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Background and Aims: DiGeorge syndrome (DGS) is a genetic disorder manifesting in polymorphic symptoms related to developmental abnormalities of various organs including thymus. DGS is caused by microdeletions in the 22q11.2 region between several low copy repeats (LCR) occurring in approximately 1 in 4000 live births. Diagnosis of DGS relies on phenotypic examination, qPCR, ultrasound, FISH, MLPA and NGS which can be relatively inaccurate, time-consuming, and costly., Materials and Methods: A novel multiplex droplet digital PCR (ddPCR) assay was designed, optimized and validated for detection and mapping 22q11.2 microdeletions by simultaneous amplification of three targets - TUPLE1, ZNF74, D22S936 - within the deletion areas and one reference target - RPP30 - as an internal control., Results: The assay reliable identified microdeletions when the template concentration was >32 copies per reaction and successfully detected LCR22A-B, LCR22A-C, LCR22A-D, and LCR22B-C deletions in clinical samples from 153 patients with signs of immunodeficiency. In patients with the microdeletions, flow cytometry detected a significant increase in B-cell and natural killer cell counts and percentages, while T-cell percentages and T-cell receptor excision circle (TREC) numbers decreased., Conclusion: The designed ddPCR assay is suitable for diagnosing DGS using whole blood and blood spots., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Recent studies have demonstrated the relationship between vitamin D deficiency, infection severity and mortality from COVID-19. This study aimed to analyze the vitamin D metabolites and cytokine expression levels of COVID-19 patients who were hospitalized with bolus cholecalciferol supplementation., Materials and Methods: This study represents the next stage of the open-label randomized pilot conducted by the Almazov National Medical Research Centre. A total of 44 hospitalized patients, comparable in demographic, clinical, laboratory and instrumental baseline characteristics, with moderate/severe COVID-19 were included. All patients had similar doses of concomitant corticosteroid therapy. Twenty-two patients received 50,000 IU cholecalciferol on the first and eighth days of hospitalization. The serum 25(OH)D, 1,25(OH)2D and 28 plasma cytokines were estimated for each group initially and on the ninth day of hospitalization., Results: Initially, there were no differences in the 1,25(OH)2D and cytokine levels in patients with vitamin D deficiency and normal 25(OH)D. Bolus cholecalciferol therapy at a total dose of 100,000 IU led to an increase in 25(OH)D levels in hospitalized patients with COVID-19, while the levels of the active metabolite (1,25(OH)2D) did not show significant differences between the groups or in its increased level over time, regardless of cholecalciferol supplementation. Furthermore, cholecalciferol supplementation at a total dose of 100,000 IU did not affect the majority of the cytokines estimated on the ninth day of hospitalization, except for the pro-inflammatory marker IL-1b, the concentration of which was lower in the group of patients without vitamin D supplementation., Conclusions: The 25(OH)D level was positively associated with an anti-inflammatory immune response, but cholecalciferol supplementation at a total dose of 100,000 IU did not affect the active-form vitamin D or cytokine expression levels. This fact may be explained by the impact of corticosteroid therapy, and it requires further investigation in a post-COVID-19 context.

Human adenoviruses (HAdVs) are common pathogens that are associated with a variety of diseases, including respiratory tract infections (RTIs). Without reliable, fast, and cost-effective detection methods for HAdVs, patients may be misdiagnosed and inappropriately treated. To address this problem, we have developed a multiplex loop-mediated isothermal amplification (LAMP) assay for the detection of the species Human adenovirus B (HAdV-B), Human adenovirus C (HAdV-C) and Human adenovirus E (HAdV-E) that cause RTIs. This multiplexing approach is based on the melting curve analysis of the amplicons with a specific melting temperature for each HAdV species. Without the need for typing of HAdVs, the LAMP results can be visually detected using colorimetric analysis. The assay reliably detects at least 375 copies of HAdV-B and -C and 750 copies of HAdV-E DNA per reaction in less than 35 min at 60 °C. The designed primers have no in silico cross-reactivity with other human respiratory pathogens. Validation on 331 nasal swab samples taken from patients with RTIs showed a 90-94% agreement rate with our in-house multiplex quantitative polymerase chain reaction (qPCR) method. Concordance between the quantitative and visual LAMP was 99%. The novel multiplexed LAMP could be an alternative to PCR for diagnostic purposes, saving personnel and equipment time, or could be used for point-of-care testing.

