401 [ * * , ( ) ] link:\doibase 10.1103/physrevlett.96.043001 [ * * , ( ) ] link:\doibase 10.1103/physrevlett.100.103601 [ * * , ( ) ] link:\doibase 10.1088/1367 - 2630/13/6/065021 [ * * , ( ) ] link:\doibase 10.1103/physreva.59.4836 [ * * , ( ) ] link:\doibase 10.1103/physrevlett.102.225301 [ * * , ( ) ] http://stacks.iop.org/1464-4266/1/i=4/a=308 [ * * , ( ) ] link:\doibase 10.1126/science.273.5271.84 [ * * , ( ) ] link:\doibase 10.1103/physrevlett.79.553 [ * * , ( ) ] link:\doibase 10.1103/physrevlett.78.985 [ * * , ( ) ] link:\doibase 10.1140/epjd / e2012 - 30038 - 0 [ * * , ( ) ] link:\doibase 10.1063/1.4818913 [ * * , ( ) ] link:\doibase 10.1103/physrevlett.83.3358 [ * * , ( ) ] link:\doibase 10.1364/ao.38.006508 [ * * , ( ) ] link:\doibase 10.1103/physrevlett.89.090402 [ * * , ( ) ] link:\doibase 10.1088/1367 - 2630/12/10/103020 [ * * , ( ) ] link:\doibase 10.1103/physrevlett.88.070403 [ * * , ( ) ] link:\doibase 10.1103/physrevlett.101.150401 [ * * , ( ) ] @noop link:\doibase 10.1103/physrevlett.108.075301 [ * * , ( ) ] link:\doibase 10.1038/nature09989 [ * * , ( ) ] link:\doibase 10.1038/nphys2637 [ * * , ( ) ] link:\doibase 10.1103/physrevlett.110.250402 [ * * ( ) , 10.1103/physrevlett.110.250402 ] link:\doibase 10.1103/physrevlett.109.020407 [ * * , ( ) ] link:\doibase 10.1038/24567 [ * * , ( ) ] link:\doibase 10.1103/physrevlett.81.1539 [ * * , ( ) ] link:\doibase 10.1103/physrevlett.107.193001 [ * * , ( ) ] link:\doibase 10.1038/nature05094 [ * * , ( ) ] link:\doibase 10.1103/physrevlett.99.190402 [ * * , ( ) ] http://arxiv.org/abs/physics/9902072 [ * * , ( ) ] @noop _ _ ( , ) link:\doibase 10.1364/ol.5.000015 [ * * , ( ) ] link:\doibase 10.1088/0953 - 4075/36/3/319 [ * * , ( ) ] link:\doibase 10.1103/physreva.77.063417 [ * * , ( ) ] @noop _ _ ( , ) @noop @noop * * , ( ) @noop * * , ( ) link:\doibase 10.1103/physrevlett.88.230403 [ * * , ( ) ] link:\doibase 10.1103/physrevlett.83.3358 [ * * , ( ) ] link:\doibase 10.1103/physreva.83.013625 [ * * , ( ) ] link:\doibase 10.1038/nnano.2011.80 [ * * , ( ) ] link:\doibase 10.1021/nl203762 g [ * * , ( ) ] | we have studied the coherent evolution of ultracold atomic rubidium clouds subjected to a microwave field driving rabi oscillations between the stretched states of the @xmath0 and @xmath1 hyperfine levels .
a phase winding of the two - level system pseudo - spin vector is encountered for elongated samples of atoms exposed to an axial magnetic field gradient and can be observed directly in state - selective absorption imaging . when dispersively recording the sample - integrated spin population during the rabi drive , we observe a damped oscillation directly related to the magnetic field gradient , which we quantify using a simple dephasing model . by analyzing such dispersively acquired data from millimeter sized atomic samples ,
we demonstrate that field gradients can be determined with an accuracy of @xmath2 nt / mm .
the dispersive probing of inhomogeneously broadened rabi oscillations in prolate samples opens up a path to gradiometry with bandwidths in the kilohertz domain . | <s>[INST]two - level systems are ubiquitous in quantum physics and have been the subject of theoretical studies for almost a century @xcite .
they constitute the fundamental building blocks for quantum information processing @xcite and time keeping with atomic clocks @xcite . for such quantum enabled technologies , physical systems that display a high degree of immunity with respect to the surrounding environment are invariably sought .
a prominent example is optical lattice clocks @xcite , where magnetically insensitive `` clock - state '' atoms are confined by `` magic '' wavelength optical fields .
the addition of coupling terms ( interaction with the environment ) to the free evolution hamiltonian for a two - level system can , however , be turned to an advantage and exploited in metrology applications . in this case
, a field induced level shift is encountered , which may be measured spectroscopically .
this may form the basis of atomic magnetometers @xcite and magnetic field imaging @xcite .
two - level atoms are typically manipulated with quasi - resonant radiation fields , giving rise to dynamics equivalent to a magnetic spin-1/2 particle in a b - field @xcite .
the physics of a two - level atom in a steady field is captured by the well - known rabi solution describing the oscillation of population between the two states , which for an atom initially in its lower energy state takes the following form for the ( single atom ) population inversion @xcite @xmath3 ^ 2\sin^2\left[\omega(\delta)t/2\right],\ ] ] where @xmath4 is the on - resonance rabi frequency and @xmath5 is the generalized rabi frequency for a field detuned by @xmath6 from the transition frequency .
the on - resonance rabi frequency is the product of the driving field amplitude and the matrix element between the two states for the atom - field interaction , and may hence display spatial variation according to the intensity distribution of the electromagnetic field .
this was recently exploited to map out the magnetic microwave near - field of a coplanar waveguide by means of ultracold @xcite and hot @xcite atomic clouds .
similarly , in the far field of a horn antenna , the effect of a spatially inhomogeneous microwave drive field has also been observed for extended atomic clouds @xcite .
the dynamics of the inversion @xmath7 may also acquire a position dependence through a spatial variation of the detuning @xmath6 .
this could , for example , arise from a position dependent differential ac stark shift imposed by a laser beam @xcite or via a nonuniform magnetic field ( zeeman shift ) @xcite . in this paper
we report on dispersive probing of microwave driven rabi oscillations between two zeeman tunable hyperfine states in a prolate sample of ultracold @xmath8rb atoms .
we organize our presentation as follows . in sec .
[ section : background ] we briefly review dispersive probing schemes and their applications , and discuss approaches for imprinting magnetic order in inhomogeneously broadened samples .
section [ section : setup ] describes our experimental setup and the acquisition and processing of data . for our atomic system , a magnetic field gradient over an elongated ( prolate )
cloud leads to an inhomogeneous shift in the resonance .
this in turn gives rise to a decay in rabi oscillations when probed dispersively along its axis .
section [ section : interplay ] presents examples of such decaying waveforms , which are interpreted in a simple dephasing model and compared to complementary data acquired by means of spatially resolved state - selective absorption imaging .
here we also discuss the small but observable effect the dispersive probe beam has on the atomic sample in terms of a differential light shift , breaking the symmetry for the resulting spin texture .
we finally summarize our findings and outline potential future directions in sec .
[ section : conclusion ] .
when a beam of light of well - defined frequency passes through a gas of atoms it may be attenuated as a result of absorption , as well as shifted in phase .
dispersive detection techniques make use of the latter effect and are a very suitable tool for tracking dynamical processes in `` real time '' for cold and ultracold atomic systems . for example
, dispersive probing has been used to follow breathing @xcite and center - of - mass oscillations @xcite , and the process of forced evaporative cooling @xcite for trapped atomic clouds . moreover , coherent phenomena such as rabi oscillations between hyperfine states @xcite , larmor precession @xcite and phase space dynamics of spinor condensates @xcite have been recorded and studied dispersively .
the phase shift measurement is obtained by comparing the phase - shifted beam to a reference beam in either homodyne or heterodyne detection schemes .
for example , the former is achieved in mach - zehnder interferometers @xcite , while the latter is achieved in frequency modulation ( fm ) spectroscopy @xcite .
furthermore , dispersive probing may also take the form of polarization spectroscopy for gases in birefringent states @xcite .
the implementations listed in the preceding paragraph all make use of non - imaging photodetectors , which are generally both faster and less expensive than low noise ccd cameras @xcite , but do , of course , imply that direct spatial information imprinted on the probe light is integrated out .
spatially resolved dispersive imaging techniques for ultracold atoms have been in play since right after the achievement of bose - einstein condensates ( becs ) @xcite , with variants thereof developing subsequently @xcite .
systems with magnetic order are of fundamental importance in condensed - matter physics and an area of substantial interest .
trapped ultracold atomic gases provide a clean and highly flexible experimental test bed where to simulate such systems and have been utilized in many studies over the last 15 years or so to investigate spatial magnetic order by using atomic spin degrees of freedom . the starting point for many such experimental studies in a continuous geometry
is to expose the gas to a spatially varying coupling field , inhomogeneously driving dynamics between spin states .
for example , matthews _
et al . _
@xcite used a spatially varying rabi drive to wind up the phase of the order parameter of a two - component @xmath9 condensate and observed the subsequent unwinding owing to its kinetic energy .
the spatial variation of the coupling resulted as a combined effect of the presence of a magnetic field gradient and the accompanying variation of the two - photon rabi frequency .
similar methods were used later to excite dipole topological modes in condensates @xcite , to create spin waves in an ultracold gas above the bec transition @xcite , to observe spatial segregation in both ultracold bose gases @xcite and fermi gases @xcite . very recently , phase - winding in an elongated two - component bec was used to generate dark - bright solitons @xcite .
the phenomenon of spin waves has direct relevance to spintronics and spin caloritronics @xcite , and studies have demonstrated universal spin transport in fermi gases near the hydrodynamic regime @xcite and engineered high - quantum number spin waves @xcite .
spatially inhomogeneous coupling has been employed in @xcite to induce spin waves and study the resulting shift of the clock frequency in an atom chip experiment . in relation to this ,
there has also been substantial interest in studying two - component becs , where spatio - temporal variation of rabi coupling was employed in association with controlling the atomic interactions to study spatial mixing - demixing dynamics @xcite , spin textures following a quench @xcite and non - equilibrium dynamics @xcite . in the present paper
, we apply a phase - winding technique similar to @xcite for imprinting magnetic order in an elongated sample of ultracold atoms .
the overall magnetization @xmath10 of the ensemble exhibits itself as a density weighted integral of the local magnetization , the latter containing information about the local coupling strength .
the temporal evolution of @xmath10 has a characteristic non - exponential profile , which we map out using both dispersive and absorptive probing . from this
, the variation in local coupling strength can be inferred , making the system a prospect tool for high bandwidth magnetic and microwave field gradiometry .
our experimental setup is shown schematically in fig . [ fig : setup ] .
the ultracold atomic samples used in our experiments typically consist of @xmath11 @xmath8rb atoms in the @xmath12 ground hyperfine state , confined in a single beam far - off - resonant dipole trap @xcite .
samples are produced using a standard bec apparatus @xcite .
atoms are initially magnetically confined in a ioffe pritchard ( ip ) trap , where they are rf evaporatively cooled to temperatures @xmath13@xmath14 , close to the bec transition . the sample is then transferred to the dipole trapping potential , produced by a 1064 nm ytterbium fiber laser with typical optical power @xmath15w and a beam waist of @xmath16@xmath17 .
the confining beam propagates along the axial ( @xmath18 ) direction of the cloud , and gives rise to radial and axial trapping frequencies of @xmath19 .
the initial peak atomic density in the dipole trap is @xmath20@xmath21 . a magnetic bias field ( @xmath22 ) pointing in the @xmath18-direction lifts the degeneracy between the zeeman states and defines a quantization axis .
the field is generated with a coil pair symmetrically placed around the cloud in an approximate helmholtz configuration . the axial field produced by
the geometry is well - approximated near the center to be linear with position with a gradient @xmath23 50 mga@xmath24cm@xmath24 . while the bias field is present , a microwave coupling field , near - resonant with the @xmath26 @xmath8rb hyperfine transition , is applied to the sample for a variable duration @xmath27 .
this microwave field is generated by mixing of signals from a waveform generator ( 6.532 ghz ) and a direct digital synthesizer ( dds ) board ( @xmath28 ) using a double - balanced frequency mixer .
the mixer output is high - pass filtered to give the up - shifted ( sum ) component , which is amplified to a power of 6.5 w. a helical end - fire antenna @xcite emits circularly polarized microwave radiation towards the atomic cloud .
the antenna is positioned @xmath29 from the atoms and , due to space constraints , at an angle of @xmath30 with the @xmath18-axis .
this configuration results in a predominantly circularly polarized microwave radiation . and @xmath31 transitions spectroscopically to be @xmath32 for this antenna orientation ( taking into account the magnetic dipole matrix elements ) . ]
the variation of microwave power over the extent of the atomic cloud is less than 2% , negligible for the purposes of the studies presented below .
the emitted microwave field induces rabi oscillations between the @xmath33 and @xmath34 states with a characteristic on - resonance rabi frequency of @xmath35 khz .
we monitor the evolution of the atomic @xmath1 population of the sample during the microwave pulse dispersively , using fm spectroscopy @xcite .
to produce an optical frequency triplet for probing , a central carrier ( c ) , far from any optical transitions in @xmath8rb , is derived from an external cavity diode laser ( ecdl ) , which is locked to the @xmath36-@xmath37 crossover peak of the @xmath38 d2 transition of the @xmath39rb isotope by means of a saturated absorption spectroscopy ( sas ) setup ( see inset panel of fig . [
fig : setup ] ) .
an acousto - optic modulator ( aom ) , used to pulse the probe beam on and off , shifts the carrier up by 80mhz , such that it is blue - detuned by 1097mhz from the @xmath8rb @xmath40 transition .
the carrier is then passed through a fiber electro - optic modulator ( eom , bandwidth 10 ghz ) , which imprints a red ( r ) and a blue ( b ) sideband shifted by @xmath41 mhz from the carrier frequency , such that the red sideband is blue - detuned by 212 mhz from the @xmath8rb @xmath40 transition .
the three frequency components have approximately equal optical power ( @xmath42 each ) . a switching routine
is administered by the aom , in which a sequence @xmath43 ( with @xmath44 typically 50 300 ) of 500 ns long probe light pulses is produced at a repetition rate of 100khz .
the probe beam is focused to a waist of 65@xmath45 m onto the atoms such that the frequency triplet propagates along the axis of our atomic sample .
the probe beam is linearly polarized , and can be decomposed into right and left circularly polarized components of equal intensity , which address the @xmath46 and @xmath47 transitions , respectively .
atom - light interactions cause each frequency ( @xmath48 ) and polarization ( @xmath49 ) component to acquire a phase shift @xmath50 . for the probe beam parameters and maximum atomic column densities in the @xmath51 state specified above , we estimate @xmath52 , @xmath53 , @xmath54 , @xmath55 , @xmath56 , and @xmath57 .
the resulting optical beat signal is detected on a fast , fiber - coupled photodiode ( finisar hdf3180 - 203 , bandwidth 4.2 ghz ) and is demodulated to baseband with a local oscillator ( lo ) at @xmath58 using an iq mixer . in this way
, components both in - phase ( i ) and in - quadrature ( q ) with the lo are obtained , so the signal can be reconstructed irrespective of the lo phase .
the signals from the two mixer output ports are simultaneously sampled at 20 ms / s by a 16-bit digitizer in @xmath59 segments centered on each pulse .
the single - pulse signal - to - noise ratio of the dispersive signal for the maximum atomic numbers we use is about 20 .
our experimental sequence is ( crucially ) triggered from the rising edge of a square wave signal synchronous to the 50 hz power line frequency .
a suitable delay is chosen to ensure that the rabi drive and dispersive probing happen around a zero crossing for the residual ac magnetic field originating from power line currents @xcite .
the timing of the microwave and the dispersive probe pulses is controlled by digital delay generators , such that similar experimental conditions are realized in every experimental run
. the cloud may be additionally ( or alternatively ) probed using conventional absorption imaging at the end of the experimental sequence , after switching off the dipole trap confinement .
atoms falling under gravity are spatially separated in the vertical direction based on their magnetic moment by a stern - gerlach gradient of @xmath60 , applied for @xmath61 .
atoms are then exposed to an optical `` repumping '' pulse , which transfers @xmath0 atoms to @xmath62 via the @xmath63 ( @xmath64 ) excited state , and finally imaged with probe light resonant with the @xmath40 transition .
this procedure produces an absorption image in which the spatial distributions of the two hyperfine states originally present are clearly distinguishable ( see fig . [ fig : setup ] ) . .
the dotted black lines indicate the integration window for each sample ( note the broken axis ) .
the lower panel shows the resulting phase shift data for this data set.,title="fig : " ] + the raw data for probe pulse @xmath65 acquired by the digitizer consists of @xmath66 and @xmath67 the voltages obtained from the i and q ports of the mixer , respectively . within each data segment
we define an integration window and numerically extract the area under the probe pulse to give the processed data sets @xmath68 .
this integration is shown schematically in fig .
[ fig : pulseanalysis](a ) and fig .
[ fig : pulseanalysis](b ) , for the first three points of a typical data set showing rabi oscillations .
the phase shift @xmath69 incurred by the red probe sideband , assumed to have a low spontaneous scattering probability , can be shown to be proportional to @xmath70 for @xmath71 , which is true under our conditions .
the resulting dispersive signal , which is proportional to population of atoms in the @xmath1 state , is plotted in fig .
[ fig : pulseanalysis](c ) , with the values corresponding to the raw data shown above indicted with yellow stars .
as described in section [ section : setupa ] , our starting point for the coherent state manipulation is an ultracold sample polarized in state @xmath72 , loaded in a focused single - beam gaussian dipole trap .
the depth of the dipole trap is @xmath73@xmath45k , such that we achieve a loading efficiency close to unity .
the small atomic sample expands along the direction of the dipole trap beam .
after 40 ms expansion , for example , the cloud has a fwhm size of 1.3 mm in the axial direction and about 60 @xmath45 m along the radial direction , such that we have a quasi-1d prolate cloud of atoms .
the typical shot - to - shot number and temperature stability of the preparation of the initial atomic sample is better than 5% . ) .
the plot is an average of five consecutive experimental runs .
the atomic sample was allowed to expand for 40 ms in the horizontal trap before applying the rabi drive and the dispersive pulses .
the line is a fit of the model described in sec .
[ section : gradient_magnetimetry ] to our data.,title="fig : " ] + in fig .
[ fig : disprecord ] , we show a typical record of the dispersive interrogation of rabi oscillations of atoms driven by microwave for 2 ms .
the expansion time of the atoms in dipole trap was 40 ms prior to microwave exposure , and the data points are averages of 5 consecutive experimental runs .
the decay of the oscillation is predominantly a result of magnetic dephasing of the zeeman - sensitive states ( which leads to the formation of spin domains , as discussed in sec .
[ section : spinwave ] ) . ) absorption images acquired at times @xmath74 during the coherent microwave manipulation .
( b ) the precession of the bloch vector at the three positions of the atomic cloud shown in ( a ) . the left- and the right - hand side cases are off - resonant , and precess at faster rates .
( c ) time evolution of the sample - integrated relative population of atoms in the @xmath1 state from absorption images ( @xmath75 ) .
the line is a fit of the model described in section [ section : gradient_magnetimetry ] to our data .
the destructive measurements based on absorption imaging are time - consuming , so we limit ourselves to recording up to 1 ms of microwave manipulation . ]
we complement our dispersive data presented in section [ section : disprabi ] with spatially resolved absorption images acquired at the end of the microwave pulse .
we chose the microwave frequency to be resonant with the atoms approximately at the location of the maximum atomic density .
figure [ fig : bloch1](a ) shows state - resolved absorption images taken after projective measurements taken at times @xmath76 , where @xmath77 is one full on - resonance rabi cycle .
the emergence of `` spin domains '' is evident , and is due to the spatial variation of rabi frequency in the presence of a small field gradient . to elucidate the time evolution of the system
, we use a bloch sphere representation of the two - level system @xcite . each point on the @xmath18-axis
is described by an effective pseudo - spin vector @xmath78 precessing in a plane perpendicular to a torque vector @xmath79 , where @xmath80 and @xmath81 are the ( local ) transverse coherences and @xmath82 is the ( local ) population difference between the two states , all defined in a frame rotating at the transition frequency .
the equation of motion of the local bloch vector is @xmath83 .
figure [ fig : bloch1](b ) illustrates the time evolution of bloch vectors at three different axial locations in the cloud . at the center of the cloud , where the microwave is resonant with the atoms ,
the torque vector is along the @xmath84 axis , and the bloch vector precesses on a great circle at a rate @xmath4 , whereas away from the center , the bloch vectors precess on minor circles at a faster rate given by eq .
( [ eqrabifreq ] ) .
since the phase advance per unit time increases monotonically away from the center of the cloud , this poses a winding mechanism by which alternating domains of the spin projection @xmath82 are formed . as an illustration of this dynamics
, @xcite shows the development of the pseudo - spin projection @xmath82 across the atomic cloud obtained by subtracting the @xmath0 part from the @xmath1 part in a series of state - selective absorption images .
figure [ fig : bloch1](c ) shows the evolution of the ensemble - integrated population of atoms in the @xmath72 state from the absorption data , which exhibits a non - exponential damping of rabi oscillations mirroring our dispersive observation [ fig .
[ fig : disprecord ] ] .
we note that the time required for the absorptive data acquisition amounted to several hours , in contrast to the dispersive measurements , which only took a few minutes . of the pseudo - spin on the bloch sphere , where @xmath85 corresponds to an atom in @xmath86 ( @xmath87 ) state .
( a ) shows the theoretical plots for the cases with @xmath88mm@xmath24 shown from top to bottom .
( b ) shows the map obtained in the experimental sequence .
( c ) zooms the theoretical map corresponding to @xmath89mm@xmath24 for easy comparison with the experimental map ( see text).,title="fig : " ] + as noted in section [ section : setupa ] , the bias magnetic field in our set up is a linear function of @xmath18 at the atomic cloud , implying that ( via the zeeman effect ) the frequency detuning of the microwave field is of the form @xmath90 . since the extent of the cloud is radially small ( @xmath91 @xmath45 m ) , we assume @xmath6 to be constant in the radial direction
furthermore , the effect of mean - field interactions are considered negligible for our experimental conditions as we are in a relatively low density regime and the s - wave scattering lengths for the various spin - states involved are similar to within a few percent .
we also neglect any identical spin rotation effect @xcite in our system , as the time scale for the exchange collision @xcite at the densities involved in our experiments is @xmath92ms , which is much longer the than the time scale of the observations made in this paper . in order to gain quantitative understanding of the ensemble - integrated evolutions presented in fig .
[ fig : disprecord ] and fig .
[ fig : bloch1 ] , we numerically solved the equation of motion for @xmath93 across the cloud assuming that a linear field gradient along @xmath18-direction is present and that the center of the cloud is resonant with the microwave field .
the maps in fig .
[ fig : bloch2](a ) show the @xmath18-dependent time evolution of the `` longitudinal angle '' [ i.e. , the bloch vector polar angle @xmath94 computed for field gradients @xmath95 .
figure [ fig : bloch2](b ) shows a corresponding map based on experimentally acquired data . as is evident , the essential features of the phase - winding in our experiments are well - captured by the model based on the presence of a linear field gradient , which suggests a field gradient of around @xmath96 ( fig . [
fig : disprecord](c ) ) . figure [ fig : bloch2](b ) shows that after about @xmath97 , the temporal evolution of the atomic pseudo - spin at positions away from the center of the cloud exhibits the emergence of spurious oscillations .
the phenomenon can not be linked to detection noises or fluctuations of magnetic fields , as the center part of the cloud remains unaffected for much longer . at the current stage
we have not been able to trace out the underlying mechanism causing this . in the analysis of _ local _ rabi frequencies in sec .
[ section : ex_local_rabi ] , we therefore only make use of the first four rabi cycles . the damping of rabi oscillations in the ensemble - integrated data obtained through absorption imaging , as shown in fig .
[ fig : bloch1](c ) , and the dispersively acquired data of fig . [
fig : disprecord ] are both non - exponential and are characterized by a rapid decay in the beginning and a much slower one at later times .
such non - exponential decays are characteristic of spatial non - uniformities , and the two obvious spatially non - uniform features of our system are the local magnetic field and the atomic density .
the full model then accounts for the overall pseudo - spin vector of the ensemble as a density - weighted integral of local spins subject to local torque vectors .
in particular the population in the @xmath12 state at time @xmath98 is described by , @xmath99 where @xmath100 is the initial normalized line density of atoms , which can be inferred from an absorption image taken at @xmath101 . ) to the dispersively obtained data .
the errorbars show the 2@xmath102 confidence intervals .
insets compare the values obtained using the dispersively ( @xmath103 ) and absorptively ( ) measured time evolution.,title="fig : " ] + when fitting the model eq .
( [ model2 ] ) to the absorptive data in fig .
[ fig : bloch1](c ) , we obtain excellent agreement . from the fit
we extract an on - resonance rabi frequency of @xmath104khz and a field gradient of @xmath105khz / mm , where the numbers in brackets are the @xmath106 confidence intervals . since the model eq .
( [ model2 ] ) does not make any assumptions on how the population measurements are made , we can also apply it to the dispersive data presented in fig . [
fig : disprecord ] .
again , we obtain excellent agreement , as in the case for absorptive data .
the fitted @xmath4 and @xmath107 parameters of the model are plotted in fig .
[ figxy1](a ) and fig .
[ figxy1](b ) , respectively , for five different spatial extents of the cloud in dipole trap .
the values of the field gradient obtained in each case are in very close proximity to that obtained from the ( time - consuming ) destructive measurements ( shown in the insets along with the corresponding values obtained dispersively).(b ) ( which corresponds to a 10ms expansion time in the dipole trap after the ip trap switch - off ) results from the instability of the field due to decaying eddy currents from the ip trap switch - off . ]
there are two important mechanisms through which the dispersive probe beam perturbs the coherent evolution of the system : the spontaneous photon scattering , and the differential light shift of the spin states involved .
in contrast , the spontaneous photon scattering and the differential light shift caused by the dipole trapping beam are small and can be completely neglected for our beam parameters . the spontaneous photon scattering results from off - resonantly populating excited atomic states during the probe pulse @xcite . for our experimental parameters
, we estimate the mean number of spontaneously scattered photons from a probe pulse ( frequency triplet ) to be about @xmath108 per atom .
this amounts to less than 0.1% of the atoms scattering a photon over 100 dispersive pulses . in our experiment
, we have about @xmath109 probe photons per pulse ( about one photon per atom ) in the red sideband of the probing triplet , and the time scale over which the decay due to spontaneously scattered photons becomes important is @xmath110 ms or longer . in the absence of light ) . without light , the bloch vectors precess about @xmath111 as encountered in fig .
[ fig : bloch1](b ) . with light pulses applied periodically , precession about @xmath112
is interleaved into this evolution , effectively decrease the cycle time for @xmath113 ( @xmath114 ) and a negative ( positive ) gradient .
( c ) the effective local rabi frequency versus @xmath18 for the cases of a negative and a positive linear field gradient and a homogeneous light shift .
also shown is the hyperbola eq .
( [ eqrabifreq ] ) symmetric about @xmath115 that describes _ both _ negative and positive field gradients in the absence of a light shift.,title="fig : " ] + we quantify the differential light shift induced by the probe beam by the ( local ) dimensionless quantity @xmath116 , where @xmath117 is the ( local ) differential light shift caused by the probe and @xmath118 is the duration of each probe pulse . for the parameters used in our experiments , the maximum differential light shift is @xmath119khz , and the corresponding @xmath120 . due to the gaussian intensity profile of the probe beam ,
the differential light shift varies across the atomic sample .
the rayleigh range is @xmath121 cm for the probe beam , which is an order of magnitude higher the axial size of the atomic sample .
this means that the light shift along this direction is essentially homogeneous . in order to gain insight into the physical process
, we again make use of the bloch sphere picture .
locally , the dispersive atom - light interaction during a probe pulse causes a rotation of the bloch vector with respect to the @xmath122-axis by an angle @xmath123 . for blue - detuned probe light ( as in our case )
, @xmath123 is positive .
when applied during the coherent microwave evolution , a series of probe pulses effectively shifts the bloch vector away from the circle on which its tip would otherwise lie , as illustrated in fig .
[ fig : dephasing2](a ) and in fig .
[ fig : dephasing2](b ) , in the presence of negative and positive field gradients , respectively .
consequently , for a positive ( negative ) field gradient , the resonance moves to the left ( right ) along the cloud .
this notion is reasserted in fig .
[ fig : dephasing2](c ) which shows the calculated local rabi frequencies along the @xmath18-direction in the presence of light pulses for both positive and negative field gradients , obtained by numerically solving the bloch equation , and assuming @xmath124 and @xmath125 khz .
-axis ( axial direction of the atomic sample ) in the presence of a positive magnetic field gradient .
the symmetry encountered in the absence of a perturbing light shift ( @xmath126 ) is broken when a _ radially _ inhomogeneous light field of increasing strength @xmath127 is applied .
in addition to a translation of the minimum also found in the homogenous case fig .
[ fig : dephasing2](c ) , the inhomogeneity leads to a `` tilt '' .
( b ) characteristic dephasing decay time @xmath128 versus position .
, title="fig : " ] + the radial size of our atomic cloud ( @xmath91@xmath45 m ) is comparable to the waist of the dispersive beam ( @xmath129@xmath45 m ) , which means that the considerations from sec .
[ section : dephasing_homogeneous ] need to be extended to include the effect of inhomogeneous light shift in the radial direction . for a given axial position @xmath18 ,
atoms at various radial distances experience different light shifts @xmath117 , which results in radially dependent azimuthal phase shifts on the bloch sphere during a probe pulse .
this leads to _ local _ dephasing at a given axial position .
the time evolution of the collective pseudospin vector @xmath130 for each point @xmath18 is the sum of the time evolution of the bloch vector for each radial position @xmath131 weighted by @xmath132 , the ( normalized ) local radial atomic density , @xmath133 .
we numerically solved this equation for @xmath130 for different values of the peak differential light shift @xmath134 while assuming a positive magnetic field gradient .
we summarize the results in terms of the distributions of local effective rabi frequency and the dephasing decay time in fig .
[ fig : dephasing3 ] . as is evident from fig .
[ fig : dephasing3](a ) , the radially inhomogeneous light shift leads to a breaking of symmetry of the local rabi frequency about the minimum point ( a `` tilt '' ) .
it also shows that the collective pseudospin vector on the right ( left ) side of the cloud precesses faster ( slower ) in the presence of dispersive pulses causing faster ( slower ) spin dynamics on the right ( left ) side of the elongated atomic sample with respect to the unperturbed case .
figure [ fig : dephasing3](b ) shows that for the probe pulse parameters used in our experiments ( @xmath124 ) , the expected characteristic decay time @xmath128 owing to the dephasing caused by the inhomogeneous light shift is much longer than the time scale of the coherent manipulation and dispersive interrogation in our experiment ( within the relevant length scale ) .
finally , we make a local analysis on the series of state resolved absorption images taken after various microwave exposure times in the absence and presence of dispersive probe pulses . figure [ figxy2](a ) and fig .
[ figxy2](b ) show the absorption images taken at @xmath135 in the two cases , respectively , revealing a clear breaking of symmetry for the latter case .
we divide the time series of absorption images in the two cases into equal sized bins and count the number of atoms in each state residing in a bin . from this the time evolution of the population in each bin is constructed and we extract the local ( effective ) rabi frequency for each bin .
the results are presented in fig .
[ figxy2](c ) for the case of a @xmath136 m bin size . evidently , dispersive probe pulses cause a small shift of the minima and break the symmetry of the curve , a result of the accompanying differential light shift of the transition , as discussed in sec .
[ section : dephasing_homogeneous ] and sec .
[ section : dephasing_inhomogeneous ] .
in particular , a behavior akin to that predicted by fig .
[ fig : dephasing3](a ) is encountered .
the inset of fig .
[ figxy2](c ) shows the corresponding local detuning @xmath137^{1/2}$ ] , where @xmath4 is the minimum of @xmath138 for the two cases .
the sign of the slope of @xmath138 is determined to be _ positive _ based on the directions of the `` shift '' and the `` tilt '' of the hyperbolic shape of fig .
[ figxy2](c ) for the dispersively probed case following the reasoning of sec .
[ section : dephasing_inhomogeneous ] .
the values of @xmath107 obtained from the corresponding linear fits [ @xmath139 khz / mm for the unperturbed case and @xmath140 khz / mm for the dispersively probed case ] are in very good agreement with each other and with the values obtained in the two sample - integrated procedures ( dispersive and absorptive ) presented in sec .
[ section : gradient_magnetimetry ] .
in this paper we have investigated a heterodyne , dispersive optical probing scheme applied to elongated ultracold rubidium clouds residing in an inhomogeneous magnetic field .
a zeeman shift gives rise to axial dephasing when driving near - resonant rabi oscillations between two hyperfine states . with the dispersive probe , the resulting decay in net polarization / magnetization of the sample
could be followed in `` real time '' . in particular , the dispersively
observed non - exponential washing out of rabi oscillations was described well by a simple model from which a value of the magnetic field gradient could be extracted .
this value for the magnetic field gradient was in excellent correspondence with complementary measurements based on absorption images . for our demonstration
we applied a field gradient of about 500 nt / mm , leading to a center - to - edge change in rabi frequency of @xmath141 from the @xmath142 khz central and on - resonance rabi frequency .
fitting our model function over a time interval @xmath143 ms ( yielding more than 10 cycles ) allows us to determine this gradient to within 25 nt .
this underscores the potential to perform gradient magnetometry to this accuracy with a @xmath144kilohertz bandwidth using the dispersive probing approach based on a single experimental run .
the absorption images of prolate clouds at the end of the rabi drive revealed the formation of ( continuous ) magnetic order along the sample similar to previously reported findings @xcite , but also how the small but finite light shift from the dispersive probe breaks the symmetry of the spin patterns .
we used this to the effect of determining the sign of the applied magnetic field gradient .
as outlined in sec .
[ section : backgroundb ] there is significant interest in spin dynamics of ultracold atomic systems , and we speculate if this mechanism can be employed for spin wave engineering similar to @xcite .
we finally point towards possible future applications of the experimental scheme outlined in this paper , in the context of probing microscopic structures .
for example , atoms have recently been used as a scanning `` soft '' probe for measuring the height and position of free - standing carbon nanotubes @xcite .
experiments of this kind have so far relied on absorption imaging for measuring the atomic loss constituting the meter variable .
dispersive probing strategies hold the promise of vastly improving the data acquisition rate over such destructive detection schemes .
furthermore , atomic clouds have been envisaged for sensing the magnetic field from oscillating micro - mechanical wires carrying a current @xcite .
we believe a rabi driven , dispersively probed , prolate atomic cloud would form an interesting interface to such systems .
we thank ana rakonjac and sascha hoinka for their contribution to the construction of the trap setup and thomas mckellar for his role in developing the dispersive probing scheme .
we are grateful to peter engels , who made results of his group on phase winding in a field gradient available to us , and to andrea bertoldi for generously surrendering some spare high speed photo diodes to us . finally , nk acknowledges motivating discussions on spin waves and spinor systems with blair blakie .
65ifxundefined [ 1 ] ifx#1 ifnum [ 1 ]
# 1firstoftwo secondoftwo ifx [ 1 ] # 1firstoftwo secondoftwo `` `` # 1''''@noop [ 0]secondoftwosanitize@url [ 0 ] + 12$12 & 12#1212_12%12@startlink[1]@endlink[0]@bib@innerbibempty link:\doibase 10.1098/rspa.1932.0165 [ * * , ( ) ] link:\doibase 10.1103/physrev.51.652 [ * * , ( ) ] link:\doibase 10.1103/physrevlett.109.060401 [ * * , ( ) ] link:\doibase 10.1140/epjd / e2005 - 00251 - 1 [ * * , ( ) ] @noop _ _ ( , ) @noop _ _ ( , ) link:\doibase 10.1103/revmodphys.83.331 [ * * , ( ) ] link:\doibase 10.1016/0375 - 9601(69)90480 - 0 [ * * , ( ) ] link:\doibase 10.1038/nature01484 [ * * , ( ) ] link:\doibase 10.1364/oe.18.002190 [ * * , ( ) ] link:\doibase 10.1364/oe.16.013062 [ * * , ( ) ] link:\doibase 10.1063/1.1722572 [ * * , ( ) ] @noop _ _ ( , ) link:\doibase 10.1063/1.3470591 [ * * , ( ) ] link:\doibase 10.1063/1.4760267 [ * * , ( ) ] link:\doibase 10.1103/physreva.87.063402 [ * * , ( ) ] http://stacks.iop.org/1367-2630/10/i=5/a=053032 [ * * , ( ) ] link:\doibase 10.1103/physreva.75.033803 [ * * , ( ) ] link:\doibase 10.1088/1367 - 2630/13/8/085006 [ * * , ( ) ] link:\doibase 10.1103/physreva.86.065401 [ * * , ( ) ] link:\doibase 10.1103/physrevlett.96.043001 [ * * , ( ) ] link:\doibase 10.1103/physrevlett.100.103601 [ * * , ( ) ] link:\doibase 10.1088/1367 - 2630/13/6/065021 [ * * , ( ) ] link:\doibase 10.1103/physreva.59.4836 [ * * , ( ) ] link:\doibase 10.1103/physrevlett.102.225301 [ * * , ( ) ] http://stacks.iop.org/1464-4266/1/i=4/a=308 [ * * , ( ) ] link:\doibase 10.1126/science.273.5271.84 [ * * , ( ) ] link:\doibase 10.1103/physrevlett.79.553 [ * * , ( ) ] link:\doibase 10.1103/physrevlett.78.985 [ * * , ( ) ] link:\doibase 10.1140/epjd / e2012 - 30038 - 0 [ * * , ( ) ] link:\doibase 10.1063/1.4818913 [ * * , ( ) ] link:\doibase 10.1103/physrevlett.83.3358 [ * * , ( ) ] link:\doibase 10.1364/ao.38.006508 [ * * , ( ) ] link:\doibase 10.1103/physrevlett.89.090402 [ * * , ( ) ] link:\doibase 10.1088/1367 - 2630/12/10/103020 [ * * , ( ) ] link:\doibase 10.1103/physrevlett.88.070403 [ * * , ( ) ] link:\doibase 10.1103/physrevlett.101.150401 [ * * , ( ) ] @noop link:\doibase 10.1103/physrevlett.108.075301 [ * * , ( ) ] link:\doibase 10.1038/nature09989 [ * * , ( ) ] link:\doibase 10.1038/nphys2637 [ * * , ( ) ] link:\doibase 10.1103/physrevlett.110.250402 [ * * ( ) , 10.1103/physrevlett.110.250402 ] link:\doibase 10.1103/physrevlett.109.020407 [ * * , ( ) ] link:\doibase 10.1038/24567 [ * * , ( ) ] link:\doibase 10.1103/physrevlett.81.1539 [ * * , ( ) ] link:\doibase 10.1103/physrevlett.107.193001 [ * * , ( ) ] link:\doibase 10.1038/nature05094 [ * * , ( ) ] link:\doibase 10.1103/physrevlett.99.190402 [ * * , ( ) ] http://arxiv.org/abs/physics/9902072 [ * * , ( ) ] @noop _ _ ( , ) link:\doibase 10.1364/ol.5.000015 [ * * , ( ) ] link:\doibase 10.1088/0953 - 4075/36/3/319 [ * * , ( ) ] link:\doibase 10.1103/physreva.77.063417 [ * * , ( ) ] @noop _ _ ( , ) @noop @noop * * , ( ) @noop * * , ( ) link:\doibase 10.1103/physrevlett.88.230403 [ * * , ( ) ] link:\doibase 10.1103/physrevlett.83.3358 [ * * , ( ) ] link:\doibase 10.1103/physreva.83.013625 [ * * , ( ) ] link:\doibase 10.1038/nnano.2011.80 [ * * , ( ) ] link:\doibase 10.1021/nl203762 g [ * * , ( ) ][/INST] we have studied the coherent evolution of ultracold atomic rubidium clouds subjected to a microwave field driving rabi oscillations between the stretched states of the @xmath0 and @xmath1 hyperfine levels .
a phase winding of the two - level system pseudo - spin vector is encountered for elongated samples of atoms exposed to an axial magnetic field gradient and can be observed directly in state - selective absorption imaging . when dispersively recording the sample - integrated spin population during the rabi drive , we observe a damped oscillation directly related to the magnetic field gradient , which we quantify using a simple dephasing model . by analyzing such dispersively acquired data from millimeter sized atomic samples ,
we demonstrate that field gradients can be determined with an accuracy of @xmath2 nt / mm .
the dispersive probing of inhomogeneously broadened rabi oscillations in prolate samples opens up a path to gradiometry with bandwidths in the kilohertz domain . </s> |
interest in tomosynthesis and its clinical applications has been revived by recent advances in digital x - ray detector technology . in tomosynthesis , an x - ray tube and an x - ray receptor
tomosynthesis captures only one set of discrete x - ray projections that can be used to reconstruct any plane of the object retrospectively .
this article will review and identify indications for x - ray digital linear tomosynthesis ( dlt ) .
the chest phantom ( n-1 type , kyoto kagaku co. , tokyo , japan ) and the artificial pulmonary nodules of type n1 are depicted in the images [ figures 1 and 2 ] .
the artificial pulmonary nodules were of the ground - glass opacity type ( 5 and 7 mm ) , and the spheres were of the same diameter and composition .
for the dual - energy evaluation study , calcification was simulated using hydroxyapatite ( powder type ) .
the relationship between the radiation attenuation properties of glass and those of real pulmonary nodules was correlated .
tomosynthesis ( sonialvision safire ii , shimadzu co. , kyoto , japan ) and ct ( 64-slice somatom definition scanner ; siemens medical systems , forchheim , germany ) images of the artificial pulmonary nodules ( ground - glass opacity type ) .
the quality of the images obtained by tomosynthesis imaging were clearer than those obtained by ct ( ct slice thickness : 5 mm ) .
des - tomosynthesis and des radiography ( sonialvision safire ii ) of the same slice , demonstrates the content of the artificial pulmonary nodules with and without calcification .
the high - contrast detectability phantom case having a clear , contrast detectability on des - tomosynthesis imaging produced for identical planes ( tomosynthesis acquisition angle : 40 ) .
owing to its high sensitivity , normal - dose helical computed tomography ( ct ) is currently considered the gold standard for lung cancer detection .
early reports indicate that low - dose helical ct has the potential to detect early lung cancer , and thus decrease morbidity .
ct has the advantage of improved detection of lesion by eliminating visual clutter of overlying anatomy [ figure 1 ] .
however , there are disadvantages of using ct when compared with chest radiography , such as high - radiation dose and cost . on the other hand , although chest radiography has advantages such as short examination time , low cost , and easy access , there are also important disadvantages such as low sensitivity and specificity . in chest radiography , the three - dimensional chest is projected onto a two - dimensional image .
consequently , the ability to detect pathological findings is limited by the overlapping anatomy rather than by quantum noise .
chest radiography has been shown to have a relatively low sensitivity for the detection of pulmonary nodules .
the poor sensitivity of chest radiography precludes its use as a screening modality , despite its advantages of low cost , low dose , and wide distribution of devices .
dlt is a method that provides some of the tomographical benefits of ct at a reduced radiation dose and cost and with an approach that can be easily implemented in conjunction with chest radiography .
current state of dlt originates from the older technique of geometric tomography , which has largely fallen out of favor in chest imaging owing to positioning difficulty , high radiation dose , and residual blur from out - of - plane structures .
dlt overcomes the difficulties of geometric tomography by permitting reconstruction of numerous slices of the image from a single low - dose acquisition of image data [ figure 1 ] .
although improving detection of pulmonary nodules may be an early area of emphasis for the application of tomosynthesis , it also has potential for use in other areas of thorax imaging.[12 ]
presence of calcification and stability of the mass over 2 years suggest its benign nature . a benign pattern of the calcifications has been considered necessary to exclude malignancy . in the evaluation of diffusely
disseminated pulmonary nodules , identification of diffusely disseminated pulmonary nodules and calcifications in the nodules has been helpful in limiting the differential diagnosis .
conventional radiography and conventional tomography have been used to detect calcifications , but they have been largely replaced by ct .
however , ct has several inherent problems , including motion artifacts and the variety of reconstruction algorithms that are used by different ct scanners . dual energy subtraction ( des ) imaging has been proposed and investigated by many researchers as a means of reducing the impact of anatomic noise on disease detection by chest radiography .
des involves making two radiographical projections of the patient using different energy x - ray beams . by exploiting the difference in the energy dependence of attenuation between bone and soft tissue ,
the bone contrast can be reduced to produce a soft tissue image and the contrast of the soft tissue can be reduced to produce a bone image .
des digital radiography has been found to be useful in detecting calcifications within pulmonary masses .
main drawback of the des technique , is that its projections may result in overlap of anatomical features ( e.g. , calcifications superimposed over the ribs or spine ) .
des dlt is a new technique , and therefore there is no guidance for its integration into the clinical practice of chest radiography .
the most reliable signs for discriminating between benign and malignant masses are the growth rate of the mass and presence or absence of calcifications within the mass .
since calcifications are commonly observed in benign masses and no other radiographical characteristic is specific in characterizing a mass , it is important to detect and characterize calcification within lesions . using des dlt , the presence , distribution , and characteristics of calcifications in lung nodules can be assessed to an extent that is not possible with currently available ct imaging and projection - type des techniques .
in addition , this technique is not susceptible to the problems of image overlap , partial volume effect , or shifting of the image plane [ figures 2 and 3 ] . calcified tuberculous foci in a 74-year - old man .
comparison of the chest images obtained with x - ray radiography , digital tomosynthesis , des - tomosynthesis , and high - resolution ct ( hr - ct ) .
des - tomosynthesis and hr - ct appear to have similar accuracy in detecting calcification in the pulmonary nodules .
ideally , structures in a given plane of interest should be clearly displayed in the corresponding tomosynthesis reconstruction plane , whereas structures located outside of that plane should not be visible .
essentially , the limited angular range of the tomosynthesis image acquisition geometry dictates that spatial resolution is limited in the dimension perpendicular to the detector plane . as a result
, out - of - plane structures can not be completely removed from the reconstruction plane and are present in every such plane
. however , most of these structures are not visible because various low - amplitude structures from projections overlap in the reconstruction plane , and therefore , appear blurred .
out - of - plane structures from high - attenuation features can not be blurred and appear as multiple replicates in every reconstruction plane , except for the one in which the actual high - attenuation feature ( e.g. , rib ) is located . at one projection angle , these ghosting features are distributed along the line made by the x - ray source and the actual feature [ figure 4 ] . out - of - plane
structures are present in every reconstruction plane , but most are not visible because the various low - amplitude structures from projections overlap each other in the reconstruction plane , and therefore are blurred .
tomosynthesis is worthy of further evaluation because it is flexible and can accurately reproduce the shape of an artificial pulmonary nodule .
tomosynthesis can be considered the modality of choice to detect and investigate simulated artificial pulmonary nodules with and without calcification . | the purpose of this paper is to identify indications for volumetric x - ray digital linear tomosynthesis ( dlt ) with single- and dual - energy subtraction techniques for artificial pulmonary nodule detection and compare x - ray dlt , x - ray digital radiography , and computed tomography . | <s>[INST]interest in tomosynthesis and its clinical applications has been revived by recent advances in digital x - ray detector technology . in tomosynthesis , an x - ray tube and an x - ray receptor
tomosynthesis captures only one set of discrete x - ray projections that can be used to reconstruct any plane of the object retrospectively .
this article will review and identify indications for x - ray digital linear tomosynthesis ( dlt ) .
the chest phantom ( n-1 type , kyoto kagaku co. , tokyo , japan ) and the artificial pulmonary nodules of type n1 are depicted in the images [ figures 1 and 2 ] .
the artificial pulmonary nodules were of the ground - glass opacity type ( 5 and 7 mm ) , and the spheres were of the same diameter and composition .
for the dual - energy evaluation study , calcification was simulated using hydroxyapatite ( powder type ) .
the relationship between the radiation attenuation properties of glass and those of real pulmonary nodules was correlated .
tomosynthesis ( sonialvision safire ii , shimadzu co. , kyoto , japan ) and ct ( 64-slice somatom definition scanner ; siemens medical systems , forchheim , germany ) images of the artificial pulmonary nodules ( ground - glass opacity type ) .
the quality of the images obtained by tomosynthesis imaging were clearer than those obtained by ct ( ct slice thickness : 5 mm ) .
des - tomosynthesis and des radiography ( sonialvision safire ii ) of the same slice , demonstrates the content of the artificial pulmonary nodules with and without calcification .
the high - contrast detectability phantom case having a clear , contrast detectability on des - tomosynthesis imaging produced for identical planes ( tomosynthesis acquisition angle : 40 ) .
owing to its high sensitivity , normal - dose helical computed tomography ( ct ) is currently considered the gold standard for lung cancer detection .
early reports indicate that low - dose helical ct has the potential to detect early lung cancer , and thus decrease morbidity .
ct has the advantage of improved detection of lesion by eliminating visual clutter of overlying anatomy [ figure 1 ] .
however , there are disadvantages of using ct when compared with chest radiography , such as high - radiation dose and cost . on the other hand , although chest radiography has advantages such as short examination time , low cost , and easy access , there are also important disadvantages such as low sensitivity and specificity . in chest radiography , the three - dimensional chest is projected onto a two - dimensional image .
consequently , the ability to detect pathological findings is limited by the overlapping anatomy rather than by quantum noise .
chest radiography has been shown to have a relatively low sensitivity for the detection of pulmonary nodules .
the poor sensitivity of chest radiography precludes its use as a screening modality , despite its advantages of low cost , low dose , and wide distribution of devices .
dlt is a method that provides some of the tomographical benefits of ct at a reduced radiation dose and cost and with an approach that can be easily implemented in conjunction with chest radiography .
current state of dlt originates from the older technique of geometric tomography , which has largely fallen out of favor in chest imaging owing to positioning difficulty , high radiation dose , and residual blur from out - of - plane structures .
dlt overcomes the difficulties of geometric tomography by permitting reconstruction of numerous slices of the image from a single low - dose acquisition of image data [ figure 1 ] .
although improving detection of pulmonary nodules may be an early area of emphasis for the application of tomosynthesis , it also has potential for use in other areas of thorax imaging.[12 ]
presence of calcification and stability of the mass over 2 years suggest its benign nature . a benign pattern of the calcifications has been considered necessary to exclude malignancy . in the evaluation of diffusely
disseminated pulmonary nodules , identification of diffusely disseminated pulmonary nodules and calcifications in the nodules has been helpful in limiting the differential diagnosis .
conventional radiography and conventional tomography have been used to detect calcifications , but they have been largely replaced by ct .
however , ct has several inherent problems , including motion artifacts and the variety of reconstruction algorithms that are used by different ct scanners . dual energy subtraction ( des ) imaging has been proposed and investigated by many researchers as a means of reducing the impact of anatomic noise on disease detection by chest radiography .
des involves making two radiographical projections of the patient using different energy x - ray beams . by exploiting the difference in the energy dependence of attenuation between bone and soft tissue ,
the bone contrast can be reduced to produce a soft tissue image and the contrast of the soft tissue can be reduced to produce a bone image .
des digital radiography has been found to be useful in detecting calcifications within pulmonary masses .
main drawback of the des technique , is that its projections may result in overlap of anatomical features ( e.g. , calcifications superimposed over the ribs or spine ) .
des dlt is a new technique , and therefore there is no guidance for its integration into the clinical practice of chest radiography .
the most reliable signs for discriminating between benign and malignant masses are the growth rate of the mass and presence or absence of calcifications within the mass .
since calcifications are commonly observed in benign masses and no other radiographical characteristic is specific in characterizing a mass , it is important to detect and characterize calcification within lesions . using des dlt , the presence , distribution , and characteristics of calcifications in lung nodules can be assessed to an extent that is not possible with currently available ct imaging and projection - type des techniques .
in addition , this technique is not susceptible to the problems of image overlap , partial volume effect , or shifting of the image plane [ figures 2 and 3 ] . calcified tuberculous foci in a 74-year - old man .
comparison of the chest images obtained with x - ray radiography , digital tomosynthesis , des - tomosynthesis , and high - resolution ct ( hr - ct ) .
des - tomosynthesis and hr - ct appear to have similar accuracy in detecting calcification in the pulmonary nodules .
ideally , structures in a given plane of interest should be clearly displayed in the corresponding tomosynthesis reconstruction plane , whereas structures located outside of that plane should not be visible .
essentially , the limited angular range of the tomosynthesis image acquisition geometry dictates that spatial resolution is limited in the dimension perpendicular to the detector plane . as a result
, out - of - plane structures can not be completely removed from the reconstruction plane and are present in every such plane
. however , most of these structures are not visible because various low - amplitude structures from projections overlap in the reconstruction plane , and therefore , appear blurred .
out - of - plane structures from high - attenuation features can not be blurred and appear as multiple replicates in every reconstruction plane , except for the one in which the actual high - attenuation feature ( e.g. , rib ) is located . at one projection angle , these ghosting features are distributed along the line made by the x - ray source and the actual feature [ figure 4 ] . out - of - plane
structures are present in every reconstruction plane , but most are not visible because the various low - amplitude structures from projections overlap each other in the reconstruction plane , and therefore are blurred .
tomosynthesis is worthy of further evaluation because it is flexible and can accurately reproduce the shape of an artificial pulmonary nodule .
tomosynthesis can be considered the modality of choice to detect and investigate simulated artificial pulmonary nodules with and without calcification .[/INST]the purpose of this paper is to identify indications for volumetric x - ray digital linear tomosynthesis ( dlt ) with single- and dual - energy subtraction techniques for artificial pulmonary nodule detection and compare x - ray dlt , x - ray digital radiography , and computed tomography .</s> |
in the following section it will be seen that we do not yet understand what determines the gravitational potentials within the universe on scales from galaxies upwards .
one suggestion is that the universe is full of material that does not emit electromagnetic radiation and which is thus hard to
see. there are a tremendous number of ideas on offer to resolve the dark matter dilemma .
these ideas cover modifications to the laws of gravity , cold conventional matter , new particles , neutrinos with non - zero mass , and exotic objects , to name just a few .
, there is no absolutely clear solution , although a number of the possibilities do lend themselves to experimental
some of the experiments are designed to look for direct signatures , i.e. the physical interaction of a dark matter particle in a detector , while others are looking for indirect evidence , such as the neutrino or -ray flux due to dark matter particle annihilations .
in addition , other types of experiments are looking for circumstantial evidence , such as the measurement of a non - zero neutrino mass in the right range , or confirmation of supersymmetry ( susy ) .
a number of the direct and indirect searches will be digging deeply into theoretically very interesting regions of parameter space over the next five years .
indeed there is , at this time , one experimental result from a direct search that has a signal consistent with the most optimistic susy predictions concerning neutralinos which just might be proven correct .
while it is true to say that most activity is currently targeted at what might be called the standard cosmological model , this model is not without its difficulties as a theory , and experimental evidence from dedicated dark matter searches could be crucial in finally clarifying the situation .
experimental searches probably are the only way to find out unambiguously what the milky way is made of .
the evidence is reviewed in section 2 , including subsection 2.2 on the standard cosmological model .
this leads to section 4 on direct and indirect detection requirements and techniques for non - baryonic dark matter .
most experiments are being carried out in the context of theoretical expectations for the neutralino , which most regard as the best motivated of the particle candidates .
a review of the current status of projects world - wide will be given in section 6 .
finally , in section 7 there is a discussion of the next logical steps for experimental searches for dark matter .
the existence of dark matter is inferred from astrophysical observations that probe gravitational potentials . the mass content required to provide the derived gravitational potential is then compared with the visible mass content .
several types of observation allow this to be done and in most cases the mismatch between the required mass and the observed mass is extreme .
the following list summarises some of the evidence that has been accumulated :
studies of the dynamics of stars in the local disk environment gave rise to the first suggestion of missing matter nearly 70 years ago [ 99 , 100 ] . the kinetic energy associated with the motion of these stars normal to the plane of the milky way
since the first work by oort , a number of further studies have given conflicting results .
however , even if present , this particular disk dark matter is not significant compared with the halo component.rotation curves for a large number of spiral galaxies have now been reliably established and it is observed that the orbital velocities of objects ( stars , globular clusters , gas clouds , etc . ) tend to a constant value , independent of the radial position r , even for objects out toward , and even far beyond , the edge of the visible disks .
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\begin{document}$$1/\sqrt r$$\end{document } behaviour expected from newtonian mechanics , assuming most mass is in the central part of the galaxies .
according to newtonian mechanics , the mass density within these galaxies is only declining as r , leading to a total mass that actually continues to increase proportional to r.within the local group of galaxies , the milkyway and andromeda ( m31 ) are approaching each other at a much faster pace than can be explained by gravitational attraction of the visible mass . to explain the approach velocity , and indeed the fact that these two galaxies are not still moving away from each other as part of the hubble expansion , requires each to have masses that are consistent with those deduced from their rotation curves.many clusters of galaxies show extended x - ray emission .
this is usually attributed to a thin plasma of hot gas . on the assumption that the hot gas is gravitationally bound to the cluster and in equilibrium
( i.e. we have a virial system ) , the gravitational potential energy can be inferred from the kinetic energy budget of the hot gas .
the cluster mass determined in this way is much higher than that seen either visibly or in the gas itself.gravitational lensing by clusters of galaxies causes images of more distant galaxies to be distorted and often split into multiple images .
the gravitational mass of the lens ( i.e. the cluster ) , and its distribution , can be recovered through detailed analysis of the image pattern surrounding the cluster .
the lenses show a far more extended spatial extent than the visible cluster.galaxy red - shift surveys have revealed large - scale galaxy - cluster streaming motions superimposed on the hubble expansion .
attempts to explain this due to gravitational attraction resulting from the overall distribution of galaxy superclusters give the right direction of motion but need more than the observed visible masses in the superclusters to explain the speed of motion
.
the next four items are not really at the same level of simple observational evidence as those above , as they require reliance on a more convoluted path to determine masses involved .
however , the first three of these have received a great deal of effort and are now heavily used as a combined strong argument in favour of the existence of dark matter , and indeed have resulted in a consensus view of standard cosmology over the past few years .
the large scale structure ( lss ) of the universe
can be studied using large surveys of distant galaxies , by measuring their spatial distribution and peculiar motions .
there is an extensive industry in n - body simulations trying to explain the lss and large - scale dynamics in terms of gravitational growth of small perturbations present in the early universe .
the only simulations that give reasonable agreement with observation are those that use a matter density somewhat higher than currently thought allowable in visible matter . indeed ,
starting from the level of the cobe observations of the density fluctuations ( 10 ) at the time of recombination ( z=1000 ) , for gravitational instability to lead to galaxy formation on a reasonable timescale it seems necessary to invoke a significant dark matter component , which only interacts gravitationally.type ia supernovae can be used as standard candles to determine distances , independently of red - shift to high red - shift galaxies in which they occur .
the implications of the results will be discussed later , but consistent cosmological models seem to require a dark matter component.the cobe satellite gave us the first measurement of the amplitude of microwave background anisotropies at the time of recombination .
it is these perturbations which subsequently grow through gravitational instabilities to form the large - scale structure seen today .
recently , new results have determined the angular power spectrum of the microwave background anisotropies at much finer angular scales , where enhancements are expected due to acoustic wave resonances in the early universe .
a clear first peak is seen in the data and its position favours a dark matter component .
even second and third peaks look to be emerging and the amplitudes and positions of these provide constraints on various cosmological parameters ( this will be discussed in more detail in the following section).for those who believe in inflation , most surviving models naturally have a density equal to the critical density , which exceeds that possible in visible matter .
with such a large volume of evidence there can be no doubt that there is a real mystery to be unravelled here .
ideally , it would be satisfying if there were a single simple solution that explained all the above .
this has proven elusive so far , but recently there has been some convergence on models that address the larger scale issues to do with the universe as a whole , and this is discussed in the next subsection .
the main aim is to establish a consensus opinion on the dark matter fraction , and more specifically the cold dark matter fraction , as this motivates most of the experimental searches for dark matter . in doing this
we will see that a strong argument for a standard cosmology , with cold dark matter as one of its components , is beginning to become established .
however , some issues clearly hint at aspects of the cosmology that have yet to be properly resolved , and some of these do have potentially serious implications for the cold dark matter component .
studies of the dynamics of stars in the local disk environment gave rise to the first suggestion of missing matter nearly 70 years ago [ 99 , 100 ] . the kinetic energy associated with the motion of these stars normal to the plane of the milky way
since the first work by oort , a number of further studies have given conflicting results .
however , even if present , this particular disk dark matter is not significant compared with the halo component .
rotation curves for a large number of spiral galaxies have now been reliably established and it is observed that the orbital velocities of objects ( stars , globular clusters , gas clouds , etc . ) tend to a constant value , independent of the radial position r , even for objects out toward , and even far beyond , the edge of the visible disks .
this is quite inconsistent with the \documentclass[12pt]{minimal }
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\begin{document}$$1/\sqrt r$$\end{document } behaviour expected from newtonian mechanics , assuming most mass is in the central part of the galaxies . according to newtonian mechanics , the mass density within these galaxies is only declining as r , leading to a total mass that actually continues to increase proportional to r. within the local group of galaxies , the milkyway and andromeda ( m31 ) are approaching each other at a much faster pace than can be explained by gravitational attraction of the visible mass . to explain the approach velocity , and indeed the fact that these two galaxies are not still moving away from each other as part of the hubble expansion , requires each to have masses that are consistent with those deduced from their rotation curves
this is usually attributed to a thin plasma of hot gas . on the assumption that the hot gas is gravitationally bound to the cluster and in equilibrium ( i.e. we have a virial system ) ,
the gravitational potential energy can be inferred from the kinetic energy budget of the hot gas .
the cluster mass determined in this way is much higher than that seen either visibly or in the gas itself .
gravitational lensing by clusters of galaxies causes images of more distant galaxies to be distorted and often split into multiple images .
the gravitational mass of the lens ( i.e. the cluster ) , and its distribution , can be recovered through detailed analysis of the image pattern surrounding the cluster .
galaxy red - shift surveys have revealed large - scale galaxy - cluster streaming motions superimposed on the hubble expansion .
attempts to explain this due to gravitational attraction resulting from the overall distribution of galaxy superclusters give the right direction of motion but need more than the observed visible masses in the superclusters to explain the speed of motion .
the large scale structure ( lss ) of the universe can be studied using large surveys of distant galaxies , by measuring their spatial distribution and peculiar motions .
there is an extensive industry in n - body simulations trying to explain the lss and large - scale dynamics in terms of gravitational growth of small perturbations present in the early universe .
the only simulations that give reasonable agreement with observation are those that use a matter density somewhat higher than currently thought allowable in visible matter . indeed ,
starting from the level of the cobe observations of the density fluctuations ( 10 ) at the time of recombination ( z=1000 ) , for gravitational instability to lead to galaxy formation on a reasonable timescale it seems necessary to invoke a significant dark matter component , which only interacts gravitationally .
type ia supernovae can be used as standard candles to determine distances , independently of red - shift to high red - shift galaxies in which they occur .
the implications of the results will be discussed later , but consistent cosmological models seem to require a dark matter component .
the cobe satellite gave us the first measurement of the amplitude of microwave background anisotropies at the time of recombination .
it is these perturbations which subsequently grow through gravitational instabilities to form the large - scale structure seen today .
recently , new results have determined the angular power spectrum of the microwave background anisotropies at much finer angular scales , where enhancements are expected due to acoustic wave resonances in the early universe .
a clear first peak is seen in the data and its position favours a dark matter component .
even second and third peaks look to be emerging and the amplitudes and positions of these provide constraints on various cosmological parameters ( this will be discussed in more detail in the following section ) . for those who believe in inflation , most surviving models naturally have a density equal to the critical density , which exceeds that possible in visible matter . within the context of a big bang creation scenario in which an inflationary phase is followed by expansion within the confines of general relativity , there are at least 11 parameters that define a cosmological model in the post inflation era .
these 11 + parameters affect what happens in the first few minutes during which nucleosynthesis of the lightest elements occurs ( bbn ) , how the geometry of space - time develops , and how structure forms through gravitational enhancement of primordial density inhomogeneities which come out of the inflationary phase .
the density inhomogeneities will leave an imprint on the microwave background radiation that survives from the era of recombination , some 300,000 years after the big bang . subsequently , they grow through gravitational instability to give rise to the structure we see in the distribution of visible objects in the universe today . hence , by bringing together observations that relate to bbn , space - time evolution , microwave background anisotropies , and large - scale structure , it is possible to define inter - related regions of the 11 parameter phase space that are consistent with all the information .
tegmark , zalderriaga , and hamilton did this just after the first release of new cmb data from boomerang and maxima .
the parameter space used was
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\begin{document}$$
\left ( { \tau , { \omega _ k},{\omega _ \lambda } , { \omega _ { \rm{d}}},{\omega _ { \rm{b}}},{f_\nu } , { n_{\rm{s}}},{n_{\rm{t}}},{a_{{\rm{s,}}}}r , b } \right )
$ $ \end{document }
where is the reionisation optical depth , as , ns , r , nt are the primodial amplitudes and tilts of the scalar and tensor inhomogeneities , b is a bias factor relating rms galaxy fluctuations to the underlying rms matter fluctuations , k and are the contributions to the overall density from curvature and the cosmological constant , d and b are the physical densities of dark matter ( both hot and cold together ) and baryonic matter , and finally f is the fraction of dark matter in the form of hot dark matter . the primary observational data that they used were all available cmb data and the recently released iras point source catalogue redshift survey ( pscz ) from which they derived the large scale structure power spectrum .
simultaneous fits were then done to these data allowing all 11 parameters to vary .
table 1allowable ranges of values of density parameters within the standard cosmological model derived from the first release cmb data of boomerang and maxima ( left - hand column , ) with corresponding values ( where quoted ) from the newest data sets ( right - hand column , ) .
h is the hubble parameter and values of 0.740.08 and 0.720.08 were used in and , respectively.0.490.740.490.760.20m0.500.11hd0.170.09hd0.170.00hhdm0.120.10hcdm0.320.20hb0.0370.01hb0.03
allowable ranges of values of density parameters within the standard cosmological model derived from the first release cmb data of boomerang and maxima ( left - hand column , ) with corresponding values ( where quoted ) from the newest data sets ( right - hand column , ) .
h is the hubble parameter and values of 0.740.08 and 0.720.08 were used in and , respectively .
table 2.2 shows the acceptable range of values for the key parameters that came out of those fits . in the table
the matter density , \documentclass[12pt]{minimal }
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\begin{document}$${\omega _ { \rm{m } } } = { \omega _ { \rm{b } } } + { \omega _ { { \rm{cdm } } } } + { \omega _ { { \rm{hdm}}}},$$\end{document } , includes both baryonic matter and dark matter , and moreover the dark matter can be classed either as hot or cold depending on whether it was relativistic or not in the early universe .
the total dark matter density is \documentclass[12pt]{minimal }
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\begin{document}$${\omega _ { \rm{d } } } = { \omega _ { { \rm{hdm } } } } + { \omega _ { { \rm{cdm}}}}$$\end{document } , and hd=d . of particular note for this review were that the cold dark matter density is non - zero and that the baryonic density has a range that just accomodates the constraints from bbn at its lowest end , but with significantly better fits for higher values .
very recently there have been significant new cmb data released from boomerang , maxima , dasi , and cbi .
these data have given better definition to the second and third peaks in the cmb power spectrum .
wang , tegmark and zaldarriaga subsequently repeated the above analysis using a combination of these and previously available cmb data .
the two left - hand plots in the top row in figure 1 are the most relevant for the dark matter .
we see that the dark matter density is again non - zero , with a similar range of values as before , and that the fraction of dark matter as hot dark matter is less than 35% , assuming no constraints on the hubble parameter , h. the allowable fraction of hot dark matter drops to only 20% if the preferred hubble parameter value is imposed . the right - hand column in table 2.2 lists
while previously the allowable range of b was only just compatible with the upper limit derived from bbn , it now comfortably embraces it .
this is illustrated in the left - hand panel in figure 2 , which shows the combined constraints on the baryonic matter and dark matter densities .
the white central region is the allowed parameter space when all constraints are applied , except for bbn of course .
relaxing the constraints by not using the pscz data enlarges the allowed region to include the cyan coloured area .
if , in addition , no assumptions are made about the value of the hubble constant , then the green area also becomes allowed .
if all constraints are accepted then figure 2 implies there is between 4.5 and 9 times as much dark matter in the universe as there is baryonic matter .
figure 1allowable parameter spaces for , k , b , d , f ,
and r. the figure is taken from and the dashed lines mark the 95% confidence limits .
figure 2the left - hand panel from shows the joint constraints on the baryonic matter and dark matter densities , together with the allowed band of baryonic density from bbn models .
the right - hand panel from shows the joint constraints on and m
which result from combined use of cmb data and high - redshift supernova data .
allowable parameter spaces for , k , b , d , f ,
and r. the figure is taken from and the dashed lines mark the 95% confidence limits . the left - hand panel from shows the joint constraints on the baryonic matter and dark matter densities , together with the allowed band of baryonic density from bbn models .
the right - hand panel from shows the joint constraints on and m
which result from combined use of cmb data and high - redshift supernova data .
constraints on cosmological models can also be derived from the observations of high red - shift type 1a supernovae . when combined with data from the cmb anisotropies ,
these limits give reasonable agreement with those cited earlier in table 2.2 . a recent result from de bernardis et al .
the solid curves are the 1 to 3 combined likelihood contours and these can be compared with the values in the table . a somewhat weaker constraint on the hubble constant was used .
hence , from the above , there does indeed seem to be a cosmological model that can simultaneously satisfy all the observational evidence used .
the ranges of values for the key parameters relevant to dark matter searches have been summarized in table 2.2 .
numerous n - body simulations have been performed to verify whether structure formation occurs properly in a number of different types of models .
simulations of gravitational collapse on the scale of galaxies have resulted in universal rotation curves that match reasonably well those observed in a wide range of galaxies [ 94 , 95 ] . from table 2.2
the main features of the emerging standard cosmology from the point of view of dark matter are :
a cdm scenario where the dominant energy density is from .the matter density m greatly exceeds that which can be present in a baryonic form , and hence there is a significant dark matter component.the dark matter density d is mostly comprised of cold dark matter.n - body simulations suggest that galaxies are comprised of similar mixes of baryonic matter and dark matter as the universe as a whole .
the origin of remains a topic of current debate , with a great deal of interest in quintessence [ 29 , 9 ] .
a cdm scenario where the dominant energy density is from . the matter density m greatly exceeds that which can be present in a baryonic form , and hence there is a significant dark matter component .
n - body simulations suggest that galaxies are comprised of similar mixes of baryonic matter and dark matter as the universe as a whole .
although the argument in section 2.2 is very persuasive and does present a formally consistent picture there are a number of concerns that continue to require attention .
firstly , it can be seen from table 2.2 that , prior to the latest cmb data , the consistency between bbn and the cmb and lss constraints was marginal . as a result of this a number of routes that allow for higher baryon density
the most recent of these invoked a degenerate bbn scenario in which additional light neutrinos ( either sterile or degenerate ) are allowed .
such a high baryon density would negate the need for dark matter . while it is comforting ( to some ) to see the new cmb data apparently removing this discrepancy , the data themselves are still not high - precision and some aspects of the data reduction remain uncertain . a second issue has arisen from high resolution n - body simulations [ 96 , 57 , 90 ] .
these simulations seem to be showing a more peaked cdm enhancement toward galaxy centres than the previous work [ 94 , 95 ] and more sub - structure in the cdm halos themselves .
there is increasing evidence that indeed the predictions are incompatible with observational data [ 26 , 112 , 21 , 43 , 80 ] .
possible ways of softening the central profile include allowing the dark matter to interact more readily , either with itself ( self - interacting cdm ) or with baryonic matter .
although the n - body simulations themselves appear robust in general , in central regions where there are few
thirdly , it can be seen that the type ia supernovae data are crucial in determining the value of . central to this is the question of whether the optical light - curves can really be used as standard candles , or whether reddening is playing a role here , as quite small amounts of absorption could significantly affect the results .
this suggestion has been countered recently by the observation of a very highredshift ( z1.7 ) supernova which is actually brighter than expected , even in a no - dust scenario .
its increased brightness is shown to be consistent with an early deceleration phase of the universe .
finally , there is a class of model in which gravity itself is assumed to be modified [ 86 , 85 ] .
a large number of effects attributed to dark matter have been addressed using modified gravity with the most recent being an analysis of the latest cmb aniostropy data . in this latest work
it is claimed that 1 with bm ( consistent with standard bbn ) is the favoured model .
however , the result rests heavily on the apparent absence of a second peak in the cmb data from boomerang ; maxima-1 data are not included .
at the moment the totality of cmb data does not constrain the second peak sufficiently strongly to rule out a significant cdm component .
it was argued in section 2.2 that there is a clear need for dark matter . in addition , it seems the baryonic density must be very close to the maximum allowed by bbn .
this last fact raises another interesting requirement in that the current best estimate places the baryonic density in the visible content of galaxies and cluster gas as \documentclass[12pt]{minimal }
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\begin{document}$${\omega _ { \rm{v } } } \sim \left ( { 2.2 + 0.6{h^ { - 1.5 } } } \right ) \times { 10^ { - 3 } } \sim 0.003$$\end{document}. this is well below the range given in table 2.2 and implies that there is a lot more baryonic matter yet to be found .
this missing baryonic matter is also generally referred to as dark matter . in the following sections the possible forms of both the baryonic and non - baryonic dark matter will be reviewed .
table 2 , adapted from carr ( 1990 ) , summarizes some of the types of objects that have been suggested as dark matter .
table 2
possible dark matter candidates ( adapted from [
30
] )
.
non - baryonicbaryonicaxions(10 ev)snowballs?neutrinos(10 ev)brown dwarfs(0.08m)wimps(110 gev)m - dwarfs(0.1m)monopoles(10 gev)white dwarfs(1m)planck relics(10 gev)neutron stars(2m)primordial black holes(>10 g)stellar black holes(10m)quark nuggets(<10 g)very massive objects(1010m)shadow matter?super massive objectscosmic strings?cold diffuse gas
possible dark matter candidates ( adapted from [
30
] ) .
figure 3 illustrates the scale - lengths on which the various dark matter candidates might be significant .
the dark grey areas are strongly disallowed on theoretical grounds , whilst the lighter grey areas are unlikely but not rigorously excluded . in the next two sections a very brief discussion of the main baryonic and non - baryonic candidates is given .
carr ( 2000 ) and turner ( 1999 ) have given more detailed reviews .
figure 3
possible scale - lengths where different types of dark matter might be present , based on a similar representation which appeared in [
30
] .
possible scale - lengths where different types of dark matter might be present , based on a similar representation which appeared in [
30
] .
according to the standard model
, baryonic dark matter is required to make up the difference between the visible matter density v and the baryon density b required by standard bbn models .
exactly where these baryons might be hiding depends on the nature of the objects being studied . for high redshifts
> 3 , most of the baryons might still be in the form of an intergalactic medium still in the process of collapse , while recent data from a large sample of nearby x - ray emitting clusters of galaxies have shown that for these clusters most of the baryon fraction f is in the surrounding hot gas of the intracluster medium ( icm ) .
indeed , if it is assumed that the cluster matter has the same fraction of baryonic matter as the universe as a whole , i.e.
fb/m , then it seems that the icm accounts for baryons up to the required bbn levels in these clusters . on the scale of individual galaxies
-cdm n - body simulations ( see figure 4 ) suggest the halo composition should follow the underlying matter distribution of the universe but with some enhancement of the baryonic proportion through more efficient dissipative collapse .
figure 4
high - resolution n - body simulation of a galactic dark matter halo [
90
] .
high - resolution n - body simulation of a galactic dark matter halo [
90
] .
this naturally leads to the conclusion that there is probably unseen baryonic matter in galaxies , but that it is unlikely to be sufficient to entirely explain the rotation curves .
the brown dwarf ( bd ) candidate entry in figure 3 includes any compact object with masses below 0.08m. many searches have been carried out looking for these massive compact halo objects ( machos ) using microlensing data .
although a number of candidate microlensing events have been seen , the apparent mass determinations for the lenses and their locations cast doubt on whether the lenses are indeed machos in the halo of the milky way .
the most recent estimates put the most likely macho contribution to the halo at 20% , and the masses of these objects appear to be 0.5m. this suggests a population of white dwarfs and might indicate an early epoch of star formation in the galactic halo .
to explain all the dark matter with compact objects larger than brown dwarfs would have produced too many heavy elements during their evolution as stars prior to collapse and so these are still excluded as halo baryons in figure 3 , at least as far as providing the bulk of the galactic dark matter . however , above 10m , super massive objects ( smos ) might collapse immediately to black holes .
smos would still produce microlensing effects and would also give rise to dynamical effects , such as the heating of disk stars and the disruption of globular clusters .
finally , it remains possible in principle that cold clouds with masses 10m might provide some of the halo dark matter [ 104 , 140 , 141 ] .
it can be seen that the standard model still allows for a small hdm component .
the neutrino would fulfill this if it had a non - zero mass , as suggested by recent experimental results from super - kamiokande [ 51 , 71 ]
. however , most of the dark matter will be cold dark matter ( cdm ) .
the best motivated of the various suggested candidates are two particles that were already invoked for other reasons .
these are the axion and the lightest supersymmetric particle ( neutralino ) , which is a member of the generic family of weakly interacting massive particles ( wimps ) .
