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Biomedical subjects

J M Wit

Publications and source records attributed to J M Wit.

At least 37 records · Page 2Linked to original sources
PubMed2004

Disturbances of growth and endocrine function after busulphan-based conditioning for haematopoietic stem cell transplantation during infancy and childhood.

It is generally assumed that busulphan/cyclophoshamide (Bu/Cy)-based conditioning regimens for haematopoietic stem cell transplantation (SCT) do not affect growth. We evaluated growth and endocrine function after Bu/Cy-based conditioning in 64 children without a history of irradiation. Mean height standard deviation scores remained stable, but unexplained disturbances of growth after SCT were found in 17/48 (35%) of the children without growth-limiting disorders (10/23 in patients treated for haematological malignancies). In 10 patients, growth hormone (GH) secretion status was evaluated, and insufficient GH secretion was diagnosed in four patients. Thyroid function was evaluable in 52 patients. Two developed antibody-mediated thyroid disorders and 10 (19%) compensated primary hypothyroidism. Gonadal function was evaluable in 21 patients and was normal in all seven patients treated with low-dose Bu (8 mg/kg), whereas seven of the 14 children receiving high-dose Bu (16-20 mg/kg) developed gonadal failure; the majority of these patients had not been exposed to gonadotoxic therapy prior to Bu/Cy. Of the 49 evaluable patients, 16 developed subclinical hyperparathyroidism. We conclude that, besides gonadal and thyroid dysfunction, impaired growth and hyperparathyroidism often occur after Bu/Cy conditioning for SCT and that growth impairment may be the result of insufficient GH secretion.

Adolescent↗
PubMed2004

Height, weight, body mass index and pubertal development references for children of Moroccan origin in The Netherlands.

AIM: To provide growth and sexual maturation reference data for Moroccan children living in The Netherlands and to compare them with the reference data of children of Dutch origin. METHODS: Cross-sectional growth and demographic data were collected from 2880 children of Moroccan origin and 14,500 children of Dutch origin living in The Netherlands in the age range 0-20 y. Growth references for length, height, weight, weight-for-height, body mass index (BMI) and head circumference were constructed with the LMS method. Predictive variables for height and BMI were assessed by regression analyses. Reference curves for sexual maturation were estimated by a generalized additive model. RESULTS: Moroccan young adults were on average 9 cm shorter than their Dutch contemporaries. Mean final height was 174.7 cm for males and 161.3 cm for females. Height differences in comparison with Dutch children increase from 2 y onwards. Height SDS was predominantly associated with target height. Compared to Dutch children, maturation started 0.2 and 0.9 y later for girls and boys, respectively. Median age at menarche was 12.9 y, 3.6 mo earlier than in Dutch girls (p = 0.001). BMI of Moroccan children was above that of Dutch children, especially for girls. BMI SDS was associated with birthweight in the age group 0 - < or = 5 y. CONCLUSION: Moroccan children living in The Netherlands are substantially shorter than Dutch children. Girls have higher weight-for-height and BMI for age. Median age at menarche occurs earlier. Given these differences, separate growth charts for the Moroccan children are useful.

Adolescent↗
PubMed2004

Towards evidence based referral criteria for growth monitoring.

AIMS: To evaluate the performance of growth monitoring in detecting diseases. Turner's syndrome (TS) is taken as the target disease. METHODS: Case-control simulation study. Three archetypal screening rules are applied to longitudinal growth data comparing a group with TS versus a reference group from birth to the age of 10 years. Main outcome measures were sensitivity, specificity, and median referral age. RESULTS: Clear differences in performance of the rules were found. The best rule takes parental height into account. Combining rules could improve diagnostic accuracy. CONCLUSION: Growth monitoring is useful to screen for TS. A combined rule that takes absolute height SDS, parental height, and deflection in height velocity into account is the best way to do this. Similar research is needed for other diseases, populations, and ages, and the results should be synthesised into evidence based referral criteria.

