Telomerase as a Therapeutic Target in Cardiovascular Disease.

Shortened telomeres have been linked to numerous chronic diseases, most importantly coronary artery disease, but the underlying mechanisms remain ill defined. Loss-of-function mutations and deletions in telomerase both accelerate telomere shortening but do not necessarily lead to a clinical phenotype associated with atherosclerosis, questioning the causal role of telomere length in cardiac pathology. The differential extranuclear functions of the 2 main components of telomerase, telomerase reverse transcriptase and telomerase RNA component, offer important clues about the complex relationship between telomere length and cardiovascular pathology. In this review, we critically discuss relevant preclinical models, genetic disorders, and clinical studies to elucidate the impact of telomerase in cardiovascular disease and its potential role as a therapeutic target. We suggest that the antioxidative function of mitochondrial telomerase reverse transcriptase might be atheroprotective, making it a potential target for clinical trials. Graphic Abstract: A graphic abstract is available for this article.Work in the VA laboratory is supported by the Spanish Ministerio de Ciencia e Innovación (MCIN) (PID2019-108489RB-I00) and the Instituto de Salud Carlos III (ISCIII) (AC17/00067) with co-funding from the European Regional Development Fund (ERDF, “Una manera de hacer Europa”), and the Progeria Research Foundation (Award PRF 2019–77). The CNIC is supported by the ISCIII, the MCIN, and the Pro CNIC Foundation. I. Spyridopoulos is funded by the British Heart Foundation (PG/18/25/33587) and National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University. The work of J. Haendeler and J. Altschmied is in part supported by the Deutsche Forschungsgemeinschaft (DFG) SFB1116, A04 (J. Haendeler and J. Altschmied), HA2868/14-1 (J. Haendeler) and AL288/5-1 (J. Altschmied). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health’. I. Spyridopoulos also receives a grant from TA-Science for the TACTIC trial (Telomerase Activator to Reverse Immunosenescence in Acute Coronary Syndrome).S

High-sensitivity cardiac troponin T and copeptin assays to improve diagnostic accuracy of exercise stress test in patients with suspected coronary artery disease

Background: The average diagnostic sensitivity of exercise stress tests (ESTs) is lower than that of other non-invasive cardiac stress tests. The aim of the study was to examine whether high-sensitivity cardiac troponin T (hs-cTnT) or copeptin concentrations rise in response to inducible myocardial ischaemia and may improve the diagnostic accuracy of ESTs. Methods and results: An EST was performed stepwise on a bicycle ergometer by 383 consecutive patients with suspected or progression of coronary artery disease (CAD). In addition venous blood samples for measurement of hs-cTnT and copeptin were collected prior to EST, at peak exercise, and 4 h after EST. Coronary angiography was assessed for all patients. Patients with significant CAD (n=224) were more likely to be male and older compared to patients with non-significant CAD (n=169). Positive EST was documented in 125 (55.8%) patients with significant CAD and in 69 (43.4%) patients with non-significant CAD. Copeptin and hs-cTnT concentrations at baseline were higher in patients with significant CAD (copeptin: 10.8 pmol/l (interquartile range (IQR) 8.1–15.6) vs 9.4 pmol/l (IQR 7.1–13.9); p=0.04; hs-cTnT: 3.0 ng/l (IQR <3.0–5.4) vs <3.0 ng/l (IQR <3.0); p=0.006). Hs-cTnT improved sensitivity (61.6% vs 55.8%), specificity (67.7% vs 56.6%) and the positive predictive value (PPV) (72.3% vs 64.4%) and negative (55.2% vs 47.6%) predictive value (NPV) of EST. Copeptin could not improve sensitivity (55.4% vs 55.8%) and reduced specificity, PPV and NPV. Conclusions: The measurement of hs-cTnT during EST improves sensitivity, specificity, and positive and negative predictive values. In contrast, measurement of copeptin does not improve diagnostic sensitivity and reduces specificity

Разработка информационной модели данных системы поощрений сотрудников и студентов

В статье рассмотрена система поощрений сотрудников и студентов. Составлена диаграмма сущность-связь процесса учета всех этапов документооборота данного процесса. Представлен пример формы разработанной информационной системы учета и анализа распределения поощрений сотрудниками студентам.The article considers the system of incentives for employees and students. A diagram is drawn of the essence-relationship of the process of accounting for all stages of the workflow of this process. An example of the form of the developed information system of the account and the analysis of distribution of encouragements by employees to students is presented

Myocardial Ischemia and Reperfusion Leads to Transient CD8 Immune Deficiency and Accelerated Immunosenescence in CMV-Seropositive Patients

