A O
novel O
SCN5A O
mutation O
manifests O
as O
a O
malignant O
form O
of O
long B
QT I
syndrome I
with O
perinatal O
onset O
of O
tachycardia B
/ O
bradycardia B
. O

OBJECTIVE O
: O
Congenital B
long I
QT I
syndrome I
( O
LQTS B
) O
with O
in O
utero O
onset O
of O
the O
rhythm O
disturbances I
is O
associated O
with O
a O
poor O
prognosis O
. O

In O
this O
study O
we O
investigated O
a O
newborn O
patient O
with O
fetal B
bradycardia I
, O
2 O
: O
1 O
atrioventricular B
block I
and O
ventricular B
tachycardia I
soon O
after O
birth O
. O

METHODS O
: O
Mutational O
analysis O
and O
DNA O
sequencing O
were O
conducted O
in O
a O
newborn O
. O

The O
2 O
: O
1 O
atrioventricular B
block I
improved O
to O
1 O
: O
1 O
conduction O
only O
after O
intravenous O
lidocaine B
infusion O
or O
a O
high O
dose O
of O
mexiletine B
, O
which O
also O
controlled O
the O
ventricular B
tachycardia I
. O

RESULTS O
: O
A O
novel O
, O
spontaneous O
LQTS O
- O
3 O
mutation O
was O
identified O
in O
the O
transmembrane O
segment O
6 O
of O
domain O
IV O
of O
the O
Na O
( O
v O
) O
1 O
. O
5 O
cardiac O
sodium O
channel O
, O
with O
a O
G O
--> O
A O
substitution O
at O
codon O
1763 O
, O
which O
changed O
a O
valine O
( O
GTG O
) O
to O
a O
methionine O
( O
ATG O
). O

The O
proband O
was O
heterozygous O
but O
the O
mutation O
was O
absent O
in O
the O
parents O
and O
the O
sister O
. O

Expression O
of O
this O
mutant O
channel O
in O
tsA201 O
mammalian O
cells O
by O
site O
- O
directed O
mutagenesis O
revealed O
a O
persistent O
tetrodotoxin B
- O
sensitive O
but O
lidocaine B
- O
resistant O
current O
that O
was O
associated O
with O
a O
positive O
shift O
of O
the O
steady O
- O
state O
inactivation O
curve O
, O
steeper O
activation O
curve O
and O
faster O
recovery O
from O
inactivation O
. O

We O
also O
found O
a O
similar O
electrophysiological O
profile O
for O
the O
neighboring O
V1764M O
mutant O
. O

But O
, O
the O
other O
neighboring O
I1762A O
mutant O
had O
no O
persistent O
current O
and O
was O
still O
associated O
with O
a O
positive O
shift O
of O
inactivation O
. O

CONCLUSIONS O
: O
These O
findings O
suggest O
that O
the O
Na O
( O
v O
) O
1 O
. O
5 O
/ O
V1763M O
channel O
dysfunction O
and O
possible O
neighboring O
mutants O
contribute O
to O
a O
persistent O
inward O
current O
due O
to O
altered O
inactivation O
kinetics O
and O
clinically O
congenital O
LQTS B
with O
perinatal O
onset O
of O
arrhythmias B
that O
responded O
to O
lidocaine B
and O
mexiletine B
. O


Allelic O
expression O
imbalance O
of O
human O
mu O
opioid O
receptor O
( O
OPRM1 O
) O
caused O
by O
variant O
A118G O
. O

As O
a O
primary O
target O
for O
opioid B
drugs O
and O
peptides O
, O
the O
mu O
opioid O
receptor O
( O
OPRM1 O
) O
plays O
a O
key O
role O
in O
pain B
perception O
and O
addiction B
. O

Genetic O
variants O
of O
OPRM1 O
have O
been O
implicated O
in O
predisposition O
to O
drug B
addiction I
, O
in O
particular O
the O
single O
nucleotide O
polymorphism O
A118G O
, O
leading O
to O
an O
N40D O
substitution O
, O
with O
an O
allele O
frequency O
of O
10 O
- O
32 O
%, O
and O
uncertain O
functions O
. O

We O
have O
measured O
allele O
- O
specific O
mRNA O
expression O
of O
OPRM1 O
in O
human O
autopsy O
brain O
tissues O
, O
using O
A118G O
as O
a O
marker O
. O

In O
8 O
heterozygous O
samples O
measured O
, O
the O
A118 O
mRNA O
allele O
was O
1 O
. O
5 O
- O
2 O
. O
5 O
- O
fold O
more O
abundant O
than O
the O
G118 O
allele O
. O

Transfection O
into O
Chinese O
hamster O
ovary O
cells O
of O
a O
cDNA O
representing O
only O
the O
coding O
region O
of O
OPRM1 O
, O
carrying O
adenosine O
, O
guanosine O
, O
cytidine O
, O
and O
thymidine O
in O
position O
118 O
, O
resulted O
in O
1 O
. O
5 O
- O
fold O
lower O
mRNA O
levels O
only O
for O
OPRM1 O
- O
G118 O
, O
and O
more O
than O
10 O
- O
fold O
lower O
OPRM1 O
protein O
levels O
, O
measured O
by O
Western O
blotting O
and O
receptor O
binding O
assay O
. O

After O
transfection O
and O
inhibition O
of O
transcription O
with O
actinomycin B
D I
, O
analysis O
of O
mRNA O
turnover O
failed O
to O
reveal O
differences O
in O
mRNA O
stability O
between O
A118 O
and O
G118 O
alleles O
, O
indicating O
a O
defect O
in O
transcription O
or O
mRNA O
maturation O
. O

These O
results O
indicate O
that O
OPRM1 O
- O
G118 O
is O
a O
functional O
variant O
with O
deleterious O
effects O
on O
both O
mRNA O
and O
protein O
yield O
. O

Clarifying O
the O
functional O
relevance O
of O
polymorphisms O
associated O
with O
susceptibility O
to O
a O
complex O
disorder O
such O
as O
drug B
addiction I
provides O
a O
foundation O
for O
clinical O
association O
studies O
. O


Genetic O
polymorphisms O
in O
the O
carbonyl O
reductase O
3 O
gene O
CBR3 O
and O
the O
NAD O
( O
P O
) O
H O
: O
quinone O
oxidoreductase O
1 O
gene O
NQO1 O
in O
patients O
who O
developed O
anthracycline B
- O
related O
congestive B
heart I
failure I
after O
childhood O
cancer B
. O

BACKGROUND O
: O
Exposure O
to O
anthracyclines B
as O
part O
of O
cancer B
therapy O
has O
been O
associated O
with O
the O
development O
of O
congestive B
heart I
failure I
( O
CHF B
). O

The O
potential O
role O
of O
genetic O
risk O
factors O
in O
anthracycline B
- O
related O
CHF O
remains O
to O
be O
defined O
. O

Thus O
, O
in O
this O
study O
, O
the O
authors O
examined O
whether O
common O
polymorphisms O
in O
candidate O
genes O
involved O
in O
the O
pharmacodynamics O
of O
anthracyclines B
( O
in O
particular O
, O
the O
nicotinamide O
adenine O
dinucleotide O
phosphate O
: O
quinone O
oxidoreductase O
1 O
gene O
NQO1 O
and O
the O
carbonyl O
reductase O
3 O
gene O
CBR3 O
) O
had O
an O
impact O
on O
the O
risk O
of O
anthracycline B
- O
related O
CHF B
. O

METHODS O
: O
A O
nested O
case O
- O
control O
study O
was O
conducted O
within O
a O
cohort O
of O
1979 O
patients O
enrolled O
in O
the O
Childhood O
Cancer B
Survivor O
Study O
who O
received O
treatment O
with O
anthracyclines B
and O
had O
available O
DNA O
. O

Thirty O
patients O
with O
CHF B
( O
cases O
) O
and O
115 O
matched O
controls O
were O
genotyped O
for O
polymorphisms O
in O
NQO1 O
( O
NQO1 O
* O
2 O
) O
and O
CBR3 O
( O
the O
CBR3 O
valine O
[ O
V O
] O
to O
methionine O
[ O
M O
] O
substitution O
at O
position O
244 O
[ O
V244M O
]). O

Enzyme O
activity O
assays O
with O
recombinant O
CBR3 O
isoforms O
( O
CBR3 O
V244 O
and O
CBR3 O
M244 O
) O
and O
the O
anthracycline B
substrate O
doxorubicin B
were O
used O
to O
investigate O
the O
functional O
impact O
of O
the O
CBR3 O
V244M O
polymorphism O
. O

RESULTS O
: O
Multivariate O
analyses O
adjusted O
for O
sex O
and O
primary O
disease O
recurrence O
were O
used O
to O
test O
for O
associations O
between O
the O
candidate O
genetic O
polymorphisms O
( O
NQO1 O
* O
2 O
and O
CBR3 O
V244M O
) O
and O
the O
risk O
of O
CHF B
. O

Analyses O
indicated O
no O
association O
between O
the O
NQO1 O
* O
2 O
polymorphism O
and O
the O
risk O
of O
anthracycline B
- O
related O
CHF B
( O
odds O
ratio O
[ O
OR O
], O
1 O
. O
4 O
; O
P O
=. O
97 O
). O

There O
was O
a O
trend O
toward O
an O
association O
between O
the O
CBR3 O
V244M O
polymorphism O
and O
the O
risk O
of O
CHF B
( O
OR O
, O
8 O
. O
16 O
; O
P O
=. O
56 O
for O
G O
/ O
G O
vs O
A O
/ O
A O
; O
OR O
, O
5 O
. O
44 O
; O
P O
=. O
92 O
for O
G O
/ O
A O
vs O
A O
/ O
A O
). O

In O
line O
, O
recombinant O
CBR3 O
V244 O
( O
G O
allele O
) O
synthesized O
2 O
. O
6 O
- O
fold O
more O
cardiotoxic O
doxorubicinol B
per O
unit O
of O
time O
than O
CBR3 O
M244 O
( O
A O
allele O
; O
CBR3 O
V244 O
[ O
8 O
. O
26 O
+/- O
3 O
. O
57 O
nmol O
/ O
hour O
. O
mg O
] O
vs O
CBR3 O
M244 O
[ O
3 O
. O
22 O
+/- O
0 O
. O
67 O
nmol O
/ O
hour O
. O
mg O
]; O
P O
=. O
1 O
). O

CONCLUSIONS O
: O
The O
functional O
CBR3 O
V244M O
polymorphism O
may O
have O
an O
impact O
on O
the O
risk O
of O
anthracycline B
- O
related O
CHF B
among O
childhood O
cancer B
survivors O
by O
modulating O
the O
intracardiac O
formation O
of O
cardiotoxic O
anthracycline B
alcohol I
metabolites O
. O

Larger O
confirmatory O
case O
- O
control O
studies O
are O
warranted O
. O


Debrisoquine B
phenotype O
and O
the O
pharmacokinetics O
and O
beta O
- O
2 O
receptor O
pharmacodynamics O
of O
metoprolol B
and O
its O
enantiomers O
. O

The O
metabolism O
of O
the O
cardioselective O
beta O
- O
blocker O
metoprolol B
is O
under O
genetic O
control O
of O
the O
debrisoquine B
/ O
sparteine O
type O
. O

The O
two O
metabolic O
phenotypes O
, O
extensive O
( O
EM O
) O
and O
poor O
metabolizers O
( O
PM O
), O
show O
different O
stereoselective O
metabolism O
, O
resulting O
in O
apparently O
higher O
beta O
- O
1 O
adrenoceptor O
antagonistic O
potency O
of O
racemic O
metoprolol B
in O
EMs B
. O

We O
investigated O
if O
the O
latter O
also O
applies O
to O
the O
beta O
- O
2 O
adrenoceptor O
antagonism O
by O
metoprolol B
. O

The O
drug O
effect O
studied O
was O
the O
antagonism O
by O
metoprolol B
of O
terbutaline B
- O
induced O
hypokalemia B
. O

By O
using O
pharmacokinetic O
pharmacodynamic O
modeling O
the O
pharmacodynamics O
of O
racemic O
metoprolol B
and O
the O
active O
S O
- I
isomer O
, O
were O
quantitated O
in O
EMs O
and O
PMs O
in O
terms O
of O
IC50 O
values O
, O
representing O
metoprolol B
plasma O
concentrations O
resulting O
in O
half O
- O
maximum O
receptor O
occupancy O
. O

Six O
EMs O
received O
0 O
. O
5 O
mg O
of O
terbutaline B
s O
. O
c O
. O

on O
two O
different O
occasions O
: O
1 O
) O
1 O
hr O
after O
administration O
of O
a O
placebo O
and O
2 O
) O
1 O
hr O
after O
150 O
mg O
of O
metoprolol B
p O
. O
o O
. O

Five O
PMs O
were O
studied O
according O
to O
the O
same O
protocol O
, O
except O
for O
a O
higher O
terbutaline B
dose O
( O
0 O
. O
75 O
mg O
) O
on O
day O
2 O
. O

Blood O
samples O
for O
the O
analysis O
of O
plasma O
potassium B
, O
terbutaline B
, O
metoprolol B
( O
racemic O
, O
R O
- O
and O
S O
- O
isomer O
), O
and O
alpha B
- I
hydroxymetoprolol I
concentrations O
were O
taken O
at O
regular O
time O
intervals O
, O
during O
8 O
hr O
after O
metoprolol B
. O

In O
PMs O
, O
metoprolol B
increased O
the O
terbutaline B
area O
under O
the O
plasma O
concentration O
vs O
. O

time O
curve O
(+ O
67 O
%). O

Higher O
metoprolol B
/ O
alpha B
- I
hydroxymetoprolol I
ratios O
in O
PMs O
were O
predictive O
for O
higher O
R O
-/ O
S O
- O
isomer O
ratios O
of O
unchanged O
drug O
. O

There O
was O
a O
difference O
in O
metoprolol B
potency O
with O
higher O
racemic O
metoprolol B
IC50 O
values O
in O
PMs O
( O
72 O
+/- O
7 O
ng O
. O
ml O
- O
1 O
) O
than O
EMs O
( O
42 O
+/- O
8 O
ng O
. O
ml O
- O
1 O
, O
P O
less O
than O
. O
1 O
). O

( O
ABSTRACT O
TRUNCATED O
AT O
250 O
WORDS O
) O


The O
first O
founder O
DGUOK O
mutation O
associated O
with O
hepatocerebral B
mitochondrial B
DNA I
depletion I
syndrome I
. O

Deoxyguanosine B
kinase I
( O
dGK O
) I
deficiency I
is O
a O
frequent O
cause O
of O
mitochondrial B
DNA I
depletion I
associated O
with O
a O
hepatocerebral B
phenotype O
. O

In O
this O
study O
, O
we O
describe O
a O
new O
splice O
site O
mutation O
in O
the O
DGUOK O
gene O
and O
the O
clinical O
, O
radiologic O
, O
and O
genetic O
features O
of O
these O
DGUOK B
patients O
. O

This O
new O
DGUOK O
homozygous O
mutation O
( O
c O
. O
444 O
- O
62C O
> O
A O
) O
was O
identified O
in O
three O
patients O
from O
two O
North O
- O
African O
consanguineous O
families O
with O
combined O
respiratory B
chain I
deficiencies I
and O
mitochondrial B
DNA O
depletion O
in O
the O
liver O
. O

Brain O
MRIs O
are O
normal O
in O
DGUOK O
patients O
in O
the O
literature O
. O

Interestingly O
, O
we O
found O
subtentorial O
abnormal O
myelination O
and O
moderate O
hyperintensity O
in O
the O
bilateral O
pallidi O
in O
our O
patients O
. O

This O
new O
mutation O
creates O
a O
cryptic O
splice O
site O
in O
intron O
3 O
( O
in O
position O
- O
62 O
) O
and O
is O
predicted O
to O
result O
in O
a O
larger O
protein O
with O
an O
in O
- O
frame O
insertion O
of O
20 O
amino O
acids O
. O

In O
silico O
analysis O
of O
the O
putative O
impact O
of O
the O
insertion O
shows O
serious O
clashes O
in O
protein O
conformation O
: O
this O
insertion O
disrupts O
the O
alpha5 O
helix O
of O
the O
dGK O
kinase O
domain O
, O
rendering O
the O
protein O
unable O
to O
bind O
purine O
deoxyribonucleosides I
. O

In O
addition O
, O
a O
common O
haplotype O
that O
segregated O
with O
the O
disease O
in O
both O
families O
was O
detected O
by O
haplotype O
reconstruction O
with O
10 O
markers O
( O
microsatellites O
and O
SNPs O
), O
which O
span O
4 O
. O
6 O
Mb O
of O
DNA O
covering O
the O
DGUOK O
locus O
. O

In O
conclusion O
, O
we O
report O
a O
new O
DGUOK O
splice O
site O
mutation O
that O
provide O
insight O
into O
a O
critical O
protein O
domain O
( O
dGK O
kinase O
domain O
) O
and O
the O
first O
founder O
mutation O
in O
a O
North O
- O
African O
population O
. O


Adenosine O
A O
( O
2A O
) O
receptor O
gene O
( O
ADORA2A O
) O
variants O
may O
increase O
autistic B
symptoms I
and O
anxiety B
in O
autism B
spectrum I
disorder I
. O

Autism B
spectrum I
disorders I
( O
ASDs B
) O
are O
heterogeneous O
disorders O
presenting O
with O
increased O
rates O
of O
anxiety B
. O

The O
adenosine O
A O
( O
2A O
) O
receptor O
gene O
( O
ADORA2A O
) O
is O
associated O
with O
panic B
disorder I
and O
is O
located O
on O
chromosome O
22q11 O
. O
23 O
. O

Its O
gene O
product O
, O
the O
adenosine O
A O
( O
2A O
) O
receptor O
, O
is O
strongly O
expressed O
in O
the O
caudate O
nucleus O
, O
which O
also O
is O
involved O
in O
ASD B
. O

As O
autistic B
symptoms I
are O
increased O
in O
individuals O
with O
22q11 B
. I
2 I
deletion I
syndrome I
, O
and O
large O
22q11 B
. I
2 I
deletions O
and O
duplications O
have O
been O
observed O
in O
ASD B
individuals O
, O
in O
this O
study O
, O
98 O
individuals O
with O
ASD B
and O
234 O
control O
individuals O
were O
genotyped O
for O
eight O
single O
- O
nucleotide O
polymorphisms O
in O
ADORA2A O
. O

Nominal O
association O
with O
the O
disorder O
was O
observed O
for O
rs2236624 O
- O
CC O
, O
and O
phenotypic O
variability O
in O
ASD B
symptoms O
was O
influenced O
by O
rs3761422 O
, O
rs5751876 O
and O
rs35320474 O
. O

In O
addition O
, O
association O
of O
ADORA2A O
variants O
with O
anxiety B
was O
replicated O
for O
individuals O
with O
ASD B
. O

Findings O
point O
toward O
a O
possible O
mediating O
role O
of O
ADORA2A O
variants O
on O
phenotypic O
expression O
in O
ASD B
that O
need O
to O
be O
replicated O
in O
a O
larger O
sample O
. O


High O
frequency O
of O
lamivudine B
resistance O
mutations O
in O
Brazilian O
patients O
co O
- O
infected O
with O
HIV B
and I
hepatitis I
B I
. O

This O
study O
analyzed O
the O
genotype O
distribution O
and O
frequency O
of O
lamivudine B
( O
LAM B
) O
and O
tenofovir O
( O
TDF O
) O
resistance O
mutations O
in O
a O
group O
of O
patients O
co O
- O
infected O
with O
HIV B
and I
hepatitis I
B I
virus I
( O
HBV I
). O

A O
cross O
- O
sectional O
study O
of O
847 O
patients O
with O
HIV B
was O
conducted O
. O

Patients O
provided O
blood O
samples O
for O
HBsAg B
detection O
. O

The O
load O
of O
HBV O
was O
determined O
using O
an O
in O
- O
house O
real O
- O
time O
polymerase O
chain O
reaction O
. O

HBV O
genotypes O
/ O
subgenotypes O
, O
antiviral O
resistance O
, O
basal O
core O
promoter O
( O
BCP O
), O
and O
precore O
mutations O
were O
detected O
by O
DNA O
sequencing O
. O

Twenty O
- O
eight O
patients O
with O
co B
- I
infection I
were O
identified O
. O

The O
distribution O
of O
HBV O
genotypes O
among O
these O
patients O
was O
A O
( O
n O
= O
9 O
; O
50 O
%), O
D O
( O
n O
= O
4 O
; O
22 O
. O
2 O
%), O
G O
( O
n O
= O
3 O
; O
16 O
. O
7 O
%), O
and O
F O
( O
n O
= O
2 O
; O
11 O
. O
1 O
%). O

Eighteen O
patients O
were O
treated O
with O
LAM B
and O
six O
patients O
were O
treated O
with O
LAM B
plus O
TDF B
. O

The O
length O
of O
exposure O
to O
LAM B
and O
TDF B
varied O
from O
4 O
to O
216 O
months O
. O

LAM B
resistance O
substitutions O
( O
rtL180M O
+ O
rtM204V O
) O
were O
detected O
in O
10 O
( O
50 O
%) O
of O
the O
20 O
patients O
with O
viremia B
. O

This O
pattern O
and O
an O
accompanying O
rtV173L O
mutation O
was O
found O
in O
four O
patients O
. O

Three O
patients O
with O
the O
triple O
polymerase O
substitution O
pattern O
( O
rtV173L O
+ O
rtL180M O
+ O
rtM204V O
) O
had O
associated O
changes O
in O
the O
envelope O
gene O
( O
sE164D O
+ O
sI195M O
). O

Mutations O
in O
the O
BCP O
region O
( O
A1762T O
, O
G1764A O
) O
and O
in O
the O
precore O
region O
( O
G1896A O
, O
G1899A O
) O
were O
also O
found O
. O

No O
putative O
TDF O
resistance O
substitution O
was O
detected O
. O

The O
data O
suggest O
that O
prolonged O
LAM B
use O
is O
associated O
with O
the O
emergence O
of O
particular O
changes O
in O
the O
HBV O
genome O
, O
including O
substitutions O
that O
may O
elicit O
a O
vaccine O
escape O
phenotype O
. O

No O
putative O
TDF O
resistance O
change O
was O
detected O
after O
prolonged O
use O
of O
TDF O
. O


Identification O
of O
a O
novel O
FBN1 O
gene O
mutation O
in O
a O
Chinese O
family O
with O
Marfan B
syndrome I
. O

PURPOSE O
: O
To O
identify O
the O
mutation O
in O
the O
fibrillin O
- O
1 O
gene O
( O
FBN1 O
) O
in O
a O
Chinese O
family O
with O
Marfan B
syndrome I
( O
MFS B
). O

METHODS O
: O
Patients O
and O
family O
members O
were O
given O
complete O
physical O
, O
ophthalmic O
, O
and O
cardiovascular O
examinations O
. O

Genomic O
DNA O
was O
extracted O
from O
leukocytes O
of O
venous O
blood O
of O
six O
individuals O
in O
the O
family O
and O
170 O
healthy O
Chinese O
individuals O
. O

All O
of O
the O
65 O
coding O
exons O
and O
their O
flanking O
intronic O
boundaries O
of O
FBN1 O
were O
amplified O
in O
the O
proband O
by O
polymerase O
chain O
reaction O
and O
followed O
by O
direct O
sequencing O
. O

The O
mutation O
identified O
in O
the O
proband O
was O
screened O
in O
the O
other O
family O
members O
and O
the O
170 O
healthy O
Chinese O
individuals O
by O
direct O
sequencing O
. O

Protein O
conservation O
analysis O
was O
performed O
in O
six O
species O
using O
an O
online O
ClustalW O
tool O
. O

Protein O
structure O
was O
modeled O
based O
on O
the O
Protein O
data O
bank O
and O
mutated O
in O
DeepView O
v4 O
. O
0 O
. O
1 O
to O
predict O
the O
functional O
consequences O
of O
the O
mutation O
. O

RESULTS O
: O
A O
novel O
heterozygous O
c O
. O
3703T O
> O
C O
change O
in O
exon O
29 O
of O
FBN1 O
was O
detected O
in O
the O
proband O
, O
which O
resulted O
in O
the O
substitution O
of O
serine O
by O
proline O
at O
codon O
1235 O
( O
p O
. O
S1235P O
). O

This O
mutation O
was O
also O
present O
in O
two O
family O
members O
but O
absent O
in O
the O
other O
, O
unaffected O
family O
members O
and O
the O
170 O
healthy O
Chinese O
individuals O
. O

The O
mutant O
residue O
located O
in O
the O
calcium B
binding O
epidermal O
growth O
factor O
- O
like O
# O
15 O
domain O
is O
highly O
conserved O
among O
mammalian O
species O
and O
could O
probably O
induce O
conformation O
change O
of O
the O
domain O
. O

CONCLUSIONS O
: O
We O
indentified O
a O
novel O
p O
. O
S1235P O
mutation O
in O
FBN1 O
, O
which O
is O
the O
causative O
mutation O
for O
MFS B
in O
this O
family O
. O

Our O
result O
expands O
the O
mutation O
spectrum O
of O
FBN1 O
and O
contributes O
to O
the O
study O
of O
the O
molecular O
pathogenesis O
of O
Marfan B
syndrome I
. O


Molecular O
and O
phenotypic O
analysis O
of O
patients O
with O
deletions O
within O
the O
deletion O
- O
rich O
region O
of O
the O
Duchenne B
muscular I
dystrophy I
( O
DMD O
) O
gene O
. O

Eighty O
unrelated O
individuals O
with O
Duchenne B
muscular I
dystrophy I
( O
DMD B
) O
or O
Becker B
muscular I
dystrophy I
( O
BMD B
) O
were O
found O
to O
have O
deletions O
in O
the O
major O
deletion O
- O
rich O
region O
of O
the O
DMD O
locus O
. O

This O
region O
includes O
the O
last O
five O
exons O
detected O
by O
cDNA5b O
- O
7 O
, O
all O
exons O
detected O
by O
cDNA8 O
, O
and O
the O
first O
two O
exons O
detected O
by O
cDNA9 O
. O

These O
80 O
individuals O
account O
for O
approximately O
75 O
% O
of O
109 O
deletions O
of O
the O
gene O
, O
detected O
among O
181 O
patients O
analyzed O
with O
the O
entire O
dystrophin O
cDNA O
. O

Endpoints O
for O
many O
of O
these O
deletions O
were O
further O
characterized O
using O
two O
genomic O
probes O
, O
p20 O
( O
DXS269 O
; O
Wapenaar O
et O
al O
.) O

and O
GMGX11 O
( O
DXS239 O
; O
present O
paper O
). O

Clinical O
findings O
are O
presented O
for O
all O
80 O
patients O
allowing O
a O
correlation O
of O
phenotypic O
severity O
with O
the O
genotype O
. O

Thirty O
- O
eight O
independent O
patients O
were O
old O
enough O
to O
be O
classified O
as O
DMD B
, O
BMD B
, O
or O
intermediate O
phenotype O
and O
had O
deletions O
of O
exons O
with O
sequenced O
intron O
/ O
exon O
boundaries O
. O

Of O
these O
, O
eight O
BMD B
patients O
and O
one O
intermediate O
patient O
had O
gene O
deletions O
predicted O
to O
leave O
the O
reading O
frame O
intact O
, O
while O
21 O
DMD B
patients O
, O
7 O
intermediate O
patients O
, O
and O
1 O
BMD B
patient O
had O
gene O
deletions O
predicted O
to O
disrupt O
the O
reading O
frame O
. O

Thus O
, O
with O
two O
exceptions O
, O
frameshift O
deletions O
of O
the O
gene O
resulted O
in O
more O
severe O
phenotype O
than O
did O
in O
- O
frame O
deletions O
. O

This O
is O
in O
agreement O
with O
recent O
findings O
by O
Baumbach O
et O
al O
. O

and O
Koenig O
et O
al O
. O

but O
is O
in O
contrast O
to O
findings O
, O
by O
Malhotra O
et O
al O
. O

at O
the O
5 O
' O
end O
of O
the O
gene O
. O


Absence O
of O
PKC O
- O
alpha O
attenuates O
lithium B
- O
induced O
nephrogenic B
diabetes I
insipidus I
. O

Lithium B
, O
an O
effective O
antipsychotic B
, O
induces O
nephrogenic B
diabetes I
insipidus I
( O
NDI B
) O
in O
40 O
% O
of O
patients O
. O

The O
decreased O
capacity O
to O
concentrate O
urine O
is O
likely O
due O
to O
lithium B
acutely O
disrupting O
the O
cAMP O
pathway O
and O
chronically O
reducing O
urea O
transporter O
( O
UT O
- O
A1 O
) O
and O
water O
channel O
( O
AQP2 O
) O
expression O
in O
the O
inner O
medulla O
. O

Targeting O
an O
alternative O
signaling O
pathway O
, O
such O
as O
PKC O
- O
mediated O
signaling O
, O
may O
be O
an O
effective O
method O
of O
treating O
lithium B
- O
induced O
polyuria B
. O

PKC O
- O
alpha O
null O
mice O
( O
PKCa O
KO O
) O
and O
strain O
- O
matched O
wild O
type O
( O
WT O
) O
controls O
were O
treated O
with O
lithium B
for O
0 O
, O
3 O
or O
5 O
days O
. O

WT O
mice O
had O
increased O
urine O
output O
and O
lowered O
urine O
osmolality O
after O
3 O
and O
5 O
days O
of O
treatment O
whereas O
PKCa O
KO O
mice O
had O
no O
change O
in O
urine O
output O
or O
concentration O
. O

Western O
blot O
analysis O
revealed O
that O
AQP2 O
expression O
in O
medullary O
tissues O
was O
lowered O
after O
3 O
and O
5 O
days O
in O
WT O
mice O
; O
however O
, O
AQP2 O
was O
unchanged O
in O
PKCa O
KO O
. O

Similar O
results O
were O
observed O
with O
UT O
- O
A1 O
expression O
. O

Animals O
were O
also O
treated O
with O
lithium B
for O
6 O
weeks O
. O

Lithium B
- O
treated O
WT O
mice O
had O
19 O
- O
fold O
increased O
urine O
output O
whereas O
treated O
PKCa O
KO O
animals O
had O
a O
4 O
- O
fold O
increase O
in O
output O
. O

AQP2 O
and O
UT O
- O
A1 O
expression O
was O
lowered O
in O
6 O
week O
lithium B
- O
treated O
WT O
animals O
whereas O
in O
treated O
PKCa O
KO O
mice O
, O
AQP2 O
was O
only O
reduced O
by O
2 O
- O
fold O
and O
UT O
- O
A1 O
expression O
was O
unaffected O
. O

Urinary O
sodium B
, O
potassium B
and O
calcium B
were O
elevated O
in O
lithium B
- O
fed O
WT O
but O
not O
in O
lithium B
- O
fed O
PKCa O
KO O
mice O
. O

Our O
data O
show O
that O
ablation O
of O
PKCa O
preserves O
AQP2 O
and O
UT O
- O
A1 O
protein O
expression O
and O
localization O
in O
lithium B
- O
induced O
NDI B
, O
and O
prevents O
the O
development O
of O
the O
severe O
polyuria B
associated O
with O
lithium B
therapy O
. O


Decreased O
Whole O
- O
Body O
Fat O
Mass O
Produced O
by O
Chronic O
Alcohol B
Consumption O
is O
Associated O
with O
Activation O
of O
S6K1 O
- O
Mediated O
Protein O
Synthesis O
and O
Increased O
Autophagy O
in O
Epididymal O
White O
Adipose O
Tissue O
. O

BACKGROUND O
: O
Chronic O
alcohol B
consumption O
leads O
to O
a O
loss O
of O
white O
adipose O
tissue O
( O
WAT O
) O
but O
the O
underlying O
mechanisms O
for O
this O
lipodystrophy B
are O
not O
fully O
elucidated O
. O

This O
study O
tested O
the O
hypothesis O
that O
the O
reduction O
in O
WAT O
mass O
in O
chronic O
alcohol B
- O
fed O
mice O
is O
associated O
with O
a O
decreased O
protein O
synthesis O
specifically O
related O
to O
impaired O
function O
of O
mammalian O
target O
of O
rapamycin O
( O
mTOR O
). O

METHODS O
: O
Adult O
male O
mice O
were O
provided O
an O
alcohol B
- O
containing O
liquid O
diet O
for O
24 O
weeks O
or O
an O
isonitrogenous O
isocaloric O
control O
diet O
. O

In O
vivo O
protein O
synthesis O
was O
determined O
at O
this O
time O
and O
thereafter O
epididymal O
WAT O
( O
eWAT O
) O
was O
excised O
for O
analysis O
of O
signal O
transduction O
pathways O
central O
to O
controling O
protein O
synthesis O
and O
degradation O
. O

RESULTS O
: O
While O
chronic O
alcohol B
feeding O
decreased O
whole O
- O
body O
and O
eWAT O
mass O
, O
this O
was O
associated O
with O
a O
discordant O
increase O
in O
protein O
synthesis O
in O
eWAT O
. O

This O
increase O
was O
not O
associated O
with O
a O
change O
in O
mTOR O
, O
4E O
- O
BP1 O
, O
Akt O
, O
or O
PRAS40 O
phosphorylation O
. O

Instead O
, O
a O
selective O
increase O
in O
phosphorylation O
of O
S6K1 O
and O
its O
downstream O
substrates O
, O
S6 O
and O
eIF4B O
was O
detected O
in O
alcohol B
- O
fed O
mice O
. O

Alcohol B
also O
increased O
eEF2K O
phosphorylation O
and O
decreased O
eEF2 O
phosphorylation O
consistent O
with O
increased O
translation O
elongation O
. O

Alcohol B
increased O
Atg12 O
- O
5 O
, O
LC3B O
- O
I O
and O
- O
II O
, O
and O
ULK1 O
S555 O
phosphorylation O
, O
suggesting O
increased O
autophagy O
, O
while O
markers O
of O
apoptosis O
( O
cleaved O
caspase O
- O
3 O
and O
- O
9 O
, O
and O
PARP O
) O
were O
unchanged O
. O

Lipolytic O
enzymes O
( O
ATGL O
and O
HSL O
phosphorylation O
) O
were O
increased O
and O
lipogenic O
regulators O
( O
PPARgamma O
and O
C O
/ O
EBPalpha O
) O
were O
decreased O
in O
eWAT O
by O
alcohol B
. O

Although O
alcohol B
increased O
TNF O
- O
alpha O
, O
IL O
- O
6 O
, O
and O
IL O
- O
1beta O
mRNA O
, O
no O
change O
in O
key O
components O
of O
the O
NLRP3 O
inflammasome O
( O
NLRP3 O
, O
ACS O
, O
and O
cleaved O
caspase O
- O
1 O
) O
was O
detected O
suggesting O
alcohol B
did O
not O
increase O
pyroptosis B
. O

Plasma O
insulin O
did O
not O
differ O
between O
groups O
. O

CONCLUSIONS O
: O
These O
results O
demonstrate O
that O
the O
alcohol B
- O
induced O
decrease O
in O
whole O
- O
body O
fat O
mass O
resulted O
in O
part O
from O
activation O
of O
autophagy O
in O
eWAT O
as O
protein O
synthesis O
was O
increased O
and O
mediated O
by O
the O
specific O
increase O
in O
the O
activity O
of O
S6K1 O
. O


Nefiracetam B
( O
DM B
- I
9384 I
) O
reverses O
apomorphine B
- O
induced O
amnesia B
of O
a O
passive O
avoidance O
response O
: O
delayed O
emergence O
of O
the O
memory O
retention O
effects O
. O

Nefiracetam B
is O
a O
novel O
pyrrolidone B
derivative I
which O
attenuates O
scopolamine B
- O
induced O
learning O
and O
post O
- O
training O
consolidation O
deficits O
. O

Given O
that O
apomorphine B
inhibits O
passive O
avoidance O
retention O
when O
given O
during O
training O
or O
in O
a O
defined O
10 O
- O
12h O
post O
- O
training O
period O
, O
we O
evaluated O
the O
ability O
of O
nefiracetam B
to O
attenuate O
amnesia B
induced O
by O
dopaminergic O
agonism O
. O

A O
step O
- O
down O
passive O
avoidance O
paradigm O
was O
employed O
and O
nefiracetam B
( O
3 O
mg O
/ O
kg O
) O
and O
apomorphine B
( O
0 O
. O
5 O
mg O
/ O
kg O
) O
were O
given O
alone O
or O
in O
combination O
during O
training O
and O
at O
the O
10 O
- O
12h O
post O
- O
training O
period O
of O
consolidation O
. O

Co O
- O
administration O
of O
nefiracetam B
and O
apomorphine B
during O
training O
or O
10h O
thereafter O
produced O
no O
significant O
anti O
- O
amnesic B
effect O
. O

However O
, O
administration O
of O
nefiracetam B
during O
training O
completely O
reversed O
the O
amnesia B
induced O
by O
apomorphine B
at O
the O
10h O
post O
- O
training O
time O
and O
the O
converse O
was O
also O
TRUE O
. O

These O
effects O
were O
not O
mediated O
by O
a O
dopaminergic O
mechanism O
as O
nefiracetam B
, O
at O
millimolar O
concentrations O
, O
failed O
to O
displace O
either O
[ B
3H I
] I
SCH I
23390 I
or O
[ B
3H I
] I
spiperone I
binding O
from O
D1 O
or O
D2 O
dopamine O
receptor O
subtypes O
, O
respectively O
. O

It O
is O
suggested O
that O
nefiracetam B
augments O
molecular O
processes O
in O
the O
early O
stages O
of O
events O
which O
ultimately O
lead O
to O
consolidation O
of O
memory O
. O


Pethidine B
- O
associated O
seizure B
in O
a O
healthy O
adolescent O
receiving O
pethidine B
for O
postoperative O
pain I
control O
. O

A O
healthy O
17 O
- O
year O
- O
old O
male O
received O
standard O
intermittent O
doses O
of O
pethidine B
via O
a O
patient O
- O
controlled O
analgesia O
( O
PCA O
) O
pump O
for O
management O
of O
postoperative B
pain I
control O
. O

Twenty O
- O
three O
h O
postoperatively O
he O
developed O
a O
brief O
self O
- O
limited O
seizure B
. O