, the level of cp violation seen in the k0 decay would give rise to a neutron electric dipole moment in excess of the limits already established .
the allowable mass range for the axion is constrained by astrophysical arguments to 10 to 10 ev / c .
wimps are naturally predicted in supersymmetry theories in which a higher level symmetry is obtained in the particle families by introducing new particles to match each of the known particles . in the so - called minimal supersymmetry models ( mssm ) ,
the lightest supersymmetric particle ( lsp ) is likely to be a neutralino , which is a mixture of two neutral gauginos and two neutral higgsinos :
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\chi = \chi _ 1 ^ 0 = { f_{11}}{w^3 } + { f_{12}}b + { f_{13}}{h_1 } + { f_{14}}{h_2}.
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there are numerous parameters required to specify a particular mssm configuration .
it turns out that there is a wide range of parameter space in which the production and annihilation rates in the early universe are such that lspcdm .
the mass range for neutralinos is 46 gev / cm2000 gev / c , where the lower limit comes from accelerator data from lep .
experimental searches for dark matter invariably are trying to detect cold dark matter within our own galaxy .
thus , it is useful to review at this stage the current thoughts about the distribution of cold dark matter within the milky way and , for terrestrial based experiments , the likely cold dark matter presence near earth .
figure 5 shows both the observational data on the rotation curve and a recent determination of various mass components .
figure 5
the rotation curve of the milky way . in the left - hand panel
are the measured rotation speeds given by the average values from a number of measurements on different objects [
50
] .
the right hand panel shows the various mass components that combine together to reproduce the observed curve between 5 and 25 kpc [
72
] .
the dotted lines are the bulge and disk contributions , and the short - dashed curve is the dark matter contribution .
the solid curve shows the combined effect of all three , and this is compared to the long - dashed curve which approximates the measured data in the left - hand panel below 25 kpc .
the rotation curve of the milky way . in the left - hand panel are the measured rotation speeds given by the average values from a number of measurements on different objects [
50
] .
the right hand panel shows the various mass components that combine together to reproduce the observed curve between 5 and 25 kpc [
72
] .
the dotted lines are the bulge and disk contributions , and the short - dashed curve is the dark matter contribution .
the solid curve shows the combined effect of all three , and this is compared to the long - dashed curve which approximates the measured data in the left - hand panel below 25 kpc .
at the position of the sun , 7.58 kpc
, it can be seen that the contributions to the enclosed mass from the bulge , the disk , and the dark matter halo are comparable . in these types of studies , the dark matter halo is assumed to be in a quasi - spherically symmetric distribution in virialised equilibrium .
the halo is usually taken to be non - rotating and the local density comes out as 0.3 gev / cm .
the velocity distribution of the dm particles is assumed to be maxwellian with an upper cut - off at the galactic escape velocity .
most calculations of event rates and energy deposits in detectors are done assuming this straight forward type of dm halo .
possible modifications to this simple dm geometry include :
a modified radial cdm density profile giving a much lower cdm local density .
. a much larger number of events have been seen than expected and this suggests an unseen stellar population within the solar radius that can apparently account for the local rotation speeds without the need for dark matter .gravitational clustering of cdm particles at the centres of massive objects , such as the sun , the earth , or the galactic centre.cdm halos with non - zero angular momentum.clumpy cdm galaxy halos [ 57 , 90 , 92].non - equilibrium situations with on - going cdm infall into the galaxy [ 116 , 115].non - equilibrium situations with on - going cdm infall into the local cluster / supercluster.cdm scattered into stable orbits around the sun .
a modified radial cdm density profile giving a much lower cdm local density .
a much larger number of events have been seen than expected and this suggests an unseen stellar population within the solar radius that can apparently account for the local rotation speeds without the need for dark matter .
gravitational clustering of cdm particles at the centres of massive objects , such as the sun , the earth , or the galactic centre .
non - equilibrium situations with on - going cdm infall into the galaxy [ 116 , 115 ] .
non - equilibrium situations with on - going cdm infall into the local cluster / supercluster .
there are a number of previous reviews on general techniques used for dark matter searches [ 105 , 119 , 131 ] .
direct searches depend on dark matter particles actually passing through detectors and physically interacting with them .
indirect searches look for secondary products produced when dark matter particles annihilate each other elsewhere .
direct searches can , in principle , be used to look for neutrinos , axions and wimps , whereas only wimps are accessible indirectly .
wimp particle - antiparticle annihilations can produce neutrinos , -ray , antiprotons , and positrons .
for neutrinos and -rays the signal rates expected depend on the wimmp - antiwimp densities .
susy neutralinos ( the wimps on which most attention is fixed ) are their own antiparticles and the annihilation process can be represented as ff or ww or zz , where f=, , c , b , t with c , b , t being quarks .
neutrino signal rates can be enhanced by the trapping of wimps in massive bodies , such as the sun , earth , or galactic centre ; the wimp density builds up until the annihilation rate equals the capture rate . for the sun
this equilibrium situation has already been reached . for earth this may not yet be the case and annihilation fluxes
the capture rate will depend on the scattering rates for wimps on the various nuclear species in the body and the energy transfer per scatter .
the scattering rate on a particular species will depend on the abundance of the species and the cross - section .
the scattering cross - sections are usually calculated within mssm constraints , abundances depend on which body the wimps are being trapped in , and energy transfer per collision normally assumes elastic scattering with the wimps starting out with a typical virial speed of 10c for particles bound to the galaxy .
once capture rates , and hence annihilation rates , have been derived , the neutrino flux is calculated from the branching ratios for wimp annihilations going into neutrinos .
neutrino products are typically in the gev energy range and are hence accessible to existing solar neutrino experiments . however , for contained events ( ones in which the muons produced by the neutrinos are stopped in the detector ) the predicted rates rc are a few events for kiloton of detector per year , while traversing signals ( muons produced in surrounding rocks and passing through the detector ) occur at a rate rt0.1rce(a/10 ) yr . a is the detector area in cm .
early studies of -ray signatures from wimp annihilation predicted both continuum emission from 0 products , and line features from z and direct wimp annihilation into photons [ 129 , 130 , 49 ] .
continuum emission fluxes were predicted to be about two orders of magnitude lower than the diffuse galactic background .
line emission features should be much easier to see above the background as long as good energy ( e / e1% ) is available .
antiproton fluxes from wimp annihilation were expected to produce measurable enhancements above typical background fluxes in the low - energy antiproton spectrum ( < 1 gev ) , which would be accessible to space instruments such as ams .
however , it is now thought that there will be additional background fluxes that will make this type of measurement difficult .
. these may be visible as bumps in the otherwise smooth background spectrum due to cosmic - ray interactions with interstellar gas .
signals are expected to be much below the background levels , and long - duration space missions will be needed to collect sufficient statistics to observe the positrons . although there have been a number of suggestions for experiments to detect neutrinos [ 119 , 123 ] ( residual primordial hot dark matter now gravitationally bound to the galaxy ) , none can yet achieve sufficient sensitivity .
axions , on the other hand , are amenable to direct detection , although it is challenging to fully explore the whole of the theoretically available parameter space . among particles proposed to solve the cp violation problem ,
axions can be converted completely into photons in what is essentially a two - photon interaction . in experiments to detect galactic dark - matter axions the second photon is provided by an intense ambient electromagnetic field .
the photon created has an energy equal to the total energy of the axion ( rest mass plus kinetic energy ) .
as noted earlier , the dark matter energy density at the position of the earth is about 0.3 gev / cm . the preferred mass range for the axion is between 10 and 10 ev / c , although there is a second window between 2 and 5 gev / c .
the lower limit of the preferred mass range keeps m1 , while the upper limit prevents excessive energy - loss mechanisms in stars and supernovae due to axion production and loss .
if the galactic dark matter is axions , then their local density is between 310 and 310 cm . with a virial velocity distribution ( 10c ) ,
the flux through a terrestrial detector is enormous , but unfortunately the two - photon conversion process is very weak . in an ambient 6 tesla field
each axion has a conversion probability around 10 per second , and the photon produced has an energy in the microwave region ( 2200 ghz ) .
such an experiment requires a tuned high - q cavity , tunable over the projected axion mass / energy range , with a sensitivity of around 10 w. two early experiments of this type [ 93 , 84 , 63 ] have been followed by a number of second generation instruments , and the preferred axion mass window has been closed over a very small range at its lowest end ( 2.910 to 3.310 ev / c ) at the 90% confidence level for ksvz axions .
a variant on the tuned cavity technique is to incorporate rydberg atoms into the cavity where the |n to |n transition is also resonant with the cavity .
in addition to the direct dark matter axion searches , there are a number of experiments looking for evidence of axion existence , such as axion telescopes pointed at the sun and torsion balance instruments looking for short - range weak force spin - coupling interactions of the type mediated by the axion [ 122 , 98 , 114 , 134 ] .
neutralinos have received by far the most attention and there are an enormous range of techniques being used to search for these particles [ 119 , 132 , 6 ] .
the basic questions that need to be addressed to assess the feasibility of detection of wimps in the halo of our galaxy are :
how often will scattering events occur?how much energy will they deposit?how easy will it be to separate any real signal from background and to convincingly prove that a signal has been seen , i.e. what characteristic signatures are expected ?
each of these three issues are dealt with in some detail for the neutralino of the mssm in the following sections .
how easy will it be to separate any real signal from background and to convincingly prove that a signal has been seen , i.e. what characteristic signatures are expected ?
the scattering rate per unit detector volume rt depends on the local density of dark matter particles nw ; their velocity distribution relative to a detector in a terrestrial laboratory nw(v ) , and the velocity dependent scattering cross - section v , via the usual equation
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{ r_t } = \int_0^\infty { { n_w}(v){n_t}{\sigma _ t}(v)vdv , }
$ $ \end{document }
where nt is the number density of nuclei of species t in the detector . the local number density of wimp particles is \documentclass[12pt]{minimal }
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\begin{document}$${n_w } = \int_0^\infty { { n_w}(v)dv = { \rho _ { { \rm{cdm}}}}/{m_w}}$$\end{document } , where mw is the wimp mass and cdm is the assumed local cold dark matter density . the wimp velocity distribution and the cross - section both have a wide range of uncertainty , which makes accurate predictions impossible .
the preferred range for mw in the context of the lightest stable neutralino within minimal mssm is 20 to 200 gev / c [ 110 , 111 ] , and han and hempfling quote a lower mass limit from lep data as 46 gev / c . in the simplest models the dark matter density distribution in the halo of the galaxy
is taken to be a spherical 1/r ( at least for large r ) distribution with a local density , at the position of the solar system , of 0.3 gev / cm .
the velocity distribution is taken to be a maxwellian , consistent with a virialised system but truncated above the galactic escape velocity .
models involving non - spherical density distributions , rotating halos [ 44 , 73 ] , and/or non - virial velocity distributions , such as galactic in - fall components with cusps or bound solar - system earth - crossing components , can individually give factor - of - two differences in the predicted scattering rates . the wimp velocity distribution as seen by a terrestrial detector has a bias imposed by the earth s velocity through the halo and its spin .
this produces a temporal modulation of the apparent wimp velocity distribution , which results in an annual modulation of the wimp scattering rate and recoil spectrum , and daily and annual modulations in the directional distributions .
different neutralino models , within mssm or sugra ( supergravity ) , exhibit an enormous range of interaction strengths that can be pure axial in nature ( coupling only to nuclei with non - zero spin ) , pure coherent ( coupling to all nucleons ) , or any combination of the two .
figure 6 shows the allowed range of parameter space for the scattering cross - sections .
the plot has been produced using output from the darksusy code , using up to 65 free parameters . even in this plot
reasonable assumptions have been made in allowing the parameters to vary ; ellis relaxes some of these and , not surprisingly , finds a wider range of resulting cross - sections .
the cross - sections are normalised to one nucleon ; to calculate the total cross - section for a target nucleus with n neutrons and nuclear spin j requires a scaling as (n/2 ) for the coherent spin - independent part of the cross - section and s2
j(j+1 ) for the spin - dependent part .
figure 6
total neutralino elastic scattering cross - section normalised to one nucleon for a range of neutralino models within mssm and msugra , taken from [
79
] .
the pink area corresponds to a neutralino in a dominantly bino state , the green bounded area is dominantly higgsino .
the cross - section includes both spin - independent and spin - dependent contributions , and in general the spindependent part is likely to be larger .
total neutralino elastic scattering cross - section normalised to one nucleon for a range of neutralino models within mssm and msugra , taken from [
79
] .
the pink area corresponds to a neutralino in a dominantly bino state , the green bounded area is dominantly higgsino .
the cross - section includes both spin - independent and spin - dependent contributions , and in general the spindependent part is likely to be larger .
form factor effects , which arise due to the finite size of the nucleus , are significant for the heavier target nuclei , are different for axial and coherent scattering , and again have uncertainties [ 47 , 107 ] . predicted event rates typically range from 10 to 10 events / day / kg . to achieve sensitivity to such rare events
requires low - background instruments operating in well shielded underground environments . the predicted differential observable recoil spectrum , assuming a standard virial maxwellian velocity distribution , is of the form
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{ \left .
{ \frac{{dr}}{{de } } } \right|_{{\rm{obs}}}}\propto \frac{{{r_0}}}{{f{e_0}r}}{e^ { - e/(f{e_0}r)}}{f^2}(e ) ,
$ $ \end{document }
where f is the quenching factor which reflects the relative efficiency with which the nuclear recoil energy is recorded in the signal channel compared to a -ray of the same energy .
e0 is the characteristic energy for the virialized wimp population , f is the form factor referred to previously , and r is a kinematic factor dependent on the relative masses of the wimp and target nuclei .
somewhat more complex formulae result when modified velocity distributions are used ( e.g. incorporating a galactic cut - off ) , or the rate is convolved through the instrument response .
a falling recoil spectrum with a maximum recoil energy 100 kev is expected . for larger target nuclei , such as iodine
-rays emitted from nuclear relaxation can be self - absorbed in the detector producing characteristic spectral lines .
experiments of this sort have been performed [ 15 , 52 , 18 ] ; the cross - sections are much lower than the elastic ones and the technique will not be discussed further .
a crucial quality of instruments and techniques is their ability to look for the signatures expected from wimp scattering interactions .
there are , in fact , a number of specific characteristics to be looked for , including :
a characteristic ( but featureless ) recoil spectrum ( following equation ( 4 ) ) that depends on target nuclear mass and spin.events distributed uniformly throughout the detector.an expected annual modulation in both the event rate and the recoil spectrum ( since a component of the earth s orbital velocity around the sun effectively adds to and subtracts from the solar system orbital velocity around the galactic centre).an expected daily modulation in the scattering rate due to wimp scattering by the earth s effectively shadowing the incident flux .a directional modulation in detector co - ordinates on daily and yearly bases for detectors locked to the earth s surface.site-independent wimp parameters provided by the wimp signal.characteristic properties
for each scattering event , where the instruments being used have an intrinsically different response to wimp nuclear recoil events as opposed to other backgrounds . for example :
wimp scattering should be single - site , whereas -ray and neutron background can be multi - site .
anti - coincidence veto systems are often used by ionization / scintillation detectors to provide multi - site signalsnuclear recoil events characteristic of wimp scattering produce different linear ionisation densities , which can result in different production ratios and different rates at which subsequent secondary processes occur .
this can produce different pulse shapes for nuclear recoils as opposed to x - ray and -ray background events .
this technique is commonly used in scintillation type experiments.similarly , the different linear ionisation densities can affect the relative efficiency with which energy propagates into different signal channels . for example
, the pulse height ratios between scintillation and ionisation signals are often used.similarly , higher linear ionization density implies a much shorter range for the nucleus before it loses all its energy .
imaging scintillation instruments or time projection chambers can make use of this .
in the next section
the various techniques on offer will be reviewed in order of increasing complexity in their ability to exploit specific wimp signatures .
a characteristic ( but featureless ) recoil spectrum ( following equation ( 4 ) ) that depends on target nuclear mass and spin .
an expected annual modulation in both the event rate and the recoil spectrum ( since a component of the earth s orbital velocity around the sun effectively adds to and subtracts from the solar system orbital velocity around the galactic centre ) .
an expected daily modulation in the scattering rate due to wimp scattering by the earth s effectively shadowing the incident flux . a directional modulation in detector co - ordinates on daily and yearly bases for detectors locked to the earth s surface .
properties for each scattering event , where the instruments being used have an intrinsically different response to wimp nuclear recoil events as opposed to other backgrounds .
for example :
wimp scattering should be single - site , whereas -ray and neutron background can be multi - site .
anti - coincidence veto systems are often used by ionization / scintillation detectors to provide multi - site signalsnuclear recoil events characteristic of wimp scattering produce different linear ionisation densities , which can result in different production ratios and different rates at which subsequent secondary processes occur .
this can produce different pulse shapes for nuclear recoils as opposed to x - ray and -ray background events .
this technique is commonly used in scintillation type experiments.similarly , the different linear ionisation densities can affect the relative efficiency with which energy propagates into different signal channels .
for example , the pulse height ratios between scintillation and ionisation signals are often used.similarly , higher linear ionization density implies a much shorter range for the nucleus before it loses all its energy .
wimp scattering should be single - site , whereas -ray and neutron background can be multi - site .
anti - coincidence veto systems are often used by ionization / scintillation detectors to provide multi - site signals nuclear recoil events characteristic of wimp scattering produce different linear ionisation densities , which can result in different production ratios and different rates at which subsequent secondary processes occur .
this can produce different pulse shapes for nuclear recoils as opposed to x - ray and -ray background events .
similarly , the different linear ionisation densities can affect the relative efficiency with which energy propagates into different signal channels .
for example , the pulse height ratios between scintillation and ionisation signals are often used .
similarly , higher linear ionization density implies a much shorter range for the nucleus before it loses all its energy .
imaging scintillation instruments or time projection chambers can make use of this . from the above dicussion
it can be seen that an ideal detector would have :
energy threshold < 1 kev.good energy resolution , to be able to see subtle modulations in the recoil spectrum.high ability to discriminate between nuclear recoil events and background events.low-background construction and site for operation.high target mass to ensure a sufficiently high wimp count rate.stable operation over a number of years .
energy threshold < 1 kev . good energy resolution , to be able to see subtle modulations in the recoil spectrum .
the first instruments to be used for wimp searches were solid state germanium ionisation type detectors .
these recorded high - resolution background energy spectra , which were then compared to the expected wimp recoil spectra to establish upper limits on interaction cross - sections ( assuming the galactic dark matter was indeed made of wimps in a straightforward spherical virialised distribution ) .
figure 7 shows examples of such spectra and the coherent limits obtained from a number of experiments of this type .
the background spectra can be coarsely characterised by two parameters , which are the threshold and the count rate just below threshold .
these approximately determine how low in wimp mass the instrument sensitivity extends and how low a crosssection limit can be set respectively .
this can be seen by comparing the cosme and twin curves in the two panels of figure 7 .
the difference between the cosme and twin background spectra is due to the use of freshly mined germanium in the production of twin , which consequently does not show the cosmogenically activated line just below 9 kev .
an alternative way of achieving the same suppression of the cosmogenic lines is to use enriched germanium as done by the heidelberg / moscow experiment .
the sierra grande curve in figure 7 is from a long exposure germanium experiment in which a search for both daily and annual modulation has been performed [ 1 , 2 ] , and the results from the daily modulation search are shown in figure 8 .
an example of an annual modulation search is shown in the right - hand panel of the figure .
the next advance expected from germanium detectors of this type will be from the heidelberg group who are developing a high - purity natural germanium crystal surrounded by an active veto that also uses natural germanium .
this will exploit the fact that any wimp scattering events will be single - site due to the very low scattering cross - section , while most other background events will be multi - site ( e.g. multiple elastic neutron scattering or multiple compton scattering for -rays ) .
figure 7
background energy spectra for two ge detectors of the pnl / usc / zaragoza group taken from [
28
] ( a upper panel ) .
coherent crosssection upper limits from ge detectors taken from [
1
] ( b lower panel ) .
figure 8
background rate from 428.1 days of data binned in 10-minute intervals and folded to look for daily modulation [
1
] ( a upper panel ) .
results of an annual modulation search using
4 years of data from the dama experiment [
16
] ( lower panel ) .
background energy spectra for two ge detectors of the pnl / usc / zaragoza group taken from [
28
] ( a upper panel ) .
coherent crosssection upper limits from ge detectors taken from [
1
] ( b lower panel ) .
background rate from 428.1 days of data binned in 10-minute intervals and folded to look for daily modulation [
1
] ( a upper panel )
. results of an annual modulation search using
4 years of data from the dama experiment [
16
] ( lower panel ) .
the next most common type of instrument in use is the scintillator , either as a solid crystal or as a liquid .
the predominantly non - zero nuclear spin of both natural na and i make these detectors much more sensitive to axial couplings than natural germanium .
while their energy thresholds and resolutions tend to be significantly worse than for germanium detectors , scintillators offer an additional discriminatory power in that the individual scintillation signals from nuclear recoil type wimp interactions are expected to show a different time profile from that of the background .
this has been studied in some detail by various authors [ 11 , 55 ] .
figure 9 shows measured comparative differential pulse shapes from the ukdmc nai group [ 106 , 118 ] .
figure 10 compares -ray and neutron induced nuclear recoil calibration time constant distributions ( using simple single exponential fits to each pulse ) with the background obtained from their working experiment .
the closer statistical match of the measured background to the -ray distribution allows the upper limits to be reduced accordingly .
there is a clear difference between the functional form for high de / dx interactions , such as nuclear recoil and alpha tracks , and -ray induced electron tracks
.
figure 10differential time constant distributions from the uk nai experiment [ 106 , 118 ] showing the measured background ( solid line + data points ) , and neutron and -ray calibration distributions .
there is a clear difference between the functional form for high de / dx interactions , such as nuclear recoil and alpha tracks , and -ray induced electron tracks .
differential time constant distributions from the uk nai experiment [ 106 , 118 ] showing the measured background ( solid line + data points ) , and neutron and -ray calibration distributions .
another advantage of some scintillators over germanium is that it is much easier to make large mass detectors out of them .
this increases the event rate and makes it feasible to look for any annual modulation signals , assuming experiment systematics can be kept under control .
this is the approach of the dama group [ 19 , 17 , 20 ] , who currently have some of the lowest axial and coherent limits , and who have claimed a positive annual modulation result ( see right - hand panel in figure 8 and later discussion ) .
various other effects in scintillators are also being studied as a means to provide additional discrimination against non - nuclear recoil backgrounds .
these include using the ratio of visible to uv light emitted by cooled undoped nai , looking for directional nuclear recoil effects in stilbene , and using pulse - shape analysis from a mixed scintillator system(with fine grains of caf2 in an organic liquid scintillator ) to take advantage of the recoil range difference between electrons and nuclei .
all the previous techniques make use of only one diagnostic signal channel , i.e. pulse shape discrimination , annual modulation , pulse height ratio , or directional dependence . a technique that makes
use of two distinct signal channels using a two - phase ( liquid / gas ) xenon detector has been demonstrated and is under development by the ukdmc group .
it has a nuclear mass that is well matched to the preferred neutralino mass range .
it has a useful electron drift lifetime in both liquid and gas phases and can be used in a proportional ionisation mode .
however , it does have some disadvantages , such as : one needs a high level of purity , liquid xenon is more difficult to handle than a crystal scintillator , its scintillation signals are well in the uv ( 1750 ) , and its scintillation signals are very fast ( < 50 ns ) .
figure 11 shows one proposed type of configuration for a two - phase system in which photomultipliers are used to record two scintillation signals for each event , s1 and s2 .
s1 is the primary scintillation signal from the liquid volume , which occurs as a direct result of the wimp/-ray scattering interaction .
in addition to scintillation , the interaction will also produce localised ionisation in the liquid .
an applied electric field is then used to drift the ionisation electrons towards and into the gaseous xenon . in the gas
there is a region in which the applied electric field is strong enough to produce secondary scintillation , or electroluminescence , which produces signal s2 .
the s1 signal itself will be amenable to pulse shape analysis as described above for nai . the s2 signal amplitude will depend on how many ionisation charges are drifted into the gas volume .
this will depend on how many are produced in the initial interaction and on what fraction of those immediately recombine .
the level of recombination is expected to be higher for events with a higher linear energy density deposit de / dx , and so nuclear recoil type events are expected to show a much lower fraction of surviving drifting electrons . hence , the ratio of s2 to s1 should be much lower for nuclear recoils compared to say -ray deposits of the same amount .
this effect has been demonstrated in low field operation [ 35 , 69 ] , and the left - hand panel of figure 12 shows some results from the chamber of figure 11 .
a 30 kg detector is being constructed in which nuclear recoil events are identified by the lack of a secondary signal .
an alternative scheme uses high - field operation in which ionisation from nuclear recoils can also be seen , and in which discrimination relies on the finite ratio of s2 to s1
. this should give much higher background rejection and a 8 kg instrument is underway .
figure 11
the two - phase xenon test chamber used by wang [
35
] .
figure 12
relative signal amplitudes for -rays and neutrons for two hybrid type experiments . on the left
is shown the primary to secondary scintillation signal amplitudes for a two - phase xenon instrument [
35
] .
the right hand panel shows the ionisation versus phonon performance of the cdms germanium bolometer [
3
] .
the circled points are experimental data thought to originate from neutron recoils .
the two - phase xenon test chamber used by wang [
35
] .
on the left is shown the primary to secondary scintillation signal amplitudes for a two - phase xenon instrument [
35
] .
the right hand panel shows the ionisation versus phonon performance of the cdms germanium bolometer [
3
] .
the potential discrimination power available using the various techniques can be described by a figure of merit as shown in figure 13 .
the top curves show the situation using pulse shape discrimination in nai , and the two lower curves then show what improvement might be expected from using pulse height ratios from cooled nai ( uvis ) and a two - phase xenon system . in this figure ,
the performance improves as the figure of merit decreases and the potential advantage of liquid xenon over nai is significant .
figure 13
relative figures of merit for the discrimination potential in nai , cooled nai and two - phase liquid xenon [
117
] . in this plot
relative figures of merit for the discrimination potential in nai , cooled nai and two - phase liquid xenon [
117
] . in this plot
a lower figure of merit implies proportionately better performance .
a variant on the above scheme is to try to image the ionisation charge distribution using tea ( or tma ) added to the liquid xenon , which will convert scintillation photons into electrons [ 142 , 101 ] .
the idea here is that for nuclear recoil events there will be relatively few direct ionisation electrons left , due to the high de / dx , and most drifting electrons will have been produced by photon absorption in the tea / tma .
this should give an exponential spatial distribution ( scale length around 2 cm ) of electrons drifting into the gas region .
whereas , for background -rays , there will be a significant core of electrons left over from the primary interaction in addition to those created by photon absorption , giving a more centrally peaked image .
most of the energy imparted to a recoiling nucleus during a wimp scattering will ultimately end up as phonons .
the specific heat at low temperatures varies as t , so the lower the temperature the greater the temperature rise as t1/t . in principle
this should yield very good energy resolution limited by the statistical fluctuations in the numbers of phonons produced . at a temperature of 20 mk , a 1 kg detector could achieve 100 ev resolution , with a correspondingly low threshold .
however , in practise , the resolution is limited partly by the efficiency of the phonon
cooling process , whereby the initial non - thermal phonons with energies of 10 to 10 ev become degraded into thermal phonons of around 10 ev .
once thermalised , the phonons then need to be coupled into the temperature sensors , which tend to be separate components bonded onto the target materials . for a 1 kg detector
the temperature rise would be 10 k / kev , dependent on the debye temperature of the material , and temperature sensors with this level of sensitivity at such very low temperatures are difficult to achieve .
one is the superconducting phase transition ( spt ) thermometer , the other is the superconducting transition edge sensor ( tes ) . in both cases
the temperature rise is measured by monitoring movement along the transition from superconductor to normal metal . for the tes
as these have not suffered the extensive scattering needed to thermalise them , some positional information can be recovered .
the use of a separate temperature sensor bonded onto a target allows a range of different material choices for the target . if semiconductor target materials are used , it is possible also to extract ionisation signals from bolometer experiments [ 121 , 33 ] .
nuclear recoils produce less ionisation compared to thermal energy than x - ray and -ray background events . for events initiated well away from surfaces ,
surface events , from external electrons for example , can be problematic as the ionisation can be inefficiently collected compared to the thermal energy , which mimics nuclear recoil signals .
the ionisation signals are collected using charge - sensitive preamplifiers in the usual way for semiconductor diodes .
the situation is analogous to the simultaneous ionisation measurement in that nuclear recoil events are much less efficient at producing ionisation and excitation than typical background events . in this case
it is even possible to use spts deposited on light absorbers ( e.g. silicon ) as the scintillation signal channel .
two are techniques currently being developed while the third has been in use for some time .
the aim here is to image tracks of interactions within the time projection chamber and measure the range of the ionisation track and the energy deposition .
nuclear recoil events have already been successfully recorded in a prototype device , and these have much shorter track lengths than an electron recoil of the same energy .
this technique offers the prospect of realising a fully direction - sensitive detector that would not only enable use of all the directional wimp signatures in attempting to extract signals , but would also allow the local wimp velocity distribution to be measured .
the second technique in this section is the use of superheated droplet detectors in which events leaving a high de / dx deposit are capable of vapourising the droplets [ 37 , 65 ] .
such detectors operate close to room temperature , exhibit low thresholds , and are insensitive to -rays that do not leave a sufficiently high density track .
finally , the ancient mica technique has already been used to derive upper limits to interaction cross - sections .
ancient mica contains an historical record of nuclear recoil interactions over exposure times of gyrs .
the defects left in the crystal can be etched and examined using an atomic force microscope .
defects left from natural radioactive processes will tend to leave much more pronounced etch pits than expected for a wimp , so the technique involves looking at the size distribution of the etch pits .
the range and breadth of experimental work now underway world - wide makes it very difficult to maintain an up - to - date and complete catalogue of activities .
table 3 presents an overview of experiments currently going on , but is far from exhaustive .
table 3
experiment overview .
experimenttypetargetquenching factormasskgdays[kg]heidelberg / moscowige2.88 > 165hdmsige0.250.20-geniusige1000-tandar / usc / ige-1.033831pnl / zaragozasnai32usc pnl zaragozaigecosme / twinneuchatel caltechigepsiukdmcsnai(tl)na(0.3)6 > 1500sxei(0.08)6-s / ixexe(0.2)20-damasnai(tl)ca(0.08)11530000scaf2f(0.12)0.3710sxexe(0.65)6.5823elegant - vsnai(tl)662241630elegant - viscaf28saclaysnaiamherst ucbomica--1 gyrsimpleofreon10.190(cern lisbon paris)montreal chalk riverof , cl1tokyo dark matterplif10.168searchmilanopteo27rosebudpsapphire0.100crrestpsapphire0.262cmdsp / ige0.262edelweissp / ige0.900orpheusosn0.032salopardosn0.100
experiment overview .
figure 14 , adapted from , shows the published upper limits on the nucleon - wimp scattering cross - section for coherent and axial coupling respectively , as they were in 1996 . in both cases , the best limits came from the large mass dama nai experiments with the ukdmc nai experiment close behind . for the coherent interactions the germanium results are comparable to the ukdmc nai .
finally , it is intriguing that both the dama and uk nai experiments have low - level signal effects that do not appear to be consistent with -ray backgrounds .
the ukdmc experiment , using pulse - shape analysis , revealed a family of short - time - constant events , which are even faster than their neutron induced recoil events .
the derived recoil spectrum for these events falls with energy as expected for wimps ( but the implied wimp mass is rather high ) , and there is even some hint of an annual modulation .
the dama experiment has an annual modulation signal , which has persisted in a consistent way through a complete rebuild of the experiment and with data accumulated over a four year period . from their data it is possible to delineate an allowed region in coherent cross - section parameter space that contains cosmologically interesting combinations of mssm parameters , as shown in figure 15 .
figure 14
latest published upper limits on ( a upper panel ) coherent and ( b lower panel ) axial coupled wimp - nucleon cross - sections adapted from [
23
] .
figure 15the upper panel shows the region of coherent cross - section parameter space consistent with the dama nai annual modulation results .
the four curves show the results from each individual year of the four year period shown in figure
8 . the lower panel shows a scatter plot of possible mssm models which populate the region defined by the first two years of data from .
open circles are cosmologically interesting .
latest published upper limits on ( a upper panel ) coherent and ( b lower panel ) axial coupled wimp - nucleon cross - sections adapted from [
23
] .
the upper panel shows the region of coherent cross - section parameter space consistent with the dama nai annual modulation results .
the four curves show the results from each individual year of the four year period shown in figure
8 .
the lower panel shows a scatter plot of possible mssm models which populate the region defined by the first two years of data from .
the left hand plot comes from the cdms collaboration , which runs a hybrid bolometer / ionisation experiment .
the limit they have produced almost excludes completely the dama coherent cross - section result ( shown as the solid grey region ) . however , cdms operates in a shallow site and experiences an ambient neutron background .
their limit relies on the assumption that the circled events shown in figure 12 are indeed due to ambient neutrons .
the numbers are consistent with this and there is a cross - check using multi - site multiple neutron scattering events .
, the edelweiss experiment has produced an upper limit that is comparable to cdms for high wimp masses .
the technique is similar to cdms , but has the advantage of no detectable neutron background as it is in a deeper site .
unfortunately , it has a higher energy threshold at present and work is ongoing to improve this .
so we are left with a tantalising claim of a wimp annual modulation signal from dama , which they have defended despite much concern over possibilities of spurious annual modulation effects , and an almost exclusive limit from cdms , which is statistically arguable .
the right - hand plot in figure 16 shows a plot from the simple experiment using superheated droplets .
the target has non - zero spin ; they present results in terms of limits to a pure spin - dependent cross - section .
the plot shows a compilation of limits from all the other experiments that have reported to date . in the bottom left - hand corner of this plot
can be seen the tip of the iceberg of mssm predictions for spin - dependent cross - sections .
figure 16
the upper panel shows the current results on the allowed coherent cross - section parameter space .
the plot is from [
14
] and shows the cdms 3 upper limit [
3
] ( dotted purple curve ) , the dama annual modulation positive detection region ( blue solid curve ) , the dama upper limit from pulse shape discrimination ( blue dot - dash curve ) , the edelweiss limits [
14
] ( red curves ) and the current limits from all combined germanium ionisation detectors [
70
] ( dashed green curve ) .
the lower panel shows an equivalent plot for the axial spin - dependent coupling cross - section . this is a composite plot produced by the simple collaboration in announcing their latest result [
38
] .
the upper panel shows the current results on the allowed coherent cross - section parameter space .
the plot is from [
14
] and shows the cdms 3 upper limit [
3
] ( dotted purple curve ) , the dama annual modulation positive detection region ( blue solid curve ) , the dama upper limit from pulse shape discrimination ( blue dot - dash curve ) , the edelweiss limits [
14
] ( red curves ) and the current limits from all combined germanium ionisation detectors [
70
] ( dashed green curve ) . the lower panel shows an equivalent plot for the axial spin - dependent coupling cross - section .
this is a composite plot produced by the simple collaboration in announcing their latest result [
38
] .
the need for more sensitive and more powerful experiments is clear as we start to impinge more and more on the allowed neutralino parameter space and as experiments begin to reveal features at levels never before investigated .
given the level of current activity it is inevitable that over the next several years there will be substantial advances in the dark matter problem .
the main issues will be :
refinement / revision of the standard cosmological model using :
new observational data on cmb anisotropies , particularly the second peak .
balloon - borne instruments may also be useful.new observational data on large - scale structure from galaxy redshift surveys.improved statistics on high - redshift type ia supernova .
this is needed to provide proper confirmation of their properties and their use as standard candles and also to define the distribution more clearly.further work on non - standard bbn models , such as those invoking degenerate neutrino species.continued theoretical modelling of the cmb anisotropies using cosmological models .
although this appears to have been developed to a fine art , there must be avenues for new development.investigation of alternative types of dark matter , such as warm dark matter .
further experimental data on the neutrino masses would be relevant here as well , although the recent evidence for neutrino mixing from sno suggests that the neutrino masses are unlikely to be cosmologically significant .
refinement of galaxy formation and structure models using :
continued high - resolution n - body simulations including more refined feedback on baryonic condensation , star formation , and massive black - hole formation.high-resolution rotation curve measurements .
these will help to establish the central density distributions and will also look for modulations at larger radii to assess dark matter infall models.high-resolution n - body simulations to establish cdm dynamics and structure within galaxy halos.continued observational searches for cold baryonic dark matter , using microlensing or infra - red , sub - millimeter observations of small clouds .
experimental searches for neutralinos , including :
improved versions of cdms , ccrest , and ukdmc experiments in the next two years , which will extend significantly below the dama region and resolve whether neutralinos have already been observed or not.several other experiments , such as genius , that may also come online in the next several years .
in fact , within about 6 years it is just possible that the whole of the parameter space in figure 6 will have been explored.a number of indirect search experiments may produce useful complementary data , such as neutrino telescopes , -ray missions ( glast ) , or particle experiments ( ams).detectors with directional response will have been developed at the prototype level , ready to become neutralino telescopes should the need arise .
supersymmetry and supergravity will have independent input from :
the large hadron collider , which will begin operation in 56 years time . within a few years of data taking
it should start to constrain much of the mssm and sugra parameter space.continued exploration of mssm and sugra models to refine calculations of scattering cross - sections .
refinement / revision of the standard cosmological model using :
new observational data on cmb anisotropies , particularly the second peak .
balloon - borne instruments may also be useful.new observational data on large - scale structure from galaxy redshift surveys.improved statistics on high - redshift type ia supernova .
this is needed to provide proper confirmation of their properties and their use as standard candles and also to define the distribution more clearly.further work on non - standard bbn models , such as those invoking degenerate neutrino species.continued theoretical modelling of the cmb anisotropies using cosmological models .
although this appears to have been developed to a fine art , there must be avenues for new development.investigation of alternative types of dark matter , such as warm dark matter .
further experimental data on the neutrino masses would be relevant here as well , although the recent evidence for neutrino mixing from sno suggests that the neutrino masses are unlikely to be cosmologically significant .
new observational data on cmb anisotropies , particularly the second peak .
this is needed to provide proper confirmation of their properties and their use as standard candles and also to define the distribution more clearly .
further work on non - standard bbn models , such as those invoking degenerate neutrino species .
although this appears to have been developed to a fine art , there must be avenues for new development .
further experimental data on the neutrino masses would be relevant here as well , although the recent evidence for neutrino mixing from sno suggests that the neutrino masses are unlikely to be cosmologically significant .
refinement of galaxy formation and structure models using :
continued high - resolution n - body simulations including more refined feedback on baryonic condensation , star formation , and massive black - hole formation.high-resolution rotation curve measurements .
these will help to establish the central density distributions and will also look for modulations at larger radii to assess dark matter infall models.high-resolution n - body simulations to establish cdm dynamics and structure within galaxy halos.continued observational searches for cold baryonic dark matter , using microlensing or infra - red , sub - millimeter observations of small clouds
.
continued high - resolution n - body simulations including more refined feedback on baryonic condensation , star formation , and massive black - hole formation .
these will help to establish the central density distributions and will also look for modulations at larger radii to assess dark matter infall models .
high - resolution n - body simulations to establish cdm dynamics and structure within galaxy halos . continued observational searches for cold baryonic dark matter , using microlensing or infra - red , sub - millimeter observations of small clouds .
experimental searches for neutralinos , including :
improved versions of cdms , ccrest , and ukdmc experiments in the next two years , which will extend significantly below the dama region and resolve whether neutralinos have already been observed or not.several other experiments , such as genius , that may also come online in the next several years .
in fact , within about 6 years it is just possible that the whole of the parameter space in figure 6 will have been explored.a number of indirect search experiments may produce useful complementary data , such as neutrino telescopes , -ray missions ( glast ) , or particle experiments ( ams).detectors with directional response will have been developed at the prototype level , ready to become neutralino telescopes should the need arise .
improved versions of cdms , ccrest , and ukdmc experiments in the next two years , which will extend significantly below the dama region and resolve whether neutralinos have already been observed or not .
several other experiments , such as genius , that may also come online in the next several years .
in fact , within about 6 years it is just possible that the whole of the parameter space in figure 6 will have been explored
. a number of indirect search experiments may produce useful complementary data , such as neutrino telescopes , -ray missions ( glast ) , or particle experiments ( ams ) .
detectors with directional response will have been developed at the prototype level , ready to become neutralino telescopes should the need arise .
supersymmetry and supergravity will have independent input from :
the large hadron collider , which will begin operation in 56 years time . within a few years of data taking
it should start to constrain much of the mssm and sugra parameter space.continued exploration of mssm and sugra models to refine calculations of scattering cross - sections .
the large hadron collider , which will begin operation in 56 years time .
within a few years of data taking it should start to constrain much of the mssm and sugra parameter space . continued exploration of mssm and sugra models to refine calculations of scattering cross - sections .
of course , the most satisfying scientific output would be the discovery of the neutralino as the dominant dark matter component of the milky way .
figure 17 shows two panels taken from in which the likely search areas to be completed by 2006 are delineated . the parameter space chosen for these plots has the universal scalar mass m0 and the gaugino mass m1/2 as the coordinates .
the two plots correspond to two illustrative values of tan. the solid dark green regions are already excluded . in the light green / yellow shaded area 0.025m1 , while in the blue shaded area 0.1m0.3 .
the curves then show which regions of parameter space are likely to be addressed over the coming years .
for each curve the forthcoming experiments will search the region between the curve and the dark green area .
the red curve corresponds to the direct search techniques such as the next generation of cdms , ccrest and ukdmc xenon experiments .
this curve should be reached in 23 years time . following that , there are already larger , better experiments being planned that could push further still .
the other curves shown correspond to various indirect search techniques , including -rays , neutrinos , and positrons .
the complementarity of the various techniques is apparent and multiple detections would provide a powerful diagnostic of susy parameters .
figure 17
expected progress in covering mssm parameter space from both indirect and direct search techniques over the next several years [
49
] .
expected progress in covering mssm parameter space from both indirect and direct search techniques over the next several years [
49
] .
the scientific impact of a positive neutralino detection would extend not only to cosmology and astrophysics in almost every aspect , but would also be of the utmost importance to supersymmetry and fundamental physics .
if , in addition to the neutralino , the axion is also implicated , then we will have a double bonanza , which also will verify the adopted solution to cp violation .
seldom has there been a problem that impinges on so many fundamentally important issues and this justifies the current level of activity on all fronts . | there is now an enormously rich variety of experimental techniques being brought to bear on experimental searches for dark matter , covering a wide range of suggested forms for it .
the existence of dark matter , in some form or other , is inferred from a number of relatively simple observations and the problem has been known for over half a century . to explain dark matter is one of the foremost challenges today the answer will be of fundamental importance to cosmologists , astrophysicists , particle physicists , and general relativists . in this article , i will give a brief review of the observational evidence ( concentrating on areas of current significant activity ) , followed by anequally brief summary of candidate solutions for the
dark matter. i will then discuss experimental searches , both direct and indirect .
finally , i will offer prospects for the future . | <s>[INST]in the following section it will be seen that we do not yet understand what determines the gravitational potentials within the universe on scales from galaxies upwards .
one suggestion is that the universe is full of material that does not emit electromagnetic radiation and which is thus hard to
see. there are a tremendous number of ideas on offer to resolve the dark matter dilemma .
these ideas cover modifications to the laws of gravity , cold conventional matter , new particles , neutrinos with non - zero mass , and exotic objects , to name just a few .
, there is no absolutely clear solution , although a number of the possibilities do lend themselves to experimental
some of the experiments are designed to look for direct signatures , i.e. the physical interaction of a dark matter particle in a detector , while others are looking for indirect evidence , such as the neutrino or -ray flux due to dark matter particle annihilations .
in addition , other types of experiments are looking for circumstantial evidence , such as the measurement of a non - zero neutrino mass in the right range , or confirmation of supersymmetry ( susy ) .
a number of the direct and indirect searches will be digging deeply into theoretically very interesting regions of parameter space over the next five years .
indeed there is , at this time , one experimental result from a direct search that has a signal consistent with the most optimistic susy predictions concerning neutralinos which just might be proven correct .
while it is true to say that most activity is currently targeted at what might be called the standard cosmological model , this model is not without its difficulties as a theory , and experimental evidence from dedicated dark matter searches could be crucial in finally clarifying the situation .
experimental searches probably are the only way to find out unambiguously what the milky way is made of .
the evidence is reviewed in section 2 , including subsection 2.2 on the standard cosmological model .
this leads to section 4 on direct and indirect detection requirements and techniques for non - baryonic dark matter .
most experiments are being carried out in the context of theoretical expectations for the neutralino , which most regard as the best motivated of the particle candidates .
a review of the current status of projects world - wide will be given in section 6 .
finally , in section 7 there is a discussion of the next logical steps for experimental searches for dark matter .
the existence of dark matter is inferred from astrophysical observations that probe gravitational potentials . the mass content required to provide the derived gravitational potential is then compared with the visible mass content .
several types of observation allow this to be done and in most cases the mismatch between the required mass and the observed mass is extreme .
the following list summarises some of the evidence that has been accumulated :
studies of the dynamics of stars in the local disk environment gave rise to the first suggestion of missing matter nearly 70 years ago [ 99 , 100 ] . the kinetic energy associated with the motion of these stars normal to the plane of the milky way
since the first work by oort , a number of further studies have given conflicting results .
however , even if present , this particular disk dark matter is not significant compared with the halo component.rotation curves for a large number of spiral galaxies have now been reliably established and it is observed that the orbital velocities of objects ( stars , globular clusters , gas clouds , etc . ) tend to a constant value , independent of the radial position r , even for objects out toward , and even far beyond , the edge of the visible disks .
this is quite inconsistent with the \documentclass[12pt]{minimal }
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\begin{document}$$1/\sqrt r$$\end{document } behaviour expected from newtonian mechanics , assuming most mass is in the central part of the galaxies .
according to newtonian mechanics , the mass density within these galaxies is only declining as r , leading to a total mass that actually continues to increase proportional to r.within the local group of galaxies , the milkyway and andromeda ( m31 ) are approaching each other at a much faster pace than can be explained by gravitational attraction of the visible mass . to explain the approach velocity , and indeed the fact that these two galaxies are not still moving away from each other as part of the hubble expansion , requires each to have masses that are consistent with those deduced from their rotation curves.many clusters of galaxies show extended x - ray emission .
this is usually attributed to a thin plasma of hot gas . on the assumption that the hot gas is gravitationally bound to the cluster and in equilibrium
( i.e. we have a virial system ) , the gravitational potential energy can be inferred from the kinetic energy budget of the hot gas .
the cluster mass determined in this way is much higher than that seen either visibly or in the gas itself.gravitational lensing by clusters of galaxies causes images of more distant galaxies to be distorted and often split into multiple images .
the gravitational mass of the lens ( i.e. the cluster ) , and its distribution , can be recovered through detailed analysis of the image pattern surrounding the cluster .
the lenses show a far more extended spatial extent than the visible cluster.galaxy red - shift surveys have revealed large - scale galaxy - cluster streaming motions superimposed on the hubble expansion .
attempts to explain this due to gravitational attraction resulting from the overall distribution of galaxy superclusters give the right direction of motion but need more than the observed visible masses in the superclusters to explain the speed of motion
.
the next four items are not really at the same level of simple observational evidence as those above , as they require reliance on a more convoluted path to determine masses involved .
however , the first three of these have received a great deal of effort and are now heavily used as a combined strong argument in favour of the existence of dark matter , and indeed have resulted in a consensus view of standard cosmology over the past few years .
the large scale structure ( lss ) of the universe
can be studied using large surveys of distant galaxies , by measuring their spatial distribution and peculiar motions .
there is an extensive industry in n - body simulations trying to explain the lss and large - scale dynamics in terms of gravitational growth of small perturbations present in the early universe .
the only simulations that give reasonable agreement with observation are those that use a matter density somewhat higher than currently thought allowable in visible matter . indeed ,
starting from the level of the cobe observations of the density fluctuations ( 10 ) at the time of recombination ( z=1000 ) , for gravitational instability to lead to galaxy formation on a reasonable timescale it seems necessary to invoke a significant dark matter component , which only interacts gravitationally.type ia supernovae can be used as standard candles to determine distances , independently of red - shift to high red - shift galaxies in which they occur .
the implications of the results will be discussed later , but consistent cosmological models seem to require a dark matter component.the cobe satellite gave us the first measurement of the amplitude of microwave background anisotropies at the time of recombination .
it is these perturbations which subsequently grow through gravitational instabilities to form the large - scale structure seen today .
recently , new results have determined the angular power spectrum of the microwave background anisotropies at much finer angular scales , where enhancements are expected due to acoustic wave resonances in the early universe .
a clear first peak is seen in the data and its position favours a dark matter component .
even second and third peaks look to be emerging and the amplitudes and positions of these provide constraints on various cosmological parameters ( this will be discussed in more detail in the following section).for those who believe in inflation , most surviving models naturally have a density equal to the critical density , which exceeds that possible in visible matter .
with such a large volume of evidence there can be no doubt that there is a real mystery to be unravelled here .
ideally , it would be satisfying if there were a single simple solution that explained all the above .
this has proven elusive so far , but recently there has been some convergence on models that address the larger scale issues to do with the universe as a whole , and this is discussed in the next subsection .
the main aim is to establish a consensus opinion on the dark matter fraction , and more specifically the cold dark matter fraction , as this motivates most of the experimental searches for dark matter . in doing this
we will see that a strong argument for a standard cosmology , with cold dark matter as one of its components , is beginning to become established .
however , some issues clearly hint at aspects of the cosmology that have yet to be properly resolved , and some of these do have potentially serious implications for the cold dark matter component .
studies of the dynamics of stars in the local disk environment gave rise to the first suggestion of missing matter nearly 70 years ago [ 99 , 100 ] . the kinetic energy associated with the motion of these stars normal to the plane of the milky way
since the first work by oort , a number of further studies have given conflicting results .
however , even if present , this particular disk dark matter is not significant compared with the halo component .
rotation curves for a large number of spiral galaxies have now been reliably established and it is observed that the orbital velocities of objects ( stars , globular clusters , gas clouds , etc . ) tend to a constant value , independent of the radial position r , even for objects out toward , and even far beyond , the edge of the visible disks .
this is quite inconsistent with the \documentclass[12pt]{minimal }
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\begin{document}$$1/\sqrt r$$\end{document } behaviour expected from newtonian mechanics , assuming most mass is in the central part of the galaxies . according to newtonian mechanics , the mass density within these galaxies is only declining as r , leading to a total mass that actually continues to increase proportional to r. within the local group of galaxies , the milkyway and andromeda ( m31 ) are approaching each other at a much faster pace than can be explained by gravitational attraction of the visible mass . to explain the approach velocity , and indeed the fact that these two galaxies are not still moving away from each other as part of the hubble expansion , requires each to have masses that are consistent with those deduced from their rotation curves
this is usually attributed to a thin plasma of hot gas . on the assumption that the hot gas is gravitationally bound to the cluster and in equilibrium ( i.e. we have a virial system ) ,
the gravitational potential energy can be inferred from the kinetic energy budget of the hot gas .
the cluster mass determined in this way is much higher than that seen either visibly or in the gas itself .
gravitational lensing by clusters of galaxies causes images of more distant galaxies to be distorted and often split into multiple images .
the gravitational mass of the lens ( i.e. the cluster ) , and its distribution , can be recovered through detailed analysis of the image pattern surrounding the cluster .
galaxy red - shift surveys have revealed large - scale galaxy - cluster streaming motions superimposed on the hubble expansion .
attempts to explain this due to gravitational attraction resulting from the overall distribution of galaxy superclusters give the right direction of motion but need more than the observed visible masses in the superclusters to explain the speed of motion .
the large scale structure ( lss ) of the universe can be studied using large surveys of distant galaxies , by measuring their spatial distribution and peculiar motions .
there is an extensive industry in n - body simulations trying to explain the lss and large - scale dynamics in terms of gravitational growth of small perturbations present in the early universe .
the only simulations that give reasonable agreement with observation are those that use a matter density somewhat higher than currently thought allowable in visible matter . indeed ,
starting from the level of the cobe observations of the density fluctuations ( 10 ) at the time of recombination ( z=1000 ) , for gravitational instability to lead to galaxy formation on a reasonable timescale it seems necessary to invoke a significant dark matter component , which only interacts gravitationally .
type ia supernovae can be used as standard candles to determine distances , independently of red - shift to high red - shift galaxies in which they occur .
the implications of the results will be discussed later , but consistent cosmological models seem to require a dark matter component .
the cobe satellite gave us the first measurement of the amplitude of microwave background anisotropies at the time of recombination .
it is these perturbations which subsequently grow through gravitational instabilities to form the large - scale structure seen today .
recently , new results have determined the angular power spectrum of the microwave background anisotropies at much finer angular scales , where enhancements are expected due to acoustic wave resonances in the early universe .
a clear first peak is seen in the data and its position favours a dark matter component .
even second and third peaks look to be emerging and the amplitudes and positions of these provide constraints on various cosmological parameters ( this will be discussed in more detail in the following section ) . for those who believe in inflation , most surviving models naturally have a density equal to the critical density , which exceeds that possible in visible matter . within the context of a big bang creation scenario in which an inflationary phase is followed by expansion within the confines of general relativity , there are at least 11 parameters that define a cosmological model in the post inflation era .
these 11 + parameters affect what happens in the first few minutes during which nucleosynthesis of the lightest elements occurs ( bbn ) , how the geometry of space - time develops , and how structure forms through gravitational enhancement of primordial density inhomogeneities which come out of the inflationary phase .
the density inhomogeneities will leave an imprint on the microwave background radiation that survives from the era of recombination , some 300,000 years after the big bang . subsequently , they grow through gravitational instability to give rise to the structure we see in the distribution of visible objects in the universe today . hence , by bringing together observations that relate to bbn , space - time evolution , microwave background anisotropies , and large - scale structure , it is possible to define inter - related regions of the 11 parameter phase space that are consistent with all the information .
tegmark , zalderriaga , and hamilton did this just after the first release of new cmb data from boomerang and maxima .
the parameter space used was
( 1)\documentclass[12pt]{minimal }
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\begin{document}$$
\left ( { \tau , { \omega _ k},{\omega _ \lambda } , { \omega _ { \rm{d}}},{\omega _ { \rm{b}}},{f_\nu } , { n_{\rm{s}}},{n_{\rm{t}}},{a_{{\rm{s,}}}}r , b } \right )
$ $ \end{document }
where is the reionisation optical depth , as , ns , r , nt are the primodial amplitudes and tilts of the scalar and tensor inhomogeneities , b is a bias factor relating rms galaxy fluctuations to the underlying rms matter fluctuations , k and are the contributions to the overall density from curvature and the cosmological constant , d and b are the physical densities of dark matter ( both hot and cold together ) and baryonic matter , and finally f is the fraction of dark matter in the form of hot dark matter . the primary observational data that they used were all available cmb data and the recently released iras point source catalogue redshift survey ( pscz ) from which they derived the large scale structure power spectrum .
simultaneous fits were then done to these data allowing all 11 parameters to vary .
table 1allowable ranges of values of density parameters within the standard cosmological model derived from the first release cmb data of boomerang and maxima ( left - hand column , ) with corresponding values ( where quoted ) from the newest data sets ( right - hand column , ) .
h is the hubble parameter and values of 0.740.08 and 0.720.08 were used in and , respectively.0.490.740.490.760.20m0.500.11hd0.170.09hd0.170.00hhdm0.120.10hcdm0.320.20hb0.0370.01hb0.03
allowable ranges of values of density parameters within the standard cosmological model derived from the first release cmb data of boomerang and maxima ( left - hand column , ) with corresponding values ( where quoted ) from the newest data sets ( right - hand column , ) .
h is the hubble parameter and values of 0.740.08 and 0.720.08 were used in and , respectively .
table 2.2 shows the acceptable range of values for the key parameters that came out of those fits . in the table
the matter density , \documentclass[12pt]{minimal }
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\begin{document}$${\omega _ { \rm{m } } } = { \omega _ { \rm{b } } } + { \omega _ { { \rm{cdm } } } } + { \omega _ { { \rm{hdm}}}},$$\end{document } , includes both baryonic matter and dark matter , and moreover the dark matter can be classed either as hot or cold depending on whether it was relativistic or not in the early universe .
the total dark matter density is \documentclass[12pt]{minimal }
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\begin{document}$${\omega _ { \rm{d } } } = { \omega _ { { \rm{hdm } } } } + { \omega _ { { \rm{cdm}}}}$$\end{document } , and hd=d . of particular note for this review were that the cold dark matter density is non - zero and that the baryonic density has a range that just accomodates the constraints from bbn at its lowest end , but with significantly better fits for higher values .
very recently there have been significant new cmb data released from boomerang , maxima , dasi , and cbi .
these data have given better definition to the second and third peaks in the cmb power spectrum .
wang , tegmark and zaldarriaga subsequently repeated the above analysis using a combination of these and previously available cmb data .
the two left - hand plots in the top row in figure 1 are the most relevant for the dark matter .
we see that the dark matter density is again non - zero , with a similar range of values as before , and that the fraction of dark matter as hot dark matter is less than 35% , assuming no constraints on the hubble parameter , h. the allowable fraction of hot dark matter drops to only 20% if the preferred hubble parameter value is imposed . the right - hand column in table 2.2 lists
while previously the allowable range of b was only just compatible with the upper limit derived from bbn , it now comfortably embraces it .
this is illustrated in the left - hand panel in figure 2 , which shows the combined constraints on the baryonic matter and dark matter densities .
the white central region is the allowed parameter space when all constraints are applied , except for bbn of course .
relaxing the constraints by not using the pscz data enlarges the allowed region to include the cyan coloured area .
if , in addition , no assumptions are made about the value of the hubble constant , then the green area also becomes allowed .
if all constraints are accepted then figure 2 implies there is between 4.5 and 9 times as much dark matter in the universe as there is baryonic matter .
figure 1allowable parameter spaces for , k , b , d , f ,
and r. the figure is taken from and the dashed lines mark the 95% confidence limits .
figure 2the left - hand panel from shows the joint constraints on the baryonic matter and dark matter densities , together with the allowed band of baryonic density from bbn models .
the right - hand panel from shows the joint constraints on and m
which result from combined use of cmb data and high - redshift supernova data .
allowable parameter spaces for , k , b , d , f ,
and r. the figure is taken from and the dashed lines mark the 95% confidence limits . the left - hand panel from shows the joint constraints on the baryonic matter and dark matter densities , together with the allowed band of baryonic density from bbn models .
the right - hand panel from shows the joint constraints on and m
which result from combined use of cmb data and high - redshift supernova data .
constraints on cosmological models can also be derived from the observations of high red - shift type 1a supernovae . when combined with data from the cmb anisotropies ,
these limits give reasonable agreement with those cited earlier in table 2.2 . a recent result from de bernardis et al .
the solid curves are the 1 to 3 combined likelihood contours and these can be compared with the values in the table . a somewhat weaker constraint on the hubble constant was used .
hence , from the above , there does indeed seem to be a cosmological model that can simultaneously satisfy all the observational evidence used .
the ranges of values for the key parameters relevant to dark matter searches have been summarized in table 2.2 .
numerous n - body simulations have been performed to verify whether structure formation occurs properly in a number of different types of models .
simulations of gravitational collapse on the scale of galaxies have resulted in universal rotation curves that match reasonably well those observed in a wide range of galaxies [ 94 , 95 ] . from table 2.2
the main features of the emerging standard cosmology from the point of view of dark matter are :
a cdm scenario where the dominant energy density is from .the matter density m greatly exceeds that which can be present in a baryonic form , and hence there is a significant dark matter component.the dark matter density d is mostly comprised of cold dark matter.n - body simulations suggest that galaxies are comprised of similar mixes of baryonic matter and dark matter as the universe as a whole .
the origin of remains a topic of current debate , with a great deal of interest in quintessence [ 29 , 9 ] .
a cdm scenario where the dominant energy density is from . the matter density m greatly exceeds that which can be present in a baryonic form , and hence there is a significant dark matter component .
n - body simulations suggest that galaxies are comprised of similar mixes of baryonic matter and dark matter as the universe as a whole .
although the argument in section 2.2 is very persuasive and does present a formally consistent picture there are a number of concerns that continue to require attention .
firstly , it can be seen from table 2.2 that , prior to the latest cmb data , the consistency between bbn and the cmb and lss constraints was marginal . as a result of this a number of routes that allow for higher baryon density
the most recent of these invoked a degenerate bbn scenario in which additional light neutrinos ( either sterile or degenerate ) are allowed .
such a high baryon density would negate the need for dark matter . while it is comforting ( to some ) to see the new cmb data apparently removing this discrepancy , the data themselves are still not high - precision and some aspects of the data reduction remain uncertain . a second issue has arisen from high resolution n - body simulations [ 96 , 57 , 90 ] .
these simulations seem to be showing a more peaked cdm enhancement toward galaxy centres than the previous work [ 94 , 95 ] and more sub - structure in the cdm halos themselves .
there is increasing evidence that indeed the predictions are incompatible with observational data [ 26 , 112 , 21 , 43 , 80 ] .
possible ways of softening the central profile include allowing the dark matter to interact more readily , either with itself ( self - interacting cdm ) or with baryonic matter .
although the n - body simulations themselves appear robust in general , in central regions where there are few
thirdly , it can be seen that the type ia supernovae data are crucial in determining the value of . central to this is the question of whether the optical light - curves can really be used as standard candles , or whether reddening is playing a role here , as quite small amounts of absorption could significantly affect the results .
this suggestion has been countered recently by the observation of a very highredshift ( z1.7 ) supernova which is actually brighter than expected , even in a no - dust scenario .
its increased brightness is shown to be consistent with an early deceleration phase of the universe .
finally , there is a class of model in which gravity itself is assumed to be modified [ 86 , 85 ] .
a large number of effects attributed to dark matter have been addressed using modified gravity with the most recent being an analysis of the latest cmb aniostropy data . in this latest work
it is claimed that 1 with bm ( consistent with standard bbn ) is the favoured model .
however , the result rests heavily on the apparent absence of a second peak in the cmb data from boomerang ; maxima-1 data are not included .
at the moment the totality of cmb data does not constrain the second peak sufficiently strongly to rule out a significant cdm component .
it was argued in section 2.2 that there is a clear need for dark matter . in addition , it seems the baryonic density must be very close to the maximum allowed by bbn .
this last fact raises another interesting requirement in that the current best estimate places the baryonic density in the visible content of galaxies and cluster gas as \documentclass[12pt]{minimal }
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\begin{document}$${\omega _ { \rm{v } } } \sim \left ( { 2.2 + 0.6{h^ { - 1.5 } } } \right ) \times { 10^ { - 3 } } \sim 0.003$$\end{document}. this is well below the range given in table 2.2 and implies that there is a lot more baryonic matter yet to be found .
this missing baryonic matter is also generally referred to as dark matter . in the following sections the possible forms of both the baryonic and non - baryonic dark matter will be reviewed .
table 2 , adapted from carr ( 1990 ) , summarizes some of the types of objects that have been suggested as dark matter .
table 2
possible dark matter candidates ( adapted from [
30
] )
.
non - baryonicbaryonicaxions(10 ev)snowballs?neutrinos(10 ev)brown dwarfs(0.08m)wimps(110 gev)m - dwarfs(0.1m)monopoles(10 gev)white dwarfs(1m)planck relics(10 gev)neutron stars(2m)primordial black holes(>10 g)stellar black holes(10m)quark nuggets(<10 g)very massive objects(1010m)shadow matter?super massive objectscosmic strings?cold diffuse gas
possible dark matter candidates ( adapted from [
30
] ) .
figure 3 illustrates the scale - lengths on which the various dark matter candidates might be significant .
the dark grey areas are strongly disallowed on theoretical grounds , whilst the lighter grey areas are unlikely but not rigorously excluded . in the next two sections a very brief discussion of the main baryonic and non - baryonic candidates is given .
carr ( 2000 ) and turner ( 1999 ) have given more detailed reviews .
figure 3
possible scale - lengths where different types of dark matter might be present , based on a similar representation which appeared in [
30
] .
possible scale - lengths where different types of dark matter might be present , based on a similar representation which appeared in [
30
] .
according to the standard model
, baryonic dark matter is required to make up the difference between the visible matter density v and the baryon density b required by standard bbn models .
exactly where these baryons might be hiding depends on the nature of the objects being studied . for high redshifts
> 3 , most of the baryons might still be in the form of an intergalactic medium still in the process of collapse , while recent data from a large sample of nearby x - ray emitting clusters of galaxies have shown that for these clusters most of the baryon fraction f is in the surrounding hot gas of the intracluster medium ( icm ) .
indeed , if it is assumed that the cluster matter has the same fraction of baryonic matter as the universe as a whole , i.e.
fb/m , then it seems that the icm accounts for baryons up to the required bbn levels in these clusters . on the scale of individual galaxies
-cdm n - body simulations ( see figure 4 ) suggest the halo composition should follow the underlying matter distribution of the universe but with some enhancement of the baryonic proportion through more efficient dissipative collapse .
figure 4
high - resolution n - body simulation of a galactic dark matter halo [
90
] .
high - resolution n - body simulation of a galactic dark matter halo [
90
] .
this naturally leads to the conclusion that there is probably unseen baryonic matter in galaxies , but that it is unlikely to be sufficient to entirely explain the rotation curves .
the brown dwarf ( bd ) candidate entry in figure 3 includes any compact object with masses below 0.08m. many searches have been carried out looking for these massive compact halo objects ( machos ) using microlensing data .
although a number of candidate microlensing events have been seen , the apparent mass determinations for the lenses and their locations cast doubt on whether the lenses are indeed machos in the halo of the milky way .
the most recent estimates put the most likely macho contribution to the halo at 20% , and the masses of these objects appear to be 0.5m. this suggests a population of white dwarfs and might indicate an early epoch of star formation in the galactic halo .
to explain all the dark matter with compact objects larger than brown dwarfs would have produced too many heavy elements during their evolution as stars prior to collapse and so these are still excluded as halo baryons in figure 3 , at least as far as providing the bulk of the galactic dark matter . however , above 10m , super massive objects ( smos ) might collapse immediately to black holes .
smos would still produce microlensing effects and would also give rise to dynamical effects , such as the heating of disk stars and the disruption of globular clusters .
finally , it remains possible in principle that cold clouds with masses 10m might provide some of the halo dark matter [ 104 , 140 , 141 ] .
it can be seen that the standard model still allows for a small hdm component .
the neutrino would fulfill this if it had a non - zero mass , as suggested by recent experimental results from super - kamiokande [ 51 , 71 ]
. however , most of the dark matter will be cold dark matter ( cdm ) .
the best motivated of the various suggested candidates are two particles that were already invoked for other reasons .
these are the axion and the lightest supersymmetric particle ( neutralino ) , which is a member of the generic family of weakly interacting massive particles ( wimps ) .