Neutrophilic pulmonary inflammation in asthmatics substantially exacerbates the severity of the disease leading to resistance to conventional corticosteroid therapy. Many studies established the involvement of Th1- and Th17-cells and cytokines produced by them (IFNg, IL-17A, IL-17F etc.) in neutrophilic pulmonary inflammation. Recent studies revealed that IL-4 - a Th2-cytokine regulates neutrophil effector functions and migration. It was showed that IL-4 substantially reduces neutrophilic inflammation of the skin in a mouse model of cutaneous bacterial infection and blood neutrophilia in a mouse model systemic bacterial infection. However, there are no data available regarding the influence of IL-4 on non-infectious pulmonary inflammation. In the current study we investigated the effects of IL-4 in a previously developed mouse model of neutrophilic bronchial asthma. We showed that systemic administration of IL-4 significantly restricts neutrophilic inflammation of the respiratory tract probably through the suppression of Th1-/Th17-immune responses and downregulation of CXCR2. Additionally, pulmonary neutrophilic inflammation could be alleviated by IL-4-dependant polarization of N2 neutrophils and M2 macrophages, expressing anti-inflammatory TGFβ. Considering these, IL-4 might be used for reduction of exaggerated pulmonary neutrophilic inflammation and overcoming corticosteroid insensitivity of asthma patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Type 2 diabetes mellitus (DM) remains the most common type of DM and is associat-ed with disabling complications, reduced quality of life and reduced life expectancy. Satisfactory control of carbohydrate metabolism remains the key way to manage them., Aim: To perform a retrospective analysis of carbohydrate metabolism (in terms of glycated hemoglobin - HbA 1c ), the prevalence of complications, and features of hypoglycemic and concomitant therapy in patients with type 2 DM., Materials and Methods: The analysis of sex and age characteristics, achieved level of HbA 1c , diabetes complications, sugar-reducing and concomitant therapy according to the data of outpatient records of the patients who are on dispensary registration with an endocrinologist in the Endocrinology Department of the Consultative and Diagnostic Polyclinic of the Tomsk Regional Clinical Hospital in Tomsk was carried out., Results: 546 outpatient medical records of patients with type 2 DM were analysed, among which there were 39.6% men ( n =216) with a history of type 2 DM 8.0 years [3.0; 13.0] , median age 64.0 years [54.5; 71.0] and 60.4% women ( n =330), history of type 2 DM 10.0 years [5.0; 15.0], median age 70.0 years [63.0; 75.0]. The achieved HbA 1c level in men was 7.6% [6.3; 9.0] and in women 7.4% [6.4; 9.1]. 19.4% of men and 13.6% of women had an aggravated history of type 2 DM. According to the history, 6.5% of men ( n =14) and 3% of women ( n =10) with type 2 DM had a history of stroke, and myocardial infarction 12% ( n =26) and 1.5% ( n =5), respectively. Among the analysed outpatient records of type 2 DM patients, 18.5% of men ( n =40) and 12.4% of women ( n =41) were found to have diabetic nephropathy. Diabetic retinopathy was reported in 9.3% ( n =20) of men and 4.2% ( n =14) of women. Diabetic macroangiopathies were detected in 29.6% ( n =64) of males and 9.7% ( n =32) of females. Among other chronic complications of DM, diabetic neuroosteoarthropathy was recorded in 1% ( n =2) of males and 3% ( n =10) of females, diabetic polyneuropathy in 25% ( n =54) and 21.5% ( n =71), respectively. Diabetic foot was diagnosed in 1.9% ( n =4) of men and 1.8% ( n =6) of women. Among comorbid pathology, obesity was diagnosed in 45.4% ( n =88) of men and 69.1% ( n =228) of women, dyslipidaemia in 10.2% ( n =22) and 10.6% ( n =35) respectively, hypertension in 39.8% ( n =86) and 32.6% ( n =108) of cases. The diagnosis of non-alcoholic fatty liver disease was verified in 3.7% of men ( n =7) and 1.8% of women ( n =6), chronic heart failure in 7.4% of men ( n =16) and 2.4% of women ( n =8) registered for type 2 DM. According to the analysed outpatient records, 4.1% ( n =23) of patients received diet therapy, 48.3% ( n =263) received monotherapy and 47.6% ( n =260) received combination therapy for type 2 DM. Metformin was the most commonly used monotherapy for type 2 DM 36.1% ( n =197), followed by insulin 6.9% ( n =38), sulfonylurea derivatives - 2.7% ( n =15). Combination of metformin and dipeptidyl peptidase-4 inhibitors (13.9%) was the most commonly used combination therapy., Conclusion: Analysis of the current situation in the diabetology service will help to identify weaknesses and strengths, which is necessary to optimise existing therapeutic approaches in accordance with current clinical recommendations.

The morphofunctional features of the ovaries were evaluated in rats with functional ovarian cysts model treated with gonadotropin-releasing hormone antagonist. Administration of the antagonist significantly (p=0.009) reduced the number of cysts and the growth of follicles in the ovaries. The obtained results attest to a possibility of successful treatment of functional ovarian cysts with gonadotropin-releasing hormone antagonist., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature.)

We studied the expression of insulin-like growth factor 1 (IGF-1), androgen receptor (AR) and luteinizing hormone receptor (LHR) in the ovaries under the conditions of the modeling and subsequent treatment of functional ovarian cysts with gonadotropin-releasing hormone antagonist (ant-GnRH). The intensity of IGF-1, LHR, and AR expression in the generative elements of rat ovaries changed under conditions of functional ovarian cysts simulation, as well as during treatment with ant-GnRH. In both experimental groups, the expression levels of the studied markers in preantral follicles and epithelial lining of cysts were found to be related to the number of growing follicles and cysts. A divergence of LHR and AR expression indices and a more pronounced decrease in the number of cystic cavities were observed in the group receiving ant-GnRH. These changes demonstrate a positive effect of ant-GnRH on intra-ovarian regulatory factors and a therapeutic effect in functional ovarian cysts., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature.)

