Prevention of nosocomial infections in cardiac surgery patients during the postoperative period is a critical task, both from an economic perspective and for improving the quality and longevity of life in patients with cardiovascular diseases. The relevance of assessing the risk of infectious complications in this population is confirmed by numerous publications in both Russian and international journals. An analysis of original studies and reviews in Embase, PubMed, ResearchGate, eLibrary, and Google Scholar indicated that effective prediction of nosocomial infections in cardiac surgery patients requires consideration of a combination of parameters that exert a synergistic influence on infection risk. Key preoperative risk factors include age over 60 years, body mass index 24 kg/m2, smoking, hypertension, diabetes mellitus, chronic obstructive pulmonary disease, severe chronic heart failure, peripheral vascular disease, and previous cardiac surgery. Upon hospital admission, the likelihood of developing nosocomial infections may be influenced by pronounced preoperative hypoalbuminemia, anemia, low hematocrit, and elevated serum creatinine. Intraoperative risk factors include cardiopulmonary bypass duration exceeding 120 minutes, intraoperative blood loss 2000 mL, and infusion of large volumes of replacement fluids. In the future, artificial intelligence could be utilized to develop a risk assessment scoring system. The role of the pathobiome and chronic infectious foci in the development of nosocomial complications in cardiac surgery patients remains insufficiently studied and requires further research. Endogenous sources of infection may play a more significant role in the development of nosocomial infections than exogenous contamination.

Послеоперационные инфекционно-воспалительные осложнения различной степени выраженности – от незначительной инфекции области хирургического вмешательство до сепсиса,- утяжеляют состояние пациентов, увеличивают сроки госпитализации и повышают стоимость лечения, наиболее эффективным является терапевтическая стратегия, учитывающая риск развития таких осложнений, выявляющая на раннем этапе характерную для осложнений динамику параметров-биомаркеров и корректирующая протокол лечения в соответствии с этими параметрами. Поиск маркеров, позволяющих определить степень риска развития инфекционно-воспалительных осложнений, является актуальной проблемой медицины. К биомаркерам, связанным с развитием инфекционных осложнений, относятся эндотоксин (липополисахарид грам-отрицательных бактерий), липолисахарид-связывающий белок и пресепсин. Целью данной работы был анализ литературных данных, касающихся возможности использования липополисахарида, пресепсина и липолисахарид-связывающего белка в качестве молекул-биомаркеров для оценки риска развития инфекционно-воспалительных осложнений у больных после хирургического вмешательства. На основе литературных данных сделан вывод о возможности применения пресепсина и ЛПС-связывающего белка для оценки риска развития инфекционно-воспалительных осложнений у кардиохирургических больных.

МЦНП «НОВАЯ НАУКА» ВЛИЯНИЕ ГИПОКСИИ НА МИКРОБИОМ КИШЕЧНИКА ХОЗЯИНА Хомякова Татьяна Ивановна к.м.н.Мхитаров Владимир Аршакович к.б.н.ФГБНУ «Российский научный центр хирургии им.акад.Б.В.Петровского» Хомяков Юрий Николаевич к.м.н., д.б.н

Hypoxia is a major pathogenetic factor in many cancers. Individual resistance to suboptimal oxygen availability is subject to broad variation and its possible role in tumorigenesis remains underexplored. This study aimed at specific characterization of glioblastoma progression in male tolerant and susceptible to hypoxia Wistar rats. Hypoxia resistance was assessed by gasping time measurement in an 11,500 m altitude-equivalent hypobaric decompression chamber. Based on the outcome, the animals were assigned to three groups termed 'tolerant to hypoxia' (n = 13), 'normal', and 'susceptible to hypoxia' (n = 24). The 'normal' group was excluded from subsequent experiments. One month later, the animals underwent inoculation with rat glioblastoma 101.8 followed by monitoring of survival, body weight dynamics and neurological symptoms. The animals were sacrificed on post-inoculation days 11 (subgroup 1) and 15 (subgroup 2). Relative vessels number, necrosis areas and Ki-67 index were assessed microscopically; tumor volumes were determined by 3D reconstruction from histological images; serum levels of HIF-1α, IL-1β, and TNFα were determined by ELISA. None of the tolerant to hypoxia animals died of the disease during observation period, cf. 85% survival on day 11 and 55% survival on day 15 in the susceptible group. On day 11, proliferative activity of the tumors in the tolerant animals was higher compared with the susceptible group. On day 15, proliferative activity, necrosis area and volume of the tumors in the tolerant to hypoxia animals were higher compared with the susceptible group. ELISA revealed no dynamics in TNFα levels, elevated levels of IL-1β in the susceptible animals on day 15 in comparison with day 11 and tolerant ones. Moreover, there were elevated levels of HIF-1α in the tolerant animals on day 15 in comparison with day 11. Thus, the proliferative activity of glioblastoma cells and the content of HIF-1α were higher in tolerant to hypoxia rats, but the mortality associated with the tumor process and IL-1β level in them were lower than in susceptible animals. Specific features of glioblastoma 101.8 progression in tolerant and susceptible to hypoxia rats, including survival, tumor growth rates and IL-1β level, can become the basis of new personalized approaches for cancer diseases treatment in accordance to individual hypoxia resistance.

