Search

Abstract Background Inflammation may be involved in the pathogenesis of Alzheimer's disease (AD). There has been little success with anti-inflammatory drugs in AD, while the promise of anti-inflammatory treatment is more evident in experimental models. A new anti-inflammatory strategy requires a better understanding of molecular mechanisms. Among the plethora of signaling pathways activated by β-amyloid (Aβ) peptides, the nuclear factor-kappa B (NF-κB) pathway could be an interesting target. In virus-infected cells, double-stranded RNA-dependent protein kinase (PKR) controls the NF-κB signaling pathway. It is well-known that PKR is activated in AD. This led us to study the effect of a specific inhibitor of PKR on the Aβ42-induced inflammatory response in primary mixed murine co-cultures, allowing interactions between neurons, astrocytes and microglia. Methods Primary mixed murine co-cultures were prepared in three steps: a primary culture of astrocytes and microglia for 14 days, then a primary culture of neurons and astrocytes which were cultured with microglia purified from the first culture. Before exposure to Aβ neurotoxicity (72 h), co-cultures were treated with compound C16, a specific inhibitor of PKR. Levels of tumor necrosis factor-α (TNFα), interleukin (IL)-1β, and IL-6 were assessed by ELISA. Levels of PT451-PKR and activation of IκB, NF-κB and caspase-3 were assessed by western blotting. Apoptosis was also followed using annexin V-FITC immunostaining kit. Subcellular distribution of PT451-PKR was assessed by confocal immunofluorescence and morphological structure of cells by scanning electron microscopy. Data were analysed using one-way ANOVA followed by a Newman-Keuls' post hoc test Results In these co-cultures, PKR inhibition prevented Aβ42-induced activation of IκB and NF-κB, strongly decreased production and release of tumor necrosis factor (TNFα) and interleukin (IL)-1β, and limited apoptosis. Conclusion In spite of the complexity of the innate immune response, PKR inhibition could be an interesting anti-inflammatory strategy in AD.

© 2015 Johnson et al.Fifty percent of variability in HIV-1 susceptibility is attributable to host genetics. Thus identifying genetic associations is essential to understanding pathogenesis of HIV-1 and important for targeting drug development. To date, how

The key-features (KFs) approach to assessment was initially proposed during the First Cambridge Conference on Medical Education in 1984 as a more efficient and effective means of assessing clinical decision-making skills. Over three decades later, we conducted a comprehensive, systematic review of the validity evidence gathered since then. The evidence was compiled according to the "Standards for Educational and Psychological Testing"'s five sources of validity evidence, namely, Content, Response process, Internal structure, Relations to other variables, and Consequences, to which we added two other types related to Cost-feasibility and Acceptability. Of the 457 publications that referred to the KFs approach between 1984 and October 2017, 164 are cited here; the remaining 293 were either redundant or the authors simply mentioned the KFs concept in relation to their work. While one set of articles reported meeting the validity standards, another set examined KFs test development choices and score interpretation. The accumulated validity evidence for the KFs approach since its inception supports the decision-making construct measured and its use to assess clinical decision-making skills at all levels of training and practice and with various types of exam formats. Recognizing that gathering validity evidence is an ongoing process, areas with limited evidence, such as item factor analyses or consequences of testing, are identified as well as new topics needing further clarification, such as the use of the KFs approach for formative assessment and its place within a program of assessment.

Information, communication, and educational technologies hold promise to connect geographically isolated rural communities, offering adults greater access to educational, financial, and numerous other resources. The Internet and computer-based network technologies are often seen as remedies for communities in economic decline, but they also have the potential to divide. When the tool of technology is not effectively introduced and proper training not offered, potential exists to widen the schism (Schiller, 1996) between the coexisting and competing social systems of indigenous people and non-Natives. This article provides insight into the issues surrounding the diffusion of information and communication technologies into rural Alaskan communities. To gain insight into the context of technology and rural Alaska, interviews were conducted with three rural Alaska educators and technology coordinators from different geographical locations. The purpose was to explore the status of educational technologies, how change and technology are perceived, and what the future holds. The effective use of information and computer technologies for education in the rural areas of Alaska necessitates many challenges. The areas of content, connectivity, capability, and cultural context are thematic issues around the larger concern of access that emerged from the interviews. (Contains 1 figure.)