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BACKGROUND: Chronic obstructive pulmonary disease is often not diagnosed as a preventable disease. The primary physician needs a diagnostic tool to detect chronic obstructive pulmonary disease at an early stage. AIM: To develop the concept of early detection of chronic obstructive pulmonary disease through a diagnostic tool that stratifies patients according to the risk of disease development. MATERIALS AND METHODS: Random sample of persons 3570 years from the lists provided by 15 polyclinics of Saint Petersburg and Arkhangelsk (cross-sectional study, n = 2388). Cohort prospective study (respondents with fixed or variable obstruction, n = 167). All respondents were asked about demographic data, smoking history, risk factors, and the presence of symptoms. Spirometry with a bronchodilator was performed for all participants. RESULTS: Fixed obstruction was found in 6.8% of the participants in the first phase; obstruction was associated with male sex, smoking status over 10 packs/years, age over 55 years, chronic cough and shortness of breath. Of the 65 members of the cohort with variable obstruction, 23.1% had a fixed obstruction after a year, the risk factors of which were a smoking status of more than 10 packs/years, a night cough and forced expiratory volume in 1 second less than lower limit of normal. CONCLUSIONS: Based on the results of the two phases of the study, a diagnostic tool was developed for the early detection of chronic obstructive pulmonary disease in the general population by identifying a group of people with preserved lung function and high-risk chronic obstructive pulmonary disease factors.

BACKGROUND: The study of the true prevalence of chronic obstructive pulmonary disease remains a significant area of research, as there is still a large gap between the official record of detected cases of the disease and epidemiological data. AIM: To study the prevalence of chronic obstructive pulmonary disease and its risk factors in two cities in the North-West region of Russia. MATERIALS AND METHODS: A random sample of respondents (2121 residents of Saint Petersburg, 1012 residents of Arkhangelsk); 2974 received qualitative results of spirometry (including 2388 with a bronchodilator test). The questionnaire included demographic, socioeconomic indicators, and risk factors for chronic obstructive pulmonary disease. RESULTS: The average age (54.9 9.2 and 52.3 9.2 years) and the proportion of respondents with higher education (37.4% and 29.7%) were higher in Saint Petersburg (compared to Arkhangelsk, p 0.0001). The proportion of ever smokers (49.5% and 44.4 %, p = 0.008), as well as the prevalence of chronic obstructive pulmonary disease (7.6% and 5.4%, p = 0.044), were higher in Saint Petersburg. In Arkhangelsk, exposure to biomass fuel and occupational hazards were more often noted. The prevalence of chronic obstructive pulmonary disease was higher in smokers and increased with age; the prevalence of smoking and chronic obstructive pulmonary disease was higher in men. CONCLUSIONS: The analysis of chronic obstructive pulmonary disease risk factors allows us to better understand not only the prevalence but also the structure and significance of each risk factor in different populations, which will improve the early diagnosis of the disease.

The aim of the study was to fabricate and characterize composite macroporous hydrogels based on a hyaluronic acid/chitosan (Hyal/Ch) polyelectrolyte complex (PEC) loaded with homogeneously distributed hydroxyapatite nanoparticles (nHAp), and to evaluate them in vitro using mouse fibroblasts (L929), osteoblast-like cells (HOS) and human mesenchymal stromal cells (hMSC). Hydrogel morphology as a function of the hydroxyapatite nanoparticle content was studied using scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM). The mean pore size in the Hyal/Ch hydrogel was 204 ± 25 μm. The entrapment of nHAp (1 and 5 wt. %) into the Hyal/Ch hydrogel led to a mean pore size decrease (94 ± 2 and 77 ± 9 μm, relatively). Swelling ratio and weight loss of the hydrogels in various aqueous media were found to increase with an enhancement of a medium ionic strength. Cell morphology and localization within the hydrogels was studied by CLSM. Cell viability depended upon the nHAp content and was evaluated by MTT-assay after 7 days of cultivation in the hydrogels. An increase of the hydroxyapatite nanoparticles loading in a range of 1–10 wt. % resulted in an enhancement of cell growth and proliferation for all hydrogels. Maximum cell viability was obtained in case of the Hyal/Ch/nHAp-10 sample (10 wt. % nHAp), while a minimal cell number was found for the Hyal/Ch/nHAp-1 hydrogel (1 wt. % nHAp). Thus, the proposed simple original technique and the design of PEC hydrogels could be promising for tissue engineering, in particular for bone tissue repair.

The effectiveness of stroma-dependent expansion of hematopoietic cells ex vivo may depend on the level of commitment of multipotent mesenchymal stromal cells (MSC). Markers of MSC osteodifferentiation and the level of soluble hematopoiesis regulators were determined during their interaction with umbilical cord blood mononuclears. After 72-h co-culturing, an increase in the expression of ALPL and alkaline phosphatase activity was revealed. In conditioned medium of co-cultures, the levels of osteopontin and osteoprotegerin were elevated and the levels of osteocalcin and sclerostin were reduced. Co-culturing of umbilical cord blood mononuclears with osteocommitted MSC was accompanied by more pronounced increase in the concentration of both positive (GM-CSF and G-CSF) and negative (IP-10, MIP-1α, and MCP-3) regulators of hematopoiesis. Thus, umbilical cord blood mononuclears induced the formation of early osteogenic progenitor phenotype in MSC ex vivo, providing the microenvironmental conditions necessary to support hematopoiesis. Preliminary osteocommitted MSC were more sensitive to the effect of umbilical cord blood mononuclears.

Pericytes are multipotent mesenchymal stromal cells playing an active role in angiogenesis, vessel stabilisation, maturation, remodelling, blood flow regulation and are able to trans-differentiate into other cells of the mesenchymal lineage. In this review, we summarised recent data demonstrating that pericytes play a key role in the pathogenesis and development of atherosclerosis (AS). Pericytes are involved in lipid accumulation, inflammation, growth, and vascularization of the atherosclerotic plaque. Decreased pericyte coverage, endothelial and pericyte dysfunction is associated with intraplaque angiogenesis and haemorrhage, calcification and cholesterol clefts deposition. At the same time, pericytes can be used as a novel therapeutic target to promote vessel maturity and stability, thus reducing plaque vulnerability. Finally, we discuss recent studies exploring effective AS treatments with pericyte-mediated anti-atherosclerotic, anti-inflammatory and anti-apoptotic effects.

