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ijp
h
s
.
ia
esco
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co
m
H
epa
toto
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icity
e
ff
ect
of
a
lco
ho
lic be
v
erag
es
on
histo
lo
g
y
and
I
L
-
6
g
ene de
tect
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in
Ra
ttus no
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p
o
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it
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h J
a
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a
s
a
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m
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ta
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c
a
n
d
d
e
to
x
ifi
c
a
ti
o
n
p
ro
c
e
ss
e
s.
Alc
o
h
o
l
c
o
n
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m
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ti
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l
c
a
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se
m
e
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o
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c
d
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th
e
li
v
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r
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n
d
c
a
n
c
a
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se
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h
a
n
g
e
s
i
n
h
isto
l
o
g
ica
l
s
tru
c
tu
re
s.
In
terle
u
k
i
n
-
6
h
a
s
a
p
ro
f
o
u
n
d
r
o
le
in
li
v
e
r
p
a
th
o
lo
g
y
a
n
d
p
lay
s
a
n
imp
o
rtan
t
ro
le
in
th
e
b
o
d
y
'
s
d
e
fe
n
se
m
e
c
h
a
n
ism
,
a
n
d
c
o
n
tr
ib
u
tes
to
th
e
m
a
n
ifes
tatio
n
o
f
ti
ss
u
e
d
a
m
a
g
e
.
Th
is
stu
d
y
w
a
s
a
n
e
x
p
e
rime
n
tal
stu
d
y
u
sin
g
20
R
a
tt
u
s
n
o
rv
e
g
icu
s
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ted
with
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5
%
a
l
c
o
h
o
l
,
a
n
d
a
n
o
rm
a
l
trea
tme
n
t
o
n
l
y
g
iv
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n
d
isti
ll
e
d
wa
ter.
Histo
l
o
g
ica
l
o
b
se
rv
a
ti
o
n
s
we
re
c
a
rried
o
u
t
o
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e
a
c
h
p
re
p
a
ra
ti
o
n
i
n
5
fiel
d
s
o
f
v
iew
.
Th
e
h
e
p
a
to
to
x
icity
e
ffe
c
t
o
f
a
lco
h
o
l
wa
s
o
b
se
rv
e
d
b
a
se
d
o
n
t
h
e
p
re
se
n
c
e
o
f
c
e
ll
d
e
g
e
n
e
ra
ti
o
n
a
n
d
n
e
c
ro
sis
in
h
isto
l
o
g
ica
l
p
re
p
a
ra
ti
o
n
s
sta
i
n
e
d
with
h
e
m
a
to
x
y
li
n
e
o
sin
.
IL
-
6
d
e
tec
ti
o
n
wit
h
p
o
l
y
m
e
ra
se
c
h
a
in
re
a
c
ti
o
n
wa
s
a
n
a
ly
z
e
d
q
u
a
li
tati
v
e
ly
u
sin
g
e
lec
tr
o
p
h
o
re
sis.
Ba
se
d
o
n
th
e
sta
ti
stica
l
tes
t
re
su
lt
s,
th
e
sig
.
(2
tailed
)
o
f
0
.
0
0
<
0
.
0
5
so
th
a
t
it
c
a
n
b
e
se
e
n
th
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t
t
h
e
re
is
a
sig
n
ifi
c
a
n
t
d
iffere
n
c
e
in
h
isto
lo
g
ica
l
re
su
lt
s
b
e
twe
e
n
th
e
n
o
rm
a
l
c
o
n
tro
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g
r
o
u
p
with
o
u
t
t
re
a
tme
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t
a
n
d
t
h
e
g
ro
u
p
in
d
u
c
e
d
b
y
a
lco
h
o
l
.
Th
e
a
d
m
i
n
istratio
n
o
f
a
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li
c
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e
v
e
ra
g
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s
with
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5
%
e
th
a
n
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l
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n
ten
t
i
n
v
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v
o
f
o
r
2
1
d
a
y
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c
a
u
se
s
n
e
c
ro
sis
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n
d
b
lee
d
i
n
g
a
r
o
u
n
d
t
h
e
h
e
p
a
to
c
y
te
c
e
ll
s.
IL
-
6
o
v
e
rv
iew
a
p
p
e
a
re
d
to
b
e
stro
n
g
e
r
in
t
h
e
g
ro
u
p
with
a
lco
h
o
l
-
i
n
d
u
c
e
d
d
ri
n
k
in
g
,
it
c
o
u
ld
i
n
d
ica
te
th
a
t
g
iv
in
g
a
lco
h
o
l
c
a
u
se
s
a
h
ig
h
e
r
i
n
flam
m
a
to
ry
re
sp
o
n
se
.
T
h
is
st
u
d
y
p
ro
v
id
e
s
sc
ien
ti
fic
e
v
i
d
e
n
c
e
th
a
t
a
lco
h
o
l
c
o
n
s
u
m
p
ti
o
n
si
g
n
i
fica
n
tl
y
d
a
m
a
g
e
s
th
e
li
v
e
r.
F
u
rt
h
e
r
re
se
a
rc
h
c
a
n
b
e
c
o
n
d
u
c
ted
t
o
in
c
re
a
se
th
e
sa
m
p
le
siz
e
a
n
d
q
u
a
n
ti
tativ
e
ly
a
ss
e
ss
IL
-
6
e
x
p
re
ss
io
n
.
K
ey
w
o
r
d
s
:
Alco
h
o
l
Hep
ato
to
x
icity
His
to
lo
g
y
I
L
-
6
PC
R
R
attu
s
n
o
r
v
eg
icu
s
T
h
is i
s
a
n
o
p
e
n
a
c
c
e
ss
a
rticle
u
n
d
e
r th
e
CC B
Y
-
SA
li
c
e
n
se
.
C
o
r
r
e
s
p
o
nd
ing
A
uth
o
r
:
Fit
r
ia
Din
iah
J
an
ah
Say
ek
ti
M
ed
ical
L
ab
o
r
ato
r
y
T
ec
h
n
o
lo
g
y
,
Sek
o
lah
T
in
g
g
i I
lm
u
Kese
h
atan
Nasio
n
al
Su
r
ak
ar
ta,
C
en
tr
al
J
av
a
,
I
n
d
o
n
esia
E
m
ail:
f
itria
.
d
in
iah
@
s
tik
esn
as
.
ac
.
id
1.
I
NT
RO
D
UCT
I
O
N
Alco
h
o
lic
b
ev
er
a
g
es
ar
e
o
n
e
t
y
p
e
o
f
a
d
d
ictiv
e
s
u
b
s
tan
ce
wh
o
s
e
ab
u
s
e
h
as
a
s
er
io
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s
im
p
ac
t
o
n
p
u
b
lic
h
ea
lth
an
d
s
o
cial
p
r
o
b
lem
s
.
Ad
d
ictio
n
to
co
n
s
u
m
in
g
alc
o
h
o
lic
b
ev
er
a
g
es
h
as
b
ec
o
m
e
a
s
er
io
u
s
h
ea
lth
p
r
o
b
lem
to
d
a
y
.
On
e
ty
p
e
o
f
a
lco
h
o
lic
d
r
in
k
th
at
is
o
f
ten
f
o
u
n
d
in
I
n
d
o
n
esia
is
th
e
tr
ad
iti
o
n
al
ciu
liq
u
o
r
[
1
]
.
C
iu
is
m
ad
e
f
r
o
m
f
er
m
e
n
ted
l
iq
u
id
waste
f
r
o
m
t
h
e
s
u
g
a
r
-
m
ak
in
g
p
r
o
ce
s
s
,
n
a
m
ely
f
er
m
en
ted
ca
n
e
m
o
lass
es
,
an
d
u
n
d
er
g
o
es
a
d
is
till
atio
n
p
r
o
ce
s
s
.
C
iu
i
s
in
clu
d
ed
in
g
r
o
u
p
C
b
ec
au
s
e
it
h
as
an
alco
h
o
l
co
n
ten
t
o
f
2
5
-
4
0
%
[
2
]
.
