Voltage-gated ion channel's gene expression in the myocardium of embryo and adult chickens.

The functioning of the cardiovascular system is critical for embryo survival. Cardiac contractions depend on the sequential activation of different classes of voltage-gated ion channels. Understanding the fundamental features of these interactions is important for identifying the mechanisms of pathologies development in the myocardium. However, at present there is no consensus on which ion channels are involved in the formation of automaticity in the early embryonic stages. The aim of this study was to elucidate the expression of genes encoding various types of ion channels that are involved in the generation of electrical activity chicken heart at different stages of ontogenesis. We analyzed the expression of 14 genes from different families of ion channels. It was revealed that the expression profiles of ion channel genes change depending on the stages of ontogenesis. The HCN4, CACNA1D, SCN1A, SCN5A, KCNA1 genes have maximum expression at the tubular heart stage. In adult, a switch occurs to the higher expression of CACNA1C, KCNH6, RYR and SLC8A1 genes. This data correlated with the results obtained by the microelectrode method. It can be assumed that the automaticity of the tubular heart is mainly due to the mechanism of the «membrane-clock¼ (hyperpolarization-activated current (If), Ca2+-current L-type (ICaL), Na+-current (INa) and the slow component of the delayed rectifier K+-current (IKs)). Whereas in adult birds, the mechanism for generating electrical impulses is determined by both « membrane- clock¼ and «Ca2+-clock¼.

[Relationships between Cxcl12, Tweak, Notch1, and Yap mRNA Expression Levels in Molecular Mechanisms of Liver Fibrogenesis].

Current data on the molecular mechanisms of liver fibrosis and cirrhosis fail to fully explain all stages of their development. Interactions between individual genes and signaling pathways are known to play an important role in their functions. However, data on their relationships are insufficient and often contradictory. For the first time, mRNA expression of Notch1, Notch2, Yap1, Tweak (Tnfsf12), Fn14 (Tnfrsf12a), Ang, Vegfa, Cxcl12 (Sdf), Nos2, and Mmp-9 was studied in detail at several stages of thioacetamide-induced liver fibrosis in Wistar rats. A factor analysis isolated three factors, which combined highly correlated target genes. The first factor included four genes: Cxcl12 (r = 0.829, p < 0.05), Tweak (r = 0.841, p < 0.05), Notch1 (r = 0.848, p < 0.05), and Yap1 (r = 0.921, p < 0.05). The second factor described the correlation between Mmp-9 (r = 0.791, p < 0.05) and Notch2 (r = 0.836, p < 0.05). The third factor included Ang (r = 0.748, p < 0.05) and Vegfa (r = 0.679, p < 0.05). The Nos2 and Fn14 genes were not included in any of the factors. The gene grouping by mRNA expression levels made it possible to assume a pathogenetic relationship between their products in the development of fibrotic changes due to liver toxicity.

[Sleep disorders in patients with medication-overuse headache]. / Narusheniya sna u bol'nykh s lekarstvenno-indutsirovannoi golovnoi bol'yu.

OBJECTIVE: To analyze complaints about sleep disorders and assess the incidence of various sleep disorders, using relevant scales, in patients with medication-overuse headache (MOH) in comparison with patients without MOH. MATERIAL AND METHODS: The prospective case-control study included 171 patients, aged 18 years and older, with MOH (main group), and173 patients with primary headaches without MOH (control group). A neurologist conducted an initial examination and professional interview before the start of treatment. To diagnose sleep disorders, the International Classification of Sleep Disorders (3rd edition, 2014) was used. Additionally, an assessment was made using the Insomnia Severity Index Scale, the Epworth Sleepiness Scale (ESS) and the Lausanne Obstructive Sleep Apnea Syndrome Scale (NoSAS). RESULTS: Statistically significant differences were revealed in the prevalence of the following complaints about sleep disorders in patients with MOH: lack of sleep (51.5%), frequent awakenings during sleep (43.3%), discomfort in legs before falling asleep or at rest in the evening (37.4%). Difficulties falling asleep occurred equally often in both patients with MOH (43.9%) and without MOH (37.0%), as well as daytime sleepiness (40.4% vs 36.4%) and the presence of snoring (13% of patients in each group). Patients with MOH were significantly more likely to suffer from chronic insomnia (60.2% and 47.4%, respectively, p=0.02; OR 1.7; 95% CI 1.1-2.6) and restless legs syndrome (37.4% and 22.0%, respectively, p=0.002; OR 2.1; 95% CI 1.3-3.4). The incidence of hypersomnia and obstructive sleep apnea syndrome did not have statistically significant differences. CONCLUSION: Patients with MOH compared to patients without MOH have a significantly higher incidence of main complaints of sleep disorders, chronic insomnia and restless legs syndrome, which indicates the importance of sleep disorders in the pathogenesis of medication-overuse headaches and requires timely diagnosis and treatment to prevent the progression of both headaches and sleep disorders.

literammp-9 mRNA Expression and Bridging Fibrosis Progression in Toxic Liver Injury.

