Impairment of adipose tissue in Prader-Willi syndrome rescued by growth hormone treatment.

BACKGROUND: Prader-Willi syndrome (PWS) results from abnormalities in the genomic imprinting process leading to hypothalamic dysfunction with an alteration of growth hormone (GH) secretion. PWS is associated with early morbid obesity and short stature which can be efficiently improved with GH treatment. OBJECTIVES: Our aims were to highlight adipose tissue structural and functional impairments in children with PWS and to study the modifications of those parameters on GH treatment. SUBJECTS AND METHODS: Plasma samples and adipose tissue biopsies were obtained from 23 research centers in France coordinated by the reference center for PWS in Toulouse, France. Lean controls (n=33), non-syndromic obese (n=53), untreated (n=26) and GH-treated PWS (n=43) children were enrolled in the study. Adipose tissue biopsies were obtained during scheduled surgeries from 15 lean control, 7 untreated and 8 GH-treated PWS children. RESULTS: Children with PWS displayed higher insulin sensitivity as shown by reduced glycemia, insulinemia and HOMA-IR compared with non-syndromic obese children. In contrast, plasma inflammatory cytokines such as TNF-α, MCP-1 and IL-8 were increased in PWS. Analysis of biopsies compared with control children revealed decreased progenitor cell content in the stromal vascular fraction of adipose tissue and an impairment of lipolytic response to ß-adrenergic agonist in PWS adipocytes. Interestingly, both of these alterations in PWS seem to be ameliorated on GH treatment. CONCLUSION: Herein, we report adipose tissue dysfunctions in children with PWS which may be partially restored by GH treatment.

Impact of COVID-19 disease on clinical research in pediatric and congenital cardiology.

BACKGROUND: COVID-19 triggered an unprecedented crisis affecting society at every level. Research in pediatric and congenital cardiology is currently in full development and may have been disrupted. The aim of the study was to determine the impact of COVID-19 on pediatric and congenital cardiology clinical research and to analyze decision-making and adaptation processes, from a panel of ongoing academic and industry-sponsored research at the time of the pandemic. METHODS: This observational study was carried out in April 2020, from a CHD clinical research network involving five tertiary care pediatric and congenital cardiology centers. Investigators and clinical research assistants from each participating research center completed an online survey questionnaire, and each principal investigator underwent a 1-h web-based videoconference interview. RESULTS: A total of 34 study questionnaires were collected, reporting that 18 studies were totally suspended. Upon the investigator's decision, after discussion on ethical issues and with facilitating support from health authorities, 16 studies were resumed. The rate of study suspension in interventional research (53%) was similar to that in non-interventional research (56%). Logistical problems were predominantly reported in both continued and suspended trials. Research protocols were adapted, largely thanks to telemedicine, which in some cases even improved the course of the study. CONCLUSION: The impact of the COVID-19 pandemic on clinical research in pediatric and congenital cardiology has been limited by a rapid adaptation of all research structures and an extensive use of telemedicine at all stages of the studies.

[New molecular mechanisms of growth hormone insensitivity]. / Nouveaux mécanismes moléculaires impliqués dans l'insensibilité à l'hormone de croissance.

Growth hormone (GH), secreted by the anterior pituitary into the circulation, binds to membrane receptors in target tissues to stimulate body growth; most of its effects is mediated by the insulin-like growth factor 1 (IGF-1). In addition to promoting growth, GH has important metabolic actions. The syndrome of GH insensitivity (GHI) was first identified in 1966 by Laron et al. in three children with clinical phenotype characteristic of growth hormone deficiency but associated with elevated serum concentration of GH. Direct evidence of a GH receptor (GHR) abnormality was provided in 1989. More recently, molecular abnormalities in the postreceptor signalling mechanism were found. Mutations of signal transducer and activator of transcription 5b (Stat5b) were reported in patients with growth retardation and primary immunodeficiency. Mutations of the tyrosin phosphatase Shp2 were identified in patients affected by Noonan syndrome characterized by short stature, cardiopathy and increased risk of leukaemia. The unmasking of the molecular bases for these defects will contribute greatly to our future understanding of both normal and aberrant growth. Moreover, this knowledge should bring insight on cancerogenesis or immunodeficiency caused by cytokines resistance.

Localization of STRO-1, BMP-2/-3/-7, BMP receptors and phosphorylated Smad-1 during the formation of mouse periodontium.