, the level of cp violation seen in the k0 decay would give rise to a neutron electric dipole moment in excess of the limits already established .
the allowable mass range for the axion is constrained by astrophysical arguments to 10 to 10 ev / c .
wimps are naturally predicted in supersymmetry theories in which a higher level symmetry is obtained in the particle families by introducing new particles to match each of the known particles . in the so - called minimal supersymmetry models ( mssm ) ,
the lightest supersymmetric particle ( lsp ) is likely to be a neutralino , which is a mixture of two neutral gauginos and two neutral higgsinos :
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\chi = \chi _ 1 ^ 0 = { f_{11}}{w^3 } + { f_{12}}b + { f_{13}}{h_1 } + { f_{14}}{h_2}.
$ $ \end{document }
there are numerous parameters required to specify a particular mssm configuration .
it turns out that there is a wide range of parameter space in which the production and annihilation rates in the early universe are such that lspcdm .
the mass range for neutralinos is 46 gev / cm2000 gev / c , where the lower limit comes from accelerator data from lep .
experimental searches for dark matter invariably are trying to detect cold dark matter within our own galaxy .
thus , it is useful to review at this stage the current thoughts about the distribution of cold dark matter within the milky way and , for terrestrial based experiments , the likely cold dark matter presence near earth .
figure 5 shows both the observational data on the rotation curve and a recent determination of various mass components .
figure 5
the rotation curve of the milky way . in the left - hand panel
are the measured rotation speeds given by the average values from a number of measurements on different objects [
50
] .
the right hand panel shows the various mass components that combine together to reproduce the observed curve between 5 and 25 kpc [
72
] .
the dotted lines are the bulge and disk contributions , and the short - dashed curve is the dark matter contribution .
the solid curve shows the combined effect of all three , and this is compared to the long - dashed curve which approximates the measured data in the left - hand panel below 25 kpc .
the rotation curve of the milky way . in the left - hand panel are the measured rotation speeds given by the average values from a number of measurements on different objects [
50
] .
the right hand panel shows the various mass components that combine together to reproduce the observed curve between 5 and 25 kpc [
72
] .
the dotted lines are the bulge and disk contributions , and the short - dashed curve is the dark matter contribution .
the solid curve shows the combined effect of all three , and this is compared to the long - dashed curve which approximates the measured data in the left - hand panel below 25 kpc .
at the position of the sun , 7.58 kpc
, it can be seen that the contributions to the enclosed mass from the bulge , the disk , and the dark matter halo are comparable . in these types of studies , the dark matter halo is assumed to be in a quasi - spherically symmetric distribution in virialised equilibrium .
the halo is usually taken to be non - rotating and the local density comes out as 0.3 gev / cm .
the velocity distribution of the dm particles is assumed to be maxwellian with an upper cut - off at the galactic escape velocity .
most calculations of event rates and energy deposits in detectors are done assuming this straight forward type of dm halo .
possible modifications to this simple dm geometry include :
a modified radial cdm density profile giving a much lower cdm local density .
. a much larger number of events have been seen than expected and this suggests an unseen stellar population within the solar radius that can apparently account for the local rotation speeds without the need for dark matter .gravitational clustering of cdm particles at the centres of massive objects , such as the sun , the earth , or the galactic centre.cdm halos with non - zero angular momentum.clumpy cdm galaxy halos [ 57 , 90 , 92].non - equilibrium situations with on - going cdm infall into the galaxy [ 116 , 115].non - equilibrium situations with on - going cdm infall into the local cluster / supercluster.cdm scattered into stable orbits around the sun .
a modified radial cdm density profile giving a much lower cdm local density .
a much larger number of events have been seen than expected and this suggests an unseen stellar population within the solar radius that can apparently account for the local rotation speeds without the need for dark matter .
gravitational clustering of cdm particles at the centres of massive objects , such as the sun , the earth , or the galactic centre .
non - equilibrium situations with on - going cdm infall into the galaxy [ 116 , 115 ] .
non - equilibrium situations with on - going cdm infall into the local cluster / supercluster .
there are a number of previous reviews on general techniques used for dark matter searches [ 105 , 119 , 131 ] .
direct searches depend on dark matter particles actually passing through detectors and physically interacting with them .
indirect searches look for secondary products produced when dark matter particles annihilate each other elsewhere .
direct searches can , in principle , be used to look for neutrinos , axions and wimps , whereas only wimps are accessible indirectly .
wimp particle - antiparticle annihilations can produce neutrinos , -ray , antiprotons , and positrons .
for neutrinos and -rays the signal rates expected depend on the wimmp - antiwimp densities .
susy neutralinos ( the wimps on which most attention is fixed ) are their own antiparticles and the annihilation process can be represented as ff or ww or zz , where f=, , c , b , t with c , b , t being quarks .
neutrino signal rates can be enhanced by the trapping of wimps in massive bodies , such as the sun , earth , or galactic centre ; the wimp density builds up until the annihilation rate equals the capture rate . for the sun
this equilibrium situation has already been reached . for earth this may not yet be the case and annihilation fluxes
the capture rate will depend on the scattering rates for wimps on the various nuclear species in the body and the energy transfer per scatter .
the scattering rate on a particular species will depend on the abundance of the species and the cross - section .
the scattering cross - sections are usually calculated within mssm constraints , abundances depend on which body the wimps are being trapped in , and energy transfer per collision normally assumes elastic scattering with the wimps starting out with a typical virial speed of 10c for particles bound to the galaxy .
once capture rates , and hence annihilation rates , have been derived , the neutrino flux is calculated from the branching ratios for wimp annihilations going into neutrinos .
neutrino products are typically in the gev energy range and are hence accessible to existing solar neutrino experiments . however , for contained events ( ones in which the muons produced by the neutrinos are stopped in the detector ) the predicted rates rc are a few events for kiloton of detector per year , while traversing signals ( muons produced in surrounding rocks and passing through the detector ) occur at a rate rt0.1rce(a/10 ) yr . a is the detector area in cm .
early studies of -ray signatures from wimp annihilation predicted both continuum emission from 0 products , and line features from z and direct wimp annihilation into photons [ 129 , 130 , 49 ] .
continuum emission fluxes were predicted to be about two orders of magnitude lower than the diffuse galactic background .
line emission features should be much easier to see above the background as long as good energy ( e / e1% ) is available .
antiproton fluxes from wimp annihilation were expected to produce measurable enhancements above typical background fluxes in the low - energy antiproton spectrum ( < 1 gev ) , which would be accessible to space instruments such as ams .
however , it is now thought that there will be additional background fluxes that will make this type of measurement difficult .
. these may be visible as bumps in the otherwise smooth background spectrum due to cosmic - ray interactions with interstellar gas .
signals are expected to be much below the background levels , and long - duration space missions will be needed to collect sufficient statistics to observe the positrons . although there have been a number of suggestions for experiments to detect neutrinos [ 119 , 123 ] ( residual primordial hot dark matter now gravitationally bound to the galaxy ) , none can yet achieve sufficient sensitivity .
axions , on the other hand , are amenable to direct detection , although it is challenging to fully explore the whole of the theoretically available parameter space . among particles proposed to solve the cp violation problem ,
axions can be converted completely into photons in what is essentially a two - photon interaction . in experiments to detect galactic dark - matter axions the second photon is provided by an intense ambient electromagnetic field .
the photon created has an energy equal to the total energy of the axion ( rest mass plus kinetic energy ) .
as noted earlier , the dark matter energy density at the position of the earth is about 0.3 gev / cm . the preferred mass range for the axion is between 10 and 10 ev / c , although there is a second window between 2 and 5 gev / c .
the lower limit of the preferred mass range keeps m1 , while the upper limit prevents excessive energy - loss mechanisms in stars and supernovae due to axion production and loss .
if the galactic dark matter is axions , then their local density is between 310 and 310 cm . with a virial velocity distribution ( 10c ) ,
the flux through a terrestrial detector is enormous , but unfortunately the two - photon conversion process is very weak . in an ambient 6 tesla field
each axion has a conversion probability around 10 per second , and the photon produced has an energy in the microwave region ( 2200 ghz ) .
such an experiment requires a tuned high - q cavity , tunable over the projected axion mass / energy range , with a sensitivity of around 10 w. two early experiments of this type [ 93 , 84 , 63 ] have been followed by a number of second generation instruments , and the preferred axion mass window has been closed over a very small range at its lowest end ( 2.910 to 3.310 ev / c ) at the 90% confidence level for ksvz axions .
a variant on the tuned cavity technique is to incorporate rydberg atoms into the cavity where the |n to |n transition is also resonant with the cavity .
in addition to the direct dark matter axion searches , there are a number of experiments looking for evidence of axion existence , such as axion telescopes pointed at the sun and torsion balance instruments looking for short - range weak force spin - coupling interactions of the type mediated by the axion [ 122 , 98 , 114 , 134 ] .
neutralinos have received by far the most attention and there are an enormous range of techniques being used to search for these particles [ 119 , 132 , 6 ] .
the basic questions that need to be addressed to assess the feasibility of detection of wimps in the halo of our galaxy are :
how often will scattering events occur?how much energy will they deposit?how easy will it be to separate any real signal from background and to convincingly prove that a signal has been seen , i.e. what characteristic signatures are expected ?
each of these three issues are dealt with in some detail for the neutralino of the mssm in the following sections .
how easy will it be to separate any real signal from background and to convincingly prove that a signal has been seen , i.e. what characteristic signatures are expected ?
the scattering rate per unit detector volume rt depends on the local density of dark matter particles nw ; their velocity distribution relative to a detector in a terrestrial laboratory nw(v ) , and the velocity dependent scattering cross - section v , via the usual equation
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{ r_t } = \int_0^\infty { { n_w}(v){n_t}{\sigma _ t}(v)vdv , }
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where nt is the number density of nuclei of species t in the detector . the local number density of wimp particles is \documentclass[12pt]{minimal }
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\begin{document}$${n_w } = \int_0^\infty { { n_w}(v)dv = { \rho _ { { \rm{cdm}}}}/{m_w}}$$\end{document } , where mw is the wimp mass and cdm is the assumed local cold dark matter density . the wimp velocity distribution and the cross - section both have a wide range of uncertainty , which makes accurate predictions impossible .
the preferred range for mw in the context of the lightest stable neutralino within minimal mssm is 20 to 200 gev / c [ 110 , 111 ] , and han and hempfling quote a lower mass limit from lep data as 46 gev / c . in the simplest models the dark matter density distribution in the halo of the galaxy
is taken to be a spherical 1/r ( at least for large r ) distribution with a local density , at the position of the solar system , of 0.3 gev / cm .
the velocity distribution is taken to be a maxwellian , consistent with a virialised system but truncated above the galactic escape velocity .
models involving non - spherical density distributions , rotating halos [ 44 , 73 ] , and/or non - virial velocity distributions , such as galactic in - fall components with cusps or bound solar - system earth - crossing components , can individually give factor - of - two differences in the predicted scattering rates . the wimp velocity distribution as seen by a terrestrial detector has a bias imposed by the earth s velocity through the halo and its spin .
this produces a temporal modulation of the apparent wimp velocity distribution , which results in an annual modulation of the wimp scattering rate and recoil spectrum , and daily and annual modulations in the directional distributions .
different neutralino models , within mssm or sugra ( supergravity ) , exhibit an enormous range of interaction strengths that can be pure axial in nature ( coupling only to nuclei with non - zero spin ) , pure coherent ( coupling to all nucleons ) , or any combination of the two .
figure 6 shows the allowed range of parameter space for the scattering cross - sections .
the plot has been produced using output from the darksusy code , using up to 65 free parameters . even in this plot
reasonable assumptions have been made in allowing the parameters to vary ; ellis relaxes some of these and , not surprisingly , finds a wider range of resulting cross - sections .
the cross - sections are normalised to one nucleon ; to calculate the total cross - section for a target nucleus with n neutrons and nuclear spin j requires a scaling as (n/2 ) for the coherent spin - independent part of the cross - section and s2
j(j+1 ) for the spin - dependent part .
figure 6
total neutralino elastic scattering cross - section normalised to one nucleon for a range of neutralino models within mssm and msugra , taken from [
79
] .
the pink area corresponds to a neutralino in a dominantly bino state , the green bounded area is dominantly higgsino .
the cross - section includes both spin - independent and spin - dependent contributions , and in general the spindependent part is likely to be larger .
total neutralino elastic scattering cross - section normalised to one nucleon for a range of neutralino models within mssm and msugra , taken from [
79
] .
the pink area corresponds to a neutralino in a dominantly bino state , the green bounded area is dominantly higgsino .
the cross - section includes both spin - independent and spin - dependent contributions , and in general the spindependent part is likely to be larger .
form factor effects , which arise due to the finite size of the nucleus , are significant for the heavier target nuclei , are different for axial and coherent scattering , and again have uncertainties [ 47 , 107 ] . predicted event rates typically range from 10 to 10 events / day / kg . to achieve sensitivity to such rare events
requires low - background instruments operating in well shielded underground environments . the predicted differential observable recoil spectrum , assuming a standard virial maxwellian velocity distribution , is of the form
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{ \left .
{ \frac{{dr}}{{de } } } \right|_{{\rm{obs}}}}\propto \frac{{{r_0}}}{{f{e_0}r}}{e^ { - e/(f{e_0}r)}}{f^2}(e ) ,
$ $ \end{document }
where f is the quenching factor which reflects the relative efficiency with which the nuclear recoil energy is recorded in the signal channel compared to a -ray of the same energy .
e0 is the characteristic energy for the virialized wimp population , f is the form factor referred to previously , and r is a kinematic factor dependent on the relative masses of the wimp and target nuclei .
somewhat more complex formulae result when modified velocity distributions are used ( e.g. incorporating a galactic cut - off ) , or the rate is convolved through the instrument response .
a falling recoil spectrum with a maximum recoil energy 100 kev is expected . for larger target nuclei , such as iodine
-rays emitted from nuclear relaxation can be self - absorbed in the detector producing characteristic spectral lines .
experiments of this sort have been performed [ 15 , 52 , 18 ] ; the cross - sections are much lower than the elastic ones and the technique will not be discussed further .
a crucial quality of instruments and techniques is their ability to look for the signatures expected from wimp scattering interactions .
there are , in fact , a number of specific characteristics to be looked for , including :
a characteristic ( but featureless ) recoil spectrum ( following equation ( 4 ) ) that depends on target nuclear mass and spin.events distributed uniformly throughout the detector.an expected annual modulation in both the event rate and the recoil spectrum ( since a component of the earth s orbital velocity around the sun effectively adds to and subtracts from the solar system orbital velocity around the galactic centre).an expected daily modulation in the scattering rate due to wimp scattering by the earth s effectively shadowing the incident flux .a directional modulation in detector co - ordinates on daily and yearly bases for detectors locked to the earth s surface.site-independent wimp parameters provided by the wimp signal.characteristic properties
for each scattering event , where the instruments being used have an intrinsically different response to wimp nuclear recoil events as opposed to other backgrounds . for example :
wimp scattering should be single - site , whereas -ray and neutron background can be multi - site .
anti - coincidence veto systems are often used by ionization / scintillation detectors to provide multi - site signalsnuclear recoil events characteristic of wimp scattering produce different linear ionisation densities , which can result in different production ratios and different rates at which subsequent secondary processes occur .
this can produce different pulse shapes for nuclear recoils as opposed to x - ray and -ray background events .
this technique is commonly used in scintillation type experiments.similarly , the different linear ionisation densities can affect the relative efficiency with which energy propagates into different signal channels . for example
, the pulse height ratios between scintillation and ionisation signals are often used.similarly , higher linear ionization density implies a much shorter range for the nucleus before it loses all its energy .
imaging scintillation instruments or time projection chambers can make use of this .
in the next section
the various techniques on offer will be reviewed in order of increasing complexity in their ability to exploit specific wimp signatures .
a characteristic ( but featureless ) recoil spectrum ( following equation ( 4 ) ) that depends on target nuclear mass and spin .
an expected annual modulation in both the event rate and the recoil spectrum ( since a component of the earth s orbital velocity around the sun effectively adds to and subtracts from the solar system orbital velocity around the galactic centre ) .
an expected daily modulation in the scattering rate due to wimp scattering by the earth s effectively shadowing the incident flux . a directional modulation in detector co - ordinates on daily and yearly bases for detectors locked to the earth s surface .
properties for each scattering event , where the instruments being used have an intrinsically different response to wimp nuclear recoil events as opposed to other backgrounds .
for example :
wimp scattering should be single - site , whereas -ray and neutron background can be multi - site .
anti - coincidence veto systems are often used by ionization / scintillation detectors to provide multi - site signalsnuclear recoil events characteristic of wimp scattering produce different linear ionisation densities , which can result in different production ratios and different rates at which subsequent secondary processes occur .
this can produce different pulse shapes for nuclear recoils as opposed to x - ray and -ray background events .
this technique is commonly used in scintillation type experiments.similarly , the different linear ionisation densities can affect the relative efficiency with which energy propagates into different signal channels .
for example , the pulse height ratios between scintillation and ionisation signals are often used.similarly , higher linear ionization density implies a much shorter range for the nucleus before it loses all its energy .
wimp scattering should be single - site , whereas -ray and neutron background can be multi - site .
anti - coincidence veto systems are often used by ionization / scintillation detectors to provide multi - site signals nuclear recoil events characteristic of wimp scattering produce different linear ionisation densities , which can result in different production ratios and different rates at which subsequent secondary processes occur .
this can produce different pulse shapes for nuclear recoils as opposed to x - ray and -ray background events .
similarly , the different linear ionisation densities can affect the relative efficiency with which energy propagates into different signal channels .
for example , the pulse height ratios between scintillation and ionisation signals are often used .
similarly , higher linear ionization density implies a much shorter range for the nucleus before it loses all its energy .
imaging scintillation instruments or time projection chambers can make use of this . from the above dicussion
it can be seen that an ideal detector would have :
energy threshold < 1 kev.good energy resolution , to be able to see subtle modulations in the recoil spectrum.high ability to discriminate between nuclear recoil events and background events.low-background construction and site for operation.high target mass to ensure a sufficiently high wimp count rate.stable operation over a number of years .
energy threshold < 1 kev . good energy resolution , to be able to see subtle modulations in the recoil spectrum .
the first instruments to be used for wimp searches were solid state germanium ionisation type detectors .
these recorded high - resolution background energy spectra , which were then compared to the expected wimp recoil spectra to establish upper limits on interaction cross - sections ( assuming the galactic dark matter was indeed made of wimps in a straightforward spherical virialised distribution ) .
figure 7 shows examples of such spectra and the coherent limits obtained from a number of experiments of this type .
the background spectra can be coarsely characterised by two parameters , which are the threshold and the count rate just below threshold .
these approximately determine how low in wimp mass the instrument sensitivity extends and how low a crosssection limit can be set respectively .
this can be seen by comparing the cosme and twin curves in the two panels of figure 7 .
the difference between the cosme and twin background spectra is due to the use of freshly mined germanium in the production of twin , which consequently does not show the cosmogenically activated line just below 9 kev .
an alternative way of achieving the same suppression of the cosmogenic lines is to use enriched germanium as done by the heidelberg / moscow experiment .
the sierra grande curve in figure 7 is from a long exposure germanium experiment in which a search for both daily and annual modulation has been performed [ 1 , 2 ] , and the results from the daily modulation search are shown in figure 8 .
an example of an annual modulation search is shown in the right - hand panel of the figure .
the next advance expected from germanium detectors of this type will be from the heidelberg group who are developing a high - purity natural germanium crystal surrounded by an active veto that also uses natural germanium .
this will exploit the fact that any wimp scattering events will be single - site due to the very low scattering cross - section , while most other background events will be multi - site ( e.g. multiple elastic neutron scattering or multiple compton scattering for -rays ) .
figure 7
background energy spectra for two ge detectors of the pnl / usc / zaragoza group taken from [
28
] ( a upper panel ) .
coherent crosssection upper limits from ge detectors taken from [
1
] ( b lower panel ) .
figure 8
background rate from 428.1 days of data binned in 10-minute intervals and folded to look for daily modulation [
1
] ( a upper panel ) .
results of an annual modulation search using
4 years of data from the dama experiment [
16
] ( lower panel ) .
background energy spectra for two ge detectors of the pnl / usc / zaragoza group taken from [
28
] ( a upper panel ) .
coherent crosssection upper limits from ge detectors taken from [
1
] ( b lower panel ) .
background rate from 428.1 days of data binned in 10-minute intervals and folded to look for daily modulation [
1
] ( a upper panel )
. results of an annual modulation search using
4 years of data from the dama experiment [
16
] ( lower panel ) .
the next most common type of instrument in use is the scintillator , either as a solid crystal or as a liquid .
the predominantly non - zero nuclear spin of both natural na and i make these detectors much more sensitive to axial couplings than natural germanium .
while their energy thresholds and resolutions tend to be significantly worse than for germanium detectors , scintillators offer an additional discriminatory power in that the individual scintillation signals from nuclear recoil type wimp interactions are expected to show a different time profile from that of the background .
this has been studied in some detail by various authors [ 11 , 55 ] .
figure 9 shows measured comparative differential pulse shapes from the ukdmc nai group [ 106 , 118 ] .
figure 10 compares -ray and neutron induced nuclear recoil calibration time constant distributions ( using simple single exponential fits to each pulse ) with the background obtained from their working experiment .
the closer statistical match of the measured background to the -ray distribution allows the upper limits to be reduced accordingly .
there is a clear difference between the functional form for high de / dx interactions , such as nuclear recoil and alpha tracks , and -ray induced electron tracks
.
figure 10differential time constant distributions from the uk nai experiment [ 106 , 118 ] showing the measured background ( solid line + data points ) , and neutron and -ray calibration distributions .
there is a clear difference between the functional form for high de / dx interactions , such as nuclear recoil and alpha tracks , and -ray induced electron tracks .
differential time constant distributions from the uk nai experiment [ 106 , 118 ] showing the measured background ( solid line + data points ) , and neutron and -ray calibration distributions .
another advantage of some scintillators over germanium is that it is much easier to make large mass detectors out of them .
this increases the event rate and makes it feasible to look for any annual modulation signals , assuming experiment systematics can be kept under control .
this is the approach of the dama group [ 19 , 17 , 20 ] , who currently have some of the lowest axial and coherent limits , and who have claimed a positive annual modulation result ( see right - hand panel in figure 8 and later discussion ) .
various other effects in scintillators are also being studied as a means to provide additional discrimination against non - nuclear recoil backgrounds .
these include using the ratio of visible to uv light emitted by cooled undoped nai , looking for directional nuclear recoil effects in stilbene , and using pulse - shape analysis from a mixed scintillator system(with fine grains of caf2 in an organic liquid scintillator ) to take advantage of the recoil range difference between electrons and nuclei .
all the previous techniques make use of only one diagnostic signal channel , i.e. pulse shape discrimination , annual modulation , pulse height ratio , or directional dependence . a technique that makes
use of two distinct signal channels using a two - phase ( liquid / gas ) xenon detector has been demonstrated and is under development by the ukdmc group .
it has a nuclear mass that is well matched to the preferred neutralino mass range .
it has a useful electron drift lifetime in both liquid and gas phases and can be used in a proportional ionisation mode .
however , it does have some disadvantages , such as : one needs a high level of purity , liquid xenon is more difficult to handle than a crystal scintillator , its scintillation signals are well in the uv ( 1750 ) , and its scintillation signals are very fast ( < 50 ns ) .
figure 11 shows one proposed type of configuration for a two - phase system in which photomultipliers are used to record two scintillation signals for each event , s1 and s2 .
s1 is the primary scintillation signal from the liquid volume , which occurs as a direct result of the wimp/-ray scattering interaction .
in addition to scintillation , the interaction will also produce localised ionisation in the liquid .
an applied electric field is then used to drift the ionisation electrons towards and into the gaseous xenon . in the gas
there is a region in which the applied electric field is strong enough to produce secondary scintillation , or electroluminescence , which produces signal s2 .
the s1 signal itself will be amenable to pulse shape analysis as described above for nai . the s2 signal amplitude will depend on how many ionisation charges are drifted into the gas volume .
this will depend on how many are produced in the initial interaction and on what fraction of those immediately recombine .
the level of recombination is expected to be higher for events with a higher linear energy density deposit de / dx , and so nuclear recoil type events are expected to show a much lower fraction of surviving drifting electrons . hence , the ratio of s2 to s1 should be much lower for nuclear recoils compared to say -ray deposits of the same amount .
this effect has been demonstrated in low field operation [ 35 , 69 ] , and the left - hand panel of figure 12 shows some results from the chamber of figure 11 .
a 30 kg detector is being constructed in which nuclear recoil events are identified by the lack of a secondary signal .
an alternative scheme uses high - field operation in which ionisation from nuclear recoils can also be seen , and in which discrimination relies on the finite ratio of s2 to s1
. this should give much higher background rejection and a 8 kg instrument is underway .
figure 11
the two - phase xenon test chamber used by wang [
35
] .
figure 12
relative signal amplitudes for -rays and neutrons for two hybrid type experiments . on the left
is shown the primary to secondary scintillation signal amplitudes for a two - phase xenon instrument [
35
] .
the right hand panel shows the ionisation versus phonon performance of the cdms germanium bolometer [
3
] .
the circled points are experimental data thought to originate from neutron recoils .
the two - phase xenon test chamber used by wang [
35
] .
on the left is shown the primary to secondary scintillation signal amplitudes for a two - phase xenon instrument [
35
] .
the right hand panel shows the ionisation versus phonon performance of the cdms germanium bolometer [
3
] .
the potential discrimination power available using the various techniques can be described by a figure of merit as shown in figure 13 .
the top curves show the situation using pulse shape discrimination in nai , and the two lower curves then show what improvement might be expected from using pulse height ratios from cooled nai ( uvis ) and a two - phase xenon system . in this figure ,
the performance improves as the figure of merit decreases and the potential advantage of liquid xenon over nai is significant .
figure 13
relative figures of merit for the discrimination potential in nai , cooled nai and two - phase liquid xenon [
117
] . in this plot
relative figures of merit for the discrimination potential in nai , cooled nai and two - phase liquid xenon [
117
] . in this plot
a lower figure of merit implies proportionately better performance .
a variant on the above scheme is to try to image the ionisation charge distribution using tea ( or tma ) added to the liquid xenon , which will convert scintillation photons into electrons [ 142 , 101 ] .
the idea here is that for nuclear recoil events there will be relatively few direct ionisation electrons left , due to the high de / dx , and most drifting electrons will have been produced by photon absorption in the tea / tma .
this should give an exponential spatial distribution ( scale length around 2 cm ) of electrons drifting into the gas region .
whereas , for background -rays , there will be a significant core of electrons left over from the primary interaction in addition to those created by photon absorption , giving a more centrally peaked image .
most of the energy imparted to a recoiling nucleus during a wimp scattering will ultimately end up as phonons .
the specific heat at low temperatures varies as t , so the lower the temperature the greater the temperature rise as t1/t . in principle
this should yield very good energy resolution limited by the statistical fluctuations in the numbers of phonons produced . at a temperature of 20 mk , a 1 kg detector could achieve 100 ev resolution , with a correspondingly low threshold .
however , in practise , the resolution is limited partly by the efficiency of the phonon
cooling process , whereby the initial non - thermal phonons with energies of 10 to 10 ev become degraded into thermal phonons of around 10 ev .
once thermalised , the phonons then need to be coupled into the temperature sensors , which tend to be separate components bonded onto the target materials . for a 1 kg detector
the temperature rise would be 10 k / kev , dependent on the debye temperature of the material , and temperature sensors with this level of sensitivity at such very low temperatures are difficult to achieve .
one is the superconducting phase transition ( spt ) thermometer , the other is the superconducting transition edge sensor ( tes ) . in both cases
the temperature rise is measured by monitoring movement along the transition from superconductor to normal metal . for the tes
as these have not suffered the extensive scattering needed to thermalise them , some positional information can be recovered .
the use of a separate temperature sensor bonded onto a target allows a range of different material choices for the target . if semiconductor target materials are used , it is possible also to extract ionisation signals from bolometer experiments [ 121 , 33 ] .
nuclear recoils produce less ionisation compared to thermal energy than x - ray and -ray background events . for events initiated well away from surfaces ,
surface events , from external electrons for example , can be problematic as the ionisation can be inefficiently collected compared to the thermal energy , which mimics nuclear recoil signals .
the ionisation signals are collected using charge - sensitive preamplifiers in the usual way for semiconductor diodes .
the situation is analogous to the simultaneous ionisation measurement in that nuclear recoil events are much less efficient at producing ionisation and excitation than typical background events . in this case
it is even possible to use spts deposited on light absorbers ( e.g. silicon ) as the scintillation signal channel .
two are techniques currently being developed while the third has been in use for some time .
the aim here is to image tracks of interactions within the time projection chamber and measure the range of the ionisation track and the energy deposition .
nuclear recoil events have already been successfully recorded in a prototype device , and these have much shorter track lengths than an electron recoil of the same energy .
this technique offers the prospect of realising a fully direction - sensitive detector that would not only enable use of all the directional wimp signatures in attempting to extract signals , but would also allow the local wimp velocity distribution to be measured .
the second technique in this section is the use of superheated droplet detectors in which events leaving a high de / dx deposit are capable of vapourising the droplets [ 37 , 65 ] .
such detectors operate close to room temperature , exhibit low thresholds , and are insensitive to -rays that do not leave a sufficiently high density track .
finally , the ancient mica technique has already been used to derive upper limits to interaction cross - sections .
ancient mica contains an historical record of nuclear recoil interactions over exposure times of gyrs .
the defects left in the crystal can be etched and examined using an atomic force microscope .
defects left from natural radioactive processes will tend to leave much more pronounced etch pits than expected for a wimp , so the technique involves looking at the size distribution of the etch pits .
the range and breadth of experimental work now underway world - wide makes it very difficult to maintain an up - to - date and complete catalogue of activities .
table 3 presents an overview of experiments currently going on , but is far from exhaustive .
table 3
experiment overview .
experimenttypetargetquenching factormasskgdays[kg]heidelberg / moscowige2.88 > 165hdmsige0.250.20-geniusige1000-tandar / usc / ige-1.033831pnl / zaragozasnai32usc pnl zaragozaigecosme / twinneuchatel caltechigepsiukdmcsnai(tl)na(0.3)6 > 1500sxei(0.08)6-s / ixexe(0.2)20-damasnai(tl)ca(0.08)11530000scaf2f(0.12)0.3710sxexe(0.65)6.5823elegant - vsnai(tl)662241630elegant - viscaf28saclaysnaiamherst ucbomica--1 gyrsimpleofreon10.190(cern lisbon paris)montreal chalk riverof , cl1tokyo dark matterplif10.168searchmilanopteo27rosebudpsapphire0.100crrestpsapphire0.262cmdsp / ige0.262edelweissp / ige0.900orpheusosn0.032salopardosn0.100
experiment overview .
figure 14 , adapted from , shows the published upper limits on the nucleon - wimp scattering cross - section for coherent and axial coupling respectively , as they were in 1996 . in both cases , the best limits came from the large mass dama nai experiments with the ukdmc nai experiment close behind . for the coherent interactions the germanium results are comparable to the ukdmc nai .
finally , it is intriguing that both the dama and uk nai experiments have low - level signal effects that do not appear to be consistent with -ray backgrounds .
the ukdmc experiment , using pulse - shape analysis , revealed a family of short - time - constant events , which are even faster than their neutron induced recoil events .
the derived recoil spectrum for these events falls with energy as expected for wimps ( but the implied wimp mass is rather high ) , and there is even some hint of an annual modulation .
the dama experiment has an annual modulation signal , which has persisted in a consistent way through a complete rebuild of the experiment and with data accumulated over a four year period . from their data it is possible to delineate an allowed region in coherent cross - section parameter space that contains cosmologically interesting combinations of mssm parameters , as shown in figure 15 .
figure 14
latest published upper limits on ( a upper panel ) coherent and ( b lower panel ) axial coupled wimp - nucleon cross - sections adapted from [
23
] .
figure 15the upper panel shows the region of coherent cross - section parameter space consistent with the dama nai annual modulation results .
the four curves show the results from each individual year of the four year period shown in figure
8 . the lower panel shows a scatter plot of possible mssm models which populate the region defined by the first two years of data from .
open circles are cosmologically interesting .
latest published upper limits on ( a upper panel ) coherent and ( b lower panel ) axial coupled wimp - nucleon cross - sections adapted from [
23
] .
the upper panel shows the region of coherent cross - section parameter space consistent with the dama nai annual modulation results .
the four curves show the results from each individual year of the four year period shown in figure
8 .
the lower panel shows a scatter plot of possible mssm models which populate the region defined by the first two years of data from .
the left hand plot comes from the cdms collaboration , which runs a hybrid bolometer / ionisation experiment .
the limit they have produced almost excludes completely the dama coherent cross - section result ( shown as the solid grey region ) . however , cdms operates in a shallow site and experiences an ambient neutron background .
their limit relies on the assumption that the circled events shown in figure 12 are indeed due to ambient neutrons .
the numbers are consistent with this and there is a cross - check using multi - site multiple neutron scattering events .
, the edelweiss experiment has produced an upper limit that is comparable to cdms for high wimp masses .
the technique is similar to cdms , but has the advantage of no detectable neutron background as it is in a deeper site .
unfortunately , it has a higher energy threshold at present and work is ongoing to improve this .
so we are left with a tantalising claim of a wimp annual modulation signal from dama , which they have defended despite much concern over possibilities of spurious annual modulation effects , and an almost exclusive limit from cdms , which is statistically arguable .
the right - hand plot in figure 16 shows a plot from the simple experiment using superheated droplets .
the target has non - zero spin ; they present results in terms of limits to a pure spin - dependent cross - section .
the plot shows a compilation of limits from all the other experiments that have reported to date . in the bottom left - hand corner of this plot
can be seen the tip of the iceberg of mssm predictions for spin - dependent cross - sections .
figure 16
the upper panel shows the current results on the allowed coherent cross - section parameter space .
the plot is from [
14
] and shows the cdms 3 upper limit [
3
] ( dotted purple curve ) , the dama annual modulation positive detection region ( blue solid curve ) , the dama upper limit from pulse shape discrimination ( blue dot - dash curve ) , the edelweiss limits [
14
] ( red curves ) and the current limits from all combined germanium ionisation detectors [
70
] ( dashed green curve ) .
the lower panel shows an equivalent plot for the axial spin - dependent coupling cross - section . this is a composite plot produced by the simple collaboration in announcing their latest result [
38
] .
the upper panel shows the current results on the allowed coherent cross - section parameter space .
the plot is from [
14
] and shows the cdms 3 upper limit [
3
] ( dotted purple curve ) , the dama annual modulation positive detection region ( blue solid curve ) , the dama upper limit from pulse shape discrimination ( blue dot - dash curve ) , the edelweiss limits [
14
] ( red curves ) and the current limits from all combined germanium ionisation detectors [
70
] ( dashed green curve ) . the lower panel shows an equivalent plot for the axial spin - dependent coupling cross - section .
this is a composite plot produced by the simple collaboration in announcing their latest result [
38
] .
the need for more sensitive and more powerful experiments is clear as we start to impinge more and more on the allowed neutralino parameter space and as experiments begin to reveal features at levels never before investigated .
given the level of current activity it is inevitable that over the next several years there will be substantial advances in the dark matter problem .
the main issues will be :
refinement / revision of the standard cosmological model using :
new observational data on cmb anisotropies , particularly the second peak .
balloon - borne instruments may also be useful.new observational data on large - scale structure from galaxy redshift surveys.improved statistics on high - redshift type ia supernova .
this is needed to provide proper confirmation of their properties and their use as standard candles and also to define the distribution more clearly.further work on non - standard bbn models , such as those invoking degenerate neutrino species.continued theoretical modelling of the cmb anisotropies using cosmological models .
although this appears to have been developed to a fine art , there must be avenues for new development.investigation of alternative types of dark matter , such as warm dark matter .
further experimental data on the neutrino masses would be relevant here as well , although the recent evidence for neutrino mixing from sno suggests that the neutrino masses are unlikely to be cosmologically significant .
refinement of galaxy formation and structure models using :
continued high - resolution n - body simulations including more refined feedback on baryonic condensation , star formation , and massive black - hole formation.high-resolution rotation curve measurements .
these will help to establish the central density distributions and will also look for modulations at larger radii to assess dark matter infall models.high-resolution n - body simulations to establish cdm dynamics and structure within galaxy halos.continued observational searches for cold baryonic dark matter , using microlensing or infra - red , sub - millimeter observations of small clouds .
experimental searches for neutralinos , including :
improved versions of cdms , ccrest , and ukdmc experiments in the next two years , which will extend significantly below the dama region and resolve whether neutralinos have already been observed or not.several other experiments , such as genius , that may also come online in the next several years .
in fact , within about 6 years it is just possible that the whole of the parameter space in figure 6 will have been explored.a number of indirect search experiments may produce useful complementary data , such as neutrino telescopes , -ray missions ( glast ) , or particle experiments ( ams).detectors with directional response will have been developed at the prototype level , ready to become neutralino telescopes should the need arise .
supersymmetry and supergravity will have independent input from :
the large hadron collider , which will begin operation in 56 years time . within a few years of data taking
it should start to constrain much of the mssm and sugra parameter space.continued exploration of mssm and sugra models to refine calculations of scattering cross - sections .
refinement / revision of the standard cosmological model using :
new observational data on cmb anisotropies , particularly the second peak .
balloon - borne instruments may also be useful.new observational data on large - scale structure from galaxy redshift surveys.improved statistics on high - redshift type ia supernova .
this is needed to provide proper confirmation of their properties and their use as standard candles and also to define the distribution more clearly.further work on non - standard bbn models , such as those invoking degenerate neutrino species.continued theoretical modelling of the cmb anisotropies using cosmological models .
although this appears to have been developed to a fine art , there must be avenues for new development.investigation of alternative types of dark matter , such as warm dark matter .
further experimental data on the neutrino masses would be relevant here as well , although the recent evidence for neutrino mixing from sno suggests that the neutrino masses are unlikely to be cosmologically significant .
new observational data on cmb anisotropies , particularly the second peak .
this is needed to provide proper confirmation of their properties and their use as standard candles and also to define the distribution more clearly .
further work on non - standard bbn models , such as those invoking degenerate neutrino species .
although this appears to have been developed to a fine art , there must be avenues for new development .
further experimental data on the neutrino masses would be relevant here as well , although the recent evidence for neutrino mixing from sno suggests that the neutrino masses are unlikely to be cosmologically significant .
refinement of galaxy formation and structure models using :
continued high - resolution n - body simulations including more refined feedback on baryonic condensation , star formation , and massive black - hole formation.high-resolution rotation curve measurements .
these will help to establish the central density distributions and will also look for modulations at larger radii to assess dark matter infall models.high-resolution n - body simulations to establish cdm dynamics and structure within galaxy halos.continued observational searches for cold baryonic dark matter , using microlensing or infra - red , sub - millimeter observations of small clouds
.
continued high - resolution n - body simulations including more refined feedback on baryonic condensation , star formation , and massive black - hole formation .
these will help to establish the central density distributions and will also look for modulations at larger radii to assess dark matter infall models .
high - resolution n - body simulations to establish cdm dynamics and structure within galaxy halos . continued observational searches for cold baryonic dark matter , using microlensing or infra - red , sub - millimeter observations of small clouds .
experimental searches for neutralinos , including :
improved versions of cdms , ccrest , and ukdmc experiments in the next two years , which will extend significantly below the dama region and resolve whether neutralinos have already been observed or not.several other experiments , such as genius , that may also come online in the next several years .
in fact , within about 6 years it is just possible that the whole of the parameter space in figure 6 will have been explored.a number of indirect search experiments may produce useful complementary data , such as neutrino telescopes , -ray missions ( glast ) , or particle experiments ( ams).detectors with directional response will have been developed at the prototype level , ready to become neutralino telescopes should the need arise .
improved versions of cdms , ccrest , and ukdmc experiments in the next two years , which will extend significantly below the dama region and resolve whether neutralinos have already been observed or not .
several other experiments , such as genius , that may also come online in the next several years .
in fact , within about 6 years it is just possible that the whole of the parameter space in figure 6 will have been explored
. a number of indirect search experiments may produce useful complementary data , such as neutrino telescopes , -ray missions ( glast ) , or particle experiments ( ams ) .
detectors with directional response will have been developed at the prototype level , ready to become neutralino telescopes should the need arise .
supersymmetry and supergravity will have independent input from :
the large hadron collider , which will begin operation in 56 years time . within a few years of data taking
it should start to constrain much of the mssm and sugra parameter space.continued exploration of mssm and sugra models to refine calculations of scattering cross - sections .
the large hadron collider , which will begin operation in 56 years time .
within a few years of data taking it should start to constrain much of the mssm and sugra parameter space . continued exploration of mssm and sugra models to refine calculations of scattering cross - sections .
of course , the most satisfying scientific output would be the discovery of the neutralino as the dominant dark matter component of the milky way .
figure 17 shows two panels taken from in which the likely search areas to be completed by 2006 are delineated . the parameter space chosen for these plots has the universal scalar mass m0 and the gaugino mass m1/2 as the coordinates .
the two plots correspond to two illustrative values of tan. the solid dark green regions are already excluded . in the light green / yellow shaded area 0.025m1 , while in the blue shaded area 0.1m0.3 .
the curves then show which regions of parameter space are likely to be addressed over the coming years .
for each curve the forthcoming experiments will search the region between the curve and the dark green area .
the red curve corresponds to the direct search techniques such as the next generation of cdms , ccrest and ukdmc xenon experiments .
this curve should be reached in 23 years time . following that , there are already larger , better experiments being planned that could push further still .
the other curves shown correspond to various indirect search techniques , including -rays , neutrinos , and positrons .
the complementarity of the various techniques is apparent and multiple detections would provide a powerful diagnostic of susy parameters .
figure 17
expected progress in covering mssm parameter space from both indirect and direct search techniques over the next several years [
49
] .
expected progress in covering mssm parameter space from both indirect and direct search techniques over the next several years [
49
] .
the scientific impact of a positive neutralino detection would extend not only to cosmology and astrophysics in almost every aspect , but would also be of the utmost importance to supersymmetry and fundamental physics .
if , in addition to the neutralino , the axion is also implicated , then we will have a double bonanza , which also will verify the adopted solution to cp violation .
seldom has there been a problem that impinges on so many fundamentally important issues and this justifies the current level of activity on all fronts .[/INST]there is now an enormously rich variety of experimental techniques being brought to bear on experimental searches for dark matter , covering a wide range of suggested forms for it .
the existence of dark matter , in some form or other , is inferred from a number of relatively simple observations and the problem has been known for over half a century . to explain dark matter is one of the foremost challenges today the answer will be of fundamental importance to cosmologists , astrophysicists , particle physicists , and general relativists . in this article , i will give a brief review of the observational evidence ( concentrating on areas of current significant activity ) , followed by anequally brief summary of candidate solutions for the
dark matter. i will then discuss experimental searches , both direct and indirect .
finally , i will offer prospects for the future .</s> |
The death from deep-vein thrombosis (DVT) of a 36-year-old passenger on a transatlantic flight has provided a frightening reminder of the risks of taking sleeping pills on aircraft, particularly when travelling long-haul.
The New England Journal of Medicine reported last week that the woman, an American citizen, had taken a single sleeping tablet shortly before departure and spent most of the flight asleep in one position – undoubtedly the critical factor in her death.
Seven hours into the flight she woke to go to the lavatory, but collapsed in the aisle. A doctor on board attempted to resuscitate her and the plane made an emergency landing in Boston, touching down two hours after her collapse. She was taken to the Massachusetts General Hospital, where tests confirmed that she had suffered a massive pulmonary embolism – with blood clots from her legs travelling through the venous system and lodging in her heart and lungs, causing brain damage from lack of oxygen and an unrecoverable coma.
The doctors caring for her faced an unusual ethical dilemma, which is the main reason her case was reported in the Journal . Devastated by what had happened, the woman's family had asked if egg cells could be taken from her ovaries to enable a child to be conceived. The doctors explored the request but could not comply with it. Eleven days after she had boarded her flight, life support was discontinued and she died.
The implications for travellers are broader than this. Here was a fit and healthy young woman, for whom the only other risk factor for DVT was the fact that – in common with millions of other female passengers – she was using the contraceptive pill.
While in the air, many fliers try to shut out noise and – particularly when travelling long-haul – attempt to catch up on some sleep. A significant number – whether to avoid jetlag or because they are nervous fliers – rely on medication to help them drop off, thinking little of the potentially fatal consequences.
Unfortunately, the human body is simply not designed for deep sleep in a sitting position. Sitting compresses the veins of the pelvis, and slows down blood flow through the veins of the calves. Calf muscle contraction – simply moving around without restriction – counteracts this effect.
Reduced blood flow leads to stagnation, activation of the blood's innate clotting mechanism, and therefore an increased tendency for blood clots to form. Reduced oxygen pressure in the cabin increases the clotting tendency still further, and so too can a variety of individual medical factors (see right). In such circumstances, a sleeping pill can make things considerably worse – by relaxing calf muscles, reducing movement, and rendering the sleeping passenger motionless for hours, even in an uncomfortable and adverse position.
The message is clear. By all means, use mild sleeping medication to avoid sleep loss and reduce fatigue after a flight, when you have reached your destination and may be struggling to adapt to a new time zone. But if you want to use medication to help you sleep on a long-haul flight, you should only ever do so when you can lie flat and move your legs comfortably. Stick to short-acting medicines, wear compression stockings, and discuss all of the issues carefully with your doctor.
How to minimise the risk
The risk of DVT is highest on long-haul flights, and especially on flights longer than eight hours. It is also greatest in people who are obese, have varicose veins, are pregnant, smoke, use hormone replacement therapy or take the contraceptive pill.
Prevention consists of keeping well hydrated during a flight, stretching and moving around, and wearing compression stockings.
The risk is even higher for people who have a history of DVT or who have recently had surgery (particularly to hip or knee) or cancer; for these, a pre-flight injection of a blood-thinning drug may be advisable.
Remember, alcohol and sleeping tablets don't mix, and raise the risk of DVT even higher. ||||| Immobility, circulatory problems and deep vein thrombosis (DVT)
Contraction of muscles is an important factor in helping to keep blood flowing through the veins, particularly in the legs. Prolonged immobility, especially when seated, can lead to pooling of blood in the legs, which in turn may cause swelling, stiffness and discomfort.
It is known that immobility is one of the factors that may lead to the development of a blood clot in a deep vein – so-called “deep vein thrombosis” or DVT. Research has shown that DVT can occur as a result of prolonged immobility, for instance during long-distance travel, whether by car, bus, train or air. WHO set up a major research study, WHO Research Into Global Hazards of Travel (WRIGHT), in order to establish whether the risk of venous thromboembolism is increased by air travel, to determine the magnitude of the risk and the effect of other factors on the risk, and to study the effect of preventive measures. The findings of the epidemiological studies indicate that the risk of venous thromboembolism is increased 2- to 3-fold after long-haul flights (more than 4 h) and also with other forms of travel involving prolonged seated immobility. The risk increases with the duration of travel and with multiple flights within a short period. In absolute terms, an average of 1 passenger in 6000 will suffer from venous thromboembolism after a long-haul flight.
In most cases of DVT, the clots are small and do not cause any symptoms. The body is able to gradually break down the clots and there are no long-term effects. Larger clots may cause symptoms such as swelling of the leg, tenderness, soreness and pain. Occasionally a piece of a clot may break off and travel with the bloodstream, to become lodged in the lungs. This is known as pulmonary embolism and may cause chest pain, shortness of breath and, in severe cases, sudden death. This can occur many hours or even days after the formation of the clot in the leg.
The risk of developing DVT when travelling is increased in the presence of other risk factors, including:
previous DVT or pulmonary embolism
history of DVT or pulmonary embolism in a close family member
use of oestrogen therapy – oral contraceptives (“the pill”) or hormonereplacement therapy (HRT)
pregnancy
recent surgery or trauma, particularly to the abdomen, pelvic region or legs
cancer
obesity
some inherited blood-clotting abnormalities.
DVT occurs more commonly in older people. Some researchers have suggested that there may be a risk from smoking and from varicose veins.
It is advisable for people with one or more of these risk factors to seek specific medical advice from their doctor or a travel medicine clinic in good time before embarking on a flight of 4 or more hours.
Precautions
The benefits of most recommended precautionary measures in travellers at particular risk for DVT are unproven and some might even result in harm. Further studies to identify effective preventive measures are ongoing. However, some general advice for such passengers is given here. ||||| Spirit offers pitch of just 28 inches on some aircraft, though the silver lining is those seats don’t recline. (Photo: Andrew Itkoff for USA TODAY)
No, this isn't yet another examination of the Knee Defender, nor another rumination on the Right to Recline vs. the Right to Defend Against Recliners.
But in the hot debate over defending knees during the last month, I've noticed few have asked just why reclining seats are suddenly causing so much trouble aloft. Simply put, has legroom—and knee room—decreased in recent years? Have seats gotten smaller back in economy class where most of us fly? Have cabins gotten fuller?
The unequivocal answers are yes, yes and yes. And you'll have to deal with what appear to be irreversible trends.
Digging into the archives
In recent years I've sent many readers to the site SeatGuru.com, which provides a wealth of information for air travelers about in-flight seating and entertainment options offered by airlines worldwide. But long before the Internet, Consumer Reports conducted in-depth examinations of airline seat size and comfort, carrier by carrier and aircraft by aircraft, starting way back in 1985. I was the editor of Consumer Reports Travel Letter when we completed the final analysis in 2002 (with painstaking research conducted by Linda Burbank, USA TODAY's Traveler's Aide).
I dug out my old copies of CRTL to determine if it's myth that airline seats seem to have gotten smaller lately. I focused on the last four remaining "major" carriers in the United States, as defined by the U.S. Department of Transportation: American (AA), Delta (DL), United (UA) and Southwest (WN). Then I compared CRTL's findings to the latest data provided by SeatGuru for short-haul and long-haul coach/economy classes, eliminating extra-cost premium economy products.
What I found was quite surprising.
Seat pitch
Pitch—or the distance in inches from a given point on one seat to the same point on the seat in the next row—has indeed changed dramatically in economy class at the nation's four largest carriers over the last 30 years.
ECONOMY CLASS SEAT PITCH IN INCHES AA DL UA WN 1985 31-33 31-33 32-36 31-35 1989 31-34 31-32 32-34 31-32 1991 31-37 31-33 31-34 31-33 1995 31-33 32-33 31-34 31-32 2000 31-34 31-35 31-33 N/A 2002 32-35 30-33 31-33 N/A 2014 30-32 30-33 30-31* 31-33 *32 inches on Boeing 787 only Sources: Consumers Union; SeatGuru
As indicated, all of the Big Three—American, Delta and United—now offer at least some aircraft with a seat pitch of only 30 inches in economy. In years past, 31 or 32 inches were the absolute minimums. What's more, the roomiest pitch offered by the Big Three and Southwest (31-33 inches) are now tighter than they were at all four carriers in recent years, by anywhere from 2 to 5 inches. The only good news is some U.S. airlines are worse: Spirit offers pitch of just 28 inches on some aircraft, though the silver lining is those seats don't recline.
One contributing factor to this trend has been the dramatic outsourcing of the Big Three's "mainline" flights to regional carriers flying smaller aircraft. A government study recently found 61% of all advertised flights for American, Delta, United and US Airways (now merging with American) were operated by regionals in 2011, up from 40% in 2000.
Some airlines maintain design advances—such as slimline seats—only give the illusion of tighter quarters on paper even though pitch has indeed been reduced. But industry claims that passengers don't notice this have been refuted.
Seat width
Seat width has changed as well, and not for the better.
ECONOMY CLASS SEAT WIDTH IN INCHES AA DL UA WN 1985 19-20 19-20 19.5-20 19 1989 19-20 19-20 19-20 19 1991 19-20 18.5-20 19-20 19-19.5 1995* 2000 17.2-18.5 17-18 17-18 N/A 2002 17.2-18.4 17-18 17-18 N/A 2014 17.2-18.5 17.2-18.3 17-18.3 17 * All airlines ranged from 18.5-23 inches Sources: Consumers Union; SeatGuru
Simply put, the roomiest economy seats you can book on the nation's four largest airlines are narrower than the tightest economy seats offered in the 1990s. The worst seats today measure either 17 or 17.2 inches, when about 19 was as tight as it got through the 1990s. In fact, even the widest seats for sale in economy today—from 17 to 18.5 inches —would not have been offered several years ago. For comparison, up in the front of the cabin, premium class seating on the Big Three usually measures 21 inches.
The big squeeze has become a global problem. Last year the European aircraft maker Airbus suggested all airline seats be at least 18 inches wide, but the U.S. trade organization Airlines for America rejected the suggestion, stating, "We believe individual airlines should be able to determine fleet configurations that best meet their customers' needs, as they do today."
Meanwhile, demographics are moving in the wrong direction. In 2002, CRTL quoted a British ergonomics firm that provided data on human hip sizes worldwide. The result? Yep, the United States ranked first (20.6 inches), ahead of Germany (19.6), Britain (19.1), France (17.2), Japan (15.9) and China (15.6). It seems safe to say such averages have only increased over the last dozen years.
Load factors
As I've stated before, I believe the U.S. airline industry's conscious decision to dramatically increase load factors since the 1990s has been the single biggest contributor to passenger dissatisfaction with flying. Domestic cabins are fuller than at any time since airlines were troop carriers during World War II, and the misery index keeps rising.
U.S. AIRLINE PASSENGER LOAD FACTORS 1995 67% 1996 70% 1997 71% 1998 71% 1999 71% 2000 73% 2001 70% 2002 72% 2003 74% 2004 76% 2005 79% 2006 80% 2007 81% 2008 80% 2009 81% 2010 83% 2011 83% 2012 83% 2013 84% Source: MIT
Among U.S. airlines, loads averaged in the 50s and 60s for most of the 20th century, and didn't break the 70% mark until the 1990s. But as this chart indicates, with the exception of slight reversals after the 9/11 attacks in 2001 and the Great Recession in 2008, loads on U.S. airlines have been soaring to new heights for 20 years now—with no leveling off in sight. The latest monthly report from the DOT shows U.S. carriers posted a load factor of 86.4% for June; such a high average, of course, means many flights are at 100%.
Fuller flights mean more than just rubbing shoulders and elbows with strangers. As I noted here last year with "Overloaded! Crowded airline cabins reach new heights," there are far-reaching negative effects to these record loads, including boarding headaches, overhead bin shortages and increases in involuntary bumping.
Higher load factors also mean there are fewer empty seats, which directly affects your comfort. Consider a Boeing 737 with 144 seats, in a standard 3x3 configuration of 24 rows of six seats. A load factor of 80% means only 29 of 48 middle seats are unoccupied, and 90% means only 14 middles are empty.
The configuration of the aircraft is critical, because empty seats affect neighboring passengers on both sides. Thankfully, on wide-body aircraft with nine-across seating, the traditional 2x5x2 configuration has largely given way to a 3x3x3 model. A veteran Boeing engineer calculated this means "millions more passengers have been seated next to an empty seat." Years ago this same engineer told CRTL that an adjacent empty seat equals another 4.25 inches in width, roughly equivalent to an upgrade to business or first in some cases.
What can you do?
As the Knee Defender uproar made clear, tempers rise as cabins become tighter. In response, one airline official adopted a "let-them-eat-cake" pose and publicly suggested unhappy passengers should pay more to sit up front. Of course, that's not an option for many of us.
Consider the following when looking for more room:
• An upgrade may not be possible, but "extra legroom" seats are available on many carriers now for much less than sitting in business or first.
• Premium economy options can work for many budgets as well.
• Confirm your seat assignment as soon as you can, even though some airlines may make this difficult, as I noted in 2012 with "Are airlines withholding seats so you'll pay a premium?"
• As many travelers know, seats in door rows, emergency exit rows and bulkhead rows offer additional legroom, and the hassles of a recliner in front are eliminated.
• On wide-body aircraft, which often operate long-haul flights, experts suggest you select an "inside aisle" seat, since middle seats in the middle section often are assigned last.
• On airlines with open seating policies, paying extra to board early could be money well spent.
Bill McGee, a contributing editor to Consumer Reports and the former editor of Consumer Reports Travel Letter, is an FAA-licensed aircraft dispatcher who worked in airline operations and management for several years. Tell him what you think of his latest column by sending him an e-mail at [email protected]. Include your name, hometown and daytime phone number, and he may use your feedback in a future column.
Read or Share this story: https://www.usatoday.com/story/travel/columnist/mcgee/2014/09/24/airplane-reclining-seat-pitch-width/16105491/ ||||| Colin Savage has spent a lifetime staying fit and healthy, but one long airplane flight changed that.
Until recently, the 64-year-old Victoria man would cycle an average of 400 kilometres a week and run marathons. Now he is short of breath and has trouble moving around.
"I have much less energy because I can't take a lot of oxygen in. I'm shuffling around like a senior," Savage told Go Public.
"Doctors in hospital emergency told me that I nearly lost my life."
In January, Savage travelled to Argentina on a hiking trip. The trip home included a 10-hour flight from Chile to Toronto on an Air Canada 777 airplane.
Knee space is limited on economy flights. Top: Air Canada Rouge, Bottom: Air Canada Economy. (Gabor Lukacs/ Facebook)
Savage says for most of the flight, passengers were discouraged from getting out of their seats because of turbulence. At 6-2", that was a problem for Savage.
"In their seats, my knees were up against the seat in front of me. I was constantly squirming around trying to get comfortable."
A day and a half after he returned home, he felt a sudden sharp pain in his lower back. When it was still there the next morning he went to a hospital.
"I went through horrible pain, I don't know if you've broken a rib, I have, and this pain was a hundred times worse," Savage says.
Two CT scans later, doctors told Savage he had deep vein thrombosis (DVT), which was likely the result of having to sit for most of the 10-hour flight, and that blood clots had migrated up his leg, through his heart and into his lungs.
What is DVT?
DVT is a condition where a blood clot develops within a deep vein, usually in the thigh or leg. It can break off and make its way to the lungs, where it can cause breathing problems.
According to the World Health Organization, passengers traveling in cramped areas for more than four hours are at risk.
Dr. James Douketis, president of Thrombosis Canada, says given the number of people who fly, deep vein thrombosis poses a public health risk. (CBC)
Savage raised the DVT issue with Air Canada and got this response:
"Medical evidence has shown that deep vein thrombosis (DVT) is the result of a pre-existing personal medical condition, related to an individual rather than a transportation system. International courts have confirmed that based on the aforementioned evidence there is no liability to air carriers for DVT that occurs during a flight."
Air Canada told Go Public in an email there is no conclusive medical evidence specifically linking deep vein thrombosis with flying.
"The WHO have advised there is no risk with air travel for healthy passengers, and that long periods of immobility in trains, buses or cars carry similar risk," the airline wrote.
