High prevalence of PRPH2 in autosomal dominant retinitis pigmentosa in France and characterization of biochemical and clinical features.

International audiencePURPOSE:To assess the prevalence of PRPH2 in autosomal dominant retinitis pigmentosa (adRP), to report six novel mutations, to characterize the biochemical features of a recurrent novel mutation and to study the clinical features of adRP patients.DESIGN:Retrospective clinical and molecular genetic study.METHODS:Clinical investigations included visual field testing, fundus examination, high-resolution spectral-domain optical coherence tomography (OCT), fundus autofluorescence imaging and electroretinogram (ERG) recording. PRPH2 was screened by Sanger sequencing in a cohort of 310 French families with adRP. Peripherin-2 protein was produced in yeast and analyzed by Western blot.RESULTS:We identified 15 mutations, including 6 novel and 9 previously reported changes in 32 families, accounting for a prevalence of 10.3% in this adRP population. We showed that a new recurrent p.Leu254Gln mutation leads to protein aggregation, suggesting abnormal folding. The clinical severity of the disease in examined patients was moderate with 78% of the eyes having 1 to 0.5 of visual acuity and 52% of the eyes retaining more than 50% of the visual field. Some patients characteristically showed vitelliform deposits or macular involvement. In some families, pericentral RP or macular dystrophy were found in family members while widespread RP was present in other members of the same families.CONCLUSIONS:The mutations in PRPH2 account for 10.3% of adRP in the French population, which is higher than previously reported (0-8%) This makes PRPH2 the second most frequent adRP gene after RHO in our series. PRPH2 mutations cause highly variable phenotypes and moderate forms of adRP, including mild cases which could be underdiagnosed

Large-scale multitrait genome-wide association analyses identify hundreds of glaucoma risk loci

Glaucoma, a leading cause of irreversible blindness, is a highly heritable human disease. Previous genome-wide association studies have identified over 100 loci for the most common form, primary open-angle glaucoma. Two key glaucoma-associated traits also show high heritability: intraocular pressure and optic nerve head excavation damage quantified as the vertical cup-to-disc ratio. Here, since much of glaucoma heritability remains unexplained, we conducted a large-scale multitrait genome-wide association study in participants of European ancestry combining primary open-angle glaucoma and its two associated traits (total sample size over 600,000) to substantially improve genetic discovery power (263 loci). We further increased our power by then employing a multiancestry approach, which increased the number of independent risk loci to 312, with the vast majority replicating in a large independent cohort from 23andMe, Inc. (total sample size over 2.8 million; 296 loci replicated at P < 0.05, 240 after Bonferroni correction). Leveraging multiomics datasets, we identified many potential druggable genes, including neuro-protection targets likely to act via the optic nerve, a key advance for glaucoma because all existing drugs only target intraocular pressure. We further used Mendelian randomization and genetic correlation-based approaches to identify novel links to other complex traits, including immune-related diseases such as multiple sclerosis and systemic lupus erythematosus

Leber Congenital Amaurosis: Comprehensive Survey of the Genetic Heterogeneity, Refinement of the Clinical Definition, and Genotype-Phenotype Correlations as a Strategy for Molecular Diagnosis

Communicated by Jean-Claude Kaplan Leber congenital amaurosis (LCA) is the earliest and most severe form of all inherited retinal dystrophies, responsible for congenital blindness. Disease-associated mutations have been hitherto reported in seven genes. These genes are all expressed preferentially in the photoreceptor cells or the retinal pigment epithelium but they are involved in strikingly different physiologic pathways resulting in an unforeseeable physiopathologic variety. This wide genetic and physiologic heterogeneity that could largely increase in the coming years, hinders the molecular diagnosis in LCA patients. The genotyping is, however, required to establish genetically defined subgroups of patients ready for therapy. Here, we report a comprehensive mutational analysis of the all known genes in 179 unrelated LCA patients, including 52 familial and 127 sporadic (27/127 consanguineous) cases. Mutations were identified in 47.5% patients. GUCY2D appeared to account for most LCA cases of our series (21.2%), followed by CRB1 (10%), RPE65 (6.1%), RPGRIP1 (4.5%), AIPL1 (3.4%), TULP1 (1.7%), and CRX (0.6%). The clinical history of all patients with mutations was carefully revisited to search for phenotype variations. Sound genotype-phenotype correlations were found that allowed us to divide patients into two main groups. The first one includes patients whose symptoms fit the traditional definition of LCA, i.e., congenital or very early cone-rod dystrophy, while the second group gathers patients affected with severe yet progressive rodcone dystrophy. Besides, objective ophthalmologic data allowed us to subdivide each group into two subtypes. Based on these findings, we have drawn decisional flowcharts directing the molecular analysis of LCA genes in a given case. These flowcharts will hopefully lighten the heavy task of genotyping new patients but only if one has access to the most precise clinical history since birth