The number of middle-aged and elderly population is increasing every year. At the same time, the course of most chronic diseases worsens with age, which can be explained by significant changes in body composition, including redistribution and increase of fat mass and decrease in muscle and skeletal mass. Thus, a decrease in muscle mass becomes intrinsic for the body from the age of 40 and develops on average by 0.5-1.0% per year. The prevalence of patients with sarcopenia is estimated to be between 11 and 50% in different age groups of population: middle, elderly and senile. In addition, the decline in physical activity associated with the urbanization and automation of labor exacerbates the disease at a younger age, which predicts an increase in the number of such patients in the future., Objective: To determine the role of physical rehabilitation in sarcopenia., Material and Methods: A systematic review including studies found in PubMed, MedLine, Scopus and Web of Science Core Collections databases for 2019-2022 was conducted. The used enrollment criteria were the following: systematic reviews, including cross-over or cohort studies targeting at persons aged from 40 to 90 years of both sexes, with available data on sarcopenia, its severe form or other combinations of physical performance markers called sarcopenia. The mandatory parameter for inclusion in the study was the presence of the effectiveness assessment of physical rehabilitation without limiting its parameters. The systematic review was performed in accordance with the recommendations of the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020., Results: The best kind of training are 30-60-minute comprehensive methods with predominance of resistance exercises with minimum duration of the course of 3 months and frequency of 3 inconsistent in-person trainings per week under the supervision of a specialist for patients with sarcopenia in order to increase muscle strength and mass, as well as performance. The intensity should consist of the following parameters: start with fewer sets but more repetitions (12-15) with less intensity (55% of maximum) and move to more sets with less repetition (4-6) and greater intensity (>80% of maximum)., Conclusion: This article describes the parameters of exercises that are most effective in terms of muscle strength and mass increase and safe for patients. The compilation and further study of this complex in practice are needed.

This study is aimed at investigating epileptic seizures, one of the consequences of traumatic brain injury (TBI). Immediate and early post-traumatic seizures, as well as late post-traumatic epileptic seizures or post-traumatic epilepsy, can have different pathogenetic bases. The following key risk factors associated with post-traumatic epilepsy are known: duration of unconsciousness, gunshot wounds, intracranial hemorrhage, diffuse axonal injury, prolonged (more than 3 days) post-traumatic amnesia, acute subdural hematoma with surgical evacuation, immediate and early post-traumatic epileptic seizures, fracture of the skull bones. The role of genetic factors in post-traumatic seizures is poorly understood due to the complexity and multiple causal mechanisms. This paper addresses the role of genetic factors in the occurrence and severity of epileptic events in patients with TBI. In particular, we investigated the role of the Cys112Arg single nucleotide polymorphism of the apolipoprotein E gene. Apolipoprotein E is known for its role in the transport and metabolism of lipids and, therefore, the development of cardiovascular diseases; it is also associated with Alzheimer's disease and has recently been studied in the context of association with epilepsy. The study shows an association between this polymorphism and the risk of immediate and early epileptic seizures in patients with severe TBI.

Alzheimer's disease (AD) is the most common cause of dementia worldwide that has an increasing impact on aging societies. Besides its critical role in the control of various physiological functions and behavior, brain serotonin (5-HT) system is involved in the regulation of migration, proliferation, differentiation, maturation, and programmed death of neurons. At the same time, a growing body of evidence indicates the involvement of 5-HT neurotransmission in the formation of insoluble aggregates of β-amyloid and tau protein, the main histopathological signs of AD. The review describes the role of various 5-HT receptors and intracellular signaling cascades induced by them in the pathological processes leading to the development of AD, first of all, in protein aggregation. Changes in the functioning of certain types of 5-HT receptors or associated intracellular signaling mediators prevent accumulation of β-amyloid plaques and tau protein neurofibrillary tangles. Based on the experimental data, it can be suggested that the use of 5-HT receptors as new drug targets will not only improve cognitive performance in AD, but will be also important in treating the causes of AD-related dementia.

A review of publications devoted to the analysis of genetic polymorphisms and features of the functioning of genes that affect the pharmacokinetics and pharmacodynamics of sodium-glucose cotransporter-2 inhibitors (SGLT2i) is presented. Objective of the study was to reveal information about genes whose polymorphism may affect the effectiveness of SGLT2i. The review was carried out in accordance with the PRISMA 2020 recommendations, the search for publications was carried out in the PubMed databases (including Medline), Web of Science, as well as Russian scientific electronic libraries eLIBRARY.RU from 1993 to 2022. Polymorphisms in the structure of several genes ( SLC5A2 , UGT1A9 , ABCB1 , PNPLA3 ) have been described that may affect the treatment of type 2 diabetes mellitus complicated by diseases such as chronic heart failure, chronic kidney disease, or non-alcoholic fatty liver disease. The information found on the genetic features of the development of the effects of SGLT2i is limited to a description of the differences in their pharmacokinetics. The relevance of currently available pharmacogenetic studies is largely constrained by small sample sizes.

Obesity is a major public health problem that requires new approaches. Despite all interventions, the behavioural and therapeutic interventions developed have demonstrated limited effectiveness in curbing the obesity epidemic. Findings from imaging studies of the brain suggest the existence of neural vulnerabilities and structural changes that are associated with the development of obesity and eating disorders. This review highlights the clinical relevance of brain neuroimaging research in obese individuals to prevent risky behaviour, early diagnosis, and the development of new safer and more effective treatments.

Autism spectrum disorders (ASDs) are among the most common neurodevelopmental diseases. These disorders are characterized by lack of social interaction, by repetitive behavior, and often anxiety and learning disabilities. The brain serotonin (5-HT) system is known to be crucially implicated in a wide range of physiological functions and in the control of different kinds of normal and pathological behavior. A growing number of studies indicate the involvement of the brain 5-HT system in the mechanisms underlying both ASD development and ASD-related behavioral disorders. There are some review papers describing the role of separate key players of the 5-HT system in an ASD and/or autistic-like behavior. In this review, we summarize existing data on the participation of all members of the brain 5-HT system, namely, 5-HT transporter, tryptophan hydroxylase 2, MAOA, and 5-HT receptors, in autism in human and various animal models. Additionally, we describe the most recent studies involving modern techniques for in vivo regulation of gene expression that are aimed at identifying exact roles of 5-HT receptors, MAOA, and 5-HT transporter in the mechanisms underlying autistic-like behavior. Altogether, results of multiple research articles show that the brain 5-HT system intimately partakes in the control of some types of ASD-related behavior, and that specific changes in a function of a certain 5-HT receptor, transporter, and/or enzyme may normalize this aberrant behavior. These data give hope that some of clinically used 5-HT-related drugs have potential for ASD treatment., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