Поиск специфических прогностических и диагностических маркеров – актуальная задача современной педиатрии. Эндотелий – активная система, которая функционирует как рецепторно-эффекторный орган, реагирующий на экзогенный или эндогенный стимул с выделением разнообразных молекул, призванных восстановить сосудисто-тканевый гомеостаз. Эндотелий, с одной стороны, участвует практически во всех процессах, определяемых как гомеостаз, гемостаз и воспаление, с другой – это первое звено патогенеза различных заболеваний как у взрослых, так и у детей и подростков. К настоящему времени сформировалось представление об эндотелиальной дисфункции как о состоянии, характеризующемся дисбалансом медиаторов, обеспечивающих в норме оптимальное течение эндотелий-зависимых процессов. В связи с доказанной ролью развития эндотелиальной дисфункции в патогенезе заболеваний сердечно-сосудистой, дыхательной систем, при метаболических нарушениях и т.д. в качестве такого прогностического и диагностического маркера эндотелиальной дисфункции может быть использован эндотелин-1 (EТ-1). Цель исследования: анализ и обобщение данных литературы по базам данных WoS, Scopus, РИНЦ. На основе клинических и экспериментальных данных можно заключить, что применение маркеров эндотелиальной дисфункции, включая уровень эндотелина-1 в сыворотке крови, может использоваться для оценки тяжести социально-значимых заболеваний при их манифестации в детском и подростковом возрасте. The search for specific prognostic and diagnostic markers is an urgent task in modern pediatrics. The endothelium is an active system that functions as a receptor-effectors organ that responds to an exogenous or endogenous stimulus with the release of various molecules designed to restore vascular-tissue homeostasis. The endothelium, on the one hand, is involved in almost all processes defined as homeostasis, homeostasis and inflammation, on the other hand, it is the first link in the pathogenesis of various diseases in both adults, children and adolescents. To date, the idea of endothelial dysfunction as a condition characterized by an imbalance of mediators that normally ensure the optimal course of endothelium-dependent processes has been formed. Due to the proven role of the development of endothelial dysfunction in the pathogenesis of diseases of the cardiovascular, respiratory systems, metabolic disorders, etc. Endothelin-1 (ET-1) can be used as such a prognostic and diagnostic marker of endothelial dysfunction. Purpose of the study: analysis and synthesis of literature data using WoS, Scopus, RSCI databases. Based on clinical and experimental data, it can be concluded that the use of markers of endothelial dysfunction, including the level of endothelin-1 in blood serum, can be used to assess the severity of socially significant diseases when they manifest in childhood and adolescence.

