Developing Effective Alzheimer's Disease Therapies: Clinical Experience and Future Directions

Alzheimer's disease (AD) clinical trials, focused on disease modifying drugs and conducted in patients with mild to moderate AD, as well as prodromal (early) AD, have failed to reach efficacy endpoints in improving cognitive function in most cases to date or have been terminated due to adverse events. Drugs that have reached clinical stage were reviewed using web resources (such as clinicaltrials.gov, alzforum.org, company press releases, and peer reviewed literature) to identify late stage (Phase II and Phase III) efficacy clinical trials and summarize reasons for their failure. For each drug, only the latest clinical trials and ongoing trials that aimed at improving cognitive function were included in the analysis. Here we highlight the potential reasons that have hindered clinical success, including clinical trial design and choice of outcome measures, heterogeneity of patient populations, difficulties in diagnosing and staging the disease, drug design, mechanism of action, and toxicity related to the long-term use. We review and suggest approaches for AD clinical trial design aimed at improving our ability to identify novel therapies for this devastating disease

Microarray detection of human parainfluenzavirus 4 infection associated with respiratory failure in an immunocompetent adult.

A pan-viral DNA microarray, the Virochip (University of California, San Francisco), was used to detect human parainfluenzavirus 4 (HPIV-4) infection in an immunocompetent adult presenting with a life-threatening acute respiratory illness. The virus was identified in an endotracheal aspirate specimen, and the microarray results were confirmed by specific polymerase chain reaction and serological analysis for HPIV-4. Conventional clinical laboratory testing using an extensive panel of microbiological tests failed to yield a diagnosis. This case suggests that the potential severity of disease caused by HPIV-4 in adults may be greater than previously appreciated and illustrates the clinical utility of a microarray for broad-based viral pathogen screening

Squirrelpox virus: assessing prevalence, transmission and environmental degradation

Red squirrels (Sciurus vulgaris) declined in Great Britain and Ireland during the last century, due to habitat loss and the introduction of grey squirrels (Sciurus carolinensis), which competitively exclude the red squirrel and act as a reservoir for squirrelpox virus (SQPV). The disease is generally fatal to red squirrels and their ecological replacement by grey squirrels is up to 25 times faster where the virus is present. We aimed to determine: (1) the seropositivity and prevalence of SQPV DNA in the invasive and native species at a regional scale; (2) possible SQPV transmission routes; and, (3) virus degradation rates under differing environmental conditions. Grey (n = 208) and red (n = 40) squirrel blood and tissues were sampled. Enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qPCR) techniques established seropositivity and viral DNA presence, respectively. Overall 8% of squirrels sampled (both species combined) had evidence of SQPV DNA in their tissues and 22% were in possession of antibodies. SQPV prevalence in sampled red squirrels was 2.5%. Viral loads were typically low in grey squirrels by comparison to red squirrels. There was a trend for a greater number of positive samples in spring and summer than in winter. Possible transmission routes were identified through the presence of viral DNA in faeces (red squirrels only), urine and ectoparasites (both species). Virus degradation analyses suggested that, after 30 days of exposure to six combinations of environments, there were more intact virus particles in scabs kept in warm (25°C) and dry conditions than in cooler (5 and 15°C) or wet conditions. We conclude that SQPV is present at low prevalence in invasive grey squirrel populations with a lower prevalence in native red squirrels. Virus transmission could occur through urine especially during warm dry summer conditions but, more notably, via ectoparasites, which are shared by both species

The Metabolic Stress Response to Burn Trauma: Current Understanding and Therapies

Summary Severe burns incur a profound stress response, which is unrivaled in terms of its magnitude and duration. Recent evidence suggests that the pathophysiological stress response to severe burns persists for several years post injury. Thus, there is a pressing need for novel strategies that mitigate this response and restore normal metabolic function in burn survivors. This is the first installment of a three-part series exploring the stress response to severe burn trauma. In this article we aim to distill the current knowledge pertaining to the stress response to burn trauma, highlighting recent developments and important knowledge gaps that need to be pursued in order to develop novel therapeutic strategies which improve outcomes in burn survivors

A slowly rotating coil system for AC field measurements of Fermilab booster correctors

A method for measurement of rapidly changing magnetic fields has been developed and applied to the testing of new room temperature corrector packages designed for the Fermilab Booster Synchrotron. The method is based on fast digitization of a slowly rotating tangential coil probe, with analysis combining the measured coil voltages across a set of successive magnet current cycles. This paper presents results on the field quality measured for the normal and skew dipole, quadrupole, and sextupole elements in several of these corrector packages

