Diastolic stress test in assessing functional state of postinfarction myocardium

Taking into account the conflicting literature data and the ambiguity in the interpretation of parameters of diastolic heart function in patients with coronary heart disease, we conducted an analysis of diastolic heart function in patients after myocardial infarction at the outpatient rehabilitation stage. Aim of the study was to investigate the diagnostic information content and the feasibility of diastolic stress testing to assess the functional condition of postinfarction myocardium. Material and methods. 86 patients were examined at the outpatient stage of rehabilitation 6 weeks after myocardial infarction with coronary artery stenting ad hoc. The control group consisted of 10 healthy volunteers. Structural and functional examination of the heart was performed at rest and immediately after exercise using stress echocardiography. Results and discussion. Patients after myocardial infarction have a larger indexed volume of the left atrium (30.71 ± 8.88 vs. 20.49 ± 4.04 ml/m2) and an E/e` ratio (8.45 ± 3.27 vs. 6.46 ± 1.42) in comparison with the control group. 38 (62.3 %) patients with normal left ventricular (LV) ejection fraction (EF) had unimpaired LV diastolic function, 19 (31.1 %) and 2 (3.3 %) patients had type 1 and type 2 diastolic dysfunction, respectively, 2 patients (3,3 %) had an indeterminate result. Patients with reduced LV EF have a significantly lower early diastolic mitral annular velocity (e`). The diastolic stress test revealed a significant post-exercise increase in E/e` in only one patient (from 8.92 to 18.37), who also had an initially reduced EF (32 %). The stress test showed no significant changes in diastolic heart parameters after exercise in patients suffering from heart failure with preserved EF, which may indicate relatively good diastolic reserves of the heart. Conclusions. Myocardial infarction is accompanied by the presence of LV diastolic dysfunction in 53,5 % of the patients at the 6th week of the rehabilitation period. The diastolic stress test is accompanied by a rare occurrence of stress-induced diastolic dysfunction (4 %) in patients with reduced LV EF after myocardial infarction

Transient accumulation of 5-carboxylcytosine indicates involvement of active demethylation in lineage specification of neural stem cells

5-Methylcytosine (5mC) is an epigenetic modificationinvolved in regulation of gene activity during differentiation. Tet dioxygenases oxidize 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). Both 5fC and 5caC can be excised from DNA by thymine-DNA glycosylase (TDG) followed by regeneration of unmodified cytosine via the base excision repair pathway. Despite evidence that this mechanism is operative in embryonic stem cells, the role of TDG-dependent demethylation in differentiation and development is currently unclear. Here, we demonstrate that widespread oxidation of 5hmC to 5caC occurs in postimplantation mouse embryos. We show that 5fC and 5caC are transiently accumulated during lineage specification of neural stem cells (NSCs) in culture and invivo. Moreover, 5caC is enriched at the cell-type-specific promoters during differentiation of NSCs, and TDG knockdown leads to increased 5fC/5caC levels in differentiating NSCs. Our data suggest that active demethylation contributes to epigenetic reprogramming determining lineage specification in embryonic brain. © 2014 The Authors

Особенности течения туберкулеза у лиц пожилого и старческого возраста

The objective: to identify specific features of the clinical course of tuberculosis in elderly and senile patients under the current epidemic situation.The specific clinical course of tuberculosis was analyzed in 54 patients at the age of 61 years and older and compared with the course of 234 patients at the age from 18 to 39 years selected by the continuous sampling of all 472 patients discharged from hospital in 2018. The following features were found to be typical of patients of 61 years and older: more frequent chronic forms of the disease (37.0%) and complications (35.2%), the major complication was chronic cor pulmonale (33.3%); more frequent concurrent chronic nonspecific lung diseases (13.0%) and coronary heart disease/arterial hypertension (14.8%); more frequent deaths (31.5%), mainly due to pulmonary heart disease; less frequent generalization of tuberculosis (5.5%) and concurrent HIV infection (7.4%).Цель исследования: выявить особенности клинического течения туберкулеза у лиц пожилого и старческого возраста в современных эпидемических условиях.Проанализированы особенности клинического течения туберкулеза ‒ у 54 больных в возрасте 61 года и старше в сравнении с 234 пациентами 18-39 лет, отобранных сплошной выборкой из всех 472 больных, выписанных в 2018 г. Выявлено, что у лиц в возрасте 61 года и старше: более частая хронизация процесса (37,0%) и осложненное (35,2%), в основном хроническим легочным сердцем (33,3%), течение; более частые сопутствующие хронические неспецифические заболевания легких (13,0%) и ишемическая болезнь сердца/артериальная гипертония (14,8%); более частые летальные исходы (31,5%), преимущественно за счет легочно-сердечной недостаточности; более редки генерализация туберкулеза (5,5%) и сопутствующая ВИЧ-инфекция (7,4%)

