Déterminants des comportements sexuels à risque pour le VIH/SIDA chez les jeunes femmes et hommes de Bamako (Mali)

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal

Automated external defibrillator geolocalization with a mobile application, verbal assistance or no assistance : a pilot randomized simulation (AED G-MAP)

Background: Shockable rythms are common among victims of witnessed public out-of-hospital cardiac arrest (OHCA), but bystander defibrillation with a public automated external defibrillator (PAED) is rare. Instructions from the emergency medical dispatcher and mobile applications were developed to expedite the localization of PAEDs, but their effectiveness has not been compared. Methods: Participants were enrolled in a three-armed randomized simulation where they witnessed a simulated OHCA on a university campus, were instructed to locate a PAED and provide defibrillation. Participants were stratified and randomized to: (1) no assistance in finding the PAED, (2) assistance from a geolocalization mobile application (AED-Quebec), or (3) verbal assistance. Data collectors tracked each participant’s time elapsed and distance traveled to shock. Results: Of the 52 volunteers participating in the study (46% male, mean age 37), 17 were randomized to the no assistance group, 18 to the mobile application group and 17 to the verbal group. Median (IQR) time to shock was respectively 10:00 min (7:49-10:00), 9:44 (6:30-10:00), and 5:23 (4:11-9:08), with statistically significant differences between the verbal group and the other groups (p≤0.01). The success rate for defibrillation in <10 minutes was 35%, 56% and 76%. Multivariate regression of all participants pooled showed that knowledge of campus geography was the strongest predictor of shock in < 10 minutes (aOR = 14.3, 95% CI: 1.85-99.9). Among participants without prior geographical knowledge, verbal assistance provided a trend towards decreased time to shock, but the differences over no assistance (7:28 vs 10:00, p=0.10) and over the mobile app (7:28 vs 10:00, p=0.11) were not statistically significant. Conclusion: In a simulated environment, verbally providing OHCA bystanders with the nearest public AED’s location appeared to be effective in reducing the time to defibrillation in comparison to no assistance and to an AED geolocalizing mobile app, but further research is required to confirm this hypothesis, ascertain the external validity of these results and evaluate the real-life implications of these strategies

Franchir l’écart

L’étude des causatifs de mouvement, particulièrement en tant qu’ils sont associés à un lieu de passage, et de leurs variations aussi bien intralingues que contrastives, permet de corroborer les schémas contrastifs des causatifs de type « make » et « have », qui veulent que la relation fondamentale de l’anglais soit d’ordre modal et télique et la relation fondamentale du français soit d’ordre modal et intersubjectif.The study of verbs like “to lead” / “mener”, “conduire” and “to open into/onto” / “s'ouvrir sur” when they are associated with passage-ways or openings (road / chemin, door / porte, window / fenêtre) proves that they imply the same underlying operations as classical causative constructions involving “have” and “make”; the basic difference between English and French is that English focuses on modality and telicity whereas French focuses on modality and intersubjective relation

Beneficial effects of reconstituted high-density lipoprotein (rHDL) on circulating CD34+ cells in patients after an acute coronary syndrome

Background: High-density lipoproteins (HDL) favorably affect endothelial progenitor cells (EPC). Circulating progenitor cell level and function are impaired in patients with acute coronary syndrome (ACS). This study investigates the short-term effects of reconstituted HDL (rHDL) on circulating progenitor cells in patients with ACS. Methods and Findings: The study population consisted of 33 patients with recent ACS: 20 patients from the ERASE trial (randomized to receive 4 weekly intravenous infusions of CSL-111 40 mg/kg or placebo) and 13 additional patients recruited as controls using the same enrolment criteria. Blood was collected from 16 rHDL (CSL-111)-treated patients and 17 controls at baseline and at 6–7 weeks (i.e. 2–3 weeks after the fourth infusion of CSL-111 in ERASE). CD34+ and CD34+/kinase insert domain receptor (KDR+) progenitor cell counts were analyzed by flow cytometry. We found preserved CD34+ cell counts in CSL-111-treated subjects at follow-up (change of 1.6%), while the number of CD34+ cells was reduced (-32.9%) in controls (p = 0.017 between groups). The level of circulating SDF-1 (stromal cell-derived factor-1), a chemokine involved in progenitor cell recruitment, increased significantly (change of 21.5%) in controls, while it remained unchanged in CSL-111-treated patients (p = 0.031 between groups). In vitro exposure to CSL-111 of early EPC isolated from healthy volunteers significantly increased CD34+ cells, reduced early EPC apoptosis and enhanced their migration capacity towards SDF-1. Conclusions: The relative increase in circulating CD34+ cells and the low SDF-1 levels observed following rHDL infusions in ACS patients point towards a role of rHDL in cardiovascular repair mechanisms

Fibulin-2: genetic mapping and exclusion as a candidate gene in Marfan syndrome type 2.

International audienceFibulin-2 (FBLN2) is a new extracellular matrix protein that has been considered a candidate gene for Marfan syndrome type 2 (locus MFS2) based on chromosomal colocation at 3p24.2-p25 and disease phenotype. In the absence of polymorphic markers reported for FBLN2, direct sequencing of the gene was performed and two intragenic polymorphisms were identified. Linkage was excluded between FBLN2 and the MFS2 gene. Furthermore, two-point lod scores were generated between these markers and anonymous markers arrayed on the genetic map of 3p and closely linked to MFS2. These analyses placed FBLN2 at marker D3S1585

