Receptor Complementation and Mutagenesis Reveal SR-BI as an Essential HCV Entry Factor and Functionally Imply Its Intra- and Extra-Cellular Domains

HCV entry into cells is a multi-step and slow process. It is believed that the initial capture of HCV particles by glycosaminoglycans and/or lipoprotein receptors is followed by coordinated interactions with the scavenger receptor class B type I (SR-BI), a major receptor of high-density lipoprotein (HDL), the CD81 tetraspanin, and the tight junction protein Claudin-1, ultimately leading to uptake and cellular penetration of HCV via low-pH endosomes. Several reports have indicated that HDL promotes HCV entry through interaction with SR-BI. This pathway remains largely elusive, although it was shown that HDL neither associates with HCV particles nor modulates HCV binding to SR-BI. In contrast to CD81 and Claudin-1, the importance of SR-BI has only been addressed indirectly because of lack of cells in which functional complementation assays with mutant receptors could be performed. Here we identified for the first time two cell types that supported HCVpp and HCVcc entry upon ectopic SR-BI expression. Remarkably, the undetectable expression of SR-BI in rat hepatoma cells allowed unambiguous investigation of human SR-BI functions during HCV entry. By expressing different SR-BI mutants in either cell line, our results revealed features of SR-BI intracellular domains that influence HCV infectivity without affecting receptor binding and stimulation of HCV entry induced by HDL/SR-BI interaction. Conversely, we identified positions of SR-BI ectodomain that, by altering HCV binding, inhibit entry. Finally, we characterized alternative ectodomain determinants that, by reducing SR-BI cholesterol uptake and efflux functions, abolish HDL-mediated infection-enhancement. Altogether, we demonstrate that SR-BI is an essential HCV entry factor. Moreover, our results highlight specific SR-BI determinants required during HCV entry and physiological lipid transfer functions hijacked by HCV to favor infection

Impact of clinical and genetic findings on the management of young patients with Brugada syndrome.

BACKGROUND: Brugada syndrome (BrS) is an arrhythmogenic disease associated with sudden cardiac death (SCD) that seldom manifests or is recognized in childhood. OBJECTIVES: The objectives of this study were to describe the clinical presentation of pediatric BrS to identify prognostic factors for risk stratification and to propose a data-based approach management. METHODS: We studied 106 patients younger than 19 years at diagnosis of BrS enrolled from 16 European hospitals. RESULTS: At diagnosis, BrS was spontaneous (n = 36, 34%) or drug-induced (n = 70, 66%). The mean age was 11.1 ± 5.7 years, and most patients were asymptomatic (family screening, (n = 67, 63%; incidental, n = 13, 12%), while 15 (14%) experienced syncope, 6(6%) aborted SCD or symptomatic ventricular tachycardia, and 5 (5%) other symptoms. During follow-up (median 54 months), 10 (9%) patients had life-threatening arrhythmias (LTA), including 3 (3%) deaths. Six (6%) experienced syncope and 4 (4%) supraventricular tachycardia. Fever triggered 27% of LTA events. An implantable cardioverter-defibrillator was implanted in 22 (21%), with major adverse events in 41%. Of the 11 (10%) patients treated with hydroquinidine, 8 remained asymptomatic. Genetic testing was performed in 75 (71%) patients, and SCN5A rare variants were identified in 58 (55%); 15 of 32 tested probands (47%) were genotype positive. Nine of 10 patients with LTA underwent genetic testing, and all were genotype positive, whereas the 17 SCN5A-negative patients remained asymptomatic. Spontaneous Brugada type 1 electrocardiographic (ECG) pattern (P = .005) and symptoms at diagnosis (P = .001) were predictors of LTA. Time to the first LTA event was shorter in patients with both symptoms at diagnosis and spontaneous Brugada type 1 ECG pattern (P = .006). CONCLUSION: Spontaneous Brugada type 1 ECG pattern and symptoms at diagnosis are predictors of LTA events in the young affected by BrS. The management of BrS should become age-specific, and prevention of SCD may involve genetic testing and aggressive use of antipyretics and quinidine, with risk-specific consideration for the implantable cardioverter-defibrillator

Registre de suivi des sondes de défibrillation Riata® et morbi-mortalité d'une cohorte de patients porteurs d'un défibrillateur automatique implantable (analyse à partir d'une base de données du CHU de Dijon )

DIJON-BU Médecine Pharmacie (212312103) / SudocSudocFranceF

Etude prospective de l'interaction racine aortique-septum interauriculaire et de son influence sur la perméabilité du foramen ovale

DIJON-BU Médecine Pharmacie (212312103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Imagerie hybride TEP/IRM dans le bilan des pathologies neurodégénératives : retour d’expérience