A review of publications devoted to the analysis of genetic polymorphisms of the gene encoding the glucagon-like peptide type 1 receptor and some other genes directly and indirectly involved in the implementation of its physiological action is presented. The aim of the study: to search for information on genes polymorphism that can affect the effectiveness of glucagon-like peptide type 1 agonists. The review was carried out in accordance with the PRISMA 2020 recommendations, the search for publications was based on PubMed databases (including Medline), Web of Science, as well as Russian scientific electronic source eLIBRARY.RU from 1993 to 2022. The several genes polymorphisms ( GLP1R, TCF7L2, CNR1, SORCS1, WFS1, PPARD, CTRB1/2 ) that may affect the course and therapy of type 2 diabetes mellitus, metabolic syndrome and obesity, was described. Single nucleotide substitutions in some regions of these genes can both decrease and increase the clinical efficacy of the treatment of diabetes mellitus and metabolic syndrome with the help of type 1 glucagon-like peptide agonists: exenatide, liraglutide. Data on the role of genetic variations in the structure of the products of these genes in the effectiveness of other type 1 glucacone-like peptide agonists have not been found.

The COVID-19 pandemic has required extensive research on the new coronavirus SARS-CoV-2 and the creation of new highly effective vaccines. The presence of T-cells in the body that respond to virus antigens suggests adequate antiviral immunity. We investigated T-cell immunity in individuals who recovered from mild and moderate COVID-19 and in individuals vaccinated with the Gam-COVID-Vac combined vector vaccine. The ELISPOT method was used to determine the number of T-cells responding with IFN-γ synthesis to stimulation by peptides containing epitopes of the S-protein or N-, M-, ORF3, and ORF7 proteins, using peripheral blood mononuclear cells (PBMCs). At the same time, the multiplex method was used to determine the accumulation of IFN-γ and other cytokines in the culture medium. According to the data obtained, the proportion of positive conclusions about the T-cell immune response to SARS-CoV-2 antigens in control, recovered, and vaccinated individuals was 12%, 70%, and 52%, respectively. At the same time, more than half of the vaccinated individuals with a T-cell response were sensitized to the antigens of N-, M-, ORF3, and ORF7 proteins not produced by Gam-COVID-Vac, indicating a high likelihood of asymptomatic SARS-CoV-2 infection. Increased IFN-γ release by single sensitized T-cells in response to specific stimulation in recovered and vaccinated individuals did not result in the accumulation of this and other cytokines in the culture medium. These findings suggest a balance between cytokine production and utilization by immunocompetent cells as a prerequisite for providing a controlled cytokine signal and avoiding a "cytokine storm".

In addition to exhibited antioxidant and anti-inflammatory activity, fullerene C60 is a promising wound healing agent. An important stage in the production of fullerene-based ointments is the stability of the aqueous fullerene dispersion (AFD) with minimum size of colloidal fullerene aggregates and sufficiently high concentration. To achieve these parameters tangential flow filtration of fullerene C60 was used ("green technology"). As estimated by small-angle neutron scattering and dynamic light scattering purified AFDs with narrow-size distribution nanoclusters have a size of 6 nm and are assembled into agglomerates which reach a size of 150 nm. The ability of the AFD to exhibit regenerative activity was studied using the animal wound model. This study shows for the first time that the fullerene-based composition stimulates the healing of wounds of various origins. We assume that the mechanism of the AFD wound-healing activity is associated with the aryl hydrocarbon receptor and macrophages activity., Competing Interests: Declaration of competing interest The authors declare no commercial or financial conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Sarcopenia is characterized by a progressive loss of muscle mass, strength, and function, leading to poor outcomes and reduced quality of life. In middle age, the decrease in muscle mass begins to be progressive. Bioimpedancemetry allows diagnosing this condition before the onset of clinical symptoms., The Purpose of the Study: to evaluate the parameters of body composition in the early diagnosis of sarcopenia in middle-aged people., Materials and Methods: The participants were divided into two groups - the main one with sarcopenia - 146 people and the control group - 75 people. The complex of examinations included: neuropsychological testing (Hospital Anxiety and Depression Scale (HADS), quality of life questionnaire for patients with sarcopenia (SarQoL), short health assessment form (SF-36)), 4-meter walking speed test, dynamometry and bioimpedancemetry. The results of neuropsychological examination did not differ in the main and control groups. Patients with sarcopenia showed a decrease in muscle strength according to dynamometry. The scores of the walking speed assessment test in the study group were significantly higher than in the control group. The main and control groups had excessive body weight. According to the results of bioimpedanceometry, the main group had increased fat mass, percentage of fat mass, visceral fat area, and fat mass index compared with the control group. Skeletal muscle mass was less in the main group, probable sarcopenia was confirmed by decreased appendicular mass, decreased protein and mineral content was also recorded. There was a more pronounced decrease in cell mass in the main group. In patients with sarcopenia the volume of intracellular and extracellular fluid was less than in the control group. Significant differences were considered at p <0.05., Conclusions: the introduction of bioimpedancemetry and dynamometry into early screening for muscle mass reduction will allow timely start of therapeutic and preventive measures even in middle age, which will lead to a decrease in the progression of sarcopenia in the elderly, as well as improve the quality of life.

