Safety, immunogenicity and kinetics of immune response to 7-valent pneumococcal conjugate vaccine in children with idiopathic nephrotic syndrome.

Abstract

Safety, immunogenicity and kinetics of 7-valent pneumococcal-conjugate vaccine (PCV7) immune response were evaluated in 33 children with idiopathic nephrotic syndrome (INS) and 16 controls. PCV7 was not associated with increased risk of relapse (RR=0.80, p=0.61). Serotype (PS)-specific antibodies increased in all subjects at 1 month (p<0.01) with inferior immunogenicity for 3/7 PS in patients on immunomodulators (p<0.02). Most patients retained protective antibodies at 12-14 months although at lower levels for 4/7 PS (p<0.08). Different PS kinetics in INS suggests antibody monitoring and revaccination when necessary for protection from pneumococcal infections.

Full text

Page 1

Vaccine
29 (2011) 6834–
6837
Contents
lists
available
at ScienceDirect
Vaccine
j ourna
l ho
me
pag
e:
www.elsevier.com/locate/vaccine
Short
Safety,
pneumococcal
communication
immunogenicity
and
kinetics
of
immune
response
to
7-valent
conjugate
vaccine
in
children
with
idiopathic
nephrotic
syndrome
Christina
Maria
D.
Liakoua,
Varvara
Askitib,
Andromachi
Mitsionib,
Constantinos
J.
Stefanidisb,
C.
Theodoridoua,
Vana
I.
Spouloua,∗
a1st
bDepartment
Department
of
Pediatrics,
Division
of
Infectious
Diseases,
“Aghia
Sophia”
Children’s
Hospital,
Athens
University
School
of
Medicine,
Athens,
Greece
of
Nephrology,
“P.
and
A.
Kyriakou”
Children‘s
Hospital,
Athens,
Greece
a
r
t
i
c
l
e

i
n
f
o
Article
Received
Received
Accepted
Available online 29 July 2011
history:
9 June
2011
in revised
form
15 July
2011
16 July
2011
Keywords:
Idiopathic
Pneumococcal
Safety
Antibody
nephrotic
syndrome
conjugate
vaccine
kinetics
a
b
s
t
r
a
c
t
Safety,
response
was
increased
immunomodulators
at
cination
immunogenicity
and
kinetics
of
7-valent
pneumococcal-conjugate
vaccine
(PCV7)
immune
were
evaluated
in
33
children
with
idiopathic
nephrotic
syndrome
(INS)
and
16
controls.
PCV7
not
associated
with
increased
risk
of
relapse
(RR
=
0.80,
p
=
0.61).
Serotype
(PS)-specific
antibodies
in
all
subjects
at
1
month
(p
<
0.01)
with
inferior
immunogenicity
for
3/7
PS
in patients
on
(p
<
0.02).
Most
patients
retained
protective
antibodies
at
12–14
months
although
lower
levels
for
4/7
PS
(p
<
0.08).
Different
PS
kinetics
in
INS
suggests
antibody
monitoring
and
revac-
when
necessary
for
protection
from
pneumococcocal
infections.
© 2011 Elsevier Ltd. All rights reserved.
1.
Introduction
Idiopathic
glomerular
rate
patients
including
and
ciated
should
However,
ity
a hurdle
To thoroughly
jugate
prospectively
with
genicity
healthy
on
months
nephrotic
syndrome
(INS)
is the
most
frequent
disease
in children
under
16
years
old
with
incidence
2–7/100,000
patients/year
depending
on
ethnicity.
Those
are
susceptible
to invasive
pneumococcal
disease
(IPD)
peritonitis,
pneumonia
with
or without
pleural
effusion
meningitis.
Due
to increased
mortality
and
risk
of
relapses
asso-
with
IPD,
it has
been
recommended
that
children
with
INS
be
immunized
with
pneumococcal
conjugate
vaccine
[1].
concerns
on
vaccine
safety
and
impaired
immunogenic-
due
to INS
pathogenesis
and
immunosuppressive
treatment
are
for
universal
implementation
of existing
guidelines.
evaluate
safety
of 7-valent
pneumococcal
con-
vaccine
(PCV7)
in children
with
INS
in remission,
we
investigated
a possible
association
of
vaccination
increased
risk
for
recurrences
of
INS.
We
also
studied
immuno-
and
kinetics
of
immune
response
in INS
patients
and
subjects
and
the
effect
of
different
types
of
treatment
primary
immune
response
and
antibody
persistence
at
12–14
following
vaccination
with
PCV7.
∗Corresponding
Diseases
Thivon
fax:
E-mail
author
at:
1st
Department
of
Pediatrics,
Division
of Infectious
‘Aghia
Sophia’
Children’s
Hospital,
Athens
University
School
of
Medicine,
and
M.
Asias
St Goudi
11527,
Athens,
Greece.
Tel.:
+30
210
7467620;
+3 01
210
7467669.
address:
vspoulou@med.uoa.gr
(V.I.
Spoulou).
2. Materials
and
methods
2.1.
Study
population
This
is a prospective
interventional
study
conducted
from
Jan-
uary
Athens
sion
and
in
low-dose
therapy
nolate
months
ticipated
Exclusion
vaccination
other
committee
parents’
2009
to May
2010
by
the
1st
Department
of
Pediatrics
at
University
Medical
School.
Patients
with
INS
in remis-
were
recruited
from
the
Department
of
Nephrology
at
“P.
A.
Kyriakou”
Children‘s
Hospital
in Athens
and
were
assigned
2 therapy
groups.
Group
A subjects
were
on treatment
with
prednisolone
(less
than
1 mg/kg
every
other
day)
or no
whereas
group
B on additional
therapy
with
mycophe-
mofetil
(MMF)
and/or
cyclosporine
A
(CyA)
for
at
least
6
previously
to enrolment.
Patients’
healthy
siblings
par-
voluntarily
in the
study
and
were
served
as
controls.
criteria
were
history
of
IPD or previous
pneumococcal
and
administration
of
intravenous
immunoglobulin
or
blood
products
during
the
last
3 months.
Hospital’s
ethics
approval
and
written
informed
consent
directly
from
participants
were
obtained
before
initiation
of
the
study.
2.2.
Immunization
schedule
All
participants
(Prevenar;
in
were
received
intramuscularly
a
0.5
ml
dose
of
PCV7
Wyeth
Vaccines).
A booster
dose
was
administered
only
patients
at 12–14
months
after
priming.
Venous
blood
samples
obtained
prior,
1 and
12–14
months
after
vaccination.
Patients
0264-410X/$
doi:10.1016/j.vaccine.2011.07.053
– see
front
matter ©

