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http://www.ncbi.nlm.nih.gov/pubmed/33191916
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1. Elife. 2020 Nov 16;9:e63274. doi: 10.7554/eLife.63274.
Efficient chromatin accessibility mapping in situ by nucleosome-tethered
tagmentation.
Henikoff S(1)(2), Henikoff JG(1), Kaya-Okur HS(1), Ahmad K(1).
Author information:
(1)Basic Sciences Division Fred Hutchinson Cancer Research Center, Seattle,
United States.
(2)Howard Hughes Medical Institute, Seattle, United States.
Chromatin accessibility mapping is a powerful approach to identify potential
regulatory elements. A popular example is ATAC-seq, whereby Tn5 transposase
inserts sequencing adapters into accessible DNA ('tagmentation'). CUT&Tag is a
tagmentation-based epigenomic profiling method in which antibody tethering of
Tn5 to a chromatin epitope of interest profiles specific chromatin features in
small samples and single cells. Here, we show that by simply modifying the
tagmentation conditions for histone H3K4me2 or H3K4me3 CUT&Tag,
antibody-tethered tagmentation of accessible DNA sites is redirected to produce
chromatin accessibility maps that are indistinguishable from the best ATAC-seq
maps. Thus, chromatin accessibility maps can be produced in parallel with
CUT&Tag maps of other epitopes with all steps from nuclei to amplified
sequencing-ready libraries performed in single PCR tubes in the laboratory or on
a home workbench. As H3K4 methylation is produced by transcription at promoters
and enhancers, our method identifies transcription-coupled accessible regulatory
sites.
Plain Language Summary: Cells keep their DNA tidy by wrapping it into structures
called nucleosomes. Each of these structures contains a short section of DNA
wound around a cluster of proteins called histones. Not only do nucleosomes keep
the genetic code organized, they also control whether the proteins that can
switch genes on or off have access to the DNA. When genes turn on, the
nucleosomes unwrap, exposing sections of genetic code called 'gene regulatory
elements'. These elements attract the proteins that help read and copy nearby
genes so the cell can make new proteins. Determining which regulatory elements
are exposed at any given time can provide useful information about what is
happening inside a cell, but the procedure can be expensive. The most popular
way to map which regulatory elements are exposed is using a technique called
Assay for Transposase-Accessible Chromatin using sequencing, or ATAC-seq for
short. The 'transposase' in the acronym is an enzyme that cuts areas of DNA that
are not wound around histones and prepares them for detection by DNA sequencing.
Unfortunately, the data from ATAC-seq are often noisy (there are random factors
that produce a signal that is detected but is not a ‘real’ result), so more
sequencing is required to differentiate between real signal and noise,
increasing the expense of ATAC-seq experiments. Furthermore, although ATAC-seq
can identify unspooled sections of DNA, it cannot provide a direct connection
between active genes and unwrapped DNA. To find the link between unspooled DNA
and active genes, Henikoff et al. adapted a technique called CUT&Tag. Like
ATAC-seq, it also uses transposases to cut the genome, but it allows more
control over where the cuts occur. When genes are switched on, the proteins
reading them leave chemical marks on the histones they pass. CUT&Tag attaches a
transposase to a molecule that recognizes and binds to those marks. This allowed
Henikoff et al. to guide the transposases to unspooled regions of DNA bordering
active genes. The maps of gene regulatory elements produced using this method
were the same as the best ATAC-seq maps. And, because the transposases could
only access gaps near active genes, the data provided evidence that genes
switching on leads to regulatory elements in the genome unwrapping. This new
technique is simple enough that Henikoff et al. were able to perform it from
home on the countertop of a laundry room. By tethering the transposases to
histone marks it was possible to detect unspooled DNA that was active more
efficiently than with ATAC-seq. This lowers laboratory costs by reducing the
cost of DNA sequencing, and may also improve the detection of gaps between
nucleosomes in single cells.
© 2020, Henikoff et al.
DOI: 10.7554/eLife.63274
PMCID: PMC7721439
PMID: 33191916 [Indexed for MEDLINE]
Conflict of interest statement: SH, HK has filed patent applications related to
this work. JH, KA No competing interests declared
|
http://www.ncbi.nlm.nih.gov/pubmed/29624723
|
1. Mov Disord. 2018 Jul;33(6):1000-1005. doi: 10.1002/mds.27353. Epub 2018 Apr 6.
Randomized, clinical trial of RT001: Early signals of efficacy in Friedreich's
ataxia.
Zesiewicz T(1), Heerinckx F(2), De Jager R(2), Omidvar O(3), Kilpatrick M(4),
Shaw J(1), Shchepinov MS(2).
Author information:
(1)Department of Neurology, University of South Florida, Tampa, Florida, USA.
(2)Retrotope, Inc., Los Altos, California, USA.
(3)Collaborative Neuroscience Network, Long Beach, California, USA.
(4)College of Education, University of South Florida, Tampa, Florida, USA.
BACKGROUND: RT001 is a deuterated ethyl linoleate that inhibits lipid
peroxidation and is hypothesized to reduce cellular damage and recover
mitochondrial function in degenerative diseases such as Friedreich's ataxia.
OBJECTIVE: To evaluate the safety, pharmacokinetics, and preliminary efficacy of
RT001 in Friedreich's ataxia patients.
DESIGN/METHODS: We conducted a phase I/II double-blind, comparator-controlled
trial with 2 doses of RT001 in Friedreich's ataxia patients (9 subjects each
cohort). Subjects were randomized 2:1 to receive either RT001 (1.8 or 9.0
g/day), or a matching dose of nondeuterated ethyl linoleate as comparator for 28
days. The primary endpoints were safety, tolerability, and pharmacokinetic
analysis. Secondary endpoints included cardiopulmonary exercise testing and
timed 25-foot walk.
RESULTS: Nineteen patients enrolled in the trial, and 18 completed all safety
and efficacy measurements. RT001 was found to be safe and tolerable, with plasma
levels approaching saturation by 28 days. One subject with a low body mass index
experienced steatorrhea taking a high dose and discontinued the study.
Deuterated arachidonic acid (a brain-penetrant metabolite of RT001) was found to
be present in plasma on day 28. There was an improvement in peak workload in the
drug group compared to placebo (0.16 watts/kg; P = 0.008), as well as an
improvement trend in peak oxygen consumption (change of 0.16 L/min; P = 0.116),
and in stride speed (P = 0.15).
CONCLUSIONS: RT001 was found to be safe and tolerable over 28 days, and improved
peak workload. Further research into the effect of RT001 in Friedreich's ataxia
is warranted. © 2018 International Parkinson and Movement Disorder Society.
© 2018 International Parkinson and Movement Disorder Society.
DOI: 10.1002/mds.27353
PMID: 29624723 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/32576878
|
1. Sci Rep. 2020 Jun 23;10(1):10150. doi: 10.1038/s41598-020-66998-4.
Comparison of differential accessibility analysis strategies for ATAC-seq data.
Gontarz P(#)(1), Fu S(#)(1), Xing X(2), Liu S(1), Miao B(1), Bazylianska V(3),
Sharma A(3), Madden P(4), Cates K(1), Yoo A(1), Moszczynska A(3), Wang T(5),
Zhang B(6).
Author information:
(1)Department of Developmental Biology, Center of Regenerative Medicine,
Washington University School of Medicine, St. Louis, MO, 63110, USA.
(2)Department of Genetics, Center for Genomic Sciences and Systems Biology,
Washington University School of Medicine, St. Louis, MO, 63110, USA.
(3)Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI,
48201, USA.
(4)Department of Psychiatry, Washington University School of Medicine, St.
Louis, MO, 63110, USA.
(5)Department of Genetics, Center for Genomic Sciences and Systems Biology,
Washington University School of Medicine, St. Louis, MO, 63110, USA.
[email protected].
(6)Department of Developmental Biology, Center of Regenerative Medicine,
Washington University School of Medicine, St. Louis, MO, 63110, USA.
[email protected].
(#)Contributed equally
ATAC-seq is widely used to measure chromatin accessibility and identify open
chromatin regions (OCRs). OCRs usually indicate active regulatory elements in
the genome and are directly associated with the gene regulatory network. The
identification of differential accessibility regions (DARs) between different
biological conditions is critical in determining the differential activity of
regulatory elements. Differential analysis of ATAC-seq shares many similarities
with differential expression analysis of RNA-seq data. However, the distribution
of ATAC-seq signal intensity is different from that of RNA-seq data, and higher
sensitivity is required for DARs identification. Many different tools can be
used to perform differential analysis of ATAC-seq data, but a comprehensive
comparison and benchmarking of these methods is still lacking. Here, we used
simulated datasets to systematically measure the sensitivity and specificity of
six different methods. We further discussed the statistical and signal density
cut-offs in the differential analysis of ATAC-seq by applying them to real data.
Batch effects are very common in high-throughput sequencing experiments. We
illustrated that batch-effect correction can dramatically improve sensitivity in
the differential analysis of ATAC-seq data. Finally, we developed a
user-friendly package, BeCorrect, to perform batch effect correction and
visualization of corrected ATAC-seq signals in a genome browser.
DOI: 10.1038/s41598-020-66998-4
PMCID: PMC7311460
PMID: 32576878 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no competing interests.
|
http://www.ncbi.nlm.nih.gov/pubmed/32213349
|
1. Cell Syst. 2020 Mar 25;10(3):298-306.e4. doi: 10.1016/j.cels.2020.02.009.
Quantification, Dynamic Visualization, and Validation of Bias in ATAC-Seq Data
with ataqv.
Orchard P(1), Kyono Y(2), Hensley J(1), Kitzman JO(2), Parker SCJ(3).
Author information:
(1)Department of Computational Medicine and Bioinformatics, University of
Michigan, Ann Arbor, MI 48109, USA.
(2)Department of Computational Medicine and Bioinformatics, University of
Michigan, Ann Arbor, MI 48109, USA; Department of Human Genetics, University of
Michigan, Ann Arbor, MI 48109, USA.
(3)Department of Computational Medicine and Bioinformatics, University of
Michigan, Ann Arbor, MI 48109, USA; Department of Human Genetics, University of
Michigan, Ann Arbor, MI 48109, USA. Electronic address: [email protected].
The assay for transposase-accessible chromatin using sequencing (ATAC-seq) has
become the preferred method for mapping chromatin accessibility due to its time
and input material efficiency. However, it can be difficult to evaluate data
quality and identify sources of technical bias across samples. Here, we present
ataqv, a computational toolkit for efficiently measuring, visualizing, and
comparing quality control (QC) results across samples and experiments. We use
ataqv to analyze 2,009 public ATAC-seq datasets; their QC metrics display a
10-fold range. Tn5 dosage experiments and statistical modeling show that
technical variation in the ratio of Tn5 transposase to nuclei and sequencing
flowcell density induces systematic bias in ATAC-seq data by changing the
enrichment of reads across functional genomic annotations including promoters,
enhancers, and transcription-factor-bound regions, with the notable exception of
CTCF. ataqv can be integrated into existing computational pipelines and is
freely available at https://github.com/ParkerLab/ataqv/.
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cels.2020.02.009
PMCID: PMC8245295
PMID: 32213349 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of Interests The authors declare no
competing interests.
|
http://www.ncbi.nlm.nih.gov/pubmed/35410609
|
1. Curr Pediatr Rev. 2022;19(1):90-98. doi: 10.2174/1573396318666220410225908.
Effect of Non-nutritive Sucking during Heel-stick Procedure in Pain Management
of Term Infants in the Neonatal Intensive Care Unit: A Systematic Review and
Meta-analysis.
Akbari N(1), Mutlu B(2), Nadali J(3).
Author information:
(1)Pediatric Nursing Doctorate Program, Institute of Graduate Studies, Istanbul
University-Cerrahpaşa, Istanbul, Turkey.
(2)Pediatric Nursing Department, Florence Nightingale Nursing Faculty, Istanbul
University-Cerrahpaşa, Istanbul, Turkey.
(3)School of Nursing and Midwifery, Shahroud University of Medical Sciences,
Shahroud, Iran.
BACKGROUND: This study aimed to evaluate the efficacy of non-nutritive sucking
for analgesia in term infants undergoing heel-stick procedures.
METHODS: Randomized controlled trials and non-randomized studies based on the
PICO framework were included in the study. Review articles, commentary, pilot,
and non-English articles were excluded. Databases, such as PubMed/MEDLINE,
Embase, Scopus, Web of Science, and Cochrane, were searched until January 31st,
2021, using the keywords "Pain management", 'Non-nutritive sucking", and "Heel
stick". All studies were reviewed and retrieved by two authors independently
using a standardized form according to the inclusion criteria, and any
disagreements were examined by a third scholar. Quality assessment was evaluated
by using the ROB-2 tool. Data were analyzed using Stata version 12.0 software,
and a random-effects model was used for analysis.
RESULTS: A total of 5,629 articles were retrieved from all databases, and after
the screening, finally, 6 relevant articles were included in the analysis. The
tools used to control pain in infants in the articles included PIPP, NFCS, NIPS,
and NPASS. The results showed that the pain scores were significantly lower in
the NNS group compared to the control group (MD, -1.05; 95% CI, -1.53 to -0.57)
and NNS had a significant effect on oxygen saturation (O2 Sat) increasing in
newborns compared to the control group, but no significant reduction in the
heart rate (HR) between two groups was observed.
CONCLUSION: NNS effectively provides analgesia in full-term neonates undergoing
heel-stick procedures; however, its effects on the long-term outcomes of infants
are unclear. The results showed that NNS was effective in improving heel-stick
pain in infants.
Copyright© Bentham Science Publishers; For any queries, please email at
[email protected].
DOI: 10.2174/1573396318666220410225908
PMID: 35410609 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/35362716
|
1. Adv Neonatal Care. 2023 Apr 1;23(2):173-181. doi:
10.1097/ANC.0000000000000968. Epub 2022 Mar 29.
Agreement of the Neonatal Pain, Agitation, and Sedation Scale (N-PASS) With NICU
Nurses' Assessments.
Benbrook K(1), Manworren RCB, Zuravel R, Entler A, Riendeau K, Myler C, Ricca P.
Author information:
(1)Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois (Mss
Benbrook, Entler, Riendeau, and Myler and Drs Manworren and Zuravel);
Northwestern University's Feinberg School of Medicine, Chicago, Illinois (Dr
Manworren); and Department of Human Development & Nursing Science, University of
Illinois at Chicago, Chicago (Dr Ricca).
BACKGROUND: Objective assessment tools should standardize and reflect nurses'
expert assessments. The Neonatal Pain, Agitation, and Sedation Scale (N-PASS)
and the Neonatal Infant Pain Scale (NIPS) are valid measures of pain. The N-PASS
also provides a sedation subscale.
PURPOSE: The objective of this study was to determine N-PASS clinical validity
and utility by evaluating agreement of N-PASS scores with bedside nurses'
assessments of pain/agitation and sedation in a 64-bed tertiary neonatal
intensive care unit.
METHODS: Fifteen bedside nurses trained to use the N-PASS and the NIPS
prospectively completed 202 pain/agitation and sedation assessments from a
convenience sample of 88 infants, including chronically ventilated, medically
fragile infants. N-PASS and NIPS scores were obtained simultaneously but
independently of nurse investigators. Bedside nurses also made recommendations
about infants' pain and sedation management.
RESULTS: There was moderate agreement between N-PASS pain scores and nurses'
recommendations (κ= 0.52), very strong agreement between N-PASS sedation scores
and nurses' recommendations (κ= 0.99), and very strong associations between
N-PASS pain and NIPS scores ( P < .001). Bedside nurse and independent
investigator interrater reliability was good for N-PASS pain and NIPS scores
(intraclass correlation coefficient [ICC] = 0.83, ICC = 0.85) and excellent for
N-PASS sedation (ICC = 0.94). During 93% of assessments, bedside nurses reported
that the N-PASS reflected the level of infant sedation well or very well.
IMPLICATIONS FOR PRACTICE AND RESEARCH: The N-PASS provides an easy-to-use,
valid, and reliable objective measure of pain and sedation that reflects nurses'
assessments. Additional studies using the N-PASS are needed to verify results
and the influence of the N-PASS on pain and sedation management for medically
fragile infants with chronic medical conditions.
Copyright © 2022 by The National Association of Neonatal Nurses.
DOI: 10.1097/ANC.0000000000000968
PMID: 35362716 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflicts of interest.
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http://www.ncbi.nlm.nih.gov/pubmed/36271296
|
1. J Perinatol. 2023 May;43(5):584-589. doi: 10.1038/s41372-022-01543-x. Epub
2022 Oct 21.
Correlation of clinical pain scores with cerebral oxygenation in preterm
neonates during acute painful procedures: a prospective observational study.
Kumar S(1), Priyadarshi M(1), Singh P(1), Pallapothu B(1), Chaurasia S(1), Basu
S(2).
Author information:
(1)Department of Neonatology, All India Institute of Medical Sciences,
Rishikesh, Uttarakhand, India.
(2)Department of Neonatology, All India Institute of Medical Sciences,
Rishikesh, Uttarakhand, India. [email protected].
OBJECTIVE: The present study evaluated the correlation of Neonatal Infant Pain
Scale (NIPS) and Premature Infant Pain Profile-Revised (PIPP-R), with changes in
cerebral oxygenation (ΔcrSO2; measured by near-infrared spectroscopy) in preterm
infants during acute painful procedures (heel lance and venepuncture).
STUDY DESIGN: Prospective observational study.
METHODS: Sixty-four stable preterm (28-36 weeks) neonates were videotaped. NIPS
and PIPP-R scores were assessed on video-recordings by two independent
assessors. The primary outcome was correlation of ΔcrSO2 with NIPS and PIPP-R
scores.
RESULTS: Moderate to strong correlations were observed between ΔcrSO2 and NIPS,
and ΔcrSO2 and PIPP-R (r = 0.71 and 0.78 during heel lance and r = 0.66 and 0.75
during venepuncture, respectively). NIPS score was found easy to understand and
perform by the bedside nurses, and took lesser time as compared to PIPP-R during
both the procedures.
CONCLUSION: Both pain scores, NIPS and PIPP-R, had good correlation with ΔcrSO2
during acute painful procedures.
© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.
DOI: 10.1038/s41372-022-01543-x
PMID: 36271296 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/36291504
|
1. Children (Basel). 2022 Oct 17;9(10):1568. doi: 10.3390/children9101568.
Effectiveness of Non-Pharmacological Methods, Such as Breastfeeding, to Mitigate
Pain in NICU Infants.
Koukou Z(1), Theodoridou A(1), Taousani E(1), Antonakou A(1), Panteris E(2),
Papadopoulou SS(1), Skordou A(1), Sifakis S(3).
Author information:
(1)School of Health Sciences, International Hellenic University (IHU), 57400
Sindos Thessaloniki, Greece.
(2)Laboratory of Forensic Medicine and Toxicology, School of Medicine, Aristotle
University of Thessaloniki, 54124 Thessaloniki, Greece.
(3)Department of Obstetrics and Gynecology, Mitera Hospital, 71202 Heraklion,
Greece.
Neonates do experience pain and its management is necessary in order to prevent
long-term, as well as, short-term effects. The most common source of pain in the
neonatal intensive care unit (NICU) is caused by medically invasive procedures.
NICU patients have to endure trauma, medical adhesive related skin injuries,
heel lance, venipuncture and intramuscular injection as well as nasogastric
catheterization besides surgery. A cornerstone in pain assessment is the use of
scales such as COMFORT, PIPP-R, NIPS and N-PASS. This narrative review provides
an up to date account of neonate pain management used in NICUs worldwide
focusing on non-pharmacological methods. Non-steroidal anti-inflammatory drugs
have well established adverse side effects and opioids are addictive thus
pharmacological methods should be avoided if possible at least for mild pain
management. Non-pharmacological interventions, particularly breastfeeding and
non-nutritive sucking as primary strategies for pain management in neonates are
useful strategies to consider. The best non-pharmacological methods are
breastfeeding followed by non-nutritive sucking coupled with sucrose sucking.
Regrettably most parents used only physical methods and should be trained and
involved for best results. Further research in NICU is essential as the
developmental knowledge changes and neonate physiology is further uncovered
together with its connection to pain.
DOI: 10.3390/children9101568
PMCID: PMC9600280
PMID: 36291504
Conflict of interest statement: The authors declare no conflict of interest.
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http://www.ncbi.nlm.nih.gov/pubmed/32599608
|
1. Pediatr Res. 2021 May;89(7):1724-1731. doi: 10.1038/s41390-020-1034-z. Epub
2020 Jun 29.
Assessment of four pain scales for evaluating procedural pain in premature
infants undergoing heel blood collection.
Xie W(1), Wang X(2), Huang R(2), Chen Y(2), Guo X(2).
Author information:
(1)Department of Pediatrics, Guangzhou Women and Children's Medical Center,
Guangzhou Medical University, Guangzhou, Guangdong Province, China.
[email protected].
(2)Neonatal Intensive Care Unit, Guangzhou Women and Children's Medical Center,
Guangzhou Medical University, Guangzhou, Guangdong Province, China.
BACKGROUND: Procedural pain is underestimated in hospitalized preterm infants.
The aim of this study was to assess the reliability, validity, and clinical
utility of the Neonatal Facial Coding System (NFCS), Douleur Aiguë du Nouveau-né
(DAN) scale, Neonatal Infant Pain Scale (NIPS), and Premature Infant Pain
Profile (PIPP) in premature infants undergoing heel blood collection. We assume
that the four scales were similar in reliablility and validity (but different in
clinical utility).
METHODS: The pain assessments were performed on 111 premature infants using the
four scales. Internal consistency was determined by Cronbach's α, and the
reliability was determined by the intraclass correlation coefficients.
Concurrent validity was evaluated by Spearman's rank correlations. Bland-Altman
plots were used to investigate the convergent validity.
RESULTS: The internal consistency and their reliability of the scales were high
(p < 0.001). Scores were significantly higher at the time of blood collection
(p < 0.001). Mean scores of clinical utility of PIPP were significantly higher
than NFCS and DAN (p < 0.05) but not higher than the NIPS (p > 0.05).
CONCLUSIONS: The four scales were reliable and valid. This study suggests that
the PIPP and NIPS has good clinical utility and are better choice for evaluating
procedural pain in premature infants.
IMPACT: The aim of this study was to assess the reliability, validity, and
clinical utility of NFCS, DAN, NIPS, and PIPP in premature infants undergoing
heel blood collection. The results showed that the four scales have high
reliability and internal consistency; the PIPP and NIPS have good clinical
utility and are better choice for evaluating procedural pain in premature
infants. Our study results provided a reference for clinical workers in choosing
pain assessment scales and conduction intervention.
DOI: 10.1038/s41390-020-1034-z
PMID: 32599608 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/29282767
|
1. Scand J Caring Sci. 2018 Sep;32(3):1074-1082. doi: 10.1111/scs.12553. Epub
2017 Dec 28.
Pain assessment practices in Swedish and Norwegian neonatal care units.
Andersen RD(1)(2), Munsters JMA(3), Vederhus BJ(4), Gradin M(5).
Author information:
(1)Department of Child and Adolescent Health Services, Telemark Hospital, Skien,
Norway.
(2)Division of Nursing, Department of Neurobiology, Care Sciences and Society,
Karolinska Institutet, Stockholm, Sweden.
(3)Department of Women's and Children's Health, University Children's Hospital
Uppsala, Uppsala, Sweden.
(4)Department of Pediatrics, Haukeland University Hospital, Bergen, Norway.
(5)Department of Paediatrics, Faculty of Medicine and Health, Örebro University,
Örebro, Sweden.
BACKGROUND: The use of measurement scales to assess pain in neonates is
considered a prerequisite for effective management of pain, but these scales are
still underutilised in clinical practice.
AIM: The aim of this study was to describe and compare pain assessment practices
including the use of pain measurement scales in Norwegian and Swedish neonatal
care units.
METHODS: A unit survey investigating practices regarding pain assessment and the
use of pain measurement scales was sent to all neonatal units in Sweden and
Norway (n = 55). All Norwegian and 92% of Swedish units responded.
RESULTS: A majority of the participating units (86.5%) assessed pain. Swedish
units assessed and documented pain and used pain measurement scales more
frequently than Norwegian units. The most frequently used scales were different
versions of Astrid Lindgren's Pain Scale (ALPS) in Sweden and Echelle Douleur
Inconfort Noveau-Ne (EDIN), ALPS and Premature Infant Pain Profile (PIPP) in
Norway. Norwegian head nurses had more confidence in their pain assessment
method and found the use of pain measurement scales more important than their
Swedish colleagues.
CONCLUSION: The persisting difference between Swedish and Norwegian units in
pain assessment and the use of pain measurement scales are not easily explained.
However, the reported increased availability and reported use of pain
measurement scales in neonatal care units in both countries may be seen as a
contribution towards better awareness and recognition of pain, better pain
management and potentially less suffering for vulnerable neonates.
© 2017 Nordic College of Caring Science.
DOI: 10.1111/scs.12553
PMID: 29282767 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/20976299
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1. Int J Pediatr. 2010;2010:496719. doi: 10.1155/2010/496719. Epub 2010 Oct 5.
COVERS Neonatal Pain Scale: Development and Validation.
Hand IL(1), Noble L, Geiss D, Wozniak L, Hall C.
Author information:
(1)Division of Neonatology, Department of Pediatrics, Queens Hospital Center,
Mount Sinai School of Medicine, 82-68 164th Street, Jamaica, NY 11432, USA.
Newborns and infants are often exposed to painful procedures during
hospitalization. Several different scales have been validated to assess pain in
specific populations of pediatric patients, but no single scale can easily and
accurately assess pain in all newborns and infants regardless of gestational age
and disease state. A new pain scale was developed, the COVERS scale, which
incorporates 6 physiological and behavioral measures for scoring. Newborns
admitted to the Neonatal Intensive Care Unit or Well Baby Nursery were evaluated
for pain/discomfort during two procedures, a heel prick and a diaper change.
Pain was assessed using indicators from three previously established scales
(CRIES, the Premature Infant Pain Profile, and the Neonatal Infant Pain Scale),
as well as the COVERS Scale, depending upon gestational age. Premature infant
testing resulted in similar pain assessments using the COVERS and PIPP scales
with an r = 0.84. For the full-term infants, the COVERS scale and NIPS scale
resulted in similar pain assessments with an r = 0.95. The COVERS scale is a
valid pain scale that can be used in the clinical setting to assess pain in
newborns and infants and is universally applicable to all neonates, regardless
of their age or physiological state.
DOI: 10.1155/2010/496719
PMCID: PMC2952799
PMID: 20976299
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http://www.ncbi.nlm.nih.gov/pubmed/29945293
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1. J Clin Nurs. 2018 Oct;27(19-20):3522-3529. doi: 10.1111/jocn.14585. Epub 2018
Jul 27.
Evaluation of three pain assessment scales used for ventilated neonates.
Huang XZ(1), Li L(1), Zhou J(2), He F(1), Zhong CX(3), Wang B(3).
Author information:
(1)Department of Nursing, Zhujiang Hospital, Southern Medical University,
Guangzhou, Guangdong, China.
(2)Department of Biostatistics, College of Public Health and Tropical Medicine,
Southern Medical University, Guangzhou, Guangdong, China.
(3)Department of Pediatrics, Zhujiang Hospital, Southern Medical University,
Guangzhou, Guangdong, China.
AIMS AND OBJECTIVES: To compare and evaluate the reliability, validity,
feasibility, clinical utility, and nurses' preference of the Premature Infant
Pain Profile-Revised, the Neonatal Pain, Agitation, and Sedation Scale, and the
Neonatal Infant Acute Pain Assessment Scale used for procedural pain in
ventilated neonates.
BACKGROUND: Procedural pain is a common phenomenon but is undermanaged and
underassessed in hospitalised neonates. Information for clinician selecting pain
measurements to improve neonatal care and outcomes is still limited.
DESIGN: A prospective observational study was used.
METHODS: A total of 1,080 pain assessments were made at 90 neonates by two
nurses independently, using three scales viewing three phases of videotaped
painful (arterial blood sampling) and nonpainful procedures (diaper change).
Internal consistency, inter-rater reliability, discriminant validity, concurrent
validity and convergent validity of scales were analysed. Feasibility, clinical
utility and nurses' preference of scales were also investigated.
RESULTS: All three scales showed excellent inter-rater coefficients (from
0.991-0.992) and good internal consistency (0.733 for the Premature Infant Pain
Profile-Revised, 0.837 for the Neonatal Pain, Agitation, and Sedation Scale and
0.836 for the Neonatal Infant Acute Pain Assessment Scale, respectively). Scores
of painful and nonpainful procedures on the three scales changed significantly
across the phases. There was a strong correlation between the three scales with
adequate limits of agreement. The mean scores of the Neonatal Pain, Agitation,
and Sedation Scale for feasibility and utility were significantly higher than
those of the Neonatal Infant Acute Pain Assessment Scale, but not significantly
higher than those of the Premature Infant Pain Profile-Revised. The Neonatal
Pain, Agitation, and Sedation Scale was mostly preferred by 55.9% of the nurses,
followed by the Neonatal Infant Acute Pain Assessment Scale (23.5%) and the
Premature Infant Pain Profile-Revised (20.6%).
CONCLUSIONS: The three scales are all reliable and valid, but the Neonatal Pain,
Agitation, and Sedation Scale and the Neonatal Infant Acute Pain Assessment
Scale perform better in reliability. The Neonatal Pain, Agitation, and Sedation
Scale appears to be a better choice for frontier nurses to assess procedural
pain in ventilated neonates based on its good feasibility, utility and nurses'
preference.
RELEVANCE TO CLINICAL PRACTICE: Choosing a valid, reliable, feasible and
practical measurement is the key step for better management of procedural pain
for ventilated newborns. Using the right and suitable tool is helpful to
accurately identify pain, ultimately improve the neonatal care and outcomes.
© 2018 John Wiley & Sons Ltd.
DOI: 10.1111/jocn.14585
PMID: 29945293 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/14747965
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1. Klin Padiatr. 2004 Jan-Feb;216(1):16-20. doi: 10.1055/s-2004-817682.
[Measures for the assessment of pain in neonates as well as a comparison between
the Bernese Pain Scale for Neonates (BPSN) with the Premature Infant Pain
Profile (PIPP)].
[Article in German]
Gessler P(1), Cignacco E.
Author information:
(1)Universitäts-Kinderklinik, Zurich, Switzerland.
BACKGROUND: Neonate's expression of pain lacks the ability to report pain.