Pericytes are mural vascular cells covering microvascular capillaries, where they contribute to the formation, maturation, maintenance, stabilisation and remodelling of vasculature. They actively interact and communicate with other cells to maintain the capillary structural integrity, vascular permeability and blood flow. Pericytes are crucial participants in the physiological and pathological processes of cardiovascular disease. In this review, we summarise recent data regarding pericyte metabolism, trans-differentiation, angiogenesis and immunomodulation in connection with different cardiovascular pathologies. Further, we discuss an application of pericytes as a new cell therapy approach to treat coronary artery disease, congenital heart disease, atherosclerotic plaques calcification and calcific valvular heart disease in different in vivo animal models and in vitro studies. Also, we discuss different methods and pharmacological therapies for CVDs treatment with pericyte-mediated effects. Finally, we present a comprehensive overview of the role of pericytes in CVDs and as a pharmacological target for different novel drugs and techniques and highlight the potential application of pericytes to treat CVDs.

We analyzed the state of intracellular compartments and production of cytokines in MSC depending on the culture density. MSC were growth-arrested with mitomycin C and seeded at a density of 300-7000 cell/cm2. MSC in low-density cultures had 2-fold higher levels of transmembrane mitochondrial potential (MitoTracker Red) and endogenous ROS (CMH2DCFDA), lysosomal compartments were less acidified (LysoTracker Green DND26), the production of immunoregulatory and angiogenic mediators VEGF, IL-6, IL-8, MCP-1, TGF-β was more intensive. It was assumed that culture density can be an effective tool for phenotypic polarization of MSC providing directional changes in their properties.

It is well known that long-term space missions influence various myeloid shoots of hemopoiesis in humans and animals. In this investigation, we used several optimized models of co-culturing mesenchymal stromal cells (MSCs) and hemopoietic stem and progenitor cells (HSPCs) to analyze the HSPCs suspension fractions following 7-day modeling of the effects of microgravity. We determined the number of developing HSPCs, presence of colony-forming units (CFU) of various hemopoietic shoots and phenotype spectrum of cells in colonies. We observed an increased number of HSPCs, decreased number of CFUs, and changes in the structure of CFU population after the exposure to modeled microgravity.

We studied interactions of mesenchymal stromal cells (MSCs) and cells from the monocyte-macrophage group (MN/MP) important in the MSCs mediated therapeutic action in vivo, their anti-inflammatory and immunomodulating properties. The MSCs effect on the MN/MP functional activity was evaluated after a 6-d co-culture in standard conditions (20 % О2) and ensuing exposure of one part of MN/MP and MN/MP+MSCs to a long-term hypoxic stress (1 % О2, 24 hrs) while the other part remained at 20 % О2. As in the normal, so hypoxic conditions the MSCs stromal activity contributed to the MN/MP viability by decreasing the numbers of MN/MP cells during early apoptosis. The paracrine interaction in 20 % О2 occurred with an elevated MN/MP phagocytic activity without influence on the lysosomal compartment activity. The hypoxic stress affected the MSCs-induced phagocytic ability and activity of lysosomes. Interaction with MSCs leads to formation of a MN/MP anti-inflammatory phenotype that unveils the phagocytic potential in the presence of MSCs despite the oxygen deprivation.

Objective To evaluate the effectiveness of triptorelin for the treatment of adenomyosis, the benign invasion of endometrial tissue into the myometrium, as a fertility‐preserving alternative to the gold standard hysterectomy. Methods In this multicenter, open‐label, observational study in Russia, performed from November 3, 2011, to August 24, 2015, we assessed the efficacy and safety of triptorelin 3.75 mg administered intramuscularly every 28 days in Russian women who were gonadotropin‐releasing hormone agonist treatment‐naïve, aged 25–40 years, and had a diagnosis of endometriosis or adenomyosis with heavy menstrual bleeding. We performed a medical record review, interviews to assess symptom severity, and pelvic assessments including transvaginal ultrasound. Data were obtained at first injection of triptorelin (visit 1), on the day of last injection (visit 2), 6 months after last injection (visit 3), and 9 months after last injection (visit 4). Significance was assessed by Wilcoxon signed rank test. Results A total of 465 women were included. There was a significant improvement from baseline in severity of heavy menstrual bleeding in 390/463 (84.2%) of women 6 months after last injection (P

Background: Patients with second-degree lumbar osteochondrosis are observed to pay more attention to their health, have higher levels of anxiety, and a lower degree of life satisfaction. Daily wearing of therapeutic-prophylactic clothes by the subjects was applied for correction of osteochondrosis signs. Levels of life-satisfaction, anxiety levels, personal self-estimation, and attention paid to their health were observed in subjects with osteochondrosis who wore the garments daily for 6 months.Methods: The study was conducted in Central Russia (Moscow City and Moscow region). Data were obtained from 37 healthy subjects as a control group and 43 subjects of second-degree lumbar spine osteochondrosis as a case group in both sexes of the second mature age (mean age – 43.5±2.5 years, 44.7±1.9 years, respectively). The doctor in the institutions diagnosed second-degree lumbar spine osteochondrosis.Results: Our results revealed subjects with osteochondrosis who daily wore the author’s version of therapeutic-prophylactic clothes for six months, had persistent remission of osteochondrosis with reduction of painful and unpleasant sensations in the lumbar spine. Furthermore, the subjects also showed a significant decrease of anxiety level, an increase of personal self-estimation and satisfaction with life at the rise of motivation to wearing of therapeutic-prophylactic clothes.Conclusion: Daily wearing of therapeutic-prophylacticclothes’ applied version for six months can ensure the correction of clinical osteochondrosis manifestations in people of mature age and the formation of psychological comfort what secures the achieved remission.

The Central Research Institute of Epidemiology of Rospotrebnadzor presents priority data obtained from the largescale population PCR-based study of the changes in the rates of circulation of SARS-CoV-2 among relatively healthy residents of Moscow and Moscow Region.