Bone morphogenetic proteins (BMPs) and BMP receptors (BMPRs) are known to regulate the development of calcified tissues by directing mesenchymal precursor cells differentiation. However, their role in the formation of tooth-supporting tissues remains unclear. We investigated the distribution pattern of STRO-1, a marker of mesenchymal progenitor cells and several members of the BMP pathway during the development of mouse molar periodontium, from the post-natal days 6 to 23 (D6 to D23). STRO-1 was mainly localized in the dental follicle (DF) at D6 and 13 then in the periodontal ligament (PDL) at D23. BMP-2 and -7 were detected in Hertwig's epithelial root sheath (HERS) and in DF, then later in differentiated periodontal cells. BMP-3 was detected after D13 of the periodontal development. BMPRs-Ib, -II, the activin receptor-1 (ActR-1) and the phosphorylated Smad1 were detected in DF and HERS at D6 and later more diffusely in the periodontium. BMPR-Ia detection was restricted to alveolar bone. These findings were in agreement with others data obtained with mouse immortalized DF cells. These results suggest that STRO-1 positive DF cells may be target of BMPs secreted by HERS. BMP-3 might be involved in the arrest of this process by inhibiting the signaling provided by cementogenic and osteogenic BMPs.

Laboratory diagnosis of hypophosphatasia.

The laboratory diagnosis of hypophosphatasia (HPP) is primarily based on the precise analysis of circulating serum alkaline phosphatase (ALP) activity, determined by biochemical assays. This analysis requires specific conditions of implementation and interpretation and should always be viewed in the light of the clinical and radiological data. Concerns regarding the normal ranges of ALP with respect to age, regarding ALP values that may overlap those of normal subjects in HPP patients, regarding apparently normal ALP values in cases of proven HPP, regarding differential diagnoses that may be responsible for low ALP values outside of HPP will be discussed. High levels of pyridoxal phosphate, a substrate of APL, are of supportive value in the diagnosis of HPP.

An in vivo method for measuring the mechanical properties of the skin using ultrasound.

In this study, we report a new and original device called the "echorheometer," comprising a suction system with an ultrasound scanner (A-mode, TM-mode and B-mode) that enables the simultaneous visualization and measurement of the deformation of skin structures in vivo. With the scanner described here, high resolution is obtained using a strongly focused, wide-band 20-MHz center frequency transducer, with an axial resolution of 0.07 mm. This device can determine, noninvasively, not only those skin structures that are involved in the deformation, but also their morphological variation and their extent of involvement with the degree of stress applied. Using this device, the behavior of the dermis and subcutaneous fat, while under suction, was investigated on the volar forearm of 10 volunteers. The results showed that the resistance to the applied vertical stress is essentially due to the dermis rather than the subcutaneous fat, and that there is a certain amount of infiltration of fluid into the tissues under suction. In addition, it was shown that the dermal response to an applied suction is initially due to its own natural tension and that, with increasing deformation, the intrinsic dermal elasticity has a greater contribution to the resistance of stress. With this information, we hope to develop a mechanical model to define appropriate mechanical parameters for skin. This will allow the evaluation of changes in the dermis and also enable therapeutic intervention to be assessed. Furthermore, it could also be applied to studies of skin ageing and the assessment of cosmetic product efficacy (emolliency, hydratation, etc.).

[Bone mineral metabolism: recent data and perspectives related to osteogenesis]. / Métabolisme minéral osseux: données récentes et perspectives relatives à l'ostéogenèse.

Important data have recently been added to our knowledge of bone mineral metabolism in children. Molecular pathophysiology of several pediatric syndromes has been clarified. Specially, the components of endocrine and metabolic regulations are tightly related with regard to the trophicity of bone. On another hand, the impact of several therapeutics of bone diseases like biphosphonates, parathormone (PTH) or growth hormone on bone anabolism is now strongly emphasized. All these points are important for the becoming of bone pediatric diseases in the adult life. Here we analyze the essential components of mineral metabolism and of its regulation in view of the recent biological data, like PTH/PTHrP (PTH-related peptide)-evoked cell signaling, the role of FGF 23 (Fibroblast growth factor 23) in hypophosphatemia and the regulation of vitamin D metabolism by 1alpha-hydroxylase. Inter-relation of these regulating elements is present in several genetic diseases and in the Mc Cune Albright syndrome. Relationships between metabolic and endocrine factors are analyzed considering their impact on PTH secretion and osteogenesis.

[Febrile toxiderma in children]. / Toxidermies fébriles de l'enfant.

Febrile cutaneous drug reactions in the child represent 6% of paediatric hospitalizations for dermatologic reasons. Diagnosis is difficult, for both infectious diseases and drug allergy can induce the same skin reaction. The same eruption can correspond to several drug-induced reactions. In a single child, there may be several causes of skin eruption and several drugs inducing similar cutaneous reactions. Clinical diagnosis and the method of clinical imputability lead to diagnosis. Paraclinical methods are of limited interest. Symptomatic treatment is begun on emergency admission. Upon identification, the responsible drug can be withheld and the authorities responsible for post-marketing surveillance can be notified.

