Notes

Inbuilt immunity within tb: how a sensing involving mycobacteria and tissue damage modulates macrophage dying.
As a critical second messenger in plants, Ca2+ is involved in numerous biological processes including biotic and abiotic stress responses. The CBL-interacting protein kinases, known as CIPKs, are essential components in Ca2+-mediated signal transduction pathways. Here, we found that CIPK14 plays a role in the process of regulating immune response in Arabidopsis. The CIPK14 loss-of-function mutants exhibited enhanced resistance to the P. syringae, whereas CIPK14 overexpression plants were more susceptible to bacterial pathogen. Enhanced resistance in cipk14 mutants were accompanied by increased accumulation of SA and elevated expression of defense marker genes (PR1, EDS1, EDS5, ICS1). Overexpression of CIPK14 suppressed Pst DC3000, Pst DC3000 hrcC and flg22 induced generation of ROS and callose deposition. As compared with wild type plants, the expression levels of MPK3/6-dependent PTI marker genes (FRK1, CYP81F2, WAK2, FOX) were up-regulated in cipk14 mutants but down-regulated in CIPK14 overexpression plants after flg22 and elf18 treatment. Additionally, both loss-of-function and gain-of-function of CIPK14 significantly altered the phosphorylation status of MPK3/6 under flg22 treatment, suggesting that CIPK14 is a general modulator of plant immunity at both transcriptional and post-transcriptional level. Taken together, our results uncover that CIPK14 acts as a negative regulator in plant immune response.Patients undergoing early surgery after coronary stent implantation are at increased risk for mortality from ischemic and hemorrhagic complications. The optimal antiplatelet strategy in patients who cannot discontinue dual antiplatelet therapy (DAPT) before surgery is unclear. Current guidelines, based on surgical and clinical characteristics, provide risk stratification for bridging therapy with intravenous antiplatelet agents, but management is guided primarily by expert opinion. This review summarizes perioperative risk factors to consider before discontinuing DAPT and reviews the data for intravenous bridging therapies. Published reports have included bridging options such as small molecule glycoprotein IIb/IIIa inhibitors (eptifibatide or tirofiban) and cangrelor, an intravenous P2Y12 inhibitor. However, optimal management of these complex patients remains unclear in the absence of randomized controlled data, without which an argument can be made both for and against the use of perioperative intravenous bridging therapy after discontinuing oral P2Y12 inhibitors. Multidisciplinary risk assessment remains a critical component of perioperative care.The need for a quantitative and operator-independent assessment of coronary microvascular function is increasingly recognized. We propose the theoretical framework of microvascular resistance reserve (MRR) as an index specific for the microvasculature, independent of autoregulation and myocardial mass, and based on operator-independent measurements of absolute values of coronary flow and pressure. In its general form, MRR equals coronary flow reserve (CFR) divided by fractional flow reserve (FFR) corrected for driving pressures. In 30 arteries, pressure, temperature, and flow velocity measurements were obtained simultaneously at baseline (BL), during infusion of saline at 10 mL/min (rest) and 20 mL/min (hyperemia). A strong correlation was found between continuous thermodilution-derived MRR and Doppler MRR (r = 0.88; 95% confidence interval 0.72-0.93; P less then 0.001). MRR was independent from the epicardial resistance, the lower the FFR value, the greater the difference between MRR and CFR. Therefore, MRR is proposed as a specific, quantitative, and operator-independent metric to quantify coronary microvascular dysfunction.
REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) randomized statin-treated patients with elevated triglycerides to icosapent ethyl (IPE) or placebo. There was a significant reduction in adjudicated events, including the primary endpoint (cardiovascular [CV] death, myocardial infarction [MI], stroke, coronary revascularization, unstable angina requiring hospitalization) and key secondary endpoint (CV death, MI, stroke) with IPE.

The purpose of this study was to determine the effects of IPE on investigator-reported events.

Potential endpoints were collected by blinded site investigators and subsequently adjudicated by a blinded Clinical Endpoint Committee (CEC) according to a prespecified charter. CDK phosphorylation Investigator-reported events were compared with adjudicated events for concordance.

There was a high degree of concordance between investigator-reported and adjudicated endpoints. The simple Kappa statistic between CEC-adjudicated vs site-reported events for the primary encular Disease or at High Risk for Cardiovascular Disease REDUCE-IT [Reduction of Cardiovascular Events With EPA - Intervention Trial]; NCT01492361).
IPE led to consistent, significant reductions in CV events, including MI and coronary revascularization, as determined by independent, blinded CEC adjudication as well as by blinded investigator-reported assessment. These results highlight the robust evidence for the substantial CV benefits of IPE seen in REDUCE-IT and further raise the question of whether adjudication of CV outcome trial endpoints is routinely required in blinded, placebo-controlled trials. (Evaluation of the Effect of AMR101 on Cardiovascular Health and Mortality in Hypertriglyceridemic Patients With Cardiovascular Disease or at High Risk for Cardiovascular Disease REDUCE-IT [Reduction of Cardiovascular Events With EPA - Intervention Trial]; NCT01492361).
Electrophysiological, imaging, and pathological studies have reported the presence of subtle structural abnormalities in hearts from patients with Brugada syndrome (BrS). However, data concerning disease involvement outside of the right ventricular outflow tract are limited.

This study sought to characterize the presence and distribution of ventricular myocardial fibrosis in a cohort of decedents experiencing sudden cardiac death caused by BrS.