Alco
h
o
l is
wid
ely
k
n
o
wn
t
o
ca
u
s
e
d
is
ea
s
e
m
an
if
estatio
n
s
in
th
e
b
o
d
y
[
3
]
.
T
h
e
o
r
g
a
n
th
at
h
as
a
r
o
le
in
n
eu
tr
alizin
g
to
x
in
s
,
m
etab
o
l
is
m
,
an
d
o
th
er
i
m
p
o
r
ta
n
t
r
o
l
es
,
an
d
is
s
en
s
itiv
e
to
d
is
o
r
d
er
s
is
th
e
liv
er
[
4
]
.
E
x
ce
s
s
iv
e
alco
h
o
l
co
n
s
u
m
p
tio
n
will
ca
u
s
e
m
etab
o
lic
d
is
o
r
d
er
s
in
th
e
Evaluation Warning : The document was created with Spire.PDF for Python.
I
n
t J
Pu
b
lic
Hea
lth
Sci
I
SS
N:
2252
-
8
8
0
6
Hep
a
to
to
xicity
effec
t o
f a
lco
h
o
lic
b
ev
era
g
es o
n
h
is
to
lo
g
y
a
n
d
I
L
-
6
g
e
n
e
…
(
F
itr
ia
Din
ia
h
Ja
n
a
h
S
a
ye
kti)
191
liv
er
.
Fatty
liv
er
,
h
e
p
atitis
,
an
d
cir
r
h
o
s
is
ar
e
th
r
ee
m
ai
n
m
an
if
estatio
n
s
o
f
liv
er
d
is
ea
s
e
ca
u
s
ed
b
y
alc
o
h
o
l.
Mo
r
e
th
an
6
0
%
o
f
th
e
p
o
p
u
lat
io
n
in
wester
n
c
o
u
n
t
r
ies
h
av
e
th
ats
,
an
d
as
m
an
y
as
4
0
%
to
5
0
%
o
f
d
ea
th
s
ar
e
ca
u
s
ed
b
y
alco
h
o
l
-
r
elate
d
cir
r
h
o
s
is
[
5
]
.
I
n
2
0
1
5
,
th
e
d
ea
th
r
ate
f
r
o
m
cir
r
h
o
s
is
o
f
th
e
liv
er
in
cr
ea
s
ed
to
1
1
th
in
th
e
wo
r
ld
with
1
5
.
8
ca
s
es
p
er
1
0
0
,
0
0
0
p
o
p
u
latio
n
[
6
]
.
T
h
e
p
r
ev
alen
ce
o
f
c
h
r
o
n
ic
liv
er
d
i
s
ea
s
e
in
I
n
d
o
n
esia
r
ea
ch
es 2
0
m
illi
o
n
p
eo
p
le,
[
7
]
o
f
wh
ich
2
0
-
4
0
% d
ev
elo
p
liv
e
r
cir
r
h
o
s
is
[
8
]
,
[
9
]
.
I
n
ter
leu
k
in
-
6
is
a
p
leio
tr
o
p
ic
c
y
to
k
in
e
t
h
at
p
lay
s
v
ar
io
u
s
b
io
l
o
g
ical
ac
tiv
ities
an
d
p
lay
s
an
im
p
o
r
tan
t
r
o
le
in
th
e
b
o
d
y
'
s
im
m
u
n
e
r
esp
o
n
s
e
in
th
e
liv
er
.
I
n
e
x
p
er
im
en
tal
an
im
als
ass
o
ciate
d
with
h
ep
ato
to
x
icity
,
I
L
-
6
p
lay
s
a
r
o
le
in
h
ep
ato
cy
tes
to
s
tim
u
late
ce
ll
r
eg
en
er
atio
n
an
d
r
ep
air
.
I
n
ter
leu
k
in
-
6
h
as
a
r
o
le
in
th
e
p
ath
o
lo
g
y
o
f
liv
er
d
is
ea
s
e
an
d
is
v
e
r
y
c
o
m
p
lex
.
I
L
-
6
was
o
r
i
g
in
ally
th
o
u
g
h
t
to
b
e
a
h
e
p
ato
p
r
o
tecto
r
in
h
ep
atic
s
teato
s
is
.
IL
-
6
is
ab
le
to
r
e
d
u
ce
liv
er
s
teato
s
is
,
ab
le
to
r
ed
u
ce
o
x
id
ati
v
e
s
tr
ess
,
an
d
p
r
ev
e
n
t
m
ito
ch
o
n
d
r
ial
d
y
s
f
u
n
ctio
n
[
1
0
]
.
IL
-
6
c
o
n
tr
ib
u
tes
to
th
e
m
an
if
estatio
n
o
f
tis
s
u
e
d
am
ag
e.
Pre
v
io
u
s
r
esear
ch
h
as
s
h
o
wn
t
h
at
elev
ated
lev
els
o
f
th
e
i
n
f
lam
m
ato
r
y
cy
t
o
k
in
es
I
L
-
6
,
I
L
-
1
b
,
a
n
d
T
NFα
ar
e
as
s
o
ciate
d
with
a
h
ig
h
-
f
at
d
iet
[
1
1
]
,
[
12
].
IL
-
6
h
as
also
r
ec
eiv
ed
p
ar
ticu
lar
atten
tio
n
as
a
n
eu
r
o
im
m
u
n
e
r
eg
u
l
ato
r
o
f
th
e
ef
f
e
cts
o
f
alco
h
o
l.
T
h
e
s
tu
d
y
f
o
u
n
d
s
ig
n
if
ican
tly
h
ig
h
er
I
L
-
6
le
v
els
in
in
d
iv
id
u
als
with
AUD
co
m
p
ar
ed
to
h
ea
lth
y
co
n
tr
o
ls
,
wh
ile
o
th
er
cy
to
k
in
es
s
h
o
wed
n
o
s
ig
n
i
f
ican
t c
h
an
g
es
[
1
3
]
.
Alco
h
o
l
in
d
u
ctio
n
ca
n
h
av
e
a
to
x
ic
ef
f
ec
t
o
n
th
e
liv
er
[
1
4
]
an
d
will
also
af
f
ec
t
th
e
ex
p
r
ess
io
n
o
f
IL
-
6
,
s
o
th
is
r
esear
ch
aim
s
to
s
ee
th
e
to
x
ic
in
f
l
u
en
ce
o
f
ciu
a
lco
h
o
l
b
ased
o
n
h
is
to
p
ath
o
lo
g
i
ca
l
ex
am
in
atio
n
o
f
th
e
liv
er
an
d
also
th
e
e
x
p
r
ess
io
n
o
f
I
L
-
6
.
T
h
is
s
tu
d
y
aim
s
to
lo
o
k
at
alc
o
h
o
l h
ep
ato
to
x
icity
b
ased
o
n
h
is
to
lo
g
y
f
ea
tu
r
es
an
d
I
L
-
6
p
r
o
f
ile
as
a
p
r
o
-
in
f
lam
m
ato
r
y
cy
t
o
k
in
e
m
ar
k
er
.
T
h
is
r
esear
ch
n
ee
d
s
to
b
e
co
n
d
u
cte
d
to
s
tu
d
y
th
e
b
asis
o
f
alco
h
o
l
to
x
icity
o
n
h
is
to
lo
g
ical
f
ea
tu
r
es
an
d
its
r
elatio
n
s
h
ip
to
th
e
in
f
lam
m
ato
r
y
cy
to
k
in
e
I
L
-
6.
2.
M
E
T
H
O
D
2
.
1
.
E
x
perim
ent
a
l
a
nim
a
l t
r
ea
t
m
ent
T
h
is
r
esear
ch
was
an
ex
p
er
im
en
tal
s
tu
d
y
with
2
0
test
an
im
als
d
iv
id
ed
in
to
2
tr
ea
tm
en
t
g
r
o
u
p
s
u
s
in
g
a
s
im
p
le
r
a
n
d
o
m
s
am
p
lin
g
te
ch
n
iq
u
e
.