2011 Elsevier Ltd. All rights reserved.

Page 2

C.D.
Liakou
et
al.
/ Vaccine
29 (2011) 6834–
6837
6835
Table
Clinical
1
characteristics
of
the
study
population
at baseline.
Characteristics

Patients
(n = 33)

Controls
(n =
16)
Group
A (n = 15)

Group
B (n = 18)
Sex
Age
Age
Yearsaon
Patients
Patients
Patients
(male/female)

6/9
8.1
5.2
2.8
8
–
–

11/7
11.4
3.4
8.1
12
14
13

10/6
13.7
–
–
–
–
–
(years)a
± 2.2†
± 3.6†
±
3.7†
at
diagnosis
of
INSa
± 1.7‡
± 1.3‡
immunosuppression
±
1.5
± 3.5
on
prednisolone

on
MMF

on
CyA

MMF,
aValues
†Group
‡Group
mycophenolate
mofetil;
CyA,
cyclosporine
A.
expressed
in years
as mean
± SD.
B versus
group
A and
controls,
Kruskal–Wallis
test,
p < 0.01
for
both
comparisons.
A versus
group
B, Mann–Whitney
test,
p < 0.01.
were
were
tested.
in remission
of
INS
at
all
bleeding
time
points.
Sample
sera
separated,
frozen
and
stored
(−20◦C)
until
simultaneously
2.3.
Methods
Vaccine-associated
recorded
pants.
the
12
relapses
sidered
A
assay
standard
cal
serum
UK)
tut,
and
goat
search
assigned
istration,
local
and
systemic
adverse
effects
were
within
7 days
after
PCV7
administration
in all
partici-
Relapses
of
INS,
defined
as
minimum
proteinuria
of
2+
with
urine
dipstick
for
3 consecutive
days,
were
recorded
within
months
following
vaccination
and
compared
with
history
of
within
the
previous
year.
Episodes
of
relapse
were
con-
independent
if they
took
place
at least
1 month
apart.
modified
pneumococcal
enzyme-linked
immunosorbent
(ELISA)
based
on
the
World
Health
Organization
(WHO)
protocol
was
performed
for
detection
of
pneumococ-
serotype
(PS)-specific
IgG
antibody
concentrations
[2].
Briefly,
samples
were
preabsorbed
with
PS
22F
(LGC
Promochem,
and
cell
wall
polysaccharide
antigen
(CPS,
Statens
Serum
Insti-
Denmark).
Antibodies
specific
for
PS
4,
6B,
9V,
14,
18C,
19F
23F
were
detected
with
an
alkaline
phosphatase-conjugated
anti-human
IgG
monoclonal
antibody
(Jackson
ImmunoRe-
Laboratories,
USA).
Results
were
calculated
on
the
officially
values
of
89-SF
reference
serum
(Food
and
Drug
Admin-
Bethesda,
donated
by Carl
Frash).
2.4.
Statistical
analysis
A
cut-off
≥0.35
?g/ml
was
used
to define
minimum
protective
PS-specific
verted
Continuous
(SD).
non-parametric
Wilcoxon
comparison
ferroni
comparisons.
with
Nominal
analysis
used
relapses
ratios
(StataCorp,
IgG
antibody
concentration.
Antibody
levels
were
con-
to and
analyzed
as
geometric
mean
concentrations
(GMC).
variables
are
presented
as
mean
±
standard
deviation
Due
to small
number
of
participants
(<30
in all
groups),
methods
(Kruskal–Wallis,
Mann–Whitney
test,
signed-rank
test
and
Spearman’s
rho)
were
applied
for
of
means
and
correlations
of
continuous
variables.
Bon-
correction
of
the
level
of
significance
was
used
in multiple
Predictors
of
antibody
concentrations
were
evaluated
linear
regressions
adjusted
for
age,
gender
and
treatment.
variables
were
compared
by Fisher’s
exact
test.
For
the
of
relapse
rate,
exact
Poisson
regression
was
applied.
We
exact
logistic
regression
analysis
to assess
any
association
of
before
and
after
vaccination
(results
