Comparative genetic analyses point to HCP5 as susceptibility locus for HCV-associated hepatocellular carcinoma.

BACKGROUND & AIMS: Recently, genetic variations in MICA (lead single nucleotide polymorphism [SNP] rs2596542) were identified by a genome-wide association study (GWAS) to be associated with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) in Japanese patients. In the present study, we sought to determine whether this SNP is predictive of HCC development in the Caucasian population as well. METHODS: An extended region around rs2596542 was genotyped in 1924 HCV-infected patients from the Swiss Hepatitis C Cohort Study (SCCS). Pair-wise correlation between key SNPs was calculated both in the Japanese and European populations (HapMap3: CEU and JPT). RESULTS: To our surprise, the minor allele A of rs2596542 in proximity of MICA appeared to have a protective impact on HCC development in Caucasians, which represents an inverse association as compared to the one observed in the Japanese population. Detailed fine-mapping analyses revealed a new SNP in HCP5 (rs2244546) upstream of MICA as strong predictor of HCV-related HCC in the SCCS (univariable p=0.027; multivariable p=0.0002, odds ratio=3.96, 95% confidence interval=1.90-8.27). This newly identified SNP had a similarly directed effect on HCC in both Caucasian and Japanese populations, suggesting that rs2244546 may better tag a putative true variant than the originally identified SNPs. CONCLUSIONS: Our data confirms the MICA/HCP5 region as susceptibility locus for HCV-related HCC and identifies rs2244546 in HCP5 as a novel tagging SNP. In addition, our data exemplify the need for conducting meta-analyses of cohorts of different ethnicities in order to fine map GWAS signals.

Gender, family and employment in comparative perspective: the realities and representations of rqual rpportunities in Britain and France

In this paper, we will explore how contrasting national discourses relating to women, and gender equality have been incorporated into and reflected in national policies. In the first section, we will outline the recent history of EU equal opportunities policy, in which positive action has been replaced by a policy of 'mainstreaming'. Second, we will describe the evolution of policies towards women and equal opportunities in Britain and France. It will be argued that whereas some degree of positive action for women has been accepted in Britain, this policy is somewhat alien to French thinking about equality - although pro-natalist French policies have resulted in favourable conditions for employed mothers in France. In the third section, we will present some attitudinal evidence, drawn from national surveys, which would appear to reflect the national policy differences we have identified in respect of the 'equality agenda'. In the fourth section, we will draw upon biographical interviews carried out with men and women in British and French banks in order to illustrate the impact of these cross-national differences within organizations and on individual lives. We demonstrate that positive action gender equality policies have made an important impact in British banks, while overt gender exclusionary practices still persist in the French banks studied. In the conclusion, we reflect on the European policy implications of our findings.

Liposome-mediated transfection of fetal lung epithelial cells: DNA degradation and enhanced superoxide toxicity.

Cationic liposomes, 1:1 (mol/mol) 1,2-dioleoyldimethylammonium chloride-1,2-dioleoyl-sn-glycero-3-phosphoethanolamine, were used to transfect primary cultures of distal rat fetal lung epithelial cells with pCMV4-based plasmids. A DNA-to-lipid ratio of 1:10 to 1:15 (wt/wt) optimized DNA uptake over a 24-h exposure. At a fixed DNA-to-lipid ratio of 1:15, chloramphenicol acetyltransferase (CAT) reporter gene expression declined at lipid concentrations > 2.5 nmol/cm2 cell surface area, whereas DNA uptake remained concentration dependent. CAT expression peaked 48 h after removal of the liposome-DNA complex, declining thereafter. Reporter gene expression was increased, and supercoiled cDNA degradation was reduced by the addition of 0.2 mM nicotinamide and 10 microM chloroquine. Rat fetal lung epithelial cells transfected with two different expression cassettes had an increased susceptibility to superoxide-mediated cytotoxicity. This could be attributed to a nonspecific delivery of exogenous DNA or some other copurified factor. The DNA-dependent increase in superoxide-mediated cytotoxicity, but not basal levels of cytotoxicity, was inhibited by the addition of 0.2 mM nicotinamide and 10 microM chloroquine.

Traitement du décollement de rétine du pseudophaque: étude rétrospective comparant la vitrectomie sans indentation au traitement ab-externo [Vitrectomy without scleral buckle versus ab-externo approach for pseudophakic retinal detachment: comparative retrospective study].