Objectives To describe a new first-trimester sonographic sign, the 'crash sign', associated with fetal open spina bifida, and to evaluate its clinical usefulness in the first-trimester diagnosis of spina bifida. Methods This was a retrospective review of patients referred to three fetal medicine centers in the first trimester (11 + 0 to 13 + 6 weeks) with suspected spina bifida. Spina bifida was confirmed by direct visualization of the spinal defect on ultrasound by two experts and, when possible, by fetal postmortem examination. Ultrasound images were reviewed for the presence of the crash sign, which is the posterior displacement of the mesencephalon and deformation against the occipital bone in the axial view. The first-trimester ultrasound images of a mixed group of 10 cases and 40 control fetuses without spina bifida were assessed for the presence of the crash sign by two assessors blinded to the diagnosis. Results The crash sign was present in 48 out of 53 confirmed cases of spina bifida. Of these, 27 had isolated spina bifida and 21 had an associated anomaly. Of the five cases without the crash sign, one had isolated spina bifida and four had an associated anomaly. The crash sign was not reported in any of the control fetuses. Conclusions We have described a new first-trimester sonographic marker for the diagnosis of spina bifida. Our results suggest that the crash sign may be a useful tool in the first-trimester detection of spina bifida. Prospective evaluation of the crash sign would be beneficial, ideally in a routine clinical screening ultrasound setting. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

We studied the effect of short-term hypoxic stress on the phenotypic polarization of monocyte-derived macrophages and their secretory activity during interaction with mesenchymal stromal cells. In the presence of mesenchymal stromal cells, monocyte-derived macrophages exhibited the signs of M2 polarization, which was evidenced by increased expression of CD206 and CD163 markers, as well as increased transcription and translation of IL-6. Short-term hypoxic stress promoted a shift of macrophage phenotype from inflammatory M1 towards anti-inflammatory M2 in monoculture and co-culture with mesenchymal stromal cells. In addition to the immunoregulatory action, mesenchymal stromal cells demonstrated stromal activity and maintained high viability of monocyte-derived macrophages.

Gravity is fundamental factor determining all processes of development and vital activity on Earth. During evolution, a complex mechanism of response to gravity alterations was formed in multicellular organisms. It includes the “gravisensors” in extracellular and intracellular spaces. Inside the cells, the cytoskeleton molecules are the principal gravity-sensitive structures, and outside the cells these are extracellular matrix (ECM) components. The cooperation between the intracellular and extracellular compartments is implemented through specialized protein structures, integrins. The gravity-sensitive complex is a kind of molecular hub that coordinates the functions of various tissues and organs in the gravitational environment. The functioning of this system is of particular importance under extremal conditions, such as spaceflight microgravity. This review covers the current understanding of ECM and associated molecules as the matrisome, the features of the above components in connective tissues, and the role of the latter in the cell and tissue responses to the gravity alterations. Special attention is paid to contemporary methodological approaches to the matrisome composition analysis under real space flights and ground-based simulation of its effects on Earth.

The transcriptomic profile associated with osteo- and adipogenic differentiation in growth-arrested multipotent mesenchymal stromal cells (MSCs) from human adipose tissue was analyzed in vitro at 20% (standard laboratory) and 5% (tissue-related) O2 levels. Compared with day 7, at 5% O2 on day 14 spontaneous upregulation of osteo- (RUNX2, SP7, BGLAP, and SPP1) and adipogenic differentiation (CEBPA, PPARG, and ADIPOQ) genes in MSCs was observed (p < 0.05). Thus, upon expansion under tissue-related O2, MSCs demonstrated a bipotent transcriptomic profile, which may contribute to the improvement of their hematopoiesis-supportive function.

Aims Stroma-dependent ex vivo expansion of hematopoietic stem progenitor cells (HSPCs) is a valid approach for cell therapy needs. Our goal was to verify whether HSPCs can affect stromal cells to optimize their functions during ex vivo expansion. Main methods HSPCs from cord blood (cb) were cocultured with growth-arrested adipose mesenchymal stromal cells (MSCs). Commitment-related transcriptional and secretory profiles as well as hematopoiesis-supportive activity of intact and osteo-induced MSCs were examined. Key findings During expansion, cbHSPCs affected the functional state of MSCs, contributing to the formation of early stromal progenitors with a bipotential osteo-adipogenic profile. This was evidenced by the upregulation of certain MSC genes of osteo- and adipodifferentiation (ALPL, RUNX2, BGLAP, CEBPA, ADIPOQ), as well as by elevated alkaline phosphatase activity and altered osteoprotein patterns. Joint paracrine profiles upon coculture were characterized by a balance of “positive” (GM-SCF) and “negative” (IP-10, MIP-1α, MCP-3) myeloid regulators, effectively supporting expansion of both committed and primitive cbHSPCs. Short-term (72 h) osteoinduction prior to coculture resulted in more pronounced shift of the bipotential transcriptomic and osteoprotein profiles. The increased proportions of late primitive CD133−/CD34+cbHSPCs and unipotent CFUs suggested that cbHSPCs after expansion on osteo-MSCs were more committed versus cbHSPCs from coculture with non-differentiated MSCs. Significance During ex vivo expansion, cbHSPCs can drive the bipotential osteo-adipogenic commitment of MSCs, providing a specific hematopoiesis-supportive milieu. Short-term preliminary osteo-induction enhanced the development of the bipotential profile, leading to more pronounced functional polarization of cbHSPCs, which may be of interest in an applied context.

