RGS6, RGS7, RGS9, and RGS11 Stimulate GTPase Activity of G i Family G-proteins with Differential Selectivity and Maximal Activity

Regulator of G-protein signaling (RGS) proteins are GTPase activating proteins (GAPs) of heterotrimeric G-proteins that alter the amplitude and kinetics of receptor-promoted signaling. In this study we defined the G-protein alpha-subunit selectivity of purified Sf9 cell-derived R7 proteins, a subfamily of RGS proteins (RGS6, -7, -9, and -11) containing a Ggamma-like (GGL) domain that mediates dimeric interaction with Gbeta(5). Gbeta(5)/R7 dimers stimulated steady state GTPase activity of Galpha-subunits of the G(i) family, but not of Galpha(q) or Galpha(11), when added to proteoliposomes containing M2 or M1 muscarinic receptor-coupled G-protein heterotrimers. Concentration effect curves of the Gbeta(5)/R7 proteins revealed differences in potencies and efficacies toward Galpha-subunits of the G(i) family. Although all four Gbeta(5)/R7 proteins exhibited similar potencies toward Galpha(o), Gbeta(5)/RGS9 and Gbeta(5)/RGS11 were more potent GAPs of Galpha(i1), Galpha(i2), and Galpha(i3) than were Gbeta(5)/RGS6 and Gbeta(5)/RGS7. The maximal GAP activity exhibited by Gbeta(5)/RGS11 was 2- to 4-fold higher than that of Gbeta(5)/RGS7 and Gbeta(5)/RGS9, with Gbeta(5)/RGS6 exhibiting an intermediate maximal GAP activity. Moreover, the less efficacious Gbeta(5)/RGS7 and Gbeta(5)/RGS9 inhibited Gbeta(5)/RGS11-stimulated GTPase activity of Galpha(o). Therefore, R7 family RGS proteins are G(i) family-selective GAPs with potentially important differences in activities

Prevalence and incidence of myalgic encephalomyelitis/chronic fatigue syndrome in Europe-the Euro-epiME study from the European network EUROMENE: a protocol for a systematic review.

INTRODUCTION: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic disease involving central nervous system and immune system disorders, as well as cardiovascular abnormalities. ME/CFS is characterised by severe chronic fatigue lasting for at least 6 months, including clinical symptoms such as tender cervical or axillary lymph nodes, muscle pain, joint pain without swelling or redness, post-exertional malaise for more than 24 hours and unrefreshing sleep. Studies on the epidemiology of ME/CFS in Europe only include single countries and, therefore, the prevalence and incidence of ME/CFS in Europe (as a whole) is unknown. One of the purposes of the European Network on ME/CFS (EUROMENE; European Union-funded COST Action; Reference number: 15111) is to address this gap in knowledge. We will systematically review the literature reporting figures from European countries to provide a robust summary and identify new challenges. METHODS AND ANALYSIS: We will systematically search the literature databases Scopus, PubMed and Web of Science for studies published in the last 10 years (ie, after 2007). No language restriction will be applied. Two independent reviewers will search, screen and select studies as well as extract data about their main characteristics and evaluate their methodological and reporting quality. When disagreements emerge, the reviewers will discuss to reach a consensus. We plan to produce a narrative summary of our findings as we anticipate that studies are scarce and heterogeneous. The possibility of performing meta-analyses will be discussed in a EUROMENE meeting. ETHICS AND DISSEMINATION: Ethical approval is not required as only publicly available data will be included. Findings will be described in EUROMENE reports, published in peer-reviewed journal(s) and presented at conferences. The findings will be also communicated to policy-makers, healthcare providers, people with ME/CFS and other sections of society through regular channels including the mass-media. PROSPERO REGISTRATION NUMBER: CRD42017078688

Drug eluting and bare metal stents in people with and without diabetes: collaborative network meta-analysis

Objective To compare the effectiveness and safety of three types of stents (sirolimus eluting, paclitaxel eluting, and bare metal) in people with and without diabetes mellitus

Percutaneous coronary angioplasty versus coronary artery bypass grafting in treatment of unprotected left main stenosis (NOBLE) : a prospective, randomised, open-label, non-inferiority trial