Взаимосвязь показателей эритроцитарного звена гемостаза со структурно-функциональными параметрами сердца у больных гипертензивной энцефалопатией

Investigation aim is to expose sex features of interdependence between erythrocytes homeostasis indices and heart remodeling in essential hypertension (EH) and hypertensive encephalopathy (HE) patients. 168 patients (110 men) with EH 2th staid, 2th degree and HE 1—2th staid were enrolled. It was executed blood test, echocardiography by standard method. In men erythrocytes homeostasis indices correlated with structural and functional alterations. In women erythrocytes homeostasis indices correlated with diastolic function. There were exposed sex-specific interdependence between erythrocytes homeostasis indices and heart remodeling.Исследованы половые особенности взаимосвязи показателей эритроцитарного гомеостаза с ремоделированием сердца у больных гипертонической болезнью (ГБ) и гипертензивной энцефалопатией (ГЭ).Обследовано 168 больных (110 мужчин, 58 женщин) ГБ II стадии II степени, осложненной ГЭ 1—2-й стадии. Проводились общеклиническое исследование крови, эхокардиография по стандартной методике.У мужчин показатели эритроцитарного гомеостаза коррелировали со структурно-функциональными изменениями, у женщин — с диастолической функцией.Выявлены пол-специфичные взаимосвязи эритроцитарного гомеостаза с ремоделированием сердца

The Methyl-CpG Binding Proteins Mecp2, Mbd2 and Kaiso Are Dispensable for Mouse Embryogenesis, but Play a Redundant Function in Neural Differentiation

The precise molecular changes that occur when a neural stem (NS) cell switches from a programme of self-renewal to commit towards a specific lineage are not currently well understood. However it is clear that control of gene expression plays an important role in this process. DNA methylation, a mark of transcriptionally silent chromatin, has similarly been shown to play important roles in neural cell fate commitment in vivo. While DNA methylation is known to play important roles in neural specification during embryonic development, no such role has been shown for any of the methyl-CpG binding proteins (Mecps) in mice.. No evidence for functional redundancy between these genes in embryonic development or in the derivation or maintenance of neural stem cells in culture was detectable. However evidence for a defect in neuronal commitment of triple knockout NS cells was found.Although DNA methylation is indispensable for mammalian embryonic development, we show that simultaneous deficiency of three methyl-CpG binding proteins genes is compatible with apparently normal mouse embryogenesis. Nevertheless, we provide genetic evidence for redundancy of function between methyl-CpG binding proteins in postnatal mice

5-Methylcytosine and 5-Hydroxymethylcytosine Spatiotemporal Profiles in the Mouse Zygote

Background: In the mouse zygote, DNA methylation patterns are heavily modified, and differ between the maternal and paternal pronucleus. Demethylation of the paternal genome has been described as an active and replication-independent process, although the mechanisms responsible for it remain elusive. Recently, 5-hydroxymethylcytosine has been suggested as an intermediate in this demethylation. Methodology/principal findings: In this study, we quantified DNA methylation and hydroxymethylation in both pronuclei of the mouse zygote during the replication period and we examined their patterns on the pericentric heterochromatin using 3D immuno-FISH. Our results demonstrate that 5-methylcytosine and 5-hydroxymethylcytosine localizations on the pericentric sequences are not complementary; indeed we observe no enrichment of either marks on some regions and an enrichment of both on others. In addition, we show that DNA demethylation continues during DNA replication, and is inhibited by aphidicolin. Finally, we observe notable differences in the kinetics of demethylation and hydroxymethylation; in particular, a peak of 5-hydroxymethylcytosine, unrelated to any change in 5-methylcytosine level, is observed after completion of replication. Conclusion/significance: Together our results support the already proposed hypothesis that 5-hydroxymethylcytosine is not a simple intermediate in an active demethylation process and could play a role of its own during early development