Molecular Spectrum of Autosomal Dominant Hypercholesterolemia in France

Autosomal Dominant Hypercholesterolemia (ADH), characterized by isolated elevation of plasmatic LDL cholesterol and premature cardiovascular complications, is associated with mutations in 3 major genes: LDLR (LDL receptor), APOB (apolipoprotein B) and PCSK9 (proprotein convertase subtilisin-kexin type 9). Through the French ADH Research Network, we collected molecular data from 1358 French probands from eleven different regions in France. Mutations in the LDLR gene were identified in 1003 subjects representing 391 unique events with 46.0% missense, 14.6% frameshift, 13.6% splice, and 11.3% nonsense mutations, 9.7% major rearrangements, 3.8% small in frame deletions/insertions, and 1.0% UTR mutations. Interestingly, 175 are novel mutational events and represent 45% of the unique events we identified, highlighting a specificity of the LDLR mutation spectrum in France. Furthermore, mutations in the APOB gene were identified in 89 probands and in the PCSK9 gene in 10 probands. Comparison of available clinical and biochemical data showed a gradient of severity for ADH-causing mutations: FH=PCSK9>FDB>‘Others’ genes. The respective contribution of each known gene to ADH in this French cohort is: LDLR 73.9%, APOB 6.6%, PCSK9 0.7%. Finally, in 19.0% of the probands, no mutation was found, thus underscoring the existence of ADH mutations located in still unknown genes. © 2010 Wiley-Liss, Inc

MAT2A Mutations Predispose Individuals to Thoracic Aortic Aneurysms

Up to 20% of individuals who have thoracic aortic aneurysms or acute aortic dissections but who do not have syndromic features have a family history of thoracic aortic disease. Significant genetic heterogeneity is established for this familial condition. Whole-genome linkage analysis and exome sequencing of distant relatives from a large family with autosomal-dominant inheritance of thoracic aortic aneurysms variably associated with the bicuspid aortic valve was used for identification of additional genes predisposing individuals to this condition. A rare variant, c.1031A>C (p.Glu344Ala), was identified in MAT2A, which encodes methionine adenosyltransferase II alpha (MAT IIα). This variant segregated with disease in the family, and Sanger sequencing of DNA from affected probands from unrelated families with thoracic aortic disease identified another MAT2A rare variant, c.1067G>A (p.Arg356His). Evidence that these variants predispose individuals to thoracic aortic aneurysms and dissections includes the following: there is a paucity of rare variants in MAT2A in the population; amino acids Glu344 and Arg356 are conserved from humans to zebrafish; and substitutions of these amino acids in MAT Iα are found in individuals with hypermethioninemia. Structural analysis suggested that p.Glu344Ala and p.Arg356His disrupt MAT IIα enzyme function. Knockdown of mat2aa in zebrafish via morpholino oligomers disrupted cardiovascular development. Co-transfected wild-type human MAT2A mRNA rescued defects of zebrafish cardiovascular development at significantly higher levels than mRNA edited to express either the Glu344 or Arg356 mutants, providing further evidence that the p.Glu344Ala and p.Arg356His substitutions impair MAT IIα function. The data presented here support the conclusion that rare genetic variants in MAT2A predispose individuals to thoracic aortic disease

Pathogenic variants in THSD4, encoding the ADAMTS-like 6 protein, predispose to inherited thoracic aortic aneurysm

Purpose Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening disease with often unrecognized inherited forms. We sought to identify novel pathogenic variants associated with autosomal dominant inheritance of TAAD. Methods We analyzed exome sequencing data from 35 French TAAD families and performed next-generation sequencing capture panel of genes in 1114 unrelated TAAD patients. Functional effects of pathogenic variants identified were validated in cell, tissue, and mouse models. Results We identified five functional variants inTHSD4of which two heterozygous variants lead to a premature termination codon.THSD4encodes ADAMTSL6 (member of the ADAMTS/L superfamily), a microfibril-associated protein that promotes fibrillin-1 matrix assembly. TheTHSD4variants studied lead to haploinsufficiency or impaired assembly of fibrillin-1 microfibrils.Thsd4(+/-)mice showed progressive dilation of the thoracic aorta. Histologic examination of aortic samples from a patient carrying aTHSD4variant and fromThsd4(+/-)mice, revealed typical medial degeneration and diffuse disruption of extracellular matrix. Conclusion These findings highlight the role of ADAMTSL6 in aortic physiology and TAAD pathogenesis. They will improve TAAD management and help develop new targeted therapies

Exome Sequencing in Suspected Monogenic Dyslipidemias

Abstract BACKGROUND: -Exome sequencing is a promising tool for gene mapping in Mendelian disorders. We utilized this technique in an attempt to identify novel genes underlying monogenic dyslipidemias. METHODS AND RESULTS: -We performed exome sequencing on 213 selected family members from 41 kindreds with suspected Mendelian inheritance of extreme levels of low-density lipoprotein (LDL) cholesterol (after candidate gene sequencing excluded known genetic causes for high LDL cholesterol families) or high-density lipoprotein (HDL) cholesterol. We used standard analytic approaches to identify candidate variants and also assigned a polygenic score to each individual in order to account for their burden of common genetic variants known to influence lipid levels. In nine families, we identified likely pathogenic variants in known lipid genes (ABCA1, APOB, APOE, LDLR, LIPA, and PCSK9); however, we were unable to identify obvious genetic etiologies in the remaining 32 families despite follow-up analyses. We identified three factors that limited novel gene discovery: (1) imperfect sequencing coverage across the exome hid potentially causal variants; (2) large numbers of shared rare alleles within families obfuscated causal variant identification; and (3) individuals from 15% of families carried a significant burden of common lipid-related alleles, suggesting complex inheritance can masquerade as monogenic disease. CONCLUSIONS: -We identified the genetic basis of disease in nine of 41 families; however, none of these represented novel gene discoveries. Our results highlight the promise and limitations of exome sequencing as a discovery technique in suspected monogenic dyslipidemias. Considering the confounders identified may inform the design of future exome sequencing studies