Over the past 40 years, the incidence of ischemic stroke in young adults (18–44 years) has tripled worldwide. Recent Russian and international studies on ischemic stroke in young patients demonstrate the significant role of genetic factors in embolism. Among the most common hereditary causes of thrombosis are thrombophilias, one of whose manifestations is hyperhomocysteinemia (9.5%). We present a clinical case of a 41yearold woman. Her history included smoking and alcohol abuse; she denied hereditary and chronic diseases and had never taken combined oral contraceptives. In 2021, at age 37, under severe stress (heavy workload) and a sharp rise in body temperature to 40 °C, she suffered an ischemic stroke. During hospitalization, hyperhomocysteinemia (326.0 µmol/L) was detected for the first time. With treatment, her condition stabilized with minimal neurological sequelae. She was discharged with recommendations for continuous antiplatelet, antihypertensive, and lipidlowering therapy, as well as B vitamins. She demonstrated poor compliance: she did not see a neurologist or hematologist and did not have her blood homocysteine level monitored for three years. In 2024, she stopped antiplatelet therapy on her own, leading to a recurrent ischemic stroke. After repeat hospitalization, her condition stabilized with minimal neurological sequelae, and her adherence improved. Young patients often demonstrate poor compliance to medical recommendations and followup, which underscores the need for an active monitoring system for this cohort. Recommendations for primary care physicians on managing such patients are provided.
BACKGROUND: Assessment of the need for prevention of decreased bone mineral density in young individuals with Hodgkin lymphoma after pathogenetic therapy is relevant, as they face an increased risk of such long-term complications as frequent fractures. AIM: This study aimed to develop prognostic models for assessing the need for prevention of decreased bone mineral density in young patients with Hodgkin lymphoma after standard pathogenetic therapy. METHODS: This single-center cross-sectional study included 93 participants: 63 patients with an established diagnosis of Hodgkin lymphoma and 30 healthy volunteers aged 17–45 years. The study was conducted at the Department of Oncohematology, Chemotherapy, and Bone Marrow Transplantation of the Sverdlovsk Regional Clinical Hospital No. 1 (Yekaterinburg). Data were collected from 2018 to 2023. Each participant completed a questionnaire recommended by the Institute of Rheumatology to assess fracture risk factors. Dual-energy x-ray absorptiometry was performed in all patients to evaluate bone tissue status. The models were constructed using multivariate logistic regression. Model performance was assessed by the area under the ROC curve (AUC), as well as by accuracy, sensitivity, and specificity. RESULTS: Two models were developed to assess the risk of osteoporosis and the need for early initiation of preventive measures for decreased bone mineral density in patients with Hodgkin lymphoma. The first model, based on questionnaire results, had an AUC of 0.727, accuracy of 71.4%, sensitivity of 75%, and specificity of 66.7%. The second model, which included densitometric parameters, demonstrated higher performance: ROC-AUC of 0.95, accuracy of 88.6%, sensitivity of 95%, and specificity of 80%. CONCLUSION: Both models may be used as screening tools; however, the model based on densitometric parameters has higher diagnostic performance. The use of the model without densitometric data appears acceptable for preliminary identification of indications for preventive measures in patients with Hodgkin lymphoma.
The blood–brain barrier is a highly selective morphofunctional structure that maintains central nervous system homeostasis and protects it from toxic and foreign substances in the systemic circulation. At the same time, the blood–brain barrier remains a major obstacle to effective pharmacotherapy of central nervous system diseases, as most drugs are unable to cross it. This review discusses current approaches to overcoming the blood–brain barrier, which rely on endogenous transport systems such as adsorptive transcytosis and receptor- or carrier-mediated transcytosis, as well as advanced nano- and biotechnologies. Of particular interest are promising strategies such as modification of therapeutic molecules with cell-penetrating peptides, the use of exosomes and biomimetic nanoplatforms, and cell-mediated delivery of biologically active molecules using autologous leukocytes as “Trojan horses.” Methods for transient disruption of blood–brain barrier integrity (e.g., osmotic modulation and focused ultrasound) and alternative delivery routes, such as intranasal administration providing direct access to the brain via the olfactory and trigeminal nerves, are discussed separately. It is emphasized that successful therapy of central nervous system diseases is not possible without safe, effective, and targeted delivery systems capable of crossing the blood–brain barrier without compromising its protective function. Recent advances in molecular and cellular biology, nanomedicine, and genetic engineering open new horizons for personalized therapeutic approaches aimed at effective traversal of the blood–brain barrier.