Sarcopenia is a condition that is characterized by a progressive loss of muscle mass, strength, and function, resulting in reduced quality of life. The aim of the study was to analyze the significance of pro-inflammatory markers in the prognostic diagnosis of sarcopenia. The participants were divided into two groups: the main group of 146 people and the control-75 people. The complex of examinations included neuropsychological testing (Hospital Anxiety and Depression Scale (HADS), quality-of-life questionnaire for patients with sarcopenia (SarQoL), and short health assessment form (MOS SF-36)), a 6 m walking speed test, manual dynamometry, bioimpedancemetry, and metabolic markers (nitrates, fibroblast growth factor 21, and malondialdehyde). When analyzing metabolic markers in the main group, a twofold increase in nitrates in the main group was recorded in a subsequent analysis adjusted for multiple variables, there was a negative association between the nitrate levels for weak grip strength and appendicular muscle mass. An additional analysis revealed that the complaint of pain in the lower extremities was more frequent in patients of the main group, as well as constipation and the pathology of thyroid gland, and they were more frequently diagnosed with arterial hypertension. At the same time, patients from the main group more frequently took vitamin D. When conducting body composition, the main group recorded a higher weight visceral fat content, as well as a decrease in appendicular and skeletal muscle mass; these changes were accompanied by a decrease in protein and minerals. Among the markers that differed significantly were nitrates, and it was this that was associated with decreased muscle strength and appendicular mass, which may indicate both a possible mechanism and a possible predictive marker. The results of this study can be used to develop a screening method for diagnosing sarcopenia at the outpatient stage.

Age-associated disorders, including cognitive functions, that often occur in geriatric patients, necessitate the use of novel approaches to provide appropriate medical care, pharmacoprophylaxis and pharmacotherapy among them. At the same time, an important objective of the national healthcare system is not only stimulating of pharmaceutical companies and pharmacies to expand the range of medicines intended for elderly patients, but also increasing availability of medicinal products, including the integration of extemporaneous formulations into clinical practice. Presented review considers several features of the regulation of the use of extemporaneous formulations in the treatment of geriatric patients. Examples of prescriptions that are used in Russian medical practice and are of the greatest interest in the treatment of elderly patients are also presented.

With an ageing of population and a splurging epidemic of diabetes mellitus (DM), the prevalence of complications associated with pathology of the central nervous system are expected to increase, which in the future may have serious consequences for public health. It is known that one of the main manifestations of brain damage in type 1 diabetes is cognitive impairment, which is possibly associated with the peculiarities of vascularization and interhemispheric asymmetry, which requires in-depth analysis using modern neuroimaging methods. The aim of the study is to assess the symmetry of structural, metabolic and neurovascularization changes in the brain in patients with type 1 diabetes and cognitive impairment. The study included 120 patients with type 1 diabetes aged 18 to 45 years suffering from cognitive impairment, and 30 people without cognitive decline and the control group (n=30) healthy people without diabetes. Neuropsychological testing included the Montreal Cognitive Dysfunction Assessment Scale (MoCA test). For neuroimaging methods, standard magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), contrast and non-contrast-enhanced perfusion were used. Statistical processing was carried out using the SPSS Statistic 2020 software. In patients with type 1 diabetes with cognitive impairment, as manifested by impaired memory and/or attention, perfusion imaging revealed the presence of brain asymmetry zones. Standard MRI allowed to demonstrate changes in the white, gray matter and hippocampus in the right hemisphere. The results obtained were refined taking into account the topical localization, so during the perfusion study, regions with asymmetric blood flow were identified - namely, the white matter of the frontal lobe and the gray matter in the occipital lobe. Spectroscopy of the brain revealed that it was in these areas of the brain that the most significant metabolic disorders were noted - in the form of significantly altered ratio of N-acetylaspartate (NAA)/choline (Cho) on the left, along with the asymmetry in phosphocreatine level (Cr 2) on the right. In conclusion, early preclinical predictive diagnostics with the use of modern neuroimaging methods allows for timely detection of impaired vascularization and brain metabolism in this group of patients, However, decreased perfusion in the region within the region of frontal lobe white matter and temporal lobe grey matter, and hippocampal cell metabolism by spectra should be highlighted among the parameters Cr right and NAA/Cho left., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Samoilova, Matveeva, Tonkih, Kudlay, Oleynik, Aremu, Kilina, Kanev and Gerget.)

The worlds older population is growing dramatically. At the same time, ensuring an appropriate high standard of living for the elderly by reducing of morbidity and disability of geriatric patients is one of the main objectives of the modern healthcare system. However, changes associated with body aging necessitate application of novel approaches to the correction of pharmacotherapy and usage of specialized dosage forms. Such medicinal products provide both an appropriate therapeutic effect and facilitate their use. Presented review considers several features of pharmacotherapy of geriatric patients.

