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Symposium edition 2010
PEDIATRIC CLINICS AMSTERDAM
Preface
Welcome to the EKZ scientific symposium edition 2010!
We proudly present the abstract book of the 10th edition of the EKZ scientific symposium. For 10 years now this
excellent meeting has been a wonderful opportunity to be informed of the developments that take place in all
fields of basic and clinical science. It enables everyone to be inspired by looking outside one’s own field of inter-
est and to present one’s own research.
Last but not least, it is a great way to meet up with colleagues and start new collaborations in a relaxed atmos-
phere. Traditionally, the authors of the six most excellent abstracts will be invited to present their research in a
Masterclass on January 22. This year’s masters will be Prof.dr. H.S.A Heymans, Prof dr.H.P. Sauerwein, and Prof.
dr. H.M.Caron and Prof.dr. R de Groot. Poster prizes in different categories will be available for the three most
excellent and original posters. I hope the EKZ scientific symposium 2010 will bring you inspiration and new op-
portunities,
Annet M. Bosch
Editor in chief
Pediatric Clinics Amsterdam
is an edition from
Emma Kinderziekenhuis
AMC
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Editorial Board
A.M. Bosch (Editor in Chief)
H.D. Bakker
A.H. van Kaam
J.H.M. Merks
R.R. van Rijn
A.B. Sprikkelman
A.F.W. van der Steeg
J.B.M. van Woensel
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A.M. Bams-Mengerink1, J.H.T.M. Koelman2, M. Duran3,
B.T. Poll-The1
1 Department of Pediatrics and Pediatric Neurology, 2 Department
of Neurology, 3 Laboratory Genetic Metabolic Disorders, Emma
Children’s Hospital, Academic Medical Center Amsterdam, The
Netherlands, Meibergdreef 9 , 1105 AZ, Amsterdam, The Nether-
lands, e-mail:[email protected]
Background:
Rhizomelic chondrodysplasia punctata (RCDP) is a
peroxisomal disorder that is, amongst other important
clinical features, characterized by severe neurological
dysfunction. Milder phenotypes exist and the severity
of the clinical phenotype is reflected in plasmalogen
content of erythrocytes. Since over 80% of patients
with RCDP develop epileptic seizures and neurological
dysfunction is such an important feature of the dis-
ease, we were interested in the diagnostic and evalua-
tive role of EEG and evoked potential (EP) studies.
Methods:
We analysed neurophysiologic assessment in a cohort
of 16 patients with RCDP. The neurophysiology studies
were related to the severity of the phenotype.
Results:
4/16 had a mild phenotype and 12/16 had a severe
phenotype of RCDP. 10/16 patients developed epilep-
tic seizures and 12/16 patients had epileptic activity
on EEG. Epilepsy was seen in both milder and severe
phenotype patients. Visual evoked potential studies
(N=14) showed initial normal latency times in12/14
patients . Deterioration occurred in 3/7 patients in
whom follow up was performed (both mild and severe
phenotype). Brain auditory evoked potential studies
( N=13) showed initial normal latency times in 12/13
patients. Deterioration occurred in 5/8 patients (all
severe phenotype). Somato sensory evoked poten-
tials were performed in 10 patients. Absent cortical
responses were seen in 3/6 patients with the severe
phenotype.
Conclusion:
Epileptic seizures and epileptiform activity on EEG are
important features of both the mild and severe pheno-
types of RCDP and develop over time. EP studies do not
seem to reflect the severity of the clinical and biochemi-
cal phenotype and are thus of no diagnostic value.
P1
Neurophysiologic assessment in patients with rhizomelic chondrodysplasia punctata
Reinout A. Bem1, Job B.M. van Woensel1, Rene Lutter2, Joseph B.
Domachowske3, Jan Paul Medema4, Helene F. Rosenberg5, Albert
P. Bos1
1 Pediatric Intensive Care Unit, Emma Children’s Hospital AMC,
Amsterdam, The Netherlands; 2 Departments of Pulmonology
and Experimental Immunology, Academic Medical Center, Am-
sterdam, The Netherlands; 3 Department of Pediatrics, Upstate
Medical University, Syracuse, NY, USA; 4 Laboratory for Experi-
mental Oncology and Radiobiology, Academic Medical Center,
Amsterdam, The Netherlands; 5 Laboratory of Allergic Diseases,
National Institute of Allergy and Infectious Diseases, National
Institutes of Health, Bethesda, MD, USA.
Gants/funding: supported in part by Ars Donandi, Amsterdam.
H.F. Rosenberg supported by National Institute of Allergy and In-
fectious Diseases Division of Intramural Research (Z01-AI000943).
Correspondence: Reinout A. Bem, Emma Children’s Hospital,
Academic Medical Center, Pediatric Intensive Care Unit, P.O. Box
22660, 1100 DD, Amsterdam, The Netherlands, Tel: +31 20 5665769,
Fax: +31 20 6919338, E-mail: [email protected]
Introduction:
Lower respiratory tract infection by the human pneu-
movirus respiratory syncytial virus is a frequent cause
of acute lung injury in children. Severe pneumovirus
disease in humans is associated with activation of the
granzyme pathway by effector lymphocytes, which may
promote pathology by exaggerating pro-apoptotic cas-
pase activity and pro-inflammatory activity. The main
goal of this study was to determine whether granzymes
contribute to the development of acute lung injury in
pneumovirus-infected mice.
Method:
Granzyme-expressing mice and granzyme A, and
B-cluster single and double-gene deleted mice were
inoculated with the rodent pneumovirus pneumonia
virus of mice strain J3666, and were studied for mark-
ers of lung inflammation and injury.
Results:
Expression of granzyme A and B is detected in effector
lymphocytes in mouse lungs in response to pneumovi-
rus infection. Mice deficient for granzyme A and the
granzyme B-cluster have unchanged virus titers in the
lungs, but show a significantly delayed clinical response
to fatal pneumovirus infection, a feature that is associ-
ated with delayed neutrophil recruitment, diminished
activation of caspase-3 and reduced lung permeability.
Conclusion:
We conclude that granzyme A and B-cluster deficiency
delays the acute progression of pneumovirus disease by
reducing alveolar injury.
P2
Granzyme a and b-cluster deficiency delays acute lung injury in pneumovirus-infected mice
F.J. Berfelo1, T.R. de Haan2, P. Govaert3, G. van Wezel-Meijler4, B.T. Poll-The5, J.R.
Vermeulen6, F. Groenendaal7, L.S. de Vries7, C.H. van Ommen8
1Neurology, AMC, Amsterdam, 2Neonatology, Emma Children's Hospital AMC, Am-
sterdam, 3Neonatology, Sophia Children's Hospital/ Erasmus Medical Center, Rotter-
dam, 4Neonatology, Leiden University Medical Centre, Leiden, 5Paediatric Neurology,
Emma Children's Hospital AMC, Amsterdam, 6Paediatric Neurology, Free University
Medical Centre, Amsterdam, 7Neonatology, Wilhelmina Children's Hospital UMCU,
Utrecht, 8Pediatric Hematology, Emma Children's Hospital AMC, Amsterdam
Neonatal cerebral sinovenous thrombosis (CSVT) is increasingly diag-
nosed due to improved neuroimaging techniques. To evaluate the clini-
cal course, possible risk factors and outcome of neonates with CSVT and
secondly to estimate the incidence in The Netherlands, a multicenter
review of prospectively collected data on neonates with radiographi-
cally confirmed sinovenous thrombosis between 1999 and 2009 was
performed.
Fifty-two neonates [39 males, median gestational age 39 weeks (range
30-42, six preterm infants) from six Dutch tertiary centres were
included. A yearly incidence of 4.2 neonatal SVT cases/100.000 term
newborns was found. Most common presenting symptoms were seizures
(39/52) and apnoea (9/52). In 8/52 CSVT was a chance finding during
cerebral ultrasound in critically ill neonates. Maternal risk factors
like pre-eclampsia and infection were present in 13/52 neonates. The
most frequent perinatal risk factor was assisted or complicated delivery
(31/52). Postnatal risk factors included sepsis/meningitis (8/52) and
asphyxia (3/52). CSVT was suspected by doppler investigation in 19/52
neonates. Diagnosis was confirmed by MRI/MR-venography in all
patients. The superior sagittal sinus was most frequently involved. In
28/52 neonates multiple sinus were affected. Associated laesions were
(haemorrhagic) infarction (35/52), thalamic haemorrhage(24/52) and
intraventricular haemorrhage.
Anticoagulants were given to 23 neonates in whom no haemorrhagic
complications occurred. Eight neonates died due to CSVT. At follow-up
[median age 19 months (range 3 -72 months)] neurological sequelae were
moderate to severe in 20 patients. In conclusion, CSVT is a severe dis-
ease which usually presented with seizures or apnoea in term neonates
after a complicated or assisted delivery.
P3
Neonatal sinovenous thrombosis: clinical presentation, riskfactors, imaging results, outcome
P4
Fas-deficiency is deleterious in a murine model of rsv infectionElske van den Berg1,3, Reinout A. Bem1, Job B.M. van Woensel1, Albert P. Bos1, William
A. Altemeier3, Thomas R. Martin2 and Gustavo Matute-Bello3
1Pediatric ICU, Emma Children’s Hospital, Academic Medical Center, Amsterdam,
The Netherlands; 2VA Puget Sound Health Care System and 3Center for Lung Biology,
Division of Pulmonary and Critical Care Medicine,, University of Washington, Seattle,
Washington
Respiratory syncytial virus (RSV) is an important cause of morbidity in
infants. RSV infections are associated with neutrophilic inflammation
and epithelial cell apoptosis. Activation of the Fas/FasL system in the
lungs can induce neutrophilic inflammation and apoptosis. We hy-
pothesized that Fas-deficient mice (lpr) would be protected in a model
of RSV infection. Lpr and WT mice (C57BL/6) received intratracheal
instillations of the RSV analog, Pneumonia Virus of Mice (PVM). Eight
days later, the mice were subjected to 4 hours of mechanical ventila-
tion with Tv = 10 cc/kg, FiO2 = 0.21 and PEEP = 3 cm H2O. Contrary to
our expectations, the lpr mice had significantly higher mortality than
the WT mice (7/7 vs 3/7, p < 0.05). Because the increased mortality
prevented a direct comparison of lung injury markers, we repeated the
studies on day 7 after PVM instillation. On day 7, all the mice survived
for the duration of the experiments. Compared to WT mice (n = 7), lpr
mice (n = 7) showed decreased BALF neutrophils (15.3 vs 7.0 x 104 cells)
but similar whole lung myeloperoxidase activity (22.5 vs 19.4 mU/ml),
suggesting that neutrophil migration into the airspaces was impaired,
but recruitment into the lungs was preserved. Accordingly, the lpr mice
showed lower BALF concentrations of the chemokine KC (130.0 vs 338.5
pg/mL). The total BAL protein content, lung caspase-3 activity and total
viral load were similar in both groups of mice.
Conclusion:
As compared to WT mice, mechanically ventilated lpr mice have sig-
nificantly increased mortality 8 days after the instillation of PVM, and
this is preceded by an impairment in neutrophil migration into the
airspaces.
O.G. Besancon1, G.A.M Tytgat2, R. Leen1, A.C. Verschuur, H.N. Caron2, A.B.P. van
Kuilenburg1
Academic Medical Centre, University of Amsterdam, 1Laboratory Genetic and Meta-
bolic Diseases, 2Department of Pediatric Oncology, Amsterdam, The Netherlands
Introduction/ Background:
Neuroblastoma is a childhood tumor with a poor prognosis and there-
fore new therapeutical options are needed.
The PI3K/AKT/mTOR pathway is a potent survival-signaling pathway
that is aberrantly activated in a variety of human cancers
We investigated the efficacy of the PI3K/mTOR inhibitor PI-103 and
determined if inhibition of the PI3K/AKT/mTOR pathway sensitized
neuroblastoma cells towards currently applied chemotherapeutic
drugs.
Material and Methods:
Six human neuroblastoma cell lines, three MYCN amplified and three
MYCN single copy, were treated with topotecan, gemcitabine, cisplatin,
etoposide or doxorubicine alone or combined with 4hr preincubation of
PI-103 (80 nM or 400 nM).
The effect of PI-103 was studied in cells growing in monolayers and in
spheroids, a three dimensional tumor model and as such a model for
micrometastases.
Viability was measured using the MTS assay and dose-effect curves
were generated to perform multiple drug effect analysis. A combination
index (CI) < 1.1 indicates a synergistic/additive effect of the combina-
tion.
Results:
In all cell lines we observed a dose- and time-dependent decrease in
viability after treatment with
PI-103 or currently applied chemotherapeutics. PI-103 showed an
inhibiting effect on tumor-spheroids growth. A synergistic effect was
observed for most combinations, with the most pronounced effect for
the combination topotecan – PI-103 (figure 1)
Conclusion:
Our results showed that the combination of PI-103 with five currently
applied chemotherapeutic drugs has a synergistic effect with respect
to viability on most neuroblastoma cell lines and might therefore be a
promising new strategy in treatment of neuroblastoma.
P5
Promising effects of the drug combination pi-103 with currently applied chemotherapeutic drugs on neuroblastoma cell lines
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Schoot R.A.1 / Bleeker G.1, Heij H.A.2, van Eck B.L.F.3, Caron H.N.1,
de Kraker J.1
First two authors contributed equally to this abstract.1Department of Paediatric oncology, 2Department of Paediatric
Surgery, 3Department of Nuclear Medicine, Emma Children's Hos-
pital AMC, F8-239, Academic Medical Centre (AMC), University of
Amsterdam, PO Box 22700, 1100 DE Amsterdam, The Netherlands.
Introduction:
In patients with localized non MYCN amplified neu-
roblastoma, observation only is justified. If organ or
life threatening symptoms arise, treatment is required.
Side effects should be minimal, since outcome is good.
Aim of this study was to evaluate response and outcome
of patients under these circumstances, when treated
with ¹³¹I-metaiodobenzylguanidine (¹³¹I-MIBG).
Patients and Methods:
Between 1989 and 2008 21 patients with a localized
neuroblastoma were treated with ¹³¹I-MIBG (table 1).
Patients were treated if the primary tumour was un-
resectable and organ or life threatening. Fixed dosages
of ¹³¹I-MIBG (6-20 mCi/kg) were infused over two to
four hours, with an interval of four weeks. The median
number of infusions was 2 (range 1-7). Response was
graded according to the International Neuroblastoma
Response Criteria.
Results:
Minimal pretreatment was given to nine patients (sur-
gery or one cycle of chemotherapy), because of organ or
life threatening symptoms. These patients responded
insufficiently or showed return of tumour growth.
After 131I-MIBG treatment 8/21 tumours regressed.
Resection became possible in 13/21 patients. In 10/13
patients resection was macroscopically complete. Three
others had an incomplete resection. They had long-
term progression free survival. At the end of treatment
16/21 patients achieved complete response and 3/21 had
stable disease (2 very good partial response, 1 partial
response) (table 2). Two patients died; one of progres-
sive disease, one due to complications of surgery. One
patient was lost to follow-up. 10 years EFS was 72.4%,
10 year OS was 90.5%. Median follow-up was 7.5 years
(range 1 to 17.4).
Conclusion:131I-MIBG treatment is an effective treatment modal-
ity in unresectable localized neuroblastoma, in case of
organ or life threatening situations.
P6
The role of 131I-metaiodobenzylguanidine (131I-MIbG) therapy in unresectable and compromising localized neuroblastoma
Number (N=21):
Percentage (%):
Sex:
Male 8 38
Female 13 62
Age at diagnosis (years):
mean (range)
<1 year
1.6 (0-5.5)
9
INSS Stage:
1 4 19
2 3 14
3 14 67
Localization:
Neck 1 5
Thoracic 5 24
Abdominal 11 52
Pelvic 4 19
Reasons for ¹³¹I-MIBG:
organ relation 12 57
Intraspinal 7 33
progressive disease 2 10
Genetics:
MNA 2/18 11
1p LOH 1/18 6
Both 1/18 6
Pretreatment:
Chemotherapy 4 19
Surgery 4 19
Both 1 5
Table 1. Patient characteristics.
Table 2.
21 patien ts treated with 131 -I-MIBG
8: 131 -I-MIBG on ly
10: surge ry
3: chemo + surgery
MR PR CR VGPR PD NR
5 2 1
3
9 1
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Bleeker G.1, Caron H.N.1, de Kraker J.1, van Eck-Smit B.L.F.3,
Versteeg R.2, Tytgat G.A.M.1
1 Department of Pediatric Oncology, Emma Children's Hospital/
Academic Medical Centre2 Department of Human Genetics, Academic Medical Centre3 Department of Nuclear Medicine, Academic Medical Centre
Emma Children's Hospital AMC, F8-239, Academic Medical
Centre (AMC), University of Amsterdam, PO Box 22700, 1100 DE
Amsterdam, The Netherlands.
Background:
Neuroblastomas show a variable clinical course rang-
ing from spontaneous regression to high risk disease.
Probably, different patterns of tumour growth and
dissemination in these patients are a reflection of
distinct biological processes. The purpose of this pilot
study was 1. to identify these patterns on MIBG scans;
and 2. to test whether these patterns correlate with
gene expression clusters.
Methods:
All patients diagnosed with a neuroblastoma stage 4
from 1996 up till now were considered for this study.
Both a MIBG scan, as well as an Affymetrix gene
expression analysis of the primary tumour at the time
of diagnosis should be available (n=12). Two inde-
pendent observers evaluated the MIBG scans. Gene
expression data (affymetrix MAS5.0) of the primary
tumours, available in the bioinformatical program R2
of the department of Human Genetics, were used for
unsupervised hierarchical clustering of the 1500 most
diferentially expressed genes. Next we correlated the
gene clusters with the growth and dissemination pat-
terns on MIBG scans.
Results:
Unsupervised hierarchical clustering resulted in
two clusters (I and II) that correlated with different
growth and dissemination patterns on MIBG scans
(table 1). Cluster II showed more extensive dissemina-
tion than cluster I.
Conclusion:
Stage 4 neuroblastoma show different patterns of
tumour growth and dissemination on MIBG scans that
seem to correlate with gene expression clusters. An
extended cohort of all stages is needed to prove the
results of this pilot study. The ultimate goal of this
project is to identify biological processes that play a
role in these patterns.
P7
Patterns of tumour growth and dissemination on MIbG scans seem to correlate with gene expression data of stage 4 neuroblastoma tumours
Table 1. MIBG imaging trat is classified according to gene clusters I and II.1 X2 / Fisher test 2 Extension score per segment: 0: no uptake, 1: one lesion, 2: more than one lesion (<50% of segment),
3: massive involvement (>50% of segment),
BOS: base of skull; FBO: facial bones and orbita; RSCS: ribs, sternum, clavicula and scapula; VC: vertebral column; FAH: fore arms and
hands; MNA: MYCN amplification; 1pLOH: 1p loss of heterozygosity.
MIBG imaging trait: Cluster I (N=5):
Cluster II (N=7):
P1:
Cold node in primary tumour 5 3 0.081
FBO metastases 0 3 0.205
RSCS metastases 0 5 0.028
VC metastases 0 5 0.028
FAH metastases 0 3 0.205
Pelvis extension (>50%) 0 5 0.008
Upper legs extension (>50%) 0 5 0.018
Number of affected body segments 0-5 segments: 4
5-10 segments: 1 0-5 segments: 2
5-10 segments: 5 0.242
Extension of metastases within body segments (total score)2 <10: 4
>10: 1 <10: 2
>10: 5 0.242
MNA 4 1 0.072
1pLOH 5 2 0.028
Machtelt G. Bouwman1; Quirine G.A. Teunissen1; Frits A. Wijburg1; Gabor E.
Linthorst2
1 Division of Metabolic disorders, Emma Children’s Hospital, 2 Division of
Endoc rinology and Metabolism, Internal medicine,Academic Medical Center,
Amsterdam,The Netherlands.
Introduction:
Internet has resulted in widespread availability of medical informa-
tion and much time is spent on the Internet by patients searching for
diagnoses. Especially for rare diseases Internet can be an important tool
in the diagnostic process. We report two cases where parents diagnosed
a lysosomal storage disorder (LSD) in their child by searching the
Internet.
Case 1:
From the age of 5 years this boy had severe pains in hands and feet
during exercise and fever. In addition he had a skin rash. A diagnosis
could not be established by several pediatricians. At the age of 11 years
concerned parents initiated a search on ‘Google’ and rapidly found a
picture of skin rash in a Fabry patient and immediate recognized it as
similar to their child’s. Diagnosis was confirmed by enzymatic studies.