Body Height↗
PubMed2004

Many referrals under Dutch short stature guidelines.

The number of referrals under strict adherence to the Dutch consensus guidelines for short stature was estimated using longitudinal data from 970 children (0-10 years). Results showed that over 38% of all children would have to be referred one or more times. There is therefore a clear need to revise the current guidelines.

Body Height↗
PubMed2004

Plasma insulin-like growth factors (IGFs), IGF-Binding proteins (IGFBPs), acid-labile subunit (ALS) and IGFBP-3 proteolysis in individuals with clinical characteristics of Sotos syndrome.

OBJECTIVE: Sotos syndrome is an overgrowth syndrome of poorly understood aetiology. We investigated whether this syndrome is related to alterations in plasma insulin-like growth factors (IGFs), IGF-binding proteins (IGFBPs), acid-labile subunit (ALS) and serum IGFBP-3 proteolysis. DESIGN: Based on clinical criteria, 32 patients with clinical characteristics of Sotos syndrome (median age 8.4 years, range 1.8-48.4) were categorised into three groups: typical (n = 10, group 1), dubious (n = 12, group 2) and atypical (n = 10, group 3). Blood samples were obtained from 29 patients. MEASUREMENTS: Plasma IGF-I, IGF-II, E-II (pro-IGF-II and E-domain fragments), IGFBP-2, IGFBP-3, IGFBP-4, IGFBP-6 and ALS were measured by specific radioimmunoassays (RIAs). Except for E-II immunoreactivity, the concentrations were compared with those of age references, and expressed as standard deviation scores (SDS). IGFBP-3 proteolysis was assessed by incubation of serum with [125I]-IGFBP-3, followed by gel electrophoresis and was then compared with that in normal serum and third trimester pregnancy serum. RESULTS: Patients in group 1 showed significantly reduced plasma levels of IGF-II (median -0.9 SDS; p = 0.01), IGFBP-4 (-0.5 SDS; p = 0.02) and IGFBP-3 (-1.0 SDS; p = 0.01). Mean IGFBP-3 proteolysis was higher than in normal standard serum (61% vs 37%; p < 0.01) but lower than in third trimester pregnancy serum (94%; p < 0.01). Plasma IGF-I showed a tendency towards low values (median -0.9 SDS; p = 0.09), IGFBP-6 and ALS a tendency towards elevated levels (median values +0.8 SDS; p = 0.07 and +2.3 SDS; p = 0.09), and IGFBP-2 was normal. The mean value of E-II immunoreactivity was 8.7 nmol/l, similar to that in pooled normal plasma (8.6 nmol/l). Plasma and serum parameters in groups 2 and 3 were similar to reference values with the exception of plasma IGFBP-3 (in groups 2 and 3 median < or = -1.1 SDS; p < or = 0.02) and ALS (in group 3 median +1.3 SDS; p < 0.01). CONCLUSIONS: Patients with typical Sotos syndrome show low plasma IGF-II, IGFBP-3, IGFBP-4, and increased proteolysis of IGFBP-3 in serum. The extent to which these findings are associated with the pathophysiology of Sotos syndrome remains uncertain.

Adolescent↗
PubMed2004

Mutations in the NSD1 gene in patients with Sotos syndrome associate with endocrine and paracrine alterations in the IGF system.

