Growth Differentiation Factor 5 Regulates Cardiac Repair After Myocardial Infarction

ObjectivesThe aim of this study was to examine the function of the bone morphogenic protein growth differentiation factor 5 (Gdf5) in a mouse model of myocardial infarction (MI).BackgroundThe Gdf5 has been implicated in skeletal development, but a potential role in the heart had not been studied.MethodsThe Gdf5-knockout (KO) and wild-type (WT) mice were subjected to permanent left anterior descending coronary artery (LAD) ligation. Cardiac pathology, function, gene expression levels, and signaling pathways downstream of Gdf5 were examined. Effects of recombinant Gdf5 (rGdf5) were tested in primary cardiac cell cultures.ResultsThe WT mice showed increased cardiac Gdf5 levels after MI, with increased expression in peri-infarct cardiomyocytes and myofibroblasts. At 1 and 7 days after MI, no differences were observed in ischemic or infarct areas between WT and Gdf5-KO mice. However, by 28 days after MI, Gdf5-KO mice exhibited increased infarct scar expansion and thinning with decreased arteriolar density compared with WT. The Gdf5-KO hearts also displayed increased left ventricular dilation, with decreased contractility after MI. At 4 days after MI, Gdf5-KO mice exhibited increased cardiomyocyte apoptosis and decreased expression of anti-apoptotic genes Bcl2 and Bcl-xL compared with WT. Unexpectedly, Gdf5-KO hearts displayed increased Smad 1/5/8 phosphorylation but decreased p38-mitogen-activated protein kinase (MAPK) phosphorylation versus WT. The latter was associated with increased collagen gene (Col1a1, Col3a1) expression and fibrosis. In cultures, rGdf5 induced p38-MAPK phosphorylation in cardiac fibroblasts and Smad-dependent increases in Bcl2 and Bcl-xL in cardiomyocytes.ConclusionsIncreased expression of Gdf5 after MI limits infarct scar expansion in vivo. These effects might be mediated by Gdf5-induced p38-MAPK signaling in fibroblasts and Gdf5-driven Smad-dependent pro-survival signaling in cardiomyocytes

A Descriptive Study on Quality of Life among Adolescents with Beta-Thalassemia Major in the Maldives

Background: The Maldives has the highest prevalence of thalassemia in the world. However, there is little research done on the psychosocial aspects of this illness. Objectives: This study aimed to examine health related quality of life (HRQOL) among adolescents with beta-thalassemia major attending the National Thalassemia and Other Hemoglobinopathies Centre (NTC), Maldives Blood Services, Maldives. Thus, appropriate recommendation could be proposed. Methods: A total of 81 adolescents (mean age 15.7 years) with beta-thalassemia major were engaged. HRQOL was assessed using the Pediatric Quality of Life Inventory (PedsQL). Other relevant information was gathered through interview or medical record. Results: The HRQOL was reduced. The mean for physical, emotional, social, school and psychosocial HRQOL was 80.50, 72.30, 88.18, 76.44, and 78.96, respectively. The total HRQOL was 79.50 and this was lower in females (75.29) compared to males (83.29). Ferritin levels of 1,001-2,499 μg/l and > 2,500 μg/l were noted in 34.2% and 53.9%, respectively. Good compliance was reported in 55% of participants. Conclusions: Adolescents with beta-thalassemia major in the Maldives have reduced HRQOL. The high ferritin level could reduce the HRQOL and hence an attempt should be made towards lowering ferritin and improving compliance to chelation treatments. The gender difference in HRQOL signifies the need for more attention to the female patients and for areas of improvement to be explore

GLP-1 receptor agonists for the reduction of atherosclerotic cardiovascular risk in patients with type 2 diabetes

