[Correlations between vessel stiffness and biomarkers of senescent cell in elderly patients].

Aim    To study the association between vascular wall stiffness and known markers for accumulation of senescent cells in blood, cells, and tissues of old patients.Material and methods    This study included male and female patients aged 65 years and older who were referred to an elective surgical intervention, that included a surgical incision in the area of the anterior abdominal wall or large joints and met the inclusion and exclusion criteria. For all patients, traditional cardiovascular (CV) risk factors and arterial wall stiffness (pulse wave velocity, PWV) were evaluated. Also, biomaterials (peripheral blood, skin, subcutaneous adipose tissue) were collected during the surgery and were used for isolation of several cell types and subsequent histological analysis to determine various markers of senescent cells.Results    The study included 80 patients aged 65 to 90 years. The correlation analysis identified the most significant indexes that reflected the accumulation of senescent cells at the systemic, tissue, and cellular levels (r>0.3, р<0.05) and showed positive and negative correlations with PWV. The following blood plasma factors were selected as the markers of ageing: insulin-like growth factor 1 (IGF-1), fibroblast growth factor 21 (FGF-21), and vascular endothelium adhesion molecule 1 (VCAM-1). A significant negative correlation between PWV and IGF-1 concentration was found. Among the tissue markers, P16INK, the key marker for tissue accumulation of senescent cells, predictably showed a positive correlation (r=0.394, p<0.05). A medium-strength correlation with parameters of the 96-h increment of mesenchymal stromal cells and fibroblasts and a weak correlation with IL-6 as a SASP (specific senescent-associated secretory phenotype) were noted. Results of the multifactorial linear regression analysis showed that the blood plasma marker, VCAM-1, and the cell marker, 96-h increment of fibroblasts, were associated with PWV regardless of the patient's age.Conclusion    Stiffness of great arteries as measured by PWV significantly correlates with a number of plasma, tissue, and cellular markers for accumulation of senescent cells. This fact suggests PWV as a candidate for inclusion in the panel of parameters for evaluation and monitoring of the biological age during the senolytic therapy.

Revisiting the multiple roles of T-cadherin in health and disease.

As a non-canonical member of cadherin superfamily, T-cadherin was initially described as a molecule involved in homophilic recognition in the nervous and vascular systems. The ensuing decades clearly demonstrated that T-cadherin is a remarkably multifunctional molecule. It was validated as a bona fide receptor for both: LDL exerting adverse atherogenic action and adiponectin mediating many protective metabolic and cardiovascular effects. Motivated by the latest progress and accumulated data unmasking important roles of T-cadherin in blood vessel function and tissue regeneration, here we revisit the original function of T-cadherin as a guidance receptor for the growing axons and blood vessels, consider the recent data on T-cadherin-induced exosomes' biogenesis and their role in myocardial regeneration and revascularization. The review expands upon T-cadherin contribution to mesenchymal stem/stromal cell compartment in adipose tissue. We also dwell upon T-cadherin polymorphisms (SNP) and their possible therapeutic applications. Furthermore, we scrutinize the molecular hub of insulin and adiponectin receptors (AdipoR1 and AdipoR2) conveying signals to their downstream targets in quest for defining a putative place of T-cadherin in this molecular circuitry.

Infective Endocarditis in Moscow General Hospital: Clinical Characteristics and Outcomes (Single-Center 7 Years' Experience).