OBJECTIVE: To investigate the effect of nuclear receptor Su-var, 3-9, enhancer of zeste, trithorax (SET) domain-containing protein 1 (NSD1) gene alteration in patients with Sotos syndrome on plasma IGFs and IGF-binding proteins (IGFBPs), as well as on the IGF/IGFBP system activity at the tissue level. DESIGN: Twenty-nine patients suspected of Sotos syndrome were divided into two groups: patients with heterozygous deletions or mutations in the NSD1 gene (NSD1(+/-)) (n=11) and subjects without (NSD1(+/+)) (n=18). Plasma samples (n=29) and skin fibroblasts (n=23) were obtained. The results of both groups were compared and related to reference values. METHODS: IGF-I, IGF-II, IGFBP-2, IGFBP-3, IGFBP-4 and IGFBP-6 levels were determined by RIAs. The mitogenic response of fibroblasts to IGFs was investigated by [methyl-(3)H]thymidine incorporation. IGFBP-3 levels in the culture media were measured by RIA. IGFBP-3 mRNA expression was determined by real time RT-PCR. RESULTS: NSD1(+/-) patients showed significantly altered levels of IGF-I (mean-1.2 SDS), IGF-II (-1.2), IGFBP-3 (-1.7), IGFBP-4 (-0.4), IGFBP-2 (+0.8) and IGFBP-6 (+1.5). The NSD1(+/+) patients did not differ from the reference, with the exception of the mean IGFBP-3 level (-1.3). Basal proliferation and mitogenic response to IGFs was diminished in NSD1(+/-) fibroblasts compared with NSD1(+/+) (basal, P=0.02; IGF-I, P<0.001; IGF-II, P=0.02). Compared with control fibroblasts, only the mitogenic response was diminished (basal, P=0.07; IGF-I, P=0.04; IGF-II, P=0.04). A trend of higher IGFBP-3 secretion after IGF-I stimulation (P=0.09) and 3.5-5 times higher mRNA expression of IGFBP-3 in basal conditions was found in NSD1(+/-) fibroblasts in comparison to controls. CONCLUSIONS: NSD1(+/-) patients show endocrine and paracrine changes in the IGF system. These changes may contribute to the abnormal growth pattern.

Abnormalities, Multiple↗
PubMed2004

Benefit of postponing normal puberty for improving final height.

Experiments of nature and clinical observations have provided indications that postponing puberty may increase final height in short children. In children with central precocious puberty, a GnRH analog (GnRHa) alone is efficacious in increasing final height, but in other conditions a combination of growth hormone (GH) and GnRHa is needed. In GH-deficient children with early onset of puberty and poor height prediction, the combination of GH and GnRHa increases final height by 1.0-1.3 s.d. In children with idiopathic short stature and persistent short stature after intrauterine growth retardation, the combination also appears to be beneficial. Potential side effects include weight gain, a negative effect on bone mineralization, and psychosocial consequences. More data on long-term safety have to be collected before the combination of GH and GnRHa in children with idiopathic short stature should be considered for clinical use outside clinical trials.

Adaptation, Psychological↗
PubMed2004

Expression of estrogen receptors and enzymes involved in sex steroid metabolism in the rat tibia during sexual maturation.

Estrogens are essential for bone mass accrual but their role before sexual maturation has remained elusive. Using in situ hybridization and immunohistochemistry, we investigated the expression of both estrogen receptor (ER) alpha and beta mRNA and protein as well as several mRNAs coding for enzymes involved in sex steroid metabolism (aromatase, type I and II 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD), steroid sulfatase (STS) and type I 5 alpha-reductase) on sections of tibial metaphyses before (1- and 4-week-old), during (7-week-old) and after (16-week-old) sexual maturation in female and male rats. ER alpha and ER beta mRNA and protein were detected in metaphyseal bone in lining cells, osteoblasts, osteoclasts and some osteocytes with no apparent differences in expression during development or between the sexes. In contrast, aromatase, type I and II 17 beta-HSD and type I 5 alpha-reductase mRNAs were first detected in osteoblasts, osteoclasts and occasionally in osteocytes from sexual maturation (7-week-old rat) and onwards. Only STS was present before sexual maturation. To study the significance of ER alpha and beta expression in bone before sexual maturation when circulating sex steroid levels are low, 26-day-old female and male rats underwent gonadectomy or 17 beta-estradiol (E(2)) supplementation (0.5 mg/21 days) during 3 weeks. Following gonadectomy, trabecular bone volume (TBV) was lower in males (P=0.03) and there was a trend towards reduction in females (P=0.057). E(2) supplementation increased tibial TBV compared with controls in both genders as assessed by Masson-Goldner staining. These data suggest that the presence of ERs in bone cells before sex maturation might be of significance for bone mass accrual. Furthermore, based on the mRNA expression of the crucial enzymes aromatase and type I 17 beta-HSD, we suggest that bone cells in the tibial metaphysis acquire the intrinsic capacity to metabolize sex steroids from sexual maturation onwards. This process may contribute to the beneficial effects of estrogen on bone mass accrual, possibly by intracrinology.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2004

