The Photoreceptor Cell-Specific Nuclear Receptor Gene (PNR ) Accounts for Retinitis Pigmentosa in the Crypto-Jews from Portugal (Marranos), Survivors from the Spanish Inquisition

The last Crypto-Jews (Marranos) are the survivors of Spanish Jews who were persecuted in the late fifteenth century, escaped to Portugal and were forced to convert to save their lives. Isolated groups still exist in mountainous areas such as Belmonte in the Beira-Baixa province of Portugal. We report here the genetic study of a highly consanguineous endogamic population of Crypto-Jews of Belmonte affected with autosomal recessive retinitis pigmentosa (RP). A genome-wide search for homozygosity allowed us to localize the disease gene to chromosome 15q22-q24 (Zmax=2.95 at θ=0 at the D15S131 locus). Interestingly, the photoreceptor cell-specific nuclear receptor (PNR) gene, the expression of which is restricted to the outer nuclear layer of retinal photoreceptor cells, was found to map to the YAC contig encompassing the disease locus. A search for mutations allowed us to ascribe the RP of Crypto-Jews of Belmonte to a homozygous missense mutation in the PNR gene. Preliminary haplotype studies support the view that this mutation is relatively ancient but probably occurred after the population settled in Belmonte

Cone rod dystrophies

Cone rod dystrophies (CRDs) (prevalence 1/40,000) are inherited retinal dystrophies that belong to the group of pigmentary retinopathies. CRDs are characterized by retinal pigment deposits visible on fundus examination, predominantly localized to the macular region. In contrast to typical retinitis pigmentosa (RP), also called the rod cone dystrophies (RCDs) resulting from the primary loss in rod photoreceptors and later followed by the secondary loss in cone photoreceptors, CRDs reflect the opposite sequence of events. CRD is characterized by primary cone involvement, or, sometimes, by concomitant loss of both cones and rods that explains the predominant symptoms of CRDs: decreased visual acuity, color vision defects, photoaversion and decreased sensitivity in the central visual field, later followed by progressive loss in peripheral vision and night blindness. The clinical course of CRDs is generally more severe and rapid than that of RCDs, leading to earlier legal blindness and disability. At end stage, however, CRDs do not differ from RCDs. CRDs are most frequently non syndromic, but they may also be part of several syndromes, such as Bardet Biedl syndrome and Spinocerebellar Ataxia Type 7 (SCA7). Non syndromic CRDs are genetically heterogeneous (ten cloned genes and three loci have been identified so far). The four major causative genes involved in the pathogenesis of CRDs are ABCA4 (which causes Stargardt disease and also 30 to 60% of autosomal recessive CRDs), CRX and GUCY2D (which are responsible for many reported cases of autosomal dominant CRDs), and RPGR (which causes about 2/3 of X-linked RP and also an undetermined percentage of X-linked CRDs). It is likely that highly deleterious mutations in genes that otherwise cause RP or macular dystrophy may also lead to CRDs. The diagnosis of CRDs is based on clinical history, fundus examination and electroretinogram. Molecular diagnosis can be made for some genes, genetic counseling is always advised. Currently, there is no therapy that stops the evolution of the disease or restores the vision, and the visual prognosis is poor. Management aims at slowing down the degenerative process, treating the complications and helping patients to cope with the social and psychological impact of blindness

A Human TREK-1/HEK Cell Line: A Highly Efficient Screening Tool for Drug Development in Neurological Diseases

TREK-1 potassium channels are involved in a number of physiopathological processes such as neuroprotection, pain and depression. Molecules able to open or to block these channels can be clinically important. Having a cell model for screening such molecules is of particular interest. Here, we describe the development of the first available cell line that constituvely expresses the TREK-1 channel. The TREK-1 channel expressed by the h-TREK-1/HEK cell line has conserved all its modulation properties. It is opened by stretch, pH, polyunsaturated fatty acids and by the neuroprotective molecule, riluzole and it is blocked by spadin or fluoxetine. We also demonstrate that the h-TREK-1/HEK cell line is protected against ischemia by using the oxygen-glucose deprivation model