Diaphorase (NQO1, NAD(P)H:quinone oxidoreductase 1) is an important biomarker of the presence and progression of cancer and also plays a key role in the activation of prodrugs used in targeted chemotherapy of tumors. This work aimed to compare data from long-term studies of the role of diaphorase in the intracellular activation of prodrugs used in targeted chemotherapy of oncologic diseases. The review includes data from relevant publications describing the biochemical functions of diaphorase, its role in oncology, and possibilities for increasing the effectiveness of antitumor therapy through induction of this enzyme. Articles published from 2000 to 2025 and indexed in the databases PubMed, ScienceDirect, and eLIBRARY.RU were analyzed. The study used methods of internet analysis, content analysis, and historical and descriptive-analytical approaches. Diaphorase accelerates the two-electron reduction of quinones to hydroquinones, preventing the formation of free radicals whereas simultaneously providing bioreductive activation of a number of cytotoxic drugs. Overexpression of diaphorase in malignant cells makes it possible to use this enzyme as a biocatalytic mechanism for selective delivery and activation of prodrugs, thereby increasing therapeutic effectiveness. The review examines modern enzyme–prodrug strategies, including ADEPT (Antibody-Directed Enzyme Prodrug Therapy), GDEPT (Gene-Directed Enzyme Prodrug Therapy), and PMT (Prodrug Monotherapy), as well as prospects for induction of diaphorase by compounds of the 1,2-dithiole-3-thione class and phytochemical agents. The relationship between NQO1 activity, mitochondrial dysfunction of tumor cells, and initiation of apoptosis is emphasized. Overall, diaphorase is considered a promising molecular target for the development of new bioreductive and mitochondria-targeted antitumor drugs.
BACKGROUND: Early and accurate assessment of inflammatory and renal tubular biomarkers is clinically relevant to diagnose and evaluate progression of type 2 cardiorenal syndrome; however, their combined diagnostic value remains insufficiently studied. AIM: This study aimed to evaluate the diagnostic value of inflammatory and renal tubular biomarkers in patients with type 2 cardiorenal syndrome. METHODS: The study was conducted at the 1st Clinical Medical Center in Baku in 2020–2024 and included 200 patients with type 2 cardiorenal syndrome and 51 apparently healthy individuals. Patients were stratified by functional class of chronic heart failure based on the New York Heart Association classification and the stage of chronic kidney disease: group 1 (n = 74) with functional class I–II and stage I–II, respectively; group 2 (n = 9) with functional class I–II and stage III–IV, respectively; group 3 (n = 73) with functional class III–IV and stage I–II, respectively; group 4 (n = 44) with functional class III–IV and stage III–IV, respectively. The levels of cystatin C, lipocalin, liver-type fatty acid–binding protein, kidney injury molecule 1 (KIM-1) in blood and urine, interleukin-6, interleukin-18, and tumor necrosis factor-alpha were determined. Diagnostic accuracy was assessed using receiver operating characteristic (ROC) analysis, and correlations were evaluated using the Spearman correlation method. RESULTS: In all groups, a pronounced increase in the studied markers compared with the control group was observed (p 0.001), with progressive elevation in line with disease severity. The levels of cystatin C, lipocalin, liver-type fatty acid–binding protein, and KIM-1 increased 2.9-, 2.1-, 3.1-, and 2.3/2.0-fold, respectively, in group 1 (p 0.001); 4.2-, 2.9-, 5.6-, and 5.1/2.7-fold in group 2 (p 0.001); 3.4-, 2.4-, 4.2-, and 2.6/2.3-fold in group 3 (p 0.001); and 6.4-, 3.4-, 7.2-, and 5.8/3.4-fold in group 4 (p 0.001). The levels of interleukin-6, interleukin-18, and tumor necrosis factor-alpha also increased: 3.9- and 2.8-fold and by 89.0%, respectively, in group 1; 5.2-, 2.9-, and 2.5-fold in group 2; 4.4-, 4.0-, and 2.1-fold in group 3; and 6.4-, 5.2-, and 3.1-fold in group 4 (p 0.001). Marker concentrations correlated with the stage of chronic kidney disease (ρ = 0.676–0.861; p 0.001) and the functional class of chronic heart failure (ρ = 0.301–0.514; p 0.001), whereas lipocalin and KIM-1 correlated with interleukin-6 and interleukin-18 levels (ρ = 0.894–0.920; p 0.001). The highest diagnostic value was identified for liver-type fatty acid–binding protein (AUC: 0.819; 95% CI: 0.761–0.876; p 0.001), lipocalin (AUC: 0.768; 95% CI: 0.702–0.834; p 0.001), and KIM-1 (AUC: 0.745; 95% CI: 0.678–0.813; p 0.001). CONCLUSION: Inflammatory and renal tubular biomarkers have high diagnostic value and are consistent with the progression of cardiorenal dysfunction in type 2 cardiorenal syndrome.