Individual resistance to hypoxia largely determines the severity of inflammatory processes and, probably, can affect the regeneration of the skin wound.The aim was to study reparative and inflammatory changes in the wound in Wistar rats with different resistance to hypoxia.Material and methods. The study was performed on mature male Wistar rats weighing 300–350 g. Before the experiment, the resistance of animals to hypoxia was determined. Rats were classified as highly resistant to hypoxia (HR), in which the time to take a lateral position in the pressure chamber “at a height” of 11,500 m was more than 360 s (n=5), to low-resistant (LR) – less than 40 s (n=5). A full-thickness wound with a diameter of 16 mm was applied to the animals in the interscapular zone of the back. On the 7th day after the infliction of the wound, a histological and morphometric study was performed. The proliferative activity of cells in the granulation tissue of the wound was determined immunohistochemically using the Ki-67 marker. Real-time PCR was used to evaluate the level of expression of the Hif-1α, Nf-κB, and Vegf genes.Results. It was shown that in rats with high resistance to hypoxia, the total number of cells and, among them, the number of inflammatory cells was higher than in rats with low resistance to hypoxia. However, the percentage of inflammatory cells in the compared groups did not differ significantly. Cell proliferative activity, as measured by the number of Ki-67 positive cells, was higher in rats with high resistance to hypoxia. In the granulation tissue of highly resistant to hypoxia rats, the expression of the Vegf gene was statistically significantly higher than in low-resistant animals, while there were no statistically significant differences in the level of expression of the Hif-1α, Nf-κB genes.Conclusion. In rats with high resistance to hypoxia, on the 7th day of healing of a full-thickness skin wound, reparative processes in it are more pronounced. In the horizontal layer of fibroblasts, there are more cells, among them inflammatory ones - histiocytes and macrophages, which is combined with a higher number of proliferating Ki-67 positive cells and the expression level of vascular endothelial growth factor (Vegf).

ЭФФЕКТ ГИПЕРОКСИЧЕСКОГО ВОЗДЕЙСТВИЯ НА РЕСПИРАТОРНЫЙ И КИШЕЧНЫЙ МИКРОБИОМХомякова Т.И., Макарова О

Dermal fibroblast cell culture is a convenient model for studying various effects on cells, including hypoxia. Fibroblasts, in addition to collagen production, are able to synthesize biogenic amines, hormones, neuropeptides, and neurotransmitters identical to those in the central nervous and endocrine systems, which allows them to be used to study cellular disorders in various diseases. The purpose of the study was to evaluate the functional changes in the culture of dermal fibroblasts under hypoxic conditions using biochemical and molecular biological methods. In cells of fibroblast culture under normoxia (air and 5% CO 2 in an incubator) and hypoxic exposure (a mixture of gases - 95% N 2 and 5% CO 2 ) at 1 and 3 hours, biochemical methods were used to determine the activity of aspartate aminotransferase (AsAT), alanine aminotransferase (AlAT), gamma-glutamyl transferase (GGT), lactate dehydrogenase (LDH), glucose levels, concentrations of ATP, ADP, AMP, as well as the level of mRNA expression of the hypoxia-induced factor Hif-1a and the nuclear factor Nf-κb by polymerase chain reaction. It was shown that under hypoxic exposure at 1 hour in fibroblast culture, cell viability, glucose levels and activity of LDH, AlAT, AsAT decrease, the amount of ATP decreases, after 3 hours there is a tendency to normalize all indicators. Adaptive mechanisms make it possible to normalize the functioning of cells under hypoxic conditions from 1 to 3 hours. The results obtained in the evaluation of metabolic changes at different times of hypoxic exposure (1 and 3 hours) in the culture of rat fibroblasts indicate a high adaptive capacity of connective tissue cells - fibroblasts at a lack of oxygen. The study of intracellular parameters during hypoxia, the determination of critical points depending on the time of exposure will determine the directions for further study of the mechanisms of cell adaptation, which, perhaps, will complement the tactics of compensatory effects in ischemia of tissues of various genesis. The revealed changes reflect the adaptive response of the fibroblast culture in response to hypoxic exposure.