T
h
e
g
r
o
u
p
th
at
was
g
iv
en
ci
u
,
t
h
e
tr
a
d
itio
n
al
alco
h
o
lic
d
r
in
k
3
.
3
m
l/
2
0
0
g
B
B
R
a
ttu
s
n
o
r
ve
g
icu
s
,
an
d
th
e
g
r
o
u
p
th
at
was
o
n
ly
g
i
v
en
d
is
till
ed
wate
r
.
T
h
e
tr
ea
t
m
en
t
was
ca
r
r
ied
o
u
t
with
in
2
1
d
a
y
s
.
T
h
e
p
r
ep
ar
atio
n
is
ca
r
r
ied
o
u
t
ac
co
r
d
i
n
g
to
[
1
5
]
,
[
1
6
]
.
T
h
e
f
ir
s
t
s
tep
is
wash
in
g
t
h
e
tis
s
u
e
with
NaCl.
T
h
is
wash
in
g
aim
s
to
r
em
o
v
e
b
l
o
o
d
,
af
ter
th
at
it
is
p
u
t
in
to
a
tis
s
u
e
ca
s
s
ette
,
th
en
f
ix
ed
with
1
0
%
NB
F
f
o
r
1
0
h
o
u
r
s
b
ef
o
r
e
h
is
to
lo
g
y
p
r
ep
ar
atio
n
.
2
.
2
.
H
is
t
o
l
o
g
y
p
re
pa
ra
t
io
ns
T
h
e
p
r
o
ce
d
u
r
e
f
o
r
m
ak
in
g
p
r
e
p
ar
atio
n
s
r
e
f
er
s
to
[
1
7
]
.
Pre
p
a
r
atio
n
o
f
h
is
to
lo
g
ical
tis
s
u
e
p
r
ep
ar
atio
n
s
ca
n
b
e
ca
r
r
ied
o
u
t
in
s
ev
e
r
al
s
tag
es
,
in
clu
d
in
g
f
ix
atio
n
,
d
eh
y
d
r
atio
n
,
clea
r
in
g
,
em
b
ed
d
in
g
,
b
lo
c
k
in
g
,
an
d
s
tain
in
g
.
T
h
e
m
ac
r
o
s
cu
t
was
p
u
t
in
to
ca
s
s
ette
tis
s
u
e
an
d
th
en
f
ix
ed
with
1
0
%
NB
F
f
o
r
1
½
h
o
u
r
s
,
th
e
n
1
0
%
NB
F
f
o
r
1
½
h
o
u
r
s
.
T
h
e
n
ex
t
s
tag
e
is
d
eh
y
d
r
atio
n
.
Deh
y
d
r
atio
n
was
p
er
f
o
r
m
ed
b
y
im
m
er
s
in
g
th
e
tis
s
u
e
in
5
0
%
alco
h
o
l
f
o
r
1
½
h
o
u
r
s
,
7
0
%
alco
h
o
l
f
o
r
1
½
h
o
u
r
s
,
9
5
%
alco
h
o
l
f
o
r
½
h
o
u
r
,
1
0
0
%
alco
h
o
l
f
o
r
2
h
o
u
r
s
,
an
d
1
0
0
%
alco
h
o
l
f
o
r
2
h
o
u
r
s
.
T
h
e
p
r
o
ce
s
s
o
f
r
em
o
v
in
g
th
e
wate
r
-
d
r
awin
g
ag
en
t
an
d
r
ep
lacin
g
it
with
ch
em
icals,
in
th
is
p
r
o
ce
s
s
,
u
s
e
d
a
s
o
lu
tio
n
o
f
x
y
lo
l I
f
o
r
1
h
o
u
r
an
d
x
y
lo
l
I
I
f
o
r
2
h
o
u
r
s
.
T
h
e
em
b
ed
d
i
n
g
p
r
o
ce
s
s
was
ca
r
r
ied
o
u
t
to
r
ep
lace
th
e
clar
if
icatio
n
m
ater
ial
with
liq
u
id
p
ar
af
f
in
s
o
th
at
th
e
tis
s
u
e
was
ea
s
i
ly
cu
t
u
s
in
g
a
m
icr
o
to
m
e.
T
h
e
tis
s
u
e
was
p
lace
d
in
liq
u
id
p
a
r
af
f
i
n
I
f
o
r
2
h
o
u
r
s
an
d
liq
u
id
p
ar
af
f
i
n
I
I
f
o
r
4
h
o
u
r
s
.
T
h
e
p
r
o
ce
d
u
r
e
is
co
n
tin
u
ed
with
b
lo
ck
in
g
.
T
h
e
p
r
o
ce
s
s
o
f
cu
ttin
g
tis
s
u
e
in
to
b
lo
ck
s
u
s
in
g
a
m
icr
o
to
m
e
at
a
th
ick
n
ess
o
f
3
-
5
m
m
an
d
ca
p
t
u
r
in
g
it
with
a
g
lass
o
b
ject
in
a
f
lo
atin
g
b
ath
(
5
5
-
60
°C
)
.
T
h
e
tis
s
u
e
th
en
s
tain
e
d
with
h
em
ato
x
y
lin
-
eo
s
in
d
y
e
[
1
8
]
.
Hem
ato
x
y
lin
is
u
s
ed
to
s
tain
c
ells
p
in
k
,
wh
ich
is
ac
id
ic
,
an
d
eo
s
in
ca
n
b
e
u
s
ed
to
co
lo
u
r
cy
to
p
lasmic
p
r
o
tein
s
to
b
e
p
u
r
p
lis
h
b
lu
e
a
n
d
is
alk
alin
e.
B
ef
o
r
e
s
tain
in
g
,
it
is
n
ec
ess
ar
y
to
ca
r
r
y
o
u
t
t
h
e
d
ep
ar
a
f
f
in
izatio
n
p
r
o
ce
s
s
b
y
im
m
er
s
in
g
th
e
tis
s
u
e
in
x
y
lo
l,
th
en
af
ter
t
h
at
it
is
p
u
t
i
n
to
a
b
s
o
lu
te
alco
h
o
l,
9
0
%
alco
h
o
l
,
a
n
d
7
0
%
alco
h
o
l.
Af
ter
th
at,
s
o
a
k
th
e
h
em
ato
x
y
lin
p
ain
t
f
o
r
5
-
1
0
m
i
n
u
tes.
T
h
e
tis
s
u
e
is
s
o
ak
ed
in
eo
s
in
p
ain
t
f
o
r
2
-
5
m
in
u
tes
an
d
wash
ed
with
alco
h
o
l.
T
h
e
tis
s
u
e
is
p
u
t
in
x
y
lo
l
f
o
r
f
u
r
th
e
r
m
o
u
n
tin
g
o
f
t
h
e
tis
s
u
e
with
en
th
ela
n
.
T
h
e
tis
s
u
e
is
th
en
r
ea
d
u
s
in
g
a
lig
h
t m
icr
o
s
co
p
e
at
u
p
t
o
4
0
0
x
m
ag
n
if
icatio
n
.
2
.
3
.
IL
-
6
det
ec
t
io
n
Gen
e
test
in
g
b
e
g
in
s
with
D
NA
is
o
latio
n
f
r
o
m
s
er
u
m
s
am
p
les
u
s
in
g
th
e
DNA
E
x
tr
a
ctio
n
an
d
I
s
o
latio
n
Kit
f
r
o
m
Gen
ea
id
(
GS1
0
0
)
.
I
L
-
6
g
en
o
ty
p
in
g
was
d
eter
m
in
ed
b
y
am
p
lify
i
n
g
D
NA
f
r
ag
m
en
ts
with
s
p
ec
if
ic
p
r
im
er
s
F:
5
'
-
GGAG
T
C
AC
A
C
A
C
T
C
C
A
C
C
T
3
'
an
d
R
:
5
'
-
C
T
GAT
T
GG
AAA
C
C
T
T
AT
T
AG
-
3
'
.