The Tito-Stalin Split 70 Years After

The goal of the Zagreb conference “The Tito-Stalin Split: 70 Years Later”, Zagreb-Goli Otok, 28-30 June 2018, as well as of the papers presented, was to show not only the new interpretations and takes on the subject, but to present the Yugoslav 1948 as a global event, one that touched lives of so many people around the world. It had a very significant impact not only on politics, international relations, prisoners, army cooperation and army relations, ideology, but also cultural life and production, especially in Yugoslavia and the Soviet Union. Most of the papers presented at the Faculty of Humanities and Social Sciences, University of Zagreb, which co-organized the whole event with colleagues from the University of Ljubljana, Slovenia, are published in this volume. A few papers were presented but the authors did not contribute the text (those were: Mark Kramer, Peter Ruggenthaler, Ondřej Vojtěchovský, Klaus Buchenau, Andreii Edemskii, Boris Stamenić, and Marie-Janine Calic). Also, one paper on China was not presented, but the text is here. We hope this volume will be an important contribution to the continuous dialogue that should be not only regional, but global. It should also be ongoing, since there is hardly an event in the history of the Cold War whose consequences were as important and as global as this one’s. (from the Preface)The book is co-published by the University of Zagreb, Faculty of Humanities and Social Sciences – Department of History (Postgraduate Doctoral Studies “Modern and Contemporary Croatian History In European and World Context”) & the University of Ljubljana Faculty of Arts – Department of History, as a volume 31 in the Historia series. The goal of the Zagreb conference “The Tito-Stalin Split: 70 Years Later”, Zagreb-Goli Otok, 28-30 June 2018, as well as of the papers presented, was to show not only the new interpretations and takes on the subject, but to present the Yugoslav 1948 as a global event, one that touched lives of so many people around the world. It had a very significant impact not only on politics, international relations, prisoners, army cooperation and army relations, ideology, but also cultural life and production, especially in Yugoslavia and the Soviet Union.Most of the papers presented at the Faculty of Humanities and Social Sciences, University of Zagreb, which co-organized the whole event with colleagues from the University of Ljubljana, Slovenia, are published in this volume. A few papers were presented but the authors did not contribute the text (those were: Mark Kramer, Peter Ruggenthaler, Ondřej Vojtěchovský, Klaus Buchenau, Andreii Edemskii, Boris Stamenić, and Marie-Janine Calic). Also, one paper on China was not presented, but the text is here. We hope this volume will be an important contribution to the continuous dialogue that should be not only regional, but global. It should also be ongoing, since there is hardly an event in the history of the Cold War whose consequences were as important and as global as this one’s. (from the Preface)The book is co-published by the University of Zagreb, Faculty of Humanities and Social Sciences – Department of History (Postgraduate Doctoral Studies “Modern and Contemporary Croatian History In European and World Context”) & the University of Ljubljana Faculty of Arts – Department of History, as a volume 31 in the Historia series.&nbsp

Identification and Specification of the Mouse Skeletal Stem Cell

SummaryHow are skeletal tissues derived from skeletal stem cells? Here, we map bone, cartilage, and stromal development from a population of highly pure, postnatal skeletal stem cells (mouse skeletal stem cells, mSSCs) to their downstream progenitors of bone, cartilage, and stromal tissue. We then investigated the transcriptome of the stem/progenitor cells for unique gene-expression patterns that would indicate potential regulators of mSSC lineage commitment. We demonstrate that mSSC niche factors can be potent inducers of osteogenesis, and several specific combinations of recombinant mSSC niche factors can activate mSSC genetic programs in situ, even in nonskeletal tissues, resulting in de novo formation of cartilage or bone and bone marrow stroma. Inducing mSSC formation with soluble factors and subsequently regulating the mSSC niche to specify its differentiation toward bone, cartilage, or stromal cells could represent a paradigm shift in the therapeutic regeneration of skeletal tissues

Measurement of χ c1 and χ c2 production with s√ = 7 TeV pp collisions at ATLAS

The prompt and non-prompt production cross-sections for the χ c1 and χ c2 charmonium states are measured in pp collisions at s√ = 7 TeV with the ATLAS detector at the LHC using 4.5 fb−1 of integrated luminosity. The χ c states are reconstructed through the radiative decay χ c → J/ψγ (with J/ψ → μ + μ −) where photons are reconstructed from γ → e + e − conversions. The production rate of the χ c2 state relative to the χ c1 state is measured for prompt and non-prompt χ c as a function of J/ψ transverse momentum. The prompt χ c cross-sections are combined with existing measurements of prompt J/ψ production to derive the fraction of prompt J/ψ produced in feed-down from χ c decays. The fractions of χ c1 and χ c2 produced in b-hadron decays are also measured

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns