EIF4G1 in familial Parkinson's disease: pathogenic mutations or rare benign variants?

International audienceMutations in the eukaryotic translation initiation factor 4-gamma (EIF4G1) gene, encoding a component of the eIF4F translation initiation complex, were recently reported as a possible cause for the autosomal dominant form of Parkinson's disease (PD). Here, we describe the screening of all 31 EIF4G1 coding exons in a series of 251 index cases with autosomal dominant PD, mostly of French origin and in 236 European control subjects. We identified 12 rare coding variants (either nonsynonymous amino acid substitutions or in frame deletions/insertions), including 6 variants present only in cases and 3 in controls. Segregation was possible only for 1 variant (p.E462delInsGK) that was found in 2 affected siblings. In addition, we found 2 previously reported pathogenic variants in 2 isolated patients (p.G686C) and in a control subject (p.R1197W). These data do not support the pathogenicity of several EIF4G1 variants in PD, at least in the French population

Mycobacterium leprae Phenolglycolipid-1 Expressed by Engineered M. bovis BCG Modulates Early Interaction with Human Phagocytes

The species-specific phenolic glycolipid 1 (PGL-1) is suspected to play a critical role in the pathogenesis of leprosy, a chronic disease of the skin and peripheral nerves caused by Mycobacterium leprae. Based on studies using the purified compound, PGL-1 was proposed to mediate the tropism of M. leprae for the nervous system and to modulate host immune responses. However, deciphering the biological function of this glycolipid has been hampered by the inability to grow M. leprae in vitro and to genetically engineer this bacterium. Here, we identified the M. leprae genes required for the biosynthesis of the species-specific saccharidic domain of PGL-1 and reprogrammed seven enzymatic steps in M. bovis BCG to make it synthesize and display PGL-1 in the context of an M. leprae-like cell envelope. This recombinant strain provides us with a unique tool to address the key questions of the contribution of PGL-1 in the infection process and to study the underlying molecular mechanisms. We found that PGL-1 production endowed recombinant BCG with an increased capacity to exploit complement receptor 3 (CR3) for efficient invasion of human macrophages and evasion of inflammatory responses. PGL-1 production also promoted bacterial uptake by human dendritic cells and dampened their infection-induced maturation. Our results therefore suggest that M. leprae produces PGL-1 for immune-silent invasion of host phagocytic cells

Facteurs limitant la pratique de l'automesure tensionnelle à domicile chez les médecins généralistes‎ : une revue de la littérature

Contexte : L'automesure tensionnelle à domicile est devenue indispensable au suivi des patients hypertendus ou suspectés de l'être. L'objectif de ce travail est de mettre en évidence les facteurs limitant la pratique de cet outil chez les médecins généralistes en France et à l'étranger. Méthode : Une revue de la littérature a été réalisée à partir des bases de données Pubmed, Google Scholar, CISMeF, Cochrane Library et du catalogue du SUDOC. Résultats : Vingt-deux articles et thèses répondant au sujet de la revue ont été inclus et analysés. Plusieurs freins à la pratique de l'automesure ont été retrouvés. Les médecins doutent en majorité de la fiabilité des autotensiomètres (et peu connaissent les listes d'appareils validés). Le manque d'appareils à prêter (lié au coût du matériel et à la peur du non-retour pour certains) est un problème, et la solution de l'achat ne peut être proposée à tous ceux de leur patientèle le justifiant. La plupart des médecins doutent aussi de la fiabilité des mesures de pression artérielle réalisées par les patients et craignent que la pratique de l'automesure ne soit source d'anxiété. Ils connaissent peu, majoritairement, les recommandations publiées pour une bonne utilisation de cet outil. Le manque de temps pour la pratique de l'automesure et l'absence de rémunération spécifique sont peu cités comme frein à son utilisation. Conclusion : Actuellement, bien que les médecins soient nombreux à dire qu'ils utilisent l'automesure tensionnelle pour le suivi de leurs patients, leur manque de formation à cet outil est un frein majeur à un développement de qualité, dans le respect des recommandations, de cette technique de mesure, certes encore récente

2015 La serre pilote Haute Performance Environnementale (HPE) de Bordeaux : détails du projet et bilan énergétique et financier après un an de fonctionnement

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Long-lasting benefit on multimodal treatment combining osimertinib and stereotaxic radiotherapy for metastatic non-small cell lung cancer with the EGFR exon 20 insertion 773-774 HVdelinsLM: a case report.

