The role of immune responses, focussing on herpes virus specificity and interferon-gamma, in Myocardial Infarction with reperfusion and in Chronic Fatigue Syndrome

Background Immune responses targeting microbes can contribute to chronic inflammation, particularly when the microbes are persistent such as herpes-family Cytomegalovirus (CMV) and EpsteinBarr virus (EBV). Such persistence of antigens can cause T cell exhaustion characterized by loss of appropriate effector functions, expression of inhibitory receptors, as well as failure to return to homeostatic pre-inflammatory conditions. This results in immune senescence and dysregulation which may cause disrupted cell populations, homing and cytokine productions that mediate immunopathology and compromise anti-microbial defences. Aims The aim of the study was to determine whether microbe specific particularly, interferongamma immune responses measured in 2 disease states, where a herpes viral inflammatory aetiology and immune dysregulation are suggested, acute Myocardial Infarction (MI) with reperfusion and Chronic Fatigue Syndrome (CFS), are indicative of disease presence and severity. Patients MI occurs due to blockage of the coronary artery, and treatment involves stent insertion, allowing reperfusion (R), which has associated immunopathology due to T cell homing. A total of 52 MI patients were studied. Blood samples were taken before and after reperfusion to investigate the dynamics of specific T cell homing to the heart, that may contribute to disease severity (reperfusion damage). For 50 CFS patients with measured disease levels, blood samples were taken to examine immune responses including those against microbes implicated in disease (CMV & EBV) compared to healthy controls. Methods T cell immunity was measured by ELIspot and flow cytometry, and cytokine levels in cell culture supernatants were measured using multiplex technology. Statistical analyses were carried out for normality in data sets. The Mann-Whitney test or unpaired t test was used to determine the difference between two unrelated groups. Differences between repeat or paired measurements were determined by Wilcoxon signed rank tests or paired t tests. Associations between measurements were investigated using Spearman correlation. Results and Discussion In MI patients, compared to before reperfusion, levels of the following cell populations fell significantly after reperfusion: terminally-differentiated CD8+ PD-1+ effector memory cells (p=0.016) and CMV-specific IFN-secreting CD4+ T cells (p=0.002) the latter also being associated with injury. This suggests specific pathogenic T cell homing to the heart during reperfusion. In CFS patients, increased disease severity was associated with increased non-specific IFNy production (p=0.008), and reduced percentage of NK cells (p=0.0047). NK cell deficiency may reduce antiviral defences and allow detrimental viral reactivation. Conclusion T cell responses against CMV appeared to have greater involvement in MI + R than CFS. Immune responses involving IFN-γ are demonstrated in both conditions as being associated with disease, and so this cytokine may be considered a disease biomarker and a therapeutic target for both

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

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

Telomerase Activation to Reverse Immunosenescence in Elderly Patients With Acute Coronary Syndrome: Protocol for a Randomized Pilot Trial

Background: Inflammation plays a key role in the pathophysiology of coronary heart disease (CHD) and its acute manifestation, acute coronary syndrome (ACS). Aging is associated with a decline of the immune system, a process known as immunosenescence. This is characterized by an increase in highly proinflammatory T cells that are involved in CHD progression, plaque destabilization, and myocardial ischemia–reperfusion injury. Telomere dysfunction has been implicated in immunosenescence of T lymphocytes. Telomerase is the enzyme responsible for maintaining telomeres during cell divisions. It has a protective effect on cells under oxidative stress and helps regulate flow-mediated dilation in microvasculature. Objective: The TACTIC (Telomerase ACTivator to reverse Immunosenescence in Acute Coronary Syndrome) trial will investigate whether a telomerase activator, TA-65MD, can reduce the proportion of senescent T cells in patients with ACS with confirmed CHD. It will also assess the effect of TA-65MD on decreasing telomere shortening, reducing oxidative stress, and improving endothelial function. Methods: The study was designed as a single-center, randomized, double-blind, parallel-group, placebo-controlled phase II trial. Recruitment started in January 2019. A total of 90 patients, aged 65 years or older, with treated ACS who have had CHD confirmed by angiography will be enrolled. They will be randomized to one of two groups: TA-65MD oral therapy (8 mg twice daily) or placebo taken for 12 months. The primary outcome is the effect on immunosenescence determined by a decrease in the proportion of CD8+ TEMRA (T effector memory cells re-expressing CD45RA [CD45 expressing exon A]) cells at 12 months. Secondary outcomes include leukocyte telomere length, endothelial function, cardiac function as measured by echocardiography and NT-proBNP (N-terminal fragment of the prohormone brain-type natriuretic peptide), systemic inflammation, oxidative stress, and telomerase activity. Results: The study received National Health Service (NHS) ethics approval on August 9, 2018; Medicines and Healthcare products Regulatory Agency approval on October 19, 2018; and NHS Health Research Authority approval on October 22, 2018. The trial began recruiting participants in January 2019 and completed recruitment in March 2020; the trial is due to report results in 2021. Conclusions: This pilot trial in older patients with CHD will explore outcomes not previously investigated outside in vitro or preclinical models. The robust design ensures that bias has been minimized. Should the results indicate reduced frequency of immunosenescent CD8+ T cells as well as improvements in telomere length and endothelial function, we will plan a larger, multicenter trial in patients to determine if TA-65MD is beneficial in the treatment of CHD in elderly patients