To compare ovarian reserve in healthy women of reproductive age - carriers of antithyroid antibodies (ATA) and in healthy women of reproductive age negative for ATA.70 healthy women of young reproductive age in the state of euthyroidism (from 18 to 38 years old) were examined. Participants were divided into equal groups (n=35) depending on the status of the presence of antithyroid antibodies (AT-TPO, AT-TG). On the 2nd-4th days of the menstrual cycle, the following markers of the ovarian reserve were determined: serum levels of anti-Müllerian hormone (AMG), inhibin B, FSH, LH, estradiol, testosterone and progesterone, as well as ultrasound parameters - the number of antral follicles and the volume of the ovaries. In addition, to determine the predisposition to premature ovarian failure, an analysis was performed to the number of CGG repeats in the FMR1 gene.Statistically significantly differs such parameters as the level of estradiol and testosterone, while the differences were not clinically significant. All the parameters evaluated were within the normal range, the main predictors of the ovarian reserve (levels of AMG and inhibin B, the number of antral follicles) remained in the normal range. An increase in the number of repeats of CGG in the FMR1 gene was not detected in any of the participants in the study.In healthy young reproductive age women, the status of ATA does not have a direct effect on the ovarian reserve.Цель исследования. Сравнить овариальный резерв у здоровых женщин репродуктивного возраста - носительниц антитиреоидных антител (АТА) - и у здоровых женщин репродуктивного возраста, негативных по АТА. Материалы и методы. Обследовано 70 здоровых женщин молодого репродуктивного возраста (от 18 до 38 лет) в состоянии эутиреоза. Участницы разделены на равные группы (n=35) в зависимости от статуса по наличию АТА (к тиреопероксидазе, тиреоглобулину). На 2-4-й день менструального цикла определяли следующие маркеры овариального резерва: сывороточные уровни антимюллерова гормона (АМГ), фолликулостимулирующего и лютеинизирующего гормонов, эстрадиола, тестостерона, а также ультразвуковые параметры - количество антральных фолликулов и объем яичников. Кроме того, для выяснения предрасположенности к преждевременной недостаточности яичников проводили анализ на количество CGG-повторов в гене FMR1. Результаты и обсуждение. Статистически достоверно различались такие параметры, как уровень эстрадиола и тестостерона, при этом различия не были клинически значимыми. Все оцениваемые параметры оказались в пределах нормы, основные показатели овариального резерва (уровень АМГ, количество антральных фолликулов) оставались в нормальном диапазоне. Увеличения количества повторов CGG в гене FMR1 не выявлено ни у одной из участниц исследования. Заключение. У здоровых женщины молодого репродуктивного возраста статус по АТА не оказывает непосредственного влияния на овариальный резерв.

The article shows the classification of the supervised objects of the Office of Service for Supervision of Consumer Rights Protection and Human Welfare in the city of Moscow depending on the index of the potential risk for harm to public health in the conditions of the application of the risk-oriented approach. There is considered the possibility of the control and surveillance activities with the redistribution of human resources of the Office of Service for Supervision of Consumer Rights Protection and Human Welfare in the city of Moscow with respect to supervised objects 1 and 2 classes of the potential risk for harm to the health of the population on the risk-oriented approach.

Endocrine Medical Research center (EMRC) of the Ministry of health of Russia is unique clinical center, that have no analogs in the world. All forms of endocrine disorders may be diagnosed and treated here by implication of innovative methods. Institute of reproductive medicine of EMRC was open on 2017, director of this institute – MD, PhD E.N. Andreeva. Staff of this institute include highly experienced investigators and physicians. One of the most ambitious projects of the institute is development of prevention, diagnostic and treatment algorithm for patients with infertility of endocrine origin. For these purposes large prospective clinical trial (5000 patients) will be conducted with implementation of most modern genetic, laboratory and instrumental diagnostic methods. Results of this trial will allow diagnose, treat and prevent reproductive pathology in patients with endocrine diseases.

To investigate the impact of menopausal hormone therapy (MHT) on the expression of risk factors for cardiovascular events (CVEs) in patients with Shereshevsky-Turner syndrome (STS); to elaborate an algorithm for patient management using MHT.From 2010 to 2012, a total of 41 patients aged 14 to 35 years with STS were examined in the framework of a prospective observational study. 100 STS case histories in 2000 to 2009 were retrospectively analyzed. The indicators of the so-called cardiometabolic risk, such as body mass index (BMI), lipidogram readings, venous plasma glucose levels, and blood pressure, were estimated in relation to the type of MHT. In the prospective part of the investigation, an angioscan was used to estimate vessel characteristics (stiffness, wall tone, endothelial function (EF)), by using the examination data.90% of the patients with STS were found to have risk factors for CVEs: atherogenic dyslipidemia (85%; 51% in the general female population of the same age), diastolic hypertension (36%; no more than 5% that is not typical for age-matched healthy general female population). In addition to increased arterial wall stiffness (AWS), obvious EF disorder is typical for STS patients. MHT was accompanied by a dose-dependent (estradiol, at least 2 mg) reduction in diastolic blood pressure by an average of 13% over 24 months, an increase in high density lipoprotein levels by more than 10% over 24 months and also contributedto a decrease in AWS and an improvement in EF.By favorably affecting the EF of vessels and reducing the severity of atherogenic dyslipidemia, MHT potentially enables a reduction in CV risk in patients with STS.Цель исследования. Изучить влияние менопаузальной гормональной терапии (МГТ) на выраженность факторов риска развития сердечно-сосудистых осложнений (ССО) у больных с синдромом Шерешевского-Тернера (СШТ); выработать алгоритм ведения пациенток с использованием МГТ. Материалы и методы. С 2010 по 2012 г. в рамках проспективного наблюдательного исследования обследовали 41 пациентку с СШТ в возрасте от 14 до 35 лет. Проведен ретроспективный анализ 100 историй болезни пациенток с СШТ за период с 2000 по 2009 г. Оценивали показатели так называемого кардиометаболического риска в зависимости от типа МГТ: индекс массы тела (ИМТ), параметры липидограммы, уровень глюкозы в венозной плазме крови, артериальное давление. В проспективной части исследования по данным обследования с помощью аппарата Ангиоскан оценивали характеристики сосудов (ригидность, тонус стенки, функция эндотелия - ФЭ). Результаты. У 90% больных с СШТ выявлялись факторы риска развития ССО: атерогенная дислипидемия (85%; в общей популяции женщин того же возраста 51%), диастолическая артериальная гипертония (36%; нехарактерно для сопоставимых по возрасту здоровых женщин общей популяции, не более 5%). Помимо увеличения жесткости артериальной стенки (ЖАС) для больных с СШТ типично выраженное нарушение ФЭ. МГТ сопровождалась зависимым от дозы (по содержанию эстрадиола не менее 2 мг) снижением уровня диастолического артериального давления в среднем на 13% за 24 мес, повышением уровня липопротеидов высокой плотности более чем на 10% за 24 мес, а также способствовала уменьшению ЖАС и улучшению ФЭ. Заключение. МГТ, благоприятно влияя на ФЭ сосудов и снижая выраженность атерогенной дислипидемии, потенциально способствует уменьшению риска развития ССО у больных с СШТ.