Patients with type 2 diabetes are at high risk for development of cardiovascular disease, including myocardial infarction, stroke, heart failure, and cardiovascular death. Multiple large cardiovascular outcome trials with novel glucose-lowering agents, namely SGLT2i (SGLT2 inhibitors) and GLP-1 RA (GLP-1 receptor agonists), have demonstrated robust and significant reductions of major adverse cardiovascular events and additional cardiovascular outcomes, such as hospitalizations for heart failure. This evidence has changed the landscape for treatment of patients with type 2 diabetes. Both diabetes and cardiology guidelines and professional societies have responded to this paradigm shift by including strong recommendations to use SGLT2i and/or GLP-1 RA, with evidence-based benefits to reduce cardiovascular risk in high-risk individuals with type 2 diabetes, independent of the need for additional glucose control. GLP-1 RA were initially developed as glucose-lowering drugs because activation of the GLP-1 receptor by these agents leads to a reduction in blood glucose and an improvement in postprandial glucose metabolism. By stimulating GLP-1R in hypothalamic neurons, GLP-1 RA additionally induce satiety and lead to weight loss. Data from cardiovascular outcome trials demonstrated a robust and consistent reduction in atherothrombotic events, particularly in patients with established atherosclerotic cardiovascular disease. Despite the consistent evidence of atherosclerotic cardiovascular disease benefit from these trials, the number of patients receiving these drugs remains low. This overview summarizes the experimental and clinical evidence of cardiovascular risk reduction offered by GLP-1 RA, and provides practical information on how these drugs should be implemented in the treatment of type 2 diabetes in the cardiology community

Multi-objective optimization of process parameters during micro-milling of nickel-based alloy Inconel 718 using Taguchi-grey relation integrated approach

This research investigates the machinability of Inconel 718 under conventional machining speeds using three different tool coatings in comparison with uncoated tool during milling operation. Cutting speed, feed rate and depth of cut were selected as variable machining parameters to analyze output responses including surface roughness, burr formation and tool wear. It was found that uncoated and AlTiN coated tools resulted in lower tool wear than nACo and TiSiN coated tools. On the other hand, TiSiN coated tools resulted in highest surface roughness and burr formation. Among the three machining parameters, feed was identified as the most influential parameter affecting burr formation. Grey relational analysis identified the most optimal experimental run with a speed of 14 m/min, feed of 1 mu m/tooth, and depth of cut of 70 mu m using an AlTiN coated tool. ANOVA of the regression model identified the tool coating parameter as most effective, with a contribution ratio of 41.64%, whereas cutting speed and depth of cut were found to have contribution ratios of 18.82% and 8.10%, respectively. Experimental run at response surface optimized conditions resulted in reduced surface roughness and tool wear by 18% and 20%, respectively.Web of Science1523art. no. 829

Lack of group X secreted phospholipase A₂ increases survival following pandemic H1N1 influenza infection

The role of Group X secreted phospholipase A2 (GX-sPLA2) during influenza infection has not been previously investigated. We examined the role of GX-sPLA2 during H1N1 pandemic influenza infection in a GX-sPLA2 gene targeted mouse (GX−/−) model and found that survival after infection was significantly greater in GX−/− mice than in GX+/+ mice. Downstream products of GX-sPLA2 activity, PGD2, PGE2, LTB4, cysteinyl leukotrienes and Lipoxin A4 were significantly lower in GX−/− mice BAL fluid. Lung microarray analysis identified an earlier and more robust induction of T and B cell associated genes in GX−/− mice. Based on the central role of sPLA2 enzymes as key initiators of inflammatory processes, we propose that activation of GX-sPLA2 during H1N1pdm infection is an early step of pulmonary inflammation and its inhibition increases adaptive immunity and improves survival. Our findings suggest that GX-sPLA2 may be a potential therapeutic target during influenza

Local proliferation dominates lesional macrophage accumulation in atherosclerosis

During the inflammatory response that drives atherogenesis, macrophages accumulate progressively in the expanding arterial wall1,2. The observation that circulating monocytes give rise to lesional macrophages3–9 has reinforced the concept that monocyte infiltration dictates macrophage build-up. Recent work indicates, however, that macrophages do not depend on monocytes in some inflammatory contexts10. We therefore revisited the mechanism of macrophage accumulation in atherosclerosis. We show that murine atherosclerotic lesions experience a surprisingly rapid, 4-week, cell turnover. Replenishment of macrophages in these experimental atheromata depends predominantly on local macrophage proliferation rather than monocyte influx. The microenvironment orchestrates macrophage proliferation via the involvement of scavenger receptor (SR)-A. Our study reveals macrophage proliferation as a key event in atherosclerosis and identifies macrophage self-renewal as a therapeutic target for cardiovascular disease

Awareness and perceptions of electroconvulsive therapy among psychiatric patients: a cross-sectional survey from teaching hospitals in Karachi, Pakistan