Several pain measures exist to assess acute pain in term and preterm neonates.
The aim of the present study is to compare them with respect to their validity
and reliability.
METHOD: Review of the literature and a description of the measures most often
cited. Additionally, the validity of the Bernese Pain Scale for Neonates (BPSN)
was assessed in a department of neonatology of a university hospital.
PATIENTS: Assessments of pain (n = 48) in term and preterm neonates with and
without respiratory support.
RESULTS: Existing pain measures are using behavioural indicators of pain (eg,
facial expression, body posture, movements, and vigilance) as well as
physiological indicators of pain (eg, changes in heart rate, respiratory rate,
blood pressure, oxygen saturation). The used measures and their feasibility in
everyday practice, the study population and the method of validation were
presented. The BPSN differentiates pain from nonpain (F = 41.27, p < 0.0001) and
the interrater- as well as the intrarater-reliability was high (r = 0.87 - 0.98
and r = 0.98 - 0.99, respectively).
CONCLUSIONS: Assessment of acute pain in neonates should take into account the
way of validation that has been performed especially with respect to the study
population. The BSN is a pain measure with good validity and reliability for the
assessment of pain in term and preterm neonates.
DOI: 10.1055/s-2004-817682
PMID: 14747965 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18446656
|
1. J Matern Fetal Neonatal Med. 2008 May;21(5):305-8. doi:
10.1080/14767050802034107.
Comparison of three neonatal pain scales during minor painful procedures.
Uyan ZS(1), Bilgen H, Topuzoğlu A, Akman I, Ozek E.
Author information:
(1)Department of Pediatrics, Marmara University Hospital, Istanbul, Turkey.
[email protected]
OBJECTIVE: There is no single or widely accepted method to define pain in
neonates. The aim of this study was to compare three different neonatal pain
scales in the estimation of the pain response to minor painful stimuli in
healthy term neonates.
METHOD: Thirty healthy neonates were included in the study. Video recordings of
infants during heel prick blood sampling were evaluated by two observers
according to the Neonatal Infant Pain Scale (NIPS), the Neonatal Facial Coding
System (NFCS), and the Douleur Aiguë du Nouveau-né (DAN). Crying times of
infants were recorded, and the correlation between the three pain scales and
crying time was calculated. The pain scores and inter-observer variability were
analyzed.
RESULTS: The highest correlation between the crying time and each of the three
different neonatal pain scales was found for NIPS (r = 0.74, p<0.001), while
similar results were found for the DAN scale (r = 0.67, p <0.001) and the NFCS
(r = 0.67, p<0.001). Inter-observer variability was similar for the three scales
(NFCS r = 0.95; DAN r = 0.97; NIPS r = 0.96). NFCS had a coefficient of
variation (CV) of 59.8 +/- 32.2%. The DAN scale and NIPS had similar CV values
(41.5 +/- 26.1% and 43.2 +/- 31.6%, respectively), but these values were
significantly lower than that of NFCS.
CONCLUSION: All three scales provided comparable results, with a slight
difference favoring NIPS. Therefore, NIPS can be used to evaluate pain during
minor painful procedures in neonates.
DOI: 10.1080/14767050802034107
PMID: 18446656 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/16885171
|
1. Br J Anaesth. 2006 Oct;97(4):540-4. doi: 10.1093/bja/ael184. Epub 2006 Aug 1.
A comparison of postoperative pain scales in neonates.
Suraseranivongse S(1), Kaosaard R, Intakong P, Pornsiriprasert S, Karnchana Y,
Kaopinpruck J, Sangjeen K.
Author information:
(1)Department of Anesthesiology, Faculty of Medicine, Siriraj Hospital, Mahidol
University, Bangkok 10700, Thailand. [email protected]
BACKGROUND: Practical, valid and reliable pain measuring tools in neonates are
required in clinical practice for effective pain management and prevention of
the evaluator bias.
METHODS: This prospective study was designed to cross-validate three pain
scales: CRIES (cry, requires O(2), increased vital signs, expression,
sleeplessness), CHIPPS (children's and infants' postoperative pain scale) and
NIPS (neonatal infant pain scale) in terms of validity, reliability and
practicality. The pain scales were translated. Concurrent validity, predictive
validity and interrater reliability in postoperative pain were studied in 22
neonates after major surgery. Construct validity and concurrent validity in
procedural pain were determined in 24 neonates before and during frenulectomy
under topical anaesthesia.
RESULTS: All scales had excellent interrater reliability (intraclass correlation
>0.9). Construct validity was determined for all pain scales by the ability to
differentiate the group with low pain scores before surgery and high scores
during surgery (P<0.001). The positive correlations among all scales, ranging
between r=0.30 and r=0.91, supported concurrent validity. CRIES showed the
lowest correlation with other scales with correlation coefficients of r=0.30 and
r=0.35. All scales yielded very good agreement (K>0.9) with routine decisions to
treat postoperative pain. High sensitivity and specificity (>90%) for
postoperative pain from all scales were achieved with the same cut-off point of
4. In terms of practicality, NIPS was the most acceptable (65%).
CONCLUSIONS: Based on our findings, we recommended NIPS as a valid, reliable and
practical tool.
DOI: 10.1093/bja/ael184
PMID: 16885171 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/26553356
|
1. An Pediatr (Barc). 2016 Oct;85(4):181-188. doi: 10.1016/j.anpedi.2015.09.019.
Epub 2015 Nov 6.
[Clinical assessment of pain in Spanish Neonatal Intensive Care Units].
[Article in Spanish]
Avila-Alvarez A(1), Carbajal R(2), Courtois E(2), Pertega-Diaz S(3), Anand
KJ(4), Muñiz-Garcia J(5); Grupo español del proyecto Europain.
Author information:
(1)Unidad de Neonatología, Servicio de Pediatría, Instituto de Investigación
Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña
(CHUAC), SERGAS, Universidade de A Coruña (UDC), A Coruña, España. Electronic
address: [email protected].
(2)Service d'Urgences Pédiatriques. Hôpital d'enfants Armand Trousseau, Inserm
UMR 1153 Equipe de recherche en Epidémiologie Obstétricale, Périnatale et
Pédiatrique (EPOPé), Université Pierre et Marie Curie, París, Francia.
(3)Grupo de Investigación de Epidemiología Clínica y Bioestadística, Instituto
de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario
Universitario de A Coruña (CHUAC), SERGAS, Universidade de A Coruña (UDC), A
Coruña, España.
(4)University of Tennessee Health Science Center, Memphis, Estados Unidos.
(5)Instituto Universitario de Ciencias de la Salud e Instituto de Investigación
Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña
(CHUAC), Sergas, Universidade de A Coruña (UDC), A Coruña, España.
INTRODUCTION: Clinical scales are currently the best method to assess pain in
the neonate, given the impossibility of self-report in this age group. A study
is designed with the aim of determining the current practices as regards the
clinical assessment of pain in Spanish Neonatal Units and the factors associated
with the use of clinical scales.
METHODS: A prospective longitudinal observational study was conducted. A total
of 30 Units participated and 468 neonates were included.
RESULTS: Only 13 Units (43.3%) had pain assessment protocols. Pain was evaluated
with a scale in 78 neonates (16.7%, 95% CI; 13.1-20.1) and the mean number of
pain assessments per patient and per day was 2.3 (Standard Deviation; 4.8), with
a median of 0.75. Of the total number of 7,189 patient-days studied, there was
at least one pain assessment in 654 (9.1%). No pain assessment was performed
with a clinical scale on any patient in 20 (66.7%) Units. Among those that did,
a wide variation was observed in the percentage of patients in whom pain was
assessed, as well as in the scales used. The CRIES (C-Crying; R-Requires
increased oxygen administration; I-Increased vital signs; E-Expression;
S-Sleeplessness) scale was that used in most Units. In the multivariate
analysis, only invasive mechanical ventilation was associated with receiving a
pain assessment with a scale (OR 1.46, P=.042).
DISCUSSION: The majority of neonates admitted into Intensive Care in Spain do
not receive a pain assessment. Many units still do not routinely use clinical
scales, and there is a wide variation between those that do use them. These
results could serve as a basis for preparing national guidelines as regards pain
in the neonate.
Copyright © 2015 Asociación Española de Pediatría. Publicado por Elsevier
España, S.L.U. All rights reserved.
DOI: 10.1016/j.anpedi.2015.09.019
PMID: 26553356 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/9535312
|
1. Clin J Pain. 1998 Mar;14(1):39-47. doi: 10.1097/00002508-199803000-00006.
A simultaneous comparison of three neonatal pain scales during common NICU
procedures.
Blauer T(1), Gerstmann D.
Author information:
(1)Division of Neonatology, Utah Valley Regional Medical Center, Provo 84604,
USA.
OBJECTIVE: This study evaluated neonatal pain scales during procedures commonly
performed in a neonatal intensive care unit.
DESIGN: Evaluated were the Neonatal Infant Pain Scale (NIPS), the Comfort scale,
and a new scale known as the Scale for Use in Newborns (SUN). Four procedures
were scored: intubation, intravenous catheter insertion, endotracheal tube
suctioning, and diaper changes. Scoring was done before, during, and after each
procedure. Thirty-three patients were tested during 68 procedures with 1,428
scale scores.
RESULTS: All scales demonstrated significant changes. In before-versus-during
for each procedure, the increase in pain scale score was significant for the
NIPS, Comfort scale, and SUN. All three scales also demonstrated a return to
baseline (before-vs.-after) for the four procedures, except for the Comfort
scale, which remained elevated (p < .05) following diaper change. The NIPS had a
significantly larger coefficient of variation (CV, 188% +/- 99%), whereas the
Comfort scale and SUN had small CVs (27% +/- 5% and 33% +/- 8%, respectively).
In evaluating potential confounding influences, it was found that infants > 2.5
kg on sedative or analgesic medications appeared to have procedure-related
accentuation and sustained elevation in scale scores, whereas swaddling seemed
to provide little added benefit.
CONCLUSIONS: The pain scale scores identify changes in an infant's
behavior/physiologic state. It is unclear whether these changes are totally
"pain specific." In comparing the three scales, the SUN overall was a preferable
tool because of its ease of use, scale symmetry, and scoring consistency.
DOI: 10.1097/00002508-199803000-00006
PMID: 9535312 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/32401971
|
1. Rev Bras Ter Intensiva. 2020 Mar;32(1):66-71. doi: 10.5935/0103-507x.20200011.
Epub 2020 May 8.
Temporal assessment of neonatal pain after airway aspiration.
Gimenez IL(1), Rodrigues RF(1), Oliveira MCF(1), Santos BAR(1), Arakaki
VDSNM(1), Santos RSD(2), Peres RT(3), Sant'Anna CC(4), Ferreira HC(2).
Author information:
(1)Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil.
(2)Departamento de Fisioterapia, Faculdade de Medicina, Universidade Federal do
Rio de Janeiro, Rio de Janeiro, RJ, Brasil.
(3)Departamento de Matemática, Centro Federal de Educação Tecnológica Celso
Suckow da Fonseca, Rio de Janeiro, RJ, Brasil.
(4)Departamento de Pediatria, Faculdade de Medicina, Universidade Federal do Rio
de Janeiro, Rio de Janeiro, RJ, Brasil.
OBJECTIVE: To temporally assess a painful stimulus in premature infants using 3
neonatal pain scales.
METHODS: A total of 83 premature infants were observed during airway aspiration
by 3 evaluators (E1, E2 and E3) using 3 pain assessment scales (Neonatal Facial
Coding System - NFCS; Neonatal Infant Pain Scale - NIPS; and Premature Infant
Pain Profile - PIPP) at 5 time points: T1 (before airway aspiration), T2 (during
airway aspiration), T3 (1 minute after airway aspiration), T4 (3 minutes after
airway aspiration), and T5 (5 minutes after airway aspiration). Light's Kappa
(agreement among examiners and among scales at each time point) and the McNemar
test (comparison among time points) were used considering p < 0.05.
RESULTS: There was a significant difference between the 3 examiners for T1 and
T2 using the 3 scales. In T3, pain was observed in 22.9%/E1, 28.9%/E2, and
24.1%/E3 according to the NFCS; 22.9%/E1, 21.7%/E2, and 16.9%/E3 according to
the NIPS; and 49.4%/E1, 53.9%/E2, and 47%/E3 according to the PIPP. There was a
difference between T1 and T3 using the 3 scales, except for 2 examiners for the
PIPP (E2: p = 0.15/E3: p = 0.17). Comparing T4 and T5 to T1, there was no
difference in the 3 scales.
CONCLUSION: Premature infants required at least 3 minutes to return to their
initial state of rest (no pain).
OBJETIVO: Avaliar temporalmente o estímulo doloroso em prematuros com o uso de
três escalas de mensuração de dor neonatal.
MÉTODOS: Foram observados 83 prematuros durante a aspiração de vias aéreas por
três avaliadores (E1, E2 e E3) utilizando três escalas de avaliação da dor
(Neonatal Facial Coding System - NFCS; Neonatal Infant Pain Scale - NIPS; e
Premature Infant Pain Profile - PIPP) em cinco momentos: T1 (antes da aspiração
de vias aéreas), T2 (durante a aspiração de vias aéreas), T3 (1 minuto após a
aspiração de vias aéreas), T4 (3 minutos após a aspiração de vias aéreas) e T5
(5 minutos após a aspiração de vias aéreas). Utilizaram-se o Light’s Kappa
(concordância entre examinadores e entre as escalas em cada tempo) e teste de
McNemar (comparação entre os tempos), considerando-se p < 0,05.
RESULTADOS: Houve diferença significativa entre T1 e T2 para os três
examinadores nas três escalas. Em T3, observou-se dor em 22,9%/E1, 28,9%/E2 e
24,1%/E3 de acordo com a NFCS; 22,9%/E1, 21,7%/E2 e 16,9%/E3, conforme a NIPS e
49,4%/E1, 53,9%/E2 e 47%/E3 considerando a PIPP dos prematuros. Houve diferença
entre T1 e T3 nas três escalas, exceto para dois examinadores na PIPP (E2: p =
0,15/ E3: p = 0,17). Ao comparar T4 e T5 ao T1, não houve diferença em nenhuma
das três escalas.
CONCLUSÃO: Os prematuros necessitaram de pelo menos 3 minutos para retornarem ao
seu estado inicial de repouso (sem dor).
DOI: 10.5935/0103-507x.20200011
PMCID: PMC7206953
PMID: 32401971 [Indexed for MEDLINE]
Conflict of interest statement: Conflicts of interest: None.
|
http://www.ncbi.nlm.nih.gov/pubmed/32801846
|
1. J Pain Res. 2020 Jul 24;13:1883-1897. doi: 10.2147/JPR.S248042. eCollection
2020.
Pain Scales in Neonates Receiving Mechanical Ventilation in Neonatal Intensive
Care Units - Systematic Review.
Popowicz H(1), Kwiecień-Jaguś K(2), Olszewska J(1), Mędrzycka-Dąbrowska WA(2).
Author information:
(1)Department of Obstetric and Gynaecological Nursing, Medical University of
Gdansk, Gdansk, Poland.
(2)Department of Anaesthesiology Nursing and Intensive Care, Medical University
of Gdansk, Gdansk, Poland.
INTRODUCTION: Recently, interest in the problem of proper prevention and
monitoring of pain, especially acute, has been increasing in relation to various
age groups. Greater awareness of the problem prompts discussion about the
purpose of analgesia in newborns treated with mechanical ventilation.
AIM: The purpose of the systematic review was to analyze current research on the
use of pain scales in newborns treated with mechanical ventilation in the
Neonatal Intensive Care Unit.
METHODS: Medline databases: PubMed, OVID, EBSCO, Web of Science and Cochrane
Library were traced using the appropriate keywords. The search was limited to
studies in English. The review took into account the years 2006-2019.
Considering the criteria, 12 articles were included in further analysis, to
which full access was obtained.
RESULTS: The analyzed scientific research showed differences in beliefs about
the validity and credibility of the scales used. Researchers indicated that
staff with practical experience in using scales in their daily practice was very
skeptical of the results obtained on their basis.
CONCLUSION: Based on this review, no explicit evidence can be obtained to
support the use of one proper scale in pain assessment. It can be inferred that
the COMFORT and N-PASS scales are effective for pain assessment and for
determining the need for analgesics in mechanically ventilated neonates. These
scales may be equally effective in assessing chronic pain, especially in
mechanically ventilated children. On the other hand, the PIPP and CRIES scales
are most commonly recommended for assessing acute and postoperative pain.
© 2020 Popowicz et al.
DOI: 10.2147/JPR.S248042
PMCID: PMC7399469
PMID: 32801846
Conflict of interest statement: None of the authors discloses potential conflict
of interest in this work.
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http://www.ncbi.nlm.nih.gov/pubmed/30738649
|
1. Lancet. 2019 Mar 9;393(10175):1009-1020. doi: 10.1016/S0140-6736(19)30194-1.
Epub 2019 Feb 6.
Prehospital transdermal glyceryl trinitrate in patients with ultra-acute
presumed stroke (RIGHT-2): an ambulance-based, randomised, sham-controlled,
blinded, phase 3 trial.
RIGHT-2 Investigators.
Collaborators: Bath PM, Scutt P, Anderson CS, Appleton JP, Berge E, Cala L,
Dixon M, England TM, Godolphin PJ, Havard D, Haywood L, Hepburn T, Krishnan K,
Mair G, Montgomery AA, Muir K, Phillips SJ, Pocock S, Potter J, Price C, Randall
M, Robinson TG, Roffe C, Rothwell PM, Sandset EC, Sanossian N, Saver JL, Shone
A, Siriwardena AN, Wardlaw JM, Woodhouse LJ, Venables G, Sprigg N, Amarenco P,
Muir K, Amoils S, Jarvis M, Rothwell PM, Sandercock P, Asplund K, Baigent C,
Ankolekar S, Howard H, Lysons C, Walker G, Gregory H, Kirby J, Smithson J,
Keeling J, Frowd N, Gray R, Dooley R, Clarke W, Robinson P, Law ZK, Hodgson S,
Millington A, Sakka E, Buchanan D, Palmer J, Shaw D, Cobb H, Johnson R, Payne T,
Spaight R, Spaight A, Sajid MA, Whileman A, Hall E, Cripps H, Toms J, Gascoyne
R, Wright S, Cooper M, Palfreman A, Rajapakse A, Wynter I, Musarrat K, Mistri A,
Patel C, Stephens C, Khan S, Patras S, Soliman M, Elmarimi A, Hewitt C, Watson
E, Wahishi I, Hindle J, Perkin L, Wills M, Arif S, Leach S, Butler S, O'Kane D,
Smith C, O'Callaghan J, Sunman W, Buck A, Jackson B, Richardson C, Wilkes G,
Clarke J, Ryan L, Matias O, Mangion D, Hardwick A, Constantin C, Thomas I,
Netherton K, Markova S, Hedstrom A, Rushton B, Hyde C, Scott J, Blair M, Maddula
M, Donnelly R, Keane S, Johnson S, McKenzie H, Banerjee A, Hutchinson D,
Goodhand H, Hill J, Mellows K, Cheeseman M, McTaggart V, Foster T, Prothero L,
Saksena P, O'Kelly A, Wyllie H, Hacon C, Nutt H, North J, Goffin K, Potter J,
Wiltshire A, Ravenhill G, Metcalf K, Ford L, Langley M, Davison W, Subramonian
S, Magezi F, Obi I, Temple N, Butterworth-Cowin N, Oqwusu-Agyei P, Azim AFM,
Nicolson A, Imam J, White J, Wood L, Fothergill R, Thompson N, Lazarus J, Werts
H, Sztriha L, Ho C, McKenzie E, Owoyele E, Lim J, Aeron-Thomas J, Dockey M,
Sylvester N, Rao P, Bloom BM, Erumere E, Norman G, Skene I, Cuenoud L, Howaniec
L, Boulton O, Daboo P, Michael R, Al-Saadi S, Harrison T, Syed H, Argandona L,
Amiani S, Perry R, Ashton A, Banaras A, Hogan C, Watchurst C, Elliott E, Francia
N, Oji N, Erande R, Obarey S, Feerick S, Tshuma S, England E, Pocock H, Poole K,
Manchanda S, Burn I, Dayal S, McNee K, Robinson M, Hancock R, South A, Holmes C,
Steele A, Guthrie LB, Oborn M, Nor AM, Hyams B, Eglinton C, Waugh D, Cann E,
Wilmhurst N, Piesley S, Shave S, Dutta D, Obeid M, Ward D, Turfrey J, Glass J,
Bowstead K, Hill L, Brown P, Beames S, O'Connell S, Hughes V, Whiting R, Gagg J,
Hussain M, Harvey M, Karunatilake D, Pusuluri B, Witcher A, Pawley C, Allen J,
Foot J, Rowe J, Lane C, Ragab S, Wadams B, Dube J, Jupp B, Ljubez A, Bagnall C,
Hann G, Tucker L, Kelton M, Orr S, Harrington F, James A, Lydon A, Courtauld G,
Bond K, Lucas L, Nisbett T, Kubie J, Bowring A, Jennings G, Thorpe K, Mason N,
Keenan S, Gbadomishi L, Howcroft D, Newton H, Choulerton J, Avis J, Shaw L,
Paterson P, Kaye P, Hierons S, Lucas S, Clatworthy P, Faulkner B, Rannigan L,
Worner R, Bhaskaran B, Saulat A, Bearne H, Garfield-Smith J, Horan K, Fitzell P,
Szabo S, Haley M, Simmons D, Cotterill D, Saunders G, Dymond H, Beech S, Rashed
K, Tanate A, Buckley C, Wood D, Matthews L, Board S, Pitt-Kirby T, Rees N,
Convery C, Jones P, Bryant C, Tench H, Dixon M, Loosley R, Coetzee S, Jones S,
Sims T, Krishnan M, Davies C, Quinn L, Connor L, Wani M, Storton S, Treadwell S,
Anjum T, Somashekar C, Chandler A, Triscott C, Bevan L, Sander M, Buckle S,
Sayed W, Andrews K, Hughes L, Hughes R, Ward M, Pretty A, Rosser A, Davidson B,
Price G, Gunson I, Lumley-Holmes J, Miller J, Larden M, Jhamat M, Horwood P,
Boldy R, Jenkins C, Price F, Harrison M, Martin T, Ahmad N, Willberry A, Stevens
A, Fotherby K, Barry A, Remegoso A, Alipio F, Maquire H, Hiden J, Finney K,
Varquez R, Ispoglou S, Hayes A, Gull D, Evans R, Epstein E, Hurdowar S, Crossley
J, Miles J, Hird K, Pilbery R, Patterson C, Ramadan H, Stewart K, Quinn O,
Bellfield R, Macquire S, Gaba W, Nair A, Wilson A, Hawksworth C, Alam I, Greig
J, Robinson M, Gomes P, Rana P, Ahmed Z, Anderston P, Neal A, Walstow D, Fong R,
Brotheridge S, Bwalya A, Gillespie A, Midgley C, Hare C, Lyon H, Stephenson L,
Broome M, Worton R, Jackson S, Rayessa R, Abdul-Hamid A, Naylor C, Clarkson E,
Hassan A, Waugh D, Veraque E, Finch L, Makawa L, Carpenter M, Datta P, Needle A,
Jackson L, Brooke HJ, Ball J, Lowry T, Punnoose S, Walker R, Murray V, Ali A,
Kamara C, Doyle C, Richards E, Howe J, Dakin K, Harkness K, Lindert R, Wanklyn
P, Willcoxson P, Clark-Brown P, Mir R.
Comment in
Lancet. 2019 Mar 9;393(10175):963-965. doi: 10.1016/S0140-6736(19)30276-4.
BACKGROUND: High blood pressure is common in acute stroke and is a predictor of
poor outcome; however, large trials of lowering blood pressure have given
variable results, and the management of high blood pressure in ultra-acute
stroke remains unclear. We investigated whether transdermal glyceryl trinitrate
(GTN; also known as nitroglycerin), a nitric oxide donor, might improve outcome
when administered very early after stroke onset.
METHODS: We did a multicentre, paramedic-delivered, ambulance-based,
prospective, randomised, sham-controlled, blinded-endpoint, phase 3 trial in
adults with presumed stroke within 4 h of onset, face-arm-speech-time score of 2
or 3, and systolic blood pressure 120 mm Hg or higher. Participants were
randomly assigned (1:1) to receive transdermal GTN (5 mg once daily for 4 days;
the GTN group) or a similar sham dressing (the sham group) in UK-based
ambulances by paramedics, with treatment continued in hospital. Paramedics were
unmasked to treatment, whereas participants were masked. The primary outcome was
the 7-level modified Rankin Scale (mRS; a measure of functional outcome) at 90
days, assessed by central telephone follow-up with masking to treatment.
Analysis was hierarchical, first in participants with a confirmed stroke or
transient ischaemic attack (cohort 1), and then in all participants who were
randomly assigned (intention to treat, cohort 2) according to the statistical
analysis plan. This trial is registered with ISRCTN, number ISRCTN26986053.
FINDINGS: Between Oct 22, 2015, and May 23, 2018, 516 paramedics from eight UK
ambulance services recruited 1149 participants (n=568 in the GTN group, n=581 in
the sham group). The median time to randomisation was 71 min (IQR 45-116). 597
(52%) patients had ischaemic stroke, 145 (13%) had intracerebral haemorrhage,
109 (9%) had transient ischaemic attack, and 297 (26%) had a non-stroke mimic at
the final diagnosis of the index event. In the GTN group, participants' systolic
blood pressure was lowered by 5·8 mm Hg compared with the sham group (p<0·0001),
and diastolic blood pressure was lowered by 2·6 mm Hg (p=0·0026) at hospital
admission. We found no difference in mRS between the groups in participants with
a final diagnosis of stroke or transient ischaemic stroke (cohort 1): 3 (IQR
2-5; n=420) in the GTN group versus 3 (2-5; n=408) in the sham group, adjusted
common odds ratio for poor outcome 1·25 (95% CI 0·97-1·60; p=0·083); we also
found no difference in mRS between all patients (cohort 2: 3 [2-5]; n=544, in
the GTN group vs 3 [2-5]; n=558, in the sham group; 1·04 [0·84-1·29]; p=0·69).
We found no difference in secondary outcomes, death (treatment-related deaths:
36 in the GTN group vs 23 in the sham group [p=0·091]), or serious adverse
events (188 in the GTN group vs 170 in the sham group [p=0·16]) between
treatment groups.
INTERPRETATION: Prehospital treatment with transdermal GTN does not seem to
improve functional outcome in patients with presumed stroke. It is feasible for
UK paramedics to obtain consent and treat patients with stroke in the
ultra-acute prehospital setting.
FUNDING: British Heart Foundation.
Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open
Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All
rights reserved.
DOI: 10.1016/S0140-6736(19)30194-1
PMCID: PMC6497986
PMID: 30738649 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/31587658
|
1. Stroke. 2019 Nov;50(11):3064-3071. doi: 10.1161/STROKEAHA.119.026389. Epub
2019 Oct 7.
Prehospital Transdermal Glyceryl Trinitrate for Ultra-Acute Intracerebral
Hemorrhage: Data From the RIGHT-2 Trial.
Bath PM(1)(2), Woodhouse LJ(1), Krishnan K(2), Appleton JP(1), Anderson
CS(3)(4)(5), Berge E(6)(7), Cala L(8), Dixon M(1)(9), England TJ(10), Godolphin
PJ(11), Hepburn T(11), Mair G(12), Montgomery AA(11), Phillips SJ(13), Potter
J(14), Price CI(15), Randall M(16), Robinson TG(17), Roffe C(18), Rothwell
PM(19), Sandset EC(20), Sanossian N(21), Saver JL(22), Siriwardena AN(6)(23),
Venables G(24), Wardlaw JM(12), Sprigg N(1)(2).
Author information:
(1)From the Stroke Trials Unit, Division of Clinical Neuroscience, University of
Nottingham, United Kingdom (P.M.B., L.J.W., J.P.A., M.D., N.S.).
(2)Stroke, Nottingham University Hospitals National Health Service (NHS) Trust,
City Hospital Campus, United Kingdom (P.M.B., K.K., N.S.).
(3)The George Institute for Global Health, Faculty of Medicine, University of
New South Wales, Sydney, Australia (C.S.A.).
(4)The George Institute China at Peking University Health Science Center,
Beijing, China (C.S.A.).
(5)Neurology Department, Royal Prince Alfred Hospital, Sydney Health Partners,
NSW, Australia (C.S.A.).
(6)Department of Internal Medicine (E.B., A.N.S), Oslo University Hospital,
Norway.
(7)Department of Neurology (E.C.S.), Oslo University Hospital, Norway.
(8)Faculty of Health and Medical Sciences, University of Western Australia
(L.C.).
(9)East Midlands Ambulance Service NHS Trust, Nottingham, United Kingdom (M.D.).
(10)Vascular Medicine, Division of Medical Sciences, GEM, Royal Derby Hospital
Centre (T.J.E.), University of Nottingham, United Kingdom.
(11)Nottingham Clinical Trials Unit, Queen's Medical Centre (P.J.G., T.H.,
A.A.M.), University of Nottingham, United Kingdom.
(12)Centre for Clinical Brain Sciences, Edinburgh Imaging and UK Dementia
Research Institute at the University of Edinburgh, Chancellor's Building (G.M.,
J.M.W.).
(13)Department of Medicine, Dalhousie University and Queen Elizabeth II Health
Sciences Centre, Halifax, Canada (S.J.P.).
(14)Bob Champion Research and Education Building, University of East Anglia,
Norwich, United Kingdom (J.P.).
(15)Institute of Neuroscience, Newcastle University, United Kingdom (C.I.P.).
(16)Department of Neurology, Leeds Teaching Hospitals NHS Trust, United Kingdom
(M.R.).
(17)Department of Cardiovascular Sciences and NIHR Leicester Biomedical Research
Centre, University of Leicester, United Kingdom (T.G.R.).
(18)Stroke Research in Stoke, Institute for Science and Technology in Medicine,
Keele University, Stoke-on-Trent, United Kingdom (C.R.).
(19)Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital,
Oxford, United Kingdom (P.M.R.).
(20)Research and Development, The Norwegian Air Ambulance Foundation, Oslo,
Norway (E.C.S.).
(21)Department of Neurology, University of Southern California Keck School of
Medicine, Los Angeles (N.S.).
(22)Department of Neurology and Comprehensive Stroke Center, David Geffen School
of Medicine at UCLA (J.L.S.).