For information on deep vein thrombosis and how to avoid it, visit the World Health Organization website.
'Public health risk'
Airline passenger leg room has shrunk 10 centimetres in the last 20 years. (CBC)
There have been a lot of studies that look at the link between DVT and flying, but not a lot of well done studies, says Dr. James Douketis, the director of vascular medicine at St. Joseph's Healthcare in Hamilton.
"Most are not what we call methodologically rigorous or of a high scientific standard. What that means is, it makes a lot of the results murky," says Douketis, who is also president of Thrombosis Canada.
"We do know that airline travel increases your risk of blood clots. We know that the longer you travel the higher the risk, and we know that if you have predispositions — like recent surgeries or previous blood clots — your risk is highest."
DVT is the third most common vascular disease next to stroke and heart attack. Douketis says one in 5,000 travellers on long flights are affected.
Air Canada and WestJet combined fly more than 57 million passengers a year. It's not clear how many of those are long-haul flights.
"Even though the risk of a blood clot is low, given the number of people who fly, it became a public health risk," Douketis says.
Air Canada says many of its airplanes now have "slimline seats" that "save cabin space while maintaining the same personal space for passengers."
WestJet tells us it doesn't warn passengers about the risks of DVT and encourages travellers to speak with their doctors before flying.
Seat size shrinking
According to the website seatguru.com, the average distance between seat rows has declined to 79 centimetres, from more than 89 centimetres in the last two decades.
Airplane seats have shrunk three centimetres in the last two decades. (CBC)
The average seat size is 43 centimetres, down from 46 centimetres.
Seth Kaplan, the editor of Airline Weekly, an online magazine that covers the airline business, says airlines are packing in more seats to make more money.
Airline Weekly editor Seth Kaplan says shrinking passenger areas are a matter of 'economics' for airlines. (CBC)
"In some respects, Canada is very much the epicentre of this densification sensation, of airlines crowding more seats on airplanes ... Both the major airlines, WestJet and Air Canada, have done that," he said.
Kaplan points to a battle in the U.S. to stop the space shrinkage. Earlier this year, a Tennessee congressman introduced an amendment to a Federal Aviation Administration bill that would have mandated the amount of legroom for passengers. In the end, the idea was rejected.
"For airlines it's very simple: this is economics, they have one airplane, same two pilots, same two engines burning about the same amount of fuel, so they can can take those costs and divide them among more seats," Kaplan says.
This side of the border, Canadian passenger advocate Gabor Lukacs is calling for seat size standards in this country.
Airline passenger advocate Gabor Lukacs is calling for seat-size standards in Canada. (Andrew Vaughan/Canadian Press)
"I'm not proposing that everyone get more legroom. What I'm talking about is safety issues … how it affects health. Not simply comfort," Gabor says.
As for Savage, he says he is slowly recovering and starting to get his energy back. "The airlines need to take a good hard look at what they're doing and the government needs to lead them in that direction," he said.
Transport Canada does regulate the maximum number of seats allowed on different types of airplanes, but says those numbers are based on safety-related criteria like emergency evacuation times, not design or comfort.
"As long as the air operator meets specific safety-related criteria, they are permitted to install as many seats as they require," Transport Canada spokeswoman Natasha Gauthier tells Go Public.
The federal agency also says it has no plans to review the minimum requirements in seat size or pitch (a measure of leg room), adding "the size of the seat occupied is not known at this time to be a risk factor."
Read Colin Savage's letter from Transport Canada here.
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Follow @CBCGoPublic on Twitter. | – An Air Canada passenger says a cramped 10-hour flight from Chile to Toronto in January has taken a serious toll on his otherwise impeccable health, and he wants the airline to "take a good hard look at what they're doing," he tells the CBC. Colin Savage, a 64-year-old avid cyclist and marathon runner, journeyed to Argentina on a hiking trip. After turbulence forced the passengers to stay seated for most of the flight, Savage, who is 6-foot-2, reports being cramped against the seat in front of him. Almost two days after his return home, Savage says he felt severe pain in his lower back. Doctors told him that he had deep vein thrombosis, and that blood clots had traveled up his legs and into his lungs, nearly killing him. The World Health Organization says anyone who travels in a cramped space for more than four hours is at risk; the CDC cites the same number of hours. Air Canada said in a statement that the WHO "have advised there is no risk with air travel for healthy passengers" and that travel by train, bus, or car carries "similar risk." A 2010 Telegraph article on the death of a healthy 36-year-old woman who spent most of a transatlantic flight asleep and died after blood clots reached her heart and lungs explains the mechanics: The veins in the pelvis are somewhat squashed when seated, making for sluggish blood flow in the calves. The reduced flow helps raise the risk of clots, an issue exacerbated by reduced oxygen pressure. As far as cramped spaces go, USA Today reported that seat pitch—the distance from a point on one seat to the same point on the one behind it, and a good approximation of legroom—has shrunk 2 to 5 inches, based on carrier, in 20 years. And while airlines are making more extra-legroom seats available—the Wall Street Journal reports they make up more than a quarter of United's coach seats—travelers have to pay extra. (This four-hour flight took 30 hours.) | <s>[INST]The death from deep-vein thrombosis (DVT) of a 36-year-old passenger on a transatlantic flight has provided a frightening reminder of the risks of taking sleeping pills on aircraft, particularly when travelling long-haul.
The New England Journal of Medicine reported last week that the woman, an American citizen, had taken a single sleeping tablet shortly before departure and spent most of the flight asleep in one position – undoubtedly the critical factor in her death.
Seven hours into the flight she woke to go to the lavatory, but collapsed in the aisle. A doctor on board attempted to resuscitate her and the plane made an emergency landing in Boston, touching down two hours after her collapse. She was taken to the Massachusetts General Hospital, where tests confirmed that she had suffered a massive pulmonary embolism – with blood clots from her legs travelling through the venous system and lodging in her heart and lungs, causing brain damage from lack of oxygen and an unrecoverable coma.
The doctors caring for her faced an unusual ethical dilemma, which is the main reason her case was reported in the Journal . Devastated by what had happened, the woman's family had asked if egg cells could be taken from her ovaries to enable a child to be conceived. The doctors explored the request but could not comply with it. Eleven days after she had boarded her flight, life support was discontinued and she died.
The implications for travellers are broader than this. Here was a fit and healthy young woman, for whom the only other risk factor for DVT was the fact that – in common with millions of other female passengers – she was using the contraceptive pill.
While in the air, many fliers try to shut out noise and – particularly when travelling long-haul – attempt to catch up on some sleep. A significant number – whether to avoid jetlag or because they are nervous fliers – rely on medication to help them drop off, thinking little of the potentially fatal consequences.
Unfortunately, the human body is simply not designed for deep sleep in a sitting position. Sitting compresses the veins of the pelvis, and slows down blood flow through the veins of the calves. Calf muscle contraction – simply moving around without restriction – counteracts this effect.
Reduced blood flow leads to stagnation, activation of the blood's innate clotting mechanism, and therefore an increased tendency for blood clots to form. Reduced oxygen pressure in the cabin increases the clotting tendency still further, and so too can a variety of individual medical factors (see right). In such circumstances, a sleeping pill can make things considerably worse – by relaxing calf muscles, reducing movement, and rendering the sleeping passenger motionless for hours, even in an uncomfortable and adverse position.
The message is clear. By all means, use mild sleeping medication to avoid sleep loss and reduce fatigue after a flight, when you have reached your destination and may be struggling to adapt to a new time zone. But if you want to use medication to help you sleep on a long-haul flight, you should only ever do so when you can lie flat and move your legs comfortably. Stick to short-acting medicines, wear compression stockings, and discuss all of the issues carefully with your doctor.
How to minimise the risk
The risk of DVT is highest on long-haul flights, and especially on flights longer than eight hours. It is also greatest in people who are obese, have varicose veins, are pregnant, smoke, use hormone replacement therapy or take the contraceptive pill.
Prevention consists of keeping well hydrated during a flight, stretching and moving around, and wearing compression stockings.
The risk is even higher for people who have a history of DVT or who have recently had surgery (particularly to hip or knee) or cancer; for these, a pre-flight injection of a blood-thinning drug may be advisable.
Remember, alcohol and sleeping tablets don't mix, and raise the risk of DVT even higher. ||||| Immobility, circulatory problems and deep vein thrombosis (DVT)
Contraction of muscles is an important factor in helping to keep blood flowing through the veins, particularly in the legs. Prolonged immobility, especially when seated, can lead to pooling of blood in the legs, which in turn may cause swelling, stiffness and discomfort.
It is known that immobility is one of the factors that may lead to the development of a blood clot in a deep vein – so-called “deep vein thrombosis” or DVT. Research has shown that DVT can occur as a result of prolonged immobility, for instance during long-distance travel, whether by car, bus, train or air. WHO set up a major research study, WHO Research Into Global Hazards of Travel (WRIGHT), in order to establish whether the risk of venous thromboembolism is increased by air travel, to determine the magnitude of the risk and the effect of other factors on the risk, and to study the effect of preventive measures. The findings of the epidemiological studies indicate that the risk of venous thromboembolism is increased 2- to 3-fold after long-haul flights (more than 4 h) and also with other forms of travel involving prolonged seated immobility. The risk increases with the duration of travel and with multiple flights within a short period. In absolute terms, an average of 1 passenger in 6000 will suffer from venous thromboembolism after a long-haul flight.
In most cases of DVT, the clots are small and do not cause any symptoms. The body is able to gradually break down the clots and there are no long-term effects. Larger clots may cause symptoms such as swelling of the leg, tenderness, soreness and pain. Occasionally a piece of a clot may break off and travel with the bloodstream, to become lodged in the lungs. This is known as pulmonary embolism and may cause chest pain, shortness of breath and, in severe cases, sudden death. This can occur many hours or even days after the formation of the clot in the leg.
The risk of developing DVT when travelling is increased in the presence of other risk factors, including:
previous DVT or pulmonary embolism
history of DVT or pulmonary embolism in a close family member
use of oestrogen therapy – oral contraceptives (“the pill”) or hormonereplacement therapy (HRT)
pregnancy
recent surgery or trauma, particularly to the abdomen, pelvic region or legs
cancer
obesity
some inherited blood-clotting abnormalities.
DVT occurs more commonly in older people. Some researchers have suggested that there may be a risk from smoking and from varicose veins.
It is advisable for people with one or more of these risk factors to seek specific medical advice from their doctor or a travel medicine clinic in good time before embarking on a flight of 4 or more hours.
Precautions
The benefits of most recommended precautionary measures in travellers at particular risk for DVT are unproven and some might even result in harm. Further studies to identify effective preventive measures are ongoing. However, some general advice for such passengers is given here. ||||| Spirit offers pitch of just 28 inches on some aircraft, though the silver lining is those seats don’t recline. (Photo: Andrew Itkoff for USA TODAY)
No, this isn't yet another examination of the Knee Defender, nor another rumination on the Right to Recline vs. the Right to Defend Against Recliners.
But in the hot debate over defending knees during the last month, I've noticed few have asked just why reclining seats are suddenly causing so much trouble aloft. Simply put, has legroom—and knee room—decreased in recent years? Have seats gotten smaller back in economy class where most of us fly? Have cabins gotten fuller?
The unequivocal answers are yes, yes and yes. And you'll have to deal with what appear to be irreversible trends.
Digging into the archives
In recent years I've sent many readers to the site SeatGuru.com, which provides a wealth of information for air travelers about in-flight seating and entertainment options offered by airlines worldwide. But long before the Internet, Consumer Reports conducted in-depth examinations of airline seat size and comfort, carrier by carrier and aircraft by aircraft, starting way back in 1985. I was the editor of Consumer Reports Travel Letter when we completed the final analysis in 2002 (with painstaking research conducted by Linda Burbank, USA TODAY's Traveler's Aide).
I dug out my old copies of CRTL to determine if it's myth that airline seats seem to have gotten smaller lately. I focused on the last four remaining "major" carriers in the United States, as defined by the U.S. Department of Transportation: American (AA), Delta (DL), United (UA) and Southwest (WN). Then I compared CRTL's findings to the latest data provided by SeatGuru for short-haul and long-haul coach/economy classes, eliminating extra-cost premium economy products.
What I found was quite surprising.
Seat pitch
Pitch—or the distance in inches from a given point on one seat to the same point on the seat in the next row—has indeed changed dramatically in economy class at the nation's four largest carriers over the last 30 years.
ECONOMY CLASS SEAT PITCH IN INCHES AA DL UA WN 1985 31-33 31-33 32-36 31-35 1989 31-34 31-32 32-34 31-32 1991 31-37 31-33 31-34 31-33 1995 31-33 32-33 31-34 31-32 2000 31-34 31-35 31-33 N/A 2002 32-35 30-33 31-33 N/A 2014 30-32 30-33 30-31* 31-33 *32 inches on Boeing 787 only Sources: Consumers Union; SeatGuru
As indicated, all of the Big Three—American, Delta and United—now offer at least some aircraft with a seat pitch of only 30 inches in economy. In years past, 31 or 32 inches were the absolute minimums. What's more, the roomiest pitch offered by the Big Three and Southwest (31-33 inches) are now tighter than they were at all four carriers in recent years, by anywhere from 2 to 5 inches. The only good news is some U.S. airlines are worse: Spirit offers pitch of just 28 inches on some aircraft, though the silver lining is those seats don't recline.
One contributing factor to this trend has been the dramatic outsourcing of the Big Three's "mainline" flights to regional carriers flying smaller aircraft. A government study recently found 61% of all advertised flights for American, Delta, United and US Airways (now merging with American) were operated by regionals in 2011, up from 40% in 2000.
Some airlines maintain design advances—such as slimline seats—only give the illusion of tighter quarters on paper even though pitch has indeed been reduced. But industry claims that passengers don't notice this have been refuted.
Seat width
Seat width has changed as well, and not for the better.
ECONOMY CLASS SEAT WIDTH IN INCHES AA DL UA WN 1985 19-20 19-20 19.5-20 19 1989 19-20 19-20 19-20 19 1991 19-20 18.5-20 19-20 19-19.5 1995* 2000 17.2-18.5 17-18 17-18 N/A 2002 17.2-18.4 17-18 17-18 N/A 2014 17.2-18.5 17.2-18.3 17-18.3 17 * All airlines ranged from 18.5-23 inches Sources: Consumers Union; SeatGuru
Simply put, the roomiest economy seats you can book on the nation's four largest airlines are narrower than the tightest economy seats offered in the 1990s. The worst seats today measure either 17 or 17.2 inches, when about 19 was as tight as it got through the 1990s. In fact, even the widest seats for sale in economy today—from 17 to 18.5 inches —would not have been offered several years ago. For comparison, up in the front of the cabin, premium class seating on the Big Three usually measures 21 inches.
The big squeeze has become a global problem. Last year the European aircraft maker Airbus suggested all airline seats be at least 18 inches wide, but the U.S. trade organization Airlines for America rejected the suggestion, stating, "We believe individual airlines should be able to determine fleet configurations that best meet their customers' needs, as they do today."
Meanwhile, demographics are moving in the wrong direction. In 2002, CRTL quoted a British ergonomics firm that provided data on human hip sizes worldwide. The result? Yep, the United States ranked first (20.6 inches), ahead of Germany (19.6), Britain (19.1), France (17.2), Japan (15.9) and China (15.6). It seems safe to say such averages have only increased over the last dozen years.
Load factors
As I've stated before, I believe the U.S. airline industry's conscious decision to dramatically increase load factors since the 1990s has been the single biggest contributor to passenger dissatisfaction with flying. Domestic cabins are fuller than at any time since airlines were troop carriers during World War II, and the misery index keeps rising.
U.S. AIRLINE PASSENGER LOAD FACTORS 1995 67% 1996 70% 1997 71% 1998 71% 1999 71% 2000 73% 2001 70% 2002 72% 2003 74% 2004 76% 2005 79% 2006 80% 2007 81% 2008 80% 2009 81% 2010 83% 2011 83% 2012 83% 2013 84% Source: MIT
Among U.S. airlines, loads averaged in the 50s and 60s for most of the 20th century, and didn't break the 70% mark until the 1990s. But as this chart indicates, with the exception of slight reversals after the 9/11 attacks in 2001 and the Great Recession in 2008, loads on U.S. airlines have been soaring to new heights for 20 years now—with no leveling off in sight. The latest monthly report from the DOT shows U.S. carriers posted a load factor of 86.4% for June; such a high average, of course, means many flights are at 100%.
Fuller flights mean more than just rubbing shoulders and elbows with strangers. As I noted here last year with "Overloaded! Crowded airline cabins reach new heights," there are far-reaching negative effects to these record loads, including boarding headaches, overhead bin shortages and increases in involuntary bumping.
Higher load factors also mean there are fewer empty seats, which directly affects your comfort. Consider a Boeing 737 with 144 seats, in a standard 3x3 configuration of 24 rows of six seats. A load factor of 80% means only 29 of 48 middle seats are unoccupied, and 90% means only 14 middles are empty.
The configuration of the aircraft is critical, because empty seats affect neighboring passengers on both sides. Thankfully, on wide-body aircraft with nine-across seating, the traditional 2x5x2 configuration has largely given way to a 3x3x3 model. A veteran Boeing engineer calculated this means "millions more passengers have been seated next to an empty seat." Years ago this same engineer told CRTL that an adjacent empty seat equals another 4.25 inches in width, roughly equivalent to an upgrade to business or first in some cases.
What can you do?
As the Knee Defender uproar made clear, tempers rise as cabins become tighter. In response, one airline official adopted a "let-them-eat-cake" pose and publicly suggested unhappy passengers should pay more to sit up front. Of course, that's not an option for many of us.
Consider the following when looking for more room:
• An upgrade may not be possible, but "extra legroom" seats are available on many carriers now for much less than sitting in business or first.
• Premium economy options can work for many budgets as well.
• Confirm your seat assignment as soon as you can, even though some airlines may make this difficult, as I noted in 2012 with "Are airlines withholding seats so you'll pay a premium?"
• As many travelers know, seats in door rows, emergency exit rows and bulkhead rows offer additional legroom, and the hassles of a recliner in front are eliminated.
• On wide-body aircraft, which often operate long-haul flights, experts suggest you select an "inside aisle" seat, since middle seats in the middle section often are assigned last.
• On airlines with open seating policies, paying extra to board early could be money well spent.
Bill McGee, a contributing editor to Consumer Reports and the former editor of Consumer Reports Travel Letter, is an FAA-licensed aircraft dispatcher who worked in airline operations and management for several years. Tell him what you think of his latest column by sending him an e-mail at [email protected]. Include your name, hometown and daytime phone number, and he may use your feedback in a future column.
Read or Share this story: https://www.usatoday.com/story/travel/columnist/mcgee/2014/09/24/airplane-reclining-seat-pitch-width/16105491/ ||||| Colin Savage has spent a lifetime staying fit and healthy, but one long airplane flight changed that.
Until recently, the 64-year-old Victoria man would cycle an average of 400 kilometres a week and run marathons. Now he is short of breath and has trouble moving around.
"I have much less energy because I can't take a lot of oxygen in. I'm shuffling around like a senior," Savage told Go Public.
"Doctors in hospital emergency told me that I nearly lost my life."
In January, Savage travelled to Argentina on a hiking trip. The trip home included a 10-hour flight from Chile to Toronto on an Air Canada 777 airplane.
Knee space is limited on economy flights. Top: Air Canada Rouge, Bottom: Air Canada Economy. (Gabor Lukacs/ Facebook)
Savage says for most of the flight, passengers were discouraged from getting out of their seats because of turbulence. At 6-2", that was a problem for Savage.
"In their seats, my knees were up against the seat in front of me. I was constantly squirming around trying to get comfortable."
A day and a half after he returned home, he felt a sudden sharp pain in his lower back. When it was still there the next morning he went to a hospital.
"I went through horrible pain, I don't know if you've broken a rib, I have, and this pain was a hundred times worse," Savage says.
Two CT scans later, doctors told Savage he had deep vein thrombosis (DVT), which was likely the result of having to sit for most of the 10-hour flight, and that blood clots had migrated up his leg, through his heart and into his lungs.
What is DVT?
DVT is a condition where a blood clot develops within a deep vein, usually in the thigh or leg. It can break off and make its way to the lungs, where it can cause breathing problems.
According to the World Health Organization, passengers traveling in cramped areas for more than four hours are at risk.
Dr. James Douketis, president of Thrombosis Canada, says given the number of people who fly, deep vein thrombosis poses a public health risk. (CBC)
Savage raised the DVT issue with Air Canada and got this response:
"Medical evidence has shown that deep vein thrombosis (DVT) is the result of a pre-existing personal medical condition, related to an individual rather than a transportation system. International courts have confirmed that based on the aforementioned evidence there is no liability to air carriers for DVT that occurs during a flight."
Air Canada told Go Public in an email there is no conclusive medical evidence specifically linking deep vein thrombosis with flying.
"The WHO have advised there is no risk with air travel for healthy passengers, and that long periods of immobility in trains, buses or cars carry similar risk," the airline wrote.
For information on deep vein thrombosis and how to avoid it, visit the World Health Organization website.
'Public health risk'
Airline passenger leg room has shrunk 10 centimetres in the last 20 years. (CBC)
There have been a lot of studies that look at the link between DVT and flying, but not a lot of well done studies, says Dr. James Douketis, the director of vascular medicine at St. Joseph's Healthcare in Hamilton.
"Most are not what we call methodologically rigorous or of a high scientific standard. What that means is, it makes a lot of the results murky," says Douketis, who is also president of Thrombosis Canada.
"We do know that airline travel increases your risk of blood clots. We know that the longer you travel the higher the risk, and we know that if you have predispositions — like recent surgeries or previous blood clots — your risk is highest."
DVT is the third most common vascular disease next to stroke and heart attack. Douketis says one in 5,000 travellers on long flights are affected.
Air Canada and WestJet combined fly more than 57 million passengers a year. It's not clear how many of those are long-haul flights.
"Even though the risk of a blood clot is low, given the number of people who fly, it became a public health risk," Douketis says.
Air Canada says many of its airplanes now have "slimline seats" that "save cabin space while maintaining the same personal space for passengers."
WestJet tells us it doesn't warn passengers about the risks of DVT and encourages travellers to speak with their doctors before flying.
Seat size shrinking
According to the website seatguru.com, the average distance between seat rows has declined to 79 centimetres, from more than 89 centimetres in the last two decades.
Airplane seats have shrunk three centimetres in the last two decades. (CBC)
The average seat size is 43 centimetres, down from 46 centimetres.
Seth Kaplan, the editor of Airline Weekly, an online magazine that covers the airline business, says airlines are packing in more seats to make more money.
Airline Weekly editor Seth Kaplan says shrinking passenger areas are a matter of 'economics' for airlines. (CBC)
"In some respects, Canada is very much the epicentre of this densification sensation, of airlines crowding more seats on airplanes ... Both the major airlines, WestJet and Air Canada, have done that," he said.
Kaplan points to a battle in the U.S. to stop the space shrinkage. Earlier this year, a Tennessee congressman introduced an amendment to a Federal Aviation Administration bill that would have mandated the amount of legroom for passengers. In the end, the idea was rejected.
"For airlines it's very simple: this is economics, they have one airplane, same two pilots, same two engines burning about the same amount of fuel, so they can can take those costs and divide them among more seats," Kaplan says.
This side of the border, Canadian passenger advocate Gabor Lukacs is calling for seat size standards in this country.
Airline passenger advocate Gabor Lukacs is calling for seat-size standards in Canada. (Andrew Vaughan/Canadian Press)
"I'm not proposing that everyone get more legroom. What I'm talking about is safety issues … how it affects health. Not simply comfort," Gabor says.
As for Savage, he says he is slowly recovering and starting to get his energy back. "The airlines need to take a good hard look at what they're doing and the government needs to lead them in that direction," he said.
Transport Canada does regulate the maximum number of seats allowed on different types of airplanes, but says those numbers are based on safety-related criteria like emergency evacuation times, not design or comfort.
"As long as the air operator meets specific safety-related criteria, they are permitted to install as many seats as they require," Transport Canada spokeswoman Natasha Gauthier tells Go Public.
The federal agency also says it has no plans to review the minimum requirements in seat size or pitch (a measure of leg room), adding "the size of the seat occupied is not known at this time to be a risk factor."
Read Colin Savage's letter from Transport Canada here.
CBC News Investigates: Stories, videos, photos and more
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We tell your stories and hold the powers that be accountable.
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Submit your story ideas at Go Public.
Follow @CBCGoPublic on Twitter.[/INST]– An Air Canada passenger says a cramped 10-hour flight from Chile to Toronto in January has taken a serious toll on his otherwise impeccable health, and he wants the airline to "take a good hard look at what they're doing," he tells the CBC. Colin Savage, a 64-year-old avid cyclist and marathon runner, journeyed to Argentina on a hiking trip. After turbulence forced the passengers to stay seated for most of the flight, Savage, who is 6-foot-2, reports being cramped against the seat in front of him. Almost two days after his return home, Savage says he felt severe pain in his lower back. Doctors told him that he had deep vein thrombosis, and that blood clots had traveled up his legs and into his lungs, nearly killing him. The World Health Organization says anyone who travels in a cramped space for more than four hours is at risk; the CDC cites the same number of hours. Air Canada said in a statement that the WHO "have advised there is no risk with air travel for healthy passengers" and that travel by train, bus, or car carries "similar risk." A 2010 Telegraph article on the death of a healthy 36-year-old woman who spent most of a transatlantic flight asleep and died after blood clots reached her heart and lungs explains the mechanics: The veins in the pelvis are somewhat squashed when seated, making for sluggish blood flow in the calves. The reduced flow helps raise the risk of clots, an issue exacerbated by reduced oxygen pressure. As far as cramped spaces go, USA Today reported that seat pitch—the distance from a point on one seat to the same point on the one behind it, and a good approximation of legroom—has shrunk 2 to 5 inches, based on carrier, in 20 years. And while airlines are making more extra-legroom seats available—the Wall Street Journal reports they make up more than a quarter of United's coach seats—travelers have to pay extra. (This four-hour flight took 30 hours.)</s> |
SECTION 1. SHORT TITLE AND TABLE OF CONTENTS.
(a) Short Title.--This Act may be cited as the ``United States-
India Nuclear Cooperation Approval and Nonproliferation Enhancement
Act''.
(b) Table of Contents.--The table of contents for this Act is as
follows:
Sec. 1. Short title and table of contents.
Sec. 2. Definitions.
TITLE I--APPROVAL OF UNITED STATES-INDIA AGREEMENT FOR COOPERATION ON
PEACEFUL USES OF NUCLEAR ENERGY
Sec. 101. Approval of Agreement.
Sec. 102. Declarations of policy; certification requirement; rule of
construction.
Sec. 103. Additional Protocol between India and the IAEA.
Sec. 104. Implementation of Safeguards Agreement between India and the
IAEA.
Sec. 105. Modified reporting to Congress.
TITLE II--STRENGTHENING UNITED STATES NONPROLIFERATION LAW RELATING TO
PEACEFUL NUCLEAR COOPERATION
Sec. 201. Procedures regarding a subsequent arrangement on reprocessing.
Sec. 202. Initiatives and negotiations relating to agreements for
peaceful nuclear cooperation.
Sec. 203. Actions required for resumption of peaceful nuclear
cooperation.
Sec. 204. United States Government policy at the Nuclear Suppliers Group
to strengthen the international nuclear nonproliferation
regime.
Sec. 205. Conforming amendments.
SEC. 2. DEFINITIONS.
In this Act:
(1) Agreement.--The term ``United States-India Agreement for
Cooperation on Peaceful Uses of Nuclear Energy'' or ``Agreement''
means the Agreement for Cooperation Between the Government of the
United States of America and the Government of India Concerning
Peaceful Uses of Nuclear Energy that was transmitted to Congress by
the President on September 10, 2008.
(2) Appropriate congressional committees.--The term
``appropriate congressional committees'' means the Committee on
Foreign Affairs of the House of Representatives and the Committee
on Foreign Relations of the Senate.
TITLE I--APPROVAL OF UNITED STATES-INDIA AGREEMENT FOR COOPERATION ON
PEACEFUL USES OF NUCLEAR ENERGY
SEC. 101. APPROVAL OF AGREEMENT.
(a) In General.--Notwithstanding the provisions for congressional
consideration and approval of a proposed agreement for cooperation in
section 123 b. and d. of the Atomic Energy Act of 1954 (42 U.S.C. 2153
(b) and (d)), Congress hereby approves the United States-India
Agreement for Cooperation on Peaceful Uses of Nuclear Energy, subject
to subsection (b).
(b) Applicability of Atomic Energy Act of 1954, Hyde Act, and Other
Provisions of Law.--The Agreement shall be subject to the provisions of
the Atomic Energy Act of 1954 (42 U.S.C. 2011 et seq.), the Henry J.
Hyde United States-India Peaceful Atomic Energy Cooperation Act of 2006
(22 U.S.C. 8001 et. seq; Public Law 109-401), and any other applicable
United States law as if the Agreement had been approved pursuant to the
provisions for congressional consideration and approval of a proposed
agreement for cooperation in section 123 b. and d. of the Atomic Energy
Act of 1954.
(c) Sunset of Exemption Authority Under Hyde Act.--Section 104(f)
of the Henry J. Hyde United States-India Peaceful Atomic Energy
Cooperation Act of 2006 (22 U.S.C. 8003(f)) is amended by striking
``the enactment of'' and all that follows through ``agreement'' and
inserting ``the date of the enactment of the United States-India
Nuclear Cooperation Approval and Nonproliferation Enhancement Act''.
SEC. 102. DECLARATIONS OF POLICY; CERTIFICATION REQUIREMENT; RULE
OF CONSTRUCTION.
(a) Declarations of Policy Relating to Meaning and Legal Effect of
Agreement.--Congress declares that it is the understanding of the
United States that the provisions of the United States-India Agreement
for Cooperation on Peaceful Uses of Nuclear Energy have the meanings
conveyed in the authoritative representations provided by the President
and his representatives to the Congress and its committees prior to
September 20, 2008, regarding the meaning and legal effect of the
Agreement.
(b) Declarations of Policy Relating to Transfer of Nuclear
Equipment, Materials, and Technology to India.--Congress makes the
following declarations of policy:
(1) Pursuant to section 103(a)(6) of the Henry J. Hyde United
States-India Peaceful Atomic Energy Cooperation Act of 2006 (22
U.S.C. 8002(a)(6)), in the event that nuclear transfers to India
are suspended or terminated pursuant to title I of such Act (22
U.S.C. 8001 et seq.), the Atomic Energy Act of 1954 (42 U.S.C. 2011
et seq.), or any other United States law, it is the policy of the
United States to seek to prevent the transfer to India of nuclear
equipment, materials, or technology from other participating
governments in the Nuclear Suppliers Group (NSG) or from any other
source.
(2) Pursuant to section 103(b)(10) of the Henry J. Hyde United
States-India Peaceful Atomic Energy Cooperation Act of 2006 (22
U.S.C. 8002(b)(10)), any nuclear power reactor fuel reserve
provided to the Government of India for use in safeguarded civilian
nuclear facilities should be commensurate with reasonable reactor
operating requirements.
(c) Certification Requirement.--Before exchanging diplomatic notes
pursuant to Article 16(1) of the Agreement, the President shall certify
to Congress that entry into force and implementation of the Agreement
pursuant to its terms is consistent with the obligation of the United
States under the Treaty on the Non-Proliferation of Nuclear Weapons,
done at Washington, London, and Moscow July 1, 1968, and entered into
force March 5, 1970 (commonly known as the ``Nuclear Non-Proliferation
Treaty''), not in any way to assist, encourage, or induce India to
manufacture or otherwise acquire nuclear weapons or other nuclear
explosive devices.
(d) Rule of Construction.--Nothing in the Agreement shall be
construed to supersede the legal requirements of the Henry J. Hyde
United States-India Peaceful Atomic Energy Cooperation Act of 2006 or
the Atomic Energy Act of 1954.
SEC. 103. ADDITIONAL PROTOCOL BETWEEN INDIA AND THE IAEA.
Congress urges the Government of India to sign and adhere to an
Additional Protocol with the International Atomic Energy Agency (IAEA),
consistent with IAEA principles, practices, and policies, at the
earliest possible date.
SEC. 104. IMPLEMENTATION OF SAFEGUARDS AGREEMENT BETWEEN INDIA AND
THE IAEA.
Licenses may be issued by the Nuclear Regulatory Commission for
transfers pursuant to the Agreement only after the President determines
and certifies to Congress that--
(1) the Agreement Between the Government of India and the
International Atomic Energy Agency for the Application of
Safeguards to Civilian Nuclear Facilities, as approved by the Board
of Governors of the International Atomic Energy Agency on August 1,
2008 (the ``Safeguards Agreement''), has entered into force; and
(2) the Government of India has filed a declaration of
facilities pursuant to paragraph 13 of the Safeguards Agreement
that is not materially inconsistent with the facilities and
schedule described in paragraph 14 of the separation plan presented
in the national parliament of India on May 11, 2006, taking into
account the later initiation of safeguards than was anticipated in
the separation plan.
SEC. 105. MODIFIED REPORTING TO CONGRESS.
(a) Information on Nuclear Activities of India.--Subsection (g)(1)
of section 104 of the Henry J. Hyde United States-India Peaceful Atomic
Energy Cooperation Act of 2006 (22 U.S.C. 8003) is amended--
(1) by redesignating subparagraphs (B), (C), and (D) as
subparagraphs (C), (D), and (E), respectively; and
(2) by inserting after subparagraph (A) the following new
subparagraph:
``(B) any material inconsistencies between the content or
timeliness of notifications by the Government of India pursuant
to paragraph 14(a) of the Safeguards Agreement and the
facilities and schedule described in paragraph (14) of the
separation plan presented in the national parliament of India
on May 11, 2006, taking into account the later initiation of
safeguards than was anticipated in the separation plan;''.
(b) Implementation and Compliance Report.--Subsection (g)(2) of
such section is amended--
(1) in subparagraph (K)(iv), by striking ``and'' at the end;
(2) in subparagraph (L), by striking the period at the end and
inserting ``; and''; and
(3) by adding at the end the following new subparagraph:
``(M) with respect to the United States-India Agreement for
Cooperation on Peaceful Uses of Nuclear Energy (hereinafter in
this subparagraph referred to as the `Agreement') approved
under section 101(a) of the United States-India Nuclear
Cooperation Approval and Nonproliferation Enhancement Act--
``(i) a listing of--
``(I) all provision of sensitive nuclear technology
to India, and other such information as may be so
designated by the United States or India under Article
1(Q); and
``(II) all facilities in India notified pursuant to
Article 7(1) of the Agreement;
``(ii) a description of--
``(I) any agreed safeguards or any other form of
verification for by-product material decided by mutual
agreement pursuant to the terms of Article 1(A) of the
Agreement;
``(II) research and development undertaken in such
areas as may be agreed between the United States and
India as detailed in Article 2(2)(a.) of the Agreement;
``(III) the civil nuclear cooperation activities
undertaken under Article 2(2)(d.) of the Agreement;
``(IV) any United States efforts to help India
develop a strategic reserve of nuclear fuel as called
for in Article 2(2)(e.) of the Agreement;
``(V) any United States efforts to fulfill
political commitments made in Article 5(6) of the
Agreement;
``(VI) any negotiations that have occurred or are
ongoing under Article 6(iii.) of the Agreement; and
``(VII) any transfers beyond the territorial
jurisdiction of India pursuant to Article 7(2) of the
Agreement, including a listing of the receiving country
of each such transfer;
``(iii) an analysis of--
``(I) any instances in which the United States or
India requested consultations arising from concerns
over compliance with the provisions of Article 7(1) of
the Agreement, and the results of such consultations;
and
``(II) any matters not otherwise identified in this
report that have become the subject of consultations
pursuant to Article 13(2) of the Agreement, and a
statement as to whether such matters were resolved by
the end of the reporting period; and
``(iv) a statement as to whether--
``(I) any consultations are expected to occur under
Article 16(5) of the Agreement; and
``(II) any enrichment is being carried out pursuant
to Article 6 of the Agreement.''.
TITLE II--STRENGTHENING UNITED STATES NONPROLIFERATION LAW RELATING TO
PEACEFUL NUCLEAR COOPERATION
SEC. 201. PROCEDURES REGARDING A SUBSEQUENT ARRANGEMENT ON
REPROCESSING.
(a) In General.--Notwithstanding section 131 of the Atomic Energy
Act of 1954 (42 U.S.C. 2160), no proposed subsequent arrangement
concerning arrangements and procedures regarding reprocessing or other
alteration in form or content, as provided for in Article 6 of the
Agreement, shall take effect until the requirements specified in
subsection (b) are met.
(b) Requirements.--The requirements referred to in subsection (a)
are the following:
(1) The President transmits to the appropriate congressional
committees a report containing--
(A) the reasons for entering into such proposed subsequent
arrangement;
(B) a detailed description, including the text, of such
proposed subsequent arrangement; and
(C) a certification that the United States will pursue
efforts to ensure that any other nation that permits India to
reprocess or otherwise alter in form or content nuclear
material that the nation has transferred to India or nuclear
material and by-product material used in or produced through
the use of nuclear material, non-nuclear material, or equipment
that it has transferred to India requires India to do so under
similar arrangements and procedures.
(2) A period of 30 days of continuous session (as defined by
section 130 g.(2) of the Atomic Energy Act of 1954 (42 U.S.C. 2159
(g)(2)) has elapsed after transmittal of the report required under
paragraph (1).
(c) Resolution of Disapproval.--Notwithstanding the requirements in
subsection (b) having been met, a subsequent arrangement referred to in
subsection (a) shall not become effective if during the time specified
in subsection (b)(2), Congress adopts, and there is enacted, a joint
resolution stating in substance that Congress does not favor such
subsequent arrangement. Any such resolution shall be considered
pursuant to the procedures set forth in section 130 i. of the Atomic
Energy Act of 1954 (42 U.S.C. 2159 (i)), as amended by section 205 of
this Act.
SEC. 202. INITIATIVES AND NEGOTIATIONS RELATING TO AGREEMENTS FOR
PEACEFUL NUCLEAR COOPERATION.
Section 123 of the Atomic Energy Act of 1954 (42 U.S.C. 2153) is
amended by adding at the end the following:
``e. The President shall keep the Committee on Foreign
Affairs of the House of Representatives and the Committee on
Foreign Relations of the Senate fully and currently informed of
any initiative or negotiations relating to a new or amended
agreement for peaceful nuclear cooperation pursuant to this
section (except an agreement arranged pursuant to section 91
c., 144 b., 144 c., or 144 d., or an amendment thereto).''.
SEC. 203. ACTIONS REQUIRED FOR RESUMPTION OF PEACEFUL NUCLEAR
COOPERATION.
Section 129 a. of the Atomic Energy Act of 1954 (42 U.S.C. 2158
(a)) is amended by striking ``Congress adopts a concurrent resolution''
and inserting ``Congress adopts, and there is enacted, a joint
resolution''.
SEC. 204. UNITED STATES GOVERNMENT POLICY AT THE NUCLEAR SUPPLIERS
GROUP TO STRENGTHEN THE INTERNATIONAL NUCLEAR NONPROLIFERATION
REGIME.
(a) Certification.--Before exchanging diplomatic notes pursuant to
Article 16(1) of the Agreement, the President shall certify to the
appropriate congressional committees that it is the policy of the
United States to work with members of the Nuclear Suppliers Group
(NSG), individually and collectively, to agree to further restrict the
transfers of equipment and technology related to the enrichment of
uranium and reprocessing of spent nuclear fuel.
(b) Peaceful Use Assurances for Certain By-Product Material.--The
President shall seek to achieve, by the earliest possible date, either
within the NSG or with relevant NSG Participating Governments, the
adoption of principles, reporting, and exchanges of information as may
be appropriate to assure peaceful use and accounting of by-product
material in a manner that is substantially equivalent to the relevant
provisions of the Agreement.
(c) Report.--
(1) In general.--Not later than six months after the date of
the enactment of this Act, and every six months thereafter, the
President shall transmit to the appropriate congressional
committees a report on efforts by the United States pursuant to
subsections (a) and (b).
(2) Termination.--The requirement to transmit the report under
paragraph (1) terminates on the date on which the President
transmits a report pursuant to such paragraph stating that the
objectives in subsections (a) and (b) have been achieved.
SEC. 205. CONFORMING AMENDMENTS.
Section 130 i. of the Atomic Energy Act of 1954 (42 U.S.C. 2159
(i)) is amended--
(1) in paragraph (1), by striking ``means a joint resolution''
and all that follows through ``, with the date'' and inserting the
following: ``means--
``(A) for an agreement for cooperation pursuant to section 123
of this Act, a joint resolution, the matter after the resolving
clause of which is as follows: `That the Congress (does or does
not) favor the proposed agreement for cooperation transmitted to
the Congress by the President on _____ .',
``(B) for a determination under section 129 of this Act, a
joint resolution, the matter after the resolving clause of which is
as follows: `That the Congress does not favor the determination
transmitted to the Congress by the President on _____ .', or
``(C) for a subsequent arrangement under section 201 of the
United States-India Nuclear Cooperation Approval and
Nonproliferation Enhancement Act, a joint resolution, the matter
after the resolving clause of which is as follows: `That the
Congress does not favor the subsequent arrangement to the Agreement
for Cooperation Between the Government of the United States of
America and the Government of India Concerning Peaceful Uses of
Nuclear Energy that was transmitted to Congress by the President on
September 10, 2008.',
with the date''; and
(2) in paragraph (4)--
(A) by inserting after ``45 days after its introduction''
the following ``(or in the case of a joint resolution related
to a subsequent arrangement under section 201 of the United
States-India Nuclear Cooperation Approval and Nonproliferation
Enhancement Act, 15 days after its introduction)''; and
(B) by inserting after ``45-day period'' the following:
``(or in the case of a joint resolution related to a subsequent
arrangement under section 201 of the United States-India
Nuclear Cooperation Approval and Nonproliferation Enhancement
Act, 15-day period)''.
Speaker of the House of Representatives.
Vice President of the United States and
President of the Senate. | United States-India Nuclear Cooperation Approval and Nonproliferation Enhancement Act - (Sec. 2) Defines specified terms.
Title I: Approval of United States-India Agreement for Cooperation on Peaceful Uses of Nuclear Energy - (Sec. 101) Approves the United States-India Agreement for Cooperation on Peaceful Uses of Nuclear Energy (Agreement), subject to the provisions of the Atomic Energy Act of 1954, the Henry J. Hyde United States-India Peaceful Atomic Energy Cooperation Act of 2006, and other applicable U.S. law.
(Sec. 102) Declares that it is the understanding of the United States that the provisions of the Agreement have the meanings conveyed in the authoritative representations provided by the President and his representatives to the Congress and its committees prior to September 20, 2008.
Declares it to be congressional policy that: (1) in the event that nuclear transfers to India are suspended or terminated it is U.S. policy to prevent the transfer to India of nuclear equipment, materials, or technology from other participating governments in the Nuclear Suppliers Group (NSG) or from any other source; and (2) any nuclear power reactor fuel reserve provided to India for use in safeguarded civilian nuclear facilities should be commensurate with reasonable reactor operating requirements.
States that before exchanging specified diplomatic notes the President shall certify to Congress that entry into force and implementation of the Agreement pursuant to its terms is consistent with the obligation of the United States under the Treaty on the Nonproliferation of Nuclear Weapons (Nuclear Nonproliferation Treaty) not to assist, encourage, or induce India to manufacture or otherwise acquire nuclear weapons or other nuclear explosive devices.
(Sec. 103) Urges the government of India to sign and adhere to an Additional Protocol with the International Atomic Energy Agency (IAEA).
(Sec. 104) States that licenses may be issued by the Nuclear Regulatory Commission (NRC) for transfers pursuant to the Agreement only after the President certifies to Congress that: (1) the Agreement Between the Government of India and the International Atomic Energy Agency for the Application of Safeguards to Civilian Nuclear Facilities has entered into force; and (2) the government of India has filed a declaration of facilities that is not materially inconsistent with the facilities and schedule of the separation plan presented in the national parliament of India.
(Sec. 105) Amends the Henry J. Hyde United States-India Peaceful Atomic Energy Cooperation Act of 2006 to revise related congressional reporting requirements.
Title II: Strengthening United States Nonproliferation Law Relating to Peaceful Nuclear Cooperation - (Sec. 201) States that no subsequent arrangement concerning reprocessing arrangements and procedures shall take effect until: (1) the President reports to the House Committee on Foreign Affairs and the Senate Committee on Foreign Relations (Committees) respecting the reasons for such arrangement and a certification that third-party reprocessing arrangements with India will be conducted under similar arrangements; and (2) a period of 30 days of continuous session has elapsed after such report's transmittal.
States that a subsequent agreement shall not become effective if during such 30-day period Congress enacts a joint resolution of disapproval.
(Sec. 202) Amends the Atomic Energy Act of 1954 to direct the President to inform the Committees of any negotiations relating to a new or amended agreement for peaceful nuclear cooperation.
(Sec. 203) Requires that Congress enact a joint resolution to override a presidential determination permitting the export of nuclear materials, equipment, or technology to a country to which such export is otherwise prohibited. (Current law provides for a concurrent resolution of disapproval.)
(Sec. 204) Directs the President to: (1) certify to the Committees that it is U.S. policy to work with members of the Nuclear Suppliers Group (NSG) to restrict transfers of equipment and technology related to the enrichment of uranium and reprocessing of spent nuclear fuel; (2) seek to achieve within NSG or with NSG participating governments the adoption of principles and exchanges of information to assure peaceful use and accounting of byproduct material; and (3) report every six months to the Committees until such purposes have been achieved.
(Sec. 205) Makes conforming amendments with respect to related congressional actions under the Atomic Energy Act of 1954. | <s>[INST]SECTION 1. SHORT TITLE AND TABLE OF CONTENTS.
(a) Short Title.--This Act may be cited as the ``United States-
India Nuclear Cooperation Approval and Nonproliferation Enhancement
Act''.
(b) Table of Contents.--The table of contents for this Act is as
follows:
Sec. 1. Short title and table of contents.
Sec. 2. Definitions.
TITLE I--APPROVAL OF UNITED STATES-INDIA AGREEMENT FOR COOPERATION ON
PEACEFUL USES OF NUCLEAR ENERGY
Sec. 101. Approval of Agreement.
Sec. 102. Declarations of policy; certification requirement; rule of
construction.
Sec. 103. Additional Protocol between India and the IAEA.
Sec. 104. Implementation of Safeguards Agreement between India and the
IAEA.
Sec. 105. Modified reporting to Congress.
TITLE II--STRENGTHENING UNITED STATES NONPROLIFERATION LAW RELATING TO
PEACEFUL NUCLEAR COOPERATION
Sec. 201. Procedures regarding a subsequent arrangement on reprocessing.
Sec. 202. Initiatives and negotiations relating to agreements for
peaceful nuclear cooperation.
Sec. 203. Actions required for resumption of peaceful nuclear
cooperation.
Sec. 204. United States Government policy at the Nuclear Suppliers Group
to strengthen the international nuclear nonproliferation
regime.
Sec. 205. Conforming amendments.
SEC. 2. DEFINITIONS.
In this Act:
(1) Agreement.--The term ``United States-India Agreement for
Cooperation on Peaceful Uses of Nuclear Energy'' or ``Agreement''
means the Agreement for Cooperation Between the Government of the
United States of America and the Government of India Concerning
Peaceful Uses of Nuclear Energy that was transmitted to Congress by
the President on September 10, 2008.
(2) Appropriate congressional committees.--The term
``appropriate congressional committees'' means the Committee on
Foreign Affairs of the House of Representatives and the Committee
on Foreign Relations of the Senate.
TITLE I--APPROVAL OF UNITED STATES-INDIA AGREEMENT FOR COOPERATION ON
PEACEFUL USES OF NUCLEAR ENERGY
SEC. 101. APPROVAL OF AGREEMENT.
(a) In General.--Notwithstanding the provisions for congressional
consideration and approval of a proposed agreement for cooperation in
section 123 b. and d. of the Atomic Energy Act of 1954 (42 U.S.C. 2153
(b) and (d)), Congress hereby approves the United States-India
Agreement for Cooperation on Peaceful Uses of Nuclear Energy, subject
to subsection (b).
(b) Applicability of Atomic Energy Act of 1954, Hyde Act, and Other
Provisions of Law.--The Agreement shall be subject to the provisions of
the Atomic Energy Act of 1954 (42 U.S.C. 2011 et seq.), the Henry J.
Hyde United States-India Peaceful Atomic Energy Cooperation Act of 2006
(22 U.S.C. 8001 et. seq; Public Law 109-401), and any other applicable
United States law as if the Agreement had been approved pursuant to the
provisions for congressional consideration and approval of a proposed
agreement for cooperation in section 123 b. and d. of the Atomic Energy
Act of 1954.
(c) Sunset of Exemption Authority Under Hyde Act.--Section 104(f)
of the Henry J. Hyde United States-India Peaceful Atomic Energy
Cooperation Act of 2006 (22 U.S.C. 8003(f)) is amended by striking
``the enactment of'' and all that follows through ``agreement'' and
inserting ``the date of the enactment of the United States-India
Nuclear Cooperation Approval and Nonproliferation Enhancement Act''.
SEC. 102. DECLARATIONS OF POLICY; CERTIFICATION REQUIREMENT; RULE
OF CONSTRUCTION.
(a) Declarations of Policy Relating to Meaning and Legal Effect of
Agreement.--Congress declares that it is the understanding of the
United States that the provisions of the United States-India Agreement
for Cooperation on Peaceful Uses of Nuclear Energy have the meanings
conveyed in the authoritative representations provided by the President
and his representatives to the Congress and its committees prior to
September 20, 2008, regarding the meaning and legal effect of the
Agreement.
(b) Declarations of Policy Relating to Transfer of Nuclear
Equipment, Materials, and Technology to India.--Congress makes the
following declarations of policy:
(1) Pursuant to section 103(a)(6) of the Henry J. Hyde United
States-India Peaceful Atomic Energy Cooperation Act of 2006 (22
U.S.C. 8002(a)(6)), in the event that nuclear transfers to India
are suspended or terminated pursuant to title I of such Act (22
U.S.C. 8001 et seq.), the Atomic Energy Act of 1954 (42 U.S.C. 2011
et seq.), or any other United States law, it is the policy of the
United States to seek to prevent the transfer to India of nuclear
equipment, materials, or technology from other participating
governments in the Nuclear Suppliers Group (NSG) or from any other
source.
(2) Pursuant to section 103(b)(10) of the Henry J. Hyde United
States-India Peaceful Atomic Energy Cooperation Act of 2006 (22
U.S.C. 8002(b)(10)), any nuclear power reactor fuel reserve
provided to the Government of India for use in safeguarded civilian
nuclear facilities should be commensurate with reasonable reactor
operating requirements.
(c) Certification Requirement.--Before exchanging diplomatic notes
pursuant to Article 16(1) of the Agreement, the President shall certify
to Congress that entry into force and implementation of the Agreement
pursuant to its terms is consistent with the obligation of the United
States under the Treaty on the Non-Proliferation of Nuclear Weapons,
done at Washington, London, and Moscow July 1, 1968, and entered into
force March 5, 1970 (commonly known as the ``Nuclear Non-Proliferation
Treaty''), not in any way to assist, encourage, or induce India to
manufacture or otherwise acquire nuclear weapons or other nuclear
explosive devices.
(d) Rule of Construction.--Nothing in the Agreement shall be
construed to supersede the legal requirements of the Henry J. Hyde
United States-India Peaceful Atomic Energy Cooperation Act of 2006 or
the Atomic Energy Act of 1954.
SEC. 103. ADDITIONAL PROTOCOL BETWEEN INDIA AND THE IAEA.
Congress urges the Government of India to sign and adhere to an
Additional Protocol with the International Atomic Energy Agency (IAEA),
consistent with IAEA principles, practices, and policies, at the
earliest possible date.
SEC. 104. IMPLEMENTATION OF SAFEGUARDS AGREEMENT BETWEEN INDIA AND
THE IAEA.
Licenses may be issued by the Nuclear Regulatory Commission for
transfers pursuant to the Agreement only after the President determines
and certifies to Congress that--
(1) the Agreement Between the Government of India and the
International Atomic Energy Agency for the Application of
Safeguards to Civilian Nuclear Facilities, as approved by the Board
of Governors of the International Atomic Energy Agency on August 1,
2008 (the ``Safeguards Agreement''), has entered into force; and
(2) the Government of India has filed a declaration of
facilities pursuant to paragraph 13 of the Safeguards Agreement
that is not materially inconsistent with the facilities and
schedule described in paragraph 14 of the separation plan presented
in the national parliament of India on May 11, 2006, taking into
account the later initiation of safeguards than was anticipated in
the separation plan.
SEC. 105. MODIFIED REPORTING TO CONGRESS.
(a) Information on Nuclear Activities of India.--Subsection (g)(1)
of section 104 of the Henry J. Hyde United States-India Peaceful Atomic
Energy Cooperation Act of 2006 (22 U.S.C. 8003) is amended--
(1) by redesignating subparagraphs (B), (C), and (D) as
subparagraphs (C), (D), and (E), respectively; and
(2) by inserting after subparagraph (A) the following new
subparagraph:
``(B) any material inconsistencies between the content or
timeliness of notifications by the Government of India pursuant
to paragraph 14(a) of the Safeguards Agreement and the
facilities and schedule described in paragraph (14) of the
separation plan presented in the national parliament of India
on May 11, 2006, taking into account the later initiation of
safeguards than was anticipated in the separation plan;''.
(b) Implementation and Compliance Report.--Subsection (g)(2) of
such section is amended--
(1) in subparagraph (K)(iv), by striking ``and'' at the end;
(2) in subparagraph (L), by striking the period at the end and
inserting ``; and''; and
(3) by adding at the end the following new subparagraph:
``(M) with respect to the United States-India Agreement for
Cooperation on Peaceful Uses of Nuclear Energy (hereinafter in
this subparagraph referred to as the `Agreement') approved
under section 101(a) of the United States-India Nuclear
Cooperation Approval and Nonproliferation Enhancement Act--
``(i) a listing of--
``(I) all provision of sensitive nuclear technology
to India, and other such information as may be so
designated by the United States or India under Article
1(Q); and
``(II) all facilities in India notified pursuant to
Article 7(1) of the Agreement;
``(ii) a description of--
``(I) any agreed safeguards or any other form of
verification for by-product material decided by mutual
agreement pursuant to the terms of Article 1(A) of the
Agreement;
``(II) research and development undertaken in such
areas as may be agreed between the United States and
India as detailed in Article 2(2)(a.) of the Agreement;
``(III) the civil nuclear cooperation activities
undertaken under Article 2(2)(d.) of the Agreement;
``(IV) any United States efforts to help India
develop a strategic reserve of nuclear fuel as called
for in Article 2(2)(e.) of the Agreement;
``(V) any United States efforts to fulfill
political commitments made in Article 5(6) of the
Agreement;
``(VI) any negotiations that have occurred or are
ongoing under Article 6(iii.) of the Agreement; and
``(VII) any transfers beyond the territorial
jurisdiction of India pursuant to Article 7(2) of the
Agreement, including a listing of the receiving country
of each such transfer;
``(iii) an analysis of--
``(I) any instances in which the United States or
India requested consultations arising from concerns
over compliance with the provisions of Article 7(1) of
the Agreement, and the results of such consultations;
and
``(II) any matters not otherwise identified in this
report that have become the subject of consultations
pursuant to Article 13(2) of the Agreement, and a
statement as to whether such matters were resolved by
the end of the reporting period; and
``(iv) a statement as to whether--
``(I) any consultations are expected to occur under
Article 16(5) of the Agreement; and
``(II) any enrichment is being carried out pursuant
to Article 6 of the Agreement.''.
TITLE II--STRENGTHENING UNITED STATES NONPROLIFERATION LAW RELATING TO
PEACEFUL NUCLEAR COOPERATION
SEC. 201. PROCEDURES REGARDING A SUBSEQUENT ARRANGEMENT ON
REPROCESSING.
(a) In General.--Notwithstanding section 131 of the Atomic Energy
Act of 1954 (42 U.S.C. 2160), no proposed subsequent arrangement
concerning arrangements and procedures regarding reprocessing or other
alteration in form or content, as provided for in Article 6 of the
Agreement, shall take effect until the requirements specified in
subsection (b) are met.
(b) Requirements.--The requirements referred to in subsection (a)
are the following:
(1) The President transmits to the appropriate congressional
committees a report containing--
(A) the reasons for entering into such proposed subsequent
arrangement;
(B) a detailed description, including the text, of such
proposed subsequent arrangement; and
(C) a certification that the United States will pursue
efforts to ensure that any other nation that permits India to
reprocess or otherwise alter in form or content nuclear
material that the nation has transferred to India or nuclear
material and by-product material used in or produced through
the use of nuclear material, non-nuclear material, or equipment
that it has transferred to India requires India to do so under
similar arrangements and procedures.
(2) A period of 30 days of continuous session (as defined by
section 130 g.(2) of the Atomic Energy Act of 1954 (42 U.S.C. 2159
(g)(2)) has elapsed after transmittal of the report required under
paragraph (1).
(c) Resolution of Disapproval.--Notwithstanding the requirements in
subsection (b) having been met, a subsequent arrangement referred to in
subsection (a) shall not become effective if during the time specified
in subsection (b)(2), Congress adopts, and there is enacted, a joint
resolution stating in substance that Congress does not favor such
subsequent arrangement. Any such resolution shall be considered
pursuant to the procedures set forth in section 130 i. of the Atomic
Energy Act of 1954 (42 U.S.C. 2159 (i)), as amended by section 205 of
this Act.
SEC. 202. INITIATIVES AND NEGOTIATIONS RELATING TO AGREEMENTS FOR
PEACEFUL NUCLEAR COOPERATION.
Section 123 of the Atomic Energy Act of 1954 (42 U.S.C. 2153) is
amended by adding at the end the following:
``e. The President shall keep the Committee on Foreign
Affairs of the House of Representatives and the Committee on
Foreign Relations of the Senate fully and currently informed of
any initiative or negotiations relating to a new or amended
agreement for peaceful nuclear cooperation pursuant to this
section (except an agreement arranged pursuant to section 91
c., 144 b., 144 c., or 144 d., or an amendment thereto).''.
SEC. 203. ACTIONS REQUIRED FOR RESUMPTION OF PEACEFUL NUCLEAR
COOPERATION.
Section 129 a. of the Atomic Energy Act of 1954 (42 U.S.C. 2158
(a)) is amended by striking ``Congress adopts a concurrent resolution''
and inserting ``Congress adopts, and there is enacted, a joint
resolution''.
SEC. 204. UNITED STATES GOVERNMENT POLICY AT THE NUCLEAR SUPPLIERS
GROUP TO STRENGTHEN THE INTERNATIONAL NUCLEAR NONPROLIFERATION
REGIME.
(a) Certification.--Before exchanging diplomatic notes pursuant to
Article 16(1) of the Agreement, the President shall certify to the
appropriate congressional committees that it is the policy of the
United States to work with members of the Nuclear Suppliers Group
(NSG), individually and collectively, to agree to further restrict the
transfers of equipment and technology related to the enrichment of
uranium and reprocessing of spent nuclear fuel.
(b) Peaceful Use Assurances for Certain By-Product Material.--The
President shall seek to achieve, by the earliest possible date, either
within the NSG or with relevant NSG Participating Governments, the
adoption of principles, reporting, and exchanges of information as may
be appropriate to assure peaceful use and accounting of by-product
material in a manner that is substantially equivalent to the relevant
provisions of the Agreement.
(c) Report.--
(1) In general.--Not later than six months after the date of
the enactment of this Act, and every six months thereafter, the
President shall transmit to the appropriate congressional
committees a report on efforts by the United States pursuant to
subsections (a) and (b).
(2) Termination.--The requirement to transmit the report under
paragraph (1) terminates on the date on which the President
transmits a report pursuant to such paragraph stating that the
objectives in subsections (a) and (b) have been achieved.
SEC. 205. CONFORMING AMENDMENTS.
Section 130 i. of the Atomic Energy Act of 1954 (42 U.S.C. 2159
(i)) is amended--
(1) in paragraph (1), by striking ``means a joint resolution''
and all that follows through ``, with the date'' and inserting the
following: ``means--
``(A) for an agreement for cooperation pursuant to section 123
of this Act, a joint resolution, the matter after the resolving
clause of which is as follows: `That the Congress (does or does
not) favor the proposed agreement for cooperation transmitted to
the Congress by the President on _____ .',
``(B) for a determination under section 129 of this Act, a
joint resolution, the matter after the resolving clause of which is
as follows: `That the Congress does not favor the determination
transmitted to the Congress by the President on _____ .', or
``(C) for a subsequent arrangement under section 201 of the
United States-India Nuclear Cooperation Approval and
Nonproliferation Enhancement Act, a joint resolution, the matter
after the resolving clause of which is as follows: `That the
Congress does not favor the subsequent arrangement to the Agreement
for Cooperation Between the Government of the United States of
America and the Government of India Concerning Peaceful Uses of
Nuclear Energy that was transmitted to Congress by the President on
September 10, 2008.',
with the date''; and
(2) in paragraph (4)--
(A) by inserting after ``45 days after its introduction''
the following ``(or in the case of a joint resolution related
to a subsequent arrangement under section 201 of the United
States-India Nuclear Cooperation Approval and Nonproliferation
Enhancement Act, 15 days after its introduction)''; and
(B) by inserting after ``45-day period'' the following:
``(or in the case of a joint resolution related to a subsequent
arrangement under section 201 of the United States-India
Nuclear Cooperation Approval and Nonproliferation Enhancement
Act, 15-day period)''.
Speaker of the House of Representatives.
Vice President of the United States and
President of the Senate.[/INST]United States-India Nuclear Cooperation Approval and Nonproliferation Enhancement Act - (Sec. 2) Defines specified terms.
Title I: Approval of United States-India Agreement for Cooperation on Peaceful Uses of Nuclear Energy - (Sec. 101) Approves the United States-India Agreement for Cooperation on Peaceful Uses of Nuclear Energy (Agreement), subject to the provisions of the Atomic Energy Act of 1954, the Henry J. Hyde United States-India Peaceful Atomic Energy Cooperation Act of 2006, and other applicable U.S. law.
(Sec. 102) Declares that it is the understanding of the United States that the provisions of the Agreement have the meanings conveyed in the authoritative representations provided by the President and his representatives to the Congress and its committees prior to September 20, 2008.
Declares it to be congressional policy that: (1) in the event that nuclear transfers to India are suspended or terminated it is U.S. policy to prevent the transfer to India of nuclear equipment, materials, or technology from other participating governments in the Nuclear Suppliers Group (NSG) or from any other source; and (2) any nuclear power reactor fuel reserve provided to India for use in safeguarded civilian nuclear facilities should be commensurate with reasonable reactor operating requirements.
States that before exchanging specified diplomatic notes the President shall certify to Congress that entry into force and implementation of the Agreement pursuant to its terms is consistent with the obligation of the United States under the Treaty on the Nonproliferation of Nuclear Weapons (Nuclear Nonproliferation Treaty) not to assist, encourage, or induce India to manufacture or otherwise acquire nuclear weapons or other nuclear explosive devices.
(Sec. 103) Urges the government of India to sign and adhere to an Additional Protocol with the International Atomic Energy Agency (IAEA).
(Sec. 104) States that licenses may be issued by the Nuclear Regulatory Commission (NRC) for transfers pursuant to the Agreement only after the President certifies to Congress that: (1) the Agreement Between the Government of India and the International Atomic Energy Agency for the Application of Safeguards to Civilian Nuclear Facilities has entered into force; and (2) the government of India has filed a declaration of facilities that is not materially inconsistent with the facilities and schedule of the separation plan presented in the national parliament of India.
(Sec. 105) Amends the Henry J. Hyde United States-India Peaceful Atomic Energy Cooperation Act of 2006 to revise related congressional reporting requirements.
Title II: Strengthening United States Nonproliferation Law Relating to Peaceful Nuclear Cooperation - (Sec. 201) States that no subsequent arrangement concerning reprocessing arrangements and procedures shall take effect until: (1) the President reports to the House Committee on Foreign Affairs and the Senate Committee on Foreign Relations (Committees) respecting the reasons for such arrangement and a certification that third-party reprocessing arrangements with India will be conducted under similar arrangements; and (2) a period of 30 days of continuous session has elapsed after such report's transmittal.
States that a subsequent agreement shall not become effective if during such 30-day period Congress enacts a joint resolution of disapproval.
(Sec. 202) Amends the Atomic Energy Act of 1954 to direct the President to inform the Committees of any negotiations relating to a new or amended agreement for peaceful nuclear cooperation.
(Sec. 203) Requires that Congress enact a joint resolution to override a presidential determination permitting the export of nuclear materials, equipment, or technology to a country to which such export is otherwise prohibited. (Current law provides for a concurrent resolution of disapproval.)
(Sec. 204) Directs the President to: (1) certify to the Committees that it is U.S. policy to work with members of the Nuclear Suppliers Group (NSG) to restrict transfers of equipment and technology related to the enrichment of uranium and reprocessing of spent nuclear fuel; (2) seek to achieve within NSG or with NSG participating governments the adoption of principles and exchanges of information to assure peaceful use and accounting of byproduct material; and (3) report every six months to the Committees until such purposes have been achieved.