International audienceObjectifsL’imagerie hybride TEP/IRM permet de combiner de façon précise l’information moléculaire fournie par la TEP avec une grande variété de séquences IRM. L’acquisition des deux examens en une session unique minimise les désagréments pour le patient tout en maximisant les informations collectées grâce à la fusion spatiale et temporelle des deux modalités. Dans ce travail, nous discuterons, à partir de cas cliniques, l’apport des deux modalités IRM et TEP dans le bilan des pathologies neuro-dégénératives, notamment la maladie d’Alzheimer (MA), la démence fronto-temporale (DFT), l’aphasie primaire progressive (APP), la démence à corps de Lewy (DCL), l’atrophie corticale postérieure (ACP) et le déficit cognitif léger (MCI).Matériels et méthodesCent vingt-trois patients ont été adressés dans le service entre le 2/10/15 et le 12/01/16 pour un bilan de troubles cognitifs. Les acquisitions ont été réalisées avec le TEP/IRM SIGNA (GE Healthcare) qui combine une technologie TEP temps de vol avec des photomultiplicateurs au silicium et une IRM 3T. Le protocole IRM a compris des acquisitions 3DFLAIR, 3DSWAN, 3DT1 et axiales diffusion. L’acquisition TEP-FDG (2 MBq/kg) centrée sur le cerveau a été réalisée simultanément aux séquences IRM en un pas de lit de 16 minutes (champ de vue axial de 24,4 cm). Les reconstructions étaient réalisées avec l’algorithme Vue Point FX (8 itérations, 28 sous-ensembles, fréquence de coupure 3 mm) incluant correction de résolution spatiale et le temps de vol. La correction de l’atténuation était basée sur un atlas TD.RésultatsLes images TEP et IRM sont de qualité très satisfaisante pour une durée d’examen d’environ 30 minutes. Il n’a pas été identifié d’artéfact de correction lié à l’atlas gênant l’interprétation. Dans les formes jeunes de MA, d’ACP et de DCL, la TEP-FDG montrait souvent des anomalies marquées du métabolisme alors que l’IRM était normale ou montrait une atrophie non spécifique. Dans les formes plus focales (DFT, démence sémantique), les anomalies IRM et TEP étaient généralement associées. Les lésions vasculaires (leucopathies, microsaignements, séquelles d’AVC) sont facilement détectées sur les nouvelles séquences de susceptibilité magnétique (3D SWAN) ; la TEP met en évidence une éventuelle composante dégénérative associée, voire le retentissement (désafférentation) d’une lésion sous corticale.ConclusionsLa fusion des images TEP de haute résolution spatiale avec le 3DT1 permet d’améliorer la confiance diagnostique, en faisant la part entre un effet de volume partiel en cas d’atrophie ou lésion et un véritable déficit fonctionnel. L’interprétation simultanée par le médecin nucléaire et le neuroradiologue apporte au clinicien un résultat diagnostique optimisé, en particulier dans les cas complexes

Relation of outcomes to ABC (Atrial Fibrillation Better Care) pathway adherent care in European patients with atrial fibrillation: an analysis from the ESC-EHRA EORP Atrial Fibrillation General Long-Term (AFGen LT) Registry

International audienceAbstract Aims There has been an increasing focus on integrated, multidisciplinary, and holistic care in the treatment of atrial fibrillation (AF). The ‘Atrial Fibrillation Better Care’ (ABC) pathway has been proposed to streamline integrated care in AF. We evaluated the impact on outcomes of an ABC adherent management in a contemporary real-life European-wide AF cohort. Methods and results Patients enrolled in the ESC-EHRA EURObservational Research Programme in AF General Long-Term Registry with baseline data to evaluate ABC criteria and available follow-up data were considered for this analysis. Among the original 11 096 AF patients enrolled, 6646 (59.9%) were included in this analysis, of which 1996 (30.0%) managed as ABC adherent. Patients adherent to ABC care had lower CHA2DS2-VASc and HAS-BLED scores (mean ± SD, 2.68 ± 1.57 vs. 3.07 ± 1.90 and 1.26 ± 0.93 vs. 1.58 ± 1.12, respectively; P < 0.001). At 1-year follow-up, patients managed adherent to ABC pathway compared to non-adherent ones had a lower rate of any thromboembolic event (TE)/acute coronary syndrome (ACS)/cardiovascular (CV) death (3.8% vs. 7.6%), CV death (1.9% vs. 4.8%), and all-cause death (3.0% vs. 6.4%) (all P < 0.0001). On Cox multivariable regression analysis, ABC adherent care showed an association with a lower risk of any TE/ACS/CV death [hazard ratio (HR): 0.59, 95% confidence interval (CI): 0.44–0.79], CV death (HR: 0.52, 95% CI: 0.35–0.78), and all-cause death (HR: 0.57, 95% CI: 0.43–0.78). Conclusion In a large contemporary cohort of European AF patients, a clinical management adherent to ABC pathway for integrated care is associated with a significant lower risk for cardiovascular events, CV death, and all-cause death