Background Coronary artery bypass grafting (CABG) is the standard treatment for revascularisation in patients with left main coronary artery disease, but use of percutaneous coronary intervention (PCI) for this indication is increasing. We aimed to compare PCI and CABG for treatment of left main coronary artery disease. Methods In this prospective, randomised, open-label, non-inferiority trial, patients with left main coronary artery disease were enrolled in 36 centres in northern Europe and randomised 1: 1 to treatment with PCI or CABG. Eligible patients had stable angina pectoris, unstable angina pectoris, or non-ST-elevation myocardial infarction. Exclusion criteria were ST-elevation myocardial infarction within 24 h, being considered too high risk for CABG or PCI, or expected survival of less than 1 year. The primary endpoint was major adverse cardiac or cerebrovascular events (MACCE), a composite of all-cause mortality, non-procedural myocardial infarction, any repeat coronary revascularisation, and stroke. Non-inferiority of PCI to CABG required the lower end of the 95% CI not to exceed a hazard ratio (HR) of 1 . 35 after up to 5 years of follow-up. The intention-to-treat principle was used in the analysis if not specified otherwise. This trial is registered with ClinicalTrials.gov identifier, number NCT01496651. Findings Between Dec 9, 2008, and Jan 21, 2015, 1201 patients were randomly assigned, 598 to PCI and 603 to CABG, and 592 in each group entered analysis by intention to treat. Kaplan-Meier 5 year estimates of MACCE were 29% for PCI (121 events) and 19% for CABG (81 events), HR 1 . 48 (95% CI 1 . 11-1 . 96), exceeding the limit for non-inferiority, and CABG was significantly better than PCI (p=0 . 0066). As-treated estimates were 28% versus 19% (1 . 55, 1 . 18-2 . 04, p= 0 . 0015). Comparing PCI with CABG, 5 year estimates were 12% versus 9% (1 . 07, 0 . 67-1 . 72, p= 0 . 77) for all-cause mortality, 7% versus 2% (2 . 88, 1 . 40-5 . 90, p= 0 . 0040) for non-procedural myocardial infarction, 16% versus 10% (1 . 50, 1 . 04-2 . 17, p= 0 . 032) for any revascularisation, and 5% versus 2% (2 . 25, 0 . 93-5 . 48, p= 0 . 073) for stroke. Interpretation The findings of this study suggest that CABG might be better than PCI for treatment of left main stem coronary artery disease.Peer reviewe

Clinical Events After Deferral of LAD Revascularization Following Physiological Coronary Assessment

BACKGROUND Physicians are not always comfortable deferring treatment of a stenosis in the left anterior descending (LAD) artery because of the perception that there is a high risk of major adverse cardiac events (MACE). The authors describe, using the DEFINE-FLAIR (Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularisation) trial, MACE rates when LAD lesions are deferred, guided by physiological assessment using fractional flow reserve (FFR) or the instantaneous wave-free ratio (iFR). OBJECTIVES The purpose of this study was to establish the safety of deferring treatment in the LAD using FFR or iFR within the DEFINE-FLAIR trial. METHODS MACE rates at 1 year were compared between groups (iFR and FFR) in patients whose physiological assessment led to LAD lesions being deferred. MACE was defined as a composite of cardiovascular death, myocardial infarction (MI), and unplanned revascularization at 1 year. Patients, and staff performing follow-up, were blinded to whether the decision was made with FFR or iFR. Outcomes were adjusted for age and sex. RESULTS A total of 872 patients had lesions deferred in the LAD (421 guided by FFR, 451 guided by iFR). The event rate with iFR was significantly lower than with FFR (2.44% vs. 5.26%; adjusted HR: 0.46; 95% confidence interval [CI]: 0.22 to 0.95; p = 0.04). This was driven by significantly lower unplanned revascularization with iFR and numerically lower MI (unplanned revascularization: 2.22% iFR vs. 4.99% FFR; adjusted HR: 0.44; 95% CI: 0.21 to 0.93; p = 0.03; MI: 0.44% iFR vs. 2.14% FFR; adjusted HR: 0.23; 95% CI: 0.05 to 1.07; p = 0.06). CONCLUSIONS iFR-guided deferral appears to be safe for patients with LAD lesions. Patients in whom iFR-guided deferral was performed had statistically significantly lower event rates than those with FFR-guided deferral. (c) 2019 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Peer reviewe

Safety of the Deferral of Coronary Revascularization on the Basis of Instantaneous Wave-Free Ratio and Fractional Flow Reserve Measurements in Stable Coronary Artery Disease and Acute Coronary Syndromes

OBJECTIVES The aim of this study was to investigate the clinical outcomes of patients deferred from coronary revascularization on the basis of instantaneous wave-free ratio (iFR) or fractional flow reserve (FFR) measurements in stable angina pectoris (SAP) and acute coronary syndromes (ACS). BACKGROUND Assessment of coronary stenosis severity with pressure guidewires is recommended to determine the need for myocardial revascularization. METHODS The safety of deferral of coronary revascularization in the pooled per-protocol population (n = 4,486) of the DEFINE-FLAIR (Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularisation) and iFR-SWEDEHEART (Instantaneous Wave-Free Ratio Versus Fractional Flow Reserve in Patients With Stable Angina Pectoris or Acute Coronary Syndrome) randomized clinical trials was investigated. Patients were stratified according to revascularization decision making on the basis of iFR or FFR and to clinical presentation (SAP or ACS). The primary endpoint was major adverse cardiac events (MACE), defined as the composite of all-cause death, nonfatal myocardial infarction, or unplanned revascularization at 1 year. RESULTS Coronary revascularization was deferred in 2,130 patients. Deferral was performed in 1,117 patients (50%) in the iFR group and 1,013 patients (45%) in the FFR group (p <0.01). At 1 year, the MACE rate in the deferred population was similar between the iFR and FFR groups (4.12% vs. 4.05%; fully adjusted hazard ratio: 1.13; 95% confidence interval: 0.72 to 1.79; p = 0.60). A clinical presentation with ACS was associated with a higher MACE rate compared with SAP in deferred patients (5.91% vs. 3.64% in ACS and SAP, respectively; fully adjusted hazard ratio: 0.61 in favor of SAP; 95% confidence interval: 0.38 to 0.99; p = 0.04). CONCLUSIONS Overall, deferral of revascularization is equally safe with both iFR and FFR, with a low MACE rate of about 4%. Lesions were more frequently deferred when iFR was used to assess physiological significance. In deferred patients presenting with ACS, the event rate was significantly increased compared with SAP at 1 year. (C) 2018 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.Peer reviewe