Case 2:
A boy failed his neonatal hearing-tests and had recurrent ENT-infec-
tions. At the age of 3 months a hydrocephalus was diagnosed. From the
age of 12 months parents noticed snoring, a kyphosis, changing facial
features, delayed cognitive development and bowed fingers. Consulted
paediatricians and a geneticist failed to establish a diagnosis. Finally
mother entered ‘bowed finger’ in ‘Google’ and recognized the facial fea-
tures of her child as typical for mucopolysaccharidosis type 1 (MPS-1).
Diagnosis of MPS I was confirmed.
Conclusion:
These cases illustrate the potential of Internet search-engines for
diagnosing rare disorders and illustrate the diagnostic odyssey which
is common in LSD’s. Physicians should consider ’Google’ as part of their
diagnostic strategy in rare disorders.
P8
‘Dr. Google’ ending the diagnostic odyssey in lysosomal storage disorders
Machtelt G. Bouwman1, Myra C.B. van Zwieten2, Gabor E. Linthorst3, Carla E.M.
Hollak3, Frits A. Wijburg1. 1 Division of Metabolic disorders, Emma Children’s Hospital, 2 Department of General
Practice/Medical Ethics, 3 Division of Endocrinology and Metabolism, Internal medi-
cine, Academic Medical Center, Amsterdam, The Netherlands
Background:
In the last decade, rapid technological advancements and new therapeu-
tic options have made newborn screening feasible for many disorders,
including Fabry disease (FD).
FD is an X-linked lysosomal storage disorder, caused by deficiency of
α-galactosidase A (α-Gal A). Accumulation of globotriaosylceramide
(Gb-3) results in renal, cardiac and neurological disease and reduced
life expectancy. Treatment with enzyme replacement therapy reduces
tissue Gb-3 and may stabilize renal disease and other disease features.
Recent studies suggest that early initiation of treatment might be more
efficacious. This observation has led to pilot studies investigating the
feasibility of newborn screening for FD. However, technical and ethical
issues need to be resolved.
Aim of the study:
The aim of this study is to explore experiences of patients with FD that
might be relevant to the current discussions on the pros and cons of in-
cluding FD in the expanded newborn screening programs. Through this
qualitative study approach we aim to enrich the decision making policy
on inclusion of FD in newborn screening programs.
Methods:
This study is a multiple case study, consisting of interviews, docu-
ment analysis and observations of patients with FD. The cases will be
purposively sampled from pre-defined subgroups of FD patients, to yield
an optimum set of relevant data. Semi structured interviews will be
performed, guided by a topic list.
P9
Ethical aspects of newborn screening for fabry disease: a multiple case study
Madeleine Bunders1,2, Chris van der Loos3, Steven Pals3, Taco Kuijpers1
1 Division of Pediatric Hematology, Immunology and Infectious diseases, 2 Dept of
Experimental Immunology, 3 Dept of Pathology, AMC, The Netherlands.
Background:
Every year 600.000 children are infected with HIV due to mother-to-
child-transmission (MTCT). However the route of transmission and resi-
dence of target cells for HIV in neonates remains unknown. The main
target cells for HIV are not present in cord blood. However secondary
lymphoid tissues may harbor a pool of resident memory T cells to offer
protection to imminent microbial exposure after birth and provide a
pool of target celsl for HIV.
Methods:
We performed immuno-histochemistry to identify memory T cells on
post-mortem gut tissues from four 4 neonates and compared these to
splenic tissue. Spectral imaging was used to analyze the images.
Results:
Three children were born prematurely, all died within 24 hrs after
birth and did not receive enteral feeding. In contrast to the blood
compartment, CD4+CCR5+ T cells were abundantly present (26.9%) in
neonatal gut epithelium. Additionally 19.6% of CD4+ T cells carried a
CD45RO phenotype. In the spleen only 3.1% of the CD4+ T cells expressed
CCR5+ and 10.5% of CD4+ T cells had a memory phenotype.
Conclusions:
Target cells for HIV present in the gut are easily accessible for HIV in
infants, which should be taken into account when developing strategies
to prevent MTCT. Furthermore, in contrast to the current paradigm, the
presence of T cells with a memory phenotype suggests that initiation of
memory development commences already during the fetal period.
R. Burgers1,2, O. Liem1,2, S. Canon2; M. Benninga1, H. Mousa2; S. Koff2, C. Di Lorenzo2
1 Emma Children's Hospital, Amsterdam Medical Center, Amsterdam, Netherlands;2 Nationwide Children's Hospital, Columbus, OH, USA
Background:
Although the association between constipation and urinary tract dys-
function in children is well established, the mechanisms underlying
this relationship are yet unknown.
Material and Methods:
Consecutive children with constipation and/or urology problems who
required urodynamic studies (UDS) for incontinence or infrequent void-
ing (< 4 times per day) were offered participation in the study. Patients
were assigned to a constipation and urology group or a urology-only
group. Definition of constipation was based on the pediatric Rome III
criteria. First, an UDS was performed according to standard protocol.
Secondly, an UDS was repeated simultaneously with pressure control-
led distension of a balloon in the rectum, using the electronic barostat.
Bladder capacity (BC), adjusted for age, and detrusor overactivity (DO)
were evaluated. A BC volume change of 30 ml or more was defined as
clinically relevant.
Results:
The final data set consisted of a total of 26 children (16 female, mean
age 7.8 years range 5-11); 20 in the combination group and 6 in the urol-
ogy-only group. At rest 16 children showed DO. Rectal balloon pressure
ranged between 6 - 39 mmHg. With inflation of the rectal balloon BC in-
creased (n=6), decreased (n=12) or did not change (n=8), three patients
showed new DO. No significant difference was found between children
with or without constipation, either in BC changes or DO appearance.
Conclusion:
This study shows that rectal distention has an unpredictable effect on
bladder capacity and detrusor overactivity in almost all children with
urology symptoms, with and without constipation.
P10
Memory T lymphocytes in the gut of newborns: target cells for neonatal HIV-infection
P11
Effect of rectal distention on bladder function
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P.M. van Brussel1, J. Ottenkamp1,2, C.M. Bilardo3, S.A. Clur1,2
1Department of Pediatric Cardiology Emma Children’s Hospital
Academic Medical Centre, Amsterdam, The Netherlands, 2Center
for Congenital Heart Disease Amsterdam-Leiden, The Nether-
lands, 3Department of Obstetrics and Gynaecology Academic
Medical Centre, Amsterdam, The Netherlands.
Background:
Fetal echocardiography allows for the early prenatal
diagnosis (PreDx) of cardiac defects .
Objectives:
To evaluate the accuracy of prenatal echocardiog-
raphy and counselling in the diagnosis of cardiac
defects.
Methods:
A retrospective study of fetuses referred for fetal
echocardiography between April 1999 and December
2008. The pre- and postnatal congenital heart disease
(CHD) diagnoses were recorded and scored using a
modified Aristotle (modA) score (Lacour-Gayet et al.
2004). The expected surgery (palliation/repair), opera-
tive complexity, repeated operations and co-morbidity
added to the score with a maximum of 25. The pre-
and postnatal scores were compared.
Results:
605 fetuses were examined. A normal heart was found
in 312(51,6%) and 293(48,4%) had cardiac pathology.
The cardiac diagnoses were; CHD in 234(79,95%), pri-
mary arrhythmia in 39(13,3%) and cardiomyopathy/
myocarditis/cardiac tumour in 20(6,8%). The most
frequent major CHD diagnoses were Hypoplastic LV
30(HLHS16, DORV8, AVSD 6), VSD28, AVSD 24, TGV 22,
Heterotaxia 17, Aorta and arch abnormalities 15, DORV
14, TOF 12(5 with PA), Hypoplastic RV 11, Ventricular
disproportion 8, DILV 6, Truncus arteriosus 4.
The average modA score was 8,4±5,4 prenatally and
8,4±5,5 postnatally. The pre- and postnatal scores
correlated well with an average difference of +1,1±4,0
between them.
In 42 fetuses the postnatal course differed from the
prenatal expectation, negatively in only 6. Suspected
aortic coarctation was the preDx in 10 of these 42
fetuses. 15 minor CHDs were missed.
Conclusions:
PreDx of cardiac defects was accurate and the counsel-
ling regarding expected postnatal course appropriate
in most cases except for aortic coarctation.
P.M. van Brussel1, J. Ottenkamp1,2, C.M. Bilardo3, S.A. Clur1,2
1Department of Pediatric Cardiology Emma Children’s Hospital
Academic Medical Centre, Amsterdam, The Netherlands, 2Center for
Congenital Heart Disease Amsterdam-Leiden, The Netherlands, 3De-
partment of Obstetrics and Gynaecology Academic Medical Centre,
Amsterdam, The Netherlands.
Objective:
To evaluate the potential benefit of fetal echocardiogra-
phy in the prenatal diagnosis(PreDx) of cardiac defects.
Methods:
A retrospective study of fetuses referred for fetal
echocar dio graphy (April 1999- December 2008). The fetal
diagnosis was recorded. Congenital heart disease (CHD)
was categorized according to the availability of and
necessity for an intervention to improve outcome (Wald
and Kennard 1998).
Results:
605 fetuses were examined and 546 scored. There were
312(51,6%) normal hearts and 293(48,4%) with cardiac
pathology. The cardiac diagnoses were; CHD-234(79,9%),
primary arrhythmia-39(13,3%) and cardiomyopathy/myo-
carditis/cardiac tumour-20(6,8%).
The classification of CHD was as follows. A: Certain intra-
uterine/neonatal death 2(0,4%), B: Defect palliable but
disabling 39(7,1%), C: Defect not satisfactorily reparable
but in-utero therapy reduces morbidity 0, D: Evidence
lacking for postnatal survival benefit 59(25,1%), E: Defect
not serious enough to warrant preDx 49(22,1%), F: Defects
with proven improved prognosis with preDx 85(35,3%),
G: Normal heart 312.
PreDx was beneficial in:
1) Categories B, C and F, arrhythmias and cardiomyopa-
thies (183).
2) 203 fetuses with a normal heart without extracardiac
abnormalities as the parents were positively reas-
sured.
3) The CHD was diagnosed before 24 weeks’ gestation
(cut-off for legal pregnancy termination (TOP) in
395(65,3%). Karyotyping was performed in 413 and
was abnormal in 97(23,5%).TOP followed in 88(21,3%)
of which 25/88(28,4%) had a normal heart or where in
category A or D.
Conclusions:
PreDx for cardiac defects using echocardiography was
potentially beneficial in 67,9% (183+203+25=411/605) of
the fetuses seen.
Limitations:
The potential benefit/detrimental emotional effect of
preDx in the parents was not evaluated.
P12 Accuracy of prenatal diagnosis of congenital heart defects over a ten year period in a referral center
P13 beneficial effect of prenatal diagnosis of congenital heart defects; ten years in a referral center
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P.M. van Brussel1, J. Ottenkamp1,2, C.M. Bilardo3, S.A. Clur1,2
1Department of Pediatric Cardiology Emma Children’s Hospital
Academic Medical Centre, Amsterdam, The Netherlands, 2Center for
Congenital Heart Disease Amsterdam-Leiden, The Netherlands, 3De-
partment of Obstetrics and Gynaecology Academic Medical Centre,
Amsterdam, The Netherlands.
Objectives:
To document the outcome of fetuses referred for
specialized fetal echocardiography.
Methods:
A retrospective study of fetuses referred for fetal
echocardiography (April 1999-December 2008). Fetal
diagnosis, karyoptye, management and outcome were
recorded. The cardiac diagnosis was scored using a modi-
fied Aristotle (modA) score (Lacour-Gayet et al. 2004)
and correlated with outcome.
Results:
605 fetuses were examined, 312(51,6%) had normal
hearts and 293(48,4%) had cardiac pathology inclu ding;
congenital heart disease (CHD)-234(79,9%), primary ar-
rhythmia-39(13,3%) and cardiomyopathy/myocarditis/
cardiac tumour (CMO)-20(6,1%).
The diagnosis was made before 24 weeks’ gestation
(cut-off for legal TOP) in 395(65,3%). TOP followed in 88
(39(44,2%) CHD and normal karyotype, 27(30,8%) CHD
and abnormal karyotype, 22(25%) no CHD).
413 fetuses were karyotyped. 97(23,5%) had kayrotypic
abnormalities and 58(59,8%) died, (pregnancy termina-
tion (TOP) in 40).
The mortality rates were; arrhythmia-3/39(7,7%), CMO
-7/20(35%) and CHD-114/235 (48,5%) (20,9% in those with
normal karyotype). A TOP was performed in 64(28,1%),
3 miscarried, 16 intrauterine deaths occurred and one
baby was stillborn. Comfort care(10) or a preoperative
death(7) occurred in 17(6,4%). 10/71 died after or during
an interventional heart catheterization or cardiac sur-
gery. 20/61(32,8%) babies surviving an intervention still
require cardiac medication. Three have pacemakers.
The average modA score of babies with CHD and normal
karyotype was 6,5±5,0 in the survivors and 12,1±3,8 in
those that died, (13,5±2,8 in those terminated).
Conclusions:
The referrals were appropriate (48,3% cardiac pathol-
ogy).The mortality was high in these high-risk fetuses.
The fetal outcome and the decision for TOP correlated
with the severity of the CHD.
Marieke van Dijk1, MSc; Marc A. Benninga2, MD PhD; Martha A.
Grootenhuis1, PhD; Bob F. Last1,3, PhD 1Psychosocial Department Emma Children’s Hospital/Academic
Medical Center, University of Amsterdam, Amsterdam, The
Netherlands2Department of Pediatric Gastroenterology and Nutrition Emma
Children’s Hospital/Academic Medical Center, University of
Amsterdam, Amsterdam, The Netherlands3Department of Developmental Psychology, Vrije Universiteit
Amsterdam, Amsterdam, The Netherlands
Introduction:
Behavior problems are common in children with func-
tional constipation. This study assessed the prevalence
of overall, internalizing and externalizing behavior
problems in children with functional constipation
and explored which clinical characteristics of consti-
pation are associated with these behavior problems.
Material and methods:
Children with functional constipation aged 4-18 years
referred to the gastrointestinal outpatient clinic at
the Emma Children’s Hospital were eligible for enrol-
ment. The current study made use from baseline data
of 133 children participating in a randomized control-
led trial evaluating the clinical effectiveness of be-
havioral therapy compared to conventional treatment.
Prevalence of behavior problems was assessed by the
Child Behavior Checklist (CBCL/4–18). Univariate and
multivariate logistic regression model were used to
test the association between clinical characteristics
and behavior problems.
Results:
The prevalence rate of overall, internalizing and
externalizing behavior problems was considerable:
respectively 36.8%, 36.1%, and 27.1% compared to 9%
in the Dutch norm population. A long duration of
treatment was found to have the strongest association
with overall and externalizing behavior problems in
constipated children. Constipated children with night-
time urinary incontinence have an increased risk of
having overall behavior problems. Fecal incontinence
and the production of large stools appeared to be ex-
clusively related to externalizing behavior problems.
Conclusion:
Behavior problems are common in children with
constipation referred to gastrointestinal outpatient
clinics implicating that a behavioral screening should
be incorporated in the diagnostic work-up of children
with constipation.
P14 Outcome of fetuses undergoing fetal echocardiography; ten years in a referral center
P15 The prevalence and associated clinical characteristics of behavior problems in children with functional constipation
C.L. Eckhardt1,2, J.G. van der Bom3, M. van der Naald1, M. Peters1, P.W. Kamphuisen2,
K. Fijnvandraat1
1Department of Pediatric Hematology, Emma Children’s Hospita/AMC, Amsterdam, 2Department of Vascular Medicine, AMC, Amsterdam, 3Department of Clinical Epide-
miology, LUMC, Leiden
Introduction:
The development of inhibiting factor VIII (FVIII) antibodies (inhibi-
tors) is the major complication in the treatment of hemophilia A. In-
hibitors compromise the management of bleeding symptoms, resulting
in a greater rate of complications, mortality and costs.
It has been suggested that surgery, with its attendant exposure to large
amounts of FVIII concentrates, is a risk factor for inhibitor develop-
ment. If the risk of surgical interventions in individual patients could
be predicted, clinicians would be able to adapt their management in
order to reduce the risk by preventive measures.
The purpose of this systematic review was to investigate the association
between surgery and inhibitor development in hemophilia A.
Methods:
A comprehensive search for randomized controlled trials, cohort studies
and case control studies was performed in Medline, Embase and the
Cochrane registry to identify studies in which hemophilia A patients
underwent surgery and inhibitor development was described.
Results:
Eighteen studies involving 2547 patients were included in this review.
Because of heterogeneity between the study populations, individual
data could not be pooled to perform a meta-analysis. Only five studies
were designed to investigate surgery as putative risk factor for inhibitor
development. In 3 studies adjusted relative risks for surgery were cal-
culated, ranging from 1.3 to 2.7 in severe hemophilia A and 186 in mild
patients. In the other two studies more than half of the patients who
underwent surgery developed an inhibitor.
Conclusion:
Available data suggest a potential relation between surgery and inhibi-
tor development, however there is limited good quality evidence that
supports this association.
C.L. Eckhardt1,2, M. Peters1, P.W. Kamphuisen2, K. Fijnvandraat1 1 Dept. of pediatric hematology, Emma Children’s hospital/AMC, Amsterdam, 2 Dept. of vascular medicine, AMC, Amsterdam
Introduction:
The development of inhibiting factor VIII [FVIII] antibodies [inhibitors]
is the most severe complication of the treatment with clothing factor
concentrates for hemophilia A. Inhibitors compromise the ability to
manage hemorrhage in affected individuals, resulting in a greater rate
of complications, costs and disability. Until now, research has focused
on inhibitors in severe hemophilia and neglected inhibitor development
in mild/moderate hemophilia A [MHA]. Since almost one third of the
newly diagnosed inhibitors occur in MHA, the clinical impact of this
problem is substantial.
The purpose of this international cohort study is to evaluate the in-
cidence of inhibitor development in MHA and to establish the source
population for a nested case-control study in which risk factors for
inhibitor development in MHA will be investigated.
Methods:
This retrospective cohort study included the clinical data of all con-
secutive MHA patients from 1-1-1980 to 1-7-2008 in twelve participat-
ing European centers. The outcome was clinically relevant inhibitor
development.
Results:
On October 1st 2009 the cohort yielded 509 MHA patients (median
FVIII:C 11 IU/dL) with a median age of 33 years (IQR, 13-55). Thirty-two
(6%, 95%CI 4.3-8.6) patients developed an inhibitor after a median of
27 (IQR, 20-35) exposures to FVIII. 55% of all non-inhibitor patients
(263/477) had less than 30 exposures and was therefore still at risk of
developing inhibitors. Inhibitor patients did not differ from non-inhibi-
tor patients regarding ethnicity and FVIII level.
Conclusion:
The incidence of inhibitor development in a large European cohort of
MHA patients was 6% during an observation period of 28 years.
P16
Is surgery a risk factor for inhibitor development in hemophilia A?
P17
Inhibitor development in mild/moderate hemophilia a: preliminary results of the insight study
Marc Engelen1, Bjorn van Geel1,4, Inge Dijkstra3, Mercan Akyüz3, Catherine E. van En-
gen3, Nellie Schutte-Lensink3, Ronald Wanders3, Marianne de Vissera, Stephan Kemp3
and Bwee Tien Poll-The2 1Departments of Neurology (a), 2Pediatric Neurology (b), 3Laboratory for Genetic
Metabolic Diseases (c), Academic Medical Center, University of Amsterdam, the
Netherlands. 4Department of Neurology (d), Medical Center Alkmaar, Alkmaar, the
Netherlands.
Introduction:
X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder
caused by mutations in the ABCD1 gene. The clinical phenotype is well
described in men, but not in female carriers. It is known that heterozy-
gotes can develop symptoms, but to date, there has been no prospective
study to characterize the phenotype of X-ALD in women. The attention
of the medical community has been focused on boys and men with se-
vere symptoms, the mothers have been largely neglected. This informa-
tion is important to better inform women diagnosed with X-ALD about
the prognosis of their condition. The primary objective of the study is
to describe the phenotype of women with X-ALD. The secondary objec-
tive is to explain the phenotypic heterogeneity.
Methods:
All adult women with confirmed X-ALD were eligible to participate. All
participants visited the hospital once for: history and physical examina-
tion, quality of life assessment (SF-36), disability assessment (ALDS),
blood sampling, skin biopsy, electromyography and evoked potentials.
Results:
A total of 46 women were examined. For analyses women were divided
in age groups: 18 – 39 (I), 40 – 59 (II) and 60 – 79 years (III). History and
neurologic examination was abnormal in 36% (I), 85% (II) and 100% (III).