Both O
plasma O
pethidine B
and O
norpethidine B
were O
elevated O
in O
the O
range O
associated O
with O
clinical O
manifestations O
of O
central B
nervous I
system I
excitation I
. O

No O
other O
risk O
factors O
for O
CNS B
toxicity I
were O
identified O
. O

This O
method O
allowed O
frequent O
self O
- O
dosing O
of O
pethidine B
at O
short O
time O
intervals O
and O
rapid O
accumulation O
of O
pethidine B
and O
norpethidine B
. O

The O
routine O
use O
of O
pethidine B
via O
PCA B
even O
for O
a O
brief O
postoperative O
analgesia O
should O
be O
reconsidered O
. O


Recovery O
of O
tacrolimus B
- O
associated O
brachial B
neuritis I
after O
conversion O
to O
everolimus B
in O
a O
pediatric O
renal O
transplant O
recipient O
-- O
case O
report O
and O
review O
of O
the O
literature O
. O

TAC B
has O
been O
shown O
to O
be O
a O
potent O
immunosuppressive O
agent O
for O
solid O
organ O
transplantation O
in O
pediatrics O
. O

Neurotoxicity B
is O
a O
potentially O
serious O
toxic O
effect O
. O

It O
is O
characterized O
by O
encephalopathy B
, O
headaches B
, O
seizures B
, O
or O
neurological B
deficits I
. O

Here O
, O
we O
describe O
an O
eight O
- O
and O
- O
a O
- O
half O
- O
yr O
- O
old O
male O
renal O
transplant O
recipient O
with O
right O
BN B
. O

MRI O
demonstrated O
hyperintense O
T2 O
signals O
in O
the O
cervical O
cord O
and O
right O
brachial O
plexus O
roots O
indicative O
of O
both O
myelitis B
and O
right O
brachial B
plexitis I
. O

Symptoms O
persisted O
for O
three O
months O
despite O
TAC B
dose O
reduction O
, O
administration O
of O
IVIG B
and O
four O
doses O
of O
methylprednisolone B
pulse O
therapy O
. O

Improvement O
and O
eventually O
full O
recovery O
only O
occurred O
after O
TAC B
was O
completely O
discontinued O
and O
successfully O
replaced O
by O
everolimus B
. O


MOL1 O
is O
required O
for O
cambium O
homeostasis O
in O
Arabidopsis O
. O

Plants O
maintain O
pools O
of O
pluripotent O
stem O
cells O
which O
allow O
them O
to O
constantly O
produce O
new O
tissues O
and O
organs O
. O

Stem O
cell O
homeostasis O
in O
shoot O
and O
root O
tips O
depends O
on O
negative O
regulation O
by O
ligand O
- O
receptor O
pairs O
of O
the O
CLE O
peptide O
and O
leucine O
- O
rich O
repeat O
receptor O
- O
like O
kinase O
( O
LRR O
- O
RLK O
) O
families O
. O

However O
, O
regulation O
of O
the O
cambium O
, O
the O
stem O
cell O
niche O
required O
for O
lateral O
growth O
of O
shoots O
and O
roots O
, O
is O
poorly O
characterized O
. O

Here O
we O
show O
that O
the O
LRR O
- O
RLK O
MOL1 O
is O
necessary O
for O
cambium O
homeostasis O
in O
Arabidopsis O
thaliana O
. O

By O
employing O
promoter O
reporter O
lines O
, O
we O
reveal O
that O
MOL1 O
is O
active O
in O
a O
domain O
that O
is O
distinct O
from O
the O
domain O
of O
the O
positively O
acting O
CLE41 O
/ O
PXY O
signaling O
module O
. O

In O
particular O
, O
we O
show O
that O
MOL1 O
acts O
in O
an O
opposing O
manner O
to O
the O
CLE41 O
/ O
PXY O
module O
and O
that O
changing O
the O
domain O
or O
level O
of O
MOL1 O
expression O
both O
result O
in O
disturbed O
cambium O
organization O
. O

Underlining O
discrete O
roles O
of O
MOL1 O
and O
PXY O
, O
both O
LRR O
- O
RLKs O
are O
not O
able O
to O
replace O
each O
other O
when O
their O
expression O
domains O
are O
interchanged O
. O

Furthermore O
, O
MOL1 O
but O
not O
PXY B
is O
able O
to O
rescue O
CLV1 O
deficiency O
in O
the O
shoot O
apical O
meristem O
. O

By O
identifying O
genes O
mis O
- O
expressed O
in O
mol1 O
mutants O
, O
we O
demonstrate O
that O
MOL1 O
represses O
genes O
associated O
with O
stress O
- O
related O
ethylene B
and O
jasmonic B
acid I
hormone O
signaling O
pathways O
which O
have O
known O
roles O
in O
coordinating O
lateral O
growth O
of O
the O
Arabidopsis O
stem O
. O

Our O
findings O
provide O
evidence O
that O
common O
regulatory O
mechanisms O
in O
different O
plant O
stem O
cell O
niches O
are O
adapted O
to O
specific O
niche O
anatomies O
and O
emphasize O
the O
importance O
of O
a O
complex O
spatial O
organization O
of O
intercellular O
signaling O
cascades O
for O
a O
strictly O
bidirectional O
tissue O
production O
. O


In O
vivo O
evidences O
suggesting O
the O
role O
of O
oxidative O
stress O
in O
pathogenesis O
of O
vancomycin B
- O
induced O
nephrotoxicity B
: O
protection O
by O
erdosteine B
. O

The O
aims O
of O
this O
study O
were O
to O
examine O
vancomycin B
( O
VCM B
)- O
induced O
oxidative O
stress O
that O
promotes O
production O
of O
reactive B
oxygen I
species I
( O
ROS B
) O
and O
to O
investigate O
the O
role O
of O
erdosteine B
, O
an O
expectorant O
agent O
, O
which O
has O
also O
antioxidant O
properties O
, O
on O
kidney O
tissue O
against O
the O
possible O
VCM B
- O
induced O
renal B
impairment I
in O
rats O
. O

Rats O
were O
divided O
into O
three O
groups O
: O
sham O
, O
VCM B
and O
VCM B
plus O
erdosteine B
. O

VCM B
was O
administrated O
intraperitoneally O
( O
i O
. O
p O
.) O

with O
200mgkg O
(- O
1 O
) O
twice O
daily O
for O
7 O
days O
. O

Erdosteine B
was O
administered O
orally O
. O

VCM B
administration O
to O
control O
rats O
significantly O
increased O
renal O
malondialdehyde B
( O
MDA B
) O
and O
urinary O
N O
- O
acetyl O
- O
beta O
- O
d O
- O
glucosaminidase O
( O
NAG O
, O
a O
marker O
of O
renal B
tubular I
injury I
) O
excretion O
but O
decreased O
superoxide O
dismutase O
( O
SOD O
) O
and O
catalase O
( O
CAT O
) O
activities O
. O

Erdosteine B
administration O
with O
VCM B
injections O
caused O
significantly O
decreased O
renal O
MDA O
and O
urinary O
NAG B
excretion O
, O
and O
increased O
SOD O
activity O
, O
but O
not O
CAT O
activity O
in O
renal O
tissue O
when O
compared O
with O
VCM B
alone O
. O

Erdosteine B
showed O
histopathological O
protection O
against O
VCM B
- O
induced O
nephrotoxicity B
. O

There O
were O
a O
significant O
dilatation O
of O
tubular O
lumens O
, O
extensive O
epithelial O
cell O
vacuolization O
, O
atrophy B
, O
desquamation O
, O
and O
necrosis B
in O
VCM B
- O
treated O
rats O
more O
than O
those O
of O
the O
control O
and O
the O
erdosteine B
groups O
. O

Erdosteine B
caused O
a O
marked O
reduction O
in O
the O
extent O
of O
tubular B
damage I
. O

It O
is O
concluded O
that O
oxidative O
tubular O
damage O
plays O
an O
important O
role O
in O
the O
VCM B
- O
induced O
nephrotoxicity B
and O
the O
modulation O
of O
oxidative O
stress O
with O
erdosteine B
reduces O
the O
VCM B
- O
induced O
kidney B
damage I
both O
at O
the O
biochemical O
and O
histological O
levels O
. O


Mutation O
screening O
of O
the O
GUCA1B O
gene O
in O
patients O
with O
autosomal O
dominant O
cone B
and I
cone I
rod I
dystrophy I
. O

Background O
: O
Heterozygous O
mutations O
in O
GUCA1A O
( O
MIM O
# O
600364 O
) O
have O
been O
identified O
to O
cause O
autosomal O
dominantly O
inherited O
cone B
dystrophy I
, O
cone B
rod I
dystrophy I
and O
macular B
dystrophy I
. O

However O
, O
the O
role O
of O
GUCA1B O
gene O
mutations O
in O
inherited B
retinal I
disease I
has O
been O
controversial O
. O

We O
therefore O
performed O
a O
mutation O
analysis O
of O
the O
GUCA1B O
gene O
in O
a O
clinically O
well O
characterized O
group O
of O
patients O
of O
European O
and O
North O
- O
American O
geographical O
origin O
with O
autosomal O
dominantly O
inherited O
cone B
dystrophy I
and O
cone B
rod I
dystrophy I
. O

Material O
and O
Methods O
: O
Twenty O
- O
four O
unrelated O
patients O
diagnosed O
with O
cone B
dystrophy I
or O
cone B
rod I
dystrophy I
according O
to O
standard O
diagnostic O
criteria O
and O
a O
family O
history O
consistent O
with O
an O
autosomal O
dominant O
mode O
of O
inheritance O
were O
included O
in O
the O
study O
. O

Mutation O
analysis O
of O
all O
coding O
exons O
of O
the O
GUCA1B O
gene O
was O
performed O
by O
polymerase O
chain O
reaction O
amplification O
of O
genomic O
DNA O
and O
subsequent O
DNA O
sequencing O
. O

Results O
: O
Three O
different O
sequence O
variants O
, O
c O
.- O
17T O
> O
C O
, O
c O
. O
171T O
> O
C O
, O
c O
. O
465G O
> O
T O
were O
identified O
. O

The O
sequence O
variant O
c O
. O
465G O
> O
T O
encodes O
a O
conservative O
amino O
acid O
substitution O
, O
p O
. O
Glu155Asp O
, O
located O
in O
EF O
- O
hand O
4 O
, O
the O
calcium B
binding O
site O
of O
GCAP2 O
protein O
. O

All O
sequence O
variants O
were O
previously O
reported O
in O
healthy O
subjects O
. O

Conclusion O
: O
The O
absence O
of O
clearly O
pathogenic O
mutations O
in O
the O
selected O
patient O
group O
suggests O
that O
the O
GUCA1B O
gene O
is O
a O
minor O
cause O
for O
retinal B
degenerations I
in O
Europeans O
or O
North O
- O
Americans O
. O


Cardioprotective O
effect O
of O
tincture O
of O
Crataegus O
on O
isoproterenol B
- O
induced O
myocardial B
infarction I
in O
rats O
. O

Tincture B
of I
Crataegus I
( O
TCR B
), O
an O
alcoholic O
extract O
of O
the O
berries O
of O
hawthorn O
( O
Crataegus O
oxycantha O
), O
is O
used O
in O
herbal O
and O
homeopathic O
medicine O
. O

The O
present O
study O
was O
done O
to O
investigate O
the O
protective O
effect O
of O
TCR B
on O
experimentally O
induced O
myocardial B
infarction I
in O
rats O
. O

Pretreatment O
of O
TCR B
, O
at O
a O
dose O
of O
0 O
. O
5 O
mL O
/ O
100 O
g O
bodyweight O
per O
day O
, O
orally O
for O
30 O
days O
, O
prevented O
the O
increase O
in O
lipid B
peroxidation O
and O
activity O
of O
marker O
enzymes O
observed O
in O
isoproterenol B
- O
induced O
rats O
( O
85 O
mg O
kg O
(- O
1 O
) O
s O
. O
c O
. O
for O
2 O
days O
at O
an O
interval O
of O
24 O
h O
). O

TCR B
prevented O
the O
isoproterenol B
- O
induced O
decrease O
in O
antioxidant O
enzymes O
in O
the O
heart O
and O
increased O
the O
rate O
of O
ADP B
- O
stimulated O
oxygen B
uptake O
and O
respiratory O
coupling O
ratio O
. O

TCR B
protected O
against O
pathological O
changes O
induced O
by O
isoproterenol B
in O
rat O
heart O
. O

The O
results O
show O
that O
pretreatment O
with O
TCR B
may O
be O
useful O
in O
preventing O
the O
damage O
induced O
by O
isoproterenol B
in O
rat O
heart O
. O


A O
novel O
splicing O
mutation O
in O
SLC12A3 O
associated O
with O
Gitelman B
syndrome I
and O
idiopathic B
intracranial I
hypertension I
. O

We O
report O
a O
case O
of O
Gitelman B
syndrome I
( O
GS B
) O
in O
a O
dizygotic O
twin O
who O
presented O
at O
12 O
years O
of O
age O
with O
growth B
delay I
, O
metabolic B
alkalosis I
, O
hypomagnesemia B
and O
hypokalemia B
with O
inappropriate O
kaliuresis O
, O
and O
idiopathic B
intracranial I
hypertension I
with O
bilateral B
papilledema I
( O
pseudotumor B
cerebri I
). O

The O
patient O
, O
her O
twin O
sister O
, O
and O
her O
mother O
also O
presented O
with O
cerebral B
cavernous I
malformations I
. O

Based O
on O
the O
early O
onset O
and O
normocalciuria B
, O
Bartter B
syndrome I
was O
diagnosed O
first O
. O

However O
, O
mutation O
analysis O
showed O
that O
the O
proband O
is O
a O
compound O
heterozygote O
for O
2 O
mutations O
in O
SLC12A3 O
: O
a O
substitution O
of O
serine O
by O
leucine O
at O
amino O
acid O
position O
555 O
( O
p O
. O
Ser555Leu O
) O
and O
a O
novel O
guanine O
to O
cytosine O
transition O
at O
the O
5 O
' O
splice O
site O
of O
intron O
22 O
( O
c O
. O
2633 O
+ O
1G O
> O
C O
), O
providing O
the O
molecular O
diagnosis O
of O
GS B
. O

These O
mutations O
were O
not O
detected O
in O
200 O
normal O
chromosomes O
and O
cosegregated O
within O
the O
family O
. O

Analysis O
of O
complementary O
DNA O
showed O
that O
the O
heterozygous O
nucleotide O
change O
c O
. O
2633 O
+ O
1G O
> O
C O
caused O
the O
appearance O
of O
2 O
RNA O
molecules O
, O
1 O
normal O
transcript O
and O
1 O
skipping O
the O
entire O
exon O
22 O
( O
r O
. O
2521_2634del O
). O

Supplementation O
with O
potassium B
and O
magnesium B
improved O
clinical O
symptoms O
and O
resulted O
in O
catch O
- O
up O
growth O
, O
but O
vision B
remained O
impaired O
. O

Three O
similar O
associations O
of O
Bartter B
syndrome I
/ O
GS B
with O
pseudotumor B
cerebri I
were O
found O
in O
the O
literature O
, O
suggesting O
that O
electrolyte B
abnormalities I
and O
secondary O
aldosteronism O
may O
have O
a O
role O
in O
idiopathic B
intracranial I
hypertension I
. O

This O
study O
provides O
further O
evidence O
for O
the O
phenotypical O
heterogeneity O
of O
GS B
and O
its O
association O
with O
severe O
manifestations O
in O
children O
. O

It O
also O
shows O
the O
independent O
segregation O
of O
familial B
cavernomatosis I
and O
GS B
. O


Association O
between O
polymorphisms O
in O
SLC30A8 O
, O
HHEX O
, O
CDKN2A O
/ O
B O
, O
IGF2BP2 O
, O
FTO O
, O
WFS1 O
, O
CDKAL1 O
, O
KCNQ1 O
and O
type B
2 I
diabetes I
in O
the O
Korean O
population O
. O

According O
to O
recent O
genome O
- O
wide O
association O
studies O
, O
a O
number O
of O
single O
nucleotide O
polymorphisms O
( O
SNPs O
) O
are O
reported O
to O
be O
associated O
with O
type B
2 I
diabetes I
mellitus I
( O
T2DM B
). O

The O
aim O
of O
the O
present O
study O
was O
to O
investigate O
the O
association O
among O
the O
polymorphisms O
of O
SLC30A8 O
, O
HHEX O
, O
CDKN2A O
/ O
B O
, O
IGF2BP2 O
, O
FTO O
, O
WFS1 O
, O
CDKAL1 O
and O
KCNQ1 O
and O
the O
risk O
of O
T2DM B
in O
the O
Korean O
population O
. O

This O
study O
was O
based O
on O
a O
multicenter O
case O
- O
control O
study O
, O
including O
908 O
patients O
with O
T2DM B
and O
502 O
non O
- O
diabetic O
controls O
. O

We O
genotyped O
rs13266634 O
, O
rs1111875 O
, O
rs10811661 O
, O
rs4402960 O
, O
rs8050136 O
, O
rs734312 O
, O
rs7754840 O
and O
rs2237892 O
and O
measured O
the O
body O
weight O
, O
body O
mass O
index O
and O
fasting O
plasma O
glucose B
in O
all O
patients O
and O
controls O
. O

The O
strongest O
association O
was O
found O
in O
a O
variant O
of O
CDKAL1 O
[ O
rs7754840 O
, O
odds O
ratio O
( O
OR O
) O
= O
1 O
. O
77 O
, O
95 O
% O
CI O
= O
1 O
. O
50 O
- O
2 O
. O
10 O
, O
p O
= O
5 O
. O
0 O
x O
10 O
(- O
11 O
)]. O

The O
G O
allele O
of O
rs1111875 O
( O
OR O
= O
1 O
. O
43 O
, O
95 O
% O
CI O
= O
1 O
. O
18 O
- O
1 O
. O
72 O
, O
p O
= O
1 O
. O
8 O
x O
10 O
(- O
4 O
)) O
in O
HHEX O
), O
the O
T O
allele O
of O
rs10811661 O
( O
OR O
= O
1 O
. O
47 O
, O
95 O
% O
CI O
= O
1 O
. O
23 O
- O
1 O
. O
75 O
, O
p O
= O
2 O
. O
1 O
x O
10 O
(- O
5 O
)) O
in O
CDKN2A O
/ O
B O
) O
and O
the O
C O
allele O
of O
rs2237892 O
( O
OR O
= O
1 O
. O
31 O
, O
95 O
% O

CI O
= O
1 O
. O
10 O
- O
1 O
. O
56 O
, O
p O
= O
0 O
. O
3 O
) O
in O
KCNQ1 O
showed O
significant O
associations O
with O
T2DM B
. O

Rs13266634 O
( O
OR O
= O
1 O
. O
19 O
, O
95 O
% O
CI O
= O
1 O
. O
0 O
- O
1 O
. O
42 O
, O
p O
= O
0 O
. O
45 O
) O
in O
SLC30A8 O
showed O
a O
nominal O
association O
with O
the O
risk O
of O
T2DM B
, O
whereas O
SNPs O
in O
IGF2BP2 O
, O
FTO O
and O
WFS1 O
were O
not O
associated O
. O

In O
conclusion O
, O
we O
have O
shown O
that O
SNPs O
in O
HHEX O
, O
CDKN2A O
/ O
B O
, O
CDKAL1 O
, O
KCNQ1 O
and O
SLC30A8 O
confer O
a O
risk O
of O
T2DM B
in O
the O
Korean O
population O
. O


Serotonin O
6 O
receptor O
gene O
is O
associated O
with O
methamphetamine B
- O
induced O
psychosis B
in O
a O
Japanese O
population O
. O

BACKGROUND O
: O
Altered O
serotonergic O
neural O
transmission O
is O
hypothesized O
to O
be O
a O
susceptibility O
factor O
for O
psychotic B
disorders I
such O
as O
schizophrenia B
. O

The O
serotonin O
6 O
( O
5 O
- O
HT6 O
) O
receptor O
is O
therapeutically O
targeted O
by O
several O
second O
generation O
antipsychotics B
, O
such O
as O
clozapine B
and O
olanzapine B
, O
and O
d B
- I
amphetamine I
- O
induced O
hyperactivity B
in O
rats O
is O
corrected O
with O
the O
use O
of O
a O
selective O
5 O
- O
HT6 O
receptor O
antagonist O
. O

In O
addition O
, O
the O
disrupted O
prepulse O
inhibition O
induced O
by O
d B
- I
amphetamine I
or O
phencyclidine B
was O
restored O
by O
5 O
- O
HT6 O
receptor O
antagonist O
in O
an O
animal O
study O
using O
rats O
. O

These O
animal O
models O
were O
considered O
to O
reflect O
the O
positive O
symptoms O
of O
schizophrenia B
, O
and O
the O
above O
evidence O
suggests O
that O
altered O
5 O
- O
HT6 O
receptors O
are O
involved O
in O
the O
pathophysiology O
of O
psychotic B
disorders I
. O

The O
symptoms O
of O
methamphetamine B
( O
METH B
)- O
induced O
psychosis B
are O
similar O
to O
those O
of O
paranoid B
type I
schizophrenia B
. O

Therefore O
, O
we O
conducted O
an O
analysis O
of O
the O
association O
of O
the O
5 O
- O
HT6 O
gene O
( O
HTR6 O
) O
with O
METH B
- O
induced O
psychosis B
. O

METHOD O
: O
Using O
five O
tagging O
SNPs O
( O
rs6693503 O
, O
rs1805054 O
, O
rs4912138 O
, O
rs3790757 O
and O
rs9659997 O
), O
we O
conducted O
a O
genetic O
association O
analysis O
of O
case O
- O
control O
samples O
( O
197 O
METH B
- O
induced O
psychosis B
patients O
and O
337 O
controls O
) O
in O
the O
Japanese O
population O
. O

The O
age O
and O
sex O
of O
the O
control O
subjects O
did O
not O
differ O
from O
those O
of O
the O
methamphetamine B
dependence I
patients O
. O

RESULTS O
: O
rs6693503 O
was O
associated O
with O
METH B
- O
induced O
psychosis B
patients O
in O
the O
allele O
/ O
genotype O
- O
wise O
analysis O
. O

Moreover O
, O
this O
association O
remained O
significant O
after O
Bonferroni O
correction O
. O

In O
the O
haplotype O
- O
wise O
analysis O
, O
we O
detected O
an O
association O
between O
two O
markers O
( O
rs6693503 O
and O
rs1805054 O
) O
and O
three O
markers O
( O
rs6693503 O
, O
rs1805054 O
and O
rs4912138 O
) O
in O
HTR6 O
and O
METH B
- O
induced O
psychosis B
patients O
, O
respectively O
. O

CONCLUSION O
: O
HTR6 O
may O
play O
an O
important O
role O
in O
the O
pathophysiology O
of O
METH B
- O
induced O
psychosis B
in O
the O
Japanese O
population O
. O


Reciprocal O
effects O
of O
NNK O
and O
SLURP O
- O
1 O
on O
oncogene O
expression O
in O
target O
epithelial O
cells O
. O

AIMS O
: O
To O
elucidate O
how O
the O
nicotinic O
acetylcholine O
receptors O
expressed O
on O
bronchial O
and O
oral O
epithelial O
cells O
targeted O
by O
the O
tobacco B
nitrosamine I
( O
4 B
-( I
methylnitrosamino I
)- I
1 I
-( I
3 I
- I
pyridyl I
)- I
1 I
- I
butanone I
) O
( O
NNK B
) O
facilitate O
carcinogenic B
transformation O
. O

MAIN O
METHODS O
: O
Since O
NNK O
- O
dependent O
transformation O
can O
be O
abolished O
by O
the O
nicotinergic O
secreted O
mammalian O
Ly O
- O
6 O
/ O
urokinase O
plasminogen O
activator O
receptor O
related O
protein O
- O
1 O
( O
SLURP O
- O
1 O
), O
we O
compared O
effects O
of O
NNK O
and O
recombinant O
( O
r O
) O
SLURP O
- O
1 O
on O
the O
expression O
of O
genes O
related O
to O
tumorigenesis B
in O
human O
immortalized O
bronchial O
and O
oral O
epithelial O
cell O
lines O
BEP2D O
and O
Het O
- O
1A O
, O
respectively O
. O

KEY O
FINDINGS O
: O
NNK O
stimulated O
expression O
of O
oncogenic O
genes O
, O
including O
MYB O
and O
PIK3CA O
in O
BEP2D O
, O
ETS1 O
, O
NRAS O
and O
SRC O
in O
Het O
- O
1A O
, O
and O
AKT1 O
, O
KIT O
and O
RB1 O
in O
both O
cell O
types O
, O
which O
could O
be O
abolished O
in O
the O
presence O
of O
rSLURP O
- O
1 O
. O

Other O
cancer B
- O
related O
genes O
whose O
upregulation O
by O
NNK O
was O
abolishable O
by O
rSLURP O
- O
1 O
were O
the O
growth O
factors O
EGF O
in O
BEP2D O
cells O
and O
HGF O
in O
Het O
- O
1A O
cells O
, O
and O
the O
transcription O
factors O
CDKN2A O
and O
STAT3 O
( O
Het O
- O
1A O
only O
). O

NNK O
also O
upregulated O
the O
anti O
- O
apoptotic O
BCL2 O
( O
Het O
- O
1A O
) O
and O
downregulated O
the O
pro O
- O
apoptotic O
TNF O
( O
Het O
- O
1A O
), O
BAX O
and O
CASP8 O
( O
BEP2D O
), O
all O
of O
which O
could O
be O
abolished O
, O
in O
part O
, O
by O
rSLURP O
- O
1 O
. O

NNK O
decreased O
expression O
of O
the O
CTNNB1 O
gene O
encoding O
the O
intercellular O
adhesion O
molecule O
beta O
- O
catenin O
( O
BEP2D O
), O
as O
well O
as O
tumor B
suppressors O
CDKN3 O
and O
FOXD3 O
in O
BEP2D O
cells O
and O
SERPINB5 O
in O
Het O
- O
1A O
cells O
. O

These O
pro O
- O
oncogenic O
effects O
of O
NNK O
were O
abolished O
by O
rSLURP O
- O
1 O
that O
also O
upregulated O
RUNX3 O
. O

SIGNIFICANCE O
: O
The O
obtained O
results O
identified O
target O
genes O
for O
both O
NNK O
and O
SLURP O
- O
1 O
and O
shed O
light O
on O
the O
molecular O
mechanism O
of O
their O
reciprocal O
effects O
on O
tumorigenic B
transformation O
of O
bronchial O
and O
oral O
epithelial O
cells O
. O


Long O
- O
term O
exposure O
of O
MCF O
- O
7 O
breast B
cancer I
cells O
to O
ethanol B
stimulates O
oncogenic O
features O
. O

Alcohol B
consumption O
is O
a O
risk O
factor O
for O
breast B
cancer I
. O

Little O
is O
known O
regarding O
the O
mechanism O
, O
although O
it O
is O
assumed O
that O
acetaldehyde B
or O
estrogen B
mediated O
pathways O
play O
a O
role O
. O

We O
previously O
showed O
that O
long O
- O
term O
exposure O
to O
2 O
. O
5 O
mM O
ethanol B
( O
blood O
alcohol B
~ O
0 O
. O
12 O
%) O
of O
MCF O
- O
12A O
, O
a O
human O
normal O
epithelial O
breast O
cell O
line O
, O
induced O
epithelial O
mesenchymal O
transition O
( O
EMT O
) O
and O
oncogenic O
transformation O
. O

In O
this O
study O
, O
we O
investigated O
in O
the O
human O
breast B
cancer I
cell O
line O
MCF O
- O
7 O
, O
whether O
a O
similar O
exposure O
to O
ethanol B
at O
concentrations O
ranging O
up O
to O
peak O
blood O
levels O
in O
heavy O
drinkers O
would O
increase O
malignant O
progression O
. O

Short O
- O
term O
( O
1 O
- O
week O
) O
incubation O
to O
ethanol B
at O
as O
low O
as O
1 O
- O
5 O
mM O
( O
corresponding O
to O
blood O
alcohol B
concentration O
of O
~ O
0 O
. O
48 O
- O
0 O
. O
24 O
%) O
upregulated O
the O
stem O
cell O
related O
proteins O
4-Oct O
and O
Nanog O
, O
but O
they O
were O
reduced O
after O
exposure O
at O
25 O
mM O
. O

Long O
- O
term O
( O
4 O
- O
week O
) O
exposure O
to O
25 O
mM O
ethanol B
upregulated O
the O
4-Oct O
and O
Nanog O
proteins O
, O
as O
well O
as O
the O
malignancy B
marker O
Ceacam6 O
. O

DNA O
microarray O
analysis O
in O
cells O
exposed O
for O
1 O
week O
showed O
upregulated O
expression O
of O
metallothionein O
genes O
, O
particularly O
MT1X O
. O

Long O
- O
term O
exposure O
upregulated O
expression O
of O
some O
malignancy B
related O
genes O
( O
STEAP4 O
, O
SERPINA3 O
, O
SAMD9 O
, O
GDF15 O
, O
KRT15 O
, O
ITGB6 O
, O
TP63 O
, O
and O
PGR O
, O
as O
well O
as O
the O
CEACAM O
, O
interferon O
related O
, O
and O
HLA O
gene O
families O
). O

Some O
of O
these O
findings O
were O
validated O
by O
RT O
- O
PCR O
. O

A O
similar O
treatment O
also O
modulated O
numerous O
microRNAs O
( O
miRs O
) O
including O
one O
regulator O
of O
4-Oct O
as O
well O
as O
miRs O
involved O
in O
oncogenesis B
and O
/ O
or O
malignancy B
, O
with O
only O
a O
few O
estrogen B
- O
induced O
miRs O
. O

Long O
- O
term O
25 O
mM O
ethanol B
also O
induced O
a O
5 O
. O
6 O
- O
fold O
upregulation O
of O
anchorage O
- O
independent O
growth O
, O
an O
indicator O
of O
malignant O
- O
like O
features O
. O

Exposure O
to O
acetaldehyde B
resulted O
in O
little O
or O
no O
effect O
comparable O
to O
that O
of O
ethanol B
. O

The O
previously O
shown O
alcohol B
induction O
of O
oncogenic O
transformation O
of O
normal O
breast O
cells O
is O
now O
complemented O
by O
the O
current O
results O
suggesting O
alcohol B
' O
s O
potential O
involvement O
in O
malignant O
progression O
of O
breast B
cancer I
. O


Large O
contiguous O
gene O
deletions O
in O
Sjogren B
- I
Larsson I
syndrome I
. O

Sjogren B
- I
Larsson I
syndrome I
( O
SLS B
) O
is O
an O
autosomal B
recessive I
disorder I
characterized O
by O
ichthyosis B
, O
mental B
retardation I
, O
spasticity B
and O
mutations O
in O
the O
ALDH3A2 O
gene O
for O
fatty O
aldehyde O
dehydrogenase O
, O
an O
enzyme O
that O
catalyzes O
the O
oxidation O
of O
fatty B
aldehyde I
to O
fatty B
acid I
. O

More O
than O
70 O
mutations O
have O
been O
identified O
in O
SLS B
patients O
, O
including O
small O
deletions O
or O
insertions O
, O
missense O
mutations O
, O
splicing O
defects O
and O
complex O
nucleotide O
changes O
. O

We O
now O
describe O
2 O
SLS B
patients O
whose O
disease O
is O
caused O
by O
large O
contiguous O
gene O
deletions O
of O
the O
ALDH3A2 O
locus O
on O
17p11 O
. O
2 O
. O

The O
deletions O
were O
defined O
using O
long O
distance O
inverse O
PCR O
and O
microarray O
- O
based O
comparative O
genomic O
hybridization O
. O

A O
24 O
- O
year O
- O
old O
SLS B
female O
was O
homozygous O
for O
a O
352 O
- O
kb O
deletion O
involving O
ALDH3A2 O
and O
4 O
contiguous O
genes O
including O
ALDH3A1 O
, O
which O
codes O
for O
the O
major O
soluble O
protein O
in O
cornea O
. O

Although O
lacking O
corneal B
disease I
, O
she O
showed O
severe O
symptoms O
of O
SLS B
with O
uncommon O
deterioration O
in O
oral O
motor I
function O
and O
loss B
of I
ambulation I
. O

The O
other O
19 O
- O
month O
- O
old O
female O
patient O
was O
a O
compound O
heterozygote O
for O
a O
1 O
. O
44 O
- O
Mb O
contiguous O
gene O
deletion O
and O
a O
missense O
mutation O
( O
c O
. O
407C O
> O
T O
, O
P136L O
) O
in O
ALDH3A2 O
. O

These O
studies O
suggest O
that O
large O
gene O
deletions O
may O
account O
for O
up O
to O
5 O
% O
of O
the O
mutant O
alleles O
in O
SLS B
. O

Geneticists O
should O
consider O
the O
possibility O
of O
compound O
heterozygosity O
for O
large O
deletions O
in O
patients O
with O
SLS B
and O
other O
inborn O
errors I
of I
metabolism O
, O
which O
has O
implications O
for O
carrier O
testing O
and O
prenatal O
diagnosis O
. O


Serum O
Amyloid O
A O
Induces O
Inflammation B
, O
Proliferation O
and O
Cell O
Death O
in O
Activated O
Hepatic O
Stellate O
Cells O
. O

Serum O
amyloid O
A O
( O
SAA O
) O
is O
an O
evolutionary O
highly O
conserved O
acute O
phase O
protein O
that O
is O
predominantly O
secreted O
by O
hepatocytes O
. O

However O
, O
its O
role O
in O
liver B
injury I
and O
fibrogenesis O
has O
not O
been O
elucidated O
so O
far O
. O

In O
this O
study O
, O
we O
determined O
the O
effects O
of O
SAA B
on O
hepatic O
stellate O
cells O
( O
HSCs O
), O
the O
main O
fibrogenic O
cell O
type O
of O
the O
liver O
. O

Serum B
amyloid I
A I
potently O
activated O
IkappaB O
kinase O
, O
c O
- O
Jun O
N O
- O
terminal O
kinase O
( O
JNK O
), O
Erk O
and O
Akt O
and O
enhanced O
NF O
- O
kappaB O
- O
dependent O
luciferase O
activity O
in O
primary O
human O
and O
rat O
HSCs O
. O

Serum B
amyloid I
A I
induced O
the O
transcription O
of O
MCP O
- O
1 O
, O
RANTES O
and O
MMP9 O
in O
an O
NF O
- O
kappaB O
- O
and O
JNK O
- O
dependent O
manner O
. O

Blockade O
of O
NF O
- O
kappaB O
revealed O
cytotoxic B
effects O
of O
SAA B
in O
primary O
HSCs O
with O
signs O
of O
apoptosis O
such O
as O
caspase O
3 O
and O
PARP O
cleavage O
and O
Annexin O
V O
staining O
. O

Serum O
amyloid O
A I
induced O
HSC O
proliferation O
, O
which O
depended O
on O
JNK O
, O
Erk O
and O
Akt O
activity O
. O

In O
primary O
hepatocytes O
, O
SAA B
also O
activated O
MAP O
kinases O
, O
but O
did O
not O
induce O
relevant O
cell O
death O
after O
NF O
- O
kappaB O
inhibition O
. O

In O
two O
models O
of O
hepatic B
fibrogenesis I
, O
CCl4 B
treatment O
and O
bile O
duct O
ligation O
, O
hepatic O
mRNA O
levels O
of O
SAA1 O
and O
SAA3 O
were O
strongly O
increased O
. O

In O
conclusion O
, O
SAA B
may O
modulate O
fibrogenic B
responses O
in O
the O
liver O
in O
a O
positive O
and O
negative O
fashion O
by O
inducing O
inflammation B
, O
proliferation O
and O
cell O
death O
in O
HSCs O
. O


Influence O
of O
interleukin O
12B O
( O
IL12B O
) O
polymorphisms O
on O
spontaneous O
and O
treatment O
- O
induced O
recovery O
from O
hepatitis B
C I
virus I
infection I
. O

BACKGROUND O
/ O
AIMS O
: O
Interleukin O
- O
12 O
( O
IL O
- O
12 O
) O
governs O
the O
Th1 O
- O
type O
immune O
response O
, O
affecting O
the O
spontaneous O
and O
treatment O
- O
induced O
recovery O
from O
HCV B
- I
infection I
. O

We O
investigated O
whether O
the O
IL12B O
polymorphisms O
within O
the O
promoter O
region O
( O
4 O
bp O
insertion O
/ O
deletion O
) O
and O
the O
3 O
'- O
UTR O
( O
1188 O
- O
A O
/ O
C O
), O
which O
have O
been O
reported O
to O
influence O
IL O
- O
12 O
synthesis O
, O
are O
associated O
with O
the O
outcome O
of O
HCV B
infection I
. O

METHODS O
: O
We O
analyzed O
186 O
individuals O
with O
spontaneous O
HCV B
clearance O
, O
501 O
chronically O
HCV B
infected I
patients O
, O
and O
217 O
healthy O
controls O
. O

IL12B O
3 O
'- O
UTR O
and O
promoter O
genotyping O
was O
performed O
by O
Taqman O
- O
based O
assays O
with O
allele O
- O
specific O
oligonucleotide O
probes O
and O
PCR O
- O
based O
allele O
- O
specific O
DNA O
- O
amplification O
, O
respectively O
. O

RESULTS O
: O
The O
proportion O
of O
IL12B O
promoter O
and O
3 O
'- O
UTR O
genotypes O
did O
not O
differ O
significantly O
between O
the O
different O
cohorts O
. O

However O
, O
HCV O
genotype O
1 I
- O
infected O
patients O
with O
high O
baseline O
viremia B
carrying O
the O
IL12B O
3 O
'- O
UTR O
1188 O
- O
C O
- O
allele O
showed O
significantly O
higher O
sustained O
virologic O
response O
( O
SVR O
) O
rates O
( O
25 O
. O
3 O
% O
vs O
. O

46 O
% O
vs O
. O

54 O
. O
5 O
% O
for O
A O
/ O
A O
, O
A O
/ O
C O
and O
C O
/ O
C O
) O
due O
to O
reduced O
relapse O
rates O
( O
24 O
. O
2 O
% O
vs O
. O

