Rabies virus-specific human T cell clones provide help for an in vitro antibody response against neutralizing antibody-inducing determinants of the viral glycoprotein.

Human T cell clones were prepared from peripheral blood mononuclear cells from a vaccinated human donor and kept in culture in the presence of rabies virus antigen and growth factors. Phenotypic analysis of the T cell clones revealed expression of the CD3 and CD4 cell surface markers, but not of CD8, consistent with a phenotype of helper/inducer T cells. The rabies virus specificity of the T cell clones was established by virus-specific proliferation in response to the rabies virus Pitman-Moore strain (PM) produced in three different cell substrates. The clones also responded to the rabies virus strains Evelyn-Rokitnicki-Abelseth (ERA) and challenge virus standard (CVS), but not to the rabies virus-related Mokola and Duvenhage-6 virus strains. Proliferative responses of T cell clones required rabies virus antigen to be presented by autologous antigen-presenting cells in association with HLA class II molecules. When cultured with rabies virus antigen, but in the absence of growth factors, some of the T cell clones provided help for an antibody response of rabies virus immune B lymphocytes. Analysis of culture supernatant fluids showed that at least a part of this antibody response was directed against neutralizing antibody-inducing determinants of the viral glycoprotein

Higher prevalence of mental disorders in socioeconomically deprived urban areas in The Netherlands: community or personal disadvantage?

OBJECTIVE: Major mental disorders occur more frequently in deprived urban areas. This study examines whether this occurs for all mental disorders, including less serious ones. It further assesses whether such a concentration can be explained by the socioeconomic status (SES) of the residents concerned or that a cumulation of problems in deprived areas reinforces their occurrence. DESIGN: Mental disorders were assessed by means of the General Health Questionnaire (GHQ) among 4892 residents. Additional data were obtained on area deprivation, and on individual SES. Multilevel logistic regression models were used to take the hierarchical structure of the data into account, residents being nested in boroughs. SETTING: General population of the city of Amsterdam, the Netherlands. MAIN OUTCOME MEASURE: Prevalence of an increased (> or = 2) score on the GHQ, 12 item version. RESULTS: Mental disorders occur more frequently in deprived areas but this can be explained by the lower SES of the residents concerned. CONCLUSIONS: The cumulation of mental disorders in deprived urban areas is mainly a result of a concentration of low SES people in these areas. Contextual factors of deprived urban areas give hardly any additional risk above that resulting from a low individual SES.

Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment

Contains fulltext : 155226.pdf (publisher's version ) (Closed access)Temozolomide (TMZ) increases the overall survival of patients with glioblastoma (GBM), but its role in the clinical management of diffuse low-grade gliomas (LGG) is still being defined. DNA hypermethylation of the O (6) -methylguanine-DNA methyltransferase (MGMT) promoter is associated with an improved response to TMZ treatment, while inactivation of the DNA mismatch repair (MMR) pathway is associated with therapeutic resistance and TMZ-induced mutagenesis. We previously demonstrated that TMZ treatment of LGG induces driver mutations in the RB and AKT-mTOR pathways, which may drive malignant progression to secondary GBM. To better understand the mechanisms underlying TMZ-induced mutagenesis and malignant progression, we explored the evolution of MGMT methylation and genetic alterations affecting MMR genes in a cohort of 34 treatment-naive LGGs and their recurrences. Recurrences with TMZ-associated hypermutation had increased MGMT methylation compared to their untreated initial tumors and higher overall MGMT methylation compared to TMZ-treated non-hypermutated recurrences. A TMZ-associated mutation in one or more MMR genes was observed in five out of six TMZ-treated hypermutated recurrences. In two cases, pre-existing heterozygous deletions encompassing MGMT, or an MMR gene, were followed by TMZ-associated mutations in one of the genes of interest. These results suggest that tumor cells with methylated MGMT may undergo positive selection during TMZ treatment in the context of MMR deficiency