Telomerase mediates lymphocyte proliferation but not the atherosclerosis-suppressive potential of regulatory T-cells

Objective: Atherosclerosis is an age-related disease characterised by systemic oxidative stress and low-grade inflammation. The role of telomerase and telomere length in atherogenesis remains contentious. Short telomeres of peripheral leukocytes are predictive for coronary artery disease. Conversely, attenuated telomerase has been demonstrated to be protective for atherosclerosis. Hence a potential causative role of telomerase in atherogenesis is critically debated. Approach and Results: In this study we used multiple mouse models to investigate the regulation of telomerase under oxidative stress as well as its impact on atherogenesis in vitro and in vivo. Using primary lymphocytes and myeloid cell cultures we demonstrate that cultivation under hyperoxic conditions induced oxidative stress resulting in chronic activation of CD4+ cells and significantly reduced CD4+ T-cell proliferation. The latter was telomerase dependent, as oxidative stress had no effect on the proliferation of primary lymphocytes isolated from telomerase-knock-out mice. In contrast, myeloid cell proliferation was unaffected by oxidative stress nor reliant on telomerase. Telomerase reverse transcriptase (TERT) deficiency had no effect on Treg numbers in vivo or suppressive function ex vivo. Adoptive transfer of TERT-/- Tregs into Rag2-/- ApoE-/- double knock out mice demonstrated that telomerase function was not required for the ability of Tregs to protect against atherosclerosis. However, telomere length was critical for Treg function. Conclusions: Telomerase contributes to lymphocyte proliferation but plays no major role in Treg function, provided that telomere length is not critically short. We suggest that oxidative stress may contribute to atherosclerosis via suppression of telomerase and acceleration of telomere attrition in Tregs.This study was supported, in part, by British Heart Foundation Project Grants PG/15/85/31744 and PG/12/47/29681 (www.BHF.org.uk) as well as the Newcastle Healthcare Charity (www.newcastle-hospitals. org.uk/patient-guides/charity-matters-at-newcastle-hospitals_charitable- funds.aspx). N.M. Al Zhrany was funded by a stipend from the Government of Saudi Arabia

Exogenous transforming growth factor-β1 and its helminth-derived mimic attenuate the heart's inflammatory response to ischemic injury and reduce mature scar size

Coronary reperfusion after acute ST-elevation myocardial infarction (STEMI) is standard therapy to salvage ischemic heart muscle. However, subsequent inflammatory responses within the infarct lead to further loss of viable myocardium. Transforming growth factor (TGF)-β1 is a potent anti-inflammatory cytokine released in response to tissue injury. The aim of this study was to investigate the protective effects of TGF-β1 after MI. In patients with STEMI, there was a significant correlation (P = 0.003) between higher circulating TGF-β1 levels at 24 hours after MI and a reduction in infarct size after 3 months, suggesting a protective role of early increase in circulating TGF-β1. A mouse model of cardiac ischemia reperfusion was used to demonstrate multiple benefits of exogenous TGF-β1 delivered in the acute phase. It led to a significantly smaller infarct size (30% reduction, P = 0.025), reduced inflammatory infiltrate (28% reduction, P = 0.015), lower intracardiac expression of inflammatory cytokines IL-1β and chemokine (C-C motif) ligand 2 (&gt;50% reduction, P = 0.038 and 0.0004, respectively) at 24 hours, and reduced scar size at 4 weeks (21% reduction, P = 0.015) after reperfusion. Furthermore, a low-fibrogenic mimic of TGF-β1, secreted by the helminth parasite Heligmosomoides polygyrus, had an almost identical protective effect on injured mouse hearts. Finally, genetic studies indicated that this benefit was mediated by TGF-β signaling in the vascular endothelium

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

Identification of kinetic triplets by results of derivatographic analysis

The method for identification of the triplet of kinetic parameters of a heterogeneous reaction using the data of the derivatographic analysis is proposed. This method is characterized by high accuracy and relative simplicity and it can be effectively realized using MS Excel software