Atypical reactive center Kunitz-type inhibitor from the sea anemone <i>Heteractis crispa</i>

The primary structure of a new Kunitz-type protease inhibitor InhVJ from the sea anemone Heteractis crispa (Radianthus macrodactylus) was determined by protein sequencing and cDNA cloning. InhVJ amino acid sequence was shown to share high sequence identity (up to 98%) with the other known Kunitz-type sea anemones sequences. It was determined that the P1 Thr at the reactive site resulted in a decrease of the Ki of InhVJ to trypsin and a-chymotrypsin (7.38 × 10-8 M and 9.93 × 10-7 M, respectively). By structure modeling the functional importance of amino acids at the reactive site as well as at the weak contact site were determined. The significant role of Glu45 for the orientation and stabilization of the InhVJ-trypsin complex was elucidated. We can suggest that there has been an adaptive evolution of the P1 residue at the inhibitor reactive site providing specialization or functional diversification of the paralogs. The appearance of a key so-called P1 Thr residue instead of Lys might lead to refinement of inhibitor specificity in the direction of subfamilies of serine proteases. The absence of Kv channel and TRPV1-receptor modulation activity was confirmed by electrophysiological screening tests

Features of the natural course of subclinical hypothyroidism in young athletes

Objective: to assess the natural course of subclinical hypothyroidism in young athletes.Methods: In the prospective single-center uncontrolled study, data from 3,062 outpatient records of young athletes (members of the Russian national team) of both sexes (middle age — 15 [14; 16] years) and underwent medical examination in the period from January 2021 to September 2022 were studied. All athletes were divided into 2 groups according to the presence of subclinical hypothyroidism (an increase in the level of thyroid-stimulating hormone from 5 to 10 mUn/l with a normal level of T4 free). During a dynamic follow-up (1 year), athletes with subclinical hypothyroidism underwent a repeated study of the concentration of thyroid-stimulating hormone, free thyroxine and antibodies to thyroperoxidase.Results: Signs of subclinical hyperthyroidism were found in 58 young athletes (30 boys (51.7 %) and 28 (48.3 %) girls). During dynamic observation with continued habitual physical activity, spontaneous normalization of the level of thyroid-stimulating hormone was observed in 74 % of young athletes. At the same time, normalization of thyroid-stimulating hormone in girls was observed less often compared to boys (p = 0,272). In no case did clinically pronounced hypothyroidism develop.Conclusion: The majority of young male and female athletes with subclinical hypothyroidism have spontaneous normalization of hormonal profile against the background of persistent physical and psycho-emotional stress. The data obtained make it possible, subject to the possibility of dynamic observation, to recommend doctors working with young elite athletes not to prescribe hormonal replacement therapy and not to modify the usual lifestyle

COMPARATIVE PHARMACOKINETICS AND EFFECT ON THE HEMODYNAMICS OF ORIGINAL AND GENERIC NEBIVOLOL IN HEALTHY VOLUNTEERS

Beta-blockers are an important part of modern pharmacotherapy in cardiology. The introduction of generics into clinical practice requires clear evidence of bioequivalence to the original drug.Aim. To study the pharmacokinetics and effect on hemodynamic parameters of the original and a generic nebivolol in healthy volunteers in the fasting state. Material and methods. 18 healthy volunteers were included into the randomized open study on cross-balanced design. They received single dose (5 mg) of two compared preparations of nebivolol under fasting condition. The concentration of unchanged nebivolol in blood plasma was determined by gas chromatography-tandem mass spectrometry. Calculation of pharmacokinetic parameters and assessment of the hemodynamic were performed.Results. The concentrations of nebivolol after the original and generic drugs intake did not differ significantly in any time point (AUC0-∞ 41.09±46.82 vs 47.16±66.58 ng•hr/mL and T1/2 30.84±10.78 vs 29.59±12.08 hours, respectively). Blood pressure reduction was slightly more pronounced when taking generic nebivolol, while the reduction in heart rate at 2 and 4 hours – after original nebivolol intake.Conclusion. A comparative pharmacokinetic study of the genetic nebivolol showed its bioequivalence to the original drug. The effect on hemodynamic parameters with single dose (5 mg) of generic and original nebivolol in healthy volunteers was comparable

