TLR1/2 Activation during Heterologous Prime-Boost Vaccination (DNA-MVA) Enhances CD8+ T Cell Responses Providing Protection against Leishmania (Viannia)

Leishmania (Viannia) are the predominant agents of leishmaniasis in Latin America. Given the fact that leishmaniasis is a zoonosis, eradication is unlikely; a vaccine could provide effective prevention of disease. However, these parasites present a challenge and we do not fully understand what elements of the host immune defense prevent disease. We examined the ability of vaccination to protect against L. (Viannia) infection using the highly immunogenic heterologous prime-boost (DNA-modified vaccinia virus) modality and a single Leishmania antigen (TRYP). Although this mode of vaccination can induce protection against other leishmaniases (cutaneous, visceral), no protection was observed against L. (V.) panamensis. However, we found that if the vaccination was modified and the innate immune response was activated through Toll-like receptor1/2(TLR1/2) during the DNA priming, vaccinated mice were protected. Protection was dependent on CD8 T cells. Vaccinated mice had higher CD8 T cell responses and decreased levels of cytokines known to promote infection. Given the long-term persistence of CD8 T cell memory, these findings are encouraging for vaccine development. Further, these results suggest that modulation of TLR1/2 signaling could improve the efficacy of DNA-based vaccines, especially where CD8 T cell activation is critical, thereby contributing to effective and affordable anti parasitic vaccines

A robust, mechanistically-based in silico structural profiler for hepatic cholestasis

Owing to the primary role which it holds within metabolism of xenobiotics, the liver stands at heightened risk of exposure to, and injury from, potentially hazardous substances. A principal manifestation of liver dysfunction is cholestasis – the impairment of physiological bile circulation from its point of origin within the organ to site of action at the small intestine. The capacity for early identification of compounds liable to exert cholestatic effect is of particular utility within the field of pharmaceutical development, where contribution towards candidate attrition is great. Shortcomings associated with present in vitro methodologies forecasting cholestasis render their predictivity questionable, permitting scope for adoption of computational toxicology techniques. As such, the intention of this study has been to construct an in silico profiler, founded upon clinical data, highlighting structural motifs most reliably associated with the endpoint. Drawing upon a list of greater than 1500 small molecular drugs, compiled and annotated by Kotsampasakou and Ecker, we have formulated a series of fifteen structural alerts. These describe fragments intrinsic within distinct pharmaceutical classes including psychoactive tricyclics, beta-lactam antimicrobials and oestrogenic/androgenic steroids. Description of the coverage and selectivity of each is provided, alongside consideration of underlying reactive mechanisms and relevant structure-activity concerns. Provision of mechanistic anchoring ensures that potential exists for framing within the adverse outcome pathway (AOP) paradigm – the chemistry conveyed through the alert in particular enabling rationalisation at the level of the molecular initiating event (MIE)

Comitê de Ética em Pesquisa da Escola de Enfermagem da USP: experiência dos primeiros seis anos Comité de Ética en Investigación de la Escuela de Enfermería de la USP: experiencia de los primeros seis años de funcionamiento Research Ethics Committee of the University of São Paulo Nursing School: experience of the first six years

O objetivo do estudo foi conhecer a experiência do Comitê de Ética em Pesquisa da Escola de Enfermagem da USP (CEP-EEUSP), nos seus primeiros seis anos. O estudo exploratório, descritivo, retrospectivo e de abordagem quantitativa foi realizado pelo levantamento dos registros do CEP-EEUSP e dos 401 protocolos de pesquisa submetidos à apreciação, no período de 31 de agosto de 1998 a 17 de setembro de 2004. Os resultados evidenciaram que 98,7% dos projetos submetidos eram de pesquisadores da EEUSP; 31,4% eram de dissertações de mestrado e 29,1% de iniciação científica. Quanto ao método, 43,8% propunham a utilização do método qualitativo. Além disso, 99,2% dos projetos pertenciam à área temática do Grupo III; 58,8% previam a utilização de instituições públicas e 31,7% tinham profissionais, principalmente enfermeiros, como sujeitos das pesquisas. O Termo de Consentimento Livre e Esclarecido foi responsável por 56,4% das pendências. A experiência do CEP-EEUSP mostra sua progressiva consolidação.<br>El objetivo de este estudio fue conocer la experiencia del Comité de Ética en Investigación de la Escuela de Enfermería de la USP en los primeros seis años de funcionamiento. Se trata de un estudio exploratorio, descriptivo, retrospectivo e de abordaje cuantitativo realizado con base en los registros del CEP-EEUSP y de los 401 protocolos de investigación presentados para evaluación en el período del 31 de agosto de 1998 hasta 17 de septiembre de 2004. Los resultados mostraron que 98,7% de los proyectos fueron presentados por investigadores de la EEUSP; 31,4% eran de trabajos de maestría y 29,1% de iniciación científica. Cuanto a los métodos utilizados, 43,8% de los proyectos eran relativos al abordaje cualitativo. Además, 99,2% pertenecían a la área temática del Grupo III; 58,8% propusieron la utilización de instituciones públicas y 31,7% tenían profesionales, principalmente enfermeros, como sujetos investigados. El Termo de Consentimiento Libre e Informado fue el responsable por 56,4% de las pendencias. La experiencia del CEP-EEUSP muestra su progresiva consolidación.<br>The aim of this study was to know the experience of the first six years of the Research Ethics Committee (REC) of the University of São Paulo Nursing School activities. The exploratory, descriptive, retrospective and quantitative study analised the records of the REC and of all the 401 research protocols submitted for appreciation from 31st August, 1998 to 17th September, 2004. The results showed that 98.7% of protocols were from in-house researchers; 31.4% were master degree dissertations and 29.1% were graduate students scientific initiation. Qualitative methods were used by 43.8%. Furthemore, 99.2% were classified as Group III thematic area; 58.8% researches were conducted in public institutions and 31.7% enrolled professionals, mostly nurses as research subjects. Informed Consent accounts for 56.4% of the REC's querries. The experience of the REC of the University of São Paulo Nursing School shows its progressive consolidation