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Free access

Bone turnover and metabolism in paediatric patients with inflammatory bowel disease treated with systemic glucocorticoids

Marianne K Vihinen, Kaija-Leena Kolho, Merja Ashorn, Matti Verkasalo, and Taneli Raivio

Objective

We investigated circulating markers of bone turnover before and during systemic glucocorticoid treatment in paediatric patients with inflammatory bowel disease (IBD).

Methods

Twenty-two children (mean age, 12.3 years) with IBD necessitating peroral steroid therapy were studied, with special reference to bone formation and resorption markers amino-terminal type I collagen propeptide (PINP) and carboxyterminal telopeptide of type I collagen (ICTP) respectively. In addition, GH-related IGF-I and sex hormone-binding protein (SHBG) were measured. Bone markers were analyzed at the initiation of the glucocorticoid treatment, at 2 and 5 weeks thereafter and at 1 month following the withdrawal of the steroid. Control group comprised 22 IBD patients in remission.

Results

PINP and IGF-I were already lower before glucocorticoid treatment serum in children with active IBD as compared with control children with IBD in remission (median PINP 271 vs 535 μg/l, P<0.05; IGF-I 23 vs 29 nmol/l, P<0.05). After 2 weeks of glucocorticoid treatment serum PINP levels had declined further, from 271 to 163 μg/l (P<0.001), serum ICTP from 14.2 to 9.6 μg/l (P<0.001), and SHBG from 54 to 35 nmol/l (P<0.001) respectively. By contrast, serum IGF-I increased from 23 to 37 nmol/l (P<0.001). One month after the withdrawal of the glucocorticoid, all bone markers restored to levels similar to the controls.

Conclusions

Bone formation in children with active IBD appears compromised and systemic glucocorticoid treatment further suppresses bone turnover. After the cessation of the glucocorticoid the bone markers show immediate improvement.

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Do insulin-like growth factor binding proteins (IGFBPs) modulate the IGF-I growth promoting and differentiating effects in human neuroblastoma cells?

Stefano Cianfarani, Daniela Germani, Paola Rossi, Anna Spagnoli, and Delio Mercanti

Cianfarani S, Germani D, Rossi P, Spagnoli A, Mercanti D. Do insulin-like growth factor binding proteins (IGFBPs) modulate the IGF-I growth promoting and differentiating effects in human neuroblastoma cells? Eur J Endocrinol 1996;135:716–23. ISSN 0804–4643

The insulin-like growth factors (IGFs) are known to stimulate both the proliferation and differentiation of neuroblastoma cells, but the role of the IGF binding proteins (IGFBPs) has not yet been established. In this study, human neuroblastoma SH-SY5Y cells have been treated with IGF-I and its potent analogue des (1–3) IGF-I alone or following preincubation with a differentiating agent such as 12-o-tetradecanoylphorbol-13-acetate (TPA). Cell proliferation and differentiation were evaluated. Conditioned medium was tested for the presence of IGFBPs by ligand blotting. The SH-SY5Y cell proliferation was maximally stimulated by des (1–3) IGF-I. The TPA-induced differentiation of SH-SY5Y, evaluated by assessment of cell morphology and GAP-43 expression as a biochemical marker of differentiation, was potentiated by nanomolar concentrations of des (1–3) IGF-I and, to a smaller extent, IGF-I. Conditioned medium showed the presence of a major IGFBP band with an approximate molecular weight of 32.5 kD and a very faint band of approximately 24 kD. The IGFBP immunoblotting results suggest that the predominant band might represent IGFBP-2. Our data represent a first demonstration of the presence of IGFBPs in conditioned medium of human neuroblastoma SH-SY5Y cells. The finding that the potent IGF-I analogue des (1–3) IGF-I with reduced affinity for IGFBPs induce major effects on cell growth and differentiation suggests that the IGFBPs may play an active role in the neuronal response to the proliferative and differentiative effects of IGF-I.

Stefano Cianfarani, Laboratory of Paediatric Endocrinology, Department of Paediatrics, "Tor Vergata" University, via di Tor Vergata 135, 00133 Rome, Italy

Free access

Bone density and metabolism in subjects with microdeletion of chromosome 22q11 (del22q11)

Stefano Stagi, Elisabetta Lapi, Eleonora Gambineri, Cristina Manoni, Maurizio Genuardi, Gloria Colarusso, Camilla Conti, Francesco Chiarelli, Maurizio de Martino, and Chiara Azzari

Introduction

Although hypoparathyroidism with hypocalcaemia is one of the most frequent clinical features of monoallelic microdeletion of chromosome 22q11 (22q11DS), bone mass and metabolism have not yet been assessed in these patients.

Design

This study aimed to evaluate bone mass and metabolism in a cohort of patients, both children and adults, with 22q11DS.