A non-small-cell-lung-cancer patient with cerebral metastasis presenting an atypical exon 20 mutation in the EGFR gene had a long-lasting tumor cotrol on mulimodal treatment with osimertinib and stereotaxic radiotherapy on oligoprogressing lesions. Most exon-20 mutations are resistant to first, second and third generation EGFR-directed TKI. This case was discussed on our molecular tumour board. As the more specific exon-20 targeted therapies were not yet available and as sporadic short responses on the third generation EGFR-directed TKI, osimertinib had been described, the patient started osimertinib. She had a prolonged tumoral response on Osimertinib. The patient is still asymptomatic up to 32 months after initiating the medication. This case confirms that not all exon20 EGFR mutations are equal to osimertinib and that the localization of the exon 20 insertion mutation is probably important to consider when treating EGFR mutated NSCLC. The long-term clinical benefit can be maintained through stereotactic radiotherapy on focal progressive lesions

Proscillaridin A exerts anti-tumor effects through GSK3β activation and alteration of microtubule dynamics in glioblastoma

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剣道 : . 武道

« Le kendô [剣術 littéralement « La voie du sabre »] est la plus ancienne, la plus respectée et la plus populaire des disciplines modernes du budô » selon Donn F. DRAEGER, spécialiste des arts martiaux japonais. Le kenjutsu 剣術 « L'art du sabre » à la fois art martial et technique guerrière pratiquée au Japon par les samouraïs, est aujourd’hui nommé kendô. Cette discipline fortifiant le corps et l'esprit était, jusqu'à la Restauration de Meiji (3 janvier 1868), uniquement réservée à classe guerrière de la société japonaise. De nos jours, conscient de son histoire et de ses bienfaits, celle-ci est devenue obligatoire pour les militaires et policiers japonais. Dès la moitié du XXème siècle, nombreux sont les maîtres du kendô envoyés à l’étranger pour transmettre leur savoir. Dans cette vidéo vous sera présenté l'un d'entre-eux, maître Yoshinori Inoue

The versatile nature of the calcium-permeable cation channel TRPP2

TRPP2 is a member of the transient receptor potential (TRP) superfamily of cation channels, which is mutated in autosomal dominant polycystic kidney disease (ADPKD). TRPP2 is thought to function with polycystin 1—a large integral protein—as part of a multiprotein complex involved in transducing Ca(2+)-dependent information. TRPP2 has been implicated in various biological functions including cell proliferation, sperm fertilization, mating behaviour, mechanosensation and asymmetric gene expression. Although its function as a Ca(2+)-permeable cation channel is well established, its precise role in the plasma membrane, the endoplasmic reticulum and the cilium is controversial. Recent studies suggest that TRPP2 function is highly dependent on the subcellular compartment of expression, and is regulated by many interactions with adaptor proteins. This review summarizes the most pertinent evidence about the properties of TRPP2 channels, focusing on the compartment-specific functions of mammalian TRPP2

Large-scale screening of the Gaucher's disease-related glucocerebrosidase gene in Europeans with Parkinson's disease

Pathogenic variants in the glucocerebrosidase gene (GBA) encoding the enzyme deficient in Gaucher's disease (GD) are associated with Parkinson's disease (PD). To investigate the sequence variants, their association with PD and the related phenotypes in a large cohort of European, mostly French, patients and controls, we sequenced all exons of GBA in 786 PD patients from 525 unrelated multiplex families, 605 patients with apparently sporadic PD and 391 ethnically matched controls. GBA mutations were significantly more frequent (odds ratio=6.98, 95% confidence interval 2.54-19.21; P=0.00002) in the PD patients (76/1130=6.7%) than in controls (4/391=1.0%) and in patients with family histories of PD (8.4%) than in isolated cases (5.3%). Twenty-eight different mutations were identified in patient and control groups, including seven novel variants. N370S and L444P accounted for 70% of all mutant alleles in the patient group. PD patients with GBA mutations more frequently had bradykinesia as the presenting symptom and levodopa-induced dyskinesias. The phenotype was similar in patients with one, two or complex GBA mutations, although the two patients with c.1263del+RecTL and N370S/RecΔ55 mutations had signs of GD. Segregation analyses in 21 multiplex families showed that 17% of the affected relatives did not carry GBA mutations found in the given family, indicating heterogeneity of the aetiology, but 46% of the unaffected relatives were GBA mutation carriers. These genotype and clinical analyses on the largest homogeneous sample of European patients studied to date confirmed that GBA mutations are the most common genetic risk factor for PD, particularly in familial forms