12 O
% O
vs O
. O

zero O
% O
for O
A O
/ O
A O
, O
A O
/ O
C O
and O
C O
/ O
C O
). O

CONCLUSIONS O
: O
IL12B O
3 O
'- O
UTR O
1188 O
- O
C O
- O
allele O
carriers O
appear O
to O
be O
capable O
of O
responding O
more O
efficiently O
to O
antiviral O
combination O
therapy O
as O
a O
consequence O
of O
a O
reduced O
relapse O
rate O
. O

No O
association O
of O
IL12B O
polymorphisms O
and O
self O
- O
limited O
HCV B
infection I
could O
be O
demonstrated O
. O


No O
Evidence O
for O
BRAF O
as O
a O
melanoma B
/ O
nevus B
susceptibility O
gene O
. O

Somatic O
mutations O
of O
BRAF O
have O
been O
identified O
in O
both O
melanoma B
tumors I
and O
benign B
nevi I
. O

Germ O
line O
mutations O
in O
BRAF O
have O
not O
been O
identified O
as O
causal O
in O
families O
predisposed O
to O
melanoma B
. O

However O
, O
a O
recent O
study O
suggested O
that O
a O
BRAF O
haplotype O
was O
associated O
with O
risk O
of O
sporadic O
melanoma B
in O
men O
. O

Polymorphisms O
or O
other O
variants O
in O
the O
BRAF O
gene O
may O
therefore O
act O
as O
candidate O
low O
- O
penetrance O
genes O
for O
nevus B
/ O
melanoma B
susceptibility O
. O

We O
hypothesized O
that O
promoter O
variants O
would O
be O
the O
most O
likely O
candidates O
for O
determinants O
of O
risk O
. O

Using O
denaturing O
high O
- O
pressure O
liquid O
chromatography O
and O
sequencing O
, O
we O
screened O
peripheral O
blood O
DNA O
from O
184 O
familial B
melanoma I
cases O
for O
BRAF O
promoter O
variants O
. O

We O
identified O
a O
promoter O
insertion O
/ O
deletion O
in O
linkage O
disequilibrium O
with O
the O
previously O
described O
BRAF O
polymorphism O
in O
intron O
11 O
( O
rs1639679 O
) O
reported O
to O
be O
associated O
with O
melanoma B
susceptibility O
in O
males O
. O

We O
therefore O
investigated O
the O
contribution O
of O
this O
BRAF O
polymorphism O
to O
melanoma B
susceptibility O
in O
581 O
consecutively O
recruited O
incident O
cases O
, O
258 O
incident O
cases O
in O
a O
study O
of O
late O
relapse O
, O
673 O
female O
general O
practitioner O
controls O
, O
and O
the O
184 O
familial O
cases O
. O

We O
found O
no O
statistically O
significant O
difference O
in O
either O
genotype O
or O
allele O
frequencies O
between O
cases O
and O
controls O
overall O
or O
between O
male O
and O
female O
cases O
for O
the O
BRAF O
polymorphism O
in O
the O
two O
incident O
case O
series O
. O

Our O
results O
therefore O
suggest O
that O
the O
BRAF O
polymorphism O
is O
not O
significantly O
associated O
with O
melanoma B
and O
the O
promoter O
insertion O
/ O
deletion O
linked O
with O
the O
polymorphism O
is O
not O
a O
causal O
variant O
. O

In O
addition O
, O
we O
found O
that O
there O
was O
no O
association O
between O
the O
BRAF O
genotype O
and O
mean O
total O
number O
of O
banal O
or O
atypical O
nevi B
in O
either O
the O
cases O
or O
controls O
. O


CFI O
- O
rs7356506 O
polymorphisms O
associated O
with O
Vogt B
- I
Koyanagi I
- I
Harada I
syndrome I
. O

PURPOSE O
: O
Complement O
factor O
I O
( O
CFI O
) O
plays O
an O
important O
role O
in O
complement O
activation O
pathways O
and O
is O
known O
to O
affect O
the O
development O
of O
uveitis B
. O

The O
present O
study O
was O
performed O
to O
investigate O
the O
existence O
of O
an O
association O
between O
CFI O
genetic O
polymorphisms O
and O
Vogt B
- I
Koyanagi I
- I
Harada I
( I
VKH B
) I
syndrome I
. O

METHODS O
: O
A O
total O
of O
100 O
patients O
diagnosed O
with O
VKH B
syndrome I
and O
300 O
healthy O
controls O
were O
recruited O
for O
the O
study O
. O

Two O
milliliters O
of O
peripheral O
blood O
were O
collected O
in O
a O
sterile O
anticoagulative O
tube O
. O

CFI O
- O
rs7356506 O
polymorphisms O
were O
genotyped O
using O
Sequenom O
MassARRAY O
technology O
. O

Allele O
and O
genotype O
frequencies O
were O
compared O
between O
patients O
and O
controls O
using O
a O
X O
( O
2 O
) O
test O
. O

The O
analyses O
were O
stratified O
for O
recurrent O
status O
, O
complicated O
cataract B
status O
, O
and O
steroid B
- O
sensitive O
status O
. O

RESULTS O
: O
No O
significant O
association O
was O
found O
between O
CFI O
- O
rs7356506 O
polymorphisms O
and O
VKH B
syndrome I
. O

However O
, O
patients O
with O
recurrent O
VKH B
syndrome I
had O
lower O
frequencies O
of O
the O
G O
allele O
and O
GG O
homozygosity O
in O
CFI O
- O
rs7356506 O
when O
compared O
to O
the O
controls O
( O
p O
= O
0 O
. O
16 O
, O
odds O
ratio O
[ O
OR O
]= O
0 O
. O
429 O
, O
95 O
% O
confidence O
interval O
[ O
CI O
]= O
0 O
. O
212 O
- O
0 O
. O
871 O
; O
p O
= O
0 O
. O
14 O
, O
OR O
= O
0 O
. O
364 O
, O
95 O
% O
CI O
= O
0 O
. O
158 O
- O
0 O
. O
837 O
, O
respectively O
). O

Furthermore O
, O
there O
were O
significant O
decreases O
in O
the O
frequencies O
of O
the O
G O
allele O
and O
GG O
homozygosity O
in O
CFI O
- O
rs7356506 O
in O
patients O
with O
VKH B
syndrome I
with O
complicated O
cataract B
compared O
to O
the O
controls O
( O
p O
< O
0 O
. O
1 O
, O
OR O
= O
0 O
. O
357 O
, O
95 O
% O
CI O
= O
0 O
. O
197 O
- O
0 O
. O
648 O
; O
p O
< O
0 O
. O
1 O
, O
OR O
= O
0 O
. O
273 O
, O
95 O
% O
CI O
= O
0 O
. O
135 O
- O
0 O
. O
551 O
, O
respectively O
). O

Nevertheless O
, O
no O
significant O
association O
with O
patients O
with O
VKH B
syndrome I
in O
steroid B
- O
sensitive O
statuses O
was O
detected O
for O
CFI O
- O
rs7356506 O
polymorphisms O
. O

CONCLUSIONS O
: O
Our O
results O
indicate O
that O
CFI O
polymorphisms O
are O
not O
significantly O
associated O
with O
VKH B
syndrome I
; O
nevertheless O
, O
we O
identified O
a O
trend O
for O
the O
association O
of O
CFI O
- O
7356506 O
with O
VKH B
syndrome I
that O
depends O
on O
the O
recurrent O
status O
and O
the O
complicated O
cataract B
status O
but O
not O
on O
the O
steroid B
- O
sensitive O
status O
. O


Two O
novel O
mutations O
in O
the O
MEN1 O
gene O
in O
subjects O
with O
multiple B
endocrine I
neoplasia I
- I
1 I
. O

Multiple B
endocrine I
neoplasia I
type I
1 O
( O
MEN1 B
) O
is O
characterized O
by O
parathyroid B
, I
enteropancreatic I
endocrine I
and I
pituitary I
adenomas I
as O
well O
as O
germline O
mutation O
of O
the O
MEN1 O
gene O
. O

We O
describe O
2 O
families O
with O
MEN1 B
with O
novel O
mutations O
in O
the O
MEN1 O
gene O
. O

One O
family O
was O
of O
Turkish O
origin O
, O
and O
the O
index O
patient O
had O
primary B
hyperparathyroidism I
( O
PHPT B
) O
plus O
a O
prolactinoma B
; O
three O
relatives O
had O
PHPT B
only O
. O

The O
index O
patient O
in O
the O
second O
family O
was O
a O
46 O
- O
yr O
- O
old O
woman O
of O
Chinese O
origin O
living O
in O
Taiwan O
. O

This O
patient O
presented O
with O
a O
complaint O
of O
epigastric B
pain I
and O
watery O
diarrhea B
over O
the O
past O
3 O
months O
, O
and O
had O
undergone O
subtotal O
parathyroidectomy O
and O
enucleation O
of O
pancreatic B
islet I
cell I
tumor I
about O
10 O
yr O
before O
. O

There O
was O
also O
a O
prolactinoma B
. O

Sequence O
analysis O
of O
the O
MEN1 O
gene O
from O
leukocyte O
genomic O
DNA O
revealed O
heterozygous O
mutations O
in O
both O
probands O
. O

The O
Turkish O
patient O
and O
her O
affected O
relatives O
all O
had O
a O
heterozygous O
A O
to O
G O
transition O
at O
codon O
557 O
( O
AAG O
--> O
GAG O
) O
of O
exon O
10 O
of O
MEN1 O
that O
results O
in O
a O
replacement O
of O
lysine O
by O
glutamic O
acid O
. O

The O
Chinese O
index O
patient O
and O
one O
of O
her O
siblings O
had O
a O
heterozygous O
mutation O
at O
codon O
418 O
of O
exon O
9 O
( O
GAC O
--> O
TAT O
) O
that O
results O
in O
a O
substitution O
of O
aspartic O
acid O
by O
tyrosine O
. O

In O
conclusion O
, O
we O
have O
identified O
2 O
novel O
missense O
mutations O
in O
the O
MEN1 O
gene O
. O


Common O
BRCA2 O
variants O
and O
modification O
of O
breast B
and I
ovarian I
cancer I
risk O
in O
BRCA1 O
mutation O
carriers O
. O

The O
HH O
genotype O
of O
the O
nonconservative O
amino O
acid O
substitution O
polymorphism O
N372H O
in O
the O
BRCA2 O
gene O
was O
reported O
to O
be O
associated O
with O
a O
1 O
. O
3 O
- O
to O
1 O
. O
5 O
- O
fold O
increase O
in O
risk O
of O
both O
breast B
and I
ovarian I
cancer I
. O

As O
these O
studies O
concerned O
sporadic O
cancer B
cases O
, O
we O
investigated O
whether O
N372H O
and O
another O
common O
variant O
located O
in O
the O
5 O
'- O
untranslated O
region O
( O
203G O
> O
A O
) O
of O
the O
BRCA2 O
gene O
modify O
breast B
or I
ovarian I
cancer I
risk O
in O
BRCA1 O
mutation O
carriers O
. O

The O
study O
includes O
778 O
women O
carrying O
a O
BRCA1 O
germ O
- O
line O
mutation O
belonging O
to O
403 O
families O
. O

The O
two O
BRCA2 O
variants O
were O
analyzed O
by O
the O
TaqMan O
allelic O
discrimination O
technique O
. O

Genotypes O
were O
analyzed O
by O
disease O
- O
free O
survival O
analysis O
using O
a O
Cox O
proportional O
hazards O
model O
. O

We O
found O
no O
evidence O
of O
a O
significant O
modification O
of O
breast B
cancer I
penetrance O
in O
BRCA1 O
mutation O
carriers O
by O
either O
polymorphism O
. O

In O
respect O
of O
ovarian B
cancer I
risk O
, O
we O
also O
saw O
no O
effect O
with O
the O
N372H O
variant O
but O
we O
did O
observe O
a O
borderline O
association O
with O
the O
5 O
'- O
untranslated O
region O
203A O
allele O
( O
hazard O
ratio O
, O
1 O
. O
43 O
; O
CI O
, O
1 O
. O
1 O
- O
2 O
. O
0 O
). O

In O
contrast O
to O
the O
result O
of O
Healey O
et O
al O
. O

on O
newborn O
females O
and O
adult O
female O
controls O
, O
we O
found O
no O
departure O
from O
Hardy O
- O
Weinberg O
equilibrium O
in O
the O
distribution O
of O
N372H O
alleles O
for O
our O
female O
BRCA1 O
carriers O
. O

We O
conclude O
that O
if O
these O
single O
- O
nucleotide O
polymorphisms O
do O
modify O
the O
risk O
of O
cancer B
in O
BRCA1 O
mutation O
carriers O
, O
their O
effects O
are O
not O
significantly O
larger O
than O
that O
of O
N372H O
previously O
observed O
in O
the O
general O
population O
. O


Transgelin O
increases O
metastatic O
potential O
of O
colorectal B
cancer I
cells O
in O
vivo O
and O
alters O
expression O
of O
genes O
involved O
in O
cell O
motility O
. O

BACKGROUND O
: O
Transgelin O
is O
an O
actin O
- O
binding O
protein O
that O
promotes O
motility O
in O
normal O
cells O
. O

Although O
the O
role O
of O
transgelin O
in O
cancer B
is O
controversial O
, O
a O
number O
of O
studies O
have O
shown O
that O
elevated O
levels O
correlate O
with O
aggressive O
tumor B
behavior O
, O
advanced O
stage O
, O
and O
poor O
prognosis O
. O

Here O
we O
sought O
to O
determine O
the O
role O
of O
transgelin O
more O
directly O
by O
determining O
whether O
experimental O
manipulation O
of O
transgelin O
levels O
in O
colorectal B
cancer I
( O
CRC B
) O
cells O
led O
to O
changes O
in O
metastatic O
potential O
in O
vivo O
. O

METHODS O
: O
Isogenic O
CRC B
cell O
lines O
that O
differ O
in O
transgelin O
expression O
were O
characterized O
using O
in O
vitro O
assays O
of O
growth O
and O
invasiveness O
and O
a O
mouse O
tail O
vein O
assay O
of O
experimental O
metastasis B
. O

Downstream O
effects O
of O
transgelin O
overexpression O
were O
investigated O
by O
gene O
expression O
profiling O
and O
quantitative O
PCR O
. O

RESULTS O
: O
Stable O
overexpression O
of O
transgelin O
in O
RKO O
cells O
, O
which O
have O
low O
endogenous O
levels O
, O
led O
to O
increased O
invasiveness O
, O
growth O
at O
low O
density O
, O
and O
growth O
in O
soft O
agar B
. O

Overexpression O
also O
led O
to O
an O
increase O
in O
the O
number O
and O
size O
of O
lung B
metastases I
in O
the O
mouse O
tail O
vein O
injection O
model O
. O

Similarly O
, O
attenuation O
of O
transgelin O
expression O
in O
HCT116 O
cells O
, O
which O
have O
high O
endogenous O
levels O
, O
decreased O
metastases B
in O
the O
same O
model O
. O

Investigation O
of O
mRNA O
expression O
patterns O
showed O
that O
transgelin O
overexpression O
altered O
the O
levels O
of O
approximately O
250 O
other O
transcripts O
, O
with O
over O
- O
representation O
of O
genes O
that O
affect O
function O
of O
actin O
or O
other O
cytoskeletal O
proteins O
. O

Changes O
included O
increases O
in O
HOOK1 O
, O
SDCCAG8 O
, O
ENAH O
/ O
Mena O
, O
and O
TNS1 O
and O
decreases O
in O
EMB O
, O
BCL11B O
, O
and O
PTPRD O
. O

CONCLUSIONS O
: O
Increases O
or O
decreases O
in O
transgelin O
levels O
have O
reciprocal O
effects O
on O
tumor B
cell O
behavior O
, O
with O
higher O
expression O
promoting O
metastasis B
. O

Chronic O
overexpression O
influences O
steady O
- O
state O
levels O
of O
mRNAs O
for O
metastasis B
- O
related O
genes O
. O


Association O
of O
sporadic O
chondrocalcinosis B
with O
a O
- O
4 O
- O
basepair O
G O
- O
to O
- O
A O
transition O
in O
the O
5 O
'- O
untranslated O
region O
of O
ANKH O
that O
promotes O
enhanced O
expression O
of O
ANKH O
protein O
and O
excess O
generation O
of O
extracellular O
inorganic B
pyrophosphate I
. O

OBJECTIVE O
: O
Certain O
mutations O
in O
ANKH O
, O
which O
encodes O
a O
multiple O
- O
pass O
transmembrane O
protein O
that O
regulates O
inorganic B
pyrophosphate I
( O
PPi B
) O
transport O
, O
are O
linked O
to O
autosomal O
- O
dominant O
familial O
chondrocalcinosis B
. O

This O
study O
investigated O
the O
potential O
for O
ANKH O
sequence O
variants O
to O
promote O
sporadic O
chondrocalcinosis B
. O

METHODS O
: O
ANKH O
variants O
identified O
by O
genomic O
sequencing O
were O
screened O
for O
association O
with O
chondrocalcinosis B
in O
128 O
patients O
with O
severe O
sporadic O
chondrocalcinosis B
or O
pseudogout B
and O
in O
ethnically O
matched O
healthy O
controls O
. O

The O
effects O
of O
specific O
variants O
on O
expression O
of O
common O
markers O
were O
evaluated O
by O
in O
vitro O
transcription O
/ O
translation O
. O

The O
function O
of O
these O
variants O
was O
studied O
in O
transfected O
human O
immortalized O
CH O
- O
8 O
articular O
chondrocytes O
. O

RESULTS O
: O
Sporadic O
chondrocalcinosis B
was O
associated O
with O
a O
G O
- O
to O
- O
A O
transition O
in O
the O
ANKH O
5 O
'- O
untranslated O
region O
( O
5 O
'- O
UTR O
) O
at O
4 O
bp O
upstream O
of O
the O
start O
codon O
( O
in O
homozygotes O
of O
the O
minor O
allele O
, O
genotype O
relative O
risk O
6 O
. O
0 O
, O
P O
= O
0 O
. O
6 O
; O
overall O
genotype O
association O
P O
= O
0 O
. O
2 O
). O

This O
- O
4 O
- O
bp O
transition O
, O
as O
well O
as O
2 O
mutations O
previously O
linked O
with O
familial O
and O
sporadic O
chondrocalcinosis B
(+ O
14 O
bp O
C O
- O
to O
- O
T O
and O
C O
- O
terminal O
GAG O
deletion O
, O
respectively O
), O
but O
not O
the O
French O
familial O
chondrocalcinosis B
kindred O
143 O
- O
bp O
T O
- O
to O
- O
C O
mutation O
, O
increased O
reticulocyte O
ANKH O
transcription O
/ O
ANKH O
translation O
in O
vitro O
. O

Transfection O
of O
complementary O
DNA O
for O
both O
the O
wild O
- O
type O
ANKH O
and O
the O
- O
4 O
- O
bp O
ANKH O
protein O
variant O
promoted O
increased O
extracellular O
PPi O
in O
CH O
- O
8 O
cells O
, O
but O
unexpectedly O
, O
these O
ANKH O
mutants O
had O
divergent O
effects O
on O
the O
expression O
of O
extracellular O
PPi O
and O
the O
chondrocyte B
hypertrophy I
marker O
, O
type O
X O
collagen O
. O

CONCLUSION O
: O
A O
subset O
of O
sporadic O
chondrocalcinosis B
appears O
to O
be O
heritable O
via O
a O
- O
4 O
- O
bp O
G O
- O
to O
- O
A O
ANKH O
5 O
'- O
UTR O
transition O
that O
up O
- O
regulates O
expression O
of O
ANKH O
and O
extracellular O
PPi O
in O
chondrocyte O
cells O
. O

Distinct O
ANKH O
mutations O
associated O
with O
heritable O
chondrocalcinosis B
may O
promote O
disease O
by O
divergent O
effects O
on O
extracellular O
PPi O
and O
chondrocyte B
hypertrophy I
, O
which O
is O
likely O
to O
mediate O
differences O
in O
the O
clinical O
phenotypes O
and O
severity O
of O
the O
disease O
. O


Contribution O
of O
STAT4 O
gene O
single O
- O
nucleotide O
polymorphism O
to O
systemic B
lupus I
erythematosus I
in O
the O
Polish O
population O
. O

The O
STAT4 O
has O
been O
found O
to O
be O
a O
susceptible O
gene O
in O
the O
development O
of O
systemic B
lupus I
erythematosus I
( O
SLE B
) O
in O
various O
populations O
. O

There O
are O
evident O
population O
differences O
in O
the O
context O
of O
clinical O
manifestations O
of O
SLE B
, O
therefore O
we O
investigated O
the O
prevalence O
of O
the O
STAT4 O
G O
> O
C O
( O
rs7582694 O
) O
polymorphism O
in O
patients O
with O
SLE B
( O
n O
= O
253 O
) O
and O
controls O
( O
n O
= O
521 O
) O
in O
a O
sample O
of O
the O
Polish O
population O
. O

We O
found O
that O
patients O
with O
the O
STAT4 O
C O
/ O
G O
and O
CC O
genotypes O
exhibited O
a O
1 O
. O
583 O
- O
fold O
increased O
risk O
of O
SLE B
incidence O
( O
95 O
% O
CI O
= O
1 O
. O
168 O
- O
2 O
. O
145 O
, O
p O
= O
0 O
. O
3 O
), O
with O
OR O
for O
the O
C O
/ O
C O
versus O
C O
/ O
G O
and O
G O
/ O
G O
genotypes O
was O
1 O
. O
967 O
( O
95 O
% O
CI O
= O
1 O
. O
152 O
- O
3 O
. O
358 O
, O
p O
= O
0 O
. O
119 O
). O

The O
OR O
for O
the O
STAT4 O
C O
allele O
frequency O
showed O
a O
1 O
. O
539 O
- O
fold O
increased O
risk O
of O
SLE B
( O
95 O
% O
CI O
= O
1 O
. O
209 O
- O
1 O
. O
959 O
, O
p O
= O
0 O
. O
4 O
). O

We O
also O
observed O
an O
increased O
frequency O
of O
STAT4 O
C O
/ O
C O
and O
C O
/ O
G O
genotypes O
in O
SLE B
patients O
with O
renal B
symptoms I
OR O
= O
2 O
. O
259 O
( O
1 O
. O
365 O
- O
3 O
. O
738 O
, O
p O
= O
0 O
. O
14 O
), O
( O
p O
( O
corr O
) O
= O
0 O
. O
238 O
) O
and O
in O
SLE B
patients O
with O
neurologic B
manifestations O
OR O
= O
2 O
. O
867 O
( O
1 O
. O
467 O
- O
5 O
. O
604 O
, O
p O
= O
0 O
. O
16 O
), O
( O
p O
( O
corr O
) O
= O
0 O
. O
272 O
). O

Moreover O
, O
we O
found O
a O
contribution O
of O
STAT4 O
C O
/ O
C O
and O
C O
/ O
G O
genotypes O
to O
the O
presence O
of O
the O
anti O
- O
snRNP O
Ab O
OR O
= O
3 O
. O
237 O
( O
1 O
. O
667 O
- O
6 O
. O
288 O
, O
p O
= O
0 O
. O
3 O
), O
( O
p O
( O
corr O
) O
= O
0 O
. O
51 O
) O
and O
the O
presence O
of O
the O
anti O
- O
Scl O
- O
70 O
Ab O
OR O
= O
2 O
. O
665 O
( O
1 O
. O
380 O
- O
5 O
. O
147 O
, O
p O
= O
0 O
. O
28 O
), O
( O
p O
( O
corr O
) O
= O
0 O
. O
476 O
). O

Our O
studies O
confirmed O
an O
association O
of O
the O
STAT4 O
C O
( O
rs7582694 O
) O
variant O
with O
the O
development O
of O
SLE B
and O
occurrence O
of O
some O
clinical O
manifestations O
of O
the O
disease O
. O


Leukemia O
inhibitory O
factor O
protects O
the O
lung O
during O
respiratory B
syncytial I
viral I
infection I
. O

BACKGROUND O
: O
Respiratory O
syncytial O
virus O
( O
RSV O
) O
infects O
the O
lung O
epithelium O
where O
it O
stimulates O
the O
production O
of O
numerous O
host O
cytokines O
that O
are O
associated O
with O
disease O
burden O
and O
acute B
lung I
injury I
. O

Characterizing O
the O
host O
cytokine O
response O
to O
RSV B
infection I
, O
the O
regulation O
of O
host O
cytokines O
and O
the O
impact O
of O
neutralizing O
an O
RSV O
- O
inducible O
cytokine O
during O
infection B
were O
undertaken O
in O
this O
study O
. O

METHODS O
: O
A549 O
, O
primary O
human O
small O
airway O
epithelial O
( O
SAE O
) O
cells O
and O
wild O
- O
type O
, O
TIR O
- O
domain O
- O
containing O
adapter O
- O
inducing O
interferon O
- O
b O
( O
Trif O
) O
and O
mitochondrial O
antiviral O
- O
signaling O
protein O
( O
Mavs O
) O
knockout O
( O
KO O
) O
mice O
were O
infected O
with O
RSV B
and O
cytokine O
responses O
were O
investigated O
by O
ELISA O
, O
multiplex O
analysis O
and O
qPCR O
. O

Neutralizing O
anti O
- O
leukemia O
inhibitory O
factor O
( O
LIF O
) O
IgG O
or O
control O
IgG O
was O
administered O
to O
a O
group O
of O
wild O
- O
type O
animals O
prior O
to O
RSV B
infection I
. O

RESULTS O
AND O
DISCUSSION O
: O
RSV O
- O
infected O
A549 O
and O
SAE O
cells O
release O
a O
network O
of O
cytokines O
, O
including O
newly O
identified O
RSV O
- O
inducible O
cytokines O
LIF O
, O
migration O
inhibitory O
factor O
( O
MIF O
), O
stem O
cell O
factor O
( O
SCF O
), O
CCL27 O
, O
CXCL12 O
and O
stem O
cell O
growth O
factor O
beta O
( O
SCGF O
- O
b O
). O

These O
RSV O
- O
inducible O
cytokines O
were O
also O
observed O
in O
the O
airways O
of O
mice O
during O
an O
infection B
. O

To O
identify O
the O
regulation O
of O
RSV O
inducible O
cytokines O
, O
Mavs O
and O
Trif O
deficient O
animals O
were O
infected O
with O
RSV O
. O

In O
vivo O
induction O
of O
airway O
IL O
- O
1b O
, O
IL O
- O
4 O
, O
IL O
- O
5 O
, O
IL O
- O
6 O
, O
IL O
- O
12 O
( O
p40 O
), O
IFN O
- O
g O
, O
CCL2 O
, O
CCL5 O
, O
CCL3 O
, O
CXCL1 O
, O
IP O
- O
10 O
/ O
CXCL10 O
, O
IL O
- O
22 O
, O
MIG O
/ O
CXCL9 O
and O
MIF O
were O
dependent O
on O
Mavs O
expression O
in O
mice O
. O

Loss O
of O
Trif O
expression O
in O
mice O
altered O
the O
RSV O
induction O
of O
IL O
- O
1b O
, O
IL O
- O
5 O
, O
CXCL12 O
, O
MIF O
, O
LIF O
, O
CXCL12 O
and O
IFN O
- O
g O
. O

Silencing O
of O
retinoic O
acid O
- O
inducible O
gene O
- O
1 O
( O
RIG O
- O
I O
) O
expression O
in O
A549 O
cells O
had O
a O
greater O
impact O
on O
RSV O
- O
inducible O
cytokines O
than O
melanoma B
differentiation O
- O
associated O
protein O
5 O
( O
MDA5 O
) O
and O
laboratory O
of O
genetics O
and O
physiology O
2 O
( O
LGP2 O
), O
and O
Trif O
expression O
. O

To O
evaluate O
the O
role O
of O
LIF O
in O
the O
airways O
during O
RSV B
infection I
, O
animals O
were O
treated O
with O
neutralizing O
anti O
- O
LIF O
IgG O
, O
which O
enhanced O
RSV B
pathology O
observed O
with O
increased O
airspace O
protein O
content O
, O
apoptosis O
and O
airway O
hyperresponsiveness O
compared O
to O
control O
IgG B
treatment O
. O

CONCLUSIONS O
: O
RSV B
infection B
in O
the O
epithelium O
induces O
a O
network O
of O
immune O
factors O
to O
counter O
infection B
, O
primarily O
in O
a O
RIG O
- O
I O
dependent O
manner O
. O

Expression O
of O
LIF O
protects O
the O
lung O
from O
lung B
injury I
and O
enhanced O
pathology O
during O
RSV B
infection I
. O


Urinary B
bladder I
cancer I
in O
Wegener O
' I
s I
granulomatosis I
: O
risks O
and O
relation O
to O
cyclophosphamide B
. O

OBJECTIVE O
: O
To O
assess O
and O
characterise O
the O
risk O
of O
bladder B
cancer I
, O
and O
its O
relation O
to O
cyclophosphamide B
, O
in O
patients O
with O
Wegener B
' I
s I
granulomatosis I
. O

METHODS O
: O
In O
the O
population O
based O
, O
nationwide O
Swedish O
Inpatient O
Register O
a O
cohort O
of O
1065 O
patients O
with O
Wegener B
' I
s I
granulomatosis I
, O
1969 O
- O
95 O
, O
was O
identified O
. O

Through O
linkage O
with O
the O
Swedish O
Cancer B
Register O
, O
all O
subjects O
in O
this O
cohort O
diagnosed O
with O
bladder B
cancer I
were O
identified O
. O

Nested O
within O
the O
cohort O
, O
a O
matched O
case O
- O
control O
study O
was O
performed O
to O
estimate O
the O
association O
between O
cyclophosphamide B
and O
bladder B
cancer I
using O
odds O
ratios O
( O
ORs O
) O
as O
relative O
risk O
. O

In O
the O
cohort O
the O
cumulative O
risk O
of O
bladder B
cancer I
after O
Wegener B
' I
s I
granulomatosis I
, O
and O
the O
relative O
prevalence O
of O
a O
history O
of O
bladder B
cancer I
at O
the O
time O
of O
diagnosis O
of O
Wegener B
' I
s I
granulomatosis I
, O
were O
also O
estimated O
. O

RESULTS O
: O
The O
median O
cumulative O
doses O
of O
cyclophosphamide B
among O
cases O
( O
n O
= O
11 O
) O
and O
controls O
( O
n O
= O
25 O
) O
were O
113 O
g O
and O
25 O
g O
, O
respectively O
. O

The O
risk O
of O
bladder B
cancer I
doubled O
for O
every O
10 O
g O
increment O
in O
cyclophosphamide B
( O
OR O
= O
2 O
. O
0 O
, O
95 O
% O
confidence O
interval O
( O
CI O
) O
0 O
. O
8 O
to O
4 O
. O
9 O
). O

Treatment O
duration O
longer O
than O
1 O
year O
was O
associated O
with O
an O
eightfold O
increased O
risk O
( O
OR O
= O
7 O
. O
7 O
, O
95 O
% O
CI O
0 O
. O
9 O
to O
69 O
). O

The O
absolute O
risk O
for O
bladder B
cancer I
in O
the O
cohort O
reached O
10 O
% O
16 O
years O
after O
diagnosis O
of O
Wegener B
' I
s I
granulomatosis I
, O
and O
a O
history O
of O
bladder B
cancer I
was O
( O
non O
- O
significantly O
) O
twice O
as O
common O
as O
expected O
at O
the O
time O
of O
diagnosis O
of O
Wegener B
' I
s I
granulomatosis I
. O

CONCLUSION O
: O
The O
results O
indicate O
a O
dose O
- O
response O
relationship O
between O
cyclophosphamide B
and O
the O
risk O
of O
bladder B
cancer I
, O
high O
cumulative O
risks O
in O
the O
entire O
cohort O
, O
and O
also O
the O
possibility O
of O
risk O
factors O
operating O
even O
before O
Wegener B
' I
s I
granulomatosis I
. O


Co O
- O
inheritance O
of O
a O
PKD1 O
mutation O
and O
homozygous O
PKD2 O
variant O
: O
a O
potential O
modifier O
in O
autosomal B
dominant I
polycystic I
kidney I
disease I
. O

BACKGROUND O
: O
Autosomal B
dominant I
polycystic I
kidney I
disease I
( O
ADPKD B
), O
which O
is O
caused O
by O
mutations O
in O
polycystins O
1 O
( O
PC1 O
) O
and O
2 O
( O
PC2 O
), O
is O
one O
of O
the O
most O
commonly O
inherited B
renal I
diseases I
, O
affecting O
~ O
1 O
: O
1000 O
Caucasians O
. O

MATERIALS O
AND O
METHODS O
: O
We O
screened O
Greek O
ADPKD B
patients O
with O
the O
denaturing O
gradient O
gel O
electrophoresis O
( O
DGGE O
) O
assay O
and O
direct O
sequencing O
. O

RESULTS O
: O
We O
identified O
a O
patient O
homozygous O
for O
a O
nucleotide O
change O
c O
. O
1445T O
> O
G O
, O
resulting O
in O
a O
novel O
homozygous O
substitution O
of O
the O
non O
- O
polar O
hydrophobic O
phenylalanine O
to O
the O
polar O
hydrophilic O
cysteine O
in O
exon O
6 O
at O
codon O
482 O
( O
p O
. O
F482C O
) O
of O
the O
PKD2 O
gene O
and O
a O
de O
- O
novo O
PKD1 O
splice O
- O
site O
variant O
IVS21 O
- O
2delAG O
. O

We O
did O
not O
find O
this O
PKD2 O
variant O
in O
a O
screen O
of O
280 O
chromosomes O
of O
healthy O
subjects O
, O
supporting O
its O
pathogenicity O
. O

The O
proband O
' O
s O
parents O
did O
not O
have O
the O
PKD1 O
mutation O
. O

Real O
- O
time O
PCR O
of O
the O
PKD2 O
transcript O
from O
a O
skin O
biopsy O
revealed O
20 O
- O
fold O
higher O
expression O
in O
the O
patient O
than O
in O
a O
healthy O
subject O
and O
was O
higher O
in O
the O
patient O
' O
s O
peripheral O
blood O
mononuclear O
cells O
( O
PBMCs O
) O
than O
in O
those O
of O
her O
heterozygote O
daughter O
and O
a O
healthy O
subject O
. O

The O
greater O
gene O
expression O
was O
also O
supported O
by O
Western O
blotting O
. O

Inner O
medullar O
collecting O
duct O
( O
IMCD O
) O
cells O
transfected O
with O
the O
mutant O
PKD2 O
mouse O
gene O
presented O
a O
perinuclear O
and O
diffuse O
cytoplasmic O
localization O
compared O
with O
the O
wild O
type O
ER O
localization O
. O

Patch O
- O
clamping O
of O
PBMCs O
from O
the O
p O
. O
F482C O
homozygous O
and O
heterozygous O
subjects O
revealed O
lower O
polycystin O
- O
2 O
channel O
function O
than O
in O
controls O
. O

CONCLUSIONS O
: O
We O
report O
for O
the O
first O
time O
a O
patient O
with O
ADPKD B
who O
is O
heterozygous O
for O
a O
de O
novo O
PKD1 O
variant O
and O
homozygous O
for O
a O
novel O
PKD2 O
mutation O
. O


Two O
novel O
mutations O
of O
the O
TSH O
- O
beta O
subunit O
gene O
underlying O
congenital B
central I
hypothyroidism I
undetectable O
in O
neonatal O
TSH O
screening O
. O

CONTEXT O
: O
Patients O
with O
TSH B
- O
beta O
subunit I
defects I
and O
congenital B
hypothyroidism I
are O
missed O
by O
TSH O
- O
based O
neonatal O
screening O
. O

OBJECTIVE O
: O
Our O
objective O
was O
to O
report O
the O
molecular O
consequences O
of O
a O
novel O
splice O
- O
junction O
mutation O
and O
a O
novel O
missense O
mutation O
in O
the O
TSH O
- O
beta O
subunit O
gene O
found O
in O
two O
patients O
with O
congenital B
central I
hypothyroidism I
and O
conventional O
treatment O
- O
resistant O
anemia B
. O

RESULTS O
: O
Patient O
1 O
had O
a O
homozygous O
G O
to O
A O
nucleotide O
change O
at O
the O
5 O
' O
donor O
splice O
site O
of O
exon O
/ O
intron O
2 O
. O

This O
resulted O
in O
a O
silent O
change O
at O
codon O
34 O
of O
the O
mature O
protein O
. O

In O
vitro O
splicing O
assays O
showed O
that O
the O
mutant O
minigene O
dramatically O
affected O
pre O
- O
mRNA O
processing O
, O
causing O
exon O
2 O
to O
be O
completely O
skipped O
. O

The O
putative O
product O
from O
a O
new O
out O
- O
of O
- O
frame O
translational O
start O
point O
in O
exon O
3 O
is O
expected O
to O
yield O
a O
nonsense O
25 O
- O
amino O
- O
acid O
peptide O
. O

In O
patient O
2 O
, O
sequence O
analysis O
revealed O
a O
compound O
heterozygosis O
for O
the O
already O
reported O
313delT O
( O
C105Vfs114X O
) O
mutation O
and O
for O
a O
second O
novel O
mutation O
in O
exon O
3 O
, O
substituting O
G O
for O
A O
at O
cDNA O
nucleotide O
position O
323 O
, O
resulting O
in O
a O
C88Y O
change O
. O

This O
cysteine O
residue O
is O
conserved O
among O
all O
dimeric O
pituitary O
and O
placental O
glycoprotein O
hormone O
- O
beta O
subunits O
. O

Data O
from O
in O
silico O
analysis O
confirmed O
that O
the O
C88Y O
mutation O
would O
affect O
subunit O
conformation O
. O

Indeed O
, O
two O
different O
bioinformatics O
approaches O
, O
PolyPhen O
and O
SIFT O
analysis O
, O
predicted O
C88Y O
to O
be O
a O
damaging O
substitution O
. O

CONCLUSIONS O
: O
In O
isolated O
TSH B
deficiency I
, O
the O
exact O
molecular O
diagnosis O
is O
mandatory O
for O
diagnosis O
of O
isolated O
pituitary B
deficiency I
, O
delineation O
of O
prognosis O
, O
and O
genetic O
counseling O
. O

Moreover O
, O
diagnosis O
of O
central B
hypothyroidism I
should O
be O
considered O
in O
the O
face O
of O
severe O
infant B
anemia I
of O
uncertain O
etiology O
. O