Clinicians' perspective on quality of life assessment in paediatric clinical practice.

AIM: This study was undertaken to investigate paediatric clinicians' views on and use of quality of life (QoL) assessment in clinical practice. METHODS: A survey was conducted among members of the Dutch Paediatric Association via e-mail. RESULTS: Over half of the 303 respondents (57%) believed that it was possible to use QoL questionnaires in clinical practice. The majority indicated that assessing QoL was beneficial and that it was especially necessary to assess QoL in children with a chronic disease (82%). Although only a minority (17%) currently used QoL questionnaires, most respondents would want to use QoL questionnaires in the future (76%). Obstacles that prevent the use of QoL questionnaires are the extra time needed for assessment, the unavailability of standardized questionnaires and insufficient knowledge about QoL. CONCLUSION: This survey shows that paediatric clinicians are positive towards QoL assessment, but that certain obstacles prevent the use of questionnaires. Thus, to facilitate future use, QoL questionnaires need to be developed from the perspective of the paediatrician. This means that they need to be developed for clinical use and brought to the attention of the paediatric health care community, demonstrating their validity to child health care.

Child↗
PubMed2003

Is hypotension a major risk factor for neurological morbidity at term age in very preterm infants?

OBJECTIVE: To investigate the influence of perinatal risk factors, especially hypotension, on neuromotor status at term in surviving preterm infants born before 32 weeks of gestation. METHODS: This study is part of the Leiden Follow-Up Project on Prematurity: a prospective, regional study of 266 live born infants with a gestational age (GA) < 32 weeks born in 1996-1997. Twenty-eight infants died before term age. Two hundred and eleven infants were examined neurologically at term according to Prechtl. The findings were classified as normal (N), mildly abnormal (MA) or definitely abnormal (DA). Hypotension was defined as a mean arterial blood pressure (MABP) < 30 mm Hg on at least two occasions. RESULTS: One hundred and six (50%) infants were classified as neurologically N, 92 (44%) infants were classified as MA and 13 (6%) infants as DA. Hypotension, bronchopulmonary dysplasia (BPD), flaring and cystic periventricular leucomalacia (PVL) were risk factors for neurological morbidity. Of the 68 infants with hypotension, 33 (49%) were classified as MA and 7 (10%) as DA. Of the 141 infants without hypotension, 58 (41%) were MA, and 5 (4%) were DA. The odds ratio of hypotension for neurological morbidity was 1.9 (95% CI 1.06-3.40), adjusted for gestational age, birth weight, small for gestational age (SGA) and gender, it was 1.96 (95% CI 1.02-3.77). The adjusted odds ratio of PVL was 18.6 (4.4-78.5), of flaring was 2.37 (1.18-4.74) and of BPD was 2.44 (1.08-5.5). CONCLUSIONS: Apart from gestational age, periventricular leucomalacia, and bronchopulmonary dysplasia, hypotension in preterm infants is a major risk factor for neurological morbidity at term.

Gestational Age↗
PubMed2003

A novel nonsense mutation in the Cyp11B1 gene from a subject with the steroid 11beta-hydroxylase form of congenital adrenal hyperplasia.