Objective: Analysis of the role of blood pressure (BP) variability in the formation of neuroplasticity in patients with type 2 diabetes mellitus (DM)., Material and Methods: 100 patients with type 2 DM were examined, which were divided into groups depending on the presence of cognitive impairment (CI), the control group consisted of 25 people. All examined patients underwent a clinical examination, a standard set of biochemical blood tests, plasma osteopontin levels, 24-hour blood pressure monitoring (ABPM) for 24-26 h MRI of the brain (dynamic contrast and arterial spin marks, proton spectroscopy, tractography)., Results: Patients with type 2 diabetes and CI had higher body mass index, blood levels of glycated hemoglobin, glucose, alanine aminotransferase, low-density lipoprotein, triglycerides, total cholesterol, osteopontin, and lower levels of high-density lipoprotein ( p ≤0.05). The level of osteopontin was higher in patients with overweight, hyperglycemia, dyslipidemia, and in patients with CI in patients with BP variability. When assessing 24-hour blood pressure monitoring (ABPM), a significant difference was found in all standard indicators, while patients with type 2 diabetes were referred to as «non-dipper», in the presence of CI they noted significantly higher values of the index of time and area of stay in the suprathreshold state. BP and variability in SBP and DBP at night, as well as the risk of occult hypertension. A decrease in cerebral blood flow was revealed according to the data of contrast and non-contrast assessment of perfusion in cortical (especially in the frontal lobe) and subcortical (mainly in the putamen) structures, associated with changes in ABPM parameters. Mean SBP and DBP day and night, as well as the index of BP variability, also affect the integrity of the corticospinal, uncinate, lower longitudinal tracts, and arcuate fasciculus. The same parameters change the metabolism of the hippocampus in terms of choline (Cho), creatine (Cr), creatine phosphate (Cr2), as well as the ratio of N-acetylaspartate (NAA)/Cho, NAA/Cr, Cho/Cr., Conclusion: In patients with type 2 diabetes, BP variability contributes to the formation of CI through a pro-inflammatory mechanism (osteopontin), leading to impaired brain vascularization in general, white matter structure, and hippocampal metabolism.

Objective: To study the relationship of the structure of the white matter of the brain, neurovascularization and cognitive functions in obese children and adolescents., Material and Methods: The study included 64 obese patients, aged 12-17 years, and 54 children without excess body weight. A general clinical examination, neuropsychological testing (the Raven's test with the calculation of IQ, MoCA, the Rey 15-Item Memory Test (RMT), 1 and 2), magnetic resonance imaging (MR) tractography and contrast-free perfusion of the brain were conducted., Results: Obese children and adolescents had both a decrease in scores on MoCA and the Raven's test, and in terms of IQ, while according to RMT-1, there were significant differences in the two groups, and in RMT-2 the results were comparable. Perfusion analysis showed a decrease in vascularization in the white matter area of the occipital lobe on the left and its increase in the temporal lobe area also on the left. When assessing the white matter according to MR tractography, a decrease in fractional anisotropy was noted in the area of the hook-shaped beam on the right and left, anterior and posterior commissural tracts. These changes were correlated with neuropsychological results., Conclusion: In obese children and adolescents, there was a destruction of the integrity of the white matter and neurovascularization of the brain associated with a deficit of cognitive functions.

Objective: To analyse a role of BP (blood pressure) variability in shaping neuroplasticity in patients with type 2 diabetes mellitus (DM)., Material and Methods: The study enrolled 100 patients with type 2 DM divided according to the presence of cognitive impairment (CI) and 25 control subjects. Biochemical blood count, plasma osteopontin, 24-hour self-blood pressure monitoring (SBPM) and brain MRI were assessed., Results: Patients with type 2 DM and CI had higher body mass index as well as glycated hemoglobin (HbA1c), glucose, alanine aminotransferase, osteopontin and hyperlipidemia ( p ≤0.05). There was a significant difference in all standard indices, patients with type 2 DM were classified as «non-dipper», and there were significantly higher values of the index of time and area of stay in the state of suprathreshold BP and BP variability at night, as well as the risk of latent arterial hypertension in CI. Neuroimaging assessment revealed decreased blood flow according to contrast and non-contrast perfusion in all parameters in cortical (especially the frontal lobe) and subcortical structures (predominantly in the shell region), and was associated with SMAD parameters. Mean systolic and diastolic BP during the day and night, as well as the variability index, also influenced the integrity between cortico-spinal tract, hook, inferior longitudinal and arcuate fascicles. The same parameters altered hippocampal metabolism in terms of N-acetylaspartate (NAA)/choline (Cho), NAA/creatine (Cr), Cho/Cr ratios., Conclusion: In patients with type 2 DM, BP variability contributes to CI through a proinflammatory mechanism (osteopontin) leading to brain neuroimaging abnormalities.

Inborn errors of immunity can be detected by evaluating circular DNA (cDNA) fragments of T- and B-cell receptors (TREC and KREC) resulting from the receptor gene rearrangement in T and B cells. Maturation and activation of the fetal immune system is known to proceed gradually according to the gestational age, which highlights the importance of the immune status in premature infants at different gestational ages. In this article, we evaluated TREC and KREC levels in infants of various gestational ages by real-time PCR with taking into account the newborn's weight and sex. The 95% confidence intervals for TREC and KREC levels (expressed in the number of cDNA copies per 105 cells) were established for different gestational groups. The importance of studying immune system development in newborns is informed by the discovered dependence of the level of naive markers on the gestational stage in the early neonatal period., (Copyright ® 2022 National Research University Higher School of Economics.)