Mutations O
in O
the O
NDP O
gene O
: O
contribution O
to O
Norrie B
disease I
, O
familial O
exudative B
vitreoretinopathy I
and O
retinopathy B
of I
prematurity I
. O

BACKGROUND O
: O
To O
examine O
the O
contribution O
of O
mutations O
within O
the O
Norrie B
disease I
( O
NDP O
) O
gene O
to O
the O
clinically O
similar O
retinal B
diseases I
Norrie B
disease I
, O
X B
- I
linked I
familial I
exudative B
vitreoretinopathy I
( O
FEVR B
), O
Coat B
' I
s I
disease I
and O
retinopathy B
of I
prematurity I
( O
ROP B
). O

METHODS O
: O
A O
dataset O
comprising O
13 O
Norrie B
- I
FEVR I
, O
one O
Coat B
' I
s I
disease I
, O
31 O
ROP B
patients O
and O
90 O
ex O
- O
premature O
babies O
of O
< O
32 O
weeks O
' O
gestation O
underwent O
an O
ophthalmologic O
examination O
and O
were O
screened O
for O
mutations O
within O
the O
NDP O
gene O
by O
direct O
DNA O
sequencing O
, O
denaturing O
high O
- O
performance O
liquid O
chromatography O
or O
gel O
electrophoresis O
. O

Controls O
were O
only O
screened O
using O
denaturing O
high O
- O
performance O
liquid O
chromatography O
and O
gel O
electrophoresis O
. O

Confirmation O
of O
mutations O
identified O
was O
obtained O
by O
DNA O
sequencing O
. O

RESULTS O
: O
Evidence O
for O
two O
novel O
mutations O
in O
the O
NDP O
gene O
was O
presented O
: O
Leu103Val O
in O
one O
FEVR B
patient O
and O
His43Arg O
in O
monozygotic O
twin O
Norrie B
disease I
patients O
. O

Furthermore O
, O
a O
previously O
described O
14 O
- O
bp O
deletion O
located O
in O
the O
5 O
' O
unstranslated O
region O
of O
the O
NDP O
gene O
was O
detected O
in O
three O
cases O
of O
regressed O
ROP B
. O

A O
second O
heterozygotic O
14 O
- O
bp O
deletion O
was O
detected O
in O
an O
unaffected O
ex O
- O
premature O
girl O
. O

Only O
two O
of O
the O
13 O
Norrie B
- O
FEVR B
index O
cases O
had O
the O
full O
features O
of O
Norrie B
disease I
with O
deafness B
and O
mental B
retardation I
. O

CONCLUSION O
: O
Two O
novel O
mutations O
within O
the O
coding O
region O
of O
the O
NDP O
gene O
were O
found O
, O
one O
associated O
with O
a O
severe O
disease O
phenotypes O
of O
Norrie B
disease I
and O
the O
other O
with O
FEVR B
. O

A O
deletion O
within O
the O
non O
- O
coding O
region O
was O
associated O
with O
only O
mild O
- O
regressed O
ROP B
, O
despite O
the O
presence O
of O
low O
birthweight O
, O
prematurity B
and O
exposure O
to O
oxygen B
. O

In O
full O
- O
term O
children O
with O
retinal B
detachment I
only O
15 O
% O
appear O
to O
have O
the O
full O
features O
of O
Norrie B
disease I
and O
this O
is O
important O
for O
counselling O
parents O
on O
the O
possible O
long O
- O
term O
outcome O
. O


Growth B
hormone I
dose O
in O
growth B
hormone I
- I
deficient I
adults O
is O
not O
associated O
with O
IGF O
- O
1 O
gene O
polymorphisms O
. O

AIMS O
: O
Several O
SNPs O
and O
a O
microsatellite O
cytosine O
- O
adenine O
repeat O
promoter O
polymorphism O
of O
the O
IGF O
- O
1 O
gene O
have O
been O
reported O
to O
be O
associated O
with O
circulating O
IGF O
- O
1 O
serum O
concentrations O
. O

Variance O
in O
IGF O
- O
1 O
concentrations O
due O
to O
genetic O
variations O
may O
affect O
different O
response O
to O
growth B
hormone I
( O
GH B
) O
treatment O
, O
resulting O
in O
different O
individually O
required O
GH B
- O
doses O
in O
GH B
- I
deficient I
patients O
. O

The O
aim O
of O
this O
study O
was O
to O
test O
if O
the O
IGF O
- O
1 O
gene O
polymorphisms O
are O
associated O
with O
the O
GH B
- O
dose O
of O
GH B
- O
deficient I
adults O
. O

MATERIALS O
& O
METHODS O
: O
A O
total O
of O
nine O
tagging O
SNPs O
, O
five O
additionally O
selected O
SNPs O
and O
a O
cytosine O
- O
adenine O
repeat O
polymorphism O
were O
determined O
in O
133 O
German O
adult O
patients O
( O
66 O
men O
, O
67 O
women O
; O
mean O
age O
45 O
. O
4 O
years O
+/- O
13 O
. O
1 O
standard O
deviation O
; O
majority O
Caucasian O
) O
with O
GH B
- I
deficiency I
( O
GHD B
) O
of O
different O
origin O
, O
derived O
from O
the O
prospective O
Pfizer O
International O
Metabolic O
Study O
( O
KIMS O
) O
Pharmacogenetics O
Study O
. O

Patients O
received O
GH B
- O
treatment O
for O
12 O
months O
with O
finished O
dose O
- O
titration O
of O
GH O
and O
centralized O
IGF O
- O
1 O
measurements O
. O

GH O
- O
dose O
after O
1 O
year O
of O
treatment O
, O
IGF O
- O
1 O
concentrations O
, O
IGF O
- O
1 O
- O
standard O
deviation O
score O
( O
SDS O
), O
the O
IGF O
- O
1 O
: O
GH O
ratio O
and O
anthropometric O
data O
were O
analyzed O
by O
genotype O
. O

RESULTS O
: O
Except O
for O
rs1019731 O
, O
which O
showed O
a O
significant O
difference O
of O
IGF O
- O
1 O
- O
SDS O
by O
genotypes O
( O
p O
= O
0 O
. O
2 O
), O
all O
polymorphisms O
showed O
no O
associations O
with O
the O
GH O
- O
doses O
, O
IGF O
- O
1 O
concentrations O
, O
IGF O
- O
1 O
- O
SDS O
and O
IGF O
- O
1 O
: O
GH O
ratio O
after O
adjusting O
for O
the O
confounding O
variables O
gender O
, O
age O
and O
BMI O
. O

CONCLUSION O
: O
IGF O
- O
1 O
gene O
polymorphisms O
were O
not O
associated O
with O
the O
responsiveness O
to O
exogenous O
GH B
in O
GHD B
. O

Therefore O
, O
genetic O
variations O
of O
the O
IGF O
- O
1 O
gene O
seem O
not O
to O
be O
major O
influencing O
factors O
of O
the O
GH O
- O
IGF O
- O
axis O
causing O
variable O
response O
to O
exogenous O
GH B
- O
treatment O
. O


Mutation O
analysis O
of O
FOXF2 O
in O
patients O
with O
disorders B
of I
sex I
development I
( O
DSD B
) O
in O
combination O
with O
cleft B
palate I
. O

In O
contrast O
to O
disorders B
of I
sexual I
differentiation I
caused O
by O
lack O
of O
androgen B
production O
or O
inhibited O
androgen B
action O
, O
defects O
affecting O
development O
of O
the O
bipotent O
genital O
anlagen O
have O
rarely O
been O
investigated O
in O
humans O
. O

We O
have O
previously O
documented O
that O
the O
transcription O
factor O
FOXF2 O
is O
highly O
expressed O
in O
human O
foreskin O
. O

Moreover O
, O
Foxf2 O
knockout O
mice O
present O
with O
cleft B
palate I
in O
combination O
with O
hypoplasia B
of I
the I
genital I
tubercle I
. O

We O
hypothesized O
that O
humans O
with O
disorders B
of I
sex I
development I
( O
DSD B
) O
in O
combination O
with O
cleft B
palate I
could O
have O
mutations O
in O
the O
FOXF2 O
gene O
. O

Eighteen O
children O
with O
DSD B
and O
cleft B
palate I
were O
identified O
in O
the O
L O
beck O
DSD B
database O
( O
about O
1 O
, O
500 O
entries O
). O

Genomic O
DNA O
sequence O
analysis O
of O
the O
FOXF2 O
gene O
was O
performed O
and O
compared O
with O
10 O
normal O
female O
and O
10 O
normal O
male O
controls O
, O
respectively O
. O

Two O
heterozygous O
DNA O
sequence O
variations O
were O
solely O
present O
in O
one O
single O
patient O
each O
but O
in O
none O
of O
the O
20 O
normal O
controls O
: O
a O
duplication O
of O
GCC O
( O
c O
. O
97GCC O
[ O
9 O
]+[ O
10 O
]) O
resulting O
in O
an O
extra O
alanine O
within O
exon O
1 O
and O
a O
25 O
* O
G O
> O
A O
substitution O
in O
the O
3 O
'- O
untranslated O
region O
. O

Two O
patients O
carried O
a O
c O
. O
262G O
> O
A O
sequence O
variation O
predicting O
for O
an O
Ala88Thr O
exchange O
which O
was O
also O
detected O
in O
2 O
normal O
controls O
. O

Two O
silent O
mutations O
, O
c O
. O
1272C O
> O
T O
( O
Ser424Ser O
) O
and O
c O
. O
1284T O
> O
C O
( O
Tyr428Tyr O
), O
respectively O
, O
occurred O
in O
the O
coding O
region O
of O
exon O
2 O
, O
again O
in O
both O
patients O
and O
normal O
controls O
. O

In O
conclusion O
, O
the O
majority O
of O
the O
detected O
sequence O
alterations O
were O
polymorphisms O
without O
obvious O
functional O
relevance O
. O

However O
, O
it O
cannot O
be O
excluded O
that O
the O
2 O
unique O
DNA O
sequence O
alterations O
could O
have O
affected O
FOXF2 O
on O
the O
mRNA O
or O
protein O
level O
thus O
contributing O
to O
the O
observed O
disturbances O
in O
genital O
and O
palate O
development O
. O


A O
novel O
mutation O
screening O
system O
for O
Ehlers B
- I
Danlos I
Syndrome I
, O
vascular O
type O
by O
high O
- O
resolution O
melting O
curve O
analysis O
in O
combination O
with O
small O
amplicon O
genotyping O
using O
genomic O
DNA O
. O

Ehlers B
- I
Danlos I
syndrome I
, O
vascular O
type O
( O
vEDS B
) O
( O
MIM B
# O
130050 O
) O
is O
an O
autosomal B
dominant I
disorder I
caused O
by O
type O
III O
procollagen O
gene O
( O
COL3A1 O
) O
mutations O
. O

Most O
COL3A1 O
mutations O
are O
detected O
by O
using O
total O
RNA O
from O
patient O
- O
derived O
fibroblasts O
, O
which O
requires O
an O
invasive O
skin O
biopsy O
. O

High O
- O
resolution O
melting O
curve O
analysis O
( O
hrMCA O
) O
has O
recently O
been O
developed O
as O
a O
post O
- O
PCR O
mutation O
scanning O
method O
which O
enables O
simple O
, O
rapid O
, O
cost O
- O
effective O
, O
and O
highly O
sensitive O
mutation O
screening O
of O
large O
genes O
. O

We O
established O
a O
hrMCA O
method O
to O
screen O
for O
COL3A1 O
mutations O
using O
genomic O
DNA O
. O

PCR O
primers O
pairs O
for O
COL3A1 O
( O
52 O
amplicons O
) O
were O
designed O
to O
cover O
all O
coding O
regions O
of O
the O
52 O
exons O
, O
including O
the O
splicing O
sites O
. O

We O
used O
15 O
DNA O
samples O
( O
8 O
validation O
samples O
and O
7 O
samples O
of O
clinically O
suspected O
vEDS B
patients O
) O
in O
this O
study O
. O

The O
eight O
known O
COL3A1 O
mutations O
in O
validation O
samples O
were O
all O
successfully O
detected O
by O
the O
hrMCA O
. O

In O
addition O
, O
we O
identified O
five O
novel O
COL3A1 O
mutations O
, O
including O
one O
deletion O
( O
c O
. O
2187delA O
) O
and O
one O
nonsense O
mutation O
( O
c O
. O
2992C O
> O
T O
) O
that O
could O
not O
be O
determined O
by O
the O
conventional O
total O
RNA O
method O
. O

Furthermore O
, O
we O
established O
a O
small O
amplicon O
genotyping O
( O
SAG O
) O
method O
for O
detecting O
three O
high O
frequency O
coding O
- O
region O
SNPs O
( O
rs1800255 O
: O
G O
> O
A O
, O
rs1801184 O
: O
T O
> O
C O
, O
and O
rs2271683 O
: O
A O
> O
G O
) O
in O
COL3A1 O
to O
differentiate O
mutations O
before O
sequencing O
. O

The O
use O
of O
hrMCA O
in O
combination O
with O
SAG O
from O
genomic O
DNA O
enables O
rapid O
detection O
of O
COL3A1 O
mutations O
with O
high O
efficiency O
and O
specificity O
. O

A O
better O
understanding O
of O
the O
genotype O
- O
phenotype O
correlation O
in O
COL3A1 O
using O
this O
method O
will O
lead O
to O
improve O
in O
diagnosis O
and O
treatment O
. O


Critical O
role O
of O
neuronal O
pentraxin O
1 O
in O
mitochondria O
- O
mediated O
hypoxic B
- I
ischemic I
neuronal I
injury I
. O

Developing O
brain O
is O
highly O
susceptible O
to O
hypoxic B
- I
ischemic I
( O
HI B
) I
injury I
leading O
to O
severe O
neurological B
disabilities I
in O
surviving O
infants O
and O
children O
. O

Previously O
, O
we O
have O
reported O
induction O
of O
neuronal O
pentraxin O
1 O
( O
NP1 O
), O
a O
novel O
neuronal O
protein O
of O
long O
- O
pentraxin O
family O
, O
following O
HI B
neuronal I
injury I
. O

Here O
, O
we O
investigated O
how O
this O
specific O
signal O
is O
propagated O
to O
cause O
the O
HI B
neuronal B
death I
. O

We O
used O
wild O
- O
type O
( O
WT O
) O
and O
NP1 O
knockout O
( O
NP1 O
- O
KO O
) O
mouse O
hippocampal O
cultures O
, O
modeled O
in O
vitro O
following O
exposure O
to O
oxygen B
glucose I
deprivation O
( O
OGD B
), O
and O
in O
vivo O
neonatal O
( O
P9 O
- O
10 O
) O
mouse O
model O
of O
HI B
brain I
injury I
. O

Our O
results O
show O
induction O
of O
NP1 O
in O
primary O
hippocampal O
neurons O
following O
OGD B
exposure O
( O
4 O
- O
8 O
h O
) O
and O
in O
the O
ipsilateral O
hippocampal O
CA1 O
and O
CA3 O
regions O
at O
24 O
- O
48 O
h O
post O
- O
HI B
compared O
to O
the O
contralateral O
side O
. O

We O
also O
found O
increased O
PTEN O
activity O
concurrent O
with O
OGD O
time O
- O
dependent O
( O
4 O
- O
8 O
h O
) O
dephosphorylation O
of O
Akt O
( O
Ser473 O
) O
and O
GSK O
- O
3b O
( O
Ser9 O
). O

OGD O
also O
caused O
a O
time O
- O
dependent O
decrease O
in O
the O
phosphorylation O
of O
Bad O
( O
Ser136 O
), O
and O
Bax O
protein O
levels O
. O

Immunofluorescence O
staining O
and O
subcellular O
fractionation O
analyses O
revealed O
increased O
mitochondrial O
translocation O
of O
Bad O
and O
Bax O
proteins O
from O
cytoplasm O
following O
OGD B
( O
4 O
h O
) O
and O
simultaneously O
increased O
release O
of O
Cyt B
C I
from O
mitochondria O
followed O
by O
activation O
of O
caspase O
- O
3 O
. O

NP1 O
protein O
was O
immunoprecipitated O
with O
Bad O
and O
Bax O
proteins O
; O
OGD O
caused O
increased O
interactions O
of O
NP1 O
with O
Bad O
and O
Bax O
, O
thereby O
, O
facilitating O
their O
mitochondrial O
translocation O
and O
dissipation O
of O
mitochondrial O
membrane O
potential O
( O
D O
( O
m O
)). O

This O
NP1 B
induction O
preceded O
the O
increased O
mitochondrial O
release O
of O
cytochrome B
C I
( O
Cyt B
C I
) O
into O
the O
cytosol O
, O
activation O
of O
caspase O
- O
3 O
and O
OGD O
time O
- O
dependent O
cell O
death O
in O
WT O
primary O
hippocampal O
neurons O
. O

In O
contrast O
, O
in O
NP1 O
- O
KO O
neurons O
there O
was O
no O
translocation O
of O
Bad O
and O
Bax O
from O
cytosol O
to O
the O
mitochondria O
, O
and O
no O
evidence O
of O
D O
( O
m O
) O
loss O
, O
increased O
Cyt B
C I
release O
and O
caspase O
- O
3 O
activation O
following O
OGD B
; O
which O
resulted O
in O
significantly O
reduced O
neuronal B
death I
. O

Our O
results O
indicate O
a O
regulatory O
role O
of O
NP1 O
in O
Bad O
/ O
Bax O
- O
dependent O
mitochondrial O
release O
of O
Cyt B
C I
and O
caspase O
- O
3 O
activation O
. O

Together O
our O
findings O
demonstrate O
a O
novel O
mechanism O
by O
which O
NP1 O
regulates O
mitochondria O
- O
driven O
hippocampal O
cell O
death O
; O
suggesting O
NP1 O
as O
a O
potential O
therapeutic O
target O
against O
HI B
brain I
injury I
in O
neonates O
. O


Neuroprotective O
effect O
of O
neuroserpin B
in O
oxygen B
- O
glucose B
deprivation O
- O
and O
reoxygenation O
- O
treated O
rat O
astrocytes O
in O
vitro O
. O

Neuroserpin B
( O
NSP B
) O
reportedly O
exerts O
neuroprotective O
effects O
in O
cerebral B
ischemic I
animal O
models O
and O
patients O
; O
however O
, O
the O
mechanism O
of O
protection O
is O
poorly O
understood O
. O

We O
thus O
attempted O
to O
confirm O
neuroprotective O
effects O
of O
NSP B
on O
astrocytes O
in O
the O
ischemic B
state O
and O
then O
explored O
the O
relative O
mechanisms O
. O

Astrocytes O
from O
neonatal O
rats O
were O
treated O
with O
oxygen B
- O
glucose B
deprivation O
( O
OGD B
) O
followed O
by O
reoxygenation O
( O
OGD B
/ O
R O
). O

To O
confirm O
the O
neuroprotective O
effects O
of O
NSP B
, O
we O
measured O
the O
cell O
survival O
rate O
, O
relative O
lactate O
dehydrogenase O
( O
LDH O
) O
release O
; O
we O
also O
performed O
morphological O
methods O
, O
namely O
Hoechst O
33342 O
staining O
and O
Annexin O
V O
assay O
. O

To O
explore O
the O
potential O
mechanisms O
of O
NSP B
, O
the O
release O
of O
nitric B
oxide I
( O
NO B
) O
and O
TNF O
- O
alpha O
related O
to O
NSP B
administration O
were O
measured O
by O
enzyme O
- O
linked O
immunosorbent O
assay O
. O

The O
proteins O
related O
to O
the O
NF O
- O
kappaB O
, O
ERK1 O
/ O
2 O
, O
and O
PI3K O
/ O
Akt O
pathways O
were O
investigated O
by O
Western O
blotting O
. O

To O
verify O
the O
cause O
- O
and O
- O
effect O
relationship O
between O
neuroprotection O
and O
the O
NF O
- O
kappaB O
pathway O
, O
a O
NF O
- O
kappaB O
pathway O
inhibitor O
sc3060 B
was O
employed O
to O
observe O
the O
effects O
of O
NSP B
- O
induced O
neuroprotection O
. O

We O
found O
that O
NSP B
significantly O
increased O
the O
cell O
survival O
rate O
and O
reduced O
LDH O
release O
in O
OGD B
/ O
R O
- O
treated O
astrocytes O
. O

It O
also O
reduced O
NO O
/ O
TNF O
- O
alpha O
release O
. O

Western O
blotting O
showed O
that O
the O
protein O
levels O
of O
p O
- O
IKKBalpha O
/ O
beta O
and O
P65 O
were O
upregulated O
by O
the O
OGD B
/ O
R O
treatment O
and O
such O
effects O
were O
significantly O
inhibited O
by O
NSP B
administration O
. O

The O
NSP B
- O
induced O
inhibition O
could O
be O
significantly O
reversed O
by O
administration O
of O
the O
NF O
- O
kappaB O
pathway O
inhibitor O
sc3060 B
, O
whereas O
, O
expressions O
of O
p O
- O
ERK1 O
, O
p O
- O
ERK2 O
, O
and O
p O
- O
AKT O
were O
upregulated O
by O
the O
OGD B
/ O
R O
treatment O
; O
however O
, O
their O
levels O
were O
unchanged O
by O
NSP B
administration O
. O

Our O
results O
thus O
verified O
the O
neuroprotective O
effects O
of O
NSP B
in O
ischemic B
astrocytes O
. O

The O
potential O
mechanisms O
include O
inhibition O
of O
the O
release O
of O
NO O
/ O
TNF O
- O
alpha O
and O
repression O
of O
the O
NF O
- O
kappaB O
signaling O
pathways O
. O

Our O
data O
also O
indicated O
that O
NSP O
has O
little O
influence O
on O
the O
MAPK O
and O
PI3K O
/ O
Akt O
pathways O
. O


Interleukin O
6 O
( O
IL O
- O
6 O
) O
and O
Tumor O
Necrosis O
Factor O
alpha O
( O
TNF O
- O
alpha O
) O
Single O
Nucleotide O
Polymorphisms O
( O
SNPs O
), O
Inflammation B
and O
Metabolism O
in O
Gestational B
Diabetes I
Mellitus I
in O
Inner O
Mongolia O
. O

BACKGROUND O
Gestational B
diabetes I
mellitus I
( O
GDM B
) O
is O
common O
all O
over O
the O
world O
. O

GDM B
women O
are O
with O
inflammatory B
and O
metabolisms O
abnormalities I
. O

However O
, O
few O
studies O
have O
focused O
on O
the O
association O
of O
IL O
- O
65 O
- O
72C O
/ O
G O
and O
TNF O
- O
alpha O
- O
857C O
/ O
T O
single O
nucleotide O
polymorphisms O
( O
SNPs O
), O
inflammatory B
biomarkers O
, O
and O
metabolic O
indexes O
in O
women O
with O
GDM B
, O
especially O
in O
the O
Inner O
Mongolia O
population O
. O

The O
aim O
of O
this O
study O
was O
to O
investigate O
the O
associations O
of O
IL O
- O
65 O
- O
72C O
/ O
G O
and O
TNF O
- O
alpha O
- O
857C O
/ O
T O
SNPs O
, O
and O
inflammation B
and O
metabolic O
biomarkers O
in O
women O
with O
GDM B
pregnancies O
. O

MATERIAL O
AND O
METHODS O
Blood O
samples O
and O
placentas O
from O
140 O
women O
with O
GDM B
and O
140 O
women O
with O
healthy O
pregnancies O
were O
collected O
. O

Matrix O
- O
assisted O
laser O
desorption O
ionization O
time O
of O
flight O
mass O
spectrometry O
( O
MALDI O
- O
TOF O
- O
MS O
) O
and O
MassARRAY O
- O
IPLEX O
were O
performed O
to O
analyze O
IL O
- O
65 O
- O
72C O
/ O
G O
and O
TNF O
- O
alpha O
- O
857C O
/ O
T O
SNPs O
. O

Enzyme O
linked O
immunosorbent O
assay O
( O
ELISA O
) O
was O
performed O
to O
analyze O
inflammatory B
biomarkers O
and O
adipokines O
. O

RESULTS O
Distribution O
frequency O
of O
TNF O
- O
alpha O
- O
857CT O
( O
OR O
= O
3 O
. O
316 O
, O
95 O
% O
CI O
= O
1 O
. O
92 O
- O
8 O
. O
304 O
, O
p O
= O
0 O
. O
25 O
) O
in O
women O
with O
GDM B
pregnancies O
were O
obviously O
higher O
than O
that O
in O
women O
with O
healthy O
pregnancies O
. O

Women O
with O
GDM B
were O
of O
older O
maternal O
age O
, O
had O
higher O
BMI O
, O
were O
more O
nulliparous O
, O
and O
had O
T2DM B
and O
GDM B
history O
, O
compared O
to O
women O
with O
healthy O
pregnancies O
( O
p O
< O
0 O
. O
5 O
). O

Inflammatory B
biomarkers O
in O
serum O
( O
hs O
- O
CRP O
, O
IL O
- O
6 O
, O
IL O
- O
8 O
, O
IL O
- O
6 O
/ O
IL O
- O
10 O
ratio O
) O
and O
placental O
( O
NF O
- O
kappaB O
, O
IL O
- O
6 O
, O
IL O
- O
8 O
, O
IL O
- O
6 O
/ O
IL O
- O
10 O
ratio O
, O
IL O
- O
1b O
, O
TNF O
- O
alpha O
) O
were O
significantly O
different O
( O
p O
< O
0 O
. O
5 O
) O
between O
women O
with O
GDM B
and O
women O
with O
healthy O
pregnancies O
. O

Differences O
were O
found O
for O
serum O
FBG O
, O
FINS O
, O
HOMA O
- O
IR O
, O
and O
HOMA O
- O
beta O
, O
and O
placental O
IRS O
- O
1 O
, O
IRS O
- O
2 O
, O
leptin O
, O
adiponectin O
, O
visfatin O
, O
RBP O
- O
4 O
, O
chemerin O
, O
nesfatin O
- O
1 O
, O
FATP O
- O
4 O
, O
EL O
, O
LPL O
, O
FABP O
- O
1 O
, O
FABP O
- O
3 O
, O
FABP O
- O
4 O
, O
and O
FABP O
- O
5 O
. O

CONCLUSIONS O
TNF O
- O
alpha O
- O
857C O
/ O
T O
SNP O
, O
hs O
- O
CRP O
, O
IL O
- O
6 O
, O
IL O
- O
8 O
, O
and O
IL O
- O
6 O
/ O
IL O
- O
10 O
were O
associated O
with O
GDM B
in O
women O
from O
Inner O
Mongolia O
, O
as O
was O
serious O
inflammation B
and O
disordered O
lipid B
and O
glucose B
metabolisms O
. O


Fine O
mapping O
and O
identification O
of O
a O
candidate O
gene O
SSH1 O
in O
disseminated O
superficial B
actinic I
porokeratosis I
. O

Disseminated B
superficial I
actinic I
porokeratosis I
( O
DSAP B
) O
is O
an O
uncommon O
autosomal B
dominant I
chronic I
keratinization I
disorder I
, O
characterized O
by O
multiple O
superficial O
keratotic B
lesions I
surrounded O
by O
a O
slightly O
raised O
keratotic O
border O
. O

Thus O
far O
, O
although O
two O
loci O
for O
DSAP B
have O
been O
identified O
, O
the O
genetic O
basis O
and O
pathogenesis O
of O
this O
disorder O
have O
not O
been O
elucidated O
yet O
. O

In O
this O
study O
, O
we O
performed O
a O
genome O
- O
wide O
linkage O
analysis O
in O
three O
Chinese O
affected O
families O
and O
localized O
the O
gene O
in O
an O
8 O
. O
0 O
cM O
interval O
defined O
by O
D12S330 O
and O
D12S354 O
on O
chromosome O
12 O
. O

Upon O
screening O
30 O
candidate O
genes O
, O
we O
identified O
a O
missense O
mutation O
, O
p O
. O
Ser63Asn O
in O
SSH1 O
in O
one O
family O
, O
a O
frameshift O
mutation O
, O
p O
. O
Ser19CysfsX24 O
in O
an O
alternative O
variant O
( O
isoform O
f O
) O
of O
SSH1 O
in O
another O
family O
, O
and O
a O
frameshift O
mutation O
, O
p O
. O
Pro27ProfsX54 O
in O
the O
same O
alternative O
variant O
in O
one O
non O
- O
familial O
case O
with O
DSAP B
. O

SSH1 O
encodes O
a O
phosphatase O
that O
plays O
a O
pivotal O
role O
in O
actin O
dynamics O
. O

Our O
data O
suggested O
that O
cytoskeleton O
disorganization O
in O
epidermal O
cells O
is O
likely O
associated O
with O
the O
pathogenesis O
of O
DSAP B
. O


Array O
- O
based O
comparative O
genomic O
hybridization O
analysis O
reveals O
recurrent O
chromosomal O
alterations O
and O
prognostic O
parameters O
in O
primary O
cutaneous B
large I
B I
- I
cell I
lymphoma I
. O

PURPOSE O
: O
To O
evaluate O
the O
clinical O
relevance O
of O
genomic O
aberrations O
in O
primary B
cutaneous I
large I
B I
- I
cell I
lymphoma I
( O
PCLBCL B
). O

PATIENTS O
AND O
METHODS O
: O
Skin O
biopsy O
samples O
of O
31 O
patients O
with O
a O
PCLBCL B
classified O
as O
either O
primary B
cutaneous I
follicle I
center I
lymphoma I
( O
PCFCL B
; O
n O
= O
19 O
) O
or O
PCLBCL B
, O
leg O
type O
( O
n O
= O
12 O
), O
according O
to O
the O
WHO O
- O
European O
Organisation O
for O
Research O
and O
Treatment O
of O
Cancer B
( O
EORTC O
) O
classification O
, O
were O
investigated O
using O
array O
- O
based O
comparative O
genomic O
hybridization O
, O
fluorescence O
in O
situ O
hybridization O
( O
FISH O
), O
and O
examination O
of O
promoter O
hypermethylation O
. O

RESULTS O
: O
The O
most O
recurrent O
alterations O
in O
PCFCL O
were O
high O
- O
level O
DNA O
amplifications O
at O
2p16 O
. O
1 O
( O
63 O
%) O
and O
deletion O
of O
chromosome O
14q32 O
. O
33 O
( O
68 O
%). O

FISH O
analysis O
confirmed O
c O
- O
REL O
amplification O
in O
patients O
with O
gains O
at O
2p16 O
. O
1 O
. O

In O
PCLBCL O
, O
leg O
type O
, O
most O
prominent O
aberrations O
were O
a O
high O
- O
level O
DNA O
amplification O
of O
18q21 O
. O
31 O
- O
q21 O
. O
33 O
( O
67 O
%), O
including O
the O
BCL O
- O
2 O
and O
MALT1 O
genes O
as O
confirmed O
by O
FISH O
, O
and O
deletions O
of O
a O
small O
region O
within O
9p21 O
. O
3 O
containing O
the O
CDKN2A O
, O
CDKN2B O
, O
and O
NSG O
- O
x O
genes O
. O

Homozygous O
deletion O
of O
9p21 O
. O
3 O
was O
detected O
in O
five O
of O
12 O
patients O
with O
PCLBCL B
, O
leg O
type O
, O
but O
in O
zero O
of O
19 O
patients O
with O
PCFCL B
. O

Complete O
methylation O
of O
the O
promoter O
region O
of O
the O
CDKN2A O
gene O
was O
demonstrated O
in O
one O
PCLBCL B
, O
leg B
type O
, O
patient O
with O
hemizygous O
deletion O
, O
in O
one O
patient O
without O
deletion O
, O
but O
in O
zero O
of O
19 O
patients O
with O
PCFCL B
. O

Seven O
of O
seven O
PCLBCL B
, O
leg O
type O
, O
patients O
with O
deletion O
of O
9p21 O
. O
3 O
and O
/ O
or O
complete O
methylation O
of O
CDKN2A O
died O
as O
a O
result O
of O
their O
lymphoma B
. O

CONCLUSION O
: O
Our O
results O
demonstrate O
prominent O
differences O
in O
chromosomal O
alterations O
between O
PCFCL B
and O
PCLBCL O
, O
leg B
type O
, O
that O
support O
their O
classification O
as O
separate O
entities O
within O
the O
WHO O
- O
EORTC O
scheme O
. O

Inactivation O
of O
CDKN2A O
by O
either O
deletion O
or O
methylation O
of O
its O
promoter O
could O
be O
an O
important O
prognostic O
parameter O
for O
the O
group O
of O
PCLBCL B
, O
leg B
type O
. O


Osteogenesis B
imperfecta I
type I
III I
with O
intracranial B
hemorrhage I
and O
brachydactyly O
associated O
with O
mutations O
in O
exon O
49 O
of O
COL1A2 O
. O

Osteogenesis B
imperfecta I
( O
OI B
) O
is O
a O
heritable O
bone B
disorder I
characterized O
by O
fractures B
with O
minimal O
trauma B
. O

Intracranial B
hemorrhage I
has O
been O
reported O
in O
a O
small O
number O
of O
OI B
patients O
. O

Here O
we O
describe O
three O
patients O
, O
a O
boy O
( O
aged O
15 O
years O
) O
and O
two O
girls O
( O
aged O
17 O
and O
7 O
years O
) O
with O
OI B
type I
III I
who O
suffered O
intracranial B
hemorrhage I
and O
in O
addition O
had O
brachydactyly O
and O
nail B
hypoplasia I
. O

In O
all O
of O
these O
patients O
, O
OI B
was O
caused O
by O
glycine O
mutations O
affecting O
exon O
49 O
of O
the O
COL1A2 O
gene O
, O
which O
codes O
for O
the O
most O
carboxy O
- O
terminal O
part O
of O
the O
triple O
- O
helical O
domain O
of O
the O
collagen O
type O
I O
alpha O
2 O
chain O
. O

These O
observations O
suggest O
that O
mutations O
in O
this O
region O
of O
the O
collagen O
type O
I O
alpha O
2 O
chain O
carry O
a O
high O
risk O
of O
abnormal B
limb I
development I
and O
intracranial B
bleeding I
. O


Bilateral O
haemorrhagic B
infarction I
of I
the O
globus I
pallidus I
after O
cocaine B
and O
alcohol B
intoxication O
. O

Cocaine B
is O
a O
risk O
factor O
for O
both O
ischemic B
and I
haemorrhagic B
stroke I
. O

We O
present O
the O
case O
of O
a O
31 O
- O
year O
- O
old O
man O
with O
bilateral O
ischemia B
of I
the I
globus I
pallidus I
after O
excessive O
alcohol B
and O
intranasal O
cocaine B
use O
. O

Drug O
- O
related O
globus B
pallidus I
infarctions B
are O
most O
often O
associated O
with O
heroin B
. O

Bilateral O
basal B
ganglia I
infarcts I
after O
the O
use O
of O
cocaine B
, O
without O
concurrent O
heroin B
use O
, O
have O
never O
been O
reported O
. O

In O
our O
patient O
, O
transient O
cardiac B
arrhythmia I
or O
respiratory B
dysfunction I
related O
to O
cocaine B
and O
/ O
or O
ethanol B
use O
were O
the O
most O
likely O
causes O
of O
cerebral B
hypoperfusion I
. O


The O
fibrinogen O
gamma O
10034C O
> O
T O
polymorphism O
is O
not O
associated O
with O
Peripheral B
Arterial I
Disease I
. O

Conversion O
of O
fibrinogen O
to O
fibrin O
plays O
an O
essential O
role O
in O
hemostasis O
and O
results O
in O
stabilization O
of O
the O
fibrin O
clot O
. O

Fibrinogen O
consists O
of O
three O
pairs O
of O
non O
- O
identical O
polypeptide O
chains O
, O
encoded O
by O
different O
genes O
( O
fibrinogen O
alpha O
[ O
FGA O
], O
fibrinogen O
beta O
[ O
FGB O
] O
and O
fibrinogen O
gamma O
[ O
FGG O
]). O

A O
functional O
single O
nucleotide O
polymorphism O
( O
SNP O
) O
in O
the O
3 O
' O
untranslated O
region O
of O
the O
FGG O
gene O
( O
FGG O
10034C O
> O
T O
, O
rs2066865 O
) O
has O
been O
associated O
with O
deep O
venous B
thrombosis I
and O
myocardial B
infarction I
. O

Aim O
of O
the O
present O
study O
was O
to O
analyze O
the O
role O
of O
this O
polymorphism O
in O
peripheral B
arterial I
disease I
( O
PAD B
). O

The O
study O
was O
designed O
as O
case O
- O
control O
study O
including O
891 O
patients O
with O
documented O
PAD B
and O
777 O
control O
subjects O
. O

FGG O
genotypes O
were O
determined O
by O
exonuclease O
( O
TaqMan O
) O
assays O
. O

FGG O
genotype O
frequencies O
were O
not O
significantly O
different O
between O
PAD B
patients O
( O
CC B
: O
57 O
. O
3 O
%, O
CT O
: O
36 O
. O
7 O
%, O
TT O
: O
5 O
. O
8 O
%) O
and O
control O
subjects O
( O
CC B
: O
60 O
. O
9 O
%, O
CT O
: O
33 O
. O
5 O
%, O
TT O
5 O
. O
6 O
%; O
p O
= O
0 O
. O
35 O
). O

In O
a O
multivariate O
logistic O
regression O
analysis O
including O
age O
, O
sex O
, O
smoking O
, O
diabetes B
, O
arterial O
hypertension B
and O
hypercholesterolemia B
, O
the O
FGG O
10034 O
T O
variant O
was O
not O
significantly O
associated O
with O
the O
presence O
of O
PAD B
( O
Odds O
ratio O
1 O
. O
7 O
, O
95 O
% O
confidence O
interval O
0 O
. O
84 O
- O
1 O
. O
37 O
; O
p O
= O
0 O
. O
60 O
). O

The O
FGG O
10034C O
> O
T O
polymorphism O
was O
furthermore O
not O
associated O
with O
age O
at O
onset O
of O
PAD B
. O

We O
conclude O
that O
the O
thrombophilic O
FGG O
10034 O
T O
gene O
variant O
does O
not O
contribute O
to O
the O
genetic O
susceptibility O
to O
PAD B
. O