(23)Community and Health Research Unit, University of Lincoln, United Kingdom
(A.N.S.).
(24)Department of Neurology, Royal Hallamshire Hospital, Sheffield, United
Kingdom (G.V.).
Background and Purpose- Pilot trials suggest that glyceryl trinitrate (GTN;
nitroglycerin) may improve outcome when administered early after stroke onset.
Methods- We undertook a multicentre, paramedic-delivered, ambulance-based,
prospective randomized, sham-controlled, blinded-end point trial in adults with
presumed stroke within 4 hours of ictus. Participants received transdermal GTN
(5 mg) or a sham dressing (1:1) in the ambulance and then daily for three days
in hospital. The primary outcome was the 7-level modified Rankin Scale at 90
days assessed by central telephone treatment-blinded follow-up. This
prespecified subgroup analysis focuses on participants with an intracerebral
hemorrhage as their index event. Analyses are intention-to-treat. Results- Of
1149 participants with presumed stroke, 145 (13%; GTN, 74; sham, 71) had an
intracerebral hemorrhage: time from onset to randomization median, 74 minutes
(interquartile range, 45-110). By admission to hospital, blood pressure tended
to be lower with GTN as compared with sham: mean, 4.4/3.5 mm Hg. The modified
Rankin Scale score at 90 days was nonsignificantly higher in the GTN group:
adjusted common odds ratio for poor outcome, 1.87 (95% CI, 0.98-3.57). A
prespecified global analysis of 5 clinical outcomes (dependency, disability,
cognition, quality of life, and mood) was worse with GTN; Mann-Whitney
difference, 0.18 (95% CI, 0.01-0.35; Wei-Lachin test). GTN was associated with
larger hematoma and growth, and more mass effect and midline shift on
neuroimaging, and altered use of hospital resources. Death in hospital but not
at day 90 was increased with GTN. There were no significant between-group
differences in serious adverse events. Conclusions- Prehospital treatment with
GTN worsened outcomes in patients with intracerebral hemorrhage. Since these
results could relate to the play of chance, confounding, or a true effect of
GTN, further randomized evidence on the use of vasodilators in ultra-acute
intracerebral hemorrhage is needed. Clinical Trial Registration- URL:
http://www.controlled-trials.com. Unique identifier: ISRCTN26986053.
DOI: 10.1161/STROKEAHA.119.026389
PMCID: PMC6824503
PMID: 31587658 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/35573317
|
1. Front Neurosci. 2022 Apr 28;16:874768. doi: 10.3389/fnins.2022.874768.
eCollection 2022.
Simultaneous Quantification of Mitochondrial Mature Frataxin and
Extra-Mitochondrial Frataxin Isoform E in Friedreich's Ataxia Blood.
Wang Q(1)(2), Laboureur L(1)(2), Weng L(1)(2), Eskenazi NM(1)(2), Hauser
LA(2)(3)(4), Mesaros C(1)(2), Lynch DR(2)(3)(4), Blair IA(1)(2).
Author information:
(1)Center of Excellence in Environmental Toxicology, Department of Systems
Pharmacology and Translational Therapeutics, Perelman School of Medicine,
University of Pennsylvania, Philadelphia, PA, United States.
(2)Penn/CHOP Center of Excellence in Friedreich's Ataxia, Philadelphia, PA,
United States.
(3)Departments of Pediatrics and Neurology, Children's Hospital of Philadelphia,
Philadelphia, PA, United States.
(4)Departments of Pediatrics and Neurology, Perelman School of Medicine,
University of Pennsylvania, Philadelphia, PA, United States.
Friedreich's ataxia (FRDA) is an autosomal recessive disease caused by an
intronic guanine-adenine-adenine (GAA) triplet expansion in the frataxin (FXN)
gene, which leads to reduced expression of full-length frataxin (1-210) also
known as isoform 1. Full-length frataxin has a mitochondrial targeting sequence,
which facilitates its translocation into mitochondria where it is processed
through cleavage at G41-L42 and K80-S81 by mitochondrial processing (MPP) to
release mitochondrial mature frataxin (81-210). Alternative splicing of FXN also
leads to expression of N-terminally acetylated extra-mitochondrial frataxin
(76-210) named isoform E because it was discovered in erythrocytes. Frataxin
isoforms are undetectable in serum or plasma, and originally whole blood could
not be used as a biomarker in brief therapeutic trials because it is present in
erythrocytes, which have a half-life of 115-days and so frataxin levels would
remain unaltered. Therefore, an assay was developed for analyzing frataxin in
platelets, which have a half-life of only 10-days. However, our discovery that
isoform E is only present in erythrocytes, whereas, mature frataxin is present
primarily in short-lived peripheral blood mononuclear cells (PBMCs),
granulocytes, and platelets, meant that both proteins could be quantified in
whole blood samples. We now report a quantitative assay for frataxin proteoforms
in whole blood from healthy controls and FRDA patients. The assay is based on
stable isotope dilution coupled with immunoprecipitation (IP) and
two-dimensional-nano-ultrahigh performance liquid chromatography/parallel
reaction monitoring/high resolution mass spectrometry (2D-nano-UHPLC-PRM/HRMS).
The lower limit of quantification was 0.5 ng/mL for each proteoform and the
assays had 100% sensitivity and specificity for discriminating between healthy
controls (n = 11) and FRDA cases (N = 100 in year-1, N = 22 in year-2,3). The
mean levels of mature frataxin in whole blood from healthy controls and
homozygous FRDA patients were significantly different (p < 0.0001) at 7.5 ± 1.5
ng/mL and 2.1 ± 1.2 ng/mL, respectively. The mean levels of isoform E in whole
blood from healthy controls and homozygous FRDA patients were significantly
different (p < 0.0001) at 26.8 ± 4.1 ng/mL and 4.7 ± 3.3 ng/mL, respectively.
The mean levels of total frataxin in whole blood from healthy controls and
homozygous FRDA patients were significantly different (p < 0.0001) at 34.2 ± 4.3
ng/mL and 6.8 ± 4.0 ng/mL, respectively. The assay will make it possible to
rigorously monitor the natural history of the disease and explore the potential
role of isoform E in etiology of the disease. It will also facilitate the
assessment of therapeutic interventions (including gene therapy approaches) that
attempt to increase frataxin protein expression as a treatment for this
devastating disease.
Copyright © 2022 Wang, Laboureur, Weng, Eskenazi, Hauser, Mesaros, Lynch and
Blair.
DOI: 10.3389/fnins.2022.874768
PMCID: PMC9098139
PMID: 35573317
Conflict of interest statement: The authors declare that the research was
conducted in the absence of any commercial or financial relationships that could
be construed as a potential conflict of interest.
|
http://www.ncbi.nlm.nih.gov/pubmed/35663795
|
1. Front Genome Ed. 2022 May 17;4:903139. doi: 10.3389/fgeed.2022.903139.
eCollection 2022.
Advantages and Limitations of Gene Therapy and Gene Editing for Friedreich's
Ataxia.
Sivakumar A(1), Cherqui S(1).
Author information:
(1)Division of Genetics, Department of Pediatrics, University of California, San
Diego, San Diego, CA, United States.
Friedreich's ataxia (FRDA) is an inherited, multisystemic disorder predominantly
caused by GAA hyper expansion in intron 1 of frataxin (FXN) gene. This expansion
mutation transcriptionally represses FXN, a mitochondrial protein that is
required for iron metabolism and mitochondrial homeostasis, leading to
neurodegerative and cardiac dysfunction. Current therapeutic options for FRDA
are focused on improving mitochondrial function and increasing frataxin
expression through pharmacological interventions but are not effective in
delaying or preventing the neurodegeneration in clinical trials. Recent research
on in vivo and ex vivo gene therapy methods in FRDA animal and cell models
showcase its promise as a one-time therapy for FRDA. In this review, we provide
an overview on the current and emerging prospects of gene therapy for FRDA, with
specific focus on advantages of CRISPR/Cas9-mediated gene editing of FXN as a
viable option to restore endogenous frataxin expression. We also assess the
potential of ex vivo gene editing in hematopoietic stem and progenitor cells as
a potential autologous transplantation therapeutic option and discuss its
advantages in tackling FRDA-specific safety aspects for clinical translation.
Copyright © 2022 Sivakumar and Cherqui.
DOI: 10.3389/fgeed.2022.903139
PMCID: PMC9157421
PMID: 35663795
Conflict of interest statement: SC is co-inventor on a patent entitled “Methods
of treating lysosomal disorders” (#20378-101530) and “Methods of treating
mitochondrial disorders” (#20378-101911), and is a cofounder, shareholder and a
member of both the Scientific Board and board of directors of Papillon
Therapeutics Inc. SC serves as a consultant for AVROBIO, Inc. and receives
compensation for these services. SC also serves as a member of the Scientific
Review Board and Board of Trustees of the Cystinosis Research Foundation. The
terms of this arrangement have been reviewed and approved by the University of
California San Diego in accordance with its conflict-of-interest policies. The
remaining author declares that the research was conducted in the absence of any
commercial or financial relationships that could be construed as a potential
conflict of interest.
|
http://www.ncbi.nlm.nih.gov/pubmed/10633128
|
1. J Med Genet. 2000 Jan;37(1):1-8. doi: 10.1136/jmg.37.1.1.
Friedreich ataxia: an overview.
Delatycki MB(1), Williamson R, Forrest SM.
Author information:
(1)Murdoch Institute, Royal Children's Hospital, Flemington Road, Parkville
3052, Victoria, Australia.
Friedreich ataxia, an autosomal recessive neurodegenerative disease, is the most
common of the inherited ataxias. The recent discovery of the gene that is
mutated in this condition, FRDA, has led to rapid advances in the understanding
of the pathogenesis of Friedreich ataxia. About 98% of mutant alleles have an
expansion of a GAA trinucleotide repeat in intron 1 of the gene. This leads to
reduced levels of the protein, frataxin. There is mounting evidence to suggest
that Friedreich ataxia is the result of accumulation of iron in mitochondria
leading to excess production of free radicals, which then results in cellular
damage and death. Currently there is no known treatment that alters the natural
course of the disease. The discovery of the FRDA gene and its possible function
has raised hope that rational therapeutic strategies will be developed.
DOI: 10.1136/jmg.37.1.1
PMCID: PMC1734457
PMID: 10633128 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/30624801
|
1. Mov Disord. 2019 Mar;34(3):323-334. doi: 10.1002/mds.27604. Epub 2019 Jan 9.
Drug repositioning screening identifies etravirine as a potential therapeutic
for friedreich's ataxia.
Alfedi G(1), Luffarelli R(1), Condò I(1), Pedini G(2), Mannucci L(2), Massaro
DS(1), Benini M(1)(3), Toschi N(4)(5), Alaimo G(1)(3), Panarello L(1), Pacini
L(2), Fortuni S(1), Serio D(1), Malisan F(1), Testi R(1)(3), Rufini A(1)(3).
Author information:
(1)Laboratory of Signal Transduction, Department of Biomedicine and Prevention,
University of Rome "Tor Vergata", Rome, Italy.
(2)Laboratory of Molecular Neurobiology, Department of Biomedicine and
Prevention, University of Rome "Tor Vergata", Rome, Italy.
(3)Fratagene Therapeutics Srl, Rome, Italy.
(4)Medical Physics Section, Department of Biomedicine and Prevention, University
of Rome "Tor Vergata", Rome, Italy.
(5)Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging
and Harvard Medical School, Boston, Massachusetts, USA.
Comment in
Mov Disord. 2019 Mar;34(3):305-306. doi: 10.1002/mds.27605.
BACKGROUND: Friedreich's ataxia is an autosomal-recessive cerebellar ataxia
caused by mutation of the frataxin gene, resulting in decreased frataxin
expression, mitochondrial dysfunction, and oxidative stress. Currently, no
treatment is available for Friedreich's ataxia patients. Given that levels of
residual frataxin critically affect disease severity, the main goal of a
specific therapy for Friedreich's ataxia is to increase frataxin levels.
OBJECTIVES: With the aim to accelerate the development of a new therapy for
Friedreich's ataxia, we took a drug repositioning approach to identify
market-available drugs able to increase frataxin levels.
METHODS: Using a cell-based reporter assay to monitor variation in frataxin
amount, we performed a high-throughput screening of a library containing 853
U.S. Food and Drug Administration-approved drugs.
RESULTS: Among the potentially interesting candidates isolated from the
screening, we focused our attention on etravirine, an antiviral drug currently
in use as an anti-human immunodeficiency virus therapy. Here, we show that
etravirine can promote a significant increase in frataxin levels in cells
derived from Friedreich's ataxia patients, by enhancing frataxin messenger RNA
translation. Importantly, frataxin accumulation in treated patient cell lines is
comparable to frataxin levels in unaffected carrier cells, suggesting that
etravirine could be therapeutically relevant. Indeed, etravirine treatment
restores the activity of the iron-sulphur cluster containing enzyme aconitase
and confers resistance to oxidative stress in cells derived from Friedreich's
ataxia patients.
CONCLUSIONS: Considering its excellent safety profile along with its ability to
increase frataxin levels and correct some of the disease-related defects,
etravirine represents a promising candidate as a therapeutic for Friedreich's
ataxia. © 2019 International Parkinson and Movement Disorder Society.
© 2019 International Parkinson and Movement Disorder Society.
DOI: 10.1002/mds.27604
PMID: 30624801 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/10982187
|
1. Hum Genet. 2000 Jan;106(1):86-92. doi: 10.1007/s004399900201.
Genotype and phenotype analysis of Friedreich's ataxia compound heterozygous
patients.
De Castro M(1), García-Planells J, Monrós E, Cañizares J, Vázquez-Manrique R,
Vílchez JJ, Urtasun M, Lucas M, Navarro G, Izquierdo G, Moltó MD, Palau F.
Author information:
(1)Unitat de Genètica, Hospital Universitari La Fe, Valencia, Spain.
Friedreich's ataxia is caused by mutations in the FRDA gene that encodes
frataxin, a nuclear-encoded mitochondrial protein. Most patients are homozygous
for the expansion of a GAA triplet repeat within the FRDA gene, but a few
patients show compound heterozygosity for a point mutation and the GAA-repeat
expansion. We analyzed DNA samples from a cohort of 241 patients with autosomal
recessive or isolated spinocerebellar ataxia for the GAA triplet expansion.
Patients heterozygous for the GAA expansion were screened for point mutations
within the FRDA coding region. Molecular analyses included the single-strand
conformation polymorphism analysis, direct sequencing, and linkage analysis with
FRDA locus flanking markers. Seven compound heterozygous patients were
identified. In four patients, a point mutation that predicts a truncated
frataxin was detected. Three of them associated classic early-onset Friedreich's
ataxia with an expanded GAA allele greater than 800 repeats. The other patient
associated late-onset disease at the age of 29 years with a 350-GAA repeat
expansion. In two patients manifesting the classical phenotype, no changes were
observed by single-strand conformation polymorphism (SSCP) analysis. Linkage
analysis in a family with two children affected by an ataxic syndrome, one of
them showing heterozygosity for the GAA expansion, confirmed no linkage to the
FRDA locus. Most point mutations in compound heterozygous Friedreich's ataxia
patients are null mutations. In the present patients, clinical phenotype seems
to be related to the GAA repeat number in the expanded allele. Complete
molecular definition in these patients is required for clinical diagnosis and
genetic counseling.
DOI: 10.1007/s004399900201
PMID: 10982187 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/30159187
|
1. Case Rep Neurol Med. 2018 Aug 9;2018:8587203. doi: 10.1155/2018/8587203.
eCollection 2018.
Friedreich's Ataxia: Clinical Presentation of a Compound Heterozygote Child with
a Rare Nonsense Mutation and Comparison with Previously Published Cases.
Rao VK(1)(2), DiDonato CJ(2)(3), Larsen PD(4).
Author information:
(1)Division of Neurology, Ann & Robert H. Lurie Children's Hospital of Chicago,
Chicago, IL 60611, USA.
(2)Department of Pediatrics, Feinberg School of Medicine, Northwestern
University, Chicago, IL 60611, USA.
(3)Human Molecular Genetics Program, Ann & Robert H. Lurie Children's Hospital,
Stanley Manne Research Institute, Chicago, IL 60611, USA.
(4)Division of Neurology, Department of Pediatrics, University of Nebraska
Medical Center and Children's Hospital and Medical Center, Omaha, NE, USA.
Friedreich's ataxia is a neurodegenerative disorder associated with a GAA
trinucleotide repeat expansion in intron 1 of the frataxin (FXN) gene. It is the
most common autosomal recessive cerebellar ataxia, with a mean age of onset at
16 years. Nearly 95-98% of patients are homozygous for a 90-1300 GAA repeat
expansion with only 2-5% demonstrating compound heterozygosity. Compound
heterozygous individuals have a repeat expansion in one allele and a point
mutation/deletion/insertion in the other. Compound heterozygosity and point
mutations are very rare causes of Friedreich's ataxia and nonsense mutations are
a further rarity among point mutations. We report a rare compound heterozygous
Friedrich's ataxia patient who was found to have one expanded GAA FXN allele and
a nonsense point mutation in the other. We summarize the four previously
published cases of nonsense mutations and compare the phenotype to that of our
patient. We compared clinical information from our patient with other nonsense
FXN mutations reported in the literature. This nonsense mutation, to our
knowledge, has only been described once previously; interestingly the individual
was also of Cuban ancestry. A comparison with previously published cases of
nonsense mutations demonstrates some common clinical characteristics.
DOI: 10.1155/2018/8587203
PMCID: PMC6106966
PMID: 30159187
|
http://www.ncbi.nlm.nih.gov/pubmed/36107856
|
1. Dis Model Mech. 2023 May 1;16(5):dmm049497. doi: 10.1242/dmm.049497. Epub 2022
Oct 26.
Acute frataxin knockdown in induced pluripotent stem cell-derived cardiomyocytes
activates a type I interferon response.
Cotticelli MG(1), Xia S(1), Truitt R(2), Doliba NM(3), Rozo AV(3), Tobias JW(4),
Lee T(1), Chen J(1), Napierala JS(5), Napierala M(5), Yang W(2), Wilson
RB(1)(6).
Author information:
(1)Department of Pathology and Laboratory Medicine, Children's Hospital of
Philadelphia, Philadelphia, PA 19104, USA.
(2)Department of Medicine, Division of Translational Medicine and Human
Genetics, University of Pennsylvania, Philadelphia, PA 19104, USA.
(3)Institute of Diabetes, Obesity, and Metabolism, University of Pennsylvania,
Philadelphia, PA 19104, USA.
(4)Department of Genetics, Penn Genomics Analysis Core, University of
Pennsylvania, Philadelphia, PA 19104, USA.
(5)Department of Neurology, UT Southwestern Medical Center, Dallas, TX 75390,
USA.
(6)Department of Pathology and Laboratory Medicine, University of Pennsylvania,
Philadelphia, PA 19104, USA.
Friedreich ataxia, the most common hereditary ataxia, is a neuro- and
cardio-degenerative disorder caused, in most cases, by decreased expression of
the mitochondrial protein frataxin. Cardiomyopathy is the leading cause of
premature death. Frataxin functions in the biogenesis of iron-sulfur clusters,
which are prosthetic groups that are found in proteins involved in many
biological processes. To study the changes associated with decreased frataxin in
human cardiomyocytes, we developed a novel isogenic model by acutely knocking
down frataxin, post-differentiation, in cardiomyocytes derived from induced
pluripotent stem cells (iPSCs). Transcriptome analysis of four biological
replicates identified severe mitochondrial dysfunction and a type I interferon
response as the pathways most affected by frataxin knockdown. We confirmed that,
in iPSC-derived cardiomyocytes, loss of frataxin leads to mitochondrial
dysfunction. The type I interferon response was activated in multiple cell types
following acute frataxin knockdown and was caused, at least in part, by release
of mitochondrial DNA into the cytosol, activating the cGAS-STING sensor pathway.
© 2022. Published by The Company of Biologists Ltd.
DOI: 10.1242/dmm.049497
PMCID: PMC9637271
PMID: 36107856 [Indexed for MEDLINE]
Conflict of interest statement: Competing interests The authors declare no
competing or financial interests.
|
http://www.ncbi.nlm.nih.gov/pubmed/15340363
|
1. Eur J Hum Genet. 2004 Nov;12(11):979-82. doi: 10.1038/sj.ejhg.5201257.
Extension of the mutation spectrum in Friedreich's ataxia: detection of an exon
deletion and novel missense mutations.
Zühlke CH(1), Dalski A, Habeck M, Straube K, Hedrich K, Hoeltzenbein M,
Konstanzer A, Hellenbroich Y, Schwinger E.
Author information:
(1)Universität Lübeck, Institut für Humangenetik, Ratzeburger Allee 160, Lübeck
D-23538, Germany. [email protected]
Friedreich's ataxia (FRDA), the most common autosomal recessively inherited
ataxia, is due to a homozygous GAA triplet repeat expansion in the first intron
of the FRDA gene in about 96% of patients. Approximately 4% of FRDA patients are
compound heterozygotes with a GAA repeat expansion in one allele and a point
mutation in the coding region of the second allele. To reinvestigate the
mutation spectrum, we searched for mutations including exon deletions in six
patients heterozygous for the GAA repeat expansion and found two unknown
missense mutations, p.Asn146Lys and p.Leu186Arg, in trans to the expanded FRDA
allele. Interestingly, we detected a heterozygous 2776 bp deletion including
exon 5a in one of our patients. This deletion removes 50 of the 210 residues of
the frataxin. Furthermore, since no FRDA case with two-point mutations is known,
we screened eight patients with FRDA phenotype but GAA alleles within the normal
range but did not reveal a mutation within the FRDA gene. In addition, DNA
polymorphisms have been found in four out of 100 control individuals in this
study.
DOI: 10.1038/sj.ejhg.5201257
PMID: 15340363 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/35038030
|
1. Cell Mol Life Sci. 2022 Jan 17;79(2):74. doi: 10.1007/s00018-021-04100-5.
Mice harboring the FXN I151F pathological point mutation present decreased
frataxin levels, a Friedreich ataxia-like phenotype, and mitochondrial
alterations.
Medina-Carbonero M(1), Sanz-Alcázar A(1), Britti E(1), Delaspre F(1), Cabiscol
E(1), Ros J(1), Tamarit J(2).
Author information:
(1)Dept. Ciències Mèdiques Bàsiques, Fac. Medicina, IRBLleida, Universitat de
Lleida, Av. Rovira Roure, 80, 25198, Lleida, Spain.
(2)Dept. Ciències Mèdiques Bàsiques, Fac. Medicina, IRBLleida, Universitat de
Lleida, Av. Rovira Roure, 80, 25198, Lleida, Spain. [email protected].
Friedreich Ataxia (FA) is a rare neuro-cardiodegenerative disease caused by
mutations in the frataxin (FXN) gene. The most prevalent mutation is a GAA
expansion in the first intron of the gene causing decreased frataxin expression.
Some patients present the GAA expansion in one allele and a missense mutation in
the other allele. One of these mutations, FXNI154F, was reported to result in
decreased content of mature frataxin and increased presence of an insoluble
intermediate proteoform in cellular models. By introducing this mutation into
the murine Fxn gene (I151F, equivalent to human I154F) we have now analyzed the
consequences of this pathological point mutation in vivo. We have observed that
FXNI151F homozygous mice present low frataxin levels in all tissues, with no
evidence of insoluble proteoforms. Moreover, they display neurological deficits
resembling those observed in FA patients. Biochemical analysis of heart,
cerebrum and cerebellum have revealed decreased content of components from
OXPHOS complexes I and II, decreased aconitase activity, and alterations in
antioxidant defenses. These mitochondrial alterations are more marked in the
nervous system than in heart, precede the appearance of neurological symptoms,
and are similar to those observed in other FA models. We conclude that the
primary pathological mechanism underlying the I151F mutation is frataxin
deficiency, like in patients carrying GAA expansions. Therefore, patients
carrying the I154F mutation would benefit from frataxin replacement therapies.
Furthermore, our results also show that the FXNI151F mouse is an excellent tool
for analyzing tissue-specific consequences of frataxin deficiency and for
testing new therapies.
© 2022. The Author(s).
DOI: 10.1007/s00018-021-04100-5
PMCID: PMC8763788
PMID: 35038030 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no conflict
of interest.
|
http://www.ncbi.nlm.nih.gov/pubmed/31020006
|
1. Ann Clin Transl Neurol. 2019 Feb 21;6(4):812-816. doi: 10.1002/acn3.728.
eCollection 2019 Apr.
Identification of a novel missense mutation in Friedreich's ataxia -FXN(W)
(168R).
Clark E(1)(2), Strawser C(2), Schadt K(2), Lynch DR(1)(2).
Author information:
(1)University of Pennsylvania Philadelphia Pennsylvania.
(2)Division of Neurology Children's Hospital of Philadelphia Philadelphia
Pennsylvania.
Friedreich's ataxia, characterized by decreased expression of frataxin protein,
is caused by GAA trinucleotide repeats within intron 1 in 98% of patients. Two
percent of patients carry GAA repeats in conjunction with a point mutation. In
this work, we find that frataxinW168R, a novel disease-causing missense
mutation, is expressed predominantly as the intermediate frataxin42-210 form,
with very little expression of mature frataxin81-210 form. Its localization to
mitochondria is not impaired. Additionally, increasing frataxinW168R precursor
levels do not lead to an increase in mature frataxin levels, suggesting these
patients will require alternative approaches to repair frataxin processing in
order to treat the disorder in a disease-modifying manner.
DOI: 10.1002/acn3.728
PMCID: PMC6469249
PMID: 31020006 [Indexed for MEDLINE]
Conflict of interest statement: All authors declare no conflict of interest.
|
http://www.ncbi.nlm.nih.gov/pubmed/9241270
|
1. Nat Genet. 1997 Aug;16(4):345-51. doi: 10.1038/ng0897-345.
Studies of human, mouse and yeast homologues indicate a mitochondrial function
for frataxin.
Koutnikova H(1), Campuzano V, Foury F, Dollé P, Cazzalini O, Koenig M.
Author information:
(1)Institut de Génétique et Biologie Moléculaire et Cellulaire (IGBMC), INSERM,
CNRS, Université Louis Pasteur, Strasbourg, France.
Friedreich's ataxia is due to loss of function mutations in the gene encoding
frataxin (FRDA). Frataxin is a protein of unknown function. In situ
hybridization analyses revealed that mouse frataxin expression correlates well
with the main site of neurodegeneration, but the expression pattern is broader
than expected from the pathology of the disease. Frataxin mRNA is predominantly
expressed in tissues with a high metabolic rate, including liver, kidney, brown
fat and heart. We found that mouse and yeast frataxin homologues contain a
potential mitochondrial targeting sequence in their N-terminal domains and that
disruption of the yeast gene results in mitochondrial dysfunction. Finally,
tagging experiments demonstrate that human frataxin co-localizes with a
mitochondrial protein. Friedreich's ataxia is therefore a mitochondrial disease
caused by a mutation in the nuclear genome.
DOI: 10.1038/ng0897-345
PMID: 9241270 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/32582297
|
1. Front Genet. 2020 Jun 5;11:584. doi: 10.3389/fgene.2020.00584. eCollection
2020.
HMTase Inhibitors as a Potential Epigenetic-Based Therapeutic Approach for
Friedreich's Ataxia.
Sherzai M(1), Valle A(2)(3), Perry N(4), Kalef-Ezra E(1), Al-Mahdawi S(1), Pook
M(1), Anjomani Virmouni S(1).
Author information:
(1)Ataxia Research Group, Division of Biosciences, Department of Life Sciences,
College of Health and Life Sciences, Brunel University London, Uxbridge, United
Kingdom.
(2)Energy Metabolism and Nutrition, Research Institute of Health Sciences
(IUNICS) and Health Research Institute of Balearic Islands (IdISBa), University
of Balearic Islands, Palma de Mallorca, Spain.
(3)Biomedical Research Networking Center for Physiopathology of Obesity and
Nutrition (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain.
(4)Division of Cancer Biology, The Institute of Cancer Research, London, United
Kingdom.
Friedreich's ataxia (FRDA) is a progressive neurodegenerative disorder caused by
a homozygous GAA repeat expansion mutation in intron 1 of the frataxin gene
(FXN), which instigates reduced transcription. As a consequence, reduced levels
of frataxin protein lead to mitochondrial iron accumulation, oxidative stress,
and ultimately cell death; particularly in dorsal root ganglia (DRG) sensory
neurons and the dentate nucleus of the cerebellum. In addition to neurological
disability, FRDA is associated with cardiomyopathy, diabetes mellitus, and
skeletal deformities. Currently there is no effective treatment for FRDA and
patients die prematurely. Recent findings suggest that abnormal GAA expansion
plays a role in histone modification, subjecting the FXN gene to heterochromatin
silencing. Therefore, as an epigenetic-based therapy, we investigated the
efficacy and tolerability of two histone methyltransferase (HMTase) inhibitor
compounds, BIX0194 (G9a-inhibitor) and GSK126 (EZH2-inhibitor), to specifically
target and reduce H3K9me2/3 and H3K27me3 levels, respectively, in FRDA
fibroblasts. We show that a combination treatment of BIX0194 and GSK126,
significantly increased FXN gene expression levels and reduced the repressive
histone marks. However, no increase in frataxin protein levels was observed.
Nevertheless, our results are still promising and may encourage to investigate
HMTase inhibitors with other synergistic epigenetic-based therapies for further
preliminary studies.
Copyright © 2020 Sherzai, Valle, Perry, Kalef-Ezra, Al-Mahdawi, Pook and
Anjomani Virmouni.
DOI: 10.3389/fgene.2020.00584
PMCID: PMC7291394
PMID: 32582297
|
http://www.ncbi.nlm.nih.gov/pubmed/27343351
|
1. Elife. 2016 Jun 25;5:e16043. doi: 10.7554/eLife.16043.
Loss of Frataxin induces iron toxicity, sphingolipid synthesis, and Pdk1/Mef2
activation, leading to neurodegeneration.
Chen K(1), Lin G(2), Haelterman NA(1), Ho TS(3), Li T(1), Li Z(2), Duraine L(4),
Graham BH(1)(2), Jaiswal M(2)(4), Yamamoto S(1)(2)(5), Rasband MN(1)(3), Bellen
HJ(1)(2)(3)(4)(5).
Author information:
(1)Program in Developmental Biology, Baylor College of Medicine, Houston, United
States.
(2)Department of Molecular and Human Genetics, Baylor College of Medicine,
Houston, United States.
