Étude des facteurs de risque de la maladie cardiovasculaire chez les patients avec maladie de l'aorte thoracique

À ce jour, on estime que 10,9 personnes par 100 000 par année sont atteintes d'un anévrisme de l'aorte thoracique. Bien que cette prévalence soit faible, la maladie est très mortelle et un suivi adéquat avec une prise en charge précoce de la condition aortique est hautement important. Ainsi, selon le récent guide de pratique de YAmehcan Heart Association, la prise en charge des facteurs de risque cardiovasculaire devrait faire partie intégrante du suivi de la maladie aortique. D'après nos observations, les individus atteints d'une maladie de l'aorte thoracique ne sont pas pris en charge de façon optimale quant à leur tension artérielle, leur dyslipidémie et leur obésité abdominale lorsque comparé à un groupe contrôle en prévention secondaire. À long terme, une prise en charge plus agressive de ces facteurs de risque aurait peut-être le potentiel de freiner la progression de la maladie

APOBEC3G/3F mediates intrinsic resistance of monocyte-derived dendritic cells to HIV-1 infection

HIV-1 infects immature dendritic cells (iDCs), but infection is inefficient compared with activated CD4+ T cells and only involves a small subset of iDCs. We analyzed whether this could be attributed to specific cellular restrictions during the viral life cycle. To study env-independent restriction to HIV-1 infection, we used a single-round infection assay with HIV-1 pseudotyped with vesicular stomatitis virus G protein (HIV-VSVG). Small interfering RNA–mediated depletion of APOBEC3G/3F (A3G/3F), but not TRIM5α, enhanced HIV-1 infection of iDCs, indicating that A3G/3F controls the sensitivity of iDCs to HIV-1 infection. Furthermore, sequences of HIV reverse transcripts revealed G-to-A hypermutation of HIV genomes during iDC infection, demonstrating A3G/3F cytidine deaminase activity in iDCs. When we separated the fraction of iDCs that was susceptible to HIV, we found the cells to be deficient in A3G messenger RNA and protein. We also noted that during DC maturation, which further reduces susceptibility to infection, A3G levels increased. These findings highlight a role for A3G/3F in explaining the resistance of most DCs to HIV-1 infection, as well as the susceptibility of a fraction of iDCs. An increase in the A3G/3F-mediated intrinsic resistance of iDCs could result in a block of HIV infection at its mucosal point of entry

The physiological burden of the 6-minute walk test compared with cardiopulmonary exercise stress test in patients with severe aortic atenosis

