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The specifics of the anticoagulant therapy after radiofrequency ablation of the cavotricuspid isthmus have not been sufficiently studied, therefore, the recommendations for prescribing the anticoagulant therapy usually do not distinguish between atrial flutter and atrial fibrillation. In contrast to the case of atrial fibrillation, the effectiveness of the interventional treatment for typical atrial flutter reaches 90%. This procedure may save the patient from a long-term anticoagulant therapy in the absence of recurrence of typical atrial flutter. The decision to stop the anticoagulant therapy after successful radiofrequency ablation of the cavotricuspid isthmus should take into account the potential induction of atrial fibrillation in patients undergoing the interventional treatment. In addition to the CHA2DS2-VASc scale, which characterizes the patient's comorbidity, it is important to take into account the echocardiographic morphofunctional criteria to assess the risk of atrial fibrillation. Currently, this protocol is not regulated in the clinical guidelines. The analysis of the literature data and the authors' own experience allow us to conclude that the optimal time for stopping the anticoagulant therapy is a relapse-free period of 34 months after the radiofrequency ablation of the cavotricuspid isthmus, since it is at this time that the effectiveness of the interventional treatment can be objectified.

Background: Atrial fibrillation (AF) is the most common arrhythmia in clinical practice and is associated with an increased risk of death, progression of heart failure, and the development of cardiogenic thromboemboli. Despite the significant success in the management of AF in the paroxysmal form, the results of the treatment for patients with persistent forms of AF remain unsatisfactory. Though the surgical approach provides higher rates of efficiency regarding the restoration of a sinus rhythm, transmural lesions are not always attainable, as a result, the rate of AF recurrence in the long-term period remains fairly high. It is also impossible to create ablative patterns to the mitral and tricuspid valves during thoracoscopic epicardial ablation, which can cause the development of recurrent AF, perimitral and typical atrial flutter. Therefore, the development of hybrid approaches combining the advantages of catheter and thoracoscopic techniques is an urgent task of contemporary surgical and interventional arrhythmology. Aims: to estimate the immediate results of a hybrid approach in the management of patients with persistent AF. Methods: We report the first experience of a hybrid treatment of patients with persistent AF. 6 patients aged 53-64 years (1 female, 5 males) were included in the study. At the first stage, thoracoscopic epicardial bipolar ablation was performed (modified GALAXY protocol); the second stage (in 3 to 6 months after the thoracoscopic stage) included an intracardiac electrophysiological study with three-dimensional endocardial mapping followed by endocardial ablation. Results: The thoracoscopic stage of the hybrid treatment included ablation according to the box lesion scheme using a bipolar irrigation equipment. No lethal outcomes and severe, life-threatening complications were registered. The duration of the inpatient period was 510 hospital-days. The 2nd stage of the hybrid treatment was limited to intracardiac electrophysiological examination only in 2 patients. In 4 patients, epicardial radiofrequency ablation was complemented by endocardial radiofrequency exposure. In 3 of the 4 patients who underwent endocardial radiofrequency ablation, catheter ablation of the mitral and cavotricuspid isthmus was required because of the induction of perimitral and typical flutter, respectively. After the 2nd stage of the hybrid treatment, at the time of discharge all the patients maintained a stable sinus rhythm. There were no severe complications or lethal outcomes. Conclusion: a hybrid approach in the AF management is a safe and effective method of treatment, which combines the advantages of minimally invasive surgery and endocardial intervention in patients with persistent AF. The technique is safe and has acceptable short-term results.

Background: Thoracoscopic ablation is an effective treatment of patients with atrial fibrillation. Nowadays, 2 types of ablative devices are available in clinical practice allowing one to perform the thoracoscopic procedure Medtronic and AtriCure. However, the contemporary clinical literature does not have enough data that would compare these two approaches. Aims: to perform a comparative analysis of the short-term results of two minimally invasive strategies in thoracoscopic ablation for atrial fibrillation. Methods: 232 patients underwent thoracoscopic ablation for atrial fibrillation in two clinical centers for the period from 2016 to August 2021. The patients were divided into 2 groups. The first group was represented by those patients to whom a Medtronic device was applied (n=140), the second group was treated with an AtriCure device (n=92). The patients were comparable in their age, gender, initial severity of the condition. The follow-up consisted of laboratory tests, chest Х-ray, electrocardiography, 24-hour Holter monitor, echocardiography. The structure and prevalence of postoperative and intraoperative complications, specifics of the postoperative period were compared between the two groups. Results: According to the structure and prevalence of intraoperative complications the 2 groups are comparable to each other: 4.3% and 1.1% for the 1st group and 2nd group, respectively (p 0.05). The postoperative complications had developed in 6 (4.3%) and 5 (5.4%) patients in groups 1 and 2, respectively (p 0.05). At the time of discharge from hospital, a sinus rhythm was registered in 93.6% of patients (1st group), and 85.9% (2nd group) (p 0.05). Conclusions: Both strategies have demonstrated comparable short-term results in patients with lone atrial fibrillation. A further research is needed to evaluate the effectiveness of this strategy in a long-term period.

