Apolipoprotein E mediates evasion from hepatitis C virus−neutralizing antibodies

Background & Aims Efforts to develop an effective vaccine against hepatitis C virus (HCV) have been hindered by the propensity of the virus to evade host immune responses. HCV particles in serum and in cell culture associate with lipoproteins, which contribute to viral entry. Lipoprotein association has also been proposed to mediate viral evasion of the humoral immune response, though the mechanisms are poorly defined. Methods We used small interfering RNAs to reduce levels of apolipoprotein E (apoE) in cell culture−derived HCV−producing Huh7.5-derived hepatoma cells and confirmed its depletion by immunoblot analyses of purified viral particles. Before infection of naïve hepatoma cells, we exposed cell culture−derived HCV strains of different genotypes, subtypes, and variants to serum and polyclonal and monoclonal antibodies isolated from patients with chronic HCV infection. We analyzed the interaction of apoE with viral envelope glycoprotein E2 and HCV virions by immunoprecipitation. Results Through loss-of-function studies on patient-derived HCV variants of several genotypes and subtypes, we found that the HCV particle apoE allows the virus to avoid neutralization by patient-derived antibodies. Functional studies with human monoclonal antiviral antibodies showed that conformational epitopes of envelope glycoprotein E2 domains B and C were exposed after depletion of apoE. The level and conformation of virion-associated apoE affected the ability of the virus to escape neutralization by antibodies. Conclusions In cell-infection studies, we found that HCV-associated apoE helps the virus avoid neutralization by antibodies against HCV isolated from chronically infected patients. This method of immune evasion poses a challenge for the development of HCV vaccines

Subjects with mild alopecia benefit from aminexil clinical 5: results of a large international observational study

Introduction and objectives: Androgenetic alopecia in men (AGA) and female pattern hair loss (FPHL) are common hair loss causes which may heavily influence self-esteem and self-image. AGA and FPHL are caused by the heightened sensitivity of scalp follicles to dihydro-testosterone leading to dysregulation of downstream signaling cascades of inflammation. As a consequence a process of hair miniaturization develops over the time usually paralleled with a characteristic pattern distribution that varies between men and women. Histological observations showed perifollicular cells infiltrates and micro-inflammation. As this is a chronic condition, efficacy of products but also tolerability, cosmetic acceptance and patient satisfaction are key to ensure a good compliance. The aim of this study was to assess the benefit and tolerability of Aminexil clinical 5 (AC5, containing Aminexil, Arginine, SP94, piroctone olamine and Vichy mineralizing water as active ingredients) in subjects with mild alopecia. Materials and methods: This was an open-label, observational, international study conducted in real life settings in 527 adult female and male subjects with mild alopecia. At baseline subjects underwent a clinical examination including Ludwig for female and Hamilton Norwood scoring for male subjects and received AC5 to be applied once daily for a minimum of 45 days. At the end of treatment, subjects assessed their hair growth and quality, satisfaction and local tolerance; investigators evaluated the impact of AC5 on the subjects’ hair. Results: Data from 421 subjects were evaluable for the efficacy analysis. Tolerability data were available for 509 subjects. 58.7% of subjects were females; the mean age was 34.1±9.1 years. Duration of hair loss was 1.3±1.8 years in women and 2.3±2.6 years, overall mean duration was 1.7±2.2 years. AC5 was used in combination with prescription treatments in 14.8% of cases (mainly topical) at inclusion with non-medical products (topicals and/or orals) in 42.2% of cases; 71.3% of women had a Ludwig score of 1 and 40.8% of males had a Hamilton Norwood score of 2. After a mean of 82.9±17.5 days of use dermatologist evaluation rated an improvement in hair loss in 87.1% of subjects compared to baseline; it was somewhat better in women (91.8%) than in men (80.3%). Subject satisfaction on a scale from 0 (not satisfied at all) to 10 (completely satisfied) was 7.9±1.7. Tolerance was good to very good in 98.6% of subjects. The texture was considered pleasant by 95% of subjects. Conclusion: In subjects with mild alopecia, AC5 reduces hair loss in both men and women with a pleasant texture. AC5 was well tolerated and highly appreciated by subjects and investigators

A Randomized Comparison of High Clopidogrel Loading Doses in Patients With Non–ST-Segment Elevation Acute Coronary Syndromes The ALBION (Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis) Trial

ObjectivesWe sought to compare the antiplatelet effects of three clopidogrel loading doses (LDs).BackgroundAdministration of a 300-mg clopidogrel LD is beneficial in situations requiring rapid platelet inhibition. Whether higher LDs can provide further benefits remains unknown.MethodsPatients (n = 103) with non–ST-segment elevation acute coronary syndromes were randomized to receive a 300-mg, 600-mg, or 900-mg clopidogrel LD, given on top of other standard therapy (including acetylsalicylic acid). The main outcome measure was inhibition of adenosine diphosphate-induced inhibition of platelet aggregation (IPA); inhibition of platelet activation, inflammatory markers, troponin I release, and major adverse cardiac events also were evaluated; all measures were blindly evaluated.ResultsCompared with the 300-mg LD, greater doses were associated with significantly greater platelet inhibition, with dose-effect relationships observed for onset of action, maximal plateau, 24-h areas under the curves of IPA, and rates of low IPA (<10% at 6 h), using 20 μmol/l major adverse cardiac events. A significant dose-response was also observed for the vasodilator-stimulated phosphoprotein index, a measure of P2Y12receptor inhibition. Similar but nonsignificant trends were observed for troponin release and major adverse cardiac events. Bleeding rates were similar in each group.ConclusionsIn low-to-moderate risk patients with non–ST-elevation acute coronary syndromes, clopidogrel LDs >300 mg provide a faster onset of action, a higher IPA plateau, and greater reductions in platelet activation during the first 24 h. A 900-mg LD may induce a greater antiplatelet effect than 600 mg, when compared with the standard 300-mg regimen. These findings require further clinical confirmation

