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Biomedical subjects

J Leger

Publications and source records attributed to J Leger.

At least 37 records · Page 2Linked to original sources
PubMed1998

Ontogeny of leptin in human fetuses and newborns: effect of intrauterine growth retardation on serum leptin concentrations.

The aim of this study was to investigate the ontogeny of serum leptin concentrations during the second half of gestation and at birth in small for gestational age and normal fetuses and newborns. Serum leptin concentrations were measured in arterial cord blood of fetuses (n = 79) and newborns (n = 132), with or without intrauterine growth retardation, at 18-42 weeks gestation. Serum leptin was detectable in fetal cord blood in all subjects as early as 18 weeks gestation. Leptin levels dramatically increased after 34 weeks gestation. In newborns, serum leptin concentrations were positively correlated with body weight (P < 0.001) and body mass index (P < 0.001). Newborns with intrauterine growth retardation had significantly lower serum leptin values (P < 0.001) than those with normal growth, and leptin levels were only positively correlated with body mass index (P < 0.001). These results suggest that the development of adipose tissue and the accumulation of fat mass are the major determinants of fetal and neonatal serum leptin levels. In addition, a gender difference, with higher leptin concentrations in female fetuses, was observed during the last weeks of gestation and was confirmed at birth regardless of growth status, suggesting that a sexual dimorphism already exists in utero.

Adolescent↗
PubMed1997

Reduced final height and indications for insulin resistance in 20 year olds born small for gestational age: regional cohort study.

OBJECTIVE: To investigate whether the association between low birth weight and increased risk of developing impaired glucose tolerance, insulin resistance, hypertriglyceridaemia, and hypertension in middle age is apparent by the age of 20 in people born small for gestational age. DESIGN: Regional cohort study. SETTING: Maternity registry, Haguenau, France. SUBJECTS: 236 full term singleton babies born small for gestational age (birth weight or length, or both, below third centile) during 1971-8 and 281 with normal birth weight (between 25th and 75th centile). All subjects were contacted and evaluated at a mean (SD) age of 20.6 (2.1) years. MAIN OUTCOME MEASURES: Adult height; concentrations of glucose, insulin, and proinsulin during an oral glucose tolerance test; lipid and fibrinogen concentrations; and blood pressure. RESULTS: After sex and target height were adjusted for, subjects who had been born small for gestational age were significantly shorter at age 20 than those with a normal birth weight (men 4.5 cm shorter (95% confidence interval 6.0 to 3.0 cm); women 3.94 cm shorter (5.2 to 2.7 cm)). After sex and body mass index were adjusted for, mean plasma glucose concentration 30 minutes after a glucose load, fasting insulin concentration (in women), and insulin and proinsulin concentrations 30 and 120 minutes after a glucose load were significantly higher in subjects who had been born small for gestational age than in those with a normal birth weight. Mean lipid and fibrinogen concentrations and blood pressure were not different between the two groups. CONCLUSIONS: Intrauterine growth retardation has long term consequences such as reduced final height Raised insulin and proinsulin concentrations are present in young adults born small for gestational age and could be markers of early changes in insulin sensitivity.

Adolescent↗
PubMed1997

Prediction of the outcome of growth at 2 years of age in neonates with intra-uterine growth retardation.

The aim of the study was to identify at birth, in infants showing intra-uterine growth retardation (IUGR), any parameters correlative with the increase in height SDS during the first 2 years of life and with short stature at 2 years of age, and to determine whether the sensitivity and specificity of such parameters would permit their use as predictors of short stature at 2 years of age. Two cohorts of children born with IUGR with birth weight < 3rd percentile, were studied. In the first group of 317 children selected at birth, 224 were effectively followed up to 2 years of age (group 1) and the second group of 48 children was evaluated at 2 years of age for short stature related to IUGR (group 2). Perinatal history, auxological data at birth and parental height were monitored in a prospective study for the group 1 children and in a retrospective study for the group 2 children. By 2 years of age, 8% of the 224 children followed (group 1), presented short stature (< or = 2 SDS). In a multiple linear regression model, gestational age, birth length (SDS), target height (SDS) and maternal tobacco consumption were found to be the strongest predictors of the magnitude of the height gain (SDS) during the first 2 years of life. Using these parameters 47% of the variability of the height gain (SDS) during the first 2 years of life could be explained at birth. Moreover, logistic regression analysis showed three risk factors at birth for short stature by 2 years of age: reduced gestational age due to premature birth (adjusted odd ratio (O.R.) = 2.10; 95% C.I. = 1.06-4.14), the greater the difference (for each S.D.) between birth length (SDS) and target height (SDS) (O.R. = 1.93; 95% C.I. = 1.40-2.66) and although as a borderline significant factor, maternal tobacco consumption (O.R. = 1.58; C.I. 95% = 0.81-3.07). Non-parametric discriminant analysis was used to investigate whether short (< or = -2 SDS) or normal stature (> -2 SDS) at 2 years could be predicted at birth using gestational age (weeks), birth length (SDS), target height (SDS) and maternal tobacco consumption as discriminant variables. We found that this discriminant model correctly predicted at birth the short stature of 57 of 59 children at 2 years of age (sensitivity 97%) and the normal stature of 142 of 159 children at 2 years of age (specificity 89%). In conclusion, an accurate prediction of short stature by 2 years of age is feasible at birth in the IUGR neonate.