(Sec. 205) Makes conforming amendments with respect to related congressional actions under the Atomic Energy Act of 1954.</s> |
in recent years , multicarrier code - division multiple - access ( mc - cdma ) based on the quasi-/perfect- complementary sequence set ( in abbreviation , qcss / pcss ) has attracted much attention due to its potential to achieve low-/zero- interference multiuser performance @xcite , @xcite . here
, a qcss ( or pcss ) refers to a set of two - dimensional matrices with low ( or zero ) non - trivial auto- and cross- correlation sums @xcite@xmath7@xcite . in this paper , a complementary sequence
is also called a complementary matrix , and vice versa . to deploy a qcss ( or pcss ) in an mc - cdma system , every data symbol of a specific user
is spread by a complementary matrix by simultaneously sending out all of its row sequences over a number of non - interfering subcarrier channels .
because of this , the number of row sequences of a complementary matrix , denoted by @xmath2 , is also called the _ number of channels_. at a matched - filter based receiver , de - spreading operations are performed separately in each subcarrier channel , followed by summing the correlator outputs of all the subcarrier channels to attain a correlation sum which will be used for detection .
a pcss may also be called a mutually orthogonal complementary sequence set ( mocss ) @xcite@xmath7@xcite , a concept extended from mutually orthogonal golay complementary pairs ( gcps ) @xcite@xmath7@xcite . however , a drawback of pcss is its small set size @xcite . specifically , the set size ( denoted by @xmath1 ) of pcss is upper bounded by the number of channels , i.e. , @xmath8 .
this means that a pcss based mc - cdma system with @xmath2 subcarriers can support at most @xmath2 users only .
against such a backdrop , there have been two approaches aiming to provide a larger set size , i.e. , @xmath9 .
the first approach is to design zero- or low- correlation zone ( zcz / lcz ) based complementary sequence sets , called zcz - css @xcite , @xcite or lcz - css @xcite .
a zcz - css ( lcz - css ) based mc - cdma system is capable of achieving zero- ( low- ) interference performance but requires a closed - control loop to dynamically adjust the timings of all users such that the received signals can be quasi - synchronously aligned within the zcz ( lcz ) .
a second approach is to design qcss which has uniformly low correlation sums over all non - trivial time - shifts . as such
, qcss can be utilized to achieve low - interference performance with a simpler timing - control system . to the authors best knowledge , the first aperiodic correlation lower bound of qcss
was derived by welch in @xcite , which states : @xmath10 where every quasi - complementary sequence is a matrix of order @xmath11 ( thus , every row sequence has length of @xmath3 ) with assumed energy of @xmath12 .
the aforementioned set size upper bound of pcss , namely , @xmath8 , can also be obtained from ( [ welch_bound_for_cc ] ) by setting @xmath13 . on the other hand , if @xmath14 , one can show that @xmath9 , meaning that a larger set size can be supported by qcss .
recently , a generalized levenshtein bound ( glb ) for qcss has been derived by liu , guan and mow in [ [ liuguanmow14 ] , _ theorem 1 _ ] .
the key idea behind the glb ( including the levenshtein bound @xcite ) is that the weighted mean square aperiodic correlation of any sequence subset over the complex roots of unity should be equal to or greater than that of the whole set which includes all possible complex roots - of - unity sequences .
the levenshtein bound was extended from binary sequences to complex roots - of - unity sequences by bozta @xcite .
a lower bound for aperiodic lcz sequence sets was derived in @xcite by an approach similar to levenshtein s . in its bounding equation ,
glb is a function of the simplex " weight vector @xmath0 , the set size @xmath1 , the number of channels @xmath2 , and the row sequence length @xmath3 .
a necessary condition ( shown in [ [ liuguanmow14 ] , _ theorem 2 _ ] ) for the glb to be tighter than the welch bound is that @xmath5 , where @xmath15 with @xmath16 although a step - function " weight vector was adopted in [ [ liuguanmow14 ] , ( 34 ) ] , it only leads to a tighter glb for @xmath17 . as a matter of fact
, the tightness of glb remains unknown for @xmath18 when @xmath3 is sufficiently large .
the main objective of this paper is to optimize and then tighten the glb for _ all _ @xmath5 ( instead of _ some _ ) . for this
, we are to find a ( locally ) optimal weight vector which is used in the bounding equation .
a similar research problem was raised in @xcite for traditional binary sequences ( i.e. , non - qcss with @xmath19 ) .
see @xcite for more details .
the optimization of glb on qcss ( with @xmath4 ) , however , is more challenging because an analytical solution to a non - convex glb ( in terms of weight vector @xmath0 ) for _ all _ possible cases of @xmath20 is in general intractable .
we first adopt a frequency - domain optimization approach in section iii - b to minimize the ( non - convex ) fractional quadratic function of glb .
this is achieved by properly exploiting the specific structure of the circulant quadratic matrix in the numerator of the fractional quadratic term of glb . following this optimization approach
, we find a new weight vector which leads to a tighter glb for _ all _ @xmath20 cases satisfying @xmath5 and @xmath4 , asymptotically ( in @xmath3 ) .
our finding shows that the condition of @xmath5 , shown in [ [ liuguanmow14 ] , theorem 2 ] , is not only necessary but also sufficient , as @xmath3 tends to infinity .
moreover , in section iii - c , it is proved that the newly found weight vector is a local minimizer to the fractional quadratic function of glb , asymptotically .
we then examine in sections iv two weight vectors which were presented in @xcite for the tightening of the levenshtein bound on conventional single - channel ( i.e. , @xmath19 ) sequence sets .
we extend their tightening capability to glb on multi - channel ( i.e. , @xmath4 ) qcss , although the proof is not straightforward .
it is shown that each of these two weight vectors gives rise to a tighter glb ( over the welch bound ) for several small values of @xmath2 provided that @xmath5 .
it is also noted that the glb from the newly found weight vector is ( in general ) tighter than the glbs from these two ( earlier found ) weight vectors , as shown by some numerical results .
in this section , we first present some necessary notations and define qcss . then
, we give a brief review of glb .
for two complex - valued sequences @xmath21 $ ] and @xmath22 $ ] , their aperiodic correlation function at time - shift @xmath23 is defined as @xmath24 when @xmath25 , @xmath26 is called the aperiodic cross - correlation function ( accf ) ; otherwise , it is called the aperiodic auto - correlation function ( aacf ) . for simplicity
, the aacf of @xmath27 is denoted by @xmath28 .
let @xmath29 be a set of @xmath1 matrices , each of order @xmath11 ( where @xmath30 ) , i.e. , @xmath31_{m\times n } = \left [ \begin{matrix } c^\nu_{0,0 } & c^\nu_{0,1 } & \cdots & c^\nu_{0,n-1}\\ c^\nu_{1,0 } & c^\nu_{1,1 } & \cdots & c^\nu_{1,n-1}\\ \vdots & \vdots & \ddots & \vdots\\ c^\nu_{m-1,0 } & c^\nu_{m-1,1 } & \cdots & c^\nu_{m-1,n-1}\\ \end{matrix } \right ] , \end{split}\ ] ] where @xmath32 .
define the aperiodic correlation sum " of matrices @xmath33 and @xmath34 as follows , @xmath35 also , define the aperiodic auto - correlation tolerance @xmath36 and the aperiodic cross - correlation tolerance @xmath37 of @xmath38 as @xmath39 respectively .
moreover , define the aperiodic tolerance ( also called the maximum aperiodic correlation magnitude " ) of @xmath38 as @xmath40 .
when @xmath13 , @xmath38 is called a _ perfect complementary sequence set _ ( pcss ) ; otherwise , it is called a _ quasi - complementary sequence set _ ( qcss ) . in particular ,
when @xmath41 and @xmath42 , a pcss reduces to a matrix consisting of two row sequences which have zero out - of - phase aperiodic autocorrelation sums .
such matrices are called golay complementary matrices ( gcms ) or golay complementary pairs ( gcps ) in this paper , and either sequence in a gcp is called a golay sequence .
note that the transmission of a pcss or a qcss requires a multi - channel system .
specifically , every matrix in a pcss ( or a qcss ) needs @xmath4 non - interfering channels for the separate transmission of @xmath2 row sequences .
this is different from the traditional single - channel sequences with @xmath19 only .
let @xmath43^{\text{t}}$ ] be a simplex " weight vector which is constrained by @xmath44 define a quadratic function @xmath45 where @xmath46 is a @xmath47 circulant matrix with all of its diagonal entries equal to @xmath48 , and its off - diagonal entries @xmath49 , where @xmath50 and @xmath51 the glb for qcss over complex roots of unity in @xcite is shown below .
[ generalized_welch_bound_for_cc ] @xmath52.\ ] ] a weaker simplified version of ( [ generalized_welch_bound_for_cc - equ ] ) is given below .
@xmath53.\ ] ] setting @xmath54 , the glb reduces to the welch bound for qcss in ( [ welch_bound_for_cc ] ) .
[ rmk_nece_cond ] [ [ liuguanmow14 ] , _ theorem 2 _ ] for the glb to be tighter than the corresponding welch bound , it is _ necessary _ that @xmath5 , where @xmath6 is defined in ( [ nece_cond_qcssbd2 ] ) .
[ [ liuguanmow14 ] , _ corollary 1 _ ] applying the weight vector @xmath55 with @xmath56 where @xmath57 , to ( [ generalized_welch_bound_for_cc - equ ] ) , we have @xmath58 the lower bound in ( [ zl_corollary_4_equ ] ) is tighter than the welch bound for qcss in ( [ welch_bound_for_cc ] ) if one of the two following conditions is fulfilled : ( 1 ) : @xmath59 , @xmath4 and @xmath60 ( 2 ) : @xmath61 , @xmath4 and @xmath62 .
the necessary condition in _ remark [ rmk_nece_cond ] _ implies that for a given @xmath63 , the welch bound for qcss can not be improved if @xmath64 , where @xmath65 is defined in ( [ nece_cond_qcssbd2 ] ) . on the other hand , the weight vector in ( [ leven_lcz_weighting_vector ] )
can only lead to a tighter glb for @xmath17 .
because of this , the tightness of glb is unknown in the following ambiguous zone .
@xmath66 for sufficiently large @xmath3 , the above @xmath67 zone further reduces to @xmath68 by recalling ( [ nece_cond_qcssbd2 _ ] ) .
one may visualize this zone in the shaded area of fig .
[ fig_glbgap ] for @xmath69 .
we are therefore interested in finding a weight vector which is capable of optimizing and tightening the glb for _ all _ ( rather than _ some _ ) @xmath5 . relating this objective to fig .
[ fig_glbgap ] , such a weight vector can give us a tighter glb for the largest @xmath67 region right above the red diamond symbols .
however , the optimization of glb in ( [ generalized_welch_bound_for_cc - equ ] ) is challenging because its fractional quadratic term ( in terms of @xmath0 ) is indefinite .
more specifically , the quadratic term @xmath70 in the numerator is indefinite as some eigenvalues of the corresponding circulant matrix are negative when @xmath5 [ [ liuguanmow14 ] , appendix b ] .
it is noted that indefinite quadratic programming ( qp ) is np - hard @xcite , even it has one negative eigenvalue only @xcite . moreover , checking local optimality of a feasible point in constrained qp is also np - hard @xcite .
although some optimality conditions for constrained qp have been derived by bomze from the copositivity perspective @xcite , the situation becomes more complicated when indefinite fractional quadratic programming ( fqp ) problems are dealt with . according to @xcite
, glb may be classified as a standard fqp ( stfqp ) as the feasible set is the standard simplex . to the best of the authors knowledge ,
preisig pioneered an iterative algorithm for which convergence to a kkt point ( but can not be guaranteed to be a local minimizer ) of the stfqp can be proved @xcite .
two algorithms for stfqp based on semidefinite programming ( sdp ) relaxations are presented in @xcite , yet the optimalities of the resultant solutions are unknown . as a matter of fact , the algorithms developed in @xcite may only be feasible for medium - scaled stfqp with @xmath71 .
in contrast , we target at an analytical solution ( as opposed to a numerical solution ) which is applicable to large scale of glb ( e.g. , the sequence length @xmath72 ) .
thus , the techniques used in @xcite may not be useful for the specific stfqp problem considered in this paper . in the sequel
, we introduce a frequency - domain optimization approach which finds a local minimizer ( i.e. , a weight vector ) of the glb .
we show that the obtained weight vector leads to a tighter glb for _ all _ @xmath5 and @xmath30 , asymptotically . to tighten the glb in ( [ generalized_welch_bound_for_cc - equ ] )
, we adopt a novel optimization approach in this subsection , motivated by the observation that any circulant matrix [ e.g. , @xmath73 in ( [ leven - quad - fun - equ ] ) which forms a part of the glb quadratic function in ( [ generalized_welch_bound_for_cc - equ ] ) ] can be decomposed in the frequency domain .
define @xmath74 and the @xmath75-point discrete fourier transform ( dft ) matrix as @xmath76_{m , n=0}^{l-1},~\text{where}~f_{m , n}=\xi^{mn}_l.\ ] ] denote by @xmath77 the first column vector of @xmath46 in ( [ leven - quad - fun - equ ] ) , i.e. , @xmath78^{\text{t}}.\ ] ] let @xmath79^{\text{t}}.\ ] ] it is noted that @xmath80 . by @xcite , the circulant matrix @xmath73 defined in ( [ leven - quad - fun - equ ] ) can be expressed as @xmath81 where @xmath82^{\text{t}},\ ] ] and @xmath83 is the matrix with @xmath84 being the diagonal vector and zero for all the non - diagonal matrix entries .
consequently [ [ nyy2014 ] , theorem 3.1 ] , @xmath85 similarly , @xmath86 by [ [ liuguanmow14 ] , appendix b ] , we have @xmath87 and @xmath88 for @xmath89 .
note that @xmath90 for @xmath91 .
moreover , we remark that @xmath92 this is because 1 .
if @xmath93 is odd : @xmath94 2 . if @xmath93 is even : @xmath95 to maximize the glb in ( [ generalized_welch_bound_for_cc - equ ] ) , it is equivalent to consider the following optimization problem .
@xmath96 since @xmath0 is real - valued , @xmath97 is conjugate symmetric , i.e. , @xmath98 for @xmath99 . having this in mind ,
we define @xmath100 taking advantage of the fact that @xmath101 are strictly smaller than other @xmath102 s with nonzero @xmath93 as shown in ( [ lambda_l1_equ ] ) , we have @xmath103 where the equality is achieved if and only if @xmath104 for @xmath105 . inspired by this observation , we relax the non - negativity constraint on @xmath0 , i.e. , some negative @xmath106 s may be allowed ( but the sum of all elements of @xmath0 must still be equal to 1 ) . with this , the optimization problem in ( [ opti_freqd ] ) can be translated to @xmath107 where @xmath108 from now on , we adopt the setting of @xmath109 where @xmath110 denote the magnitude and phase of @xmath111 , respectively . since @xmath112 , we have @xmath113^{\text{t}}. \end{split}\ ] ] to optimize the fractional function in ( [ opti_freqd_trans ] ) , we have the following lemma .
[ lem_monofun ] the fractional function @xmath114 in terms of @xmath115 in ( [ opti_freqd_trans ] ) is 1 .
case 1 : monotonically decreasing in @xmath115 if @xmath116 and @xmath117 ; 2 .
case 2 : monotonically increasing in @xmath115 if @xmath118 , or @xmath5 and @xmath119 . to prove case 1 ,
we first show that @xmath120 if and only if @xmath121 where @xmath6 is defined in ( [ nece_cond_qcssbd2 ] ) . for ease of analysis , we write @xmath122 where @xmath123 is a positive integer and @xmath124 .
thus , @xmath125 .
consequently , we have @xmath126\\ & \leq \frac{n(mn-1)}{k } \left ( 1- \frac{n+1}{n+\epsilon } \right ) \\ & < 0 , \end{split}\ ] ] with which the proof of case 1 follows . the proof of case 2
can be easily obtained by following a similar argument . for case 2 of _ lemma [ lem_monofun ]
_ , it can be readily shown that the minimum of the fractional function @xmath114 in ( [ opti_freqd_trans ] ) is achieved at @xmath127 .
thus , the weight vector in ( [ wtvec3_equ ] ) reduces to @xmath128^{\text{t } } , \end{split}\ ] ] where the corresponding glb reduces to the welch bound in ( [ welch_bound_for_cc ] ) .
next , let us focus on the application of case 1 for glb tightening . in this case
, we wish to know the upper bound of @xmath115 in order to minimize the fractional function of @xmath115 in ( [ opti_freqd_trans ] ) .
coming back to the constraint of @xmath0 given in ( [ leven_weight_vector ] ) , @xmath129 and @xmath130 should satisfy @xmath131 thus , @xmath132 where the upper bound is achieved with equality when @xmath133 for any integer @xmath134 . by substituting @xmath135 into ( [ wtvec3_equ ] )
, we obtain the following weight vector .
@xmath136 where @xmath137 and @xmath134 is any integer .
the resultant glb from this weight vector is shown in the following lemma .
[ coro_glb_from_wetvec3 ] for @xmath116 and @xmath117 , we have @xmath138,\ ] ] where @xmath139 are given in ( [ lambdas ] ) .
to analyze the asymptotic tightness of the lower bound in ( [ coro_glb_from_wetvec3-equ ] ) , we note that when @xmath3 is sufficiently large , the second condition in _ lemma [ coro_glb_from_wetvec3 ] _ , i.e. , @xmath140 is true for @xmath5 . to show this
, we substitute @xmath139 into ( [ cond_case1 ] ) .
after some manipulations , one can see that the inequality in ( [ cond_case1 ] ) holds if and only if @xmath141 carrying on the expression in ( [ k_split_equ ] ) , we require @xmath142 which is guaranteed to hold for sufficiently large @xmath3 because @xmath143 is strictly smaller than 1 by assumption . furthermore , we note that @xmath144 therefore , @xmath145}=\frac{3m}{4k}+\frac{1}{2}-\frac{1}{\pi^2}.\ ] ] on the other hand , let us rewrite the welch bound expression ( [ welch_bound_for_cc ] ) as @xmath146 with @xmath147 then , @xmath148 with ( [ r1 ] ) and ( [ ch4_r1_largen ] ) , one can show that the lower bound in _
lemma [ coro_glb_from_wetvec3 ] _ is asymptotically tighter than the welch bound in ( [ welch_bound_for_cc ] ) if and only if the following equation is satisfied .
@xmath149 equivalently , we need to prove that for @xmath150 ( as @xmath151 ) , the following inequality holds .
@xmath152 one can readily show that the condition @xmath153 given in ( [ bdfromoptwtvec2 ] ) is true for _ all _ @xmath30 .
therefore , we have the following theorem .
[ th4optwtvec ] the glb in ( [ coro_glb_from_wetvec3-equ ] ) which arises from the weight vector in ( [ wgtvec3_equ ] ) reduces to @xmath154,\ ] ] for sufficiently large @xmath3 .
such an asymptotic lower bound is tighter than the welch bound for _ all _ @xmath5 and for _ all _ @xmath30 . in this subsection
, we prove the proposed weight vector in ( [ wgtvec3_equ ] ) is a local minimizer of the glb in ( [ generalized_welch_bound_for_cc - equ ] ) under certain condition .
we consider the weight vector @xmath0 by setting @xmath155 in ( [ wgtvec3_equ ] ) because other values of @xmath134 will lead to identical value of glb [ cf .
( [ glb_quadra_fd ] ) and ( [ glb_quadra_fd _ ] ) ] .
@xmath156 note that the frequency domain vector @xmath157 has @xmath158 and @xmath104 for all @xmath159 .
our problem in this subsection can be formally cast as follows .
define the fractional quadratic function @xmath160 is essentially the fractional quadratic term in ( [ generalized_welch_bound_for_cc - equ ] ) by replacing @xmath0 with @xmath161 . ] as follows .
@xmath162 where @xmath163 , @xmath73 is the circulant matrix defined in ( [ leven - quad - fun - equ ] ) which has order @xmath164 and with @xmath165 . when @xmath166 and @xmath63 becomes sufficiently large ,
prove that the weight vector @xmath0 in ( [ proposed_wgtvec ] ) is a local minimizer of @xmath160 , i.e. , @xmath167 holds for any feasible perturbation @xmath168 which has sufficiently small norm .
to get started , we define @xmath169 it is easy to show that ( [ local_mini_equ ] ) is equivalent to the following inequality .
@xmath170 let @xmath171 . since @xmath168 is a real vector , @xmath172 is conjugate symmetric in that @xmath173 for @xmath99 . by taking advantage of ( [ qa_in_freqdomain ] ) , we present the following properties which will be useful in the sequel .
@xmath174 by ( [ multi_equ4 ] ) , ( [ multi_equ5 ] ) , ( [ multi_equ7 ] ) and ( [ multi_equ8 ] ) , we have @xmath175 |e_i|^2\right \}. \end{split}\ ] ] by ( [ multi_equ3 ] ) , ( [ multi_equ5 ] ) , ( [ multi_equ6 ] ) and ( [ multi_equ7 ] ) , we have @xmath176 therefore , @xmath177 can be expressed in the form shown in ( [ gamma_equ ] ) .
@xmath178 since @xmath168 is a small perturbation , let us assume @xmath179 next , we proceed with the following two cases . 1 .
case i : if there exists @xmath180 for @xmath181 .
+ since we consider @xmath166 with sufficiently large @xmath63 , it is readily to show that @xmath182 holds for any @xmath181 [ see ( [ lambda_even_equ ] ) and ( [ lambda_odd_equ ] ) ] . by ( [ multi_equ4 ] ) , let us write @xmath183 where @xmath184 .
furthermore , write @xmath185\cdot ( 2n-1)=\lambda_1 a+b,\ ] ] where @xmath186 + [ rmk_on_ab ] since @xmath187 , @xmath188 and @xmath189 approach to + @xmath190 and @xmath191 , respectively , as @xmath2 grows sufficiently large .
+ to show ( [ local_mini_equ ] ) [ and ( [ local_mini_equ2 ] ) ] holds , we only need to prove the right - hand term of ( [ local_mini_equ3 ] ) divided by @xmath48 is nonnegative , asymptotically . for this , our idea is to consider a fixed @xmath3 ( sufficiently large ) and prove that : ( 1 ) @xmath192 is lower bounded by a nonnegative value determined by @xmath3 only ; ( 2 ) @xmath193 tends to zero ( with an upper bounded @xmath194 ) regardless the value of @xmath3 . + from ( [ lambda_i_equ ] ) , we have @xmath195 for ease of analysis , let @xmath3 be an even integer is odd , we can prove ( [ local_mini_equ ] ) [ and ( [ local_mini_equ2 ] ) ] holds by almost the same arguments . ] .
hence , @xmath196 .
since @xmath197 is a decreasing function of @xmath198 , we have @xmath199 also , @xmath200 where @xmath201 by noting @xmath202 ( @xmath203 a small positive angle ) and @xmath166 , we have @xmath204 by ( [ lambda_even_equ ] ) and ( [ lambda_odd_equ ] ) , we obtain @xmath205 on the other hand , @xmath206\\ \rightarrow & ~ 0^{- } , \end{split}\ ] ] where @xmath207 denotes a sufficiently small value ( negative ) that approaches zero from the left .
therefore , we have @xmath208\cdot ( 2n-1)}{a}\\ = & { \lim\limits_{m\rightarrow+\infty}\frac{\lambda_1}{a } } \cdot \underbrace{\lim\limits_{m\rightarrow+\infty}a}_{\text{upper bounded } } + { \lim\limits_{m\rightarrow+\infty}\frac{b}{a}}%\rightarrow \frac{\xi}{a}.% > \frac{2}{3}\cdot \left ( 2\sum\limits_{i=2}^{n-1}|e_i|^2 \right ) \end{split}\ ] ] by ( [ lim_xi_a_equ ] ) and ( [ lambda1_equ ] ) , we assert that when @xmath2 is sufficiently large , the sign of the limit in ( [ lim_gep_equ ] ) will be identical to that of @xmath209 [ cf .
( [ lim_xi_a_equ ] ) ] which is nonnegative .
this shows that ( [ local_mini_equ ] ) [ and ( [ local_mini_equ2 ] ) ] holds for case i , asymptotically .
2 . case ii : if @xmath210 for all @xmath181 .
+ in this case , ( [ ab_equ ] ) reduces to @xmath211 since @xmath171 , we have @xmath212 where @xmath213 denotes the real part of complex data @xmath203 . consider @xmath214 which takes the following form .
@xmath215 where @xmath216 and @xmath217 denotes the phase shift of @xmath214 .
as a result , @xmath218 can be expressed as @xmath219 thus , @xmath220 since @xmath221 , we assert that for sufficiently large @xmath63 , @xmath222 holds because it will be dominated by the negative @xmath223 .
our next task is to show that @xmath224 . by ( [ ei_equ ] ) , we have @xmath225 it is required in ( [ multi_equ2 ] ) that @xmath226 for all @xmath198 , i.e. , @xmath227 setting @xmath228 , we have @xmath229 setting @xmath228 , we have @xmath230 therefore , @xmath231 this shows @xmath232 holds provided @xmath233
. this can be easily satisfied by a sufficiently small @xmath234 .
together with ( [ lambda1ab_caseii])-([lambda1ab_caseii_3 ] ) , we conclude that ( [ local_mini_equ ] ) [ and ( [ local_mini_equ2 ] ) ] holds for case ii , asymptotically .
this completes the proof of the local optimality of the proposed weight vector in ( [ proposed_wgtvec ] ) . following a proof similar to the above
, one can easily show that the weight vector @xmath0 in ( [ proposed_wgtvec ] ) is also a local minimizer of the constrained qp of @xmath235 when @xmath166 and @xmath63 are sufficiently large .
in this section , we first consider another two weight vectors and study the tightness of their resultant glbs .
then , we compare them with the proposed weight vector in ( [ wgtvec3_equ ] ) by some numerical results . in @xcite , liu _
et al _ showed that the following positive - cycle - of - sine " weight vector @xmath0 @xmath236 where @xmath237 , asymptotically leads to a tighter levenshtein bound ( i.e. , @xmath19 ) for all @xmath238 @xcite . by [ [ liuparaguanbozas14 ] , _ proposition 1 _ ]
, one can show that the resultant glb from the weight vector in ( [ sine_shape_weight_vector ] ) can be written as follows .
[ new_lwerbd_from_new_wv ] @xmath239 , % ~~\text{for}~2\leq m\leq 2n-1,\ ] ] where @xmath240 in what follows , we analyze the asymptotic tightness of the lower bound in ( [ zl - corollary - new - weight - vector - equ ] ) .
define @xmath241 . obviously , @xmath129 is a real - valued constant with @xmath242 when @xmath243 is on the same order of @xmath244 ( i.e. , @xmath245 ) ; and @xmath246 when @xmath243 is dominated by @xmath3 asymptotically ( i.e. , @xmath247 ) .
furthermore , define the fractional term in ( [ zl - corollary - new - weight - vector - equ ] ) as @xmath248 it is easy to see that the lower bound in ( [ zl - corollary - new - weight - vector - equ ] ) is tighter than the welch bound in ( [ welch_bound_for_cc ] ) if and only if @xmath249 where @xmath250 is defined in ( [ r1 ] ) . as @xmath3 tends to infinity , the inequality in ( [ iff ] ) is equivalent to @xmath251 when @xmath247 , we have @xmath246 and @xmath252 as @xmath253 . in this case , one can show that @xmath254 which can be ignored without missing the minimum point of interest in the right - hand side of ( [ asymp_iff ] ) .
hence , we shall assume @xmath129 to be a non - vanishing real - valued constant with @xmath255 , and rewrite ( [ asymp_iff ] ) as @xmath256 here , the order of the limit and minimization operations can be exchanged because @xmath257 as a function of @xmath129 exists , as shown below .
next , noting that @xmath258 , we can express ( [ r2 ] ) as @xmath259 where @xmath260 and after some manipulations , @xmath261 by ( [ ch4_r1_largen ] ) , ( [ r2_2a ] ) and ( [ ch4_q_largen ] ) , it follows that ( [ asymp_iff _ ] ) reduces to @xmath262 equivalently , we assert that the asymptotic lower bound in ( [ zl - corollary - new - weight - vector - equ ] ) is tighter than the welch bound if and only if @xmath263 where @xmath264 in fig .
[ fig_optimal_r2 ] , @xmath265 and @xmath266 versus @xmath129 over the range of @xmath267 are plotted
. it can be obtained from ( [ overlinek ] ) and fig . [ fig_optimal_r2 ]
that @xmath268 by ( [ asym_bd_wtvec2_equ ] ) , one can see that the proposed weight vector in ( [ sine_shape_weight_vector ] ) asymptotically leads to a tighter glb for _ all _ @xmath5 if and only if the value of @xmath2 satisfies the following condition [ c.f .
( [ nece_cond_qcssbd2_2 ] ) ] @xmath269 in fig .
[ fig_dm ] , @xmath270 versus @xmath2 is also plotted . by identifying @xmath2 satisfying @xmath271 [ shown in ( [ ch5_dm_equ ] ) ] , we arrive at the following theorem .
[ tighter_m_rmk ] the glb in ( [ zl - corollary - new - weight - vector - equ ] ) which arises from the weight vector in ( [ sine_shape_weight_vector ] ) reduces to @xmath272,\ ] ] for sufficiently large @xmath3 , where @xmath273 is given in ( [ ch4_q_largen ] ) . such an asymptotic lower bound is tighter than the welch bound for _ all _ @xmath5 if and only if @xmath274 let us consider the weight vector obtained by minimizing the following function using the lagrange multiplier .
@xmath275 where @xmath276 for @xmath277 and @xmath237 .
the idea is to optimize the weaker glb in ( [ simplified_glb ] ) . by relating the quadratic minimization solution of @xmath278 to the chebyshev polynomials of the second kind ,
one can obtain the weight vector , lemma 2 ] , such a weight vector is more generic as it applies to qcss with different @xmath30 .
] below .
let @xmath279 and @xmath280 .
also , let @xmath243 be an even positive integer with @xmath281 .
for @xmath282 , define the following weight vector @xmath283 setting @xmath284 , one can minimize @xmath278 in ( [ mini_f ] ) over different @xmath243 and get a generalized version of the levenshtein bound in [ [ levenshtein99 ] , _ corollary 4 _ ] as follows .
[ coro_bd1 ] @xmath285 as @xmath253 , the lower bound in ( [ lev_bd_cor4 ] ) is tighter than the welch bound in ( [ welch_bound_for_cc ] ) if and only if @xmath286 or equivalently , @xmath287 where the right - hand side of ( [ equ_coro2_tighter ] ) is obtained from ( [ lev_bd_cor4 ] ) .
recall that as @xmath253 , a necessary condition ( cf .
_ remark [ rmk_nece_cond ] _ ) for the glb to be tighter than the corresponding welch bound is @xmath288 clearly , @xmath289 which is smaller than the right - hand side of ( [ equ_coro2_tighter2 ] ) .
it can be asserted that the resultant glb obtained from the weight vector in ( [ levwtvec_equ ] ) with @xmath290 is tighter if and only if the value of @xmath2 satisfies the condition @xmath291
> 0.\ ] ] this is because when condition ( [ ch5_dm_equ2 ] ) is satisfied , @xmath292 is not only a necessary condition [ cf .
( [ nece_cond_qcssbd2_2 ] ) ] but also a sufficient condition [ cf .
( [ equ_coro2_tighter2 ] ) ] for the glb to be asymptotically tighter than the welch bound . in fig .
[ fig_dm ] , @xmath293 versus @xmath2 is plotted . by identifying @xmath2 satisfying @xmath294 [
shown in ( [ ch5_dm_equ2 ] ) ] , we have the following theorem .
[ tighter_m_rmk2 ] the glb in ( [ lev_bd_cor4 ] ) which arises from the weight vector in ( [ levwtvec_equ ] ) is asymptotically tighter than the welch bound for _ all _ @xmath5 if and only if @xmath295 denote by @xmath296 the optimized asymptotic lower bounds in ( [ aym_lwrbd_wec3_equ ] ) , ( [ aym_lwrbd_wec2_equ ] ) , ( [ lev_bd_cor4 ] ) , respectively .
we remark that ( 1 ) , both @xmath297 and @xmath298 are greater than @xmath299 for any @xmath4 ; ( 2 ) , @xmath300 except for @xmath301 .
the proof is omitted as it can be easily obtained from the tightness analysis in section iii - b and section iv . to further visualize their relative strengths of these three lower bounds ,
we calculate in table i the ratio values of @xmath302 with @xmath303 , where @xmath304 and @xmath305 denotes the corresponding welch bound . a ratio value which is larger than 1 corresponds to a tighter glb ( over the welch bound ) . with table
i , one may verify the three sets of @xmath2 for tighter glb in _ theorems 1 - 3 _ as well as the above - mentioned remark in this subsection .
in particular , we can see that @xmath306 for all @xmath4 , showing that weight vector 1 is superior than the other two as it is capable of tightening the glb for all possible @xmath2 , asymptotically .
[ table_of_small_value ] [ cols="^,^,^,^,^,^,^,^,^,^,^,^,^,^",options="header " , ]
the generalized levenshtein bound ( glb ) in [ [ liuguanmow14 ] , _ theorem 1 _ ] is an aperiodic correlation lower bound for quasi - complementary sequence sets ( qcsss ) with _ number of channels _ not less than 2 ( i.e. , @xmath4 ) .
although glb was shown to be tighter than the corresponding welch bound [ i.e. , ( [ welch_bound_for_cc ] ) ] for certain cases , there exists an ambiguous zone [ shown in ( [ glbgap _ ] ) and ( [ glbgap ] ) ] in which the tightness of glb over welch bound is unknown . motivated by this
, we aim at finding a properly selected weight vector in the bounding equation for a tighter glb for _ all _ ( other than _ some _ ) @xmath5 , where @xmath1 denotes the set size , and @xmath6 is a value depending on @xmath2 and @xmath3 ( the sequence length ) . as the glb is in general a non - convex fractional quadratic function of the weight vector ,
the derivation of an analytical solution for a tighter glb for _ all _ possible cases is a challenging task .
the most significant finding of this paper is weight vector 1 in ( [ wgtvec3_equ ] ) which is obtained from a frequency - domain optimization approach .
we have shown that its resultant glb in ( [ coro_glb_from_wetvec3-equ ] ) is tighter than welch bound for _ all _ @xmath5 and for _ all _ @xmath4 , asymptotically .
this finding is interesting as it explicitly shows that the glb tighter condition given in [ [ liuguanmow14 ] , _ theorem 2 _ ] is not only necessary but also sufficient , asymptotically , as shown in _ theorem [ th4optwtvec]_. interestingly , we have proved in section iii - c that weight vector 1 in ( [ wgtvec3_equ ] ) is local minimizer of the glb under certain asymptotic conditions .
we have shown that both weight vectors 2 and 3 [ given in ( [ sine_shape_weight_vector ] ) and ( [ levwtvec_equ ] ) , respectively ] lead to tighter glbs for _ all _ @xmath5 but only for certain small values of @xmath2 not less than 2 .
note that although they were proposed in @xcite , the focus of @xcite was on the tightening of levenshtein bound for traditional single - channel ( i.e. , @xmath19 ) sequence sets , whereas in this paper we have extended their tightening capability to glb for multi - channel ( i.e. , @xmath4 ) qcss .
furthermore , we have shown in _ theorem [ tighter_m_rmk ] _ and _ theorem [ tighter_m_rmk2 ] _ that weight vector 2 is superior as its admissible set of @xmath2 [ see ( [ distri_optimal_m ] ) ] is larger and subsumes that of weight vector 3 .
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209 - 222 , 2014 . | a quasi - complementary sequence set ( qcss ) refers to a set of two - dimensional matrices with low non - trivial aperiodic auto- and cross- correlation sums . for multicarrier code - division multiple - access applications ,
the availability of large qcsss with low correlation sums is desirable .
the generalized levenshtein bound ( glb ) is a lower bound on the maximum aperiodic correlation sum of qcsss .
the bounding expression of glb is a fractional quadratic function of a weight vector @xmath0 and is expressed in terms of three additional parameters associated with qcss : the set size @xmath1 , the number of channels @xmath2 , and the sequence length @xmath3 .
it is known that a tighter glb ( compared to the welch bound ) is possible only if the condition @xmath4 and @xmath5 , where @xmath6 is a certain function of @xmath2 and @xmath3 , is satisfied .
a challenging research problem is to determine if there exists a weight vector which gives rise to a tighter glb for _ all _ ( not just _ some _ )
@xmath5 and @xmath4 , especially for large @xmath3 , i.e. , the condition is asymptotically both necessary and sufficient . to achieve this
, we _ analytically _ optimize the glb which is ( in general ) non - convex as the numerator term is an indefinite quadratic function of the weight vector .
our key idea is to apply the frequency domain decomposition of the circulant matrix ( in the numerator term ) to convert the non - convex problem into a convex one . following this optimization approach , we derive a new weight vector meeting the aforementioned objective and prove that it is a local minimizer of the glb under certain conditions .
fractional quadratic programming , convex optimization , welch bound , levenshtein bound , perfect complementary sequence set ( pcss ) , quasi - complementary sequence set ( qcss ) , golay complementary pair . | <s>[INST]in recent years , multicarrier code - division multiple - access ( mc - cdma ) based on the quasi-/perfect- complementary sequence set ( in abbreviation , qcss / pcss ) has attracted much attention due to its potential to achieve low-/zero- interference multiuser performance @xcite , @xcite . here
, a qcss ( or pcss ) refers to a set of two - dimensional matrices with low ( or zero ) non - trivial auto- and cross- correlation sums @xcite@xmath7@xcite . in this paper , a complementary sequence
is also called a complementary matrix , and vice versa . to deploy a qcss ( or pcss ) in an mc - cdma system , every data symbol of a specific user
is spread by a complementary matrix by simultaneously sending out all of its row sequences over a number of non - interfering subcarrier channels .
because of this , the number of row sequences of a complementary matrix , denoted by @xmath2 , is also called the _ number of channels_. at a matched - filter based receiver , de - spreading operations are performed separately in each subcarrier channel , followed by summing the correlator outputs of all the subcarrier channels to attain a correlation sum which will be used for detection .
a pcss may also be called a mutually orthogonal complementary sequence set ( mocss ) @xcite@xmath7@xcite , a concept extended from mutually orthogonal golay complementary pairs ( gcps ) @xcite@xmath7@xcite . however , a drawback of pcss is its small set size @xcite . specifically , the set size ( denoted by @xmath1 ) of pcss is upper bounded by the number of channels , i.e. , @xmath8 .
this means that a pcss based mc - cdma system with @xmath2 subcarriers can support at most @xmath2 users only .
against such a backdrop , there have been two approaches aiming to provide a larger set size , i.e. , @xmath9 .
the first approach is to design zero- or low- correlation zone ( zcz / lcz ) based complementary sequence sets , called zcz - css @xcite , @xcite or lcz - css @xcite .
a zcz - css ( lcz - css ) based mc - cdma system is capable of achieving zero- ( low- ) interference performance but requires a closed - control loop to dynamically adjust the timings of all users such that the received signals can be quasi - synchronously aligned within the zcz ( lcz ) .
a second approach is to design qcss which has uniformly low correlation sums over all non - trivial time - shifts . as such
, qcss can be utilized to achieve low - interference performance with a simpler timing - control system . to the authors best knowledge , the first aperiodic correlation lower bound of qcss
was derived by welch in @xcite , which states : @xmath10 where every quasi - complementary sequence is a matrix of order @xmath11 ( thus , every row sequence has length of @xmath3 ) with assumed energy of @xmath12 .
the aforementioned set size upper bound of pcss , namely , @xmath8 , can also be obtained from ( [ welch_bound_for_cc ] ) by setting @xmath13 . on the other hand , if @xmath14 , one can show that @xmath9 , meaning that a larger set size can be supported by qcss .
recently , a generalized levenshtein bound ( glb ) for qcss has been derived by liu , guan and mow in [ [ liuguanmow14 ] , _ theorem 1 _ ] .
the key idea behind the glb ( including the levenshtein bound @xcite ) is that the weighted mean square aperiodic correlation of any sequence subset over the complex roots of unity should be equal to or greater than that of the whole set which includes all possible complex roots - of - unity sequences .
the levenshtein bound was extended from binary sequences to complex roots - of - unity sequences by bozta @xcite .
a lower bound for aperiodic lcz sequence sets was derived in @xcite by an approach similar to levenshtein s . in its bounding equation ,
glb is a function of the simplex " weight vector @xmath0 , the set size @xmath1 , the number of channels @xmath2 , and the row sequence length @xmath3 .
a necessary condition ( shown in [ [ liuguanmow14 ] , _ theorem 2 _ ] ) for the glb to be tighter than the welch bound is that @xmath5 , where @xmath15 with @xmath16 although a step - function " weight vector was adopted in [ [ liuguanmow14 ] , ( 34 ) ] , it only leads to a tighter glb for @xmath17 . as a matter of fact
, the tightness of glb remains unknown for @xmath18 when @xmath3 is sufficiently large .
the main objective of this paper is to optimize and then tighten the glb for _ all _ @xmath5 ( instead of _ some _ ) . for this
, we are to find a ( locally ) optimal weight vector which is used in the bounding equation .
a similar research problem was raised in @xcite for traditional binary sequences ( i.e. , non - qcss with @xmath19 ) .
see @xcite for more details .
the optimization of glb on qcss ( with @xmath4 ) , however , is more challenging because an analytical solution to a non - convex glb ( in terms of weight vector @xmath0 ) for _ all _ possible cases of @xmath20 is in general intractable .
we first adopt a frequency - domain optimization approach in section iii - b to minimize the ( non - convex ) fractional quadratic function of glb .
this is achieved by properly exploiting the specific structure of the circulant quadratic matrix in the numerator of the fractional quadratic term of glb . following this optimization approach
, we find a new weight vector which leads to a tighter glb for _ all _ @xmath20 cases satisfying @xmath5 and @xmath4 , asymptotically ( in @xmath3 ) .
our finding shows that the condition of @xmath5 , shown in [ [ liuguanmow14 ] , theorem 2 ] , is not only necessary but also sufficient , as @xmath3 tends to infinity .
moreover , in section iii - c , it is proved that the newly found weight vector is a local minimizer to the fractional quadratic function of glb , asymptotically .
we then examine in sections iv two weight vectors which were presented in @xcite for the tightening of the levenshtein bound on conventional single - channel ( i.e. , @xmath19 ) sequence sets .
we extend their tightening capability to glb on multi - channel ( i.e. , @xmath4 ) qcss , although the proof is not straightforward .
it is shown that each of these two weight vectors gives rise to a tighter glb ( over the welch bound ) for several small values of @xmath2 provided that @xmath5 .
it is also noted that the glb from the newly found weight vector is ( in general ) tighter than the glbs from these two ( earlier found ) weight vectors , as shown by some numerical results .
in this section , we first present some necessary notations and define qcss . then
, we give a brief review of glb .
for two complex - valued sequences @xmath21 $ ] and @xmath22 $ ] , their aperiodic correlation function at time - shift @xmath23 is defined as @xmath24 when @xmath25 , @xmath26 is called the aperiodic cross - correlation function ( accf ) ; otherwise , it is called the aperiodic auto - correlation function ( aacf ) . for simplicity
, the aacf of @xmath27 is denoted by @xmath28 .
let @xmath29 be a set of @xmath1 matrices , each of order @xmath11 ( where @xmath30 ) , i.e. , @xmath31_{m\times n } = \left [ \begin{matrix } c^\nu_{0,0 } & c^\nu_{0,1 } & \cdots & c^\nu_{0,n-1}\\ c^\nu_{1,0 } & c^\nu_{1,1 } & \cdots & c^\nu_{1,n-1}\\ \vdots & \vdots & \ddots & \vdots\\ c^\nu_{m-1,0 } & c^\nu_{m-1,1 } & \cdots & c^\nu_{m-1,n-1}\\ \end{matrix } \right ] , \end{split}\ ] ] where @xmath32 .
define the aperiodic correlation sum " of matrices @xmath33 and @xmath34 as follows , @xmath35 also , define the aperiodic auto - correlation tolerance @xmath36 and the aperiodic cross - correlation tolerance @xmath37 of @xmath38 as @xmath39 respectively .
moreover , define the aperiodic tolerance ( also called the maximum aperiodic correlation magnitude " ) of @xmath38 as @xmath40 .
when @xmath13 , @xmath38 is called a _ perfect complementary sequence set _ ( pcss ) ; otherwise , it is called a _ quasi - complementary sequence set _ ( qcss ) . in particular ,
when @xmath41 and @xmath42 , a pcss reduces to a matrix consisting of two row sequences which have zero out - of - phase aperiodic autocorrelation sums .
such matrices are called golay complementary matrices ( gcms ) or golay complementary pairs ( gcps ) in this paper , and either sequence in a gcp is called a golay sequence .
note that the transmission of a pcss or a qcss requires a multi - channel system .
specifically , every matrix in a pcss ( or a qcss ) needs @xmath4 non - interfering channels for the separate transmission of @xmath2 row sequences .
this is different from the traditional single - channel sequences with @xmath19 only .
let @xmath43^{\text{t}}$ ] be a simplex " weight vector which is constrained by @xmath44 define a quadratic function @xmath45 where @xmath46 is a @xmath47 circulant matrix with all of its diagonal entries equal to @xmath48 , and its off - diagonal entries @xmath49 , where @xmath50 and @xmath51 the glb for qcss over complex roots of unity in @xcite is shown below .
[ generalized_welch_bound_for_cc ] @xmath52.\ ] ] a weaker simplified version of ( [ generalized_welch_bound_for_cc - equ ] ) is given below .
@xmath53.\ ] ] setting @xmath54 , the glb reduces to the welch bound for qcss in ( [ welch_bound_for_cc ] ) .
[ rmk_nece_cond ] [ [ liuguanmow14 ] , _ theorem 2 _ ] for the glb to be tighter than the corresponding welch bound , it is _ necessary _ that @xmath5 , where @xmath6 is defined in ( [ nece_cond_qcssbd2 ] ) .
[ [ liuguanmow14 ] , _ corollary 1 _ ] applying the weight vector @xmath55 with @xmath56 where @xmath57 , to ( [ generalized_welch_bound_for_cc - equ ] ) , we have @xmath58 the lower bound in ( [ zl_corollary_4_equ ] ) is tighter than the welch bound for qcss in ( [ welch_bound_for_cc ] ) if one of the two following conditions is fulfilled : ( 1 ) : @xmath59 , @xmath4 and @xmath60 ( 2 ) : @xmath61 , @xmath4 and @xmath62 .
the necessary condition in _ remark [ rmk_nece_cond ] _ implies that for a given @xmath63 , the welch bound for qcss can not be improved if @xmath64 , where @xmath65 is defined in ( [ nece_cond_qcssbd2 ] ) . on the other hand , the weight vector in ( [ leven_lcz_weighting_vector ] )
can only lead to a tighter glb for @xmath17 .
because of this , the tightness of glb is unknown in the following ambiguous zone .
@xmath66 for sufficiently large @xmath3 , the above @xmath67 zone further reduces to @xmath68 by recalling ( [ nece_cond_qcssbd2 _ ] ) .
one may visualize this zone in the shaded area of fig .
[ fig_glbgap ] for @xmath69 .
we are therefore interested in finding a weight vector which is capable of optimizing and tightening the glb for _ all _ ( rather than _ some _ ) @xmath5 . relating this objective to fig .
[ fig_glbgap ] , such a weight vector can give us a tighter glb for the largest @xmath67 region right above the red diamond symbols .
however , the optimization of glb in ( [ generalized_welch_bound_for_cc - equ ] ) is challenging because its fractional quadratic term ( in terms of @xmath0 ) is indefinite .
more specifically , the quadratic term @xmath70 in the numerator is indefinite as some eigenvalues of the corresponding circulant matrix are negative when @xmath5 [ [ liuguanmow14 ] , appendix b ] .
it is noted that indefinite quadratic programming ( qp ) is np - hard @xcite , even it has one negative eigenvalue only @xcite . moreover , checking local optimality of a feasible point in constrained qp is also np - hard @xcite .
although some optimality conditions for constrained qp have been derived by bomze from the copositivity perspective @xcite , the situation becomes more complicated when indefinite fractional quadratic programming ( fqp ) problems are dealt with . according to @xcite
, glb may be classified as a standard fqp ( stfqp ) as the feasible set is the standard simplex . to the best of the authors knowledge ,
preisig pioneered an iterative algorithm for which convergence to a kkt point ( but can not be guaranteed to be a local minimizer ) of the stfqp can be proved @xcite .
two algorithms for stfqp based on semidefinite programming ( sdp ) relaxations are presented in @xcite , yet the optimalities of the resultant solutions are unknown . as a matter of fact , the algorithms developed in @xcite may only be feasible for medium - scaled stfqp with @xmath71 .
in contrast , we target at an analytical solution ( as opposed to a numerical solution ) which is applicable to large scale of glb ( e.g. , the sequence length @xmath72 ) .
thus , the techniques used in @xcite may not be useful for the specific stfqp problem considered in this paper . in the sequel
, we introduce a frequency - domain optimization approach which finds a local minimizer ( i.e. , a weight vector ) of the glb .
we show that the obtained weight vector leads to a tighter glb for _ all _ @xmath5 and @xmath30 , asymptotically . to tighten the glb in ( [ generalized_welch_bound_for_cc - equ ] )
, we adopt a novel optimization approach in this subsection , motivated by the observation that any circulant matrix [ e.g. , @xmath73 in ( [ leven - quad - fun - equ ] ) which forms a part of the glb quadratic function in ( [ generalized_welch_bound_for_cc - equ ] ) ] can be decomposed in the frequency domain .
define @xmath74 and the @xmath75-point discrete fourier transform ( dft ) matrix as @xmath76_{m , n=0}^{l-1},~\text{where}~f_{m , n}=\xi^{mn}_l.\ ] ] denote by @xmath77 the first column vector of @xmath46 in ( [ leven - quad - fun - equ ] ) , i.e. , @xmath78^{\text{t}}.\ ] ] let @xmath79^{\text{t}}.\ ] ] it is noted that @xmath80 . by @xcite , the circulant matrix @xmath73 defined in ( [ leven - quad - fun - equ ] ) can be expressed as @xmath81 where @xmath82^{\text{t}},\ ] ] and @xmath83 is the matrix with @xmath84 being the diagonal vector and zero for all the non - diagonal matrix entries .
consequently [ [ nyy2014 ] , theorem 3.1 ] , @xmath85 similarly , @xmath86 by [ [ liuguanmow14 ] , appendix b ] , we have @xmath87 and @xmath88 for @xmath89 .
note that @xmath90 for @xmath91 .
moreover , we remark that @xmath92 this is because 1 .
if @xmath93 is odd : @xmath94 2 . if @xmath93 is even : @xmath95 to maximize the glb in ( [ generalized_welch_bound_for_cc - equ ] ) , it is equivalent to consider the following optimization problem .
@xmath96 since @xmath0 is real - valued , @xmath97 is conjugate symmetric , i.e. , @xmath98 for @xmath99 . having this in mind ,
we define @xmath100 taking advantage of the fact that @xmath101 are strictly smaller than other @xmath102 s with nonzero @xmath93 as shown in ( [ lambda_l1_equ ] ) , we have @xmath103 where the equality is achieved if and only if @xmath104 for @xmath105 . inspired by this observation , we relax the non - negativity constraint on @xmath0 , i.e. , some negative @xmath106 s may be allowed ( but the sum of all elements of @xmath0 must still be equal to 1 ) . with this , the optimization problem in ( [ opti_freqd ] ) can be translated to @xmath107 where @xmath108 from now on , we adopt the setting of @xmath109 where @xmath110 denote the magnitude and phase of @xmath111 , respectively . since @xmath112 , we have @xmath113^{\text{t}}. \end{split}\ ] ] to optimize the fractional function in ( [ opti_freqd_trans ] ) , we have the following lemma .
[ lem_monofun ] the fractional function @xmath114 in terms of @xmath115 in ( [ opti_freqd_trans ] ) is 1 .
case 1 : monotonically decreasing in @xmath115 if @xmath116 and @xmath117 ; 2 .
case 2 : monotonically increasing in @xmath115 if @xmath118 , or @xmath5 and @xmath119 . to prove case 1 ,
we first show that @xmath120 if and only if @xmath121 where @xmath6 is defined in ( [ nece_cond_qcssbd2 ] ) . for ease of analysis , we write @xmath122 where @xmath123 is a positive integer and @xmath124 .
thus , @xmath125 .
consequently , we have @xmath126\\ & \leq \frac{n(mn-1)}{k } \left ( 1- \frac{n+1}{n+\epsilon } \right ) \\ & < 0 , \end{split}\ ] ] with which the proof of case 1 follows . the proof of case 2
can be easily obtained by following a similar argument . for case 2 of _ lemma [ lem_monofun ]
_ , it can be readily shown that the minimum of the fractional function @xmath114 in ( [ opti_freqd_trans ] ) is achieved at @xmath127 .
thus , the weight vector in ( [ wtvec3_equ ] ) reduces to @xmath128^{\text{t } } , \end{split}\ ] ] where the corresponding glb reduces to the welch bound in ( [ welch_bound_for_cc ] ) .
next , let us focus on the application of case 1 for glb tightening . in this case
, we wish to know the upper bound of @xmath115 in order to minimize the fractional function of @xmath115 in ( [ opti_freqd_trans ] ) .
coming back to the constraint of @xmath0 given in ( [ leven_weight_vector ] ) , @xmath129 and @xmath130 should satisfy @xmath131 thus , @xmath132 where the upper bound is achieved with equality when @xmath133 for any integer @xmath134 . by substituting @xmath135 into ( [ wtvec3_equ ] )
, we obtain the following weight vector .
@xmath136 where @xmath137 and @xmath134 is any integer .
the resultant glb from this weight vector is shown in the following lemma .
[ coro_glb_from_wetvec3 ] for @xmath116 and @xmath117 , we have @xmath138,\ ] ] where @xmath139 are given in ( [ lambdas ] ) .
to analyze the asymptotic tightness of the lower bound in ( [ coro_glb_from_wetvec3-equ ] ) , we note that when @xmath3 is sufficiently large , the second condition in _ lemma [ coro_glb_from_wetvec3 ] _ , i.e. , @xmath140 is true for @xmath5 . to show this
, we substitute @xmath139 into ( [ cond_case1 ] ) .
after some manipulations , one can see that the inequality in ( [ cond_case1 ] ) holds if and only if @xmath141 carrying on the expression in ( [ k_split_equ ] ) , we require @xmath142 which is guaranteed to hold for sufficiently large @xmath3 because @xmath143 is strictly smaller than 1 by assumption . furthermore , we note that @xmath144 therefore , @xmath145}=\frac{3m}{4k}+\frac{1}{2}-\frac{1}{\pi^2}.\ ] ] on the other hand , let us rewrite the welch bound expression ( [ welch_bound_for_cc ] ) as @xmath146 with @xmath147 then , @xmath148 with ( [ r1 ] ) and ( [ ch4_r1_largen ] ) , one can show that the lower bound in _
lemma [ coro_glb_from_wetvec3 ] _ is asymptotically tighter than the welch bound in ( [ welch_bound_for_cc ] ) if and only if the following equation is satisfied .
@xmath149 equivalently , we need to prove that for @xmath150 ( as @xmath151 ) , the following inequality holds .
@xmath152 one can readily show that the condition @xmath153 given in ( [ bdfromoptwtvec2 ] ) is true for _ all _ @xmath30 .
therefore , we have the following theorem .
[ th4optwtvec ] the glb in ( [ coro_glb_from_wetvec3-equ ] ) which arises from the weight vector in ( [ wgtvec3_equ ] ) reduces to @xmath154,\ ] ] for sufficiently large @xmath3 .
such an asymptotic lower bound is tighter than the welch bound for _ all _ @xmath5 and for _ all _ @xmath30 . in this subsection
, we prove the proposed weight vector in ( [ wgtvec3_equ ] ) is a local minimizer of the glb in ( [ generalized_welch_bound_for_cc - equ ] ) under certain condition .
we consider the weight vector @xmath0 by setting @xmath155 in ( [ wgtvec3_equ ] ) because other values of @xmath134 will lead to identical value of glb [ cf .
( [ glb_quadra_fd ] ) and ( [ glb_quadra_fd _ ] ) ] .
@xmath156 note that the frequency domain vector @xmath157 has @xmath158 and @xmath104 for all @xmath159 .
our problem in this subsection can be formally cast as follows .
define the fractional quadratic function @xmath160 is essentially the fractional quadratic term in ( [ generalized_welch_bound_for_cc - equ ] ) by replacing @xmath0 with @xmath161 . ] as follows .
@xmath162 where @xmath163 , @xmath73 is the circulant matrix defined in ( [ leven - quad - fun - equ ] ) which has order @xmath164 and with @xmath165 . when @xmath166 and @xmath63 becomes sufficiently large ,
prove that the weight vector @xmath0 in ( [ proposed_wgtvec ] ) is a local minimizer of @xmath160 , i.e. , @xmath167 holds for any feasible perturbation @xmath168 which has sufficiently small norm .
to get started , we define @xmath169 it is easy to show that ( [ local_mini_equ ] ) is equivalent to the following inequality .
@xmath170 let @xmath171 . since @xmath168 is a real vector , @xmath172 is conjugate symmetric in that @xmath173 for @xmath99 . by taking advantage of ( [ qa_in_freqdomain ] ) , we present the following properties which will be useful in the sequel .
@xmath174 by ( [ multi_equ4 ] ) , ( [ multi_equ5 ] ) , ( [ multi_equ7 ] ) and ( [ multi_equ8 ] ) , we have @xmath175 |e_i|^2\right \}. \end{split}\ ] ] by ( [ multi_equ3 ] ) , ( [ multi_equ5 ] ) , ( [ multi_equ6 ] ) and ( [ multi_equ7 ] ) , we have @xmath176 therefore , @xmath177 can be expressed in the form shown in ( [ gamma_equ ] ) .
@xmath178 since @xmath168 is a small perturbation , let us assume @xmath179 next , we proceed with the following two cases . 1 .
case i : if there exists @xmath180 for @xmath181 .
+ since we consider @xmath166 with sufficiently large @xmath63 , it is readily to show that @xmath182 holds for any @xmath181 [ see ( [ lambda_even_equ ] ) and ( [ lambda_odd_equ ] ) ] . by ( [ multi_equ4 ] ) , let us write @xmath183 where @xmath184 .
furthermore , write @xmath185\cdot ( 2n-1)=\lambda_1 a+b,\ ] ] where @xmath186 + [ rmk_on_ab ] since @xmath187 , @xmath188 and @xmath189 approach to + @xmath190 and @xmath191 , respectively , as @xmath2 grows sufficiently large .
+ to show ( [ local_mini_equ ] ) [ and ( [ local_mini_equ2 ] ) ] holds , we only need to prove the right - hand term of ( [ local_mini_equ3 ] ) divided by @xmath48 is nonnegative , asymptotically . for this , our idea is to consider a fixed @xmath3 ( sufficiently large ) and prove that : ( 1 ) @xmath192 is lower bounded by a nonnegative value determined by @xmath3 only ; ( 2 ) @xmath193 tends to zero ( with an upper bounded @xmath194 ) regardless the value of @xmath3 . + from ( [ lambda_i_equ ] ) , we have @xmath195 for ease of analysis , let @xmath3 be an even integer is odd , we can prove ( [ local_mini_equ ] ) [ and ( [ local_mini_equ2 ] ) ] holds by almost the same arguments . ] .
hence , @xmath196 .
since @xmath197 is a decreasing function of @xmath198 , we have @xmath199 also , @xmath200 where @xmath201 by noting @xmath202 ( @xmath203 a small positive angle ) and @xmath166 , we have @xmath204 by ( [ lambda_even_equ ] ) and ( [ lambda_odd_equ ] ) , we obtain @xmath205 on the other hand , @xmath206\\ \rightarrow & ~ 0^{- } , \end{split}\ ] ] where @xmath207 denotes a sufficiently small value ( negative ) that approaches zero from the left .
therefore , we have @xmath208\cdot ( 2n-1)}{a}\\ = & { \lim\limits_{m\rightarrow+\infty}\frac{\lambda_1}{a } } \cdot \underbrace{\lim\limits_{m\rightarrow+\infty}a}_{\text{upper bounded } } + { \lim\limits_{m\rightarrow+\infty}\frac{b}{a}}%\rightarrow \frac{\xi}{a}.% > \frac{2}{3}\cdot \left ( 2\sum\limits_{i=2}^{n-1}|e_i|^2 \right ) \end{split}\ ] ] by ( [ lim_xi_a_equ ] ) and ( [ lambda1_equ ] ) , we assert that when @xmath2 is sufficiently large , the sign of the limit in ( [ lim_gep_equ ] ) will be identical to that of @xmath209 [ cf .
( [ lim_xi_a_equ ] ) ] which is nonnegative .
this shows that ( [ local_mini_equ ] ) [ and ( [ local_mini_equ2 ] ) ] holds for case i , asymptotically .
2 . case ii : if @xmath210 for all @xmath181 .
+ in this case , ( [ ab_equ ] ) reduces to @xmath211 since @xmath171 , we have @xmath212 where @xmath213 denotes the real part of complex data @xmath203 . consider @xmath214 which takes the following form .
@xmath215 where @xmath216 and @xmath217 denotes the phase shift of @xmath214 .
as a result , @xmath218 can be expressed as @xmath219 thus , @xmath220 since @xmath221 , we assert that for sufficiently large @xmath63 , @xmath222 holds because it will be dominated by the negative @xmath223 .
our next task is to show that @xmath224 . by ( [ ei_equ ] ) , we have @xmath225 it is required in ( [ multi_equ2 ] ) that @xmath226 for all @xmath198 , i.e. , @xmath227 setting @xmath228 , we have @xmath229 setting @xmath228 , we have @xmath230 therefore , @xmath231 this shows @xmath232 holds provided @xmath233
. this can be easily satisfied by a sufficiently small @xmath234 .
together with ( [ lambda1ab_caseii])-([lambda1ab_caseii_3 ] ) , we conclude that ( [ local_mini_equ ] ) [ and ( [ local_mini_equ2 ] ) ] holds for case ii , asymptotically .
this completes the proof of the local optimality of the proposed weight vector in ( [ proposed_wgtvec ] ) . following a proof similar to the above
, one can easily show that the weight vector @xmath0 in ( [ proposed_wgtvec ] ) is also a local minimizer of the constrained qp of @xmath235 when @xmath166 and @xmath63 are sufficiently large .
in this section , we first consider another two weight vectors and study the tightness of their resultant glbs .
then , we compare them with the proposed weight vector in ( [ wgtvec3_equ ] ) by some numerical results . in @xcite , liu _
et al _ showed that the following positive - cycle - of - sine " weight vector @xmath0 @xmath236 where @xmath237 , asymptotically leads to a tighter levenshtein bound ( i.e. , @xmath19 ) for all @xmath238 @xcite . by [ [ liuparaguanbozas14 ] , _ proposition 1 _ ]
, one can show that the resultant glb from the weight vector in ( [ sine_shape_weight_vector ] ) can be written as follows .
[ new_lwerbd_from_new_wv ] @xmath239 , % ~~\text{for}~2\leq m\leq 2n-1,\ ] ] where @xmath240 in what follows , we analyze the asymptotic tightness of the lower bound in ( [ zl - corollary - new - weight - vector - equ ] ) .
define @xmath241 . obviously , @xmath129 is a real - valued constant with @xmath242 when @xmath243 is on the same order of @xmath244 ( i.e. , @xmath245 ) ; and @xmath246 when @xmath243 is dominated by @xmath3 asymptotically ( i.e. , @xmath247 ) .
furthermore , define the fractional term in ( [ zl - corollary - new - weight - vector - equ ] ) as @xmath248 it is easy to see that the lower bound in ( [ zl - corollary - new - weight - vector - equ ] ) is tighter than the welch bound in ( [ welch_bound_for_cc ] ) if and only if @xmath249 where @xmath250 is defined in ( [ r1 ] ) . as @xmath3 tends to infinity , the inequality in ( [ iff ] ) is equivalent to @xmath251 when @xmath247 , we have @xmath246 and @xmath252 as @xmath253 . in this case , one can show that @xmath254 which can be ignored without missing the minimum point of interest in the right - hand side of ( [ asymp_iff ] ) .
hence , we shall assume @xmath129 to be a non - vanishing real - valued constant with @xmath255 , and rewrite ( [ asymp_iff ] ) as @xmath256 here , the order of the limit and minimization operations can be exchanged because @xmath257 as a function of @xmath129 exists , as shown below .
next , noting that @xmath258 , we can express ( [ r2 ] ) as @xmath259 where @xmath260 and after some manipulations , @xmath261 by ( [ ch4_r1_largen ] ) , ( [ r2_2a ] ) and ( [ ch4_q_largen ] ) , it follows that ( [ asymp_iff _ ] ) reduces to @xmath262 equivalently , we assert that the asymptotic lower bound in ( [ zl - corollary - new - weight - vector - equ ] ) is tighter than the welch bound if and only if @xmath263 where @xmath264 in fig .
[ fig_optimal_r2 ] , @xmath265 and @xmath266 versus @xmath129 over the range of @xmath267 are plotted
. it can be obtained from ( [ overlinek ] ) and fig . [ fig_optimal_r2 ]
that @xmath268 by ( [ asym_bd_wtvec2_equ ] ) , one can see that the proposed weight vector in ( [ sine_shape_weight_vector ] ) asymptotically leads to a tighter glb for _ all _ @xmath5 if and only if the value of @xmath2 satisfies the following condition [ c.f .
( [ nece_cond_qcssbd2_2 ] ) ] @xmath269 in fig .
[ fig_dm ] , @xmath270 versus @xmath2 is also plotted . by identifying @xmath2 satisfying @xmath271 [ shown in ( [ ch5_dm_equ ] ) ] , we arrive at the following theorem .
[ tighter_m_rmk ] the glb in ( [ zl - corollary - new - weight - vector - equ ] ) which arises from the weight vector in ( [ sine_shape_weight_vector ] ) reduces to @xmath272,\ ] ] for sufficiently large @xmath3 , where @xmath273 is given in ( [ ch4_q_largen ] ) . such an asymptotic lower bound is tighter than the welch bound for _ all _ @xmath5 if and only if @xmath274 let us consider the weight vector obtained by minimizing the following function using the lagrange multiplier .
@xmath275 where @xmath276 for @xmath277 and @xmath237 .
the idea is to optimize the weaker glb in ( [ simplified_glb ] ) . by relating the quadratic minimization solution of @xmath278 to the chebyshev polynomials of the second kind ,
one can obtain the weight vector , lemma 2 ] , such a weight vector is more generic as it applies to qcss with different @xmath30 .
] below .
let @xmath279 and @xmath280 .
also , let @xmath243 be an even positive integer with @xmath281 .
for @xmath282 , define the following weight vector @xmath283 setting @xmath284 , one can minimize @xmath278 in ( [ mini_f ] ) over different @xmath243 and get a generalized version of the levenshtein bound in [ [ levenshtein99 ] , _ corollary 4 _ ] as follows .
[ coro_bd1 ] @xmath285 as @xmath253 , the lower bound in ( [ lev_bd_cor4 ] ) is tighter than the welch bound in ( [ welch_bound_for_cc ] ) if and only if @xmath286 or equivalently , @xmath287 where the right - hand side of ( [ equ_coro2_tighter ] ) is obtained from ( [ lev_bd_cor4 ] ) .
recall that as @xmath253 , a necessary condition ( cf .
_ remark [ rmk_nece_cond ] _ ) for the glb to be tighter than the corresponding welch bound is @xmath288 clearly , @xmath289 which is smaller than the right - hand side of ( [ equ_coro2_tighter2 ] ) .
it can be asserted that the resultant glb obtained from the weight vector in ( [ levwtvec_equ ] ) with @xmath290 is tighter if and only if the value of @xmath2 satisfies the condition @xmath291
> 0.\ ] ] this is because when condition ( [ ch5_dm_equ2 ] ) is satisfied , @xmath292 is not only a necessary condition [ cf .
( [ nece_cond_qcssbd2_2 ] ) ] but also a sufficient condition [ cf .
( [ equ_coro2_tighter2 ] ) ] for the glb to be asymptotically tighter than the welch bound . in fig .
[ fig_dm ] , @xmath293 versus @xmath2 is plotted . by identifying @xmath2 satisfying @xmath294 [
shown in ( [ ch5_dm_equ2 ] ) ] , we have the following theorem .
[ tighter_m_rmk2 ] the glb in ( [ lev_bd_cor4 ] ) which arises from the weight vector in ( [ levwtvec_equ ] ) is asymptotically tighter than the welch bound for _ all _ @xmath5 if and only if @xmath295 denote by @xmath296 the optimized asymptotic lower bounds in ( [ aym_lwrbd_wec3_equ ] ) , ( [ aym_lwrbd_wec2_equ ] ) , ( [ lev_bd_cor4 ] ) , respectively .
we remark that ( 1 ) , both @xmath297 and @xmath298 are greater than @xmath299 for any @xmath4 ; ( 2 ) , @xmath300 except for @xmath301 .
the proof is omitted as it can be easily obtained from the tightness analysis in section iii - b and section iv . to further visualize their relative strengths of these three lower bounds ,
we calculate in table i the ratio values of @xmath302 with @xmath303 , where @xmath304 and @xmath305 denotes the corresponding welch bound . a ratio value which is larger than 1 corresponds to a tighter glb ( over the welch bound ) . with table
i , one may verify the three sets of @xmath2 for tighter glb in _ theorems 1 - 3 _ as well as the above - mentioned remark in this subsection .
in particular , we can see that @xmath306 for all @xmath4 , showing that weight vector 1 is superior than the other two as it is capable of tightening the glb for all possible @xmath2 , asymptotically .