presented
as
odds
(OR)).
Data
were
analyzed
with
Stata
11.2
statistical
software
College
Station,
USA).
3.
Results
Fourty-nine
and
subjects
(15
and
18
in groups
A and
B,
respectively,
16 controls)
were
enrolled
in the
study
(Table
1).
Fourteen
and
15
pleted
for
No
A
and
respectively;
enrolment
patients
in groups
A and
B,
respectively,
and
15
controls
com-
follow-up
at 12–14
months.
All
33
patients
were
observed
potential
episodes
of
relapse
according
to the
initial
protocol.
significant
differences
were
found
for
gender,
whereas
group
patients
were
significantly
younger
compared
with
group
B
controls
(mean
±
SD
= 8.1
± 2.2,
11.4
± 3.6
and
13.7
±
3.7
years,
p < 0.01).
Treatment
with
prednisolone
at the
time
of
did
not
differ
significantly
between
patient
groups.
3.1.
PCV7
safety
Similar
were
adverse
over
reported
During
(mean
year
0.61
95%
within
tical
was
for
p
the
Similarly,
cination
relapse
local
and
systemic
reactions
within
7 days
after
PCV7
recorded
in patients
and
controls.
Solicited
injection-site
effects
were
reported
in 30.6%
of
total
vaccinations.
Fever
38◦C was
referred
in 2.0%
of
all
cases.
No
cases
of
IPD
were
within
the
12-month
follow-up
period.
12
months
before
and
after
vaccination,
36
INS
relapses
3.6)
occurred
in 10
patients.
Sixteen
relapses
occurred
in the
post
compared
with
20
pre
PCV7
(incidence
rate
0.49
versus
relapses/patient-year,
respectively,
relative
risk
(RR)
= 0.80,
C.I.:
0.38–1.62;
p = 0.61).
When
we
assessed
the
risk
of relapse
the
first
3 months
post
vaccination,
there
was
also
no statis-
difference
with
the
pre
vaccination
period
as a
reference.
There
a positive
correlation
between
the
relapse
rate
per
patient
the
year
before
and
after
vaccination
(Spearman‘s
rho
= 0.34;
= 0.05).
Subjects
with
relapses
before
were
more
prone
to relapses
year
after
vaccination
(OR
= 6.0,
95%
C.I.:
1.06–41.06;
p = 0.04).
less
patients
with
no relapse
in the
12 months
before
vac-
relapsed
thereafter
compared
with
those
with
at least
one
(20.0%
versus
61.5%,
respectively,
p =
0.027).
3.2.
PCV7
immunogenicity
At
baseline,
20%,
0% and
25%
of
subjects
in groups
A,
B and
controls,
threshold
primed.
between
B compared
One
body
controls,
pre-
groups.
post-vaccination
4,
trols
antibody
no
respectively,
had
antibody
levels
above
the
protective
of
0.35
?g/ml
for
≥5
PS and
were
considered
naturally
Geometric
mean
antibody
concentrations
were
similar
groups
for
all
PS
except
6B
levels
that
were
lower
in group
to controls
(p < 0.01)
(Table
2).
month
after
PCV7,
most
participants
had
protective
anti-
levels
for
≥5
PS
(100%,
94%
and
100%
in groups
A,
B and
respectively)
and
probabilities
of
switching
from
negative
to post-vaccination
status
did
not
differ
significantly
between
A
significant
increase
(p < 0.01)
in GMC
for
all
PS
at
1 month
was
observed
in all
groups.
However,
GMC
for PS
9V
and
18C
were
significantly
lower
in group
B compared
to con-
(p = 0.017,
<0.01
and
<0.01,
respectively);
group
A had
higher
titers
for
PS
18C
(p = 0.036)
compared
with
group
B and
significant
differences
were
observed
compared
with
controls.

