A new TRPV3 missense mutation in a patient with Olmsted syndrome and erythromelalgia

IMPORTANCE: Olmsted syndrome (OS) is a rare keratinizing disorder characterized by excessive epidermal thickening of the palms and soles, with clinical and genetic heterogeneity. Approximately 50 cases have been reported, with the molecular basis described in only 9. Recently, TRPV3 (transient receptor potential vanilloid 3) mutations were identified in autosomal-dominant OS in 7 sporadic cases and 1 familial case, whereas an MBTPS2 (membrane-bound transcription factor protease, site 2) mutation was reported in X-linked recessive OS. We report a new sporadic case of severe, atypical OS and its underlying genetic basis. OBSERVATIONS: Our patient is a young girl with severe nonmutilating (palmo)plantar keratoderma without periorificial keratotic plaques associated with intense acute flares of inflammation, itching, burning pain, vasodilatation, and redness of the extremities consistent with erythromelalgia. Whole exome sequencing of patient DNA identified a novel de novo heterozygous missense mutation within TRPV3, p.Leu673Phe, predicted to be damaging. CONCLUSIONS AND RELEVANCE: This case study further implicates TRPV3 in OS pathogenesis. In addition, previous reports of OS have not described erythromelalgia as a clinical feature. Its occurrence in our patient could be a chance event, but, if associated with OS, the features of erythromelalgia may expand the phenotypic spectrum of this rare syndrome. Copyright 2014 American Medical Association. All rights reserved

Reducing C-terminal truncation mitigates synucleinopathy and neurodegeneration in a transgenic model of multiple system atrophy

Multiple system atrophy (MSA) is a sporadic orphan neurodegenerative disorder. No treatment is currently available to slow down the aggressive neurodegenerative process, and patients die within a few years after disease onset. The cytopathological hallmark of MSA is the accumulation of alpha-synuclein (α-syn) aggregates in affected oligodendrocytes. Several studies point to α-syn oligomerization and aggregation as a mediator of neurotoxicity in synucleinopathies including MSA. C-terminal truncation by the inflammatory protease caspase-1 has recently been implicated in the mechanisms that promote aggregation of α-syn in vitro and in neuronal cell models of α-syn toxicity. We present here an in vivo proof of concept of the ability of the caspase-1 inhibitor prodrug VX-765 to mitigate α-syn pathology and to mediate neuroprotection in proteolipid protein α-syn (PLP-SYN) mice, a transgenic mouse model of MSA. PLP-SYN and age-matched wild-type mice were treated for a period of 11 wk with VX-765 or placebo. VX-765 prevented motor deficits in PLP-SYN mice compared with placebo controls. More importantly, VX-765 was able to limit the progressive toxicity of α-syn aggregation by reducing its load in the striatum of PLP-SYN mice. Not only did VX-765 reduce truncated α-syn, but it also decreased its monomeric and oligomeric forms. Finally, VX-765 showed neuroprotective effects by preserving tyrosine hydroxylase-positive neurons in the substantia nigra of PLP-SYN mice. In conclusion, our results suggest that VX-765, a drug that was well tolerated in a 6 wk-long phase II trial in patients with epilepsy, is a promising candidate to achieve disease modification in synucleinopathies by limiting α-syn accumulation

The anti-caspase inhibitor Q-VD-OPH prevents AIDS disease progression in SIV-infected rhesus macaques

Apoptosis has been proposed as a key mechanism responsible for CD4+ T cell depletion and immune dysfunction during HIV infection. We demonstrated that Q-VD-OPH, a caspase inhibitor, inhibits spontaneous and activation-induced death of T cells from SIV-infected rhesus macaques (RMs). When administered during the acute phase of infection, Q-VD-OPH was associated with (a) reduced levels of T cell death, (b) preservation of CD4+/CD8+ T cell ratio in lymphoid organs and in the gut, (c) maintenance of memory CD4+ T cells, and (d) increased specific CD4+ T cell response associated with the expression of cytotoxic molecules. Although therapy was limited to the acute phase of infection, Q-VD-OPH-treated RMs showed lower levels of both viral load and cell-associated SIV DNA as compared with control SIV-infected RMs throughout the chronic phase of infection, and prevented the development of AIDS. Overall, our data demonstrate that Q-VD-OPH injection in SIV-infected RMs may represent an adjunctive therapeutic agent to control HIV infection and delaying disease progression to AIDS.This article is dedicated to the memory of Bruno Hurtrel. We also thank Jean-Claude Ameisen for his initial support. We acknowledge Celine Gommet (Institut Pasteur) for her expertise in the follow-up of our primate cohort. We also acknowledge Francois Villinger, who performed TRIM5a polymorphism. ML and JG were supported by fellowships from ANRS. RS thanks Fundacao para a Ciencia e a Tecnologia (FCT) for Investigator FCT Grant IF/00021/2014. This study was supported by research funding from ANRS and CIHR (MOP-133476) to JE. VR is supported by a fellowship from FCT (code SFRH/BD/64064/2009). JE thanks the Canada Research Chair program for financial assistance

Polymorphisms of Pyrimidine Pathway Enzymes Encoding Genes and HLA-B*40∶01 Carriage in Stavudine-Associated Lipodystrophy in HIV-Infected Patients.