[ table_of_small_value ] [ cols="^,^,^,^,^,^,^,^,^,^,^,^,^,^",options="header " , ]
the generalized levenshtein bound ( glb ) in [ [ liuguanmow14 ] , _ theorem 1 _ ] is an aperiodic correlation lower bound for quasi - complementary sequence sets ( qcsss ) with _ number of channels _ not less than 2 ( i.e. , @xmath4 ) .
although glb was shown to be tighter than the corresponding welch bound [ i.e. , ( [ welch_bound_for_cc ] ) ] for certain cases , there exists an ambiguous zone [ shown in ( [ glbgap _ ] ) and ( [ glbgap ] ) ] in which the tightness of glb over welch bound is unknown . motivated by this
, we aim at finding a properly selected weight vector in the bounding equation for a tighter glb for _ all _ ( other than _ some _ ) @xmath5 , where @xmath1 denotes the set size , and @xmath6 is a value depending on @xmath2 and @xmath3 ( the sequence length ) . as the glb is in general a non - convex fractional quadratic function of the weight vector ,
the derivation of an analytical solution for a tighter glb for _ all _ possible cases is a challenging task .
the most significant finding of this paper is weight vector 1 in ( [ wgtvec3_equ ] ) which is obtained from a frequency - domain optimization approach .
we have shown that its resultant glb in ( [ coro_glb_from_wetvec3-equ ] ) is tighter than welch bound for _ all _ @xmath5 and for _ all _ @xmath4 , asymptotically .
this finding is interesting as it explicitly shows that the glb tighter condition given in [ [ liuguanmow14 ] , _ theorem 2 _ ] is not only necessary but also sufficient , asymptotically , as shown in _ theorem [ th4optwtvec]_. interestingly , we have proved in section iii - c that weight vector 1 in ( [ wgtvec3_equ ] ) is local minimizer of the glb under certain asymptotic conditions .
we have shown that both weight vectors 2 and 3 [ given in ( [ sine_shape_weight_vector ] ) and ( [ levwtvec_equ ] ) , respectively ] lead to tighter glbs for _ all _ @xmath5 but only for certain small values of @xmath2 not less than 2 .
note that although they were proposed in @xcite , the focus of @xcite was on the tightening of levenshtein bound for traditional single - channel ( i.e. , @xmath19 ) sequence sets , whereas in this paper we have extended their tightening capability to glb for multi - channel ( i.e. , @xmath4 ) qcss .
furthermore , we have shown in _ theorem [ tighter_m_rmk ] _ and _ theorem [ tighter_m_rmk2 ] _ that weight vector 2 is superior as its admissible set of @xmath2 [ see ( [ distri_optimal_m ] ) ] is larger and subsumes that of weight vector 3 .
chen , j .- f .
yeh , and n. suehiro , a multicarrier cdma architecture based on orthogonal complementary codes for new generations of wideband wireless communications , " _ ieee commun .
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z. liu , u. parampalli , y. l. guan , and s. bozta , `` constructions of optimal and near - optimal quasi - complementary sequence sets from singer difference sets , '' _ ieee wireless commun .
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2013 . h. h. chen , s. w. chu , and m. guizani , on next generation cdma techonogies : the real approach for perfect orthogonal code generation , " _ ieee trans .
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s. bozta , new lower bounds on aperiodic cross - correlation of codes over @xmath123th roots of unity , " research report 13 , department of mathematics , royal melbourne institudte of technology , australia , 1998 .
[ liuparaguanbozas14 ] z. liu , u. parampalli , y. l. guan and s. bozta , a new weight vector for a tighter levenshtein bound on aperiodic correlation , " _ ieee trans .
theory , _ vol .
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j. c. preisig , copositivity and the minimization of quadratic functions with nonnegativity and quadratic equality constraints , " _
siam j. control and optimization _ , vol .
1135 - 1150 , 1996 . [ nyy2014 ] n. y. yu , a fourier transform approach for improving the levenshteing lower bound on aperiodic correlation of binary sequences , " _ advances in mathematics of communications _ , vol
209 - 222 , 2014 .[/INST] a quasi - complementary sequence set ( qcss ) refers to a set of two - dimensional matrices with low non - trivial aperiodic auto- and cross- correlation sums . for multicarrier code - division multiple - access applications ,
the availability of large qcsss with low correlation sums is desirable .
the generalized levenshtein bound ( glb ) is a lower bound on the maximum aperiodic correlation sum of qcsss .
the bounding expression of glb is a fractional quadratic function of a weight vector @xmath0 and is expressed in terms of three additional parameters associated with qcss : the set size @xmath1 , the number of channels @xmath2 , and the sequence length @xmath3 .
it is known that a tighter glb ( compared to the welch bound ) is possible only if the condition @xmath4 and @xmath5 , where @xmath6 is a certain function of @xmath2 and @xmath3 , is satisfied .
a challenging research problem is to determine if there exists a weight vector which gives rise to a tighter glb for _ all _ ( not just _ some _ )
@xmath5 and @xmath4 , especially for large @xmath3 , i.e. , the condition is asymptotically both necessary and sufficient . to achieve this
, we _ analytically _ optimize the glb which is ( in general ) non - convex as the numerator term is an indefinite quadratic function of the weight vector .
our key idea is to apply the frequency domain decomposition of the circulant matrix ( in the numerator term ) to convert the non - convex problem into a convex one . following this optimization approach , we derive a new weight vector meeting the aforementioned objective and prove that it is a local minimizer of the glb under certain conditions .
fractional quadratic programming , convex optimization , welch bound , levenshtein bound , perfect complementary sequence set ( pcss ) , quasi - complementary sequence set ( qcss ) , golay complementary pair . </s> |
well - characterized osteoblast cultures provide an adequate model for the study of cell behavior and for the determination of biological aspects of the interaction between materials and bone tissue . however , when isolated , bone cell lineages lose their morphological identity22 .
various protocols have been established for the characterization of isolated bone cells , including the determination of the level of alkaline phosphatase ( ap ) activity , specific bone proteins ( osteonectin and osteocalcin ) and type i collagen4,18 .
deboni , et al.10 ( 1996 ) identified and characterized cells obtained from the calvaria of neonatal albino wistar rats , called osteo-1 cells .
after first passage , phenotypic differentiation of the cultures was induced by supplementation of the medium with 10 mm sodium - glycerophosphate , 50 g / ml ascorbic acid and 10 m dexamethasone .
the authors confirmed the osteoblastic nature of the primary cultured cells based on the analysis of morphology , the presence of ap activity , production of calcified nodules , and the immunocytochemical expression of collagen ( type i collagen ) and non - collagen ( osteonectin and bone sialoprotein ii ) bone proteins .
however , no study has evaluated the maintenance of the cellular characteristics that lead to cell differentiation over time . because of the small amount of biological material available from the first culture , various cell passages are generally necessary to obtain a sufficient number of cells for experiments11 . in this respect
some studies have shown the loss of the osteoblastic phenotype when diploid cells are subcultured8,27 .
the expression of a cellular phenotype in culture also depends on the biological material used , its manipulation and culture conditions such as culture medium , time of growth and the presence of components that influence cell proliferation and differentiation7,9 .
( 2000 ) , analyzing human bone marrow cells , showed similar cell proliferation in two different culture media but ap activity and the ability to form mineralized deposits were lower in the dmem culture . in both experimental situations ,
osteoblastic parameters were strongly reduced on cell passage , particularly from the first to the second subculture .
bone morphogenetic protein ( bmp ) plays a crucial role in the growth and differentiation of a variety of cell types including osteoblasts5 .
osteogenic protein-1 ( op-1 ) promotes the maturation of committed cells to differentiate into osteoblasts , increases the expression of osteoblast marker genes and bone - like nodule formation in calvaria - derived cells , and promotes the differentiation of bone marrow cells into osteoblastic cells13,20 .
( 2004 ) demonstrated that op-1 added to bone cell cultures enriched with osteoblasts at different stages of differentiation stimulates cell proliferation , collagen synthesis , induction of ap and osteocalcin synthesis .
however , the effects of different concentrations of op-1 at the cellular level have not been clearly defined .
the objective of the present study was to investigate whether primary cultured cells obtained from parietal bone of neonatal rats , called osteo-1 , preserve their osteoblastic phenotype over serial passages or subcultures .
in addition , the behavior of these cells cultured in the presence of different concentrations of rhop-1 was analyzed .
the osteo-1 cell line was derived from the primary culture of calvaria of neonatal ( 1 to 4 days old ) albino wistar rats and obtained by enzymatic isolation , with the culture medium being supplemented with sodium 0-glycerophosphate , ascorbic acid and dexamethasone after semi - confluence10 .
subcultured and frozen cells from this cell line , previously identified and characterized by deboni , et al.10 ( 1996 ) , were used in the present experiments .
all cells used in this study were kindly provided by the laboratory of cell culture , department of dentistry , school of dentistry , university of so paulo , and the study was approved by the ethics committee of this institution . during the culture period , subcultured and frozen rat bone cells ( osteo-1 ) , primary human bone cells , called osteo - af cells , human pulp fibroblasts ( fp5 ) , mouse embryo fibroblasts ( nh3t3 ) , human gingival fibroblasts ( fmm1 ) and canine kidney epithelial cells ( mdck ) were maintained at 37c in a humidified atmosphere containing 5% co2 and 95% atmospheric air .
the cells were enzymatically removed from the culture flasks using a solution of 1 nm edta ( gibco , life technologies , grand island , ny , usa ) and 0.25% trypsin ( gibco ) and plated at a concentration of 2 10 cells / well onto 24-well culture plates24 in the first and second experiment .
three experiments were carried out in the present study : 1 ) characterization of subcultured and frozen rat bone cells ( osteo-1 ) , 2 ) analysis of the behavior of osteo-1 cells in two different culture media , and 3 ) determination of the effective concentration of op-1 . to characterize osteo-1 cells as osteoblasts , osteo-1 , nh3t3
the formation of calcified nodules was evaluated by staining with alizarin red s. the cells were grown on dmem ( sigma chemical co. , st .
louis , mo , usa ) supplemented with 10% fetal bovine serum ( cultilab , campinas , sp , brazil ) and 1% of an antibiotic - antimycotic solution ( sigma chemical co. ) . in the second experiment for the evaluation of the behavior of osteo-1 cells in two different culture media , osteo-1 , osteo - af , fp5 and fmm1 cultures were compared regarding total protein content and ap activity .
the following culture media were used : -mem ( gibco ) supplemented with 10% fetal bovine serum ( gibco ) , 50 mg/ ml gentamicin ( gibco ) , 0.3 mg / ml fungizone ( gibco ) , 10 m dexamethasone ( sigma ) , 5 mg / l ascorbic acid ( gibco ) and 7 mm 0-glycerophosphate ( sigma ) , called fully supplemented medium ( fsm ) , and dmem ( sigma ) containing 10% fetal bovine serum and 1% of an antibiotic - antimycotic solution .
after 7 , 14 and 21 days of culture , total protein content in the culture was calculated according to the modified method of lowry16 and ap activity was evaluated by the release of thymolphthalein monophosphate from thymolphthalein using a commercial kit ( labtest diagnostica as ) . at 14 and 21 days , adhered cells were fixed , dehydrated and processed for staining with alizarin red s , which stains calcium - rich areas3 . in the third experiment for the determination of the effective dose of op-1
, osteo-1 cells were plated at a concentration of 5 10 cells / well onto 96-well culture plates and treated with the following concentrations : 4 , 10 , 20 , 50 and 100 ng / ml op-1 ( sigma - aldrich , st .
cell viability was calculated after 1 , 3 , 5 and 7 days by the mtt ( 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide ) method21 .
the effect of treatment with op-1 was assessed as follows : 1 ) osteo-1 cells were cultured in medium containing different concentrations of op-1 , with complete change of the medium every 2 days , and 2 ) cells were treated with different concentrations of op-1 only on the first day of the experiment and cells were incubated without op-1 and the medium was changed every 2 days throughout the study period .
data were analyzed by analysis of variance and statistical significance was determined by the tukey s test . a p value < 0.05 was considered to be significant .
the ap activity / total protein content ratio differed between cell types ( anova : f=102.97 ; d.f.=3.6 ; p=0.0000 ) , being higher for osteo-1 cells , and was affected by culture time ( anova : f=4.10 ; d.f.=2.6 ; p=0.02 ) , with a higher ratio being observed at 14 and 21 days ( figure 1 ) . at 14 days
, no production of mineralized matrix was observed for cultured osteo-1 , nh3t3 , mdck or fmm1 cells , whereas at 21 days only subcultured and frozen osteoblasts ( osteo-1 cells ) showed positive alizarin red s staining ( figure 2 ) .
total protein content differed between bone cells and fibroblasts cultured on the two media ( anova : f=117.78 ; d.f.=7.4 ; p=0.0000 ) , with total protein being higher for osteo-1 cells grown on dmem at 21 days and for fmm1 cells grown on fsm after the same period .
total protein content was also affected by culture time ( anova : f=442.80 ; d.f.=2.4 ; p=0.0000 ) , with 21 > 14 = 7 days ( figure 3a and b ) .
ap activity differed between bone cells and fibroblasts cultured on the two media as follows ( anova : f=551.90 ; d.f.=7.4 ; p=0.0000 ) : osteo-1 > osteo - af = fp5 = fmm1 when grown on dmem ; however , the same order was not observed when cells were grown on fsm .
ap activity differed between osteo-1 and osteo - af cells and was affected by culture time ( anova : f=46.51 ; d.f.=2.4 ; p=0.0000 ) : osteo - af > osteo-1 >
fp5 = fmm1 , being higher after 21 days ( figure 4a and b ) .
cells treated with 10 and 20 ng / ml rhop-1 on the first day showed a significant increase in cell viability when compared to control .
no significant difference between the control and treatment with 100 ng / ml rhop-1 was observed at 1 , 3 or 7 days ( figures 5 and 6 ) .
the results showed a significant reduction in cell viability ( anova : f=131.32 ; df=5.72 ; p=0.0000 ) between the control and groups treated with 4 , 10 , 20 and 50 ng / ml rhop-1 added to the medium every 2 days after 3 , 5 and 7 days ( figure 5 ) .
when cells were treated with 4 , 10 , 20 and 50 ng / ml rhop-1 only on the first day of the experiment , cell viability decreased ( anova : f=13.81 ; df=5.72 ; p=0.0000 ) compared to the control at 5 and 7 days ( figure 6 ) .
the ap activity / total protein content ratio differed between cell types ( anova : f=102.97 ; d.f.=3.6 ; p=0.0000 ) , being higher for osteo-1 cells , and was affected by culture time ( anova : f=4.10 ; d.f.=2.6 ; p=0.02 ) , with a higher ratio being observed at 14 and 21 days ( figure 1 ) . at 14 days
, no production of mineralized matrix was observed for cultured osteo-1 , nh3t3 , mdck or fmm1 cells , whereas at 21 days only subcultured and frozen osteoblasts ( osteo-1 cells ) showed positive alizarin red s staining ( figure 2 ) .
total protein content differed between bone cells and fibroblasts cultured on the two media ( anova : f=117.78 ; d.f.=7.4 ; p=0.0000 ) , with total protein being higher for osteo-1 cells grown on dmem at 21 days and for fmm1 cells grown on fsm after the same period .
total protein content was also affected by culture time ( anova : f=442.80 ; d.f.=2.4 ; p=0.0000 ) , with 21 > 14 = 7 days ( figure 3a and b ) .
ap activity differed between bone cells and fibroblasts cultured on the two media as follows ( anova : f=551.90 ; d.f.=7.4 ; p=0.0000 ) : osteo-1 > osteo - af = fp5 = fmm1 when grown on dmem ; however , the same order was not observed when cells were grown on fsm .
ap activity differed between osteo-1 and osteo - af cells and was affected by culture time ( anova : f=46.51 ; d.f.=2.4 ; p=0.0000 ) : osteo - af > osteo-1 >
fp5 = fmm1 , being higher after 21 days ( figure 4a and b ) .
cells treated with 10 and 20 ng / ml rhop-1 on the first day showed a significant increase in cell viability when compared to control . no significant difference between the control and treatment with 100 ng / ml rhop-1
was observed at 1 , 3 or 7 days ( figures 5 and 6 ) .
the results showed a significant reduction in cell viability ( anova : f=131.32 ; df=5.72 ; p=0.0000 ) between the control and groups treated with 4 , 10 , 20 and 50 ng / ml rhop-1 added to the medium every 2 days after 3 , 5 and 7 days ( figure 5 ) . when cells were treated with 4 , 10 , 20 and 50 ng / ml rhop-1 only on the first day of the experiment , cell viability decreased ( anova : f=13.81 ; df=5.72 ; p=0.0000 ) compared to the control at 5 and 7 days ( figure 6 ) .
many biological events associated with bone healing can be investigated using isolated osteoblastic cells . in the present two experiments investigating the maintenance of the osteoblastic phenotype of osteo-1 cells subcultured and frozen over a period of 10 years
, osteo-1 cells showed mean ap activity levels ranging from 1.5 to 2.5 mol thymolphthalein / h / ml when grown on dmem at 14 and 21 days .
the specific time of expression of ap has been shown to coincide with the process of osteogenesis in the cell culture model described by malaval , et al.17 ( 1994 ) and beck jr 1(2003 ) .
beloti , et al.3 ( 2005 ) demonstrated a mean ap activity of 0.73 ( 0.07 ) mol thymolphthalein / h/10 cells after the first passage of human bone marrow mesenchymal cells cultured on titanium .
comparison of ap activity between the dmem and fsm culture media revealed a significant increase for osteo-1 cells grown on dmem , and ap activity differed between osteo-1 and osteo - af cells grown on fsm . as the dmem medium used was not supplemented with ascorbic acid , -glycerophosphate or dexamethasone , osteo - af cells were unable to differentiate . in the case of fsm , the presence of differentiation inducers permitted the expression of ap activity by osteo - af cells . on the other hand , no increase in ap activity was observed for osteo-1 cells which had been induced previously .
, calcium deposits demonstrated by positive alizarin red s staining were only observed in osteo-1 cultures at 21 days , a finding indicative of mineralization .
the present results showed that osteo-1 cells produced significant amounts of total protein irrespective of the culture medium used or period analyzed . in the experiment for the characterization of osteo-1 cells , mean
in addition to ap activity , these data represent a complementary osteoblastic parameter since bone formation requires high levels of protein biosynthesis for the production of a protein matrix for mineralization .
mean total protein content was higher than 150 mg protein / ml at 21 days when cells were grown on dmem , whereas mean total protein was significantly lower when cells were cultured on fsm ( about 103 mg protein / ml ) .
the specificity of the studied osteoblastic parameters was confirmed using fibroblast and epithelial cultures as negative controls in the experiments .
the results of the present study suggest that low concentrations of rhop-1 ( 10 and 20 ng / ml ) stimulated osteo-1 cell growth on the first day .
the increase in cell viability was statistically significant for rhop-1 concentrations of 10 and 20 ng / ml when compared to the control at the same time point , in agreement with knutsen , et al.14 ( 1993 ) , who observed elevated levels of ap activity for op-1 concentrations ranging from 10 to 30 ng / ml .
sampath , et al.25 ( 1992 ) showed high levels of osteocalcin production when cells were grown in the presence of 25 ng / ml op-1 and increased mineralization in osteoblast cultures treated with 20 ng / ml op-1 , suggesting that this concentration is a suitable and effective dose .
( 2004 ) and yeh , et al.28 ( 2004 ) demonstrated that the osteogenic effect of op-1 was determined by the time of treatment with op-1 .
although fernandes , et al.11 ( 1997 ) have shown that ap activity and the capacity to form mineralized areas decrease with successive passages , it is important to emphasize that even after a long period of induction with ascorbic acid , - glycerophosphate and dexamethasone , osteo-1 cells continued to show the basic specific functions of osteoblasts , i.e. , ap activity and ability of mineralization .
the time of supplementation of the culture medium is probably an important factor for the induction of cell differentiation .
although deboni , et al.10 ( 1996 ) observed that modifications of osteo-1 cells did not represent phenotypic changes or transformation of the culture able to originate a continuous or established cell line12 with a finite life cycle , i.e. , cells undergoing senescence and death after some passages , laboratory observations over the 10 years of culture of these cells have shown that they behave like continuous cells showing a certain degree of uniformity and stability .
subcultured and frozen osteo-1 cells showed an osteoblastic phenotype characterized by the presence of ap activity and calcified nodules and can be considered a viable lineage for the use in experiments .
the dmem culture medium seems to be able to sustain continuous culture of these cells and to support their differentiation and mineralization .
the presence of low concentrations of op-1 in the culture medium may promote an osteogenic effect that it is determined by the time of treatment with bmp . | the objective of the present study was to characterize bone cells grown in two culture media , and to determine the effective concentration of op-1 on the growth of osteo-1 cells .
subcultured rat bone cells ( osteo-1 ) were grown in alpha - modified eagle s minimal essential medium ( -mem ) and dulbecco s modified eagle s medium ( dmem ) and total protein content , alkaline phosphatase activity and the formation of mineralized nodules were evaluated after 7 , 14 and 21 days .
cells were exposed to different concentrations of rhop-1 for 1 , 3 , 5 and 7 days and compared with an untreated control .
osteo-1 cells presented a significant increase in alkaline phosphatase activity and calcium deposits were observed at 21 days .
cells treated with 10 and 20 ng / ml rhop-1 for 24 h showed a significant increase in cell viability when compared to control .
osteo-1 cells cultured on dmem demonstrated an osteoblastic phenotype as indicated by high alkaline phosphatase activity and the presence of calcified nodules .
the results suggest that low concentrations of op-1 may promote an osteogenic effect on osteo-1 cells . | <s>[INST]well - characterized osteoblast cultures provide an adequate model for the study of cell behavior and for the determination of biological aspects of the interaction between materials and bone tissue . however , when isolated , bone cell lineages lose their morphological identity22 .
various protocols have been established for the characterization of isolated bone cells , including the determination of the level of alkaline phosphatase ( ap ) activity , specific bone proteins ( osteonectin and osteocalcin ) and type i collagen4,18 .
deboni , et al.10 ( 1996 ) identified and characterized cells obtained from the calvaria of neonatal albino wistar rats , called osteo-1 cells .
after first passage , phenotypic differentiation of the cultures was induced by supplementation of the medium with 10 mm sodium - glycerophosphate , 50 g / ml ascorbic acid and 10 m dexamethasone .
the authors confirmed the osteoblastic nature of the primary cultured cells based on the analysis of morphology , the presence of ap activity , production of calcified nodules , and the immunocytochemical expression of collagen ( type i collagen ) and non - collagen ( osteonectin and bone sialoprotein ii ) bone proteins .
however , no study has evaluated the maintenance of the cellular characteristics that lead to cell differentiation over time . because of the small amount of biological material available from the first culture , various cell passages are generally necessary to obtain a sufficient number of cells for experiments11 . in this respect
some studies have shown the loss of the osteoblastic phenotype when diploid cells are subcultured8,27 .
the expression of a cellular phenotype in culture also depends on the biological material used , its manipulation and culture conditions such as culture medium , time of growth and the presence of components that influence cell proliferation and differentiation7,9 .
( 2000 ) , analyzing human bone marrow cells , showed similar cell proliferation in two different culture media but ap activity and the ability to form mineralized deposits were lower in the dmem culture . in both experimental situations ,
osteoblastic parameters were strongly reduced on cell passage , particularly from the first to the second subculture .
bone morphogenetic protein ( bmp ) plays a crucial role in the growth and differentiation of a variety of cell types including osteoblasts5 .
osteogenic protein-1 ( op-1 ) promotes the maturation of committed cells to differentiate into osteoblasts , increases the expression of osteoblast marker genes and bone - like nodule formation in calvaria - derived cells , and promotes the differentiation of bone marrow cells into osteoblastic cells13,20 .
( 2004 ) demonstrated that op-1 added to bone cell cultures enriched with osteoblasts at different stages of differentiation stimulates cell proliferation , collagen synthesis , induction of ap and osteocalcin synthesis .
however , the effects of different concentrations of op-1 at the cellular level have not been clearly defined .
the objective of the present study was to investigate whether primary cultured cells obtained from parietal bone of neonatal rats , called osteo-1 , preserve their osteoblastic phenotype over serial passages or subcultures .
in addition , the behavior of these cells cultured in the presence of different concentrations of rhop-1 was analyzed .
the osteo-1 cell line was derived from the primary culture of calvaria of neonatal ( 1 to 4 days old ) albino wistar rats and obtained by enzymatic isolation , with the culture medium being supplemented with sodium 0-glycerophosphate , ascorbic acid and dexamethasone after semi - confluence10 .
subcultured and frozen cells from this cell line , previously identified and characterized by deboni , et al.10 ( 1996 ) , were used in the present experiments .
all cells used in this study were kindly provided by the laboratory of cell culture , department of dentistry , school of dentistry , university of so paulo , and the study was approved by the ethics committee of this institution . during the culture period , subcultured and frozen rat bone cells ( osteo-1 ) , primary human bone cells , called osteo - af cells , human pulp fibroblasts ( fp5 ) , mouse embryo fibroblasts ( nh3t3 ) , human gingival fibroblasts ( fmm1 ) and canine kidney epithelial cells ( mdck ) were maintained at 37c in a humidified atmosphere containing 5% co2 and 95% atmospheric air .
the cells were enzymatically removed from the culture flasks using a solution of 1 nm edta ( gibco , life technologies , grand island , ny , usa ) and 0.25% trypsin ( gibco ) and plated at a concentration of 2 10 cells / well onto 24-well culture plates24 in the first and second experiment .
three experiments were carried out in the present study : 1 ) characterization of subcultured and frozen rat bone cells ( osteo-1 ) , 2 ) analysis of the behavior of osteo-1 cells in two different culture media , and 3 ) determination of the effective concentration of op-1 . to characterize osteo-1 cells as osteoblasts , osteo-1 , nh3t3
the formation of calcified nodules was evaluated by staining with alizarin red s. the cells were grown on dmem ( sigma chemical co. , st .
louis , mo , usa ) supplemented with 10% fetal bovine serum ( cultilab , campinas , sp , brazil ) and 1% of an antibiotic - antimycotic solution ( sigma chemical co. ) . in the second experiment for the evaluation of the behavior of osteo-1 cells in two different culture media , osteo-1 , osteo - af , fp5 and fmm1 cultures were compared regarding total protein content and ap activity .
the following culture media were used : -mem ( gibco ) supplemented with 10% fetal bovine serum ( gibco ) , 50 mg/ ml gentamicin ( gibco ) , 0.3 mg / ml fungizone ( gibco ) , 10 m dexamethasone ( sigma ) , 5 mg / l ascorbic acid ( gibco ) and 7 mm 0-glycerophosphate ( sigma ) , called fully supplemented medium ( fsm ) , and dmem ( sigma ) containing 10% fetal bovine serum and 1% of an antibiotic - antimycotic solution .
after 7 , 14 and 21 days of culture , total protein content in the culture was calculated according to the modified method of lowry16 and ap activity was evaluated by the release of thymolphthalein monophosphate from thymolphthalein using a commercial kit ( labtest diagnostica as ) . at 14 and 21 days , adhered cells were fixed , dehydrated and processed for staining with alizarin red s , which stains calcium - rich areas3 . in the third experiment for the determination of the effective dose of op-1
, osteo-1 cells were plated at a concentration of 5 10 cells / well onto 96-well culture plates and treated with the following concentrations : 4 , 10 , 20 , 50 and 100 ng / ml op-1 ( sigma - aldrich , st .
cell viability was calculated after 1 , 3 , 5 and 7 days by the mtt ( 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide ) method21 .
the effect of treatment with op-1 was assessed as follows : 1 ) osteo-1 cells were cultured in medium containing different concentrations of op-1 , with complete change of the medium every 2 days , and 2 ) cells were treated with different concentrations of op-1 only on the first day of the experiment and cells were incubated without op-1 and the medium was changed every 2 days throughout the study period .
data were analyzed by analysis of variance and statistical significance was determined by the tukey s test . a p value < 0.05 was considered to be significant .
the ap activity / total protein content ratio differed between cell types ( anova : f=102.97 ; d.f.=3.6 ; p=0.0000 ) , being higher for osteo-1 cells , and was affected by culture time ( anova : f=4.10 ; d.f.=2.6 ; p=0.02 ) , with a higher ratio being observed at 14 and 21 days ( figure 1 ) . at 14 days
, no production of mineralized matrix was observed for cultured osteo-1 , nh3t3 , mdck or fmm1 cells , whereas at 21 days only subcultured and frozen osteoblasts ( osteo-1 cells ) showed positive alizarin red s staining ( figure 2 ) .
total protein content differed between bone cells and fibroblasts cultured on the two media ( anova : f=117.78 ; d.f.=7.4 ; p=0.0000 ) , with total protein being higher for osteo-1 cells grown on dmem at 21 days and for fmm1 cells grown on fsm after the same period .
total protein content was also affected by culture time ( anova : f=442.80 ; d.f.=2.4 ; p=0.0000 ) , with 21 > 14 = 7 days ( figure 3a and b ) .
ap activity differed between bone cells and fibroblasts cultured on the two media as follows ( anova : f=551.90 ; d.f.=7.4 ; p=0.0000 ) : osteo-1 > osteo - af = fp5 = fmm1 when grown on dmem ; however , the same order was not observed when cells were grown on fsm .
ap activity differed between osteo-1 and osteo - af cells and was affected by culture time ( anova : f=46.51 ; d.f.=2.4 ; p=0.0000 ) : osteo - af > osteo-1 >
fp5 = fmm1 , being higher after 21 days ( figure 4a and b ) .
cells treated with 10 and 20 ng / ml rhop-1 on the first day showed a significant increase in cell viability when compared to control .
no significant difference between the control and treatment with 100 ng / ml rhop-1 was observed at 1 , 3 or 7 days ( figures 5 and 6 ) .
the results showed a significant reduction in cell viability ( anova : f=131.32 ; df=5.72 ; p=0.0000 ) between the control and groups treated with 4 , 10 , 20 and 50 ng / ml rhop-1 added to the medium every 2 days after 3 , 5 and 7 days ( figure 5 ) .
when cells were treated with 4 , 10 , 20 and 50 ng / ml rhop-1 only on the first day of the experiment , cell viability decreased ( anova : f=13.81 ; df=5.72 ; p=0.0000 ) compared to the control at 5 and 7 days ( figure 6 ) .
the ap activity / total protein content ratio differed between cell types ( anova : f=102.97 ; d.f.=3.6 ; p=0.0000 ) , being higher for osteo-1 cells , and was affected by culture time ( anova : f=4.10 ; d.f.=2.6 ; p=0.02 ) , with a higher ratio being observed at 14 and 21 days ( figure 1 ) . at 14 days
, no production of mineralized matrix was observed for cultured osteo-1 , nh3t3 , mdck or fmm1 cells , whereas at 21 days only subcultured and frozen osteoblasts ( osteo-1 cells ) showed positive alizarin red s staining ( figure 2 ) .
total protein content differed between bone cells and fibroblasts cultured on the two media ( anova : f=117.78 ; d.f.=7.4 ; p=0.0000 ) , with total protein being higher for osteo-1 cells grown on dmem at 21 days and for fmm1 cells grown on fsm after the same period .
total protein content was also affected by culture time ( anova : f=442.80 ; d.f.=2.4 ; p=0.0000 ) , with 21 > 14 = 7 days ( figure 3a and b ) .
ap activity differed between bone cells and fibroblasts cultured on the two media as follows ( anova : f=551.90 ; d.f.=7.4 ; p=0.0000 ) : osteo-1 > osteo - af = fp5 = fmm1 when grown on dmem ; however , the same order was not observed when cells were grown on fsm .
ap activity differed between osteo-1 and osteo - af cells and was affected by culture time ( anova : f=46.51 ; d.f.=2.4 ; p=0.0000 ) : osteo - af > osteo-1 >
fp5 = fmm1 , being higher after 21 days ( figure 4a and b ) .
cells treated with 10 and 20 ng / ml rhop-1 on the first day showed a significant increase in cell viability when compared to control . no significant difference between the control and treatment with 100 ng / ml rhop-1
was observed at 1 , 3 or 7 days ( figures 5 and 6 ) .
the results showed a significant reduction in cell viability ( anova : f=131.32 ; df=5.72 ; p=0.0000 ) between the control and groups treated with 4 , 10 , 20 and 50 ng / ml rhop-1 added to the medium every 2 days after 3 , 5 and 7 days ( figure 5 ) . when cells were treated with 4 , 10 , 20 and 50 ng / ml rhop-1 only on the first day of the experiment , cell viability decreased ( anova : f=13.81 ; df=5.72 ; p=0.0000 ) compared to the control at 5 and 7 days ( figure 6 ) .
many biological events associated with bone healing can be investigated using isolated osteoblastic cells . in the present two experiments investigating the maintenance of the osteoblastic phenotype of osteo-1 cells subcultured and frozen over a period of 10 years
, osteo-1 cells showed mean ap activity levels ranging from 1.5 to 2.5 mol thymolphthalein / h / ml when grown on dmem at 14 and 21 days .
the specific time of expression of ap has been shown to coincide with the process of osteogenesis in the cell culture model described by malaval , et al.17 ( 1994 ) and beck jr 1(2003 ) .
beloti , et al.3 ( 2005 ) demonstrated a mean ap activity of 0.73 ( 0.07 ) mol thymolphthalein / h/10 cells after the first passage of human bone marrow mesenchymal cells cultured on titanium .
comparison of ap activity between the dmem and fsm culture media revealed a significant increase for osteo-1 cells grown on dmem , and ap activity differed between osteo-1 and osteo - af cells grown on fsm . as the dmem medium used was not supplemented with ascorbic acid , -glycerophosphate or dexamethasone , osteo - af cells were unable to differentiate . in the case of fsm , the presence of differentiation inducers permitted the expression of ap activity by osteo - af cells . on the other hand , no increase in ap activity was observed for osteo-1 cells which had been induced previously .
, calcium deposits demonstrated by positive alizarin red s staining were only observed in osteo-1 cultures at 21 days , a finding indicative of mineralization .
the present results showed that osteo-1 cells produced significant amounts of total protein irrespective of the culture medium used or period analyzed . in the experiment for the characterization of osteo-1 cells , mean
in addition to ap activity , these data represent a complementary osteoblastic parameter since bone formation requires high levels of protein biosynthesis for the production of a protein matrix for mineralization .
mean total protein content was higher than 150 mg protein / ml at 21 days when cells were grown on dmem , whereas mean total protein was significantly lower when cells were cultured on fsm ( about 103 mg protein / ml ) .
the specificity of the studied osteoblastic parameters was confirmed using fibroblast and epithelial cultures as negative controls in the experiments .
the results of the present study suggest that low concentrations of rhop-1 ( 10 and 20 ng / ml ) stimulated osteo-1 cell growth on the first day .
the increase in cell viability was statistically significant for rhop-1 concentrations of 10 and 20 ng / ml when compared to the control at the same time point , in agreement with knutsen , et al.14 ( 1993 ) , who observed elevated levels of ap activity for op-1 concentrations ranging from 10 to 30 ng / ml .
sampath , et al.25 ( 1992 ) showed high levels of osteocalcin production when cells were grown in the presence of 25 ng / ml op-1 and increased mineralization in osteoblast cultures treated with 20 ng / ml op-1 , suggesting that this concentration is a suitable and effective dose .
( 2004 ) and yeh , et al.28 ( 2004 ) demonstrated that the osteogenic effect of op-1 was determined by the time of treatment with op-1 .
although fernandes , et al.11 ( 1997 ) have shown that ap activity and the capacity to form mineralized areas decrease with successive passages , it is important to emphasize that even after a long period of induction with ascorbic acid , - glycerophosphate and dexamethasone , osteo-1 cells continued to show the basic specific functions of osteoblasts , i.e. , ap activity and ability of mineralization .
the time of supplementation of the culture medium is probably an important factor for the induction of cell differentiation .
although deboni , et al.10 ( 1996 ) observed that modifications of osteo-1 cells did not represent phenotypic changes or transformation of the culture able to originate a continuous or established cell line12 with a finite life cycle , i.e. , cells undergoing senescence and death after some passages , laboratory observations over the 10 years of culture of these cells have shown that they behave like continuous cells showing a certain degree of uniformity and stability .
subcultured and frozen osteo-1 cells showed an osteoblastic phenotype characterized by the presence of ap activity and calcified nodules and can be considered a viable lineage for the use in experiments .
the dmem culture medium seems to be able to sustain continuous culture of these cells and to support their differentiation and mineralization .
the presence of low concentrations of op-1 in the culture medium may promote an osteogenic effect that it is determined by the time of treatment with bmp .[/INST]the objective of the present study was to characterize bone cells grown in two culture media , and to determine the effective concentration of op-1 on the growth of osteo-1 cells .
subcultured rat bone cells ( osteo-1 ) were grown in alpha - modified eagle s minimal essential medium ( -mem ) and dulbecco s modified eagle s medium ( dmem ) and total protein content , alkaline phosphatase activity and the formation of mineralized nodules were evaluated after 7 , 14 and 21 days .
cells were exposed to different concentrations of rhop-1 for 1 , 3 , 5 and 7 days and compared with an untreated control .
osteo-1 cells presented a significant increase in alkaline phosphatase activity and calcium deposits were observed at 21 days .
cells treated with 10 and 20 ng / ml rhop-1 for 24 h showed a significant increase in cell viability when compared to control .
osteo-1 cells cultured on dmem demonstrated an osteoblastic phenotype as indicated by high alkaline phosphatase activity and the presence of calcified nodules .
the results suggest that low concentrations of op-1 may promote an osteogenic effect on osteo-1 cells .</s> |
the term mild cognitive impairment ( mci ) refers to a transitional state between normal cognitive aging and pathological decline , i.e. , the propensity to develop incipient dementia syndromes .
subjects with mci are non - demented individuals , yet they have demonstrable impairment in cognitive functions according to their performance on tests adjusted for age and educational level . these deficits minimally , if at all , affect the ability to undertake activities of daily living.1 individuals diagnosed with mci have a higher risk for developing dementia , most notably alzheimer s disease ( ad ) ; for this reason , at least a subset of mci patients may in fact represent a prodromal stage of ad.2,3 despite its clinical importance , the proper identification of mci remains a challenging issue in non - specialized settings .
the evaluation of patients with mci usually involves a comprehensive neuropsychological assessment , along with sophisticated laboratory tests ( e.g. , analysis of cerebrospinal fluid biomarkers ) and neuroimaging exams ( e.g. , structural magnetic resonance with volumetric measures , functional exams such as spect / pet ) .
these methods are expensive , need highly specialized professionals , and are not routinely available in most clinical settings .
the majority of cognitive screening tests that are commonly used in clinical practice ( e.g. , the mini - mental state examination , the verbal fluency test and the clock drawing test ) , as well as informant - based questionnaires ( e.g. , the informant questionnaire of cognitive decline in the elderly iqcode ) , have been developed for the diagnosis of dementia and are thus not sensitive enough to discriminate mci patients from cognitively unimpaired older adults.4,5 as a consequence , a large number of elderly subjects with mci remain unidentified in clinical practice in spite of having presented their concerns to the clinician.6 this challenge is even more difficult to overcome if one considers populations with varying degrees of schooling , given the relevant education bias that affects most cognitive tests .
the rationale for this strategy is that different tests may provide supplementary information about the cognitive functioning of a given patient , increasing the probability of identifying those with mild deficits .
several different combination strategies may be used , such as the and/or rule and the weighted sum of test scores,7 which allow the examiner to improve the sensitivity and/or specificity of individual tests according to the combination rule .
brief cognitive batteries , such as the cambridge cognitive test ( camcog),8 also lack sensitivity to discriminate patients with mci from cognitively unimpaired subjects , in spite of having a better diagnostic accuracy as compared to its subcomponents , e.g. , the mini - mental state examination ( mmse ) , verbal fluency test ( vft ) and clock drawing test ( cdt).9 in clinical settings , the qualitative analysis of the performance in specific cognitive screening may help to improve diagnostic accuracy to detect mild but relevant deficits.10 although the combination of screening tests can improve the detection of mild to moderate cases of dementia11 , few data exist about the validity of these instruments for the correct identification of elderly persons with mci . in one study ,
the combination of mmse and cdt reached good sensitivity and specificity values for the multiple - domain mci ; however , this combination was not appropriate for identifying single - domain ( amnestic or non - amnestic ) mci subtypes.4,12 in another study , the association of an informant - based screening test ( the iqcode ) and the mmse showed low sensitivity for screening mci patients , regardless of their subtype5 .
few studies have been conducted so far with this objective , and there is room for several other combinations to be investigated .
therefore , the aim of the present study was to determine the diagnostic properties of the combination of three widely used cognitive screening tests ( the mmse , cdt and vft ) to identify subjects with mci . the tests are timely - effective , and their results are easy to interpret .
we hypothesized that the combination of these instruments may yield a higher accuracy in the identification of mci subjects than each test alone .
all subjects included in this analysis are participants of an ongoing prospective study on ageing and cognition carried out at a specialized memory clinic at the institute of psychiatry , university of so paulo , so paulo , brazil .
recruitment started in june of 2003 , and subjects were continuously enrolled for cognitive evaluation .
patients and controls were recruited from the hospital catchment area through information provided by media advertisements and lectures about health and aging .
we also included subjects presenting with spontaneous demand for memory assessment and referrals from other medical services .
this study was approved by the local ethics committee and was performed in accordance with the helsinki declaration . for the purpose of this study , we included 247 elderly outpatients ( 73% women ) ( mean age : 71.37.2 years ; mean educational level : 10.65.9 years ) with the baseline diagnosis of mild cognitive impairment ( mci , n=83 ) , alzheimer s disease ( ad , n=81 ) and normal cognition ( controls , n=83 ) .
clinical and neuropsychological evaluations were carried out according to a standardized protocol and by trained physicians and neuropsychologists .
detailed information about the medical evaluation , cognitive and neuropsychological assessments , and diagnostic algorithms of this cohort can be found elsewhere.13 in brief , the cognitive evaluation consisted of the administration of the brazilian version of the cambridge examination for mental disorders in the elderly ( camdex ) semi - structured interview,8,14 which yields scores for the cambridge cognitive test ( camcog ) , the mini - mental state examination ( mmse)15 , and a verbal fluency test .
the clock drawing test , which is part of the camcog schedule , was additionally scored accordingly to sunderland s guidelines.16 the 21-item hamilton depression scale ( ham - d ) was administered to all subjects prior to neuropsychological assessment in order to rule out the presence of clinically relevant depressive symptoms;17 patients with a ham - d score of 7 or more were referred to psychiatric attention and not included in the study .
a comprehensive neuropsychological evaluation included the culturally adapted , brazilian portuguese versions of the following tests : the rivermead behavioral memory test ( rbmt),18 the fuld object - memory evaluation ( fome),19 a verbal fluency test ( category : fruits ) , the trail making test ( tmt ) a and b20 , the short cognitive test ( skt),21,22 and the wechsler adult intelligence scale - revised ( wais - r ) vocabulary and block design tests.23 evidence of functional decline was based on the scores of the informant questionnaire of cognitive disorders of the elderly ( iqcode)24 , as well as all available evidence concerning difficulties performing basic and instrumental activities of daily living , as reported by a close relative or caregiver and on the patient s self - report .
consensus diagnoses were reached at expert multidisciplinary sessions taking into account all information about the current medical history and evidence of objective cognitive decline as assessed by the neuropsychological exams .
the scores on the mmse , vf and cdt were obtained at the screening assessment of every patient , and this information was not added to the diagnostic protocol .
objective cognitive impairment was defined as performance below 1.5 standard deviations in the neuropsychological evaluation , adjusted by age and educational level in the so paulo elderly population.9,25 diagnosis of amnestic mci was made according to the following criteria26,27 : ( 1 ) subjective cognitive complaint , preferably corroborated by an informant ; ( 2 ) objective memory impairment in the neuropsychological assessment ; ( 3 ) preserved global intellectual function ; ( 4 ) preserved or minimal impairments in activities of daily living ; ( 5 ) no signs of dementia .
the control group comprised individuals without objective evidence of cognitive impairment and subjects with cognitive complaints but normal performance in neuropsychological tests ( i.e. , subjective cognitive complainers ) .
we performed a pearson s chi - square analysis to assess the differences in the distribution of gender among different diagnostic groups .
kolmogorov - smirnov tests were used to evaluate the normality of the distribution for each continuous variable .
since these analyses showed that all variables had a normal or near - normal distribution , we decided to carry out parametric statistical tests for all analyses .
for the purpose of this study , we analyzed data only for the mini - mental state examination , the verbal fluency test and the clock drawing test .
we carried out a univariate analysis of variance ( anova ) to assess the mean differences for socio - demographic data , clinical variables , and scores on cognitive and neuropsychological tests among the diagnostic groups .
receiver operating characteristic ( roc ) analyses were performed to calculate the sensitivity , specificity and accuracy of the suggested cut - off points adjusted by educational level suggestive of cognitive impairment proposed by the mmse ( illiterate , < 20 , 1 4 years of education , < 25 , 4 8 years of education , < 26 , 9 years of education and above , < 28 ) , the vft ( illiterate , < 10 , one year of education and above < 14 ) and the cdt ( 0 8 years of education , < 6 , above 8 years of education , < 8)29 to identify mci or ad cases versus controls . we addressed if different combinations of the above mentioned tests were more accurate for identifying mci and ad cases in this cohort . therefore , the following combinations were assessed : ( 1 ) subjects who scored below the cut - off points in the mmse , the vft and the cdt were regarded as cognitively impaired ( the and rule ) ; ( 2 ) subjects who scored below the cut - off points in at least the mmse , the vft or the cdt were regarded as cognitively impaired ( the or rule ) ; ( 3 ) the combination of mmse and the vft ; ( 4 ) the combination of the mmse and cdt , mmse and vft and the combination of the cdt and vft .
all statistical analyses were performed using spss v14.0 for windows ( spss inc . , chicago , il ) , and the value was set at 5% .
all subjects included in this analysis are participants of an ongoing prospective study on ageing and cognition carried out at a specialized memory clinic at the institute of psychiatry , university of so paulo , so paulo , brazil .
recruitment started in june of 2003 , and subjects were continuously enrolled for cognitive evaluation .
patients and controls were recruited from the hospital catchment area through information provided by media advertisements and lectures about health and aging .
we also included subjects presenting with spontaneous demand for memory assessment and referrals from other medical services .
this study was approved by the local ethics committee and was performed in accordance with the helsinki declaration . for the purpose of this study , we included 247 elderly outpatients ( 73% women ) ( mean age : 71.37.2 years ; mean educational level : 10.65.9 years ) with the baseline diagnosis of mild cognitive impairment ( mci , n=83 ) , alzheimer s disease ( ad , n=81 ) and normal cognition ( controls , n=83 ) .
clinical and neuropsychological evaluations were carried out according to a standardized protocol and by trained physicians and neuropsychologists .
detailed information about the medical evaluation , cognitive and neuropsychological assessments , and diagnostic algorithms of this cohort can be found elsewhere.13 in brief , the cognitive evaluation consisted of the administration of the brazilian version of the cambridge examination for mental disorders in the elderly ( camdex ) semi - structured interview,8,14 which yields scores for the cambridge cognitive test ( camcog ) , the mini - mental state examination ( mmse)15 , and a verbal fluency test .
the clock drawing test , which is part of the camcog schedule , was additionally scored accordingly to sunderland s guidelines.16 the 21-item hamilton depression scale ( ham - d ) was administered to all subjects prior to neuropsychological assessment in order to rule out the presence of clinically relevant depressive symptoms;17 patients with a ham - d score of 7 or more were referred to psychiatric attention and not included in the study .
a comprehensive neuropsychological evaluation included the culturally adapted , brazilian portuguese versions of the following tests : the rivermead behavioral memory test ( rbmt),18 the fuld object - memory evaluation ( fome),19 a verbal fluency test ( category : fruits ) , the trail making test ( tmt ) a and b20 , the short cognitive test ( skt),21,22 and the wechsler adult intelligence scale - revised ( wais - r ) vocabulary and block design tests.23 evidence of functional decline was based on the scores of the informant questionnaire of cognitive disorders of the elderly ( iqcode)24 , as well as all available evidence concerning difficulties performing basic and instrumental activities of daily living , as reported by a close relative or caregiver and on the patient s self - report .
consensus diagnoses were reached at expert multidisciplinary sessions taking into account all information about the current medical history and evidence of objective cognitive decline as assessed by the neuropsychological exams .
the scores on the mmse , vf and cdt were obtained at the screening assessment of every patient , and this information was not added to the diagnostic protocol .
objective cognitive impairment was defined as performance below 1.5 standard deviations in the neuropsychological evaluation , adjusted by age and educational level in the so paulo elderly population.9,25 diagnosis of amnestic mci was made according to the following criteria26,27 : ( 1 ) subjective cognitive complaint , preferably corroborated by an informant ; ( 2 ) objective memory impairment in the neuropsychological assessment ; ( 3 ) preserved global intellectual function ; ( 4 ) preserved or minimal impairments in activities of daily living ; ( 5 ) no signs of dementia .
the control group comprised individuals without objective evidence of cognitive impairment and subjects with cognitive complaints but normal performance in neuropsychological tests ( i.e. , subjective cognitive complainers ) .
we performed a pearson s chi - square analysis to assess the differences in the distribution of gender among different diagnostic groups .
kolmogorov - smirnov tests were used to evaluate the normality of the distribution for each continuous variable .
since these analyses showed that all variables had a normal or near - normal distribution , we decided to carry out parametric statistical tests for all analyses .
for the purpose of this study , we analyzed data only for the mini - mental state examination , the verbal fluency test and the clock drawing test .
we carried out a univariate analysis of variance ( anova ) to assess the mean differences for socio - demographic data , clinical variables , and scores on cognitive and neuropsychological tests among the diagnostic groups .
receiver operating characteristic ( roc ) analyses were performed to calculate the sensitivity , specificity and accuracy of the suggested cut - off points adjusted by educational level suggestive of cognitive impairment proposed by the mmse ( illiterate , < 20 , 1 4 years of education , < 25 , 4 8 years of education , < 26 , 9 years of education and above , < 28 ) , the vft ( illiterate , < 10 , one year of education and above < 14 ) and the cdt ( 0 8 years of education , < 6 , above 8 years of education , < 8)29 to identify mci or ad cases versus controls .
we addressed if different combinations of the above mentioned tests were more accurate for identifying mci and ad cases in this cohort .
therefore , the following combinations were assessed : ( 1 ) subjects who scored below the cut - off points in the mmse , the vft and the cdt were regarded as cognitively impaired ( the and rule ) ; ( 2 ) subjects who scored below the cut - off points in at least the mmse , the vft or the cdt were regarded as cognitively impaired ( the or
rule ) ; ( 3 ) the combination of mmse and the vft ; ( 4 ) the combination of the mmse and cdt , mmse and vft and the combination of the cdt and vft .
all statistical analyses were performed using spss v14.0 for windows ( spss inc . , chicago , il ) , and the value was set at 5% .
demographic and cognitive variables are summarized in table 1 . as expected , patients with ad were older , less educated and performed worse on the cognitive tests as compared to mci and control individuals ( anova , p<.001 ) .
subjects with mci attained intermediate scores on cognitive screening tests ( mmse , cdt and vft ) as compared to ad and control individuals . although significant , the magnitude of the difference between subjects with mci and healthy controls on these test scores was small , and scores were above the cut - off values that are usually accepted as positive screening for dementia .
all tests ( separately and in combination ) showed good accuracy for the identification of ad .
the cut - off scores of the mmse alone and the combination of mmse and vft showed the best accuracy for identifying ad patients ( table 2 ) .
the mmse scores alone yielded an area under the roc curve of 0.85 0.03 ( p<0.001 ) , indicating the best combination of sensitivity and specificity ( 98% and 71% , respectively ) .
( i.e. , mmse and cdt and vft scores ) had maximum ( 100% ) specificity , and the or rule
( i.e. , mmse or cdt or vft ) had maximum sensitivity ( 100% ) .
however , the auc obtained from the separation of patients with mci from controls was smaller regardless of whether the tests were analyzed separately or in combination .
all tests alone , the combinations of two tests ( mmse + vft , mmse + cdt , and vft + cdt ) and the and rule had good specificity for separating mci from controls , albeit with very low sensitivity .
our results indicate that the mmse , the verbal fluency test ( vft ) , and the clock drawing test ( cdt ) do not have a good diagnostic accuracy for identifying cases of mci , in spite of their usefulness in the diagnostic screening for dementia .
in addition , the combined use of these tests did not satisfactorily increase overall diagnostic accuracy when separating mci from controls .
our results are in accordance with previous studies from our group and others in which the association of cognitive and/or functional tests did not provide a good sensitivity in the diagnostic screening for mci.4,5,12 regarding the identification of cases of dementia in this sample , our roc curves do not demonstrate any additional benefit of the combination of tests as compared to the analysis of each test score separately .
this finding is somewhat surprising because other authors have proposed that this strategy may improve overall diagnostic accuracy .
in fact , the present data demonstrate that the combination of tests did not or minimally , at best change diagnostic accuracy , as shown by the aucs .
this effect was primarily due to the detriment of sensitivity , since specificity was substantially increased through a combination of test scores .
we also observed this phenomenon in the analysis of non - demented subjects , where the separation of patients with mci from cognitively healthy controls yielded aucs between 0.5 and 0.6 irrespective of the analysis strategy .
in other words , the combination of tests substantially reduced sensitivity , but it increased specificity up to 97100% . the only exception to this tendency was with the or rule , which yielded a specificity below 50%
. a few considerations must be made with respect to the clinical implications of the present findings .
the combination of two or three cognitive screening tests is a common approach used by physicians to substantiate the clinical diagnosis of cognitive impairment , particularly in settings where a thorough neuropsychological evaluation is not available or because of time constraints .
we understand that the qualitative observation of the performance on such tests , in addition to the score itself , may add important insights to the diagnostic workup , as we have previously shown that the analysis of mmse sub - scores supports the identification of mci subtypes10 .
however , when translating this clinical impression into the screening for cognitive impairment in larger patient groups , we recommend that the output of this strategy be interpreted with caution , since the combination of test scores according to the and rule significantly impairs diagnostic sensitivity . in other words , caseness will be met only when a given patient shows abnormal performance on all tests utilized for assessment .
this strategy will deliver a high number of false negative cases that correspond to patients who in fact have subtle abnormalities that might have been detected by one single test . on the other hand
, the specificity of estimates based on the and rule will be significantly increased in the presence of abnormal performance in all tests together .
brief cognitive tests are developed to provide good sensitivity in the screening for dementia , whereas specificity is usually attained with more inclusive batteries or through formal neuropsychological evaluation .
specificity can be further increased by adding information from laboratory and neuroimaging tests , both for the purpose of ruling out comorbidities that concur with a high prevalence of cognitive impairment30 and to ascertain underlying pathological features of ad31 .
the complexity of this procedure is a limitation for the large - scale diagnosis of mci , particularly in primary care settings .
the basic purpose of the tests that we addressed in this study ( i.e. , good for screening ) was met by all three tests when the target was identifying dementia ( ad ) , but not when attempting to detect subtle deficits ( i.e. , mci ) .
one possible explanation is that these tests are prone to ceiling effects , particularly among more educated mci patients .
in other words , subjects with mild deficits may still be able to perform well in spite of the existence of symptoms compatible with incipient ad32 .
since most available cognitive screening tests have been developed to separate dementia from non - dementia , the development of new tests specially designed to screen for mild cognitive deficits , such as the montreal cognitive assessment ( moca)33 and the computer - assisted neuropsychological screening for mci ( cans - mci),34 may overcome this limitation .
in addition , the combination of cognitive tests and functional scales , or functional scales alone , may serve as alternatives for screening subjects with cognitive complaints .
bottino et al.35 found that the association of fome and mmse with two informant - based functional scales ( iqcode and bayer activities of daily living scale ) was sensitive enough to identify cases with mild to moderate dementia .
perroco and colleagues36 recently reported that the iqcode ( and its shorter version ) was also sensitive enough to screen for patients with mild dementia .
the objective functional assessment , as provided by the dafs ( direct assessment of functional state ) , discriminated mci patients from patients with dementia with high accuracy ; nonetheless , it had a lower accuracy for discriminating patients with mci from cognitively unimpaired elderly subjects37 .
therefore , despite the fact that several screening strategies may be useful for the identification of mild to moderate dementia cases , there is still a long road ahead when addressing the screening for pre - dementia cases .
the sample of patients and controls on which the present analysis was based has certain characteristics that may explain the discrepancy between our findings and previous notions that supported the advantage of combining tests .
first , the ad patients included in this study had mild or incipient dementia , as opposed the predominance of patients with mild to moderate dementia in previous studies , rendering patients in our ad group less impaired and narrowing the difference between their mean scores and those obtained by patients in the comparison groups ( mci and controls ) .
conversely , our controls are not only non - demented but also cognitively unimpaired , since we separated cognitively healthy subjects ( controls ) from those with mci through a neuropsychological assessment .
most studies conducted in the late 1980s and 1990s did not separate these two states , leading to contamination of the control group with subtle forms of cognitive impairment ; in this case , the scores obtained by historical controls tend to be lower than the ones observed in our sample . in both instances ( i.e. , less impaired ad patients and above average controls )
, the range of cognitive deficits will be smaller , affecting the cut - off scores that best separate groups .
we understand that educational level is an important issue when assessing patients with cognitive complaints / impairment , particularly in populations with heterogeneous backgrounds . in this analysis
, we controlled for this effect by using different cut - off scores for the cognitive screening tests , which have been established for the brazilian population.29 in addition , the clinical diagnoses provided by the multidisciplinary expert consensus meeting yield important insights as to whether any given finding is clinically relevant or not .
the present results highlight three important issues that have practical implications for the diagnostic workup of cognitive disorders .
first , the mmse alone may be sufficient in the screening for dementia , since the combinations of tests did not increase diagnostic accuracy .
second , the combination of the mmse , the vft and the cdt ( by means of several different analytical strategies ) did not accurately identify cases of mci in a clinical setting .
finally , the diagnosis of mci still depends on the information provided by a comprehensive neuropsychological assessment .
alternatively , the clinical evaluation along with other supportive diagnostic techniques , such as the measurement of ad - related biomarkers in cerebrospinal fluid and/or structural and functional neuroimaging , may be necessary to substantiate the diagnosis of mci and the subsequent risk of developing ad.3941 of course , these resources are restricted to specialized settings and are not appropriate for large - scale screening of cognitive impairment . from the clinician s perspective , the identification of patients with mci , as well as the evaluation of the risk for progression to dementia , still relies on careful clinical judgment and the longitudinal determination of cognitive status with the available tools.42 | objectiveto determine the accuracy of the mini - mental state examination combined with the verbal fluency test and clock drawing test for the identification of patients with mild cognitive impairment and alzheimer s disease ( ad).methodthese tests were used to evaluate cognitive function in 247 older adults .
subjects were divided into three groups according to their cognitive state : mild cognitive impairment ( n=83 ) , ad ( n=81 ) , cognitively unimpaired controls ( n=83 ) , based on clinical and neuropsychological data .
the diagnostic accuracy of each test for discriminating between these diagnostic groups ( mild cognitive impairment or ad vs. controls ) was examined with the aid of receiver operating characteristic ( roc ) curves .
additionally , we evaluated the benefit of the combination of tests on diagnostic accuracy.resultsalthough they were accurate enough for the identification of alzheimer s disease , neither test alone proved adequate for the correct separation of patients with mild cognitive impairment from healthy subjects . combining these tests did not improve diagnostic accuracy , as compared to the mini - mental state examination alone , in the identification of patients with mild cognitive impairment or alzheimer s disease.conclusionsthe present data do not warrant the combined use of the mini - mental state examination , the verbal fluency test and the clock drawing test as a sufficient diagnostic schedule in screening for mild cognitive impairment .
the present data do not support the notion that the combination of test scores is better that the use of mini - mental state examination scores alone in the screening for alzheimer s disease . | <s>[INST]the term mild cognitive impairment ( mci ) refers to a transitional state between normal cognitive aging and pathological decline , i.e. , the propensity to develop incipient dementia syndromes .
subjects with mci are non - demented individuals , yet they have demonstrable impairment in cognitive functions according to their performance on tests adjusted for age and educational level . these deficits minimally , if at all , affect the ability to undertake activities of daily living.1 individuals diagnosed with mci have a higher risk for developing dementia , most notably alzheimer s disease ( ad ) ; for this reason , at least a subset of mci patients may in fact represent a prodromal stage of ad.2,3 despite its clinical importance , the proper identification of mci remains a challenging issue in non - specialized settings .
the evaluation of patients with mci usually involves a comprehensive neuropsychological assessment , along with sophisticated laboratory tests ( e.g. , analysis of cerebrospinal fluid biomarkers ) and neuroimaging exams ( e.g. , structural magnetic resonance with volumetric measures , functional exams such as spect / pet ) .
these methods are expensive , need highly specialized professionals , and are not routinely available in most clinical settings .
the majority of cognitive screening tests that are commonly used in clinical practice ( e.g. , the mini - mental state examination , the verbal fluency test and the clock drawing test ) , as well as informant - based questionnaires ( e.g. , the informant questionnaire of cognitive decline in the elderly iqcode ) , have been developed for the diagnosis of dementia and are thus not sensitive enough to discriminate mci patients from cognitively unimpaired older adults.4,5 as a consequence , a large number of elderly subjects with mci remain unidentified in clinical practice in spite of having presented their concerns to the clinician.6 this challenge is even more difficult to overcome if one considers populations with varying degrees of schooling , given the relevant education bias that affects most cognitive tests .
the rationale for this strategy is that different tests may provide supplementary information about the cognitive functioning of a given patient , increasing the probability of identifying those with mild deficits .
several different combination strategies may be used , such as the and/or rule and the weighted sum of test scores,7 which allow the examiner to improve the sensitivity and/or specificity of individual tests according to the combination rule .
brief cognitive batteries , such as the cambridge cognitive test ( camcog),8 also lack sensitivity to discriminate patients with mci from cognitively unimpaired subjects , in spite of having a better diagnostic accuracy as compared to its subcomponents , e.g. , the mini - mental state examination ( mmse ) , verbal fluency test ( vft ) and clock drawing test ( cdt).9 in clinical settings , the qualitative analysis of the performance in specific cognitive screening may help to improve diagnostic accuracy to detect mild but relevant deficits.10 although the combination of screening tests can improve the detection of mild to moderate cases of dementia11 , few data exist about the validity of these instruments for the correct identification of elderly persons with mci . in one study ,
the combination of mmse and cdt reached good sensitivity and specificity values for the multiple - domain mci ; however , this combination was not appropriate for identifying single - domain ( amnestic or non - amnestic ) mci subtypes.4,12 in another study , the association of an informant - based screening test ( the iqcode ) and the mmse showed low sensitivity for screening mci patients , regardless of their subtype5 .
few studies have been conducted so far with this objective , and there is room for several other combinations to be investigated .
therefore , the aim of the present study was to determine the diagnostic properties of the combination of three widely used cognitive screening tests ( the mmse , cdt and vft ) to identify subjects with mci . the tests are timely - effective , and their results are easy to interpret .
we hypothesized that the combination of these instruments may yield a higher accuracy in the identification of mci subjects than each test alone .
all subjects included in this analysis are participants of an ongoing prospective study on ageing and cognition carried out at a specialized memory clinic at the institute of psychiatry , university of so paulo , so paulo , brazil .
recruitment started in june of 2003 , and subjects were continuously enrolled for cognitive evaluation .
patients and controls were recruited from the hospital catchment area through information provided by media advertisements and lectures about health and aging .
we also included subjects presenting with spontaneous demand for memory assessment and referrals from other medical services .
this study was approved by the local ethics committee and was performed in accordance with the helsinki declaration . for the purpose of this study , we included 247 elderly outpatients ( 73% women ) ( mean age : 71.37.2 years ; mean educational level : 10.65.9 years ) with the baseline diagnosis of mild cognitive impairment ( mci , n=83 ) , alzheimer s disease ( ad , n=81 ) and normal cognition ( controls , n=83 ) .
clinical and neuropsychological evaluations were carried out according to a standardized protocol and by trained physicians and neuropsychologists .
detailed information about the medical evaluation , cognitive and neuropsychological assessments , and diagnostic algorithms of this cohort can be found elsewhere.13 in brief , the cognitive evaluation consisted of the administration of the brazilian version of the cambridge examination for mental disorders in the elderly ( camdex ) semi - structured interview,8,14 which yields scores for the cambridge cognitive test ( camcog ) , the mini - mental state examination ( mmse)15 , and a verbal fluency test .
the clock drawing test , which is part of the camcog schedule , was additionally scored accordingly to sunderland s guidelines.16 the 21-item hamilton depression scale ( ham - d ) was administered to all subjects prior to neuropsychological assessment in order to rule out the presence of clinically relevant depressive symptoms;17 patients with a ham - d score of 7 or more were referred to psychiatric attention and not included in the study .
a comprehensive neuropsychological evaluation included the culturally adapted , brazilian portuguese versions of the following tests : the rivermead behavioral memory test ( rbmt),18 the fuld object - memory evaluation ( fome),19 a verbal fluency test ( category : fruits ) , the trail making test ( tmt ) a and b20 , the short cognitive test ( skt),21,22 and the wechsler adult intelligence scale - revised ( wais - r ) vocabulary and block design tests.23 evidence of functional decline was based on the scores of the informant questionnaire of cognitive disorders of the elderly ( iqcode)24 , as well as all available evidence concerning difficulties performing basic and instrumental activities of daily living , as reported by a close relative or caregiver and on the patient s self - report .
consensus diagnoses were reached at expert multidisciplinary sessions taking into account all information about the current medical history and evidence of objective cognitive decline as assessed by the neuropsychological exams .
the scores on the mmse , vf and cdt were obtained at the screening assessment of every patient , and this information was not added to the diagnostic protocol .
objective cognitive impairment was defined as performance below 1.5 standard deviations in the neuropsychological evaluation , adjusted by age and educational level in the so paulo elderly population.9,25 diagnosis of amnestic mci was made according to the following criteria26,27 : ( 1 ) subjective cognitive complaint , preferably corroborated by an informant ; ( 2 ) objective memory impairment in the neuropsychological assessment ; ( 3 ) preserved global intellectual function ; ( 4 ) preserved or minimal impairments in activities of daily living ; ( 5 ) no signs of dementia .
the control group comprised individuals without objective evidence of cognitive impairment and subjects with cognitive complaints but normal performance in neuropsychological tests ( i.e. , subjective cognitive complainers ) .
we performed a pearson s chi - square analysis to assess the differences in the distribution of gender among different diagnostic groups .
kolmogorov - smirnov tests were used to evaluate the normality of the distribution for each continuous variable .
since these analyses showed that all variables had a normal or near - normal distribution , we decided to carry out parametric statistical tests for all analyses .
for the purpose of this study , we analyzed data only for the mini - mental state examination , the verbal fluency test and the clock drawing test .
we carried out a univariate analysis of variance ( anova ) to assess the mean differences for socio - demographic data , clinical variables , and scores on cognitive and neuropsychological tests among the diagnostic groups .
receiver operating characteristic ( roc ) analyses were performed to calculate the sensitivity , specificity and accuracy of the suggested cut - off points adjusted by educational level suggestive of cognitive impairment proposed by the mmse ( illiterate , < 20 , 1 4 years of education , < 25 , 4 8 years of education , < 26 , 9 years of education and above , < 28 ) , the vft ( illiterate , < 10 , one year of education and above < 14 ) and the cdt ( 0 8 years of education , < 6 , above 8 years of education , < 8)29 to identify mci or ad cases versus controls . we addressed if different combinations of the above mentioned tests were more accurate for identifying mci and ad cases in this cohort . therefore , the following combinations were assessed : ( 1 ) subjects who scored below the cut - off points in the mmse , the vft and the cdt were regarded as cognitively impaired ( the and rule ) ; ( 2 ) subjects who scored below the cut - off points in at least the mmse , the vft or the cdt were regarded as cognitively impaired ( the or rule ) ; ( 3 ) the combination of mmse and the vft ; ( 4 ) the combination of the mmse and cdt , mmse and vft and the combination of the cdt and vft .
all statistical analyses were performed using spss v14.0 for windows ( spss inc . , chicago , il ) , and the value was set at 5% .
all subjects included in this analysis are participants of an ongoing prospective study on ageing and cognition carried out at a specialized memory clinic at the institute of psychiatry , university of so paulo , so paulo , brazil .
recruitment started in june of 2003 , and subjects were continuously enrolled for cognitive evaluation .
patients and controls were recruited from the hospital catchment area through information provided by media advertisements and lectures about health and aging .
we also included subjects presenting with spontaneous demand for memory assessment and referrals from other medical services .
this study was approved by the local ethics committee and was performed in accordance with the helsinki declaration . for the purpose of this study , we included 247 elderly outpatients ( 73% women ) ( mean age : 71.37.2 years ; mean educational level : 10.65.9 years ) with the baseline diagnosis of mild cognitive impairment ( mci , n=83 ) , alzheimer s disease ( ad , n=81 ) and normal cognition ( controls , n=83 ) .
clinical and neuropsychological evaluations were carried out according to a standardized protocol and by trained physicians and neuropsychologists .
detailed information about the medical evaluation , cognitive and neuropsychological assessments , and diagnostic algorithms of this cohort can be found elsewhere.13 in brief , the cognitive evaluation consisted of the administration of the brazilian version of the cambridge examination for mental disorders in the elderly ( camdex ) semi - structured interview,8,14 which yields scores for the cambridge cognitive test ( camcog ) , the mini - mental state examination ( mmse)15 , and a verbal fluency test .
the clock drawing test , which is part of the camcog schedule , was additionally scored accordingly to sunderland s guidelines.16 the 21-item hamilton depression scale ( ham - d ) was administered to all subjects prior to neuropsychological assessment in order to rule out the presence of clinically relevant depressive symptoms;17 patients with a ham - d score of 7 or more were referred to psychiatric attention and not included in the study .
a comprehensive neuropsychological evaluation included the culturally adapted , brazilian portuguese versions of the following tests : the rivermead behavioral memory test ( rbmt),18 the fuld object - memory evaluation ( fome),19 a verbal fluency test ( category : fruits ) , the trail making test ( tmt ) a and b20 , the short cognitive test ( skt),21,22 and the wechsler adult intelligence scale - revised ( wais - r ) vocabulary and block design tests.23 evidence of functional decline was based on the scores of the informant questionnaire of cognitive disorders of the elderly ( iqcode)24 , as well as all available evidence concerning difficulties performing basic and instrumental activities of daily living , as reported by a close relative or caregiver and on the patient s self - report .
consensus diagnoses were reached at expert multidisciplinary sessions taking into account all information about the current medical history and evidence of objective cognitive decline as assessed by the neuropsychological exams .
the scores on the mmse , vf and cdt were obtained at the screening assessment of every patient , and this information was not added to the diagnostic protocol .
objective cognitive impairment was defined as performance below 1.5 standard deviations in the neuropsychological evaluation , adjusted by age and educational level in the so paulo elderly population.9,25 diagnosis of amnestic mci was made according to the following criteria26,27 : ( 1 ) subjective cognitive complaint , preferably corroborated by an informant ; ( 2 ) objective memory impairment in the neuropsychological assessment ; ( 3 ) preserved global intellectual function ; ( 4 ) preserved or minimal impairments in activities of daily living ; ( 5 ) no signs of dementia .
the control group comprised individuals without objective evidence of cognitive impairment and subjects with cognitive complaints but normal performance in neuropsychological tests ( i.e. , subjective cognitive complainers ) .
we performed a pearson s chi - square analysis to assess the differences in the distribution of gender among different diagnostic groups .
kolmogorov - smirnov tests were used to evaluate the normality of the distribution for each continuous variable .
since these analyses showed that all variables had a normal or near - normal distribution , we decided to carry out parametric statistical tests for all analyses .
for the purpose of this study , we analyzed data only for the mini - mental state examination , the verbal fluency test and the clock drawing test .
we carried out a univariate analysis of variance ( anova ) to assess the mean differences for socio - demographic data , clinical variables , and scores on cognitive and neuropsychological tests among the diagnostic groups .
receiver operating characteristic ( roc ) analyses were performed to calculate the sensitivity , specificity and accuracy of the suggested cut - off points adjusted by educational level suggestive of cognitive impairment proposed by the mmse ( illiterate , < 20 , 1 4 years of education , < 25 , 4 8 years of education , < 26 , 9 years of education and above , < 28 ) , the vft ( illiterate , < 10 , one year of education and above < 14 ) and the cdt ( 0 8 years of education , < 6 , above 8 years of education , < 8)29 to identify mci or ad cases versus controls .
we addressed if different combinations of the above mentioned tests were more accurate for identifying mci and ad cases in this cohort .
therefore , the following combinations were assessed : ( 1 ) subjects who scored below the cut - off points in the mmse , the vft and the cdt were regarded as cognitively impaired ( the and rule ) ; ( 2 ) subjects who scored below the cut - off points in at least the mmse , the vft or the cdt were regarded as cognitively impaired ( the or
rule ) ; ( 3 ) the combination of mmse and the vft ; ( 4 ) the combination of the mmse and cdt , mmse and vft and the combination of the cdt and vft .
all statistical analyses were performed using spss v14.0 for windows ( spss inc . , chicago , il ) , and the value was set at 5% .
demographic and cognitive variables are summarized in table 1 . as expected , patients with ad were older , less educated and performed worse on the cognitive tests as compared to mci and control individuals ( anova , p<.001 ) .
subjects with mci attained intermediate scores on cognitive screening tests ( mmse , cdt and vft ) as compared to ad and control individuals . although significant , the magnitude of the difference between subjects with mci and healthy controls on these test scores was small , and scores were above the cut - off values that are usually accepted as positive screening for dementia .
all tests ( separately and in combination ) showed good accuracy for the identification of ad .
the cut - off scores of the mmse alone and the combination of mmse and vft showed the best accuracy for identifying ad patients ( table 2 ) .
the mmse scores alone yielded an area under the roc curve of 0.85 0.03 ( p<0.001 ) , indicating the best combination of sensitivity and specificity ( 98% and 71% , respectively ) .