Background: Using common and rare molecular genetic markers, genetic risk scores for ischemic heart disease are being developed, and their associations with the severity of atherosclerosis, levels of low-density lipoprotein cholesterol, triglycerides, and nonHDL cholesterol are being studied. Aim: To analyze nucleotide sequence variants in genes associated with metabolic processes, depending on the presence of unstable atherosclerotic plaques in the coronary arteries of patients with and without abdominal obesity. Methods: The study included 42 men aged 42–69 years (mean age 55.74 ± 5.85 years) with coronary atherosclerosis, either with or without abdominal obesity (22 patients without obesity and 17 with obesity). Wholeexome sequencing was performed using standard kits. Normality testing for variable distribution was performed using the Shapiro–Wilk test. Data for categorical variables are presented as absolute and relative values—n (%), for continuous variables—as Me (25; 75), where Me is the median, 25th and 75th percentiles (1st and 3rd quartiles). Results: Patients with coronary atherosclerosis and abdominal obesity were found to have rare variants with a minor allele frequency ≤0.001 (dbGaP) in the ADIPOQ (rs76533408) and APLNR (rs199589565, rs150922621) genes. Patients with coronary atherosclerosis, abdominal obesity, and unstable atherosclerotic plaques were found to have a rare variant rs190996557 in the CCL2 gene. A number of genetic variants associated with an increased risk of metabolic disorders and cardiovascular disease were identified in patients with coronary atherosclerosis and overweight. The rs4994 variant (G = 0.07) in the ADRB3 gene, associated with decreased hormone-sensitive lipase expression and an increased risk of developing obesity and ischemic heart disease, was identified. The rs3745368 variant of the RETN gene (A = 0.04) was associated with a predisposition to type 2 diabetes mellitus, hypertension, and insulin resistance. The rs696217 variant of the GHRL gene (T = 0.08) was associated with the risk of developing obesity. Conclusion: Rare genetic variants in the ADIPOQ (rs76533408), APLNR (rs199589565, rs150922621) and CCL2 (rs190996557) genes were identified in patients with coronary atherosclerosis and abdominal obesity.
BACKGROUND: Identifying risk factors for overweight among representatives of different professional groups is necessary to develop a unified strategy for preventing obesity and associated diseases in the working-age population. AIM: This study aimed to assess the prevalence of leading risk factors for overweight and obesity among teachers living in a large city, taking age characteristics into account. METHODS: The study included 141 female teachers of secondary general education facilities in Volgograd. Three age groups were formed: 18–29 years (n = 30), 30–44 years (n = 33), and 45–64 years (n = 78). The frequency of food intake, behavioral risk factors for health, and anthropometric characteristics were assessed. Statistical analysis was performed using Statistica 10 software. The normality of distribution of quantitative variables was assessed using the Kolmogorov–Smirnov test. The Kruskal–Wallis test was used to evaluate intergroup differences. Differences were considered statistically significant at р 0.05. A multiple regression model was used to assess the contribution of factors to the development of overweight and obesity. RESULTS: The proportion of teachers with overweight increased with age (from 30.0% to 70.5%; p = 0.001). The expected increase in BMI with a 1-year increase in age, estimated using paired linear regression, was 0.186 kg/m2. Disturbances in dietary patterns and nutritional adequacy were identified: long intervals between meals (from 50.0% to 39.7%; р = 0.0103), dry meals at the workplace (from 70.0% to 47.4%; р = 0.002), deficiency of complete protein intake (from 56.7% to 44.9%; р = 0.046), insufficient consumption of fresh vegetables and fruits (from 30.3% to 50.0%; р = 0.046), and excessive consumption of simple carbohydrates (from 26.7% to 52.6%; р = 0.021). Most teachers demonstrated high levels of emotional (mean score, 2.8) and restrictive (mean score, 3.0) types of eating behavior. Lifestyle factors also contributed to weight gain (sleep disturbances, low physical activity, prolonged use of electronic devices, smoking; р 0.05). CONCLUSION: The most common risk factors for obesity among female teachers are sleep disturbances, sedentary lifestyle, unbalanced diet, and the high prevalence of emotional and restrictive types of eating behavior.