Rationale: There is mounting evidence of a higher incidence of coronary heart disease (CHD) in cytomegalovirus (CMV) seropositive individuals. Objective: The aim of this study was to investigate whether acute MI triggers an inflammatory T-cell response that might lead to accelerated immunosenescence in CMV-seropositive patients. Methods and Results: Thirty-four patients with acute MI undergoing primary PCI (PPCI) were longitudinally studied within 3 months following reperfusion (Cohort A). In addition, 54 patients with acute and chronic MI were analyzed in a cross-sectional study (Cohort B). CMV-seropositive patients demonstrated a greater fall in the concentration of terminally differentiated CD8 effector memory T cells (TEMRA) in peripheral blood during the first 30 min of reperfusion compared with CMV-seronegative patients (-192 vs. -63 cells/µl; p=0.008), correlating with the expression of programmed cell death-1 (PD-1) before PPCI (r=0.8; p=0.0002). A significant proportion of TEMRA cells remained depleted for at least 3 months in CMV-seropositive patients. Using high-throughput 13-parameter flow cytometry and HLA class I CMV-specific dextramers, we confirmed an acute and persistent depletion of terminally differentiated TEMRA and CMV-specific CD8+ cells in CMV-seropositive patients. Long-term reconstitution of the TEMRA pool in chronic CMV-seropositive post-MI patients was associated with signs of terminal differentiation including an increase in KLRG1 and shorter telomere length in CD8+ T cells (2225 bp vs. 3397 bp; p<0.001). Conclusions: Myocardial ischemia and reperfusion in CMV-seropositive patients undergoing PPCI leads to acute loss of antigen-specific, terminally differentiated CD8 T-cells, possibly through PD-1-dependent programmed cell death. Our results suggest that acute MI and reperfusion accelerate immunosenescence in CMV-seropositive patients

CMV-independent increase in CD27−CD28+ CD8+ EMRA T cells is inversely related to mortality in octogenarians

Funder: The author is supported by the British Heart FoundationFunder: British Heart Foundation PG/15/85/31744 and PG/18/25/33587, Newcastle Healthcare Charity, Medical Research Council (G0500997 to TK, CJ and TvZ, G0601333 to TvZ) and the NIHR Biomedical Research Centre in Ageing and Chronic Disease.Funder: BK holds a British Heart Foundation personal chair.Abstract: Cytomegalovirus (CMV) seropositivity in adults has been linked to increased cardiovascular disease burden. Phenotypically, CMV infection leads to an inflated CD8 T-lymphocyte compartment. We employed a 8-colour flow cytometric protocol to analyse circulating T cells in 597 octogenarians from the same birth cohort together with NT-proBNP measurements and followed all participants over 7 years. We found that, independent of CMV serostatus, a high number of CD27−CD28+ CD8 EMRA T-lymphocytes (TEMRA) protected from all-cause death after adjusting for known risk factors, such as heart failure, frailty or cancer (Hazard ratio 0.66 for highest vs lowest tertile; confidence interval 0.51–0.86). In addition, CD27−CD28+ CD8 EMRA T-lymphocytes protected from both, non-cardiovascular (hazard ratio 0.59) and cardiovascular death (hazard ratio 0.65). In aged mice treated with the senolytic navitoclax, in which we have previously shown a rejuvenated cardiac phenotype, CD8 effector memory cells are decreased, further indicating that alterations in T cell subpopulations are associated with cardiovascular ageing. Future studies are required to show whether targeting immunosenescence will lead to enhanced life- or healthspan

The Quality of Surgical Instrument Surfaces Machined with Robotic Belt Grinding

Belt grinding is commonly used in the finishing of non-functional shaped surfaces of surgical instruments. Most often it is carried out manually. The subject of this article is the possibility of replacing manual belt grinding with robotic grinding. A research stand was built, the machining process was programmed, and a comparative study of manual and robotic grinding was carried out. The subject of the research were the arms of orthodontic forceps. The condition of the treated surface, defined by its structure and roughness and the geometric accuracy and the error of the shape of the arm in the selected cross-section were adopted as the comparative criteria. Research has shown that robotic belt grinding is more efficient in terms of quality and produces more consistent results than manual grinding

CMV-independent increase in CD27-CD28+ CD8+ EMRA T cells is inversely related to mortality in octogenarians.

Cytomegalovirus (CMV) seropositivity in adults has been linked to increased cardiovascular disease burden. Phenotypically, CMV infection leads to an inflated CD8 T-lymphocyte compartment. We employed a 8-colour flow cytometric protocol to analyse circulating T cells in 597 octogenarians from the same birth cohort together with NT-proBNP measurements and followed all participants over 7 years. We found that, independent of CMV serostatus, a high number of CD27-CD28+ CD8 EMRA T-lymphocytes (TEMRA) protected from all-cause death after adjusting for known risk factors, such as heart failure, frailty or cancer (Hazard ratio 0.66 for highest vs lowest tertile; confidence interval 0.51-0.86). In addition, CD27-CD28+ CD8 EMRA T-lymphocytes protected from both, non-cardiovascular (hazard ratio 0.59) and cardiovascular death (hazard ratio 0.65). In aged mice treated with the senolytic navitoclax, in which we have previously shown a rejuvenated cardiac phenotype, CD8 effector memory cells are decreased, further indicating that alterations in T cell subpopulations are associated with cardiovascular ageing. Future studies are required to show whether targeting immunosenescence will lead to enhanced life- or healthspan