( i.e. , mmse and cdt and vft scores ) had maximum ( 100% ) specificity , and the or rule
( i.e. , mmse or cdt or vft ) had maximum sensitivity ( 100% ) .
however , the auc obtained from the separation of patients with mci from controls was smaller regardless of whether the tests were analyzed separately or in combination .
all tests alone , the combinations of two tests ( mmse + vft , mmse + cdt , and vft + cdt ) and the and rule had good specificity for separating mci from controls , albeit with very low sensitivity .
our results indicate that the mmse , the verbal fluency test ( vft ) , and the clock drawing test ( cdt ) do not have a good diagnostic accuracy for identifying cases of mci , in spite of their usefulness in the diagnostic screening for dementia .
in addition , the combined use of these tests did not satisfactorily increase overall diagnostic accuracy when separating mci from controls .
our results are in accordance with previous studies from our group and others in which the association of cognitive and/or functional tests did not provide a good sensitivity in the diagnostic screening for mci.4,5,12 regarding the identification of cases of dementia in this sample , our roc curves do not demonstrate any additional benefit of the combination of tests as compared to the analysis of each test score separately .
this finding is somewhat surprising because other authors have proposed that this strategy may improve overall diagnostic accuracy .
in fact , the present data demonstrate that the combination of tests did not or minimally , at best change diagnostic accuracy , as shown by the aucs .
this effect was primarily due to the detriment of sensitivity , since specificity was substantially increased through a combination of test scores .
we also observed this phenomenon in the analysis of non - demented subjects , where the separation of patients with mci from cognitively healthy controls yielded aucs between 0.5 and 0.6 irrespective of the analysis strategy .
in other words , the combination of tests substantially reduced sensitivity , but it increased specificity up to 97100% . the only exception to this tendency was with the or rule , which yielded a specificity below 50%
. a few considerations must be made with respect to the clinical implications of the present findings .
the combination of two or three cognitive screening tests is a common approach used by physicians to substantiate the clinical diagnosis of cognitive impairment , particularly in settings where a thorough neuropsychological evaluation is not available or because of time constraints .
we understand that the qualitative observation of the performance on such tests , in addition to the score itself , may add important insights to the diagnostic workup , as we have previously shown that the analysis of mmse sub - scores supports the identification of mci subtypes10 .
however , when translating this clinical impression into the screening for cognitive impairment in larger patient groups , we recommend that the output of this strategy be interpreted with caution , since the combination of test scores according to the and rule significantly impairs diagnostic sensitivity . in other words , caseness will be met only when a given patient shows abnormal performance on all tests utilized for assessment .
this strategy will deliver a high number of false negative cases that correspond to patients who in fact have subtle abnormalities that might have been detected by one single test . on the other hand
, the specificity of estimates based on the and rule will be significantly increased in the presence of abnormal performance in all tests together .
brief cognitive tests are developed to provide good sensitivity in the screening for dementia , whereas specificity is usually attained with more inclusive batteries or through formal neuropsychological evaluation .
specificity can be further increased by adding information from laboratory and neuroimaging tests , both for the purpose of ruling out comorbidities that concur with a high prevalence of cognitive impairment30 and to ascertain underlying pathological features of ad31 .
the complexity of this procedure is a limitation for the large - scale diagnosis of mci , particularly in primary care settings .
the basic purpose of the tests that we addressed in this study ( i.e. , good for screening ) was met by all three tests when the target was identifying dementia ( ad ) , but not when attempting to detect subtle deficits ( i.e. , mci ) .
one possible explanation is that these tests are prone to ceiling effects , particularly among more educated mci patients .
in other words , subjects with mild deficits may still be able to perform well in spite of the existence of symptoms compatible with incipient ad32 .
since most available cognitive screening tests have been developed to separate dementia from non - dementia , the development of new tests specially designed to screen for mild cognitive deficits , such as the montreal cognitive assessment ( moca)33 and the computer - assisted neuropsychological screening for mci ( cans - mci),34 may overcome this limitation .
in addition , the combination of cognitive tests and functional scales , or functional scales alone , may serve as alternatives for screening subjects with cognitive complaints .
bottino et al.35 found that the association of fome and mmse with two informant - based functional scales ( iqcode and bayer activities of daily living scale ) was sensitive enough to identify cases with mild to moderate dementia .
perroco and colleagues36 recently reported that the iqcode ( and its shorter version ) was also sensitive enough to screen for patients with mild dementia .
the objective functional assessment , as provided by the dafs ( direct assessment of functional state ) , discriminated mci patients from patients with dementia with high accuracy ; nonetheless , it had a lower accuracy for discriminating patients with mci from cognitively unimpaired elderly subjects37 .
therefore , despite the fact that several screening strategies may be useful for the identification of mild to moderate dementia cases , there is still a long road ahead when addressing the screening for pre - dementia cases .
the sample of patients and controls on which the present analysis was based has certain characteristics that may explain the discrepancy between our findings and previous notions that supported the advantage of combining tests .
first , the ad patients included in this study had mild or incipient dementia , as opposed the predominance of patients with mild to moderate dementia in previous studies , rendering patients in our ad group less impaired and narrowing the difference between their mean scores and those obtained by patients in the comparison groups ( mci and controls ) .
conversely , our controls are not only non - demented but also cognitively unimpaired , since we separated cognitively healthy subjects ( controls ) from those with mci through a neuropsychological assessment .
most studies conducted in the late 1980s and 1990s did not separate these two states , leading to contamination of the control group with subtle forms of cognitive impairment ; in this case , the scores obtained by historical controls tend to be lower than the ones observed in our sample . in both instances ( i.e. , less impaired ad patients and above average controls )
, the range of cognitive deficits will be smaller , affecting the cut - off scores that best separate groups .
we understand that educational level is an important issue when assessing patients with cognitive complaints / impairment , particularly in populations with heterogeneous backgrounds . in this analysis
, we controlled for this effect by using different cut - off scores for the cognitive screening tests , which have been established for the brazilian population.29 in addition , the clinical diagnoses provided by the multidisciplinary expert consensus meeting yield important insights as to whether any given finding is clinically relevant or not .
the present results highlight three important issues that have practical implications for the diagnostic workup of cognitive disorders .
first , the mmse alone may be sufficient in the screening for dementia , since the combinations of tests did not increase diagnostic accuracy .
second , the combination of the mmse , the vft and the cdt ( by means of several different analytical strategies ) did not accurately identify cases of mci in a clinical setting .
finally , the diagnosis of mci still depends on the information provided by a comprehensive neuropsychological assessment .
alternatively , the clinical evaluation along with other supportive diagnostic techniques , such as the measurement of ad - related biomarkers in cerebrospinal fluid and/or structural and functional neuroimaging , may be necessary to substantiate the diagnosis of mci and the subsequent risk of developing ad.3941 of course , these resources are restricted to specialized settings and are not appropriate for large - scale screening of cognitive impairment . from the clinician s perspective , the identification of patients with mci , as well as the evaluation of the risk for progression to dementia , still relies on careful clinical judgment and the longitudinal determination of cognitive status with the available tools.42[/INST]objectiveto determine the accuracy of the mini - mental state examination combined with the verbal fluency test and clock drawing test for the identification of patients with mild cognitive impairment and alzheimer s disease ( ad).methodthese tests were used to evaluate cognitive function in 247 older adults .
subjects were divided into three groups according to their cognitive state : mild cognitive impairment ( n=83 ) , ad ( n=81 ) , cognitively unimpaired controls ( n=83 ) , based on clinical and neuropsychological data .
the diagnostic accuracy of each test for discriminating between these diagnostic groups ( mild cognitive impairment or ad vs. controls ) was examined with the aid of receiver operating characteristic ( roc ) curves .
additionally , we evaluated the benefit of the combination of tests on diagnostic accuracy.resultsalthough they were accurate enough for the identification of alzheimer s disease , neither test alone proved adequate for the correct separation of patients with mild cognitive impairment from healthy subjects . combining these tests did not improve diagnostic accuracy , as compared to the mini - mental state examination alone , in the identification of patients with mild cognitive impairment or alzheimer s disease.conclusionsthe present data do not warrant the combined use of the mini - mental state examination , the verbal fluency test and the clock drawing test as a sufficient diagnostic schedule in screening for mild cognitive impairment .
the present data do not support the notion that the combination of test scores is better that the use of mini - mental state examination scores alone in the screening for alzheimer s disease .</s> |
n - methylpyrrole ( py )
and n - methylimidazole
( i m ) polyamides are heterocycle - based oligomers that bind the minor
groove of dna in a sequence - specific manner .
investigations
of py - im polyamide biological properties have demonstrated that these
compounds are cell permeable , localize to the nucleus , and display transcriptional inhibition , likely through an allosteric
mechanism by disrupting the transcription factor dna interface . this compression may be responsible for the observed reduction in
transcription factor occupancy upon polyamide dna complexation .
gene regulation properties have been illustrated in cell culture
models targeting transcription factors androgen receptor ( ar ) , glucocorticoid receptor ( gr ) , hypoxia inducible factor ( hif ) , nuclear
factor kappab ( nf-b ) , aurka / aurkb , and tgf-. we have investigated
the utility of py - im polyamides in organismal models through in vitro
admet studies , real - time biodistribution
monitoring methods , and , most recently ,
the development of mouse pharmacokinetic and toxicity profiles .
recent efforts to develop more potent polyamides ,
however , have been hindered by poor solubility .
if aggregation is an issue , how does particle
size correlate with structural features such as size , charge , shape ,
turn substitution , and py / im composition of the oligomer ?
recent
studies of the aggregation of small - molecule drug candidates
through dynamic light scattering ( dls ) and detergent - based assays
have highlighted the importance of such considerations in drug design .
indeed , a screen of over 70000 potential drug candidates by shoichet
and co - workers found that 95% of the initial hits acted as aggregate - based
inhibitors . at the same time , several
currently approved drugs can be classified as aggregate - based inhibitors and in some cases aggregate particle size may
be linked to pharmaceutical efficacy .
we thus decided to investigate this important pharmacokinetic
parameter and its relationship to the biological activity of py - im
polyamides .
as our laboratory explores the efficacy of polyamides
in animal disease models , there becomes a pressing need to characterize
the aggregation and solubility properties of these compounds as well
as to investigate the use of formulating reagents to solubilize polyamides
at the high concentrations required for animal injections .
we selected two libraries of py - im hairpin
polyamides , 16 and 711 ,
targeting the ar / gr consensus sequence 5-wgwwcw-3
( w = a / t ) or the nf-b consensus sequence 5-wggwww-3 ,
respectively ( figure 1 ) .
these two different heterocyclic cores were diversified
with a variety of substituents at the 4-aminobutyric acid ( gaba ) turn
positions ( r1 , r2 ) and at the c - terminus ( r3 ) .
for example , the first - generation modification at the c - terminus ,
-alanine-3-(dimethylamino)-propylamine , was shown to be a negative
determinant of cell uptake .
this study focuses on
the second - generation modification of the c - terminus without a -alanine
linker and with incorporation of isophthalic acid used in our cell
culture studies .
in addition , the employment
of cyclic polyamide architectures has resulted in increased dna binding
affinities and selectivities as well
as improved efficacy against ar - regulated genes . taken in context with our recent finding of increased murine
toxicity of cyclic polyamides
, we decided
to also investigate the properties of cycles 1214 ( figure 2 ) .
all py - im polyamides
were synthesized according to previously published solid - phase procedures .
chemical
structures of hairpin polyamide library along with the
corresponding circle stick models and target dna sequences .
legend : black circle = i m ; white circle = py ; semicircle = -aminobutyric
acid unit with dashed ( r , ) or wedge ( r , ) substituents ;
hexagon = isophthalic acid / ipa ; rectangle = fluorescein / fitc ; w =
a / t bases .
legend :
black circle = i m ; white circle = py ; semicircle = -aminobutyric
acid unit with dashed ( r , ) substituents ; w = a / t bases .
the aggregation propensity of py - im polyamides
was investigated
through dynamic light scattering ( dls ) .
compounds 114 were studied at 1 , 4 , and 10 m concentrations in
a 0.1% dmso / pbs solution in order to approximate the dmso concentration
and salt content present in cell culture experiments .
stock solutions
( 1000 ) of each polyamide in dmso were rapidly mixed with pbs ,
and the scattered light intensity was measured over the course of
10 min .
the minimum concentration at which each compound was found
to give a significant signal intensity ( 3 the buffer signal
as per manufacturer guidelines ) , along with the respective particle
sizes derived from a cumulant fit of the autocorrelation functions ,
are listed in table 1 .
hairpin polyamides generally formed particles with radii of 70200
nm at 4 m concentration .
one notable trend is that the benzamide
substituted compounds ( 4 and 10 ) formed
measurable particles at lower concentrations ( 1 vs 4 m ) than
their free amine counterparts ( 2 and 8) .
py - im polyamides containing fluorescein substituents ( 5 and 6 ) formed significantly larger particles when compared
to the isophthalic acid conjugates ( 2 and 4 ) , and compound 11 precipitated from the solution before
particle size could be determined .
interestingly , cyclic polyamides 1214 formed larger particles than the
hairpin polyamides , with the bis--amino substituted cycle 13 forming the largest particles in this data set .
similar
results were observed for a number of additional polyamides ( see supporting information , table s1 ) , except for
compounds containing three or four consecutive imidazole rings ( 17 , 18 ) , which formed particles too large to
be accurately measured ( radii > 1 m ) .
radii derived from a cumulant fit
of the average autocorrelation functions collected over 10 min .
radius could not be determined
due
to rapid precipitation of the compound at 1 m concentration .
next , the macroscopic solubility properties of these
compounds
were investigated by measuring the concentration of selected py - im
polyamides in the soluble fraction of solutions with similar maximum
concentrations ( 4 m , figure 3 ) .
each
compound was added as a 1000 ( 4 mm ) stock in dmso to pbs in
accord with the light scattering experiments .
solutions were sonicated
and then allowed to equilibrate for 2 h at room temperature before
aggregates were removed through centrifugation . to measure the concentration
of polyamide in the supernatant ,
a plot of hplc peak area vs concentration
was generated using polyamide 7 with detection at 310
nm , the wavelength at which each compound was quantified ( see supporting information , figure s1 ) . in general ,
the 5-wgwwcw-3-targeted hairpin polyamides ( 14 ) were found to be more soluble than
their 5-wggwww-3-targeted counterparts ( 710 ) . within each set of polyamide hairpin cores ,
a relationship between turn substituents and solubility was observed .
polyamides with -amine - substituted turns ( 2 , 8) were found
to be more soluble than those compounds with -amine - substituted
turns ( 1 , 7 ) , and the former compounds were further solubilized upon acetylation
( 3 , 9 ) . increased solubility upon incorporation
of acetylated turn units was also observed in the cyclic architecture
( 13 vs 14 ) . the benzamide - substituted compounds
( 4 , 10 ) and
the bis--amine substituted cycle 14(18,28 ) were found to be the least soluble , in good agreement with the light
scattering measurements .
calculated soluble concentration
of select polyamides in 0.1% dmso / pbs
at 25 c .
maximum concentration estimated at 4 m ( dotted
line ) based on quantitation of starting material in 0.1% dmso / water .
resultant concentrations determined by hplc peak area at 310 nm detection
after comparison with a standard curve ( see supporting
information ) .
we thus decided to investigate the ability of known
formulating
reagents , in particular cyclodextrins ( cds ) , to decrease aggregation and/or precipitation among the less soluble
hairpin polyamides 710 ( figure 4 ) .
2-hydroxypropyl--cyclodextrin ( hpcd )
was chosen initially due to its high water solubility and low animal
toxicity . using procedures identical
to the solubility analyses , peak areas of py - im polyamides in the
presence of 0 , 5 , or 50
was observed for all compounds
studied , with compounds 7 and 8 near the
maximum expected concentration in solutions of 50 mm hpcd ( figure 4a ) .
impressively , 50 mm hpcd increased the
concentration of the least soluble derivative ( benzamide - substituted
polyamide 10 ) over 50-fold .
surprisingly , the soluble
concentration observed for polyamide 9 was significantly
higher than expected based on the quantitation of the corresponding
dmso stock solution .
this result likely derives from aggregation and/or
precipitation of compound 9 upon dilution of the polyamide
in water before the absorbance is measured , resulting in an underestimation
of the stock concentration .
we further probed the specificity of these
effects by studying the solubilization of polyamide 7 by other carbohydrate formulating reagents , namely -cd , -cd ,
hydroxypropyl methylcellulose ( hypromellose ) , and dextrose ( see supporting information , figure s2 ) .
the three
cyclodextrin derivatives were studied at 5 mm concentrations , while
hypromellose , a linear substituted glucose polymer , and dextrose ,
the glucose monomer , were normalized for total sugar content against
5 mm hpcd .
in addition to hpcd , polyamide 7 was solubilized by -cd and hypromellose ( figure 4b ) .
polyamide 12 , which would seem less likely
to form an inclusion complex with cyclodextrin due to its cyclic form ,
was screened against the same formulating agents .
notably ,
neither polyamide displayed an increased solubility in the monomer
( dextrose ) solution .
( a ) calculated soluble concentration of polyamides 710 in 0.1% dmso / pbs containing 0 , 5 ,
or 50 mm
hpcd at 25 c .
( b ) calculated soluble concentration of
polyamides 7 and 12 in 0.1% dmso / pbs containing :
5 mm - , hp- , -cyclodextrin ( , ,
, respectively ) , 6 mg / ml hypromellose ( hm ) , 35 mm dextrose
( dx ) . maximum concentration estimated at 4 m ( dotted line )
based on quantitation of starting material in 0.1% dmso / water .
resultant
concentrations determined by hplc peak area ( = 310 nm ) after
comparison with a standard curve ( see supporting
information ) .
the utility of these results was further probed
in an animal model
system .
our laboratory recently found that high blood levels of polyamide 7 can be achieved in mice following an intraperitoneal ( ip )
injection of 120 nmol compound in a vehicle of 20% dmso / pbs ( 600 m
concentration , figure 5a ) .
using hpcd , the dmso content could be reduced to
1% with no loss in solubility .
ip injections of 120 nmol polyamide 7 in a 1% dmso/80 mm hpcd / pbs vehicle and the subsequent
blood collection were performed under identical conditions to those
previously reported .
after blood collection , the plasma was isolated
through centrifugation and the bulk proteins removed through methanol
precipitation .
the supernatant was then mixed with dilute aqueous
trifluoroacetic acid ( tfa ) , and a reference compound in acetonitrile
was added .
the injection vehicle containing hpcd yielded circulating
polyamide concentrations comparable to those previously reported ( figure 5b ) . in both cases ,
polyamide concentrations of 1314
m were detected in mouse plasma 1.5 h after injection , with
no polyamide detected after 24 h. furthermore , fitc - labeled compound 11 , which formed a precipitate in 20% dmso / pbs solutions ,
was fully solubilized upon addition of hpcd ( 80 mm ) , allowing
the compound to be injected into mice . slightly reduced plasma concentrations
of compound 11 were observed as compared to compound 7 , which may indicate reduced bioavailability of the fitc - modified
polyamide ( figure 6a ) .
hplc traces of mouse
plasma isolated from four mice at three time
points after injection with 120 nmol polyamide 7 in two
different vehicles : 20% pbs / dmso ( a ) and 1% dmso/80 mm hpcd / pbs
( b ) .
( a ) hplc traces of mouse plasma isolated from four mice
at three
time points after injection with 120 nmol polyamide 11 in 20% dmso/80 mm hpcd / pbs .
( b ) confocal image of a549 cells
after 16 h incubation with mouse plasma isolated 1.5 h after injection
with polyamide 11 .
we then sought to investigate the availability
of the circulating
polyamide to human cells by taking advantage of the nuclear staining
generally observed with fitc polyamide conjugates .
plasma samples
isolated from mice injected with compound 11 were added
to a549 ( human lung cancer ) cells 16 h prior to imaging live cells
with confocal microscopy . in cells treated with plasma collected at
1.5 h postinjection , strong nuclear fluorescent signals were observed
( figure 6b ) .
greatly reduced levels were observed
with plasma isolated 4.5 h postinjection , and no significant signal
was observed with the addition of the 24 h plasma sample ( see supporting information , figure s3 ) .
dynamic light scattering
measurements revealed that both hairpin
and cyclic polyamides form measurable particles between 50 and 500
nm in size at biologically relevant concentrations ( table 1 ) .
interestingly , particles of similar size were
observed for all polyamides containing an isophthalic acid ( ipa ) at
the c - terminus despite the differing activities of these compounds
in cell culture .
these results support a mechanism of polyamide activity
in which aggregation may not be a key factor .
another interesting
observation is that neither aggregation nor
solubility is affected by the overall ionic charge of the polyamide .
while organic compounds with ionizable groups are generally expected
to be more soluble in aqueous salt solutions , neither light scattering
nor solubility analyses revealed such a dependence .
indeed , hairpins
and cycles in which the gaba amino turn units were modified with acetyl
groups were found to be the most soluble . at first glance ,
the
lack of solubility observed for some polyamides
is surprising as similar concentrations are commonly used in cell
culture experiments , often without evidence of aggregation or precipitation .
however , the experimental conditions required for the solubility experiments
are a limited comparison to those in cell culture . for example , cell
media generally contain a variety of small molecule and protein nutrients ,
and cell cultures are kept at higher temperatures ( 37 c vs 25
c ) . in addition , the soluble fraction isolated by centrifugation
is not necessarily representative of the available polyamide concentration
during a typical cell incubation period ( 4872 h ) , particularly
if aggregation is a dynamic process .
we note that similar solubility
issues have been reported by sugiyama and co - workers , who enhanced
the biological activity of seco - cbi polyamide conjugates
through pegylation or liposomal formulations .
we were able to mitigate the problem of
polyamide solubility through
the addition of carbohydrate formulating reagents , in particular hpcd .
as cyclodextrins are generally thought to form discrete inclusion
complexes with small organic molecules , we postulated
that the linear conformation of hairpin polyamides may be well - solubilized
by such additives .
indeed , the solubilization of polyamide 7 by the larger cyclodextrins ( and ) is consistent
with the formation of possible cyclodextrin inclusion complexes , which in this case may result from interactions
with the isophthalic acid unit at the c - terminus or the n - methylimidazole group at the n - terminus
. such interactions would
not be expected , however , between cyclodextrins and cyclic polyamide 12 .
interestingly , solubilization of compound 12 was observed with hpcd but not the other cyclodextrin derivatives .
the lack of solubilization with cd would be consistent with
a model in which the interactions between hpcd and cycle 12 rely more on the hydroxypropyl substituents unique to hpcd ,
perhaps through additional hydrogen bonding interactions , rather than
encapsulation .
while both the linear 7 and cyclic 12 polyamide compounds were solubilized by hypromellose , presumably
through encapsulation within the polymer matrix , it is notable that
no significant solubilization was observed with the dextrose monomer .
this latter observation may indicate the importance of an ordered
carbohydrate structure , such as that available with cyclodextrins
and hypromellose , for efficient polyamide solubilization .
further
studies are necessary , however , before conclusions can be drawn regarding
the interactions between py - im polyamides and carbohydrate derivatives ,
and such investigations fall outside the scope of this work .
further evidence of the utility of hpcd as a formulating
reagent was gathered in mouse experiments .
first , we demonstrated
that the hpcd vehicle did not significantly affect circulating
levels of polyamide 7 . on the other hand , the fluorescently
labeled derivative 11 was only sufficiently soluble in
hpcd solutions . as a result ,
this tagged compound was
of particular interest due to the high plasma protein binding levels
( > 99% ) that had been previously reported for py - im polyamides during
admet studies .
evidence of nuclear uptake
was observed in a549 cells following incubation with plasma from hairpin 11-treated mice , thus demonstrating the availability of circulating
polyamides to human cancer cells . in summary , these studies
have provided evidence that the aggregation
propensity of py - im polyamides likely does not contribute
to biological activity and may not be a critical concern in pharmacokinetic
analyses .
solubility experiments revealed important trends , such as
the increased solubility achieved by acetylation of the gaba amino
turn unit , which will impact the design of next generation polyamides .
furthermore , the identification of an effective delivery vehicle will
allow for the in vivo study of otherwise inaccessible py - im polyamides .
these studies represent a contribution to the field of small molecule
transcriptional inhibitors and their ultimate utility as tools for
perturbing gene expression networks in vivo .
the synthesis
of py - im polyamides has been extensively described in previous work and is summarized as follows : reagents were
purchased from sigma - aldrich or novabiochem .
py - im cores were synthesized
on kaiser oxime resin using boc - based chemistry , cleaved using 3,3-diamino - n - methyldipropylamine , and purified by reverse phase preparative
hplc .
the c - terminal amine was then derivatized with either isophthalic
acid ( ipa ) or fluorescein isothiocyanate ( fitc ) and the crude intermediate
isolated through ether precipitation .
the gaba turn protecting groups
( -nhboc or -nhcbz ) were removed under acidic conditions .
if applicable , the crude intermediate was again isolated through ether
precipitation and further derivatized at the gaba turn amine with
either acetic anhydride or pybop - activated benzoic acid .
final products
were purified through reverse phase hplc and the identity confirmed
through matrix - assisted laser desorption ionization time - of - flight
( maldi - tof ) mass spectrometry . the synthesis and characterization
of compounds 1;26;7 , 11;15 , 2532 were
in line with literature reports .
results from maldi - tof characterization
for compounds 810 , 1214 , and 1624 are available in the supporting information
( table s2 ) . the synthesis and characterization of polyamides 12 and 13 have been previously described . in brief , the heterocyclic cores of these polyamides
were synthesized on kaiser oxime resin as above , except that a terminal
gaba turn unit ( boc - gaba oh or ( r)-4-(boc - amino)-3-(z - amino)butyric acid ) was added .
following deprotection
of the terminal boc unit , the core was cleaved from the resin with
dbu / h2o and the resulting acid purified by reverse phase
hplc .
the crude intermediate was isolated through
ether precipitation and the cbz group(s ) removed as above .
polyamide 14 was synthesized
by reaction of 13 with acetic anhydride under basic conditions
and then purified be reverse phase hplc .
results from maldi - tof characterization
for compound 14 are available in the supporting information ( table s2 ) .
polyamide concentrations were
measured by uv - absorption analysis on an agilent 8453 diode array
spectrophotometer in distilled and deionized water containing up to
0.1% dmso using a molar extinction coefficient ( ) of 69500
m cm at 310 nm .
dmso and pbs were passed through
a 0.02 m syringe filter ( whatman ) immediately prior to use .
stock solutions of each polyamide in dmso were quantified as above
and the purity determined by hplc to be greater than 95% .
solutions
of 1 , 4 , and 10 mm in dmso were prepared and then centrifuged for
15 min at 16 g to remove particulates .
immediately
before measurement , 0.5 l of the dmso stock was added to 500
l of pbs in a microcentrifuge tube .
the solution was mixed
briefly with a pipet tip and transferred to a disposable plastic cuvette
( fisher ) .
measurements were performed on a wyatt dynapro nanostar
instrument using a 659 nm/100 mw laser at 100% power and a 90
detection angle at 25 c .
acquisition times of 1015 s
were collected over 10 min and analyzed using the cumulant fit tool
in the dynamics ( 6.11.1.3 ) software with pbs as the referenced solvent .
acquisitions in which the baseline value of the fit was greater than
0.1 were omitted and the remaining traces averaged .
measurements
in which the intensity ( cts / s ) was less than 3 the buffer signal
intensity were considered below the detection limit .
stock solutions of each polyamide
in dmso were quantified as above and the purity checked by hplc .
polyamide ( 0.5 l ) was
added to 500 l of pbs in a microcentrifuge tube , and the solution
was immediately vortexed and placed in a sonicating water bath at
25 c for 20 min .
the tubes were then removed from the bath and
allowed to equilibrate for 2 h at room temperature .
samples were centrifuged
for 20 min at 16 g and 100 l of the supernatant
removed for hplc analysis .
analytical hplc analysis was conducted
on a beckman gold instrument equipped with a phenomenex gemini analytical
column ( 250 mm 4.6 mm , 5 m ) and a diode array detector
( mobile phase : 1080% ch3cn in 0.1% cf3co2h ( aqueous ) over 17.5 min .
sample concentrations
were determined through comparison to a standard curve of concentration
vs peak area that was generated using compound 7 ( supporting information , figure s1 ) .
solubilization
by formulating agents proceeded similarly except that the dmso stock
solutions were added to pbs containing 5 or 50 mm hpcd , 5 mm
cd , 5 mm cd , 35 mm dextrose , or 6.00 mg / ml hypromellose
( approximately 35 mm relative glucose units based on reported substitution
for aldrich lot no .
murine experiments were performed
as described previously . in brief , c57bl/6
mice ( 812 weeks of age , jackson laboratory ) were injected
intraperitoneally with 200 l of a pbs solution containing :
( a ) 120 nmol compound 7 , 20% dmso , ( b ) 120 nmol compound 7 , 1% dmso , 80 mm hpcd , or ( c ) 120 nmol compound 11 , 20% dmso , 80 mm hpcd .
blood was collected from
anesthetized animals ( 25% isoflurane ) by retro - orbital withdrawal .
immediately after the third blood draw
, animals were euthanized by
asphyxiation in a co2 chamber ( 2 atm ) .
the samples from
the four replicate mice were combined at 5 l / sample , yielding
20 l combined plasma that was then treated with 40 l
of ch3oh , vortexed , and centrifuged .
then 50 l of
the supernatant were combined with 1 equiv of the hplc loading solution
( 4:1 water / ch3cn , 0.08% cf3co2h )
containing boc - py - ome ( methyl 4-((tert - butoxycarbonyl)amino)-1-methyl - pyrrole-2-carboxylate )
as an internal spike - in control .
analytical hplc analyses were conducted
with a phenomenex kinetex c18 analytical column ( 100 mm 4.6
mm , 2.6 m , 100 ) and a diode array detector ( mobile phase :
560% ch3cn in 0.1% ( v / v ) aqueous cf3co2h over 12.5 min .
peaks were detected and integrated at 310 nm absorbance ,
and sample concentrations were determined through comparison to the
previously published standard curve for this column . for confocal microscopy experiments ,
a549 cells in f-12k medium supplemented with 10% fbs ( 1 ml , 100k cells / ml )
were applied to culture dishes equipped with glass bottoms for direct
imaging ( mattek ) .
cells were allowed to adhere for 18 h in a 5% co2 atmosphere at 37 c .
the medium was then removed and
replaced with 200 l of fresh medium supplemented with 20 l
of plasma collected 1.5 , 4.5 , or 24 h after injection of compound 11 .
after an additional 16 h incubation period , 100 l
of untreated medium was added to each slide prior to imaging .
imaging
was performed at the caltech beckman imaging center using a zeiss
lsm 5 pascal inverted laser scanning microscope equipped with a 63
oil - immersion objective lens .
fluorescence and visible - light images
were obtained using standard filter sets for fluorescein and analyzed
using zeiss lsm software . | to optimize the biological activity of pyrrole
imidazole
polyamide dna - binding molecules , we characterized the aggregation
propensity of these compounds through dynamic light scattering and
fractional solubility analysis .
nearly all studied polyamides were
found to form measurable particles 50500 nm in size under
biologically relevant conditions , while hplc - based analyses revealed
solubility trends in both core sequences and peripheral substituents
that did not correlate with overall ionic charge .
the solubility of
both hairpin and cyclic polyamides was increased upon addition of
carbohydrate solubilizing agents , in particular , 2-hydroxypropyl--cyclodextrin
( hpcd ) . in mice ,
the use of hpcd allowed for improved
injection conditions and subsequent investigations of the availability
of polyamides in mouse plasma to human cells .
the results of these
studies will influence the further design of py - im polyamides and
facilitate their study in animal models . | <s>[INST]n - methylpyrrole ( py )
and n - methylimidazole
( i m ) polyamides are heterocycle - based oligomers that bind the minor
groove of dna in a sequence - specific manner .
investigations
of py - im polyamide biological properties have demonstrated that these
compounds are cell permeable , localize to the nucleus , and display transcriptional inhibition , likely through an allosteric
mechanism by disrupting the transcription factor dna interface . this compression may be responsible for the observed reduction in
transcription factor occupancy upon polyamide dna complexation .
gene regulation properties have been illustrated in cell culture
models targeting transcription factors androgen receptor ( ar ) , glucocorticoid receptor ( gr ) , hypoxia inducible factor ( hif ) , nuclear
factor kappab ( nf-b ) , aurka / aurkb , and tgf-. we have investigated
the utility of py - im polyamides in organismal models through in vitro
admet studies , real - time biodistribution
monitoring methods , and , most recently ,
the development of mouse pharmacokinetic and toxicity profiles .
recent efforts to develop more potent polyamides ,
however , have been hindered by poor solubility .
if aggregation is an issue , how does particle
size correlate with structural features such as size , charge , shape ,
turn substitution , and py / im composition of the oligomer ?
recent
studies of the aggregation of small - molecule drug candidates
through dynamic light scattering ( dls ) and detergent - based assays
have highlighted the importance of such considerations in drug design .
indeed , a screen of over 70000 potential drug candidates by shoichet
and co - workers found that 95% of the initial hits acted as aggregate - based
inhibitors . at the same time , several
currently approved drugs can be classified as aggregate - based inhibitors and in some cases aggregate particle size may
be linked to pharmaceutical efficacy .
we thus decided to investigate this important pharmacokinetic
parameter and its relationship to the biological activity of py - im
polyamides .
as our laboratory explores the efficacy of polyamides
in animal disease models , there becomes a pressing need to characterize
the aggregation and solubility properties of these compounds as well
as to investigate the use of formulating reagents to solubilize polyamides
at the high concentrations required for animal injections .
we selected two libraries of py - im hairpin
polyamides , 16 and 711 ,
targeting the ar / gr consensus sequence 5-wgwwcw-3
( w = a / t ) or the nf-b consensus sequence 5-wggwww-3 ,
respectively ( figure 1 ) .
these two different heterocyclic cores were diversified
with a variety of substituents at the 4-aminobutyric acid ( gaba ) turn
positions ( r1 , r2 ) and at the c - terminus ( r3 ) .
for example , the first - generation modification at the c - terminus ,
-alanine-3-(dimethylamino)-propylamine , was shown to be a negative
determinant of cell uptake .
this study focuses on
the second - generation modification of the c - terminus without a -alanine
linker and with incorporation of isophthalic acid used in our cell
culture studies .
in addition , the employment
of cyclic polyamide architectures has resulted in increased dna binding
affinities and selectivities as well
as improved efficacy against ar - regulated genes . taken in context with our recent finding of increased murine
toxicity of cyclic polyamides
, we decided
to also investigate the properties of cycles 1214 ( figure 2 ) .
all py - im polyamides
were synthesized according to previously published solid - phase procedures .
chemical
structures of hairpin polyamide library along with the
corresponding circle stick models and target dna sequences .
legend : black circle = i m ; white circle = py ; semicircle = -aminobutyric
acid unit with dashed ( r , ) or wedge ( r , ) substituents ;
hexagon = isophthalic acid / ipa ; rectangle = fluorescein / fitc ; w =
a / t bases .
legend :
black circle = i m ; white circle = py ; semicircle = -aminobutyric
acid unit with dashed ( r , ) substituents ; w = a / t bases .
the aggregation propensity of py - im polyamides
was investigated
through dynamic light scattering ( dls ) .
compounds 114 were studied at 1 , 4 , and 10 m concentrations in
a 0.1% dmso / pbs solution in order to approximate the dmso concentration
and salt content present in cell culture experiments .
stock solutions
( 1000 ) of each polyamide in dmso were rapidly mixed with pbs ,
and the scattered light intensity was measured over the course of
10 min .
the minimum concentration at which each compound was found
to give a significant signal intensity ( 3 the buffer signal
as per manufacturer guidelines ) , along with the respective particle
sizes derived from a cumulant fit of the autocorrelation functions ,
are listed in table 1 .
hairpin polyamides generally formed particles with radii of 70200
nm at 4 m concentration .
one notable trend is that the benzamide
substituted compounds ( 4 and 10 ) formed
measurable particles at lower concentrations ( 1 vs 4 m ) than
their free amine counterparts ( 2 and 8) .
py - im polyamides containing fluorescein substituents ( 5 and 6 ) formed significantly larger particles when compared
to the isophthalic acid conjugates ( 2 and 4 ) , and compound 11 precipitated from the solution before
particle size could be determined .
interestingly , cyclic polyamides 1214 formed larger particles than the
hairpin polyamides , with the bis--amino substituted cycle 13 forming the largest particles in this data set .
similar
results were observed for a number of additional polyamides ( see supporting information , table s1 ) , except for
compounds containing three or four consecutive imidazole rings ( 17 , 18 ) , which formed particles too large to
be accurately measured ( radii > 1 m ) .
radii derived from a cumulant fit
of the average autocorrelation functions collected over 10 min .
radius could not be determined
due
to rapid precipitation of the compound at 1 m concentration .
next , the macroscopic solubility properties of these
compounds
were investigated by measuring the concentration of selected py - im
polyamides in the soluble fraction of solutions with similar maximum
concentrations ( 4 m , figure 3 ) .
each
compound was added as a 1000 ( 4 mm ) stock in dmso to pbs in
accord with the light scattering experiments .
solutions were sonicated
and then allowed to equilibrate for 2 h at room temperature before
aggregates were removed through centrifugation . to measure the concentration
of polyamide in the supernatant ,
a plot of hplc peak area vs concentration
was generated using polyamide 7 with detection at 310
nm , the wavelength at which each compound was quantified ( see supporting information , figure s1 ) . in general ,
the 5-wgwwcw-3-targeted hairpin polyamides ( 14 ) were found to be more soluble than
their 5-wggwww-3-targeted counterparts ( 710 ) . within each set of polyamide hairpin cores ,
a relationship between turn substituents and solubility was observed .
polyamides with -amine - substituted turns ( 2 , 8) were found
to be more soluble than those compounds with -amine - substituted
turns ( 1 , 7 ) , and the former compounds were further solubilized upon acetylation
( 3 , 9 ) . increased solubility upon incorporation
of acetylated turn units was also observed in the cyclic architecture
( 13 vs 14 ) . the benzamide - substituted compounds
( 4 , 10 ) and
the bis--amine substituted cycle 14(18,28 ) were found to be the least soluble , in good agreement with the light
scattering measurements .
calculated soluble concentration
of select polyamides in 0.1% dmso / pbs
at 25 c .
maximum concentration estimated at 4 m ( dotted
line ) based on quantitation of starting material in 0.1% dmso / water .
resultant concentrations determined by hplc peak area at 310 nm detection
after comparison with a standard curve ( see supporting
information ) .
we thus decided to investigate the ability of known
formulating
reagents , in particular cyclodextrins ( cds ) , to decrease aggregation and/or precipitation among the less soluble
hairpin polyamides 710 ( figure 4 ) .
2-hydroxypropyl--cyclodextrin ( hpcd )
was chosen initially due to its high water solubility and low animal
toxicity . using procedures identical
to the solubility analyses , peak areas of py - im polyamides in the
presence of 0 , 5 , or 50
was observed for all compounds
studied , with compounds 7 and 8 near the
maximum expected concentration in solutions of 50 mm hpcd ( figure 4a ) .
impressively , 50 mm hpcd increased the
concentration of the least soluble derivative ( benzamide - substituted
polyamide 10 ) over 50-fold .
surprisingly , the soluble
concentration observed for polyamide 9 was significantly
higher than expected based on the quantitation of the corresponding
dmso stock solution .
this result likely derives from aggregation and/or
precipitation of compound 9 upon dilution of the polyamide
in water before the absorbance is measured , resulting in an underestimation
of the stock concentration .
we further probed the specificity of these
effects by studying the solubilization of polyamide 7 by other carbohydrate formulating reagents , namely -cd , -cd ,
hydroxypropyl methylcellulose ( hypromellose ) , and dextrose ( see supporting information , figure s2 ) .
the three
cyclodextrin derivatives were studied at 5 mm concentrations , while
hypromellose , a linear substituted glucose polymer , and dextrose ,
the glucose monomer , were normalized for total sugar content against
5 mm hpcd .
in addition to hpcd , polyamide 7 was solubilized by -cd and hypromellose ( figure 4b ) .
polyamide 12 , which would seem less likely
to form an inclusion complex with cyclodextrin due to its cyclic form ,
was screened against the same formulating agents .
notably ,
neither polyamide displayed an increased solubility in the monomer
( dextrose ) solution .
( a ) calculated soluble concentration of polyamides 710 in 0.1% dmso / pbs containing 0 , 5 ,
or 50 mm
hpcd at 25 c .
( b ) calculated soluble concentration of
polyamides 7 and 12 in 0.1% dmso / pbs containing :
5 mm - , hp- , -cyclodextrin ( , ,
, respectively ) , 6 mg / ml hypromellose ( hm ) , 35 mm dextrose
( dx ) . maximum concentration estimated at 4 m ( dotted line )
based on quantitation of starting material in 0.1% dmso / water .
resultant
concentrations determined by hplc peak area ( = 310 nm ) after
comparison with a standard curve ( see supporting
information ) .
the utility of these results was further probed
in an animal model
system .
our laboratory recently found that high blood levels of polyamide 7 can be achieved in mice following an intraperitoneal ( ip )
injection of 120 nmol compound in a vehicle of 20% dmso / pbs ( 600 m
concentration , figure 5a ) .
using hpcd , the dmso content could be reduced to
1% with no loss in solubility .
ip injections of 120 nmol polyamide 7 in a 1% dmso/80 mm hpcd / pbs vehicle and the subsequent
blood collection were performed under identical conditions to those
previously reported .
after blood collection , the plasma was isolated
through centrifugation and the bulk proteins removed through methanol
precipitation .
the supernatant was then mixed with dilute aqueous
trifluoroacetic acid ( tfa ) , and a reference compound in acetonitrile
was added .
the injection vehicle containing hpcd yielded circulating
polyamide concentrations comparable to those previously reported ( figure 5b ) . in both cases ,
polyamide concentrations of 1314
m were detected in mouse plasma 1.5 h after injection , with
no polyamide detected after 24 h. furthermore , fitc - labeled compound 11 , which formed a precipitate in 20% dmso / pbs solutions ,
was fully solubilized upon addition of hpcd ( 80 mm ) , allowing
the compound to be injected into mice . slightly reduced plasma concentrations
of compound 11 were observed as compared to compound 7 , which may indicate reduced bioavailability of the fitc - modified
polyamide ( figure 6a ) .
hplc traces of mouse
plasma isolated from four mice at three time
points after injection with 120 nmol polyamide 7 in two
different vehicles : 20% pbs / dmso ( a ) and 1% dmso/80 mm hpcd / pbs
( b ) .
( a ) hplc traces of mouse plasma isolated from four mice
at three
time points after injection with 120 nmol polyamide 11 in 20% dmso/80 mm hpcd / pbs .
( b ) confocal image of a549 cells
after 16 h incubation with mouse plasma isolated 1.5 h after injection
with polyamide 11 .
we then sought to investigate the availability
of the circulating
polyamide to human cells by taking advantage of the nuclear staining
generally observed with fitc polyamide conjugates .
plasma samples
isolated from mice injected with compound 11 were added
to a549 ( human lung cancer ) cells 16 h prior to imaging live cells
with confocal microscopy . in cells treated with plasma collected at
1.5 h postinjection , strong nuclear fluorescent signals were observed
( figure 6b ) .
greatly reduced levels were observed
with plasma isolated 4.5 h postinjection , and no significant signal
was observed with the addition of the 24 h plasma sample ( see supporting information , figure s3 ) .
dynamic light scattering
measurements revealed that both hairpin
and cyclic polyamides form measurable particles between 50 and 500
nm in size at biologically relevant concentrations ( table 1 ) .
interestingly , particles of similar size were
observed for all polyamides containing an isophthalic acid ( ipa ) at
the c - terminus despite the differing activities of these compounds
in cell culture .
these results support a mechanism of polyamide activity
in which aggregation may not be a key factor .
another interesting
observation is that neither aggregation nor
solubility is affected by the overall ionic charge of the polyamide .
while organic compounds with ionizable groups are generally expected
to be more soluble in aqueous salt solutions , neither light scattering
nor solubility analyses revealed such a dependence .
indeed , hairpins
and cycles in which the gaba amino turn units were modified with acetyl
groups were found to be the most soluble . at first glance ,
the
lack of solubility observed for some polyamides
is surprising as similar concentrations are commonly used in cell
culture experiments , often without evidence of aggregation or precipitation .
however , the experimental conditions required for the solubility experiments
are a limited comparison to those in cell culture . for example , cell
media generally contain a variety of small molecule and protein nutrients ,
and cell cultures are kept at higher temperatures ( 37 c vs 25
c ) . in addition , the soluble fraction isolated by centrifugation
is not necessarily representative of the available polyamide concentration
during a typical cell incubation period ( 4872 h ) , particularly
if aggregation is a dynamic process .
we note that similar solubility
issues have been reported by sugiyama and co - workers , who enhanced
the biological activity of seco - cbi polyamide conjugates
through pegylation or liposomal formulations .
we were able to mitigate the problem of
polyamide solubility through
the addition of carbohydrate formulating reagents , in particular hpcd .
as cyclodextrins are generally thought to form discrete inclusion
complexes with small organic molecules , we postulated
that the linear conformation of hairpin polyamides may be well - solubilized
by such additives .
indeed , the solubilization of polyamide 7 by the larger cyclodextrins ( and ) is consistent
with the formation of possible cyclodextrin inclusion complexes , which in this case may result from interactions
with the isophthalic acid unit at the c - terminus or the n - methylimidazole group at the n - terminus
. such interactions would
not be expected , however , between cyclodextrins and cyclic polyamide 12 .
interestingly , solubilization of compound 12 was observed with hpcd but not the other cyclodextrin derivatives .
the lack of solubilization with cd would be consistent with
a model in which the interactions between hpcd and cycle 12 rely more on the hydroxypropyl substituents unique to hpcd ,
perhaps through additional hydrogen bonding interactions , rather than
encapsulation .
while both the linear 7 and cyclic 12 polyamide compounds were solubilized by hypromellose , presumably
through encapsulation within the polymer matrix , it is notable that
no significant solubilization was observed with the dextrose monomer .
this latter observation may indicate the importance of an ordered
carbohydrate structure , such as that available with cyclodextrins
and hypromellose , for efficient polyamide solubilization .
further
studies are necessary , however , before conclusions can be drawn regarding
the interactions between py - im polyamides and carbohydrate derivatives ,
and such investigations fall outside the scope of this work .
further evidence of the utility of hpcd as a formulating
reagent was gathered in mouse experiments .
first , we demonstrated
that the hpcd vehicle did not significantly affect circulating
levels of polyamide 7 . on the other hand , the fluorescently
labeled derivative 11 was only sufficiently soluble in
hpcd solutions . as a result ,
this tagged compound was
of particular interest due to the high plasma protein binding levels
( > 99% ) that had been previously reported for py - im polyamides during
admet studies .
evidence of nuclear uptake
was observed in a549 cells following incubation with plasma from hairpin 11-treated mice , thus demonstrating the availability of circulating
polyamides to human cancer cells . in summary , these studies
have provided evidence that the aggregation
propensity of py - im polyamides likely does not contribute
to biological activity and may not be a critical concern in pharmacokinetic
analyses .
solubility experiments revealed important trends , such as
the increased solubility achieved by acetylation of the gaba amino
turn unit , which will impact the design of next generation polyamides .
furthermore , the identification of an effective delivery vehicle will
allow for the in vivo study of otherwise inaccessible py - im polyamides .
these studies represent a contribution to the field of small molecule
transcriptional inhibitors and their ultimate utility as tools for
perturbing gene expression networks in vivo .
the synthesis
of py - im polyamides has been extensively described in previous work and is summarized as follows : reagents were
purchased from sigma - aldrich or novabiochem .
py - im cores were synthesized
on kaiser oxime resin using boc - based chemistry , cleaved using 3,3-diamino - n - methyldipropylamine , and purified by reverse phase preparative
hplc .
the c - terminal amine was then derivatized with either isophthalic
acid ( ipa ) or fluorescein isothiocyanate ( fitc ) and the crude intermediate
isolated through ether precipitation .
the gaba turn protecting groups
( -nhboc or -nhcbz ) were removed under acidic conditions .
if applicable , the crude intermediate was again isolated through ether
precipitation and further derivatized at the gaba turn amine with
either acetic anhydride or pybop - activated benzoic acid .
final products
were purified through reverse phase hplc and the identity confirmed
through matrix - assisted laser desorption ionization time - of - flight
( maldi - tof ) mass spectrometry . the synthesis and characterization
of compounds 1;26;7 , 11;15 , 2532 were
in line with literature reports .
results from maldi - tof characterization
for compounds 810 , 1214 , and 1624 are available in the supporting information
( table s2 ) . the synthesis and characterization of polyamides 12 and 13 have been previously described . in brief , the heterocyclic cores of these polyamides
were synthesized on kaiser oxime resin as above , except that a terminal
gaba turn unit ( boc - gaba oh or ( r)-4-(boc - amino)-3-(z - amino)butyric acid ) was added .
following deprotection
of the terminal boc unit , the core was cleaved from the resin with
dbu / h2o and the resulting acid purified by reverse phase
hplc .
the crude intermediate was isolated through
ether precipitation and the cbz group(s ) removed as above .
polyamide 14 was synthesized
by reaction of 13 with acetic anhydride under basic conditions
and then purified be reverse phase hplc .
results from maldi - tof characterization
for compound 14 are available in the supporting information ( table s2 ) .
polyamide concentrations were
measured by uv - absorption analysis on an agilent 8453 diode array
spectrophotometer in distilled and deionized water containing up to
0.1% dmso using a molar extinction coefficient ( ) of 69500
m cm at 310 nm .
dmso and pbs were passed through
a 0.02 m syringe filter ( whatman ) immediately prior to use .
stock solutions of each polyamide in dmso were quantified as above
and the purity determined by hplc to be greater than 95% .
solutions
of 1 , 4 , and 10 mm in dmso were prepared and then centrifuged for
15 min at 16 g to remove particulates .
immediately
before measurement , 0.5 l of the dmso stock was added to 500
l of pbs in a microcentrifuge tube .
the solution was mixed
briefly with a pipet tip and transferred to a disposable plastic cuvette
( fisher ) .
measurements were performed on a wyatt dynapro nanostar
instrument using a 659 nm/100 mw laser at 100% power and a 90
detection angle at 25 c .
acquisition times of 1015 s
were collected over 10 min and analyzed using the cumulant fit tool
in the dynamics ( 6.11.1.3 ) software with pbs as the referenced solvent .
acquisitions in which the baseline value of the fit was greater than
0.1 were omitted and the remaining traces averaged .
measurements
in which the intensity ( cts / s ) was less than 3 the buffer signal
intensity were considered below the detection limit .
stock solutions of each polyamide
in dmso were quantified as above and the purity checked by hplc .
polyamide ( 0.5 l ) was
added to 500 l of pbs in a microcentrifuge tube , and the solution
was immediately vortexed and placed in a sonicating water bath at
25 c for 20 min .
the tubes were then removed from the bath and
allowed to equilibrate for 2 h at room temperature .
samples were centrifuged
for 20 min at 16 g and 100 l of the supernatant
removed for hplc analysis .
analytical hplc analysis was conducted
on a beckman gold instrument equipped with a phenomenex gemini analytical
column ( 250 mm 4.6 mm , 5 m ) and a diode array detector
( mobile phase : 1080% ch3cn in 0.1% cf3co2h ( aqueous ) over 17.5 min .
sample concentrations
were determined through comparison to a standard curve of concentration
vs peak area that was generated using compound 7 ( supporting information , figure s1 ) .
solubilization
by formulating agents proceeded similarly except that the dmso stock
solutions were added to pbs containing 5 or 50 mm hpcd , 5 mm
cd , 5 mm cd , 35 mm dextrose , or 6.00 mg / ml hypromellose
( approximately 35 mm relative glucose units based on reported substitution
for aldrich lot no .
murine experiments were performed
as described previously . in brief , c57bl/6
mice ( 812 weeks of age , jackson laboratory ) were injected
intraperitoneally with 200 l of a pbs solution containing :
( a ) 120 nmol compound 7 , 20% dmso , ( b ) 120 nmol compound 7 , 1% dmso , 80 mm hpcd , or ( c ) 120 nmol compound 11 , 20% dmso , 80 mm hpcd .
blood was collected from
anesthetized animals ( 25% isoflurane ) by retro - orbital withdrawal .
immediately after the third blood draw
, animals were euthanized by
asphyxiation in a co2 chamber ( 2 atm ) .
the samples from
the four replicate mice were combined at 5 l / sample , yielding
20 l combined plasma that was then treated with 40 l
of ch3oh , vortexed , and centrifuged .
then 50 l of
the supernatant were combined with 1 equiv of the hplc loading solution
( 4:1 water / ch3cn , 0.08% cf3co2h )
containing boc - py - ome ( methyl 4-((tert - butoxycarbonyl)amino)-1-methyl - pyrrole-2-carboxylate )
as an internal spike - in control .
analytical hplc analyses were conducted
with a phenomenex kinetex c18 analytical column ( 100 mm 4.6
mm , 2.6 m , 100 ) and a diode array detector ( mobile phase :
560% ch3cn in 0.1% ( v / v ) aqueous cf3co2h over 12.5 min .
peaks were detected and integrated at 310 nm absorbance ,
and sample concentrations were determined through comparison to the
previously published standard curve for this column . for confocal microscopy experiments ,
a549 cells in f-12k medium supplemented with 10% fbs ( 1 ml , 100k cells / ml )
were applied to culture dishes equipped with glass bottoms for direct
imaging ( mattek ) .
cells were allowed to adhere for 18 h in a 5% co2 atmosphere at 37 c .
the medium was then removed and
replaced with 200 l of fresh medium supplemented with 20 l
of plasma collected 1.5 , 4.5 , or 24 h after injection of compound 11 .
after an additional 16 h incubation period , 100 l
of untreated medium was added to each slide prior to imaging .
imaging
was performed at the caltech beckman imaging center using a zeiss
lsm 5 pascal inverted laser scanning microscope equipped with a 63
oil - immersion objective lens .
fluorescence and visible - light images
were obtained using standard filter sets for fluorescein and analyzed
using zeiss lsm software .[/INST]to optimize the biological activity of pyrrole
imidazole
polyamide dna - binding molecules , we characterized the aggregation
propensity of these compounds through dynamic light scattering and
fractional solubility analysis .
nearly all studied polyamides were
found to form measurable particles 50500 nm in size under
biologically relevant conditions , while hplc - based analyses revealed
solubility trends in both core sequences and peripheral substituents
that did not correlate with overall ionic charge .
the solubility of
both hairpin and cyclic polyamides was increased upon addition of
carbohydrate solubilizing agents , in particular , 2-hydroxypropyl--cyclodextrin
( hpcd ) . in mice ,
the use of hpcd allowed for improved
injection conditions and subsequent investigations of the availability
of polyamides in mouse plasma to human cells .
the results of these
studies will influence the further design of py - im polyamides and
facilitate their study in animal models .</s> |
The most "Portlandia" thing happened during the Bernie Sanders rally at the Moda Center on Friday.
The Vermont senator put a bird on it -- the podium, that is. Or was it that the bird put itself there? Either way, in his bid for the Democratic presidential nomination, Sanders didn't miss a beat.
"I think there may be some symbolism here," he said. "I know it doesn't look like it, but that bird is really a dove asking us for world peace. No more wars."
And the crowd went wild.
Bernie Sanders holds rally at the Moda Center in Portland 59 Gallery: Bernie Sanders holds rally at the Moda Center in Portland
--Eder Campuzano
503.221.4344
@edercampuzano
[email protected] ||||| Published on Mar 25, 2016
A bird flew on the podium at the Bernie Sanders rally in Portland hosted at the Moda Center.
Subscribe! https://www.youtube.com/subscription_...
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Find us on Snapchat: the.oregonian (or click here for mobile users: https://www.snapchat.com/add/the.oreg...) | – You know what they say: When in Portland, do as the Portlanders do. The Oregonian reports Bernie Sanders put a bird on it during a rally at the Moda Center in Portland on Friday. According to CNN, Sanders noticed a small green bird land near where he was speaking and started to address it, saying, "Now you see, this little bird doesn't know it…" But before he could finish, the bird fluttered up to the podium for a closer look, bringing a smile to the candidate's face and the crowd to its feet. The bird quickly flew away, but Sanders wasn't done with it yet. "I think there may be some symbolism here," he said. "I know it doesn't look like it, but that bird is really a dove asking us for world peace. No more wars." See the Bernie bird video here. | <s>[INST]The most "Portlandia" thing happened during the Bernie Sanders rally at the Moda Center on Friday.
The Vermont senator put a bird on it -- the podium, that is. Or was it that the bird put itself there? Either way, in his bid for the Democratic presidential nomination, Sanders didn't miss a beat.
"I think there may be some symbolism here," he said. "I know it doesn't look like it, but that bird is really a dove asking us for world peace. No more wars."
And the crowd went wild.
Bernie Sanders holds rally at the Moda Center in Portland 59 Gallery: Bernie Sanders holds rally at the Moda Center in Portland
--Eder Campuzano
503.221.4344
@edercampuzano
[email protected] ||||| Published on Mar 25, 2016
A bird flew on the podium at the Bernie Sanders rally in Portland hosted at the Moda Center.
Subscribe! https://www.youtube.com/subscription_...
See more on our website: http://www.oregonlive.com/#/0
Follow us on Twitter: https://twitter.com/Oregonian
Follow us on Instagram: https://www.instagram.com/theoregonian/
Like us on Facebook: https://www.facebook.com/theoregonian/
Find us on Snapchat: the.oregonian (or click here for mobile users: https://www.snapchat.com/add/the.oreg...)[/INST]– You know what they say: When in Portland, do as the Portlanders do. The Oregonian reports Bernie Sanders put a bird on it during a rally at the Moda Center in Portland on Friday. According to CNN, Sanders noticed a small green bird land near where he was speaking and started to address it, saying, "Now you see, this little bird doesn't know it…" But before he could finish, the bird fluttered up to the podium for a closer look, bringing a smile to the candidate's face and the crowd to its feet. The bird quickly flew away, but Sanders wasn't done with it yet. "I think there may be some symbolism here," he said. "I know it doesn't look like it, but that bird is really a dove asking us for world peace. No more wars." See the Bernie bird video here.</s> |
branchial fistulas and cysts , involving soft tissues of neck , are uncommon anomalies of embryonic development that are commonly encountered by otolaryngologists .
in fact , approximately 17% of all pediatric cervical masses are due to branchial anomalies . although branchial cleft cysts are benign , superinfection , mass effect , and surgical complications account for its morbidity .
branchial apparatus , seen in the early embryonic life , has a vital role to play in the development of head and neck structures .
branchia is the greek word for gill , and the same word represents these anomalies owing to their resemblance to gills of certain species as fish .
six paired branchial arches , which appear in the fourth week of embryonic life , give rise to many structures of the head and neck .
each branchial arch consists of core of mesenchyme covered externally by ectoderm and internally by endoderm .
many anomalies of the head and neck region have been attributed to the aberrant development of these structures .
depending on the anatomic location , branchial anomalies are classified into first , second , third , and fourth anomalies .
the course of a particular branchial anomaly is caudal to the structures derived from the corresponding arch and dorsal to the structures that develop from the following arch .
cysts are considered to be entrapped remnants of branchial cleft or sinuses ; sinuses are remnants of cleft or pouches ; and fistulae result from persistence of both pouch and cleft .
different anomalies of the head and neck area have been attributed to the maldevelopment of branchial apparatus .
the importance of knowing the development of branchial apparatus and their anomalies is in applying the knowledge during surgery , as vital structures like facial nerve and parotid are in intimate relation with many of these anomalies .
we performed a ten - year retrospective study to analyze the pathophysiology , clinical features , and management of branchial anomalies .
ours is a retrospective study of 30 cases of branchial anomalies , which presented to the department of otolaryngology , head and neck surgery , kasturba medical college , over a period of 10 years from 2000 to 2010 .
family history and previous history of infection and/or surgery were noted . the side and site of the lesion and the site of opening of sinuses and fistula were noted .
patients with sinus and fistulas underwent sino-/fistulogram , by injecting contrast material urografin into the tract ( figure 1 ) .
all patients were operated upon . in cases of acute infection , patients were put on intravenous antibiotics and in cases of abscess incision and drainage were done .
such patients were taken up for surgical excision of tract four weeks later . during surgery , a conscious attempt was made to remove some fascia and tissues adjacent to the branchial tracts along their path to avoid leaving behind ramifications that might lead to recurrences .
this fistulous communication between the external auditory canal and the neck in the upper part of anterior border of sternocleidomastoid ( scm ) muscle was identified by injecting methylene blue dye into the neck opening which was seen coming of an opening in the external auditory canal .
the tract was then dissected from the surrounding tissue and followed till its opening in the external auditory canal ( figure 2 ) .
the tract was excised off its attachment to the external auditory canal and wound closed in layers .
scm muscle was retracted away from the field taking care not to injure the greater auricular nerve .
elliptical skin incision was made over the skin opening and the dissection proceeded in the direction of the tract .
this second incision was given at the level of the hyoid and the whole tract was brought out through this incision .
it was then followed to its opening into the pharynx . during their course towards the oropharynx , the second branchial fistulae ,
were seen passing between the carotid bifurcations , where they were in close relation to the hypoglossal nerve .
the third branchial fistulae were seen piercing the thyrohyoid membrane to open into the pyriform fossa ( figure 3 ) .
the tracts were followed to the pharynx and were excised ; the pharyngeal defects were sutured .
the suture lines were reinforced by a second layer of suture in the pharyngeal musculature .
the fourth branchial fistulae were seen opening into the lower part of neck near the scm muscle .
the tract then passed inferiorly into the mediastinum , looping around the arch of aorta in the left and subclavian artery in the right and back in to the neck , ascending posterior to the carotid .
the tract was followed from its neck opening into the mediastinum using blunt finger dissection .
the intramediastinal part of the fistulae was left behind with their ends ligated and the rest of the tract was dissected out from the superior mediastinum up to the pyriform fossa ( figure 4 ) .
thirty patients with 34 branchial anomalies were studied retrospectively over a period of 10 years from 2000 to 2010 in the department of otolaryngology , head and neck surgery , kasturba medical college , mangalore .
there was maximum incidence of second branchial anomalies with 17(50% ) cases . among the first branchial anomalies , seven ( 20.59% ) cases belonged to work ii , while six ( 17.65% ) cases belonged to work i ( according to the work classification ) .
of these , branchial cyst constituted eight ( 26.53% ) cases while branchial fistula constituted nine ( 26.47% ) cases .
fourth branchial arch anomaly was seen in two ( 5.88% ) patients ( figure 5 ) . among the anatomical types of the lesion
, we had a maximum incidence of fistula seen in 20 ( 58.82% ) cases , followed by cyst in 14 ( 41.12% ) cases .
the youngest patient in our study was one and a half years and the oldest one 48 years .
the mean age of presentation was 18.67 years with a standard deviation of 11.06 . only 1 ( 3.3% )
the mean age of onset among this late onset group was 15.97 years . among the first branchial anomalies ,
the maximum incidence of the lesion was seen in the 1120 age group with 5 ( 14.70% ) cases followed by 4 ( 11.76% ) cases in the 610 and 2140 age groups . in the second arch anomalies
, we had four ( 11.76% ) cases in the 610 age group and seven ( 20.59% ) cases in the 1120 and five ( 14.70% ) in 2040 age groups .
considering all the anomalies together , 55.88% were males and 44.12% were females with a male to female ratio of 1.27 : 1 .
in the first branchial anomalies , the incidence in males was 17.65% and 20.59% in females . among the second arch anomalies
the overall incidence of the anomalies was more on the right side ( 57.08% ) while 42.92% of the lesions occurred on the left side . in the first arch anomalies , 8 ( 23.53% ) cases were present on the right and 5 ( 14.71% ) cases on the left . in the second arch anomalies 11 ( 32.35% ) cases occurred on the right side and six ( 17.65% ) cases on the left including one patient with bilateral branchial cysts ( figure 6 ) .
the third anomalies occurred on the right side and the fourth anomalies on the left side . in all anomalies put together ,
the most common clinical feature was a swelling seen in 21 ( 61.76 ) and fistula opening in 18 ( 52.94% ) cases .