BACKGROUND: Primary hyperparathyroidism is associated with a risk of postoperative hypocalcemia and decreased bone mineral density. AIM: This study aimed to assess the need for prophylactic vitamin D supplementation in patients with primary hyperparathyroidism after parathyroidectomy to reduce the risk of hypocalcemia and increase bone mineral density. METHODS: An interventional study conducted at the Republican Clinical Hospital for War Veterans of the Chuvash Republic in 2023–2025 included 126 patients with verified primary hyperparathyroidism who underwent parathyroidectomy. The main group (n = 63) consisted of patients who received cholecalciferol at 2800 IU/day in the postoperative period for 6 months. Depending on the clinical and laboratory variant of the disease course, subgroups with hypercalcemic (n = 28) and normocalcemic (n = 35) forms were identified in the main group. The control group (n = 63) consisted of patients who did not receive prophylactic vitamin D. The groups were comparable in terms of sex, age, baseline parathyroid hormone and calcium levels, and X-ray densitometry data of the lumbar spine and femoral neck. The groups were formed using simple randomization. One year after surgery, bone mineral density was assessed using dual-energy X-ray absorptiometry. StatTech 4.4.1 was used for statistical analysis. Quantitative variables are presented as median and interquartile range [Me (Q1; Q3)], and categorical data as absolute values and percentages (n; %). Mann–Whitney U test was used to compare independent groups by quantitative variables, and the Wilcoxon test was used to assess changes in paired observations. Differences were considered significant at p 0.05. RESULTS: One year after surgery, patients were invited for an outpatient visit. Patients in the main group demonstrated higher bone mineral density in the lumbar spine (median T score: −1.5 vs −2.1; p = 0.011) and femoral neck (−1.7 vs −2.0; p = 0.031), as well as lower parathyroid hormone levels (3.4 nmol/L vs 5.2 nmol/L; p = 0.001) compared with the control group. Total calcium levels did not differ significantly between the groups. The increase in bone mineral density in the lumbar spine was 4.25% in the main group and 3.41% in the control group (p = 0.011). The increase bone mineral density in the femoral neck area was 5.05% in the main group, which was significantly higher than in the control group (4.06%; p = 0.031). CONCLUSION: Prophylactic vitamin D supplementation after parathyroidectomy reduces the risk of postoperative hypocalcemia and promotes higher bone mineral density. Patients receiving cholecalciferol demonstrated a greater increase in bone mineral density and lower parathyroid hormone levels.
Background: The dynamics of growth indicators during the transition from school to higher education in male and female adolescents aged 17–18 years remains insufficiently studied. Aim: To study the physical development of students during the completion of growth processes in the age range of 17–18 years. Methods: An analysis of physical development indicators (body length and weight) of male and female adolescents aged 17–18 years living in various regions of the Russian Federation was conducted. The study was performed using data obtained from 2021 to 2024 and included in the following databases: “Physical development of children, adolescents, and youth of the Russian Federation in 2021–2023,” “Anthropometric indicators of students aged 7–18 years living in various regions of the Russian Federation,” and “Physical development of children and adolescents aged 7–17 years depending on socio economic factors.” Results were described using the sample mean (M), standard error of the mean (m), and standard deviation (σ). Statistical significance of differences was assessed using Student’s t test (p 0.05). Results: Seventeen regions of the Russian Federation were randomly selected; the total sample size was 29,351 individuals. In male adolescents aged 17–18 years, anthropometric indicators continued to increase: a significant increase in mean body length of 1.29 cm (p = 0.027) and a significant increase in mean body weight of 1.86 kg (p = 0.025) were found. In contrast, no significant differences in mean body length or body weight were found in female adolescents, which may indicate that the main growth processes are completed by age 17. A high proportion of regions of the Russian Federation (58.8%) showed significant differences in mean body length in male adolescents, indicating preserved variability in the timing of growth completion and reflecting the existence of “regional scenarios” of physical development. Conclusion: The results demonstrate persistent heterogeneity in growth processes among male and female adolescents aged 17–18 years across different regions of the Russian Federation.