Page 3

6836
C.D.
Liakou
et
al.
/ Vaccine
29 (2011) 6834–
6837
Table
2
IgG antibody
concentrations
expressed
as
GMC
(95%
C.I.)
at baseline,
1 month
and
12–14
months
after
vaccination
with
PCV7
in
INS
subjects
on
low-dose
prednisolone/no
therapy
(group
A)
or on additional
therapy
with
mycophenolate
mofetil
(MMF)
and/or
cyclosporine
A (CyA)
(group
B) and
controls.
PS
Patients
Controls
Group
A

Group
B
Pre

Post-1
montha
Post-1
yearb,c
Pre
Post-1
montha
Post-1
yearb,c
Pre
Post-1
montha
Post-1
yearb,c
4
0.02(0.006–0.60)
2.30(1.12–4.71)
0.19(0.11–0.34)††
0.009(0.003–0.30)
2.17(1.20–3.90)†
0.51(0.24–1.07)
0.06(0.02–0.22)
6.89(3.32–14.28)†
1.08(0.49–2.40)††
6B
0.05(0.01–0.24)
4.93(1.93–12.59)
1.26(0.47–3.38)
0.02(0.006–0.10)‡
2.85(1.25–6.48)
1.20(0.61–2.38)‡‡
0.42(0.17–1.00)‡
9.22(4.47–19.03)
3.74(1.89–7.39)‡‡
9V
0.18(0.06–0.61)
6.02(3.42–10.60)
1.36(0.66–2.79)££
0.28(0.18–0.44)
3.98(2.39–6.62)£
2.00(1.20–3.35)
0.52(0.18–1.50)
13.13(6.24–27.63)£
5.10(2.21–11.75)££
14
0.18(0.05–0.65)
11.50(5.43–24.35)
3.50(1.52–8.07)
0.09(0.02–0.42)
4.37(1.91–10.01)
2.84(1.21–6.66)
0.51(0.26–1.01)
11.64(5.34–25.37)
4.92(2.63–9.22)
18C
0.17(0.07–0.42)
5.11(3.44–7.58)§
0.73(0.35–1.55)§§
0.17(0.12–0.24)
1.70(0.94–3.09)§
0.88(0.46–1.67)§§
0.17(0.07–0.40)
8.55(5.62–13.03)§
2.53(1.84–3.48)§§
19F
0.93(0.52–1.63)
4.35(2.56–7.37)
2.29(1.44–3.64)
0.61(0.24–1.51)
3.32(1.90–5.82)
2.27(1.26–4.10)
0.61(0.33–1.15)
5.72(3.96–8.25)
2.93(2.05–4.20)
23F
0.21(0.08–0.53)
12.24(5.43–27.58)
3.56(1.51–8.41)
0.17(0.08–0.37)
4.92(2.18–11.10)
2.89(1.13–7.38)
0.44(0.23–0.84)
10.09(5.26–19.35)
4.20(1.79–9.82)
aAll
PS
compared
with
baseline,
Wilcoxon
signed-rank
test,
p < 0.01.
bAll
PS
compared
with
post-1
month,
Wilcoxon
signed-rank
test,
p <
0.01.
cAll
PS
compared
with
baseline,
Wilcoxon
signed-rank
test,
p
<
0.01.
†Group
B versus
controls,
Mann–Whitney
test,
p <
0.01.
‡Group
B versus
controls,
Mann–Whitney
test,
p =
0.017.
£Groups
B versus
controls,
Mann–Whitney
test,
p <
0.01.
§Group
B versus
controls
and
group
A versus
group
B,
Mann–Whitney
test,
p <
0.01
and
p = 0.036,
respectively.
††Group
A
versus
controls,
Mann–Whitney
test,
p =
0.009.
‡‡Group
B versus
controls,
Mann–Whitney
test,
p =
0.08.
££Group
A versus
controls,
Mann–Whitney
test,
p =
0.08.
§§Group
A versus
controls
and
group
B versus
controls,
Mann–Whitney
test,
p = 0.01
for
both
comparisons.
3.3.
Kinetics
of
PS antibodies
At
12–14
months,
despite
significant
decrease
in GMC
compared
to
tive
and
maintaining
significantly
at
a
nificantly
for
p
above
comparison
group
respectively)
and
The
the
0.23,
p
Knowledge
diction
post
vaccination
levels
in all
groups
(p < 0.01
for
all
PS),
protec-
antibodies
for
≥5
PS
were
sustained
in most
subjects
(86%,
94%
100%
in groups
A,
B and
controls,
respectively).
Probability
of
antibodies
for
≥5
PS
above
0.35
?g/ml
did
not
differ
between
groups.
However,
when
data
were
analyzed
a higher
cut-off
concentration
of 1.00
?g/ml,
used
previously
as
marker
for
protection
in asplenic
subjects
[3],
there
was
a sig-
higher
probability
of
controls
to retain
antibody
levels
≥5
PS compared
with
patients
(OR