Background Management of aortic stenosis (AS) relies on symptoms. Exercise testing is recommended for asymptomatic patients with significant AS but is often experienced as forbidding and/or technically unrealistic for patients who are often frail, deconditioned, and intimidated by the exercise test. We compared the physiological burden assessed with gas exchange assessments to gauge and respiratory exchange ratio (RER) of a 6-minute walk test (6MWT) to a cardiopulmonary exercise stress test (CPET) in patients with severe AS. peak oxygen utilization Methods Adults with equivocal symptoms and severe AS (1-aortic valve area [AVA] ≤ 1.0 cm2 or AVA index ≤ 0.6 cm2/m2, 2-peak aortic jet velocity ≥ 4.0 m/sec, 3-mean transvalvular pressure gradient ≥ 40 mm Hg by rest or dobutamine stress echocardiography, or 4-aortic valve calcification ≥ 1200 in women or ≥ 2000 AU in men) were studied. All participants completed both a 6MWT and symptom-limited progressive bicycle exercise testing. Breath-by-breath gas analysis and 12-lead electrocardiography were completed during 6MWT and CPET. Results: Eleven patients were studied. Patients walked on average 330 ± 75 m during the 6MWT and achieved a maximal workload of 48 ± 14 watts during the CPET. During the 6MWT, peak maximal oxygen uptake (O2peak) was 12.8 ± 2.5 vs 10.8 ± 4.2 mL/kg/min during the CPET. Respiratory exchange ratio exceeded 1.1 in both the 6MWT and CPET indicating similarly high exertion. Compared with the CPET, a larger proportion of the 6MWT was performed at a high intensity level (78% ± 28% vs 33% ± 24% at > 85% V̇O2peak; P = 0.004). Conclusions The 6MWT with breath-by-breath gas analysis was well tolerated and able to achieve a physiological intense RER and O2peak that are similar to symptom-limited CPET in patients with severe AS.Introduction La prise en charge de la sténose aortique (SA) dépend des symptômes. L’épreuve d’effort est recommandée aux patients asymptomatiques qui ont une SA significative, mais elle est souvent perçue comme dangereuse et/ou théoriquement irréaliste chez ces patients qui sont souvent fragiles, en mauvaise forme et craintifs par l’épreuve d’effort. Nous avons comparé le fardeau physiologique calculé par la consommation maximale de l’oxygène (O2max) et le quotient respiratoire (QR) d’un test de marche de 6 minutes (TM6) et d'une épreuve d’effort maximal chez des patients avec une SA sévère. Méthodes Tous les patients présentaient une SA symptomatique et sévère (1-aire valvulaire aortique [AVA] ≤ 1,0 cm2 ouAVA ≤ 0,6 cm2/m2, 2-une vélocité maximale du flux aortique ≥ 4,0 m/sec, 3-un gradient de pression transvalvulaire moyen ≥ 40 mmHg au repos ou à l’échocardiographie à l’effort sous dobutamine ou 4-une calcification valvulaire aortique (AU) ≥ 1200 chez les femmes ou ≥ 2000 AU chez les hommes). Les participants ont effectué un TM6 et une ’épreuve d’effort maximal de type rampe sur vélo. L’analyse des échanges gazeux respiration par respiration et un électrocardiogramme à 12 dérivations ont été effectués durant le TM6 et l'épreuve d'effort maximal. Résultats Un total de 11 patients ont participé à l'étude. Les patients ont marché en moyenne 330 ± 75 m durant le TM6 et ont atteint une charge de travail maximale de 48 ± 14 watts durant l’épreuve d'effort maximal. Durant le TM6, le O2max était de 12,8 ± 2,5 vs 10,8 ± 4,2 ml/kg/min durant l’épreuve d'effort maximal. Le QR était supérieur à 1,1 au TM6 ainsi qu'à l’épreuve d'effort maximal. Comparativement à l’épreuve d'effort maximal, un pourcentage plus important au TM6 a été réalisée à une intensité élevée (78 % ± 28 % vs 33 % ± 24 % à > 85 % V̇O2max; P = 0,004). Conclusions Le TM6 avec mesure directe des échanges gazeux était bien toléré et susceptible d’atteindre des valeurs physiologiques d'intensité élevée pour le QR et le O2max. Les valeurs atteintes au TM6 étaient semblables à celles de l'épreuve d'effort maximal chez les patients avec une SA sévère

Functional analysis of the Parkinson's disease associated genes, parkin and PINK1, in vitro

Parkinson's disease (PD) is the most common neurodegenerative movement disorder. Our understanding of the disease has been enhanced by the discovery of gene mutations in rare families with eariy-onset autosomal recessive juvenile parkinsonism (ARJP). The first gene to be identified was parkin and two further genes have been identified namely, DJ-1 and PINK1. The latter was discovered in our laboratory. The work of this thesis has aimed to increase our understanding of how these newly discovered genes play a role in neuronal survival and how disease-causing mutations result in neurodegenerarJon. Utilising gene transfer techniques and transient and stable cell culture expression systems, the function of parkin and PINK1 was investigated in human dopaminergic SH-SY5Y neuroblastoma cell lines. The work of this thesis has confirmed and extended previous reports that parkin over-expression confers neuroprotection against a variety of cellular stresses implicated in PD. Moreover, this work has showed for the first time that endogenous parkin protein can localize to aggregates known as "aggresomes' following stress and that the formation of these parkin positive aggresomes can be dissociated from parkin's effect on neuronal survival. Furthermore, this work describes the first functional characterization of PINK1. It demonstrates that PINK1 localizes to the mitochondria in neuronal cells where it may play a neuroprotective role against cellular stress. Moreover, this effect is abrogated by disease causing mutations in PINK1. This work also reports on the characterisation of novel PINK1 antibodies and shows for the first time that PINK1 can localize to aggresomes and the mechanism is linked to mitochondrial recruitment. The work of this thesis sheds light on the increasing importance of the ubiquitin proteasome system and mitochondria in the pathogenesis of PD. Improved understanding of these cellular processes should lead to more effective treatments for this devastating disease