New variants of SARS-CoV-2 such as Omicron BA.2, BA.4/5, BA.2.12.1 and BA 2.75 are characterized by higher infectivity and the ability to escape virus-neutralizing antibodies against previous coronavirus variants. The S-trimer of BA.2 and its phylogenetic derivatives are characterized by a predominant Up-conformation, which facilitates the interaction with ACE2 on target cells and promotes the resistance to neutralizing antibodies. The immunity acquired from the infection with earlier strains is non-sterile for both early and later strains; the booster systemic immunization does not significantly affect the effectiveness of antiviral immunity, and its feasibility is currently being questioned. Studies of the mucosal immune response have shown that intranasal immunization with adenovirus vaccines provides more pronounced protective immunity than systemic reimmunization does. A promising approach is the creation of multivalent inhaled next generation vaccines containing immunoadjuvants that activate B- and T-cell mucosal immunity. Currently, a large number of intranasal vaccines are undergoing phase I/II trials, while the preclinical and preliminary clinical results indicate that this method of vaccination provides a better mucosal immune response at the entry site of the virus than systemic immunization does. This strategy may provide a long-term immune protection against the currently existing and yet unknown new strains of SARS-CoV-2.

Background One of the most arrhythmias associated with atrial fibrillation (AF) is typical atrial flutter (AFL). The main methods of surgical treatment of these arrhythmias is catheter ablation. The problem of catheter ablation strategy for these coexistentarrhythmias is not solved. Purpose: To assess the effectiveness of long-term maintenance of sinus rhythm in a two-stage approach to the interventional treatment of atrial fibrillation associated with typical atrial flutter. Methods: The study included 34 patients aged 41-82 years with AF and coexistent typical AFL. Female 11 (32,35%), male 23 (67,35%). Randomization 1:1. Group 1 (n=17) has been performed radiofrequency ablation (RFA) of the cavotricuspid isthmus (CTI) with radiofrequency catheter isolation of the PV. Group 2 (n=17) has been performed only RFA of CTI. AF and AFL recurrences rate has been evaluated in both groups. Follow-up period 12 months. Results: Procedure duration and fluoroscopy time were less in group 2 that those in group 1. Extended intervention in group 1 was accompanied with complications in two cases. There were no significant differences in AF recurrence rate in both groups (p=0,43183). AFL recurrences has not been found in both groups. Conclusion: One stage ablation approach in AF patients with coexistent AFLassociated with increaseprocedure duration and fluoroscopy time. The frequency of AF recurrence in patients who underwent extended intervention (catheter isolation of the PV and RFA CTI) and in patients who underwent only the elimination of typical atrial flutter, was not statistically significantly different (p = 0.43183). In the presence of AF and typical atrial flutter, a two-stage approach to interventional treatment should be regarded as appropriate.

Objective: to evaluate the role of cardiopulmonary test in the diagnosis of heart failure with preserved ejection fraction in patients with atrial fibrillation. Material and Methods: 138 patients with atrial fibrillation were included in our study. Using HFA-PEFF algorithm (algorithm for diagnosis of heart failure with preserved left ventricular ejection fraction) all patients were initially divided into 3 groups: low probability of heart failure - 23 patients, intermediate probability - 96 and high probability - 19 patients. The stress-test allowed to precisely assess of patients at intermediate risk and finally form the groups: Group 1 without heart failure, 85 patients (61.6%); Group 2 patients with heart failure and preserved ejection fraction, 53 patients (38.4%). The next diagnostic stage was cardiopulmonary test. Results: during CPT, the maximum anaerobic exercise threshold was 6.8 and 4.85 METS for the first and second groups, respectively (p0.001), reflecting lower exercise tolerance in the second group of patients. Analysis of variance (ANOVA) demonstrated a statistically significant increase in pro-BNP levels with a decrease in peak VO2 (p0.001). Also, analysis of variance demonstrated a significant statistical difference with respect to systolic pulmonary artery pressure in the subgroups with severely, moderately reduced oxygen consumption and in the group with normal peak VO2 (p=0.01). ROC analysis determined a peak VO2 of 20 ml/kg/min, above which the HFA-PEFF algorithm was unlikely to detect heart failure (AUC 0.73; confidence interval 0.65-0.82; p=0.043; sensitivity 85%; specificity 51%). Conclusion: Cardiopulmonary test is a reliable instrumental noninvasive method of investigation in the diagnosis of heart failure with preserved ejection fraction. Keywords: atrial fibrillation; chronic heart failure; cardiopulmonary test; ergospirometry

