The perception of indoor and outdoor exercise environments and their effect on mood states, heart rate, and running time

This study investigated indoor and outdoor exercise environments and their effect on mood states, heart rate, and running time. [This is an excerpt from the abstract. For the complete abstract, please see the document.

Dietary nutrients implicated in the etiopathogenesis of human and animal diseases

Hyperthyroidism is a spontaneous disease that results in an abnormal elevation of circulating concentrations of one or more thyroid hormones. Despite being the most commonly diagnosed endocrine disorder of domestic cats, the etiopathogenesis remains unknown. My dissertation research sought to investigate whether the dietary nutrients selenium, water, and taurine cause an overstimulation of the thyroid gland and alter the function of the hypothalamic-pituitary-thyroid axis. Because feline hyperthyroidism is clinically and pathologically similar to toxic nodular goiter or Plummer's disease, one of the most common types of hyperthyroidism in humans, I sought to determine if cats are a better animal model than rats for studying dietary causes of hyperthyroidism. To my knowledge, this is the first project to conduct simultaneous animal studies where two species are assessed for suitability as animal models for a human disease and concurrently conduct hypothesis-driven research on potential dietary etiologies of a disease that affects both the domestic feline population and humans. This unique experimental design provided strong support that cats are a better animal model of toxic multinodular goiter, because we were able to establish that cats have an individual set-point for thyroid-stimulating hormone (TSH) which similar to humans. Additionally, we showed that there was a positive correlation with taurine consumption and circulating triiodothyronine (T3) in female rats but not male rats. Women are five to eight times more likely to suffer from a thyroid disease. Our findings indicate future research is needed to determine if supplemental taurine and consumption of high taurine diets predisposes women to thyroid gland disorders. Furthermore, in cats, consumption of water significantly altered the production of T3 and caused a 20% increase in activity level. Because consumption of canned cat food has been the only consistently identified risk factor in epidemiological studies, our results indicate future studies should focus on the relationship between water consumption and feline thyroid physiology.Includes biblographical reference

A small-molecule PI3Kα activator for cardioprotection and neuroregeneration

Harnessing the potential beneficial effects of kinase signalling through the generation of direct kinase activators remains an underexplored area of drug development1,2,3,4,5. This also applies to the PI3K signalling pathway, which has been extensively targeted by inhibitors for conditions with PI3K overactivation, such as cancer and immune dysregulation. Here we report the discovery of UCL-TRO-1938 (referred to as 1938 hereon), a small-molecule activator of the PI3Kα isoform, a crucial effector of growth factor signalling. 1938 allosterically activates PI3Kα through a distinct mechanism by enhancing multiple steps of the PI3Kα catalytic cycle and causes both local and global conformational changes in the PI3Kα structure. This compound is selective for PI3Kα over other PI3K isoforms and multiple protein and lipid kinases. It transiently activates PI3K signalling in all rodent and human cells tested, resulting in cellular responses such as proliferation and neurite outgrowth. In rodent models, acute treatment with 1938 provides cardioprotection from ischaemia–reperfusion injury and, after local administration, enhances nerve regeneration following nerve crush. This study identifies a chemical tool to directly probe the PI3Kα signalling pathway and a new approach to modulate PI3K activity, widening the therapeutic potential of targeting these enzymes through short-term activation for tissue protection and regeneration. Our findings illustrate the potential of activating kinases for therapeutic benefit, a currently largely untapped area of drug development

The geographical distribution and burden of trachoma in Africa.