Biochemical analysis was performed and will be correlated to the clinical
data.
Conclusion:
A large proportion of women with X-ALD have signs and symptoms
attributable to X-ALD and signs of myelopathy are most prominent,
especially urinary and fecal incontinence. There is a strong correlation
between age and symptomatology. Most women also have detectable
abnormalities on biochemical assays and electrophysiological testing. A
correlation between biochemical abnormalities and clinical phenotype
is being investigated.
V. Engelen MSc1, H.M. Koopman PhD2, S.D. Detmar PhD3, M.D. van de Wetering PhD4,
P. Brons PhD5, R. Bredius PhD6, F. Abbink PhD7, M.A. Grootenhuis PhD1.1Academic Medical Centre / Emma Children’s Hospital, Paediatric Psychosocial
Department, Amsterdam; 2Leiden University Medical Center, Medical Psychology,
Leiden; 3TNO Prevention and Health, Leiden; 4Academic Medical Center/ Emma Chil-
dren’s Hospital, Paediatric Oncology Department, Amsterdam; 5Radboud University
Medical Center, Paediatric Oncology Department, Nijmegen; 6Leiden University Medi-
cal Center, Pediatric Oncology Department, Leiden, 7VU University Medical Center,
Amsterdam, Netherlands.
Introduction:
Health related quality of life (HRQOL) in children and adolescents with
cancer immediately after end of treatment, has only been studied to a
limited extend. We aimed to gain more insight in self-reported HRQOL
of children and adolescents that have recently finished cancer treat-
ment.
Methods:
As part of a multicenter intervention study (QLIC-ON), 157 children (8
to 11 years) and adolescents (12 to 18 years) with cancer were requested
to complete the Kidscreen-52 questionnaire, when 0-3 months off treat-
ment. Ninety-nine children and adolescents participated. Differences
in HRQOL between the patient and Dutch norm group were analysed by
one-sample t-tests and effect sizes (e.s.).
Results:
Children (N=26, M=9.4 years of age, 42.3% girls) and adolescents (N=65,
M=15.1 years of age, 52.3% girls) scored significantly lower on physi-
cal well-being compared to the norm population (respectively, M=48.26,
p<.01, e.s.=0.95 and M=43.63, p<.01, e.s.=0.72). In the child group
the mean score on psychological well-being was also significantly lower
(M=50.49, p<.05, e.s.=0.58) than the norm. Adolescents with cancer,
however, obtained significantly higher scores than their healthy peers
on five out of the other nine scales: moods and emotions (M=53.67, p<.05,
e.s.=0.34), parent relation and home life (M=57.46, p<.01, e.s.=0.55), school en-
vironment (M=54.40, p<.01, e.s.=0.43), bullying (M=51.95, p<.01, e.s.=0.31)
and financial resources (M=56.17, p<.01, e.s.=0.37).
Conclusions:
Children and adolescents with cancer immediately after end of treat-
ment experience a decreased physical well-being. Psychological well-being of
children is also affected. Although, overall, children and adolescents
seem resilient, we recommend physicians to monitor HRQOL to make
early detection of psychosocial problems possible.
P18
The clinical phenotype of x-linked adrenoleukodystrophy in women: a prospective cross-sectional clinical & biochemical study
P19
Health related quality of life of children and adolescents with cancer immediately after end of treatment
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F.A. Falix, V.B. Weeda, I.G. Gaemers, D.C. Aronson, W.H. Lamers
Introduction:
Hepatoblastoma (HB) is the most common pediat-
ric liver malignancy, but its pathogenesis remains
unclear. Five-year survival of children with HB is
now 75-80%, often due to unresponsiveness to chemo-
therapy. It is therefore unfortunate that an animal
model for HB to develop new treatment modalities is
not available.
The evolutionarily conserved Delta-Notch signaling
pathway regulates growth in several tissues during de-
velopment and shows altered expression in HB. Recent
data has shown that suppression of Notch receptor
signaling is associated with impaired growth control
of hepatocytes and cholangiocytes. In agreement, the
Notch ligand Delta-like-1 (Dlk1), a negative regulator
of Notch signaling, is highly expressed in HBs. How-
ever, transgenic mice with liver-specific overexpres-
sion of Dlk1, which have been generated in our group,
do not develop liver tumors. A possible explanation
could be that interference with the ligand does not
induce enough dysregulation of Notch signaling for
tumor formation to occur. Therefore, we hypothesize
that early, prenatal inactivation of Notch receptors
in the liver will affect hepatoblast proliferation and
eventually lead to hepatoblastoma.
Materials and methods:
We tested this hypothesis by generating transgenic
mice with liver-specific inactivation of the two rele-
vant Notch pathway receptors (Notch1 and -2) in hepa-
toblasts. (Alfp-Cre mice crossed with Notch1/2-Floxed
mice). The effects of Notch deficiency on hepatocyte
and cholangiocyte differentiation, proliferation and
tumor formation were assessed in postnatal mice.
Results:
Liverspecific knockout of the Notch1 receptor did not
lead to disturbed hepatocyte or cholangiocyte develop-
ment and did not affect liver proliferation. However,
liverspecific knockout of the Notch2 receptor led to
a severe phenotype with jaundice, growth retarda-
tion and complete absence of intrahepatic bile ducts
immediately after birth untill approximately 3 weeks
of age. At 6 weeks of age, knockout livers showed in-
creased hepatocyte proliferation, areas of extensive
necrosis and also early signs of cholangiocyte develop-
ment with a few mature bile ducts. At 6 months of
age knockout livers showed disturbed cholangiocyte
proliferation with a few dilated bile ducts, absence of
necrotic areas and signs of extensive fibrosis.
Conclusion:
Liverspecific knockout of Notch2 in mice leads to
absence of intrahepatic bile ducts prenatally and early
postnatally. These mice survive and show postna-
tal cholangiocyte differentiation with subsequent
bile duct formation in the absence of Notch2. The
responsible compensatory mechanisms are now being
investigated.
E.J. van de Griendt, Pediatrician MD1, O.H. van der Baan-Sloot-
weg, Pediatrician MD2, E.E.M. van Essen-Zandvliet, Pediatric
pulmonologist MD PhD2, J. van der Palen, Clinical Epidemiologist
PhD3, C.L.J. Tamminga-Smeulders, Research Nurse MSc2, M.A.
Benninga, Pediatric Gastroenterologist MD PhD4, W.M.C. van
Aalderen, Pediatric Pulmonologist MD PhD1 1Department of Pediatric Respiratory Medicine and Allergy,
Emma Children's Hospital, Academic Medical Centre, Amster-
dam, The Netherlands 2Department of Pediatrics, Asthma Centre Heideheuvel,
Hilversum, The Netherlands3Department of Epidemiology, Medisch Spectrum Twente, Ensch-
ede, The Netherlands and department of Research Methodology,
Measurement and Data Analysis, University Twente, Enschede4Department of Pediatric Gastroenterology, Emma Children’s
Hospital, Academic Medical Centre, Amsterdam, The Netherlands
Background:
Recent data suggest that obesity has a negative
influence on pulmonary function. However, effect of
weight loss on pulmonary function testing has not
been studied in obese children.
Aim: to evaluate lung function changes in extreme
obese children who significantly lost weight.
Methods:
Obese children participated in a 26 weeks in-hospital
or outpatient multidisciplinary treatment program.
The diagnosis of asthma was appointed after history
and reversible airflow limitation. Pulmonary func-
tion testing was performed at enrollment and after 6
months.
Results:
Data of 133 children were analyzed, mean age 14.4
years (range 8.5 – 18.9 years), 61.7% girls. Asthma was
present in 22 (16.5%) patients (girls 59.0%). Mean
weight at baseline was 109.64 kg (range 52.3 – 192.2 kg)
P21
Changes in lung function after weight reduction in severe obese children: a prospective uncontrolled study
P20
Notch2 regulates biliary development without affecting hepatocyte differentiation
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and after the intervention 96.26 kg (range 43.7 – 200.3
kg). At baseline the mean SDS-BMI score was +3.38
(range 2.50 – 4.62) and after the intervention +2.89
(range 1.67-4.79).
Lung function outcomes: δ FVC (difference between
baseline value and after the intervention) 3.31± 2.0%,
δ FEV1 2.97 ± 1.76%, δ TLC 2.27 ± 1.34% and δ ERV 13.3
± 5.65%. All these changes were statistically signifi-
cant. Only the increase in ERV correlated with the
reduction in SDS-BMI (Pearson correlation coefficient
of -0.220 (p = 0.026) (see table). In the Asthma group
similar results were found, although significance was
less strong, due to the small number of patients.
Conclusion:
Obstructive changes in pulmonary function are most
likely caused by the obstructing abdominal mass. This
study adds evidence for the co-incidence of (obstruc-
tive and non-obstructive) lung function changes in
the severe obesity, but does not add evidence for the
causal relation between obesity and asthma.
DeltaSDSBMI
0,500,00-0,50-1,00-1,50
30,00
20,00
10,00
0,00
-10,00
-20,00
-30,00
R Sq Linear = 1,06E-4
DeltaSDSBMI
0,500,00-0,50-1,00-1,50
75,00
50,00
25,00
0,00
-25,00
-50,00
R Sq Linear = 0,049
Del
taF
EV
1pct
Pre
dD
elta
ER
Vp
ctP
red
1A.
1B.
Figure 1a. Absence of correlation in difference of SDS body mass
index (DeltaSDS-BMI) and difference FEV1 in forced expiratoy
volume in 1 second %predicted (DeltaFEV1pctpred).
Figure 1b. Obvious correlation of difference of SDS body mass
index (DeltaSDS-BMI) and difference in expiratory reserve volume
(DeltaERVpctpred).
Heynric B. Grotenhuis1, Jaap Ottenkamp1, Liesbeth de Bruijn1, Jos
J.M. Westenberg2, Hubert W. Vliegen3, Lucia J.M. Kroft2, Albert
de Roos2.
Afdeling kindercardiologie, AMC/LUMC1, Afdeling radiologie,
LUMC2, Afdeling cardiologie, LUMC3
Introduction/background:
Aortic wall pathology and concomitant aortic dilata-
tion have been described in tetralogy of Fallot (TOF)
patients, which may negatively affect aortic valve and
left ventricular (LV) systolic function. The objectives
of the current study were therefore to assess aortic
dimensions, aortic elasticity, aortic valve competence
and biventricular function in repaired TOF patients
after pulmonary valve replacement (PVR) by using
magnetic resonance imaging (MRI).
Material and Methods:
MRI was performed in 16 patients with TOF after PVR
(10 male; mean age±standard deviation: 31years±15)
and 16 age- and gender matched healthy subjects.
Results:
TOF patients showed aortic root dilatation (mean dif-
ference 7.8-8.8mm, P<0.01 at all 4 predefined levels)
(Figure 1) and reduced aortic elasticity (pulse wave
velocity in aortic arch: 5.5m/s±1.2 vs. 4.6m/s±0.9,
P=0.04; aortic root distensibility: 1.4*10-3mmHg-1 ±
1.7 vs. 5.7*10-3 mmHg-1±3.6,P<0.01). Minor degrees of
aortic regurgitation (AR) (AR fraction 6%±8 vs. 1%±1,
P<0.01) (Figure 2) and reduced LV ejection fraction
were present (51%±8 vs. 58%±6, P=0.01), whereas right
ventricular (RV) ejection fraction was within normal
limits (47%±8 vs. 52%±7, P=0.06). Degree of AR frac-
tion was associated with dilatation of the aortic root
(r=0.39-0.49, P<0.05) and reduced aortic root disten-
sibility (r=0.44, P=0.02), while reduced LV ejection
fraction was correlated with degree of AR and RV
ejection fraction (r=0.41, P=0.02, and r=0.49, P<0.01,
respectively).
Conclusions:
Aortic root dilatation and reduced aortic elasticity are
frequently present in patients with TOF, in addition to
minor degrees of AR and reduced LV systolic function.
Aortic wall pathology in repaired TOF patients may
therefore represent a separate mechanism leading to
LV dysfunction, in addition to possible adverse right-
to-left ventricular interaction.
P22
Aortic elasticity and size are associated with aortic regurgitation and left ventricular dysfunction in tetralogy of Fallot after pulmonary valve replacement
Kirsten van Ham, medical student1, A.C. Knottnerus1, A.P. Cohen2, E. Kohnhorst2,
M. Strijbos2, H.H.F. Derkx1, Y.Q. Jagt, medical student.1 Emma Kinderziekenhuis AMC Amsterdam; 2 De Bascule, Amsterdam
Introduction/background:
The relationship between Medically Unexplained Symptoms (MUS) and
psychiatric disorders has often been reported in literature. For exam-
ple: there is a broad consensus about the fact that psychiatric disorders
are often present in patients with functional Gastro Intestinal(GI)-tract
syndroms. (Mayer e.a., 2001).
Emotional dysregulation (ED) refers to an emotional response that is
poorly modulated, not falling within the conventionally accepted range
of emotional response. This could result in a DSM-IV classified psychiat-
ric disorder, or might be more delicate such as depressive feelings, mood
fluctuations, or obsessive thoughts.
The question arises whether there is also a more general relation be-
tween emotional dysregulation and MUS in our patient population.
Materials and methods:
The charts of patients with GI-tract problems (nausea, vomiting and
defecation problems) (14 patients) and abdominal pain (ap) (43 patients)
as primary complaints visiting the Psy Med Unit (PMU) (a tertiary re-
ferral centre for invalidating, therapy resistant functional complaints)
were evaluated for the incidence of ED in the patients and their close
relatives (brothers, sisters or parents).
Results:
See table
Conclusion:
There seems to be a correlation between the MUS and ED, as we ex-
pected. This confirms the statement that you cannot divide body and
mind. A considerable amount of the children has a relative with ED as
well. General emotional regulation, genetics and family circumstances
might therefore be of importance in the pathogenesis of MUS.
P23
Is there a high incidence of emotional dysregulation in patients with medically unexplained symptoms?
ED in ap pt group (43 pt) ED in GI-tract problems
pt group (14pt)
Patients 12 (28%) 7 (50%)
Relatives 16 (37%) 5 (36%)
Table. Results.
P24
At risk: health related quality of life in children and adolescents with jIAL. Haverman1, M.A.J. van Rossum2,3, T.W. Kuijpers2, J.M. van den Berg2,3, M. van
Veenendaal2, K.M. Dolman3,4, J. Swart3,5, M.A. Grootenhuis1
1 Academic Medical Centre / Emma Children’s Hospital, Pediatric Psychosocial
Department, Amsterdam, 2 Academic Medical Centre / Emma Children’s Hospital,
Pediatric Rheumatology, Amsterdam, 3 Jan van Breemen Institute, Amsterdam, 4 Sint
Lucas Andreas Hospital, Amsterdam, 5 VU Medical Center, Amsterdam
Introduction:
In the Netherlands the estimated prevalence of children with Juvenile
Idiopathic Arthritis (JIA) is 3000 - 4000 children with yearly 300 new
patients. Research on Quality of Life (QoL) of these children, however,
is lacking behind. The purpose of this study is to investigate QoL of
children with JIA.
Material and Methods:
This study is part of the KLIK study, which assesses the effect of iden-
tifying and discussing QoL problems using Patient Reported Outcomes
(PROs). The study sample includes all children (8-18 years) visiting the
rheumatologist at four different hospitals in Amsterdam. Patients were
invited to complete questionnaires online, at home, before visiting the
rheumatologist. QoL was measured using the Pediatric Quality of Life
Inventory 4.0 (Pedsql 4.0), which assesses four domains of QoL; physi-
cal, emotional, social and school. The study sample was compared with
healthy sample and a chronic ill condition sample (Engelen, et al. 2009)
using one sample t-tests. In addition, effect sizes were calculated. Data
collection will continue until January 2010.
Results:
Approximately 70% of the patients participated (n=123). Data of 57
children aged 8-12 years (m = 10,8 years) and 66 adolescents aged 13-18
years (m = 15,9 years) were available. Both children with JIA as well as
adolescents differed on almost all domains significantly with healthy
controls and children with a chronic ill condition. Effect sizes were
moderate to large, with the exception of emotional functioning (table
1).
Conclusions:
QoL is severely affected in children and adolescents with JIA. Specific
limitations of this group seem to influence their QoL. These findings
underline the need to systematically pay attention to QoL in clinical
practice and to investigate the effectiveness of QoL feedback to the
pediatric rheumatologist.
Referentie:
Engelen V, Haentjens MM, Detmar SB, Koopman HM, Grootenhuis MA:
Health related quality of life of Dutch children: psychometric proper-
ties of the PedsQL in the Netherlands. BMC Pediatrics. In press.
[see table]
L. Haverman, V. Engelen, M.A.J. van Rossum, H.N. Caron, T.W. Kuijpers, H.S.A.
Heymans, M.A. Grootenhuis
Aims:
Children with a chronic illness can experience quality of life (QoL)
problems. These problems are usually not systematically checked by
the pediatrician. Two multicenter sequential cohort studies (QLIC-ON
& KLIK), measured the effect of the use of Patient Reported Outcomes
(PROs) about QoL in clinical pediatric practice.
Methods:
Participants are children with cancer immediately after end of treat-
ment (QLIC-ON) or with Juvenile Idiopathic Arthritis (KLIK). Before
the consultation with the pediatrician, the child (8-18 years) or parent
(0-8 years) completes a digital QoL questionnaire. The outcome (PROfile)
is presented to the pediatrician, parent and child of the intervention
group, to help identify and discuss possible QoL problems. To optimize
the effect of the PROfile pediatricians receive training using cases on
DVD. Preliminary results in terms of evaluation and satisfaction are
presented.
Results:
Approximately 95% of the parents thought the PROfile correctly repre-
sented the child’s QoL. About 80% of the parents considered the PROfile
as a useful addition to standard health care, also for the future (80%)
(Table 1). Moreover, pediatricians are significantly more satisfied about
the consultations in the intervention group compared to the control
group (p<0.01).
Conclusions:
The results are promising. Parents and pediatricians are positive about
the use of the PROfile in clinical practice. The PROfile can be used for
different patient groups and also by different users (e.g. psychologists,
nurses or social workers). With the use of internet (www.hetklikt.nu)
the PROfile is easy to implement in clinical practice and helpful in
facilitating communication about QoL.
Who wants to profit next?
Interested?
Log in as a pediatrician on www.hetklikt.nu with ‘PRO’ as username
and ‘KLIK’ as password and see a demo.
Subscale N Mean SD N Mean SD N Mean SD
Group 8-12 192 26 15
Total score 82.31 8.83 80.64 9.32 74.86* 12.75
Physical health 85.25 8.85 82.21 12.14 74.58 20.07
Psychosocial health 80.75 10.34 79.81 10.43 75.00 11.25
Emotional functioning 76.85 13.76 78.85 13.21 73.67 14.07
Social functioning 86.51 12.24 83.27 12.80 81.33 11.87
School functioning 78.88 11.90 77.31 13.13 70.00 19.27
Group 13-18 148 25 38
Total score 83.14 8.99 77.09 9.40 67.11**^^ 17.07
Physical health 86.76 9.21 81.00 12.00 63.24**^^ 25.32
Psychosocial health 81.21 10.22 75.00 9.56 69.17**^ 14.92
Emotional functioning 77.53 15.01 71.40 16.62 68.86* 21.82
Social functioning 90.14 11.37 83.40 12.97 79.87** 13.63
School functioning 75.95 12.68 70.20 15.17 58.81**^^ 20.22
Healthy sample Chronic illness JIA sample
Table 1. QoL scores on the Pedsql of a healthy sample, a chronic ill condition sample and a JIA sample.
JIA vs. Healthy sample (ES)
0.85
1.21
0.56
0.2
0.42
0.75
1.78
1.35
*Significant p < .05 compare to healthy sample, **Significant p < .01 compare to healthy sample^Significant p < .05 compare to chronic illness sample, ^^Significant p < .01 compare to chronic illness sample
2.56
1.18
0.58
0.90
P25
Patient reported outcomes (pro’s) in clinical practice: who will profit next?
QLIC-ON KLIK QLIC-ON KLIK
n = 57 n = 49 n = 68 n = 80
Useful 74% 84% 63% 94%
Unnecessary 30% 10% 44% 3%
Clarifying 54% 67% 57% 89%
Practical 63% 78% 59% 91%
Emotional 5% 10% 3% 6%
Unpleasent 7% 0% 3% 5%
Pediatric ianParents
Table 1: Evaluation of the PROfile.
