H008 Le blocage des récepteurs AT1 de L′angiotensine II inhibe L′hypertrophie ventriculaire gauche et L′activation de FHL1 chez la souris hétérozygote déficiente en cMyBP-C

Les mutations de la protéine C cardiaque (cMyBP-C) sont une cause de cardiomyopathies hypertrophiques (CMH). Les souris transgéniques hétérozygotes défi cientes en cMyBP-C (HET) présentent une CMH d′apparition tardive à fonction systolique conservée. Le système rénine angiotensine (SRA) cardiaque joue un rôle important dans l′hypertrophie, mais son rôle dans le développement d′une CMH génétiquement déterminée a été peu étudié.Cette étude évaluait le rôle du SRA dans l′induction de la CMH chez la souris HET. Des souris HET et sauvages (WT), âgées de 5 mois, ont été traitées par irbésartan (50mg/kg/jour) ou placebo pendant 8 semaines. L′expression dans le ventricule gauche (VG) des gènes de l′enzyme de conversion de l′angiotensine I (ACE), du récepteur AT1 de l′angiotensine II (AGTR1), de la calcineurine A (PPP3CB) de la calcipressin 1 (RCAN1), et de FHL1 (four and a half LIM domains 1, une protéine associée à cMyBP-C au sein du sarcomère) a été analysée par RT-qPCR.Après 8 semaines de traitement, la pression artérielle est normale dans tous les groupes. Le poids du VG/poids du corps des souris HET est augmenté par rapport aux WT (3,9±0,3 vs. 3,3±0,4mg/g; p<0.01) dans le groupe placebo. Dans les groupes traités par irbésartan, ce rapport est comparable pour les souris HET (3,4±0,5mg/g) et WT (3,2±0,4mg/g; p=ns). L′expression des gènes de l′ACE, PPP3CB et RCAN1 est comparable entre les souris HET et WT et n′est pas affectée par le traitement par irbésartan. L′expression d′AGTR1 est similaire chez les souris HET et WT traitées par placebo mais augmente après traitement par irbésartan uniquement chez les souris HET. A l′inverse, l′expression de FHL1 est activée chez les souris HET par rapport aux souris WT mais cette augmentation est prévenue par le traitement par irbésartan.En conclusion, chez la souris cMyBP-C, le développement de l′hypertrophie est accompagné par une augmentation de l′expression du gène FHL1 dans le VG. Le traitement par irbésartan inhibe l′hypertrophie et l′activation de l′expression de FHL1 don′t le mécanisme reste à déterminer

Myosin binding protein C: implications for signal-transduction

Myosin binding protein C (MYBPC) is a crucial component of the sarcomere and an important regulator of muscle function. While mutations in different myosin binding protein C (MYBPC) genes are well known causes of various human diseases, such as hypertrophic (HCM) and dilated (DCM) forms of cardiomyopathy as well as skeletal muscular disorders, the underlying molecular mechanisms remain not well understood. A variety of MYBPC3 (cardiac isoform) mutations have been studied in great detail and several corresponding genetically altered mouse models have been generated. Most MYBPC3 mutations may cause haploinsufficiency and with it they may cause a primary increase in calcium sensitivity which is potentially able to explain major features observed in HCM patients such as the hypercontractile phenotype and the well known secondary effects such as myofibrillar disarray, fibrosis, myocardial hypertrophy and remodelling including arrhythmogenesis. However the presence of poison peptides in some cases cannot be fully excluded and most probably other mechanisms are also at play. Here we shall discuss MYBPC interacting proteins and possible pathways linked to cardiomyopathy and heart failure

The genetic basis of hypertrophic cardiomyopathy in cats and humans

Mutations in genes that encode for muscle sarcomeric proteins have been identified in humans and two breeds of domestic cats with hypertrophic cardiomyopathy (HCM). This article reviews the history, genetics, and pathogenesis of HCM in the two species in order to give veterinarians a perspective on the genetics of HCM. Hypertrophic cardiomyopathy in people is a genetic disease that has been called a disease of the sarcomere because the preponderance of mutations identified that cause HCM are in genes that encode for sarcomeric proteins (Maron and Maron, 2013). Sarcomeres are the basic contractile units of muscle and thus sarcomeric proteins are responsible for the strength, speed, and extent of muscle contraction. In people with HCM, the two most common genes affected by HCM mutations are the myosin heavy chain gene (MYH7), the gene that encodes for the motor protein β-myosin heavy chain (the sarcomeric protein that splits ATP to generate force), and the cardiac myosin binding protein-C gene (MYBPC3), a gene that encodes for the closely related structural and regulatory protein, cardiac myosin binding protein-C (cMyBP-C). To date, the two mutations linked to HCM in domestic cats (one each in Maine Coon and Ragdoll breeds) also occur in MYBPC3 (Meurs et al., 2005, 2007). This is a review of the genetics of HCM in both humans and domestic cats that focuses on the aspects of human genetics that are germane to veterinarians and on all aspects of feline HCM genetics