Comparison of Enzymatic and Non-Enzymatic Means of Dissociating Adherent Monolayers of Mesenchymal Stem Cells

The dissociation of adherent mesenchymal stem cell (MSC) monolayers with trypsin and enzyme-free dissociation buffer was compared. A significantly lower proportion of viable cells were obtained with enzyme-free dissociation buffers compared to trypsin. Subsequently, the dissociated cells were re-seeded on new cell culture dishes and were subjected to the MTT assay 24 h later. The proportion of viable cells that reattached was significantly lower for cells obtained by dissociation with enzyme-free dissociation buffer compared to trypsin. Frozen–thawed MSC displayed a similar trend, yielding consistently higher cell viability and reattachment rates when dissociated with trypsin compared to enzyme-free dissociation buffer. It was also demonstrated that exposure of trypsin-dissociated MSC to enzyme-free dissociation buffer for 1 h had no significant detrimental effect on cell viability

La dissection de l'aorte descendante dans le syndrome de Marfan

Le syndrome de Marfan est une maladie héréditaire à transmission autosomique dominante généralement due à une mutation du gène codant pour la fibrilline de type 1(FBN 1) situé sur le chromosome 15. C'est une maladie du tissu conjonctif qui est caractérisée par une atteinte squelettique, cutanée, oculaire et cardio-vasculaire. Les manifestations cardio-vasculaires (dilatation et dissection de l'aorte ascendante principalement) conditionnent le pronostic vital et sont présentes dans 90 % des cas. La dissection de l'aorte descendante dans le syndrome de Marfan est peu décrite dans la littérature. C'est pourquoi nous avons réalisé une étude rétrospective afin d'étudier la prévalence et l'évolution de la dissection de l'aorte descendante parmi les 415 patients porteurs d'un syndrome de Marfan suivis à Ambroise Paré. Une dissection de l'aorte descendante a été observée chez 30 patients (soit 7.2 %) de notre population Marfan. C'est une extension d'une dissection de l'aorte ascendante dans ß des cas. L'évènements au cours du suivi sont une chirurgie de l'aorte descendante chez sept patients (une en urgence et six pour dilatation anévrismale après 0.4, 2.3, 3.4, 4.3, 4.8, et 7.1 années de suivi), un traitement endo-vasculaire chez un patient pour dilatation anévrismale après 2.2 années de suivi et un décès chez quatre patients 1.5, 4.2, 9.8, 2.3 années après le diagnostic. Après 50 mois de suivi, seulement 53 % des patients n'ont présenté aucun événement et la survie est de 87 %. En conclusion, la dissection de l'aorte descendante est habituellement une extension d'une dissection de l'aorte ascendante et se complique de chirurgie ou de décès dans plus de 50 % des cas. Il faut donc proposer une intervention prophylactique de remplacement de l'aorte ascendante avant la survenue d'une dissection de l'aorte ascendante et ainsi prévenir une extension au niveau de l'aorte descendante qui aggrave le pronostic.PARIS7-Xavier Bichat (751182101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Surgical management of patients with Marfan syndrome: Evolution throughout the years

International audienceTo evaluate the evolution of surgical management in a large population of patients with Marfan syndrome

Immuno-comparative screening of adult-derived human liver stem/progenitor cells for immune-inflammatory-associated molecules

Objective: One of the main challenges in liver cell therapy is the replacement of damaged cells and the induction of a tolerogenic microenvironment to promote graft acceptance by the recipient. Adult-derived human liver stem/progenitor cells (ADHLSCs) are currently evaluated at the clinical levels as a promising pro-regenerative and immune-modulatory tool. The expression profile of several immunological molecules may influence the local immune-inflammatory response and, therefore, modulate the tissue healing process. To increase the quality and safety of ADHLSCs before transplantation requires an appropriate analysis and characterization of their pattern expression of immune-inflammatory-associated molecules. Methods: The expression of 27 molecules belonging to T-cell co-stimulatory pathway, CD47 partners, Ikaros family, CD300 family and TNF family were analyzed using flow cytometry. We compared their expression profiles to PBMCs, hepatocytes and ADHLSCs in both expansion and after hepatogenic differentiation culture conditions. Results: This original immuno-comparative screening revealed that liver cell populations do not constitutively present significant immunological pattern compared to PBMCs. Moreover, our findings highlight that neither the expansion nor the hepatogenic differentiation induces the expression of immune-inflammatory molecules. The detailed expression characteristics (percentage of positive cells and median fluorescence intensity) of each molecule were analyzed and presented. Conclusion: By analyzing 27 relevant molecules, our immuno-comparative screening demonstrates that ADHLSCs keep a non-immunogenic profile independent of their expansion or hepatogenic differentiation state. Accordingly, the immunological profile of ADHLSCs seems to support their safe and efficient use in liver tissue therapeutic repair strategy

How to predict poor outcome in older patients receiving chemotherapy for malignant lymphoma: a new frailty scoring

info:eu-repo/semantics/publishe