The impact of transposable element activity on therapeutically relevant human stem cells

Human stem cells harbor significant potential for basic and clinical translational research as well as regenerative medicine. Currently ~ 3000 adult and ~ 30 pluripotent stem cell-based, interventional clinical trials are ongoing worldwide, and numbers are increasing continuously. Although stem cells are promising cell sources to treat a wide range of human diseases, there are also concerns regarding potential risks associated with their clinical use, including genomic instability and tumorigenesis concerns. Thus, a deeper understanding of the factors and molecular mechanisms contributing to stem cell genome stability are a prerequisite to harnessing their therapeutic potential for degenerative diseases. Chemical and physical factors are known to influence the stability of stem cell genomes, together with random mutations and Copy Number Variants (CNVs) that accumulated in cultured human stem cells. Here we review the activity of endogenous transposable elements (TEs) in human multipotent and pluripotent stem cells, and the consequences of their mobility for genomic integrity and host gene expression. We describe transcriptional and post-transcriptional mechanisms antagonizing the spread of TEs in the human genome, and highlight those that are more prevalent in multipotent and pluripotent stem cells. Notably, TEs do not only represent a source of mutations/CNVs in genomes, but are also often harnessed as tools to engineer the stem cell genome; thus, we also describe and discuss the most widely applied transposon-based tools and highlight the most relevant areas of their biomedical applications in stem cells. Taken together, this review will contribute to the assessment of the risk that endogenous TE activity and the application of genetically engineered TEs constitute for the biosafety of stem cells to be used for substitutive and regenerative cell therapiesS.R.H. and P.T.R. are funded by the Government of Spain (MINECO, RYC-2016- 21395 and SAF2015–71589-P [S.R.H.]; PEJ-2014-A-31985 and SAF2015–71589- P [P.T.R.]). GGS is supported by a grant from the Ministry of Health of the Federal Republic of Germany (FKZ2518FSB403)

A new class of glycomimetic drugs to prevent free fatty acid-induced endothelial dysfunction

Background: Carbohydrates play a major role in cell signaling in many biological processes. We have developed a set of glycomimetic drugs that mimic the structure of carbohydrates and represent a novel source of therapeutics for endothelial dysfunction, a key initiating factor in cardiovascular complications. Purpose: Our objective was to determine the protective effects of small molecule glycomimetics against free fatty acid­induced endothelial dysfunction, focusing on nitric oxide (NO) and oxidative stress pathways. Methods: Four glycomimetics were synthesized by the stepwise transformation of 2,5­dihydroxybenzoic acid to a range of 2,5­substituted benzoic acid derivatives, incorporating the key sulfate groups to mimic the interactions of heparan sulfate. Endothelial function was assessed using acetylcholine­induced, endotheliumdependent relaxation in mouse thoracic aortic rings using wire myography. Human umbilical vein endothelial cell (HUVEC) behavior was evaluated in the presence or absence of the free fatty acid, palmitate, with or without glycomimetics (1µM). DAF­2 and H2DCF­DA assays were used to determine nitric oxide (NO) and reactive oxygen species (ROS) production, respectively. Lipid peroxidation colorimetric and antioxidant enzyme activity assays were also carried out. RT­PCR and western blotting were utilized to measure Akt, eNOS, Nrf­2, NQO­1 and HO­1 expression. Results: Ex vivo endothelium­dependent relaxation was significantly improved by the glycomimetics under palmitate­induced oxidative stress. In vitro studies showed that the glycomimetics protected HUVECs against the palmitate­induced oxidative stress and enhanced NO production. We demonstrate that the protective effects of pre­incubation with glycomimetics occurred via upregulation of Akt/eNOS signaling, activation of the Nrf2/ARE pathway, and suppression of ROS­induced lipid peroxidation. Conclusion: We have developed a novel set of small molecule glycomimetics that protect against free fatty acidinduced endothelial dysfunction and thus, represent a new category of therapeutic drugs to target endothelial damage, the first line of defense against cardiovascular disease