Developing liver disease treatments, in which fibrosis is a key pathogenetic link, still remains an urgent problem in hepatology. In the present study, the level of mmp-9 mRNA expression and the number of FAP+, α-SMA+, CD45+ cells were analyzed at nine time points of fibrosis and cirrhosis. It was found that in the case of liver fibrosis, the choice of the optimal reference gene depended on the stage of fibrogenesis. When studying the specific stages rather than the entire process in a long-term experiment, it was shown that choosing an optimal reference gene has to be done additionally. In this case, the mmp-9 mRNA expression level should be considered as a marker of liver fibrosis initiation and development but not as that of cirrhosis progression. In the liver, two morphologically heterogeneous populations of myofibroblasts were simultaneously identified as able to synthesize various types of immunohistochemical markers. It was found that the FAP+ cells were the main contributor to the development of portal fibrosis and the initial stages of bridging fibrosis. In the selected experimental model, fibrosis initiation and the development stages preceding parenchyma restructuring were accompanied by a low level of inflammation.

Changes in Macrophage Subpopulations in Rat Liver at Different Stages of Experimental Fibrosis.

The number, phenotypic composition, and functional properties of macrophages in the liver of Wistar rats change depending on the stages of fibrosis induced by thioacetamide. In the sinusoidal capillaries of the liver of control rats, CD68+ wing-shaped cells were mainly detected. The number of CD68+ cells at the stages of fibrosis before the process of its transformation into cirrhosis was 2-fold higher (p=0.0000) than in the control. At later terms of the experiment, no significant differences were found. Immunohistochemical method revealed two morphologically different groups of CD68+ cells differing in shape and localization. At all stages of the experiment, round and elongated CD206+ cells of were detected in the sinusoidal capillaries. At the stage of cirrhosis (13 weeks), the number of CD206+ cells was higher than during the third week of the experiment by 3.21 times (p=0.0000). Later, a decrease in the number of CD206+ cells was observed. At the same time, in the portal zones and connective tissue septa around the false hepatic lobules, round CX3CR1+ cells were noted. By the end of the experiment (17 weeks), their number exceeded that on the third week of the experiment by 5.66 times (p=0.0000).

[An analysis of complaints about sleep disorders as an indicator of poor sleep quality in patients with primary headache disorders]. / Analiz zhalob na narusheniya sna kak indikator nizkogo kachestva sna u bol'nykh s pervichnymi golovnymi bolyami.

OBJECTIVE: To assess the prevalence of various complaints indicating poor sleep quality and its disturbances in men and women with primary headaches. MATERIAL AND METHODS: In total 305 patients (mean age 45 years, age range 18-89 years) with primary headache disorders and complaints of poor quality of sleep were included in the study. Women prevailed among these patients (79%). The average age of men (41.6) and women (45.8) had no statistically significant differences (p=0.8). The initial examination and professional face-to-face interview were initially conducted by an experienced neurologist specializing in the treatment of headaches. Within a week after that, before the start of treatment, patients were interviewed by telephone using standardized questionnaires by specially trained students and physicians. RESULTS: A frequent occurrence of many complaints of sleep disturbances were found in primary headache disorders, both in men and women, they included daytime sleepiness (75.7%), lack of sleep (69.2%), difficulty in falling asleep (57.4%), sleep disruption (51.5%), early morning awakening (47.5%), snoring (18.7%). We found the predominance of these complaints in people over 50 years old. Women had these complaints more frequently than men, besides we determined sex differences in the prevalence of these complaints. CONCLUSION: Complaints about poor sleep quality are quite common in patients with primary headache disorders and have sex and age differences. Identification of the described complaints of poor sleep quality is a simple tool for the initial analysis of sleep disorders in the practice of any specialist. We recommend paying great attention to these complaints for further diagnostics of sleep disorders and their timely treatment.

[Treatment of toxic hepatitis in COVID-19 patients].