PC
R
r
ea
ctio
n
m
ix
tu
r
e
(
2
5
µL
f
in
al
v
o
lu
m
e)
.
T
h
e
tem
p
e
r
atu
r
e
co
n
d
itio
n
s
f
o
r
th
e
I
L
-
6
g
en
e
PC
R
r
ea
ctio
n
wer
e
as
f
o
llo
ws:
I
n
itial
d
en
atu
r
atio
n
at
9
5
°C
,
f
o
llo
win
g
56
°C
f
o
r
1
m
i
n
u
te
,
72
°C
f
o
r
1
m
in
u
te,
an
d
7
2
°C
1
0
m
in
u
tes
f
o
r
ex
ten
s
io
n
.
T
h
e
PC
R
p
r
o
d
u
ct
o
b
tain
e
d
f
r
o
m
th
e
PC
R
p
r
o
ce
s
s
with
th
e
ad
ju
s
t
ed
PC
R
co
n
d
itio
n
s
was th
en
elec
tr
o
p
h
o
r
esed
u
s
in
g
an
ag
a
r
o
s
e
g
el.
Evaluation Warning : The document was created with Spire.PDF for Python.
I
SS
N
:
2
2
5
2
-
8
8
0
6
I
n
t J Pu
b
lic
Hea
lth
Sci
,
Vo
l.
15
,
No
.
1
,
M
ar
ch
20
26
:
1
9
0
-
1
9
6
192
2
.
4
.
Da
t
a
a
na
ly
s
is
T
h
is
s
tu
d
y
u
s
ed
a
s
im
p
le
r
an
d
o
m
s
am
p
lin
g
tech
n
iq
u
e
with
h
is
to
lo
g
ical
o
b
s
er
v
atio
n
s
ca
r
r
ied
o
u
t
o
n
all
p
r
ep
ar
atio
n
s
in
a
b
lin
d
e
d
m
an
n
er
.
T
h
e
p
ar
a
m
eter
s
o
b
s
er
v
ed
in
th
is
s
tu
d
y
wer
e
th
e
m
ac
r
o
s
co
p
ic
ass
ess
m
en
t
o
f
th
e
liv
er
,
in
cl
u
d
in
g
t
h
e
tex
t
u
r
e,
co
lo
u
r
,
an
d
s
ize
o
f
th
e
liv
er
in
a
d
escr
ip
tiv
e
way
.
Mic
r
o
s
co
p
ic
o
b
s
er
v
atio
n
with
4
0
0
x
m
ag
n
i
f
icatio
n
in
5
f
ield
s
o
f
v
iew
ca
lcu
late
d
th
e
av
er
ag
e
d
am
ag
e
v
alu
e
b
y
o
b
s
er
v
in
g
th
e
p
r
ep
ar
atio
n
s
.
−
Scale
1
: n
o
r
m
al
ce
ll,
th
e
ce
ll n
u
cleu
s
is
r
o
u
n
d
an
d
b
lu
e,
a
n
d
t
h
e
cy
to
p
lasm
is
r
ed
.
−
Scale
2
:
d
eg
en
er
atio
n
,
th
e
c
ell
ap
p
ea
r
s
s
wo
llen
,
p
ale,
an
d
clea
r
,
co
n
tain
in
g
a
lo
t
o
f
wate
r
(
h
y
d
r
o
p
ic
d
eg
en
er
atio
n
)
.
T
h
e
in
ter
ce
llu
l
ar
s
p
ac
es
ap
p
ea
r
s
wo
llen
,
th
e
cy
to
p
lasm
is
r
o
u
g
h
,
a
n
d
th
e
r
e
ar
e
g
r
a
n
u
les
(
p
ar
en
c
h
y
m
ato
u
s
d
eg
en
e
r
atio
n
)
.
−
Scale
3
:
Nec
r
o
tic,
th
e
d
en
s
e
n
u
cleu
s
ap
p
ea
r
s
d
ar
k
(
p
y
k
n
o
s
is
)
,
th
e
n
u
cleu
s
ap
p
ea
r
s
b
r
o
k
e
n
(
k
ar
y
o
r
r
h
e
x
is
)
,
an
d
th
e
n
u
cleu
s
ap
p
ea
r
s
lo
s
t d
u
e
to
ch
r
o
m
atin
h
y
d
r
o
ly
s
is
(
k
a
r
y
o
ly
s
is
)
.
T
h
e
d
ata
o
b
tain
ed
wer
e
a
n
aly
s
ed
u
s
in
g
b
y
T
-
test
to
f
in
d
th
e
d
if
f
er
en
t
h
is
to
p
ath
o
lo
g
ical
p
ic
tu
r
es
o
f
th
e
liv
er
o
f
wh
ite
r
ats (
R
a
ttu
s
n
o
r
ve
g
icu
s
)
in
d
u
ce
d
b
y
ciu
,
tr
ad
itio
n
al
alc
o
h
o
l.
3.
RE
SU
L
T
S AN
D
D
I
SCU
SS
I
O
N
T
h
e
h
ep
ato
to
x
icity
ef
f
ec
t
o
f
a
lco
h
o
l
was
o
b
s
er
v
ed
b
ased
o
n
m
icr
o
s
co
p
ic
o
b
s
er
v
atio
n
s
o
f
liv
er
s
th
at
h
ad
b
e
en
tr
ea
te
d
in
v
iv
o
.
Ass
ess
m
en
t
o
f
th
e
h
is
to
p
ath
o
l
o
g
ica
l
p
ictu
r
e
o
f
th
e
liv
er
d
u
e
to
alc
o
h
o
l
e
x
p
o
s
u
r
e
ca
n
b
e
s
ee
n
in
T
a
b
le
1
.
Ob
s
er
v
ati
o
n
s
wer
e
m
ad
e
u
s
in
g
5
v
is
u
a
l
f
ield
s
.
His
to
lo
g
ical
an
aly
s
is
was
p
er
f
o
r
m
ed
to
d
eter
m
in
e
th
e
e
f
f
ec
ts
o
f
alco
h
o
l
.
T
ab
le
1
.
T
h
e
r
esu
lts
o
f
th
e
m
icr
o
s
co
p
ic
o
b
s
er
v
atio
n
o
f
th
e
liv
er
o
f
wh
ite
r
ats
T
r
e
a
t
me
n
t
H
i
st
o
l
o
g
i
c
a
l
o
b
j
e
c
t
F
i
e
l
d
o
f
v
i
e
w
1
2
3
4
5
C
o
n
t
r
o
l
g
r
o
u
p
w
i
t
h
o
u
t
t
r
e
a
t
me
n
t
1
1
1
1
1
1
2
1
1
1
1
1
3
1
1
1
1
1
4
1
1
1
1
1
5
1
1
1
1
1
A
l
c
o
h
o
l
i
n
d
u
c
t
i
o
n
g
r
o
u
p
1
3
2
2
3
2
2
2
2
3
3
2
3
2
3
3
3
3
4
2
3
3
3
3
5
3
2
2
3
3
D
e
scri
p
t
i
o
n
:
r
e
s
u
l
t
s
o
f
mi
c
r
o
s
c
o
p
i
c
o
b
serv
a
t
i
o
n
o
f
t
h
e
l
i
v
e
r
o
f
R
a
t
t
u
s
n
o
rv
e
g
i
c
u
s
:
1
=
N
o
r
m
a
l
;
2
=
D
e
g
e
n
e
r
a
t
i
o
n
;
3
=
N
e
c
r
o
s
i
s
Mic
r
o
s
co
p
ic
o
b
s
er
v
atio
n
o
f
th
e
liv
er
o
f
wh
ite
r
ats
was
an
aly
s
ed
b
ased
o
n
th
e
p
r
esen
ce
o
r
a
b
s
en
ce
o
f
n
o
r
m
al
ce
lls
,
ep
ith
elial
ce
ll
s
w
ellin
g
(
p
ar
e
n
ch
y
m
ato
u
s
an
d
h
y
d
r
o
p
ic
d
eg
e
n
er
atio
n
)
,
an
d
ep
i
th
elial
ce
ll
d
am
ag
e
o
r
n
ec
r
o
s
is
[
1
9
]
.