Genotype O
rs8099917 O
near O
the O
IL28B O
gene O
and O
amino O
acid O
substitution O
at O
position O
70 O
in O
the O
core O
region O
of O
the O
hepatitis O
C O
virus O
are O
determinants O
of O
serum O
apolipoprotein O
B O
- O
100 O
concentration O
in O
chronic O
hepatitis B
C I
. O

The O
life O
cycle O
of O
the O
hepatitis O
C O
virus O
( O
HCV O
) O
is O
closely O
related O
to O
host O
lipoprotein B
metabolism O
. O

Serum O
levels O
of O
lipid B
are O
associated O
with O
the O
response O
to O
pegylated B
interferon I
plus O
ribavirin B
( O
PEG B
- I
IFN I
/ O
RBV B
) O
therapy O
, O
while O
single O
nucleotide O
polymorphisms O
( O
SNPs O
) O
around O
the O
human O
interleukin O
28B O
( O
IL28B O
) O
gene O
locus O
and O
amino O
acid O
substitutions O
in O
the O
core O
region O
of O
the O
HCV O
have O
been O
reported O
to O
affect O
the O
efficacy O
of O
PEG O
- I
IFN I
/ O
RBV B
therapy O
in O
chronic B
hepatitis I
with I
HCV B
genotype I
1b I
infection I
. O

The O
aim O
of O
this O
study O
was O
to O
elucidate O
the O
relationship O
between O
serum O
lipid B
and O
factors O
that O
are O
able O
to O
predict O
the O
efficacy O
of O
PEG O
- I
IFN I
/ O
RB B
therapy O
, O
with O
specific O
focus O
on O
apolipoprotein O
B O
- O
100 O
( O
apoB O
- O
100 O
) O
in O
148 O
subjects O
with O
chronic B
HCV I
G1b I
infection I
. O

Our O
results O
demonstrated O
that O
both O
the O
aa O
70 O
substitution O
in O
the O
core O
region O
of O
the O
HCV O
and O
the O
rs8099917 O
SNP O
located O
proximal O
to O
the O
IL28B O
were O
independent O
factors O
in O
determining O
serum O
apoB O
- O
100 O
and O
low B
- I
density I
lipoprotein I
( I
LDL B
) I
cholesterol I
levels O
. O

A O
significant O
association O
was O
noted O
between O
higher O
levels O
of O
apoB O
- O
100 O
( O
P O
= O
1 O
. O
1 O
10 O
(- O
3 O
)) O
and O
LDL O
cholesterol B
( O
P O
= O
0 O
. O
2 O
) O
and O
the O
subjects O
having O
Arg70 O
. O

A O
significant O
association O
was O
also O
observed O
between O
subjects O
carrying O
the O
rs8099917 O
TT O
responder O
genotype O
and O
higher O
levels O
of O
apoB O
- O
100 O
( O
P O
= O
6 O
. O
4 O
10 O
(- O
3 O
)) O
and O
LDL O
cholesterol B
( O
P O
= O
4 O
. O
2 O
10 O
(- O
3 O
)). O

Our O
results O
suggest O
that O
apoB O
- O
100 O
and O
LDL O
cholesterol B
are O
markers O
of O
impaired O
cellular O
lipoprotein O
pathways O
and O
/ O
or O
host O
endogenous O
interferon O
response O
to O
HCV O
in O
chronic O
HCV B
infection I
. O

In O
particular O
, O
serum O
apoB O
- O
100 O
concentration O
might O
be O
an O
informative O
marker O
for O
judging O
changes O
in O
HCV O
- O
associated O
intracellular O
lipoprotein O
metabolism O
in O
patients O
carrying O
the O
rs8099917 O
responder O
genotype O
. O


Phosphatidylinositol O
4 O
- O
kinase O
IIb O
negatively O
regulates O
invadopodia O
formation O
and O
suppresses O
an O
invasive O
cellular O
phenotype O
. O

The O
type O
II O
phosphatidylinositol O
4 O
- O
kinase O
( O
PI4KII O
) O
enzymes O
synthesize O
the O
lipid B
phosphatidylinositol I
4 I
- I
phosphate I
( O
PI B
( I
4 I
) I
P I
), O
which O
has O
been O
detected O
at O
the O
Golgi O
complex O
and O
endosomal O
compartments O
and O
recruits O
clathrin B
adaptors O
. O

Despite O
common O
mechanistic O
similarities O
between O
the O
isoforms O
, O
the O
extent O
of O
their O
redundancy O
is O
unclear O
. O

We O
found O
that O
depletion O
of O
PI4KIIa O
and O
PI4KIIb O
using O
small O
interfering O
RNA O
led O
to O
actin O
remodeling O
. O

Depletion O
of O
PI4KIIb O
also O
induced O
the O
formation O
of O
invadopodia O
containing O
membrane O
type O
I O
matrix O
metalloproteinase O
( O
MT1 O
- O
MMP O
). O

Depletion O
of O
PI4KII O
isoforms O
also O
differentially O
affected O
trans O
- O
Golgi O
network O
( O
TGN O
) O
pools O
of O
PI O
( O
4 O
) O
P O
and O
post O
- O
TGN O
traffic O
. O

PI4KIIb B
depletion O
caused O
increased O
MT1 O
- O
MMP O
trafficking O
to O
invasive O
structures O
at O
the O
plasma O
membrane O
and O
was O
accompanied O
by O
reduced O
colocalization O
of O
MT1 O
- O
MMP O
with O
membranes O
containing O
the O
endosomal O
markers O
Rab5 O
and O
Rab7 O
but O
increased O
localization O
with O
the O
exocytic O
Rab8 O
. O

Depletion O
of O
PI4KIIb O
was O
sufficient O
to O
confer O
an O
aggressive O
invasive O
phenotype O
on O
minimally O
invasive O
HeLa B
and O
MCF O
- O
7 O
cell O
lines O
. O

Mining O
oncogenomic O
databases O
revealed O
that O
loss O
of O
the O
PI4K2B O
allele O
and O
underexpression O
of O
PI4KIIb O
mRNA O
are O
associated O
with O
human O
cancers B
. O

This O
finding O
supports O
the O
cell O
data O
and O
suggests O
that O
PI4KIIb O
may O
be O
a O
clinically O
significant O
suppressor O
of O
invasion O
. O

We O
propose O
that O
PI4KIIb O
synthesizes O
a O
pool O
of O
PI O
( O
4 O
) O
P O
that O
maintains O
MT1 O
- O
MMP O
traffic O
in O
the O
degradative O
pathway O
and O
suppresses O
the O
formation O
of O
invadopodia O
. O


CenpH O
regulates O
meiotic O
G2 O
/ O
M O
transition O
by O
modulating O
the O
APC O
/ O
CCdh1 O
- O
cyclin O
B1 O
pathway O
in O
oocytes O
. O

Meiotic O
resumption O
( O
G2 O
/ O
M O
transition O
) O
and O
progression O
through O
meiosis O
I O
( O
MI O
) O
are O
two O
key O
stages O
for O
producing O
fertilization O
- O
competent O
eggs O
. O

Here O
, O
we O
report O
that O
CenpH O
, O
a O
component O
of O
the O
kinetochore O
inner O
plate O
, O
is O
responsible O
for O
G2 O
/ O
M O
transition O
in O
meiotic O
mouse O
oocytes O
. O

Depletion O
of O
CenpH O
by O
morpholino O
injection O
decreased O
cyclin O
B1 O
levels O
, O
resulting O
in O
attenuation O
of O
maturation O
- O
promoting O
factor O
( O
MPF O
) O
activation O
, O
and O
severely O
compromised O
meiotic O
resumption O
. O

CenpH O
protects O
cyclin O
B1 O
from O
destruction O
by O
competing O
with O
the O
action O
of O
APC O
/ O
C O
( O
Cdh1 O
) O
Impaired O
G2 O
/ O
M O
transition O
after O
CenpH O
depletion O
could O
be O
rescued O
by O
expression O
of O
exogenous O
cyclin O
B1 O
. O

Unexpectedly O
, O
blocking O
CenpH O
did O
not O
affect O
spindle O
organization O
and O
meiotic O
cell O
cycle O
progression O
after O
germinal O
vesicle O
breakdown O
. O

Our O
findings O
reveal O
a O
novel O
role O
of O
CenpH O
in O
regulating O
meiotic O
G2 O
/ O
M O
transition O
by O
acting O
via O
the O
APC O
/ O
C O
( O
Cdh1 O
)- O
cyclin O
B1 O
pathway O
. O


CRYBA3 O
/ O
A1 O
gene O
mutation O
associated O
with O
suture O
- O
sparing O
autosomal O
dominant O
congenital O
nuclear I
cataract I
: O
a O
novel O
phenotype O
. O

PURPOSE O
: O
To O
identify O
the O
genetic O
defect O
leading O
to O
the O
congenital B
nuclear I
cataract I
affecting O
a O
large O
five O
- O
generation O
Swiss O
family O
. O

METHODS O
: O
Family O
history O
and O
clinical O
data O
were O
recorded O
. O

The O
phenotype O
was O
documented O
by O
both O
slit O
lamp O
and O
Scheimpflug O
photography O
. O

One O
cortical O
lens O
was O
evaluated O
by O
electron O
microscopy O
after O
cataract B
extraction O
. O

Lenticular O
phenotyping O
and O
genotyping O
were O
performed O
independently O
with O
short O
tandem O
repeat O
polymorphism O
. O

Linkage O
analysis O
was O
performed O
, O
and O
candidate O
genes O
were O
PCR O
amplified O
and O
screened O
for O
mutations O
on O
both O
strands O
using O
direct O
sequencing O
. O

RESULTS O
: O
Affected O
individuals O
had O
a O
congenital O
nuclear O
lactescent O
cataract B
in O
both O
eyes O
. O

Linkage O
was O
observed O
on O
chromosome O
17 O
for O
DNA O
marker O
D17S1857 O
( O
lod O
score O
: O
3 O
. O
44 O
at O
theta O
= O
0 O
). O

Direct O
sequencing O
of O
CRYBA3 O
/ O
A1 O
, O
which O
maps O
to O
the O
vicinity O
, O
revealed O
an O
in O
- O
frame O
3 O
- O
bp O
deletion O
in O
exon O
4 O
( O
279delGAG O
). O

This O
mutation O
involved O
a O
deletion O
of O
glycine O
- O
91 O
, O
cosegregated O
in O
all O
affected O
individuals O
, O
and O
was O
not O
observed O
in O
unaffected O
individuals O
or O
in O
250 O
normal O
control O
subjects O
from O
the O
same O
ethnic O
background O
. O

Electron O
microscopy O
showed O
that O
cortical O
lens O
fiber O
morphology O
was O
normal O
. O

CONCLUSIONS O
: O
The O
DeltaG91 O
mutation O
in O
CRYBA3 O
/ O
A1 O
is O
associated O
with O
an O
autosomal O
dominant O
congenital O
nuclear O
lactescent I
cataract B
. O

A O
splice O
mutation O
( O
IVS3 O
+ O
1G O
/ O
A O
) O
in O
this O
gene O
has O
been O
reported O
in O
a O
zonular B
cataract I
with O
sutural O
opacities I
. O

These O
results O
indicate O
phenotypic O
heterogeneity O
related O
to O
mutations O
in O
this O
gene O
. O


Vitamin O
D O
- O
binding O
protein O
gene O
polymorphism O
association O
with O
IA O
- O
2 O
autoantibodies O
in O
type B
1 I
diabetes I
. O

BACKGROUND O
: O
Vitamin O
D O
- O
binding O
protein O
( O
DBP O
) O
is O
the O
main O
systemic O
transporter O
of O
1 O
. O
25 O
( O
OH O
) O
2D3 O
and O
is O
essential O
for O
its O
cellular O
endocytosis O
. O

There O
are O
two O
known O
polymorphisms O
in O
exon O
11 O
of O
the O
DBP O
gene O
resulting O
in O
amino O
acid O
variants O
: O
GAT O
--> O
GAG O
substitution O
replaces O
aspartic O
acid O
by O
glutamic O
acid O
in O
codon O
416 O
; O
and O
ACG O
--> O
AAG O
substitution O
in O
codon O
420 O
leads O
to O
an O
exchange O
of O
threonine O
for O
lysine O
. O

These O
DBP O
variants O
lead O
to O
differences O
in O
the O
affinity O
for O
1 O
. O
25 O
( O
OH O
) O
2D3 O
. O

Correlations O
between O
DBP O
alleles O
and O
type B
1 I
diabetes I
have O
been O
described O
in O
different O
populations O
. O

Therefore O
, O
we O
investigated O
the O
polymorphism O
in O
codon O
416 O
of O
the O
DBP O
gene O
for O
an O
association O
with O
autoimmune B
markers O
of O
type B
1 I
diabetes I
. O

DESIGN O
AND O
METHODS O
: O
The O
present O
analysis O
was O
a O
case O
control O
study O
. O

110 O
patients O
, O
68 O
controls O
, O
and O
115 O
first O
- O
degree O
relatives O
were O
genotyped O
for O
the O
DBP O
polymorphism O
in O
codon O
416 O
. O

DNA O
typing O
of O
DBP O
locus O
was O
performed O
by O
the O
PCR O
- O
restriction O
fragment O
length O
polymorphism O
method O
( O
RFLP O
). O

RESULTS O
: O
The O
frequencies O
of O
the O
Asp O
/ O
Glu O
and O
Glu O
/ O
Glu O
were O
significantly O
increased O
in O
diabetic B
subjects O
with O
detectable O
IA O
- O
2 O
antibodies O
( O
P O
< O
0 O
. O
1 O
). O

On O
the O
contrary O
, O
the O
DBP O
Glu O
- O
containing O
genotype O
was O
not O
accompanied O
by O
differences O
in O
the O
prevalence O
of O
GAD65 O
antibodies O
. O

These O
finding O
supports O
a O
role O
of O
the O
vitamin B
D I
endocrine O
system O
in O
the O
autoimmune O
process O
of O
type B
1 I
diabetes I
. O


Characterization O
of O
Bietti B
crystalline I
dystrophy I
patients O
with O
CYP4V2 O
mutations O
. O

PURPOSE O
: O
Mutations O
of O
the O
CYP4V2 O
gene O
, O
a O
novel O
family O
member O
of O
the O
cytochrome O
P450 O
genes O
on O
chromosome O
4q35 O
, O
have O
recently O
been O
identified O
in O
patients O
with O
Bietti B
crystalline I
dystrophy I
( O
BCD B
). O

The O
aim O
of O
this O
study O
was O
to O
investigate O
the O
spectrum O
of O
mutations O
in O
this O
gene O
in O
BCD B
patients O
from O
Singapore O
, O
and O
to O
characterize O
their O
phenotype O
. O

METHODS O
: O
Nine O
patients O
with O
BCD B
from O
six O
families O
were O
recruited O
into O
the O
study O
. O

The O
11 O
exons O
of O
the O
CYP4V2 O
gene O
were O
amplified O
from O
genomic O
DNA O
of O
patients O
by O
polymerase O
chain O
reaction O
and O
then O
sequenced O
. O

Detailed O
characterization O
of O
the O
patients O
' O
phenotype O
was O
performed O
with O
fundal O
photography O
, O
visual O
field O
testing O
, O
fundal O
fluorescein B
angiography O
, O
and O
electroretinography O
( O
ERG O
). O

RESULTS O
: O
Three O
pathogenic O
mutations O
were O
identified O
; O
two O
mutations O
, O
S482X O
and O
K386T O
, O
were O
novel O
and O
found O
in O
three O
patients O
. O

The O
third O
mutation O
, O
a O
previously O
identified O
15 O
- O
bp O
deletion O
that O
included O
the O
3 O
' O
splice O
site O
for O
exon O
7 O
, O
was O
found O
in O
all O
nine O
patients O
, O
with O
six O
patients O
carrying O
the O
deletion O
in O
the O
homozygous O
state O
. O

Haplotype O
analysis O
in O
patients O
and O
controls O
indicated O
a O
founder O
effect O
for O
this O
deletion O
mutation O
in O
exon O
7 O
. O

Clinical O
heterogeneity O
was O
present O
in O
the O
patients O
. O

Compound O
heterozygotes O
for O
the O
deletion O
in O
exon O
7 O
seemed O
to O
have O
more O
severe O
disease O
compared O
to O
patients O
homozygous O
for O
the O
deletion O
. O

There O
was O
good O
correlation O
between O
clinical O
stage O
of O
disease O
and O
ERG O
changes O
, O
but O
age O
did O
not O
correlate O
with O
disease O
severity O
. O

CONCLUSIONS O
: O
This O
study O
identified O
novel O
mutations O
in O
the O
CYP4V2 O
gene O
as O
a O
cause O
of O
BCD B
. O

A O
high O
carrier O
frequency O
for O
the O
15 O
- O
bp O
deletion O
in O
exon O
7 O
may O
exist O
in O
the O
Singapore O
population O
. O

Phenotype O
characterization O
showed O
clinical O
heterogeneity O
, O
and O
age O
did O
not O
correlate O
with O
disease O
severity O
. O


An O
extremely O
rare O
case O
of O
delusional B
parasitosis B
in O
a O
chronic O
hepatitis B
C I
patient O
during O
pegylated B
interferon I
alpha I
- I
2b I
and O
ribavirin B
treatment O
. O

During O
treatment O
of O
chronic O
hepatitis B
C I
patients O
with O
interferon B
and O
ribavirin B
, O
a O
lot O
of O
side O
effects O
are O
described O
. O

Twenty O
- O
three O
percent O
to O
44 O
% O
of O
patients O
develop O
depression B
. O

A O
minority O
of O
patients O
evolve O
to O
psychosis B
. O

To O
the O
best O
of O
our O
knowledge O
, O
no O
cases O
of O
psychogenic B
parasitosis I
occurring O
during O
interferon B
therapy O
have O
been O
described O
in O
the O
literature O
. O

We O
present O
a O
49 O
- O
year O
- O
old O
woman O
who O
developed O
a O
delusional B
parasitosis I
during O
treatment O
with O
pegylated B
interferon I
alpha I
- I
2b I
weekly O
and O
ribavirin B
. O

She O
complained O
of O
seeing O
parasites O
and O
the O
larvae O
of O
fleas O
in O
her O
stools O
. O

This O
could O
not O
be O
confirmed O
by O
any O
technical O
examination O
. O

All O
the O
complaints O
disappeared O
after O
stopping O
pegylated B
interferon I
alpha I
- I
2b I
and O
reappeared O
after O
restarting O
it O
. O

She O
had O
a O
complete O
sustained O
viral O
response O
. O


Protein O
- O
Trap O
Insertional O
Mutagenesis O
Uncovers O
New O
Genes O
Involved O
in O
Zebrafish O
Skin O
Development O
, O
Including O
a O
Neuregulin O
2a O
- O
Based O
ErbB O
Signaling O
Pathway O
Required O
during O
Median O
Fin O
Fold O
Morphogenesis O
. O

Skin B
disorders I
are O
widespread O
, O
but O
available O
treatments O
are O
limited O
. O

A O
more O
comprehensive O
understanding O
of O
skin O
development O
mechanisms O
will O
drive O
identification O
of O
new O
treatment O
targets O
and O
modalities O
. O

Here O
we O
report O
the O
Zebrafish O
Integument O
Project O
( O
ZIP O
), O
an O
expression O
- O
driven O
platform O
for O
identifying O
new O
skin O
genes O
and O
phenotypes O
in O
the O
vertebrate O
model O
Danio O
rerio O
( O
zebrafish O
). O

In O
vivo O
selection O
for O
skin O
- O
specific O
expression O
of O
gene O
- O
break O
transposon O
( O
GBT O
) O
mutant O
lines O
identified O
eleven O
new O
, O
revertible O
GBT O
alleles O
of O
genes O
involved O
in O
skin O
development O
. O

Eight O
genes O
-- O
fras1 O
, O
grip1 O
, O
hmcn1 O
, O
msxc O
, O
col4a4 O
, O
ahnak O
, O
capn12 O
, O
and O
nrg2a O
-- O
had O
been O
described O
in O
an O
integumentary O
context O
to O
varying O
degrees O
, O
while O
arhgef25b O
, O
fkbp10b O
, O
and O
megf6a O
emerged O
as O
novel O
skin O
genes O
. O

Embryos O
homozygous O
for O
a O
GBT O
insertion O
within O
neuregulin O
2a O
( O
nrg2a O
) O
revealed O
a O
novel O
requirement O
for O
a O
Neuregulin O
2a O
( O
Nrg2a O
)- O
ErbB2 O
/ O
3 O
- O
AKT O
signaling O
pathway O
governing O
the O
apicobasal O
organization O
of O
a O
subset O
of O
epidermal O
cells O
during O
median O
fin O
fold O
( O
MFF O
) O
morphogenesis O
. O

In O
nrg2a O
mutant O
larvae O
, O
the O
basal O
keratinocytes O
within O
the O
apical O
MFF O
, O
known O
as O
ridge O
cells O
, O
displayed O
reduced O
pAKT O
levels O
as O
well O
as O
reduced O
apical O
domains O
and O
exaggerated O
basolateral O
domains O
. O

Those O
defects O
compromised O
proper O
ridge O
cell O
elongation O
into O
a O
flattened O
epithelial O
morphology O
, O
resulting O
in O
thickened O
MFF B
edges O
. O

Pharmacological O
inhibition O
verified O
that O
Nrg2a O
signals O
through O
the O
ErbB O
receptor O
tyrosine O
kinase O
network O
. O

Moreover O
, O
knockdown O
of O
the O
epithelial O
polarity O
regulator O
and O
tumor B
suppressor O
lgl2 O
ameliorated O
the O
nrg2a O
mutant O
phenotype O
. O

Identifying O
Lgl2 O
as O
an O
antagonist O
of O
Nrg2a O
- O
ErbB O
signaling O
revealed O
a O
significantly O
earlier O
role O
for O
Lgl2 O
during O
epidermal O
morphogenesis O
than O
has O
been O
described O
to O
date O
. O

Furthermore O
, O
our O
findings O
demonstrated O
that O
successive O
, O
coordinated O
ridge O
cell O
shape O
changes O
drive O
apical O
MFF O
development O
, O
making O
MFF O
ridge O
cells O
a O
valuable O
model O
for O
investigating O
how O
the O
coordinated O
regulation O
of O
cell O
polarity O
and O
cell O
shape O
changes O
serves O
as O
a O
crucial O
mechanism O
of O
epithelial O
morphogenesis O
. O


Mutation O
analysis O
of O
CHRNA1 O
, O
CHRNB1 O
, O
CHRND O
, O
and O
RAPSN O
genes O
in O
multiple B
pterygium I
syndrome I
/ O
fetal B
akinesia I
patients O
. O

Multiple B
pterygium I
syndromes I
( O
MPS B
) O
comprise O
a O
group O
of O
multiple O
congenital B
anomaly I
disorders I
characterized O
by O
webbing O
( O
pterygia B
) O
of O
the O
neck O
, O
elbows O
, O
and O
/ O
or O
knees O
and O
joint B
contractures I
( O
arthrogryposis B
). O

MPS B
are O
phenotypically O
and O
genetically O
heterogeneous O
but O
are O
traditionally O
divided O
into O
prenatally O
lethal O
and O
nonlethal O
( O
Escobar O
) O
types O
. O

Previously O
, O
we O
and O
others O
reported O
that O
recessive O
mutations O
in O
the O
embryonal O
acetylcholine O
receptor O
g O
subunit O
( O
CHRNG O
) O
can O
cause O
both O
lethal O
and O
nonlethal O
MPS B
, O
thus O
demonstrating O
that O
pterygia B
resulted O
from O
fetal O
akinesia B
. O

We O
hypothesized O
that O
mutations O
in O
acetylcholine O
receptor O
- O
related O
genes O
might O
also O
result O
in O
a O
MPS B
/ O
fetal B
akinesia I
phenotype O
and O
so O
we O
analyzed O
15 O
cases O
of O
lethal O
MPS B
/ O
fetal B
akinesia I
without O
CHRNG O
mutations O
for O
mutations O
in O
the O
CHRNA1 O
, O
CHRNB1 O
, O
CHRND O
, O
and O
rapsyn O
( O
RAPSN O
) O
genes O
. O

No O
CHRNA1 O
, O
CHRNB1 O
, O
or O
CHRND O
mutations O
were O
detected O
, O
but O
a O
homozygous O
RAPSN O
frameshift O
mutation O
, O
c O
. O
1177 O
- O
1178delAA O
, O
was O
identified O
in O
a O
family O
with O
three O
children O
affected O
with O
lethal O
fetal B
akinesia I
sequence O
. O

Previously O
, O
RAPSN O
mutations O
have O
been O
reported O
in O
congenital B
myasthenia I
. O

Functional O
studies O
were O
consistent O
with O
the O
hypothesis O
that O
whereas O
incomplete O
loss O
of O
rapsyn O
function O
may O
cause O
congenital B
myasthenia I
, O
more O
severe O
loss O
of O
function O
can O
result O
in O
a O
lethal O
fetal O
akinesia I
phenotype O
. O


Pure O
monosomy O
and O
pure O
trisomy O
of O
13q21 O
. O
2 O
- O
31 O
. O
1 O
consequent O
to O
a O
familial O
insertional O
translocation O
: O
exclusion O
of O
PCDH9 O
as O
the O
responsible O
gene O
for O
autosomal B
dominant I
auditory I
neuropathy I
( O
AUNA1 B
). O

Insertional O
translocations O
( O
IT O
) O
are O
rare O
structural O
rearrangements O
. O

Offspring O
of O
IT O
balanced O
carriers O
are O
at O
high O
risk O
to O
have O
either O
pure O
partial O
trisomy O
or O
monosomy O
for O
the O
inserted O
segment O
as O
manifested O
by O
pure O
phenotypes O
. O

We O
describe O
an O
IT O
between O
chromosomes O
3 O
and O
13 O
segregating O
in O
a O
three O
- O
generation O
pedigree O
. O

Short O
tandem O
repeat O
( O
STR O
) O
segregation O
analysis O
and O
array O
- O
comparative O
genomic O
hybridization O
were O
used O
to O
define O
the O
IT O
as O
a O
25 O
. O
1 O
Mb O
segment O
spanning O
13q21 O
. O
2 O
- O
q31 O
. O
1 O
. O

The O
phenotype O
of O
pure O
monosomy O
included O
deafness B
, O
duodenal B
stenosis I
, O
developmental B
and I
growth I
delay I
, O
vertebral B
anomalies I
, O
and O
facial B
dysmorphisms I
; O
the O
trisomy O
was O
manifested O
by O
only O
minor O
dysmorphisms O
. O

As O
the O
AUNA1 B
deafness I
locus O
on O
13q14 O
- O
21 O
overlaps O
the O
IT O
in O
the O
PCDH9 O
( O
protocadherin O
- O
9 O
) O
gene O
region O
, O
PCDH9 O
was O
investigated O
as O
a O
candidate O
gene O
for O
deafness B
in O
both O
families O
. O

Genotyping O
of O
STRs O
and O
single O
nucleotide O
polymorphisms O
defined O
the O
AUNA1 O
breakpoint O
as O
35 O
kb O
5 O
' O
to O
PCDH9 O
, O
with O
a O
2 O
. O
4 O
Mb O
area O
of O
overlap O
with O
the O
IT O
. O

DNA O
sequencing O
of O
coding O
regions O
in O
the O
AUNA1 O
family O
and O
in O
the O
retained O
homologue O
chromosome O
in O
the O
monosomic O
patient O
revealed O
no O
mutations O
. O

We O
conclude O
that O
AUNA1 B
deafness I
does O
not O
share O
a O
common O
etiology O
with O
deafness B
associated O
with O
monosomy O
13q21 O
. O
2 O
- O
q31 O
. O
3 O
; O
deafness B
may O
result O
from O
monosomy O
of O
PCHD9 O
or O
another O
gene O
in O
the O
IT O
, O
as O
has O
been O
demonstrated O
in O
contiguous O
gene O
deletion O
syndromes O
. O

Precise O
characterization O
of O
the O
breakpoints O
of O
the O
translocated O
region O
is O
useful O
to O
identify O
which O
genes O
may O
be O
contributing O
to O
the O
phenotype O
, O
either O
through O
haploinsufficiency O
or O
extra O
dosage O
effects O
, O
in O
order O
to O
define O
genotype O
- O
phenotype O
correlations O
. O


A O
Taiwanese O
boy O
with O
congenital B
generalized I
lipodystrophy I
caused O
by O
homozygous O
Ile262fs O
mutation O
in O
the O
BSCL2 O
gene O
. O

Congenital B
generalized I
lipodystrophy I
( O
CGL B
) O
is O
a O
rare O
autosomal B
recessive I
disease I
that O
is O
characterized O
by O
a O
near O
- O
complete O
absence O
of O
adipose O
tissue O
from O
birth O
or O
early O
infancy O
. O

Mutations O
in O
the O
BSCL2 O
gene O
are O
known O
to O
result O
in O
CGL2 O
, O
a O
more O
severe O
phenotype O
than O
CGL1 O
, O
with O
earlier O
onset O
, O
more O
extensive O
fat B
loss I
and O
biochemical O
changes O
, O
more O
severe O
intellectual B
impairment I
, O
and O
more O
severe O
cardiomyopathy B
. O

We O
report O
a O
3 O
- O
month O
- O
old O
Taiwanese O
boy O
with O
initial O
presentation O
of O
a O
lack O
of O
subcutaneous O
fat O
, O
prominent O
musculature O
, O
generalized O
eruptive B
xanthomas I
, O
and O
extreme O
hypertriglyceridemia B
. O

Absence O
of O
mechanical O
adipose O
tissue O
in O
the O
orbits O
and O
scalp O
was O
revealed O
by O
head O
magnetic O
resonance O
imaging O
. O

Hepatomegaly B
was O
noticed O
, O
and O
histological O
examination O
of O
a O
liver O
biopsy O
specimen O
suggested O
severe O
hepatic B
steatosis I
and O
periportal O
necrosis I
. O

However O
, O
echocardiography O
indicated O
no O
sign O
of O
cardiomyopathy B
and O
he O
showed O
no O
distinct O
intellectual B
impairment I
that O
interfered O
with O
daily O
life O
. O

About O
1 O
year O
later O
, O
abdominal O
computed O
tomography O
revealed O
enlargement B
of I
kidneys I
. O

He O
had O
a O
homozygous O
insertion O
of O
a O
nucleotide O
, O
783insG O
( O
Ile262fs O
mutation O
), O
in O
exon O
7 O
of O
the O
BSCL2 O
gene O
. O

We O
reviewed O
the O
genotype O
of O
CGL B
cases O
from O
Japan O
, O
India O
, O
China O
and O
Taiwan O
, O
and O
found O
that O
BSCL2 O
is O
a O
major O
causative O
gene O
for O
CGL B
in O
Asian O
. O


Concordance O
between O
PIK3CA O
mutations O
in O
endoscopic O
biopsy O
and O
surgically O
resected O
specimens O
of O
esophageal B
squamous I
cell I
carcinoma I
. O

BACKGROUND O
: O
PIK3CA O
mutations O
are O
expected O
to O
be O
potential O
therapeutic O
targets O
for O
esophageal B
squamous I
cell I
carcinoma I
( O
ESCC B
). O

We O
aimed O
to O
clarify O
the O
concordance O
between O
PIK3CA O
mutations O
detected O
in O
endoscopic O
biopsy O
specimens O
and O
corresponding O
surgically O
resected O
specimens O
. O

METHODS O
: O
We O
examined O
five O
hotspot O
mutations O
in O
the O
PIK3CA O
gene O
( O
E542K O
, O
E545K O
, O
E546K O
, O
H1047R O
, O
and O
H1047L O
) O
in O
formalin B
- O
fixed O
and O
paraffin B
- O
embedded O
tissue O
sections O
of O
paired O
endoscopic O
biopsy O
and O
surgically O
resected O
specimens O
from O
181 O
patients O
undergoing O
curative O
resection O
for O
ESCC B
between O
2000 O
and O
2011 O
using O
a O
Luminex O
technology O
- O
based O
multiplex O
gene O
mutation O
detection O
kit O
. O

RESULTS O
: O
Mutation O
analyses O
were O
successfully O
performed O
for O
both O
endoscopic O
biopsy O
and O
surgically O
resected O
specimens O
in O
all O
the O
cases O
. O

A O
PIK3CA O
mutation O
was O
detected O
in O
either O
type O
of O
specimen O
in O
13 O
cases O
( O
7 O
. O
2 O
%, O
95 O
% O
confidence O
interval O
: O
3 O
. O
9 O
- O
12 O
. O
0 O
). O

The O
overall O
concordance O
rate O
, O
positive O
predictive O
value O
, O
and O
negative O
predictive O
value O
were O
98 O
. O
3 O
% O
( O
178 O
/ O
181 O
), O
90 O
. O
9 O
% O
( O
10 O
/ O
11 O
), O
and O
98 O
. O
8 O
% O
( O
168 O
/ O
170 O
), O
respectively O
. O

Among O
patients O
with O
a O
PIK3CA O
mutation O
detected O
in O
both O
types O
of O
specimens O
, O
the O
concordance O
between O
PIK3CA O
mutation O
genotypes O
was O
100 O
%. O

There O
were O
three O
cases O
with O
a O
discordant O
mutation O
status O
between O
the O
types O
of O
specimens O
( O
PIK3CA O
mutation O
in O
surgically O
resected O
specimen O
and O
wild O
- O
type O
in O
biopsy O
specimen O
in O
two O
cases O
, O
and O
the O
opposite O
pattern O
in O
one O
case O
), O
suggesting O
possible O
intratumoral O
heterogeneity O
in O
the O
PIK3CA O
mutation O
status O
. O

CONCLUSIONS O
: O
The O
PIK3CA O
mutation O
status O
was O
highly O
concordant O
between O
endoscopic O
biopsy O
and O
surgically O
resected O
specimens O
from O
the O
same O
patient O
, O
suggesting O
that O
endoscopic O
biopsy O
specimens O
can O
be O
clinically O
used O
to O
detect O
PIK3CA O
mutations O
in O
patients O
with O
ESCC B
. O


Polymorphisms O
of O
the O
DNA O
mismatch O
repair O
gene O
HMSH2 O
in O
breast B
cancer I
occurence O
and O
progression O
. O

The O
response O
of O
the O
cell O
to O
DNA O
damage O
and O
its O
ability O
to O
maintain O
genomic O
stability O
by O
DNA O
repair O
are O
crucial O
in O
preventing O
cancer B
initiation O
and O
progression O
. O

Therefore O
, O
polymorphism O
of O
DNA O
repair O
genes O
may O
affect O
the O
process O
of O
carcinogenesis B
. O

The O
importance O
of O
genetic O
variability O
of O
the O
components O
of O
mismatch O
repair O
( O
MMR O
) O
genes O
is O
well O
documented O
in O
colorectal B
cancer I
, O
but O
little O
is O
known O
about O
its O
role O
in O
breast B
cancer I
. O

hMSH2 O
is O
one O
of O
the O
crucial O
proteins O
of O
MMR O
. O

We O
performed O
a O
case O
- O
control O
study O
to O
test O
the O
association O
between O
two O
polymorphisms O
in O
the O
hMSH2 O
gene O
: O
an O
A O
--> O
G O
transition O
at O
127 O
position O
producing O
an O
Asn O
--> O
Ser O
substitution O
at O
codon O
127 O
( O
the O
Asn127Ser O
polymorphism O
) O
and O
a O
G O
--> O
A O
transition O
at O
1032 O
position O
resulting O
in O
a O
Gly O
--> O
Asp O
change O
at O
codon O
322 O
( O
the O
Gly322Asp O
polymorphism O
) O
and O
breast B
cancer I
risk O
and O
cancer B
progression O
. O

Genotypes O
were O
determined O
in O
DNA O
from O
peripheral O
blood O
lymphocytes O
of O
150 O
breast B
cancer I
patients O
and O
150 O
age O
- O
matched O
women O
( O
controls O
) O
by O
restriction O
fragment O
length O
polymorphism O
and O
allele O
- O
specific O
PCR O
. O

We O
did O
not O
observe O
any O
correlation O
between O
studied O
polymorphisms O
and O
breast B
cancer I
progression O
evaluated O
by O
node B
- I
metastasis I
, O
tumor B
size O
and O
Bloom O
- O
Richardson O
grading O
. O

A O
strong O
association O
between O
breast B
cancer I
occurrence O
and O
the O
Gly O
/ O
Gly O
phenotype O
of O
the O
Gly322Asp O
polymorphism O
( O
odds O
ratio O
8 O
. O
39 O
; O
95 O
% O
confidence O
interval O
1 O
. O
44 O
- O
48 O
. O
8 O
) O
was O
found O
. O

Therefore O
, O
MMR O
may O
play O
a O
role O
in O
the O
breast B
carcinogenesis I
and O
the O
Gly322Asp O
polymorphism O
of O
the O
hMSH2 O
gene O
may O
be O
considered O
as O
a O
potential O
marker O
in O
breast B
cancer I
. O


Atorvastatin B
prevented O
and O
reversed O
dexamethasone B
- O
induced O
hypertension B
in O
the O
rat O
. O

To O
assess O
the O
antioxidant O
effects O
of O
atorvastatin B
( O
atorva B
) O
on O
dexamethasone B
( O
dex B
)- O
induced O
hypertension B
, O
60 O
male O
Sprague O
- O
Dawley O
rats O
were O
treated O
with O
atorva B
30 O
mg O
/ O
kg O
/ O
day O
or O
tap O
water O
for O
15 O
days O
. O

Dex B
increased O
systolic O
blood O
pressure O
( O
SBP O
) O
from O
109 O
+/- O
1 O
. O
8 O
to O
135 O
+/- O
0 O
. O
6 O
mmHg O
and O
plasma O
superoxide B
( O
5711 O
+/- O
284 O
. O
9 O
saline O
, O
7931 O
+/- O
392 O
. O
8 O
U O
/ O
ml O
dex B
, O
P O
< O
0 O
. O
1 O
). O

In O
this O
prevention O
study O
, O
SBP O
in O
the O
atorva B
+ O
dex B
group O
was O
increased O
from O
115 O
+/- O
0 O
. O
4 O
to O
124 O
+/- O
1 O
. O
5 O
mmHg O
, O
but O
this O
was O
significantly O
lower O
than O
in O
the O
dex B
- O
only O
group O
( O
P O
' O
< O
0 O
. O
5 O
). O