Atrial fibrillation is one of the most common types of cardiac arrhythmia observed in clinical practice. Despite advances in the diagnosis and treatment, atrial fibrillation remains one of the leading causes of cardiovascular mortality and morbidity. In addition, atrial fibrillation is quite often combined with other pathologies of the cardiovascular system and is a marker of an unfavorable outcome. Several previous studies have demonstrated reduced survival in patients with coronary artery disease and atrial fibrillation who have not undergone surgery for arrhythmia. According to other data, the presence of preoperative atrial fibrillation among patients undergoing isolated coronary artery bypass grafting was associated with significantly higher rates of major postoperative complications. Nowadays, no one doubts the fact that atrial fibrillation during a coronary artery bypass surgery is a risk factor for increased hospital mortality, postoperative morbidity and leads to a decrease in the long-term survival. The studies confirm the necessity of surgical ablation for atrial fibrillation during coronary revascularization to reduce both short-term and long-term postoperative mortality and late complications.

Background: Adequate diagnosis of recurrent atrial fibrillation after the surgical treatment in patients with paroxysmal forms of the disease appears to be a difficult task. Aims: The manuscript is devoted to a comparative analysis of the results of subjective and objective assessment of atrial fibrillation recurrence after cryoballoon ablation of the pulmonary veins. Material and methods: 301 patients were included in the study. All of them consequentially underwent cryoballoon ablation of the pulmonary veins in the period of October, 2016 November, 2019. The inclusion criteria were as follows: symptomatic atrial fibrillation; confirmation of atrial fibrillation by instrumental diagnostic methods. The exclusion criteria were the following: a combination of atrial fibrillation and atrial flutter at the time of surgery; history of open-heart procedures and catheter procedures to cease atrial fibrillation; the presence of concomitant cardiac and "arrhythmogenic" pathology. Results: In the period of May 01-30, 2020, 100% (n=301) of the patients included in the study were assessed by the method of targeted survey. The median duration of the postoperative period to the time of a patient's survey was 21 (3; 43) months. The interviews have shown that 136 (45%) patients noted a return of complaints associated with atrial fibrillation recurrence in the postoperative period. There was a clear tendency towards a decrease in the total number of patients with complaints of the clinical recurrence of the disease, depending on the time elapsed since the surgical procedure. The longer the period from the moment of surgery, the lower the number of patients with recurrence. Of 136 patients with recurrent complaints associated with atrial fibrillation, 97 (71%) were able to conduct the daily electrocardiogram monitoring. Of these, the instrumental recurrence of atrial fibrillation was confirmed in 59 patients, which amounted to 20% of all the patients included in the study (n=301). Conclusion: To establish the true number of atrial fibrillation recurrence after cryoballoon ablation of the pulmonary veins, a targeted survey of patients is desirable for up to 12 months after the surgery. The patients with complaints which suggest atrial fibrillation recurrence, even if these complaints do not correspond to the preoperative ones, should be invited for the instrumental diagnostics of arrhythmia.

BACKGROUND The development of regenerative therapy for human spinal cord injury (SCI) is dramatically restricted by two main challenges: the need for a safe source of functionally active and reproducible neural stem cells and the need of adequate animal models for preclinical testing. Direct reprogramming of somatic cells into neuronal and glial precursors might be a promising solution to the first challenge. The use of non-human primates for preclinical studies exploring new treatment paradigms in SCI results in data with more translational relevance to human SCI. AIM To investigate the safety and efficacy of intraspinal transplantation of directly reprogrammed neural precursor cells (drNPCs). METHODS Seven non-human primates with verified complete thoracic SCI were divided into two groups: drNPC group (n = 4) was subjected to intraspinal transplantation of 5 million drNPCs rostral and caudal to the lesion site 2 wk post injury, and lesion control (n = 3) was injected identically with the equivalent volume of vehicle. RESULTS Follow-up for 12 wk revealed that animals in the drNPC group demonstrated a significant recovery of the paralyzed hindlimb as well as recovery of somatosensory evoked potential and motor evoked potential of injured pathways. Magnetic resonance diffusion tensor imaging data confirmed the intraspinal transplantation of drNPCs did not adversely affect the morphology of the central nervous system or cerebrospinal fluid circulation. Subsequent immunohistochemical analysis showed that drNPCs maintained SOX2 expression characteristic of multipotency in the transplanted spinal cord for at least 12 wk, migrating to areas of axon growth cones. CONCLUSION Our data demonstrated that drNPC transplantation was safe and contributed to improvement of spinal cord function after acute SCI, based on neurological status assessment and neurophysiological recovery within 12 wk after transplantation. The functional improvement described was not associated with neuronal differentiation of the allogeneic drNPCs. Instead, directed drNPCs migration to the areas of active growth cone formation may provide exosome and paracrine trophic support, thereby further supporting the regeneration processes.