Heterogeneity symptoms of urgency in patients with benign prostatic hyperplasia

Background One of the relevant tasks of modern urology is the correct understanding of symptoms of the lower urinary tract (LUTS). The social aspect of overactive bladder syndrome (OAB) and the lack of objective ways for non-invasive diagnostics make it necessary to search for new study methods. There is increasing evidence that urination diary can be a clinically powerful tool for assessing bladder sensation, especially in cases of obtaining information not only about the volume of micturition, but also about the degree of urgency with each individual urination. To date, several tools have been developed to assess the severity of OAB, including the international scale of Overactive Bladder Symptom Score (OABSS), proposed by Y. Homma and J. G. Blaivas in 2006–2007.Objective Тo identify the most significant signs of urgency in men with benign prostatic hyperplasia and overactive bladder with and without detrusor hyperactivity (DH).Material and Methods To assess the OAB, patients completed the OABSS, visual analogue scale (VAS), and also kept urination diaries. After the results were obtained, the severity of symptoms was evaluated, considering the data of the urination diary. All patients underwent a complex urodynamic study (CUDI), the results of which were compared with subjective criteria for the severity of urgency and the most significant clinical signs of detrusor hyperactivity.Results Against the background of the analysis of the data obtained, it was possible to classify nocturia by type in 93 patients. One patient (1.07%) had diurnal polyuria. Nocturnal polyuria was in 39 (41.9%) people. Decreased bladder capacity was found in 43 (46.2%) men. Ten (10.7%) patients had various sleep disorders. The IPSS was 24 ± 0.91, the mean score was 14 ± 0.7 points for irritative symptoms according to IPSS (questions 2, 4 and 7) and 13 ± 0.8 points for obstructive symptoms. From the data reported by CUDI, spontaneous detrusor activity was detected in 49 (43.7%) patients, in 63 (56.2%) it was not registered. When analyzing the VAS, it was found that the urgency in patients with BPH and DH, reflecting the initiation of the urge to urinate, is 31 ± 0.6 mm (p &lt; 0.05). On average the indices of the difficulty of holding the urge are higher by 2.9 ± 0.2 points (p &lt; 0.05) in those patients who have DH. When answering the question "How often cannot you retain urine with a strong sudden urge?", the indicators were recorded higher by 3.1 ± 0.3 points (p &lt; 0.05), in patients with detrusor hyperactivity.Conclusions In patients with BPH and the presence of urgency, the frequency of the urge to urinate is 32% higher, and the difficulty of maintaining the urge is 46% more pronounced, compared with the examined men who do not have detrusive hyperactivity

The role of active herpesvirus infection in the formation of atopic dermatitis and psoriasis

The results of previous studies suggest the involvement of herpes viruses in the development of atopic dermatitis and psoriasis, but there is no convincing evidence. Aim of the study was to evaluate the role of active herpesvirus infection in exacerbation of atopic dermatitis and psoriasis. Material and methods. The analysis of the incidence of infectious mononucleosis, genital herpes, cytomegalovirus infection, skin and subcutaneous tissue diseases, atopic dermatitis, psoriasis in Russia in 2000–2020 was carried out. 92 blood donors and 97 patients with skin and subcutaneous tissue diseases (44 with atopic dermatitis and 53 with psoriasis) were examined for the presence of immunoglobulins M and G to herpes simplex viruses (HSV1,2), Epstein-Barr (EBV), cytomegalovirus (CMV), human herpes type 6 (HНV6). Results and discussion. A significant strong direct correlation was revealed between the incidence of genital herpes and diseases of the skin and subcutaneous tissue (p = 0.85), atopic dermatitis (p = 0.85); infectious mononucleosis and psoriasis (p = 0.85). The frequency of detection of IgM to HSV1,2, in total, IgG EA and IgM VCA EBV in the group of patients is significantly higher than in donors (p &lt; 0.05). In patients with atopic dermatitis, IgM to HSV1 were detected significantly more often than in individuals with psoriasis, and markers of active EBV infection were significantly less common. The presence of IgM HSV-1 statistically significantly increases the incidence of atopic dermatitis (relative risk (RR) = 2.3, 95 % confidence interval (95 % CI) 1.6–3.3)), IgM VCA and IgG EA EBV – the incidence of psoriasis (RR = 2.3, 95 % CI 1.5–3.3). Conclusions. It has been shown for the first time that active HSV1,2 infection is a trigger factor for the development of atopic dermatitis, EBV infection is psoriasis

Overview of Hantavirus Infections in the World, the Epidemiological Situation on Hemorrhagic Fever with Renal Syndrome in the Russian Federation in 2021, and Forecast for 2022