26.47% of the patients had pain at the site of the lesion . among the first arch anomaly patients , swelling in the neck and postauricular region was the most common presenting feature ( 29.41% ) .
the most common presenting feature of second branchial arch anomaly was neck swelling , seen in 26.47% , while 23.53% presented with opening in the neck .
the third arch anomaly patient had swelling and opening in the neck along with discharge .
the fourth arch anomaly patient had swelling and opening in the neck along with discharge and pain .
ct scan and ultrasound were done in all cases of third and fourth arch anomalies and nine cases of second arch anomaly .
acute infection was treated by a course of antibiotics in 18 ( 60% ) cases and incision and drainage in one case ( before proceeding to the excision of the lesion ) .
73.33% of the cases were managed by single incision , while 23.33% required stepladder incision .
though described first in the early nineteenth century , the origin and classification of different branchial anomalies are highly controversial even today .
second branchial anomalies are considered to be the commonest with figures up to 95% being reported .
the remainder of branchial anomalies is derived from first branchial remnants ( 18% ) with third and fourth branchial anomalies being quite rare .
several theories proposed for the development of branchial anomalies include branchial apparatus theory , cervical sinus theory , thymopharyngeal theory , and inclusion theory .
of these , the widely accepted theory is that branchial anomalies result from incomplete involution of the branchial apparatus . according to ford et al .
, most of the branchial anomalies arise from the second branchial cleft ( 92.45% ) .
remaining is derived from first arch remnants ( 4.72% ) and third ( 1.87% ) and fourth arch anomalies ( 0.94% ) are quite rare .
bajaj et al . also reported higher incidence of second branchial anomalies ( 78% ) in their series of 80 patients .
choi and zalzal who reported a higher incidence of first branchial arch anomalies ( 25% ) in their series still had the maximum incidence of second branchial arch anomalies ( 40% ) . in our series ,
we had the maximum incidence of second arch anomalies ( 50% ) followed by first arch anomalies ( 38.24% ) .
choi and zalzal reported a maximum incidence of sinuses , followed by fistula . in our series cysts were the most common lesion followed by sinuses .
the age of onset of these anomalies has been seen to vary according to the type of the lesion .
choi and zalzal have noted that mean age of presentation of cyst ( 18.35 years ) was late compared to that of fistulae ( 6.28 years ) and sinuses ( 7.82 years ) .
this finding was confirmed in our study . in our group , it was found that fistulas ( 1.14 years ) had an early age of onset followed by that of sinuses ( 4.21 years ) .
cysts ( 7.51 years ) were found to have a late onset compared to the other two lesions .
ford et al . have pointed out that the branchial anomalies occur more on the right side .
they had 60% incidence on the right side and 40% on the left side . in the present study
, we have a similar picture with right side incidence of 55.38% and left side incidence of 44.62% . in the study by choi and zalzal , the most common presenting features were discharge from the openings , cervical mass , and repeated infection . in our study , the most common clinical feature was a swelling seen in 21 ( 61.76 ) .
an initial correct diagnosis is crucial because experience shows that recurrence rates after surgical excision of branchial anomalies are 14% and 22% with previous infection and surgery , respectively , whereas the recurrence rate for primary lesion is 3% .
although physical examination and history are the most important elements in the diagnosis , radio - diagnostic studies can add valuable information to the evaluation of a congenital neck mass .
a ct scan is an accurate and noninvasive diagnostic tool , which can confirm the diagnosis or suggest an alternative diagnosis , define both the location and extent of a neck lesion , and delineate infectious process or possible malignant degeneration .
ct scan is useful in evaluating first branchial anomaly and the position of facial nerve .
ct scan is reported to be more useful than mri in evaluating branchial anomalies . in case of sinus or fistula , sinogram or conray contrast study
can delineate the course of branchial anomaly . in the series by choi and zalzal ,
ct scan was performed on 15.38% of patients , sonogram / contrast study was performed on 7.69% of patients , and ultrasound / mri was done on 1.92% of patients . in our series
, intraoperative methylene blue injection was performed in all cases ; ct scan was done in 10.77% of cases .
surgery is definitive mode of treatment because there is lack of spontaneous regression , a high rate of recurrent infection , the possibility of other diagnoses , and rare malignant degeneration .
acute inflammation is treated medically unless incision and drainage or aspiration of an abscess is required .
three to four weeks should pass after an acute infection before a definitive surgical exploration is undertaken . in our series 60%
of patients took medical treatment and 3.33% underwent drainage of abscess before definitive surgical excision of the lesion .
surgical excision of lesion was done in all patients . in the series by ford et al .
it is our observation that while methylene blue dye enhances visualization of the larger and more proximal ( in relation to the punctum ) part of the tracts and ramifications , it does not demarcate the most peripheral ramifications and hence a conscious attempt must be made to follow the tracts till the end . using magnification loops or
the microscope at the time of dissection may enhance prospects of complete removal . while it may be impossible to guarantee a complete removal ,
we believe that this along with the practice of excision of the tract along with surrounding tissue has led to a low recurrence rate seen in our series . in our series ,
this relatively high incidence can be attributed to the fact that a high percentage of the patients in this series were from a low socioeconomic stratum .
though facial nerve paralysis / weakness has been reported in patients undergoing superficial parotidectomy for first branchial cleft anomalies , none of our patients had involvement of facial nerve .
first branchial cleft anomalies are thought to develop as a result of incomplete obliteration of the cleft between the mandibular process of the first arch and the second arch .
a sinus will have an opening in the upper neck or in the floor of the external auditory canal , and a fistula will have an opening in both of these sites .
the first branchial cleft anomalies have been classified as type i or type ii by work .
a cystic mass in the postauricular area extends medially and anteriorly along the external auditory canal .
type ii is considered to be a duplication of the cartilaginous external auditory canal and pinna . a sinus passes from an external opening high in the neck along the anterior border of scm muscle , superficial or deep to the facial nerve in close relation to the parotid gland .
it can either end blindly at the floor of the cartilaginous external auditory canal or open in to the external auditory canal , which is called the collaural fistula . in both types entrapment of desquamating squamous epithelium
will result in the production of a cholesteatoma process resulting in erosion of bony external meatus , tympanic annulus , and hypotympanum .
in the series by belenky and medina 66.66% of patients belonged to work i and 33.33% to work ii . in the study by nofsinger et al .
in our study , work i constituted 17.65% and work ii constituted 20.59% . in the study by triglia et al .
on the first branchial cleft anomalies , 30.77% were male and 69.23% female . in the study by belenky and medina
the incidence in male was 22.22% and in female was 77.77% . in our study , 17.65% were male and 20.59% were female .
the symptoms and signs related to these anomalies in this series are similar to those described by various authors . in general , both types of anomalies may present as a progressively enlarging or recurrent mass or as a draining sinus .
incision and drainage of an abscess are frequently needed before definitive surgical treatment can be performed .
histopathology of the work i lesions in our study showed that 100% of cases lined by squamous epithelium and 20% had cartilage components in the subepithelial layer . in the study by belenky and medina 16.7% of work i had cartilage component in the subepithelium .
intraoperatively the lesion was found superficial to the facial nerve in 100% of our cases .
belenky and medina reported that the lesion was superficial to facial nerve in 88.88% of cases . in the study by triglia et al .
lesion was deep to facial nerve in 39% cases . in the series by nofsinger et al . , the lesion was deep to the facial nerve in 55% of cases .
[ 4 , 11 ] that it is advisable to perform a superficial parotidectomy in cases of first cleft anomalies while identifying the tract in relation to the facial nerve . during embryonic development
, the second arch grows caudally , enveloping the third , fourth , and sixth arches and fusing with skin caudal to these arches , forming a deep groove ( cervical sinus ) .
a persistent fistula of the second branchial cleft and pouch usually has its external opening in the neck near mid or lower part of scm muscle .
as it ascends it pierces platysma . at the level of hyoid it curves medially and
passes between the external and internal carotids in relation to the hypoglossal and glossopharyngeal nerves .
it opens in to the oropharynx usually in the intratonsillar cleft of palatine tonsil . in series of 98 cases by ford
78% presented by the age of five years and in vast majority there was history of intermittent discharge and infection of neck sinus since birth . in seven percent
there was history of incision and drainage of an associated neck abscess . in his series 60% sinus opening was on the right side and 40% on left . in our series of 17 cases 70% presented at age above 11 years .
. there may be only a simple sinus opening that extends up the neck for a variable distance .
branchial fistulas commonly present with persistent mucoid discharge from an opening in the skin of the neck . but
they have been documented as to present as parapharyngeal mass located in the supratonsillar fossa and extending to the lateral nasopharynx .
exceedingly rarely , a branchial cleft anomaly may be found to be malignant on presentation .
the completeness of a fistula is diagnosed by a dye test in which methylene blue is injected through the outer opening and appears in the throat .
a negative preoperative outcome on the test might become positive under general anaesthesia because of muscle relaxation .
occasionally , the fistula tract may be blocked by secretion or granulation giving negative fistula test .
in many a case , saliva is seen dribbling from the neck opening , which itself proves the completeness of the tract ( figure 7 ) . in the 62 pediatric second branchial cleft anomalies , bajaj et al . reported 50 of them to be unilateral and 12 to be bilateral .
the fistulous tract can be approached through a series of stepladder incision first encompassing the sinus opening and second overlying the carotid bifurcation .
subsequently the parapharyngeal portion of the fistula can be approached perorally after tonsillectomy . a wide cervicotomy incision ( hockey stick )
can also be used which allows for adequate exposure of neck structure for accurate dissection . in all our cases , we traced the fistula up to the tonsillar area and excised the tract .
third branchial anomalies are rare and constitute less than 1% of all such cases . here
the fistula opening is seen in the lower neck and it passes along the carotid sheath and then passes between the glossopharyngeal and hypoglossal nerve , piercing the thyrohyoid membrane to enter pharynx in the region of pyriform fossa .
third pouch remnants are described as passing superior to superior laryngeal nerve and posterior to the common carotid artery .
a persistent fistula of the fourth branchial cleft and pouch is theoretically possible but is very rare .
here the fistula opens in to the lower part of neck near the scm muscle .
the tract then passes inferiorly between superior and recurrent laryngeal nerve into the mediastinum , looping around the arch of aorta in the left and subclavian artery in the right and passes back in to the neck , ascending posterior to the carotid .
then it passes between the thyroid and cricoid cartilages and opens in to the pyriform fossa .
, almost all the fourth arch anomalies reported occurred in the left side . in our series also , the fourth arch fistula occurred in the left side .
, these anomalies can be dangerous because of rapid enlargement leading to tracheal compression and respiratory distress .
noncommunicating or noninfected communicating cysts may present as cold thyroid nodules . when infected , diagnosis and successful excision of a pyriform fossa sinus are very challenging and require meticulous approach .
a history of recurrent upper respiratory tract infection , neck or thyroid pain and tenderness , and neck mass is common .
other presentations include cellulites , hoarseness , odynophagia , thyroiditis , abscess , and stridor .
a combination of ultrasound and ct with or without oral contrast will assist in the diagnosis .
all these patients came to us with after recurrences following surgeries done elsewhere . in cases of fourth cleft anomalies ,
the third branchial anomalies showed a fistulous opening in the lower neck , which , on dissection , passed between the glossopharyngeal and hypoglossal nerve as classically described , piercing the thyrohyoid membrane to enter pharynx in the region of pyriform fossa . in the cases of fourth branchial anomalies ,
the intramediastinal part of the fistula was left behind with their ends ligated and the rest of the tract was dissected out from the superior mediastinum up to the pyriform fossa .
our series confirms a higher incidence of first branchial cleft anomaly among females , the cause of which needs to be investigated.none of our patients had involvement of facial nerve .
all patients had tracts going superficial to the facial nerve.all the fourth arch anomalies in our series occurred on the left side which is consistent with the literature.while it may be impossible to guarantee a complete removal , injection of dye and microscopic removal may be vital in preventing recurrences .
we believe that this along with the practice of excision of the tract along with surrounding tissue has led to a low recurrence rate seen in our series .
our series confirms a higher incidence of first branchial cleft anomaly among females , the cause of which needs to be investigated .
all the fourth arch anomalies in our series occurred on the left side which is consistent with the literature .
while it may be impossible to guarantee a complete removal , injection of dye and microscopic removal may be vital in preventing recurrences .
we believe that this along with the practice of excision of the tract along with surrounding tissue has led to a low recurrence rate seen in our series .
diagnosis is rather easy with a proper knowledge of the anatomy of the branchial anomalies . confirming the extent of the tract is mandatory before any surgery as these lesions pass in relation to some of the most vital structures of the neck .
surgery must always be the treatment option for these lesions due to the fact that these lesions do not regress spontaneously and they have a high incidence of recurrent infection .
surgery also gives a chance to diagnose by means of histopathology , the rare occurence of branchogenic carcinoma . | objective . to find out the incidence of involvement of individual arches , anatomical types of lesions , the age and sex incidence , the site and side of predilection , the common clinical features , the common investigations , treatment , and complications of the different anomalies . setting .
academic department of otolaryngology , head and neck surgery .
design .
a 10 year retrospective study . participants .
30 patients with clinically proven branchial anomalies including patients with bilateral disease totaling 34 lesions .
main outcome measures .
the demographical data , clinical features , type of branchial anomalies , and the management details were recorded and analyzed .
results and observations .
the mean age of presentation was 18.67 years .
male to female sex ratio was 1.27 : 1 with a male preponderance . of the 34 lesions ,
maximum incidence was of second arch anomalies ( 50% ) followed by first arch .
we had two cases each of third and fourth arch anomalies . only 1 ( 3.3% ) patients of the 30 presented with lesion at birth .
the most common pathological type of lesions was fistula ( 58.82% ) followed by cyst .
41.18% of the lesions occurred on the right side .
all the patients underwent surgical excision .
none of our patients had involvement of facial nerve in first branchial anomaly .
all patients had tracts going superficial to the facial nerve .
conclusion . confirming
the extent of the tract is mandatory before any surgery as these lesions pass in relation to some of the most vital structures of the neck .
surgery should always be the treatment option .
injection of dye , microscopic removal and inclusion of surrounding tissue while excising the tract leads to a decreased incidence of recurrence . | <s>[INST]branchial fistulas and cysts , involving soft tissues of neck , are uncommon anomalies of embryonic development that are commonly encountered by otolaryngologists .
in fact , approximately 17% of all pediatric cervical masses are due to branchial anomalies . although branchial cleft cysts are benign , superinfection , mass effect , and surgical complications account for its morbidity .
branchial apparatus , seen in the early embryonic life , has a vital role to play in the development of head and neck structures .
branchia is the greek word for gill , and the same word represents these anomalies owing to their resemblance to gills of certain species as fish .
six paired branchial arches , which appear in the fourth week of embryonic life , give rise to many structures of the head and neck .
each branchial arch consists of core of mesenchyme covered externally by ectoderm and internally by endoderm .
many anomalies of the head and neck region have been attributed to the aberrant development of these structures .
depending on the anatomic location , branchial anomalies are classified into first , second , third , and fourth anomalies .
the course of a particular branchial anomaly is caudal to the structures derived from the corresponding arch and dorsal to the structures that develop from the following arch .
cysts are considered to be entrapped remnants of branchial cleft or sinuses ; sinuses are remnants of cleft or pouches ; and fistulae result from persistence of both pouch and cleft .
different anomalies of the head and neck area have been attributed to the maldevelopment of branchial apparatus .
the importance of knowing the development of branchial apparatus and their anomalies is in applying the knowledge during surgery , as vital structures like facial nerve and parotid are in intimate relation with many of these anomalies .
we performed a ten - year retrospective study to analyze the pathophysiology , clinical features , and management of branchial anomalies .
ours is a retrospective study of 30 cases of branchial anomalies , which presented to the department of otolaryngology , head and neck surgery , kasturba medical college , over a period of 10 years from 2000 to 2010 .
family history and previous history of infection and/or surgery were noted . the side and site of the lesion and the site of opening of sinuses and fistula were noted .
patients with sinus and fistulas underwent sino-/fistulogram , by injecting contrast material urografin into the tract ( figure 1 ) .
all patients were operated upon . in cases of acute infection , patients were put on intravenous antibiotics and in cases of abscess incision and drainage were done .
such patients were taken up for surgical excision of tract four weeks later . during surgery , a conscious attempt was made to remove some fascia and tissues adjacent to the branchial tracts along their path to avoid leaving behind ramifications that might lead to recurrences .
this fistulous communication between the external auditory canal and the neck in the upper part of anterior border of sternocleidomastoid ( scm ) muscle was identified by injecting methylene blue dye into the neck opening which was seen coming of an opening in the external auditory canal .
the tract was then dissected from the surrounding tissue and followed till its opening in the external auditory canal ( figure 2 ) .
the tract was excised off its attachment to the external auditory canal and wound closed in layers .
scm muscle was retracted away from the field taking care not to injure the greater auricular nerve .
elliptical skin incision was made over the skin opening and the dissection proceeded in the direction of the tract .
this second incision was given at the level of the hyoid and the whole tract was brought out through this incision .
it was then followed to its opening into the pharynx . during their course towards the oropharynx , the second branchial fistulae ,
were seen passing between the carotid bifurcations , where they were in close relation to the hypoglossal nerve .
the third branchial fistulae were seen piercing the thyrohyoid membrane to open into the pyriform fossa ( figure 3 ) .
the tracts were followed to the pharynx and were excised ; the pharyngeal defects were sutured .
the suture lines were reinforced by a second layer of suture in the pharyngeal musculature .
the fourth branchial fistulae were seen opening into the lower part of neck near the scm muscle .
the tract then passed inferiorly into the mediastinum , looping around the arch of aorta in the left and subclavian artery in the right and back in to the neck , ascending posterior to the carotid .
the tract was followed from its neck opening into the mediastinum using blunt finger dissection .
the intramediastinal part of the fistulae was left behind with their ends ligated and the rest of the tract was dissected out from the superior mediastinum up to the pyriform fossa ( figure 4 ) .
thirty patients with 34 branchial anomalies were studied retrospectively over a period of 10 years from 2000 to 2010 in the department of otolaryngology , head and neck surgery , kasturba medical college , mangalore .
there was maximum incidence of second branchial anomalies with 17(50% ) cases . among the first branchial anomalies , seven ( 20.59% ) cases belonged to work ii , while six ( 17.65% ) cases belonged to work i ( according to the work classification ) .
of these , branchial cyst constituted eight ( 26.53% ) cases while branchial fistula constituted nine ( 26.47% ) cases .
fourth branchial arch anomaly was seen in two ( 5.88% ) patients ( figure 5 ) . among the anatomical types of the lesion
, we had a maximum incidence of fistula seen in 20 ( 58.82% ) cases , followed by cyst in 14 ( 41.12% ) cases .
the youngest patient in our study was one and a half years and the oldest one 48 years .
the mean age of presentation was 18.67 years with a standard deviation of 11.06 . only 1 ( 3.3% )
the mean age of onset among this late onset group was 15.97 years . among the first branchial anomalies ,
the maximum incidence of the lesion was seen in the 1120 age group with 5 ( 14.70% ) cases followed by 4 ( 11.76% ) cases in the 610 and 2140 age groups . in the second arch anomalies
, we had four ( 11.76% ) cases in the 610 age group and seven ( 20.59% ) cases in the 1120 and five ( 14.70% ) in 2040 age groups .
considering all the anomalies together , 55.88% were males and 44.12% were females with a male to female ratio of 1.27 : 1 .
in the first branchial anomalies , the incidence in males was 17.65% and 20.59% in females . among the second arch anomalies
the overall incidence of the anomalies was more on the right side ( 57.08% ) while 42.92% of the lesions occurred on the left side . in the first arch anomalies , 8 ( 23.53% ) cases were present on the right and 5 ( 14.71% ) cases on the left . in the second arch anomalies 11 ( 32.35% ) cases occurred on the right side and six ( 17.65% ) cases on the left including one patient with bilateral branchial cysts ( figure 6 ) .
the third anomalies occurred on the right side and the fourth anomalies on the left side . in all anomalies put together ,
the most common clinical feature was a swelling seen in 21 ( 61.76 ) and fistula opening in 18 ( 52.94% ) cases .
26.47% of the patients had pain at the site of the lesion . among the first arch anomaly patients , swelling in the neck and postauricular region was the most common presenting feature ( 29.41% ) .
the most common presenting feature of second branchial arch anomaly was neck swelling , seen in 26.47% , while 23.53% presented with opening in the neck .
the third arch anomaly patient had swelling and opening in the neck along with discharge .
the fourth arch anomaly patient had swelling and opening in the neck along with discharge and pain .
ct scan and ultrasound were done in all cases of third and fourth arch anomalies and nine cases of second arch anomaly .
acute infection was treated by a course of antibiotics in 18 ( 60% ) cases and incision and drainage in one case ( before proceeding to the excision of the lesion ) .
73.33% of the cases were managed by single incision , while 23.33% required stepladder incision .
though described first in the early nineteenth century , the origin and classification of different branchial anomalies are highly controversial even today .
second branchial anomalies are considered to be the commonest with figures up to 95% being reported .
the remainder of branchial anomalies is derived from first branchial remnants ( 18% ) with third and fourth branchial anomalies being quite rare .
several theories proposed for the development of branchial anomalies include branchial apparatus theory , cervical sinus theory , thymopharyngeal theory , and inclusion theory .
of these , the widely accepted theory is that branchial anomalies result from incomplete involution of the branchial apparatus . according to ford et al .
, most of the branchial anomalies arise from the second branchial cleft ( 92.45% ) .
remaining is derived from first arch remnants ( 4.72% ) and third ( 1.87% ) and fourth arch anomalies ( 0.94% ) are quite rare .
bajaj et al . also reported higher incidence of second branchial anomalies ( 78% ) in their series of 80 patients .
choi and zalzal who reported a higher incidence of first branchial arch anomalies ( 25% ) in their series still had the maximum incidence of second branchial arch anomalies ( 40% ) . in our series ,
we had the maximum incidence of second arch anomalies ( 50% ) followed by first arch anomalies ( 38.24% ) .
choi and zalzal reported a maximum incidence of sinuses , followed by fistula . in our series cysts were the most common lesion followed by sinuses .
the age of onset of these anomalies has been seen to vary according to the type of the lesion .
choi and zalzal have noted that mean age of presentation of cyst ( 18.35 years ) was late compared to that of fistulae ( 6.28 years ) and sinuses ( 7.82 years ) .
this finding was confirmed in our study . in our group , it was found that fistulas ( 1.14 years ) had an early age of onset followed by that of sinuses ( 4.21 years ) .
cysts ( 7.51 years ) were found to have a late onset compared to the other two lesions .
ford et al . have pointed out that the branchial anomalies occur more on the right side .
they had 60% incidence on the right side and 40% on the left side . in the present study
, we have a similar picture with right side incidence of 55.38% and left side incidence of 44.62% . in the study by choi and zalzal , the most common presenting features were discharge from the openings , cervical mass , and repeated infection . in our study , the most common clinical feature was a swelling seen in 21 ( 61.76 ) .
an initial correct diagnosis is crucial because experience shows that recurrence rates after surgical excision of branchial anomalies are 14% and 22% with previous infection and surgery , respectively , whereas the recurrence rate for primary lesion is 3% .
although physical examination and history are the most important elements in the diagnosis , radio - diagnostic studies can add valuable information to the evaluation of a congenital neck mass .
a ct scan is an accurate and noninvasive diagnostic tool , which can confirm the diagnosis or suggest an alternative diagnosis , define both the location and extent of a neck lesion , and delineate infectious process or possible malignant degeneration .
ct scan is useful in evaluating first branchial anomaly and the position of facial nerve .
ct scan is reported to be more useful than mri in evaluating branchial anomalies . in case of sinus or fistula , sinogram or conray contrast study
can delineate the course of branchial anomaly . in the series by choi and zalzal ,
ct scan was performed on 15.38% of patients , sonogram / contrast study was performed on 7.69% of patients , and ultrasound / mri was done on 1.92% of patients . in our series
, intraoperative methylene blue injection was performed in all cases ; ct scan was done in 10.77% of cases .
surgery is definitive mode of treatment because there is lack of spontaneous regression , a high rate of recurrent infection , the possibility of other diagnoses , and rare malignant degeneration .
acute inflammation is treated medically unless incision and drainage or aspiration of an abscess is required .
three to four weeks should pass after an acute infection before a definitive surgical exploration is undertaken . in our series 60%
of patients took medical treatment and 3.33% underwent drainage of abscess before definitive surgical excision of the lesion .
surgical excision of lesion was done in all patients . in the series by ford et al .
it is our observation that while methylene blue dye enhances visualization of the larger and more proximal ( in relation to the punctum ) part of the tracts and ramifications , it does not demarcate the most peripheral ramifications and hence a conscious attempt must be made to follow the tracts till the end . using magnification loops or
the microscope at the time of dissection may enhance prospects of complete removal . while it may be impossible to guarantee a complete removal ,
we believe that this along with the practice of excision of the tract along with surrounding tissue has led to a low recurrence rate seen in our series . in our series ,
this relatively high incidence can be attributed to the fact that a high percentage of the patients in this series were from a low socioeconomic stratum .
though facial nerve paralysis / weakness has been reported in patients undergoing superficial parotidectomy for first branchial cleft anomalies , none of our patients had involvement of facial nerve .
first branchial cleft anomalies are thought to develop as a result of incomplete obliteration of the cleft between the mandibular process of the first arch and the second arch .
a sinus will have an opening in the upper neck or in the floor of the external auditory canal , and a fistula will have an opening in both of these sites .
the first branchial cleft anomalies have been classified as type i or type ii by work .
a cystic mass in the postauricular area extends medially and anteriorly along the external auditory canal .
type ii is considered to be a duplication of the cartilaginous external auditory canal and pinna . a sinus passes from an external opening high in the neck along the anterior border of scm muscle , superficial or deep to the facial nerve in close relation to the parotid gland .
it can either end blindly at the floor of the cartilaginous external auditory canal or open in to the external auditory canal , which is called the collaural fistula . in both types entrapment of desquamating squamous epithelium
will result in the production of a cholesteatoma process resulting in erosion of bony external meatus , tympanic annulus , and hypotympanum .
in the series by belenky and medina 66.66% of patients belonged to work i and 33.33% to work ii . in the study by nofsinger et al .
in our study , work i constituted 17.65% and work ii constituted 20.59% . in the study by triglia et al .
on the first branchial cleft anomalies , 30.77% were male and 69.23% female . in the study by belenky and medina
the incidence in male was 22.22% and in female was 77.77% . in our study , 17.65% were male and 20.59% were female .
the symptoms and signs related to these anomalies in this series are similar to those described by various authors . in general , both types of anomalies may present as a progressively enlarging or recurrent mass or as a draining sinus .
incision and drainage of an abscess are frequently needed before definitive surgical treatment can be performed .
histopathology of the work i lesions in our study showed that 100% of cases lined by squamous epithelium and 20% had cartilage components in the subepithelial layer . in the study by belenky and medina 16.7% of work i had cartilage component in the subepithelium .
intraoperatively the lesion was found superficial to the facial nerve in 100% of our cases .
belenky and medina reported that the lesion was superficial to facial nerve in 88.88% of cases . in the study by triglia et al .
lesion was deep to facial nerve in 39% cases . in the series by nofsinger et al . , the lesion was deep to the facial nerve in 55% of cases .
[ 4 , 11 ] that it is advisable to perform a superficial parotidectomy in cases of first cleft anomalies while identifying the tract in relation to the facial nerve . during embryonic development
, the second arch grows caudally , enveloping the third , fourth , and sixth arches and fusing with skin caudal to these arches , forming a deep groove ( cervical sinus ) .
a persistent fistula of the second branchial cleft and pouch usually has its external opening in the neck near mid or lower part of scm muscle .
as it ascends it pierces platysma . at the level of hyoid it curves medially and
passes between the external and internal carotids in relation to the hypoglossal and glossopharyngeal nerves .
it opens in to the oropharynx usually in the intratonsillar cleft of palatine tonsil . in series of 98 cases by ford
78% presented by the age of five years and in vast majority there was history of intermittent discharge and infection of neck sinus since birth . in seven percent
there was history of incision and drainage of an associated neck abscess . in his series 60% sinus opening was on the right side and 40% on left . in our series of 17 cases 70% presented at age above 11 years .
. there may be only a simple sinus opening that extends up the neck for a variable distance .
branchial fistulas commonly present with persistent mucoid discharge from an opening in the skin of the neck . but
they have been documented as to present as parapharyngeal mass located in the supratonsillar fossa and extending to the lateral nasopharynx .
exceedingly rarely , a branchial cleft anomaly may be found to be malignant on presentation .
the completeness of a fistula is diagnosed by a dye test in which methylene blue is injected through the outer opening and appears in the throat .
a negative preoperative outcome on the test might become positive under general anaesthesia because of muscle relaxation .
occasionally , the fistula tract may be blocked by secretion or granulation giving negative fistula test .
in many a case , saliva is seen dribbling from the neck opening , which itself proves the completeness of the tract ( figure 7 ) . in the 62 pediatric second branchial cleft anomalies , bajaj et al . reported 50 of them to be unilateral and 12 to be bilateral .
the fistulous tract can be approached through a series of stepladder incision first encompassing the sinus opening and second overlying the carotid bifurcation .
subsequently the parapharyngeal portion of the fistula can be approached perorally after tonsillectomy . a wide cervicotomy incision ( hockey stick )
can also be used which allows for adequate exposure of neck structure for accurate dissection . in all our cases , we traced the fistula up to the tonsillar area and excised the tract .
third branchial anomalies are rare and constitute less than 1% of all such cases . here
the fistula opening is seen in the lower neck and it passes along the carotid sheath and then passes between the glossopharyngeal and hypoglossal nerve , piercing the thyrohyoid membrane to enter pharynx in the region of pyriform fossa .
third pouch remnants are described as passing superior to superior laryngeal nerve and posterior to the common carotid artery .
a persistent fistula of the fourth branchial cleft and pouch is theoretically possible but is very rare .
here the fistula opens in to the lower part of neck near the scm muscle .
the tract then passes inferiorly between superior and recurrent laryngeal nerve into the mediastinum , looping around the arch of aorta in the left and subclavian artery in the right and passes back in to the neck , ascending posterior to the carotid .
then it passes between the thyroid and cricoid cartilages and opens in to the pyriform fossa .
, almost all the fourth arch anomalies reported occurred in the left side . in our series also , the fourth arch fistula occurred in the left side .
, these anomalies can be dangerous because of rapid enlargement leading to tracheal compression and respiratory distress .
noncommunicating or noninfected communicating cysts may present as cold thyroid nodules . when infected , diagnosis and successful excision of a pyriform fossa sinus are very challenging and require meticulous approach .
a history of recurrent upper respiratory tract infection , neck or thyroid pain and tenderness , and neck mass is common .
other presentations include cellulites , hoarseness , odynophagia , thyroiditis , abscess , and stridor .
a combination of ultrasound and ct with or without oral contrast will assist in the diagnosis .
all these patients came to us with after recurrences following surgeries done elsewhere . in cases of fourth cleft anomalies ,
the third branchial anomalies showed a fistulous opening in the lower neck , which , on dissection , passed between the glossopharyngeal and hypoglossal nerve as classically described , piercing the thyrohyoid membrane to enter pharynx in the region of pyriform fossa . in the cases of fourth branchial anomalies ,
the intramediastinal part of the fistula was left behind with their ends ligated and the rest of the tract was dissected out from the superior mediastinum up to the pyriform fossa .
our series confirms a higher incidence of first branchial cleft anomaly among females , the cause of which needs to be investigated.none of our patients had involvement of facial nerve .
all patients had tracts going superficial to the facial nerve.all the fourth arch anomalies in our series occurred on the left side which is consistent with the literature.while it may be impossible to guarantee a complete removal , injection of dye and microscopic removal may be vital in preventing recurrences .
we believe that this along with the practice of excision of the tract along with surrounding tissue has led to a low recurrence rate seen in our series .
our series confirms a higher incidence of first branchial cleft anomaly among females , the cause of which needs to be investigated .
all the fourth arch anomalies in our series occurred on the left side which is consistent with the literature .
while it may be impossible to guarantee a complete removal , injection of dye and microscopic removal may be vital in preventing recurrences .
we believe that this along with the practice of excision of the tract along with surrounding tissue has led to a low recurrence rate seen in our series .
diagnosis is rather easy with a proper knowledge of the anatomy of the branchial anomalies . confirming the extent of the tract is mandatory before any surgery as these lesions pass in relation to some of the most vital structures of the neck .
surgery must always be the treatment option for these lesions due to the fact that these lesions do not regress spontaneously and they have a high incidence of recurrent infection .
surgery also gives a chance to diagnose by means of histopathology , the rare occurence of branchogenic carcinoma .[/INST]objective . to find out the incidence of involvement of individual arches , anatomical types of lesions , the age and sex incidence , the site and side of predilection , the common clinical features , the common investigations , treatment , and complications of the different anomalies . setting .
academic department of otolaryngology , head and neck surgery .
design .
a 10 year retrospective study . participants .
30 patients with clinically proven branchial anomalies including patients with bilateral disease totaling 34 lesions .
main outcome measures .
the demographical data , clinical features , type of branchial anomalies , and the management details were recorded and analyzed .
results and observations .
the mean age of presentation was 18.67 years .
male to female sex ratio was 1.27 : 1 with a male preponderance . of the 34 lesions ,
maximum incidence was of second arch anomalies ( 50% ) followed by first arch .
we had two cases each of third and fourth arch anomalies . only 1 ( 3.3% ) patients of the 30 presented with lesion at birth .
the most common pathological type of lesions was fistula ( 58.82% ) followed by cyst .
41.18% of the lesions occurred on the right side .
all the patients underwent surgical excision .
none of our patients had involvement of facial nerve in first branchial anomaly .
all patients had tracts going superficial to the facial nerve .
conclusion . confirming
the extent of the tract is mandatory before any surgery as these lesions pass in relation to some of the most vital structures of the neck .
surgery should always be the treatment option .
injection of dye , microscopic removal and inclusion of surrounding tissue while excising the tract leads to a decreased incidence of recurrence .</s> |
several medications are effective for treating depression ; however , they take weeks or months to achieve their full effects .
a more rapidly acting antidepressant would have a significant impact on the management of depression .
recently , case reports and studies have brought to light , the short term efficacy of intravenous ketamine on severe depression and suicidality .
considering the favorable safety profile of parenteral ketamine , it was tried in the same dose in the intramuscular route in two acutely depressed and suicidal patients with similar rapid response .
while so far , the focus has been on neurotransmitters and related neuro - modulation , recent interest has been on the role of neuro - plasticity .
depression is now believed to be characterized by stress- and cortisol - induced impairment of neuro - genesis , dendritic arborization , and new synapse formation in the hippocampus and prefrontal cortex along with opposite changes in the amygdala .
antidepressant treatments are now believed to restore normalcy by restoring hippocampal , pre - frontal cortex , and amygdala functioning through promotion of neuro - genesis , dendritic arborization , and synaptic connectivity .
relearning and re - adaptation may be an essential part of the healing process , imprinting healthy cognitions and behaviors on the newly - formed connections .
there is a growing evidence that glutamate - driven neuro - plasticity may be the final common pathway in antidepressant action with both conventional drugs and electro - convulsive therapy ( ect ) .
a few case reports and small randomized clinical trials using intravenous infusions of ketamine have shown significant , rapid , but short - lived antidepressant benefits . in these studies , ketamine was shown to produce a rapid antidepressant effect within hours , but the effect lasted less than 1 week . in a recent article , andrade has reviewed the various case reports and studies on the short term efficacy of intravenous ketamine on severe depression and suicidality . in
most of these studies , ketamine was administered in the dose of 0.5 mg / kg as an intravenous infusion in 50 - 100 ml of normal saline over a period of 40 minutes .
understanding how ketamine works may lead us to a better understanding of the causes of depression and may facilitate designing a rapidly acting yet longer lasting antidepressant .
it has half - life of just 17 mins and its urinary excretion occurs in just 2 hours .
ketamine in the dose of 1 mg / kg i.m . has been used with proven safety for narcoanalysis in what has been termed
a 23-year - old bachelor reported with symptoms of obsessive compulsive disorder ( ocd ) of over 5 years duration characterized predominantly by obscene thoughts leading to guilt feelings and consequent depression .
he was , therefore , placed on fluoxetine 40 mg / day and bupropion 150 mg bid .
however , due to the stress of ensuing exams and the unbearable guilt feelings caused by his obsessive thoughts , he attempted suicide on december 27 , 2010 by slashing his throat with a blade
. luckily , he immediately informed his friend on phone , who promptly rushed him to the casualty and got him saved in time .
he was still harboring suicidal thoughts while his hamilton depression rating scale ( hdrs ) was rated at 17 .
his bupropion was hiked to 150 mg tid and fluoxetine to 60 mg / day .
ect was considered , but , in view of his ensuing exams , it was not favored .
he was therefore , administered inj ketamine in the dose of 0.5 mg / kg intramuscularly and kept under observation for the following two hours .
after two hours , his hdrs score dropped down to 4 i.e. , an improvement by over 70% .
ketamine , which brought down his hdrs scores from 10 to 7 within 2 hours i.e. , a 30% improvement . during the subsequent weekly ratings of hdrs for a month , while his medication was continued , he was found to be maintaining the remission while suicidal thoughts never returned .
he appeared in his final year examinations of bachelor of medicine and surgery ( mbbs ) and did well to his satisfaction .
a 21-yr - old bachelor , a medico , suffering from recurrent depressive episodes since last 5 years , has reported with a recent worsening of his symptoms along with suicidal ideas .
his hdrs score was 21 with a high score on the suicidality item . as he did not like to inform his family due to depressive illnesses in all of them , and as he was not willing for ect , he was taken up for ketamine injection to induce a quick relief from depression . a dose of 0.5 mg / kg of i.m .
after 2 hours , his hdrs score dropped down to 6 i.e. , an improvement of over 70% .
after 2 hours , his hdrs dropped to 6 signifying an improvement by over 50% .
a 23-year - old bachelor reported with symptoms of obsessive compulsive disorder ( ocd ) of over 5 years duration characterized predominantly by obscene thoughts leading to guilt feelings and consequent depression .
he was , therefore , placed on fluoxetine 40 mg / day and bupropion 150 mg bid .
however , due to the stress of ensuing exams and the unbearable guilt feelings caused by his obsessive thoughts , he attempted suicide on december 27 , 2010 by slashing his throat with a blade
. luckily , he immediately informed his friend on phone , who promptly rushed him to the casualty and got him saved in time .
he was still harboring suicidal thoughts while his hamilton depression rating scale ( hdrs ) was rated at 17 .
his bupropion was hiked to 150 mg tid and fluoxetine to 60 mg / day .
ect was considered , but , in view of his ensuing exams , it was not favored .
he was therefore , administered inj ketamine in the dose of 0.5 mg / kg intramuscularly and kept under observation for the following two hours .
after two hours , his hdrs score dropped down to 4 i.e. , an improvement by over 70% .
ketamine , which brought down his hdrs scores from 10 to 7 within 2 hours i.e. , a 30% improvement . during the subsequent weekly ratings of hdrs for a month , while his medication was continued , he was found to be maintaining the remission while suicidal thoughts never returned .
he appeared in his final year examinations of bachelor of medicine and surgery ( mbbs ) and did well to his satisfaction .
a 21-yr - old bachelor , a medico , suffering from recurrent depressive episodes since last 5 years , has reported with a recent worsening of his symptoms along with suicidal ideas .
his hdrs score was 21 with a high score on the suicidality item . as he did not like to inform his family due to depressive illnesses in all of them , and as he was not willing for ect , he was taken up for ketamine injection to induce a quick relief from depression . a dose of 0.5 mg / kg of i.m .
after 2 hours , his hdrs score dropped down to 6 i.e. , an improvement of over 70% .
after 2 hours , his hdrs dropped to 6 signifying an improvement by over 50% .
in the two cases described , the subjects were suffering from severe depression with suicidal intent .
they had a promising career ahead of them which faced jeopardy due to their illness .
the response to drugs was rather slow and both were not willing for ect due to risks of cognitive impairment just before their exams and for other social reasons . at this juncture ,
an injection of ketamine brought about dramatic improvement especially with regards to their suicidal ideation and saved them .
it can be seen that the improvement with the first injection was much greater than that after the second injection .
nevertheless , the improvement was continued in both of them and appeared to have speeded up the action of the ongoing antidepressant medication .
it is likely that their glutamatergic action had certainly brought about a rapid relief from their suicidal ideation as well as from depression .
it can also be noted that intramuscular route of administration was much easier method than an i.v .
infusion , and could be taken up as an emergency procedure especially as in the first case , where it was given soon after the suicidal attempt without waiting for pre - operative preparation of a day as is required for ect . even in the second case , as there were practical hurdles in giving ect due to lack of availability of his next of kin , i.m .
intramuscular ketamine injection has been found to bring about rapid relief from depression , especially the suicidal ideation comparable to administration as an i.v .
it is thus foreseen as a promising tool in the emergency kit of not only psychiatrists but also primary care physicians .
it is also envisaged as an effective alternative to ect in severe depression especially where ect is not preferred due to its related cognitive side effects and other social reasons .
ketamine and ect would elucidate the issue and possibly give us an important gadget in our armamentarium against severe depression . | it takes about 2 weeks for the onset of antidepressant action of drugs while electroconvulsive therapy though faster , is a cumbersome procedure requiring an anaesthetist and at least a minor operation theatre .
recent studies have shown that ketamine , when given to severely depressed patients in the dose of 0.5 mg / kg as a slow intravenous infusion over 40 minutes , brought about acute relief from depression and amelioration of suicidal risk within a few hours .
the improvement , however , was transient and lasted for up to a week but could be sustained by further weekly or biweekly injections . as the dose of ketamine administered was found to be safe , it was now tried in the intramuscular route in two severely depressed patients with similar rapid improvement .
the cases are reported here which pave way for an easier mode of treating acute depression . | <s>[INST]several medications are effective for treating depression ; however , they take weeks or months to achieve their full effects .
a more rapidly acting antidepressant would have a significant impact on the management of depression .
recently , case reports and studies have brought to light , the short term efficacy of intravenous ketamine on severe depression and suicidality .
considering the favorable safety profile of parenteral ketamine , it was tried in the same dose in the intramuscular route in two acutely depressed and suicidal patients with similar rapid response .
while so far , the focus has been on neurotransmitters and related neuro - modulation , recent interest has been on the role of neuro - plasticity .
depression is now believed to be characterized by stress- and cortisol - induced impairment of neuro - genesis , dendritic arborization , and new synapse formation in the hippocampus and prefrontal cortex along with opposite changes in the amygdala .
antidepressant treatments are now believed to restore normalcy by restoring hippocampal , pre - frontal cortex , and amygdala functioning through promotion of neuro - genesis , dendritic arborization , and synaptic connectivity .
relearning and re - adaptation may be an essential part of the healing process , imprinting healthy cognitions and behaviors on the newly - formed connections .
there is a growing evidence that glutamate - driven neuro - plasticity may be the final common pathway in antidepressant action with both conventional drugs and electro - convulsive therapy ( ect ) .
a few case reports and small randomized clinical trials using intravenous infusions of ketamine have shown significant , rapid , but short - lived antidepressant benefits . in these studies , ketamine was shown to produce a rapid antidepressant effect within hours , but the effect lasted less than 1 week . in a recent article , andrade has reviewed the various case reports and studies on the short term efficacy of intravenous ketamine on severe depression and suicidality . in
most of these studies , ketamine was administered in the dose of 0.5 mg / kg as an intravenous infusion in 50 - 100 ml of normal saline over a period of 40 minutes .
understanding how ketamine works may lead us to a better understanding of the causes of depression and may facilitate designing a rapidly acting yet longer lasting antidepressant .
it has half - life of just 17 mins and its urinary excretion occurs in just 2 hours .
ketamine in the dose of 1 mg / kg i.m . has been used with proven safety for narcoanalysis in what has been termed
a 23-year - old bachelor reported with symptoms of obsessive compulsive disorder ( ocd ) of over 5 years duration characterized predominantly by obscene thoughts leading to guilt feelings and consequent depression .
he was , therefore , placed on fluoxetine 40 mg / day and bupropion 150 mg bid .
however , due to the stress of ensuing exams and the unbearable guilt feelings caused by his obsessive thoughts , he attempted suicide on december 27 , 2010 by slashing his throat with a blade
. luckily , he immediately informed his friend on phone , who promptly rushed him to the casualty and got him saved in time .
he was still harboring suicidal thoughts while his hamilton depression rating scale ( hdrs ) was rated at 17 .
his bupropion was hiked to 150 mg tid and fluoxetine to 60 mg / day .
ect was considered , but , in view of his ensuing exams , it was not favored .
he was therefore , administered inj ketamine in the dose of 0.5 mg / kg intramuscularly and kept under observation for the following two hours .
after two hours , his hdrs score dropped down to 4 i.e. , an improvement by over 70% .
ketamine , which brought down his hdrs scores from 10 to 7 within 2 hours i.e. , a 30% improvement . during the subsequent weekly ratings of hdrs for a month , while his medication was continued , he was found to be maintaining the remission while suicidal thoughts never returned .
he appeared in his final year examinations of bachelor of medicine and surgery ( mbbs ) and did well to his satisfaction .
a 21-yr - old bachelor , a medico , suffering from recurrent depressive episodes since last 5 years , has reported with a recent worsening of his symptoms along with suicidal ideas .
his hdrs score was 21 with a high score on the suicidality item . as he did not like to inform his family due to depressive illnesses in all of them , and as he was not willing for ect , he was taken up for ketamine injection to induce a quick relief from depression . a dose of 0.5 mg / kg of i.m .
after 2 hours , his hdrs score dropped down to 6 i.e. , an improvement of over 70% .
after 2 hours , his hdrs dropped to 6 signifying an improvement by over 50% .
a 23-year - old bachelor reported with symptoms of obsessive compulsive disorder ( ocd ) of over 5 years duration characterized predominantly by obscene thoughts leading to guilt feelings and consequent depression .
he was , therefore , placed on fluoxetine 40 mg / day and bupropion 150 mg bid .
however , due to the stress of ensuing exams and the unbearable guilt feelings caused by his obsessive thoughts , he attempted suicide on december 27 , 2010 by slashing his throat with a blade
. luckily , he immediately informed his friend on phone , who promptly rushed him to the casualty and got him saved in time .
he was still harboring suicidal thoughts while his hamilton depression rating scale ( hdrs ) was rated at 17 .
his bupropion was hiked to 150 mg tid and fluoxetine to 60 mg / day .
ect was considered , but , in view of his ensuing exams , it was not favored .
he was therefore , administered inj ketamine in the dose of 0.5 mg / kg intramuscularly and kept under observation for the following two hours .
after two hours , his hdrs score dropped down to 4 i.e. , an improvement by over 70% .
ketamine , which brought down his hdrs scores from 10 to 7 within 2 hours i.e. , a 30% improvement . during the subsequent weekly ratings of hdrs for a month , while his medication was continued , he was found to be maintaining the remission while suicidal thoughts never returned .
he appeared in his final year examinations of bachelor of medicine and surgery ( mbbs ) and did well to his satisfaction .
a 21-yr - old bachelor , a medico , suffering from recurrent depressive episodes since last 5 years , has reported with a recent worsening of his symptoms along with suicidal ideas .
his hdrs score was 21 with a high score on the suicidality item . as he did not like to inform his family due to depressive illnesses in all of them , and as he was not willing for ect , he was taken up for ketamine injection to induce a quick relief from depression . a dose of 0.5 mg / kg of i.m .
after 2 hours , his hdrs score dropped down to 6 i.e. , an improvement of over 70% .
after 2 hours , his hdrs dropped to 6 signifying an improvement by over 50% .
in the two cases described , the subjects were suffering from severe depression with suicidal intent .
they had a promising career ahead of them which faced jeopardy due to their illness .
the response to drugs was rather slow and both were not willing for ect due to risks of cognitive impairment just before their exams and for other social reasons . at this juncture ,
an injection of ketamine brought about dramatic improvement especially with regards to their suicidal ideation and saved them .
it can be seen that the improvement with the first injection was much greater than that after the second injection .
nevertheless , the improvement was continued in both of them and appeared to have speeded up the action of the ongoing antidepressant medication .
it is likely that their glutamatergic action had certainly brought about a rapid relief from their suicidal ideation as well as from depression .
it can also be noted that intramuscular route of administration was much easier method than an i.v .
infusion , and could be taken up as an emergency procedure especially as in the first case , where it was given soon after the suicidal attempt without waiting for pre - operative preparation of a day as is required for ect . even in the second case , as there were practical hurdles in giving ect due to lack of availability of his next of kin , i.m .
intramuscular ketamine injection has been found to bring about rapid relief from depression , especially the suicidal ideation comparable to administration as an i.v .
it is thus foreseen as a promising tool in the emergency kit of not only psychiatrists but also primary care physicians .
it is also envisaged as an effective alternative to ect in severe depression especially where ect is not preferred due to its related cognitive side effects and other social reasons .
ketamine and ect would elucidate the issue and possibly give us an important gadget in our armamentarium against severe depression .[/INST]it takes about 2 weeks for the onset of antidepressant action of drugs while electroconvulsive therapy though faster , is a cumbersome procedure requiring an anaesthetist and at least a minor operation theatre .
recent studies have shown that ketamine , when given to severely depressed patients in the dose of 0.5 mg / kg as a slow intravenous infusion over 40 minutes , brought about acute relief from depression and amelioration of suicidal risk within a few hours .
the improvement , however , was transient and lasted for up to a week but could be sustained by further weekly or biweekly injections . as the dose of ketamine administered was found to be safe , it was now tried in the intramuscular route in two severely depressed patients with similar rapid improvement .
the cases are reported here which pave way for an easier mode of treating acute depression .</s> |
we work with the prime numbers in ascending order , denoting the @xmath3 prime by @xmath4 . accompanying
the sequence of primes is the sequence of gaps between consecutive primes .
we denote the gap between @xmath4 and @xmath5 by @xmath6 these sequences begin @xmath7 a number @xmath8 is the _ difference _ between prime numbers if there are two prime numbers , @xmath9 and @xmath10 , such that @xmath11 .
there are already many interesting results and open questions about differences between prime numbers ; a seminal and inspirational work about differences between primes is hardy and littlewood s 1923 paper @xcite .
a number @xmath12 is a _ gap _ between prime numbers if it is the difference between consecutive primes ; that is , @xmath13 and @xmath14 and @xmath15 .
differences of length @xmath0 or @xmath16 are also gaps ; so open questions like the twin prime conjecture , that there are an infinite number of gaps @xmath17 , can be formulated as questions about differences as well . a _ constellation among primes _
@xcite is a sequence of consecutive gaps between prime numbers .
let @xmath18 be a sequence of @xmath19 numbers .
then @xmath20 is a constellation among primes if there exists a sequence of @xmath21 consecutive prime numbers @xmath22 such that for each @xmath23 , we have the gap @xmath24 .
equivalently , @xmath20 is a constellation if for some @xmath25 and all @xmath23 , @xmath26 .
we will write the constellations without marking a separation between single - digit gaps .
for example , a constellation of @xmath27 denotes a gap of @xmath17 followed immediately by a gap @xmath28 . for the small primes we will consider explicitly , most of these gaps are single digits , and the separators introduce a lot of visual clutter .
we use commas only to separate double - digit gaps in the cycle .
for example , a constellation of @xmath29 denotes a gap of @xmath0 followed by a gap of @xmath30 , followed by another gap of @xmath0 .
in @xcite we introduced a recursion that works directly on the gaps among the generators in each stage of eratosthenes sieve .
these are the generators of @xmath31 in which @xmath32 is the product of the prime numbers from @xmath0 through @xmath9 , known as the _ primorial _ of @xmath9 . for a constellation @xmath20 ,
this recursion enables us to enumerate exactly how many copies of @xmath20 occur in the @xmath3 stage of the sieve .
we denote this number of copies of @xmath20 as @xmath33 .
for example , after the primes @xmath0 , @xmath34 , and @xmath35 and their multiples have been removed , we have the cycle of gaps @xmath36 .
this cycle of @xmath37 gaps sums to @xmath2 . in this cycle , for the constellation @xmath38 , we have @xmath39 . for the constellation @xmath40 , we have @xmath41 .
the cycle of gaps @xmath42 has @xmath43 gaps that sum to @xmath32 .
in @xcite we assumed that copies of a constellation were approximately uniformly distributed within the cycle of gaps @xmath44 , from which we could then estimate the numbers of these constellations that survive to occur as constellations among prime numbers .
for a few select constellations we compared our estimates to actual counts up through @xmath45 .
for these constellations , our estimates in @xcite appear to have the correct asymptotic behavior , but our estimates also seem to have a systematic error correlated with the number of gaps in the constellation . in this paper , we identify a discrete dynamic system that provides exact counts of a gap and its driving terms , which are constellations that under successive closures produce the gap at later stages of the sieve .
these raw counts grow superexponentially , and so to better understand their behavior we take the ratio of a raw count to the number of gaps @xmath46 at each stage of the sieve . for a gap @xmath12 that has driving terms of lengths @xmath47
, we form a vector of initial values @xmath48 , whose @xmath49 entry is the ratio of the number of driving terms for @xmath12 of length @xmath50 in @xmath51 to the number of gaps @xmath0 in this cycle of gaps . recasting the discrete dynamic system to work with these ratios
, we have @xmath52 the matrix @xmath53 does not depend on the gap @xmath12 .
it does depend on the prime @xmath4 , and we use the exponential notation @xmath54 to indicate the product of the @xmath55 s over the indicated range of primes .
although the matrix @xmath53 depends on the prime @xmath4 , its eigenvectors do not .
we are therefore able to give a simple exact expression of the dynamic system that reveals its asymptotic behavior .
we show that as @xmath56 , the following ratios describe the relative frequency of occurrence of gaps in eratosthenes sieve : the values @xmath57 are the actual ratios between the numbers of these gaps at the corresponding stage of eratosthenes sieve .
so these ratios , when computed exactly , represent the exact proportions of the relative occurrences among these gaps .
if there are significant deviations from these ratios among gaps in the cycle compared to the ratios of those that survive to be gaps among primes over this range , what can we understand about the mechanism that would selectively close gaps of certain values ? this column @xmath58 provides the ratios in @xmath59 , which covers the interval @xmath60 to @xmath61 .
as the recursion continues , many closures will occur within this range .
the final column @xmath62 provides the asymptotic ratios of the occurrences of the indicated gap to the occurrences of the gap @xmath0 . to understand the convergence to @xmath62 , from the eigenstructure of @xmath54 we can approximate @xmath63 by truncating : @xmath64 note that for @xmath59 the value of @xmath65 , so the convergence to @xmath66 is very gradual .
this work supports the conjecture that @xmath2 eventually is a more common gap among primes than @xmath1 . in the table above , we see that asymptotically there are in the cycles of gaps for eratosthenes sieve twice as many @xmath1 s as @xmath0 s and @xmath67 times as many @xmath2 s as @xmath0 s . however , even at the prime @xmath68 , these ratios are @xmath69 and @xmath70 .
truncating @xmath63 as suggested and using the initial conditions for @xmath71 and @xmath72 in @xmath73 , we see that @xmath2 s will outnumber @xmath1 s in eratosthenes sieve when @xmath74 .
the asymptotic ratios appear to follow the formula : @xmath75{}}q>2 } \frac{q-1}{q-2}.\ ] ] it would be interesting to see whether this formula holds up for larger gaps , since it provides supporting evidence for conjecture b in @xcite ; these ratios among gaps hold asymptotically in eratosthenes sieve . from lemma [ asymlemma ] this means that for a given set of prime factors ( no matter what the powers on these factors ) , any gap with this same set of prime factors has the same total number of driving terms in any stage of eratosthenes sieve that satisfies the conditions of theorem [ countthm ] . one more observation about primorial gaps and their driving terms .
since the length of @xmath76 is @xmath37 with sum @xmath2 , in all subsequent cycles of gaps the sum of every constellation of length @xmath37 will be at least @xmath2 .
since @xmath77 , there are @xmath78 complete copies of @xmath76 in @xmath73 .
complete copies are only preserved for @xmath76 , @xmath79 , and @xmath80 .
these are preserved since the elementwise products in step r3 of the recursion are large enough to pass completely over one of the copies concatenated in step r2 . starting with @xmath81 ,
the primorial @xmath82 is larger than any of the elementwise products , and no complete copies of these longer cycles are preserved in their entirety . | a few years ago we identified a recursion that works directly with the gaps among the generators in each stage of eratosthenes sieve .
this recursion provides explicit enumerations of sequences of gaps among the generators , which are known as constellations .
as the recursion proceeds , adjacent gaps within longer constellations are added together to produce shorter constellations of the same sum .
these additions or closures correspond to removing composite numbers that are divisible by the prime for that stage of eratosthenes sieve .
although we do nt know where in the cycle of gaps a closure will occur , we can enumerate exactly how many copies of various constellations will survive each stage . in this paper
, we study these systems of constellations of a fixed sum . viewing them as discrete dynamic systems
, we are able to characterize the populations of constellations for sums including the first few primorial numbers : @xmath0 , @xmath1 , @xmath2 .
since the eigenvectors of the discrete dynamic system are independent of the prime that is , independent of the stage of the sieve we can characterize the asymptotic behavior exactly . in this way we can give exact ratios of the occurrences of the gap @xmath0 to the occurrences of other small gaps for all stages of eratosthenes sieve . | <s>[INST]we work with the prime numbers in ascending order , denoting the @xmath3 prime by @xmath4 . accompanying
the sequence of primes is the sequence of gaps between consecutive primes .
we denote the gap between @xmath4 and @xmath5 by @xmath6 these sequences begin @xmath7 a number @xmath8 is the _ difference _ between prime numbers if there are two prime numbers , @xmath9 and @xmath10 , such that @xmath11 .
there are already many interesting results and open questions about differences between prime numbers ; a seminal and inspirational work about differences between primes is hardy and littlewood s 1923 paper @xcite .
a number @xmath12 is a _ gap _ between prime numbers if it is the difference between consecutive primes ; that is , @xmath13 and @xmath14 and @xmath15 .
differences of length @xmath0 or @xmath16 are also gaps ; so open questions like the twin prime conjecture , that there are an infinite number of gaps @xmath17 , can be formulated as questions about differences as well . a _ constellation among primes _
@xcite is a sequence of consecutive gaps between prime numbers .
let @xmath18 be a sequence of @xmath19 numbers .
then @xmath20 is a constellation among primes if there exists a sequence of @xmath21 consecutive prime numbers @xmath22 such that for each @xmath23 , we have the gap @xmath24 .
equivalently , @xmath20 is a constellation if for some @xmath25 and all @xmath23 , @xmath26 .
we will write the constellations without marking a separation between single - digit gaps .
for example , a constellation of @xmath27 denotes a gap of @xmath17 followed immediately by a gap @xmath28 . for the small primes we will consider explicitly , most of these gaps are single digits , and the separators introduce a lot of visual clutter .
we use commas only to separate double - digit gaps in the cycle .
for example , a constellation of @xmath29 denotes a gap of @xmath0 followed by a gap of @xmath30 , followed by another gap of @xmath0 .
in @xcite we introduced a recursion that works directly on the gaps among the generators in each stage of eratosthenes sieve .
these are the generators of @xmath31 in which @xmath32 is the product of the prime numbers from @xmath0 through @xmath9 , known as the _ primorial _ of @xmath9 . for a constellation @xmath20 ,
this recursion enables us to enumerate exactly how many copies of @xmath20 occur in the @xmath3 stage of the sieve .
we denote this number of copies of @xmath20 as @xmath33 .
for example , after the primes @xmath0 , @xmath34 , and @xmath35 and their multiples have been removed , we have the cycle of gaps @xmath36 .
this cycle of @xmath37 gaps sums to @xmath2 . in this cycle , for the constellation @xmath38 , we have @xmath39 . for the constellation @xmath40 , we have @xmath41 .
the cycle of gaps @xmath42 has @xmath43 gaps that sum to @xmath32 .
in @xcite we assumed that copies of a constellation were approximately uniformly distributed within the cycle of gaps @xmath44 , from which we could then estimate the numbers of these constellations that survive to occur as constellations among prime numbers .
for a few select constellations we compared our estimates to actual counts up through @xmath45 .
for these constellations , our estimates in @xcite appear to have the correct asymptotic behavior , but our estimates also seem to have a systematic error correlated with the number of gaps in the constellation . in this paper , we identify a discrete dynamic system that provides exact counts of a gap and its driving terms , which are constellations that under successive closures produce the gap at later stages of the sieve .
these raw counts grow superexponentially , and so to better understand their behavior we take the ratio of a raw count to the number of gaps @xmath46 at each stage of the sieve . for a gap @xmath12 that has driving terms of lengths @xmath47
, we form a vector of initial values @xmath48 , whose @xmath49 entry is the ratio of the number of driving terms for @xmath12 of length @xmath50 in @xmath51 to the number of gaps @xmath0 in this cycle of gaps . recasting the discrete dynamic system to work with these ratios
, we have @xmath52 the matrix @xmath53 does not depend on the gap @xmath12 .
it does depend on the prime @xmath4 , and we use the exponential notation @xmath54 to indicate the product of the @xmath55 s over the indicated range of primes .
although the matrix @xmath53 depends on the prime @xmath4 , its eigenvectors do not .
we are therefore able to give a simple exact expression of the dynamic system that reveals its asymptotic behavior .
we show that as @xmath56 , the following ratios describe the relative frequency of occurrence of gaps in eratosthenes sieve : the values @xmath57 are the actual ratios between the numbers of these gaps at the corresponding stage of eratosthenes sieve .
so these ratios , when computed exactly , represent the exact proportions of the relative occurrences among these gaps .
if there are significant deviations from these ratios among gaps in the cycle compared to the ratios of those that survive to be gaps among primes over this range , what can we understand about the mechanism that would selectively close gaps of certain values ? this column @xmath58 provides the ratios in @xmath59 , which covers the interval @xmath60 to @xmath61 .
as the recursion continues , many closures will occur within this range .
the final column @xmath62 provides the asymptotic ratios of the occurrences of the indicated gap to the occurrences of the gap @xmath0 . to understand the convergence to @xmath62 , from the eigenstructure of @xmath54 we can approximate @xmath63 by truncating : @xmath64 note that for @xmath59 the value of @xmath65 , so the convergence to @xmath66 is very gradual .
this work supports the conjecture that @xmath2 eventually is a more common gap among primes than @xmath1 . in the table above , we see that asymptotically there are in the cycles of gaps for eratosthenes sieve twice as many @xmath1 s as @xmath0 s and @xmath67 times as many @xmath2 s as @xmath0 s . however , even at the prime @xmath68 , these ratios are @xmath69 and @xmath70 .
truncating @xmath63 as suggested and using the initial conditions for @xmath71 and @xmath72 in @xmath73 , we see that @xmath2 s will outnumber @xmath1 s in eratosthenes sieve when @xmath74 .
the asymptotic ratios appear to follow the formula : @xmath75{}}q>2 } \frac{q-1}{q-2}.\ ] ] it would be interesting to see whether this formula holds up for larger gaps , since it provides supporting evidence for conjecture b in @xcite ; these ratios among gaps hold asymptotically in eratosthenes sieve . from lemma [ asymlemma ] this means that for a given set of prime factors ( no matter what the powers on these factors ) , any gap with this same set of prime factors has the same total number of driving terms in any stage of eratosthenes sieve that satisfies the conditions of theorem [ countthm ] . one more observation about primorial gaps and their driving terms .
since the length of @xmath76 is @xmath37 with sum @xmath2 , in all subsequent cycles of gaps the sum of every constellation of length @xmath37 will be at least @xmath2 .
since @xmath77 , there are @xmath78 complete copies of @xmath76 in @xmath73 .
complete copies are only preserved for @xmath76 , @xmath79 , and @xmath80 .
these are preserved since the elementwise products in step r3 of the recursion are large enough to pass completely over one of the copies concatenated in step r2 . starting with @xmath81 ,
the primorial @xmath82 is larger than any of the elementwise products , and no complete copies of these longer cycles are preserved in their entirety .[/INST] a few years ago we identified a recursion that works directly with the gaps among the generators in each stage of eratosthenes sieve .
this recursion provides explicit enumerations of sequences of gaps among the generators , which are known as constellations .
as the recursion proceeds , adjacent gaps within longer constellations are added together to produce shorter constellations of the same sum .
these additions or closures correspond to removing composite numbers that are divisible by the prime for that stage of eratosthenes sieve .
although we do nt know where in the cycle of gaps a closure will occur , we can enumerate exactly how many copies of various constellations will survive each stage . in this paper
, we study these systems of constellations of a fixed sum . viewing them as discrete dynamic systems
, we are able to characterize the populations of constellations for sums including the first few primorial numbers : @xmath0 , @xmath1 , @xmath2 .
since the eigenvectors of the discrete dynamic system are independent of the prime that is , independent of the stage of the sieve we can characterize the asymptotic behavior exactly . in this way we can give exact ratios of the occurrences of the gap @xmath0 to the occurrences of other small gaps for all stages of eratosthenes sieve . </s> |
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