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Maaike van der Heide, Paul Keating, Jacorina van Hoften,
Sebastiaan Mastenbroek, Moniek Twisk, Arend F. Bos, Jan
Maarten Cobben, Joke Kok
Department of neonatology EKZ/AMC, Amsterdam and depart-
ment of Neonatology Beatrix kinderkliniek UMCG Groningen,
Reproductive medicine AMC, Amsterdam
Background:
Pre-implantation genetic screening (PGS) can be used
to detect aneuploidies after embryo biopsy.
In a multicenter trial 408 women 35 through 41 years
of age undergoing IVF / ICSI were randomized for PGS
(n=206) to detect aneuploidies before embryo transfer
or no PGS (n=202). The primary endpoint of the trial
was the number of ungoing pregnancies at 12 weeks
gestation. Significantly more women had an ongoing
pregnancy in the no PGS group (37% vs 25%).
Patients and methods:
In the ongoing pregnancies surviving children were
followed until the age of 2 years. Perinatal data were
obtained from obstetricians or midwives after birth.
At 2 years of age children were examined for morpho-
logical abnormalities using the Amsterdam Morphol-
ogy scale. Other clinical abnormalities were obtained
from history.
Results:
144 children were born alive, 2 died shortly after
birth. 54 children in the PGS+ group (of which 9
twins) and 77 in the PGS – group (14 twins) were
examined at 2 years of age, 3 were lost to follow up in
PGS + and 8 in the PGS – group. Basic characteristics
and the number of morphological abnormalities in
both groups are given in the table. No differences
were found between the groups in morphological
abnormalities.
Conclusion:
The number of morphological abnormalities found in
children following a PGS procedure after ICF or ICSI
as studied by the Amsterdam Morphology Scale is not
significant different from children born after IVF or
ICSI alone. The PGS procedure seems to have no effect
on phenotypic development.
P26
Morphological abnormalities in children born after Pre Implantation Genetic Screening in a multicenter trial of IVF /ICSI with and without PGS
Table.
Children PGS + (N=54) Children PGS - (N=77)
Gestational age (weeks) 38,8 (±2,6) 37,7 (±2,8)
Birth weight (gram) 3264 (±710) 3028 (±736)
Short stature 5,6%(N=3) 3,9%(N=3)
Trigonocephaly - 1,3%(N=1)
Generalized hypopigmentation hair - 1,3%(N=1)
Iris (coloboma/hypopigmentation) 1,9%(N=1) 2,6%(N=2)
Lens (Size/shape abnormality) 1,9%(N=1) -
Hernia inguinalis - 1,3%(N=1)
Syndactyly toes II-III - 3,9%(N=3)
Ear (pits, tags, cupshaped) 5,6% (N=3) 3,9% (N=3)
Clefts (upper jaw, lower lip, palate) 1,9% (N=1) 5,2% (N=4)
Café au lait (multiple) 1,9% (N=1) 1,3% (N=1)
Hemangioma 7,5% (N=4) 9,1%(N=7)
Hypermobility joints 5,6% (N=3) 1,3% (N=1)
Extra nipples 1,9% (N=1) -
Syndrome 1,9% (N=1) -
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Channa T. Hijmans1,2, Karin Fijnvandraat2, Martha A. Grooten-
huis1, Nan van Geloven3, Harriët Heijboer2, Marjolein Peters2,
and Jaap Oosterlaan4
1Psychosocial Department, Emma Children’s Hospital, Academic
Medical Center, Amsterdam, The Netherlands; 2Department
of Pediatric Hematology, Emma Children’s Hospital, Academic
Medical Center, Amsterdam, The Netherlands; 3Department of
Clinical Epidemiology, Biostatistics and Bioinformatics, Academic
Medical Center, Amsterdam, The Netherlands; 4Department of
Clinical Neuropsychology, VU University Amsterdam, Amster-
dam, The Netherlands
Background:
Although sickle cell disease (SCD) is increasingly
prevalent in children living in Western Europe and
can lead to profound cerebral damage, European stud-
ies on the neurocognitive consequences are scarce. The
aim of this study was to investigate neurocognitive
functioning of children with SCD living in the Nether-
lands, compared to healthy siblings.
Material and Methods:
Forty-one children with homozygous SCD (HbSS or
HbS-β0-thalassemia) and 36 healthy siblings were
assessed on a comprehensive set of well-defined and
validated measures of neurocognitive functions. These
included general intelligence, response inhibition,
sustained attention, planning, visuo-spatial and ver-
bal working memory, and visuo-motor functioning.
Results:
SCD was associated with lower intelligence and poor
performance on measures of visuo-spatial working
memory and visuo-motor functioning. Some evidence
was found for lower levels of sustained attention
and planning. No significant differences were found
between children with SCD and healthy siblings in
terms of response inhibition and verbal working
memory.
Conclusions:
Children with SCD are at increased risk of specific
neurocognitive deficits. Such deficits may underlie
high rates of scholastic impairments and both behav-
ioral and emotional problems in these children. These
findings further illuminate the importance of regular
neurocognitive evaluations in children with SCD in
daily clinical practice.
Channa T. Hijmans1,2, Karin Fijnvandraat2, Jaap Oosterlaan3,
Harriët Heijboer2, Marjolein Peters2 and Martha A. Grootenhuis1
1Psychosocial Department, Emma Children’s Hospital, Academic
Medical Center, Amsterdam, The Netherlands; 2Department of
Pediatric Hematology, Emma Children’s Hospital, Academic Medi-
cal Center, Amsterdam, The Netherlands; 3Department of Clinical
Neuropsychology, VU University Amsterdam, Amsterdam, The
Netherlands
Background:
Low health-related quality of life (HRQoL) of children
with sickle cell disease (SCD) may be associated with
disease factors, or socio-demographic factors. The aim
of this study was to investigate the HRQoL of children
with SCD compared to healthy siblings (matched on
age, gender, ethnicity and socio-economic status), and
to a Dutch norm population.
Material and Methods:
The HRQoL of 40 children with homozygous SCD and 36
healthy siblings was evaluated by the KIDSCREEN-52.
This self-report questionnaire assesses ten domains of
HRQoL: Physical well-being, Psychological well-being,
Moods and emotions, Self perception, Autonomy, Parent
relations, Financial resources, Peers, School environ-
ment, and Bullying. Differences between children with
SCD and healthy siblings were analyzed using linear
mixed models. One-sample t-tests were used to analyze
differences with the Dutch norm population.
Results:
Young children with SCD and healthy siblings (aged
6-11) had comparable HRQoL, apart from somewhat
lower scores on Physical well being. Compared to the
Dutch norm population, young children with SCD had
significantly lower HRQoL on 7 domains. Adolescents
with SCD had a significantly lower HRQoL on Autono-
my compared to both healthy siblings and the Dutch
norm population. Trends were found for a lower HRQoL
of adolescents with SCD on 5 domains, compared to the
Dutch norm population.
Conclusions:
Children with SCD generally experience lower HRQoL
than the Dutch norm population, which mainly seems
to be associated with socio-demographic factors.
However, the low HRQoL on Autonomy, as reported
by adolescents with SCD, seems to be associated with
disease factors.
P27
Neurocognitive deficits in children with sickle cell disease: a comparison with healthy siblings
P28
Health-related quality of life of children with sickle cell disease and healthy siblings
A.E. ten Hoedt1, L.M. de Sonneville2, B. Francois3, N.M. ter Horst4, M.C.H. Janssen5,
M.E. Rubio-Gozalbo6, N.G. Abeling7, F.A. Wijburg1, C.E. Hollak8, A.M. Bosch1
1department of pediatrics, Academic Medical Center, university of Amsterdam, Am-
sterdam; the Netherlands, 2department of clinical neuropsychology, Leiden University
Medical Center, Leiden; the Netherlands, 3department of metabolic diseases, Centrum
Pinocchio, Diepenbeek; Belgium, 4department of dietetics, Academic Medical Center,
university of Amsterdam, Amsterdam; the Netherlands, 5department of internal
medicine, Radboud University Medical Centre, 6department of pediatrics, Maastricht
University Medical Center, Maastricht, the Netherlands, 7laboratory of genetic meta-
bolic disease, Academic Medical Center, university of Amsterdam, Amsterdam; the
Netherlands, 8department of internal medicine, Academic Medical Center, university
of Amsterdam, Amsterdam; the Netherlands
Introduction:
Phenylketonuria (PKU) is an autosomal recessive disorder of pheny-
lalanine (Phe) metabolism. Intellectual disability and neurological
sequelae are prevented with early initiation of a Phe-restricted diet and
amino acid supplementation. Currently, there is much debate whether
this strict and socially invalidating diet is necessary for adults. Aim of
our study is to evaluate the effects of short term elevation of Phe levels
on neuropsychological functions and wellbeing of adults with PKU.
Methods:
9 continuously treated adults with PKU participated in a double blind
randomized crossover trial. During two 4 week periods, patients used
either placebo or Phe as a supplement to their diet. The amount of sup-
plemented Phe was individually calculated to reach a normal intake
for a healthy adult. Each study period patients underwent neuropsy-
chological tests, and both patients and one significant other completed
a weekly questionnaire evaluating the patients’ mood and wellbeing
(Profile of mood states: POMS). Phe levels were measured twice every
week during both study periods.
Results:
Phe levels were significantly higher during Phe supplementation than
during the placebo phase. Neuropsychological tests demonstrated a
significant impairment in sustained attention at the time of high Phe
levels. Furthermore, both patients and their significant other reported
a significant lower score on the POMS questionnaire at the time of high
Phe levels.
Conclusion:
High Phe levels have a direct and negative effect on both neuropsy-
chological performance as well as mood of adult patients with PKU.
Therefore, a Phe restricted “diet for life” should be advised for adults
with phenylketonuria.
Sander M. Houten1,2, Cory Wagg3, Heleen te Brinke1, Ronald J.A. Wanders1,2, Gary D.
Lopaschuk3
Department of 1Clinical Chemistry, Laboratory Genetic Metabolic Diseases and 2Department of Pediatrics, Emma Children's Hospital, AMC; 3Departments of Pedi-
atrics and Pharmacology, Heritage Medical Research Center, University of Alberta,
Edmonton, Canada
Introduction:
Inherited defects of mitochondrial long chain fatty acid oxidation (FAO)
such as very long chain acyl-CoA dehydrogenase (VLCAD) deficiency
may present with cardiomyopathy and arrhythmias. The pathophysi-
ology of these cardiac symptoms is poorly understood and rational
therapeutic strategies are lacking. The LCAD KO mouse reproduces
many aspects of human long chain FAO defects. In mice, LCAD plays
an important role in the oxidation of unsaturated fatty acids. LCAD
KO mice display fasting-induced fatty liver with a marked hypoketotic
hypoglycemia. Moreover, LCAD KO mice have a non-progressive heart
hypertrophy (26% at 2 months and 23% at 6 months of age), but expres-
sion of molecular markers for cardiomyopathy such ANF and β-MHC is
not increased.
Methods:
We determined whether LCAD KO mice have alterations in cardiac en-
ergy metabolism using isolated working heart perfusions.
Results:
Hearts from LCAD KO mice functioned normally during 30 minutes of
low workload, but also during a 30 minute period of increased workload
and pacing. Remarkably, palmitate as well as oleate oxidation was in-
creased in LCAD KO hearts, with a parallel decrease in glucose oxidation
rates. Expression analysis of LCAD KO hearts revealed elevated PDK4,
PGC-1α and UCP3 levels and normal VLCAD, ACC and MCD levels.
Conclusion:
Our results suggest that a defect in LCAD does not lead to a decrease in
FAO, but rather leads to decreased glucose oxidation as a consequence of
changes at the level of pyruvate dehydrogenase activity.
P29
High phenylalanine levels directly affect mood and performance in adults with Phenylketonuria
P30
Increased fatty acid oxidation in long chain acyl-coa dehydrogenase-deficient hearts
G.J. Hutten1,2, L.A van Eykern1, P. Latzin2, U. Frey2, W.M.C van Aalderen1
1Department of Paediatrics Pulmonology, Emma Children’s Hospital, University of
Amsterdam, Netherlands, 2Department of Respiratory Medicine, University Children’s Hospital of Bern, Switzer-
land
Rationale:
Wheeze is a common symptom during infancy and the treatment of
wheezy infants with bronchodilators remains controversial. We hypoth-
esise that administration of β2-agonist may lead to differences in the
relationship between respiratory muscle activity (rEMG), flow pattern
and lung volume.
Methods:
Simultaneous measurements of lung function and transcutaneous rEMG
were performed in 25 sedated infants with recurrent wheeze before and
after inhalation of β2-agonist. We compared the coefficient of variation
(CV) of rEMG and its temporal relationship to flow and lung volume (FRC
before and after inhalation of β2-agonist).
Results:
The time delay between start of inspiratory muscle activity and resulting
flow (tria) in relation to respiratory cycle time was significantly shorter
after administration of the inhaled β2-agonist. The breath to breath vari-
ability (CV) of the diaphragm was significantly increased after inhala-
tion of the β2-agonist. Although FRC remained unchanged, tidal volume
increased significantly after administration of the β2-agonist.
Conclusion:
The temporal relationship of rEMG to flow and the profit of adaptive
breath to breath variability provide additional information on the
response of wheezy infants to inhaled β2-agonist, which becomes not
obvious from lung function measurements alone. Thus, non-invasive
combined rEMG and tidal flow measurements could be a potential new
technique to assess bronchodilator response in a bedside manner.
P31
Response to 2-agonist of respiratory muscle activity, flow and lung volume in wheezy infants
P32
Are there major differences in the severity of invalidation between the patient groups with headaches and abdominal pain as primary complaint?Y.Q. Jagt medical student1, A.C. Knottnerus1, A.P. Cohen2, E. Kohnhorst2,
M. Strijbos2, H.H.F. Derkx1
1Emma Kinderziekenhuis AMC; 2De Bascule, Amsterdam
Introduction:
Psy Med Unit (PMU), Emma Children’s hospital, Amsterdam, is a
tertiary referral centre for children with severe long-lasting therapy
resistant functional complaints. The question arose if there were major
differences in the severity of invalidation between patients with ab-
dominal pain (ap) and headache as primary complaint before and after
treatment.
Methods:
retrospective observational study of consecutive patients with ap and
headache as primary complaint. Charts of patients were evaluated
for severity of invalidation; school absenteeism, given up hobbies and
state of social lives before and after treatment at PMU. Duration of
complaints before treatment, duration of treatment and amount of
complaints after treatment were included.
Results:
Conclusions:
Before treatment; patients with headache as primary complaint had
complaints for longer than 2 years in 63% comparing to 37% in patients
with ap. Patients with ap seemed more invalidated concerning school
absenteeism and their hobbies. The suggestion could be made that the
duration of the complaints had no leading influence on the degree of
invalidation.
After treatment; patients with headache more often seemed to have no
or less complaints after treatment. This suggests that for the treatment
to be effective, the duration of the complaints does not play a leading
role.
It looked like more patients with ap still had >80% school absenteeism,
no hobbies and no social life and less often no or less complaints. The
hypothesis could be made that the patients with ap were more invali-
dated before and therefore more difficult to treat.
Before treatment Abdominal pain Headache
Number of patients 43 32
Duration of complaints longer than 2 years
37% 63%
>80% school absenteeism 40% 19%
Hobbies given up 77% 59%
No social life 30% 28%
Table 1.
Table 2.
After treatment Abdominal pain Headache
Number of patients
(finished treatment) 22 14
Duration of treatment longer than 1 year 36% 36%
No or less complaints after treatment 63% 86%
>80% school absenteeism 14% 0%
Hobbies given up 27% 14%
No social life 18% 7%
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F. Jonker, J. Calis ,M. Boele van Hensbroek, T. Leenstra
Background:
Anaemia is a major global (child) health problem. Iron
deficiency is considered as an important cause and
uniform iron supplementation in all children forms
part of national and international health policies to
prevent and treat anaemia. Recent studies have shown
increased morbidity and mortality in children receiv-
ing iron supplementation.. We hypothesize that this
may be due to an increased incidence of malaria and
other infections in children with an excess of (free)
iron. We are studying the effect of iron status and
iron supplementation on the risk of malaria and other
infections in children in areas with high infection
pressure.
Methods:
A cohort of 532 preschool children (6-60 months) in a
rural and urban setting in Malawi has been followed
over a 6 months period after receiving iron supple-
mentation ( for one month). Incidence of malaria, gas-
tro-intestinal and respiratory tract infectious episodes
were observed in iron deplete (ferritin < 30 ug/l) and
iron replete children and compared using multivari-
ate Poisson regression analyses.
Results:
Iron deplete children (n=146, 27.8%) had less malaria
infections than iron replete children (adjusted rate
ratio 0.56; 95% CI 0.42 to 0.74 p <0.001). There was no
significant difference in incidence of gastro intesti-
nal and respiratory infections (p-values respectively
0.6 and 0.2). There was no significant difference in
mortality. Iron deficient children and iron replete
children had a mortality of respectively 0.53% and
0.68% (p = 0.8).
Conclusion:
Giving iron supplementing to iron repleded children
in Africa may be harmfull by increasing their suscep-
tibilty to clinical malaria infections.
Rob Ofman, Inge M.E. Dijkstra, Ronald J.A. Wanders and
Stephan Kemp
Laboratory for Genetic Metabolic Diseases, Academic Medical
Center, University of Amsterdam, the Netherlands.
Introduction:
X-linked adrenoleukodystrophy (X-ALD) is the most
common peroxisomal disorder. Mutations in the ABCD1
gene that encodes ALDP result in impaired peroxiso-
mal beta-oxidation and subsequent accumulation of
very long-chain fatty acids (VLCFA; >C22) in plasma
and tissues. Recently, patients have been described
with large genomic deletions spanning the ABCD1 gene
and its neighboring gene DXS1357E that codes for the
B-cell associated protein 31 (BCAP31). This disorder
is referred to as CADDS and patients have a clinical
presentation that is more severe than X-ALD and more
consistent with a peroxisomal biogenesis disorder.
Isolated BCAP31 deficiency has never been reported
before. Hence, it is unclear what the contribution of
BCAP31 to this phenotype is. We set up a method to
get more insight in the relation between BCAP31 and
VLCFA metabolism.
Material and Methods:
Cultured skin fibroblasts derived from patients with
X-ALD or CADDS were cultured in the presence of VL-
CFA and the effect on cell viability was studied.
Results/Conclusion:
Initial results revealed a poor survival of fibroblasts
from CADDS patients when cultured in the presence
of docosanoic acid (C22:0). We demonstrate that the
increased sensitivity of CADDS fibroblasts towards
VLCFA is caused by the combined defect of both ALDP
and BCAP31.
P33
Iron and the susceptibility to infection
P34
Toxicity of very long-chain fatty acid in relation with a combined deficiency of ALDP and bCAP31
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Rob Ofman, Inge M.E. Dijkstra, Ronald J.A. Wanders and
Stephan Kemp
Laboratory for Genetic Metabolic Diseases, Academic Medical
Center, University of Amsterdam, the Netherlands.
Introduction:
X-linked adrenoleukodystrophy (X-ALD) is the most
common peroxisomal disorder characterized by rap-
idly progressive cerebral demyelination or gradually
progressive myelopathy with or without adrenocorti-
cal insufficiency. The disease is caused by mutations
in the ABCD1 gene that encodes ALDP an ATP-binding-
cassette (ABC) transporter located in the peroxisomal
membrane. A defect in ALDP results in impaired
peroxisomal beta-oxidation and the subsequent accu-
mulation of very long-chain fatty acids (VLCFA; >C22)
in plasma and tissues. There is no curative therapy for
X-ALD. Recently, we identified ELOVL1 as the key en-
zyme involved in the synthesis of VLCFA. We hypoth-
esized that inhibition of ELOVL1 would result in the
prevention or reduction of the formation of VLCFA.
Material and Methods:
Human primary fibroblasts from X-ALD patients were
transfected with Accell SMARTpool siRNA to ELOVL1.
The effect on ELOVL1 expression, de novo VLCFA syn-
thesis and VLCFA levels was determined.
Results and Conclusions:
We demonstrate that knockdown of ELOVL1 results
in lowering in de novo C26:0 synthesis and a reduction
of C26:0 levels. Our findings pave the way to gener-
ate new therapeutic options for X-ALD aimed at the
inhibition of ELOVL1 activity.
Inge M.E. Dijkstra, Rob Ofman, Catherine E. van Engen, Marc
Engelen, Ronald J.A. Wanders and Stephan Kemp.
Laboratory for Genetic Metabolic Diseases, Academic Medical
Center, University of Amsterdam, the Netherlands.