Les pieux maritimes du pont Vasco da Gama

Les pieux maritimes du pont Vasco da Gama constituaient un de ses enjeux techniques principaux pour le groupement d’entreprises NOVAPONTE (piloté par Campenon Bernard SGE), qui avait pris à son compte les aléas de fondations. Quelques chiffres en témoignent :– 8 km d’estuaire à franchir, soumis à l’action de la marée ;– 860 pieux de 1,70 à 2,20 m de diamètre pour des capacités portantes supérieures à 3 000 t sous séisme, fondés jusqu’à – 85 m sous le niveau moyen du fleuve ;– des cadences de production moyennes de deux pieux battus et un pieu foré par jour

I(Ks) blockade in border zone arrhythmias from guinea-pig ventricular myocardium submitted to simulated ischemia and reperfusion.

I(Ks) blockade might be a promising way to treat tachyarrhythmia because of the accumulation of activated potassium channels. However, I(Ks) blockade during ischemia/reperfusion has not been investigated. Thus, the electrophysiological effects of two I(Ks) blockers, chromanol 293B (10 μm) and HMR 1556 (1 μm), were assessed in an in vitro model of border zone between normal and ischemic/reperfused right ventricular myocardium from guinea-pigs, and classic electrophysiological parameters and the incidence of arrhythmias were studied. HMR 1556 and chromanol 293B exhibited slight conventional class III effects on action potential duration in the normal zone (NZ) (APD(90) : -2 ± 5%, not significant (NS); +6 ± 3%, NS; and +5 ± 1%, P < 0.05, respectively, in control, HMR 1556, and chromanol 293B groups) but failed to oppose its decrease after 30 min of simulated ischemic superfusion (APD(90) : -52 ± 5%, P < 0.01; -64 ± 5%, P < 0.01; and -61 ± 3%, P < 0.01, respectively, in control, HMR 1556, and chromanol 293B groups), leading to repolarization dispersion between normal and ischemic zones. Chromanol 293B and HMR 1556 prolonged APD(90) during reperfusion, respectively, by +11 ± 1%, P < 0.01 and +25 ± 4%, P < 0.01 in the NZ and by +13 ± 3%, NS and +31 ± 2%, P < 0.01 in the simulated ischemic zone. Both compounds exhibited neutral arrhythmogenic effects during ischemia or reperfusion. Thus, I(Ks) blockade was neutral on the occurrence of ventricular arrhythmias during ischemia and reperfusion in guinea-pig ventricular tissue. © 2011 The Authors Fundamental and Clinical Pharmacology © 2011 Société Française de Pharmacologie et de Thérapeutique

Increasing the forecasting lead-time of weather driven flash-floods

Rapport H01/812/02/D9056/AG/ct de 47 p. [Annexe : p. 32 à 47]This document is organized in two main sections.In the first section we define the problem of flash-flood forecasting and we list the main scientific issuesthat need to be addressed. In the second section we briefly describe the previous European programmes devoted to flash flood. The dispersion of the efforts within programmes that were not only concerned by flash flood lead to the difficulty to highlight major results. Suggestions for future improvements in flash flood risk reduction are then proposed through research proposals and possible actions at European level. Figures and tables are put together in the ANNEX Section at the end of the document.This report constitutes a first step of the writing of a blueprint dedicated to the storm driven floods in theMediterranean. This blueprint will be used at national and European level in support to hydrometeorological laboratories and associated research projects

Climate change, hydrological extremes and a multifractal analysis of a mesoscale model

The IPPC 4th report emphasizes the question of scales and the necessity to obtain in climate scenarios much finer resolutions for hydrological processes to assess the time evolution of the hydrological extremes. The present gap between climatological and hydrological scales led to consider downscaling techniques, which are statically or/and physically based. In particular, one may exploit the scaling properties of the precipitation to downscale it either numerically by stochastic subgrid modeling or theoretically with the help of a few scaling exponents (Royer et al. C.R. Geoscience, 340, 2008). We first discuss how these techniques can be validated with the help of a multifractal analysis of a mesoscale model. We then present the results obtained the Meso-NH model (Meteo-France/CNRM and Laboratoire d'Aérologie, Toulouse, France), a model which has been rather extensively used for mesoscale research and is partly included (its physical part) in the AROME model, the new operational meteorological model at 2.5 km resolution on France. These results are compared with the one obtained analyzing radar data