Analysis of the spectral and angular response of the vegetated surface polarization for the purpose of aerosol remote sensing over land.

A precise estimate of the polarization induced by the surface in reflected radiation is crucial for remote sensing applications dedicated to monitoring the atmosphere. Here we present airborne observations acquired during a field campaign in the North of France over vegetated surfaces. Polarized reflectances were measured in four spectral bands in the range between 0.67 and 2.2 µm and for scattering angles between 75° and 145°. Our results confirm that the polarization generated by the reflection of vegetated surfaces can be understood as being primarily a specular reflection process. It is not possible from our measurements to see any spectral dependence of the surface polarization in the given spectral channels. The surface polarization is well fitted by existing surface models which have two degrees of freedom that allow the magnitude and angular behavior of the surface-polarized reflectance to be adjusted.

GH responsiveness in a large multinational cohort of SGA children with short stature (NESTEGG) is related to the exon 3 GHR polymorphism.

OBJECTIVE: The polymorphic deletion of exon 3 of the GH receptor (d3-GHR) has recently been linked to the magnitude of growth response to recombinant human GH (rhGH) therapy in short children with or without GH deficiency. We investigated this association in a large multinational cohort from the Network of European Studies of Genes in Growth (NESTEGG), comprising short children born small for gestational age (SGA). DESIGN: The study included short prepubertal SGA children treated with rhGH for 1 or 2 years. POPULATION: Two hundred and forty white Caucasian SGA children (138 male, 102 female) aged 6.6 +/- 2.3 years with a height at -3.0 +/- 0.7 SDS at start of rhGH treatment; 193 ethnically matched controls. METHODS: The GHR polymorphism (fl/fl, fl/d3 or d3/d3) was genotyped by polymerase chain reaction (PCR) multiplex assay. Growth velocity (G/V) in cm/year and changes in GV during the first and second year of rhGH treatment were evaluated. RESULTS: The change in GV was significantly greater in SGA children carrying one or two copies of the d3-GHR allele (P = 0.038 for the first year and P = 0.041 for the second year of GH treatment), but the change in height was not significantly different. Birthweight was significantly lower in SGA children with the d3/d3 genotype than in SGA children with the fl/fl genotype (P = 0.034) and in those with the fl/d3 genotype (P = 0.016). CONCLUSION: Our data, based on a large cohort, showed that the exon 3 GHR polymorphism is associated with responsiveness to rhGH treatment in SGA children with short stature.

Acral erythema in children receiving high-dose methotrexate.

Scant information is available concerning the occurrence and evolution of chemotherapy-induced acral erythema in children receiving intravenous high-dose methotrexate (MTX). Among 50 children with acute lymphoblastic leukemia or lymphoblastic lymphoma receiving a total of 203 courses of high-dose MTX (3-8 g/m2), 3 cases of acral erythema were observed. Painful erythema of finger and toe pads was noted in three children 3 days to 2 weeks after MTX infusion. The lesions resolved completely after blister formation and desquamation. These patients subsequently received high-dose MTX therapy without cutaneous problems. The present work points out that the chemotherapeutic schedule need not be modified in selected patients who develop acral erythema following high-dose MTX infusion.

Effects of short-time hydration on skin extensibility.

Vertical cutaneous extensibility was studied before and after 1, 2, 5 and 10 min hydration by application of tap water. After hydration, we noted an increase in all rheological parameters linked to elasticity whereas viscosity and hysteresis parameters were unmodified. These modifications took place from the first minute and increased thereafter. Men and women showed identical values prior to hydration. After hydration, an extensibility gain was noted only in the women, men's extensibility being unmodified. Studying rheological behaviour as a function of age, we showed similar modifications in younger and older groups, the extensibility gain being greater in the older group. Prior to hydration, the stratum corneum was extremely rigid and extensibility was comparable between men and women. Hydration, softening the horny layer, allows a rapid extensibility gain proportional to the reduced thickness of the dermis, especially in women and older subjects.

Study of cutaneous extensibility in lymphoedema of the lower limbs.

We have studied changes in the elasticity and viscosity of the skin in patients with lymphoedema, using a technique involving vertical extensibility by suction. We measured parameters which included immediate extensibility (Ue, which reflects the elastic properties of the skin), and delayed extensibility (Uv which reflects intracutaneous movements of a viscous type). In grade III lymphoedema, Ue is decreased and Uv is increased. These changes are explained by volume variations and histological alterations, and tend to normalize after treatment. Our study shows that measurement of extensibility is useful in evaluation of volume variations, effects of therapy, and disease evolution, as Ue variations correlate with volume variations and with Uv changes. This technique also provides information which is useful in assessing patients' functional difficulties in relation to skin infiltration, and might be of value in lymphoedema follow-up.