Prions are proteins that under the same conditions can exist in two or more conformations, and at least one of the conformations has infectious properties. The prionization of a protein is typically accompanied by its functional inactivation due to sequestration of monomers by the prion aggregates. The most of prions has been identified in the yeast Saccharomyces cerevisiae. One of them is [SWI+], a prion isoform of the Swi1 protein, which is a component of the evolutionarily conserved chromatin remodeling complex SWI/SNF. Earlier, it was shown that the prionization of [SWI+] induces a nonsense suppression, which leads to weak growth of the [SWI+] strains containing mutant variants of the SUP35 gene and the nonsense allele ade1-14UGA on selective medium without adenine. This effect occurs because of [SWI+] induction that causes a decrease in the amount of the SUP45 mRNA. Strains carrying the SWI1 deletion exhibit significantly higher suppression of the ade1-14UGA nonsense mutation than the [SWI+] strains. In the present study, we identified genes whose expression is altered in the background of the SWI1 deletion using RNA sequencing. We found that the ade1-14UGA suppression in the swi1Δ strains is caused by an increase in the expression of this mutant allele of the ADE1 gene. At the same time, the SUP45 expression level in the swi1Δ strains does not significantly differ from the expression level of this gene in the [swi-] strains. Thus, we have shown that the phenotypic effects of Swi1 prionization and deletion are mediated by different molecular mechanisms. Based on these data, we have concluded that the prionization of proteins is not only unequal to their inactivation, but also can lead to the acquisition of novel phenotypic effects and functions.

Polycystic ovary syndrome (PCOS) is the most common chronic endocrine disease in women. The prevailing complaints at a young age are menstrual irregularities, infertility, and hyperandrogenism-related problems. However, metabolic disorder-induced complications have been in the foreground over years. The review gives the current ideas on a change of clinical manifestations in the natural course of PCOS, as well as the pathogenetically grounded prevention of complications in patients.Синдром поликистозных яичников (СПЯ) - самое распространенное хроническое эндокринное заболевание у женщин. В молодом возрасте преобладающими жалобами являются нарушения менструального цикла, бесплодие и проблемы, связанные с гиперандрогенией. Однако с годами на первый план выходят осложнения, обусловленные нарушением метаболизма. В обзоре представлены современные сведения о смене клинических проявлений в естественном течении СПЯ и патогенетически обоснованные мероприятия по профилактике осложнений у больных.

The content of myeloid stem CFU in bone marrow karyocytes from the tibial bone of C57Bl/6 mice was evaluated after a 30-day Bion-M1 pace flight/ground control experiment and subsequent 7-day recovery period. After the space flight, we observed a significant decrease in the number of erythroid progenitors in the bone marrow, including common myeloid precursor - granulocyte, erythrocyte, monocyte/macrophage, megakaryocyte CFU. After 7-day readaptation, CFU level in flight animals did not recover completely. In the ground control, the count of erythroid burst-forming units was higher than in vivarium animals. Comparison of the changes observed in fight and ground experiments demonstrated effects associated space flight factors and manifesting in suppression of the bone marrow erythropoiesis.

Multipotent mesenchymal stromal cells (MSCs) are characterized by immunomodulatory properties along with the high proliferative and paracrine activity, as well as multilineage potency. The effects of MSCs on the T cell adaptive immunity are of a special interest. Low O2 level (1-7 %) is known to be typical for the putative site of the MSC - T cell interactions. A comparative evaluation of the effects of adipose tissue derived MSC (ASCs) on the mitogen-stimulated T cells at the ambient (20 %) and tissue-related (5 %) O2 levels demonstrated reduced T cell activation by the HLA-DR expression, decreased pro-inflammatory and increased anti-inflammatory cytokine production in co-culture, inhibited T cell proliferation, with the effects increased at hypoxia. T cell interactions with ASCs resulted in the up-regulation of PDCD1, Foxp3, and TGFβ1 known to play an important role in the immune response suppression, and in the down-regulation of genes involved in the inflammatory reaction (IL2, IFNG). These changes were significantly increased under hypoxia. At the same time, neither ASCs nor the reduced O2 level had negative effects on the viability of T cells.

Adipose-tissue derived stromal cells (ASCs) are currently considered as a full value alternative source of bone marrow MSCs for prevention of graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation due to their immunosuppressive potential. Besides, ASCs are known to support ex vivo expansion of hematopoietic stem and progenitor cells (HSPCs). Ex vivo expansion enables to amplify significantly the number of HSPCs of different commitment. Mononuclear cells (MNCs) from cord blood (cb) contain HSPCs and are easily assessed. The rarity of those HSPCs is a serious limitation of its application in cell therapy. Here we expanded cbMNCs in stroma-dependent setting to generate heterocellular associates consisting of ASCs and undifferentiated and low committed hematopoietic cbHSPCs. A part of cbHSPCs in associates demonstrated a primitive phenotype confirmed by formation of "cobblestone areas". ASCs associated with cbHSPCs demonstrated up-regulation of immunosuppressive indoleamine 2,3-dioxygenase (IDO), leukemia inhibitory factor (LIF), cyclooxygenase-2 (PTGS2) genes. ASC-cbHSPCs as well as ASCs provoked the suppression of HLA-DR activation and apoptosis of mitogen-stimulated T cells. VEGF transcription and secretion were elevated providing stimulation of blood vessel formation in ovo. Thus, ASCs retain immunosuppressive and proangiogenic capacities evidencing "third party" potential along with the effective support of ex vivo expansion of cbHSPCs. Above functions expand the relevance of ASCs for needs of regenerative medicine.

Objective. To evaluate the ovarian reserve function in female patients with obesity in comparison with women without obesity. Materials and methods. This study evaluated 500 caucasian women, age 20-30 years, 250 with obesity (body mass index, BMI ≥30 kg/m2) and 250 without obesity (BMI