Atorva B
reversed O
dex B
- O
induced O
hypertension B
( O
129 O
+/- O
0 O
. O
6 O
mmHg O
, O
vs O
. O

135 O
+/- O
0 O
. O
6 O
mmHg O
P O
' O
< O
0 O
. O
5 O
) O
and O
decreased O
plasma O
superoxide B
( O
7931 O
+/- O
392 O
. O
8 O
dex B
, O
1187 O
+/- O
441 O
. O
2 O
atorva B
+ O
dex B
, O
P O
< O
0 O
. O
1 O
). O

Plasma O
nitrate B
/ O
nitrite B
( O
NOx B
) O
was O
decreased O
in O
dex B
- O
treated O
rats O
compared O
to O
saline O
- O
treated O
rats O
( O
11 O
. O
2 O
+/- O
1 O
. O
8 O
microm O
, O
15 O
. O
3 O
+/- O
1 O
. O
17 O
microm O
, O
respectively O
, O
P O
< O
0 O
. O
5 O
). O

Atorva B
affected O
neither O
plasma O
NOx B
nor O
thymus O
weight O
. O

Thus O
, O
atorvastatin B
prevented O
and O
reversed O
dexamethasone B
- O
induced O
hypertension B
in O
the O
rat O
. O


Gene O
polymorphisms O
implicated O
in O
influencing O
susceptibility O
to O
venous B
and I
arterial I
thromboembolism I
: O
frequency O
distribution O
in O
a O
healthy O
German O
population O
. O

Evolvement O
and O
progression O
of O
cardiovascular B
diseases I
affecting O
the O
venous O
and O
arterial O
system O
are O
influenced O
by O
a O
multitude O
of O
environmental O
and O
hereditary O
factors O
. O

Many O
of O
these O
hereditary O
factors O
consist O
of O
defined O
gene O
polymorphisms O
, O
such O
as O
single O
nucleotide O
polymorphisms O
( O
SNPs O
) O
or O
insertion O
- O
deletion O
polymorphisms O
, O
which O
directly O
or O
indirectly O
affect O
the O
hemostatic O
system O
. O

The O
frequencies O
of O
individual O
hemostatic O
gene O
polymorphisms O
in O
different O
normal O
populations O
are O
well O
defined O
. O

However O
, O
descriptions O
of O
patterns O
of O
genetic O
variability O
of O
a O
larger O
extent O
of O
different O
factors O
of O
hereditary B
hypercoagulability I
in O
single O
populations O
are O
scarce O
. O

The O
aim O
of O
this O
study O
was O
i O
) O
to O
give O
a O
detailed O
description O
of O
the O
frequencies O
of O
factors O
of O
hereditary B
thrombophilia I
and O
their O
combinations O
in O
a O
German O
population O
( O
n O
= O
282 O
) O
and O
ii O
) O
to O
compare O
their O
distributions O
with O
those O
reported O
for O
other O
regions O
. O

Variants O
of O
coagulation O
factors O
[ O
factor O
V O
1691G O
> O
A O
( O
factor O
V O
Leiden O
), O
factor O
V O
4070A O
> O
G O
( O
factor O
V O
HR2 O
haplotype O
), O
factor O
VII O
Arg353Gln O
, O
factor O
XIII O
Val34Leu O
, O
beta O
- O
fibrinogen O
- O
455G O
> O
A O
, O
prothrombin O
20210G O
> O
A O
], O
coagulation O
inhibitors O
[ O
tissue O
factor O
pathway O
inhibitor O
536C O
> O
T O
, O
thrombomodulin O
127G O
> O
A O
], O
fibrinolytic O
factors O
[ O
angiotensin O
converting O
enzyme O
intron O
16 O
insertion O

/ O
deletion O
, O
factor O
VII O
- O
activating O
protease O
1601G O
> O
A O
( O
FSAP O
Marburg O
I O
), O
plasminogen O
activator O
inhibitor O
1 O
- O
675 O
insertion O
/ O
deletion O
( O
5G O
/ O
4G O
), O
tissue O
plasminogen O
activator O
intron O
h O
deletion O
/ O
insertion O
], O
and O
other O
factors O
implicated O
in O
influencing O
susceptibility O
to O
thromboembolic B
diseases I
[ O
apolipoprotein O
E2 O
/ O
E3 O
/ O
E4 O
, O
glycoprotein O
Ia O
807C O
> O
T O
, O

methylenetetrahydrofolate O
reductase O
677C O
> O
T O
] O
were O
included O
. O

The O
distribution O
of O
glycoprotein O
Ia O
807C O
> O
T O
deviated O
significantly O
from O
the O
Hardy O
- O
Weinberg O
equilibrium O
, O
and O
a O
comparison O
with O
previously O
published O
data O
indicates O
marked O
region O
and O
ethnicity O
dependent O
differences O
in O
the O
genotype O
distributions O
of O
some O
other O
factors O
. O


Necrotising B
fasciitis I
after O
bortezomib B
and O
dexamethasone B
- O
containing O
regimen O
in O
an O
elderly O
patient O
of O
Waldenstrom B
macroglobulinaemia I
. O

Bortezomib B
and O
high O
- O
dose O
dexamethasone B
- O
containing O
regimens O
are O
considered O
to O
be O
generally O
tolerable O
with O
few O
severe O
bacterial B
infections I
in O
patients O
with O
B B
- I
cell I
malignancies I
. O

However O
, O
information O
is O
limited O
concerning O
the O
safety O
of O
the O
regimen O
in O
elderly O
patients O
. O

We O
report O
a O
case O
of O
a O
76 O
- O
year O
- O
old O
man O
with O
Waldenstrom B
macroglobulinaemia I
who O
suffered O
necrotising B
fasciitis I
without O
neutropenia B
after O
the O
combination O
treatment O
with O
bortezomib B
, O
high O
- O
dose O
dexamethasone B
and O
rituximab B
. O

Despite O
immediate O
intravenous O
antimicrobial O
therapy O
, O
he O
succumbed O
23 O
h O
after O
the O
onset O
. O

Physicians O
should O
recognise O
the O
possibility O
of O
fatal O
bacterial B
infections I
related O
to O
bortezomib B
plus O
high O
- O
dose O
dexamethasone B
in O
elderly O
patients O
, O
and O
we O
believe O
this O
case O
warrants O
further O
investigation O
. O


rTMS O
of O
supplementary O
motor O
area O
modulates O
therapy O
- O
induced O
dyskinesias B
in O
Parkinson B
disease I
. O

The O
neural O
mechanisms O
and O
circuitry O
involved O
in O
levodopa B
- O
induced O
dyskinesia B
are O
unclear O
. O

Using O
repetitive O
transcranial O
magnetic O
stimulation O
( O
rTMS O
) O
over O
the O
supplementary O
motor O
area O
( O
SMA O
) O
in O
a O
group O
of O
patients O
with O
advanced O
Parkinson B
disease I
, O
the O
authors O
investigated O
whether O
modulation O
of O
SMA O
excitability O
may O
result O
in O
a O
modification O
of O
a O
dyskinetic B
state O
induced O
by O
continuous O
apomorphine B
infusion O
. O

rTMS O
at O
1 O
Hz O
was O
observed O
to O
markedly O
reduce O
drug O
- O
induced O
dyskinesias B
, O
whereas O
5 B
- I
Hz I
rTMS O
induced O
a O
slight O
but O
not O
significant O
increase O
. O


Angiotensin O
converting O
enzyme O
gene O
polymorphism O
in O
Turkish O
asthmatic B
patients O
. O

Asthma B
is O
a O
chronic B
inflammatory B
disease I
of O
the O
airways O
. O

Several O
candidate O
genes O
have O
been O
identified O
with O
a O
potential O
role O
in O
the O
pathogenesis O
of O
asthma B
, O
including O
the O
angiotensin O
converting O
enzyme O
( O
ACE O
) O
gene O
. O

We O
aimed O
to O
investigate O
the O
frequency O
of O
an O
ACE O
gene O
polymorphism O
in O
Turkish O
asthmatic B
patients O
and O
to O
determine O
its O
impact O
on O
clinical O
parameters O
and O
disease O
severity O
. O

Ninety O
- O
seven O
asthmatic B
patients O
( O
M O
/ O
F O
25 O
/ O
72 O
, O
mean O
age O
39 O
+/- O
13 O
years O
) O
and O
96 O
healthy O
subjects O
( O
M O
/ O
F O
26 O
/ O
70 O
, O
mean O
age O
38 O
+/- O
12 O
years O
) O
were O
included O
. O

At O
baseline O
, O
all O
participants O
completed O
a O
questionnaire O
on O
demographics O
, O
symptoms O
, O
triggering O
factors O
, O
severity O
of O
asthma B
, O
and O
the O
presence O
of O
atopism B
. O

Blood O
samples O
were O
obtained O
from O
all O
patients O
and O
genomic O
DNA O
was O
isolated O
. O

The O
frequency O
of O
the O
ACE O
genotypes O
( O
I O
= O
insertion O
and O
D O
= O
deletion O
) O
among O
asthmatics B
and O
controls O
were O
compared O
: O
asthmatics B
showed O
a O
40 O
. O
2 O
% O
prevalence O
of O
the O
DD O
genotype O
( O
n O
= O
39 O
), O
ID O
was O
45 O
. O
4 O
% O
( O
n O
= O
44 O
), O
and O
II O
was O
14 O
. O
4 O
% O
( O
n O
= O
14 O
. O
4 O
). O

In O
the O
control O
subjects O
, O
the O
frequency O
of O
DD B
was O
18 O
. O
8 O
% O
( O
n O
= O
18 O
), O
ID O
was O
50 O
% O
( O
n O
= O
48 O
) O
and O
II O
was O
31 O
. O
3 O
% O
( O
n O
= O
30 O
). O

The O
DD O
ACE O
genotype O
was O
significantly O
more O
frequent O
in O
asthmatics B
compared O
with O
controls O
( O
p O
< O
0 O
. O
1 O
). O

Asthmatics B
with O
the O
ID O
ACE O
genotype O
showed O
a O
higher O
frequency O
of O
drug O
allergies O
, O
although O
this O
was O
not O
statistically O
significant O
( O
p O
= O
0 O
. O
8 O
). O

Asthmatics B
with O
the O
DD O
genotype O
appeared O
to O
have O
a O
higher O
incidence O
of O
asthmatic B
episode O
exacerbations O
due O
to O
viral B
infections I
, O
but O
again O
this O
was O
not O
statistically O
significant O
( O
p O
= O
0 O
. O
8 O
). O

Patients O
with O
mild O
or O
moderate O
- O
severe O
asthma B
had O
similar O
frequencies O
of O
these O
mutations O
. O

We O
found O
a O
higher O
frequency O
of O
the O
ACE O
DD O
gene O
mutation O
in O
Turkish O
asthmatic B
patients O
compared O
with O
non O
- O
asthmatics B
, O
suggesting O
that O
this O
ACE O
gene O
polymorphism O
may O
be O
a O
risk O
factor O
for O
asthma B
but O
does O
not O
increase O
the O
severity O
of O
the O
disease O
. O


The O
impact O
of O
PPARa O
activation O
on O
whole O
genome O
gene O
expression O
in O
human O
precision O
cut O
liver O
slices O
. O

BACKGROUND O
: O
Studies O
in O
mice O
have O
shown O
that O
PPARa O
is O
an O
important O
regulator O
of O
lipid B
metabolism O
in O
liver O
and O
key O
transcription O
factor O
involved O
in O
the O
adaptive O
response O
to O
fasting O
. O

However O
, O
much O
less O
is O
known O
about O
the O
role O
of O
PPARa O
in O
human O
liver O
. O

METHODS O
: O
Here O
we O
set O
out O
to O
study O
the O
function O
of O
PPARa O
in O
human O
liver O
via O
analysis O
of O
whole O
genome O
gene O
regulation O
in O
human O
liver O
slices O
treated O
with O
the O
PPARa O
agonist O
Wy14643 B
. O

RESULTS O
: O
Quantitative O
PCR O
indicated O
that O
PPARa O
is O
well O
expressed O
in O
human O
liver O
and O
human O
liver O
slices O
and O
that O
the O
classical O
PPARa O
targets O
PLIN2 O
, O
VLDLR O
, O
ANGPTL4 O
, O
CPT1A O
and O
PDK4 O
are O
robustly O
induced O
by O
PPARa O
activation O
. O

Transcriptomics O
analysis O
indicated O
that O
617 O
genes O
were O
upregulated O
and O
665 O
genes O
were O
downregulated O
by O
PPARa O
activation O
( O
q O
value O
< O
0 O
. O
5 O
). O

Many O
genes O
induced O
by O
PPARa O
activation O
were O
involved O
in O
lipid B
metabolism O
( O
ACSL5 O
, O
AGPAT9 O
, O
FADS1 O
, O
SLC27A4 O
), O
xenobiotic O
metabolism O
( O
POR O
, O
ABCC2 O
, O
CYP3A5 O
) O
or O
the O
unfolded O
protein O
response O
, O
whereas O
most O
of O
the O
downregulated O
genes O
were O
involved O
in O
immune O
- O
related O
pathways O
. O

Among O
the O
most O
highly O
repressed O
genes O
upon O
PPARa O
activation O
were O
several O
chemokines O
( O
e O
. O
g O
. O

CXCL9 O
- O
11 O
, O
CCL8 O
, O
CX3CL1 O
, O
CXCL6 O
), O
interferon O
g O
- O
induced O
genes O
( O
e O
. O
g O
. O

IFITM1 O
, O
IFIT1 O
, O
IFIT2 O
, O
IFIT3 O
) O
and O
numerous O
other O
immune O
- O
related O
genes O
( O
e O
. O
g O
. O

TLR3 O
, O
NOS2 O
, O
and O
LCN2 O
). O

Comparative O
analysis O
of O
gene O
regulation O
by O
Wy14643 O
between O
human O
liver O
slices O
and O
primary O
human O
hepatocytes O
showed O
that O
down O
- O
regulation O
of O
gene O
expression O
by O
PPARa O
is O
much O
better O
captured O
by O
liver O
slices O
as O
compared O
to O
primary O
hepatocytes O
. O

In O
particular O
, O
PPARa O
activation O
markedly O
suppressed O
immunity O
/ O
inflammation B
- O
related O
genes O
in O
human O
liver O
slices O
but O
not O
in O
primary O
hepatocytes O
. O

Finally O
, O
several O
putative O
new O
target O
genes O
of O
PPARa O
were O
identified O
that O
were O
commonly O
induced O
by O
PPARa O
activation O
in O
the O
two O
human O
liver O
model O
systems O
, O
including O
TSKU O
, O
RHOF O
, O
CA12 O
and O
VSIG10L O
. O

CONCLUSION O
: O
Our O
paper O
demonstrates O
the O
suitability O
and O
superiority O
of O
human O
liver O
slices O
over O
primary O
hepatocytes O
for O
studying O
the O
functional O
role O
of O
PPARa O
in O
human O
liver O
. O

Our O
data O
underscore O
the O
major O
role O
of O
PPARa O
in O
regulation O
of O
hepatic O
lipid B
and O
xenobiotic O
metabolism O
in O
human O
liver O
and O
reveal O
a O
marked O
immuno O
- O
suppressive O
/ O
anti O
- O
inflammatory B
effect O
of O
PPARa O
in O
human O
liver O
slices O
that O
may O
be O
therapeutically O
relevant O
for O
non B
- I
alcoholic I
fatty I
liver I
disease I
. O


Oncogenic O
activity O
of O
amplified O
miniature O
chromosome O
maintenance O
8 O
in O
human O
malignancies B
. O

Miniature O
chromosome O
maintenance O
( O
MCM O
) O
proteins O
play O
critical O
roles O
in O
DNA O
replication O
licensing O
, O
initiation O
and O
elongation O
. O

MCM8 O
, O
one O
of O
the O
MCM O
proteins O
playing O
a O
critical O
role O
in O
DNA O
repairing O
and O
recombination O
, O
was O
found O
to O
have O
overexpression O
and O
increased O
DNA O
copy O
number O
in O
a O
variety O
of O
human O
malignancies B
. O

The O
gain O
of O
MCM8 O
is O
associated O
with O
aggressive O
clinical O
features O
of O
several O
human O
cancers B
. O

Increased O
expression O
of O
MCM8 O
in O
prostate B
cancer I
is O
associated O
with O
cancer B
recurrence O
. O

Forced O
expression O
of O
MCM8 O
in O
RWPE1 O
cells O
, O
the O
immortalized O
but O
non O
- O
transformed O
prostate O
epithelial O
cell O
line O
, O
exhibited O
fast O
cell O
growth O
and O
transformation O
, O
while O
knock O
down O
of O
MCM8 O
in O
PC3 O
, O
DU145 O
and O
LNCaP O
cells O
induced O
cell O
growth O
arrest O
, O
and O
decreased O
tumour B
volumes O
and O
mortality O
of O
severe O
combined B
immunodeficiency I
mice O
xenografted O
with O
PC3 O
and O
DU145 O
cells O
. O

MCM8 O
bound O
cyclin O
D1 O
and O
activated O
Rb O
protein O
phosphorylation O
by O
cyclin O
- O
dependent O
kinase O
4 O
in O
vitro O
and O
in O
vivo O
. O

The O
cyclin O
D1 O
/ O
MCM8 O
interaction O
is O
required O
for O
Rb O
phosphorylation O
and O
S O
- O
phase O
entry O
in O
cancer B
cells O
. O

As O
a O
result O
, O
our O
study O
showed O
that O
copy O
number O
increase O
and O
overexpression O
of O
MCM8 O
may O
play O
critical O
roles O
in O
human O
cancer B
development O
. O


Enhanced O
isoproterenol B
- O
induced O
cardiac B
hypertrophy I
in O
transgenic O
rats O
with O
low O
brain O
angiotensinogen O
. O

We O
have O
previously O
shown O
that O
a O
permanent O
deficiency O
in O
the O
brain O
renin O
- O
angiotensin O
system O
( O
RAS O
) O
may O
increase O
the O
sensitivity O
of O
the O
baroreflex O
control O
of O
heart O
rate O
. O

In O
this O
study O
we O
aimed O
at O
studying O
the O
involvement O
of O
the O
brain O
RAS O
in O
the O
cardiac O
reactivity O
to O
the O
beta O
- O
adrenoceptor O
( O
beta O
- O
AR O
) O
agonist O
isoproterenol B
( O
Iso B
). O

Transgenic O
rats O
with O
low O
brain O
angiotensinogen O
( O
TGR O
) O
were O
used O
. O

In O
isolated O
hearts O
, O
Iso B
induced O
a O
significantly O
greater O
increase O
in O
left O
ventricular O
( O
LV O
) O
pressure O
and O
maximal O
contraction O
(+ O
dP O
/ O
dt O
( O
max O
)) O
in O
the O
TGR O
than O
in O
the O
Sprague O
- O
Dawley O
( O
SD O
) O
rats O
. O

LV B
hypertrophy I
induced O
by O
Iso B
treatment O
was O
significantly O
higher O
in O
TGR O
than O
in O
SD O
rats O
( O
in O
g O
LV O
wt O
/ O
100 O
g O
body O
wt O
, O
0 O
. O
28 O
+/- O
0 O
. O
4 O
vs O
. O

0 O
. O
24 O
+/- O
0 O
. O
4 O
, O
respectively O
). O

The O
greater O
LV B
hypertrophy I
in O
TGR O
rats O
was O
associated O
with O
more O
pronounced O
downregulation O
of O
beta O
- O
AR O
and O
upregulation O
of O
LV O
beta O
- O
AR O
kinase O
- O
1 O
mRNA O
levels O
compared O
with O
those O
in O
SD O
rats O
. O

The O
decrease O
in O
the O
heart O
rate O
( O
HR O
) O
induced O
by O
the O
beta O
- O
AR O
antagonist O
metoprolol B
in O
conscious O
rats O
was O
significantly O
attenuated O
in O
TGR O
compared O
with O
SD O
rats O
(- O
9 O
. O
9 O
+/- O
1 O
. O
7 O
% O
vs O
. O

- O
18 O
. O
1 O
+/- O
1 O
. O
5 O
%), O
whereas O
the O
effect O
of O
parasympathetic O
blockade O
by O
atropine B
on O
HR O
was O
similar O
in O
both O
strains O
. O

These O
results O
indicate O
that O
TGR O
are O
more O
sensitive O
to O
beta B
- I
AR I
agonist I
- O
induced O
cardiac O
inotropic O
response O
and O
hypertrophy B
, O
possibly O
due O
to O
chronically O
low O
sympathetic O
outflow O
directed O
to O
the O
heart O
. O


Intronic O
deletions O
in O
the O
SLC34A3 O
gene O
cause O
hereditary B
hypophosphatemic I
rickets I
with I
hypercalciuria B
. O

CONTEXT O
: O
Hereditary B
hypophosphatemic I
rickets I
with I
hypercalciuria I
( O
HHRH B
) O
is O
a O
rare O
metabolic B
disorder I
, O
characterized O
by O
hypophosphatemia B
and O
rickets B
/ O
osteomalacia B
with O
increased O
serum O
1 B
, I
25 I
- I
dihydroxyvitamin I
D I
[ O
1 B
, I
25 I
-( I
OH I
)( I
2 I
) I
D I
] O
resulting O
in O
hypercalciuria B
. O

OBJECTIVE O
: O
Our O
objective O
was O
to O
determine O
whether O
mutations O
in O
the O
SLC34A3 O
gene O
, O
which O
encodes O
sodium O
- O
phosphate O
cotransporter O
type O
IIc O
, O
are O
responsible O
for O
the O
occurrence O
of O
HHRH B
. O

DESIGN O
AND O
SETTING O
: O
Mutation O
analysis O
of O
exons O
and O
adjacent O
introns O
in O
the O
SLC34A3 O
gene O
was O
conducted O
at O
an O
academic O
research O
laboratory O
and O
medical O
center O
. O

PATIENTS O
OR O
OTHER O
PARTICIPANTS O
: O
Members O
of O
two O
unrelated O
families O
with O
HHRH B
participated O
in O
the O
study O
. O

RESULTS O
: O
Two O
affected O
siblings O
in O
one O
family O
were O
homozygous O
for O
a O
101 O
- O
bp O
deletion O
in O
intron O
9 O
. O

Haplotype O
analysis O
of O
the O
SLC34A3 O
locus O
in O
the O
family O
showed O
that O
the O
two O
deletions O
are O
on O
different O
haplotypes O
. O

An O
unrelated O
individual O
with O
HHRH B
was O
a O
compound O
heterozygote O
for O
an O
85 O
- O
bp O
deletion O
in O
intron O
10 O
and O
a O
G O
- O
to O
- O
A O
substitution O
at O
the O
last O
nucleotide O
in O
exon O
7 O
. O

The O
intron O
9 O
deletion O
( O
and O
likely O
the O
other O
two O
mutations O
) O
identified O
in O
this O
study O
causes O
aberrant O
RNA O
splicing O
. O

Sequence O
analysis O
of O
the O
deleted O
regions O
revealed O
the O
presence O
of O
direct O
repeats O
of O
homologous O
sequences O
. O

CONCLUSION O
: O
HHRH B
is O
caused O
by O
biallelic O
mutations O
in O
the O
SLC34A3 O
gene O
. O

Haplotype O
analysis O
suggests O
that O
the O
two O
intron O
9 O
deletions O
arose O
independently O
. O

The O
identification O
of O
three O
independent O
deletions O
in O
introns O
9 O
and O
10 O
suggests O
that O
the O
SLC34A3 O
gene O
may O
be O
susceptible O
to O
unequal O
crossing O
over O
because O
of O
sequence O
misalignment O
during O
meiosis O
. O


Vitamin O
D O
receptor O
expression O
is O
associated O
with O
PIK3CA O
and O
KRAS O
mutations O
in O
colorectal B
cancer I
. O

Vitamin B
D I
is O
associated O
with O
decreased O
risks O
of O
various O
cancers B
, O
including O
colon B
cancer I
. O

The O
vitamin O
D O
receptor O
( O
VDR O
) O
is O
a O
transcription O
factor O
, O
which O
plays O
an O
important O
role O
in O
cellular O
differentiation O
and O
inhibition O
of O
proliferation O
. O

A O
link O
between O
VDR B
and O
the O
RAS O
- O
mitogen O
- O
activated O
protein O
kinase O
( O
MAPK O
) O
or O
phosphatidylinositol O
3 O
- O
kinase O
( O
PI3K O
)- O
AKT O
pathway O
has O
been O
suggested O
. O

However O
, O
the O
prognostic O
role O
of O
VDR O
expression O
or O
its O
relationship O
with O
PIK3CA O
or O
KRAS O
mutation O
remains O
uncertain O
. O

Among O
619 O
colorectal B
cancers I
in O
two O
prospective O
cohort O
studies O
, O
233 O
( O
38 O
%) O
tumors B
showed O
VDR O
overexpression O
by O
immunohistochemistry O
. O

We O
analyzed O
for O
PIK3CA O
and O
KRAS O
mutations O
and O
LINE O
- O
1 O
methylation O
by O
Pyrosequencing O
, O
microsatellite B
instability I
( O
MSI B
), O
and O
DNA O
methylation O
( O
epigenetic O
changes O
) O
in O
eight O
CpG O
island O
methylator O
phenotype O
( O
CIMP O
)- O
specific O
promoters O
[ O
CACNA1G O
, O
CDKN2A O
( O
p16 O
), O
CRABP1 O
, O
IGF2 O
, O
MLH1 O
, O
NEUROG1 O
, O
RUNX3 O
, O
and O
SOCS1 O
] O
by O
MethyLight O
( O
real O

- O
time O
PCR O
). O

VDR O
overexpression O
was O
significantly O
associated O
with O
KRAS O
mutation O
( O
odds O
ratio O
, O
1 O
. O
55 O
; O
95 O
% O
confidence O
interval O
, O
1 O
. O
11 O
- O
2 O
. O
16 O
) O
and O
PIK3CA O
mutation O
( O
odds O
ratio O
, O
2 O
. O
17 O
; O
95 O
% O
confidence O
interval O
, O
1 O
. O
36 O
- O
3 O
. O
47 O
), O
both O
of O
which O
persisted O
in O
multivariate O
logistic O
regression O
analysis O
. O

VDR B
was O
not O
independently O
associated O
with O
body O
mass O
index O
, O
family O
history O
of O
colorectal B
cancer I
, O
tumor B
location O
( O
colon O
versus O
rectum O
), O
stage O
, O
tumor B
grade O
, O
signet O
ring O
cells O
, O
CIMP O
, O
MSI O
, O
LINE O
- O
1 O
hypomethylation O
, O
BRAF O
, O
p53 O
, O
p21 O
, O
beta O
- O
catenin O
, O
or O
cyclooxygenase O
- O
2 O
. O

VDR O
expression O
was O
not O
significantly O
related O
with O
patient O
survival O
, O
prognosis O
, O
or O
clinical O
outcome O
. O

In O
conclusion O
, O
VDR O
overexpression O
in O
colorectal B
cancer I
is O
independently O
associated O
with O
PIK3CA O
and O
KRAS O
mutations O
. O

Our O
data O
support O
potential O
interactions O
between O
the O
VDR O
, O
RAS O
- O
MAPK O
and O
PI3K O
- O
AKT O
pathways O
, O
and O
possible O
influence O
by O
KRAS O
or O
PIK3CA O
mutation O
on O
therapy O
or O
chemoprevention O
targeting O
VDR B
. O


Cultured O
mycelium O
Cordyceps O
sinensis O
protects O
liver O
sinusoidal O
endothelial O
cells O
in O
acute B
liver I
injured I
mice O
. O

Cultured O
mycelium O
Cordyceps O
sinensis O
( O
CMCS B
) O
was O
widely O
used O
for O
a O
variety O
of O
diseases O
including O
liver B
injury I
, O
the O
current O
study O
aims O
to O
investigate O
the O
protective O
effects O
of O
CMCS B
on O
liver O
sinusoidal O
endothelial O
cells O
( O
LSECs O
) O
in O
acute B
injury I
liver I
and O
related O
action O
mechanisms O
. O

The O
mice O
were O
injected O
intraperitoneally O
with O
lipopolysaccharide B
( O
LPS B
) O
and O
D B
- I
galactosamine I
( O
D B
- I
GalN I
). O

39 O
male O
BABL O
/ O
c O
mice O
were O
randomly O
divided O
into O
four O
groups O
: O
normal O
control O
, O
model O
control O
, O
CMCS B
treatment O
and O
1 B
, I
10 I
- I
phenanthroline I
treatment O
groups O
. O

The O
Serum O
liver O
function O
parameters O
including O
alanine B
aminotransferase I
( O
ALT B
) O
and O
aspartate B
aminotransferase I
( O
AST B
) O
levels O
were O
assayed O
with O
the O
commercial O
kit O
. O

The O
inflammation B
and O
scaffold O
structure O
in O
liver O
were O
stained O
with O
hematoxylin O
and O
eosin O
and O
silver O
staining O
respectively O
. O

The O
LSECs O
and O
sub O
- O
endothelial O
basement O
membrane O
were O
observed O
with O
the O
scanning O
and O
transmission O
electronic O
microscope O
. O

The O
protein O
expressions O
of O
intercellular O
adhesion O
molecule O
- O
1 O
( O
ICAM O
- O
1 O
) O
and O
vascular O
cell O
adhesion O
molecule O
- O
1 O
( O
VCAM O
- O
1 O
) O
in O
liver O
were O
analyzed O
with O
Western O
blotting O
. O

Expression O
of O
von O
Willebrand O
factor O
( O
vWF O
) O
was O
investigated O
with O
immunofluorescence O
staining O
. O

The O
lipid B
peroxidation O
indicators O
including O
antisuperoxideanion B
( O
ASAFR B
), O
hydroxyl B
free O
radical O
(. O
OH O
), O
superoxide O
dismutase O
( O
SOD O
), O
malondialdehyde B
and O
glutathione O
S O
- O
transferase O
( O
GST O
) O
were O
determined O
with O
kits O
, O
and O
matrix O
metalloproteinase O
- O
2 O
and O
9 O
( O
MMP O
- O
2 O
/ O
9 O
) O
activities O
in O
liver O
were O
analyzed O
with O
gelatin O
zymography O
and O
in O
situ O
fluorescent O
zymography O
respectively O
. O

The O
model O
mice O
had O
much O
higher O
serum O
levels O
of O
ALT O
and O
AST O
than O
the O
normal O
mice O
. O

Compared O
to O
that O
in O
the O
normal O
control O
, O
more O
severe O
liver B
inflammation I
and O
hepatocyte O
apoptosis O
, O
worse O
hepatic O
lipid B
peroxidation O
demonstrated O
by O
the O
increased O
ASAFR O
, O
. O
OH O
and O
MDA B
, O
but O
decreased O
SOD O
and O
GST O
, O
increased O
MMP O
- O
2 O
/ O
9 O
activities O
and O
VCAM O
- O
1 O
, O
ICAM O
- O
1 O
and O
vWF O
expressions O
, O
which O
revealed O
obvious O
LSEC B
injury I
and O
scaffold O
structure O
broken O
, O
were O
shown O
in O
the O
model O
control O
. O

Compared O
with O
the O
model O
group O
, O
CMCS B
and O
1 B
, I
10 I
- I
phenanthroline I
significantly O
improved O
serum O
ALT B
/ O
AST O
, O
attenuated O
hepatic B
inflammation I
and O
improved O
peroxidative B
injury I
in O
liver O
, O
decreased O
MMP O
- O
2 O
/ O
9 O
activities O
in O
liver O
tissue O
, O
improved O
integration O
of O
scaffold O
structure O
, O
and O
decreased O
protein O
expression O
of O
VCAM O
- O
1 O
and O
ICAM O
- O
1 O
. O

CMCS O
could O
protect O
LSECs O
from O
injury B
and O
maintain O
the O
microvasculature O
integration O
in O
acute B
injured I
liver I
of O
mice O
induced O
by O
LPS B
/ O
D O
- O
GalN O
. O

Its O
action O
mechanism O
was O
associated O
with O
the O
down O
- O
regulation O
of O
MMP O
- O
2 O
/ O
9 O
activities O
and O
inhibition O
of O
peroxidation O
in O
injured O
liver I
. O


A O
Type B
2 I
Diabetes I
- O
Associated O
Functional O
Regulatory O
Variant O
in O
a O
Pancreatic O
Islet O
Enhancer O
at O
the O
ADCY5 O
Locus O
. O

Molecular O
mechanisms O
remain O
unknown O
for O
most O
type B
2 I
diabetes I
genome O
- O
wide O
association O
study O
identified O
loci O
. O

Variants O
associated O
with O
type B
2 I
diabetes I
and O
fasting O
glucose B
levels O
reside O
in O
introns O
of O
ADCY5 O
, O
a O
gene O
that O
encodes O
adenylate O
cyclase O
5 O
. O

Adenylate O
cyclase O
5 O
catalyzes O
the O
production O
of O
cyclic B
AMP I
, O
which O
is O
a O
second O
messenger O
molecule O
involved O
in O
cell O
signaling O
and O
pancreatic O
b O
- O
cell O
insulin O
secretion O
. O

We O
demonstrated O
that O
type B
2 I
diabetes I
risk O
alleles O
are O
associated O
with O
decreased O
ADCY5 O
expression O
in O
human O
islets O
and O
examined O
candidate O
variants O
for O
regulatory O
function O
. O

rs11708067 O
overlaps O
a O
predicted O
enhancer O
region O
in O
pancreatic O
islets O
. O

The O
type B
2 I
diabetes I
risk O
rs11708067 O
- O
A O
allele O
showed O
fewer O
H3K27ac O
ChIP O
- O
seq O
reads O
in O
human O
islets O
, O
lower O
transcriptional O
activity O
in O
reporter O
assays O
in O
rodent O
b O
- O
cells O
( O
rat O
832 O
/ O
13 O
and O
mouse O
MIN6 O
), O
and O
increased O
nuclear O
protein O
binding O
compared O
with O
the O
rs11708067 O
- O
G O
allele O
. O

Homozygous O
deletion O
of O
the O
orthologous O
enhancer O
region O
in O
832 O
/ O
13 O
cells O
resulted O
in O
a O
64 O
% O
reduction O
in O
expression O
level O
of O
Adcy5 O
, O
but O
not O
adjacent O
gene O
Sec22a O
, O
and O
a O
39 O
% O
reduction O
in O
insulin O
secretion O
. O

Together O
, O
these O
data O
suggest O
that O
rs11708067 O
- O
A O
risk O
allele O
contributes O
to O
type B
2 I
diabetes I
by O
disrupting O
an O
islet O
enhancer O
, O
which O
results O
in O
reduced O
ADCY5 O
expression O
and O
impaired B
insulin I
secretion I
. O


Homozygously O
deleted O
gene O
DACH1 O
regulates O
tumor B
- O
initiating O
activity O
of O
glioma B
cells O
. O

Loss O
or O
reduction O
in O
function O
of O
tumor B
suppressor O
genes O
contributes O
to O
tumorigenesis B
. O

Here O
, O
by O
allelic O
DNA O
copy O
number O
analysis O
using O
single O
- O
nucleotide O
polymorphism O
genotyping O
array O
and O
mass O
spectrometry O
, O
we O
report O
homozygous O
deletion O
in O
glioblastoma B
multiformes I
at O
chromosome O
13q21 O
, O
where O
DACH1 O
gene O
is O
located O
. O

We O
found O
decreased O
cell O
proliferation O
of O
a O
series O
of O
glioma B
cell O
lines O
by O
forced O
expression O
of O
DACH1 O
. O

We O
then O
generated O
U87TR O
- O
Da O
glioma B
cells O
, O
where O
DACH1 O
expression O
could O
be O
activated O
by O
exposure O
of O
the O
cells O
to O
doxycycline B
. O

Both O
ex O
vivo O
cellular O
proliferation O
and O
in O
vivo O
growth O
of O
s O
. O
c O
. O

transplanted O
tumors B
in O
mice O
are O
reduced O
in O
U87TR O
- O
Da O
cells O
with O
DACH1 O
expression O
( O
U87 O
- O
DACH1 O
- O
high O
), O
compared O
with O
DACH1 O
- O
nonexpressing O
U87TR O
- O
Da O
cells O
( O
U87 O
- O
DACH1 O
- O
low O
). O

U87 O
- O
DACH1 O
- O
low O
cells O
form O
spheroids O
with O
CD133 O
and O
Nestin O
expression O
in O
serum O
- O
free O
medium O
but O
U87 O
- O
DACH1 O
- O
high O
cells O
do O
not O
. O

Compared O
with O
spheroid O
- O
forming O
U87 O
- O
DACH1 O
- O
low O
cells O
, O
adherent O
U87 O
- O
DACH1 O
- O
high O
cells O
display O
lower O
tumorigenicity B
, O
indicating O
DACH1 O
decreases O
the O
number O
of O
tumor B
- O
initiating O
cells O
. O

Gene O
expression O
analysis O
and O
chromatin O
immunoprecipitation O
assay O
reveal O
that O
fibroblast O
growth O
factor O
2 O
( O
FGF2 O
/ O
bFGF O
) O
is O
transcriptionally O
repressed O
by O
DACH1 O
, O
especially O
in O
cells O
cultured O
in O
serum O
- O
free O
medium O
. O

Exogenous O
bFGF O
rescues O
spheroid O
- O
forming O
activity O
and O
tumorigenicity B
of O
the O
U87 O
- O
DACH1 O
- O
high O
cells O
, O
suggesting O
that O
loss O
of O
DACH1 O
increases O
the O
number O
of O
tumor B
- O
initiating O
cells O
through O
transcriptional O
activation O
of O
bFGF O
. O

These O
results O
illustrate O
that O
DACH1 O
is O
a O
distinctive O
tumor B
suppressor O
, O
which O
does O
not O
only O
suppress O
growth O
of O
tumor B
cells O
but O
also O
regulates O
bFGF O
- O
mediated O
tumor B
- O
initiating O
activity O
of O
glioma B
cells O
. O


Definition O
and O
management O
of O
anemia B
in O
patients O
infected O
with O
hepatitis O
C O
virus O
. O