Body Constitution↗
PubMed1997

Bone mineral density and metabolism in children with congenital hypothyroidism after prolonged L-thyroxine therapy.

The effect of long-term L-thyroxine (LT4) replacement therapy on bone mineral density and on biochemical markers of bone turnover were studied in children with congenital hypothyroidism (CH). Forty-four children and adolescents (mean age 8.5 +/- 3.5 years) with primary CH who began LT4 replacement therapy within the first month of life were studied. Bone mineral density (BMD) of the lumbar vertebrae and the upper femoral bone was measured by dual energy X-ray absorptiometry. Serum osteocalcin (OC) and bone alkaline phosphatase were measured as markers of bone formation and urinary deoxypyridinoline was taken as a marker of bone resorption. Bone mineral densities of CH children were not different from those in age-matched controls. The biochemical markers of bone turnover were normal except for the serum OC levels which were found to be higher than in controls and positively correlated with the free thyroid hormone levels (for FT4 r = 0.42, p = 0.02). Eight CH children demonstrated low BMD values (below -1 SDS) at -2 +/- 0.7 SDS for the lumbar spine and -1.6 +/- 0.5 SDS for the femoral site. These eight children showed lower mean weight (p < 0.05) and their dietary calcium intake tended to be less (p <0.06) than that seen in the normal BMD group. In conclusion, our results show that LT4 replacement therapy for 8 years is not detrimental to the skeletal mineralization of CH children. As in a healthy population, weight and current intake of calcium seem to be major determinants of bone density. Dietary recommendations, especially when calcium intake is below the recommended dietary allowance, may have to be reconsidered.

Absorptiometry, Photon↗
PubMed1997

A 5-year prospective study of growth hormone (GH)-deficient children treated with GH before the age of 3 years. French Serono Study Group.

The aim of the study was to assess the efficacy of GH therapy in GH-deficient children treated before the age of 3 yr. A noncomparative multicenter prospective study included 49 children (22 girls and 27 boys) with isolated GH deficiency (n = 19) or multiple pituitary hormone deficiency (n = 30) treated with daily s.c. injections (0.6 U/kg.week) for 3-5 yr. They were divided into two groups according to their height SD score for chronological age (CA) at the initiation of therapy: group A consisted of 8 patients presenting an initial height within the normal range (< 2 SD below the mean) followed for 2-5 yr, and group B consisted of 25 children followed for 5 yr among 41 patients with initial growth retardation. In group A, the mean height SD score increased from -1.1 +/- 0.6 to 0.35 +/- 1.0 SD (P < 0.001) in the first year and remained in the normal range throughout the following 4 yr. In group B after 4 yr of treatment, the mean height SD score for age had increased from -3.6 +/- 1.0 SD (time zero) to -0.9 +/- 1.2 SD. During the fourth year of therapy, the mean height gain of 0.2 +/- 0.2 SD was significant (P < 0.001). After 5 yr of treatment, a plateau was reached with a corresponding height SD score (CA) of -0.8 +/- 1.2 SD (95% confidence interval between -1.3 and -0.2 SD). This value remained significantly below normal for age (P < 0.001), indicating that catch-up growth was incomplete. Only four patients (16%) remained below -2SD for CA. The 5-yr height gain was negatively correlated with the height SD score at the start of treatment (r = -0.6; P < 0.005) and the first year height gain was the most predictive parameter. There was no significant influence of intrauterine growth retardation, body mass index and age at the start of treatment, or parental target height. Bone maturation was significantly retarded over CA by a mean value of 1.1 +/- 0.9 yr (P < 0.0001), with a mean bone age/CA ratio of 0.8 +/- 0.2 after a mean treatment duration of 5.1 +/- 1.1 yr. In conclusion, the rapid and almost complete return to normal height obtained in this study supports the need for GH treatment in early diagnosed GH-deficient children. The present dosage may be considered the minimum to obtain satisfactory catch-up growth ensuring a favorable outcome for these children. In addition, it allowed growth at a rate normal for age in patients diagnosed before growth retardation.