= 5.23,
95%
C.I.:
1.06–33.61;
= 0.02).
Geometric
mean
concentrations
were
still
significantly
baseline
levels
for
all
groups
(p < 0.01
for
all
PS),
however
between
groups
revealed
significantly
lower
GMC
in
A
patients
for
PS
4,
9V and
18C
(p =
0.009,
0.08
and
0.01,
and
in group
B patients
for
PS
6B
and
18C
(p = 0.08
0.01,
respectively)
(Table
2).
12-month
antibody
levels
could
be
predicted
for
all
PS
from
1-month
concentration
(adjusted
R2= 0.19,
0.36,
0.68,
0.60,
0.44,
0.70
for
PS
4,
6B,
9V,
14,
18C,
19F
and
23F,
respectively;
= 0.02,
<0.001,
<0.001,
<0.001,
0.01,
<0.001,
<0.001,
respectively).
of
the
baseline
concentrations
did
not
improve
the
pre-
(p > 0.05
for
all
models).
4.
Discussion
This
is the
first
reported
study
to evaluate
safety,
immunogenic-
ity
Despite
size,
pediatric
and
healthy
controls
B lymphocytes
polysaccharides
[4].
Despite
we found
per
and
tion
cannot
Previous
rate
nary
meningococcal
to
prospective
ciation
stimulation
absence
Vaccination
patients
body
patients
Impaired
temic
previously
of
both
duration
system
of
and
kinetics
of
immune
response
to PCV7
in children
with
INS.
the
lack
of
a
placebo
control
group
due
to limited
study
our
findings
suggest
that
PCV7
is
safe
and
immunogenic
in
patients
with
INS
in remission,
although
the
magnitude
persistence
of
response
to some
PS is inferior
compared
with
subjects.
The
observed
differences
between
patients
and
should
not
be
age-related
since
low
frequencies
of CD21+
in childhood
associated
with
impaired
responses
to
have
been
described
only
in the
first
years
of
life
concerns
for
association
of
PCV7
with
INS
recurrence,
no such
evidence
in our
patients.
The
incidence
of
relapses
patient
was
not
affected
by
vaccination
and
relapse
rates
before
after
PCV7
were
positively
correlated,
suggesting
that
vaccina-
did
not
alter
the
natural
course
of
INS
although
our
results
be
conclusive
due
to the
relatively
small
size
of our
study.
studies
on
association
of conjugate
vaccines
with
relapse
in nephrotic
syndrome
are
controversial.
Despite
a
prelimi-
retrospective
report
on
increased
risk
of relapse
following
protein
conjugate
vaccine,
which
was
attributed
upregulation
of
different
cytokines
by vaccination
[5],
a larger
study
by Taylor
et al.
demonstrated
lack
of
such
asso-
[6],
supporting
the
hypothesis
that
a
transient
cytokine
by
vaccination
can
not
trigger
relapses
of
INS
in the
of
other
contributing
factors
[7].
with
PCV7
was
adequately
immunogenic
in
and
controls
and
most
subjects
obtained
protective
anti-
titers;
however,
the
magnitude
of
immune
response
in
on immunomodulators
was
inferior
for
PS
4, 9V and
18C.
induction
of
PCV7
immunity
in other
populations
on sys-
therapy
with
immunosuppressants
has
also
been
reported
[8,9]
and
could
be
attributed
to indirect
intervention
CyA
with
T-helper
signals
[10]
as
well
as
the
effect
of
MMF
on
T-
and
B-cell
proliferation
[11]. Although
the
exact
amount
and
of
systemic
use
of
corticoids
required
to suppress
immune
is
not
yet
well
defined
[12], the
observed
little
impact
low-dose
corticoid
therapy
on
PCV7
immunogenicity
in INS

