Pattern of Disease after Murine Hepatitis Virus Strain 3 Infection Correlates with Macrophage Activation and Not Viral Replication

Murine hepatitis virus strain (MHV-3) produces a strain-dependent pattern of disease which has been used as a model for fulminant viral hepatitis. This study was undertaken to examine whether there was a correlation between macrophage activation and susceptibility or resistance to MHV-3 infection. Peritoneal macrophages were isolated from resistant A/J and susceptible BALB/cJ mice and, following stimulation with MHV-3 or lipopolysaccharide (LPS), analyzed for transcription of mRNA and production of interleukin-1 (IL-1), tumor necrosis factor alpha (TNF-alpha), transforming growth factor beta (TGF-beta), mouse fibrinogen-like protein (musfiblp), tissue factor (TF), leukotriene B4, and prostaglandin E2 (PGE2). Macrophages from BALB/cJ mice produced greater amounts of IL-1, TNF-alpha, TGF-beta, leukotriene B4, and musfiblp following MHV-3 infection than macrophages from resistant A/J mice, whereas in response to LPS, equivalent amounts of IL-1, TNF-alpha, TGF-beta, and TF were produced by macrophages from both strains of mice. Levels of mRNA of IL-1, TNF-alpha, and musfiblp were greater and more persistent in BALB/cJ than in A/J macrophages, whereas the levels and kinetics of IL-1, TNF-alpha, and TF mRNA following LPS stimulation were identical in macrophages from both strains of mice. Levels of production of PGE2 by MHV-3-stimulated macrophages from resistant and susceptible mice were equivalent; however, the time course for induction of PGE2, differed, but the total quantity of PGE2 produced was insufficient to inhibit induction of musfiblp, a procoagulant known to correlate with development of fulminant hepatic necrosis in susceptible mice. These results demonstrate marked differences in production of inflammatory mediators to MHV-3 infection in macrophages from resistant A/J and susceptible BALB/cJ mice, which may explain the marked hepatic necrosis and fibrin deposition and account for the lethality of MHV-3 in susceptible mice

Reduced expression of monocyte CD200R is associated with enhanced proinflammatory cytokine production in sarcoidosis

In sarcoidosis, the proinflammatory cytokines interferon gamma, tumour necrosis factor and interleukin-6 are released by monocyte-derived macrophages and lymphocytes in the lungs and other affected tissues. Regulatory receptors expressed on monocytes and macrophages act to suppress cytokine production, and reduced expression of regulatory receptors may thus promote tissue inflammation. The aim of this study was to characterise the role of regulatory receptors on blood monocytes in patients with sarcoidosis. Cytokine release in response to stimulation of whole blood was measured in healthy controls and Caucasian non-smoking patients with sarcoidosis who were not taking disease modifying therapy. Expression of the regulatory molecules IL-10R, SIRP-α/β, CD47, CD200R, and CD200L was measured by flow cytometry, and functional activity was assessed using blocking antibodies. Stimulated whole blood and monocytes from patients with sarcoidosis produced more TNF and IL-6 compared with healthy controls. 52.9% of sarcoidosis patients had monocytes characterised by low expression of CD200R, compared with 11.7% of controls (p < 0.0001). Patients with low monocyte CD200R expression produced higher levels of proinflammatory cytokines. In functional studies, blocking the CD200 axis increased production of TNF and IL-6. Reduced expression of CD200R on monocytes may be a mechanism contributing to monocyte and macrophage hyper-activation in sarcoidosis

LGBTQI+ inclusion in sport and exercise psychology teaching

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The Effectiveness of Pharmacological and Non-Pharmacological Interventions for Improving Glycaemic Control in Adults with Severe Mental Illness: A Systematic Review and Meta-Analysis