AIM: to investigate clinical properties of course and outcomes of infective endocarditis (IE) depending on source of infection, to find predictors of mortality in a Moscow general hospital. MATERIALS AND METHODS: We included in this study 176 patients with definite and possible infective endocarditis (the Duke criteria), admitted in our hospital in 2010-2017. Patients were divided in three groups according to source of infection. All patients underwent standard clinical and laboratory assessment, echocardiography, blood culture test combined with blood PCR with sequencing. Inhospital and 1-year outcome were evaluated. RESULTS: Among 176 patients with IE 65.3 % were men (median age 57 [35-72] years), most patients (n=149, 84.7 %) had native valve IE. Etiological factor was identified in 127 (72.2 %) cases. Gram-positive infective agents prevailed (54 %). Surgery in active phase of the disease was performed in 30 (17 %) patients. Among patients with healthcare-associated IE (n=76, 43.9 %) prevailed those older than 60 years, with high Charlson comorbidity index, with culture-negative IE, and complicated clinical course (mainly progressing heart failure). Patients with intravenous drug use associated IE (n=50, 28.4 %) had low Charlson index, association with hepatitis C viral infection, involvement of tricuspid valve with big vegetations, high frequency of embolic complications, and low inhospital mortality. Group of patients with community acquired IE (n=50, 28.4 %) more often had uncommon causative microorganisms, and had better long-term outcome. In-hospital mortality was 30.1 % (n=53) mostly due to sepsis with multi-organ failure, and heart failure. Risk factors of inhospital death were history of cardiovascular diseases, old age, kidney damage, methicillin-resistant Staphylococcus aureus (MRSA) infection, uncontrolled infection, and embolic events. Risk factors of 1-year mortality were history of stroke, and heart failure as IE complication. Independent predictors of in-hospital death were MRSA infection (odds ratio [OR] 50.32, 95 % confidence interval [CI] 1.66-213.92; p=0.002), persistent infection (OR 18.6, 95 %CI 5.37-64.40; p=0.001), duration of fever >7 days after initiation of antibacterial therapy (OR 13.41, 95 %CI 3.51-51.24; p=0.001); and of death during first year - history of cerebral infarction (OR 4.39, 95 %CI 1.32-14.70; p=0.016)), and heart failure as IE complication (OR 8.1, 95 %CI 1.97-67.09; p=0.016). Among patients subjected to surgery there were no fatal outcomes during 1 year after hospital discharge, while among conservatively treated patients were 21 (14.4 %) deaths (p<0.009). CONCLUSION: Main clinical features of IE course in patients urgently admitted to a general hospital was dominance of healthcare-associated  IE among patients, who were older than 60 years with severe comorbidities. These patients had more complications and worse outcome. Modeling of prognosis identified uncontrolled infection as key factor of unfavorable outcome. Surgery significantly reduced long-term mortality.

Systems biology insights into the meaning of the platelet's dual-receptor thrombin signaling.

Essentials Roles of the two thrombin receptors in platelet signaling are poorly understood. Computational systems biology modeling was used together with continuous flow cytometry. Dual-receptor system has wide-range sensitivity to thrombin and optimal response dynamics. Procoagulant platelet formation is determined by donor-specific activities of the two receptors. SUMMARY: Background Activation of human platelets with thrombin proceeds via two protease-activated receptors (PARs), PAR1 and PAR4, that have identical main intracellular signaling responses. Although there is evidence that they have different cleavage/inactivation kinetics (and some secondary variations in signaling), the reason for such redundancy is not clear. Methods We developed a multicompartmental stochastic computational systems biology model of dual-receptor thrombin signaling in platelets to gain insight into the mechanisms and roles of PAR1 and PAR4 functioning. Experiments employing continuous flow cytometry of washed human platelets were used to validate the model and test its predictions. Activity of PAR receptors in donors was evaluated by mRNA measurement and by polymorphism sequencing. Results Although PAR1 activation produced rapid and short-lived response, signaling via PAR4 developed slowly and propagated in time. Response of the dual-receptor system was both rapid and prolonged in time. Inclusion of PAR1/PAR4 heterodimer formation promoted PAR4 signaling in the medium range of thrombin concentration (about 10 nm), with little contribution at high and low thrombin. Different dynamics and dose-dependence of procoagulant platelet formation in healthy donors was associated with individual variations in PAR1 and PAR4 activities and particularly by the Ala120Thr polymorphism in the F2RL3 gene encoding PAR4. Conclusions The dual-receptor combination is critical to produce a response combining three critical advantages: sensitivity to thrombin concentration, rapid onset and steady propagation; specific features of the protease-activated receptors do not allow combination of all three in a single receptor.