BACKGROUND: There remains a lack of epidemiological data on the geographical distribution of trachoma to support global mapping and scale up of interventions for the elimination of trachoma. The Global Atlas of Trachoma (GAT) was launched in 2011 to address these needs and provide standardised, updated and accessible maps. This paper uses data included in the GAT to describe the geographical distribution and burden of trachoma in Africa. METHODS: Data assembly used structured searches of published and unpublished literature to identify cross-sectional epidemiological data on the burden of trachoma since 1980. Survey data were abstracted into a standardised database and mapped using geographical information systems (GIS) software. The characteristics of all surveys were summarized by country according to data source, time period, and survey methodology. Estimates of the current population at risk were calculated for each country and stratified by endemicity class. RESULTS: At the time of writing, 1342 records are included in the database representing surveys conducted between 1985 and 2012. These data were provided by direct contact with national control programmes and academic researchers (67%), peer-reviewed publications (17%) and unpublished reports or theses (16%). Prevalence data on active trachoma are available in 29 of the 33 countries in Africa classified as endemic for trachoma, and 1095 (20.6%) districts have representative data collected through population-based prevalence surveys. The highest prevalence of active trachoma and trichiasis remains in the Sahel area of West Africa and Savannah areas of East and Central Africa and an estimated 129.4 million people live in areas of Africa confirmed to be trachoma endemic. CONCLUSION: The Global Atlas of Trachoma provides the most contemporary and comprehensive summary of the burden of trachoma within Africa. The GAT highlights where future mapping is required and provides an important planning tool for scale-up and surveillance of trachoma control

Phase 1 Trials of rVSV Ebola Vaccine in Africa and Europe.

BACKGROUND: The replication-competent recombinant vesicular stomatitis virus (rVSV)-based vaccine expressing a Zaire ebolavirus (ZEBOV) glycoprotein was selected for rapid safety and immunogenicity testing before its use in West Africa. METHODS: We performed three open-label, dose-escalation phase 1 trials and one randomized, double-blind, controlled phase 1 trial to assess the safety, side-effect profile, and immunogenicity of rVSV-ZEBOV at various doses in 158 healthy adults in Europe and Africa. All participants were injected with doses of vaccine ranging from 300,000 to 50 million plaque-forming units (PFU) or placebo. RESULTS: No serious vaccine-related adverse events were reported. Mild-to-moderate early-onset reactogenicity was frequent but transient (median, 1 day). Fever was observed in up to 30% of vaccinees. Vaccine viremia was detected within 3 days in 123 of the 130 participants (95%) receiving 3 million PFU or more; rVSV was not detected in saliva or urine. In the second week after injection, arthritis affecting one to four joints developed in 11 of 51 participants (22%) in Geneva, with pain lasting a median of 8 days (interquartile range, 4 to 87); 2 self-limited cases occurred in 60 participants (3%) in Hamburg, Germany, and Kilifi, Kenya. The virus was identified in one synovial-fluid aspirate and in skin vesicles of 2 other vaccinees, showing peripheral viral replication in the second week after immunization. ZEBOV-glycoprotein-specific antibody responses were detected in all the participants, with similar glycoprotein-binding antibody titers but significantly higher neutralizing antibody titers at higher doses. Glycoprotein-binding antibody titers were sustained through 180 days in all participants. CONCLUSIONS: In these studies, rVSV-ZEBOV was reactogenic but immunogenic after a single dose and warrants further evaluation for safety and efficacy. (Funded by the Wellcome Trust and others; ClinicalTrials.gov numbers, NCT02283099, NCT02287480, and NCT02296983; Pan African Clinical Trials Registry number, PACTR201411000919191.)

Addressing disparities in maternal health care in Pakistan: gender, class and exclusion