The paper presents a description of the epidemiological situation on Hantavirus infection incidence in the countries around the world. Comparative analysis of the intensity and dynamics of the epidemiological process of hemorrhagic fever with renal syndrome (HFRS) in the Russian Federation by Federal Districts in 2021 has been carried out and forecast of the HFRS incidence for 2022 prepared. The study has revealed that tense situation on incidence of hantavirus diseases was observed in the world in 2021. On the territory of the Russian Federation, there was a decrease in the HFRS incidence in 2021 (by 1.7 times compared to 2020). However, the results of epidemiological analysis of the HFRS incidence, epizootiological data and laboratory studies in certain Federal Districts of the Russian Federation indicate that the epidemiological situation on HFRS remains tense. High risk of HFRS infection is predicted in a number of regions of the country due to the favorable natural and climatic conditions in the winter period of 2021–2022 with a heavy snow cover, which contributed to the under-snow reproduction of small mammals, the main carriers of HFRS. The presence of infected rodents testifies to a high likelihood of complication of the epidemiological situation in areas of increased epidemic risk of HFRS

Algorithm for determining the authenticity of biomedical cell preparations containing mesenchymal stem cells

The use of mesenchymal stem cells (MSCs), which have a pronounced immunomodulatory activity, is a promising direction in the development of biomedical cell preparations (BMCPs). In oncohematology, the use of BMCPs containing MSCs is aimed at supporting hematopoiesis during cotransplantation with hematopoietic stem cells (HSCs) and suppressing immune conflicts during allogeneic unrelated transplantation and severe autoimmune processes. An obligatory stage of registration of BMCPs is confirmation of the identity of the MSC cell line (CL), which includes the establishment of morphological characteristics, evaluation of the expression of specific markers and proteins, and confirmation of the genetic stability of CL during cultivation. Determination of markers of genetic stability is possible using various methods, however, according to the recommendations of the American National Standardization Institute, the standard is the analysis of short tandem repeats (STR analysis). The purpose of the study is to develop an algorithm for determining the authenticity of BMCPs containing MSCs, including STR analysis. Material and methods. Identification of MSC cells in BMCP was performed according to the criteria of the International Society for Cell Therapy. Viable cells were counted in a Goryaev chamber. Immunophenotypic characteristics of MSCs were determined by flow cytometry. The level of production of specific proteins was assessed using enzyme immunoassay. Genetic stability markers were identified by STR analysis. Results and discussion. The methods were tested in triplicate for ten BMCP samples to confirm the reproducibility and reliability of the results. The developed algorithm for determining the authenticity of BMCP has a high accuracy, as it includes the STR analysis technique, which makes it possible to identify 19 polymorphic STR markers located on different alleles. Using the method will allow BMCP manufacturers to go through the procedure of state registration of drugs

Влияние поведенческого фактора водителя на образование транспортного затора

Driving in a traffic flow implies involvement in difficult traffic situations that adversely affects response time of a driver, which in turn is considered when estimating stopping distance of a vehicle and determines road safety. This relationship shows the effect of driver behaviour in traffic flow on the road traffic situation. The objective of the study was to study behavioural factors that influence driver’s decisions. The study used methods of driver behaviour modelling, mathematical modelling, experimental studies of the mental and psychological functions of drivers. Modelling the driver’s behaviour, considering various combinations of many behavioural and other factors, leads to a large number of options for mathematical description of driver behaviour, which makes it difficult to use this approach to describe behaviour of drivers under the conditions of a real street-road network. The research has analysed several works devoted to the study of control action of drivers, using unknown coefficients, describing a model of movement of vehicles considering accuracy of their control. Driving through an unregulated intersection is considered as the most complex and informative version of driver’s behaviour. It is found that when modelling a traffic flow, it is necessary to take into account the degree of resoluteness of drivers (through determination of a coefficient of resoluteness which is a random variable that takes into account the probability distribution of the coefficient’s value in conjunction with the probability distribution of the function of traffic flow intensity). The distribution of the coefficient of resoluteness of drivers, obtained from experimental data, was subject to analysis. It is determined that the driving style affects formation of traffic congestion. The assessment of the driving style is made through conditional classification of driver behaviour on the road, namely marked by manifestation of aggression and timidity. When studying the behaviour of timid and aggressive drivers, several pairs of trajectories and the dynamics of the corresponding traffic flow density, were considered and calculated based on Edie’s model. It has been confirmed that traffic congestion has the greatest negative effect on choleric drivers and sanguine drivers. Besides, there is a relationship between the response time of a driver and the change in his functional condition. It is concluded that to improve road safety thanks to a more accurate assessment of possible risks of formation of congestion situations, it is necessary to consider behavioural characteristics and temperaments of the drivers.Движение вавтомобильном потоке подразумевает вовлечение в сложные дорожные ситуации, отрицательно влияющие на время реакции водителя, которая в свою очередь учитывается при определении тормозного пути транспортного средства и определяет безопасность дорожного движения. Эта взаимосвязь показывает влияние поведения водителей в транспортном потоке на дорожнотранспортную ситуацию. Целью исследования было изучение поведенческих факторов, влияющих на принятие водителями решений. В ходе исследования использованы методы моделирования поведения водителей, математического моделирования, экспериментальные исследования психических и психологических функций водителей. Моделирование поведения водителя с учётом различного сочетания множества поведенческих и иных факторов приводит к большому количеству вариантов математического описания такого поведения, что затрудняет применение данного подхода при описании поведения водителей в условиях реальной улично-дорожной сети. Проанализированы работы, посвящённые изучению управляющего воздействия водителя с использованием неизвестных коэффициентов, описывающих модель движения транспортных средств с учётом точности управления им. Рассмотрен наиболее сложный и показательный вариант поведения водителя при проезде нерегулируемого пересечения. Установлено, что при моделировании транспортного потока необходимо учитывать степень решительности водителей (через определение коэффициента решительности– случайную величину с учётом распределения вероятности его значения в совокупности с распределением вероятностей функции интенсивности транспортного потока). Проанализировано распределение коэффициента решительности водителей, полученное по экспериментальным данным. Определено, что на формирование транспортного затора оказывает влияние стиль вождения, для оценки которого используют условную классификацию поведения водителей на дороге, аименно проявление агрессии и робости. При изучении поведения робких и агрессивных водителей рассмотрено несколько пар траекторий движения и динамика соответствующей плотности транспортного потока, которые рассчитаны на основе модели Edie’s. Подтверждено, что наибольшее отрицательное влияние транспортные заторы оказывают на водителей-холериков ина водителей-сангвиников. Кроме того, прослеживается взаимосвязь между временем реакции водителя и изменением его функционального состояния. Сделан вывод, что в целях повышения безопасности дорожного движения за счёт более точной оценки возможных рисков возникновения заторовых ситуаций необходимо учитывать поведенческие характеристики водителей и их темпераменты