Background: Patients with cystic fibrosis (CF) need costly medical care and adequate therapy with expensive medicinal products. Tigerase® is the first biosimilar of dornase alfa, developed by the lead Russian biotechnology company GENERIUM. The aim of the manuscript to present post hoc sub-analysis of patients' data with cystic fibrosis and severe pulmonary impairment of a larger comparative study (phase III open label, prospective, multi-centre, randomized study (NCT04468100)) of a generic version of recombinant human DNase Tigerase® to the only comparable drug, Pulmozyme®., Methods: In the analyses included subgroup of 46 severe pulmonary impairment patients with baseline FEV1 level 40-60% of predicted (23 patients in each treatment group) out of 100 patients registered in the study phase III open label, prospective, multi-center, randomized study (NCT04468100), and compared efficacy endpoints (FEV1, FVC, number and time of exacerbations, body weight, St.George's Respiratory Questionnaire) as well as safety parameters (AEs, SAEs, anti-drug antibody) within 24 treatment weeks., Results: All outcomes were comparable among the studied groups. In the efficacy dataset, the similar mean FEV1 and mean FVC changes for 24 weeks of both treatment groups were observed. The groups were also comparable in safety, all the secondary efficacy parameters and immunogenicity., Conclusions: The findings from this study support the clinical Tigerase® biosimilarity to Pulmozyme® administered in CF patients with severe impairment of pulmonary function., Competing Interests: Elena L. Amelina, Stanislav A. Krasovsky, Nataliya Yu. Kashirskaya, Diana I. Abdulganieva, Irina K. Asherova, Ilya E. Zilber, Liliya S. Kozyreva, Lubov M. Kudelya, Natalya D. Ponomareva, Nataliya P. Revel-Muroz, Elena M. Reutskaya, Tatiana A. Stepanenko, Gulnara N. Seitova, Olga P. Ukhanova, Olga V. Magnitskaya received payment for the above-mentioned clinical trial. Dmitry A. Kudlay, Nina E. Akhtyamova-Givirovskaya, Oksana A. Markova, Elena V. Gapchenko are the employees of JSC GENERIUM. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Cognitive dysfunction, including mild cognitive impairment and dementia, is increasingly recognized as a serious complication of diabetes mellitus (DM) that affects patient well-being and disease management. Magnetic resonance imaging (MRI)-studies have shown varying degrees of cortical atrophy, cerebral infarcts, and deep white matter lesions. To explain the relationship between DM and cognitive decline, several hypotheses have been proposed, based on the variability of glycemia leading to morphometric changes in the brain. The ability to predict cognitive decline even before its clinical development will allow the early prevention of this pathology, as well as to predict the course of the existing pathology and to adjust medication regimens., Aim: To create a computer neural network model for predicting the development of cognitive impairment in DM on the basis of brain neuroimaging techniques., Materials and Methods: The study was performed in accordance with the standards of good clinical practice; the protocol was approved by the Ethics Committee. The study included 85 patients with type 1 diabetes and 95 patients with type 2 diabetes, who were divided into a group of patients with normal cognitive function and a group with cognitive impairment. The patient groups were comparable in age and duration of disease. Cognitive impairment was screened using the Montreal Cognitive Assessment Scale. Data for glycemic variability were obtained using continuous glucose monitoring (iPro2, Libre). A standard MRI scan of the brain was performed axially, sagittally, and coronally on a Signa Creator E, GE Healthcare, 1.5 Tesla, China. For MRI data processing we used Free Surfer program (USA) for analysis and visualization of structural and functional neuroimaging data from cross-sectional or longitudinal studies, and for segmentation we used Recon-all batch program directly. All statistical analyses and data processing were performed using Statistica Statsofi software (version 10) on Windows 7/XP Pro operating systems. The IBM WATSON cognitive system was used to build a neural network model., Results: As a result of the study, cognitive impairment in DM type 1was predominantly of mild degree 36.9% (n=24) and moderate degree 30.76% (n=20), and in DM type 2 mild degree 37% (n=30), moderate degree 49.4% (n=40) and severe degree 13.6% (n=11). Cognitive functions in DM type 1 were impaired in memory and attention, whereas in DM type 2 they were also impaired in tasks of visual-constructive skills, fluency, and abstraction (p0.001). The analysis revealed differences in glycemic variability indices in patients with type 1 and type 2 DM and cognitive impairment. Standard MRI of the brain recorded the presence of white and gray matter changes (gliosis and leukoareosis). General and regional cerebral atrophy is characteristic of type 1 and type 2 DM, which is associated with dysglycemia. When building neural network models for type 1 diabetes, the parameters of decreased volumes of the brain regions determine the development of cognitive impairment by 93.5%, whereas additionally, the coefficients of glycemic variability by 98.5%. The same peculiarity was revealed in type 2 DM 95.3% and 97.9%, respectively., Conclusion: In DM type 1 and type 2 with cognitive impairment, elevated coefficients of glycemic variability are more frequently recorded. This publication describes laboratory and instrumental parameters as potential diagnostic options for effective management of DM and prevention of cognitive impairment. Neural network models using glycemic variability coefficients and MR morphometry allow for predictive diagnosis of cognitive disorders in both types of diabetes.

Currently, eculizumab is the main effective treatment for paroxysmal nocturnal hemoglobinuria (PNH). The aim of this randomized multicenter noninferiority study was to evaluate the efficacy and safety of the Biosimilar (Elizaria) in comparison with the Originator (Soliris) in patients with PNH. Biosimilar and Originator were administered at a dose of 600 mg weekly for 4 weeks at the initial stage in naive patients, as well as for maintenance therapy at a dose of 900 mg every 2 weeks in all patients. The primary endpoint was a comparative assessment of hemolytic activity based on the area under the lactate dehydrogenase (LDH) concentration-time curve during the maintenance therapy. Thirty-two (32) patients were randomized for therapy with Biosimilar (n = 16) or Originator (n = 16). The mean values of LDH concentration-time curve were similar in both treatment groups without statistically significant differences (p > 0.05). Evaluation of secondary endpoints has shown no statistically significant differences between the groups. Safety values were comparable in both treatment groups. The data obtained confirm that the Biosimilar is not inferior to the Originator in terms of the main efficacy parameter, and is also comparable with it in terms of safety and additional efficacy parameters. Clinicaltrials.gov identifier: NCT04463056., (© 2021. The Author(s).)