BACKGROUND: The article reflects the clinical significance of the early diagnosis of toxic hepatitis in patients who have undergone a new coronavirus infection with the determination of clinical and laboratory predictors of the response to therapy. A dynamic analysis of the effectiveness of toxic hepatitis therapy in patients of three experimental groups and a control group is presented. AIM: The aim of the present study is to increase the effectiveness of the treatment of toxic hepatitis in patients who have undergone COVID-19. MATERIALS AND METHODS: On the basis of the newly created infection centers of the Central Clinical Hospital "RZhD-Medicine" and Vishnevsky 3-rd Central Military Clinical Hospital 996 patients with COVID-19, who had clinical and laboratory signs of toxic liver damage (cytolytic and/or cholestatic syndromes) against the background of COVID-19 therapy. RESULTS: On the 14th day from the start of therapy in group 3, there was a significant decrease in the clinical manifestations of jaundice in 163 (72.8%) patients, on the 21st day of treatment, this symptom was stopped in all patients. In groups 1 and 2, the decrease in clinical manifestations of jaundice was significantly lower - 122 (55.2%) and 134 (58.8%); p<0.05. At the end of therapy, no manifestations of jaundice were observed in all experimental groups, while in the control group, symptom reduction was achieved only in 47 (14.5%) patients. CONCLUSION: The use of drugs with hepatoprotective effect in the form of monotherapy in groups 1 (UDCA) and 2 (ademethionine) showed a low therapeutic effect with positive dynamics of clinical and laboratory indicators of toxic hepatitis activity. The use of combined treatment in group 3 (UDCA and ademethionine) demonstrated the maximum therapeutic effect, pronounced positive dynamics in the form of normalization of clinical and laboratory indicators of toxic hepatitis activity.

Cellular and Molecular Mechanisms of Toxic Liver Fibrosis in Rats Depending on the Stages of Its Development.

The aim is to study the cellular and molecular features of toxic liver fibrosis in rats and its dependence on development stages of this pathological condition. Materials and Methods: Liver fibrogenesis in male Wistar rats was induced with the thioacetamide solution by introducing into the stomach with a probe at a dose of 200 mg/kg of animal body weight 2 times per week. The process dynamics was studied at 5 time points (control, week 3, week 5, week 7, and week 9). The mRNA levels of tweak, fn14, ang, vegfa, cxcl12, and mmp-9 genes in liver were detected by real-time polymerase chain reaction. Immunohistochemical study was performed on paraffin sections. The CD31, CD34, CK19, α-SMA, FAP, CD68, CD206, CX3CR1, and CD45 cells were used as markers. Fibrosis degree was determined in histological sections, stained in line with the Mallory technique, according to the Ishak's semi-quantitative scale. Results: Two simultaneously existing morphologically heterogeneous populations of myofibroblasts expressing different types of markers (FAP, α-SMA) were identified in rat liver. Prior to the onset of transformation of fibrosis into cirrhosis (F1-F4, weeks 3-7), FAP+ and SMA+ cells were localized in different places on histological specimens. All stages of liver fibrosis development were accompanied by an increase in the number (p=0.0000), a change in the phenotypic structure and functional properties of macrophages. The CK19+ cells of the portal areas differentiated into cholangiocytes that formed interlobular bile ducts and ductules, as well as hepatocytes that formed rudiments of new hepatic microlobules. Pathological venous angiogenesis and heterogeneity of endotheliocytes of the intrahepatic vascular bed were detected. Two options for changes in mRNA expression of the selected genes were identified. The level of the fn14 and mmp-9 mRNAs at all stages of fibrosis was higher (p=0.0000) than in control rats. For tweak, ang, vegfa, and cxcl12 mRNAs, the situation was the opposite - the level of genes decreased (p=0.0000). There were strong and moderate correlations between the studied target genes (p<0.05). Conclusion: It was established that the stages of toxic fibrosis had morphological and molecular genetic features. The FAP+ cells make the main contribution to development of portal and initial stage of bridging fibrosis. The stellate macrophages and infiltrating monocytes/ macrophages can potentially be used for development of new therapeutic strategies for liver pathology treatment. One should take into account the features of the markers' expression by endothelial cells during the study of the intrahepatic vascular bed. Joint study of genes is a necessary ad-hoc parameter in fundamental and preclinical research.

[Prevalence of combination of functional dyspepsia and irritable bowel syndrome: a meta-analysis of studies using the Rome III-IV Criteria].