Chronic B
infection I
with O
hepatitis O
C I
virus I
( O
HCV B
) O
can O
progress O
to O
cirrhosis B
, O
hepatocellular B
carcinoma I
, O
and O
end O
- O
stage O
liver I
disease I
. O

The O
current O
best O
treatment O
for O
HCV B
infection I
is O
combination O
therapy O
with O
pegylated B
interferon I
and O
ribavirin B
. O

Although O
this O
regimen O
produces O
sustained O
virologic O
responses O
( O
SVRs O
) O
in O
approximately O
50 O
% O
of O
patients O
, O
it O
can O
be O
associated O
with O
a O
potentially O
dose O
- O
limiting O
hemolytic B
anemia I
. O

Hemoglobin O
concentrations O
decrease O
mainly O
as O
a O
result O
of O
ribavirin B
- O
induced O
hemolysis B
, O
and O
this O
anemia B
can O
be O
problematic O
in O
patients O
with O
HCV B
infection I
, O
especially O
those O
who O
have O
comorbid O
renal B
or I
cardiovascular I
disorders I
. O

In O
general O
, O
anemia B
can O
increase O
the O
risk O
of O
morbidity O
and O
mortality O
, O
and O
may O
have O
negative O
effects O
on O
cerebral O
function O
and O
quality O
of O
life O
. O

Although O
ribavirin B
- O
associated O
anemia B
can O
be O
reversed O
by O
dose O
reduction O
or O
discontinuation O
, O
this O
approach O
compromises O
outcomes O
by O
significantly O
decreasing O
SVR B
rates O
. O

Recombinant O
human O
erythropoietin O
has O
been O
used O
to O
manage O
ribavirin B
- O
associated O
anemia B
but O
has O
other O
potential O
disadvantages O
. O

Viramidine B
, O
a O
liver O
- O
targeting O
prodrug O
of O
ribavirin B
, O
has O
the O
potential O
to O
maintain O
the O
virologic O
efficacy O
of O
ribavirin B
while O
decreasing O
the O
risk O
of O
hemolytic B
anemia I
in O
patients O
with O
chronic B
hepatitis I
C I
. O


Association O
between O
an O
endoglin O
gene O
polymorphism O
and O
systemic B
sclerosis I
- O
related O
pulmonary B
arterial I
hypertension I
. O

Systemic B
sclerosis I
( O
SSc B
) O
is O
a O
connective B
tissue I
disorder I
characterized O
by O
early O
generalized O
microangiopathy O
with O
disturbed O
angiogenesis O
. O

Endoglin O
gene O
( O
ENG O
) O
encodes O
a O
transmembrane O
glycoprotein O
which O
acts O
as O
an O
accessory O
receptor O
for O
the O
transforming O
growth O
factor O
- O
beta O
( O
TGF O
- O
beta O
) O
superfamily O
, O
and O
is O
crucial O
for O
maintaining O
vascular O
integrity O
. O

A O
6 O
- O
base O
insertion O
in O
intron O
7 O
( O
6bINS O
) O
of O
ENG O
has O
been O
reported O
to O
be O
associated O
with O
microvascular B
disturbance I
. O

OBJECTIVES O
: O
Our O
objective O
was O
to O
investigate O
the O
relationship O
between O
6bINS B
and O
the O
vascular O
complication O
pulmonary B
arterial I
hypertension I
( O
PAH B
) O
in O
SSc B
in O
a O
French O
Caucasian O
population O
. O

METHODS O
: O
Two O
hundred O
eighty O
SSc B
cases O
containing O
29 O
/ O
280 O
having O
PAH B
diagnosed O
by O
catheterism O
were O
compared O
with O
140 O
patients O
with O
osteoarthritis B
. O

Genotyping O
was O
performed O
by O
polymerase O
- O
chain O
- O
reaction O
- O
based O
fluorescence O
and O
direct O
sequencing O
of O
genomic O
DNA O
. O

RESULTS O
: O
The O
polymorphism O
was O
in O
Hardy O
- O
Weinberg O
equilibrium O
. O

We O
observed O
a O
significant O
lower O
frequency O
of O
6bINS O
allele O
in O
SSc B
patients O
with O
associated O
PAH B
compared O
with O
controls O
[ O
10 O
. O
3 O
vs O
23 O
. O
9 O
%, O
P O
= O
0 O
. O
1 O
; O
odds O
ratio O
( O
OR O
) O
0 O
. O
37 O
, O
95 O
% O
confidence O
interval O
( O
CI O
) O
0 O
. O
15 O
- O
0 O
. O
89 O
], O
and O
a O
trend O
in O
comparison O
with O
SSc B
patients O
without O
PAH B
( O
10 O
. O
3 O
vs O
20 O
. O
3 O
%, O
P O
= O
0 O
. O
5 O
; O
OR O
: O
0 O
. O
45 O
, O
95 O
% O
CI O
: O
0 O
. O
19 O
- O
1 O
. O
8 O
). O

Genotypes O
carrying O
allele O
6bINS O
were O
also O
less O
frequent O
in O
SSc B
patients O
with O
PAH B
than O
in O
controls O
( O
20 O
. O
7 O
vs O
42 O
. O
9 O
%, O
P O
= O
0 O
. O
2 O
). O

CONCLUSIONS O
: O
Thus O
the O
frequency O
of O
6bINS O
differs O
between O
SSc B
patients O
with O
or O
without O
PAH B
, O
suggesting O
the O
implication O
of O
ENG O
in O
this O
devastating O
vascular O
complication I
of O
SSc B
. O


Assessment O
of O
a O
new O
non O
- O
invasive O
index O
of O
cardiac O
performance O
for O
detection O
of O
dobutamine B
- O
induced O
myocardial B
ischemia I
. O

BACKGROUND O
: O
Electrocardiography O
has O
a O
very O
low O
sensitivity O
in O
detecting O
dobutamine B
- O
induced O
myocardial B
ischemia I
. O

OBJECTIVES O
: O
To O
assess O
the O
added O
diagnostic O
value O
of O
a O
new O
cardiac O
performance O
index O
( O
dP O
/ O
dtejc O
) O
measurement O
, O
based O
on O
brachial O
artery O
flow O
changes O
, O
as O
compared O
to O
standard O
12 O
- O
lead O
ECG O
, O
for O
detecting O
dobutamine B
- O
induced O
myocardial B
ischemia I
, O
using O
Tc99m O
- O
Sestamibi B
single O
- O
photon O
emission O
computed O
tomography O
as O
the O
gold O
standard O
of O
comparison O
to O
assess O
the O
presence O
or O
absence O
of O
ischemia B
. O

METHODS O
: O
The O
study O
group O
comprised O
40 O
patients O
undergoing O
Sestamibi B
- O
SPECT O
/ O
dobutamine B
stress O
test O
. O

Simultaneous O
measurements O
of O
ECG O
and O
brachial O
artery O
dP O
/ O
dtejc O
were O
performed O
at O
each O
dobutamine B
level O
. O

In O
19 O
of O
the O
40 O
patients O
perfusion O
defects O
compatible O
with O
ischemia B
were O
detected O
on O
SPECT O
. O

The O
increase O
in O
dP O
/ O
dtejc O
during O
infusion O
of O
dobutamine B
in O
this O
group O
was O
severely O
impaired O
as O
compared O
to O
the O
non O
- O
ischemic B
group O
. O

dP O
/ O
dtejc O
outcome O
was O
combined O
with O
the O
ECG O
results O
, O
giving O
an O
ECG O
- O
enhanced O
value O
, O
and O
compared O
to O
ECG O
alone O
. O

RESULTS O
: O
The O
sensitivity O
improved O
dramatically O
from O
16 O
% O
to O
79 O
%, O
positive O
predictive O
value O
increased O
from O
60 O
% O
to O
68 O
% O
and O
negative O
predictive O
value O
from O
54 O
% O
to O
78 O
%, O
and O
specificity O
decreased O
from O
90 O
% O
to O
67 O
%. O

CONCLUSIONS O
: O
If O
ECG O
alone O
is O
used O
for O
specificity O
, O
the O
combination O
with O
dP O
/ O
dtejc O
improved O
the O
sensitivity O
of O
the O
test O
and O
could O
be O
a O
cost O
- O
savings O
alternative O
to O
cardiac O
imaging O
or O
perfusion O
studies O
to O
detect O
myocardial B
ischemia I
, O
especially O
in O
patients O
unable O
to O
exercise O
. O


Effects O
of O
common O
germline O
genetic O
variation O
in O
cell O
cycle O
control O
genes O
on O
breast B
cancer I
survival O
: O
results O
from O
a O
population O
- O
based O
cohort O
. O

INTRODUCTION O
: O
Somatic O
alterations O
have O
been O
shown O
to O
correlate O
with O
breast B
cancer I
prognosis O
and O
survival O
, O
but O
less O
is O
known O
about O
the O
effects O
of O
common O
inherited O
genetic O
variation O
. O

Of O
particular O
interest O
are O
genes O
involved O
in O
cell O
cycle O
pathways O
, O
which O
regulate O
cell O
division O
. O

METHODS O
: O
We O
examined O
associations O
between O
common O
germline O
genetic O
variation O
in O
13 O
genes O
involved O
in O
cell O
cycle O
control O
( O
CCND1 O
, O
CCND2 O
, O
CCND3 O
, O
CCNE1 O
, O
CDK2 O
[ O
p33 O
], O
CDK4 O
, O
CDK6 O
, O
CDKN1A O
[ O
p21 O
, O
Cip1 O
], O
CDKN1B O
[ O
p27 O
, O
Kip1 O
], O
CDKN2A O
[ O
p16 O
], O
CDKN2B O
[ O
p15 O
], O
CDKN2C O
[ O
p18 O
], O
and O
CDKN2D O
[ O
p19 O
]) O

and O
survival O
among O
women O
diagnosed O
with O
invasive O
breast B
cancer I
participating O
in O
the O
SEARCH O
( O
Studies O
of O
Epidemiology O
and O
Risk O
factors O
in O
Cancer B
Heredity O
) O
breast B
cancer I
study O
. O

DNA O
from O
up O
to O
4 O
, O
470 O
women O
was O
genotyped O
for O
85 O
polymorphisms O
that O
tag O
the O
known O
common O
polymorphisms O
( O
minor O
allele O
frequency O
> O
0 O
. O
5 O
) O
in O
the O
genes O
. O

The O
genotypes O
of O
each O
polymorphism O
were O
tested O
for O
association O
with O
survival O
using O
Cox O
regression O
analysis O
. O

RESULTS O
: O
The O
rare O
allele O
of O
the O
tagging O
single O
nucleotide O
polymorphism O
( O
SNP O
) O
rs2479717 O
is O
associated O
with O
an O
increased O
risk O
of O
death B
( O
hazard O
ratio O
= O
1 O
. O
26 O
per O
rare O
allele O
carried O
, O
95 O
% O
confidence O
interval O
: O
1 O
. O
12 O
to O
1 O
. O
42 O
; O
P O
= O
0 O
. O
1 O
), O
which O
was O
not O
attenuated O
after O
adjusting O
for O
tumour B
stage O
, O
grade O
, O
and O
treatment O
. O

This O
SNP O
is O
part O
of O
a O
large O
linkage O
disequilibrium O
block O
, O
which O
contains O
CCND3 O
, O
BYSL O
, O
TRFP O
, O
USP49 O
, O
C6ofr49 O
, O
FRS3 O
, O
and O
PGC O
. O

We O
evaluated O
the O
association O
of O
survival O
and O
somatic O
expression O
of O
these O
genes O
in O
breast B
tumours I
using O
expression O
microarray O
data O
from O
seven O
published O
datasets O
. O

Elevated O
expression O
of O
the O
C6orf49 O
transcript O
was O
associated O
with O
breast B
cancer I
survival O
, O
adding O
biological O
interest O
to O
the O
finding O
. O

CONCLUSION O
: O
It O
is O
possible O
that O
CCND3 O
rs2479717 O
, O
or O
another O
variant O
it O
tags O
, O
is O
associated O
with O
prognosis O
after O
a O
diagnosis O
of O
breast B
cancer I
. O

Further O
study O
is O
required O
to O
validate O
this O
finding O
. O


Upregulation O
of O
centrosomal O
protein O
55 O
is O
associated O
with O
unfavorable O
prognosis O
and O
tumor B
invasion O
in O
epithelial B
ovarian I
carcinoma I
. O

Centrosomal O
protein O
55 O
( O
CEP55 O
) O
is O
a O
cell O
cycle O
regulator O
implicated O
in O
development O
of O
certain O
cancers B
. O

However O
, O
characteristics O
of O
CEP55 O
expression O
and O
its O
clinical O
/ O
prognostic O
significance O
are O
unclear O
in O
human O
epithelial B
ovarian I
carcinoma I
( O
EOC B
). O

Therefore O
, O
we O
investigated O
the O
expression O
and O
clinicopathological O
significance O
of O
CEP55 O
in O
patients O
with O
EOC B
and O
its O
role O
in O
regulating O
invasion O
and O
metastasis B
of O
ovarian I
cell O
lines O
. O

CEP55 O
mRNA O
and O
protein O
expression O
levels O
were O
detected O
by O
quantitative O
real O
- O
time O
PCR O
( O
qRT O
- O
PCR O
), O
Western O
blotting O
, O
and O
immunohistochemistry O
( O
IHC O
). O

Potential O
associations O
of O
CEP55 O
expression O
scores O
with O
clinical O
parameters O
and O
patient O
survival O
were O
evaluated O
. O

CEP55 O
function O
was O
investigated O
further O
using O
RNA O
interference O
, O
wound O
healing O
assay O
, O
transwell O
assay O
, O
immunofluorescence O
analysis O
, O
qRT O
- O
PCR O
, O
and O
Western O
blotting O
. O

CEP55 O
was O
significantly O
upregulated O
in O
ovarian B
cancer I
cell O
lines O
and O
lesions O
compared O
with O
normal O
cells O
and O
adjacent O
noncancerous O
ovarian O
tissues O
. O

In O
the O
213 O
EOC B
samples O
, O
CEP55 O
protein O
levels O
were O
positively O
correlated O
with O
clinical O
stage O
( O
P O
< O
0 O
. O
1 O
), O
lymph B
node I
metastasis I
( O
P O
< O
0 O
. O
1 O
), O
intraperitoneal B
metastasis I
( O
P O
< O
0 O
. O
1 O
), O
tumor B
recurrence O
( O
P O
< O
0 O
. O
1 O
), O
differentiation O
grade O
( O
P O
< O
0 O
. O
1 O
), O
residual O
tumor B
size O
( O
P O
< O
0 O
. O
1 O
), O
ascites B
see O
tumor B
cells O
( O
P O
= O
0 O
. O
20 O
), O
and O
serum O
CA153 O
level O
( O
P O
< O
0 O
. O
1 O
). O

Moreover O
, O
patients O
with O
aberrant O
CEP55 O
protein O
expression O
showed O
tendencies O
to O
receive O
neoadjuvant O
chemotherapy O
( O
P O
< O
0 O
. O
1 O
) O
and O
cytoreductive O
surgery O
( O
P O
= O
0 O
. O
20 O
). O

By O
contrast O
, O
no O
significant O
correlation O
was O
detected O
between O
the O
protein O
levels O
and O
patient O
age O
, O
histological O
type O
, O
or O
serum O
CA125 O
, O
CA199 O
, O
CA724 O
, O
NSE O
, O
CEA O
, O
and O
b O
- O
HCG O
levels O
. O

Patients O
with O
high O
CEP55 O
protein O
expression O
had O
shorter O
overall O
survival O
and O
disease O
- O
free O
survival O
compared O
with O
those O
with O
low O
CEP55 O
expression O
. O

Multivariate O
analysis O
implicated O
CEP55 O
as O
an O
independent O
prognostic O
indicator O
for O
EOC B
patients O
. O

Additionally O
, O
downregulation O
of O
CEP55 O
in O
ovarian B
cancer I
cells O
remarkably O
inhibited O
cellular O
motility O
and O
invasion O
. O

Aberrant O
CEP55 O
expression O
may O
predict O
unfavorable O
clinical O
outcomes O
in O
EOC B
patients O
and O
play O
an O
important O
role O
in O
regulating O
invasion O
in O
ovarian B
cancer I
cells O
. O

Thus O
, O
CEP55 O
may O
serve O
as O
a O
prognostic O
marker O
and O
therapeutic O
target O
for O
EOC B
. O


Male O
11b O
- O
HSD1 O
Knockout O
Mice O
Fed O
Trans O
- O
Fats O
and O
Fructose B
Are O
Not O
Protected O
From O
Metabolic B
Syndrome I
or O
Nonalcoholic B
Fatty I
Liver I
Disease I
. O

Nonalcoholic B
fatty I
liver I
disease I
( O
NAFLD B
) O
defines O
a O
spectrum O
of O
conditions O
from O
simple O
steatosis B
to O
nonalcoholic B
steatohepatitis I
( O
NASH B
) O
and O
cirrhosis B
and O
is O
regarded O
as O
the O
hepatic O
manifestation O
of O
the O
metabolic B
syndrome I
. O

Glucocorticoids B
can O
promote O
steatosis B
by O
stimulating O
lipolysis O
within O
adipose O
tissue O
, O
free B
fatty I
acid I
delivery O
to O
liver O
and O
hepatic O
de O
novo O
lipogenesis O
. O

Glucocorticoids B
can O
be O
reactivated O
in O
liver O
through O
11b O
- O
hydroxysteroid O
dehydrogenase O
type O
1 O
( O
11b O
- O
HSD1 O
) O
enzyme O
activity O
. O

Inhibition O
of O
11b O
- O
HSD1 O
has O
been O
suggested O
as O
a O
potential O
treatment O
for O
NAFLD B
. O

To O
test O
this O
, O
male O
mice O
with O
global O
( O
11b O
- O
HSD1 O
knockout O
[ O
KO O
]) O
and O
liver O
- O
specific O
( O
LKO O
) O
11b O
- O
HSD1 O
loss O
of O
function O
were O
fed O
the O
American O
Lifestyle O
Induced O
Obesity B
Syndrome I
( O
ALIOS B
) O
diet O
, O
known O
to O
recapitulate O
the O
spectrum O
of O
NAFLD B
, O
and O
metabolic O
and O
liver O
phenotypes O
assessed O
. O

Body O
weight O
, O
muscle O
and O
adipose O
tissue O
masses O
, O
and O
parameters O
of O
glucose B
homeostasis O
showed O
that O
11b O
- O
HSD1KO O
and O
LKO O
mice O
were O
not O
protected O
from O
systemic O
metabolic B
disease I
. O

Evaluation O
of O
hepatic O
histology O
, O
triglyceride B
content O
, O
and O
blinded O
NAFLD O
activity O
score O
assessment O
indicated O
that O
levels O
of O
steatosis B
were O
similar O
between O
11b O
- O
HSD1KO O
, O
LKO O
, O
and O
control O
mice O
. O

Unexpectedly O
, O
histological O
analysis O
revealed O
significantly O
increased O
levels O
of O
immune O
foci O
present O
in O
livers O
of O
11b O
- O
HSD1KO O
but O
not O
LKO O
or O
control O
mice O
, O
suggestive O
of O
a O
transition O
to O
NASH B
. O

This O
was O
endorsed O
by O
elevated O
hepatic O
expression O
of O
key O
immune O
cell O
and O
inflammatory B
markers O
. O

These O
data O
indicate O
that O
11b O
- O
HSD1 O
- O
deficient O
mice O
are O
not O
protected O
from O
metabolic B
disease I
or O
hepatosteatosis B
in O
the O
face O
of O
a O
NAFLD O
- O
inducing O
diet O
. O

However O
, O
global O
deficiency O
of O
11b O
- O
HSD1 O
did O
increase O
markers O
of O
hepatic B
inflammation I
and O
suggests O
a O
critical O
role O
for O
11b O
- O
HSD1 O
in O
restraining O
the O
transition O
to O
NASH B
. O


Single O
- O
strand O
conformation O
polymorphism O
analysis O
of O
the O
FMR1 O
gene O
in O
autistic B
and I
mentally I
retarded I
children O
in O
Japan O
. O

Fragile B
X I
syndrome I
is O
one O
of O
the O
most O
common O
causes O
of O
mental B
retardation I
in O
males O
, O
and O
patients O
with O
fragile B
X I
syndrome I
occasionally O
develop O
autism B
. O

It O
is O
usually O
caused O
by O
an O
expansion O
of O
the O
trinucleotide O
repeat O
in O
the O
5 O
'- O
untranslated O
region O
of O
the O
FMR1 O
gene O
, O
but O
in O
a O
small O
number O
of O
patients O
deletions O
and O
point O
mutations O
have O
been O
identified O
. O

We O
screened O
all O
17 O
exons O
of O
the O
FMR1 O
gene O
for O
mutations O
in O
90 O
autistic B
or I
mentally I
retarded I
children O
using O
polymerase O
chain O
reaction O
( O
PCR O
)- O
single O
strand O
conformation O
polymorphism O
( O
SSCP O
) O
analysis O
. O

No O
mutations O
were O
found O
in O
76 O
male O
patients O
. O

However O
, O
one O
female O
patient O
was O
heterozygous O
for O
a O
normal O
allele O
and O
a O
mutant O
allele O
with O
an O
A O
to O
C O
substitution O
at O
nucleotide O
879 O
in O
exon O
9 O
. O

This O
mutation O
was O
not O
found O
in O
50 O
controls O
. O

Reverse O
transcription O
- O
PCR O
revealed O
that O
a O
large O
proportion O
of O
the O
mutant O
transcripts O
were O
spliced O
aberrantly O
, O
causing O
premature O
termination O
of O
the O
protein O
synthesis O
. O

Although O
uncommon O
, O
point O
mutations O
in O
the O
FMR1 O
gene O
may O
be O
a O
cause O
of O
autism B
and O
mental B
retardation I
in O
Japanese O
patients O
. O


Pheochromocytoma B
unmasked O
by O
amisulpride B
and O
tiapride B
. O

OBJECTIVE O
: O
To O
describe O
the O
unmasking O
of O
pheochromocytoma B
in O
a O
patient O
treated O
with O
amisulpride B
and O
tiapride B
. O

CASE O
SUMMARY O
: O
A O
42 O
- O
year O
- O
old O
white O
man O
developed O
acute O
hypertension B
with O
severe O
headache B
and O
vomiting B
2 O
hours O
after O
the O
first O
doses O
of O
amisulpride B
100 O
mg O
and O
tiapride B
100 O
mg O
. O

Both O
drugs O
were O
immediately O
discontinued O
, O
and O
the O
patient O
recovered O
after O
subsequent O
nicardipine B
and O
verapamil B
treatment O
. O

Abdominal O
ultrasound O
showed O
an O
adrenal B
mass I
, O
and O
postoperative O
histologic O
examination O
confirmed O
the O
diagnosis O
of O
pheochromocytoma B
. O

DISCUSSION O
: O
Drug O
- O
induced O
symptoms O
of O
pheochromocytoma B
are O
often O
associated O
with O
the O
use O
of O
substituted O
benzamide B
drugs O
, O
but O
the O
underlying O
mechanism O
is O
unknown O
. O

In O
our O
case O
, O
use O
of O
the O
Naranjo O
probability O
scale O
indicated O
a O
possible O
relationship O
between O
the O
hypertensive B
crisis I
and O
amisulpride B
and O
tiapride B
therapy O
. O

CONCLUSIONS O
: O
As O
of O
March O
24 O
, O
2005 O
, O
this O
is O
the O
first O
reported O
case O
of O
amisulpride B
- O
and O
tiapride B
- O
induced O
hypertensive B
crisis I
in O
a O
patient O
with O
pheochromocytoma B
. O

Physicians O
and O
other O
healthcare O
professionals O
should O
be O
aware O
of O
this O
potential O
adverse O
effect O
of O
tiapride B
and O
amisulpride B
. O


Phenylephrine B
but O
not O
ephedrine B
reduces O
frontal O
lobe O
oxygenation O
following O
anesthesia O
- O
induced O
hypotension B
. O

BACKGROUND O
: O
Vasopressor O
agents O
are O
used O
to O
correct O
anesthesia O
- O
induced O
hypotension B
. O

We O
describe O
the O
effect O
of O
phenylephrine B
and O
ephedrine B
on O
frontal O
lobe O
oxygenation O
( O
S O
( O
c O
) O
O O
( O
2 O
)) O
following O
anesthesia O
- O
induced O
hypotension B
. O

METHODS O
: O
Following O
induction O
of O
anesthesia O
by O
fentanyl B
( O
0 O
. O
15 O
mg O
kg O
(- O
1 O
)) O
and O
propofol B
( O
2 O
. O
0 O
mg O
kg O
(- O
1 O
)), O
13 O
patients O
received O
phenylephrine B
( O
0 O
. O
1 O
mg O
iv O
) O
and O
12 O
patients O
received O
ephedrine B
( O
10 O
mg O
iv O
) O
to O
restore O
mean O
arterial O
pressure O
( O
MAP O
). O

Heart O
rate O
( O
HR O
), O
MAP O
, O
stroke O
volume O
( O
SV O
), O
cardiac O
output O
( O
CO O
), O
and O
frontal O
lobe O
oxygenation O
( O
S O
( O
c O
) O
O O
( O
2 O
)) O
were O
registered O
. O

RESULTS O
: O
Induction O
of O
anesthesia O
was O
followed O
by O
a O
decrease O
in O
MAP O
, O
HR O
, O
SV O
, O
and O
CO O
concomitant O
with O
an O
elevation O
in O
S B
( I
c I
) I
O I
( I
2 I
). I

After O
administration O
of O
phenylephrine B
, O
MAP O
increased O
( O
51 O
+/- O
12 O
to O
81 O
+/- O
13 O
mmHg O
; O
P O
< O
0 O
. O
1 O
; O
mean O
+/- O
SD O
). O

However O
, O
a O
14 O
% O
( O
from O
70 O
+/- O
8 O
% O
to O
60 O
+/- O
7 O
%) O
reduction O
in O
S O
( O
c O
) O
O O
( O
2 O
) O
( O
P O
< O
0 O
. O
5 O
) O
followed O
with O
no O
change O
in O
CO O
( O
3 O
. O
7 O
+/- O
1 O
. O
1 O
to O
3 O
. O
4 O
+/- O
0 O
. O
9 O
l O
min O
(- O
1 O
)). O

The O
administration O
of O
ephedrine B
led O
to O
a O
similar O
increase O
in O
MAP O
( O
53 O
+/- O
9 O
to O
79 O
+/- O
8 O
mmHg O
; O
P O
< O
0 O
. O
1 O
), O
restored O
CO O
( O
3 O
. O
2 O
+/- O
1 O
. O
2 O
to O
5 O
. O
0 O
+/- O
1 O
. O
3 O
l O
min O
(- O
1 O
)), O
and O
preserved O
S O
( I
c I
) I
O I
( I
2 I
). I

CONCLUSIONS O
: O
The O
utilization O
of O
phenylephrine B
to O
correct O
hypotension B
induced O
by O
anesthesia O
has O
a O
negative O
impact O
on O
S O
( O
c O
) O
O O
( O
2 O
) O
while O
ephedrine B
maintains O
frontal O
lobe O
oxygenation O
potentially O
related O
to O
an O
increase O
in O
CO O
. O


Somatic O
and O
gonadal O
mosaicism O
in O
X B
- I
linked I
retinitis I
pigmentosa I
. O

The O
g O
. O
ORF15 O
+ O
652 O
- O
653delAG O
mutation O
in O
the O
RPGR O
gene O
is O
the O
most O
frequent O
mutation O
in O
X B
- I
linked I
retinitis I
pigmentosa I
( O
XLRP B
). O

The O
objective O
of O
this O
study O
was O
to O
investigate O
the O
possibility O
of O
mosaicism O
in O
an O
XLRP B
family O
. O

Eight O
subjects O
in O
the O
RP B
family O
were O
recruited O
. O

Blood O
samples O
were O
collected O
for O
DNA O
extraction O
. O

Haplotype O
analysis O
and O
mutational O
screening O
on O
the O
RPGR O
gene O
were O
performed O
. O

Additionally O
, O
samples O
of O
hair O
follicles O
and O
buccal O
cells O
from O
the O
mother O
of O
the O
proband O
were O
acquired O
for O
DNA O
extraction O
and O
molecular O
analysis O
. O

Phenotype O
was O
characterized O
with O
routine O
ophthalmic O
examination O
, O
Goldmann O
perimetry O
, O
electroretinography O
, O
and O
color O
fundus O
photography O
. O

A O
g O
. O
ORF15 O
+ O
652 O
- O
653delAG O
mutation O
was O
identified O
in O
second O
- O
and O
third O
- O
generation O
patients O
/ O
carriers O
. O

A O
first O
- O
generation O
female O
, O
who O
was O
considered O
to O
be O
an O
obligate O
carrier O
, O
demonstrated O
a O
normal O
phenotype O
as O
well O
as O
a O
normal O
genotype O
in O
lymphocytic O
DNA O
, O
indicating O
the O
gonadal O
mosaicism O
; O
however O
, O
a O
heterozygous O
AG O
- O
deletion O
at O
nucleotide O
652 O
and O
653 O
was O
identified O
in O
the O
genomic O
DNA O
of O
hair O
follicles O
, O
hair O
shaft O
, O
and O
buccal O
cells O
, O
indicating O
that O
the O
mutation O
is O
somatic O
. O

In O
conclusion O
, O
we O
reported O
on O
a O
family O
in O
which O
an O
asymptomatic O
woman O
with O
somatic O
- O
gonadal O
mosaicism O
for O
a O
RPGR O
gene O
mutation O
transmitted O
the O
mutation O
to O
an O
asymptomatic O
daughter O
and O
to O
a O
son O
with O
XLRP B
. O

Gonadal O
mosaicism O
may O
be O
responsible O
for O
a O
proportion O
of O
multiplex O
or O
simplex O
RP B
families O
, O
in O
which O
more O
than O
50 O
% O
of O
all O
cases O
of O
RP B
are O
found O
. O

( O
c O
) O
2007 O
Wiley O
- O
Liss O
, O
Inc O
. O


Complete O
atrioventricular B
block I
secondary O
to O
lithium B
therapy O
. O

Sinus B
node I
dysfunction I
has O
been O
reported O
most O
frequently O
among O
the O
adverse O
cardiovascular O
effects O
of O
lithium B
. O

In O
the O
present O
case O
, O
complete O
atrioventricular B
( I
AV I
) I
block I
with O
syncopal B
attacks I
developed O
secondary O
to O
lithium B
therapy O
, O
necessitating O
permanent O
pacemaker O
implantation O
. O

Serum O
lithium B
levels O
remained O
under O
or O
within O
the O
therapeutic O
range O
during O
the O
syncopal B
attacks I
. O

Lithium B
should O
be O
used O
with O
extreme O
caution O
, O
especially O
in O
patients O
with O
mild O
disturbance B
of I
AV O
conduction O
. O


Organophosphate B
- O
induced O
convulsions B
and O
prevention O
of O
neuropathological B
damages I
. O

Such O
organophosphorus B
( O
OP B
) O
compounds O
as O
diisopropylfluorophosphate B
( O
DFP B
), O
sarin B
and O
soman B
are O
potent O
inhibitors O
of O
acetylcholinesterases O
( O
AChEs O
) O
and O
butyrylcholinesterases O
( O
BChEs O
). O

The O
acute O
toxicity B
of O
OPs B
is O
the O
result O
of O
their O
irreversible O
binding O
with O
AChEs O
in O
the O
central O
nervous O
system O
( O
CNS O
), O
which O
elevates O
acetylcholine B
( O
ACh B
) O
levels O
. O

The O
protective O
action O
of O
subcutaneously O
( O
SC O
) O
administered O
antidotes O
or O
their O
combinations O
in O
DFP B
( O
2 O
. O
0 O
mg O
/ O
kg O
BW O
) O
intoxication B
was O
studied O
in O
9 O
- O
10 O
- O
weeks O
- O
old O
Han O
- O
Wistar O
male O
rats O
. O

The O
rats O
received O
AChE O
reactivator O
pralidoxime B
- I
2 I
- I
chloride I
( O
2PAM B
) O
( O
30 O
. O
0 O
mg O
/ O
kg O
BW O
), O
anticonvulsant O
diazepam B
( O
2 O
. O
0 O
mg O
/ O
kg O
BW O
), O
A O
( O
1 O
)- O
adenosine O
receptor O
agonist O
N B
( I
6 I
)- I
cyclopentyl I
adenosine I
( O
CPA B
) O
( O
2 O
. O
0 O
mg O
/ O
kg O
BW O
), O
NMDA O
- O
receptor O
antagonist O
dizocilpine B
maleate I
(+- O
MK801 B
hydrogen I
maleate I
) O
( O
2 O
. O
0 O
mg O
/ O

kg O
BW O
) O
or O
their O
combinations O
with O
cholinolytic O
drug O
atropine B
sulfate I
( O
50 O
. O
0 O
mg O
/ O
kg O
BW O
) O
immediately O
or O
30 O
min O
after O
the O
single O
SC O
injection O
of O
DFP B
. O

The O
control O
rats O
received O
atropine B
sulfate I
, O
but O
also O
saline O
and O
olive B
oil I
instead O
of O
other O
antidotes O
and O
DFP B
, O
respectively O
. O

All O
rats O
were O
terminated O
either O
24 O
h O
or O
3 O
weeks O
after O
the O
DFP B
injection O
. O

The O
rats O
treated O
with O
DFP B
- I
atropine I
showed O
severe O
typical O
OP B
- O
induced O
toxicity B
signs O
. O

When O
CPA B
, O
diazepam B
or O
2PAM B
was O
given O
immediately O
after O
DFP B
- I
atropine I
, O
these O
treatments O
prevented O
, O
delayed O
or O
shortened O
the O
occurrence O
of O
serious O
signs O
of O
poisoning B
. O

Atropine B
- I
MK801 I
did O
not O
offer O
any O
additional O
protection O
against O
DFP B
toxicity B
. O

In O
conclusion O
, O
CPA B
, O
diazepam B
and O
2PAM B
in O
combination O
with O
atropine B
prevented O
the O
occurrence O
of O
serious O
signs O
of O
poisoning B
and O
thus O
reduced O
the O
toxicity B
of O
DFP B
in O
rat O
. O


The O
activation O
of O
spinal O
N O
- O
methyl O
- O
D O
- O
aspartate O
receptors O
may O
contribute O
to O
degeneration O
of O
spinal O
motor O
neurons O
induced O
by O
neuraxial O
morphine B
after O
a O
noninjurious O
interval O
of O
spinal B
cord I
ischemia I
. O

We O
investigated O
the O
relationship O
between O
the O
degeneration O
of O
spinal O
motor O
neurons O
and O
activation O
of O
N O
- O
methyl O
- O
d O
- O
aspartate O
( O
NMDA O
) O
receptors O
after O
neuraxial O
morphine B
following O
a O
noninjurious O
interval O
of O
aortic O
occlusion O
in O
rats O
. O

Spinal B
cord I
ischemia I
was O
induced O
by O
aortic O
occlusion O
for O
6 O
min O
with O
a O
balloon O
catheter O
. O

In O
a O
microdialysis O
study O
, O
10 O
muL O
of O
saline O
( O
group O
C O
; O
n O
= O
8 O
) O
or O
30 O
mug O
of O
morphine B
( O
group O
M O
; O
n O
= O
8 O
) O
was O
injected O
intrathecally O
( O
IT O
) O
0 O
. O
5 O
h O
after O
reflow O
, O
and O
30 O
mug O
of O
morphine B
( O
group O
SM O
; O
n O
= O
8 O
) O
or O
10 O
muL O
of O
saline O
( O
group O
SC O
; O
n O
= O
8 O
) O
was O
injected O
IT O
0 O
. O
5 O
h O
after O
sham O
operation O
. O

Microdialysis O
samples O
were O
collected O
preischemia O
, O
before O
IT O
injection O
, O
and O
at O
2 O
, O
4 O
, O
8 O
, O
24 O
, O
and O
48 O
h O
of O
reperfusion O
( O
after O
IT O
injection O
). O

Second O
, O
we O
investigated O
the O
effect O
of O
IT B
MK B
- I
801 I
( O
30 O
mug O
) O
on O
the O
histopathologic O
changes O
in O
the O
spinal O
cord O
after O
morphine B
- O
induced O
spastic B
paraparesis I
. O

After O
IT O
morphine B
, O
the O
cerebrospinal O
fluid O
( O
CSF O
) O
glutamate B
concentration O
was O
increased O
in O
group O
M O
relative O
to O
both O
baseline O
and O
group O
C O
( O
P O
< O
0 O
. O
5 O
). O

This O
increase O
persisted O
for O
8 O
hrs O
. O

IT O
MK B
- I
801 I
significantly O
reduced O
the O
number O
of O
dark O
- O
stained O
alpha O
- O
motoneurons O
after O
morphine B
- O
induced O
spastic B
paraparesis I
compared O
with O
the O
saline O
group O
. O

These O
data O
indicate O
that O
IT O
morphine B
induces O
spastic B
paraparesis I
with O
a O
concomitant O
increase O
in O
CSF O
glutamate B
, O
which O
is O
involved O
in O
NMDA O
receptor O
activation O
. O

We O
suggest O
that O
opioids B
may O
be O
neurotoxic B
in O
the O
setting O
of O
spinal B
cord I
ischemia I
via O
NMDA O
receptor O
activation O
. O


Growth O
- O
associated O
protein O
43 O
expression O
in O
hippocampal O
molecular O
layer O
of O
chronic O
epileptic B
rats O
treated O
with O
cycloheximide B
. O

PURPOSE O
: O
GAP43 O
has O
been O
thought O
to O
be O
linked O
with O
mossy O
fiber O
sprouting O
( O
MFS O
) O
in O
various O
experimental O
models O
of O
epilepsy B
. O

To O
investigate O
how O
GAP43 O
expression O
( O
GAP43 O
- O
ir O
) O
correlates O
with O
MFS O
, O
we O
assessed O
the O
intensity O
( O
densitometry O
) O
and O
extension O
( O
width O
) O
of O
GAP43 O
- O
ir O
in O
the O
inner O
molecular O
layer O
of O
the O
dentate O
gyrus O
( O
IML O
) O
of O
rats O
subject O
to O
status B
epilepticus I
induced O
by O
pilocarpine B
( O
Pilo B
), O
previously O
injected O
or O
not O
with O
cycloheximide B
( O
CHX B
), O
which O
has O
been O
shown O
to O
inhibit O
MFS O
. O