Body Height↗
PubMed1997

Fetal cord blood sampling in the diagnosis and the treatment of fetal hyperthyroidism in the offsprings of a euthyroid mother, producing thyroid stimulating immunoglobulins.

We described here three individual pregnancies in a euthyroid mother with a past history of Graves disease and high levels of thyrotropin receptor stimulating antibodies. Ten years prior to her first pregnancy the mother underwent a partial thyroidectomy for Graves disease and remained euthyroid since, but still produced high levels of thyrotropin receptor stimulating antibodies. Fetal and postnatal hyperthyroidism was not recognized for the first child who was referred to us at one year of age for craniostenosis. During the two next pregnancies fetal hyperthyroidism was suspected on the basis of fetal tachycardia, growth retardation, fetal goiter and fetal cord blood sampling confirmed high levels of free T3, free T4, suppressed fetal TSH levels, and high levels of fetal TRAb. The mother received propylthiouracil to control fetal hyperthyroidism. Neither baby was premature and each had a more favorable outcome than the first. Fetal cord blood sampling proved to be useful during these two pregnancies to ascertain the diagnosis of fetal hyperthyroidism and to monitor the dose of PTU administered to this euthyroid mother.

Adult↗
PubMed1996

Growth factors and intrauterine growth retardation. I. Serum growth hormone, insulin-like growth factor (IGF)-I, IGF-II, and IGF binding protein 3 levels in normally grown and growth-retarded human fetuses during the second half of gestation.

The aim of this study was to relate human fetal growth retardation to specific hormone alterations. Serum levels of GH, IGF-I, IGF-II, and IGF binding protein (BP) 3 were measured during the second half of gestation after cordocentesis in 230 fetuses who were classified into normally grown (n = 166) and growth-retarded (n = 64) groups according to ante- and neonatal measurements. The normally grown group showed a progressive decline in serum GH levels toward term (r = -0.42, p = 0.0001), whereas serum IGF-I was increased (r = 0.55, p = 0.0001), as were serum IGF-II (r = 0.21, p = 0.008) and IGFBP3 levels (r = 0.19, p = 0.02), although less markedly. For all hormone levels, wide individual differences were found at any given age of gestation. The incidental presence of fetal malformations in either the normally grown group (n = 107 cases) or the growth-retarded group (n = 50 cases) had no apparent effect on these hormone levels as compared with members of the groups showing no fetal malformations (n = 73 cases). Comparison of the normally grown group with the growth-retarded group showed that serum IGF-I levels were significantly lower in the growth-retarded group (p = 0.001). No differences were found between the groups in serum GH, IGF-II, and IGFBP3 levels, although if data for the third trimester were taken alone, serum IGF-II levels were found to be lower in the growth-retarded group (p = 0.05). In conclusion, during the second half of gestation, fetal serum IGF-I levels may be influenced by nutritional factors controlling fetal growth. However, the wide individual differences in measurements make it a very poor biologic marker of intrauterine growth retardation.

Biomarkers↗
PubMed1996

Growth factors and intrauterine growth retardation. II. Serum growth hormone, insulin-like growth factor (IGF) I, and IGF-binding protein 3 levels in children with intrauterine growth retardation compared with normal control subjects: prospective study from birth to two years of age. Study Group of IUGR.

The aim of this study was to describe serum GH, IGF-I, and IGF binding protein (BP) 3 levels at birth and during the first 2 y of life in intrauterine growth-retarded (IUGR) children and to correlate these hormonal values with auxologic parameters noted during this period to investigate their predictive value on the postnatal growth pattern. Three hundred and seventeen children were included at birth and studied for auxologic and biologic parameters at birth, 3 and 30 d, and 3, 6, 12, 18, and 24 mo of age. At birth, when analyzed according to gestational age, serum GH levels were increased (p = 0.0001) and serum IGF-I and IGFBP3 levels were decreased (p = 0.0001) in IUGR as compared with normal neonates. When two cohorts were established at birth as a function of the ponderal index (PI) (< or = or > 3rd percentile), serum IGF-I and IGFBP3 levels were found to be significantly reduced in the case of low PI. All parameters were within normal limits at 1 mo of age and remained normal thereafter. During the first 3 mo of life, a positive correlation was found between IGF-I increment and weight gain (r = 0.28, p = 0.002). None of the biologic parameters at birth were predictive either of later growth or of short stature at 2 y of age. In conclusion, low serum IGF-I and IGFBP3 levels at birth were related to fetal malnutrition and were not predictive parameters for later growth.

