34 research outputs found

    Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

    Get PDF
    Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

    Effects of fluoxetine on functional outcomes after acute stroke (FOCUS): a pragmatic, double-blind, randomised, controlled trial

    Get PDF
    Background Results of small trials indicate that fluoxetine might improve functional outcomes after stroke. The FOCUS trial aimed to provide a precise estimate of these effects. Methods FOCUS was a pragmatic, multicentre, parallel group, double-blind, randomised, placebo-controlled trial done at 103 hospitals in the UK. Patients were eligible if they were aged 18 years or older, had a clinical stroke diagnosis, were enrolled and randomly assigned between 2 days and 15 days after onset, and had focal neurological deficits. Patients were randomly allocated fluoxetine 20 mg or matching placebo orally once daily for 6 months via a web-based system by use of a minimisation algorithm. The primary outcome was functional status, measured with the modified Rankin Scale (mRS), at 6 months. Patients, carers, health-care staff, and the trial team were masked to treatment allocation. Functional status was assessed at 6 months and 12 months after randomisation. Patients were analysed according to their treatment allocation. This trial is registered with the ISRCTN registry, number ISRCTN83290762. Findings Between Sept 10, 2012, and March 31, 2017, 3127 patients were recruited. 1564 patients were allocated fluoxetine and 1563 allocated placebo. mRS data at 6 months were available for 1553 (99·3%) patients in each treatment group. The distribution across mRS categories at 6 months was similar in the fluoxetine and placebo groups (common odds ratio adjusted for minimisation variables 0·951 [95% CI 0·839–1·079]; p=0·439). Patients allocated fluoxetine were less likely than those allocated placebo to develop new depression by 6 months (210 [13·43%] patients vs 269 [17·21%]; difference 3·78% [95% CI 1·26–6·30]; p=0·0033), but they had more bone fractures (45 [2·88%] vs 23 [1·47%]; difference 1·41% [95% CI 0·38–2·43]; p=0·0070). There were no significant differences in any other event at 6 or 12 months. Interpretation Fluoxetine 20 mg given daily for 6 months after acute stroke does not seem to improve functional outcomes. Although the treatment reduced the occurrence of depression, it increased the frequency of bone fractures. These results do not support the routine use of fluoxetine either for the prevention of post-stroke depression or to promote recovery of function. Funding UK Stroke Association and NIHR Health Technology Assessment Programme

    Impact Of Cardiorespiratory Fitness On Markers Of Cardiovascular Disease Among Law Enforcement Officers

    Get PDF
    Law enforcement officers (LEOs) have heightened cardiovascular disease (CVD) risk due to the stressful nature of their occupations. The prevalence of CVD among LEOs is 1.7 times higher compared to that of the general public. Higher cardiorespiratory fitness (CRF) levels (VO2max) are associated with lower oxidative stress and inflammatory markers, as well as lower cardiovascular disease (CVD) risk; however, there is a lack of data examining this relationship among law enforcement officers (LEO). PURPOSE: To examine differences in markers of CVD risk between LEOs classified as having either high or low levels of CRF. METHODS: Seventy-three career male and female LEOs completed a maximal cardiopulmonary exercise test (CPXT), where VO2max was estimated from the foster equation. Fasted blood samples were taken to assess traditional and non-traditional CVD risk biomarkers: high-density lipoprotein (HDL), low-density lipoprotein (LDL), glucose, total cholesterol, triglycerides, advanced oxidation protein products (AOPP), cortisol, and C-reactive protein (CRP). Body fat percentage (BF%) was determined via dual-energy X-ray absorptiometry (DEXA), VO2max values were categorized based on American College of Sports Medicine (ACSM) guidelines to establish a high-fitness (HF) group (n=25) and a low fitness (LF) group (n=23). Shapiro-Wilk tests were used to assess normality. Independent sample T-tests or non-parametric Mann-Whitney U tests (if normality was violated) were used to assess differences in CVD risk biomarkers, fitness, and body composition between LEO categorized as HF and LF. Effect sizes were calculated as Cohen’s d (i.e., small [0.2-0.5], medium [0.5-0.8], large [\u3e0.8]). RESULTS: Participants classified as HF had significantly (p2max (HF: 38.5 ml/kg/min; LF: 32.4 ml/kg/min, d=1.30) and CPXT exercise times (HF: 11.05 min; LF: 9.54 min; d=1.28). In addition, the HF group had significantly (p=0.029) higher HDL concentrations (HF: 58.3 mg/dL; LF: 46.9 mg/dL; d=0.65). While not statistically significant (p=0.052), the LF group had greater fat mass compared to the HF group (HF: 48.3 lbs.; LF: 57.4 lbs.; d=-0.576). CONCLUSION: Given the cardioprotective benefits of higher HDL concentrations, these findings support the cardiometabolic benefits of having higher fitness levels among LEOs