An organism’s hypoxia tolerance depends on many factors, including age. High newborn organism tolerance and high levels of oxidative stress throughout aging have been demonstrated by many studies. However, there is still lack of investigations reflecting the intensity of systemic inflammatory response in organisms of different ages in correlation to hypoxia tolerance. The aim of this study was to determine the relationship between age-related tolerance to hypoxia, HIF-1 and PHD2 (prolyl hydroxylase domain protein) expression levels and the intensity of systemic inflammatory response in newborn, prepubertal and adult Wistar rats. In case of investigation of the tolerance to hypoxia, rats were placed into a decompression chamber at altitude simulation of 11,500 m. It was demonstrated that prepubertal rats are the least tolerant to hypoxia and newborns are the most tolerant. Newborn rats are characterized by high mRNA Hif-1α expression level in the liver, accompanied by low content of HIF-1 protein and a high level of PHD2. The growth in HIF-1α protein level with age is accompanied by growth in the level of proinflammatory cytokines. Prepubertal animals are the least hypoxia tolerant, and their HIF-1α mRNA expression level was higher than in adult animals. The PHD2 activity in prepubertal animals was significantly reduced in comparison to newborn rats, and the HIF-1α protein level was not changed. The lowest tolerance of the prepubertal males to hypoxia correlated with the greatest manifestations of hepatic inflammation and elevated endotoxin, neopterin, and C-reactive protein levels in LPS-induced systemic inflammatory response. The growth in serum HIF-1α 3 h after LPS injection was observed only in prepubertal rats. The obtained data should be taken into account during the development of a therapeutic strategy for prepubertal children with infectious and inflammatory diseases. Hopefully, this study will provide new insights into age-related differences in tolerance to hypoxia. The possible perspectives of this investigation could be understanding the aspects of HIF-1 mRNA and protein expression in aged animals. Moreover, further studies are required for the identification of additional mechanisms to determine HIF-1α protein level regulation in prepubertal animals.

Hypoxia tolerance of the organism depends on many factors, including age. High newborn organisms tolerance and high level of oxidative stress throughout aging were demonstrated by many studies. However, there is lack of investigations reflecting the expression of key hypoxia-inducible factor HIF in different age organisms in correlation to levels of pro-inflammatory and anti-inflammatory cytokines. Liver is a sensitive to hypoxia organ, and is an important organ in providing an acute reaction to infections – it synthesizes acute inflammation phase proteins, in particular, C-reactive protein. The aim of study was to determine relationship between age-related tolerance to hypoxia and HIF-1 and PHD2 (prolyl hydroxylase domain protein) expression levels in the liver and the production of cytokines in the spleen in newborn, prepubertal and adult Wistar rats. Newborn rats are characterized by high mRNA Hif-1α expression level in the liver, accompanied by a low content of HIF-1 protein and high level of PHD2. The growth in HIF-1α protein level throughout age is accompanied by the growth of pro-inflammatory cytokines level. Prepubertal animals are the least hypoxia resistant and their HIF-1α mRNA expression level was higher than in adult animals. The PHD2 activity in prepubertal animals was significantly reduced in comparison to newborn rats, and the HIF-1α protein level did not change. Further studies require the identification of additional mechanisms, determining the regulation of the HIF-1α level in prepubertal animals.

Introduction. Doxorubicin is an anticancer chemotherapy drug that has cardiotoxic, hepatotoxic, and nephrotoxic effects. To reduce the toxic effects of doxorubicin, its nanosomal form, PLGA-doxorubicin [Poly(Lactic-co-Glycolic Acid)], has been developed. PLGA is a biodegradable polymer used as a drug delivery system. The nephrotoxic effects of PLGA-doxorubicin have not been studied yet. The aim was to compare the nephrotoxic effects of therapeutic doses of doxorubicin in standard form (Dox) and PLGA-doxorubicin (PLGA-Dox). Materials and methods. Mature male Wistar rats were injected intravenously three times with Dox or PLGA-Dox solution, at a therapeutic dose of 1.75 mg/kg. The animals were sacrificed on days 8 and 21. We carried out morphological, histochemical, and ultrastructural studies of the kidneys. Results. Under the influence of Dox or PLGA-Dox in the kidneys on days 8 and 21 of the experiment, histological and ultrastructural examination revealed dystrophic changes in the proximal tubules with the destruction of the brush border; in the distal tubules and collecting ducts, protein cylinders were located. Dystrophic changes were more pronounced on day 21 than on day 8. During both periods of the experiment, PLGA-Dox caused less pronounced dystrophic changes in the epithelium than Dox that is confirmed by a morphometric assessment of the number of proximal tubules with a destroyed brush border. Conclusion. The nanosomal PLGA-doxorubicin form has a less pronounced nephrotoxic effect than the classical form of doxorubicin. Keywords: nephrotoxic effect, doxorubicin, nanoparticles, PLGA, morphology