AIM: To systematize data on the prevalence of the combination of functional dyspepsia (FD) and irritable bowel syndrome (IBS) using the Rome IIIIV Criteria. MATERIALS AND METHODS: A search in electronic databases MEDLINE/PubMed, EMBASE, and Cochrane was conducted. The depth of search was 17 years (from January 2006 to May 2022). Original publications from peer-reviewed periodicals that applied the Rome IIIIV Criteria for diagnosis of FD and IBS in an adult patient population with detailed descriptive statistics to allow the resulting data to be included in the meta-analysis were selected for final analysis. RESULTS: The final analysis included 38 studies involving 17,993 patients with FD and 15,883 patients with IBS. In the overall pool of studies using the Rome IIIIV Criteria, the pooled prevalence of FD in patients with IBS was 34.625% (95% confidence interval [CI] 28.15941.390), and the pooled prevalence of IBS in patients with FD was 37.549% (95% [CI] 31.51143.787). A random-effects model was used in the analyses since significant heterogeneity between results was found (p0.0001; I298%). Using the Rome III Criteria, the pooled prevalence of FD in patients with IBS was 31.993% (95% CI 26.13538.150; I2=98.17%), while the prevalence of IBS in patients with FD was 34.694% (95% [CI] 29.31940.273; I2=97,89%). An analysis of papers using the Rome IV Criteria demonstrated that the pooled prevalence of FD in patients with IBS was 42.614% (95% CI 18.58868.675; I2=98.97%), and the prevalence of IBS in patients with FD was 50.444% (95% CI 37.95662.904; I2=94,39%). CONCLUSION: This meta-analysis demonstrated that the prevalence of the combination of FD and IBS identified using the Rome IIIIV Criteria is high and is reported in approximately 1 in 3 patients with the functional gastrointestinal disorders concerned. The prevalence of a combination of FD and IBS identified using the Rome IV Criteria is at least 10% higher than that using the Rome III Criteria.

[Technoagism and technical behavior of the elderly citizens: results of Russian and Belarusian researches.]

The article is aimed to analyze social effects of digitalization using the example of the elderly in big city. Digitalization in this article is considered in two aspects: as introduction of digital technologies in everyday life (as well as «smart city¼); and digital transformation of professional practices. Special attention is paid to such phenomena as techno-ageism (exclusion of older people from the digital sphere) and related technostress.

[The sarcopenia: a multicomponent strategy for therapy (review of literature).]

Sarcopenia is an age-related loss of muscle mass, accompanied by a decrease in muscle function and/or strength, is increasingly recognized as a major risk factor for adverse outcomes in the weak elderly. The proven Association between hypodynamia, low-calorie diet, insufficient protein intake, and sarcopenia in older individuals suggests that exercise and targeted dietary supplements may have a significant therapeutic effect on the treatment and prevention of this condition. In this literature review, we summarize available data on the positive effects of various therapeutic interventions on muscle tissue.

[Variants of postoperative delirium suppression in elderly patients.]

To study the effectiveness of the inclusion of Cytoflavin in the management of postoperative delirium treating in elderly patients. Analyzed the results of treatment of 89 elderly patients (65-74 years) who, according to similar emergency indications, underwent surgery and postoperatively showed signs of delirium (according to the DDS scale ≥8 points). Depending on the treatment regimen, the patients were divided into three groups: in the first (n=32) group, bromodihydrochlorophenylbenzodiazepine was administered intravenously (1-5 min) in a dose of 1 mg in the 1st group (n=32) to the group (patients of the 2nd group (n=28) with the same purpose and at the same time cytoflavin was injected: 10 ml of the drug in dilution per 200 ml of 10% glucose solution intravenously at a rate of 140 drops (7 ml) per minute. Patients of 3rd group (n=29) were injected with ethylmethylhydroxypyridine succinate intravenous (within 5-7 min) at a dose of 200 mg. The condition was assessed using the SOFA, DDS and RASS scales. The inclusion of drugs with antioxidant/membrane-protective action (Cytoflavin and ethylmethylhydroxypyridine succinate) in the treatment regimen of postoperative delirium in the elderly increases the effectiveness of treatment, which is manifested in more rapid relief of the condition. When comparing the efficacy of Cytoflavin and ethylmethylhydroxypyridine succinate, it was noted that in a number of indicators (restoration of spontaneous breathing, improvement after the first dose and complete relief of signs of delirium) both drugs showed comparable results, however, when assessing the depth of sedation (on the RASS scale), Cytoflavin was more effective (p=0,001).The obtained results of the effectiveness of cytoflavin in combination with good patient tolerance allows us to recommend the inclusion of the drug in the treatment regimens of this pathology.