Methods

In twenty-eight patients with 22q11DS (median age 12.5, range 6.1–42.8 years), serum levels of ionised and total calcium, phosphate, parathyroid hormone (PTH), 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, osteocalcin and bone-specific alkaline phosphatase (BSAP), and urinary deoxypyridinoline concentrations were evaluated. In these patients, bone mineral density (BMD) was evaluated by dual-energy X-ray absorptiometry (DXA) examination, and volumetric BMD (bone mineral apparent density (BMAD)) was calculated.

The data obtained from paediatric and adult patients were compared with two age-, sex- and body size-matched healthy subject control groups.

Results

Patients with 22q11DS showed a reduced BMAD Z-score compared with controls (P<0.001). These patients also had significantly lower ionised (P<0.001) and total calcium (P<0.05) levels as well as lower PTH levels (P<0.05), compared with the controls. In particular, children and young patients with 22q11DS had significantly lower serum osteocalcin levels (P<0.001), BSAP levels (P<0.001) and urinary deoxypyridinoline concentrations (P<0.001) than controls. These results were not confirmed in adults.

Finally, patients with hypoparathyroidism and/or hypocalcaemia at the time of the study showed significantly lower ionised (P<0.001) and total calcium levels (P<0.001), PTH levels (P<0.05), BSAP levels (P<0.001), osteocalcin levels (P<0.001) and urinary deoxypyridinoline concentrations (P<0.001), compared with patients without hypoparathyroidism and/or hypocalcaemia. Nonetheless, the BMAD Z-score did not show substantial differences between these two groups.

Conclusions

Subjects with 22q11DS have a significant reduction in bone mass that appears to be more severe in adults who have already attained peak bone mass than in children who are still growing. Therefore, we suggest a close monitoring of bone mass and metabolism in 22q11DS patients.

Free access

Relationship between circulating endothelial progenitor cells and endothelial dysfunction in children with type 1 diabetes: a novel paradigm of early atherosclerosis in high-risk young patients

Barbara Głowińska-Olszewska, Marcin Moniuszko, Andrzej Hryniewicz, Marta Jeznach, Małgorzata Rusak, Milena Dąbrowska, Włodzimierz Łuczyński, Anna Bodzenta-Łukaszyk, and Artur Bossowski

Objective

The low number of circulating endothelial progenitor cells (EPCs) has emerged as a biomarker of cardiovascular (CV) risk in adults. Data regarding EPCs in paediatric populations with CV risk factors are limited. The aim of the study was to estimate the EPC number and its relationship with vascular function and structure in children with type 1 diabetes mellitus (T1DM).

Design and methods

We performed a comparative analysis of 52 children with T1DM (mean age 14.5 years; diabetes duration, 6.0 years; HbA1c level, 8.5%) and 36 healthy age- and gender-matched control children. EPCs were identified and analysed by flow cytometry with the use of MABs directed against CD34, CD144 (VE-cadherin) and CD309 (VEGFR-2). sICAM-1, hsCRP, thrombomodulin and adiponectin levels were also assessed. We evaluated vascular function (flow-mediated dilation (FMD)) and structure (carotid intima–media thickness (IMT)) ultrasonographically.

Results

Frequencies of CD34+ cells were similar in both groups (P=0.30). In contrast, frequencies of CD34+VE-cadherin+ cells were significantly higher in diabetic children compared with the healthy group (P=0.003). Similarly, diabetic patients tended to present with higher frequencies of CD34+VEGFR+ cells (P=0.06). FMD was lower (6.9 vs 10.5%, P=0.002) and IMT was higher (0.50 vs 0.44 mm, P=0.0006) in diabetic children. We demonstrated a significant relationship between CD34+VEGFR-2+ cells and BMI (r=0.3, P=0.014), HDL (r=−0.27, P=0.04), sICAM-1 (r=0.47, P=0.023) and FMD (r=−0.45, P<0.001). Similarly, frequencies of CD34+VE-cadherin+ cells were significantly correlated with BMI (r=0.32, P=0.02) and FMD (r=−0.31, P=0.03).

Conclusions

We demonstrated here that increased frequencies of EPCs observed in diabetic children are negatively correlated with endothelial function. Further studies are warranted to assess whether this phenomenon might result from effective mobilisation of EPCs in order to repair damaged endothelium in children at increased risk for atherosclerosis.