Introduction:
The two most common phenotypes of X-linked adreno-
leukodystrophy are childhood cerebral ALD (CCALD)
and adrenomyeloneuropathy (AMN). While all X-ALD
patients have elevated levels of very long-chain fatty
acids (VLCFA), it remains unknown how elevated
levels of VLCFA result in cerebral ALD. A mouse
model for X-ALD is available, but knockout mice do
not develop cerebral ALD. Feeding experiments with
high-fat diets resulted in mild myelin abnormalities.
VLCFA are derived from endogenous synthesis through
elongation of long-chain fatty acids. ELOVL1 is the
most important enzyme in the synthesis of VLCFA and
over-expression of ELOVL1 in fibroblasts results in a
strong increase in VLCFA. We developed a new mouse
model for X-ALD in which ELOVL1 expression can be
activated in a tissue-specific or time-specific manner.
Materials and Methods:
The human ELOVL1 transgene under the control of the
pCAG promoter was introduced into the Rosa26 locus
by homologous recombination in embryonic stem
cells. Expression of the transgene will be dependent
upon the Cre recombinase mediated excision of a tran-
scriptional STOP cassette placed between the promoter
and the ELOVL1 cDNA.
Results and Conclusion:
The conditional ELOVL1 mice are ready and are
currently crossed with X-ALD mice. The resulting
mouse line will then be crossed with various Cre
recombinase lines to activate ELOVL1 expression.
Based on the high-fat diet study results, we expect
that this will induce myelin instability and cause the
onset of cerebral ALD. This improved mouse model
will allow us to resolve the role of VLCFA in the patho-
genesis of X-ALD.
P35
ELOVL1 is a potential target for therapeutic intervention in x-linked adrenoleukodystrophy
P36
Development of a mouse model to investigate the role of VLCFA in the onset of cerebral adrenoleukodystrophy
Rutger R.G. Knops1, Charles B. Majoie2, Huib N. Caron1 and Antoinette Y.N. Schouten-
van Meeteren1
1 Department of Pediatric Oncology, Emma Children’s Hospital/Academic Medical
Centre, Amsterdam.2 Department of Radiology, Academic Medical Centre, Amsterdam.
Introduction/Background:
Medulloblastoma is the most common malignant brain tumor in
childhood. Several molecular genetic pathways are involved in the
development of medulloblastoma which are also crucial in early CNS
development. This suggests a relationship between neurogenesis and
oncogenesis in medulloblastoma patients. The purpose of this study is
to detect developmental CNS variations in medulloblastoma patients by
means of MRI.
Material and Methods:
We measured MRI-based volumes of 14 brain structures in medullob-
lastoma patients. From our retrospective cohort of 66 medulloblastoma
patients only 8 met the technical criteria for precise MRI 3D volume
measurement. To establish normal CNS morphometry we performed a
literature search to identify age and gender specific volumes of these
brain structures in healthy children as measured by MR imaging. The
literature derived MRI-based brain volumetric data of healthy children
were compared with the volumes of brain structures in the medulloblas-
toma patients.
Results:
The measured brain volumes of medulloblastoma patients were all with-
in the range of those of the normal population. Only the corpus cal-
losum showed a slightly increased volume compared to normal values,
maybe due to early radiation effects. Also revision of the MRI’s of the
medulloblastoma patients showed no remarkable structural anomalies.
Conclusion:
We found no significant variations in CNS-development of medulloblas-
toma patients.
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Developmental CNS variations in medulloblastoma patients: a MRI-based volumetric study
Case 1 2 3 4 5 6 7 8 Mean difference
measurements
regarding normal
values
Range
Age 9y 9y 13y 7y 10y 4y 10y 12y
Gender Male Male Male Female Male Female Male Male
Location tumor Midline Left cerebellum Midline Midline Midline Midline Midline Midline
Histology tumor Classical/
desmoplastic
Classical Desmoplastic Classical Classical Classical/
desmoplastic
Desmoplastic Classical
Cerebrum (ml) 1419 (1397) 1387 (1397) 1363 (1397) 1077 (1397) 1424 (1397) 1028 1376 (1397) 1312 (1397) -60 -320 to +27
Nucl caud R (ml) 5.0 4.3 4.8 3.9 5.0 4.2 4.3 4.2
Nucl caud L (ml) 4.7 4.2 4.2 3.8 4.8 3.9 4.2 4.0
Nucl caud tot (ml) 9.7 (7.6) 8.5 (7.6) 9.0 (7.6) 7.7 (7.6) 9.8 (7.6) 8.1 8.5 (7.6) 8.2 (7.6) +1.2 +0.1 to +2.2
Corp call opp (mm2) 831 (530) 671 (530) 694 (540) 634 (520) 697 (530) 335 649 (530) 595 (540) +149 +45 to +301
Cerebellum (ml) 159 (158) 117 (158) 152 (158) 124 (158) 151 (158) 132 124 (158) 140 (158) -20 -41 to +1
Putamen R (ml) 4.7 4.1 5.6 4.7 5.3 3.7 4.6 4.3
Putamen L (ml) 4.5 4.3 5.8 4.7 5.2 3.3 4.4 4.7
Putamen tot (ml) 9.2 (9.5) 8.4 (9.5) 11.4 (9.5) 9.4 (9.5) 10.5 (9.5) 7.0 9.1 (9.5) 9.0 (9.5) -0.3 -2.5 to +1.9
Glob pal R (ml) 1.6 1.4 XXXX 1.1 1.3 1.5 1.3 1.3
Glob pal L (ml) 1.5 1.8 XXXX 1.1 1.3 1.7 0.9 1.2
Glob pal tot (ml) 3.1 (2.6) 3.2 (2.6) XXXX 2.2 (2.5) 2.6 (2.6) 3.2 (2.6) 2.2 (2.6) 2.5 (2.6) +0.1 -0.4 to +0.6
Thalamus area (mm2 ) 23 (160) 210 (160) 178 (150) 40 (140) 329 (160) 215 (120) 284 (160) 56 (160) +16 -137 to +169
Hippocampus R (ml) 3.4 (2.7) 3.1 (2.7) 2.7 (3.4) 2.4 (2.4) 3.5 (2.8) 3.1 (2.1) 3.7 (2.8) 3.1 (3.3) +0.4 -0.7 to +1.0
Hippocampus L (ml) 3.1 (2.4) 2.8 (2.2) 3.3 (2.9) 2.2 (2.1) 3.4 (2.4) 2.9 (1.9) 3.0 (2.4) 2.7 (2.8) +0.5 -0.1 to +1.0
Hippocampus tot (ml) 6.5 5.9 6.0 4.6 6.9 6.0 6.7 5.8
Pituitary gland (ml) 0.25 (0.30) 0.11 (0.30) 0.47 0.16 (0.26) 0.09 (0.30) 0.16 (0.21) 0.41 (0.30) 0.21 -0.08 -0.21 to +0.11
Pinealis (ml) 0.109 (0.058) 0.096 (0.058) 0.073 (0.064) XXXX 0.123 (0.048) 0.087 (0.052) 0.047 (0.048) 0.058 (0.050) +0.031 -0.001 to +0.075
Septum pellucidum
length (mm)
45 (28) 40 (28) 38 (28) 36 (28) 38 (28) 29 (28) 43 (28) 40 (28) +11 +1 to +17
Brain abnormalities Hygroma
after surgery, VPD
removed
Cavum septum
pellucidum
Globus pallidum
unclear, cavum
septum pellucidum
Pinalis unclear.
Omaya drain, Cavum
septum pellucidum
VPD left, hygroma
after surgery, cavum
septum pellucidum
Hygroma after
surgery, Omaya
drain, 2x VPD,
cavum septum
pellucidum, asym-
metric ventricles
Hygroma after
surgery,
cavum septum
pellucidum
VPD right, cyst right
cerebellum after
surgery
Table 1. MRI based volumes of brain structures in 8 medulloblastoma patients and the mean differences between the measurements and the normal values from literature with
their range
(); mean age dependent values derived from literature
VPD: ventriculo peritoneal drain
XXXX: No measurements could be performed due to poor contrast.
Astrid König, ent-department, AMC
Introduction/Background:
Tracheotomy in children is still often perceived as last choice treat-
ment. There are fears about its risks as blockage and dislocation of the
cannula, especially in the homecare setting. On the other hand the in-
dications have changed during the years from temporarily tracheotomy
during acute infections to long term tracheotomy required by long term
diseases of the children.
Material and Methods:
A retrospective evaluation were performed of 66 patients who under-
went a tracheotomy between 1996 and 2008. We compared our indica-
tions with the literature as well as the ratio of complications.
Results:
On average 5 to 6 tracheotomies were performed per year, with 37 boys
and 29 girls, aged between 28 days until 18 years, with 53% younger
than 4 years. Airway obstruction (AO) was the most common indication,
with ventilation dependency (VD) as the second most common group
and thirdly high energetic trauma (HET). The average age of patients
differed per indication group, as did the ratio of decannulation and the
duration of the tracheotomy. No cannula related mortality occurred,
although 15 patients died of their primary diseases. The most common
complication were development of granulations (n=25), suprastomal
collaps (n=11), accidential decannulation (n=11), pneumonia (n=7), irria-
tion of the stoma (n=4) and tracheal ulceration (n=1). The parents were
after the training capable to handle especially the accidental decannu-
lation themselves. Conclusion: Even longterm tracheotomy of children
is safe after optimal training of parents.
André B.P. van Kuilenburg1, Judith Meijer1, Adri N.P.M. Mul1, Raoul C. M.
Hennekam1, Christine E.M. de Die-Smulders2, Peter Weber3, Andrea Capone Mori4,
Jörgen Bierau2, Brian Fowler3, Klaus Macke5, Jörn O. Sass6, Rutger Meinsma1, Julia
B. Hennermann7, Peter Miny3, Lida Zoetekouw1, Raymon Vijzelaar8, Joosr Nicolai2,
Bauke Ylstra9 and M. Estela Rubio-Gozalbo2
1Academic Medical Center, Amsterdam, The Netherlands. 2University Hospital
Maastricht, Maastricht, The Netherlands. 3University Children’s Hospital Basel,
Basel, Switzerland. 4Children’s Hospital Aarau, Aarau, Switzerland. 5Rheinhessen-
Fachklinik, Alzey, Germany. 6Universitätsklikum Freiburg, Zentrum für Kinder- und
Jugendmedizin, Freiburg, Germany. 7Charité Universitätsmedizin Berlin, Berlin,
Germany. 8MRC-Holland bv, Amsterdam, The Netherlands. 9VU University Medical
Center, Department of Pathology, Amsterdam, The Netherlands
Background:
Dihydropyrimidine dehydrogenase (DPD) deficiency is an infrequently
described autosomal recessive disorder of the pyrimidine degradation
pathway. Various mutations and polymorphisms have been identified in
the DPD gene (DPYD) leading to a phenotype that is mainly characterized
by mental and motor retardation and convulsions.
Methods:
In an ongoing study of 72 DPD deficient patients, we analysed the mo-
lecular background of 5 patients in more detail, using sequencing of all
coding exons and flanking intronic regions, cDNA analysis, multiplex
ligation-dependent probe amplification (MLPA), FISH analysis and
array-based comparative genomic hydridization.
Results:
Clinical features in the patients include psychomotor retardation,
convulsions, respiratory distress syndrome, skeletal abnormalities and
marked craniofacial dysmorphia. In three patients, including two sib-
lings, a 13.8 kb deletion of exon 12 was found and in one patient a 122 kb
deletion of exon 14-16 of DPYD. In the fifth patient, a c.299_302delTCAT
mutation in exon 4 was found and also loss of heterozygosity of the
entire DPD gene. Further analysis demonstrated a de novo deletion of ap-
proximately 14 Mb of chromosome 1p13.3-1p21.3, which included DPYD.
Haploinsufficiency of NTNG1, LPPR4, GPSM2, COL11A1 and VAV3 might have
contributed to the severe psychomotor retardation and unusual cranio-
facial features in this patient.
Conclusion:
Our study showed for the first time the presence of large genomic dele-
tions affecting DPYD in 7% (5/72) of all DPD deficient patients. Screen-
ing of DPD deficient patients for genomic deletions should be consid-
ered, especially those patients with an unusual clinical presentation.
P38
Tracheotomy in children: indications, complications and impact on the family
P39
Dihydropyrimidine dehydrogenase deficiency caused by intragenic rearrangements of DPyD and a de novo interstitial deletion del(1)(p13.3p21.3)
Table of patients
Number of patients
Average age Ratio of decannu-lation
Duration of tracheotomy
AO 35 (53%) 48 months 48,6% 32 months 18 days
VD 21 (31,8%) 73 months 52,4% 15 months 27 days
HET 10 (15,2%) 12 years 7 months
70% 2 months 22 days
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F. Lamers, J.J. Molenaar, I. van der Ploeg, M.E. Ebus, J. Koster,
R. Versteeg, H.N. Caron
Department of Human Genetics, Academic Medical Center,
University of Amsterdam.
Neuroblastoma are pediatric tumors with a bad
prognosis, despite extensive treatment. Therefore new
therapeutic targets should be identified. The inhibi-
tor of apoptosis protein BIRC5 (Survivin) is one of the
genes located on 17q in the region that is often gained
in neuroblastoma.
Using Affymetrix mRNA expression data, we could
show that BIRC5 expression is strongly upregulated in
neuroblastoma compared to normal tissue, other adult
malignancies and also compared to non malignant
fetal adrenal neuroblasts. The high BIRC5 expression
is correlated to 17q gain indicating that the genetic ab-
erration on 17q is contributing to the overexpression.
Finally the overexpression of BIRC5 strongly corre-
lates to a bad prognosis independent of the presence of
17q gain. To further validate BIRC5 as a potential drug
target we used both LNA and siRNA to inhibit BIRC5
in neuroblastoma cell lines. Both BIRC5 siRNAs caused
a specific knock down on mRNA and protein level.
This resulted in massive apoptosis as indicated by
PARP cleavage and an increase of the sub-G1 fraction
on FACS analysis. We were not able to show interac-
tion of BIRC5 with DIABLO or XIAP. On the contrary,
we could show P53 activation after BIRC5 inhibition
and we could rescue apoptosis after BIRC5 silencing by
CASP2 (caspase-2) inhibition.
We conclude that both the BIRC5 LNA and the siRNA
cause a specific inhibition of BIRC5 which results in a
pro-apoptotic effect on neuroblastoma cells via mitotic
catastrophe in vitro.
C.M. Loots1, M.A. Benninga1, G.P. Davidson2, T.I. Omari2
1Dept of Pediatric Gastroenterology and Nutrition, Emma Chil-
dren Hospital, AMC, Amsterdam, the Netherlands2Dept. of Pediatric Gastroenterology, Women’s and Children’s Hos-
pital, Adelaide, Australia
Introduction:
Since the introduction of pH-impedance (pH-MII)
monitoring, more accurate assessment of gastroesopha-
geal reflux (GER)-symptom associations has been pos-
sible. The aim of this study was to assess the ability of
pH-MII to predict therapeutic response to PPI therapy.
Methods:
Fifty-one pediatric GER patients who underwent 24
pH-impedance monitoring received clinical follow-up
via retrospective parental telephone questionnaire
(surveying patient management and clinical out-
comes). Three diagnostic outcomes were assessed: (1)
pathological 24h esophageal acid exposure (defined by
positive reflux index (RI)); the association between
bolus GER and symptoms, defined by (2) positive
symptom association probability (SAP≥95%) or (3) posi-
tive symptom index (SI>50%). Parents were informed
about the RI only.
Results:
Twenty-eight infants (14 female, median age [IQR]
130 days [53-160]) and 23 children (10 female, median
age [IQR] 5.8 year [2.2-13.0]) were included. Follow-up
occurred 35-53 weeks after study. Fourteen patients
had a positive RI, 14 patients had a positive SI and 32
patients had a positive SAP. Forty-four patients were
prescribed PPI, at the time of follow up, 15 were still
on PPI. For patients treated with PPI therapy (N=44),
a response was requested to the proposition; ‘I think the
medication has improved the wellbeing of my child’. In Table 1,
the correlation between parental response and diag-
nostic outcome is presented.
Conclusion:
In pediatric patients undergoing pH-impedance moni-
toring, a positive SAP was shown to be predictive for
symptomatic improvement on PPI therapy as judged
by the parents whereas a positive SI and RI have no
predictive value.
P40
Survivin (bIRC5) inhibition in neuroblastoma causes cell death via mitotic catastrophe
P41
Positive symptom association probability predicts symptomatic improvement in children with gastroesophageal reflux
Pos. test and im-proved on PPI
Neg. test and not improved on PPI
Sensitivity Specificity p-value*
RI 8 8 25% 67% 0.7
SI 9 9 75% 28% 1
SAP 23 9 72% 75% 0.007
Table 1. Diagnostic test outcome compared to symptomatic improvement on PPI therapy as judged by parents (n=44).
* P-values are calculated with a 2-tailed Fisher’s-exact test.
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Iris M. Markusse, Andrieke C. Knottnerus, A.P. Cohen, E. Kohn-
horst, Bert H. Derkx
Emma Children’s Hospital, Amsterdam
Introduction:
Childhood experience of illness in parents is an inde-
pendent risk factor for later unexplained symptoms
(Hotopf 2002). Gilleland (2009) suggests parent somati-
zation as an important factor in developing medically
unexplained symptoms (MUS) in children.
Methods:
At Psy Med Unit of the Emma Children’s Hospital,
tertiary referral centre for children with invalidating
therapy resistant MUS, an observational retrospective
study of patients presenting with fatigue or pain as
primary complaint was completed. Patients’ charts were
evaluated for somatic/psychiatric disease or MUS in
their parents.
Results:
Healthiness is defined as absence of somatic/psychiatric
disease and MUS. Somatic is defined as a common admit-
ted physical disease; psychiatric as DSM IV diagnosis.
This table shows 22% / 23% of the children having two
healthy parents. When a child has one parent with a
somatic disease and one with a psychiatric disease both
are counted. This declares the total percentage over a
100%.
Parents Patients with fatigue
Patients with pain
Healthiness 22% 23%
Somatic disease 48% 62%
Psychiatric disease
13% 15%
MUS 17% 23%
Unknown 4% -
Table 1.
Conclusions:
Almost 80% of our patients has an unhealthy parent.
This could mean a correlation between somatic/psy-
chiatric disease or MUS in parents and the presence of
MUS in their children . Hotopf suggests this relation-
ship, in grown-up children.
About 20% of the parents has MUS, which supports
the statement of Gilleland. It is important to note that
information is provided by the family. Thus, underesti-
mation is likely.
P42
Do patients with unexplained chronic fatigue/pain have healthy parents?
P43
benefit and burden scale for children (bbSC): validation in a sample of young dutch cancer survivorsH. Maurice-Stam1, A. Broek1, C.J.M. Vrijmoet-Wiersma2, E. Meijer-
van den Bergh3, E.M. van Dijk4, M.A. Grootenhuis1
1Emma Children’s Hospital AMC, Paediatric Psychosocial Depart-
ment, Amsterdam; 2Leiden University Medical Centre, Paediatric
Department, Leiden; 3Radboud University Medical Centre, Medical
Psychology, Nijmegen; 4VU University Medical Centre, Medical
Psychology, Amsterdam
Introduction:
Understanding of survivor-specific quality of life is-
sues such as disease-related burden and benefit could
yield a more complete picture of the impact of cancer
on (daily) life of survivors. To date, a survivor-specific
Dutch questionnaire is not available.
The aim of the study is to validate the Benefit and
Burden Scale for Children (BBSC; Phipps, 2008) and
to assess the psychometric characteristics in a Dutch
population.
Method:
Children aged 8 to 18, who had successfully finished
cancer treatment six months to three years before,
completed eight questionnaires measuring psychologi-
cal outcomes (benefit and burden of the disease, quality
of life, self-esteem, cognitions about the disease, PTSS,
anxiety, behavioural functioning and coping). For
measuring test-retest reliability, the BBSC was adminis-
tered again after two weeks.
Principal component analyses and reliability analyses
were conducted to assess psychometric characteristics;
Pearson correlations and ANOVAs to test validity.
Results:
A total of 78 (61%) children completed the question-
naires. Response rate for the retest was 89%. The BBSC
demonstrated good internal consistency (0.72<α< 0.84)
and high test-retest reliability (0.74<r<0.78). Children’s
benefit and burden scores did not differ as a function of
gender, ethnicity, socioeconomic status and treatment.
Brain tumour (versus other diagnosis) and shorter time
elapsed since treatment were related to higher levels of
burden. Especially disease-related burden was related
to negative psychological outcomes.