Purpose To assess in a cohort of Caucasian patients exposed to stavudine (d4T) the association of polymorphisms in pyrimidine pathway enzymes and HLA-B*40∶01 carriage with HIV/Highly active antiretroviral therapy (HAART)-associated lipodystrophy syndrome (HALS). Methods Three-hundred and thirty-six patients, 187 with HALS and 149 without HALS, and 72 uninfected subjects were recruited. The diagnosis of HALS was performed following the criteria of the Lipodystrophy Severity Grading Scale. Polymorphisms in the thymidylate synthase (TS) and methylene-tetrahydrofolate reductase (MTHFR) genes were determined by direct sequencing, HLA-B genotyping by PCR-SSOr Luminex Technology, and intracellular levels of stavudine triphosphate (d4T-TP) by a LC-MS/MS assay method. Results HALS was associated with the presence of a low expression TS genotype polymorphism (64.7% vs. 42.9%, OR = 2.43; 95%CI: 1.53-3.88, P<0.0001). MTHFR gene polymorphisms and HLA-B*40∶01 carriage were not associated with HALS or d4T-TP intracellular levels. Low and high expression TS polymorphisms had different d4T-TP intracellular levels (25.60 vs. 13.60 fmol/106 cells, P<0.0001). Independent factors associated with HALS were(OR [95%CI]: (a) Combined TS and MTHFR genotypes (p = 0.006, reference category (ref.): 'A+A'; OR for 'A+B' vs. ref.: 1.39 [0.69-2.80]; OR for 'B+A' vs. ref.: 2.16 [1.22-3.83]; OR for 'B+B' vs. ref.: 3.13, 95%CI: 1.54-6.35), (b) maximum viral load ≥5 log10 (OR: 2.55, 95%CI: 1.56-4.14, P = 0.001), (c) use of EFV (1.10 [1.00-1.21], P = 0.008, per year of use). Conclusion HALS is associated with combined low-expression TS and MTHFR associated with high activity polymorphisms but not with HLA-B*40∶01 carriage in Caucasian patients with long-term exposure to stavudine

Polymorphisms of Pyrimidine Pathway Enzymes Encoding Genes and HLA-B*40∶01 Carriage in Stavudine-Associated Lipodystrophy in HIV-Infected Patients

Altres ajuts: Fundación para la Investigación y Prevención del SIDA en España (FIPSE 36610, 36572/06); Red de Investigación en SIDA (RIS RD12/0017/0005, RD12/0017/0014).To assess in a cohort of Caucasian patients exposed to stavudine (d4T) the association of polymorphisms in pyrimidine pathway enzymes and HLA-B*40∶01 carriage with HIV/Highly active antiretroviral therapy (HAART)-associated lipodystrophy syndrome (HALS). Three-hundred and thirty-six patients, 187 with HALS and 149 without HALS, and 72 uninfected subjects were recruited. The diagnosis of HALS was performed following the criteria of the Lipodystrophy Severity Grading Scale. Polymorphisms in the thymidylate synthase (TS) and methylene-tetrahydrofolate reductase (MTHFR) genes were determined by direct sequencing, HLA-B genotyping by PCR-SSOr Luminex Technology, and intracellular levels of stavudine triphosphate (d4T-TP) by a LC-MS/MS assay method. HALS was associated with the presence of a low expression TS genotype polymorphism (64.7% vs. 42.9%, OR = 2.43; 95%CI: 1.53-3.88, P<0.0001). MTHFR gene polymorphisms and HLA-B*40∶01 carriage were not associated with HALS or d4T-TP intracellular levels. Low and high expression TS polymorphisms had different d4T-TP intracellular levels (25.60 vs. 13.60 fmol/10 6 cells, P<0.0001). Independent factors associated with HALS were(OR [95%CI]: (a) Combined TS and MTHFR genotypes (p = 0.006, reference category (ref.): 'A+A'; OR for 'A+B' vs. ref.: 1.39 [0.69-2.80]; OR for 'B+A' vs. ref.: 2.16 [1.22-3.83]; OR for 'B+B' vs. ref.: 3.13, 95%CI: 1.54-6.35), (b) maximum viral load ≥5 log10 (OR: 2.55, 95%CI: 1.56-4.14, P = 0.001), (c) use of EFV (1.10 [1.00-1.21], P = 0.008, per year of use). HALS is associated with combined low-expression TS and MTHFR associated with high activity polymorphisms but not with HLA-B*40∶01 carriage in Caucasian patients with long-term exposure to stavudine

