European cystic fibrosis bone mineralisation guidelines

Patients with cystic fibrosis (CF) are at risk of developing low bone mineral density (BMD) and fragility fractures. This paper presents consensus statements that summarise current knowledge of the epidemiology and pathophysiology of CF-related skeletal deficits and provides guidance on its assessment, prevention and treatment. The statements were validated using a modified Delphi methodology

Functional characterization of the novel sequence variant p.S304R in the hinge region of TSHR in a congenital hypothyroidism patients and analogy with other formerly known mutations of this gene portion

Context: Thyroid dysgenesis may be associated with loss-of-function mutations in the thyrotropin receptor (TSHR) gene. Objectives: The aim of this study was to characterize a novel TSHR gene variant found in one patient harboring congenital hypothyroidism (CH) from a cohort of patients with various types of thyroid defects. Materials and methods: This cross-sectional cohort study involved 118 patients with CH and their family members, including 45 with familial and 73 with sporadic diseases. The thyroid gland was normal in 23 patients, 25 patients had hypoplasia, 25 hemithyroid agenesis, 21 had athyreosis, and 21 had ectopy. Genomic DNA was extracted, and 10 exons of the TSHR gene were amplified and sequenced. Mutations in other candidate genes were investigated. Ortholog alignment was performed, and TSHR functional assays were evaluated. Results: We identified one previously unknown missense variation in the hinge region (HinR) of the TSHR gene (p.S304R) in one patient with thyroid hypoplasia. This variant is conserved in our ortholog alignment. However, the p.S304R TSHR variant presented a normal glycosylation pattern and signal transduction activity in functional analysis. Conclusion: We report the ocurrence of a novel nonsynonymous substitution in the HinR of the large N-terminal extracellular domain of the TSHR gene in a patient with thyroid hypoplasia. In contrast with four others in whom TSHR mutations of the hinge portion were previously identified, the p.S304R TSHR variation neither affected TSH binding nor cAMP pathway activation. This TSHR gene variant was documented in a CH patient, but the current data do not support its role in the clinical phenotype

Hes1 Is Required for Appropriate Morphogenesis and Differentiation during Mouse Thyroid Gland Development

Notch signalling plays an important role in endocrine development, through its target gene Hes1. Hes1, a bHLH transcriptional repressor, influences progenitor cell proliferation and differentiation. Recently, Hes1 was shown to be expressed in the thyroid and regulate expression of the sodium iodide symporter (Nis). To investigate the role of Hes1 for thyroid development, we studied thyroid morphology and function in mice lacking Hes1. During normal mouse thyroid development, Hes1 was detected from E9.5 onwards in the median anlage, and at E11.5 in the ultimobranchial bodies. Hes1−/− mouse embryos had a significantly lower number of Nkx2-1-positive progenitor cells (p<0.05) at E9.5 and at E11.5. Moreover, Hes1−/− mouse embryos showed a significantly smaller total thyroid surface area (−40 to −60%) compared to wild type mice at all study time points (E9.5−E16.5). In both Hes1−/− and wild type mouse embryos, most Nkx2-1-positive thyroid cells expressed the cell cycle inhibitor p57 at E9.5 in correlation with low proliferation index. In Hes1−/− mouse embryos, fusion of the median anlage with the ultimobranchial bodies was delayed by 3 days (E16.5 vs. E13.5 in wild type mice). After fusion of thyroid anlages, hypoplastic Hes1−/− thyroids revealed a significantly decreased labelling area for T4 (−78%) and calcitonin (−65%) normalized to Nkx2-1 positive cells. Decreased T4-synthesis might be due to reduced Nis labelling area (−69%). These findings suggest a dual role of Hes1 during thyroid development: first, control of the number of both thyrocyte and C-cell progenitors, via a p57-independent mechanism; second, adequate differentiation and endocrine function of thyrocytes and C-cells

Fertility Preservation in Klinefelter Syndrome Patients during the Transition Period.

International audienceSpermatozoa have occasionally been identified in ejaculate of adult Klinefelter syndrome (KS) patients but very exceptionally in KS adolescents. Spermatozoa can also be retrieved in testicular tissue of KS adolescents. The testis may also harbor spermatogonia and noncompletely differentiated germ cells. Neither clinical features nor hormonal parameters could predict germ cell recovery in KS adults or adolescents. No predictive factors can actually demonstrate that early diagnosis of KS would allow increasing the chance of sperm retrieval even if it has been suggested that semen quality may decline with age in KS patients. Leydig cell dysfunction may also be another factor that might affect the spermatogenesis process in XXY adolescents. Fertility preservation might be preferentially proposed in KS adolescents when semen sampling is possible, when the patient is able to consider alternative options to become a father, and to accept germ cell retrieval failure. However, precocious diagnosis of KS has also to be considered because it might not solely improve the possibility of fertility preservation after the onset of puberty, but also the medical care and the quality of life of these patients