People with severe mental illness (SMI) have reduced life expectancy compared with the general population, which can be explained partly by their increased risk of diabetes. We conducted a meta-analysis to determine the clinical effectiveness of pharmacological and non-pharmacological interventions for improving glycaemic control in people with SMI (PROSPERO registration: CRD42015015558). A systematic literature search was performed on 30/10/2015 to identify randomised controlled trials (RCTs) in adults with SMI, with or without a diagnosis of diabetes that measured fasting blood glucose or glycated haemoglobin (HbA1c). Screening and data extraction were carried out independently by two reviewers. We used random effects meta-analysis to estimate effectiveness, and subgroup analysis and univariate meta-regression to explore heterogeneity. The Cochrane Collaboration’s tool was used to assess risk of bias. We found 54 eligible RCTs in 4,392 adults (40 pharmacological, 13 behavioural, one mixed intervention). Data for meta-analysis were available from 48 RCTs (n = 4052). Both pharmacological (mean difference (MD), -0.11mmol/L; 95% confidence interval (CI), [-0.19, -0.02], p = 0.02, n = 2536) and behavioural interventions (MD, -0.28mmol//L; 95% CI, [-0.43, -0.12], p<0.001, n = 956) were effective in lowering fasting glucose, but not HbA1c (pharmacological MD, -0.03%; 95% CI, [-0.12, 0.06], p = 0.52, n = 1515; behavioural MD, 0.18%; 95% CI, [-0.07, 0.42], p = 0.16, n = 140) compared with usual care or placebo. In subgroup analysis of pharmacological interventions, metformin and antipsychotic switching strategies improved HbA1c. Behavioural interventions of longer duration and those including repeated physical activity had greater effects on fasting glucose than those without these characteristics. Baseline levels of fasting glucose explained some of the heterogeneity in behavioural interventions but not in pharmacological interventions. Although the strength of the evidence is limited by inadequate trial design and reporting and significant heterogeneity, there is some evidence that behavioural interventions, antipsychotic switching, and metformin can lead to clinically important improvements in glycaemic measurements in adults with SMI

Parameters of Reserpine Analogs That Induce MSH2/MSH6-Dependent Cytotoxic Response

Mismatch repair proteins modulate the cytotoxicity of several chemotherapeutic agents. We have recently proposed a “death conformation” of the MutS homologous proteins that is distinguishable from their “repair conformation.” This conformation can be induced by a small molecule, reserpine, leading to DNA-independent cell death. We investigated the parameters for a small reserpine-like molecule that are required to interact with MSH2/MSH6 to induce MSH2/MSH6-dependent cytotoxic response. A multidisciplinary approach involving structural modeling, chemical synthesis, and cell biology analyzed reserpine analogs and modifications. We demonstrate that the parameters controlling the induction of MSH2/MSH6-dependent cytotoxicity for reserpine-analogous molecules reside in the specific requirements for methoxy groups, the size of the molecule, and the orientation of molecules within the protein-binding pocket. Reserpine analog rescinnamine showed improved MSH2-dependent cytotoxicity. These results have important implications for the identification of compounds that require functional MMR proteins to exhibit their full cytotoxicity, which will avoid resistance in MMR-deficient cells

Toward Facilitating the Collection and Utilization of Patient-reported Outcomes in the Military Health System: Lessons Learned from a Pragmatic Clinical Trial on Physical Therapy Management for Low Back Pain

In pursuit of delivering \u27the right care to the right patient at the right time,\u27 the Military Health System (MHS) advocates for collecting and using patient-reported outcomes (PROs) to help demonstrate value-based care.1 PROs identify patients’ perceptions of their health, function, and well-being, which can enhance patient-centered communication and guide data-driven healthcare. 2 The MHS recognizes the value of incorporating PRO data into clinical decision-making and has established a number of platforms for PRO collection across health conditions (eg, behavioral health, traumatic brain injury, musculoskeletal injuries). The Military Orthopedics Tracking Injuries and Outcomes Network (MOTION)3 was started as a research endeavor specific to collecting PROs relevant to postsurgical conditions, which later expanded to cover rehabilitation settings and all musculoskeletal injuries. In MHS physical therapy clinics, the Defense Health Agency’s Clinical Assessment Management Portal (CAMP), a digital PRO collection platform, enables point-of-care capture of MOTION-recommended PROs