BACKGROUND: In autoimmune thyroiditis, hormone replacement therapy generally does not inhibit the activity of autoreactive T lymphocytes destroying the thyroid gland and promoting the antithyroid antibody response at the early stages of the disease. AIM: This work aimed to find an approach aimed at suppressing the autoimmune reaction in autoimmune thyroiditis. METHODS: Experimental autoimmune thyroiditis (EAT) was induced by double (at day 1 and day 14) thyroglobulin immunization of 15 weeks old C57BL/6 mice using complete and incomplete Freund’s adjuvant. Experimental animals were given a 0.05% NaI solution during feeding. The mice were divided into three groups; group 1 included intact mice (n = 5), group 2 included mice with induced EAT (n = 7), and group 3 included mice with induced EAT and subsequently administered sirolimus (n = 7). CD4+, CD8+, double-positive and double-negative T lymphocytes, and CD4+CD25+FoxP3+ T cell levels were determined using flow cytometry. Follicle destruction was measured by hematoxylin and eosin staining and the apoptosis was measured by staining with active caspase-3 antibodies. Thyroid antibodies were determined using enzyme-linked immunosorbent assay. Statistical processing was performed using one-way ANOVA and Student’s t-test (p 0.05); data were presented as mean ± standard deviation (SD). Distribution normality was tested using the Shapiro–Wilk and Bartlett tests. RESULTS: In the EAT group, the mTOR protein inhibitor (sirolimus) prevented thymus involution, increased the number of thymic regulatory T cells, and suppressed the secretion of IFN-γ and IL-17A cytokines. The inhibitor reduced lymphoid infiltration (D450 = 0.25) compared to mice with EAT (D450 = 2.4) and cellular apoptosis (D450 = 0.005 vs 0.0125 in the EAT group). This, in turn, resulted in lower levels of thyroid peroxidase autoantibodies (D450 = 3.0 compared to 19 in the experimental group). Therefore, sirolimus suppresses the autoimmune reaction by activating regulatory T immunity. CONCLUSION: Sirolimus helps reduce the autoimmune aggression, improve the thyroid gland structure, and mitigate the severity of the disease.
Background: In the Arctic, circadian rhythm disruption, driven by melatonin deficiency, serves as an additional pathogenetic factor in the development and progression of inflammatory periodontal diseases. Aim: To study the role of melatonin and oxidative stress in the pathogenesis of periodontal inflammation among residents of the Russian Arctic. Methods: The gingival crevicular fluid was collected from patients with chronic periodontitis (54 samples), chronic gingivitis (46 samples), and with intact periodontium (28 samples). Melatonin and malondialdehyde (an oxidative stress marker) levels were measured by ELISA in the gingival crevicular fluid. Periodontopathogen markers were detected using real-time PCR. Statistical analyses were performed using Stata 14 with nonparametric tests. Results: In patients with chronic periodontitis and gingivitis, melatonin levels were significantly lower than in individuals with intact periodontium [median: 2.1 (1.4; 2.8) pg/mL and 3.0 (2.2; 3.7) pg/mL vs 5.8 (4.9; 6.5) pg/mL, p 0.001]. Malondialdehyde levels were elevated in inflammatory periodontal diseases. Melatonin correlated negatively with malondialdehyde in periodontitis patients (r = −0.712; p 0.001). Periodontopathogens (Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Treponema denticola) were frequently detected in inflamed cases, and melatonin levels correlated negatively with pathogen associations (r = −0.80; p 0.001). Conclusion: In the Russian Arctic, low oral melatonin levels in chronic periodontitis patients are associated with increased oxidative stress and immune activation, thereby exacerbating periodontal inflammation.
Modern dietary trends, marked by high consumption of animal products, drive the search for metabolic predictors of adverse course of cardiovascular pathology. Trimethylamine-N-oxide (TMAO), a metabolite derived from dietary precursors, is associated with mortality risk. However, a systemic understanding of the specific mechanisms by which TMAO promotes the progression of existing diseases warrants detailed investigation, including the strategies to regulate it. This review examines the biochemical transformation pathway of TMAO, analyzes its role as a predictor of vascular endothelial dysfunction, and explores potential ways to control its blood concentration. Based on an analysis of studies published over the last five years, a clear link exists between plasma TMAO levels and the risk of cardiovascular disease. A tendency towards high TMAO levels is observed in people consuming animal products. The increase from the excessive synthesis of its precursor, trimethylamine, which is synthesized from dietary precursors. High TMAO concentrations exert pro-inflammatory effects, stimulate atherogenesis, and serve as a significant factor in vascular endothelial dysfunction. The cumulative effect of these pathological processes directly increases the risk of complications in patients with cardiac pathologies. Dietary restriction of animal products is a potential strategy to correct plasma TMAO levels. However, dietary modification alone cannot be regarded as the sole factor for reducing TMAO, as the functioning of the gut microbiota, which directly influences the formation of the TMAO precursor trimethylamine, is equally important. This work provides a comprehensive understanding of the pathophysiological mechanisms by which TMAO affects the vascular wall and explains why dietary correction cannot be considered as the only method of prevention must be integrated with the management of gut microbiocenosis to effectively prevent disease.