Conclusion:
The Dutch BBSC appears to be a valid instrument
with good psychometric characteristics, similar to the
original version. The instrument has the potential to
be used as a screener in Dutch paediatric survivors of
childhood cancer.
A. Klassen1, S. Strohm1, H. Maurice-Stam2, M.A. Grootenhuis2
1McMaster University, Department of Paediatrics, Hamilton, Canada; 2Emma Chil-
dren’s Hospital AMC, Paediatric Psychosocial Department, Amsterdam.
Introduction:
A systematic review was completed to identify and appraise all pub-
lished QoL questionnaires developed for use with children with cancer
and childhood cancer survivors. Aim was to discuss the nature of
the different measures available along with considerations on how to
choose an appropriate QoL questionnaire.
Methods:
MEDLINE, CINAHL, EMBASE, PsycINFO, CancerLit, and Sociological
Abstracts were searched from the inception of each database to June
2009. Included articles were ones that described the development and/
or psychometric evaluation of a QOL measure developed for use with
children with cancer or childhood cancer survivors. Articles were ap-
praised for adherence to internationally recommended guidelines for
item generation, item reduction, and psychometric evaluation.
Results:
Thirteen QOL questionnaires were identified. Eleven measures are ap-
plicable to measuring QOL in children with any type of cancer, and two
are specific to children with brain cancer. Four measures can be used to
measure QOL in children undergoing cancer treatment, six can be used
with children on or off treatment, and three are specific to childhood
cancer survivors.
While all measures underwent some degree of formal development and
validation, item generation often did not involve children with cancer
or their parents, and a number of measures did not describe or utilize
recommended methods for item reduction and psychometric evaluation.
Conclusion:
Most of the measures identified in this review were designed to meas-
ure QOL concerns of children with any type of cancer and at any time,
during treatment or survivorship. The review can help researchers and
clinicians identify scientifically sound measures.
P44
Systematic review of paediatric oncology-specific quality of life questionnaires
J.J. Molenaar, E.M. Westerhout, M.L. den Boer, S.C. Clifford, O. Delattre, B. Geoerger,
C. Lanvers, T. Pietsch, M. Serra, J. Shipley, G. Vassal, R. Versteeg, A.C. Verschuur,
H.N. Caron
Dept of human genetics and dept of pediatric oncology of the university of Amsterdam
The KCK consortium has validated CDK2 as potential drug target in six
highly malignant pediatric tumor types (i.e Ewing sarcoma, osteosar-
coma, rhabdomyosarcoma, neuroblastoma, medulloblastoma and ALL).
The stepwise procedure started with the selection of genes that can be
targeted using small molecule inhibitors. Drug target genes and signal
transduction routes were studied using Affymetrix mRNA profiles of
over 500 tumors and cell lines. CDK2 and cell cycle signal transduction
genes showed expression patterns that were significantly different
from reference tissues and expression was related to poor prognosis.
The next step to evaluate the potential drug targets consisted of tar-
geted knock down using RNA interference. Inhibition of CDK2 resulted
in significant phenotypes in several pediatric tumor models. Cell lines
from most tumor types showed growth inhibition and differentiation.
Neuroblastoma cell lines showed extensive apoptosis. Highly interest-
ing was the synthetic lethal relation between CDK2 and the driving
oncogene MYCN. These findings warranted further evaluation using the
CDK2 inhibiting small molecule Roscovitine. This compound was tested
in the core panel of pediatric tumor cell lines and more extensive in
tumor types that showed high sensitivity for the compound. Neurob-
lastoma cell lines were most sensitive with IC50 in the low uM range.
Neuroblastoma, which showed high sensitivity for Roscovitine, are now
being evaluated in in vivo mouse xenograft models.
P45
Validation of CDk2 as potential drug target in pediatric tumors
Renée L. Mulder, MSc1, Elvira C. van Dalen, MD, PhD1,2, Dorine Bresters, MD, PhD3,
Yoon K. Loke, MD, PhD4, Edith Leclercq, PhD1,2, Aleida Postma, MD, PhD5, Piet N.
Post, MD, PhD6, Bart G.P. Koot, MD7, Huib N. Caron, MD, PhD1, Leontien C.M.
Kremer, MD, PhD1,2
1Department of Paediatric Oncology, Emma Children’s Hospital/Academic Medical
Center, Amsterdam, The Netherlands, 2Cochrane Childhood Cancer Group, 3Depart-
ment of Paediatric Immunology, Haemato-Oncology, Bone Marrow Transplantation
and Auto-Immune Diseases, Willem-Alexander Kinder- en Jeugdcentrum/Leiden
University Medical Center, Leiden, The Netherlands, 4School of Medicine, University
of East Anglia, Norwich, United Kingdom, 5Department of Paediatric Oncology,
University Medical Center Groningen and University of Groningen, Beatrix Children's
Hospital, Groningen, The Netherlands, 6Dutch Institute for Healthcare Improvement
CBO, Utrecht, The Netherlands, 7Department of Paediatric Gastroenterology and
Nutrition, Emma Children’s Hospital/Academic Medical Center, Amsterdam, The
Netherlands
Background:
Until now, no Cochrane systematic reviews about late adverse effects
after treatment for childhood cancer have been performed. Because
of a growing number of studies in the field of late adverse effects in
survivors of childhood cancer, there is a need for overviews of the best
evidence. In this way, clinicians are enabled to make well-informed deci-
sions about treatment and follow-up policies. The aim of this Cochrane
systematic review is to evaluate the existing evidence involving the ef-
fect of treatment for childhood cancer on hepatic late adverse effects.
Materials and Methods:
MEDLINE, EMBASE and CENTRAL will be searched to identify all studies
reporting on hepatic late adverse effects after treatment for childhood
cancer. Information about study characteristics, hepatic late adverse
effects and risk factors will be abstracted and a risk of bias assessment
will be performed.
Results:
Not applicable.
Conclusions:
This will be the first Cochrane systematic review on late adverse effects
after treatment for childhood cancer. We now provide a framework for
the performance of Cochrane systematic reviews on late adverse effects.
For the development of future treatment policies for childhood cancer
more insight into the effect of the cancer treatment on late adverse
effects is essential. Furthermore, for the follow-up of childhood cancer
survivors it is crucial to know the risk and associated risk factors so that
patients at greatest risk can be identified and adequate follow-up proto-
cols can be established. Therefore, more Cochrane systematic reviews on
late adverse effects in survivors of childhood cancer are essential.
P46
Protocol of the first cochrane systematic review on late adverse effects in childhood cancer survivors
P47
Reproductive choices after genetic counselling for sickle cell diseaseH.E. Peters, Medical student AMC/UvA, M.A. Legdeur, Department of Clinical Genet-
ics, AMC, Dr. E.M.A. Smets, Department of Medical Psychology and Clinical Genetics,
AMC, Dr. C.A.J.M. de Borgie, Department of Clinical Epidemiology and Biostatistics,
AMC, Drs. I.B. Mathijssen, Department of Clinical Genetics, AMC, Dr. M. Peters,
Department of Paediatric-Haematology, Emma Children’s Hospital AMC
Introduction:
Sickle cell disease (SCD) is an autosomal recessive disorder with its
highest incidence in people of African ancestry. When both parents in
a couple are carriers of SCD, in each pregnancy there is a 25% risk of
having a child with SCD. Couples at risk can receive genetic counseling
to support them in making reproductive choices. The aim of this study
was to evaluate the impact and uptake of information after such coun-
seling and the subsequent reproductive decisions of risk couples.
Material and Methods:
Risk couples, counseled after the birth of a child with SCD, were invited
to participate in a qualitative interview study. In total 45 couples who
received counseling in the Academic Medical Centre in the period 2001-
2008 were selected and 21 of them participated (19 interviews with only
the mother, 2 with both parents). The semi-structured interviews con-
tained knowledge questions about SCD and inheritance and questions
about reproductive choices.
Results:
48% of the participants were of Surinam origin and 39% of African
origin. Sixteen parents were Christian, 5 Muslim and 2 had no religion.
All interviewees were aware of the different reproductive options, such
as prenatal diagnosis (PND) in a subsequent pregnancy. After the birth
of their child with SCD, 14 couples refrained from further pregnancy
for different reasons. Seven mothers gave birth to 8 children of whom 3
had SCD. PND was performed in 2 cases. Religion was an important bar-
rier for PND because it rules out the option of abortion.
Conclusion:
The reproductive choice of risk couples for SCD is mainly influenced by
cultural and religious background not by lack of knowledge.
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Evelyn M. van der Plas1, Xandra W. van den Tweel2, Harriët
Heijboer3, Ronald B. Geskus4, B.J. Biemond5, Marjolein Peters,
MD, PhD6 and Karin Fijnvandraat2
1Department of Pediatric Hematology, Emma Children's Hospital,
Academic Medical Center Amsterdam, Amsterdam, Netherlands; 2Pediatric Hematology, Emma Children's Hospital/Academic
Medical Center, Amsterdam, Netherlands; 3Department of Pedi-
atric Hematology, Emma Children's Hospital, AMC, Amsterdam; 4Department of Clinical Epidemiology, Biostatistics and Bioin-
formatics, Academic Medical Center, Asmterdam, Netherlands; 5Academic Medical Center, Amsterdam, Netherlands; 6Pediatric
hematology, Academic Medical center, Amsterdam, Netherlands
Introduction:
Despite the increasing incidence of sickle cell disease
(SCD) in the Netherlands, mortality among this pa-
tient group has never been investigated. This informa-
tion is essential to provide a baseline for monitoring
the effect of health care interventions, such as the
introduction of nationwide neonatal screening (2007).
Patients and Methods:
All patients that were diagnosed with sickle cell
disease (HbSS, HBSC, HbS-beta0, HbS-beta+) before
the age of 18 years at the laboratory of the Academic
Medical Center (AMC) in Amsterdam in 1985-2006
were included in the study. Vital status at the end of
study was determined by the last hospital visit or per-
sonal contact between January 2007 and March 2008.
Survival estimates were obtained using the Kaplan-
Meier estimator
Results:
In this time period we identified 298 pediatric pa-
tients with SCD. Homozygous sickle cell disease (HbSS)
was present in 189 (63%) patients. The total time of
follow-up was 2621 patient years. Twelve patients
had died and all deaths were SCD related. Stroke (3
patients; 25%) and sepsis/meningitis (3 patients; 25%)
were the most common causes of death. A similar pro-
portion of patients with the HbSS and HbSC genotype
died (respectively 4.2% (95% CI: 1.9-7.9%) and 4.2%
(95% CI: 1.0-10.8%). The estimated survival rate of
children with SCD at the age of three years was 93%
(95% CI: 87-100%). At the age of 18 the survival was
91% (95% CI: 84 -99%).
Conclusions:
In children with SCD living in the Netherlands, born
before nationwide neonatal screening was implement-
ed in 2007, 91% survives until the age of 18. Infection
and stroke are the most common causes of death.
Further study of children with SCD born after 2007,
will elucidate whether neonatal screening for SCD has
improved survival in these patients.
P48
Mortality and Causes of Death in Children with Sickle Cell Disease in the Netherlands
P49
Less than 30 percent of very preterm children is without disability at age fiveEva S. Potharst, MSc1, Aleid G. Van Wassenaer, MD, PhD1, Bregje
A. Houtzager, PhD1, Janeline W.P. van Hus, MSc1, Bob F. Last,
PhD2 and Joke H. Kok, MD, PhD1.1Emma Children's Hospital Academic Medical center, Amsterdam,
Netherlands and 2Psychology, Free University, Amsterdam,
Netherlands.
Background:
Children born preterm are at risk of disabilities on
multiple domains. It is unclear how many of them, in
comparison with term born peers, are without disabil-
ities if assessed on multiple domains with inclusion of
components of IQ and behaviour.
Objective:
To study how many preterm born, 5 year old children
are without disability in comparison with term born
comparison children.
Design/Methods:
Children (n = 127) born at <30 weeks GA or BW <1000
g, born in our hospital, participating in our follow-
up program, reaching the corrected age of 5 between
December 2007 and August 2009, were eligible. Term
born class mates in main stream school, were re-
cruited via the preterm child. Children were assessed
using the Movement Assessment Battery for Children
(M-ABC II) and the Touwen neurological examination,
while the Wechsler Preschool and Primary Scale of
Intelligence was used to assess verbal and performal
intelligence and processing speed quotient. Parents
and teachers filled out the Strengths and Difficulties
Questionnaire. A disability was defined as a (mildly)
abnormal result on the different tests (most often
>1SD below the test mean), based on the age corrected
for prematurity.
Results:
105 preterms (mean GA 28.8 weeks (SD 1.6), mean BW
1043 grams (SD 253)) and 92 controls (mean gestational
age 39.9 weeks (SD 1.8), mean birth weight 3441 (SD
519)) participated. Non-participant preterms were ei-
ther too handicapped (n = 5), had a genetic syndrome
(n = 2), moved abroad (n = 5), were lost to follow up (n
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= 4) or refused (n=7). In the preterm group more often
fathers (p = .01) and mothers (p = .02) were not born
in the Netherlands, and mothers (not fathers) more of-
ten had a low education (p = .00) compared to terms.
Significantly less preterms were without disabilities
(28%) compared to terms (77%) ( OR 7.02, p = .00, after
correction for SES) (see table).
Conclusions:
Three times as many preterm as term born five yr old
children has one or more disability on the neurologi-
cal, motor, cognitive and/or behavioural domain. Al-
though evaluation of children with major disabilities
is important for medical decision making, survival
with a minimum of mild and major disabilities must
be the ultimate goal of neonatal medicine.
Disabilities in preterm and term born children at age 5 yr
Number of disabilities
preterm group
term group p-value
n=105 n=92
0 28% 77%
1 22% 13%
2 30% 8%
3 13% 2%
4 7% 0% 0.00
P50
job-aid: ‘nursing report on ethical discussion in the nicu’G. Royé, RN1, M.J. Hemmink, RN1, A.T.A.M Claassen, RN1,
J.M. Wielenga, RN PhD1
1IC neonatology, Emma Children’s Hospital/Academic Medical
Centre, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Objectives:
As neonatal medicine and technical capabilities in
the NICU have developed, clinical ethics and ethical
decision-making have increased. A (moral) dilemma
requires an effective, efficient and structured ap-
proach and data should be current, complete and
comprehensive.
Complicated ethical issues can become (more) compre-
hensible, manageable, (more) transparent and easier
to assess.
In 2006 the nursing staff of the Emma Children's
Hospital / AMC NICU assigned us to develop an instru-
ment to facilitate nurses in writing an univocal and
efficient report with all aspects of the dilemma taken
into consideration and help to act only based on agree-
ments and facts.
Methods:
By systematic evaluation of literature on ethical
and moral dilemma’s, decision-making processes and
requirements on reporting such an instrument is
developed.
Results:
The instrument called a “Job-Aid” can be used before,
during and after a meeting as a questionnaire, step-
by-step plan as well as a checklist.The job-aid contains
nine questions (medical and nursing) to gather
information on a patient from different perspective,
providing a more integrated and holistic view. The
job-aid consists of five steps; collection and analysis of
objective data (facts); clarifying standards and values
(principles); clarifying the perception of the people
concerned (interests); substantiate the decision, tak-
ing the standards and values into consideration; and
evaluation and reflection.
Conclusions:
The Job-Aid reflects the thoughtful consideration by
professionals. It does not provide an absolute answer
but provides possible answers, stimulates self reflect-
ed behaviour, increases nurses input in ethical discus-
sions and improves the quality of written reports.
M.A. de Ruiter¹, A.Y.N. Schouten-van Meeteren², J. Oosterlaan³ and M.A. Grootenhuis¹1 Paediatric Psychosocial department, Emma Children’s Hospital AMC2 Department of Pediatric Oncology, Emma Children’s Hospital AMC 3 Department of Clinical Neuropsychology, VU University Amsterdam
Introduction:
The aim of this study is to investigate the efficacy of neurofeedback
(NFB) to improve attention, memory and processing speed in children
treated for a Brain Tumour (BT). In the Netherlands every year approxi-
mately 100 children are diagnosed with a BT. Nowadays over 65% of
these children have a 5-year survival. Neurotoxicity caused by treat-
ment for a BT is a major cause of neurocognitive decline in Childhood
Brain Tumour Survivors (CBTS).
Approach:
Several studies have shown that NFB has the capacity to improve the
brain systems mediating selective attention and response inhibition in
children with Attention Deficit/Hyperactive Disorder (AD/HD). CBTS
exhibit symptoms comparable to those of children with AD/HD and
positive response to methylphenidate has been found in CBTS. However,
NFB has not been used as an intervention in CBTS yet. The effectiveness
of NFB in CBTS will be investigated in a randomized controlled trial.
The intervention group of 35 patients will receive 30 sessions of NFB;
the control group, also consisting of 35 patients, will receive 30 session
of placebo neurofeedback. Neuropsychological tests and psychosocial
questionnaires will be used to evaluate pre- and post-NFB intervention
functioning, as well as a 6-month follow-up. To control for test-retest
effect, a group of 35 healthy siblings will be included in the study. They
will not receive any intervention.
Relevance:
If NFB proofs to be effective for CBTS this will be a great improvement
for their (neuro-) psychological functioning and quality of life, without
the disadvantage of the side effects of medication.
P51
PRISMA: Pediatric oncologic Research on Improving Speed, Memory and AttentionThe efficacy of neurofeedback to improve speed, memory and attention in childhood brain tumour survivors: a randomized controlled trial
P52
Intra and inter rater reproducibility of ultrasound cardiography in children with end stage renal diseaseN.J. Schoenmaker1, I.M. Kuipers2, J.H. van der Lee3; J.W. Groothoff1 on behalf of the
RICH-Q working group1Department of Pediatric Nephrology, 2Department of Pediatric Cardiology, 3Depart-
ment of Pediatric Clinical Epidemiology, Emma Children’s Hospital AMC, Amsterdam,
The Netherlands
Introduction:
Cardiovascular disease is the main cause of death in young adults with
end stage renal disease (ESRD) since childhood. Therefore, early detec-
tion and therapeutic intervention is essential in children with ESRD.
The prevalence of left ventricle hypertrophy appears to vary consider-
ably between various dialysis centers. This might be due to differences
in measurement and interpretation of the heart ultrasounds.
The aim of this study is to assess the intra and inter rater reproducibil-
ity of ultra sound cardiography with respect to the assessment of LVH
and diastolic dysfunction. This study will help to improve standardiza-
tion of measurement of cardiological parameters in children.
Material and Methods:
All patients on chronic dialysis aged <19 years in the Netherlands for
whom informed consent is obtained were included. The number of eligi-
ble patients is 101. Heart ultrasounds were performed by cardiologists in
the local medical centers and the digital files were sent to one expertise
center for assessment. The ultrasound recordings will be assessed twice
by two blinded observers independently according to a measurement
protocol. The intra and inter rater reproducibility of the measurements
underlying cardiological diagnoses such as left ventricle hypertrophy
will be estimated using Bland-Altman plots and coefficients of varia-
tion.
Results:
The results will become available from January 2010.
L. Scholten¹, A.M. Willemen², M.A. Grootenhuis¹, H. Maurice-Stam¹, C. Schuengel²,
B.F. Last1,2
¹ Emma Kinderziekenhuis AMC, Psychosociale Afdeling
² Vrije Universiteit, Faculteit Psychologie & Pedagogiek
Background:
Children with a chronic illness (CI), like asthma, diabetes, sickle cell
anemia and inflammatory bowel diseases, are twice as likely to develop
psychosocial problems as healthy children. To adequately prevent chil-
dren with CI from developing psychosocial problems, evidenced based
intervention programs are needed. A standardized group-based inter-
vention program was developed in the Emma Kinderziekenhuis AMC,
called Op Koers. Based on cognitive-behavioural principles, children
learn to use skills to help them to cope with the consequences of their
disease. Children that participated in Op Koers reported significant
improvement of social-emotional functioning than before the interven-
tion. Parents were, however, not involved in this program, while they
may be the best support of their ill child. To enhance the effect of in-
tervention, a complementary program for parents was developed (called
Samen op Koers). This program is expected to strengthen the interven-
tion effects of Op Koers.
Methods:
Effects will be evaluated in a randomized controlled design. First, the
effects of Op Koers on social-emotional outcomes will be compared with
a control group. Secondly, the additional value of the intervention for
parents will be investigated in relation to both conditions. Effects of
the different conditions will be investigated in a moderate (6 months)
to long term (12 months) schedule. Five hospitals will cooperate in
this study. If proven effective, Op Koers will be made available to all
medical centres. The ultimate goal of this study is that children with a
chronic illness and their parents will have access to an evidence based
program that limits the mental health consequences of their physical
health.