Décomposition en valeurs singulières randomisée et positionnement multidimensionel à base de tâches

The multidimensional scaling (MDS) is an important and robust algorithm for representing individual cases of a dataset out of their respective dissimilarities. However, heuristics, possibly trading-off with robustness, are often preferred in practice due to the potentially prohibitive memory and computational costs of the MDS. The recent introduction of random projection techniques within the MDS allowed it to be become competitive on larger testcases. The goal of this manuscript is to propose a high-performance distributed-memory MDS based on random projection for processing data sets of even larger size (up to one million items). We propose a task-based design of the whole algorithm and we implement it within an efficient software stack including state-of-the-art numerical solvers, runtime systems and communication layers. The outcome is the ability to efficiently apply robust MDS to large datasets on modern supercomputers. We assess the resulting algorithm and software stack to the point cloud visualization for analyzing distances between sequencesin metabarcoding.Le positionnement multidimensionnel (MDS) est un algorithme important et robuste pour représenter les cas individuels d’un ensemble de données en fonction de leurs dissimilarités respectives. Cependant, les heuristiques, qui peuvent être un compromis avec la robustesse, sont souvent préférées en pratique en raison de sa consommation mémoire et de ses coûts potentiellement prohibitifs. L’introduction récente de techniques de projection aléatoire dans le MDS lui a permis de devenir compétitif sur des cas test plus importants. L’objectif de ce manuscrit est de proposer un MDS haute performance basé sur la projection aléatoire pour le traitement d’ensembles de données de taille encore plus grande (jusqu’à un million d’éléments). Nous proposons une conception de l’algorithme et nous l’implémentons dans une pile logicielle efficace, comprenant des solveurs numériques de pointe ainsi des systèmes d’exécution et des couches de communication optimisés. L’aboutissement de ce travail résultat est la capacité d’appliquer efficacement le MDS robuste à de grands ensembles de données sur des super-ordinateurs modernes. Nous évaluons l’algorithme etla pile logicielle résultants à la visualisation de nuages de points pour l’analyse des distances entre séquences de metabarcoding

Activity of bisnaphthalimidopropyl derivatives against trypanosoma brucei.

Current treatments for African trypanosomiasis are either toxic, costly, difficult to administer, or prone to elicit resistance. This study evaluated the activity of bisnaphthalimidopropyl (BNIP) derivatives against Trypanosoma brucei. BNIPDiaminobutane (BNIPDabut), the most active of these compounds, showed in vitro inhibition in the single-unit nanomolar range, similar to the activity in the reference drug pentamidine, and presented low toxicity and adequate metabolic stability. Additionally, using a murine model of acute infection and live imaging, a significant decrease in parasite load in BNIPDabut-treated mice was observed. However, cure was not achieved. BNIPDabut constitutes a new scaffold for antitrypanosomal drugs that deserves further consideration

Outils et pratiques de diffusion de l’information géographique. Le SIG de la Région Nord - Pas-de-Calais : SIGALE®

Pruvost Alain. Outils et pratiques de diffusion de l’information géographique. Le SIG de la Région Nord - Pas-de-Calais : SIGALE®. In: Géographes associés n°30,2006. Savoir, penser et partager l'information géographique : les SIG. Géoforum Lille, 10-11 juin 2005. pp. 249-252

Sylvofaciès et paysages en Forêt Domaniale de Nieppe

Having studied the criteria of the notion of «sylvofaciès », the author presents a few examples of them, out of a more complete biogeographie study of «Bois d'Amont» (a third West of the forest). He shows that the main factors of différenciation are based on the relations existing between : the floristic associations, the edaphic caracters, bound themselves to the nature of the humus and to the micro-topography having an effect on the degree of the hydromorphy, the physionomie distinctions created by the anthropic actions. Starting from the different types put to evidence, a resuming map reveals the forest landscapes.Après avoir discuté les critères de la notion de sylvofaciès, l'auteur en présente quelques exemples, extraits d'une étude biogéographique plus complète du Bois d'Amont (tiers Ouest de la forêt). Il montre que les principaux facteurs de différenciation sont fondés sur les relations existant entre : les associations floristiques, les caractères édaphiques, eux-mêmes liés à la nature des humus et à la microtopographie retentissant sur les degrés d'hydromorphie, les distinctions physionomiques créées par les actions anthropiques. A partir des types mis en évidence, une carte de synthèse révèle les paysages forestiers.Pruvost A. Sylvofaciès et paysages en Forêt Domaniale de Nieppe. In: Hommes et Terres du Nord, 1984/3. Géographie physique. pp. 156-168

Bonnes feuilles : «Femmes d’Algérie : Société, famille et citoyenneté», Alger, 2002

Pruvost A. Bonnes feuilles : «Femmes d’Algérie : Société, famille et citoyenneté», Alger, 2002. In: Recherches Internationales, n°67-68, 1-2-2003. Algérie. Etat des lieux : politique, société, culture. pp. 185-192