The authors evaluated 28 whole hearts from consecutive sudden cardiac death cases attributed to BrS and 29 hearts from a comparator group comprised of noncardiac deaths (control subjects). Cardiac tissue from 6 regions across the right and left ventricle were stained with Picrosirius red for collagen and tissue composition was determined using image analysis software. Postmortem genetic testing was performed in cases with DNA retained for analysis.

Of 28 BrS decedents (75% men; median age of death 25 years), death occurred in sleep or at rest in 24 of 28 (86%). The highest proportion of collagen was observed in the epicardial right ventricular outflow tract of the BrS group (23.7%; 95%CI 20.8%-26.9%). Ventricular myocardium from BrS decedents demonstrated a higher proportion of collagen compared with control subjects (ratio 1.45; 95%CI 1.22-1.71; P< 0.001), with no significant interactions with respect to sampling location or tissue layer. There was insufficient evidence to support differences in collagen proportion in SCN5A-positive cases (n=5) when compared with control subjects (ratio 1.23; 95%CI 0.75-1.43; P = 0.27).

Brugada syndrome is associated with increased collagen content throughout right and left ventricular myocardium, irrespective of sampling location or myocardial layer.
Brugada syndrome is associated with increased collagen content throughout right and left ventricular myocardium, irrespective of sampling location or myocardial layer.
The 2018 U.S. cholesterol management guideline recommends additional lipid-lowering therapy with ezetimibe for secondary prevention in very high-risk patients with low-density lipoprotein cholesterol (LDL-C)≥70mg/dL despite maximally tolerated statin.

The purpose of this study was to evaluate the relationship between baseline LDL-C above and below 70mg/dL and the benefit of adding ezetimibe to statin in patients post-acute coronary syndrome (ACS).

IMPROVE-IT (Improved Reduction of Outcomes Vytorin Efficacy International Trial) was a double-blind, placebo-controlled, randomized trial of ezetimibe/simvastatin vs placebo/simvastatin in post-ACS patients followed for 6 years (median). A total of 17,999 patients were stratified by LDL-C at qualifying event into 3 groups (50-<70, 70-<100, and 100-125mg/dL). The primary endpoint was a composite of cardiovascular death, major coronary events, or stroke.

Absolute differences in median LDL-C achieved at 4 months between treatment arms were similar (17-20m[P04103]; NCT00202878).
Adding ezetimibe to statin consistently reduced the risk for cardiovascular events in post-ACS patients irrespective of baseline LDL-C values, supporting the use of intensive lipid-lowering therapy with ezetimibe even in patients with baseline LDL-C less then 70 mg/dL. (IMPROVE-IT Examining Outcomes in Subjects With Acute Coronary Syndrome Vytorin [Ezetimibe/Simvastatin] vs Simvastatin [P04103]; NCT00202878).
Benefits of intensive blood pressure lowering on health outcomes have been demonstrated in high-risk patients. However, little is known about such benefits in patients with left ventricular hypertrophy (LVH).

This study sought to investigate the association of on-treatment blood pressure with cardiovascular disease (CVD) risk in adults with hypertension and LVH.

From a nationwide health examination database, this study identified 95,545 participants aged 40-79 years who were taking antihypertensive medication and had LVH on baseline electrocardiography. Using Cox models, HRs and 95%CIs for CVD events were calculated according to systolic blood pressure (SBP) or diastolic blood pressure (DBP).

Over a median follow-up of 11.5 years, 12,035 new CVD events occurred. An SBP of<130mmHg and DBP of<80mmHg were associated with the lowest risk for CVD events in cubic spline models. When the group with SBP of 120-129mmHg was the reference, multivariable-adjusted HRs were 1.31 (95%CI 1.24-1.38) in the≥140mmHg group, 1.08 (95%CI 1.02-1.15) in the 130-139mmHg group, and 1.03 (95%CI 0.93-1.15) in the<120mmHg group. Likewise, when the group with DBP of 70-79mmHg was the reference, multivariable-adjusted HRs were 1.30 (95%CI 1.24-1.37) in the≥90mmHg group, 1.06 (95%CI 1.01-1.12) in the 80-89mmHg group, and 1.08 (95%CI 0.96 to 1.20) in the<70mmHg group.

In adults with hypertension and LVH, the risk for CVD events was the lowest at SBP <130mmHg and DBP <80mmHg. Further randomized trials are warranted to establish optimal blood pressure-lowering strategies for these patients.
In adults with hypertension and LVH, the risk for CVD events was the lowest at SBP less then 130 mm Hg and DBP less then 80 mm Hg. Further randomized trials are warranted to establish optimal blood pressure-lowering strategies for these patients.
This study was performed to investigate long-term, clinically important outcomes in patients who underwent permanent pacemaker implantation after transcatheter aortic valve replacement (TAVR).

The impact of permanent pacemaker implantation after TAVR is unknown, and prior studies have produced conflicting results.

In this nationwide, population-based cohort study, the study included all patients who underwent transfemoral TAVR in Sweden from 2008 to 2018 from the SWEDEHEART (Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies) register. Additional baseline characteristics and information about outcomes were obtained by individual crosslinking with other national health data registers. Unadjusted and multivariable-adjusted analyses were performed using Cox proportional hazards regression.

Of 3,420 patients, 481 (14.1%) underwent permanent pacemaker implantation within 30days after TAVR. The survival rate at 1, 5, and 10 years was 90.
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