There are individual differences in the tolerance to hypoxia and stress. Stress can contribute to the development of various diseases, including inflammatory bowel disease. It was found that inflammatory bowel diseases in animals susceptible to hypoxia runs more severe course than in tolerant animals. We studied morphofunctional changes in the colon under conditions of modeled cold stress in male C57BL/6 mice susceptible and tolerant to hypoxia. The animals were daily subjected to cold stress (20 min at -20°C) for 2 weeks. Cold stress was followed by an increase in the volume fraction of goblet cells in the colon and production of mucins by these cells in mice tolerant to hypoxia and an increase in cell content in the lamina propria of the colon mucous membrane in animals susceptible to hypoxia. The number of serotoninproducing endocrine cells increased in both groups, but these changes were more pronounced in mice susceptible to hypoxia.

Traumatic stress causes posttraumatic stress disorder (PTSD). PTSD is associated with cardiovascular diseases and risk of sudden cardiac death in some subjects. We compared effects of predator stress (PS, cat urine scent, 10 days) on mechanisms of cardiac injury and protection in experimental PTSD-vulnerable (PTSD) and -resistant (PTSDr) rats. Fourteen days post-stress, rats were evaluated with an elevated plus-maze test, and assigned to PTSD and PTSDr groups according to an anxiety index calculated from the test results. Cardiac injury was evaluated by: 1) exercise tolerance; 2) ECG; 3) myocardial histomorphology; 4) oxidative stress; 5) pro- and anti-inflammatory cytokines. Myocardial heat shock protein 70 (HSP70) was also measured. Experimental PTSD developed in 40% of rats exposed to PS. Exercise tolerance of PTSD rats was 25% less than control rats and 21% less than PTSDr rats. ECG QRS, QT, and OTc intervals were significantly longer in PTSD rats than in control and PTSDr rats. Only cardiomyocytes of PTSD rats had histomorphological signs of metabolic and hypoxic injury and impaired contractility. Oxidative stress markers were higher in PTSD than in PTSDr rats. Pro-inflammatory IL-6 was higher in PTSD rats than in control and PTSDr rats, and anti-inflammatory IL-4 was lower in PTSD than in control and PTSDr rats. Myocardial HSP70 was lower in PTSD rats than in PTSDr and control rats. Our conclusion was that rats with PTSD developed multiple signs of cardiac injury. PTSDr rats were resistant also to cardiac injury. Factors that limit cardiac damage in PS rats include reduced inflammation and oxidative stress and increased protective HSP70.NEW & NOTEWORTHY For the first time, rats exposed to stress were segregated into experimental PTSD (ePTSD)-susceptible and ePTSD-resistant rats. Cardiac injury, ECG changes, and impaired exercise tolerance were more pronounced in ePTSD-susceptible rats. Resistance to ePTSD was associated with decreased inflammation and oxidative stress and with increased protective heat shock protein 70. Results may help identify individuals at high risk of PTSD and also provide a foundation for developing preventive and therapeutic means to restrict PTSD-associated cardiac morbidity.

We studied morphological changes in the prostate ventral lobe, proliferative activity of the epithelium in prostate acini, and the levels of prolactin and prostate-specific antigen in the blood serum of Sprague-Dawley rats after repeated injections of sulpiride in a dose of 40 mg/ kg over 30 and 60 days and in 10 and 30 days after withdrawal. Morphological and morphometrical analysis of hyperplastic changes in the prostate ventral lobe was performed. Ki-67(+) proliferating epithelial cells in the acini were counted. The dynamics of serum concentrations of prolactin and prostate-specific antigen was evaluated by ELISA. Morphological and morphometrical analysis and evaluation of the content of Ki-67(+) cells demonstrated epithelium hyperplasia in the prostate ventral lobe after sulpiride treatment for 30 or 60 days and in 10 days after withdrawal, but serum level of prostate-specific antigen did not differ from the control. After 60-day sulpiride treatment and in 30 days after withdrawal, pronounced hyperplastic changes of prostate and elevated concentrations of prostate-specific antigen (but not prolactin) were observed. Thus, administration of sulpiride (40 mg/kg) to Sprague-Dawley rats for 60 days allows, by morphological criteria and serum level of prostate-specific antigen, to model stable hyperplastic changes in the prostate corresponding to benign prostatic hyperplasia in humans.

