Cytokines inflammatoires et cerveau du prématuré (étude des mécanismes d'action dans un modèle murin de leucomalacie périventriculaire)

TOURS-BU Médecine (372612103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Impact de l'interleukine-1b systémique sur le développement cérébral du souriceau (modélisation de la leucoencéphalopathie du nouveau-né prématuré)

Le pronostic des enfants nés prématurés est conditionné par leur devenir neurologique marqué par la survenue d'atteintes de la substance blanche cérébrale plus fréquentes en cas d'infection. Au moyen d'injections intra-péritonéales d'interleukine-1b (IL-1b) chez le souriceau, l'action des cytokines systémiques a été étudiée sur le cerveau en développement sous 2 aspects : i) La modulation de la réaction inflammatoire cérébrale générée par un stress excitotoxique. L'inflammation systémique à cette période de développement sensibilise le cerveau à l'agression excitotoxique par un défaut de la réponse anti-inflammatoire potentialisant l'effet toxique du TNFa. ii) La myélinisation et les fonctions cognitives. Une hypomyélinisation diffuse à gaine de myéline intacte avec axonopathie est observée. Ces anomalies s'accompagnent d' altérations des fonctions cognitives. Ainsi, l'élévation des cytokines circulantes est impliquée dans la physiopathologie des leucoencéphalopathies du nouveau-né.Prematurity compromizes the neurological outcome. Indeed, white matter damage is linked to preterm birth and occurs more frequently in the infectious context. We have sujected pups to intra-peritoneal injections of interleukin-1b (IL-1b) and aimed to explore the effect of systemic cytokines on brain development under 2 aspects: i) The inflammatory reaction secondary to a brain excitotoxic stress. IL-lp sensitizes the brain to a subsequent excitotoxic stress. This result can be explained by a reduction of the anti-inflammatory response and a potentialization of the noxious effect of TNFa. ii) Myelination and cognitive functions. An alteration of myelination is observed associated with an axonopathy. In contrast, the morphological aspect of myelin sheath is conserved. Furthermore, mice treated with IL-1b exhibit cognitive dysfunctions at P30. Systemic cytokines are implicated in the pathophysiology of white matter damage, modeling the leucoencephalopathy of the preterm.PARIS5-BU Méd.Cochin (751142101) / SudocSudocFranceF

Effet de la prostaglandine E2 sur la maturation oligodendrocytaire in vitro

TOURS-BU Médecine (372612103) / SudocSudocFranceF

Impact of common treatments given in the perinatal period on the developing brain

International audienceBACKGROUND: Over the last decades, considerable progress has been made in the perinatal management of high-risk preterm neonates, changing the landscape of pathological conditions associated with neurological impairments. Major focal destructive lesions are now less common, and the predominant neuropathological lesion is diffuse white-matter damage in the most immature infants. Similarly, over the last few years, we have observed a trend towards a decrease in neurological impairment in the absence of treatments specifically aimed at neuroprotection. OBJECTIVES: We examined whether recent changes in treatment strategies in perinatal care during the perinatal period could have had an indirect beneficial impact on the occurrence of brain lesions and their consequences. METHODS: Thus, we reviewed the effects of the most common treatments administered during the perinatal period to the mother or to very preterm infants on brain damage and neurocognitive follow-up. RESULTS: Antenatal steroids and exogenous surfactant are the two main treatments capable of leading to neuroprotection in very preterm infants. Randomized controlled trials are currently investigating the effects of inhaled nitric oxide and erythropoietin, while antenatal magnesium sulphate and caffeine are also likely to provide some neuroprotection, but this needs to be further investigated. Finally, other common treatments against pain, haemodynamic failure and patent ductus arteriosus have conflicting or no effects on the developing brain. CONCLUSION: While specific neuroprotective drugs are still awaited, recent advances in perinatal care have been associated with an unexpected but significant decrease in the incidence of both severe brain lesions and neurological impairment

Multifocal Lymphangioendotheliomatosis With Thrombocytopenia: Clinical Features and Response to Sirolimus

International audienceMultifocal lymphangioendotheliomatosis with thrombocytopenia (MLT) is a recently described glucose transporter 1-negative multifocal vascular disorder with significant morbidity and mortality. However, data are lacking on the clinical spectrum, long-term prognosis, and treatment of MLT. It is often confused with multifocal infantile hemangioma, but the conditions must be differentiated for appropriate assessment and therapeutic management. Treatments for MLT have been disappointing, and the treatments classically used for infantile hemangioma are often ineffective. We report 3 newborn cases featuring various clinical and biological phenotypes of MLT: 1 patient had severe brain involvement and died early; another had no thrombocytopenia; and the third had nearly no skin involvement. Histologically, all were negative for glucose transporter 1 and positive for the lymphatic marker lymphatic vessel endothelial hyaluronan receptor 1 or D2-40 (∼38-kDa O-linked transmembrane sialoglycoprotein podoplanin). Two cases with severe gastrointestinal bleeding were treated with sirolimus 0.1 mg/k per day, which was efficient after the first month of treatment. MLT clinically presents in various forms, and when complicated by widespread or severe extracutaneous involvement, initial aggressive therapeutic intervention is justified. The pathogenesis of MLT remains unclear, but lymphatic differentiation is widely acknowledged. Because of its antiangiogenic properties, including anti-lymphangiogenesis, sirolimus offers an adequate and targeted therapeutic approach for ML

Levetiracetam optimal dose-finding as first-line treatment for neonatal seizures occurring in the context of hypoxic-ischaemic encephalopathy (LEVNEONAT-1) study protocol of a phase II trial

International audienceIntroduction - Therapeutic schedules for treating neonatal seizures remain elusive. First-line treatment with phenobarbital is widely supported but without strong scientific evidence. Levetiracetam (LEV) is an emerging and promising antiepileptic drug (AED). The aim of this phase II trial is to determine the benefits of LEV by applying a strict methodology and to estimate the optimal dose of LEV as a first-line AED to treat seizures in newborns suffering from hypoxic-ischaemic encephalopathy.Methods and analysis - LEVNEONAT-1 is an open and sequential LEV dose-finding study. The optimal dose is that which is estimated to be associated with a toxicity not exceeding 10% and an efficacy higher than 60%. Efficacy is defined by a seizure burden reduction of 80% after the loading dose. Four increasing dose regimens will be assessed including one loading dose of 30, 40, 50 or 60 mg/kg followed by eight maintenance doses (ie, a quarter of the loading dose) injected every 8 hours. A two-patient cohort will be necessary at each dose level to consider an upper dose level assignment. The maximal sample size expected is 50 participants with a minimum of 24 patients or fewer in the case of a high rate of toxicity. Patients will be recruited in five neonatal intensive care units beginning in October 2017 and continuing for 2 years. In parallel, the LEV pharmacokinetics will be measured five times (ie, 30 min; 4 and 7 hours after the loading dose; 1-3 hours and 12-18 hours after the last maintenance dose).Ethics and dissemination - Ethics approval has been obtained from the regional ethical committee (2016-R25) and the French Drug Safety Agency (160652A-31). The results will be published in a peer-reviewed journal. The results will also be presented at medical meetings. Trial registration number - NCT02229123; Pre-results

Efficacy of Sirolimus Combined with Sclerotherapy for Giant Cervical Lymphatic Macrocystic Malformations: Two Newborn Cases

International audienc