The interaction of adipose mesenchymal stromal cells (ASCs) and allogeneic peripheral blood mononuclear cells (PBMCs) is regulated either through direct or paracrine mechanisms. Here, we examined the impact of direct contact in reciprocal regulation of ASC-PBMC functions. Activated PBMCs in vitro induced ASC immunomodulatory activity, while direct and paracrine intercellular interactions regulated PBMCs themselves: the functional state of the organelles was altered, and activation decreased. Direct contact with immune cells affected the activity of ASC intracellular compartments, in particular, reactive oxygen species (ROS) production, and decreased the growth rate. Some ASC properties, including motility, intercellular adhesion molecule-1 (ICAM-1), and major histocompatibility complex class I and II antigens (HLA-ABC and HLA-DR, respectively) expression, did not depend on contact with PBMCs and were only regulated by paracrine means. Direct ASC and PBMC contact favoured an angiogenesis-supportive microenvironment, possibly due to the greater production of VEGF by ASCs; this microenvironment also contained a higher leukemia inhibitory factor (LIF) level. Thus, a change in the functional activity of ASCs and PBMCs upon interaction promoted the formation of an immunosuppressive, anti-inflammatory, and proangiogenic microenvironment. This environment could help resolve inflammation and further restore damaged tissue. SIGNIFICANCE OF THE STUDY: Numerous studies have demonstrated the beneficial effects of transplanted mesenchymal stromal cells, particularly ASCs, for the treatment of a number of autoimmune diseases as well as various tissue injuries. To improve the efficiency of these methods, it is necessary to understand the principal events that occur when ASCs are introduced, primarily the molecular mechanisms of interaction between ASCs and the recipient immune system. We demonstrated that an anti-inflammatory, immunosuppressive, and angiostimulatory shift in the paracrine profile upon the interaction of activated PBMCs and ASCs changes the functional activity of both cell types, a phenomenon that is potentiated by direct cell-cell contact.

Pregnancy in women with type 1 or 2 diabetes mellitus (DM) is associated with an increased risk for complications in both the mother and her fetus. The impact of these complications on modifiable risk factors may substantially improve pregnancy outcomes and reduce malformation rates in children. This is a goal of pregravid preparation (PGP) in this category of patients. The review gives the main points of PGP in patients with types 1 and DM and shows the results of main studies providing evidence for PGP in DM. In particular, by the moment of conception, DM patients should achieve a glycosylated hemoglobin (HbA1c) goal of6% no later than 4 weeks before conception and during the first trimester of pregnancy, take folic acid in a high dose (at least 4000 µg, or 4 mg, daily), quit tobacco smoking and alcohol use, receive potentially teratogenic drugs, and, if need be, lose weight (the target body mass index of27 kg/m2).Беременность у женщин, больных сахарным диабетом (СД) 1-го типа или 2-го типа, ассоциирована с повышенным риском развития осложнений как у матери, так и плода. Воздействие на модифицируемые факторы риска таких осложнений позволяет существенно улучшить исходы беременности, снизить частоту формирования пороков развития у детей. Это является целью прегравидарной подготовки (ПГП) больных данной категории. В обзоре представлены основные положения ПГП у больных СД 1-го и 2-го типов, отражены результаты основных исследований, обосновывающих проведение ПГП при СД. В частности, к моменту зачатия больным СД рекомендуется достижение целевого уровня гликированного гемоглобина HbA1c6% не позднее чем за 4 нед до зачатия и на протяжении I триместра беременности, а также прием фолиевой кислоты в высокой дозе (не менее 4000 мкг, или 4 мг, в сутки); отказ от табакокурения, употребления алкоголя, приема потенциально тератогенных препаратов; при необходимости рекомендуется снижение массы тела (целевой индекс массы тела27 кг/м2).

We studied the effect of endothelial cells on in vitro migration and differentiation potential of multipotent mesenchymal stromal cells. Down-regulation of stemness genes OCT4, SOX2, and chondrogenic differentiation regulator SOX9 gene and upregulation of osteogenesis master-gene RUNX2 in mesenchymal stromal cells were observed in the presence of intact and TNFα-activated endothelial cells, which indicated an increase in commitment of mesenchymal stromal cells.The medium conditioned by endothelial cells stimulated migration activity of mesenchymal stromal cells; migration rate increased significantly in conditioned medium from activated cells in comparison with medium from non-activated cells. It was concluded that the interaction with endothelial cells modulated functional activity of mesenchymal stromal cells; moreover, activated endothelial cells produced more pronounced effects on differentiation potential and migration activity of mesenchymal stromal cells both in direct contact and through paracrine regulation.

The dynamics of the expression of genes encoding adhesion molecules, molecules of the connective tissue matrix, and its remodeling enzymes was studied in multipotent mesenchymal stromal cells (MSCs) from human adipose tissue after interaction with cord blood hematopoietic progenitors (HSPCs). An upregulation of ICAM1 and VCAM1, directly proportional to the coculture time (24–72 h), was found. After 72 h of culturing, a downregulation of the genes encoding the majority of matrix molecules (SPP1; COL6A2,7A1; MMP1,3; TIMP1,3; and HAS1) and cell-matrix adhesion molecules (ITGs) was revealed. The detected changes may ensure the realization of the stromal MSC function due to improvement of adhesion and transmigration of HSPCs into the subcellular space.

The impact of culture conditions and interaction with activated peripheral blood mononuclear cells on the interleukin (IL) gene expression profile and proinflammatory IL-6 and IL-8 production by adipose-derived stromal cells (ASCs) was investigated. A microarray analysis revealed a wide range of IL genes either under standard (20%) or hypoxic (5%) O2 concentrations, some highly up-regulated at hypoxia. IL-6 and IL-8 production was inversely dependent on cell culture density. In early (first–third) passages, IL-6 and IL-8 concentration was higher at 20% O2 and in late (8th-12th) passages under 5% O2. Interaction between ASCs and mononuclear cells in indirect setting was accompanied with a significant decrease of IL-6 and did not result in the elevation of IL-8 concentration. Thereby, the production of proinflammatory interleukins (IL-6 and IL-8) may be affected by the ASC intrinsic features (density in culture, and duration of expansion), as well as by microenvironmental factors, such as hypoxia and the presence of blood-borne cells. These data are important for elucidating ASC paracrine activity regulation in vitro. They would also be on demand for optimisation of the cell therapy protocols, based on the application of ASC biologically active substances. Copyright © 2015 John Wiley & Sons, Ltd. SIGNIFICANCE PARAGRAPH Ex vivo expansion is widely used for increasing the number of adipose-derived stromal cells (ASCs) and improving of their quality. The present study was designed to elucidate the particular factors influencing the interleukin production in ASCs. The presented data specified the parameters (i.e. cell density, duration of cultivation, hypoxia, etc.) that should be taken in mind when ASCs are intended to be used in protocols implying their paracrine activity. These data would be of considerable interest for researchers and clinicians working in the biomedical science.