Body Height↗
PubMed1996

A novel substitution (Leu707Arg) in exon 4 of the androgen receptor gene causes complete androgen resistance.

A wide spectrum of androgen receptor (AR) gene mutations has been reported in complete androgen insensitivity syndromes. The molecular basis of androgen resistance was investigated in a female newborn with complete testicular feminization. Sequencing identified a point mutation in exon 4 responsible for a leucine (CTG) to arginine (CGG) replacement at codon 707. This novel mutation is located in the amino-terminal part of the ligand-binding domain of the AR. To determine the functional properties of the mutated AR and to establish the correlation with the clinical phenotype of androgen resistance, the mutation was reproduced in AR wild-type complementary DNA, and the plasmid was transfected into AR-free mammalian cells. In vitro studies showed that the mutant AR was functionally defective as an androgen-binding molecule. Electrophoretic mobility shift assay revealed that the binding of mutated AR to DNA was reduced. Finally, the mutant was unable to induce the transcriptional activation of androgen-responsive reporter gene. This amino acid defect in the primary sequence probably involves the rupture of hydropathicity in a region that is conserved among members of the steroid receptor subfamily. Our data substantiate the major contribution of leucine 707 to normal AR function and demonstrate that its substitution by an arginine caused the complete androgen insensitivity in this patient. Our findings also contribute to the elaboration of the structure-function map of the AR based on naturally occurring mutations.

Amino Acid Sequence↗
PubMed1996

A neomutation of the thyroid-stimulating hormone receptor in a severe neonatal hyperthyroidism.

Until recently, neonatal hyperthyroidism has been considered to be related to the transplacental passage of thyroid-stimulating Ig present in the serum of the mother. We report here the case of a newborn who presented with severe hyperthyroidism, diffuse goiter, and important ocular signs (eyelid retraction and possibly proptosis). However, the absence of thyroid pathology in the parents and the lack of antithyroid antibodies in the mother and in the patient led us to suspect a nonimmune aetiology. Direct genomic sequencing of the last exon of the TSH receptor in the patient revealed a T-->C transversion yielding to a Met453-->Thr heterozygous substitution in the second transmembrane domain of the receptor. The mutation was absent in both parents. Eukaryotic expression analysis in COS-7 cells yielded a mutated receptor that produced constitutive activation of adenylate cyclase without enhancement of phospholipase C activity.

Amino Acid Sequence↗
PubMed1995

Progressive normalization of growth hormone-binding protein and IGF-I levels in treated growth hormone-deficient children.

The short- and long-term effects of hGH treatment on growth hormone (GH)-binding protein (GHBP) were examined in 18 prepubertal children, aged 1.5-10 y, with isolated idiopathic GH deficiency. The patients were studied before and at regular intervals during 24 mo of hGH therapy (0.6 IU/kg/wk, given daily). Pretreatment GHBP values were low: 14.6 +/- 1.2% of radioactivity (p < 0.0001 versus normal prepubertal children). After the first hGH injection, GHBP levels fell significantly at 6 h (8.2 +/- 1.3% of radioactivity) and then remained at basal level during the first week. Under hGH therapy, an increase in GHBP was observed, but it occurred at different times of treatment, from 1 to 12 mo, and the mean GHBP value became significantly higher than the value before treatment after 12 mo of therapy. An increase in serum IGF-I level was observed as soon as 1 wk of hGH therapy, and after 3 mo, the mean IGF-I value was normal. No correlation was found between the increase in GHBP, IGF-I levels, and the growth velocity at 12 and 24 mo of treatment. These findings support the role of GH in the regulation of GHBP/receptor in man. The time course of the GH effect appears to be progressive and variable.

Carrier Proteins↗
PubMed1994

Role of congenital hypothyroidism in hearing loss in children.

No significant difference was found for the auditory thresholds at conversational and high frequencies between 42 children with congenital hypothyroidism treated with L-thyroxine and an age-matched control group, regardless of the cause of the thyroid failure or hormone level and the age at the start of treatment.

Adolescent↗
PubMed1994

Magnetic resonance imaging evaluation of adipose tissue and muscle tissue mass in children with growth hormone (GH) deficiency, Turner's syndrome, and intrauterine growth retardation during the first year of treatment with GH.