Background: After more than two decades of the Safe Motherhood Initiative and Millennium Development Goals aimed at reducing maternal mortality, women continue to die in childbirth at unacceptably high rates in Pakistan. While an extensive literature describes various programmatic strategies, it neglects the rigorous analysis of the reasons these strategies have been unsuccessful, especially for women living at the economic and social margins of society. A critical gap in current knowledge is a detailed understanding of the root causes of disparities in maternal health care, and in particular, how gender and class influence policy formulation and the design and delivery of maternal health care services. Taking Pakistan as a case study, this research builds upon two distinct yet interlinked conceptual approaches to understanding the phenomenon of inequity in access to maternal health care: social exclusion and health systems as social institutions. Methods/Design: This four year project consists of two interrelated modules that focus on two distinct groups of participants: (1) poor, disadvantaged women and men and (2) policy makers, program managers and health service providers. Module one will employ critical ethnography to understand the key axes of social exclusion as related to gender, class and zaat and how they affect women’s experiences of using maternal health care. Through health care setting observations, interviews and document review, Module two will assess policy design and delivery of maternal health services. Discussion: This research will provide theoretical advances to enhance understanding of the power dynamics of gender and class that may underlie poor women’s marginalization from health care systems in Pakistan. It will also provide empirical evidence to support formulation of maternal health care policies and health care system practices aimed at reducing disparities in maternal health care in Pakistan. Lastly, it will enhance inter-disciplinary research capacity in the emerging field of social exclusion and maternal health and help reduce social inequities and achieve the Millennium Development Goal No. 5

In Vivo Electroporation Enhances the Immunogenicity of an HIV-1 DNA Vaccine Candidate in Healthy Volunteers

DNA-based vaccines have been safe but weakly immunogenic in humans to date.We sought to determine the safety, tolerability, and immunogenicity of ADVAX, a multigenic HIV-1 DNA vaccine candidate, injected intramuscularly by in vivo electroporation (EP) in a Phase-1, double-blind, randomized placebo-controlled trial in healthy volunteers. Eight volunteers each received 0.2 mg, 1 mg, or 4 mg ADVAX or saline placebo via EP, or 4 mg ADVAX via standard intramuscular injection at weeks 0 and 8. A third vaccination was administered to eleven volunteers at week 36. EP was safe, well-tolerated and considered acceptable for a prophylactic vaccine. EP delivery of ADVAX increased the magnitude of HIV-1-specific cell mediated immunity by up to 70-fold over IM injection, as measured by gamma interferon ELISpot. The number of antigens to which the response was detected improved with EP and increasing dosage. Intracellular cytokine staining analysis of ELISpot responders revealed both CD4+ and CD8+ T cell responses, with co-secretion of multiple cytokines.This is the first demonstration in healthy volunteers that EP is safe, tolerable, and effective in improving the magnitude, breadth and durability of cellular immune responses to a DNA vaccine candidate.ClinicalTrials.gov NCT00545987

Hydrological Partitioning in the Critical Zone: Recent Advances and Opportunities for Developing Transferable Understanding of Water Cycle Dynamics

Hydrology is an integrative discipline linking the broad array of water-related research with physical, ecological, and social sciences. The increasing breadth of hydrological research, often where subdisciplines of hydrology partner with related sciences, reflects the central importance of water to environmental science, while highlighting the fractured nature of the discipline itself. This lack of coordination among hydrologic subdisciplines has hindered the development of hydrologic theory and integrated models capable of predicting hydrologic partitioning across time and space. The recent development of the concept of the critical zone (CZ), an open system extending from the top of the canopy to the base of groundwater, brings together multiple hydrological subdisciplines with related physical and ecological sciences. Observations obtained by CZ researchers provide a diverse range of complementary process and structural data to evaluate both conceptual and numerical models. Consequently, a cross-site focus on ‘‘critical zone hydrology’’ has potential to advance the discipline of hydrology and to facilitate the transition of CZ observatories into a research network with immediate societal relevance. Here we review recent work in catchment hydrology and hydrochemistry, hydrogeology, and ecohydrology that highlights a common knowledge gap in how precipitation is partitioned in the critical zone: ‘‘how is the amount, routing, and residence time of water in the subsurface related to the biogeophysical structure of the CZ?’’ Addressing this question will require coordination among hydrologic subdisciplines and interfacing sciences, and catalyze rapid progress in understanding current CZ structure and predicting how climate and land cover changes will affect hydrologic partitioning