Landscape-level human disturbance results in loss and contraction of mammalian populations in tropical forests

Tropical forests hold most of Earth's biodiversity and a higher concentration of threatened mammals than other biomes. As a result, some mammal species persist almost exclusively in protected areas, often within extensively transformed and heavily populated landscapes. Other species depend on remaining remote forested areas with sparse human populations. However, it remains unclear how mammalian communities in tropical forests respond to anthropogenic pressures in the broader landscape in which they are embedded. As governments commit to increasing the extent of global protected areas to prevent further biodiversity loss, identifying the landscape-level conditions supporting wildlife has become essential. Here, we assessed the relationship between mammal communities and anthropogenic threats in the broader landscape. We simultaneously modeled species richness and community occupancy as complementary metrics of community structure, using a state-of-the-art community model parameterized with a standardized pan-tropical data set of 239 mammal species from 37 forests across 3 continents. Forest loss and fragmentation within a 50-km buffer were associated with reduced occupancy in monitored communities, while species richness was unaffected by them. In contrast, landscape-scale human density was associated with reduced mammal richness but not occupancy, suggesting that sensitive species have been extirpated, while remaining taxa are relatively unaffected. Taken together, these results provide evidence of extinction filtering within tropical forests triggered by anthropogenic pressure occurring in the broader landscape. Therefore, existing and new reserves may not achieve the desired biodiversity outcomes without concurrent investment in addressing landscape-scale threats

Yoga for schizophrenia: a systematic review and meta-analysis

BACKGROUND: The aim of this review was to systematically review and meta-analyze the effects of yoga on symptoms of schizophrenia, quality of life, function, and hospitalization in patients with schizophrenia. METHODS: MEDLINE/Pubmed, Scopus, the Cochrane Library, PsycInfo, and IndMED were screened through August 2012. Randomized controlled trials (RCTs) comparing yoga to usual care or non-pharmacological interventions were analyzed when they assessed symptoms or quality of life in patients with schizophrenia. Cognitive function, social function, hospitalization, and safety were defined as secondary outcomes. Risk of bias was assessed using the risk of bias tool recommended by the Cochrane Back Review Group. Standardized mean differences (SMD) and 95% confidence intervals (CI) were calculated. RESULTS: Five RCTs with a total of 337 patients were included; 2 RCTs had low risk of bias. Two RCTs compared yoga to usual care; 1 RCT compared yoga to exercise; and 2 3-arm RCTs compared yoga to usual care and exercise. No evidence was found for short-term effects of yoga compared to usual care on positive symptoms (SMD = -0.58; 95% CI -1.52 to 0.37; P = 0.23), or negative symptoms (SMD = -0.59; 95% CI -1.87 to 0.69; P = 0.36). Moderate evidence was found for short-term effects on quality of life compared to usual care (SMD = 2.28; 95% CI 0.42 to 4.14; P = 0.02). These effects were only present in studies with high risk of bias. No evidence was found for short-term effects on social function (SMD = 1.20; 95% CI -0.78 to 3.18; P = 0.23). Comparing yoga to exercise, no evidence was found for short-term effects on positive symptoms (SMD = -0.35; 95% CI -0.75 to 0.05; P = 0.09), negative symptoms (SMD = -0.28; 95% CI -1.42 to 0.86; P = 0.63), quality of life (SMD = 0.17; 95% CI -0.27 to 0.61; P = 0.45), or social function (SMD = 0.20; 95% CI -0.27 to 0.67; P = 0.41). Only 1 RCT reported adverse events. CONCLUSIONS: This systematic review found only moderate evidence for short-term effects of yoga on quality of life. As these effects were not clearly distinguishable from bias and safety of the intervention was unclear, no recommendation can be made regarding yoga as a routine intervention for schizophrenia patients