T
h
e
r
esu
lts
o
f
m
icr
o
s
co
p
ic
o
b
s
er
v
atio
n
s
ca
n
b
e
s
ee
n
in
T
ab
le
1
.
B
ased
o
n
th
e
s
tatis
t
ical
tes
t
r
esu
lts
,
th
e
s
ig
.
(
2
tailed
)
o
f
0
.
0
0
0
<
0
.
0
5
,
s
o
th
at
it
ca
n
b
e
s
ee
n
th
at
th
er
e
is
a
s
ig
n
if
ican
t
d
if
f
er
e
n
ce
i
n
h
is
to
lo
g
ical
r
esu
lts
b
etwe
en
t
h
e
n
o
r
m
al
co
n
tr
o
l
g
r
o
u
p
,
with
o
u
t
m
icr
o
s
co
p
ic
o
b
s
er
v
atio
n
o
f
th
e
liv
er
o
f
wh
ite
r
ats
,
wh
ich
was
an
aly
ze
d
b
ased
o
n
th
e
p
r
esen
ce
o
r
ab
s
en
ce
o
f
n
o
r
m
al
ce
lls
,
e
p
ith
elial
ce
ll
s
wellin
g
(
p
ar
en
c
h
y
m
ato
u
s
an
d
h
y
d
r
o
p
i
c
d
eg
en
er
atio
n
)
,
a
n
d
e
p
ith
elial
ce
ll d
am
ag
e
o
r
n
ec
r
o
s
is
.
B
ased
o
n
th
e
r
esu
lts
o
f
th
e
s
tu
d
y
,
it c
an
b
e
s
ee
n
th
at
th
e
ciu
alco
h
o
l in
d
u
ce
d
in
R
a
ttu
s
n
o
r
ve
g
icu
s
h
as
a
h
is
to
p
ath
o
lo
g
ical
ef
f
e
ct
o
n
t
h
e
liv
er
.
I
n
t
h
e
n
o
r
m
al
co
n
tr
o
l w
ith
o
u
t tr
ea
tm
en
t,
wh
ich
ca
n
b
e
s
ee
n
in
Fig
u
r
e
1
,
th
e
liv
er
ce
lls
ar
e
well
d
is
tr
ib
u
ted
,
an
d
th
e
ar
r
a
n
g
em
e
n
t
o
f
th
e
n
u
cleu
s
an
d
c
y
to
p
las
m
is
clea
r
ly
s
tain
ed
.
Fig
u
r
e
2
s
h
o
ws
n
o
v
is
ib
le
d
e
g
en
er
atio
n
o
r
n
ec
r
o
s
is
,
in
d
icatin
g
th
at
th
e
h
ep
ato
cy
tes
ar
e
n
o
t
s
wo
llen
.
T
h
is
is
b
ec
au
s
e
th
e
g
r
o
u
p
with
o
u
t tr
ea
tm
en
t w
as o
n
ly
g
iv
e
n
d
is
till
ed
wate
r
,
wh
ich
is
n
o
t to
x
ic
to
th
e
liv
er
.
Aq
u
a
d
es is
clea
r
,
tast
eless
,
an
d
d
is
till
ed
wate
r
,
s
o
th
e
p
er
ce
n
tag
e
o
f
p
o
s
s
ib
le
co
n
tam
in
atio
n
b
y
to
x
i
c
co
m
p
o
u
n
d
s
an
d
m
icr
o
o
r
g
an
is
m
s
is
v
er
y
s
m
all.
W
ater
th
at
en
ter
s
th
e
b
o
d
y
will
b
e
im
m
ed
iately
ab
s
o
r
b
ed
b
y
th
e
d
ig
esti
v
e
s
y
s
tem
an
d
d
is
tr
ib
u
ted
th
r
o
u
g
h
o
u
t
th
e
b
o
d
y
b
y
b
lo
o
d
v
e
s
s
els.
T
h
e
ab
s
en
ce
o
f
h
ep
atic
alter
atio
n
s
in
th
e
u
n
tr
ea
ted
g
r
o
u
p
m
ay
b
e
attr
i
b
u
ted
to
th
e
ad
m
i
n
is
tr
atio
n
o
f
d
is
till
ed
wate
r
,
wh
ich
is
co
n
s
id
er
ed
b
io
lo
g
ically
in
er
t a
n
d
n
o
n
-
h
ep
ato
t
o
x
ic
u
n
d
er
n
o
r
m
al
ex
p
er
im
e
n
tal
co
n
d
itio
n
s
[
2
0
]
.
Fig
u
r
e
2
is
th
e
h
is
to
lo
g
ical
s
tr
u
ctu
r
e
o
f
th
e
liv
er
th
at
h
a
s
b
ee
n
i
n
d
u
ce
d
b
y
alco
h
o
l.
B
ased
o
n
o
b
s
er
v
atio
n
s
,
it
ca
n
b
e
s
ee
n
i
n
th
e
p
ictu
r
e
th
at
th
er
e
is
ce
l
l
d
am
ag
e
in
th
e
f
o
r
m
o
f
d
eg
en
er
ated
ce
lls
an
d
n
ec
r
o
tic
ce
lls
.
I
n
alco
h
o
l
-
in
d
u
ce
d
liv
er
s
,
it
ca
n
b
e
s
ee
n
t
h
at
th
e
h
is
to
lo
g
ical
s
tr
u
ct
u
r
e
c
o
n
tain
s
m
an
y
b
lo
o
d
v
ess
els
ar
o
u
n
d
th
e
h
ep
ato
cy
t
e
ce
lls
.
Nec
r
o
s
is
an
d
d
eg
e
n
er
atio
n
ar
e
also
f
o
u
n
d
in
s
o
m
e
p
ar
ts
.
Deg
e
n
er
ated
Evaluation Warning : The document was created with Spire.PDF for Python.
I
n
t J
Pu
b
lic
Hea
lth
Sci
I
SS
N:
2252
-
8
8
0
6
Hep
a
to
to
xicity
effec
t o
f a
lco
h
o
lic
b
ev
era
g
es o
n
h
is
to
lo
g
y
a
n
d
I
L
-
6
g
e
n
e
…
(
F
itr
ia
Din
ia
h
Ja
n
a
h
S
a
ye
kti)
193
ce
lls
ca
n
s
till
r
ec
o
v
er
o
r
r
e
tu
r
n
to
n
o
r
m
al
if
e
x
p
o
s
u
r
e
to
th
e
to
x
in
is
s
to
p
p
e
d
[
2
1
]
.
Par
en
ch
y
m
at
o
u
s
d
eg
en
er
atio
n
is
ch
ar
ac
te
r
ized
b
y
s
wellin
g
o
f
th
e
cy
to
p
lasm
an
d
g
r
an
u
lar
cy
to
p
lasm
.
T
h
is
i
s
b
ec
au
s
e
th
e
ce
ll
is
u
n
ab
le
to
elim
in
ate
wate
r
,
s
o
it
ac
cu
m
u
lates
in
s
id
e
th
e
ce
l
l
,
an
d
t
h
e
ce
ll
o
r
g
an
elles
also
ab
s
o
r
b
wate
r
an
d
s
well,
ca
u
s
in
g
th
e
c
y
to
p
lasm
to
ap
p
ea
r
g
r
an
u
lar
[
2
2
]
.