The TLR4 Agonist Immunomax Affects the Phenotype of Mouse Lung Macrophages during Respiratory Syncytial Virus Infection.

In the study, the effect of the TLR4 agonist Immunomax was investigated in vitro and in vivo. In particular, Immunomax was shown to polarize mouse bone marrow macrophages from the M0 and M2 states into the M1 state (ARG1 and iNOS mRNA expression levels were used to identify the mouse M1 and M2 phenotypes). Next, we investigated the prophylactic antiviral effect of Immunomax in both a model of mouse respiratory syncytial virus (RSV) infection and a model of RSV-induced bronchial asthma (BA) exacerbation. In the experiment with RSV-induced BA exacerbation, Immunomax-treated mice were characterized by a significant decrease of the viral load in lung homogenates, an increased amount of M1 macrophages in the lung, a tendency toward Th2-dependent ovalbumin-specific IgG1 antibodies decrease in blood serum, a significant increase in RSV-activated CD4+ T cells secreting IFNγ (Th1 cells), and a simultaneous significant decrease in the amount of CD4+ cells secreting IL-4 (Th2 cells) in the mouse spleen, which were detected by ELISPOT 1.5 months after experiment. These findings suggest that treatment with the TLR4 agonist Immunomax polarizes the immune response towards antiviral Th1 and may be used for short-term antiviral prophylaxis to prevent acute respiratory viral infections in asthmatics.

[Diagnosis and treatment of migraine: Recommendations of the Russian experts]. / Diagnostika i lechenie migreni: rekomendatsii rossiiskikh ékspertov.

These recommendations on the diagnosis and treatment of migraine were elaborated by Russian headache experts in accordance with the evidence-based practice. Together with the latest classification, diagnostic principles and criteria of different clinical sub-forms the consensus contains basic data on migraine epidemiology, pathophysiological mechanisms, differential diagnosis and most effective and evidence based approaches to pharmacological and non-pharmacological management of migraine patients.

[ROLE OF MAST CELLS IN BRONCHIAL CONTRACTION IN NONALLERGIC OBSTRUCTIVE LUNG PATHOLOGY].

In model of chronic obstructive pulmonary disease induced in rats by 60-day intermittent exposure to nitrogen dioxide mast cells participation in the mechanism of bronchial smooth muscle contractile activity patterns was evaluated. Since the 31st day, one group of rats was inhaled with sodium cromoglycate every day before the nitrogen dioxide exposure to stabilize the mast cell membrane. The other group (control) hasn't been treated. Isometric contraction of the bronchial isolated preparations in response to nerve or smooth muscle stimulation were determined. Inhibition of mast cell degranulation and the release of endogenous histamine by stabilizing cell membranes prevented the development of bronchial smooth muscle hyperactivity caused by prolonged inhalation of nitrogen dioxide. It is believed that a mechanism to increase the contractile activity of the bronchial wall smooth muscles is mediated by activation of the transmembrane adenosine receptor in resident mast cells, leading to their partial degranulation with release of histamine, acting on the histamine Hl-receptors with the launch of reflex pathways through intramural ganglion neurons.

[ANTIINFLAMMATORY AND REGENERATIVE EFFECT OF PEPTIDE THERAPY IN THE MODEL OF OBSTRUCTIVE LUNG PATHOLOGY].

The effect of the tetrapeptide bronchogen on the structural and functional state of the bronchial epithelium and inflammatory activity in the lungs was studied in the chronic obstructive pulmonary disease (COPD) model, created in rats by a 60-day intermittent exposure to nitrogen dioxide. The cell composition and cytokine-enzyme profile of bronchoalveolar lavage fluid (BALF), the content of secretory immunoglobulin A and surfactant protein B in BALF were determined. Following the course of peptide treatment the decreased activity of neutrophilic inflammation with the normalization of cellular composition and profile of pro-inflammatory cytokines and enzymes in the bronchoalveolar space was observed. The structure of bronchial epithelium, disturbed during formation of COPD model, was restored and accompanied by restoration of its functional activity as evidenced by an increase of secretory immunoglobulin A (local immunity marker) and surfactant protein B, responsible for reducing the alveolar surface tension.