11beta-Hydroxylase deficiency (11beta-OHD) inherited in an autosomal recessive manner accounts for about 5-8% of congenital adrenal hyperplasia (CAH). In order to clarify the underlying mechanism causing 11beta-OHD, we have done the molecular genetic analysis on the CYP11B1 gene in a patient diagnosed as 11beta-OHD. The nucleotide sequence of the patient's CYP11B1 revealed a novel nonsense mutation that converts codon 265 CAG (glutamine) to TAG (stop) of exon 4. Restriction fragment length polymorphism (RFLP) data showed that the patient was homozygous for the mutation. The above results confirm that the patient suffers from complete loss of the final step in cortisol biosynthesis pathway because of the nonsense mutation.

Adrenal Hyperplasia, Congenital↗
PubMed2003

Effect of x-irradiation on growth and the expression of parathyroid hormone-related peptide and Indian hedgehog in the tibial growth plate of the rat.

AIM: To study the effect of irradiation on the longitudinal growth and the expression of parathyroid hormone-related peptide (PTHrP) and Indian hedgehog (IHh) in tibial growth plates of rats. METHODS: At 3 weeks of age, 30 male rats received a single fraction of irradiation (8 Gy) to their right hind limb, and small groups of animals were sacrificed 1, 2, 3, 5, 7, 10, 15, and 26 weeks after irradiation. Weight and length of both irradiated and nonirradiated tibiae were measured, and sections of the tibiae were stained with HE. PTHrP and IHh were visualized using immunohistochemical techniques. RESULTS: Radiation resulted in persistent growth delay of the irradiated tibiae, with a difference in length of more than 10% between the irradiated and the nonirradiated tibiae 15 weeks or more after irradiation. The growth plate architecture was disturbed, and the expression of both PTHrP and IHh was decreased in the irradiated tibiae. CONCLUSION: As PTHrP and IHh are key regulators of both the pace and the synchronization of the differentiation of growth plate chondrocytes, the reduced expression of PTHrP and IHh may contribute to the changes found after irradiation.

Animals↗
PubMed2003

Genetic analysis of short stature.

Short stature is a major concern for patients and their parents, and represents a diagnostic challenge to the clinician. A correct diagnosis is of particular importance in view of the availability of effective, but costly, therapy in a small subset of cases. Many different genetic etiologies of short stature are known. Therefore, chromosome as well as molecular analysis are requisite diagnostic investigations in children with short stature. Particularly in the group of children with idiopathic short stature, possibilities of molecular analysis are often underestimated. Important options are UPD7 and the FGFR3, SHOX, GH1 and GHR genes. Furthermore, analysis of the IGF and IGF1R genes should be considered. We propose a flow chart for molecular analysis in short stature.

Body Height↗
PubMed2003

Systemic and local regulation of the growth plate.

The growth plate is the final target organ for longitudinal growth and results from chondrocyte proliferation and differentiation. During the first year of life, longitudinal growth rates are high, followed by a decade of modest longitudinal growth. The age at onset of puberty and the growth rate during the pubertal growth spurt (which occurs under the influence of estrogens and GH) contribute to sex difference in final height between boys and girls. At the end of puberty, growth plates fuse, thereby ceasing longitudinal growth. It has been recognized that receptors for many hormones such as estrogen, GH, and glucocorticoids are present in or on growth plate chondrocytes, suggesting that these hormones may influence processes in the growth plate directly. Moreover, many growth factors, i.e., IGF-I, Indian hedgehog, PTHrP, fibroblast growth factors, bone morphogenetic proteins, and vascular endothelial growth factor, are now considered as crucial regulators of chondrocyte proliferation and differentiation. In this review, we present an update on the present perception of growth plate function and the regulation of chondrocyte proliferation and differentiation by systemic and local regulators of which most are now related to human growth disorders.

Animals↗
PubMed2003

Behaviour at 2 years of age in very preterm infants (gestational age < 32 weeks).