T
h
e
lev
el
o
f
d
am
a
g
e
to
p
ar
e
n
ch
y
m
ato
u
s
d
eg
e
n
er
ativ
e
ce
lls
was
m
o
r
e
co
m
m
o
n
in
th
e
g
r
o
u
p
in
d
u
ce
d
b
y
ciu
alco
h
o
l
d
u
e
to
th
e
in
d
u
ctio
n
o
f
th
e
to
x
ic
s
u
b
s
tan
ce
o
f
tr
ad
itio
n
al
alco
h
o
lic
b
ev
er
a
g
es c
iu
wh
ich
was
ab
le
to
d
am
ag
e
th
e
liv
er
s
o
f
wh
ite
r
ats.
Fig
u
r
e
1
.
His
to
p
ath
o
l
o
g
ical
p
i
ctu
r
e
o
f
t
h
e
liv
er
o
f
wh
ite
r
ats in
th
e
co
n
tr
o
l g
r
o
u
p
with
o
u
t tr
ea
tm
en
t,
h
em
ato
x
y
lin
eo
s
in
s
tain
in
g
wi
th
4
0
0
x
m
ag
n
if
icatio
n
.
Descr
ip
tio
n
:
b
l
u
e
ar
r
o
w
=
n
o
r
m
al
ce
ll
an
d
V
=
v
ein
Fig
u
r
e
2
.
His
to
p
ath
o
l
o
g
ical
p
i
ctu
r
e
o
f
t
h
e
liv
er
in
d
u
ce
d
b
y
k
is
s
in
g
alco
h
o
l w
ith
Hem
at
o
x
y
lin
-
E
o
s
in
s
tain
in
g
an
d
4
0
0
x
m
ag
n
if
icatio
n
.
Descr
ip
tio
n
:
b
lu
e
a
r
r
o
ws:
d
eg
en
er
atio
n
,
y
ello
w
a
r
r
o
ws:
n
ec
r
o
s
is
,
an
d
b
lac
k
ar
r
o
ws:
lo
ts
o
f
b
lo
o
d
v
ess
els ar
o
u
n
d
h
ep
at
o
cy
tes
Nec
r
o
s
is
is
a
m
o
r
p
h
o
lo
g
ical
c
h
an
g
e
as
a
r
esu
lt
o
f
p
r
o
g
r
ess
iv
e
d
eg
r
ad
atio
n
b
y
en
zy
m
es
in
ce
lls
th
at
ex
p
er
ien
ce
leth
al
in
ju
r
y
ch
ar
a
cter
ized
b
y
ch
an
g
es
an
d
n
u
clea
r
d
estru
ctio
n
[
2
3
]
.
T
h
e
f
o
r
m
a
tio
n
o
f
n
ec
r
o
s
is
ca
n
b
e
s
ee
n
f
r
o
m
th
e
f
o
r
m
atio
n
o
f
p
y
k
n
o
s
is
,
wh
ich
is
ch
a
r
ac
ter
i
ze
d
b
y
s
h
r
i
n
k
ag
e
o
f
th
e
ce
ll
n
u
cleu
s
,
co
m
p
ac
tio
n
an
d
d
a
r
k
co
lo
u
r
.
Nec
r
o
s
is
ar
e
ir
r
ev
er
s
ib
le
ce
ll
c
h
an
g
es
d
u
e
t
o
d
am
a
g
e
to
th
e
p
lasma
m
em
b
r
an
e
o
r
l
y
s
o
s
o
m
al
m
em
b
r
an
e,
as
well
as
lo
s
s
o
f
DNA
o
r
m
ito
ch
o
n
d
r
ia.
Dy
s
f
u
n
ctio
n
o
f
th
e
ce
ll
m
em
b
r
an
e
a
n
d
m
ito
ch
o
n
d
r
ia
is
th
e
m
ain
f
ac
to
r
ca
u
s
in
g
ir
r
e
v
er
s
ib
le
ce
ll
d
am
ag
e
[
2
4
]
.
T
h
e
p
h
y
s
ical
ef
f
ec
ts
ex
p
e
r
ien
ce
d
f
r
o
m
co
n
s
u
m
in
g
alco
h
o
lic
b
ev
e
r
ag
es in
clu
d
e
d
am
ag
e
to
th
e
liv
e
r
an
d
p
an
c
r
ea
tic
[
2
5
]
.
An
o
th
er
p
a
r
am
eter
th
at
ca
n
b
e
u
s
ed
to
o
b
s
er
v
e
li
v
er
f
u
n
ctio
n
af
ter
alco
h
o
l
i
n
d
u
ctio
n
is
I
L
-
6
d
etec
tio
n
.
Acc
o
r
d
in
g
to
[
2
6
]
,
A
lo
w
an
n
ea
lin
g
tem
p
er
atu
r
e
d
u
r
in
g
p
o
ly
m
er
ase
ch
ain
r
e
ac
tio
n
(
PC
R
)
m
ay
r
ed
u
ce
p
r
im
e
r
s
p
ec
if
icity
,
allo
win
g
p
r
im
er
s
to
h
y
b
r
id
ize
to
p
ar
tially
co
m
p
lem
en
ta
r
y
o
r
n
o
n
-
tar
g
et
DNA
s
eq
u
en
ce
s
,
th
er
eb
y
in
cr
ea
s
in
g
th
e
lik
elih
o
o
d
o
f
n
o
n
-
s
p
ec
if
ic
am
p
lific
atio
n
p
r
o
d
u
cts
.
A
cc
o
r
d
in
g
to
[
2
7
]
,
p
r
o
p
er
ad
ju
s
tm
en
t o
f
th
is
p
ar
a
m
eter
en
h
an
ce
s
am
p
lific
atio
n
y
ield
wh
ile
m
in
im
izin
g
n
o
n
-
s
p
ec
if
ic
p
r
o
d
u
cts
.
I
n
ter
leu
k
in
-
6
is
a
p
leio
tr
o
p
ic
c
y
to
k
in
e
th
at
is
s
ec
r
eted
f
r
o
m
b
o
d
y
tis
s
u
es d
u
r
in
g
th
e
ac
u
te
a
n
d
ch
r
o
n
ic
p
h
ases
o
f
in
f
ec
tio
n
[
2
7
]
.
IL
-
6
ex
p
r
ess
io
n
ca
n
b
e
v
is
u
alize
d
i
n
th
e
elec
tr
o
p
h
o
r
esis
r
esu
lts
,
wh
ich
ar
e
r
ea
d
u
s
in
g
Gel
Do
c.
I
L
-
6
ex
p
r
ess
io
n
ca
n
b
e
o
b
s
er
v
e
d
i
n
Fig
u
r
e
3
.
B
ased
o
n
Fig
u
r
e
3
,
it
ca
n
b
e
s
ee
n
th
at
in
t
h
e
g
r
o
u
p
with
alco
h
o
l
-
in
d
u
ce
d
k
is
s
in
g
,
it
ap
p
ea
r
s
th
at
I
L
-
6
is
ex
p
r
ess
ed
m
o
r
e
s
tr
o
n
g
ly
o
n
elec
tr
o
p
h
o
r
etic
v
is
u
aliza
tio
n
co
m
p
ar
ed
to
th
e
co
n
tr
o
l
g
r
o
u
p
with
o
u
t
an
y
tr
ea
tm
e
n
t.
I
n
ter
leu
k
in
-
6
is
a
p
h
o
s
p
h
o
r
y
lated
g
ly
co
p
r
o
tein
co
n
tain
in
g
1
8
5
am
in
o
ac
id
s
,
i
n
clu
d
in
g
p
leio
tr
o
p
ic
cy
to
k
in
es
in
v
o
lv
e
d
in
i
n
f
lam
m
atio
n
,
b
o
n
e
m
etab
o
lis
m
,
C
-
r
ea
ctiv
e
p
r
o
tein
s
y
n
th
esis
,
an
d
ca
r
cin
o
g
en
esis
.
T
h
ese
cy
to
k
i
n
es
an
d
r
ec
ep
to
r
s
ar
e
a
class
o
f
p
o
ly
p
ep
tid
es
th
at
m
ed
iate
th
e
in
f
lam
m
ato
r
y
p
r
o
ce
s
s
.