Subcellular specificity of cannabinoid effects in striatonigral circuits

Recent advances in neuroscience have positioned brain circuits as key units in controlling behavior, implying that their positive or negative modulation necessarily leads to specific behavioral outcomes. However, emerging evidence suggests that the activation or inhibition of specific brain circuits can actually produce multimodal behavioral outcomes. This study shows that activation of a receptor at different subcellular locations in the same neuronal circuit can determine distinct behaviors. Pharmacological activation of type 1 cannabinoid (CB1) receptors in the striatonigral circuit elicits both antinociception and catalepsy in mice. The decrease in nociception depends on the activation of plasma membrane-residing CB1 receptors (pmCB1), leading to the inhibition of cytosolic PKA activity and substance P release. By contrast, mitochondrial-associated CB1 receptors (mtCB1) located at the same terminals mediate cannabinoid-induced catalepsy through the decrease in intra-mitochondrial PKA-dependent cellular respiration and synaptic transmission. Thus, subcellular-specific CB1 receptor signaling within striatonigral circuits determines multimodal control of behavior

Identification of an Arsenic-Sensitive Block to Primate Lentiviral Infection of Human Dendritic Cells▿

Dendritic cells are central to the early events of human immunodeficiency virus type 1 (HIV-1) transmission, but HIV-1 infects dendritic cells inefficiently in vitro compared to activated CD4+ T cells. There is a strong postentry restriction of HIV-1 infection in dendritic cells, partly mediated by the cellular restriction factor APOBEC3G. Here, we reveal that arsenic trioxide markedly increases HIV infection of immature and mature dendritic cells as well as blood-derived myeloid dendritic cells in an APOBEC3G- and TRIM5α-independent way. Our data suggest the presence of powerful, arsenic-sensitive antiviral activities in primary human immune cells of the dendritic cell lineage

Acute post-bariatric surgery increase in orexin levels associates with preferential lipid profile improvement.

Orexin is a recently identified neuropeptide hormone.Acute and long-term post-bariatric changes in Orexin and relationship to post-operative metabolic outcomes.Men and women undergoing biliopancreatic diversion with duodenal switch bariatric surgery (n = 76, BMI≥35 kg/m(2)) were evaluated for body composition and plasma parameters at baseline, acutely (1 and 5 days) and long-term (6 and 12 months) post-surgery.University Hospital Centre, Canada.Groups were subdivided based on acute (average 1 and 5 day) changes in Orexin prior to weight loss: (i)>10% Orexin decrease (n = 33, OrexinDEC) and (ii)>10% Orexin increase (n = 20, OrexinINC), to evaluate impact on long-term changes.Both groups had comparable preoperative Orexin levels, BMI, age, sex distribution, diabetes and lipid lowering medication, plasma glucose and lipid parameters except for apolipoproteinB (p<0.007). Orexin increase was rapid and maintained throughout one year, while OrexinDEC subjects remained significantly lower throughout. Over 12 months, changes in BMI, fat mass, and %fat mass were comparable. Fasting glucose and insulin increased immediately 1-day post-operatively, decreasing rapidly (5-day) and declining thereafter with the OrexinINC group remaining lower than the OrexinDEC group throughout (p = 0.001). Similarly, plasma cholesterol, triglyceride, LDL-C and HDL-C decreased at 1-day, increased slightly (5-day), except HDL-C, then decreased over 1 year, with greater decreases in OrexinINC group relative to OrexinDEC group.Rapid postoperative increases in plasma Orexin are associated with better improvement of glucose and lipid profiles following bariatric surgery

Increased vaspin levels are associated with beneficial metabolic outcome pre- and post-bariatric surgery.