PURPOSE: Retinal detachment (RD) is a major complication of cataract surgery, which can be treated by either primary vitrectomy without indentation or the scleral buckling procedure. The aim of this study is to compare the results of these two techniques for the treatment of pseudophakic RD. PATIENTS AND METHODS: The charts of 40 patients (40 eyes) treated with scleral buckling for a primary pseudophakic RD were retrospectively studied and compared to the charts of 32 patients (32 eyes) treated with primary vitrectomy without scleral buckle during the same period by the same surgeons. To obtain comparable samples, patients with giant retinal tears, vitreous hemorrhage, and severe preoperative proliferative vitreoretinopathy (PVR) were not included. Minimal follow-up was 6 months. RESULTS: The primary success rate was 84% in the vitrectomy group and 82.5% in the ab-externo group. Final anatomical success was observed in 100% of cases in the vitrectomy group and in 95% of cases in the ab-externo group. Final visual acuity was 0.5 or better in 44% of cases in the vitrectomy group and 37.5% in the ab-externo group. The duration of the surgery was significantly lower in the ab-externo group, whereas the hospital stay tended to be lower in the vitrectomy group. In the vitrectomy group, postoperative PVR developed in 3 eyes and new or undetected breaks were responsible for failure of the initial procedure in 2 eyes. CONCLUSION: Primary vitrectomy appears to be as effective as scleral buckling procedures for the treatment of pseudophakic RD.

Evaluation of aggregating brain cell cultures for the detection of acute organ-specific toxicity.

As part of the ACuteTox project aimed at the development of non-animal testing strategies for predicting human acute oral toxicity, aggregating brain cell cultures (AGGR) were examined for their capability to detect organ-specific toxicity. Previous multicenter evaluations of in vitro cytotoxicity showed that some 20% of the tested chemicals exhibited significantly lower in vitro toxicity as expected from in vivo toxicity data. This was supposed to be due to toxicity at supracellular (organ or system) levels. To examine the capability of AGGR to alert for potential organ-specific toxicants, concentration-response studies were carried out in AGGR for 86 chemicals, taking as endpoints the mRNA expression levels of four selected genes. The lowest observed effect concentration (LOEC) determined for each chemical was compared with the IC20 reported for the 3T3/NRU cytotoxicity assay. A LOEC lower than IC20 by at least a factor of 5 was taken to alert for organ-specific toxicity. The results showed that the frequency of alerts increased with the level of toxicity observed in AGGR. Among the chemicals identified as alert were many compounds known for their organ-specific toxicity. These findings suggest that AGGR are suitable for the detection of organ-specific toxicity and that they could, in conjunction with the 3T3/NRU cytotoxicity assay, improve the predictive capacity of in vitro toxicity testing.

Effect of a Road Safety Training Program on Drivers' Comparative Optimism

Reducing comparative optimism regarding risk perceptions in traffic accidents has been proven to be particularly difficult (Delhomme, 2000). This is unfortunate because comparative optimism is assumed to impede preventive action. The present study tested whether a road safety training course could reduce drivers' comparative optimism in high control situations. Results show that the training course efficiently reduced comparative optimism in high control, but not in low control situations. Mechanisms underlying this finding and implications for the design of road safety training courses are discussed.

The novel hydroxylamine derivative NG-094 suppresses polyglutamine protein toxicity in Caenorhabditis elegans.

Aggregation-prone polyglutamine (polyQ) expansion proteins cause several neurodegenerative disorders, including Huntington disease. The pharmacological activation of cellular stress responses could be a new strategy to combat protein conformational diseases. Hydroxylamine derivatives act as co-inducers of heat-shock proteins (HSPs) and can enhance HSP expression in diseased cells, without significant adverse effects. Here, we used Caenorhabditis elegans expressing polyQ expansions with 35 glutamines fused to the yellow fluorescent protein (Q35-YFP) in body wall muscle cells as a model system to investigate the effects of treatment with a novel hydroxylamine derivative, NG-094, on the progression of polyQ diseases. NG-094 significantly ameliorated polyQ-mediated animal paralysis, reduced the number of Q35-YFP aggregates and delayed polyQ-dependent acceleration of aging. Micromolar concentrations of NG-094 in animal tissues with only marginal effects on the nematode fitness sufficed to confer protection against polyQ proteotoxicity, even when the drug was administered after disease onset. NG-094 did not reduce insulin/insulin-like growth factor 1-like signaling, but conferred cytoprotection by a mechanism involving the heat-shock transcription factor HSF-1 that potentiated the expression of stress-inducible HSPs. NG-094 is thus a promising candidate for tests on mammalian models of polyQ and other protein conformational diseases.