Page 4

C.D.
Liakou
et
al.
/ Vaccine
29 (2011) 6834–
6837
6837
patients
with
sant,.
The
although
controls.
ics
immunogenicity
compared
PS
that
be
patients
and
via
mediated
tenance
T cell
induced
finding
antibodies
[15]
ing
at
cellular
In
immunogenic
for
coccal
in subjects
antibody
suggest
sary
pneumococcal
compared
with
controls
implies
that,
long-term
treatment
prednisolone
in low
doses
is not
a sufficient
immunosuppres-
majority
of
patients
retained
antibodies
at 12–14
months
at lower
concentrations
for
some
PS compared
with
Our
finding
could
be
explained
because
antibody
kinet-
were
associated
with
PCV7
primary
immune
response
and
after
priming
was
inferior
for
some
PS
in patients
with
controls.
Interestingly,
GMC
were
lower
for
3/7
in patients
not
treated
with
immunosuppressants,
suggesting
other
factors
than
immunosuppressive
therapy
should
also
associated
with
impaired
antibody
maintenance.
Most
of
our
had
no significant
proteinuria
at the
time
of
enrolment
through
the
whole
study
period
therefore
immunoglobulin
loss
the
urine
alone
could
not
explain
different
PS
kinetics.
T cell
immunological
memory
associated
with
antibody
main-
[13]
could
be impaired
in INS
subjects
with
well
described
abnormalities
[7,14]
and
could
result
in reduced
vaccine-
long-term
protection.
Such
hypothesis
is supported
by the
that
children
with
INS
had
lower
probability
of retaining
above
1 ?g/ml,
associated
with
long-term
protection
at 12–14
months
compared
with
controls.
As
part
of
an
ongo-
study,
we
have
boosted
our
patients
in remission
with
PCV7
12–14
months
after
priming
and
results
at both
serological
and
level
are
expected
to be
presented
in the
future.
conclusion,
our
study
demonstrates
that
PCV7
is safe
and
in patients
with
INS
in remission,
providing
evidence
compliance
to existing
guidelines
for
vaccination
with
pneumo-
conjugate
vaccines
[1].
The
inferior
PCV7
immunogenicity
on
immunomodulatory
treatment
and
the
different
kinetics
in patients
compared
with
healthy
individuals,
that
regular
monitoring
and
revaccination
when
neces-
are
essential
for
optimal
protection
of
INS
children
against
infections.
Acknowledgments
We are
statistical
Conflict
Funding: Athens
indebted
to George
Chouliaras
and
Marios
Detsis
for
analysis.
of
interests: The
authors
declare
no conflict
of
interests.
University
School
of
Medicine
(grant
70/4/9687).
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