Étude de l évolution du trichlorure d azote et des trihalométhanes dans l eau et l air des piscines chlorées (exploration des voies de réduction de cette contamination)

Dans l eau des piscines, le chlore utilisé comme désinfectant réagit avec la pollution apportée par les baigneurs (sueur, urine, ), pour former des sous-produits. Certains de ces composés, tels que la trichloramine et les trihalométhanes sont très volatils et se transfèrent dans l air des piscines couvertes. Ce travail renseigne d une part les niveaux et les facteurs déterminants de la contamination de l eau et de l air des piscines par les trihalométhanes, jusqu ici mal connus. D autre part, en raison des préoccupations sanitaires liées à la présence des sous-produits de désinfection dans les piscines, ce travail explore deux stratégies de réduction de cette contamination. Nous avons ainsi amélioré les connaissances relatives au traitement de l eau des bassins par les UV et à leur impact sur la formation des trihalométhanes. Nous avons également développé au laboratoire un dispositif innovant permettant de réduire significativement les teneurs en trichloramine dans les bassins.Chlorination of swimming pool water generates various disinfection by-products like trihalomethanes and nitrogen trichloride, arising from the reaction between organic compounds released by the swimmers and chlorine. These compounds are of great volatility and also contaminate indoor air of swimming pools. This work brings on the one hand useful information on trihalomethane levels in pool water and indoor air, which are poorly documented, and highlights the important contributors to this contamination. Given the great concern for public health authorities caused by exposure of the population to disinfection by-products, this work explores on the other hand two ways of reduction of this contamination. UV treatment of pool water was first studied and particularly its impact on trihalomethane levels. We also developed a promising lab-scale to remove nitrogen trichloride from water.RENNES1-BU Sciences Philo (352382102) / SudocSudocFranceF

Etude morpho-anatomique approfondie de l'endocrâne d'Actinoptérygiens du carbonifère des EUA et recherche du message phylogénétique des carctères de l'endocrâne des Actinoptérygiens basaux

Les Paléonisciformes sont un vaste ensemble paraphylétique d'Actinoptérygiens essentiellement paléozoïques, connus surtout par leur exosquelette. Leur endocrâne est rarement préservé et son anatomie n est connue que chez quelques rares taxons. Le présent travail vient accroître notre connaissance de l anatomie de ces structures par l étude morpho-anatomique détaillée de l endocrâne de trois taxons Carbonifères : Lawrenciella schaefferi Poplin 1984, le Paléoniscide C de Rayner (1951) et Kentuckia deani Rayner 1951. Pour ce faire, des méthodes d analyse modernes (CT scan, reconstruction de modèles 3D virtuels, analyses chimiques par MEB/EDX) ont été utilisées. Une étude phylogénétique a été réalisée uniquement sur la base de caractères de l endocrâne et du parasphénoïde. L arbre obtenu a permis de confirmer la paraphylie des Paléonisciformes ainsi que d élaborer de nouvelles hypothèses de relations de parenté différentes des analyses phylogénétiques antérieures.The "Paleonisciforms are a vast paraphyletic group composed essentially of Paleozoic Actinopterygians mainly known by their exoskeleton. Their endocranium is rarely preserved and its anatomy is only known for some taxa. The present work increases our knowledge of the anatomy of these structures thanks to detailed morpho-anatomical study of the endocranium of three Carboniferous taxa: Lawrenciella schaefferi Poplin 1984, Paleoniscid C of Rayner (1951) and Kentuckia deani Rayner 1951. In this purpose, modern analytical methods (CT scan, reconstruction of 3D models, chemical analyses by SEM / EDX) were used. A phylogenetic analysis is made uniquely on the basis of features from the endocranium and parasphenoid. The resulted tree confirms the paraphyly of the "Paleonisciforms" as well as elaborates new hypotheses of relationships different from previous phylogenetic analysesPARIS-Museum Hist.Naturelle (751052304) / SudocSudocFranceF

Les tableaux de bord sur les données dans les urgences : comment mieux les comprendre

Cet article a pour but de présenter les outils existants servant à la consultation des données concernant les services d’urgence par le personnel du réseau de la santé et des services sociaux (RSSS) et par le public. Ceux-ci peuvent s’avérer utiles pour la prise de décision afin de mieux répondre aux besoins des utilisateurs et des décideurs

Élaborer son propre portfolio : démarche individuelle accélérée : guide et outils

Éd. rév.Titre du portefeuille: Élaborer son propre portfolio : démarche individuelle accélérée : guide et outil

L'utilisation, par les élèves, du temps disponible : recherche locale /

Inséré dans un portefeuilleBibliogr.: p. 1