Measurement of muscle and fat tissue mass by magnetic resonance imaging of the thighs was used to study the metabolic effect of human (h) GH in 23 GH deficiency, 8 Turner's syndrome, and 14 intrauterine growth retardation prepubertal patients. They were evaluated before and 1, 3, 6, and 12 months after the onset of hGH treatment. Seven normal children were followed longitudinally as controls. During hGH treatment, a significant increase in muscle tissue and decrease in adipose tissue cross-sectional areas was observed, leading to a dramatic increase in the muscle/adipose tissue cross-sectional area ratio in each period studied. These findings remained highly significant when corrected for the small variation observed in controls. The body mass index was correlated with muscle and adipose tissue cross-sectional area at each time point (P < 0.0001). The muscle cross-sectional area increment correlated with the first year height velocity (P < 0.01). This study indicates that in children with and without GH deficiency, hGH therapy induces rapid and intense variation of muscle and adipose tissue mass, and that magnetic resonance imaging can be used to study some aspects of the metabolic actions of GH.

Adipose Tissue↗
PubMed1994

Negative correlation between plasma GHRH values and growth velocity in short prepubertal children.

Numerous data suggest that impaired growth hormone secretion in short children is usually related to abnormal regulation of the hormone at the hypothalamic level. In order to improve our understanding of neurohypothalamic dysfunction in short children, we measured basal and peak (after L-dopa stimulation) plasma growth hormone-releasing hormone levels in 43 prepubertal children. Among them, in 23 children suspected of having hypothalamic growth hormone dysregulation, growth hormone-releasing hormone values were significantly higher than those observed in normal short stature children (n = 20), no longer correlated with peak growth hormone following L-dopa, and negatively correlated with growth velocity. This suggests that a predominant inhibitor of growth hormone secretion, such as an increase in somatostatin tone, might be prevalent in a large number of children with partial growth hormone deficiency and suspected hypothalamic growth hormone dysregulation.

Adolescent↗
PubMed1993

Dystrophin and dystrophin-related protein expression in Torpedo marmorata electric organ.

The presence of different dystrophin-related protein forms was investigated in electric organ as compared to cardiac, white or red skeletal muscles from Torpedo marmorata. Two strategies were followed. First, we used specific C-terminal dystrophin and dystrophin-related protein monoclonal antibodies which we characterized in the present study. 400 kDa protein bands were detected in the tissues mentioned above with both specific types of antibodies. Second, we produced monoclonal antibodies raised against a dystrophin-enriched preparation from T. marmorata electric organ. Western blot and immunofluorescence analyses showed the tissue specificity of T. marmorata antibodies and allowed us to classify them as types I, II and III. Vessel walls and neuromuscular junctions were labeled with T. marmorata type II and III antibodies in human muscles (skeletal and smooth). Both approaches demonstrated that the T. marmorata electric organ contained different proteins related with dystrophin: a dystrophin form, a dystrophin-related protein form and a dystrophin-related protein isoform, homologous to the dystrophin-related protein present in muscle vessel walls and at the neuromuscular junctions of human tissues. The presence of dystrophin and dystrophin-related protein is finally discussed relative to their functions and organ specificities.

Animals↗
PubMed1993

Probing functional regions in cardiac isomyosins with monoclonal antibodies.

Seven Mabs prepared against subfragment 1 (S1) of either bovine cardiac beta-specific or rabbit fast skeletal muscle myosin were used to identify functional regions in cardiac isomyosin heavy chains. This approach was designed to improve the understanding of structure-function relationships within the myosin molecule and between alpha and beta myosin heavy chains (MHCs). We used bacterial expression of human beta myosin fragments and determined that the seven antibodies were localized within four different MHC subdomains: amino acid residues 33-37 (one beta-specific antibody), 67-84 (one alpha/beta-specific antibody), 85-106 (four alpha/beta-specific antibodies) and 215-248 (one alpha/beta-specific antibody). All epitopes were accessible on myosin and actomyosin with the same affinities. Therefore, none of these MHC epitopes were located on the interfaces between the myosin head and actin. Three antibodies reacting at three out of the four investigated epitopes enhanced acto-S1 ATPase activities but not myosin, S1, or actomyosin activities. One antibody, which was strictly beta-specific and bound to five amino acid residues near the most N-terminal MHC end, substantially inhibited all myosin or S1 ATPase activities measured with or without actin. The epitope of this antibody coincides with one difference cluster observed between both cardiac MHC isoforms [McNally et al (1989) J. Mol. Biol. 210, 665-671], suggesting that this small variable MHC area could be one of the structural bases to explain observed functional differences in cardiac alpha and beta myosin isoforms.

Amino Acid Sequence↗