(3)Department of Neuroscience, Baylor College of Medicine, Houston, United
States.
(4)Howard Hughes Medical Institute, Baylor College of Medicine, Houston, United
States.
(5)Jan and Dan Duncan Neurological Research Institute, Texas Children's
Hospital, Houston, United States.
Mutations in Frataxin (FXN) cause Friedreich's ataxia (FRDA), a recessive
neurodegenerative disorder. Previous studies have proposed that loss of FXN
causes mitochondrial dysfunction, which triggers elevated reactive oxygen
species (ROS) and leads to the demise of neurons. Here we describe a ROS
independent mechanism that contributes to neurodegeneration in fly FXN mutants.
We show that loss of frataxin homolog (fh) in Drosophila leads to iron toxicity,
which in turn induces sphingolipid synthesis and ectopically activates
3-phosphoinositide dependent protein kinase-1 (Pdk1) and myocyte enhancer
factor-2 (Mef2). Dampening iron toxicity, inhibiting sphingolipid synthesis by
Myriocin, or reducing Pdk1 or Mef2 levels, all effectively suppress
neurodegeneration in fh mutants. Moreover, increasing dihydrosphingosine
activates Mef2 activity through PDK1 in mammalian neuronal cell line suggesting
that the mechanisms are evolutionarily conserved. Our results indicate that an
iron/sphingolipid/Pdk1/Mef2 pathway may play a role in FRDA.
DOI: 10.7554/eLife.16043
PMCID: PMC4956409
PMID: 27343351 [Indexed for MEDLINE]
Conflict of interest statement: HJB: Reviewing editor, eLife. The other authors
declare that no competing interests exist.
|
http://www.ncbi.nlm.nih.gov/pubmed/32291635
|
1. Mol Neurobiol. 2020 Jun;57(6):2639-2653. doi: 10.1007/s12035-020-01899-1. Epub
2020 Apr 14.
A Comprehensive Transcriptome Analysis Identifies FXN and BDNF as Novel Targets
of miRNAs in Friedreich's Ataxia Patients.
Misiorek JO(1), Schreiber AM(2), Urbanek-Trzeciak MO(3), Jazurek-Ciesiołka M(3),
Hauser LA(4)(5), Lynch DR(4)(5), Napierala JS(2), Napierala M(6)(7).
Author information:
(1)Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan,
Poland. [email protected].
(2)Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute,
University of Alabama at Birmingham, Birmingham, AL, USA.
(3)Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan,
Poland.
(4)Department of Pediatrics and Neurology, Perelman School of Medicine,
University of Pennsylvania, Philadelphia, PA, USA.
(5)Children's Hospital of Philadelphia, Philadelphia, PA, USA.
(6)Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan,
Poland. [email protected].
(7)Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute,
University of Alabama at Birmingham, Birmingham, AL, USA. [email protected].
Friedreich's ataxia (FRDA) is a genetic neurodegenerative disease that is caused
by guanine-adenine-adenine (GAA) nucleotide repeat expansions in the first
intron of the frataxin (FXN) gene. Although present in the intron, this mutation
leads to a substantial decrease in protein expression. Currently, no effective
treatment is available for FRDA, and, in addition to FXN, other targets with
therapeutic potential are continuously sought. As miRNAs can regulate the
expression of a broad spectrum of genes, are used as biomarkers, and can serve
as therapeutic tools, we decided to identify and characterize differentially
expressed miRNAs and their targets in FRDA cells compared to unaffected control
(CTRL) cells. In this study, we performed an integrated miRNAseq and RNAseq
analysis using the same cohort of primary FRDA and CTRL cells. The results of
the transcriptome studies were supported by bioinformatic analyses and validated
by qRT-PCR. miRNA interactions with target genes were assessed by luciferase
assays, qRT-PCR, and immunoblotting. In silico analysis identified the FXN
transcript as a target of five miRNAs upregulated in FRDA cells. Further studies
confirmed that miRNA-224-5p indeed targets FXN, resulting in decreases in mRNA
and protein levels. We also validated the ability of miRNA-10a-5p to bind and
regulate the levels of brain-derived neurotrophic factor (BDNF), an important
modulator of neuronal growth. We observed a significant decrease in the levels
of miRNA-10a-5p and increase in the levels of BDNF upon correction of FRDA cells
via zinc-finger nuclease (ZFN)-mediated excision of expanded GAA repeats. Our
comprehensive transcriptome analyses identified miRNA-224-5p and miRNA-10a-5p as
negative regulators of the FXN and BDNF expression, respectively. These results
emphasize not only the importance of miRNAs in the pathogenesis of FRDA but also
their potential as therapeutic targets for this disease.
DOI: 10.1007/s12035-020-01899-1
PMCID: PMC7253519
PMID: 32291635 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no competing
interests.
|
http://www.ncbi.nlm.nih.gov/pubmed/22798143
|
1. J Biol Chem. 2012 Aug 24;287(35):29861-72. doi: 10.1074/jbc.M112.391961. Epub
2012 Jul 13.
Role of mismatch repair enzymes in GAA·TTC triplet-repeat expansion in
Friedreich ataxia induced pluripotent stem cells.
Du J(1), Campau E, Soragni E, Ku S, Puckett JW, Dervan PB, Gottesfeld JM.
Author information:
(1)Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA
92037, USA.
The genetic mutation in Friedreich ataxia (FRDA) is a hyperexpansion of the
triplet-repeat sequence GAA·TTC within the first intron of the FXN gene.
Although yeast and reporter construct models for GAA·TTC triplet-repeat
expansion have been reported, studies on FRDA pathogenesis and therapeutic
development are limited by the availability of an appropriate cell model in
which to study the mechanism of instability of the GAA·TTC triplet repeats in
the human genome. Herein, induced pluripotent stem cells (iPSCs) were generated
from FRDA patient fibroblasts after transduction with the four transcription
factors Oct4, Sox2, Klf4, and c-Myc. These cells were differentiated into
neurospheres and neuronal precursors in vitro, providing a valuable cell model
for FRDA. During propagation of the iPSCs, GAA·TTC triplet repeats expanded at a
rate of about two GAA·TTC triplet repeats/replication. However, GAA·TTC triplet
repeats were stable in FRDA fibroblasts and neuronal stem cells. The mismatch
repair enzymes MSH2, MSH3, and MSH6, implicated in repeat instability in other
triplet-repeat diseases, were highly expressed in pluripotent stem cells
compared with fibroblasts and neuronal stem cells and occupied FXN intron 1. In
addition, shRNA silencing of MSH2 and MSH6 impeded GAA·TTC triplet-repeat
expansion. A specific pyrrole-imidazole polyamide targeting GAA·TTC
triplet-repeat DNA partially blocked repeat expansion by displacing MSH2 from
FXN intron 1 in FRDA iPSCs. These studies suggest that in FRDA, GAA·TTC
triplet-repeat instability occurs in embryonic cells and involves the highly
active mismatch repair system.
DOI: 10.1074/jbc.M112.391961
PMCID: PMC3436184
PMID: 22798143 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/34573098
|
1. Antioxidants (Basel). 2021 Sep 15;10(9):1466. doi: 10.3390/antiox10091466.
The Effects of Two Nrf2 Activators, Bardoxolone Methyl and Omaveloxolone, on
Retinal Ganglion Cell Survival during Ischemic Optic Neuropathy.
Chien JY(1), Chou YY(2), Ciou JW(2), Liu FY(2), Huang SP(1)(2)(3).
Author information:
(1)Institute of Medical Sciences, Tzu Chi University, Hualien 970, Taiwan.
(2)Department of Molecular Biology and Human Genetics, Tzu Chi University,
Hualien 970, Taiwan.
(3)Department of Ophthalmology, Tzu Chi University, Hualien 970, Taiwan.
Nonarteritic anterior ischemic optic neuropathy (NAION) is one of the most
common acute optic neuropathies that affect the over 55-year-old population.
NAION causes the loss of visual function, and it has no safe and effective
therapy. Bardoxolone methyl (methyl
2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate; CDDO-Me; RTA 402) is a
semisynthetic triterpenoid with effects against antioxidative stress and
inflammation in neurodegeneration and kidney disease that activates the nuclear
factor erythroid 2-related factor 2 (Nrf2) signaling pathway. Moreover, RTA 402
is an FDA-approved compound for the treatment of solid tumors, lymphoid
malignancies, melanoma, and chronic kidney disease. Omaveloxolone (RTA 408) is
an activator of Nrf2 and an inhibitor of NFκB, possessing antioxidative and
anti-inflammatory activities in mitochondrial bioenergetics. RTA 408 is also
under clinical investigation for Friedreich ataxia (FA). In this study, a rodent
anterior ischemic optic neuropathy (rAION) model induced by photothrombosis was
used to examine the therapeutic effects of RTA 402 and RTA 408. Treatment with
RTA402 results in antiapoptotic, antioxidative stress, anti-inflammatory, and
myelin-preserving effects on retinal ganglion cell (RGC) survival and visual
function via regulation of NQO1 and HO-1, reduced IL-6 and Iba1 expression in
macrophages, and promoted microglial expression of TGF-β and Ym1 + 2 in the
retina and optic nerve. However, these effects were not observed after RTA 408
treatment. Our results provide explicit evidence that RTA 402 modulates the Nrf2
and NFκB signaling pathways to protect RGCs from apoptosis and maintain the
visual function in an rAION model. These findings indicate that RTA 402 may a
potential therapeutic agent for ischemic optic neuropathy.
DOI: 10.3390/antiox10091466
PMCID: PMC8470542
PMID: 34573098
Conflict of interest statement: The authors declare no conflict of interest. The
funders had no role in the design of the study; in the collection, analyses, or
interpretation of data; in the writing of the manuscript; or in the decision to
publish the results.
|
http://www.ncbi.nlm.nih.gov/pubmed/36282969
|
1. J Perinat Med. 2022 Oct 24;51(4):564-572. doi: 10.1515/jpm-2022-0320. Print
2023 May 25.
Assessment of salivary cortisol concentrations for procedural pain monitoring in
newborns.
Olszewska M(1), Pointinger-Tomasik S(2), Kwinta P(1).
Author information:
(1)Department of Pediatrics, Institute of Pediatrics, Faculty of Medicine,
Jagiellonian University Medical College, Kraków, Poland.
(2)Faculty of Health Science, Jagiellonian University Medical College, Kraków,
Poland.
OBJECTIVES: The study aimed to evaluate the usefulness of salivary cortisol (SC)
for the assessment of procedural pain intensity in preterm and term newborns.
METHODS: Three groups of neonates (term, 370-416 weeks; moderate to late
preterm, 320-366; and very preterm, <320) hospitalized in neonatal intensive
care unit were assessed for the study. Response to nappy change, lung ultrasound
(LUS), and blood sampling was analyzed. The intensity of pain was evaluated
using continuous heart rate and blood oxygen saturation (SpO2) monitoring,
Neonatal Infant Pain Scale (NIPS), and SC concentrations. Saliva samples were
collected before and 20 min after the procedure's end.
RESULTS: Seventy-one infants were examined: 30 term, 21 moderate to late
preterm, and 20 very preterm. SC has increased significantly in response to
nappy change only in very preterm newborns (2.13 ng/mL [1.55-3.68] vs.
2.84 ng/mL [1.93-9.06], p = 0.01). LUS did not affect concentrations of SC in
any group. Significant increase in SC was observed after blood sampling in term
and very preterm infants (2.2 ng/mL [1.45-2.92] vs. 4.29 ng/mL [3.88-5.73],
p = 0.002, and 1.88 ng/mL [1.47-4.13] vs. 5.3 ng/mL [3.42-8.02], p = 0.002,
respectively). A significant correlation between values of SC increase and NIPS
scores was found (Spearman's rank correlation coefficient [rs] = 0.31,
p = 0.001).
CONCLUSIONS: We observed the increase in SC concentrations in response to
painful stimulus. The presence of a correlation between NIPS scores and SC
increase suggests that SC can be used as an objective parameter to assess pain
in neonates.
© 2022 Walter de Gruyter GmbH, Berlin/Boston.
DOI: 10.1515/jpm-2022-0320
PMID: 36282969 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/35421369
|
1. Lancet Oncol. 2022 May;23(5):650-658. doi: 10.1016/S1470-2045(22)00158-9. Epub
2022 Apr 11.
Addition of nintedanib or placebo to neoadjuvant gemcitabine and cisplatin in
locally advanced muscle-invasive bladder cancer (NEOBLADE): a double-blind,
randomised, phase 2 trial.
Hussain SA(1), Lester JF(2), Jackson R(3), Gornall M(3), Qureshi M(4), Elliott
A(5), Crabb SJ(6), Huddart RA(7), Vasudev N(8), Birtle AJ(9), Worlding J(10),
James ND(7), Parikh O(9), Vilarino-Varela M(11), Alonzi R(12), Linch MD(13),
Riaz IB(14), Catto JWF(15), Powles T(16), Jones RJ(17).
Author information:
(1)Department of Oncology and Metabolism, Academic Unit of Oncology, University
of Sheffield, Sheffield, UK. Electronic address: [email protected].
(2)Velindre Cancer Centre, Cardiff, UK.
(3)Department of Oncology, University of Liverpool, Liverpool, UK.
(4)Department of Oncology and Metabolism, Academic Unit of Oncology, University
of Sheffield, Sheffield, UK.
(5)Christie Hospital, Manchester, UK.
(6)Department of Oncology, University of Southampton, Southampton, UK.
(7)Institute of Cancer Research, The Royal Marsden NHS Foundation Trust, London,
UK.
(8)St James's University Hospital, Leeds, UK.
(9)Rosemere Cancer Centre, Royal Preston Hospital, Preston, UK.
(10)University Hospital Coventry, Coventry, UK.
(11)Royal Free Hospital, London, UK.
(12)Mount Vernon Cancer Centre, Northwood, UK.
(13)University College London Cancer Institute, London, UK.
(14)Mayo Clinic, Phoenix, AZ, USA.
(15)Academic Urology Unit, University of Sheffield, Sheffield, UK.
(16)Barts Cancer Institute, Queen Mary University London, London, UK.
(17)University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, UK.
Comment in
Eur Urol. 2023 Oct;84(4):440-441. doi: 10.1016/j.eururo.2023.05.026.
BACKGROUND: Recurrence is common after neoadjuvant chemotherapy and radical
treatment for muscle-invasive bladder cancer. We investigated the effect of
adding nintedanib to neoadjuvant chemotherapy on response and survival in
muscle-invasive bladder cancer.
METHODS: NEOBLADE was a parallel-arm, double-blind, randomised,
placebo-controlled, phase 2 trial of neoadjuvant gemcitabine and cisplatin
chemotherapy with nintedanib or placebo in locally advanced muscle-invasive
bladder cancer. Patients aged 18 years or older, with an Eastern Cooperative
Oncology Group performance status of 0-1, were recruited from 15 hospitals in
the UK. Patients were randomly assigned (1:1) to nintedanib or placebo using
permuted blocks with random block sizes of two or four, stratified by centre and
glomerular filtration rate. Treatments were allocated using an interactive
web-based system, and patients and investigators were masked to treatment
allocation throughout the study. Patients received oral nintedanib (150 mg or
200 mg twice daily for 12 weeks) or placebo, in addition to usual neoadjuvant
chemotherapy with intravenous gemcitabine 1000 mg/m2 on days 1 and 8 and
intravenous cisplatin 70 mg/m2 on day 1 of a 3-weekly cycle. The primary
endpoint was pathological complete response rate, assessed at cystectomy or at
day 8 of cyclde 3 (plus or minus 7 days) if cystectomy did not occur. Primary
analyses were done in the intention-to-treat population. The trial is registered
with EudraCT, 2012-004895-01, and ISRCTN, 56349930, and has completed planned
recruitment.
FINDINGS: Between Dec 4, 2014, and Sept 3, 2018, 120 patients were recruited and
were randomly allocated to receive nintedanib (n=57) or placebo (n=63). The
median follow-up for the study was 33·5 months (IQR 14·0-44·0). Pathological
complete response in the intention-to-treat population was reached in 21 (37%)
of 57 patients in the nintedanib group and 20 (32%) of 63 in the placebo group
(odds ratio [OR] 1·25, 70% CI 0·84-1·87; p=0·28). Grade 3 or worse toxicities
were observed in 53 (93%) of 57 participants who received nintedanib and 50
(79%) of 63 patients in the placebo group (OR 1·65, 95% CI 0·74-3·65; p=0·24).
The most common grade 3 or worse adverse events were thromboembolic events (17
[30%] of 57 patients in the nintedanib group vs 13 [21%] of 63 patients in the
placebo group [OR 1·63, 95% CI 0·71-3·76; p=0·29]) and decreased neutrophil
count (22 [39%] in the nintedanib group vs seven [11%] in the placebo group
[5·03, 1·95-13·00; p=0·0006]). 45 treatment-related serious adverse events
occurred in the nintedanib group and 43 occurred in the placebo group. One
treatment-related death occurred in the placebo group, which was due to
myocardial infarction.
INTERPRETATION: The addition of nintedanib to chemotherapy was safe but did not
improve the rate of pathological complete response in muscle-invasive bladder
cancer.
FUNDING: Boehringer Ingelheim.
Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open
Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All
rights reserved.
DOI: 10.1016/S1470-2045(22)00158-9
PMID: 35421369 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interests SAH reports fees for
consulting or honoraria from Janssen, Roche, Merck, Bristol-Myers Squibb (BMS),
AstraZeneca, Pfizer, Astellas, GlaxoSmithKline, and Eisai; grants from
Boehringer Ingelheim, Roche, Janssen, and AstraZeneca; and support for attending
meetings or travel from Janssen, Boehringer Ingelheim, Pfizer, Roche, BMS,
AstraZeneca, and Merck Sharp & Dohme (MSD) Oncology. SJC reports fees for
consulting from Astellas, Roche, AstraZeneca, MSD, and Pfizer; grants from
AstraZeneca, Astex Pharmaceuticals, Roche, and Clovis Oncology; speaker
honoraria from AstraZeneca, Roche, MSD, and Astellas; payment for expert
testimony from MSD and Pfizer; and support for attending meetings or travel from
BMS, MSD, and Roche. RAH reports leading the Cancer Centre London; honoraria
from Janssen Oncology; fees for consulting or an advisory role from BMS, Janssen
Oncology, MSD, Nektar, and Roche; speakers' bureau fees from MSD and Roche;
research funding from BMS, Janssen, MSD, and Roche; royalties from Janssen; and
payment for travel, accommodation, and expenses from MSD and Roche. NV reports
grants or contracts from BMS; consulting fees from Merck Serono and 4D Pharma;
and honoraria: EUSA Pharma, IPSEN, and BMS. AJB reports consulting fees from
Janssen, Merck, Pfizer, Astellas, and BMS; honoraria from Janssen, Pfizer,
Astellas, Roche, and MSD; support for attending meetings or travel from Janssen;
and participation on a data safety monitoring board or advisory board for
Janssen, Astellas, Merck, and Pfizer. MDL reports grants or contracts from BMS,
Shionogi, and AstraZeneca; consulting fees from BioNTech, Bicycle Therapeutics,
Janssen, Merck Sorano, Pfizer, and ADC Therapeutics; honoraria from AstraZeneca
and Pfizer; and support for attending meetings or travel from MSD, Janssen, and
Bayer. IBR reports support for attending meetings or travel from the American
Society of Clinical Oncology; and a patent planned, issued, or pending for a
Living Evidence Synthesis platform for creating living systematic reviews and
meta-analysis. JWFC reports grants or contracts from Roche; consulting fees from
AstraZeneca, BMS, Gilead, QED Therapeutics, Roche, Ferring, Steba Biotech,
UroGen, Janssen, and Photocure; payment or honoraria from BMS, AstraZeneca, and
Roche; and a leadership or fiduciary role in Fight Bladder Cancer UK. TP reports
grants or contracts from AstraZeneca, Roche, BMS, Exelixis, Ipsen, Merck, MSD,
Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson,
and Eisai; consulting fees or honoraria from AstraZeneca, Roche, BMS, Exelixis,
Ipsen, Incyte, Merck, MSD, Novartis, Pfizer, Seattle Genetics, Merck Serono,
Astellas, Johnson & Johnson, and Eisai; and payment for travel, accommodation,
or expenses from Roche, Pfizer, MSD, AstraZeneca, and Ipsen. RJJ reports
consulting fees from Janssen, Astellas, Bayer, Novartis, Pfizer, Merck, Serono,
MSD, Roche, Ipsen, and BMS; research grants from Exelixis, Astellas, Clovis, and
Bayer; speaker honoraria from Janssen, Astellas, Bayer, Pfizer, Merck, Serono,
MSD, Roche, Ipsen, BMS; support for travel and attending meetings from Bayer;
and participation on a data safety monitoring board or advisory board for Roche.
All other authors declare no competing interests.
|
http://www.ncbi.nlm.nih.gov/pubmed/18508540
|
1. Front Biosci. 2008 May 1;13:4707-25. doi: 10.2741/3034.
Antisense DNA and RNA agents against picornaviruses.
Lim T(1), Yuan J, Zhang HM, Sall A, Liu Z, Su Y, Yang D.
Author information:
(1)Providence Heart and Lung Institute, Department of Pathology and Laboratory
Medicine, University of British Columbia-St. Paul's Hospital, Vancouver, Canada.
Anti-picornaviral antisense agents are part of a broader group of nucleic
acid-based molecules developed for sequence-specific inhibition of translation
and/or transcription of the target sequence through induced nuclease activity or
physical hindrance. Three types of nucleic acid-based gene silencing molecules
can be distinguished, including DNA-base antisense oligonucleotides (ASO),
nucleic acid enzymes (ribozyme and DNAzyme) and double-stranded small
interfering RNA (siRNA or microRNA). These antisense DNA and RNA molecules have
been widely studied for gene functional studies and therapeutic purposes. In
this review, we focus on drug development using ASO and siRNA strategies to
inhibit picornavirus infections. The picornavirus genome organization and life
cycle is described, followed by discussion of design considerations, chemical
modifications and drug delivery approaches. Recent studies using antisense
against picornavirus are reviewed. Finally, we compare the advantages and
disadvantages of the antisense agents with those of other therapeutics, taking
into consideration their limitations which need to be overcome to achieve the
final goal of clinical application.
DOI: 10.2741/3034
PMID: 18508540 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/32800852
|
1. Biochem Pharmacol. 2021 Jul;189:114196. doi: 10.1016/j.bcp.2020.114196. Epub
2020 Aug 13.
Antisense drug discovery and development technology considered in a
pharmacological context.
Crooke ST(1), Liang XH(2), Crooke RM(3), Baker BF(4), Geary RS(5).
Author information:
(1)Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA. Electronic address:
[email protected].
(2)Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA. Electronic address:
[email protected].
(3)Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA. Electronic address:
[email protected].
(4)Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA. Electronic address:
[email protected].
(5)Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA. Electronic address:
[email protected].
When coined, the term "antisense" included oligonucleotides of any structure,
with any chemical modification and designed to work through any post-RNA
hybridization mechanism. However, in practice the term "antisense" has been used
to describe single stranded oligonucleotides (ss ASOs) designed to hybridize to
RNAswhile the term "siRNA" has come to mean double stranded oligonucleotides
designed to activate Ago2. However, the two approaches share many common
features. The medicinal chemistry developed for ASOs greatly facilitated the
development of siRNA technology and remains the chemical basis for both
approaches. Many of challenges faced and solutions achieved share many common
features. In fact, because ss ASOs can be designed to activate Ago2, the two
approaches intersect at this remarkably important protein. There are also
meaningful differences. The pharmacokinetic properties are quite different and
thus potential routes of delivery differ. ASOs may be designedto use a variety
of post-RNA binding mechanismswhile siRNAs depend solely on the robust activity
of Ago2. However, siRNAs and ASOs are both used for therapeutic purposes and
both must be and can be understood in a pharmacological context. Thus, the goals
of this review are to put ASOs in pharmacological context and compare their
behavior as pharmacological agents to the those of siRNAs.
Copyright © 2020. Published by Elsevier Inc.
DOI: 10.1016/j.bcp.2020.114196
PMID: 32800852 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/31663454
|
1. Ther Deliv. 2019 Oct;10(10):621-625. doi: 10.4155/tde-2019-0051. Epub 2019 Oct
30.
Preliminary evaluation of YUTIQ™ (fluocinolone acetonide intravitreal implant
0.18 mg) in posterior uveitis.
Testi I(1), Pavesio C(1).
Author information:
(1)Moorfields Eye Hospital, NHS Foundation Trust, 162 City Rd, London EC1V 2PD,
UK.
Uveitis is a major cause of ocular morbidity, potentially leading to significant
visual impairment. The recent adoption of alternative drug delivery options has
led to the development of new sustained-delivery corticosteroid systems, able to
manage successfully chronic noninfectious posterior uveitis. The treatment goal
is to target the site of inflammation with low dose of corticosteroids,
delivered over an extended period of time, to minimize the cumulative damage
resulting from repeated recurrences, reducing both injections frequency and
ocular side effects. This article will review the pharmacology and preliminary
clinical data of the 0.18 mg fluocinolone acetonide intravitreal implant
(YUTIQ™), to show its efficacy and safety in the treatment of noninfectious
posterior uveitis.
DOI: 10.4155/tde-2019-0051
PMCID: PMC6880290
PMID: 31663454 [Indexed for MEDLINE]
Conflict of interest statement: Financial and competing interests disclosure
This work was supported by the National Institute for Health Research (NIHR)
Biomedical Research Centre based at Moorfields Eye Hospital NHS Foundation Trust
and UCL Institute of Ophthalmology. The views expressed are those of the authors
and not necessarily those of the NHS, the NIHR or the Department of Health. The
authors have no other relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript apart from those
disclosed. No writing assistance was utilized in the production of this
manuscript.
|
http://www.ncbi.nlm.nih.gov/pubmed/35562557
|
1. Neurol Sci. 2022 Jul;43(7):4563-4566. doi: 10.1007/s10072-022-06128-2. Epub
2022 May 13.
Duchenne muscular dystrophy newborn screening: the first 50,000 newborns
screened in Taiwan.
Chien YH(1)(2)(3), Lee NC(4)(5)(6), Weng WC(5)(6), Chen LC(4), Huang YH(4), Wu
CS(4), Hwu WL(4)(5)(6).
Author information:
(1)Department of Medical Genetics, National Taiwan University Hospital, Taipei,
Taiwan. [email protected].
(2)Department of Pediatrics, National Taiwan University Hospital, Taipei,
Taiwan. [email protected].
(3)Department of Pediatrics, National Taiwan University College of Medicine,
Taipei, Taiwan. [email protected].
(4)Department of Medical Genetics, National Taiwan University Hospital, Taipei,
Taiwan.
(5)Department of Pediatrics, National Taiwan University Hospital, Taipei,
Taiwan.
(6)Department of Pediatrics, National Taiwan University College of Medicine,
Taipei, Taiwan.
BACKGROUND: Duchenne muscular dystrophy (DMD/Duchenne) is a progressive X-linked
muscular disease with an overall incidence of 1:5,000 live male births. Recent
availability in treatment for DMD raised the need of early diagnosis, and DMD
became as a selective item of newborn screening (NBS) since Feb. 2021 in our
center.
MATERIALS AND METHODS: Dried blood spots (DBS) muscle-type creatine kinase (CK)
isoform was measured with a commercialized kit with age-adjusted cutoffs.
Subjects with an elevation of CK in the first screen were requested for a
re-screen 2 weeks later. A DBS whole-exome sequencing (WES) panel for dystrophin
and other neuromuscular-related genes was applied to confirm the diagnosis for
subjects with persistent hyperCKemia.
RESULTS: During a 1-year period, 50,572 newborns (male 26,130) received DMD
screening at a mean age of 2 days (SD 1 day). Among them, 632 (1.2%) had an
elevated CK value. A re-screen at a mean age of 14 days (SD 8 days) revealed 14
subjects with persistent hyperCKemia, and DMD was confirmed in 3 of them. The
incidence of DMD in Taiwan was 1:8,710 (95% CI 1 in 2,963 to 1 in 25,610) live
birth males. Results of DMD DBS also assisted in Pompe newborn screening.
CONCLUSIONS: NBS for DMD enables earlier management of the disease. The high
re-screening rate could potentially be waived by moving the DBS WES assay to a
second-tier test. The long-term benefit and the impact of newborn screening on
the prognosis of DMD, however, remain further elucidated.
© 2022. The Author(s).
DOI: 10.1007/s10072-022-06128-2
PMCID: PMC9106269
PMID: 35562557 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no competing interests.
|
http://www.ncbi.nlm.nih.gov/pubmed/18055393
|
1. Orv Hetil. 2007 Dec 23;148(51):2403-9. doi: 10.1556/OH.2007.28190.
[Carrier detection in families affected by Duchenne/Becker muscular dystrophy].
[Article in Hungarian]
Pikó H(1), Nagy B, Balog J, Bán Z, Herczegfalvi A, Karcagi V.
Author information:
(1)Országos Környezetegészségügyi Intézet Molekuláris Genetikai és Diagnosztikai
Osztály Budapest Gyáli út 2-6. 1097. [email protected]
Duchenne/Becker muscular dystrophy is a severe, recessive, X-linked
neuromuscular disease with an incidence of 1/3500 (Duchenne type) and 1/30,000
(Becker type) in newborn boys. The gene responsible for the Duchenne/Becker
muscular dystrophy phenotype is located at Xp21 and its 427 kD protein product
is called dystrophin. Deletions, point mutations and rarely duplications can
occur almost anywhere in the DMD gene, which makes the molecular diagnosis
difficult. Multiple polymerase chain reactions detect 95% of deletions in
affected males [2, 4], but are not suitable for carrier detection in female
relatives. Southern-blot analysis with six different cDNA probes covers the
whole 14 kb dystrophin transcript and allows the detection of female carriers by
comparing the intensity of the signals corresponding to the different exons.
This method is time consuming compared to the newly introduced multiple
ligation-dependent probe amplification method. Multiple ligation-dependent probe
amplification is a method suitable for relative quantification of several DNA
sequences in one reaction. The authors report results on 93 cases where the
carrier status was analysed simultaneously by cDNA hybridisation and multiple
ligation-dependent probe amplification technique. In 42 cases the carrier state
was confirmed and in this carrier population the authors additionally detected
two cases with duplication, two cases with one copy of the whole dystrophin gene
and three manifest carrier females. On the basis of these results the MLPA
technique, which has been newly introduced in Hungary, proved to be a sensitive
and quick method for the detection of carrier state in the DMD/BMD disease.