AIM: The objective of this study was to determine behavioural outcome and risk factors for abnormal behaviour at 2 y corrected age in very premature infants in a regionally defined, prospective cohort study. METHODS: The Leiden Follow-Up Project on Prematurity includes all liveborn infants of < 32 wk gestational age, born in 1996/1997 (n = 266). Behaviour was assessed with the Child Behaviour Checklist 2-3. RESULTS: An analysis of 158 questionnaires of 206 survivors (77%) was carried out. Fourteen children (9%) had a total problem score > p90 ("clinical range"). This percentage is comparable with the 10% found in a sample of 2- to 3-y-olds from the Dutch general population. Univariate analysis showed higher syndrome scale scores in one or more of the Child Behaviour Checklist scales in children of lower gestational age, small for gestational age (birthweight < p10), with neurological abnormalities at term or at 2 y and of non-Dutch origin. Lower socioeconomic status and postnatal treatment with dexamethasone were associated with higher scores in the somatic problems scale and lower maternal age at birth with a higher total problem score. After correction for confounding variables, the associations between small for gestational age, neurological abnormalities at 2 y and the anxious/depressed and/or withdrawn scales remained significant. CONCLUSION: The prevalence of behavioural problems at 2 y corrected age in this cohort of very premature infants (gestational age < 32 wk) was comparable with that in a general population sample. Children born small for gestational age or with neurological abnormalities at 2 y of age had higher syndrome scale scores, mainly for anxious/depressed and/or withdrawn behaviour.

Child Behavior Disorders↗
PubMed2002

[Osteomyelitis in children: sometimes hard to recognize].

In a 15-year-old girl with pain in the right lower abdomen and a 9-year-old boy with pain in the left thigh, an elevated sedimentation rate and C-reactive protein were reason to suspect osteomyelitis. Although no abnormalities could be seen on X-rays, skeletal scintigraphy revealed pathology in Liv-v and the sacroiliac joint, respectively. In the girl, Staphylococcus aureus was cultivated from material obtained by puncture and biopsy. After treatment with antibiotics, rest and gradual mobilisation, the girl retained a scoliosis; the boy was cured without residual complaints or abnormalities. Osteomyelitis of the spine and sacroiliac joint are rare disorders in children. The subtle and non-specific symptoms sometimes make the diagnosis difficult. Conventional X-ray is the primary radiological investigation. Bone scintigraphy (99mTc-oxidronate) is useful in the initial evaluation of children with suspected osteomyelitis. It is sensitive, relatively inexpensive, often does not require sedation and can detect multiple foci of disease. MRI is also highly sensitive and more specific than bone scintigraphy, but it cannot be used as a screening technique when the site of pathology is unclear. MRI is useful when the bone scintigram is inconclusive and in complicated cases for better anatomic details.

Abdominal Pain↗
PubMed2002

[A flow diagram for the diagnosis of acute, non-traumatic joint complaints during childhood, retrospectively applied to 115 children].

Acute, non-traumatic joint complaints during childhood can be caused by conditions which require a quick and adequate recognition and treatment as well as by conditions in which an expectant policy can be pursued. On the basis of certain data from the anamnesis, supplemented with findings from the physical examination it is often possible to arrive at a (probable) diagnosis. An algorithm was designed, the differential steps of which were: fever, C-reactive protein titre, involvement of the hip joint, the presence of extra-articular manifestations and the results of a full blood count, erythrocyte sedimentation rate and imaging techniques. When this algorithm was retrospectively applied to the disease data of 115 children with acute, non-traumatic joint complaints, for whom the diagnosis in the status was taken as the gold standard, the correct diagnosis was established for every single child: for 98 (85.2%) by the shortest route and for 17 (14.8%) indirectly. In the case of 4 children, use of this algorithm would have led to unnecessary laboratory investigations and/or treatment. None of the diseases requiring immediate treatment were missed.

Acute Disease↗