The interaction of neural progenitor cells (NPCs) with the extracellular matrix (ECM) plays an important role in neural tissue regeneration. Understanding which motifs of the ECM proteins are crucial for normal NPC adhesion, proliferation, and differentiation is important in order to create more adequate tissue engineered models of neural tissue and to efficiently study the central nervous system regeneration mechanisms. We have shown earlier that anisotropic matrices prepared from a mixture of recombinant dragline silk proteins, such as spidroin 1 and spidroin 2, by electrospinning are biocompatible with NPCs and provide good proliferation and oriented growth of neurites. This study objective was to find the effects of spidroin-based electrospun materials, modified with peptide motifs of the extracellular matrix proteins (RGD, IKVAV, and VAEIDGIEL) on adhesion, proliferation, and differentiation of directly reprogrammed neural precursor cells (drNPCs). The structural and biomechanical studies have shown that spidroin-based electrospun mats (SBEM), modified with ECM peptides, are characterized by a uniaxial orientation and elastic moduli in the swollen state, comparable to those of the dura mater. It has been found for the first time that drNPCs on SBEM mostly preserve their stemness in the growth medium and even in the differentiation medium with brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor, while addition of the mentioned ECM-peptide motifs may shift the balance toward neuroglial differentiation. We have demonstrated that the RGD motif promotes formation of a lower number of neurons with longer neurites, while the IKVAV motif is characterized by formation of a greater number of NF200-positive neurons with shorter neurites. At the same time, all the studied matrices preserve up to 30% of neuroglial progenitor cells, phenotypically similar to radial glia derived from the subventricular zone. We believe that, by using this approach and modifying spidroin by various ECM-motifs or other substances, one may create an in vitro model for the neuroglial stem cell niche with the potential control of their differentiation.

The article presents two clinical cases of delayed restoration of the sinus rhythm in patients with long-term persistent atrial fibrillation after the procedure of thoracoscopic radiofrequency fragmentation of the left atrium. The necessity of continuing attempts to restore the sinus rhythm up to the end of the "blind period" (90 days) is discussed.

The article presents a comparative retrospective analysis of clinical, laboratory data and outcomes in 39 patients with severe COVID-19 complicated by acute respiratory distress syndrome, who received high-flow oxygen therapy Of which, 19 patients additionally received 75 mg of inhaled surfactant BL twice daily for 5 days using a nebulizer As a result, mortality rate in the group of patients receiving surfactant was 10 5%, while in the standard therapy group — 50%;the number of patients transferred to the mechanical ventilation was 21% and 70%, respectively As the patients receiving the surfactant were injected with COVID-19 hyperimmune convalescent plasma and monoclonal antibodies to interleukin-6 receptors more often than those from the control group, we recalculated the results regardless of these patients However, a significant difference between the mechanical ventilation rate (2 5 times less often in the surfactant group) and mortality rate (3 5 times less in the surfactant group) was observed The duration of hospitalization and stay at the intensive care unit was not significantly different between patients with and without surfactant treatment Inhalation therapy with surfactant BL was well tolerated even by patients with chronic obstructive pulmonary disease In no case did therapy have to be stopped due to side effects, the most common of which was coughing during inhalation This retrospective analysis shows that the prescription of an inhaled surfactant prior to transferring patients to mechanical ventilation can prevent the progression of respiratory failure, put down mechanical ventilation, and improve survival © 2020, Remedium Group Ltd All rights reserved

The method of non-invasive proton-beam ablation of an arrhythmogenic substrate of ventricular tachycardia in patients with structural heart disease is aimed at eliminating triggers and/or destroying re-entry mechanisms using a proton beam described.