Morphological, morphometric, and ultrastructural analysis of the nerve fibers in the colon mucosa was performed in C57BL/6 mice at various terms of development of acute colitis induced by dextran sodium sulphate. The nerve fibers were labeled with antibodies to pan-neuronal marker βIII-tubulin. The progression of inflammatory and ulcerative processes in the mucosa on days 3-5 was associated with hyperplasia and hypertrophy of nerve fibers that peaked on day 7 after colitis induction. Ultrastructural analysis at all terms of colitis development showed moderate degeneration of axons. Thus, hypertrophy and hyperplasia of the nervous fibers in colon mucosa in experimental acute colitis correlated with aggravation of the ulcerative process in the mucosa. These changes are determined by alteration of histoarchitectonics and regenerative processes in the mucosa.

It is a common fact, that the content of sex hormones in humans and animals varies in different age periods. The functional state of the immune system also changes with age. However, sex differences studies of inflammatory and immune responses during puberty prevail in literature. Investigation of immune responses to LPS peculiarities in prepubertal females and males may contribute to the development of more effective immunotherapy and minimize side effects of children vaccination. Therefore, the aim of this work was to investigate the LPS-induced SIRS sex differences in prepubertal Wistar rats. Despite the absence of sex differences in estradiol and testosterone levels, LPS-induced inflammatory changes in liver and lungs are more pronounced among males. Males demonstrate the increasing neopterin, corticosterone levels and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity. Not less important is that in females, demonstrating less morphological changes in liver and lungs, endotoxin level is tenfold higher, and corticosterone level decreases. Thus, endotoxin cannot be used as a marker of the severity of multiple organ failure in prepubertal period. The LPS-induced immune reactions in females and males are similar and are characterized by immunosuppression. Both females and males have decreased production of cytokines (IL-2, IL-4, TNF-α, TGF-β) and the absolute number of CD3 + and CD3 + CD8 + lymphocytes in blood. The acute atrophy of thymus and apoptosis of thymic cells are revealed in animals of both sexes. However, the number of CD3 + CD4 + T-helpers and CD4 + CD25 + Foxp3 + T-cells decreases only in females with SIRS, and in males there was a decrease of CD45R + B-cells. The least expressed sex differences in immune responses in the prepubertal period can be determined by the low levels of sex steroids and the absence of their immunomodulatory effect. Further studies require the identification of mechanisms, determining the sex differences in the inflammatory and immune responses in prepubertal animals.

INTRODUCTION:Influenza is a severe viral disease, a frequent complication of which is a secondary bacterial pneumonia. Influenza vaccines prevent secondary bacterial complications. Virus-like particles are one of the promising areas for the development of new vaccines. The aim of this work is to study the correlation of the pathomorphological characteristics of the lungs with clinical, virological, and microbiological markers of the disease at vaccination with virus-like particles (VLPs), containing hemagglutinin (HA) of influenza virus (HA-Gag-VLPs) in a murine model of secondary bacterial pneumonia induced by S. pneumoniae after influenza infection.MATERIAL AND METHODS:BALB/c mice were vaccinated with VLPs containing influenza HA. After 21 days, mice were infected with two strains of influenza viruses, homologous and non-homologous, and 5 days after viral infection, were infected with S. pneumoniae. The vaccination effect was evaluated by morphological, virological (titer of the virus in the lungs) and microbiological (titer of bacteria in the lungs) data, and was confirmed by clinical data (survival, change in body weight).RESULTS:Immunization with HA-Gag-VLPs, followed by infection with a homologous influenza virus and S. pneumoniae, reduced the area of foci of inflammation, inhibited the replication of the virus and bacteria in the lungs, and also protected animals from death and reduced their weight loss. Immunization with HA-Gag-VLPs upon infection with a heterologous strain and S. pneumoniae did not affect these criteria.CONCLUSION:The immunization with HA-Gag-VLPs prevented the viral replication, providing a reduction of S. pneumoniae titer and the degree of lung damage, protecting animals from the disease in a murine model of secondary bacterial pneumonia, induced by S. pneumoniae, after influenza infection with homologous strain of the virus.