    Resident Memory T Cells and Their Effect on Cancer

    No full text
    Resident memory T (TRM) cells are a unique subset of CD8+ T cells that are present within certain tissues and do not recirculate through the blood. Long term memory establishment and maintenance are dependent on tissue population of memory T cells. They are characterized by dual CD69/CD103 positivity, and play a role in both response to viral infection and local cancer immunosurveillance. Human TRM cells demonstrate the increased expression of adhesion molecules to facilitate tissue retention, have reduced proliferation and produce both regulatory and immune responsive cytokines. TRM cell phenotype is often characterized by a distinct expression profile driven by Runx3, Blimp1, and Hobit transcription factors. The accumulation of TRM cells in tumors is associated with increased survival and response to immunotherapies, including anti-PD-1 and anti-CTLA-4. In this review, we explore potential mechanisms of TRM cell transformation and maintenance, as well as potential applications for the use of TRM cells in both the development of supportive therapies and establishing more accurate prognoses

    Suppressing Hepatic UGT1A1 Increases Plasma Bilirubin, Lowers Plasma Urobilin, Reorganizes Kinase Signaling Pathways and Lipid Species and Improves Fatty Liver Disease

    No full text
    Several population studies have observed lower serum bilirubin levels in patients with non-alcoholic fatty liver disease (NAFLD). Yet, treatments to target this metabolic phenotype have not been explored. Therefore, we designed an N-Acetylgalactosamine (GalNAc) labeled RNAi to target the enzyme that clears bilirubin from the blood, the UGT1A1 glucuronyl enzyme (GNUR). In this study, male C57BL/6J mice were fed a high-fat diet (HFD, 60%) for 30 weeks to induce NAFLD and were treated subcutaneously with GNUR or sham (CTRL) once weekly for six weeks while continuing the HFD. The results show that GNUR treatments significantly raised plasma bilirubin levels and reduced plasma levels of the bilirubin catabolized product, urobilin. We show that GNUR decreased liver fat content and ceramide production via lipidomics and lowered fasting blood glucose and insulin levels. We performed extensive kinase activity analyses using our PamGene PamStation kinome technology and found a reorganization of the kinase pathways and a significant decrease in inflammatory mediators with GNUR versus CTRL treatments. These results demonstrate that GNUR increases plasma bilirubin and reduces plasma urobilin, reducing NAFLD and inflammation and improving overall liver health. These data indicate that UGT1A1 antagonism might serve as a treatment for NAFLD and may improve obesity-associated comorbidities

    Suppressing Hepatic UGT1A1 Increases Plasma Bilirubin, Lowers Plasma Urobilin, Reorganizes Kinase Signaling Pathways and Lipid Species and Improves Fatty Liver Disease

    No full text
    Several population studies have observed lower serum bilirubin levels in patients with non-alcoholic fatty liver disease (NAFLD). Yet, treatments to target this metabolic phenotype have not been explored. Therefore, we designed an N-Acetylgalactosamine (GalNAc) labeled RNAi to target the enzyme that clears bilirubin from the blood, the UGT1A1 glucuronyl enzyme (GNUR). In this study, male C57BL/6J mice were fed a high-fat diet (HFD, 60%) for 30 weeks to induce NAFLD and were treated subcutaneously with GNUR or sham (CTRL) once weekly for six weeks while continuing the HFD. The results show that GNUR treatments significantly raised plasma bilirubin levels and reduced plasma levels of the bilirubin catabolized product, urobilin. We show that GNUR decreased liver fat content and ceramide production via lipidomics and lowered fasting blood glucose and insulin levels. We performed extensive kinase activity analyses using our PamGene PamStation kinome technology and found a reorganization of the kinase pathways and a significant decrease in inflammatory mediators with GNUR versus CTRL treatments. These results demonstrate that GNUR increases plasma bilirubin and reduces plasma urobilin, reducing NAFLD and inflammation and improving overall liver health. These data indicate that UGT1A1 antagonism might serve as a treatment for NAFLD and may improve obesity-associated comorbidities
    corecore