METHODS O
: O
CHX B
was O
injected O
before O
the O
Pilo O
injection O
in O
adult O
Wistar O
rats O
. O

The O
Pilo B
group O
was O
injected O
with O
the O
same O
drugs O
, O
except O
for O
CHX B
. O

Animals O
were O
killed O
between O
30 O
and O
60 O
days O
later O
, O
and O
brain O
sections O
were O
processed O
for O
GAP43 O
immunohistochemistry O
. O

RESULTS O
: O
Densitometry O
showed O
no O
significant O
difference O
regarding O
GAP43 O
- O
ir O
in O
the O
IML O
between O
Pilo B
, O
CHX B
+ O
Pilo B
, O
and O
control O
groups O
. O

However O
, O
the O
results O
of O
the O
width O
of O
the O
GAP43 O
- O
ir O
band O
in O
the O
IML O
showed O
that O
CHX B
+ O
Pilo B
and O
control O
animals O
had O
a O
significantly O
larger O
band O
( O
p O
= O
0 O
. O
3 O
) O
as O
compared O
with O
that O
in O
the O
Pilo B
group O
. O

CONCLUSIONS O
: O
Our O
current O
finding O
that O
animals O
in O
the O
CHX B
+ O
Pilo B
group O
have O
a O
GAP43 O
- O
ir O
band O
in O
the O
IML O
, O
similar O
to O
that O
of O
controls O
, O
reinforces O
prior O
data O
on O
the O
blockade O
of O
MFS O
in O
these O
animals O
. O

The O
change O
in O
GAP43 O
- O
ir O
present O
in O
Pilo B
- O
treated O
animals O
was O
a O
thinning O
of O
the O
band O
to O
a O
very O
narrow O
layer O
just O
above O
the O
granule O
cell O
layer O
that O
is O
likely O
to O
be O
associated O
with O
the O
loss O
of O
hilar O
cell O
projections O
that O
express O
GAP O
- O
43 O
. O


Daidzein B
activates O
choline O
acetyltransferase O
from O
MC O
- O
IXC O
cells O
and O
improves O
drug O
- O
induced O
amnesia B
. O

The O
choline B
acetyltransferase O
( O
ChAT O
) O
activator O
, O
which O
enhances O
cholinergic B
transmission O
via O
an O
augmentation O
of O
the O
enzymatic O
production O
of O
acetylcholine B
( O
ACh B
), O
is O
an O
important O
factor O
in O
the O
treatment O
of O
Alzheimer B
' I
s I
disease I
( O
AD B
). O

Methanolic O
extracts O
from O
Pueraria O
thunbergiana O
exhibited O
an O
activation O
effect O
( O
46 O
%) O
on O
ChAT O
in O
vitro O
. O

Via O
the O
sequential O
isolation O
of O
Pueraria O
thunbergiana O
, O
the O
active O
component O
was O
ultimately O
identified O
as O
daidzein B
( O
4 B
', I
7 I
- I
dihydroxy I
- I
isoflavone I
). O

In O
order O
to O
investigate O
the O
effects O
of O
daidzein B
from O
Pueraria O
thunbergiana O
on O
scopolamine B
- O
induced O
impairments B
of I
learning I
and I
memory I
, O
we O
conducted O
a O
series O
of O
in O
vivo O
tests O
. O

Administration O
of O
daidzein B
( O
4 O
. O
5 O
mg O
/ O
kg O
body O
weight O
) O
to O
mice O
was O
shown O
significantly O
to O
reverse O
scopolamine B
- O
induced O
amnesia B
, O
according O
to O
the O
results O
of O
a O
Y O
- O
maze O
test O
. O

Injections O
of O
scopolamine B
into O
mice O
resulted O
in O
impaired O
performance O
on O
Y O
- O
maze O
tests O
( O
a O
37 O
% O
decreases O
in O
alternation O
behavior O
). O

By O
way O
of O
contrast O
, O
mice O
treated O
with O
daidzein B
prior O
to O
the O
scopolamine B
injections O
were O
noticeably O
protected O
from O
this O
performance O
impairment O
( O
an O
approximately O
12 O
%- O
21 O
% O
decrease O
in O
alternation O
behavior O
). O

These O
results O
indicate O
that O
daidzein B
might O
play O
a O
role O
in O
acetylcholine B
biosynthesis O
as O
a O
ChAT O
activator O
, O
and O
that O
it O
also O
ameliorates O
scopolamine B
- O
induced O
amnesia B
. O


Effect O
of O
alpha B
- I
tocopherol I
and O
deferoxamine B
on O
methamphetamine B
- O
induced O
neurotoxicity B
. O

Methamphetamine B
( O
MA B
)- O
induced O
dopaminergic B
neurotoxicity B
is O
believed O
to O
be O
associated O
with O
the O
increased O
formation O
of O
free O
radicals O
. O

This O
study O
examined O
the O
effect O
of O
alpha B
- I
tocopherol I
( O
alpha B
- I
TC I
), O
a O
scavenger O
of O
reactive B
oxygen I
species I
, O
and O
deferoxamine B
( O
DFO B
), O
an O
iron B
chelator O
, O
on O
the O
MA B
- O
induced O
neurotoxicity B
. O

Male O
rats O
were O
treated O
with O
MA B
( O
10 O
mg O
/ O
kg O
, O
every O
2 O
h O
for O
four O
injections O
). O

The O
rat O
received O
either O
alpha B
- I
TC I
( O
20 O
mg O
/ O
kg O
) O
intraperitoneally O
for O
3 O
days O
and O
30 O
min O
prior O
to O
MA B
administration O
or O
DFO B
( O
50 O
mg O
/ O
kg O
) O
subcutaneously O
30 O
min O
before O
MA B
administration O
. O

The O
concentrations O
of O
dopamine B
( O
DA B
), O
serotonin B
and O
their O
metabolites O
decreased O
significantly O
after O
MA B
administration O
, O
which O
was O
inhibited O
by O
the O
alpha B
- I
TC I
and O
DFO B
pretreatment O
. O

alpha B
- I
TC I
and O
DFO B
attenuated O
the O
MA B
- O
induced O
hyperthermia B
as O
well O
as O
the O
alterations O
in O
the O
locomotor O
activity O
. O

The O
level O
of O
lipid B
peroxidation O
was O
higher O
and O
the O
reduced O
glutathione B
concentration O
was O
lower O
in O
the O
MA B
- O
treated O
rats O
. O

These O
changes O
were O
significantly O
attenuated O
by O
alpha O
- O
TC O
and O
DFO B
. O

This O
suggests O
that O
alpha B
- I
TC I
and O
DFO B
ameliorate O
the O
MA B
- O
induced O
neuronal B
damage I
by O
decreasing O
the O
level O
of O
oxidative O
stress O
. O


Cardiac O
Angiography O
in O
Renally B
Impaired I
Patients O
( O
CARE O
) O
study O
: O
a O
randomized O
double O
- O
blind O
trial O
of O
contrast B
- O
induced O
nephropathy B
in O
patients O
with O
chronic B
kidney I
disease I
. O

BACKGROUND O
: O
No O
direct O
comparisons O
exist O
of O
the O
renal O
tolerability O
of O
the O
low O
- O
osmolality O
contrast O
medium O
iopamidol B
with O
that O
of O
the O
iso O
- O
osmolality O
contrast O
medium O
iodixanol B
in O
high O
- O
risk O
patients O
. O

METHODS O
AND O
RESULTS O
: O
The O
present O
study O
is O
a O
multicenter O
, O
randomized O
, O
double O
- O
blind O
comparison O
of O
iopamidol B
and O
iodixanol B
in O
patients O
with O
chronic B
kidney I
disease I
( O
estimated O
glomerular O
filtration O
rate O
, O
20 O
to O
59 O
mL O
/ O
min O
) O
who O
underwent O
cardiac O
angiography O
or O
percutaneous O
coronary O
interventions O
. O

Serum O
creatinine B
( O
SCr B
) O
levels O
and O
estimated O
glomerular O
filtration O
rate O
were O
assessed O
at O
baseline O
and O
2 O
to O
5 O
days O
after O
receiving O
medications O
. O

The O
primary O
outcome O
was O
a O
postdose O
SCr O
increase O
> O
or O
= O
0 O
. O
5 O
mg O
/ O
dL O
( O
44 O
. O
2 O
micromol O
/ O
L O
) O
over O
baseline O
. O

Secondary O
outcomes O
were O
a O
postdose O
SCr O
increase O
> O
or O
= O
25 O
%, O
a O
postdose O
estimated O
glomerular O
filtration O
rate O
decrease O
of O
> O
or O
= O
25 O
%, O
and O
the O
mean O
peak O
change O
in O
SCr O
. O

In O
414 O
patients O
, O
contrast B
volume O
, O
presence O
of O
diabetes B
mellitus I
, O
use O
of O
N B
- I
acetylcysteine I
, O
mean O
baseline O
SCr O
, O
and O
estimated O
glomerular O
filtration O
rate O
were O
comparable O
in O
the O
2 O
groups O
. O

SCr O
increases O
> O
or O
= O
0 O
. O
5 O
mg O
/ O
dL O
occurred O
in O
4 O
. O
4 O
% O
( O
9 O
of O
204 O
patients O
) O
after O
iopamidol B
and O
6 O
. O
7 O
% O
( O
14 O
of O
210 O
patients O
) O
after O
iodixanol B
( O
P O
= O
0 O
. O
39 O
), O
whereas O
rates O
of O
SCr O
increases O
> O
or O
= O
25 O
% O
were O
9 O
. O
8 O
% O
and O
12 O
. O
4 O
%, O
respectively O
( O
P O
= O
0 O
. O
44 O
). O

In O
patients O
with O
diabetes B
, O
SCr O
increases O
> O
or O
= O
0 O
. O
5 O
mg O
/ O
dL O
were O
5 O
. O
1 O
% O
( O
4 O
of O
78 O
patients O
) O
with O
iopamidol B
and O
13 O
. O
0 O
% O
( O
12 O
of O
92 O
patients O
) O
with O
iodixanol B
( O
P O
= O
0 O
. O
11 O
), O
whereas O
SCr O
increases O
> O
or O
= O
25 O
% O
were O
10 O
. O
3 O
% O
and O
15 O
. O
2 O
%, O
respectively O
( O
P O
= O
0 O
. O
37 O
). O

Mean O
post O
- O
SCr O
increases O
were O
significantly O
less O
with O
iopamidol B
( O
all O
patients O
: O
0 O
. O
7 O
versus O
0 O
. O
12 O
mg O
/ O
dL O
, O
6 O
. O
2 O
versus O
10 O
. O
6 O
micromol O
/ O
L O
, O
P O
= O
0 O
. O
3 O
; O
patients O
with O
diabetes B
: O
0 O
. O
7 O
versus O
0 O
. O
16 O
mg O
/ O
dL O
, O
6 O
. O
2 O
versus O
14 O
. O
1 O
micromol O
/ O
L O
, O
P O
= O
0 O
. O
1 O
). O

CONCLUSIONS O
: O
The O
rate O
of O
contrast B
- O
induced O
nephropathy B
, O
defined O
by O
multiple O
end O
points O
, O
is O
not O
statistically O
different O
after O
the O
intraarterial O
administration O
of O
iopamidol B
or O
iodixanol B
to O
high O
- O
risk O
patients O
, O
with O
or O
without O
diabetes B
mellitus I
. O

Any O
TRUE O
difference O
between O
the O
agents O
is O
small O
and O
not O
likely O
to O
be O
clinically O
significant O
. O


Estrogen B
prevents O
cholesteryl B
ester I
accumulation O
in O
macrophages O
induced O
by O
the O
HIV O
protease O
inhibitor O
ritonavir B
. O

Individuals O
with O
HIV B
can O
now O
live O
long O
lives O
with O
drug O
therapy O
that O
often O
includes O
protease O
inhibitors O
such O
as O
ritonavir B
. O

Many O
patients O
, O
however O
, O
develop O
negative O
long O
- O
term O
side O
effects O
such O
as O
premature O
atherosclerosis B
. O

We O
have O
previously O
demonstrated O
that O
ritonavir B
treatment O
increases O
atherosclerotic B
lesion I
formation O
in O
male O
mice O
to O
a O
greater O
extent O
than O
in O
female O
mice O
. O

Furthermore O
, O
peripheral O
blood O
monocytes O
isolated O
from O
ritonavir B
- O
treated O
females O
had O
less O
cholesteryl B
ester I
accumulation O
. O

In O
the O
present O
study O
, O
we O
have O
investigated O
the O
molecular O
mechanisms O
by O
which O
female O
hormones O
influence O
cholesterol B
metabolism O
in O
macrophages O
in O
response O
to O
the O
HIV O
protease O
inhibitor O
ritonavir B
. O

We O
have O
utilized O
the O
human O
monocyte O
cell O
line O
, O
THP O
- O
1 O
as O
a O
model O
to O
address O
this O
question O
. O

Briefly O
, O
cells O
were O
differentiated O
for O
72 O
h O
with O
100 O
nM O
PMA B
to O
obtain O
a O
macrophage O
- O
like O
phenotype O
in O
the O
presence O
or O
absence O
of O
1 O
nM O
17beta B
- I
estradiol I
( O
E2 B
), O
100 O
nM O
progesterone B
or O
vehicle O
( O
0 O
. O
1 O
% O
ethanol B
). O

Cells O
were O
then O
treated O
with O
30 O
ng O
/ O
ml O
ritonavir B
or O
vehicle O
in O
the O
presence O
of O
aggregated O
LDL B
for O
24 O
h O
. O
Cell O
extracts O
were O
harvested O
, O
and O
lipid B
or O
total O
RNA O
was O
isolated O
. O

E2 B
decreased O
the O
accumulation O
of O
cholesteryl B
esters I
in O
macrophages O
following O
ritonavir B
treatment O
. O

Ritonavir B
increased O
the O
expression O
of O
the O
scavenger O
receptor O
, O
CD36 O
mRNA O
, O
responsible O
for O
the O
uptake O
of O
LDL B
. O

Additionally O
, O
ritonavir B
treatment O
selectively O
increased O
the O
relative O
levels O
of O
PPARgamma O
mRNA O
, O
a O
transcription O
factor O
responsible O
for O
the O
regulation O
of O
CD36 O
mRNA O
expression O
. O

Treatment O
with O
E2 B
, O
however O
, O
failed O
to O
prevent O
these O
increases O
at O
the O
mRNA O
level O
. O

E2 B
did O
, O
however O
, O
significantly O
suppress O
CD36 O
protein O
levels O
as O
measured O
by O
fluorescent O
immunocytochemistry O
. O

This O
data O
suggests O
that O
E2 O
modifies O
the O
expression O
of O
CD36 O
at O
the O
level O
of O
protein O
expression O
in O
monocyte O
- O
derived O
macrophages O
resulting O
in O
reduced O
cholesteryl B
ester I
accumulation O
following O
ritonavir B
treatment O
. O


Clinical O
comparison O
of O
cardiorespiratory O
effects O
during O
unilateral O
and O
conventional O
spinal O
anaesthesia O
. O

BACKGROUND O
: O
Spinal O
anaesthesia O
is O
widely O
employed O
in O
clinical O
practice O
but O
has O
the O
main O
drawback O
of O
post O
- O
spinal O
block O
hypotension B
. O

Efforts O
must O
therefore O
continue O
to O
be O
made O
to O
obviate O
this O
setback O
OBJECTIVE O
: O
To O
evaluate O
the O
cardiovascular O
and O
respiratory O
changes O
during O
unilateral O
and O
conventional O
spinal O
anaesthesia O
. O

METHODS O
: O
With O
ethical O
approval O
, O
we O
studied O
74 O
American O
Society O
of O
Anesthesiologists O
( O
ASA O
), O
physical O
status O
class O
1 O
and O
2 O
patients O
scheduled O
for O
elective O
unilateral O
lower O
limb O
surgery O
. O

Patients O
were O
randomly O
allocated O
into O
one O
of O
two O
groups O
: O
lateral O
and O
conventional O
spinal O
anaesthesia O
groups O
. O

In O
the O
lateral O
position O
with O
operative O
side O
down O
, O
patients O
recived O
10 O
mg O
( O
2mls O
) O
of O
0 O
. O
5 O
% O
hyperbaric O
bupivacaine B
through O
a O
25 O
- O
gauge O
spinal O
needle O
. O

Patients O
in O
the O
unilateral O
group O
were O
maintained O
in O
the O
lateral O
position O
for O
15 O
minutes O
following O
spinal O
injection O
while O
those O
in O
the O
conventional O
group O
were O
turned O
supine O
immediately O
after O
injection O
. O

Blood O
pressure O
, O
heart O
rate O
, O
respiratory O
rate O
and O
oxygen B
saturation O
were O
monitored O
over O
1 O
hour O
. O

RESULTS O
: O
Three O
patients O
( O
8 O
. O
1 O
%) O
in O
the O
unilateral O
group O
and O
5 O
( O
13 O
. O
5 O
%) O
in O
the O
conventional O
group O
developed O
hypotension B
, O
P O
= O
0 O
. O
71 O
. O

Four O
( O
10 O
. O
8 O
%) O
patients O
in O
the O
conventional O
group O
and O
1 O
( O
2 O
. O
7 O
%) O
in O
the O
unilateral O
group O
, O
P O
= O
0 O
. O
17 O
required O
epinephrine B
infusion O
to O
treat O
hypotension B
. O

Patients O
in O
the O
conventional O
group O
had O
statistically O
significant O
greater O
fall O
in O
the O
systolic O
blood O
pressures O
at O
15 O
, O
30 O
and O
45 O
minutes O
when O
compared O
to O
the O
baseline O
( O
P O
= O
0 O
. O
3 O
, O
0 O
. O
1 O
and O
0 O
. O
4 O
). O

The O
mean O
respiratory O
rate O
and O
oxygen B
saturations O
in O
the O
two O
groups O
were O
similar O
. O

CONCLUSION O
: O
Compared O
to O
conventional O
spinal O
anaesthesia O
, O
unilateral O
spinal O
anaesthesia O
was O
associated O
with O
fewer O
cardiovascular O
perturbations I
. O

Also O
, O
the O
type O
of O
spinal O
block O
instituted O
affected O
neither O
the O
respiratory O
rate O
nor O
the O
arterial O
oxygen B
saturation O
. O


Acute O
effects O
of O
N B
-( I
2 I
- I
propylpentanoyl I
) I
urea I
on O
hippocampal O
amino O
acid O
neurotransmitters B
in O
pilocarpine B
- O
induced O
seizure B
in O
rats O
. O

The O
present O
study O
aimed O
to O
investigate O
the O
anticonvulsant O
activity O
as O
well O
as O
the O
effects O
on O
the O
level O
of O
hippocampal O
amino O
acid O
neurotransmitters B
( O
glutamate B
, O
aspartate B
, O
glycine B
and O
GABA B
) O
of O
N B
-( I
2 I
- I
propylpentanoyl I
) I
urea I
( O
VPU B
) O
in O
comparison O
to O
its O
parent O
compound O
, O
valproic B
acid I
( O
VPA B
). O

VPU B
was O
more O
potent O
than O
VPA B
, O
exhibiting O
the O
median O
effective O
dose O
( O
ED O
( O
50 O
)) O
of O
49 O
mg O
/ O
kg O
in O
protecting O
rats O
against O
pilocarpine B
- O
induced O
seizure B
whereas O
the O
corresponding O
value O
for O
VPA B
was O
322 O
mg O
/ O
kg O
. O

In O
vivo O
microdialysis O
demonstrated O
that O
an O
intraperitoneal O
administration O
of O
pilocarpine B
induced O
a O
pronounced O
increment O
of O
hippocampal O
glutamate B
and O
aspartate B
whereas O
no O
significant O
change O
was O
observed O
on O
the O
level O
of O
glycine B
and O
GABA B
. O

Pretreatment O
with O
either O
VPU B
( O
50 O
and O
100 O
mg O
/ O
kg O
) O
or O
VPA B
( O
300 O
and O
600 O
mg O
/ O
kg O
) O
completely O
abolished O
pilocarpine B
- O
evoked O
increases O
in O
extracellular O
glutamate B
and O
aspartate B
. O

In O
addition O
, O
a O
statistically O
significant O
reduction O
was O
also O
observed O
on O
the O
level O
of O
GABA B
and O
glycine B
but O
less O
than O
a O
drastic O
reduction O
of O
glutamate B
and O
aspartate B
level O
. O

Based O
on O
the O
finding O
that O
VPU B
and O
VPA B
could O
protect O
the O
animals O
against O
pilocarpine B
- O
induced O
seizure B
it O
is O
suggested O
that O
the O
reduction O
of O
inhibitory O
amino O
acid O
neurotransmitters B
was O
comparatively O
minor O
and O
offset O
by O
a O
pronounced O
reduction O
of O
glutamate B
and O
aspartate B
. O

Therefore O
, O
like O
VPA B
, O
the O
finding O
that O
VPU B
could O
drastically O
reduce O
pilocarpine B
- O
induced O
increases O
in O
glutamate B
and O
aspartate B
should O
account O
, O
at O
least O
partly O
, O
for O
its O
anticonvulsant O
activity O
observed O
in O
pilocarpine B
- O
induced O
seizure B
in O
experimental O
animals O
. O

Some O
other O
mechanism O
than O
those O
being O
reported O
herein O
should O
be O
further O
investigated O
. O


Delirium B
in O
a O
patient O
with O
toxic O
flecainide B
plasma O
concentrations O
: O
the O
role O
of O
a O
pharmacokinetic O
drug O
interaction O
with O
paroxetine B
. O

OBJECTIVE O
: O
To O
describe O
a O
case O
of O
flecainide B
- O
induced O
delirium B
associated O
with O
a O
pharmacokinetic O
drug O
interaction O
with O
paroxetine B
. O

CASE O
SUMMARY O
: O
A O
69 O
- O
year O
- O
old O
white O
female O
presented O
to O
the O
emergency O
department O
with O
a O
history O
of O
confusion B
and O
paranoia B
over O
the O
past O
several O
days O
. O

On O
admission O
the O
patient O
was O
taking O
carvedilol B
12 O
mg O
twice O
daily O
, O
warfarin B
2 O
mg O
/ O
day O
, O
folic B
acid I
1 O
mg O
/ O
day O
, O
levothyroxine B
100 O
microg O
/ O
day O
, O
pantoprazole B
40 O
mg O
/ O
day O
, O
paroxetine B
40 O
mg O
/ O
day O
, O
and O
flecainide B
100 O
mg O
twice O
daily O
. O

Flecainide B
had O
been O
started O
2 O
weeks O
prior O
for O
atrial B
fibrillation I
. O

Laboratory O
test O
findings O
on O
admission O
were O
notable O
only O
for O
a O
flecainide B
plasma O
concentration O
of O
1360 O
microg O
/ O
L O
( O
reference O
range O
200 O
- O
1000 O
). O

A O
metabolic O
drug O
interaction O
between O
flecainide B
and O
paroxetine B
, O
which O
the O
patient O
had O
been O
taking O
for O
more O
than O
5 O
years O
, O
was O
considered O
. O

Paroxetine B
was O
discontinued O
and O
the O
dose O
of O
flecainide B
was O
reduced O
to O
50 O
mg O
twice O
daily O
. O

Her O
delirium B
resolved O
3 O
days O
later O
. O

DISCUSSION O
: O
Flecainide B
and O
pharmacologically O
similar O
agents O
that O
interact O
with O
sodium B
channels O
may O
cause O
delirium B
in O
susceptible O
patients O
. O

A O
MEDLINE O
search O
( O
1966 O
- O
January O
2009 O
) O
revealed O
one O
in O
vivo O
pharmacokinetic O
study O
on O
the O
interaction O
between O
flecainide B
, O
a O
CYP2D6 O
substrate O
, O
and O
paroxetine B
, O
a O
CYP2D6 O
inhibitor O
, O
as O
well O
as O
3 O
case O
reports O
of O
flecainide B
- O
induced O
delirium B
. O

According O
to O
the O
Naranjo O
probability O
scale O
, O
flecainide B
was O
the O
probable O
cause O
of O
the O
patient O
' O
s O
delirium B
; O
the O
Horn O
Drug O
Interaction O
Probability O
Scale O
indicates O
a O
possible O
pharmacokinetic O
drug O
interaction O
between O
flecainide B
and O
paroxetine B
. O

CONCLUSIONS O
: O
Supratherapeutic O
flecainide B
plasma O
concentrations O
may O
cause O
delirium B
. O

Because O
toxicity B
may O
occur O
when O
flecainide B
is O
prescribed O
with O
paroxetine B
and O
other O
potent O
CYP2D6 B
inhibitors I
, O
flecainide B
plasma O
concentrations O
should O
be O
monitored O
closely O
with O
commencement O
of O
CYP2D6 B
inhibitors I
. O


Depression B
, O
impulsiveness O
, O
sleep O
, O
and O
memory O
in O
past O
and O
present O
polydrug O
users O
of O
3 B
, I
4 I
- I
methylenedioxymethamphetamine I
( O
MDMA B
, O
ecstasy B
). O

RATIONALE O
: O
Ecstasy B
( O
3 B
, I
4 I
- I
methylenedioxymethamphetamine I
, O
MDMA B
) O
is O
a O
worldwide O
recreational O
drug O
of O
abuse O
. O

Unfortunately O
, O
the O
results O
from O
human O
research O
investigating O
its O
psychological O
effects O
have O
been O
inconsistent O
. O

OBJECTIVES O
: O
The O
present O
study O
aimed O
to O
be O
the O
largest O
to O
date O
in O
sample O
size O
and O
5HT B
- O
related O
behaviors O
; O
the O
first O
to O
compare O
present O
ecstasy B
users O
with O
past O
users O
after O
an O
abstinence O
of O
4 O
or O
more O
years O
, O
and O
the O
first O
to O
include O
robust O
controls O
for O
other O
recreational O
substances O
. O

METHODS O
: O
A O
sample O
of O
997 O
participants O
( O
52 O
% O
male O
) O
was O
recruited O
to O
four O
control O
groups O
( O
non O
- O
drug O
( O
ND O
), O
alcohol B
/ O
nicotine B
( O
AN B
), O
cannabis B
/ O
alcohol B
/ O
nicotine B
( O
CAN B
), O
non O
- O
ecstasy B
polydrug O
( O
PD O
)), O
and O
two O
ecstasy B
polydrug O
groups O
( O
present O
( O
MDMA B
) O
and O
past O
users O
( O
EX O
- O
MDMA B
). O

Participants O
completed O
a O
drug O
history O
questionnaire O
, O
Beck O
Depression B
Inventory O
, O
Barratt O
Impulsiveness O
Scale O
, O
Pittsburgh O
Sleep O
Quality O
Index O
, O
and O
Wechsler O
Memory O
Scale O
- O
Revised O
which O
, O
in O
total O
, O
provided O
13 O
psychometric O
measures O
. O

RESULTS O
: O
While O
the O
CAN B
and O
PD B
groups O
tended O
to O
record O
greater O
deficits B
than O
the O
non O
- O
drug O
controls O
, O
the O
MDMA B
and O
EX O
- O
MDMA B
groups O
recorded O
greater O
deficits O
than O
all O
the O
control O
groups O
on O
ten O
of O
the O
13 O
psychometric O
measures O
. O

Strikingly O
, O
despite O
prolonged O
abstinence O
( O
mean O
, O
4 O
. O
98 O
; O
range O
, O
4 O
- O
9 O
years O
), O
past O
ecstasy B
users O
showed O
few O
signs O
of O
recovery O
. O

Compared O
with O
present O
ecstasy B
users O
, O
the O
past O
users O
showed O
no O
change O
for O
ten O
measures O
, O
increased O
impairment B
for O
two O
measures O
, O
and O
improvement O
on O
just O
one O
measure O
. O

CONCLUSIONS O
: O
Given O
this O
record O
of O
impaired B
memory I
and O
clinically O
significant O
levels O
of O
depression B
, O
impulsiveness B
, O
and O
sleep B
disturbance I
, O
the O
prognosis O
for O
the O
current O
generation O
of O
ecstasy B
users O
is O
a O
major O
cause O
for O
concern O
. O


A O
comparison O
of O
severe O
hemodynamic B
disturbances I
between O
dexmedetomidine B
and O
propofol B
for O
sedation O
in O
neurocritical O
care O
patients O
. O

OBJECTIVE O
: O
Dexmedetomidine B
and O
propofol B
are O
commonly O
used O
sedatives B
in O
neurocritical O
care O
as O
they O
allow O
for O
frequent O
neurologic O
examinations O
. O

However O
, O
both O
agents O
are O
associated O
with O
significant O
hemodynamic O
side O
effects O
. O

The O
primary O
objective O
of O
this O
study O
is O
to O
compare O
the O
prevalence O
of O
severe O
hemodynamic O
effects O
in O
neurocritical O
care O
patients O
receiving O
dexmedetomidine B
and O
propofol B
. O

DESIGN O
: O
Multicenter O
, O
retrospective O
, O
propensity O
- O
matched O
cohort O
study O
. O

SETTING O
: O
Neurocritical O
care O
units O
at O
two O
academic O
medical O
centers O
with O
dedicated O
neurocritical O
care O
teams O
and O
board O
- O
certified O
neurointensivists O
. O

PATIENTS O
: O
Neurocritical O
care O
patients O
admitted O
between O
July O
2009 O
and O
September O
2012 O
were O
evaluated O
and O
then O
matched O
1 O
: O
1 O
based O
on O
propensity O
scoring O
of O
baseline O
characteristics O
. O

INTERVENTIONS O
: O
Continuous O
sedation O
with O
dexmedetomidine B
or O
propofol B
. O

MEASUREMENTS O
AND O
MAIN O
RESULTS O
: O
A O
total O
of O
342 O
patients O
( O
105 O
dexmedetomidine B
and O
237 O
propofol B
) O
were O
included O
in O
the O
analysis O
, O
with O
190 O
matched O
( O
95 O
in O
each O
group O
) O
by O
propensity O
score O
. O

The O
primary O
outcome O
of O
this O
study O
was O
a O
composite O
of O
severe O
hypotension B
( O
mean O
arterial O
pressure O
< O
60 O
mm O
Hg O
) O
and O
bradycardia B
( O
heart O
rate O
< O
50 O
beats O
/ O
min O
) O
during O
sedative O
infusion O
. O

No O
difference O
in O
the O
primary O
composite O
outcome O
in O
both O
the O
unmatched O
( O
30 O
% O
vs O
30 O
%, O
p O
= O
0 O
. O
94 O
) O
or O
matched O
cohorts O
( O
28 O
% O
vs O
34 O
%, O
p O
= O
0 O
. O
35 O
) O
could O
be O
found O
. O

When O
analyzed O
separately O
, O
no O
differences O
could O
be O
found O
in O
the O
prevalence O
of O
severe O
hypotension B
or O
bradycardia B
in O
either O
the O
unmatched O
or O
matched O
cohorts O
. O

CONCLUSIONS O
: O
Severe O
hypotension B
and O
bradycardia B
occur O
at O
similar O
prevalence O
in O
neurocritical O
care O
patients O
who O
receive O
dexmedetomidine B
or O
propofol B
. O

Providers O
should O
similarly O
consider O
the O
likelihood O
of O
hypotension B
or O
bradycardia B
before O
starting O
either O
sedative O
. O


Effects O
of O
dehydroepiandrosterone B
in O
amphetamine B
- O
induced O
schizophrenia B
models O
in O
mice O
. O

OBJECTIVE O
: O
To O
examine O
the O
effects O
of O
dehydroepiandrosterone B
( O
DHEA B
) O
on O
animal O
models O
of O
schizophrenia B
. O

METHODS O
: O
Seventy O
Swiss O
albino O
female O
mice O
( O
25 O
- O
35 O
g O
) O
were O
divided O
into O
4 O
groups O
: O
amphetamine B
- O
free O
( O
control O
), O
amphetamine B
, O
50 O
, O
and O
100 O
mg O
/ O
kg O
DHEA O
. O

The O
DHEA B
was O
administered O
intraperitoneally O
( O
ip O
) O
for O
5 O
days O
. O

Amphetamine B
( O
3 O
mg O
/ O
kg O
ip O
) O
induced O
hyper B
locomotion I
, O
apomorphine B
( O
1 O
. O
5 O
mg O
/ O
kg O
subcutaneously O
[ O
sc O
]) O
induced O
climbing O
, O
and O
haloperidol B
( O
1 O
. O
5 O
mg O
/ O
kg O
sc O
) O
induced O
catalepsy B
tests O
were O
used O
as O
animal O
models O
of O
schizophrenia B
. O

The O
study O
was O
conducted O
at O
the O
Animal O
Experiment O
Laboratories O
, O
Department O
of O
Pharmacology O
, O
Medical O
School O
, O
Eskisehir O
Osmangazi O
University O
, O
Eskisehir O
, O
Turkey O
between O
March O
and O
May O
2012 O
. O

Statistical O
analysis O
was O
carried O
out O
using O
Kruskal O
- O
Wallis O
test O
for O
hyper B
locomotion O
, O
and O
one O
- O
way O
ANOVA O
for O
climbing O
and O
catalepsy B
tests O
. O

RESULTS O
: O
In O
the O
amphetamine B
- O
induced O
locomotion O
test O
, O
there O
were O
significant O
increases O
in O
all O
movements O
compared O
with O
the O
amphetamine B
- O
free O
group O
. O

Both O
DHEA B
50 O
mg O
/ O
kg O
( O
p O
< O
0 O
. O
5 O
), O
and O
100 O
mg O
/ O
kg O
( O
p O
< O
0 O
. O
1 O
) O
significantly O
decreased O
all O
movements O
compared O
with O
the O
amphetamine B
- O
induced O
locomotion O
group O
. O

There O
was O
a O
significant O
difference O
between O
groups O
in O
the O
haloperidol B
- O
induced O
catalepsy B
test O
( O
p O
< O
0 O
. O
5 O
). O

There O
was O
no O
significant O
difference O
between O
groups O
in O
terms O
of O
total O
climbing O
time O
in O
the O
apomorphine B
- O
induced O
climbing O
test O
( O
p O
> O
0 O
. O
5 O
). O

CONCLUSION O
: O
We O
observed O
that O
DHEA B
reduced O
locomotor O
activity O
and O
increased O
catalepsy B
at O
both O
doses O
, O
while O
it O
had O
no O
effect O
on O
climbing O
behavior O
. O

We O
suggest O
that O
DHEA B
displays O
typical O
neuroleptic B
- O
like O
effects O
, O
and O
may O
be O
used O
in O
the O
treatment O
of O
schizophrenia B
. O


Aconitine B
- O
induced O
Ca2 B
+ I
overload O
causes O
arrhythmia B
and O
triggers O
apoptosis O
through O
p38 O
MAPK O
signaling O
pathway O
in O
rats O
. O

Aconitine B
is O
a O
major O
bioactive O
diterpenoid B
alkaloid I
with O
high O
content O
derived O
from O
herbal O
aconitum O
plants O
. O

Emerging O
evidence O
indicates O
that O
voltage O
- O
dependent O
Na B
(+) O
channels O
have O
pivotal O
roles O
in O
the O
cardiotoxicity B
of O
aconitine B
. O

However O
, O
no O
reports O
are O
available O
on O
the O
role O
of O
Ca B
( I
2 I
+) I
in O
aconitine B
poisoning I
. O

In O
this O
study O
, O
we O
explored O
the O
importance O
of O
pathological O
Ca B
( I
2 I
+) I
signaling O
in O
aconitine B
poisoning I
in O
vitro O
and O
in O
vivo O
. O

We O
found O
that O
Ca B
( I
2 I
+) I
overload O
lead O
to O
accelerated O
beating O
rhythm O
in O
adult O
rat O
ventricular O
myocytes O
and O
caused O
arrhythmia B
in O
conscious O
freely O
moving O
rats O
. O

To O
investigate O
effects O
of O
aconitine B
on O
myocardial B
injury I
, O
we O
performed O
cytotoxicity B
assay O
in O
neonatal O
rat O
ventricular O
myocytes O
( O
NRVMs O
), O
as O
well O
as O
measured O
lactate O
dehydrogenase O
level O
in O
the O
culture O
medium O
of O
NRVMs O
and O
activities O
of O
serum O
cardiac O
enzymes O
in O
rats O
. O

The O
results O
showed O
that O
aconitine B
resulted O
in O
myocardial B
injury I
and O
reduced O
NRVMs O
viability O
dose O
- O
dependently O
. O

To O
confirm O
the O
pro O
- O
apoptotic O
effects O
, O
we O
performed O
flow O
cytometric O
detection O
, O
cardiac O
histology O
, O
transmission O
electron O
microscopy O
and O
terminal O
deoxynucleotidyl O
transferase O
- O
mediated O
dUTP B
- O
biotin B
nick O
end O
labeling O
assay O
. O

The O
results O
showed O
that O
aconitine B
stimulated O
apoptosis O
time O
- O
dependently O
. O

The O
expression O
analysis O
of O
Ca B
( I
2 I
+) I
handling O
proteins O
demonstrated O
that O
aconitine B
promoted O
Ca B
( I
2 I
+) I
overload O
through O
the O
expression O
regulation O
of O
Ca B
( I
2 I
+) I
handling O
proteins O
. O

The O
expression O
analysis O
of O
apoptosis O
- O
related O
proteins O
revealed O
that O
pro O
- O
apoptotic O
protein O
expression O
was O
upregulated O
, O
and O
anti O
- O
apoptotic O
protein O
BCL O
- O
2 O
expression O
was O
downregulated O
. O

Furthermore O
, O
increased O
phosphorylation O
of O
MAPK O
family O
members O
, O
especially O
the O
P O
- O
P38 O
/ O
P38 O
ratio O
was O
found O
in O
cardiac O
tissues O
. O

Hence O
, O
our O
results O
suggest O
that O
aconitine B
significantly O
aggravates O
Ca B
( I
2 I
+) I
overload I
and O
causes O
arrhythmia B
and O
finally O
promotes O
apoptotic O
development O
via O
phosphorylation O
of O
P38 O
mitogen O
- O
activated O
protein O
kinase O
. O