Moreover, the exact deletion or duplication border can be detected and as a
result, prediction on the phenotype can be given. This will provide the right
therapeutic intervention for the affected patients in the future.
DOI: 10.1556/OH.2007.28190
PMID: 18055393 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/1673177
|
1. Lancet. 1991 Apr 27;337(8748):1022-4. doi: 10.1016/0140-6736(91)92671-n.
Prevalence and incidence of Becker muscular dystrophy.
Bushby KM(1), Thambyayah M, Gardner-Medwin D.
Author information:
(1)Department of Neurobiology and Genetics, University of Newcastle upon Tyne,
UK.
We measured the prevalence and incidence of Becker muscular dystrophy in the
Northern Health Region of England, UK. Patients were identified from the records
of the Regional Neurological Centre and Muscular Dystrophy Group laboratories,
Newcastle upon Tyne, and by writing to local doctors. We used cDNA probes and/or
dystrophin immunolabelling of muscle-biopsy samples to prove the diagnosis of
all cases. Results were compared with the known prevalence and incidence of
Duchenne muscular dystrophy. 73 patients alive and resident in the Northern
Health Region were identified, giving a prevalence rate of 2.38/100,000. This
compares with a prevalence of Duchenne muscular dystrophy of 2.48/100,000. The
cumulative birth incidence of Becker muscular dystrophy (at least 1 in 18 450
male live births) was about one third that of Duchenne muscular dystrophy (1 in
5618 male live births), suggesting that the disorder is more common than
previously thought.
DOI: 10.1016/0140-6736(91)92671-n
PMID: 1673177 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/28064104
|
1. Biomed Pharmacother. 2017 Mar;87:311-320. doi: 10.1016/j.biopha.2016.12.118.
Epub 2017 Jan 5.
Dermal/transdermal delivery of small interfering RNA and antisense
oligonucleotides- advances and hurdles.
Ita K(1).
Author information:
(1)College of Pharmacy, Touro University, Mare Island-Vallejo, CA 94592, USA.
Electronic address: [email protected].
A diverse array of nucleic acids has been studied by several researchers for the
management of several diseases. Among these compounds, small interfering RNA and
antisense oligonucleotides have attracted considerable attention. Antisense
oligonucleotides are synthetic single stranded strings of nucleic acids that
bind to RNA and thereby alter or reduce expression of the target RNA while
siRNAs, on the other hand, are double-stranded RNA molecules which can hybridize
with a specific mRNA sequence and block the translation of numerous genes. One
of the main obstacles in the dermal or transdermal delivery of these compounds
is their low skin permeability. In this review, various techniques used to
enhance the delivery of these molecules into or across the skin are described
and in some cases, the correlation between enhanced dermal/transdermal delivery
and therapeutic efficacy is highlighted.
Copyright © 2016 Elsevier Masson SAS. All rights reserved.
DOI: 10.1016/j.biopha.2016.12.118
PMID: 28064104 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/7922631
|
1. Bratisl Lek Listy. 1994 Feb;95(2):78-82.
[Incidence of spinal muscular atrophy and Duchenne's muscular dystrophy in the
juvenile population of central Slovakia].
[Article in Slovak]
Kvasnicová M(1), Styková J, Hudec P.
Author information:
(1)Oddelenie lekárskej genetiky Nemocnice F.D. Roosevelta v Banskej Bystrici,
Slovakia.
Spinal muscular atrophy, type I-III and Duchenne muscular dystrophy belong to
the most frequent neuromuscular diseases in children. The purpose of this work
was to determine the incidence of these two diseases in liveborn children in the
years 1975 to 1989 in the south part of middle Slovakia. The common incidence of
all three types of spinal muscular atrophy was 1 in 5631 liveborn children (most
frequent was the Werdnig-Hoffmann disease, type I--1 in 12,286). This fact
confirms, that this disease belongs to the most frequent autosomal recessive
diseases in children of our region too. The incidence of Duchenne muscular
dystrophy was 1 in 4827 liveborn boys. The figure is in the range of the
published data of the incidence of this disease. The deletion in the dystrofin
gene was proved in 70% of affected boys. (Tab. 3, Fig. 1, Ref. 24).
PMID: 7922631 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/28802771
|
1. Neuromuscul Disord. 2017 Oct;27(10):911-913. doi: 10.1016/j.nmd.2017.07.008.
Epub 2017 Jul 19.
DMD and West syndrome.
Cardas R(1), Iliescu C(2), Butoianu N(2), Seferian A(3), Gataullina S(4),
Gargaun E(3), Nectoux J(5), Bienvenu T(5), Craiu D(2), Gidaro T(3), Servais
L(6).
Author information:
(1)I-Motion, Platform for Pediatric Clinical Trials, Arnold Trousseau Hospital,
Paris, France; "Prof. Dr. Al. Obregia" Hospital, Bucharest, Romania.
(2)"Prof. Dr. Al. Obregia" Hospital, Bucharest, Romania; Clinical Neurosciences
Department, "Carol Davila" University of Medicine and Pharmacy, Bucharest,
Romania.
(3)I-Motion, Platform for Pediatric Clinical Trials, Arnold Trousseau Hospital,
Paris, France.
(4)Service de Neuropédiatrie, Kremlin Bicêtre Hospital, Le Kremlin Bicêtre,
France.
(5)Laboratory of Biochemistry and Molecular Genetics, HUPC Paris Centre, Cochin
Hospital, Paris, France.
(6)I-Motion, Platform for Pediatric Clinical Trials, Arnold Trousseau Hospital,
Paris, France; Neuromuscular Center, CHU of Liège, Liège, Belgium. Electronic
address: [email protected].
Duchenne Muscular Dystrophy (DMD) is the most frequent muscular dystrophy in
childhood, with a worldwide incidence of one in 5000 live male births. It is due
to mutations in the dystrophin gene leading to absence of full-length dystrophin
protein. Central nervous system involvement is well-known in Duchenne Muscular
Dystrophy. The multiple dystrophin isoforms expressed in brain have important
roles in cerebral development and functioning. The association of Duchenne
Muscular Dystrophy with seizures has been reported, and there is a higher
prevalence of epilepsy in Duchenne Muscular Dystrophy patients (between 6.3% and
12.3%) than in the general pediatric population (0.5-1%). Duchenne Muscular
Dystrophy patients may present with focal seizures, generalized tonic-clonic
seizures or absences. We report on two boys in whom Duchenne Muscular Dystrophy
is associated with epileptic spasms and hypsarrhythmia that fulfil the criteria
for West syndrome, thus extending the spectrum of seizure types described in
Duchenne Muscular Dystrophy patients.
Copyright © 2017 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.nmd.2017.07.008
PMID: 28802771 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/35754057
|
1. Eur J Hum Genet. 2022 Dec;30(12):1398-1404. doi: 10.1038/s41431-022-01138-2.
Epub 2022 Jun 27.
Incidence of Duchenne muscular dystrophy in the modern era; an Australian study.
Kariyawasam D(1)(2), D'Silva A(3), Mowat D(3)(4), Russell J(4), Sampaio H(5),
Jones K(6)(7), Taylor P(8), Farrar M(5)(3).
Author information:
(1)Department of Neurology, Sydney Children's Hospital, Randwick, Sydney, NSW,
Australia. [email protected].
(2)School of Clinical Medicine, UNSW Medicine and Health, Randwick Clinical
Campus, Discipline of Paediatrics, University of New South Wales, Sydney, NSW,
Australia. [email protected].
(3)School of Clinical Medicine, UNSW Medicine and Health, Randwick Clinical
Campus, Discipline of Paediatrics, University of New South Wales, Sydney, NSW,
Australia.
(4)Centre for Clinical Genetics, Sydney Children's Hospital, Randwick, Sydney,
NSW, Australia.
(5)Department of Neurology, Sydney Children's Hospital, Randwick, Sydney, NSW,
Australia.
(6)Department of Clinical Genetics, Children's Hospital Westmead, Westmead, NSW,
Australia.
(7)Paediatrics and Child Health, Sydney Medical School, University of Sydney NSW
Australia, Sydney, NSW, Australia.
(8)Genomic Diagnostics, Healius Pathology, Melbourne, Vic, Australia.
Duchenne muscular dystrophy (DMD), an X-linked recessive condition is maternally
inherited in two-thirds of affected boys. It is important to establish carrier
status of female relatives to restore reproductive confidence for non-carriers
and facilitate reproductive options and cardiac surveillance for carriers. This
study investigates disease incidence within an Australian model of cascade
screening and evolving genetic diagnostic technologies. A retrospective
population-based cohort study of all genetically and/or histopathologically
confirmed males with DMD, born in New South Wales and the Australian Capital
Territory was undertaken from 2002-2012. Cases were identified using state-wide
molecular laboratory and clinical databases. The annual disease incidence and
"theoretically" preventable cases were extrapolated over the study period.
Proband genotype/phenotype, pedigree analysis, carrier-risk and extent of
cascade screening were also determined. The cumulative incidence of disease was
19.7 per 100,000 male live births and 1 in 5076 live born males were diagnosed
with DMD. Differences in disease incidence were not statistically different when
compared between 2002-2007 and 2008-2012 (incidence rate ratio = 1.13, 95% CI
0.76-1.69, p = 0.52). The incidence rate ratio of theoretically preventable
cases did not significantly change between 2002-2007 and 2008-2012 (incidence
rate ratio = 2.07, 95% CI 0.58-9.21, p = 0.23). Current diagnostic and cascade
screening models have limitations in their impact on disease incidence, due to a
spectrum of logistical, patient and condition related factors. Innovative
approaches to reduce DMD incidence may be better achieved by preconception or
early pregnancy carrier screening, prenatal exome sequencing and newborn
screening.
© 2022. The Author(s).
DOI: 10.1038/s41431-022-01138-2
PMCID: PMC9712523
PMID: 35754057 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no competing interests.
|
http://www.ncbi.nlm.nih.gov/pubmed/20080524
|
1. Clin Pediatr (Phila). 2010 Feb;49(2):177-9. doi: 10.1177/0009922809347777.
Duchenne muscular dystrophy: a 30-year population-based incidence study.
Dooley J(1), Gordon KE, Dodds L, MacSween J.
Author information:
(1)IWK Health Centre, Dalhousie University, Nova Scotia, Canada. [email protected]
Duchenne muscular dystrophy (DMD) is among the most common lethal genetic
diseases. It has been proposed that genetic counseling and prenatal diagnosis
have begun to lower the incidence. We reviewed the records of all patients with
confirmed DMD who were born between 1969 and 2008. Statistics Canada data on
annual male births in Nova Scotia were obtained for each year.The overall
incidence of 1 per 4700 male births remained stable during the 30-year period of
the study. Similarly, the age at diagnosis did not change during that time.
DOI: 10.1177/0009922809347777
PMID: 20080524 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/31603849
|
1. Medicina (B Aires). 2019;79 Suppl 3:77-81.
[Advances in the treatment of Duchenne muscular dystrophy].
[Article in Spanish; Abstract available in Spanish from the publisher]
Ortez C(1), Natera de Benito D(2), Carrera García L(2), Expósito J(2), Nolasco
G(2), Nascimento A(2).
Author information:
(1)Unidad de Patología Neuromuscular, Servicio de Neurología Pediátrica,
Hospital Sant Joan de Déu, Universidad de Barcelona, España. E-mail:
[email protected].
(2)Unidad de Patología Neuromuscular, Servicio de Neurología Pediátrica,
Hospital Sant Joan de Déu, Universidad de Barcelona, España.
Duchenne muscular dystrophy is a genetically determined disease, linked to the X
chromosome, c haracterized clinically by producing progressive muscle weakness,
with an incidence of 1 per 3500-6000 males born. It is caused by the mutation of
the DMD gene, which encodes dystrophin, a sub-sarcolemmal protein essential for
structural muscle stability. The genetic defects in the DMD gene are divided
into: deletions (65%) duplications (5.10%) and point mutations (10-15%). At
present there is no curative treatment, the only drug that has been shown to
modify the natural history of the disease (independently of the genetic
mutation) are corticosteroids, currently indicated in early stages of the
disease. In relation to clinical trials, in the last ten years, has experienced
great advances in the field of therapeutic options, divided into two major
therapeutic targets: 1) the area of gene therapies and 2) trying to reverse or
block the pathophysiological processes of the disease, such as inflammation,
fibrosis, muscle regeneration, etc. It is likely that an effective treatment for
Duchenne muscular dystrophy requires combinations of therapies that address both
the primary defect and its secondary pathophysiological consequences.
Publisher: La distrofia muscular de Duchenne es una enfermedad genéticamente
determinada, ligada al cromosoma X y caracterizada clínicamente por producir
debilidad muscular progresiva, con una incidencia de 1 por cada 3500-6000
varones nacidos. Es causada por la mutaciones en el gen DMD, el cual codifica la
distrofina, una proteína sub-sarcolémica esencial para la estabilidad
estructural del músculo. Los defectos genéticos en el gen DMD, se dividen en:
deleciones (65%) duplicaciones (5-10%) y mutaciones puntuales (10-15%).
Actualmente no se dispone de tratamiento curativo, el único fármaco que ha
demostrado modificar la historia natural de la enfermedad (independientemente de
la mutación genética) son los corticoides, los cuales están indicados en
estadios tempranos de la enfermedad. En relación a los ensayos clínicos, en los
últimos diez años se han experimentado grandes avances en el campo de las
opciones terapéuticas, divididos en dos grandes dianas terapéuticas: 1) el área
de las terapias génicas y 2) tratar de revertir o bloquear los procesos
fisiopatológicos de la enfermedad, tales como inflamación, fibrosis,
regeneración muscular, etc. Es probable que un tratamiento eficaz para la
distrofia muscular de Duchenne requiera combinaciones que se apliquen tanto al
defecto primario como las consecuencias fisiopatológicas secundarias.
PMID: 31603849 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/29386334
|
1. Postgrad Med J. 2018 May;94(1111):296-304. doi:
10.1136/postgradmedj-2017-135377. Epub 2018 Jan 31.
Duchenne muscular dystrophy: genome editing gives new hope for treatment.
Crispi V(1), Matsakas A(1).
Author information:
(1)Molecular Physiology Laboratory, Centre for Atherothrombotic and Metabolic
Disease, Hull York Medical School, University of Hull, Hull, UK.
Duchenne muscular dystrophy (DMD) is a progressive wasting disease of skeletal
and cardiac muscles, representing one of the most common recessive fatal
inherited genetic diseases with 1:3500-1:5000 in yearly incidence. It is caused
by mutations in the DMD gene that encodes the membrane-associated dystrophin
protein. Over the years, many have been the approaches to management of DMD, but
despite all efforts, no effective treatment has yet been discovered. Hope for
the development of potential therapeutics has followed the recent advances in
genome editing and gene therapy. This review gives an overview to DMD and
summarises current lines of evidence with regard to treatment and disease
management alongside the appropriate considerations.
© Article author(s) (or their employer(s) unless otherwise stated in the text of
the article) 2018. All rights reserved. No commercial use is permitted unless
otherwise expressly granted.
DOI: 10.1136/postgradmedj-2017-135377
PMID: 29386334 [Indexed for MEDLINE]
Conflict of interest statement: Competing interests: None declared.
|
http://www.ncbi.nlm.nih.gov/pubmed/25996334
|
1. Arch Argent Pediatr. 2015 Jun;113(3):e149-52. doi: 10.5546/aap.2015.e149.
[Duchenne muscular dystrophy: Case of atypical presentation and early
diagnosis].
[Article in Spanish]
Cabezudo García P(1), Moreno Medinilla E(2), Calvo Medina R(2), Mora Ramírez
MD(2), Martínez Antón J(2).
Author information:
(1)Unidad de Neurociencias, Hospital Clínico Universitario Virgen de la
Victoria.
(2)Hospital Materno Infantil, Málaga, España.
INTRODUCTION: Duchenne muscular dystrophy is the most common form of muscular
dystrophy, with an incidence of 1/3300 male live births and a prevalence rate in
the total population of 3/100000 individuals. It is often hereditary (X-linked
recessive) but sporadic cases are also frequent. The average age at diagnosis is
4.83 years but an early diagnosis is possible.
CLINICAL CASE: An 18-month male infant in ambulatory study for failure to thrive
and malnutrition was admitted in our hospital for respiratory problems.
Hypertransaminasemia without other data of hepatic involvement in addition to
hypotonia detected in the examination oriented diagnosis towards myopathy,
confirmed by elevated creatine kinase and electromyogram. The genetic study for
Duchenne muscular dystrophy was negative. Mutations were not detected. Muscle
biopsy showed complete absence of dystrophin. A more sensitive genetic study
showed a previously undescribed mutation.
DOI: 10.5546/aap.2015.e149
PMID: 25996334 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/16114258
|
1. J Soc Biol. 2005;199(1):5-11. doi: 10.1051/jbio:2005001.
[Molecular bases of dystrophinopathies].
[Article in French]
Leturcq F(1), Kaplan JC.
Author information:
(1)Laboratoire de Biochimie et Génétique Moléculaire, Hôpital Cochin et Institut
Cochin, 123 Boulevard de Port-Royal, 75014 Paris.
Duchenne muscular dystrophy (DMD) is inherited in an X-linked recessive pattern
and occurs at an incidence of 1 in 3500 male births, which means that it is a
so-called "orphan" or rare disease (frequency < 1/2000). Yet it is one of the
most frequent myopathies and is observed in all populations. We review here the
spectacular advances made in our understanding of this disease since the
identification in 1986 of the responsible gene. This gene encodes a
subsar-colemmal component of the cytoskeleton, dystrophin. We consider the
impact of this discovery on molecular diagnosis at the protein and DNA levels.
Despite the time that has passed since, the discovery of the gene has not led to
any treatment, and we review the therapeutic prospect.
DOI: 10.1051/jbio:2005001
PMID: 16114258 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/8629099
|
1. Southeast Asian J Trop Med Public Health. 1995;26 Suppl 1:166-71.
Duchenne muscular dystrophy.
Matsuo M(1).
Author information:
(1)International Center for Medical Research, Kobe University School of
Medicine, Japan.
Duchenne muscular dystrophy (DMD) is a common inherited disease with a worldwide
incidence of 1 in 3,500 male births. Recent molecular study on the DMD gene
identified a 14-kb mRNA encoded by 79 exons distributed over 2.5 million bp of
the X-chromosome. The protein named dystrophin contains 3,685 amino acids. Most
of the genetic events (mutations) that inactivate the dystrophin gene have been
shown to be deletions, with over 65% of patients exhibiting the loss of one or
more of the exons at the genomic DNA level. The mechanism of the inactivation of
the dystrophin gene in one third of patients with DMD/BMD is unknown.
PMID: 8629099 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/36012442
|
1. Int J Mol Sci. 2022 Aug 16;23(16):9176. doi: 10.3390/ijms23169176.
Full-Length Dystrophin Restoration via Targeted Exon Addition in DMD-Patient
Specific iPSCs and Cardiomyocytes.
Xiao R(1), Zhou M(1), Wang P(1), Zeng B(1), Wu L(1), Hu Z(1), Liang D(1).
Author information:
(1)Center for Medical Genetics, School of Life Sciences, Central South
University, Changsha 410078, China.
Duchenne muscular dystrophy (DMD) is the most common fatal muscle disease, with
an estimated incidence of 1/3500-1/5000 male births, and it is associated with
mutations in the X-linked DMD gene encoding dystrophin, the largest known human
gene. There is currently no cure for DMD. The large size of the DMD gene hampers
exogenous gene addition and delivery. The genetic correction of DMD
patient-derived induced pluripotent stem cells (DMD-iPSCs) and differentiation
into suitable cells for transplantation is a promising autologous therapeutic
strategy for DMD. In this study, using CRISPR/Cas9, the full-length dystrophin
coding sequence was reconstructed in an exon-50-deleted DMD-iPSCs by the
targeted addition of exon 50 at the junction of exon 49 and intron 49 via
homologous-directed recombination (HDR), with a high targeting efficiency of
5/15, and the genetically corrected iPSCs were differentiated into
cardiomyocytes (iCMs). Importantly, the full-length dystrophin expression and
membrane localization were restored in genetically corrected iPSCs and iCMs.
Thus, this is the first study demonstrating that full-length dystrophin can be
restored in iPSCs and iCMs via targeted exon addition, indicating potential
clinical prospects for DMD gene therapy.
DOI: 10.3390/ijms23169176
PMCID: PMC9409156
PMID: 36012442 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest.
|
http://www.ncbi.nlm.nih.gov/pubmed/35940183
|
1. RETRACTED ARTICLE
Lancet Oncol. 2022 Sep;23(9):1145-1155. doi: 10.1016/S1470-2045(22)00452-1. Epub
2022 Aug 5.
Atezolizumab, vemurafenib, and cobimetinib in patients with melanoma with CNS
metastases (TRICOTEL): a multicentre, open-label, single-arm, phase 2 study.
Dummer R(1), Queirolo P(2), Abajo Guijarro AM(3), Hu Y(3), Wang D(3), de Azevedo
SJ(4), Robert C(5), Ascierto PA(6), Chiarion-Sileni V(7), Pronzato P(8),
Spagnolo F(8), Mujika Eizmendi K(9), Liszkay G(10), de la Cruz Merino L(11),
Tawbi H(12).
Author information:
(1)Department of Dermatology, Skin Cancer Center, University Hospital Zurich,
Zurich, Switzerland. Electronic address: [email protected].
(2)IRCCS Istituto Europeo di Oncologia, Milan, Italy.
(3)F Hoffman-La Roche, Basel, Switzerland.
(4)Hospital de Clínicas de Porto Alegre, Unidade de Pesquisa Clinica em
Oncologia, Porto Alegre, Brazil.
(5)Gustave Roussy and Université Paris-Saclay, Villejuif-Paris, France.
(6)Istituto Nazionale Tumori IRCCS Fondazione "G Pascale," Naples, Italy.
(7)Istituto Oncologico Veneto IOV-IRCCS, Padua, Italy.
(8)IRCCS Ospedale Policlinico San Martino, Genova, Italy.
(9)Onkologikoa Hospital, Donostia, Spain.
(10)Országos Onkológiai Intézet, Budapest, Hungary.
(11)Hospital Universitario Virgen Macarena, Clinical Oncology Department and
Medicine Department, University of Seville, Seville, Spain.
(12)Department of Melanoma Medical Oncology, University of Texas MD Anderson
Cancer Center, Houston, TX, USA.
Retraction in
Lancet Oncol. 2023 Aug;24(8):832. doi: 10.1016/S1470-2045(23)00327-3.
Retracted and republished in
Lancet Oncol. 2023 Aug;24(8):e327. doi: 10.1016/S1470-2045(23)00292-9.
Expression of concern in
Lancet Oncol. 2023 Apr;24(4):e145. doi: 10.1016/S1470-2045(23)00111-0.
Corrected and republished in
Lancet Oncol. 2023 Dec;24(12):e461-e471. doi: 10.1016/S1470-2045(23)00334-0.
Comment in
Lancet Oncol. 2022 Nov;23(11):e481. doi: 10.1016/S1470-2045(22)00566-6.
Lancet Oncol. 2022 Nov;23(11):e482. doi: 10.1016/S1470-2045(22)00647-7.
Ann Transl Med. 2023 Mar 31;11(6):273. doi: 10.21037/atm-2022-78.
BACKGROUND: Targeted therapy and immunotherapy have shown intracranial activity
in melanoma with CNS metastases, but there remains an unmet need, particularly
for patients with symptomatic CNS metastases. We aimed to evaluate atezolizumab
in combination with cobimetinib or vemurafenib plus cobimetinib in patients with
melanoma with CNS metastases.
METHODS: TRICOTEL was a multicentre, open-label, single-arm, phase 2 study done
in two cohorts: a BRAFV600 wild-type cohort and a BRAFV600 mutation-positive
cohort, recruited at 21 hospitals and oncology centres in Brazil, France,
Germany, Hungary, Italy, Spain, and Switzerland. Eligible patients were aged 18
years or older with previously untreated metastatic melanoma, CNS metastases of
5 mm or larger in at least one dimension, and an Eastern Cooperative Oncology
Group performance status of 2 or less. Patients in the BRAFV600 wild-type cohort
received intravenous atezolizumab (840 mg, days 1 and 15 of each 28-day cycle)
plus oral cobimetinib (60 mg once daily, days 1-21). Patients in the BRAFV600
mutation-positive cohort received intravenous atezolizumab (840 mg, days 1 and
15 of each 28-day cycle) plus oral vemurafenib (720 mg twice daily) plus oral
cobimetinib (60 mg once daily, days 1-21); atezolizumab was withheld in cycle 1.
Treatment was continued until progression, toxicity, or death. The primary
outcome was intracranial objective response rate confirmed by assessments at
least 4 weeks apart, as assessed by independent review committee (IRC) using
modified Response Evaluation Criteria in Solid Tumours version 1.1. Because of
early closure of the BRAFV600 wild-type cohort, the primary endpoint of
intracranial objective response rate by IRC assessment was not done in this
cohort; intracranial objective response rate by investigator assessment was
reported instead. Efficacy and safety were analysed in all patients who received
at least one dose of study medication. This trial is closed to enrolment and is
registered with ClinicalTrials.gov, NCT03625141.
FINDINGS: Between Dec 13, 2018, and Dec 7, 2020, 65 patients were enrolled in
the BRAFV600 mutation-positive cohort; the BRAFV600 wild-type cohort was closed
early after enrolment of 15 patients. Median follow-up was 9·7 months (IQR
6·3-15·0) for the BRAFV600 mutation-positive cohort and 6·2 months (3·5-23·0)
for the BRAFV600 wild-type cohort. Intracranial objective response rate was 42%
(95% CI 29-54) by IRC assessment in the BRAFV600 mutation-positive cohort and
27% (95% CI 8-55) by investigator assessment in the BRAFV600 wild-type cohort.
Treatment-related grade 3 or worse adverse events occurred in 41 (68%) of 60
patients who received atezolizumab plus vemurafenib plus cobimetinib in the
BRAFV600 mutation-positive cohort, the most common of which were lipase
increased (15 [25%] of 60 patients) and blood creatine phosphokinase increased
(ten [17%]). Eight (53%) of 15 patients treated with atezolizumab plus
cobimetinib in the BRAFV600 wild-type cohort had treatment-related grade 3 or
worse adverse events, most commonly anaemia (two [13%]) and dermatitis acneiform
(two [13%]). Treatment-related serious adverse events occurred in 14 (23%) of 60
patients in the BRAFV600 mutation-positive cohort and two (13%) of 15 in the
BRAFV600 wild-type cohort. One death in the BRAFV600 mutation-positive cohort
(limbic encephalitis) was considered to be related to atezolizumab treatment.
INTERPRETATION: Adding atezolizumab to vemurafenib plus cobimetinib provided
promising intracranial activity in patients with BRAFV600-mutated melanoma with
CNS metastases.
FUNDING: F Hoffmann-La Roche.
Copyright © 2022 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1470-2045(22)00452-1
PMID: 35940183 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interests RD reports consulting
fees and honoraria from Alligator, Amgen, Bristol Myers Squibb, Catalym, Merck
Sharp & Dohme, MaxiVAX, Novartis, Pfizer, Pierre Fabre, Regeneron, Roche,
Sanofi, Second Genome, Sun Pharma, T3 Pharma, Takeda, and touchIME, and research
funding from Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, and
Roche. PQ reports consulting fees and honoraria from Bristol Myers Squibb,
Merck, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Sanofi, and Sun
Pharma, and travel, accommodations, or other expenses from Merck Sharp & Dohme
and Sanofi. AMAG reports former employment with F Hoffmann-La Roche, current
employment with Daiichi-Sankyo, and stock or other ownership with
Daiichi-Sankyo. YH and DW report employment with Roche. SJdA reports research
funding from Roche-Genentech. CR reports consulting fees and honoraria from
AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pfizer, Pierre
Fabre, Roche, and Sanofi. PAA reports consulting fees from 4SC, Bio-Al Health,
Bristol Myers Squibb, Idera, Italfarmaco, Lunaphore, Medicenna, Merck Serono,
Merck Sharp & Dohme, Nektar, Novartis, Pfizer/Array, Pierre-Fabre,
Roche-Genentech, Sandoz, Sanofi, and Sun Pharma; research funding from Bristol
Myers Squibb, Pfizer/Array, Roche-Genentech, and Sanofi; and participation on a
data safety monitoring board or advisory board for AstraZeneca,
Boehringer-Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Immunocore,
iTeos, Merck Sharp & Dohme, Nouscom, Novartis, Oncosec, Regeneron,
Roche-Genentech, and Seagen. VC-S reports consulting fees from Bristol Myers
Squibb, Merck-Serono, Novartis, and Pierre Fabre; honoraria from Bristol Myers
Squibb and Novartis; and travel, accommodations, or other expenses from Bristol
Myers Squibb and Pierre Fabre. FS reports honoraria from Bristol Myers Squibb,
Merck, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Sanofi, and Sun
Pharma, and consulting fees from Merck Sharp & Dohme, Novartis, Philogen, Pierre
Fabre, and Sun Pharma. GL reports consulting fees, honoraria, and participation
on a data safety monitoring board or advisory board for Bristol Myers Squibb,
Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Sanofi; research funding from
Roche, Clinical Excellence Program, establishment of The National Tumor Biology
Laboratory, and Investment of the Future; and a leadership role with College of
Dermatology, Hungarian Medical Research Council, and CEEAO. LdlCM reports
consulting fees from Bristol Myers Squibb, Gilead, Incyte, Merck Sharp & Dohme,
Novartis, and Roche, and research funding from Celgene, Merck Sharp & Dohme, and
Roche. HT reports consulting fees from Boxer Capital, Bristol Myers Squibb,
Eisai, Genentech, Iovance, Jazz Pharmaceuticals, Karyopharm, Medicenna, Merck,
and Novartis, and research funding from Bristol Myers Squibb, Celgene,
Dragonfly, Eisai, EMD Serono, Genentech, GlaxoSmithKline, Merck, Novartis, and
RAPT Therapeutics. All other authors declare no competing interests.
|
http://www.ncbi.nlm.nih.gov/pubmed/22425592
|
1. Placenta. 2012 Jun;33(6):502-10. doi: 10.1016/j.placenta.2012.02.017. Epub
2012 Mar 17.
Expression of aquaporin water channels in canine fetal adnexa in respect to the
regulation of amniotic fluid production and absorption.
Aralla M(1), Mobasheri A, Groppetti D, Cremonesi F, Arrighi S.