The autonomic nervous system is a critical regulator of cardiovascular function, and its imbalance contributes substantially to cardiovascular diseases and their complications. This work aimed to analyze studies addressing the impact of the autonomic nervous system on the course and prognosis of chronic heart failure, including in patients with comorbidities. The review included 47 papers published between 2000 and 2025 in PubMed and eLIBRARY.RU journals that investigated the role of the autonomic nervous system in chronic heart failure. The article discusses the origins of heart rate variability assessment and diagnostic tools for evaluating autonomic nervous system function in various cardiovascular diseases. The review describes the pathogenetic mechanisms underlying changes in autonomic status and the key parameters used to assess it, predominantly based on noninvasive time- and frequency-domain heart rate variability analysis for a more accurate evaluation of adaptation level, stress reactivity, and the degree of autonomic imbalance. Data on age- and sex-related differences in heart rate variability in patients with chronic heart failure are presented, including those with comorbidities such as chronic kidney disease, chronic obstructive pulmonary disease, and diabetes mellitus. Evidence is provided to support the prognostic value of heart rate variability parameters that influence disease course and cardiovascular risk in patients with chronic heart failure. Investigating the pathogenetic mechanisms underlying autonomic dysfunction in patients with cardiovascular diseases is relevant for developing new therapeutic approaches to restore autonomic nervous system balance. Time- and frequency-domain heart rate variability analysis is an accessible and convenient noninvasive method that can be used in a wide patient population to provide valuable information for personalized therapeutic strategies.
Persistent insufficient responsiveness to β₂-adrenergic receptor agonists and anti-inflammatory therapy in some patients with obstructive airway diseases necessitates the search for nonadrenergic targets, including bitter taste receptors. This work aimed to evaluate published data on the mechanisms of bronchodilation mediated by bitter taste receptors, compare them with β₂-adrenergic signaling, and assess the potential of TAS2Rs as bronchodilator therapy targets. A review of publications in Russian and English indexed in PubMed, eLIBRARY.RU, CyberLeninka, ResearchGate, and Google Scholar from 2006 to 2025 was performed. Bitter taste receptors are expressed in airway smooth muscle cells, epithelial cells, and immune cells. Their activation induces rapid smooth muscle relaxation through three mechanisms: (1) local Ca²⁺ elevation with activation of BKCa channels and subsequent membrane hyperpolarization; (2) Gβγ-mediated inhibition of L-type Ca²⁺ channels; and (3) cofilin-dependent remodeling of the actin cytoskeleton without changes in myosin phosphorylation. The response is preserved under conditions of Th2-mediated inflammation and β₂-adrenergic receptor desensitization; additive effects have been observed when combined with β₂-agonists. Furthermore, antiproliferative effects in airway smooth muscle cells, suppression of IgE-mediated mast cell activation, and enhancement of mucociliary clearance have been described. Clinical trials of inhaled bitter taste receptor agonists for obstructive airway diseases have not been registered. The main limitations include interspecies differences, the requirement for high concentrations of certain ligands, toxicity of individual compounds, and irritant and organoleptic effects. Conclusion: Bitter taste receptors in airway smooth muscle cells are an alternative bronchodilator therapy target in obstructive airway diseases. In experimental models, bitter taste receptor agonists induce rapid bronchodilation, retain efficacy in the presence of β₂-adrenoceptor desensitization, and exhibit antiproliferative and antiremodeling properties. Unresolved issues regarding clinical applicability include the low affinity and selectivity of currently available ligands, polypharmacology, a pronounced irritant and taste profile, interspecies differences, and the absence of completed clinical trials.
BACKGROUND: At present, there is a lack of detailed information on the activities of organizations engaged in drug compounding, the state of their infrastructure, and the demand for services related to drug compounding for state and municipal needs. AIM: This work aimed to systematize indicators characterizing the activities of organizations engaged in drug compounding and to determine future directions for the development of drug compounding in the Volga Federal District. METHODS: A sociological study of medical and pharmacy organizations licensed for pharmaceutical activity with authorization to compound medicinal products was conducted using remote questionnaire-based surveys. Data from the Unified Register of Licenses; data from the Unified Register of Licenses for Activities Related to the Circulation of Narcotic Drugs, Psychotropic Substances, and Their Precursors; results of the socioeconomic assessment conducted by the Federal State Statistics Service; and data from the Unified Information System for Procurement were used. The work applied a survey method in the form of remote questionnaires as well as desk research methods. RESULTS: The findings indicate a more than 1.5-fold increase in demand for drug compounding services in the public healthcare sector of the Volga Federal District from 2021 to 2024, reaching 487.16 million rubles. Procurement of drug compounding services for medical use funded by regional budgets was carried out in 8 of the 14 constituent entities of the Volga Federal District, with an annual increase in demand of 40.2%. It was established that at least 127 organizations engaged in drug compounding (by registered addresses of pharmaceutical activity) operate within the district, accounting for 18.6% of the total number in the Russian Federation. Authorization to compound medicinal products from the list of narcotic drugs and psychotropic substances is held by pharmacy organizations operating in 9 of the 14 analyzed constituent entities of the Russian Federation, indicating limited accessibility of personalized pharmacotherapy. In 2023, a total of 6320 medicinal products were compounded, representing approximately 14.0% of the total compounding volume in the Russian Federation. Compounding was performed using at least 128 pharmaceutical substances. During compounding, at least 147 international nonproprietary names of registered medicinal products were used. CONCLUSION: The study identified the main qualitative and quantitative characteristics of organizations engaged in drug compounding in the Volga Federal District and determined the demand within public procurement of services related to drug compounding in the district.