Background. Tumor Infiltrating Lymphocytes (TILs) is one of the most promising sources of autologous cytotoxic T-cells for adoptive immunotherapy, which has already shown high efficiency in the treatment of metastatic melanoma. However, the isolation of TILs from solid tumors is technically difficult. A suppressive tumor microenvironment, in particular, a high level of expression of check-point inhibitors PD-1 CTLA4, tissue hypoxia and other factors cause that T cells isolated from the tumor do not proliferate well and do not exhibit cytotoxic properties. Aims. In this study, we isolated TILs from surgical material obtained by resection of solid tumors (primary and metastatic adenocarcinomas of various localization, melanoma, glioblastoma), studied their population composition and developed protocols for the purification expanding, and activation of CD4+, CD8+ cytotoxic antitumor lymphocytes. Methods. An urgent task is the activation of TILs, turning off immunosuppressive mechanisms and increasing their antitumor cytotoxic activity. Various approaches are used for this: activation by a cocktail of cytokines and antibodies, editing the lymphocyte genome by knocking out suppressor genes or, conversely, transduction of activating genes, coincubation with feeder cells, etc. Cells were obtained from samples of resected tumors in 16 patients; in each case we obtain an autologous pair: the primary tumor culture and the TILs culture. Results. We could isolate viable lymphocytes in 100% of cases. Isolated TILs were successfully expanded in our specialized medium using various combinations of IL-2, IL-15, IL-21, IL-7, anti-CD3 and anti-CD28. Immunophenotyping showed that the obtained TILs are a heterogeneous mixture of CD4+, CD8+ cells containing populations of CD3+CD8+CD45+(CTL) CD3+CD4+CD45+ (T-helpers), CD4+CD25+CD127- (Т-regulatory cells), CD3-CD56+CD45+ (NK-cells), CD3+CD56+CD45+ (Т-NK-cells). The initial cultures of TILs were also characterized by a high level of PD1 expression, indicating their low antitumor cytotoxicity. Using different protocols of isolation, expansion, and activation, we obtained a cell preparation containing 80% of CD8+ PD-1- activated TILs in an amount sufficient for adoptive therapy (500×106 or more). An in vitro study of the cytotoxicity of obtained TILs in primary cultures of homologous tumors using RTCA Icelligence showed high cytotoxicity, providing almost 100% tumor cell death. Conclusion. Our developed protocol for the production and activation of TILs can be recommended for the phase I–II clinical trials of adoptive immunotherapy of recurrent, highly metastatic solid tumors.

This review summarizes current understanding of the interaction between circadian rhythms of gene expression and epigenetic clocks characterized by the specific profile of DNA methylation in CpG-islands which mirror the chronological age of individual cells and the entire organism. Basic mechanisms of regulation for circadian genes CLOCK- BMAL1 as well as downstream clock-controlled genes (ССG) are also discussed here. It has been shown that circadian rhythms operate by finely tuned regulation of transcription and rely on various epigenetic mechanisms including activation of enhancers / suppressors, acetylation / deacetylation of histones and other proteins as well as DNA methylation. Overall, up to 20% of all genes expressed by the cell are subject to expression oscillations associated with circadian rhythms. Also included in the review is a brief list of genes involved in the regulation of circadian rhythms, along with genes important for metabolic control, aging, and oncogenesis. Knocking out some of them (for example, Sirt1) accelerates the aging process, while overexpression of Sirt1, on the contrary, protects against age-related changes. Circadian regulators control a number of genes that activate the cell cycle (Wee1, c-Myc, p20, p21, and Cyclin D1) and regulate histone modification and DNA methylation. Approaches for determining the epigenetic age from methylation profiles across CpG islands in individual cells are described. DNA methylation, which characterizes the function of the epigenetic clock, appears to link together such key biological processes as regeneration and functioning of stem cells, aging and malignant transformation. Finally, main features of adult stem cell aging in stem cell niches and current possibilities for modulating the epigenetic clock as part of antiaging therapy are discussed.

In in vitro experiments on cultures of human multipotent stem cells from the human bonearrow and dental pulp, we studied direct reprogramming towards neuro-glial lineage cells using a cocktail of small molecules. Reprogramming by the previously published protocol (with a cocktail containing β-mercaptoethanol, LIF, VPA, CHIR99021, and RepSox) and by the optimized protocol (VPA, RG108, А83-01, dorsomorphin, thiazovivin, CHIR99021, forskolin, and Isx9) allows obtaining cells with immunophenotypic and genetic signs of neural stem cells. However, neither the former, nor the optimized protocols allowed preparing neural progenitors capable of adequate terminal differentiation from both bone marrow-derived mesenchymal stem cells and nestin-positive neural crest-derived mesenchymal stem cells. Real-time PCR demonstrated the expression of some neurogenesis markers, but neural stem cell-specific expression pattern was not observed. The findings lead us to a conclusion that reprogramming with small molecules without additional factors modifying gene expression does not allow reproducible production of human neural stem cell-like progenitors that can be used as the source of neural tissue for the regenerative therapy.