Free access

Pubertal androgenization and gonadal histology in two 46,XY adolescents with NR5A1 mutations and predominantly female phenotype at birth

M Cools, P Hoebeke, K P Wolffenbuttel, H Stoop, R Hersmus, M Barbaro, A Wedell, H Brüggenwirth, L H J Looijenga, and S L S Drop

Objective

Most patients with NR5A1 (SF-1) mutations and poor virilization at birth are sex-assigned female and receive early gonadectomy. Although studies in pituitary-specific Sf-1 knockout mice suggest hypogonadotropic hypogonadism, little is known about endocrine function at puberty and on germ cell tumor risk in patients with SF-1 mutations. This study reports on the natural course during puberty and on gonadal histology in two adolescents with SF-1 mutations and predominantly female phenotype at birth.

Design and methods

Clinical and hormonal data and histopathological studies are reported in one male and one female adolescent with, respectively, a nonsense mutation (c.9T>A, p.Tyr3X) and a deletion of the first two coding exons (NCBI36/hg18 Chr9:g.(126306276-126307705)_(126303229-126302828)del) of NR5A1, both predicted to fully disrupt gene function.

Results

LH and testosterone concentrations were in the normal male range, virilization was disproportionate to the neonatal phenotype. In the girl, gonadectomy at 13 years revealed incomplete spermatogenesis and bilateral precursor lesions of testicular carcinoma in situ. In the boy, at the age of 12, numerous germ cells without signs of malignancy were present in bilateral testicular biopsy specimen.

Conclusions

In SF-1 mutations, the neonatal phenotype poorly predicts virilization at puberty. Even in poorly virilized cases at birth, male gender assignment may allow spontaneous puberty without signs of hypogonadotropic hypogonadism, and possibly fertility. Patients with SF-1 mutations are at increased risk for malignant germ cell tumors. In case of preserved gonads, early orchidopexy and germ cell tumor screening is warranted. The finding of premalignant and/or malignant changes should prompt gonadectomy or possibly irradiation.

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URINARY TESTOSTERONE GLUCURONIDE AND SULPHATE IN NEWBORNS AND YOUNG INFANTS

H. Krawczynska, M. Zachmann, and A. Prader

ABSTRACT

Urinary testosterone glucuronide and sulphate was determined separately by gas chromatography in 39 newborns and young infants (34 males and 5 females). In all cases, testosterone sulphate was higher than glucuronide. Boys excreted more of both conjugates (sulphate 6.7, glucuronide 2.2 μg/24 h) than girls (1.1 and 0.7 μg/24 h, respectively). Boys older than 3 weeks had higher values than boys younger than 2 weeks. The levels correlated positively with chronological age, negatively with the gestational age and not at all with the bilirubin levels. It is concluded that testosterone is excreted preferentially as the sulphate in the newborn period and that the high sulphokinase activity in foetal and neonatal testes is more likely responsible for this phenomenon than an impaired glucuronizing capacity of the liver.

Free access

Longitudinal growth, sexual maturation and final height in patients with congenital hypothyroidism detected by neonatal screening

M Salerno, M Micillo, S Di Maio, D Capalbo, P Ferri, T Lettiero, and A Tenore

OBJECTIVE: To evaluate longitudinal growth, pubertal development and final height in patients with congenital hypothyroidism (CH) detected by a neonatal screening programme, and to identify factors potentially affecting growth outcome. PATIENTS: Fifty-five patients (41 females) detected by neonatal screening and followed longitudinally from the time of diagnosis and treatment (25+/-5 days) up to the age of 17+/-0.5 years were evaluated retrospectively. RESULTS: Pubertal development began and progressed normally in both males and females. In boys, a testicular volume of 4 ml was reached at 11.3+/-1.0 years. In girls breast enlargement (B2) occurred at a mean age of 10.3+/-1.2 years and the mean age of menarche was 12.5+/-1.2 years. The onset and the progression of puberty were independent of the aetiology, the severity of CH and the timing of the beginning of treatment. Girls treated with an initial amount of L-thyroxine (L-T4) greater than 8 microg/kg per day showed an earlier onset of puberty (B2 9.4+/-0.9 years; menarche 11.5+/-0.8 years) compared with girls treated with a lower initial dose of L-T4 (B2 10.5+/-1.2 years; menarche 12.6+/-1.2 years; P<0.02). However, both groups attained a similar final height (-0.1+/-1.0 SDS and 0.4+/-1.0 SDS, respectively), which in both cases was above the target height (P=0.03). All the patients in the study attained a mean final height (0.1+/-1.1 SDS) within the normal range for the reference population and above the target height (-0.9+/-0.9 SDS, P<0.0001). No significant relationship was found between final height and severity of CH at diagnosis, initial L-T4 dosage or aetiology of the defect. Patients with ectopic gland, thyroid aplasia or in situ gland attained a similar mean final height (0.1+/-1.1 SDS, 0.5+/-1.0 SDS and -0.5+/-1.0 SDS, respectively), which was in all cases greater than target height (-1.0+/-0.9, -0.6+/-0.8, -0.9+/-0.8 respectively; P<0.05). CONCLUSIONS: Our results suggest that conventional management of children with CH detected by neonatal screening leads to normal sexual development and normal adult height, and that the major factor determining height in these children is familial genetic growth potential.