Author information:
(1)Department of Veterinary Sciences and Technologies for Food Safety,
Laboratory of Anatomy, Università degli Studi di Milano, Via Trentacoste 2,
I-20134 Milan, Italy. [email protected]
Amniotic fluid (AF) is created by the flow of fluid from the fetal lung and
bladder and reabsorbed in part by fetal swallowing and partly by the transfer
across the amnion to the fetal circulation. Placental water flux is an important
factor in determining AF volume and fetal hydration. In addition the fetal
membranes might be involved in the regulation of fluid composition. To
understand the mechanisms responsible for maintaining a correct balance of AF
volume we evaluated the expression of aquaporins (AQPs) in canine fetal adnexa.
AQPs are a family of integral membrane proteins permitting passive but
physiologically rapid transcellular water movement. The presence of AQP1, 3, 5,
8 and -9 was immunohistochemically assessed in canine fetal adnexa, collected in
early, middle and late-gestation during ovario-hysterectomies performed with
fully informed owners' consent. Changes in AF volume and biochemical composition
were also evaluated throughout pregnancy. Our results show distinct aquaporin
expression patterns in maternal and extraembryonic tissues in relation to
pregnancy period. AQP1 was localized in placental endothelia, allantochorion,
amnion, allantois and yolk sac. AQP3 was present in the placental labyrinth,
amnion, allantois and yolk sac. AQP8 was especially evident on the epithelia
lining the glandular chambers, the amniotic and allantois sacs. AQP9, a channel
highly permeable to water and urea, was observed in epithelia of amnion,
allantois and yolk sac. In summary, AQP1, 3, 5, 8 and -9 have distinct
expression patterns in canine fetal membranes and placenta in relation to
pregnancy period, suggesting an involvement in mediating the AF changes during
gestation.
Copyright © 2012 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.placenta.2012.02.017
PMID: 22425592 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17303237
|
1. Placenta. 2007 Aug-Sep;28(8-9):824-32. doi: 10.1016/j.placenta.2006.12.004.
Epub 2007 Feb 15.
Regulation of amniotic fluid volume.
Beall MH(1), van den Wijngaard JP, van Gemert MJ, Ross MG.
Author information:
(1)Department of Obstetrics and Gynecology, Harbor-UCLA Medical Center, 1000 W.
Carson Street, Box 3, Torrance, CA 90502, USA. [email protected]
Water arrives in the mammalian gestation from the maternal circulation across
the placenta. It then circulates between the fetal water compartments, including
the fetal body compartments, the placenta and the amniotic fluid. Amniotic fluid
is created by the flow of fluid from the fetal lung and bladder. A major pathway
for amniotic fluid resorption is fetal swallowing; however, in many cases the
amounts of fluid produced and absorbed do not balance. A second resorption
pathway, the intramembranous pathway (across the amnion to the fetal
circulation), has been proposed to explain the maintenance of normal amniotic
fluid volume. Amniotic fluid volume is thus a function both of the amount of
water transferred to the gestation across the placental membrane, and the flux
of water across the amnion. Water flux across biologic membranes may be driven
by osmotic or hydrostatic forces; existing data suggest that intramembranous
flow in humans is driven by the osmotic difference between the amniotic fluid
and the fetal serum. The driving force for placental flow is more controversial,
and both forces may be in effect. The mechanism(s) responsible for regulating
water flow to and from the amniotic fluid is unknown. In other parts of the
body, notably the kidney, water flux is regulated by the expression of aquaporin
water channels on the cell membrane. We hypothesize that aquaporins have a role
in regulating water flux across both the amnion and the placenta, and present
evidence in support of this theory. Current knowledge of gestational water flow
is sufficient to allow prediction of fetal outcome when water flow is abnormal,
as in twin-twin transfusion syndrome. Further insight into these mechanisms may
allow novel treatments for amniotic fluid volume abnormalities with resultant
improvement in clinical outcome.
DOI: 10.1016/j.placenta.2006.12.004
PMID: 17303237 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/15301291
|
1. Acta Biomed. 2004;75 Suppl 1:53-5.
Excess of amniotic fluid: pathophysiology, correlated diseases and clinical
management.
Nobile de Santis MS(1), Radaelli T, Taricco E, Bertini S, Cetin I.
Author information:
(1)Department of Medicine, Surgery and Dentistry, San Paolo Hospital, University
of Milan, Italy.
The evaluation of amniotic fluid volume represents, together with the evaluation
of fetal growth, one of the most important indicators of fetal wellbeing.
Amniotic fluid is produced by fetal urines with small aliquots from fetal
membranes and lung fluids. The main determinant of its turnover is fetal
swallowing together with a small absorption through fetal skin and membranes.
The pathologic conditions that lead to an excess of amniotic fluid are
represented by excessive production or by a reduction of the physiologic
turnover. The most frequent cause is gestational diabetes. This complication can
be diagnosed in 2-3% of pregnancies, as a result of increased insulin
resistance, most frequently found in association with risk factors such as high
maternal BMI. Placental hormones, such as HPL, act indeed to increase insulin
resistance and can therefore lead to post-prandial hyperglycemia in predisposed
mothers. Maternal hyperglicemia leads in turn to fetal hyperglycemia and fetal
hyperinsulinemia. Increased amniotic fluid volume is not a constant feature,
being associated with the most severe cases, but its evaluation is very useful
in the clinical management. The resulting increase in uterine volume, also
related to accelerated fetal growth, is a potential cause of premature delivery,
a severe complication also considering the delay in fetal lung maturation
observed with fetal hyperinsulinemia. The evaluation of the degree of
polyhydramnios has to be pursued by ultrasound. Precise diagnostic steps must be
followed in order to rule out other potentially associated causes. Amongst
these, malformations of the intestinal tract, such as hesophageal atresia, that
are associated with decreased or absent fetal swallowing, must be considered.
The clinical workout must therefore include an ultrasound evaluation of fetal
morphology together with an oral glucose tolerance test. The therapeutic
approach will be defined according to the definition of the underlying cause.
Many cases will benefit from bedrest, tocolysis and induction of lung
maturation.
PMID: 15301291 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/7705851
|
1. Hum Genet. 1995 Apr;95(4):475-7. doi: 10.1007/BF00208985.
Two polymorphic dinucleotide repeats in intron 44 of the dystrophin gene.
Köchling S(1), den Dunnen JT, Dworniczak B, Horst J.
Author information:
(1)Institut für Humangenetik, Westfälische Wilhelms Universität, Münster,
Germany.
Duchenne muscular dystrophy (DMD) is one of the most common and severe X-linked
disorders with an incidence of approximately 1 in 3500 newborn males. In more
than 60% of DMD patients, deletions of part or all of the dystrophin gene have
been shown. Despite this, carrier detection still poses a problem in some cases,
because of the enormous size of the gene and the lack of sufficient numbers of
informative markers. Here, we report the isolation and characterization of two
additional microsatellite markers (IVS44SK12 and IVS44SK21) in intron 44 of the
dystrophin gene. Both markers are useful for carrier detection either by
indirect DNA analysis or by direct proof of loss of heterozygosity.
DOI: 10.1007/BF00208985
PMID: 7705851 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/29684686
|
1. J Proteomics. 2019 Feb 10;192:1-9. doi: 10.1016/j.jprot.2018.04.023. Epub 2018
Apr 22.
A comprehensive profile and inter-individual variations analysis of the human
normal amniotic fluid proteome.
Liu X(1), Song Y(2), Guo Z(1), Sun W(3), Liu J(4).
Author information:
(1)Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences,
School of Basic Medicine, Peking Union Medical College, Beijing, China.
(2)Department of Obstetrics and Gynecology, Peking Union Medical College
Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences,
Beijing, China.
(3)Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences,
School of Basic Medicine, Peking Union Medical College, Beijing, China.
Electronic address: [email protected].
(4)Department of Obstetrics and Gynecology, Peking Union Medical College
Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences,
Beijing, China. Electronic address: [email protected].
Amniotic fluid contains large amounts of proteins produced by amnion epithelial
cells, fetal tissues, fetal excretions and placental tissues; thus, it is an
important potential source of biomarkers for identifying fetal pathologies. In
this study, a pooled AF sample from 7 healthy volunteers was used to provide a
comprehensive profile of normal human AF proteome using immunoaffinity depletion
of 14 high-abundance proteins. Each individual AF sample was used to analyze
inter-individual variations with iTRAQ method. As a result, a total of 2881
non-redundant proteins were identified, and 1624 proteins were quantified based
on the peak intensity-based semi-quantification (iBAQ) method. Gene Ontology
(GO) analysis showed that the AF proteome was enriched in extracellular region
and extracellular matrix. Further function annotation showed that the top
canonical pathway was axonal guidance signaling. The inter-individual variation
analysis of 7 individual AF samples showed that the median inter-individual CV
(Coefficient of variation) was 0.22. iBAQ quantification analysis revealed that
the inter-individual variations were not correlated with protein abundance. GO
analysis indicated that intracellular proteins tended to have higher CVs, and
extracellular proteins tended to have lower CVs. These data will contribute to a
better understanding of amniotic fluid proteomic analysis and biomarker
discovery. SIGNIFICANCE: Amniotic fluid is an important potential source of
biomarkers for identifying fetal pathologies. This study provided a large
database for the normal human amniotic fluid proteome and analysis of
inter-individual variations in amniotic fluid proteomes, which will offer a
baseline reference for further AF proteomic analysis and pregnancy-related
disease biomarker discovery.
Copyright © 2018. Published by Elsevier B.V.
DOI: 10.1016/j.jprot.2018.04.023
PMID: 29684686 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17254633
|
1. Placenta. 2007 Aug-Sep;28(8-9):816-23. doi: 10.1016/j.placenta.2006.11.009.
Epub 2007 Jan 23.
Amniotic fluid water dynamics.
Beall MH(1), van den Wijngaard JP, van Gemert MJ, Ross MG.
Author information:
(1)Department of Obstetrics and Gynecology, Harbor-UCLA Medical Center, 1000 W.
Carson St., Box 3, Torrance, CA 90502, USA. [email protected]
Water arrives in the mammalian gestation from the maternal circulation across
the placenta. It then circulates between the fetal water compartments, including
the fetal body compartments, the placenta and the amniotic fluid. Amniotic fluid
is created by the flow of fluid from the fetal lung and bladder. A major pathway
for amniotic fluid resorption is fetal swallowing; however in many cases the
amounts of fluid produced and absorbed do not balance. A second resorption
pathway, the intramembranous pathway (across the amnion to the fetal
circulation), has been proposed to explain the maintenance of normal amniotic
fluid volume. Amniotic fluid volume is thus a function both of the amount of
water transferred to the gestation across the placental membrane, and the flux
of water across the amnion. Membrane water flux is a function of the water
permeability of the membrane; available data suggests that the amnion is the
structure limiting intramembranous water flow. In the placenta, the
syncytiotrophoblast is likely to be responsible for limiting water flow across
the placenta. In human tissues, placental trophoblast membrane permeability
increases with gestational age, suggesting a mechanism for the increased water
flow necessary in late gestation. Membrane water flow can be driven by both
hydrostatic and osmotic forces. Changes in both osmotic/oncotic and hydrostatic
forces in the placenta my alter maternal-fetal water flow. A normal amniotic
fluid volume is critical for normal fetal growth and development. The study of
amniotic fluid volume regulation may yield important insights into the
mechanisms used by the fetus to maintain water homeostasis. Knowledge of these
mechanisms may allow novel treatments for amniotic fluid volume abnormalities
with resultant improvement in clinical outcome.
DOI: 10.1016/j.placenta.2006.11.009
PMID: 17254633 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22439042
|
1. J Prenat Med. 2009 Jul;3(3):39-41.
Proteomic analysis for the study of amniotic fluid protein composition.
Perluigi M(1), Di Domenico F, Cini C, Coccia R, Giorlandino FR, Giorlandino M,
Cignini P, Mesoraca A, Giorlandino C.
Author information:
(1)Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of
Rome, Rome, Italy.
Amniotic fluid (AF), routinely used for prenatal diagnosis, contains large
amounts of proteins produced by the amnion epithelial cells, fetal tissues,
fetal excretions and placental tissuesAlthough many amniotic fluid proteins have
been identified and are currently used to detect potential fetal anomalies,
little is known about the functions of these proteins and how they interact with
one another. Identification of changes in the protein content of amniotic fluid,
therefore, may be used to detect a particular type of pathology, or to ascertain
a specific genetic disorder. In the present work we used a proteomic approach,
combining 2DE and MS, in order to study the protein composition of AFS.
PMCID: PMC3279107
PMID: 22439042
|
http://www.ncbi.nlm.nih.gov/pubmed/36274226
|
1. Discov Med. 2022 Mar-Apr;33(169):85-92.
Bacillus Calmette-Guerin for the Treatment of Non-muscle Invasive Bladder
Cancer: History and Current Status.
Liu G(#)(1)(2), Li B(#)(1), Xu Z(#)(1), Wang J(1), Ma S(1), Kan Y(1), Mao
L(1)(3).
Author information:
(1)Department of Urology, the Affiliated Hospital of Xuzhou Medical University,
Xuzhou, Jiangsu 221000, China.
(2)Department of Urology, Ganyu District Hospital, Lianyungang, Jiangsu 222100,
China.
(3)Corresponding author.
(#)Contributed equally
In the past decades, the bacillus Calmette-Guerin (BCG) treatment for non-muscle
invasive bladder cancer, especially for intermediate and high-risk groups, is
increasingly accepted by multiple guidelines. Currently, the front-line setting
for the high-risk group is still intravesical BCG instillation. However, the BCG
mechanism, usage, adverse events, and the definition of BCG failure are not yet
fully understood or defined. In addition, despite BCG being generally
efficacious, a number of bladder cancer patients are unresponsive to the BCG
immunotherapy. In this review, we summarize the history and current status of
BCG immunotherapy, and highlight recent developments in designing novel
strategies for the treatment of BCG-unresponsive patients.
PMID: 36274226 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/31794464
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1. Continuum (Minneap Minn). 2019 Dec;25(6):1640-1661. doi:
10.1212/CON.0000000000000792.
Congenital Muscular Dystrophy and Congenital Myopathy.
Butterfield RJ.
PURPOSE OF REVIEW: Congenital muscular dystrophies and congenital myopathies are
a heterogeneous group of disorders resulting in hypotonia, muscle weakness, and
dystrophic or myopathic features on muscle biopsy. This article summarizes the
clinical and genetic aspects of these disorders.
RECENT FINDINGS: Historically, diagnoses of congenital muscular dystrophy and
congenital myopathy have been made by clinical features and histopathology;
however, recent advances in genetics have changed diagnostic practice by relying
more heavily on genetic findings. This article reviews the clinical and genetic
features of the most common congenital muscular dystrophies including laminin
subunit alpha 2 (LAMA2)-related (merosin deficient), collagen VI-related, and
α-dystroglycan-related congenital muscular dystrophies and reviews the most
common congenital myopathies including nemaline rod, core, and centronuclear
myopathies. With the increasing accessibility of genetic testing, the number of
genes found to be associated with these disorders has increased dramatically. A
wide spectrum of severity and onset (from birth to adulthood) exist across all
subtypes. Progression and other features are variable depending on the subtype
and severity of the specific genetic mutation.
SUMMARY: Congenital muscular dystrophy and congenital myopathy are increasingly
recognized disorders. A growing appreciation for the breadth of phenotypic
variability and overlap between established subtypes has challenged
long-standing phenotypic and histopathologic classifications of these disorders
but has driven a greater understanding of pathogenesis and opened the door to
the development of novel treatments.
DOI: 10.1212/CON.0000000000000792
PMID: 31794464 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/35562158
|
1. Indian J Pathol Microbiol. 2022 May;65(Supplement):S259-S270. doi:
10.4103/ijpm.ijpm_1074_21.
Genetics and muscle pathology in the diagnosis of muscular dystrophies: An
update.
Narasimhaiah D(1), Uppin MS(2), Ranganath P(3).
Author information:
(1)Department of Pathology, Sree Chitra Tirunal Institute for Medical Sciences
and Technology, Thiruvananthapuram, Kerala, India.
(2)Department of Pathology, Nizam's Institute of Medical Sciences, Punjagutta,
Hyderabad, Telangana, India.
(3)Department of Medical Genetics, Nizam's Institute of Medical Sciences,
Punjagutta, Hyderabad, Telangana, India.
Muscular dystrophies are a clinically and genetically heterogeneous group of
disorders involving the skeletal muscles. They have a progressive clinical
course and are characterized by muscle fiber degeneration. Congenital muscular
dystrophies (CMD) include dystroglycanopathies, merosin-deficient CMD, collagen
VI-deficient CMD, SELENON-related rigid spine muscular dystrophy, and
LMNA-related CMD. Childhood and adult-onset muscular dystrophies include
dystrophinopathies, limb-girdle muscular dystrophies, Emery-Dreifuss muscular
dystrophy, facioscapulohumeral muscular dystrophy, and myotonic dystrophy.
Traditionally, muscle biopsy and histopathology along with special pathology
techniques such as immunohistochemistry or immunoblotting were used for the
diagnosis of muscular dystrophies. However, recent advances in molecular genetic
testing, especially the next-generation sequencing technology, have
revolutionized the diagnosis of muscular dystrophies. Identification of the
underlying genetic basis helps in appropriate management and prognostication of
the affected individual and genetic counseling of the family. In addition,
identification of the exact disease-causing mutations is necessary for accurate
prenatal genetic testing and carrier testing, to prevent recurrence in the
family. Mutation identification is also essential for initiating
mutation-specific therapies (which have been developed recently, especially for
Duchenne muscular dystrophy) and for enrolment of patients into ongoing
therapeutic clinical trials. The 'genetic testing first' approach has now become
the norm in most centers. Nonetheless, muscle biopsy-based testing still has an
important role to play, especially for cases where genetic testing is negative
or inconclusive for the etiology.
DOI: 10.4103/ijpm.ijpm_1074_21
PMID: 35562158 [Indexed for MEDLINE]
Conflict of interest statement: None
|
http://www.ncbi.nlm.nih.gov/pubmed/23622361
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1. Handb Clin Neurol. 2013;113:1377-85. doi: 10.1016/B978-0-444-59565-2.00008-3.
Congenital muscular dystrophies.
Kirschner J(1).
Author information:
(1)Division of Neuropediatrics and Muscle Disorders, Center for Pediatrics and
Adolescent Medicine, University Medical Center Freiburg, Germany. Electronic
address: [email protected].
The congenital muscular dystrophies are a heterogeneous group of disorders in
which weakness and dystrophic pattern on muscle biopsy are present at birth or
during the first months of life. This chapter reviews the most common forms of
congenital muscular dystrophies, including laminin α-2 (merosin) deficiency,
Ullrich congenital muscular dystrophy, fukutin-related proteinopathy, rigid
spine syndrome, and glycosylation disorders of α-dystroglycan. The latter group
is often associated with neuronal migration defects including lissencephaly,
pachygyria, cerebellar and brainstem abnormalities, and variable ocular
anomalies. Typical clinical findings and underlying genetic defects are
discussed to assist in the differential diagnosis and diagnostic work-up of
patients with congenital muscular dystrophies. There are still no curative
treatment options for patients with congenital muscular dystrophies but regular
follow-up and symptomatic care by a multidisciplinary team considering the
peculiarities of each disorder are important to maintain or improve patients'
quality of life.
Copyright © 2013 Elsevier B.V. All rights reserved.
DOI: 10.1016/B978-0-444-59565-2.00008-3
PMID: 23622361 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/29933045
|
1. Matrix Biol. 2018 Oct;71-72:188-204. doi: 10.1016/j.matbio.2018.06.005. Epub
2018 Jun 19.
Extracellular matrix-driven congenital muscular dystrophies.
Mohassel P(1), Foley AR(1), Bönnemann CG(2).
Author information:
(1)Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics
Branch, National Institute of Neurological Disorders and Stroke, National
Institutes of Health, United States of America.
(2)Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics
Branch, National Institute of Neurological Disorders and Stroke, National
Institutes of Health, United States of America. Electronic address:
[email protected].
Skeletal muscle function relies on the myofibrillar apparatus inside myofibers
as well as an intact extracellular matrix surrounding each myofiber. Muscle
extracellular matrix (ECM) plays several roles including but not limited to
force transmission, regulation of growth factors and inflammatory responses, and
influencing muscle stem cell (i.e. satellite cell) proliferation and
differentiation. In most myopathies, muscle ECM undergoes remodeling and
fibrotic changes that may be maladaptive for normal muscle function and
recovery. In addition, mutations in skeletal muscle ECM and basement proteins
can cause muscle disease. In this review, we summarize the clinical features of
two of the most common congenital muscular dystrophies, COL6-related dystrophies
and LAMA2-related dystrophies, which are caused by mutations in muscle ECM and
basement membrane proteins. The study of clinical features of these diseases has
helped to inform basic research and understanding of the biology of muscle ECM.
In return, basic studies of muscle ECM have provided the conceptual framework to
develop therapeutic interventions for these and other similar disorders of
muscle.
Copyright © 2018. Published by Elsevier B.V.
DOI: 10.1016/j.matbio.2018.06.005
PMID: 29933045 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/2286751
|
1. J Dev Physiol. 1990 May;13(5):283-7.
Maternal dehydration: impact on ovine amniotic fluid volume and composition.
Schreyer P(1), Sherman DJ, Ervin MG, Day L, Ross MG.
Author information:
(1)Perinatal Research Laboratories, Harbor-UCLA Medical Center, UCLA School of
Medicine, Torrance 90502.
Maternal dehydration consistent with mild water deprivation or moderate exercise
results in maternal and fetal plasma hyperosmolality and increased plasma
arginine vasopressin (AVP). Previous studies have demonstrated a reduction in
fetal urine and lung fluid production in response to maternal dehydration or
exogenous fetal AVP. As fetal urine and perhaps lung liquid combine to produce
amniotic fluid, maternal dehydration may affect the amniotic fluid volume and/or
composition. In the present study, six chronically-prepared pregnant ewes with
singleton fetuses (128 +/- 1 day) were water deprived for 54 h to determine the
effect on amniotic fluid. Maternal plasma osmolality (306.5 +/- 0.9 to 315.6 +/-
1.9 mOsm/kg) and AVP (1.9 +/- 0.2 to 22.2 +/- 3.2 pg/ml) significantly increased
during dehydration. Similarly, fetal plasma osmolality (300.0 +/- 0.9 to 312.7
+/- 1.7 mOsm/kg) and AVP (1.4 +/- 0.1 to 10.4 +/- 2.4 pg/ml) increased in
parallel to maternal values. Amniotic fluid osmolality (276.8 +/- 5.7 to 311.6
+/- 6.5 mOsm/kg) and sodium (139.8 +/- 4.8 to 154.0 +/- 5.4 mEq/l) and potassium
(9.1 +/- 1.3 to 13.9 +/- 2.4 mEq/l) concentrations increased while a significant
(35%) reduction in amniotic fluid volume occurred (871 +/- 106 to 520 +/- 107
ml). These results indicate that maternal dehydration may have marked effects on
maternal-fetal-amniotic fluid dynamics, possibly contributing to the development
of oligohydramnios.
PMID: 2286751 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/31308722
|
1. Appl Clin Genet. 2019 Jul 3;12:113-130. doi: 10.2147/TACG.S187481. eCollection
2019.
Current understanding and treatment of cardiac and skeletal muscle pathology in
laminin-α2 chain-deficient congenital muscular dystrophy.
Nguyen Q(#)(1), Lim KRQ(#)(1), Yokota T(1)(2).
Author information:
(1)Department of Medical Genetics, Faculty of Medicine and Dentistry, University
of Alberta, Edmonton, AB, Canada.
(2)The Friends of Garrett Cumming Research & Muscular Dystrophy Canada, HM
Toupin Neurological Science Research Chair, Edmonton, AB, Canada.
(#)Contributed equally
Congenital muscular dystrophy (CMD) is a class of severe early-onset muscular
dystrophies affecting skeletal/cardiac muscles as well as the central nervous
system (CNS). Laminin-α2 chain-deficient congenital muscular dystrophy (LAMA2
MD), also known as merosin-deficient congenital muscular dystrophy type 1A
(MDC1A), is an autosomal recessive CMD characterized by severe muscle weakness
and degeneration apparent at birth or in the first 6 months of life. LAMA2 MD is
the most common congenital muscular dystrophy, affecting approximately 4 in
500,000 children. The most common cause of death in early-onset LAMA2 MD is
respiratory tract infection, with 30% of them dying within the first decade of
life. LAMA2 MD is caused by loss-of-function mutations in the LAMA2 gene
encoding for the laminin-α2 chain, one of the subunits of laminin-211.
Laminin-211 is an extracellular matrix protein that functions to stabilize the
basement membrane and muscle fibers during contraction. Since laminin-α2 is
expressed in many tissue types including skeletal muscle, cardiac muscle,
Schwann cells, and trophoblasts, patients with LAMA2 MD experience a
multi-systemic clinical presentation depending on the extent of laminin-α2 chain
deficiency. Cardiac manifestations are typically associated with a complete
absence of laminin-α2; however, recent case reports highlight cardiac
involvement in partial laminin-α2 chain deficiency. Laminin-211 is also
expressed in the brain, and many patients have abnormalities on brain imaging;
however, mental retardation and/or seizures are rarely seen. Currently, there is
no cure for LAMA2 MD, but various therapies are being investigated in an effort
to lessen the severity of LAMA2 MD. For example, antisense
oligonucleotide-mediated exon skipping and CRISPR-Cas9 genome editing have
efficiently restored the laminin-α2 chain in mouse models in vivo. This review
consolidates information on the clinical presentation, genetic basis, pathology,
and current treatment approaches for LAMA2 MD.
DOI: 10.2147/TACG.S187481
PMCID: PMC6618038
PMID: 31308722
Conflict of interest statement: The authors report no conflicts of interest in
this work.
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http://www.ncbi.nlm.nih.gov/pubmed/23288328
|
1. Brain. 2013 Jan;136(Pt 1):269-81. doi: 10.1093/brain/aws312. Epub 2013 Jan 3.
ISPD gene mutations are a common cause of congenital and limb-girdle muscular
dystrophies.
Cirak S(1), Foley AR, Herrmann R, Willer T, Yau S, Stevens E, Torelli S, Brodd
L, Kamynina A, Vondracek P, Roper H, Longman C, Korinthenberg R, Marrosu G,
Nürnberg P; UK10K Consortium; Michele DE, Plagnol V, Hurles M, Moore SA, Sewry
CA, Campbell KP, Voit T, Muntoni F.
Author information:
(1)Dubowitz Neuromuscular Centre, UCL Institute of Child Health, University
College London, 30 Guilford Street, London WC1N 1EH, UK.
Dystroglycanopathies are a clinically and genetically diverse group of
recessively inherited conditions ranging from the most severe of the congenital
muscular dystrophies, Walker-Warburg syndrome, to mild forms of adult-onset
limb-girdle muscular dystrophy. Their hallmark is a reduction in the functional
glycosylation of α-dystroglycan, which can be detected in muscle biopsies. An
important part of this glycosylation is a unique O-mannosylation, essential for
the interaction of α-dystroglycan with extracellular matrix proteins such as
laminin-α2. Mutations in eight genes coding for proteins in the glycosylation
pathway are responsible for ∼50% of dystroglycanopathy cases. Despite multiple
efforts using traditional positional cloning, the causative genes for unsolved
dystroglycanopathy cases have escaped discovery for several years. In a recent
collaborative study, we discovered that loss-of-function recessive mutations in
a novel gene, called isoprenoid synthase domain containing (ISPD), are a
relatively common cause of Walker-Warburg syndrome. In this article, we report
the involvement of the ISPD gene in milder dystroglycanopathy phenotypes ranging
from congenital muscular dystrophy to limb-girdle muscular dystrophy and
identified allelic ISPD variants in nine cases belonging to seven families. In
two ambulant cases, there was evidence of structural brain involvement, whereas
in seven, the clinical manifestation was restricted to a dystrophic skeletal
muscle phenotype. Although the function of ISPD in mammals is not yet known,
mutations in this gene clearly lead to a reduction in the functional
glycosylation of α-dystroglycan, which not only causes the severe Walker-Warburg
syndrome but is also a common cause of the milder forms of dystroglycanopathy.
DOI: 10.1093/brain/aws312
PMCID: PMC3562076
PMID: 23288328 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/10734260
|
1. Neuromuscul Disord. 2000 Mar;10(3):153-9. doi: 10.1016/s0960-8966(99)00109-1.
The Fukuyama congenital muscular dystrophy story.
Toda T(1), Kobayashi K, Kondo-Iida E, Sasaki J, Nakamura Y.
Author information:
(1)Laboratory of Genome Medicine, Human Genome Center, Institute of Medical
Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, Japan.
[email protected]
Fukuyama congenital muscular dystrophy is one of the most common autosomal
recessive disorders in the Japanese population, characterized by congenital
muscular dystrophy in combination with cortical dysgenesis (micropolygyria).
Recently, we have identified the gene responsible for fukuyama congenital
muscular dystrophy on 9q31, which encodes a novel 461-amino-acid protein termed
fukutin. Most Fukuyama congenital muscular dystrophy-bearing chromosomes are
derived from a single ancestral founder (87%), and a 3 kb-retrotransposal
insertion into the 3' untranslated region of this gene was found to be a founder
mutation. Two independent point mutations causing premature termination
confirmed that that this gene is responsible for Fukuyama congenital muscular
dystrophy. Fukuyama congenital muscular dystrophy is the first human disease to
be caused by an ancient retrotransposal integration. Fukutin contains an
amino-terminal signal sequence, which together with results from transfection
experiments suggests that it is an extracellular protein. Discovery of the
Fukuyama congenital muscular dystrophy gene represents an important step toward
greater understanding of the pathogenesis of muscular dystrophies and also of
normal brain development.
DOI: 10.1016/s0960-8966(99)00109-1
PMID: 10734260 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/29244830
|
1. PLoS One. 2017 Dec 15;12(12):e0189664. doi: 10.1371/journal.pone.0189664.
eCollection 2017.
Transcriptome profiling identifies regulators of pathogenesis in collagen VI
related muscular dystrophy.
Butterfield RJ(1), Dunn DM(2), Hu Y(3), Johnson K(4), Bönnemann CG(3), Weiss
RB(2).
Author information:
(1)University of Utah, Departments of Pediatrics and Neurology, Salt Lake City,
Utah, United States of America.