<p>Abstract</p> <p>Background</p> <p>Electroconvulsive therapy (ECT) is shown to be effective in many psychiatric illnesses, but its distorted projection by the Pakistani media and its unregulated use by many physicians across the country have adversely affected its acceptability. Given this situation we aimed to assess the awareness and perceptions regarding ECT as a treatment modality among the psychiatric patients.</p> <p>Methods</p> <p>This was a questionnaire based cross-sectional study carried out at 2 tertiary care hospitals in Karachi, Pakistan.</p> <p>Results</p> <p>We interviewed 190 patients of which 140 were aware of ECT. The study showed that the level of education had a significant impact on the awareness of ECT (p = 0.009). The most common source of awareness was electronic and print media (38%), followed by relatives (24%) and doctors (23%). Physical injuries (42%) and neurological (12%) and cognitive disturbances (11%) were the commonly feared side effects. The most popular belief about ECT was that it was a treatment of last resort (56%). Thirty-nine percent thought that ECT could lead to severe mental and physical illness and 37% considered it inhumane. Patients' willingness to receive ECT was dependant on whether or not they were convinced of its safety (p = 0.001) and efficacy (p = 0.0001).</p> <p>Conclusion</p> <p>We identified a serious lack of dissemination of information regarding ECT by the psychiatrists and the mental health care providers. This may be the result of an inadequate postgraduate training in Pakistan or just a lack of concern about the mentally ill patients. The media seemed to be the major source of information for our patients. We also saw the prevalence of a variety of myths regarding ECT in our society, which we feel may be responsible for the patients' adverse attitudes. Given the widespread applicability of ECT there is a dire need to dispel these misconceptions and improve its acceptability.</p

Self-renewing resident arterial macrophages arise from embryonic CX3CR1+ precursors and circulating monocytes immediately after birth

Resident macrophages densely populate the normal arterial wall, yet their origins and the mechanisms that sustain them are poorly understood. Here we use gene-expression profiling to show that arterial macrophages constitute a distinct population among macrophages. Using multiple fate-mapping approaches, we show that arterial macrophages arise embryonically from CX3CR1+ precursors and postnatally from bone marrow–derived monocytes that colonize the tissue immediately after birth. In adulthood, proliferation (rather than monocyte recruitment) sustains arterial macrophages in the steady state and after severe depletion following sepsis. After infection, arterial macrophages return rapidly to functional homeostasis. Finally, survival of resident arterial macrophages depends on a CX3CR1-CX3CL1 axis within the vascular niche

Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial

Background: Tranexamic acid reduces surgical bleeding and reduces death due to bleeding in patients with trauma. Meta-analyses of small trials show that tranexamic acid might decrease deaths from gastrointestinal bleeding. We aimed to assess the effects of tranexamic acid in patients with gastrointestinal bleeding. Methods: We did an international, multicentre, randomised, placebo-controlled trial in 164 hospitals in 15 countries. Patients were enrolled if the responsible clinician was uncertain whether to use tranexamic acid, were aged above the minimum age considered an adult in their country (either aged 16 years and older or aged 18 years and older), and had significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding. Patients were randomly assigned by selection of a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients received either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0·9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0·9%). Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was death due to bleeding within 5 days of randomisation; analysis excluded patients who received neither dose of the allocated treatment and those for whom outcome data on death were unavailable. This trial was registered with Current Controlled Trials, ISRCTN11225767, and ClinicalTrials.gov, NCT01658124. Findings: Between July 4, 2013, and June 21, 2019, we randomly allocated 12 009 patients to receive tranexamic acid (5994, 49·9%) or matching placebo (6015, 50·1%), of whom 11 952 (99·5%) received the first dose of the allocated treatment. Death due to bleeding within 5 days of randomisation occurred in 222 (4%) of 5956 patients in the tranexamic acid group and in 226 (4%) of 5981 patients in the placebo group (risk ratio [RR] 0·99, 95% CI 0·82–1·18). Arterial thromboembolic events (myocardial infarction or stroke) were similar in the tranexamic acid group and placebo group (42 [0·7%] of 5952 vs 46 [0·8%] of 5977; 0·92; 0·60 to 1·39). Venous thromboembolic events (deep vein thrombosis or pulmonary embolism) were higher in tranexamic acid group than in the placebo group (48 [0·8%] of 5952 vs 26 [0·4%] of 5977; RR 1·85; 95% CI 1·15 to 2·98). Interpretation: We found that tranexamic acid did not reduce death from gastrointestinal bleeding. On the basis of our results, tranexamic acid should not be used for the treatment of gastrointestinal bleeding outside the context of a randomised trial

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700