Role of Mast Cells in the Control of Aldosterone Secretion

International audienc

Pharmacokinetic study of metopimazine by oral route in children

International audienceMetopimazine (MPZ) is an antiemetic considered as a currently used drug. In France, it has become the leading antiemetic mediator due to its good tolerance, however, its pharmacokinetics has never previously been studied in children. MPZ was administered by oral route to 8 children with a single dose of 0.33 mg/kg during an endocrine exploration using stimuli well known for its adverse emetic effects. We used biological remnants from sera following an hGH test in order to obtain the MPZ pharmacokinetics. Plasmatic concentrations of MPZ and the active acid metabolite AMPZ, were quantified by HPLC-MS/MS during a 270 min test period. MPZ is quickly absorbed with a median C max of 17.2 ng/mL at one hour and its half-life is 2.18 h. The plasmatic concentrations of AMPZ were higher than MPZ with a median C max of 76.3 ng/mL, a T max to 150 min and its concentration was approximately maintained at 50 ng/mL from 1 to 4 h. The plasmatic concentrations in children are similar to those observed in adults. No adverse effects, nausea or vomiting occurred during the trial. Therefore, these results confirm the MPZ dosage that should be used in children under 15 kg administered as 0.33 mg/kg up to 3 times a day

Metallic Profile of Whole Blood and Plasma in a Series of 99 Healthy Children

International audienceIn recent years, special emphasis has been put on heavy metals. Children are very sensitive to accumulation of metals. Furthermore, as regards elements, the reference values in children are scarce in the literature as it is difficult to obtain the large quantity of blood necessary to analyze many metals by the conventional atomic absorption spectrometry technique. An inductively coupled plasma mass spectrometry (ICP-MS) procedure that uses a reduced sample of 0.3 mL whole blood or plasma is adapted to multielemental determinations. We applied a previously validated technique for adults that simultaneously quantifies 25 elements by ICP-MS in whole blood and 23 in plasma in a series of 99 healthy children ranging from under 5 years to <18 years, without exposure to metal or drug-containing metals. The aims of the study were to compare metallic concentrations according to the age among children and metallic concentration differences between children and adults. The blood and plasma pediatric metallic profile is a practical useful tool for many purposes in clinical toxicology, forensic toxicology and any cases of metal environmental exposure

Steroidogenic cell microenvironment and adrenal function in physiological and pathophysiological conditions

International audienceThe human adrenal cortex is a complex organ which is composed of various cell types including not only steroidogenic cells but also mesenchymal cells, immunocompetent cells and neurons. Intermingling of these diverse cell populations favors cell-to-cell communication processes involving local release of numerous bioactive signals such as biogenic amines, cytokines and neuropeptides. The resulting paracrine interactions play an important role in the regulation of adrenocortical cell functions both in physiological and pathophysiological conditions. Especially, recent evidence indicates that adrenocortical cell microenvironment is involved in the pathogenesis of adrenal disorders associated with corticosteroid excess. The paracrine factors involved in these intraadrenal regulatory mechanisms may thus represent valuable targets for future pharmacological treatments of adrenal diseases

Synthèse des minéralocorticoïdes, mastocytes surrénaliens et adaptation à la vie extra-utérine

International audienceChez le nouveau-né, l’aldostéronémie élevée, indépendante des valeurs maternelles fait évoquer une régulation autonome de la synthèse des minéralocorticoïdes. Chez l’adulte, les mastocytes intrasurrénaliens régulent de façon paracrine la synthèse d’aldostérone via la sécrétion de sérotonine. Récemment chez le fœtus, la présence de mastocytes intrasurrénaliens dès 20 semaines d’aménorrhée (SA) suggère l’existence d’un mécanisme similaire. Le but de notre étude était : (i) d’analyser la densité mastocytaire ; (ii) d’étudier l’expression des enzymes de la voie de synthèse des minéralocorticoïdes et des protéines de la voie de signalisation sérotoninergique, dans la glande surrénale en période fœtale et néonatale selon le terme et les conditions de naissance. Nous avons réalisé une étude immunohistochimique sur des tissus fœtaux (n =17) et néonataux (n =7) humains entre 23 et 41 SA. Un comptage des cellules tryptase-immunopositives (mastocytes) a été effectué dans la zone 3β-hydroxystéroïde déshydrogénase de type 2 (3β-HSD2) positive. Une expression des enzymes 3β-HSD2 et aldostérone synthase (CYP11B2) plus intense ainsi qu’une densité mastocytaire plus élevée sont observées chez les nouveau-nés comparés aux fœtus entre 28 SA et 32 SA. Les mastocytes sont détectés au voisinage des cellules immunopositives pour la tryptophane hydroxylase de type 1, le récepteur sérotoninergique de type 4, la 3β-HSD2 et CYP11B2. Enfin, la densité mastocytaire apparaît plus élevée en cas d’hypoxie anténatale. Collectivement, ces résultats suggèrent un contrôle de la synthèse d’aldostérone néonatale par les mastocytes dans l’adaptation à la vie extra-utérine, notamment en cas de grande prématurité, via la voie de signalisation sérotoninergique