A new class of glycomimetic drugs to prevent free fatty acid-induced endothelial dysfunction

Background: Carbohydrates play a major role in cell signaling in many biological processes. We have developed a set of glycomimetic drugs that mimic the structure of carbohydrates and represent a novel source of therapeutics for endothelial dysfunction, a key initiating factor in cardiovascular complications. Purpose: Our objective was to determine the protective effects of small molecule glycomimetics against free fatty acid­induced endothelial dysfunction, focusing on nitric oxide (NO) and oxidative stress pathways. Methods: Four glycomimetics were synthesized by the stepwise transformation of 2,5­dihydroxybenzoic acid to a range of 2,5­substituted benzoic acid derivatives, incorporating the key sulfate groups to mimic the interactions of heparan sulfate. Endothelial function was assessed using acetylcholine­induced, endotheliumdependent relaxation in mouse thoracic aortic rings using wire myography. Human umbilical vein endothelial cell (HUVEC) behavior was evaluated in the presence or absence of the free fatty acid, palmitate, with or without glycomimetics (1µM). DAF­2 and H2DCF­DA assays were used to determine nitric oxide (NO) and reactive oxygen species (ROS) production, respectively. Lipid peroxidation colorimetric and antioxidant enzyme activity assays were also carried out. RT­PCR and western blotting were utilized to measure Akt, eNOS, Nrf­2, NQO­1 and HO­1 expression. Results: Ex vivo endothelium­dependent relaxation was significantly improved by the glycomimetics under palmitate­induced oxidative stress. In vitro studies showed that the glycomimetics protected HUVECs against the palmitate­induced oxidative stress and enhanced NO production. We demonstrate that the protective effects of pre­incubation with glycomimetics occurred via upregulation of Akt/eNOS signaling, activation of the Nrf2/ARE pathway, and suppression of ROS­induced lipid peroxidation. Conclusion: We have developed a novel set of small molecule glycomimetics that protect against free fatty acidinduced endothelial dysfunction and thus, represent a new category of therapeutic drugs to target endothelial damage, the first line of defense against cardiovascular disease

Structure, genetic localization, and identification of the cardiac and skeletal muscle transcripts of the human integrin alpha7 gene (ITGA7)

We have determined the structure and the exon size pattern of the human integrin alpha7 subunit gene (ITGA7), which has been shown to be affected in a form of congenital myopathy. The gene is composed of at least 27 exons spanning a region of about 22.5 kb. The sequence of all exon/intron boundaries was determined and conforms to the GT/AG splicing consensus. We investigated the different splicing forms previously described in human and rodents. The major cytoplasmic variants alpha7A and alpha7B, which are developmentally regulated and tissue specific, were identified in human tissues, as well as the extracellular isoforms X1 and X2. The recently described D variant was detected in adult tissues by RT-PCR but not the C variant. We localized ITGA7 on chromosome 12q13 by high-resolution radiation hybrid mapping between D12S312 and D12S90 and identified a new CA-repeat microsatellite in intron 1

15. - Etude qualitative et quantitative de l’effet de berge : application à la nappe alluviale de Flins-Aubergenville