The research purpose is to analyze changes in the labor market based on the needs and values of a new generation of young professionals. The authors consider the theory of generations, changes in the interaction between employers and candidates related to the development of digital technologies, open communications, the application of flexible schedules and remote work. The results of sociological surveys of professional aspirations, career preferences and expectations of millennials are summarized. The list of bonuses provided by Russian companies in addition to wages is formed. The most popular compensations are marked. Priority factors have been established for Russian young professionals when choosing an employer company. It is revealed that opportunities for professional development, participation in innovative projects, flexible working hours that allow combining work and private life (work-life-balance) are more relevant for young people than monetary values and the capital accumulation. An overview of the indicators of a successful career. It is noted that most young people are ready to invest in the own additional professional education, participate in international projects and internships. The issues of attracting young and talented candidates are considered in this paper too.

Coronary artery bypass grafting techniques have been unchangeable for many years, whereas development and enhancement of myocardial protection methods in coronary bypass grafting for patients with ischemic heart disease are still actual issues of current coronary surgery. Coronary artery bypass grafting techniques include the traditional/conventional technique with cardiopulmonary bypass, aortic cross-clamping and cardioplegia, off-pump and on-pump beating heart coronary artery bypass grafting. Coronary artery bypass grafting with cardiopulmonary bypass and cardioplegia remains the most common method of coronary revascularization. However the cardiac arrest inevitably leads to global cardiac ischemia, and current cardioplegias do not prevent ischemic damage to the myocardium in all cases, especially in high-risk surgical patients. Off-pump coronary artery bypass grafting allows preventing global myocardial ischemia (due to the constant native coronary blood-flow) and avoiding possible negative consequences of cardiopulmonary bypass use. The main limitations of this technique are associated with high risk of hemodynamic instability due to low cardiac output and systolic output caused by target arteries exposition. On-pump beating heart technique is a reasonable compromise between conventional on-pump coronary artery bypass grafting, cardioplegia and off-pump procedure. It is a safe and effective technique with outcomes that are equivalent or superior to the outcomes reported for conventional coronary artery bypass grafting in patients with unstable hemodynamics, low left ventricular ejection fraction and in high-risk patients. The literature review presents the results of on-pump beating heart coronary artery bypass grafting.

Cell therapy is one of the most promising directions in the treatment of critical limb ischemia (CLI). In spite of certain advances achieved in this field in the last decades, which are related to application of bone marrow stem cells (BMSC), a large number of problems still remain unsolved. In this review, we discuss the BMSC biology, mechanisms of their therapeutic effect in the CLI treatment and results of the most notable BMSC-based clinical studies in detail.

This review summarizes the current understanding of the interaction between circadian rhythms of gene expression and epigenetic clocks characterized by the specific profile of DNA methylation in CpG-islands which mirror the senescence of all somatic cells and stem cells in particular. Basic mechanisms of regulation for circadian genes CLOCK-BMAL1 as well as downstream clock-controlled genes (ССG) are also discussed here. It has been shown that circadian rhythms operate by the finely tuned regulation of transcription and rely on various epigenetic mechanisms including the activation of enhancers/suppressors, acetylation/deacetylation of histones and other proteins as well as DNA methylation. Overall, up to 20% of all genes expressed by the cell are subject to expression oscillations associated with circadian rhythms. Additionally included in the review is a brief list of genes involved in the regulation of circadian rhythms, along with genes important for cell aging, and oncogenesis. Eliminating some of them (for example, Sirt1) accelerates the aging process, while the overexpression of Sirt1, on the contrary, protects against age-related changes. Circadian regulators control a number of genes that activate the cell cycle (Wee1, c-Myc, p20, p21, and Cyclin D1) and regulate histone modification and DNA methylation. Approaches for determining the epigenetic age from methylation profiles across CpG islands in individual cells are described. DNA methylation, which characterizes the function of the epigenetic clock, appears to link together such key biological processes as regeneration and functioning of stem cells, aging and malignant transformation. Finally, the main features of adult stem cell aging in stem cell niches and current possibilities for modulating the epigenetic clock and stem cells rejuvenation as part of antiaging therapy are discussed.