(2)University of Utah, Department of Human Genetics, Salt Lake City, Utah,
United States of America.
(3)Neurogenetics Branch, National Institute of Neurological Disorders and
Stroke, NIH, Bethesda, Maryland, United States of America.
(4)Bioinformatics section, National Institute of Neurological Disorders and
Stroke, NIH, Bethesda, Maryland, United States of America.
OBJECTIVES: The collagen VI related muscular dystrophies (COL6-RD), Ullrich
congenital muscular dystrophy (UCMD) and Bethlem myopathy (BM) are among the
most common congenital muscular dystrophies and are characterized by distal
joint laxity and a combination of distal and proximal joint contractures.
Inheritance can be dominant negative (DN) or recessive depending on the type and
location of the mutation. DN mutations allow incorporation of abnormal chains
into secreted tetramers and are the most commonly identified mutation type in
COL6-RD. Null alleles (nonsense, frameshift, and large deletions) do not allow
incorporation of abnormal chains and act recessively. To better define the
pathways disrupted by mutations in collagen VI, we have used a transcriptional
profiling approach with RNA-Seq to identify differentially expressed genes in
COL6-RD individuals from controls.
METHODS: RNA-Seq allows precise detection of all expressed transcripts in a
sample and provides a tool for quantification of expression data on a genomic
scale. We have used RNA-Seq to identify differentially expressed genes in
cultured dermal fibroblasts from 13 COL6-RD individuals (8 dominant negative and
5 null) and 6 controls. To better assess the transcriptional changes induced by
abnormal collagen VI in the extracellular matrix (ECM); we compared
transcriptional profiles from subjects with DN mutations and subjects with null
mutations to transcriptional profiles from controls.
RESULTS: Differentially expressed transcripts between COL6-RD and control
fibroblasts include upregulation of ECM components and downregulation of factors
controlling matrix remodeling and repair. DN and null samples are differentiated
by downregulation of genes involved with DNA replication and repair in null
samples.
CONCLUSIONS: Differentially expressed genes identified here may help identify
new targets for development of therapies and biomarkers to assess the efficacy
of treatments.
DOI: 10.1371/journal.pone.0189664
PMCID: PMC5731705
PMID: 29244830 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: Russell J. Butterfield is
supported by NIH grant 1K08NS097631-01 and CureCMD. He is receiving funding via
contracts for clinical trials from PTC Therapeutics, Sarepta Therapeutics,
Pfizer, Marathon, Biogen, Summit Therapeutics, Santhera Pharmaceuticals, and
aTyr Pharmaceuticals. Dr. Butterfield serves on scientific advisory boards for
Sarepta Therapeutics, Biogen, PTC Therapeutics, and Wave Life Sciences. Diane M.
Dunn has no competing interests. Ying Hu has no competing interests. Kory
Johnson has no competing interests. Carsten G. Bönnemann no competing interests.
Robert B. Weiss has no competing interests. This does not alter our adherence to
PLOS ONE policies on sharing data and materials.
|
http://www.ncbi.nlm.nih.gov/pubmed/25653289
|
1. Neurology. 2015 Mar 3;84(9):904-11. doi: 10.1212/WNL.0000000000001303. Epub
2015 Feb 4.
Prevalence of congenital muscular dystrophy in Italy: a population study.
Graziano A(1), Bianco F(1), D'Amico A(1), Moroni I(1), Messina S(1), Bruno C(1),
Pegoraro E(1), Mora M(1), Astrea G(1), Magri F(1), Comi GP(1), Berardinelli
A(1), Moggio M(1), Morandi L(1), Pini A(1), Petillo R(1), Tasca G(1), Monforte
M(1), Minetti C(1), Mongini T(1), Ricci E(1), Gorni K(1), Battini R(1),
Villanova M(1), Politano L(1), Gualandi F(1), Ferlini A(1), Muntoni F(1),
Santorelli FM(1), Bertini E(1), Pane M(1), Mercuri E(2).
Author information:
(1)From the Departments of Paediatrics and Neurology (A.G., F.B., G.T., M.
Monforte, E.R., M.P., E.M.), Catholic University, Rome; Unit of Neuromuscular
and Neurodegenerative Disorders (A.D., G.T., E.B.), Department of Neurosciences,
Bambino Gesù Children's Hospital, Rome; Pediatric Neurology and Neuromuscular
Disease and Immunology Unit (I.M., M. Mora, L.M.), Istituto Neurologico Besta,
Milan; Department of Neurosciences, Psychiatry and Anaesthesiology (S.M.),
University of Messina; Neuromuscular Disease Unit (C.B., C.M.), G. Gaslini
Institute, Genoa; Department of Neurosciences (E.P.), University of Padua,
Italy; Department of Developmental Neuroscience and Molecular Medicine
Neuromuscular Unit (G.A., R.B., F.M.S.), Stella Maris Institute, Pisa;
Department of Neurological Sciences (F. Magri, G.P.C.), IRCCS Ospedale Maggiore
Policlinico, University of Milan; Child Neurology and Psychiatry Unit (A.B.),
IRCCS C. Mondino Foundation; Neuromuscular and Rare Diseases Unit (M. Moggio),
IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Dino Ferrari Center,
Milano; Child Neurology and Psychiatry Unit (A.P.), IRCCS Istituto delle Scienze
Neurologiche di Bologna, Bellaria Hospital, Bologna; Cardiomiologia e Genetica
Medica (R.P., L.P.), Dipartimento di Medicina Sperimentale Seconda Università di
Napoli; Neuromuscular Center (T.M.), S.G. Battista Hospital, University of
Turin; Centro Nemo (K.G.), Milan; Neuromuscular Unit (M.V.), Nigrisoli Hospital,
Bologna; Section of Medical Genetics (F.G., A.F.), Department of Experimental
and Diagnostic Medicine, Ferrara, Italy; and Dubowitz Neuromuscular Centre (F.
Muntoni), UCL Institute of Child Health & Great Ormond Street Hospital for
Children, London, UK.
(2)From the Departments of Paediatrics and Neurology (A.G., F.B., G.T., M.
Monforte, E.R., M.P., E.M.), Catholic University, Rome; Unit of Neuromuscular
and Neurodegenerative Disorders (A.D., G.T., E.B.), Department of Neurosciences,
Bambino Gesù Children's Hospital, Rome; Pediatric Neurology and Neuromuscular
Disease and Immunology Unit (I.M., M. Mora, L.M.), Istituto Neurologico Besta,
Milan; Department of Neurosciences, Psychiatry and Anaesthesiology (S.M.),
University of Messina; Neuromuscular Disease Unit (C.B., C.M.), G. Gaslini
Institute, Genoa; Department of Neurosciences (E.P.), University of Padua,
Italy; Department of Developmental Neuroscience and Molecular Medicine
Neuromuscular Unit (G.A., R.B., F.M.S.), Stella Maris Institute, Pisa;
Department of Neurological Sciences (F. Magri, G.P.C.), IRCCS Ospedale Maggiore
Policlinico, University of Milan; Child Neurology and Psychiatry Unit (A.B.),
IRCCS C. Mondino Foundation; Neuromuscular and Rare Diseases Unit (M. Moggio),
IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Dino Ferrari Center,
Milano; Child Neurology and Psychiatry Unit (A.P.), IRCCS Istituto delle Scienze
Neurologiche di Bologna, Bellaria Hospital, Bologna; Cardiomiologia e Genetica
Medica (R.P., L.P.), Dipartimento di Medicina Sperimentale Seconda Università di
Napoli; Neuromuscular Center (T.M.), S.G. Battista Hospital, University of
Turin; Centro Nemo (K.G.), Milan; Neuromuscular Unit (M.V.), Nigrisoli Hospital,
Bologna; Section of Medical Genetics (F.G., A.F.), Department of Experimental
and Diagnostic Medicine, Ferrara, Italy; and Dubowitz Neuromuscular Centre (F.
Muntoni), UCL Institute of Child Health & Great Ormond Street Hospital for
Children, London, UK. [email protected].
OBJECTIVE: We provide a nationwide population study of patients with congenital
muscular dystrophy in Italy.
METHODS: Cases were ascertained from the databases in all the tertiary referral
centers for pediatric neuromuscular disorders and from all the genetic
diagnostic centers in which diagnostic tests for these forms are performed.
RESULTS: The study includes 336 patients with a point prevalence of 0.563 per
100,000. Mutations were identified in 220 of the 336 (65.5%). The cohort was
subdivided into diagnostic categories based on the most recent classifications
on congenital muscular dystrophies. The most common forms were those with
α-dystroglycan glycosylation deficiency (40.18%) followed by those with laminin
α2 deficiency (24.11%) and collagen VI deficiency (20.24%). The forms of
congenital muscular dystrophy related to mutations in SEPN1 and LMNA were less
frequent (6.25% and 5.95%, respectively).
CONCLUSIONS: Our study provides for the first time comprehensive epidemiologic
information and point prevalence figures for each of the major diagnostic
categories on a large cohort of congenital muscular dystrophies. The study also
reflects the diagnostic progress in this field with an accurate classification
of the cases according to the most recent gene discoveries.
© 2015 American Academy of Neurology.
DOI: 10.1212/WNL.0000000000001303
PMCID: PMC4351663
PMID: 25653289 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/29376585
|
1. Turk J Pediatr. 2017;59(3):338-341. doi: 10.24953/turkjped.2017.03.018.
Occipital cortex dysgenesis with white matter changes due to mutations in
Laminin a2.
Yiş U(1), Dixit V(2), Işıkay S(3), Karakaya M(2), Baydan F(4), Diniz G(5), Polat
İ(1), Hız-Kurul S(1), Çırak S(2).
Author information:
(1)Division of Child Neurology, Department of Pediatrics, Dokuz Eylül University
School of Medicine, İzmir.
(2)Institut für Humangenetik am Universitätsklinikum, Köln, Germany.
(3)Division of Child Neurology, Department of Pediatrics, Sütçü İmam University,
School of Medicine, Kahramanmaraş.
(4)Division of Child Neurology, Tepecik Training and Research Hospital, İzmir.
(5)Neuromuscular Disease Center, Tepecik Training and Research Hospital, İzmir.
Yiş U, Dixit V, Işıkay S, Karakaya M, Baydan F, Diniz G, Polat İ, Hız-Kurul S,
Çırak S. Occipital cortex dysgenesis with white matter changes due to mutations
in Laminin a2. Turk J Pediatr 2017; 59: 338-341. Laminin α2 related congenital
muscular dystrophy is one of the most common congenital muscular dystrophies of
childhood with or without clinical evidence of central nervous system
involvement. It may be associated with significant white matter abnormalities
resembling leukodystrophies. In this study, we elaborated on two cases with
laminin α2 related congenital muscular dystrophy who had occipital cortex
dysgenesis in addition to characteristic white matter abnormalities. Although
laminin α2 related congenital muscular dystrophy with white matter abnormalities
is known, the association with occipital cortex dysplasia has been not well
recognized by clinical colleagues.
DOI: 10.24953/turkjped.2017.03.018
PMID: 29376585 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/34568901
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1. Hum Mol Genet. 2022 Mar 3;31(5):733-747. doi: 10.1093/hmg/ddab278.
Lysosomes and the pathogenesis of merosin-deficient congenital muscular
dystrophy.
Smith SJ(1)(2)(3), Fabian L(2), Sheikh A(2)(4), Noche R(2)(5), Cui X(5), Moore
SA(6), Dowling JJ(1)(2)(7)(8).
Author information:
(1)Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8,
Canada.
(2)Program for Genetics & Genome Biology, Hospital for Sick Children, Toronto,
ON M5G 0A4, Canada.
(3)Department of Family Medicine, University of Calgary, Calgary T2R 0X7,
Alberta.
(4)Schulich School of Medicine and Dentistry, Western University, London, ON N6A
5C1, Canada.
(5)Zebrafish Genetics and Disease Models Core Facility, Hospital for Sick
Children, Toronto, ON M5G 0A4, Canada.
(6)Department of Pathology, University of Iowa Medical Center, Iowa City, IA,
USA.
(7)Division of Neurology, Hospital for Sick Children, Toronto, ON M5G 1X8,
Canada.
(8)Department of Paediatrics, University of Toronto, Toronto, ON M5G 1X8,
Canada.
Congenital muscular dystrophy type 1A (MDC1A), the most common congenital
muscular dystrophy in Western countries, is caused by recessive mutations in
LAMA2, the gene encoding laminin alpha 2. Currently, no cure or disease
modifying therapy has been successfully developed for MDC1A. Examination of
patient muscle biopsies revealed altered distribution of lysosomes. We
hypothesized that this redistribution was a novel and potentially druggable
aspect of disease pathogenesis. We explored this hypothesis using candyfloss
(caf), a zebrafish model of MDC1A. We found that lysosome distribution in caf
zebrafish was also abnormal. This altered localization was significantly
associated with fiber detachment and could be prevented by blocking myofiber
detachment. Overexpression of transcription factor EB, a transcription factor
that promotes lysosomal biogenesis, led to increased lysosome content and
decreased fiber detachment. We conclude that genetic manipulation of the
lysosomal compartment is able to alter the caf zebrafish disease process,
suggesting that lysosome function may be a target for disease modification.
© The Author(s) 2021. Published by Oxford University Press. All rights reserved.
For Permissions, please email: [email protected].
DOI: 10.1093/hmg/ddab278
PMCID: PMC9989739
PMID: 34568901 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/36334577
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1. Stem Cell Res. 2022 Dec;65:102957. doi: 10.1016/j.scr.2022.102957. Epub 2022
Oct 31.
Establishment of a PBMC-derived induced pluripotent stem cell (NJUCMi001-A) from
a patient with LAMA2-related congenital muscular dystrophy (MDC1A) carrying
frameshift deletion c.3367delA in LAMA2 gene.
Rui Q(1), Tan J(1), Jin J(1), Ye W(2), Zhou Y(2), Chen J(3).
Author information:
(1)Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing
University of Chinese Medicine, Nanjing, Jiangsu, China.
(2)Department of Human Anatomy and Histoembryology, Nanjing University of
Chinese Medicine, Nanjing, Jiangsu, China.
(3)Department of Human Anatomy and Histoembryology, Nanjing University of
Chinese Medicine, Nanjing, Jiangsu, China. Electronic address:
[email protected].
LAMA2-related congenital muscular dystrophy (MDC1A), the most commonly
recognized type of congenital muscular dystrophies, is a severe neonatal onset
muscle disease caused by recessive mutations in the LAMA2 gene. Here, we
established an induced pluripotent stem cell line from a MDC1A patient carrying
a frameshift deletion c.3367delA in LAMA2 gene. The iPSC line expressed
pluripotency markers, retained normal karyotype, showed capability of
differentiating into three germ layers. The iPSC line will help to further
elucidate the pathogenic mechanisms of LAMA2 mutation, and benefit treatment for
congenital muscular dystrophies in the future.
Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.
DOI: 10.1016/j.scr.2022.102957
PMID: 36334577 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of Competing Interest The authors
declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this
paper.
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http://www.ncbi.nlm.nih.gov/pubmed/29191403
|
1. Matrix Biol. 2018 Oct;71-72:174-187. doi: 10.1016/j.matbio.2017.11.009. Epub
2017 Nov 27.
Laminin-deficient muscular dystrophy: Molecular pathogenesis and structural
repair strategies.
Yurchenco PD(1), McKee KK(2), Reinhard JR(3), Rüegg MA(4).
Author information:
(1)Dept. Pathology & Laboratory Medicine, Rutgers University, Robert Wood
Johnson Medical School, Piscataway, NJ 08854, USA. Electronic address:
[email protected].
(2)Dept. Pathology & Laboratory Medicine, Rutgers University, Robert Wood
Johnson Medical School, Piscataway, NJ 08854, USA.
(3)Biozentrum, University of Basel, 4056 Basel, Switzerland.
(4)Biozentrum, University of Basel, 4056 Basel, Switzerland. Electronic address:
[email protected].
Laminins are large heterotrimers composed of the α, β and γ subunits with
distinct tissue-specific and developmentally regulated expression patterns. The
laminin-α2 subunit, encoded by the LAMA2 gene, is expressed in skeletal muscle,
Schwann cells of the peripheral nerve and astrocytes and pericytes of the
capillaries in the brain. Mutations in LAMA2 cause the most common type of
congenital muscular dystrophies, called LAMA2 MD or MDC1A. The disorder
manifests mostly as a muscular dystrophy but slowing of nerve conduction
contributes to the disease. There are severe, non-ambulatory or milder,
ambulatory variants, the latter resulting from reduced laminin-α2 expression
and/or deficient laminin-α2 function. Lm-211 (α2β1γ1) is responsible for
initiating basement membrane assembly. This is primarily accomplished by
anchorage of Lm-211 to dystroglycan and α7β1 integrin receptors, polymerization,
and binding to nidogen and other structural components. In LAMA2 MD, Lm-411
replaces Lm-211; however, Lm-411 lacks the ability to polymerize and bind to
receptors. This results in a weakened basement membrane leading to the disease.
The possibility of introducing structural repair proteins that correct the
underlying abnormality is an attractive therapeutic goal. Recent studies in
mouse models for LAMA2 MD reveal that introduction of laminin-binding linker
proteins that restore lost functional activities can substantially ameliorate
the disease. This review discusses the underlying mechanism of this repair and
compares this approach to other developing therapies employing pharmacological
treatments.
Copyright © 2018 International Society of Matrix Biology. Published by Elsevier
B.V. All rights reserved.
DOI: 10.1016/j.matbio.2017.11.009
PMCID: PMC5971131
PMID: 29191403 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/35661166
|
1. N Engl J Med. 2022 Aug 11;387(6):495-505. doi: 10.1056/NEJMoa2203478. Epub
2022 Jun 5.
Teclistamab in Relapsed or Refractory Multiple Myeloma.
Moreau P(1), Garfall AL(1), van de Donk NWCJ(1), Nahi H(1), San-Miguel JF(1),
Oriol A(1), Nooka AK(1), Martin T(1), Rosinol L(1), Chari A(1), Karlin L(1),
Benboubker L(1), Mateos MV(1), Bahlis N(1), Popat R(1), Besemer B(1),
Martínez-López J(1), Sidana S(1), Delforge M(1), Pei L(1), Trancucci D(1),
Verona R(1), Girgis S(1), Lin SXW(1), Olyslager Y(1), Jaffe M(1), Uhlar C(1),
Stephenson T(1), Van Rampelbergh R(1), Banerjee A(1), Goldberg JD(1), Kobos
R(1), Krishnan A(1), Usmani SZ(1).
Author information:
(1)From the Hematology Clinic, University Hospital Hôtel-Dieu, Nantes (P.M.),
Service d'Hématologie Clinique, Centre Hospitalier Lyon Sud, Pierre-Bénite
(L.K.), and Service d'Hématologie et Thérapie Cellulaire, Hôpital Bretonneau,
Centre Hospitalier Régional Universitaire, Tours (L.B.) - all in France;
Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania,
Philadelphia (A.L.G.), and Janssen Research and Development, Spring House (R.V.,
S.G., S.X.W.L., C.U., T.S., A.B.) - both in Pennsylvania; the Department of
Hematology, Amsterdam University Medical Center, Vrije Universiteit Amsterdam,
Cancer Center Amsterdam, Amsterdam (N.W.C.J.D.); Karolinska University Hospital
at Huddinge, Stockholm (H.N.); Clínica Universidad de Navarra, Centro de
Investigación Médica Aplicada, Centro de Investigación Biomédica en Red de
Cáncer (CIBERONC), Instituto de Investigación Sanitaria de Navarra, Pamplona
(J.F.S.-M.), Institut Català d'Oncologia and Institut Josep Carreras, Hospital
Germans Trias i Pujol, Badalona (A.O.), Hospital Clínic, August Pi i Sunyer
Biomedical Research Institute, University of Barcelona, Barcelona (L.R.),
University Hospital of Salamanca, Instituto de Investigación Biomédica de
Salamanca, Centro del Investigación del Cáncer, CIBERONC, Salamanca (M.-V.M.),
and Hematological Malignancies Clinical Research Unit, Hospital 12 de Octubre
Universidad Complutense, Centro Nacional de Investigaciones Oncológicas,
CIBERONC, Madrid (J.M.-L.) - all in Spain; Winship Cancer Institute, Emory
University, Atlanta (A.K.N.); the University of California, San Francisco, San
Francisco (T.M.), Stanford University School of Medicine, Stanford (S.S.), and
City of Hope Comprehensive Cancer Center, Duarte (A.K.) - all in California;
Mount Sinai School of Medicine (A.C.) and Memorial Sloan Kettering Cancer Center
(S.Z.U.) - both in New York; Arnie Charbonneau Cancer Institute, University of
Calgary, Calgary, AB, Canada (N.B.); Clinical Research Facility, National
Institute for Health Research University College London Hospitals, NHS
Foundation Trust, London (R.P.); the Department of Hematology, Oncology, and
Immunology, University of Tübingen, Tübingen, Germany (B.B.); the University of
Leuven, Leuven (M.D.), and Janssen Research and Development, Antwerp (Y.O.,
R.V.R.) - both in Belgium; Janssen Research and Development, Raritan, NJ (L.P.,
D.T., M.J., J.D.G., R.K.); and Levine Cancer Institute-Atrium Health, Charlotte,
NC (S.Z.U.).
Comment in
N Engl J Med. 2022 Aug 11;387(6):558-561. doi: 10.1056/NEJMe2209692.
N Engl J Med. 2022 Nov 3;387(18):1721. doi: 10.1056/NEJMc2211969.
N Engl J Med. 2022 Nov 3;387(18):1721-1722. doi: 10.1056/NEJMc2211969.
BACKGROUND: Teclistamab is a T-cell-redirecting bispecific antibody that targets
both CD3 expressed on the surface of T cells and B-cell maturation antigen
expressed on the surface of myeloma cells. In the phase 1 dose-defining portion
of the study, teclistamab showed promising efficacy in patients with relapsed or
refractory multiple myeloma.
METHODS: In this phase 1-2 study, we enrolled patients who had relapsed or
refractory myeloma after at least three therapy lines, including triple-class
exposure to an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38
antibody. Patients received a weekly subcutaneous injection of teclistamab (at a
dose of 1.5 mg per kilogram of body weight) after receiving step-up doses of
0.06 mg and 0.3 mg per kilogram. The primary end point was the overall response
(partial response or better).
RESULTS: Among 165 patients who received teclistamab, 77.6% had triple-class
refractory disease (median, five previous therapy lines). With a median
follow-up of 14.1 months, the overall response rate was 63.0%, with 65 patients
(39.4%) having a complete response or better. A total of 44 patients (26.7%)
were found to have no minimal residual disease (MRD); the MRD-negativity rate
among the patients with a complete response or better was 46%. The median
duration of response was 18.4 months (95% confidence interval [CI], 14.9 to not
estimable). The median duration of progression-free survival was 11.3 months
(95% CI, 8.8 to 17.1). Common adverse events included cytokine release syndrome
(in 72.1% of the patients; grade 3, 0.6%; no grade 4), neutropenia (in 70.9%;
grade 3 or 4, 64.2%), anemia (in 52.1%; grade 3 or 4, 37.0%), and
thrombocytopenia (in 40.0%; grade 3 or 4, 21.2%). Infections were frequent (in
76.4%; grade 3 or 4, 44.8%). Neurotoxic events occurred in 24 patients (14.5%),
including immune effector cell-associated neurotoxicity syndrome in 5 patients
(3.0%; all grade 1 or 2).
CONCLUSIONS: Teclistamab resulted in a high rate of deep and durable response in
patients with triple-class-exposed relapsed or refractory multiple myeloma.
Cytopenias and infections were common; toxic effects that were consistent with
T-cell redirection were mostly grade 1 or 2. (Funded by Janssen Research and
Development; MajesTEC-1 ClinicalTrials.gov numbers, NCT03145181 and
NCT04557098.).
Copyright © 2022 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa2203478
PMCID: PMC10587778
PMID: 35661166 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/32444167
|
1. Neuromuscul Disord. 2020 Jun;30(6):457-471. doi: 10.1016/j.nmd.2020.03.009.
Epub 2020 Apr 17.
Clinical and genomic characteristics of LAMA2 related congenital muscular
dystrophy in a patients' cohort from Qatar. A population specific founder
variant.
Abdel Aleem A(1), Elsaid MF(2), Chalhoub N(3), Chakroun A(3), Mohamed KAS(2),
AlShami R(2), Kuzu O(3), Mohamed RB(4), Ibrahim K(2), AlMudheki N(5), Osman
O(6), Ross ME(3), ELalamy O(7).
Author information:
(1)Departments of Neurology, Weill Cornell Medicine Qatar, Education City, P.O.
24144, Doha, Qatar; Departments of Center for Neurogenetics, Brain and Mind
Research Institute, Weill Cornell Medicine, NY, USA. Electronic address:
[email protected].
(2)Departments of Neuropediatric, Hamad Medical Corporation and Sidra Medicine,
Doha, Qatar.
(3)Departments of Center for Neurogenetics, Brain and Mind Research Institute,
Weill Cornell Medicine, NY, USA.
(4)Departments of Pediatric, Hamad Medical Corporation and Sidra Medicine, Doha,
Qatar.
(5)Departments of Physiotherapy, Hamad Medical Corporation, Doha, Qatar.
(6)Department of Radiology, Hamad Medical Corporation, Doha, Qatar.
(7)Department of Adult Neurology, Hamad Medical Corporation, Doha, Qatar.
Congenital LAMA2 related muscular dystrophy (LAMA2-RD), the most commonly
recognized type of congenital muscular dystrophies, has been described in
patients' cohorts from Europe and the UK but not from Middle-Eastern. This study
aimed to reveal the prevalence, clinical and genomic characteristics of
congenital LAMA2-RD in a patient's cohort of 17 families (21 patients) from the
Gulf and Middle East. Affected subjects exhibited the classic phenotype of
generalized hypotonia, developmental delay, and progressive muscular weakness.
Despite the homogeneous background of most of our patients, clinical variability
was evident; however, none of our patients was able to achieve independent
ambulation. The associated features of nephrocalcinosis, infantile-onset
osteopenia, and cardiac arrest were first described in this study. LAMA2
mutations constituted 48% of the genetic causes underlying congenital muscular
dystrophies (CMDs) in our patients. We estimated a point prevalence of 0.8 in
100.000 for LAMA2-RD in Qatar, relatively higher compared to that described in
Europe's studies. The founder mutation and high rate of consanguinity are
potential contributors. This study identified five LAMA2 truncating variants,
two novel and three recurrent, of which the c.6488delA-frameshift that was found
in 12 unrelated Qatari families, highlighting a founder mutation in Qatari
patients. The two novel variants involved an acceptor splice site and N-terminus
deletion that removes the LAMA2 promoter, exon1, and part of intron1. The
"residual" expression of LAMA2 transcript and protein associated with this large
N-terminus deletion suggested an alternative promoter that, while seems to be
activated, acts less efficiently.
Copyright © 2020 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.nmd.2020.03.009
PMID: 32444167 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/36152606
|
1. Talanta. 2023 Feb 1;253:123859. doi: 10.1016/j.talanta.2022.123859. Epub 2022
Aug 22.
Sensitive detection of heart-failure biomarkers natriuretic peptides using
multi-photon laser wave-mixing spectroscopy.
Suprapto J(1), Tong WG(2).
Author information:
(1)Department of Chemistry and Biochemistry, San Diego State University, San
Diego, CA, 92182, USA.
(2)Department of Chemistry and Biochemistry, San Diego State University, San
Diego, CA, 92182, USA. Electronic address: [email protected].
Nonlinear laser wave-mixing spectroscopy is demonstrated as a fast and sensitive
detection method for heart-failure biomarkers, pro-atrial natriuretic peptide
(proANP) and brain natriuretic peptide (BNP). Wave mixing is an ultrasensitive
optical absorption-based method and analytes can be detected in their native
form or labeled with fluorophore and chromophore labels. In this study, we
utilized Chromeo P540 dye to label the peptides for wave-mixing detection. The
wave-mixing signal is created from the diffraction of incoming photons by the
thermal grating at the capillary analyte cell. The signal beam is strong,
collimated, and coherent (laser-like) and it is collected using a simple
photodetector with an excellent signal-to-noise ratio. We demonstrated
advantages of this technique over conventional assays including shorter analysis
times, smaller sample requirements, and higher throughput. To enhance detection
selectivity and sensitivity levels, wave mixing is effectively coupled to
capillary zone electrophoresis (CZE) and field-amplified sample stacking (FASS)
methods. We determined detection limits of 7.4 × 10-10 M or 55 zmol and
6.8 × 10-10 M or 51 zmol for proANP and BNP, respectively, and separated and
detected both peptides within 2 min. Due to the challenges in the confirmatory
diagnoses of heart failure, wave-mixing serves as a potentially beneficial
screening tool in addition to the commonly used echocardiographic tests.
Copyright © 2022. Published by Elsevier B.V.
DOI: 10.1016/j.talanta.2022.123859
PMID: 36152606 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of competing interest The authors
declare the following financial interests/personal relationships which may be
considered as potential competing interests:William Tong reports financial
support was provided by San Diego State University.
|
http://www.ncbi.nlm.nih.gov/pubmed/35749004
|
1. Target Oncol. 2022 Jul;17(4):433-439. doi: 10.1007/s11523-022-00893-y. Epub
2022 Jun 24.
Translational Modeling Predicts Efficacious Therapeutic Dosing Range of
Teclistamab for Multiple Myeloma.
Girgis S(1), Lin SXW(2), Pillarisetti K(2), Banerjee A(2), Stephenson T(2), Ma
X(2), Shetty S(2), Yang TY(2), Hilder BW(2), Jiao Q(2), Hanna B(2), Adams HC
3rd(2), Sun YN(2), Sharma A(3), Smit J(2), Infante JR(4), Goldberg JD(4),
Elsayed Y(2).
Author information:
(1)Janssen Research & Development, 920 Route 202, Raritan, NJ, 08869, USA.
[email protected].
(2)Janssen Research & Development, Spring House, PA, USA.
(3)Janssen Research & Development, Tokyo, Japan.
(4)Janssen Research & Development, 920 Route 202, Raritan, NJ, 08869, USA.
Erratum in
Target Oncol. 2022 Sep;17(5):609. doi: 10.1007/s11523-022-00904-y.
BACKGROUND: Teclistamab (JNJ-64007957), a B-cell maturation antigen × CD3
bispecific antibody, displayed potent T-cell-mediated cytotoxicity of multiple
myeloma cells in preclinical studies.