Since 1989 a research program on bank filtration has been set up by : the Lyonnaise des Eaux-Dumez group (LED), "Ecole des Mines de Paris" (CIG), "Agence de l'Eau Seine-Normandie" (AESN) and the Institut de Protection et de Sûreté Nucléaire (IPSN). The object of this program is to study transfer of pollutants between a river and it's connected aquifer. This program is a major concern for water resources managers in the Seine-Normandie area. In fact, these aquifers provide more than 50% of drinking water for the urban communities. This communication is an overview of the research program. Three sorts of pollutants are analyzed : • Nitrogen, due to the increase of nitrate concentration in the river Seine, especially downstream the Achères sewage treatment plant ; • Radio elements coming from normal and accidental operating of nuclear power plant (Co, Cs, Ag, Sb, I, Sr, Cs, Ru, Te) ; • Pesticides (Atrazine and Simazine). High concentrations were detected in aquifers and rivers within agricultural areas, at spring time. First results show an important biochemical activity in the first centimeters of river Seine deposits as well as a considerable water purification in the first meters of the river bank.Depuis 1989, à l’initiative de la Lyonnaise des Eaux-Dumez (LED), un programme de recherche consacré à l’effet de berges a été entrepris avec l’École des Mines de Paris (CIG), l’Agence de l’Eau Seine-Normandie (AESN) et l’Institut de Protection et de Sûreté Nucléaire (IPSN). Il a pour objectif d’étudier dans le détail le transfert de polluants entre une rivière et la nappe alluviale connectée répondant ainsi, à une préoccupation majeure des gestionnaires de l’eau. En effet, ces aquifères fournissent, en Seine-Normandie, plus de 50 % de l’eau potable destinée aux collectivités. Cette communication présente brièvement le programme de recherche et donne un aperçu des résultats acquis. L’étude entreprise intéresse trois familles de polluants : • l’azote, du fait de l’augmentation sensible des teneurs en nitrates dans les cours d’eau, en particulier en Seine en aval de la station d’épuration d’Achères ; • des radioéléments, issus des rejets normaux ou accidentels d’une installation nucléaire (Co, Cs, Ag, Sb, I, Sr, Cs, Ru, Te) ; • des pesticides (Atrazine et Simazine) dont il a été détecté des concentrations importantes au printemps dans les aquifères et les cours d’eau des zones cultivées. Les premiers résultats montrent, notamment, une activité biochimique importante dans les premiers centimètres de boues de Seine ainsi qu’une épuration notable dans les premiers mètres de berge.Detay Michel, Doussan C., Grenet B., Ledoux Emmanuel, Poitevin G., Picat P., Vignier V. 15. - Etude qualitative et quantitative de l’effet de berge : application à la nappe alluviale de Flins-Aubergenville. In: L'avenir de l'eau. Quelques réponses des sciences hydrotechniques à une inquiétude mondiale. Vingt deuxièmes journées de l'hydraulique. Paris, 15-17 septembre 1992. Tome 3, 1992

Screening for active and latent TB among migrants in France

International audienceMigrants to Europe face a disproportionate burden of infections, including TB, yet little is known about the approach taken by primary and secondary care providers to screening and treatment. We therefore explored policy and practice relating to screening of active TB and latent TB infection (LTBI) in France. METHODS: We conducted an online national survey of French primary and secondary care physicians regarding their practices in relation to TB/LTBI screening among migrants. RESULTS: 367 physicians responded to the questionnaire among which 195 (53.1%) were primary care physicians, 126 (34.3%) were TB specialists in secondary care, and 46 (12.5%) other physicians; 303 (85.5%) were involved daily in the care of migrants. Most respondents recommended systematic TB screening with chest X-ray for migrants from medium and highincidence countries (71.9%). Primary care physicians were less likely to offer screening than physicians in other settings (aOR 0.21, 95% CI 0.09-0.48). 220 (61.8%) offered LTBI screening for children (<15 years) and 34.0% for all migrants from high incidence countries. CONCLUSION: Improving awareness on TB screening is a critical next step to improve health outcomes in migrant groups and meet regional targets for tackling TB

Sensitivity of eastern oyster ( Crassostrea virginica) spermatozoa and oocytes to dispersed oil: Cellular responses and impacts on fertilization and embryogenesis

The 2010 Deepwater Horizon (DWH) oil spill released millions of barrels of oil and dispersant into the Gulf of Mexico. The timing of the spill coincided with the spawning season of Crassostrea virginica. Consequently, gametes released in the water were likely exposed to oil and dispersant. This study aimed to (i) evaluate the cellular effects of acute exposure of spermatozoa and oocytes to surface slick oil, dispersed mechanically (HEWAF) and chemically (CEWAF), using flow-cytometric (FCM) analyses, and (ii) determine whether the observed cellular effects relate to impairments of fertilization and embryogenesis of gametes exposed to the same concentrations of CEWAF and HEWAF. Following a 30-min exposure, the number of spermatozoa and their viability were reduced due to a physical action of oil droplets (HEWAF) and a toxic action of CEWAF respectively. Additionally, reactive oxygen species (ROS) production in exposed oocytes tended to increase with increasing oil concentrations suggesting that exposure to dispersed oil resulted in an oxidative stress. The decrease in fertilization success (1-h), larval survival (24-h) and increase in abnormalities (6-h and 24-h) may be partly related to altered cellular characteristics. FCM assays are a good predictor of sublethal effects especially on fertilization success. These data suggest that oil/dispersant are cytotoxic to gametes, which may affect negatively the reproduction success and early development of oysters

État de santé des immigrés à travers les grandes enquêtes

International audienc