The studied the expression of intercellular adhesion molecules and transcription of the corresponding genes in intact and activated endothelial cells both in monoculture and during interaction with mesenchymal stromal cells. It was found that the levels of integrin-α1 and VE-cadherin mRNA increased during co-culturing. TNFα-induced activation of endothelial cells enhanced expression of integrin-α1 both at the mRNA and protein synthesis stages and had no effect on the level of VE-cadherin. Direct contact with mesenchymal stromal cells did not eliminate the effect of endothelial cell activation, but expression of integrin-α1 and VE-cadherin in activated endothelial cells tended to decrease.

Yuri D Ivanov,1 Natalia S Bukharina,1 Tatyana O Pleshakova,1 Pavel A Frantsuzov,1 Elena Yu Andreeva,1 Anna L Kaysheva,1,2 Victor G Zgoda,1 Alexander A Izotov,1 Tatyana I Pavlova,1 Vadim S Ziborov,1 Sergey P Radko,1 Sergei A Moshkovskii,1 Alexander I Archakov1 1Department of Personalized Medicine, Orekhovich Institute of Biomedical Chemistry of the Russian Academy of Medical Sciences, Moscow, Russia; 2PostgenTech Ltd., Moscow, Russia Abstract: Atomic force microscopy (AFM) was applied to carry out direct and label-free detection of gp120 human immunodeficiency virus type 1 envelope glycoprotein as a target protein. This approach was based on the AFM fishing of gp120 from the analyte solution using anti-gp120 aptamers immobilized on the AFM chip to count gp120/aptamer complexes that were formed on the chip surface. The comparison of image contrasts of fished gp120 against the background of immobilized aptamers and anti-gp120 antibodies on the AFM images was conducted. It was shown that an image contrast of the protein/aptamer complexes was two-fold higher than the contrast of the protein/antibody complexes. Mass spectrometry identification provided an additional confirmation of the target protein presence on the AFM chips after biospecific fishing to avoid any artifacts. Keywords: gp120 HIV-1 envelope glycoprotein, aptamer, atomic force microscopy, mass spectrometry

We studied the kinetics of accumulation and elimination of Photosens and accumulation of protoporphyrin IX in macrophages, endothelial cells, and mesenchymal stromal cells of the human adipose tissue in vitro. In all studied cells, the dynamics of Photosens accumulation was described by a multiphase curve and the maximum accumulation of the dye was observed during the second exponential phase. Elimination of Photosens did not depend on the cell function. Accumulation of protoporphyrin IX differed considerably in different cells: it was maximum in mesenchymal stromal cells was practically not detected in endothelial cells. Accumulation of the dye by macrophages depended on individual donor characteristics.

During last two decades multipotent mesenchymal stromal (stem) cells (MMSCs) were not only identified and isolated from many tissues, but their immunopriviledge and immunosupressive potential along with high proliferative activity and multilineage differentiation were demonstrated. At the same time there is an increasing evidence of the MMSC plasticity due to a wide range of microenvironmental factors: extracellular matrix, cell-to-cell interactions, oxygen content, etc. In this paper, a comparative study of direct cell-to-cell and paracrine effects of MMSCs on human PHA-activated peripheral blood mononuclear cells (MNCs) in the standard (20%) and reduced to 5% O2 concentration in the culture medium was conducted. It is shown that after coculture with MMSCs the proliferative activity of PHA-MNCs, the share of HLA-DR(+) -T cells and IL-6, -8 and TNF-alpha concentrations were reduced, but IL-10 and IFN-gamma were increased in the medium. Potentiating effect on the MMSC immunomodulating properties was noted at low oxygen, which is of great importance for increasing the efficiency of immunosuppression.

The present study was undertaken in order to extend of our earlier work, focusing on the analysis of roles of cell-to-cell communications in the regulation of the subendothelial cell function. In present study, we have found that the expression of connexin43 (Cx43) is dramatically reduced in human atherosclerotic lesions, compared with undiseased intima. In atherosclerotic lesions, the number of so-called 'connexin plaques' was found to be lower in lipid-laden cells than in cells which were free from lipid inclusions. In primary cell culture, subendothelial intimal cells tended to create multicellular structures in the form of clusters. Cluster creation was accompanied by the formation of gap junctions between cells; the degree of gap junctional communication correlated with the density of cells in culture. We found that atherosclerosis-related processes such as DNA synthesis, protein synthesis and accumulation of intracellular cholesterol correlated with the degree of cell-to-cell communication. The relation of DNA and protein synthesis with cell-to-cell communication could be described as "bell-shaped". We further incubated cells, cultured from undiseased subendothelial intima, with various forms of modified LDL causing intracellular cholesterol accumulation. After the incubation of intimal cells with modified LDL, intercellular communication has "dropped" considerably. The findings indicate that intracellular lipid accumulation might be a reason for a decrease of the number of gap junctions. The findings also suggest that the disintegration of cellular network is associated with foam cell formation, the process known as a key event of atherogenesis.

The effect of short-term stress on the expression of 84 Wnt-related genes in mesenchymal stromal cells (MSCs) was analyzed. In MSCs permanently expanded at 5% O2, Dkk1, RHOA, CSNK1A1, CSNK2A1, GSK3β, and PORCN genes were most highly expressed. FZD1, FZD3, SFRP1, and SFRP4 genes were up-regulated after short-term hypoxic stress (0.1% O2), whereas the expression of LEF-1 and RUVBL1 genes was significantly inhibited (down-regulated). The data suggest that Wnt signal transduction was suppressed under hypoxic stress, whereas the noncanonical Wnt signaling prevailed under the "physiological hypoxia" (5% O2).

The effects of silicon dioxide-based nanoparticles on the viability and proliferative activity of human peripheral blood cultured lymphocytes were studied. All nanoparticles in a concentration of 100 μg/ml produced a significant cytotoxic effect, its intensity depending on particles' structure: SiO2 nanoparticles were least toxic, while Ce3(+)-intercaled montmorillonite nanoparticles were most toxic. The cells died mainly by apoptosis and postapoptotic necrosis. Incubation with nanoparticles in a concentration of 100 μg/ml for 72 h caused death of all phytohemagglutinin-activated lymphocytes, while in concentrations of 1 and 10 μg/ml the nanoparticles had no effect of proliferative activity of cells. The results suggest that the effects of nanoparticles on cells are determined by the nanoparticle concentration and size, as well as by their structure.