Free access

Molecular genetic study in two patients with congenital hypoaldosteronism (types I and II) in relation to previously published hormonal studies

M Peter, K Bunger, SL Drop, and WG Sippell

We performed a molecular genetic study in two patients with congenital hypoaldosteronism. An original study of these patients was published in this Journal in 1982. Both index cases, a girl (patient 1) and a boy (patient 2). presented with salt-wasting and failure to thrive in the neonatal period. Parents of patient 1 were not related, whereas the parents of patient 2 were cousins. Endocrine studies had shown a defect in 18-oxidation of 18-OH-corticosterone in patient 1 and a defect in the 18-hydroxylation of corticosterone in patient 2. Plasma aldosterone was decreased in both patients, whereas 18-OH-corticosterone was elevated in patient 1 and decreased in patient 2. Plasma corticosterone and 11-deoxycorticosterone were elevated in both patients, whereas cortisol and its precursors were in the normal range. According to the nomenclature proposed by Ulick, the defects are termed corticosterone methyl oxidase (CMO) deficiency type II in patient 1, and type I in patient 2 respectively. Genetic defects in the gene CYP11B2 encoding aldosterone synthase have been described in a few cases. In patient 1, we identified only one heterozygous amino acid substitution (V386A) in exon 7, which has no deleterious effect on the enzyme activity. In patient 2 and his older brother, we identified a homozygous single base exchange (G to T) in codon 255 (GAG), causing a premature stop codon E255X (TAG). The mutant enzyme has lost the five terminal exons containing the haem binding site, and is thus a loss of function enzyme. This is only the second report of a patient with CMO deficiency type II without a mutation in the exons and exon-intron boundaries, whereas the biochemical phenotype of the two brothers with CMO deficiency type I can be explained by the patient's genotype.

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Effects of high dose oestrogen and testosterone treatment in adolescents upon trabecular and compact bone measured by 125I computed tomography. A preliminary study

Gerhard Ulrich Exner, Andrea Prader, Urs Elsasser, and Max Anliker

Abstract.

125I Computed Tomography (CT) allows for the selective determination of trabecular and compact bone mineral parameters in the radius. Using this technique the effects of high dose oestrogen treatment in 11 tall girls, and of high dose testosterone treatment in 5 tall boys were monitored. In both groups trabecular bone density (TBD) increased steadily during treatment at a rate of about 1% per month. Also in both groups the compact bone mineral increased steadily. These results are compared with those from a cross sectional study on 49 normal children and 36 normal adults, in whom TBD was found to be independent of age and sex, so that the increases in TBD in both treatment groups can be attributed directly to the influence of the sex hormones. Since the compact bone mineral is higher in adults than in children it cannot yet be decided whether the increases seen in the treated patients are related to the sex hormone treatment, or reflect only the normal development of the bone during adolescence.

Free access

Distribution of the homeostasis model assessment of insulin resistance in Mexican children and adolescents

Celia Aradillas-García, Martha Rodríguez-Morán, María Eugenia Garay-Sevilla, Juan Manuel Malacara, Ramón Alberto Rascon-Pacheco, and Fernando Guerrero-Romero

Objective

Several cutoff points of the homeostasis model assessment of insulin resistance (HOMA-IR; varying from 2.5 to 4.0) have been suggested for diagnosing IR in youth. In this study, we determined the distribution of the HOMA-IR in Mexican children and adolescents.

Design and methods

A total of 6132 children and adolescents from San Luis Potosi, León, Queretaro, and Durango, which are cities in central and northern Mexico, were enrolled in a population-based cross-sectional study. Eligible participants were apparently healthy children and adolescents aged 6–18 years. Pregnancy and the presence of chronic illnesses were exclusion criteria.

Results

A total of 3701 (60.3%) girls and 2431 (39.7%) boys were included in this study. In the overall population, the mean body mass index, insulin levels, and fasting glucose levels were 21.8±1.3 kg/m2, 7.1±3.2 μU/ml, and 86.2±10.0 mg/dl respectively. The concentrations of insulin and fasting glucose gradually increased from 6 to 12 years of age, whereas the concentrations tended to plateau in the 13- to 18-year-old population. The absolute mean of the HOMA-IR was 2.89±0.7. The HOMA-IR gradually increased with age and reached a plateau at 13 years of age.

Conclusions

Because the insulin concentrations, glucose levels, and HOMA-IR exhibited a gradual increase with age that was not related to obesity, our results suggested that the evaluation of IR in children should be based on percentiles of the HOMA-IR rather than a dichotomous value derived from a single cutoff point.