T
h
ese
p
o
ly
p
e
p
tid
es
ar
e
d
iv
id
ed
in
to
p
r
o
-
a
n
d
a
n
ti
-
in
f
la
m
m
ato
r
y
c
y
to
k
in
es.
I
n
n
o
n
s
p
ec
if
ic
im
m
u
n
ity
,
i
n
t
er
leu
k
in
-
6
s
tim
u
lates
h
ep
ato
c
y
tes
to
p
r
o
d
u
c
e
ac
u
te
p
h
ase
p
r
o
tein
(
APP)
an
d
ce
r
eb
r
o
s
p
in
al
f
lu
i
d
(
C
SF
)
,
w
h
ich
s
tim
u
late
p
r
o
g
en
ito
r
s
in
th
e
b
o
n
e
m
ar
r
o
w
to
p
r
o
d
u
c
e
n
eu
tr
o
p
h
ils
.
T
h
e
in
ter
leu
k
in
6
g
en
e
is
at
th
e
7
th
ch
r
o
m
o
s
o
m
e
p
o
s
itio
n
2
1
(
7
p
2
1
)
.
I
n
ter
leu
k
i
n
-
6
is
a
m
u
ltifu
n
ctio
n
al
cy
to
k
i
n
e
with
an
im
p
o
r
tan
t
r
o
le
i
n
v
ar
i
o
u
s
ce
ll
b
io
lo
g
ical
ac
tiv
ities
[
2
8
]
.
I
n
ad
d
itio
n
,
i
n
ter
leu
k
in
6
p
lay
s
a
r
o
le
i
n
th
e
n
o
r
m
al
im
m
u
n
e
r
esp
o
n
s
e
to
f
o
r
eig
n
an
tig
en
s
[
2
9
]
.
Fu
r
th
er
m
o
r
e,
alco
h
o
l d
r
i
n
k
in
g
h
as a
ls
o
b
ee
n
s
h
o
wn
to
alter
IL
-
6
ex
p
r
ess
io
n
in
v
ar
io
u
s
tis
s
u
es
ac
r
o
s
s
h
u
m
an
s
an
d
an
im
al
s
[
3
0
]
-
[
33]
.
Acc
o
r
d
in
g
to
W
ijay
an
ti
an
d
Say
ek
ti
[
3
4
]
,
co
n
v
en
tio
n
al
PC
R
ca
n
b
e
s
ee
n
q
u
alitativ
ely
b
u
t
q
u
an
ti
tativ
ely
it
ca
n
n
o
t
b
e
a
n
aly
ze
d
.
T
h
is
r
esear
ch
ca
n
b
e
ex
p
an
d
e
d
b
y
ex
a
m
in
in
g
g
e
n
e
ex
p
r
ess
io
n
q
u
an
titativ
ely
a
n
d
ad
d
tr
ea
tm
en
t
v
a
r
iatio
n
s
f
o
r
f
u
r
th
er
an
al
y
s
is
o
f
th
e
r
elatio
n
s
h
ip
b
etwe
en
h
is
to
lo
g
ical
s
tr
u
ctu
r
e
,
g
en
e
,
a
n
d
p
r
o
tein
lev
el
o
f
IL
-
6
.
Evaluation Warning : The document was created with Spire.PDF for Python.
I
SS
N
:
2
2
5
2
-
8
8
0
6
I
n
t J Pu
b
lic
Hea
lth
Sci
,
Vo
l.
15
,
No
.
1
,
M
ar
ch
20
26
:
1
9
0
-
1
9
6
194
Fig
u
r
e
3
.
I
L
-
6
o
v
er
v
iew
q
u
alit
ativ
ely
u
s
in
g
elec
tr
o
p
h
o
r
esis
.
Descr
ip
tio
n
: A
:
n
o
r
m
al
co
n
tr
o
l w
ith
o
u
t tr
ea
tm
en
t
an
d
B
:
a
lco
h
o
l
-
in
d
u
ce
d
g
r
o
u
p
4.
CO
NCLU
SI
O
N
B
ased
o
n
th
e
r
esear
ch
r
esu
lt
s
it
ca
n
b
e
s
ee
n
th
at
ci
u
alc
o
h
o
lic
d
r
in
k
h
as
a
to
x
ic
ef
f
e
ct
o
n
th
e
h
is
to
p
ath
o
lo
g
ical
p
ictu
r
e
o
f
t
h
e
liv
er
in
t
h
e
f
o
r
m
o
f
ce
ll
d
eg
en
er
atio
n
an
d
n
ec
r
o
s
is
,
an
d
lo
ts
o
f
b
leed
in
g
ar
o
u
n
d
th
e
h
e
p
ato
cy
te
ce
lls
.
B
ased
o
n
th
e
s
tatis
tical
te
s
t
r
e
s
u
lts
,
th
e
s
ig
.
(
2
tailed
)
o
f
0
.
0
0
0
<
0
.
0
5
,
s
o
th
at
it
ca
n
b
e
s
ee
n
th
at
th
er
e
is
a
s
ig
n
if
ican
t
d
if
f
e
r
en
ce
in
h
is
to
l
o
g
ical
r
esu
lts
b
etwe
en
th
e
n
o
r
m
al
co
n
tr
o
l
g
r
o
u
p
with
o
u
t
tr
ea
tm
en
t
a
n
d
th
e
g
r
o
u
p
in
d
u
ce
d
b
y
k
is
s
in
g
alco
h
o
l
.
T
h
e
I
L
-
6
g
en
e
was
d
etec
te
d
m
o
r
e
clea
r
ly
in
th
e
g
r
o
u
p
with
th
e
in
d
u
ctio
n
o
f
alco
h
o
l
;
th
is
in
d
icate
s
th
at
g
iv
in
g
alco
h
o
l
ca
u
s
es
a
h
ig
h
er
in
f
lam
m
ato
r
y
r
esp
o
n
s
e.
Fu
r
th
er
r
esear
c
h
ca
n
b
e
co
n
d
u
cted
to
in
c
r
ea
s
e
th
e
s
am
p
le
s
ize
an
d
q
u
an
titativ
ely
ass
es
s
IL
-
6
ex
p
r
ess
io
n
.
ACK
NO
WL
E
DG
M
E
N
T
S
T
h
e
au
th
o
r
th
an
k
s
th
e
Stu
d
y
P
r
o
g
r
am
Me
d
ical
L
ab
o
r
ato
r
y
T
ec
h
n
o
lo
g
y
,
STI
KE
S Na
s
io
n
al.
F
UNDING
I
NF
O
R
M
A
T
I
O
N
T
h
is
r
esear
ch
was f
u
n
d
e
d
b
y
L
PP
M
STI
KE
S Na
s
io
n
al,
Su
r
ak
ar
ta,
J
awa
T
en
g
ah
,
I
n
d
o
n
esi
a.
AUTHO
R
CO
NT
RI
B
UT
I
O
NS ST
A
T
E
M
E
N
T
T
h
is
jo
u
r
n
al
u
s
es
th
e
C
o
n
t
r
ib
u
to
r
R
o
les
T
a
x
o
n
o
m
y
(
C
R
ed
iT)
to
r
ec
o
g
n
ize
in
d
iv
i
d
u
al
au
th
o
r
co
n
tr
ib
u
tio
n
s
,
r
ed
u
ce
au
th
o
r
s
h
ip
d
is
p
u
tes,
an
d
f
ac
ilit
ate
co
llab
o
r
atio
n
.
Na
m
e
o
f
Aut
ho
r
C
M
So
Va
Fo
I
R
D
O
E
Vi
Su
P
Fu
Fit
r
ia
Din
iah
J
an
ah
Say
ek
ti
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
Vec
to
r
Step
h
en
Dew
an
g
g
a
✓
✓
✓
✓
✓
✓
✓
M
u
h
am
m
ad
T
au
f
iq
Qu
r
r
o
h
m
a
n
✓
✓
✓
✓
✓
✓
✓
C
:
C
o
n
c
e
p
t
u
a
l
i
z
a
t
i
o
n
M
:
M
e
t
h
o
d
o
l
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So
:
So
f
t
w
a
r
e
Va
:
Va
l
i
d
a
t
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Fo
:
Fo
r
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n
a
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n
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t
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so
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r
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D
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r
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r
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d
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NF
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C
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F
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R
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ST
A
T
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M
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NT
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h
e
au
th
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s
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ec
lar
e
th
at
th
e
r
e
is
n
o
co
n
f
lict o
f
in
ter
est.