Experience of the successful treatment with canakinumab of a patient with NLPC4-associated autoinflammatory syndrome with enterocolitis

The article shows the observation of rare NLPC4-associated autoinflammatory syndrome with enterocolitis and familial cold urticaria. Diagnosis is confirmed molecularly-genetically: previously not described mutation c.928C&gt;T in the heterozygous state in NLRC4 gene is discovered by a method of the new generation sequencing. The use of a monoclonal antibody to the interleukin 1 canakinumab provided complete relief of fever and skin and intestinal symptoms in just 1 week of treatment. Later the signs of inflammation have disappeared completely; the patient’s quality of life improved and life-threatening complications were prevented. The above example demonstrates the high clinical efficacy of canakinumab in the patient with NLRC4-associated autoinflammatory syndrome and suggests promising therapeutic use of interleukin 1 blockers in such patients. There were no adverse events during canakinumab therapy

Review of Hantavirus Infections in the World, Epidemiological Situation on Hemorrhagic Fever with Renal Syndrome in the Russian Federation in 2020 and a Forecast for 2021

The review used the data from operational monitoring carried out by the Reference Center for Monitoring over HFRS – “Kazan Research Institute of Epidemiology and Microbiology of the Rospotrebnadzor”, based on official data provided by the Rospotrebnadzor institutions in the constituent entities of the Russian Federation. Statistical processing was conducted using conventional methods of variation statistics applying the Excel program. Over the past decades, hantavirus diseases have become very relevant and spread throughout the world. In the territory of the Russian Federation, natural foci of HFRS are located in the European part of the country, Western Siberia and Far East. The most epidemically active foci are situated in the European part of Russia. Over the past decade, the intensive incidence rate of HFRS in the Russian Federation stayed within the range of 3.0–9.5 per 100 thousand of the population, the long-term average annual indicator – 5.2 per 100 thousand of the population. In 2020, 3845 cases of HFRS were registered (2.62 per 100,000 of the population). There was a decrease in the incidence of HFRS by 3.6 times, compared with the indicators of 2019. A factor that may have influenced the decrease in the incidence of HFRS was the depression of the epizootic process among small mammals, the main carriers of HFRS pathogens, due to natural and climatic factors. The nature of the distribution of HFRS incidence across the territory of the Russian Federation in 2020 was heterogeneous. Statistical processing of the data made it possible to identify 5 groups of territories that differ in the level of HFRS incidence. Almost all constituent entities of the Volga Federal District and the Kostroma Region belonging to the Central Federal District were classified as groups of territories with high and very high incidence rates. In 2021, the deterioration of the epidemiological situation is predicted in the summer-autumn period of the year in the Volga Federal District and four entities of the Central Federal District