P53
Samen op koers: effectiveness of a cognitive behavioral based group intervention for children with a chronic illness: a randomized controlled trail
E. Sieswerda, L.C.M. Kremer, H.N. Caron, E.C. van Dalen
Department of Pediatric Oncology, Emma Children's Hospital/Academic Medical
Center Amsterdam, The Netherlands
Category:
Oncology
Background:
Currently, nearly 60% of children diagnosed with a malignancy receive
conventional anthracyclines as part of their treatment and are there-
fore at risk to develop anthracycline-induced cardiotoxicity.
Liposomal anthracyclines have been shown to decrease the risk of
cardiotoxicity in adults with solid tumors while attaining similar anti-
tumour efficacy compared to conventional anthracyclines.
We aimed to evaluate the available evidence of the benefits and harms
of liposomal anthracyclines in childhood cancer patients.
Methods
We searched the databases of MEDLINE, EMBASE and CENTRAL as
well as relevant reference lists and ongoing trial databases for studies
reporting on the use of liposomal anthracyclines in childhood cancer
patients. Two reviewers independently selected studies, extracted data
on study characteristics and outcomes and performed quality-assess-
ments.
Results:
A total of 15 studies met our inclusion criteria. No randomized control-
led trials were reported. Incidence of cardiotoxicity was evaluated in
ten studies and ranged from 0% to 67%. The studies were heterogene-
ous and had methodological limitations. Almost all patients had a poor
prognosis and had been treated extensively previously. Therefore, no
conclusions could be made about risks of cardiotoxicity of liposomal
anthracyclines alone. Similarly, no conclusions could be made about
anti-tumor efficacy and risks of other toxicities.
Conclusions:
There is currently no evidence to support or discourage the use of lipo-
somal anthracyclines in childhood cancer patients. There is an urgent
need for well-designed (randomized controlled) studies that accurately
evaluate if the benefits of liposomal anthracyclines found in adults
apply to children with cancer.
P54
The use of liposomal anthracycline analogues for childhood malignancies: a systematic review
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J. Stutterheim1,2, L. Zappeij-Kannegieter2, H.N. Caron1, C.E. van
der Schoot2, G.A.M. Tytgat1
1Department of pediatric oncology, Emma Children’s Hospital,
Academic Medical Center, Amsterdam, the Netherlands2Department of Immunohematology, Sanquin-AMC Landsteiner
Laboratory, Amsterdam, the Netherlands
Aims (264):
Real-time quantitative (RQ)-PCR for detection of mini-
mal residual disease (MRD) in children with neurob-
lastoma (NBL) is studied for evaluation of molecular
bone marrow (BM) response, however its prognostic
value has still to be established. We previously devel-
oped a new panel of specific neuroblastoma RQ-PCR
markers for MRD testing. The goal of this study was to
determine whether molecular sequential assessment
of bone marrow using this new panel of markers was
prognostic for ultimate overall survival (OS).
Methods:
RQ–PCR was performed with five NBL-specific mark-
ers: homeobox2b (PHOX2B), tyrosine hydroxylase (TH),
dopamine decarbohydroxylase (DDC), growth associ-
ated protein 43 (GAP43) and cholinergic receptor3
(CHRNA3), on 67 retrospectively collected samples of
48 patients with metastatic disease > 1 year. The prog-
nostic impact of MRD at 2-4 months after diagnosis
(n=38) and after induction chemotherapy (n=29) for
predicting outcome was assessed using univariate log-
rank test and multivariate Cox regression analysis.
Results:
All patients had BM positive disease at initial diagno-
sis. At the early time point, 29% (11/38) of the patients
had no molecular BM disease anymore and this was
associated with good outcome (5-y-OS 62,3±15,0%
versus 18,5±7,5%;p=0,004). After induction chemo-
therapy, BM of 41% (12/29) of the patients was still
MRD positive which was associated with poor outcome
(5-y-OS 0% versus 52,3±12,3;p<0,001). For both time
points, the prognostic value of molecular response was
independent of other response parameters (p=0.05,
p=0.004, respectively).
Conclusion:
MRD detection as reliably measured by a panel of NBL
specific-PCR targets could identify fast responders,
who clear their BM early during treatment. Fast mo-
lecular response was associated with better outcome.
P55
Fast molecular response of bone marrow disease is highly prognostic for survival in metastatic neuroblastoma > 1 year
P56
The FOCUS study (FOllow Up of Children with Sickle cell disease)First follow-up resultsM. Suijker, N. Dors, F. van Herrewegen, H. Heijboer, M. Peters,
K. Fijnvandraat
Department of Pediatric Hematology, Emma Children’s Hospital/
AMC Amsterdam
Introduction:
Sickle cell disease (SCD) is an inherited disorder of
haemoglobin. Patients with SCD may die early in life
from complications as sepsis and splenic sequestra-
tion. Neonatal screening enables early diagnosis and
installation of antibiotic prophylaxis and vaccina-
tion to prevent severe infections. National neonatal
screening for SCD was introduced in the Netherlands
in 2007. At the same moment the FOCUS study was
started with the objectives to assess the effects of
neonatal screening on mortality and morbidity.
Methods:
Longitudinal data are collected from all children
diagnosed with SCD in the Netherlands by neonatal
screening from January 2007 till July 2009.
Results:
Fifty-eight children with SCD were included in our
study. Data from 25 (43%) of these children, under the
care of the EKZ/AMC, are presented.
The median follow up is 17.4 months (6-24 months).
No SCD related mortality nor pneumococcal sepsis
occurred. Seven children (28%) were admitted to
the hospital at least once (1-5 admissions). The most
frequent reason for hospitalization was vaso-occlusive
crises (45% of hospitalizations). The risk of hospital
admission for children with SS/SBeta0 genotype was
increased in comparison to children with the SC/
SBeta+ genotype (0.49 versus 0.09; Relative Risk: 5.5,
95% CI 0.8-39).
Conclusions:
No SCD related mortality nor pneumococcal sepsis was
found. Morbidity is more severe in the HbSS group.
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C.E.A. Tacke¹, I.M. Kuipers², M. Groenink³, T.W. Kuijpers¹
¹Department of Pediatric Hematology, Immunology & Infectious
Disease ²Department of Pediatric Cardiology ³Department of Radi-
ology, Academic Medical Center, Amsterdam, the Netherlands
Background: Kawasaki disease (KD) contributes to
coronary artery aneurysm (CAA) in 15-25% of patients.
Transthoracic echocardiography is accepted as first
choice for coronary surveillance. Cardiac magnetic
resonance imaging (CMRI) is increasingly used as a
non-invasive and radiation-free imaging method. This
study evaluates the feasibility of CMRI during follow-up
of KD patients.
Methods: In this single-center study KD patients were
recruited over a 2-year period for contrast-enhanced
CMRI with adenosine-stress testing. Until CMRI assess-
ment, patients had been followed by serial echocar-
diography. CMRI findings were compared with these
longitudinal data.
Results: Thirty-nine patients (74% male, median age
14.6 years) underwent CMRI. CAAs were identified in
12 patients (30.8%) and were unexpected in 7 (17.9%)
because of the normal echocardiography findings. Only
in 2 patients the CAAs were discarded as false-positive
findings, following further imaging. Coronary artery
evaluation was incomplete in 6 patients (15.4%) due to
motion artifacts. Reversible ischemia was observed in
4 (10.3%) and an area of infarction in 3 patients (7.7%).
Only in 2 patients reversible ischemia evaluation was
not possible due to side-effects of adenosine. CMRI
led to conventional or CT-scanning angiography in 6
patients, and resulted to a change in treatment in 7
(17.9%), including coronary artery bypass grafting in 2
(5.2%).
Conclusion: CMRI is a reliable imaging tool for CAA and
cardiac function during follow-up of KD when compared
to echocardiography. In the near future functional CMRI
may replace the recommended conventional angiography
and nuclear left-ventricle scanning for follow-up after
KD, as being sensitive, non-invasive and radiation-free.
P57 Functional cardiac magnetic resonance imaging for non-invasive assessment of cardiovascular disease folluwing kawasaki Disease
Bastiaan Schouten1, Anders O.J. van Thuijl2, Betty C.A.M. van
Esch1,3, Bart R.J. Blokhuis1, Tom Groot Kormelink1, Gerard A. Hof-
man1, Guido E. Moro4,, Günther Boehm5,6, Sertac Arslanoglu4, Linette
E.M. Willemsen1, Léon M.J. Knippels3, Aline B. Sprikkelman2, Wim
M.C. van Aalderen2, Frank A. Redegeld1 and Johan Garssen1,3
1Department of Pharmacology and Pathophysiology, Utrecht Insti-
tute for Pharmaceutical Sciences, Faculty of Science, Utrecht Univer-
sity, Utrecht, The Netherlands; 2Department of Pediatric Respiratory
Medicine and Allergy, Emma Children’s Hospital, Amsterdam, The
Netherlands; 3Danone Research - Centre for Specialised Nutrition,
Wageningen, The Netherlands; 4Center for infant Nutrition, Mac-
edonio Melloni Maternity Hospital, Milan, Italy; 5Danone Research
- Centre for Specialised Nutrition, Friedrichsdorf, Germany; 6Sophia
Children’s Hospital, Erasmus University, Rotterdam,The Netherlands
Background: Cow’s milk allergy (CMA) is affecting 2.5%
of young infants. A substantial number of patients has
no detectable cow’s milk specific serum immunoglobulin
(Ig)E. In previous studies it was observed that allergic
sensitization of mice to the major cow’s milk allergens,
casein and whey, led respectively to non-IgE and IgE im-
munoglobulin profiles.
Objective: To investigate the mechanism of the IgE-
independent hypersensitivity response to casein with
respect to immunoglobulin free light chains (Ig-fLC) in
mice and children with and without CMA.
Methods: Animal study: Mice were orally sham- ca-
sein- or whey-sensitized. Acute allergen specific skin
responses were determined, serum IgE and Ig-fLC were
measured. Ig-fLC dependency was investigated using a
specific blocker and passive transfer studies of spleen
supernatants. Human study: Ig-fLC concentrations were
determined in plasma of children with CMA and non-
allergic controls.
Results: Animal study: After sensitization, no specific
IgE was detectable in serum of casein-sensitized mice,
while in whey-sensitized mice specific IgE was enhanced.
Instead, Ig-fLC levels were increased in serum from
casein-sensitized mice. Furthermore, blocking Ig-fLC
strongly diminished allergic skin responses in casein-
sensitized mice. Also allergic sensitization could be trans-
ferred using spleen cell culture supernatant from casein-
sensitized mice and was found to be Ig-fLC dependent.
Human study: Significant higher Ig-fLC concentrations
were measured in children with CMA as compared to
non-allergic controls.
Conclusions: The results of the mice study indicate
that sensitization with cow’s milk proteins can lead to
both IgE-dependent and Ig free light chain-dependent
allergic hypersensitivity responses. As free light chains
were significantly increased in children with CMA in
comparison with non-allergic controls, the possible
clinical relevance of Ig-fLC was further substantiated.
These findings suggest an important role of Ig-fLC in the
diagnosis and pathophysiology of CMA.
P58 Contribution of IgE and Immunoglobulin free light chain in the allergic reaction to cow's milk proteins
Joost A. Aalberse1,2, Anders O. van Thuijl3, Maarten O. Hoekstra1, Wilco de Jager2,
Tjitske van der Palen-Merkus4, Aline B. Sprikkelman3, Berent J. Prakken2 and Femke
van Wijk2
1Department of General Paediatrics, 2Centre for Molecular and Cellular Intervention;
Department of Paediatric Immunology, Wilhelmina Children's Hospital, Utrecht,
Netherlands, 3Department of Pediatric Respiratory Medicine and Allergy, Emma
Children’s Hospital, Amsterdam, Netherlands, 4Department of Immunopathology,
Sanquin, Amsterdam, Netherlands.
Background:
Different patterns of cytokines can initiate, maintain or suppress the
occurence of an allergic immune response. In the current study we
addressed the question whether there is a different cytokine profile in
plasma of children previously sensitized and/ or allergic to peanut that
either remained allergic or became tolerant to peanut later in childhood.
Objective:
The purpose of this study was to compare plasma cytokine levels in
peanut allergic and peanut tolerant children.
Methods:
A panel of 18 cytokines was measured in thirty children (age 3-17 years)
suspected of peanut allergy, who performed a double-blind placebo-
controlled food challenge. Next, to understand the potential role of two
outstanding cytokines more clearly, IL-17 and IL-25, were also tested in
three control groups, namely a younger group of food allergic children
(age <12 months) suspected of cow milk allergy (n=32), secondly an age
matched healthy control group (n=20), and finally an age matched group
of children with juvenile idiopathic arthritis, a Th1-disease (n=20).
Results:
IL-25 was highly elevated only in children with a proven peanut allergy
(figure 1). These high levels of IL-25 were not measured in non-peanut
allergic children, nor in young food allergic infants, in healthy controls
or in children with juvenile arthritis. Interestingly IL-17 was lower in
peanut responsive- than in the peanut tolerant children. We did not
find differences in the conventional Th2 cytokines, IL-4, IL-5 and IL-13.
Conclusion:
Our data indicate that IL-25 is a prominent secreted cytokine only in
children with a clinical allergic response to peanut. In combination
with the finding that IL-17 is more secreted in peanut tolerant children,
this study suggests that the IL-17 cytokine family plays an important
role in peanut allergy.
P59
Plasma IL-25 contributes to a peanut allergic response in children
Figure 1. Plasma IL-25 cytokine levels in children suspected of peanut and cow’s milk allergy who performed a double blind placebo controlled food challenge
(with positive or negative result), children with juvenile idiopathic arthritis (JIA) and healthy non-allergic controls.
W.F. Tromp1, J.H. van der Lee2, M. Offringa2 and J.W. Groothoff1
1Department of Pediatric Nephrology Emma Children’s Hospital AMC Amsterdam 2Department of Pediatric Clinical Epidemiology Emma Children’s Hospital AMC
Amsterdam
Introduction:
Applanation tonometry by SphygmoCor is frequently used to measure
Pulse Wave Velocity in adults and children. However, its validity in
children is uncertain since most reports lack data on reproducibility.
We studied the intra-observer variability of the carotid-femoral Pulse
Wave Velocity (PWVcf) in children with End Stage Renal Disease.
Material and Methods:
PWVcf was measured twice in 48 children with End Stage Renal Disease
using applanation tonometry (SphygmoCor) by a single well trained
investigator during one visit. Intra-observer reproducibility was as-
sessed by the Bland-Altman method. Coefficient of variation (CV) was
calculated and compared to reported CVs in studies in adults.
Results:
he mean difference [95% Confidence Interval] between the repeated
measurements was 0.16 [-0.01 - 0.32] m/s. The Limits of Agreement
were -0.91 - 1.23 m/s (Fig. 1). Splitting up the group by age (6-10 years,
n=16, and 11-18 years, n=32) made almost no difference (Mean Diff.
[95% Confidence Interval] 6-10 years: 0.12 [-0.17 - 0.40] m/s LoA: -0.95 -
1.19 m/s (Fig. 2a) and Mean Diff. [95% Confidence Interval] 11-18 years:
0.18 [-0.01 - 0.38] m/s and LoA -0.89 – 1.26 m/s (Fig. 2b). CV was 6 %,
relatively low compared to reported CVs in studies in adults.
Conclusion:
In children PWVcf changes, measured with the SphygmoCor by a single,
well-trained observer, smaller than 1.23 m/s cannot be distinguished
from measurement error, despite the fact that the CV is lower than
those presented in adult studies, where the feasibility might be better.
This device is not suitable for pediatric studies.
Figure 2b. Intra-observer variability SphygmoCor in children aged 11-18 years
Figure 1. Intra-observer variability SphygmoCor in a pediatric population with End
Stage Renal Disease
Figure 2a. Intra-observer variability SphygmoCor in children aged 6-10 years
P60
Intra-observer variability of pulse wave velocity measurement in children
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M. van Veenendaal1, M. Maas2, J.M. van den Berg1,3, K.M.
Dolman1,3, J. Swart3, J. Anink1, R. Hemke2, E. Deurloo2, R.R. van
Rijn2, T.W. Kuijpers1, M.A.J. van Rossum1,3
1 Emma Children’s Hospital, Academic Medical Center (AMC),
Dept of Pediatric Rheumatology, 2AMC, Dept of Radiology, 3Jan
van Breemen Institute (JBI), Dept of Rheumatology, Amsterdam,
the Netherlands
Background:
MRI has shown to be superior in detecting inflamma-
tory changes and early damage in the joint. The objec-
tive of our study was to investigate the use of an open
MRI in evaluating children with juvenile idiopathic
arthritis (JIA) compared to clinical and conventional
radiographic assessment.
Material and Methods:
We analyzed data of 77 patients (> 5 years) who
underwent an open non-enhanced MRI. The target
joints were selected by the treating physician and all
patients had a rheumatologic work-up including X-rays
of the selected joints. Clinical and radiological data
were related with the MRI results.
Results:
The mean age was 12 years (range 6-18) and 65% was
female. The study group consisted of 30 new patients
suspected for JIA (group I), 19 JIA patients with clini-
cal exacerbation of arthritis (group II) and 28 patients
with clinical remission (group III). Target joints
comprised 65% knees, 22% wrists and 13 % ankles.
MRI findings in group I showed in 20% findings not
recognized by clinical examination or X-ray, such
as joint erosions and orthopedic pathology. Group
II, with recurrence of arthritis, 10% did not show
synovitis on MRI however clinically suspect. Although
clinically considered in remission 61% in group III
had synovitis on MRI. Damage (erosions or joint space
narrowing) was observed in 23% as compared to 9% by
conventional X-rays.
Conclusion:
MRI is a valuable tool for detection of joint inflam-
mation and is often superior to clinical examination.
Furthermore it is more sensitive than conventional
joint radiographs in detecting early damage.
P61
Value of non-enhanced open-MRI in the evaluation of juvenile arthritis
E.J. Verhoof, H. Maurice-Stam, H.S.A. Heymans,
M.A. Grootenhuis
Psychosociale Afdeling, Emma Kinderziekenhuis AMC
Background:
A growing number of young adults with a somatic
disorder since childhood is claiming a Wajong-benefit,
a Dutch benefit for partially disabled who have not
yet joined the work force (Wajongers). Despite care-
ful guidance and support, many Wajongers are not
successfully integrating into workforce. We assume
that the achievement of milestones while growing
up (course of life) is related to job participation. The
aim of this study was to assess the course of life of
Wajongers with a somatic disorder since childhood
compared to peers from the general population.
Methods:
Young adults aged 22 to 30, who have claimed a
Wajong-benefit in 2003 or 2004 at the UWV because of
a somatic disorder, completed among others the Course
of Life Questionnaire. This instrument assesses the
achievement of developmental milestones (Autonomy,
range 6-12; Psycho-sexual, range 4-8; Social develop-
ment, range 12-24), and risk behaviour (Anti-social
behaviour, range 4-8; Substance use and gambling,
range 12-24). Differences between Wajongers and peers
from the general Dutch population were tested using
analysis of variance by group, age and gender.
Results:
Wajongers (N=416; response rate approximately 31%)
scored significantly lower (p<0.001) than their peers
(N=500) on all course of life domains: autonomy (8,7
versus 9,5), psychosexual (6,3 versus 7,1), social (19,1
versus 21,0), antisocial behaviour (4,3 versus 4,7) and
substance use and gambling (13,5 versus 15,0).
Conclusions:
Young adults with a Wajong-benefit because of a
somatic disorder since childhood are at risk of a
delayed course of life. Further research is directed at
correlations of course of life with job participation.
More insight into determinants of integration into
workforce will enable us to intervene during treat-
ment in childhood.
P62
Course of life of young adults with a Wajong-benefit as a result of a somatic disorder since childhood
PEDI
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J.L. Vogelzang¹; dr. J.W. Groothoff¹; dr. K.J. Jager²; prof. dr.
H.S.A. Heymans³
1Emma Children’s Hospital AMC Amsterdam, Department of
Pediatric Nephrology
²AMC Amsterdam, Department of Clinical Epidemiology
³Emma Children’s Hospital AMC Amsterdam
Background:
The LERIC study (Late Effects of Renal Insufficiency
in Children), 1998-2000, is a long-term follow up study
which describes the late somatic, social and psycholog-
ical consequences in renal insufficiency in children.
The cohort consisted of all 249 patients who started
chronic renal replacement therapy at age <15 years
between 1972 and 1992 and who were born before 1979.
Mean age of living patients was 30 years (range 20-42).