In recent years, the amount of scientific data indicating the key role of the gut microbiome in modulating immune responses that influence myocardial remodeling and the progression of chronic heart failure has been growing. Modulating the composition and function of the gut microbiome to reduce the severity of lowgrade inflammation and slow the progression of chronic heart failure appears to be an innovative approach. This review aimed to analyze the role of the gut microbiome in cytokine-dependent inflammation in heart failure. Fifty-two sources containing data on associations between cytokine levels and gut microbiome bacterial genera in patients with heart failure, published from 1999 to 2025 in journals indexed in PubMed and eLibrary.ru, were analyzed. The review includes a description of modern molecular methods for studying the gut microbiome, along with their advantages and disadvantages. Changes in the taxonomic and quantitative composition of the gut microbiome and in the cytokine profile of patients with heart failure are presented. The data presented in the analyzed publications demonstrate a link between specific bacterial taxa and cytokine levels in certain phenotypic groups of chronic heart failure; however, the mechanisms underlying these relationships often remain the subject of further research. The identified limitations in the design of the reviewed studies, such as the presence of comorbidities, medication use, and unadjusted analyses that do not always account for confounding variables (diet and physical activity), underscore the need for further research to confirm these associations. Promising directions include research into diseasemodifying treatment for chronic heart failure, including the development of methods to modulate the microbiota in order to reduce cytokinemediated myocardial damage.
This review presents data from contemporary studies of the neurobiological and physiological bases of stuttering. According to the International Classification of Diseases, 10th Revision, stuttering is characterized by repetitions or prolongations of sounds, syllables, or words, as well as by delays or pauses that disrupt the rhythm of speech. Stuttering affects social communication as well as family, educational, professional, and other areas of life. Behavioral modification of speech patterns (speech therapy) is mainly used in the treatment of stuttering. When considering the physiological bases of stuttering, abnormal cortical activation is observed (hyperactivation of speech and motor areas of the right hemisphere and the supplementary motor area), as well as dysfunction of the basal ganglia. These changes may be associated with altered activity and reduced gray matter volume in speech motor areas, white matter deficits (in the regions of the motor representation of the tongue and larynx), and abnormalities of conducting pathways (the frontal aslant tract, corticobulbar, and corticospinal pathways). The review also discusses methods of noninvasive neuromodulation, such as transcranial magnetic stimulation, used both to study the neurophysiology of stuttering and for therapy. During transcranial magnetic stimulation, a short magnetic field pulse passes through the scalp and induces an electrical current in the cerebral cortex. The delivered impulses can modulate neuronal activity, depolarize neurons, alter intracortical excitability, and activate distant corticosubcortical and spinal structures. Prospects for further development of transcranial magnetic stimulation protocols to optimize the correction of stuttering are presented.