The study examined effectiveness of liposomal form of dextrazide (inhaled or intraperitoneal), free dextrazide (intraperitoneal), and isoniazid (intraperitoneal) in the treatment of BALB/c mice with BCG-induced granulomatosis. The mice were infected with mycobacteria tuberculosis 3 months prior to onset of treatment. The preparations under examinations were administered twice a week over 2 months. The decrease of the number and size of macrophagal granulomas in mice BCG-induced granulomatosis during treatment was determined by the number of living mycobacteria tuberculosis in these granulomas. The most effective treatment was achieved with liposomal form of dextrazide (a conjugate of oxidized dextran with isonicotinic acid hydrazide). Macrophages with captured mycobacteria tuberculosis, dextrazide, and dextrazide-loaded liposomes can be incorporated into granulomas. The antimycobacterial effect of dextrazide is an important factor preventing the destructive processes in granulomas and organs via a decrease in the prodestructive potential of lysosomes in macrophages realized after their migration from granulomas.

The study compared antituberculous efficacy of individual or combined administration of "free" isoniazid and liposomal form of dextrazide (a composition consisted of isoniazid and oxidized dextran) inhaled in standard (15 mg/kg) or low (3 mg/kg) dose. The therapy started 1 month after contamination of outbred ICR male mice with Mycobacterium tuberculosis strain H37Rv. Combined inhalation of liposomal form of dextrazide and isoniazid in the low dose was most effective against mycobacterium tuberculosis due to diminished prodestructive pulmonary effect and a low hepatotoxicity. A minor prodestructive effect of this combination was observed starting from 1.5 month after the onset of therapy (12 inhalations, 2 times a week), and it augmented after 24 inhalations administered during 3 months.

Background Nonhuman primates (NHP) may provide the most adequate (in terms of neuroanatomy and neurophysiology) model of spinal cord injury (SCI) for testing regenerative therapies, but bioethical considerations exclude their use in severe SCI. New Method A reproducible model of SCI at the lower thoracic level has been developed in Rhesus macaques. The model comprises surgical resection of 25% of the spinal cord in the projection of the dorsal funiculus and dorsolateral corticospinal pathways, controlled via registration of intraoperative evoked potentials (EPs). The animals were evaluated using the modified Hindlimb score, MRI, SSEP, and MEP over a time period of 8–12 weeks post-SCI, followed by histological examination. Results Complete disappearance of intraoperative EPs from distal hindlimb muscles without restoration within two weeks post-SCI was an indicator for irreversible disruption of the abovementioned pathways. As a result, controlled damage to the spinal cord was achieved in three NHPs, clinically manifested as irreversible lower monoplegia. No significant functional restoration was observed in these NHPs up to 12 weeks post-SCI. Demyelination of the damaged ascending tracts was detected. Disturbances in pelvic organ function were not observed in all animals. Comparison with existing methods The new method of EPs-guided SCI allows a more controlled and irreversible damage to the spinal cord compared with contusion and other transection approaches. Conclusions This method to induce complete SCI in NHP is well tolerated, reproducible and ethically acceptable: these are valuable attributes in a preclinical model that will hopefully help advance testing of new regenerative therapies in SCI.

Ischemic Heart Disease (IHD) has been recognized as the main cause of mortality in the modern world. Application of cell therapy technologies for the IHD treatment has been actively studied from the beginning of 2000s. The review is dedicated to the use of mesenchymal stem cells (MSC) in the therapy of IHD. The strategies of the MSC modification in vitro for improvement of their regenerative potential are extensively discussed, including preconditioning to enhance the cell survival, boosting their paracrine effect and manipulating their cardiomyogenic differentiation. The optimization of the MSC delivery and opportunities related to the use of biomaterials as cell carriers are also discussed. The results of the most important clinical studies on the MSC-based IHD therapy are presented, including those completed and published in the literature and the ongoing clinical trials registered at clinicaltrials.gov by June 2018.

We have designed a novel two-component matrix (SPRPix) for the encapsulation of directly reprogrammed human neural precursor cells (drNPC). The matrix is comprised of 1) a solid anisotropic complex scaffold prepared by electrospinning a mixture of recombinant analogues of the spider dragline silk proteins – spidroin 1 (rS1/9) and spidroin 2 (rS2/12) - and polycaprolactone (PCL) (rSS-PCL), and 2) a “liquid matrix” based on platelet-rich plasma (PRP). The combination of PRP and spidroin promoted drNPC proliferation with the formation of neural tissue organoids and dramatically activated neurogenesis. Differentiation of drNPCs generated large numbers of βIII-tubulin and MAP2 positive neurons as well as some GFAP-positive astrocytes, which likely had a neuronal supporting function. Interestingly the SPRPix microfibrils appeared to provide strong guidance cues as the differentiating neurons oriented their processes parallel to them. Implantation of the SPRPix matrix containing human drNPC into the brain and spinal cord of two healthy Rhesus macaque monkeys showed good biocompatibility: no astroglial and microglial reaction was present around the implanted construct. Importantly, the human drNPCs survived for the 3 month study period and differentiated into MAP2 positive neurons. Tissue engineered constructs based on SPRPix exhibits important attributes that warrant further examination in spinal cord injury treatment.