In this study, we found a 40 times increased mortal-
ity risk, cardiovascular disease accounting for most
deaths. Mean arterial wall stiffness of all patients
was increased as compared to the normal population.
39% of all female and 47% of all male patients had
apparent left ventricular hypertrophy. 40% of all liv-
ing patients had apparent co-morbidity. The risk for
malignancies was 10 times increased. The mean IQ was
-10 points as compared to the Dutch population. This
study is designed as a 10 years follow up study.
Methods:
All eligible 187 patients of the LERIC cohort who
were alive in 2000 are included. Data on therapeutic
characteristics and outcome covering the period 1999-
2009 will be derived from all available medical charts.
Outcome measures include mortality, causes of death
and co-morbidity with special focus on malignancies
and cardiovascular disease and its determinants. Also,
we will evaluate the prospective value of arterial
wall and cardiac ultrasound measurements in 1999.
Patients who participated in the former cross-section-
al part of the study will be contacted to in order to
establish their current psychosocial status. Data on
mortality and causes of death will be compared with
data from the ESPN and ERA-EDTA database. The
study will take place between November 2009 and
November 2012.
Results and discussion:
Results will be reported from 2010.
P63
Leric-2: late effects of renal insufficiency in children – a 10 years follow up study
Michel van Weeghel1, Heleen te Brinke1, Ronald J.A. Wanders1,2,
Sander M. Houten1,2
1Department of Clinical Chemistry, Laboratory Genetic Metabolic
Diseases, 2Department of Pediatrics, Emma Children’s Hospital,
Academic Medical Center, University of Amsterdam, Meib-
ergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Introduction:
Mitochondrial β-oxidation of saturated and unsatu-
rated fatty acids plays a pivotal role in metabolism
and energy homeostasis in organs such as the liver,
heart and muscle. Mitochondrial 3,2-trans-enoyl-
CoA isomerase (mECI) is an auxiliary enzyme of the
mitochondrial β-oxidation of unsaturated fatty acids,
which catalyzes the isomerisation of the double bond
in cis-3-enoyl-CoA or trans-3-enoyl-CoA to trans-2-
enoyl-CoA. After isomerisation, trans-2-enoyl-CoA
re-enters the β-oxidation cycle. Interestingly, a
deficiency of mECI has not yet been found in humans.
However, a mECI KO mouse (dci -/- mouse) was recently
described. Upon fasting, dci -/- mice had a fatty liver
with increased unsaturated fatty acyl chains. In addi-
tion, the dci -/- mouse showed dicarboxylic aciduria. The
dci -/- mouse could therefore be a good model to identify
the potential presentation of human mECI deficiency.
In this study, we characterised the dci -/- mouse.
Materials and Methods:
Wild type and dci -/- mice were placed in a metabolic
cage and urine was collected for three days. On the
last day the mice were fasted for 24h, sacrificed and
dissected. Biochemical studies were performed in
plasma, urine, tissues and fibroblasts.
Results/conclusion:
Upon fasting, the dci -/- mouse showed hypoglycaemia
and slightly elevated levels of unsaturated acylcar-
nitines in plasma and blood. Surprisingly, there was
no accumulation of unsaturated acylcarnitines in
tissues. Moreover oleate oxidation in dci -/- fibroblasts
was normal, providing challenging questions for our
future studies.
P64
Characterisation 3,2-trans-enoyl-coa isomerase deficient mice
C.S. van Woerden1, M. Zwols2, F.C.B. Abbad2, F.D. Muskiet2
1,2Academic Medical Center, Department of Pediatrics, University of Amsterdam,
Amsterdam, The Netherlands and 2St Elizabeth Hospital, Department of Pediatrics,
Curaçao, Netherlands Antilles. E-mail: [email protected]
Background:
Bacterial infections frequently occur in febrile infants. No information
is available about the incidence of serious bacterial infections in infants
in our hospital. Our aim is to investigate the incidence of infections in
young infants less than 12 months of age, in relation to age and labora-
tory parameters.
Material and Methods:
Retrospective cohort study in a pediatric referral hospital; review of
clinical and laboratory data of patients below 12 months of age, admit-
ted with fever or history of persistent fever. Review period: between
January 2007 and December 2007.
Results:
Sixty-three patients were selected for the study. Bacterial infections
were found in 11 of them (17%) mostly occurring as urinary tract infec-
tions (eight out of 11, 73%), with E. coli as the predominant pathogen in
four. Of all children with bacterial infections, 64% was less than three
months of age. Viral cultures were occasionally performed and showed
positive results in three patients. Median level of CRP (range) was 69
(0-230) mg/l in patients with positive cultures and median level of CRP
(range) was 5 (0-240) mg/l in patients without positive cultures.
Conclusions:
Serious bacterial infections occur predominantly in infants below three
months of age, mostly as urinary tract infections. Levels of infection
parameters may vary widely in patients even in the absence of a proven
bacterial pathogen. Complete sepsis work-up including urine culture is
warranted in febrile infants.
P65
Epidemiology of infections in infants less than 12 months of age – the curaçao experience
PEDI
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INIC
S AM
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0Aalberse, J.A. 35
Aalderen, W.M.C van 13, 20, 34
Abbad, F.C.B. 39
Abbink, F. 12
Abeling, N.G. 19
Akyüz, M. 12
Altemeier, W.A. 3
Anink, J. 37
Aronson, D.C. 13
Arslanoglu, S. 34
Baan-Slootweg, O.H. van der 13
Bams-Mengerink, A.M. 2
Bem, R.A. 2, 3
Benninga, M.A. 8, 10, 13, 25
Berfelo, F.J. 3
Berg, E. van den 3
Berg, J.M. van den 15, 37
Besancon, O.G. 4
Biemond, B.J. 29
Bierau, J. 24
Bilardo, C.M. 9, 10
Bleeker G. 5, 6
Blokhuis, B.R.J. 34
Boehm, G. 34
Boer, M.L. den 27
Bom, J.G. van der 11
Borgie, C.A.J.M. de 28
Bos, A.F. 17
Bos, A.P. 2, 3
Bosch, A.M. 19
Bouwman, M.G. 7
Bredius, R. 12
Bresters, D. 28
Brinke, H. te 19, 38
Broek, A. 26
Brons, P. 12
Bruijn, L. de 14
Brussel, P.M. van 9, 10
Bunders, M. 8
Burgers, R. 8
Calis, J. 21
Canon, S. 8
Caron, H.N. 4, 5, 6, 16, 23, 25, 27, 28, 32, 33
Claassen, A.T.A.M 30
Clifford, S.C. 27
Clur, S.A. 9, 10
Cobben, J.M. 17
Cohen, A.P. 15, 20, 26
Dalen, E.C. van 28, 32
Davidson, G.P. 25
Delattre, O. 27
Derkx, B.H. 26
Derkx, H.H.F. 15, 20
Detmar, S.D. 12
Deurloo, E. 37
Die-Smulders, C.E.M. de 24
Dijk, E.M. van 26
Dijk, M. van 10
Dijkstra, I.M.E. 12, 21, 22
Dolman, K.M. 15, 37
Domachowske, J.B. 2
Dors, N. 33
Duran, M. 2
Ebus, M.E. 25
Eck, B.L.F. van 5
Eckhardt, C.L. 11
Eck-Smit, B.L.F. van 6
Engelen, M. 12, 22
Engelen, V. 12, 16
Engen, C.E. van 12, 22
Esch, B.C.A.M. van 34
Essen-Zandvliet, E.E.M. van 13
Eykern, L.A van 20
Falix, F.A. 13
Fijnvandraat, K. 11, 18, 29, 33
Fowler, B. 24
Francois, B. 19
Frey, U. 20
Gaemers, I.G. 13
Garssen, J. 34
Geel, B. van 12
Geloven, N. van 18
Geoerger, B. 27
Geskus, R.B. 29
Govaert, P. 3
Griendt, E.J. van de 13
Groenendaal, F. 3
Groenink, M. 34
Grootenhuis, M.A. 10, 12, 15, 16, 18, 26, 27, 31, 32, 37
Groothoff, J.W. 31, 36, 38
Grotenhuis, H.B. 14
Haan, T.R. de 3
Ham, K. van 15
Haverman, L. 15, 16
Heide, M. van der 17
Heijboer, H. 18, 29, 33
Heij, H.A. 5
Hemke, R. 37
Hemmink, M.J. 30
Hennekam, R.C.M. 24
Hennermann, J.B. 24
Hensbroek, M.B. van 21
Herrewegen, F. van 33
Heymans, H.S.A. 16, 37, 38
Hijmans, C.T. 18
Hoedt, A.E. ten 19
Hoekstra, M.O. 35
Hofman, G.A. 34
Hoften, J. van 17
Hollak, C.E.M. 7, 19
Horst, N.M. ter 19
Houten, S.M. 19, 38
Houtzager, B.A. 29
Hus, J.W.P. van 29
Hutten, G.J. 20
Jager, K.J. 38
Jager, W. de 35
Jagt, Y.Q. 15, 20
Janssen, M.C.H. 19
Jonker, F. 21
Index
PEDI
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INIC
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GE 4
1
Kamphuisen, P.W. 11
Keating, P. 17
Kemp, S. 12, 21, 22
Klassen, A. 27
Knippels, L.M.J. 34
Knops, R.R.G. 23
Knottnerus, A.C. 15, 20, 26
Koelman, J.H.T.M. 2
Koff, S. 8
Kohnhorst, E. 15, 20, 26
Kok, J.H. 17, 29
König, A. 24
Koopman, H.M. 12
Koot, B.G.P. 28
Kormelink, T.G. 34
Koster, J. 25
Kraker, J. de 5, 6
Kremer, L.C.M. 28, 32
Kroft, L.J.M. 14
Kuijpers, T. 8
Kuijpers, T.W. 15, 16, 34, 37
Kuilenburg, A.B.P. van 4, 24
Kuipers, I.M. 31, 34
Lamers, F. 25
Lamers, W.H. 13
Lanvers, C. 27
Last, B.F. 10, 29, 32
Latzin, P. 20
Leclercq, E. 28
Lee, J.H. van der 31, 36
Leen, R. 4
Leenstra, T. 21
Legdeur, M.A. 28
Liem, O. 8
Linthorst, G.E. 7
Loke, Y.K. 28
Loos, C. van der 8
Loots, C.M. 25
Lopaschuk, G.D. 19
Lorenzo, C. Di 8
Lutter, R. 2
Maas, M. 37
Macke, K. 24
Majoie, C.B. 23
Markusse, I.M. 26
Martin, T.R. 3
Mastenbroek, S. 17
Mathijssen, I.B. 28
Matute-Bello, G. 3
Maurice-Stam, H. 26, 27, 32, 37
Medema, J.P. 2
Meijer, J. 24
Meijer-van den Bergh, E. 26
Meinsma, R. 24
Miny, P. 24
Molenaar, J.J. 25, 27
Mori, A.C. 24
Moro, G.E. 34
Mousa, H. 8
Mul, A.N.P.M. 24
Mulder, R.L. 28
Muskiet, F.D. 39
Naald, M. van der 11
Nicolai, J. 24
Offringa, M. 36
Ofman, R. 21, 22
Omari, T.I. 25
Ommen, C.H. van 3
Oosterlaan, J. 18, 31
Ottenkamp, J. 9, 10, 14
Palen, J. van der 13
Palen-Merkus, T. van der 35
Pals, S. 8
Peters, H.E. 28
Peters, M. 11, 18, 28, 29, 33
Pietsch, T. 27
Plas, E.M. van der 29
Ploeg, I. van der 25
Poll-The, B.T. 2, 3, 12
Postma, A. 28
Post, P.N. 28
Potharst, E.S. 29
Prakken, B.J. 35
Redegeld, F.A. 34
Rijn, R.R. van 37
Roos, A. de 14
Rosenberg, H.F. 2
Rossum, M.A.J. van 15, 16, 37
Royé, G. 30
Rubio-Gozalbo, M.E. 19, 24
Ruiter, M.A. de 31
Sass, J.O. 24
Schoenmaker, N.J. 31
Scholten, L. 32
Schoot, C.E. van der 33
Schoot R.A. 5
Schouten, B. 34
Schouten-van Meeteren, A.Y.N. 23, 31
Schuengel, C. 32
Schutte-Lensink, N. 12
Serra, M. 27
Shipley, J. 27
Sieswerda, E. 32
Smets, E.M.A. 28
Sonneville, L.M. de 19
Sprikkelman, A.B. 34, 35
Strijbos, M. 15, 20
Strohm, S. 27
Stutterheim, J. 33
Suijker, M. 33
Swart, J. 15, 37
Tacke, C.E.A. 34
Tamminga-Smeulders, C.L.J. 13
Teunissen, Q.G.A. 7
Thuijl, A.O.J. van 34, 35
Tromp, W.F. 36
Tweel, X.W. van den 29
Twisk, M. 17
Tytgat, G.A.M 4, 6, 33
Vassal, G. 27
Veenendaal, M. van 15, 37
Verhoof, E.J. 37
Vermeulen, J.R. 3
Verschuur, A.C. 4, 27
Versteeg, R. 6, 25, 27
Vijzelaar, R. 24
Visser, M. de 12
Vliegen, H.W. 14
PEDI
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Vogelzang, J.L. 38
Vries, L.S. de 3
Vrijmoet-Wiersma, C.J.M. 26
Wagg, C. 19
Wanders, R.J.A. 12, 19, 21, 22, 38
Wassenaer, A.G. Van 29
Weber, P. 24
Weeda, V.B. 13
Weeghel, M. van 38
Westenberg, J.J.M. 14
Westerhout, E.M. 27
Wetering, M.D. van de 12
Wezel-Meijler, G. van 3
Wielenga, J.M. 30
Wijburg, F.A. 7, 19
Wijk, F. van 35
Willemen, A.M. 32
Willemsen, L.E.M. 34
Woensel, J.B.M. van 2, 3
Woerden, C.S. van 39
Ylstra, B. 24
Zappeij-Kannegieter, L. 33
Zoetekouw, L. 24
Zwieten, M.C.B. van 7
Zwols, M. 39
PCA_symposium 06-01-2006 09:36 Pagina 31
Verkort IB-tekst:
Samenstelling: CARNITENE bevat L-carnitine en is verkrijgbaar als: CARNITENE tabletten, 330 mg, CARNITENE drank 1 gram/ 10 ml (100 mg/ml) CARNITENE injectievloeistof, 1 gram / 5 ml(200 mg/ml). Indicaties: Primaire (systemische) carnitine deficiënties, Eigenschappen: CARNITENE, L-carnitine (y-trimethylamino-B-hydroxybutyraat) is een lichaamseigen stof. L-carnitine wordtbij de mens hoofdzakelijk gevormd door endogene synthese uit lysine en methionine in de lever en de nier, maar kan ook verkregen worden uit de voeding. De L-isomeer, is biologisch actief enspeelt een essentiële rol zowel in het lipide metabolisme als in het metabolisme van ketonlichamen en vertakte-keten aminozuren. L-carnitine is noodzakelijk voor het transport van lang-keten vet-zuren over het binnenmembraan van de mitochondria naar de mitochondriale matrix, waar de B-oxidatie plaatsvindt met als resultaat productie van ATP. Bij een systemische carnitinedeficiëntie iser een tekort aan L-carnitine in het serum en in een of meerdere weefsels. De meest voorkomende symptomen van een systemische carnitine-deficiëntie zijn: 1. manifestatie begint in de eerstelevensjaren, 2. acute episoden van encefalopathie (braken gevolgd door een progressief verlopende stupor, verwarring en coma) die geassocieerd wordt met leverfunctie stoornissen, zeer vaakgeïnduceerd door een verminderde opname en/of fysieke inspanningen, 3. progressieve spierfunctie achteruitgang, 4. vetopstapeling in de spier- en andere weefsels (lever, nier enz.), 5. sterk ver-laagde carnitinespiegels zowel in het bloed als in weefsel. Laboratorium onderzoek toont aan een hypoglykemie, een verhoging van CPK en leverenzymen in het serum, verhoogde ketose tijdensvasten, EMG (electromyogram) veranderingen. De rationale om patiënten met een carnitinedeficiëntie te behandelen met L-carnitine ligt in het normaliseren van de weefselspiegels en/of deze in overeenstemming te brengen met de behoefte vanhet organisme op dat moment en de spierfunctie te herstellen. Waarschuwingen voorzorgsmaatregelen: Daar L-carnitine slechts in geringe mate gemetaboliseerd wordt, en als L-carnitine doorde nier wordt uitgescheiden, wordt bij patiënten met een verminderde nierfunctie (GFR < 10 ml/min) aangeraden de medicatie te doen plaatsvinden op geleide van plasmaspiegels. Toediening vaneen hoge orale doses Levocarnitine gedurende lange perioden wordt niet aanbevolen in patiënten met een chronische nierinsufficiëntie, die gedialyseerd worden. Er vindt dan een cumulatie plaatsvan belangrijke metabolieten zoals trimethylamine (TMA) en trimethylamine-N-oxide (TMAO) omdat deze niet in voldoende mate door de nier geëlimineerd kunnen worden. Dit verschijnsel treedt nietin dezelfde mate op na intraveneuze toediening. Een cumulatie van TMA is nadelig omdat hiermee de stikstofhoudende afval producten die door dialyse verwijderd worden, verhoogd wordt. Boven-dien worden de verhoogde TMA spiegels geassocieerd met neurofysiolosche effecten. De onvolledige eliminatie van TMA kan resulteren in de ontwikkeling van een vislucht geur. Indien overwogenwordt om deze patiënten levocarnitine toe te dienen wordt aangeraden dit intraveneus te doen. Gebruik in de zwangerschap: Over het gebruik van deze stof in de zwangerschap bij de mensbestaan onvoldoende gegevens om de mogelijke schadelijkheid te beoordelen. Er zijn tot dusver geen aanwijzingen verkregen voor schadelijkheid bij dierproeven. Bijwerkingen: Een lichte vormvan diarree bij sommige patiënten is na hoge orale toediening gerapporteerd. Dosering: De dosering wordt bepaald door de mate van carnitine deficiëntie. Indien mogelijk moet op geleide van car-nitine bloed-/weefselspiegels behandeld worden.
Primaire (systemische) carnitine deficiëntie. Aanbevolen wordt de volgende dosering per os per dag:Zuigelingen 100-150 mg/kg lichaamsgewicht Kinderen tot 12 jaar 50-100 mg/kg lichaamsgewicht Volwassen en kinderen boven de 12 jaar 20-40 mg/kg lichaamsgewicht
In de praktijk betekent dit dat de gemiddelde dosering per os per dag ligt voor: Zuigelingen 1 gram Kinderen tot 12 jaar 2 gram Volwassen en kinderen boven de 12 jaar 2-4 gram (in twee a drie giften)
Indien er geen verbetering optreedt in de klinische en biochemische symptomen/spierzwakte, kan de dosering verhoogd worden tot 15 gram per dag, gedurende korte tijd. De CARNITENE injectie-vloeistof is bedoeld voor acute gevallen en wanneer toediening per os niet mogelijk is. De injectievloeistof dient langzaam (3 minuten) intraveneus toegediend te worden. Met de intraveneuze vormkan met lagere doseringen (maximaal 30 mg/kg lichaamsgewicht per dag) worden volstaan, gezien de volledige beschikbaarheid van de stof na i.v. toediening ten opzichte van < 10% na orale toe-diening.
Onderverdeeld naar leeftijd betekent dit per dag: Zuigelingen maximaal 30 mg/kg lichaamsgewichtKinderen tot 12 jaar maximaal 20 mg/kg lichaamsgewichtVolwassen en kinderen boven de 12 jaar maximaal 10 mg/kg lichaamsgewicht
Registratie: Ingeschreven in het register onder: RVG 11192 CARNITENE sigma tau injectievloeistof 1 gram RVG 11193 CARNITENE sigma tau drank 1 gram RVG 11194 CARNITENE sigma tau tabletten 330 mg Registratiehouder: Sigma Tau Ethifarma B.V., Postbus 10072, 9400 CB Assen. Voor inlichtingen: Sigma Tau Ethifarma B.V.,Postbus 10072, 9400 CB Assen, telnr. 0592 333000.
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Dos Medical BV Tel 073 64 44 831 Fax 084 22 88 954 www.dermel.nl
verbetert de huidbarrière
verlaagt de kolonisatie van S. aureus op de huid
wondhelend, ontstekingsremmend
geschikt voor baby’s, kinderen en volwassenen
bevat geen corticosteroïden
wordt volledig vergoed
de basisbehandeling bij constitutioneel eczeem
gratis proefverpakking aanvragen via www.dermel.nl
1627-Pag-12 13-04-2004 11:39 Pagina 1