Vaspin (visceral-adipose-tissue-derived-serine-protease-inhibitor) is a recently identified adipokine with putative insulin-sensitizing properties. Plasma vaspin responses to surgery-induced weight loss are sparse and contradictory.We evaluated changes in vaspin levels and relationship to post-operative outcomes in men (n = 22) and women (n = 55) undergoing biliopancreatic-diversion/duodenal-switch bariatric surgery. Body composition and plasma parameters were measured at baseline, acutely (1 and 5 days) and medium-term (6 and 12 months) post-surgery.Fasting preoperative vaspin concentrations were comparable in men vs women. The distribution was biphasic (both men and women) with a nadir of 2.5 ng/ml. Subjects were divided into high (≥2.5 ng/mL, HI-group) and low (<2.5 ng/mL, LO-group) vaspin level. Both groups had comparable sex distribution, age and BMI, but the HI-vaspin group had lower insulin, HOMA, and triglyceride and higher HDL-cholesterol, acylation stimulating protein (ASP) and IL-6 levels (all p<0.05). Post-operatively, both groups decreased BMI comparably over 12 months; the HI-vaspin group maintained high vaspin levels, while the LO-vaspin group gradually increased their levels with weight loss over 12 months. The HI-vaspin group maintained a better glucose, insulin, HOMA, fructosamine, HDL-cholesterol, and triglyceride profile throughout. The HI-vaspin group also had higher gamma-glutamyltransferase and ASP profiles. Finally, baseline vaspin level inversely correlated significantly with baseline and 12-month insulin, HOMA, triglyceride and positively correlated with HDL and ASP. Twelve-month vaspin also correlated similarly, including an inverse correlation with BMI.Globally, this study supports the concept of vaspin as a beneficial adipokine in obesity, which may potentially lead to possible therapeutic targets

Biogeochemical variability in the southern Ross Sea as observed by a glider deployment

High-resolution autonomous glider data (including temperature, salinity, fluorescence, and optical backscatter) collected during the 2010-2011 austral summer identified variations in phytoplankton biomass along two glider sections near 76°40'S. Sea surface temperatures were warmer during the latter, westward section, while mixed layer depths were deeper. Substantial quantities of Modified Circumpolar Deep Water, identified by neutral density criteria, were located within both sections. Chlorophyll (Chl) concentrations computed from fluorescence exhibited daily quenching near the surface, and deep chlorophyll concentrations at 200. m became periodically elevated, suggesting substantial export on small space and time scales. The concentrations of particulate organic carbon (POC) computed from backscatter increased abruptly during the latter, westward section, concurrent with a decrease in chlorophyll. These higher POC:Chl ratios were not strongly correlated with presence of MCDW or with shallower mixed layer depths, but were strongly associated with higher surface temperatures and wind speed. The observed POC:Chl increase suggests a marked spatial and temporal transition between a Phaeocystis antarctica-dominated assemblage characterized by modest POC:Chl ratios to a diatom-dominated assemblage. Finally, a subsampling analysis highlights the capability of high-resolution glider data to resolve these biological/physical parameter correlations that are not discernible from lower frequency data typical of traditional cruise stations. © 2014 The Authors

Influence of cardiac dysfunction and systemic inflammation on pulmonary function and airway responsiveness in obese subjects

Purpose: Obesity is associated with left ventricular diastolic dysfunction and altered heart rate variability, as well as pulmonary dysfunction. The relationship between asthma and cardiac dysfunction in severely obese subjects is unknown, although it has been hypothesized that cardiac dysfunction may contribute to increase airway hyper-responsiveness (AHR). This study aimed to determine if AHR is associated with left ventricular diastolic dysfunction and heart rate variability in severely obese subjects. Methods: Sixty-one subjects with severe obesity (BMI ≥35 kg/m2 with comorbidities) completed this study. All subjects completed respiratory questionnaires, spirometry, lung volume measurements, methacholine inhalation test, 24hour Holter monitoring and a complete echocardiography evaluation. Blood samples were obtained for measurement of metabolic markers. Subjects with AHR, defined by a provocative concentration of methacholine inducing a 20% fall in FEV1 (PC20) < 8 mg/ml, were compared with those with no AHR (PC20 ≥8 mg/ml). Results: According to these criteria, 32 subjects had AHR and 29 had no AHR(mean PC201.70 mg/ml and 15.3 mg/ml respectively, p 0.05). CRP level correlated with PC20 (AHR, r=0.38, p=0.03). Indices of heart rate variability and overall cardiac function were similar in subjects with or without AHR but grade 2 left ventricular diastolic dysfunction was more prevalent in subjects with AHR (p=0.037). Conclusions: Altered cardiac function, dysglycemia and dyslipidemia do not seem to be significantly associated with AHR in severely obese subjects in contrast to systemic inflammation