Voix inouïes : étude comparative de l'enchâssement dans "Leucippé et Clitophon" d'Achille Tatius et les "Métamorphoses" d'Apulée

Cette thèse de doctorat propose une analyse comparative détaillée du phénomène de l'enchâssement narratif dans deux textes antiques du IIe s. apr. J.-C. : Leucippé et Clitophon d'Achille Tatius, écrit en grec ancien, et les Métamorphoses d'Apulée, en latin. Ces deux oeuvres sont rattachées par la critique moderne à un genre désigné comme le roman antique.Si le corpus est abordé de façon minutieuse, ce travail n'a pas la forme du commentaire philologique traditionnel, mais d'une nouvelle forme de commentaire, inspirée du Narratological Commentary de VOdyssée par Irene de Jong. L'analyse est sous-tendue par divers mouvements de synthèse et de comparaison ; cela est fait en recourant à diverses méthodes provenant de différents domaines de recherche : philologie grecque et latine, rhétorique antique, narratologie moderne et comparaison différentielle, telle que proposée par Ute Heidmann, qui défend une approche des textes non-hiérarchisante, focalisée autant sur les ressemblances que les dissemblances et les différences entre les textes étudiés.A la croisée de ces différents domaines de recherche, la thèse tente d'offrir de nouveaux apports. Sur le plan philologique, cette étude comparative de l'enchâssement dans deux textes antiques porte l'attention sur des voix et des récits qui étaient encore restés « in-ouïs » par la critique ; en ce sens qu'ils n'avaient pas encore été tous étudiés. Appliquant une comparaison non-hiérarchisante et différentielle, cette thèse va à l'encontre de deux opinions communes en philologie classique. Elle nuance l'idée générale d'une séparation étanche entre roman grec et roman latin, ainsi que l'idée reçue selon laquelle le dialogue entre la culture grecque et latine serait unilatéral, allant seulement du grec au latin et non pas aussi vice-versa. En ce qui concerne la critique sur l'enchâssement en philologie classique et plus concrètement dans les travaux sur le roman antique, l'apport de cette thèse peut être résumé par les termes « contextualisant » et « englobant ». Le contexte culturel de la Seconde Sophistique, mouvement fortement marqyé par la performance, l'oralité et la rhétorique, est pris en compte en prenant appui, en particulier, sur les traités d'art oratoire et les exercices de rhétorique. Si l'importance de ces derniers a été récemment reconnue et leur intérêt renouvelé par la critique, un rapprochement explicite avec le phénomène de l'enchâssement n'avait pas encore été effectué. Par ailleurs, l'étude du récit enchâssé dans deux romans antiques est ici, pour la première fois, effectuée dans son intégralité, en vue de mieux comprendre le procédé de l'enchâssement au sein des oeuvres étudiées, mais aussi en tant que phénomène à part entière.Sur le plan narratologique, la prise en considération de tous les récits enchâssés a permis de proposer l'ébauche d'une « grammaire de l'enchâssement narratif », applicable aussi à d'autres textes. Pour ce faire, le dispositif conceptuel proposé, entre autres, par Genette a été étendu et affiné. Les notions de récit et d'histoire ont également été élargies. Considérant l'histoire comme tout contenu comportant des séquences logico-temporelles, la narrativité a été étendue à tout discours portant sur cette histoire, ce qui a permis d'intégrer dans l'étude des rêves, oracles, plans, lamentations aussi bien que des actes comme les menaces, promesses, reproches, et même les énumérations et descriptions.Soulignant le dialogue entre la culture grecque et latine, la comparaison menée dans ce travail peut être qualifiée d'interculturelle et d'interdisciplinaire, en raison de l'intégration dialogique des philologies grecque et latine, de la narratologie et de la rhétorique.

Comparative study and identification of potent eukaryotic transcriptional repressors in gene switch systems.

In mammalian cells, proper gene regulation is achieved by the complex interplay of transcription factors that activate or repress gene expression by binding to the regulatory regions of target promoters. While transcriptional activators have been extensively characterised and classified into functional groups, relatively little is known about the comparative strength and cell type-specificity of transcriptional repressors. Here, we have compared the ability of a series of eukaryotic repression domains to silence basal and activated transcription. A series of the most potent repression domains was further tested in the context of a gene therapy gene-switch system in various cell types. The results indicate that the analysed repression domains exert varying silencing activities in different promoter contexts. Furthermore, their potential for gene silencing varies also depending on the cellular context. When multimerised within one chimeric repressor protein, particular combinations of repressor domains were found to display synergistic repressing effects and efficient repression in a panel of cell lines. This approach thus allowed the identification of transcriptional repressors that are both potent and versatile in terms of cellular specificity as a basis for gene switch systems.