BACKGROUND: Identifying predictors of chronic heart failure is an essential preventive step in patients with pre–heart failure. AIM: This study aimed to identify predictors of chronic heart failure development in outpatients with hypertension and pre–heart failure. METHODS: A single-center study included 356 outpatients with hypertension and pre–heart failure. The mean age was 62.65 ± 10.59 years; 128 (36%) participants were men. The patients received drug therapy for hypertension, with treatment adjustment after 1 and 3 months and subsequently annually for 3 years. Later on, outcomes defined as the development of chronic heart failure were evaluated. Multiple binary logistic regression analysis was used to identify predictors of chronic heart failure onset. RESULTS: Over a 3-year period (2022–2025), chronic heart failure with preserved ejection fraction developed in 8.7% of patients with hypertension and pre–heart failure. Analysis of risk factors showed that patients who developed chronic heart failure were older (66.37 ± 9.55 years; p 0.001), had a longer duration of hypertension (17.85 ± 10.43 years; p 0.001), higher body mass index (29.41 ± 4.85 kg/m2; p = 0.002), and a lower glomerular filtration rate (73.23 ± 18.19 mL/min/1.73 m2; p 0.001). In this group, paroxysmal (p 0.001) and persistent atrial fibrillation (p 0.001), as well as type 2 diabetes mellitus (p 0.001), were observed more frequently. In these patients, more pronounced structural and functional cardiac changes were already present at enrollment into the study, namely, indexed left atrial volume (47.93 ± 14.85 vs 33.68 ± 5.57 mL/m2; p 0.001), indexed myocardial mass (104.18 ± 29.34 vs 92.55 ± 19.36 g/m2; p = 0.045), maximum pulmonary vein diameter (21.23 ± 2.24 vs 17.34 ± 1.64 mm; p 0.001), and minimum pulmonary vein diameter (11.09 ± 2.42 vs 7.36 ± 1.53 mm; p 0.001). The predictors associated with the onset of chronic heart failure after 3 years in patients with hypertension included maximum pulmonary vein diameter, left atrial volume, age, body mass index, and the presence of atrial fibrillation. CONCLUSION: Within 3 years, chronic heart failure with preserved ejection fraction developed in 8.7% of patients with pre–heart failure. Predictors of its development in patients with hypertension included maximum pulmonary vein diameter, left atrial volume, age, body mass index, and the presence of atrial fibrillation.
Chronic periodontitis is a widespread infectious inflammatory disease that leads to the destruction of the connective tissue and bony structures of the periodontium and is a primary cause of tooth loss in the adult population. Analysis of published data confirms the increasing incidence of periodontitis worldwide, regardless of age and sex, necessitating the development of not only early diagnostic methods but also effective treatment and preventive approaches. Conventional treatments aimed at controlling infection and inflammation cannot achieve complete regeneration of destroyed tissues. Consequently, a promising area of research involves investigating the potential of cell therapy using mesenchymal stromal cells. This review summarizes current data on the role of mesenchymal stromal cells from various origins (dental pulp, periodontal ligament, bone marrow, gingiva) in the pathogenesis and treatment of periodontitis. It examines both direct mechanisms (differentiation into osteoblasts and cementoblasts) and paracrine effects, including pronounced immunomodulation (restoration of the Th17/Treg cell balance, macrophage polarization), effects on angiogenesis, as well as the secretion of extracellular vesicles and exosomes. The results of preclinical studies on the efficacy of both mesenchymal stromal cells and their secretome in in vivo and in vitro models were analyzed. Particular attention was paid to the molecular mechanisms regulating the osteogenic differentiation of these cells under inflammatory conditions, including the role of long noncoding RNAs, microRNAs, and key signaling pathways in the pathogenesis of chronic periodontitis. The review also addresses the impact of systemic factors such as diabetes mellitus and aging on the regenerative potential of mesenchymal stromal cells. Based on a systematic analysis of the available data, it can be concluded that these cells and their derivatives possess high therapeutic potential for periodontal regeneration, opening new horizons for their application in clinical practice.
In the context of an aging population, the number of older and elderly patients requiring pancreatoduodenectomy is growing. Chronological age is not a reliable predictor of outcomes, whereas frailty syndrome, reflecting biological age, serves as a key risk factor for postoperative complications and adverse outcomes. Frailty, defined as a state of reduced physiological reserves, is a powerful independent predictor of postoperative outcomes. It is associated with a marked increase in the risk of 30day mortality (by 1.5–2.5 times), the overall frequency, and development of serious complications, including those specific to pancreaticobiliary surgery. Frail patients have longer hospital stays and are significantly more likely to require discharge to rehabilitation facilities. In the long term, frailty negatively impacts overall survival, increases the risks of functional complications and deterioration in quality of life, and also reduces the likelihood of receiving adjuvant cancer therapy. Various instruments are used to assess frailty (Fried phenotype, modified frailty index, clinical frailty scale); their integration into preoperative evaluation allows for improved risk stratification. Optimization strategies aimed at correcting identified deficits include preoperative prehabilitation (a combination of physical training, nutritional support, and psychological support), implementation of enhanced recovery protocols, multimodal analgesia, and multidisciplinary management involving a geriatrician and an intensivist. For patients over 80 years of age, the decision to proceed with surgery should be based not on chronological age but on a comprehensive assessment of biological age, functional reserves, and the feasibility of adjuvant therapy. Routine frailty assessment and subsequent targeted, multistep optimization of patient management within a multidisciplinary approach are essential prerequisites for improving the safety and outcomes of pancreatoduodenectomy in older patients.