Evaluation Warning : The document was created with Spire.PDF for Python.
I
n
t J
Pu
b
lic
Hea
lth
Sci
I
SS
N:
2252
-
8
8
0
6
Hep
a
to
to
xicity
effec
t o
f a
lco
h
o
lic
b
ev
era
g
es o
n
h
is
to
lo
g
y
a
n
d
I
L
-
6
g
e
n
e
…
(
F
itr
ia
Din
ia
h
Ja
n
a
h
S
a
ye
kti)
195
I
NF
O
RM
E
D
CO
NS
E
N
T
T
h
is
r
esear
ch
d
id
n
o
t u
s
e
h
u
m
an
s
u
b
jects.
T
h
is
r
esear
ch
h
as
p
ass
ed
eth
ical
r
ev
iew
.
E
T
H
I
CAL AP
P
RO
V
AL
T
h
is
s
tu
d
y
was
a
p
p
r
o
v
ed
b
y
th
e
Hea
lth
R
esear
ch
E
th
ics
C
o
m
m
ittee
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UM
P,
I
n
d
o
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es
ia
(
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th
ical
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lear
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ce
No
.
KE
PK/UMP/
3
4
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/2
0
2
3
)
.
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th
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ap
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ir
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e
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at
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l
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s
titu
tio
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al
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d
in
ter
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atio
n
al
eth
ical
s
tan
d
ar
d
s
.
DATA AV
AI
L
AB
I
L
I
T
Y
T
h
e
d
ata
t
h
at
s
u
p
p
o
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d
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o
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tu
d
y
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r
e
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ailab
le
f
r
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m
th
e
c
o
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r
esp
o
n
d
in
g
au
th
o
r
,
[
FDJ
S],
u
p
o
n
r
ea
s
o
n
ab
le
r
eq
u
est.
RE
F
E
R
E
NC
E
S
[
1
]
S
.
H
.
P
a
r
k
a
n
d
D
.
J
.
K
i
m
,
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G
l
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l
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n
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o
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m
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m
p
h
a
si
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p
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”
C
l
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n
i
c
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l
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n
d
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l
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r He
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1
0
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3
3
5
0
/
c
mh
.
2
0
2
0
.
0
1
6
0
.
[
2
]
Y
.
S
.
D
a
d
t
u
n
,
H
.
A
.
D
a
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d
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,
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n
d
S
u
sa
n
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o
,
“
C
i
u
b
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k
o
n
a
n
g
a
s
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t
r
a
d
i
t
i
o
n
a
l
a
l
c
o
h
o
l
i
c
d
r
i
n
k
:
so
c
i
o
h
i
s
t
o
r
i
c
a
l
p
h
e
n
o
me
n
a
a
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d
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e
a
l
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h
c
o
n
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e
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n
s,
”
J
o
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:
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0
.
4
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0
3
/
JD
A
R
/
2
3
6
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4
9
.
[
3
]
V
.
B
o
r
g
o
n
e
t
t
i
e
t
a
l
.
,
“
Ta
r
g
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t
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n
g
i
l
-
6
a
s
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n
o
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c
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a
b
st
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n
e
n
c
e
–
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l
a
t
e
d
m
e
c
h
a
n
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c
a
l
a
l
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o
d
y
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i
a
,
”
N
e
u
ro
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h
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rm
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7
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r
m
.
2
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5
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1
1
0
5
8
4
.
[
4
]
J.
H
y
u
n
,
J.
H
a
n
,
C
.
Le
e
,
M
.
Y
o
o
n
,
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n
d
Y
.
Ju
n
g
,
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P
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me
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sm
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n
t
h
e
l
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v
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r
,
”
I
n
t
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t
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o
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rn
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3
9
0
/
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j
ms
2
2
1
1
5
7
1
7
.
[
5
]
B
.
G
a
o
a
n
d
R
.
B
a
t
a
l
l
e
r
,
“
A
l
c
o
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l
i
c
l
i
v
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d
i
sea
s
e
:
p
a
t
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g
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n
e
s
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s
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n
d
n
e
w
t
h
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r
a
p
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t
i
c
t
a
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t
s,”
G
a
st
ro
e
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t
e
r
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y
,
v
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l
.
1
4
1
,
n
o
.
5
,
p
p
.
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:
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/
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.
g
a
s
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o
.
2
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1
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0
9
.
0
0
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.
[
6
]
W
o
r
l
d
H
e
a
l
t
h
O
r
g
a
n
i
z
a
t
i
o
n
,
“
G
l
o
b
a
l
st
a
t
u
s
r
e
p
o
r
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a
l
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n
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a
l
t
h
,
”
Wo
r
l
d
H
e
a
l
t
h
O
r
g
a
n
i
za
t
i
o
n
.
[
O
n
l
i
n
e
]
,
A
v
a
i
l
a
b
l
e
:
h
t
t
p
s
:
/
/
w
w
w
.
w
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.
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n
t
/
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.
[
7
]
C
.
M
u
r
r
a
y
e
t
a
l
.
,
“
G
l
o
b
a
l
b
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9
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a
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,
v
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3
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p
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4
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0
.
[
8
]
S
.
K
.
A
sr
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n
i
,
H
.
D
e
v
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r
b
h
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v
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,
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E
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,
a
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.
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.
K
a
ma
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,
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d
,
”
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o
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.
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.
[
9
]
R
i
s
k
e
s
d
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s
Te
a
m,
Ri
s
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k
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.
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a
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:
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e
me
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s
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,
2
0
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3
.
[
1
0
]
M
.
A
k
d
i
s
e
t
a
l
.
,
“
I
n
t
e
r
l
e
u
k
i
n
s
(
f
r
o
m
IL
-
1
t
o
IL
-
3
8
)
,
i
n
t
e
r
f
e
r
o
n
s
,
t
r
a
n
sf
o
r
mi
n
g
g
r
o
w
t
h
f
a
c
t
o
r
β,
a
n
d
t
n
f
-
α:
r
e
c
e
p
t
o
r
s,
f
u
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t
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s,
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n
d
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s,
”
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o
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Al
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[
1
1
]
S
.
C
.
B
.
R
.
N
a
k
a
n
d
a
k
a
r
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e
t
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l
.
,
“
S
h
o
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mm
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e
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m
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,
”
Br
a
i
n
,
Be
h
a
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a
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.
b
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.
[
1
2
]
M
.
G
o
n
z
á
l
e
z
-
P
o
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t
i
l
l
a
e
t
a
l
.
,
“
P
a
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mi
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e
,
”
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n
t
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r
n
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n
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o
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3
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/
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j
ms
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0
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.
[
1
3
]
H
.
F
.
M
o
u
r
a
e
t
a
l
.
,
“
I
n
f
l
a
mm
a
t
o
r
y
c
y
t
o
k
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n
e
s
a
n
d
a
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o
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s
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d
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s
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r
d
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r
:
sy
st
e
mat
i
c
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e
v
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e
w
a
n
d
met
a
-
a
n
a
l
y
s
i
s,
”
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a
zi
l
i
a
n
J
o
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rn
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Psy
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.
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4
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o
.
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,
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1
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4
4
6
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0
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1
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1
8
9
3
.
[
1
4
]
B
.
G
a
o
,
M
.
F
.
A
h
m
a
d
,
L.
E.
N
a
g
y
,
a
n
d
H
.
Ts
u
k
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m
o
t
o
,
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I
n
f
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mm
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t
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c
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s,
”
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o
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v
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.
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