European Society of Cardiology: Cardiovascular Disease Statistics 2019

Aims The 2019 report from the European Society of Cardiology (ESC) Atlas provides a contemporary analysis of cardiovascular disease (CVD) statistics across 56 member countries, with particular emphasis on international inequalities in disease burden and healthcare delivery together with estimates of progress towards meeting 2025 World Health Organization (WHO) non-communicable disease targets. Methods and results In this report, contemporary CVD statistics are presented for member countries of the ESC. The statistics are drawn from the ESC Atlas which is a repository of CVD data from a variety of sources including the WHO, the Institute for Health Metrics and Evaluation, and the World Bank. The Atlas also includes novel ESC sponsored data on human and capital infrastructure and cardiovascular healthcare delivery obtained by annual survey of the national societies of ESC member countries. Across ESC member countries, the prevalence of obesity (body mass index ≥30 kg/m2) and diabetes has increased two- to three-fold during the last 30 years making the WHO 2025 target to halt rises in these risk factors unlikely to be achieved. More encouraging have been variable declines in hypertension, smoking, and alcohol consumption but on current trends only the reduction in smoking from 28% to 21% during the last 20 years appears sufficient for the WHO target to be achieved. The median age-standardized prevalence of major risk factors was higher in middle-income compared with high-income ESC member countries for hypertension {23.8% [interquartile range (IQR) 22.5–23.1%] vs. 15.7% (IQR 14.5–21.1%)}, diabetes [7.7% (IQR 7.1–10.1%) vs. 5.6% (IQR 4.8–7.0%)], and among males smoking [43.8% (IQR 37.4–48.0%) vs. 26.0% (IQR 20.9–31.7%)] although among females smoking was less common in middle-income countries [8.7% (IQR 3.0–10.8) vs. 16.7% (IQR 13.9–19.7%)]. There were associated inequalities in disease burden with disability-adjusted life years per 100 000 people due to CVD over three times as high in middle-income [7160 (IQR 5655–8115)] compared with high-income [2235 (IQR 1896–3602)] countries. Cardiovascular disease mortality was also higher in middle-income countries where it accounted for a greater proportion of potential years of life lost compared with high-income countries in both females (43% vs. 28%) and males (39% vs. 28%). Despite the inequalities in disease burden across ESC member countries, survey data from the National Cardiac Societies of the ESC showed that middle-income member countries remain severely under-resourced compared with high-income countries in terms of cardiological person-power and technological infrastructure. Under-resourcing in middle-income countries is associated with a severe procedural deficit compared with high-income countries in terms of coronary intervention, device implantation and cardiac surgical procedures. Conclusion A seemingly inexorable rise in the prevalence of obesity and diabetes currently provides the greatest challenge to achieving further reductions in CVD burden across ESC member countries. Additional challenges are provided by inequalities in disease burden that now require intensification of policy initiatives in order to reduce population risk and prioritize cardiovascular healthcare delivery, particularly in the middle-income countries of the ESC where need is greatest

Allergic disease, immunoglobulins, exposure to mercury and dental amalgam in Swedish adolescents

High-dose exposure to inorganic mercury in man can influence the immune system and in rare cases cause immune-related disease. Some experimental animals also react with autoimmunity after low doses of inorganic mercury. Glomerulonephritis and an increased formation of immunoglobulin type E (IgE) are characteristic of these reactions. A recent study of 15-year-old adolescents demonstrated an association between immunoglobulin type A (IgA) and mercury concentration in plasma (P-Hg). There was also an association between allergic disease and IgA levels. The present study included 54 male and 23 female 19-year-old students who were recruited from a cohort that had been previously defined in a survey of allergic disease. Of the students, 39 (51%) had asthma, allergic rhinoconjunctivitis or eczema. Similar amalgam burden and P-Hg levels were observed in students with (n = 39) and without (n = 38) allergic disease (P = 0.48 and P = 0.98, respectively). As expected, IgE levels were significantly higher in the group with allergic disease (P = 0.006), but there was no association between P-Hg and IgE. The P-Hg levels were very low (median 1.50 nmol/l) and correlated significantly (r = 0.31) with the small number of amalgam surfaces (P = 0.007). Thirty-seven students had no amalgam fillings. P-Hg levels did not associate significantly with IgA, but did so with IgG2 (r = 0.33; P = 0.003). No conclusive correlation was observed between IgG2 and amalgam fillings. The findings of this study in 19-year-old subjects differ from earlier data obtained in a sample 4 years younger. The possibility of chance in the association between P-Hg levels and IgG2 must, however, be considered