Over many decades, constructing genetically and phenotypically stable lines of neural stem cells (NSC) for clinical purposes with the aim of restoring irreversibly lost functions of nervous tissue has been one of the major goals for multiple research groups. The unique ability of stem cells to maintain their own pluripotent state even in the adult body has made them into the choice object of study. With the development of the technology for induced pluripotent stem cells (iPSCs) and direct transdifferentiation of somatic cells into the desired cell type, the initial research approaches based on the use of allogeneic NSCs from embryonic or fetal nervous tissue are gradually becoming a thing of the past. This review deals with basic molecular mechanisms for maintaining the pluripotent state of embryonic/induced stem and reprogrammed somatic cells, as well as with currently existing reprogramming strategies. The focus is on performing direct reprogramming while bypassing the stage of iPSCs which is known for genetic instability and an increased risk of tumorigenesis. A detailed description of various protocols for obtaining reprogrammed neural cells used in the therapy of the nervous system pathology is also provided.

This article is dedicated to international legal and national legal basis of minimization and liquidation of serious crimes consequences, particularly terrorism and extremism. In the article essence of new component of international legal crime counteraction - minimization and liquidation of serious crimes consequences - is disclosured in general. In this article theoretical suggestions on improvement of crime counteraction system are taken up. It is paid attention to activization of international collaboration between governments, inter-governmental and non-governmental organizations on all types of questions related to minimization and liquidation of serious crimes consequences.

The paper presents design and test results for a conduction cooled 8 T superconducting magnetic system with a variable temperature insert for electrical measurements. The system is based on one Pulse Tube cryocooler. The helium gas gap heat switch is used as controllable thermal link between variable temperature chamber and the 4 K stage to avoid overheating of the magnet at high temperatures of the insert. The superconducting magnet is manufactured from NbTi wire and impregnated with epoxy resin by ?wet? technology. The clear diameter of variable temperature chamber is 20 mm. The system provides sample temperature range of 5.4-300 K. The maximum operating magnetic field depends on the temperature of the insert and belongs to the range of 7.1-8.2 T. The cool down time of the magnet from room temperature to 3.6 K is 6 hours.

In order to remove internal stresses in composite 2-G YBCO(123) high-temperature superconductors (HTS), they are irradiated with 40Ar8+ ions with an energy of 48 MeV or 84Kr17+ ions with an energy of 107 MeV and a fluence of (1–2) ×1010 ion/cm2. Growth stresses in samples have been studied by scanning electron microscopy and X-ray diffraction analysis. It has been found that initial samples contain significant internal stresses, which, over the course of time, lead to the destruction of the superconducting layer. These stresses disappear after ion irradiation in the regimes specified. Possible mechanisms of stress relaxation are discussed.

Possibility of electron beam usage for immobilization of hydrazidum of an isonicotinic acid (HIA) on dextrane was studied to produce a drug for treatment of a tuberculosis. As a result of irradiation of dextrane the processes of oxidation and formation of polysaccharide occur due to carbonyl groups which are to link isoniasidum. The HIA immobilized on dextrane may be used as an effective medical preparation having prolonged action for action on endo and extracellular population of Micobacterium tuberculosis .

Oxidized dextran (60 kDa) exerted a pronounced preventive effect in laboratory mice infected with avian influenza subtype H5N1 A/Goose/Krasnoozerskoye/627/05 virus, which manifested in a significant increase in mouse lifetime (by 24.4%) and a decrease in mortality rate (3.3-fold). This was probably related to significant alleviation of pathological changes in the lungs and severity of hemodynamic and inflammatory complications and early fibrosis [corrected].

A conduction cooled 8 T superconducting magnetic system with variable temperature insert is developed and tested. The cryomagnetic system is based on a commercial two-stage pulse tube cryocooler with cooling power of 1W at 4.2 K. The compact superconducting magnet is manufactured from NbTi wire and impregnated with epoxy resin by wet technology. The clear diameter of variable temperature space is 20 mm. The system provides temperature range of 5.5-300 K. The variable temperature space is filled by low pressure helium gas. To eliminate the overheating of the magnet at high temperatures the heat switch is used in thermal coupling between variable temperature space and the 4K stage. The system design, manufacturing and test results are presented.