Intercellular communication via gap junctions plays an important role in the regulation and homeostasis. The presence of gap junctions and the efficiency of their function directly correlates with the degree of cell differentiation in a tissue. In the present study, gap junctional communication has been investigated in a primary culture of highly differentiated mesenchymal cells (subendothelial smooth muscle cells isolated from grossly normal and atherosclerotic areas of human aorta) and in poorly differentiated cells of mesenchymal origin (adult human skin fibroblasts as well as skin fibroblasts and aortic smooth muscle cells, derived from human fetus). The fluorescent dye transfer technique was used in this study. In cell cultures isolated from grossly normal and atherosclerotic aorta, the number of cells coupled via gap junctions increased with cell density and reached a plateau at a cell density of 50 to 70 cells/mm2. In cultures of normal aortic cells the number of coupled cells was 23.0 +/- 4.1 per injected cell and was significantly higher than in cultures of atherosclerotic cells (16.4 +/- 2.1, p0.05). Gap junctional communication between cells loaded with lipid inclusions was 2.4-fold lower than between cells free of excess intracellular lipids. In cultures of human skin fibroblasts the rate of intercellular communication was lower than in cultures of normal aortic cells and was comparable to that in cultures of atherosclerotic cells. There was practically no cell-to-cell communication in cultures of fetal cells. It is hypothesized that the reduced gap junctional communication in atherosclerotic human aorta is associated with the alterations in the degree of smooth muscle cell differentiation and impairs the function of the intima in atherosclerosis.

Scavenger receptor was soughtin situ in human aortic smooth-muscle cells and in a primary culture of intact human aortic intima using antibodies to scavenger receptor. For identification of smooth-muscle cells, double staining making use of antibodies to murine α-actin was used. The presence of scavenger receptor in smooth-muscle cells of the intima and media of human aorta was demonstrated on aortic slices. In cultured smooth-muscle cells from normal human aortic intima scavenger receptor was distributed over the entire surface of the cell membrane, forming clusters in some places. These results suggest that human aortic smooth-muscle cells express scavenger receptor.

Cellular composition of aortas from 5- to 12-week and 18- to 28-week-old human embryos were investigated using immunocytochemistry, scanning and transmission electron microscopy. The aorta of the 5- to 12-week-old embryos consisted of three sublayers differing in cellular composition. The inner sublayer adjacent to the endothelium contained round and ovoid cells with synthetic phenotype. In the intermediate sublayer, spindle-like cells ultrastructurally similar to smooth muscle cells were found. Cells of the outer sublayer resembled fibroblasts or poorly differentiated mesenchymal cells. There were not definite morphological borders between sublayers. In the 18- to 28-week-old embryo aorta the intima was separated from media by internal elastic lamina. Intimal and innermost medial cells had predominately stellate shape and synthetic phenotype. The outer part of media contained spindle-like cells that had well developed contractile structures. Both the 5- to 12-week-old and the 18- to 28-week-old embryo aortic cells were positively stained for alpha-actin and myosin and negatively stained for macrophage antigens. Thus, the majority of embryo aortic cells appeared smooth muscle cells, however there was a regional difference in shape and synthetic state of these cells.

We demonstrated the possibility of enrichment of umbilical cord blood mononuclear fraction with early non-differentiated precursors under conditions of co-culturing with mesenchymal stromal cells from the human adipose tissue. It was established that umbilical cord blood mononuclear cells adhered to mesenchymal stromal cell feeder and then proliferate and differentiate into hemopoietic cells. In comparison with the initial umbilical cord blood mononuclear fraction, the cell population obtained after 7-day expansion contained 2-fold more CFU and 33.4 ± 9.5 and 24.2 ± 11.2% CD34(+) and CD133(+) cells, respectively, which corresponds to enrichment of precursor cell population by 148 ± 60. The proposed scheme of expansion of hemopoietic cells from umbilical cord blood is economically expedient and can widely used in biology and medicine.

The concentration of O(2) during coculturing practically did not affect the subpopulation composition of T lymphocytes (CD3(+)/CD4(+), CD3(+)/CD8(+), CD3(+)/CD16(+)/CD56(+) T cells) under conditions of PHA-induced activation. Coculturing with mesenchymal stromal cells (MSC) led to a significant decrease in the ratio of lymphocytes carrying activation markers (CD3(+)/CD25(+) and CD3(+)/HLA-DR(+)) and increase in the number of CD3(+)/CD16(+)/CD56(+) T cells. The percent of activated HLA-DR(+) T cells in a heterotypic culture with MSC at 5% O(2) was much lower than that observed under normal conditions of culturing (20% O(2)). Our results suggest that antigen presentation by T lymphocytes due to HLA-DR expression can be reduced in the target tissues at low concentration of O(2), while the interaction between allogeneic MSC probably contributes to more significant inhibition of the immune response.

We studied the effect of low-fluence photodynamic treatment with Photosence preparation on functional properties of macrophages and endothelium in vitro. It was shown that low-intensity photodynamic treatment did not affect viability of these cells. Exposure (0.25 J/cm(2)) of endothelial cells loaded with Photosence did not change the expression of adhesion molecules, but reduced adhesion of peripheral blood mononuclears to these cells. The same low-intensity exposure inhibited phagocytic activity of macrophages and reduced activity of matrix metalloproteinase-9 produced by them.

Experiments on cultured human umbilical vein endotheliocytes showed that accumulation of photosensitive dye (aluminum phthalocyanin; PHOTOSENSE) in cells and laser exposure alone were inessential for the viability of endothelial cells. Contrary to this, exposure of the cells which have accumulated aluminum phthalocyanin (an average of 111.1 ng/mg protein) to low-intensity laser (λ=675 nm) led to a dose-dependent reduction of endotheliocyte viability. Hence, cultured endothelial cells can be used for screening of various photosensitizers and preliminary optimization of photodynamic therapy.

Mesenchymal stromal precursor cells from human lipoaspirate (lMSC) cultured at 5% O(2) formed 50% less mineralized matrix in response to osteogenic induction than cells cultured under standard conditions (20% O(2)). After lMSC percultured at 5% O(2) were transferred to normoxic conditions (20% O(2)), they produced the same amount of matrix as lMSC permanently cultured at 20% O(2). Hence, hypoxia inhibited the commitment of lMSC under the effect of osteogenic stimuli, which can be important in reparative and regenerative medicine.