OBJECTIVE: A first-in-human, Phase I, dose escalation study (MajesTEC-1) is
evaluating teclistamab in patients with relapsed/refractory multiple myeloma.
PATIENTS AND METHODS: To estimate the efficacious therapeutic dosing range of
teclistamab, pharmacokinetic (PK) data following the first cycle doses in the
low-dose cohorts in the Phase I study were modeled using a 2-compartment model
and simulated to predict the doses that would have average and trough serum
teclistamab concentrations in the expected therapeutic range (between EC50 and
EC90 values from an ex vivo cytotoxicity assay).
RESULTS: The doses predicted to have average serum concentrations between the
EC50 and EC90 range were validated. In addition, simulations showed that weekly
intravenous and subcutaneous doses of 0.70 mg/kg and 0.72 mg/kg, respectively,
resulted in mean trough levels comparable to the maximum EC90. The most active
doses in the Phase I study were weekly intravenous doses of 0.27 and 0.72 mg/kg
and weekly subcutaneous doses of 0.72 and 1.5 mg/kg, with the weekly 1.5 mg/kg
subcutaneous doses selected as the recommended Phase II dose (RP2D). With active
doses, exposure was maintained above the mean EC90. All patients who responded
to the RP2D of teclistamab had exposure above the maximum EC90 in both serum and
bone marrow on cycle 3, Day 1 of treatment.
CONCLUSIONS: Our findings show that PK simulations of early clinical data
together with ex vivo cytotoxicity estimates can inform the identification of a
bispecific antibody's therapeutic range.
CLINICAL TRIAL REGISTRATION: NCT03145181, date of registration: May 9, 2017.
© 2022. The Author(s).
DOI: 10.1007/s11523-022-00893-y
PMCID: PMC9345835
PMID: 35749004 [Indexed for MEDLINE]
Conflict of interest statement: B. Hanna, H. Adams, S. Shetty, and Y. Sun were
employees of Johnson & Johnson during the completion of this work. All other
authors are current employees of Johnson & Johnson and may hold stock in Johnson
& Johnson.
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http://www.ncbi.nlm.nih.gov/pubmed/33520785
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1. Avicenna J Med. 2021 Jan 5;11(1):20-26. doi: 10.4103/ajm.ajm_169_20.
eCollection 2021 Jan-Mar.
The prognostic effect of brain natriuretic peptide levels on outcomes of
hospitalized patients with COVID-19.
Abdeen Y(1), Kaako A(2), Alnabulsi M(3), Okeh A(4), Meng W(3), Miller R(3).
Author information:
(1)Pulmonary and Sleep Physicians of Houston, PA, USA.
(2)Mercy Hospital Fort Smith, Fort Smith, AR, USA.
(3)Saint Michael's Medical Center, Newark, NJ, USA.
(4)University of Illinois at Chicago, Chicago, IL, USA.
Natriuretic peptides are biomarkers of myocardial stress and are frequently
elevated among patients with severe respiratory illnesses, typically in the
absence of elevated cardiac-filling pressures or clinical heart failure.
Elevation of brain natriuretic peptide (BNP) or NT-proBNP is associated with
worse outcomes among patients with Acute Respiratory Distress Syndrome (ARDS).
We conducted a retrospective cohort study based on a comprehensive review of
Electronic Medical Records (EMRs) of patients with Coronavirus Disease 2019
(COVID-19) to evaluate whether BNP on admission has prognostic value on
mortality and hospital length of stay (LOS) among patients admitted with
confirmed COVID-19 along with the inclusion of additional prognostic variables.
Overall, 146 patients were included after analyzing 230 patients' EMR and
excluding potential confounding factors for abnormal BNP. Our statistical
analysis did not show a statistically significant association between BNP level
and mortality rate (P = 0.722) or ICU LOS ( P = 0.741). A remarkable secondary
outcome to our study was that impaired renal function (GFR<60) on admission was
significantly associated with an increased mortality rate (P = 0.026) and an
increased ICU LOS (P = 0.022). Although various studies have presented the
predictive role of pro-BNP among patients with respiratory distress in the past
years, our study did not find BNP to be an accurate predictive and prognostic
factor among patients with COVID-19 in our study population. Renal impairment
and high Acute Physiology and Chronic Health Evaluation (APACHE) II scores on
admission, on the other hand, have demonstrated to be strong predictors for
COVID-19 morbidity and mortality. This study could represent an introduction to
more prominent multicenter studies to evaluate additional prognostic factors and
minimize the ordering of nonspecific testing.
Copyright: © 2021 Avicenna Journal of Medicine.
DOI: 10.4103/ajm.ajm_169_20
PMCID: PMC7839264
PMID: 33520785
Conflict of interest statement: There are no conflicts of interest.
|
http://www.ncbi.nlm.nih.gov/pubmed/33002457
|
1. Prog Cardiovasc Dis. 2020 Sep-Oct;63(5):649-655. doi:
10.1016/j.pcad.2020.09.006. Epub 2020 Sep 28.
Diagnostic and prognostic considerations for use of natriuretic peptides in
obese patients with heart failure.
Singh S(1), Pandey A(1), Neeland IJ(2).
Author information:
(1)Department of Internal Medicine, University of Texas Southwestern Medical
Center, Dallas, TX, United States of America.
(2)University Hospitals Harrington Heart and Vascular Institute and Case Western
Reserve University, Cleveland, OH, United States of America. Electronic address:
[email protected].
Natriuretic peptides (NPs, B-type natriuretic peptide /BNP and NT-proBNP) are
universally used biomarkers with established cut-points to aid in the diagnosis
of heart failure (HF). It has been demonstrated that an inverse relationship
exists between obesity, defined by the body mass index (BMI), and NPs, such that
the application of NPs to diagnostic algorithms in HF remains challenging in
overweight and obese patients. Some have advocated that lowering the cut-offs
for NPs or using a correction for high BMI may improve the diagnostic accuracy
in obese individuals. The inverse relationship of NPs with high BMI is present
in both HF with reduced (HFrEF) and with preserved (HFpEF) ejection fraction,
although levels tend to be higher in HFrEF. Nevertheless, data from several
studies have shown that the prognostic value of NPs is preserved across BMI
classes, and that increasing circulating levels of NPs correlate with adverse
outcomes including all-cause mortality and HF hospitalizations. While NPs can
still be used in diagnosis of HF in obese individuals, lower thresholds and the
clinical context should be utilized in decision making. Additionally, given the
validated prognostic value even in obesity, NPs can be employed in
risk-stratification of individuals with obesity and HF, although there remains
limited evidence about use in those with severe obesity (BMI >40 kg/m2).
Copyright © 2020 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.pcad.2020.09.006
PMCID: PMC8446810
PMID: 33002457 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/19747125
|
1. Curr Med Chem. 2009;16(30):4020-31. doi: 10.2174/092986709789352330.
Natriuretic peptides in septic patients.
Piechota M(1), Barylski M, Hannam S, Mikhailidis DP, Rysz J, Banach M.
Author information:
(1)Department of Anaesthesiology and Intensive Care Unit, Medical University of
Lodz, Poland, Hallera Sq 1, 90-647 Lodz, Poland. [email protected]
The natriuretic peptide family is comprised of atrial natriuretic peptide (ANP),
brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP), dendroaspis
natriuretic peptide - DNP and urodilatin. They play a role in the diagnosis of
several diseases, especially those involving the cardiovascular system. Sepsis
is a complex condition that can lead to multiorgan failure, shock and death. The
number of people developing sepsis is still increasing (approximately 750,000
cases of sepsis occur annually in the USA). Both ANP and pro-ANP have attracted
interest as new markers for sepsis. Reports indicate that ANP or BNP levels are
elevated in septic patients. However, many mechanisms are still unexplained.
This situation is complicated by the fact that contradictory results have been
published. There are several reasons for this controversy including differences
in the techniques used to assay natriuretic peptides. Nevertheless, natriuretic
peptides might eventually prove useful for the diagnosis and/or the treatment of
septic patients.
DOI: 10.2174/092986709789352330
PMID: 19747125 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/16548773
|
1. Expert Opin Ther Targets. 2006 Apr;10(2):239-52. doi:
10.1517/14728222.10.2.239.
Natriuretic peptides as therapeutic targets.
Mukaddam-Daher S(1).
Author information:
(1)Centre Hospitalier de L'Université de Montréal Research Center, Laboratory of
Cardiovascular Biochemistry, 3840 St-Urbain Street (6-816), Montreal, Quebec,
Canada. [email protected]
Natriuretic peptides (atrial natriuretic peptide, brain natriuretic peptide and
C-type natriuretic peptide) are cardiac and vascular peptides with vasodilatory,
diuretic, natriuretic, anti-inflammatory, antifibrotic and antimitogenic
actions. Natriuretic peptides are implicated in normal pressure and volume
homeostasis and in the defence against excessive increases in overload-related
factors, vasopressive and cardiotoxic factors and their impact on the heart,
blood vessels and brain. Genetic manipulation studies confirmed the importance
of natriuretic peptides in these functions. Natriuretic peptides are metabolised
by NPR-C (clearance receptors) and by enzymatic degradation by neutral
endopeptidase. Natriuretic peptide levels (mainly brain natriuretic peptide)
correlate with left ventricular hypertrophy and with the severity of heart
failure, and are reduced by effective treatment, thus used as diagnostic and
prognostic tools. Based on the multiple protective effects of natriuretic
peptides, pharmacological therapy has been approved and includes potentiating
natriuretic peptide levels by intravenous infusion or by inhibition of
endogenous natriuretic peptide degradation. Because each approach has its
limitations, the field remains open for improvement.
DOI: 10.1517/14728222.10.2.239
PMID: 16548773 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/12843686
|
1. Cardiovasc Drugs Ther. 2003 Jan;17(1):41-52. doi: 10.1023/a:1024255808831.
Cardiovascular effects of natriuretic peptides and their interrelation with
endothelin-1.
Han B(1), Hasin Y.
Author information:
(1)Department of Cardiology, Poriyya Medical Center, Tiberias, POB 15208,
Israel.
The natriuretic peptides are a group of structurally related but genetically
distinct peptides. Four types of natriuretic peptides have been found thus far:
atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C-type
natriuretic peptide (CNP) and Dendroaspis natriuretic peptide (DNP). ANP and BNP
are secreted mainly from the heart and function as hormones with vasodilatory
and natriuretic effects. CNP originates mainly from endothelial cells with a
paracrine effect to induce vasodilation. Other effects of natriuretic peptides
including negative inotropy, antimitogenic and anticoagulation have been
described. Three types of natriuretic peptide receptors mediate their functions,
and among them two are cGMP-coupled. Clearance of natriuretic peptides is via
its clearance receptor through the action of neutral endopeptidases. Natriuretic
peptides interact with other vasoactive peptides including endothelin. The
putative role of natriuretic peptides in the pathophysiology of various
cardiovascular diseases including congestive heart failure, hypertension,
ischemic heart disease, and cardiomyopathy are discussed. Natriuretic peptide
plasma levels are used for the diagnosis and therapeutic follow-up of congestive
heart failure patients. Increasing the levels of natriuretic peptides by
natriuretic peptide mimetics and neutral endopeptidase inhibitors may provide a
new therapeutic strategy for the treatment of cardiovascular diseases such as
congestive heart failure and hypertension.
DOI: 10.1023/a:1024255808831
PMID: 12843686 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22382054
|
1. Yi Chuan. 2012 Feb;34(2):127-33. doi: 10.3724/sp.j.1005.2012.00127.
[Recent advances in natriuretic peptide family genes and cardiovascular
diseases].
[Article in Chinese]
Wu ZJ(1), Jin W, Zhang FR, Liu Y.
Author information:
(1)Department of Cardiology, Shanghai Jiao Tong University, Shanghai, China.
[email protected]
Natriuretic peptide family consists of several hormones produced by
cardiomyocyte, including atrial natriuretic peptide (ANP), brain natriuretic
peptide (BNP) and C-type natriuretic peptide (CNP). They possess similar gene
structures and protective effects of cardiovascular physiology, such as
anti-hypertrophy, anti-fibrosis, myocardial relaxation and blood pressure
regulation. The corresponding natriuretic peptide receptor A, B and C mediate
multiple effects of natriuretic peptides to maintain cardiovascular homeostasis.
Specially, natriuretic peptide receptor-A preferentially binds ANP and BNP,
while natriuretic peptide receptor-B is more selective for C-type natriuretic
peptides. Natriuretic peptide receptor-C(NPR-C), binding all kinds of
natriuretic peptides, clears natriuretic peptides from the circulation through
receptor-mediated internalization and degradation. BNP levels were reported to
be a good predictor of left ventricular dysfunction and decompensated heart
failure from a clinical standpoint. BNP infusion is an effective treatment for
acute heart failure. Investigations on natriuretic peptides' single nucleotide
polymorphisms and biological function suggested that they could be associated
with several cardiovascular diseases, such as atrial fibrillation,
cardiomyopathy, heart failure and so on. Transgenic mice with natriuretic
peptides and their receptors gene deletion display myocardial hypertrophy and
fibrosis, which are associated with the development of hypertension,
cardiomyopathy and heart failure. Certain stimuli triggering cardiac hypertrophy
and ischemic injuries may be involved in regulating gene expression of
natriuretic peptides and their receptors. Therefore, advances in understanding
of natriuretic peptide family genes and their regulatory mechanisms will lead to
greater insight into the pathogenesis of cardiovascular diseases and blaze a new
trail in clinical treatment.
DOI: 10.3724/sp.j.1005.2012.00127
PMID: 22382054 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/7496058
|
1. Curr Opin Cardiol. 1995 Sep;10(5):495-500. doi:
10.1097/00001573-199509000-00009.
The natriuretic peptides in hypertension.
Januszewicz A(1).
Author information:
(1)Department of Hypertension and Angiology, Academy of Medicine, Warsaw,
Banacha, Poland.
The natriuretic peptide family consists of three members: atrial natriuretic
peptide, brain natriuretic peptide, and C-type natriuretic peptide. Atrial and
brain natriuretic peptides possess similar effects, causing natriuresis,
vasodilation, and suppression of the renin-angiotensin-aldosterone system.
C-type natriuretic peptide has been suggested to exert its predominant effect on
the vasculature, eliciting vasodilation and inhibiting the proliferation of
vascular smooth muscle cells. Numerous studies have broadened our current
knowledge of the regulation of natriuretic peptide gene expression,
biosynthesis, and secretion, as well as structure of specific receptors. This
has led to a better understanding of the renal, cardiovascular, and endocrine
actions of natriuretic peptides in both normal and pathophysiological states,
including hypertensive disease. Development of nonpeptide neutral endopeptidase
inhibitors and antagonists for natriuretic peptide receptors may reveal the
range of potential therapeutic application of atrial and other natriuretic
peptides in hypertension.
DOI: 10.1097/00001573-199509000-00009
PMID: 7496058 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/34871602
|
1. Ann Endocrinol (Paris). 2022 Feb;83(1):59-62. doi: 10.1016/j.ando.2021.11.006.
Epub 2021 Dec 3.
The heart, an endocrine gland: Natriuretic peptides.
Lemaitre M(1), Jannin A(1), Chevalier B(1), Vantyghem MC(2).
Author information:
(1)Endocrinology, Diabetology and Metabolism Department, Université de Lille,
CHU de Lille, Lille, France.
(2)Endocrinology, Diabetology and Metabolism Department, Université de Lille,
CHU de Lille, Lille, France; Inserm U1190, 59000 Lille, France. Electronic
address: [email protected].
The natriuretic peptide family consists of three biologically active peptides:
atrial natriuretic peptide (ANP), brain (or B-type) natriuretic peptide (BNP),
and C-type natriuretic peptide (CNP). ANP and BNP, secreted by the heart, act as
cardiac hormones, whereas CNP is an endothelial peptide. The aim of this
manuscript is to review the production, action mechanisms, effects and clinical
applications of natriuretic peptides.
Copyright © 2021. Published by Elsevier Masson SAS.
DOI: 10.1016/j.ando.2021.11.006
PMID: 34871602 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/33130802
|
1. Pol Merkur Lekarski. 2020 Oct 23;48(287):370-374.
Natriuretic peptides in diagnostics and therapy.
Romańczyk M(1), Surma S(1), Łabuzek K(2).
Author information:
(1)Faculty of Medical Sciences in Katowice, Medical University of Silesia in
Katowice, Poland.
(2)Specialist Medical Practice in Jaworzno, Poland.
Natriuretic peptides are peptide hormones which are involved in the regulation
of blood pressure, water-mineral balance and multiple metabolic processes. The
beginning of research on this group of hormones starts in 1981, when the deBold
and collaborators discovered ANP. Eight natriuretic peptides have been described
so far: ANP, BNP, CNP, DNP, urodilatin, uroguanylin, osteocrin, musculin and
three receptors: NPR-A, NPR-B and NPR-C thanks to which these hormones
accomplish their physiological functions. Determination of natriuretic peptide
concentration in plasma is used in the diagnosis and treatment of heart failure
and pulmonary embolism. Research results indicate that the determination of
natriuretic peptides concentration in plasma may also be important in the acute
coronary syndromes, subclinical complications of hypertension and atrial
fibrillation. The concentration of natriuretic peptides is changing in many
diseases. The beneficial effects of natriuretic peptides have led to the
production of drugs that are their synthetic derivatives. These drugs are mainly
used among patients with heart failure. Research is currently underway on the
efficacy and safety of other synthetic natriuretic peptides.
© 2020 MEDPRESS.
PMID: 33130802 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17965966
|
1. Cell Mol Biol Lett. 2008;13(2):155-81. doi: 10.2478/s11658-007-0046-6. Epub
2008 Apr 10.
Natriuretic peptides in cardiovascular diseases.
Piechota M(1), Banach M, Jacoń A, Rysz J.
Author information:
(1)Department of Anaesthesiology and Intensive Care Unit, Boleslaw Szarecki
University Hospital No. 5 in Łódź, Medical University in Łódź, Łódź, Poland.
The natriuretic peptide family comprises atrial natriuretic peptide (ANP), brain
natriuretic peptide (BNP), C-type natriuretic peptide (CNP), dendroaspis
natriuretic peptide (DNP), and urodilatin. The activities of natriuretic
peptides and endothelins are strictly associated with each other. ANP and BNP
inhibit endothelin-1 (ET-1) production. ET-1 stimulates natriuretic peptide
synthesis. All natriuretic peptides are synthesized from polypeptide precursors.
Changes in natriuretic peptides and endothelin release were observed in many
cardiovascular diseases: e.g. chronic heart failure, left ventricular
dysfunction and coronary artery disease.
DOI: 10.2478/s11658-007-0046-6
PMCID: PMC6275881
PMID: 17965966 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23776857
|
1. Indian J Endocrinol Metab. 2013 Jan;17(1):83-90. doi:
10.4103/2230-8210.107869.
Physiology and clinical significance of natriuretic hormones.
Chopra S(1), Cherian D, Verghese PP, Jacob JJ.
Author information:
(1)Department of Cardiology, Christian Medical College, Ludhiana, India.
The natriuretic system consists of the atrial natriuretic peptide (ANP) and four
other similar peptides including the wrongly named brain natriuretic peptide
(BNP). Chemically they are small peptide hormones predominantly secreted by the
cardiac myocytes in response to stretching forces. The peptide hormones have
multiple renal, hemodynamic, and antiproliferative effects through three
different kinds of natriuretic receptors. Clinical interest in these peptide
hormones was initially stimulated by the use of these peptides as markers to
differentiate cardiac versus noncardiac causes of breathlessness. Subsequently
work has been done on using these peptides to prognosticate patients with acute
and chronic heart failure and those with acute myocardial infraction. Synthetic
forms of both atrial- and brain-natriuretic peptides have been studied and
approved for use in acute heart failure with mixed results. This review focuses
on the biochemistry and physiology of this fascinating hormone system and the
clinical application of these hormones.
DOI: 10.4103/2230-8210.107869
PMCID: PMC3659912
PMID: 23776857
Conflict of interest statement: Conflict of Interest: None declared
|
http://www.ncbi.nlm.nih.gov/pubmed/22145138
|
1. Indian J Endocrinol Metab. 2011 Oct;15 Suppl 4(Suppl4):S345-53. doi:
10.4103/2230-8210.86978.
Natriuretic peptides: Diagnostic and therapeutic use.
Pandit K(1), Mukhopadhyay P, Ghosh S, Chowdhury S.
Author information:
(1)Department of Endocrinology, Institute of Post Graduate Medical Education and
Research and S.S.K.M. Hospital, Kolkata, India.
Natriuretic peptides (NPs) are hormones which are mainly secreted from heart and
have important natriuretic and kaliuretic properties. There are four different
groups NPs identified till date [atrial natriuretic peptide (ANP), B-type
natriuretic peptide (BNP), C-type natriuretic peptide (CNP) and dendroaspis
natriuretic peptide, a D-type natriuretic peptide (DNP)], each with its own
characteristic functions. The N-terminal part of the prohormone of BNP,
NT-proBNP, is secreted alongside BNP and has been documented to have important
diagnostic value in heart failure. NPs or their fragments have been subjected to
scientific observation for their diagnostic value and this has yielded important
epidemiological data for interpretation. However, little progress has been made
in harnessing the therapeutic potential of these cardiac hormones.
DOI: 10.4103/2230-8210.86978
PMCID: PMC3230091
PMID: 22145138
Conflict of interest statement: Conflict of Interest: None declared.
|
http://www.ncbi.nlm.nih.gov/pubmed/12189309
|
1. Congest Heart Fail. 1999 Jul-Aug;5(4):171-179.
Atrial natriuretic peptides in the diagnosis and treatment of congestive heart
failure.
Vesely DL(1).
Author information:
(1)Departments of Medicine, Physiology, and Biophysics, University of South
Florida Health Sciences Center and James A. Haley Veterans Hospital, Tampa, FL
33612.
Atrial natriuretic peptides (ANPs) consist of a family of peptides (atrial
natriuretic factor [ANF], long acting natriuretic peptide, vessel dilator,
kaliuretic peptide, urodilatin, brain natriuretic peptide [BNP], and C type
natriuretic peptide [CNP]) which are synthesized within the heart, except for
urodilatin. Of these natriuretic peptides, the vessel dilator radioimmunoassay
(RIA) of a single plasma sample is the most sensitive and specific in the
diagnosis of early (i.e., NYHA class I) congestive heart failure (CHF). Vessel
dilator is beneficial in the treatment of CHF, enhancing of urine flow two- to
13-fold and sodium excretion three- to four-fold for 3 hours after stopping its
infusion. This 37 amino acid peptide hormone simultaneously decreases systemic
vascular resistance 24%, pulmonary vascular resistance 25%, pulmonary capillary
wedge pressure 33%, and central venous pressure 27% while increasing cardiac
output 34%, cardiac index 35%, and stroke volume index 24% in individuals with
CHF. (c)1999 by CHF, Inc.
PMID: 12189309
|
http://www.ncbi.nlm.nih.gov/pubmed/18407084
|
1. Trends Endocrinol Metab. 1992 Apr;3(3):86-90. doi:
10.1016/1043-2760(92)90018-v.
Natriuretic peptides A family of hormones.
Samson WK(1).
Author information:
(1)Willis K. Samson is at the Department of Anatomy and Neurobiology, University
of Missouri, School of Medicine, Columbia, MO 65212, USA.
The natriuretic peptides are a family of structurally related peptides, products
of at least three genes, which share a common, 17-membered, internal disulfide
ring. Three major subtypes (A-, B-, and C-type natriuretic peptides) exist, and
each is present in various tissues in multiple N- and C-terminally extended or
shortened forms. The recent description of the C-type peptide CNP, the major
brain-derived peptide, has suggested that original studies examining the
endocrine actions of the natriuretic peptides using A-type (ANP) or B-type (BNP)
isoforms might have underestimated some of the biopotency of the natriuretic
peptides or even failed to detect the full spectrum of the family's bioactivity.
The identification of multiple, often species-specific, subtypes of the
natriuretic peptides, together with the characterization of at least two classes
of receptors for these hormones, indicates a variety of potential avenues for
the development of therapeutic strategies for the use of these factors.
Importantly, the description of protease inhibitors that prolong and enhance the
actions of the natriuretic peptides in humans suggests potential for the
recruitment of the natriuretic peptides in the treatment of endocrine as well as
cardiovascular disease.
DOI: 10.1016/1043-2760(92)90018-v
PMID: 18407084
|
http://www.ncbi.nlm.nih.gov/pubmed/18703404
|
1. Int Rev Cell Mol Biol. 2008;268:59-93. doi: 10.1016/S1937-6448(08)00803-4.
Natriuretic peptides in vascular physiology and pathology.
Woodard GE(1), Rosado JA.
Author information:
(1)National Institute of Allergy and Infectious Diseases, MSC 1876, Bethesda,
Maryland 20892-1876, USA.
Four major natriuretic peptides have been isolated: atrial natriuretic peptide
(ANP), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP), and
Dendroaspis-type natriuretic peptide (DNP). Natriuretic peptides play an
important role in the regulation of cardiovascular homeostasis maintaining blood
pressure and extracellular fluid volume. The classical endocrine effects of
natriuretic peptides to modulate fluid and electrolyte balance and vascular
smooth muscle tone are complemented by autocrine and paracrine actions that
include regulation of coronary blood flow and, therefore, myocardial perfusion;
modulation of proliferative responses during myocardial and vascular remodeling;
and cytoprotective anti-ischemic effects. The actions of natriuretic peptides
are mediated by the specific binding of these peptides to three cell surface
receptors: type A natriuretic peptide receptor (NPR-A), type B natriuretic
peptide receptor (NPR-B), and type C natriuretic peptide receptor (NPR-C). NPR-A
and NPR-B are guanylyl cyclase receptors that increase intracellular cGMP
concentration and activate cGMP-dependent protein kinases. NPR-C has been
presented as a clearance receptor and its activation also results in inhibition
of adenylyl cyclase activity. The wide range of effects of natriuretic peptides
might be the base for the development of new therapeutic strategies of great
benefit in patients with cardiovascular problems including coronary artery
disease or heart failure. This review summarizes current literature concerning
natriuretic peptides, their receptors and their effects on fluid/electrolyte
balance, and vascular and cardiac physiology and pathology, including primary
hypertension and myocardial infarction. In addition, we will attempt to provide
an update on important issues regarding natriuretic peptides in congestive heart
failure.
DOI: 10.1016/S1937-6448(08)00803-4
PMID: 18703404 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/16487258
|
1. Clin Exp Pharmacol Physiol. 2006 Mar;33(3):169-76. doi:
10.1111/j.1440-1681.2006.04344.x.
Which of the cardiac natriuretic peptides is most effective for the treatment of
congestive heart failure, renal failure and cancer?
Vesely DL(1).
Author information:
(1)University of South Florida Cardiac Hormone Center and James A Haley
Veteran's Medical Center, Tampa, Florida, USA. [email protected]
Cardiac natriuretic peptides consist of a family of six peptide hormones that
are synthesised by three separate genes and then stored as three separate
prohormones (i.e. 126 amino acid atrial natriuretic peptide (ANP), 108 amino
acid B-type natriuretic peptide (BNP) and 103 amino acid C-type natriuretic
peptide (CNP) prohormones). The ANP prohormone contains four peptide hormones:
long-acting natriuretic peptide (LANP), vessel dilator, kaliuretic peptide and
ANP. 2. Currently, the only natriuretic peptide available commercially to treat
congestive heart failure (CHF) is BNP (Nesiritide/Natrecor; SCIOS, Sunnyvale,
CA, USA), which causes a small increase in the urine volume of 90 38 mL/h
compared with 67 27 mL/h and no significant natriuresis, but has beneficial
haemodynamic effects in acute CHF individuals. These haemodynamic effects
probably contribute to the side-effects of BNP in patients with acute CHF with a
27% incidence of hypotension and possibly to 22% worsening of renal function,
defined as an increase in serum creatinine of 0.5 mg/dL, associated with a worse
prognosis. A review of clinical trials suggests a twofold increased risk of
death at 30 days post-nesiritide treatment, a finding that needs further
investigation. 3. The best of the natriuretic peptides for treating chronic CHF
is the vessel dilator, which increases urinary flow up to 13-fold and sodium
excretion up to fourfold, without the previously mentioned side-effects. The
natriuretic and diuretic effects of vessel dilators last 6 h, which would allow
them to be used on a four times per day basis in treating chronic CHF. 4. Atrial
natriuretic peptide does not cause significant improvement in acute renal
failure (ARF) in humans. The only natriuretic peptide that significantly
improves ARF is the vessel dilator. Even when ARF has been established for 2
days before treatment in an ischaemic ARF animal model, vessel dilator decreases
serum creatinine from 8.2 0.5 to 0.98 0.12 mg/dL in 6 days. At day 6 of ARF,
mortality decreases to 14% (from 88%) without the vessel dilator. After 6 days
of treatment with the vessel dilator, the proximal and distal tubules
regenerate. 5. In cancer, vessel dilator, LANP, kaliuretic peptide and ANP at 1
mmol/L, decrease up to 97% of human breast, pancreatic and prostate
adenocarcinoma cells, as well as small cell and squamous cell lung cancer cells
within 24 h. In vivo, vessel dilator, LANP and kaliuretic peptide completely
stop the growth of human pancreatic adenocarcinomas in athymic mice and decrease
their tumour volume by 49, 28 and 11%, respectively in 1 week.
DOI: 10.1111/j.1440-1681.2006.04344.x
PMID: 16487258 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/8834155
|
1. Curr Opin Nephrol Hypertens. 1996 Jan;5(1):4-11. doi:
10.1097/00041552-199601000-00003.
The natriuretic peptide family.
Nakao K(1), Itoh H, Saito Y, Mukoyama M, Ogawa Y.
Author information:
(1)Department of Medicine and Clinical Science, Kyoto University Graduate School
of Medicine, Japan.
The natriuretic peptide system is a complicated system comprising at least three
endogenous peptides (atrial natriuretic peptide, brain natriuretic peptide and
C-type natriuretic peptide) and three receptors [the atrial natriuretic
peptide-A receptor (guanylyl cyclase A), the atrial natriuretic peptide-B
receptor (guanylyl cyclase B) and the clearance receptor]. The accumulated
evidence indicates that this system is implicated in the control of blood
pressure, body fluid homeostasis and vascular remodelling as cardiac hormone and
local regulator.
DOI: 10.1097/00041552-199601000-00003
PMID: 8834155 [Indexed for MEDLINE]
|
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