The data of a comparative enzyme-linked immunosorbent assay of the content of the soluble form of the immunity checkpoint VISTA in the blood serum of 30 healthy donors (control group), 79 patients with primary malignant (osteosarcoma - 30, chondrosarcoma - 31, chordoma - 14) and 14 borderline (giant cell tumor) bone neoplasms are presented. In the general group of patients with malignant neoplasms of bones, the median sVISTA content in blood serum is statistically significant lower than in the control (p = 0.040). In patients with bone tumors and healthy donors over 18 years of age, there was a decrease with age in serum sVISTA levels. There were no significant differences in sVISTA concentration between patients with osteosarcoma, chondrosarcoma and healthy donors. Only in patients with chordoma were sVISTA levels statistically significant lower than in controls (p = 0.013). In the groups of patients with chondrosarcoma and osteosarcoma of the bone, there were no significant associations between the serum sVISTA content and the main clinical and morphological characteristics of the disease. In patients with osteosarcoma, no relationship was found between sVISTA levels and overall survival rates, while in patients with bone chondrosarcoma, there was a tendency towards a favorable prognosis with a high content of the marker in the blood serum., Competing Interests: The authors declare no conflict of interest.

The content of the soluble form of protein of the key point of immunity B7-H3 (sB7-H3) in the blood plasma of 75 patients with epithelial ovarian cancer before treatment was measured by ELISA. It is known that B7-H3 belongs to the immunoglobulin superfamily (B7 molecule family) and is involved in the regulation of the immune response mediated by T cells. The sB7-H3 concentration correlated with the clinical and morphological parameters of ovarian cancer. The content of sB7-H3 was higher at the later stages of the disease, in the presence of ascites, and in patients with poorly differentiated ovarian cancer. It was revealed that increased plasma content of sB7-H3 in patients with epithelial ovarian cancer is associated with unfavorable prognosis of the disease. Therefore, sB7-H3 can be used as a prognostic marker in ovarian cancer patients., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

The data of a complex immunoassay comparative study of the content of soluble forms of sPD-1, sPD-L1, sNKG2D, sNKG2DL1, sB7-H3 and sHLA-G in the blood plasma of 75 patients with epithelial ovarian cancer and 20 healthy donors of the control group are presented. The diagnostic significance of the studied proteins was determined. The study showed that the profile of soluble immunity checkpoints differs when malignant ovarian pathology occurs. There was a statistically significant decrease in the content of sPD-L1, sNKG2DL1, sB7-H3, and sHLA-G in the blood plasma of patients compared with the control group. Differences were found in the content of the studied markers depending on the histological type of tumors. Correlations between the soluble forms of some of the studied proteins are shown, indicating the presence of independent mechanisms of immune regulation in ovarian cancer, which may explain the insufficient effectiveness of the existing immunotherapy for this type of tumor. The results obtained will undoubtedly facilitate the development of new effective methods for the diagnostics and therapy of ovarian cancer., Competing Interests: The authors declare no conflict of interest.

Aim: Study of the remodeling of the carotid arteries with violation of intracardiac hemodynamics in patients with MFA, and the estimation of the main parameters of dyslipidemia, apoptosis, and oxidative stress in patients with high vascular risk older age group (6175 years) in a Regional vascular center of Ufa., Materials and Methods: Depending on the predominant lesion of the vascular pool, patients were divided into 3 clusters by the method of hierarchical analysis of categorical variables according to the clinical manifestation of atherosclerotic lesions of the heart, brain and lower limb arteries confirmed by coronary angiography, ultrasound Doppler of the main arteries of the head and lower extremities. 96 of them were IPA with a primary lesion of the heart (1st cluster), the 96 IPA with a predominance of lesions of the carotid arteries (2nd cluster), 96 patients with ischemia of lower extremities (3rd cluster). At the hospital stage, electrocardiography, echocardiography, magnetic resonance imaging of the chest and abdomen, ultrasound of the OBP and kidneys, if necessary, ultrasound of the pelvis were performed. Determination of 8-ON-deoxyguanosine, annexin-5 (An-5) and Aan-5 in blood by ELISA was performed in all patients with MFA, as well as standard biochemical screening for lipidogram examination., Results: We have found that most often in different combinations and with different degrees of severity according to our data are observed: Clinical manifestation of atherosclerotic heart disease (cluster 1) mainly due to its history in combination with stage III hypertension with increasing thickness of intima-media complex and stenosis of the right WASP, left ventricular dilatation, as well as a higher concentration of Aan-5IgMand LP-A as a risk factor for coronary heart disease, atherosclerosis, atherothrombosis. 2. Hemodynamically significant violations of the main arteries of the head in patients of the 2nd cluster mainly with acute ischemic cerebral circulation, in which there was a development of left ventricular hypertrophy with an increase in the size of the left atrium and the presence of atherosclerotic plaque of the right and left WASP. The higher prevalence of stroke was combined with a marked cognitive deficit among patients of cluster 2 with the lowest level of An-5, an increase in total cholesterol and low-density lipoprotein cholesterol. 3. The total severity of the condition in patients with hemodynamic ischemia with clinical manifestation of vascular lesions of the lower extremities was accompanied by a predominant increase in stable angina with FC2, lerish syndrome with occlusion of the iliac, superficial femoral arteries, the presence of insulin-independent type 2 diabetes, which in this group was established in 59.4% of cases, combined with a higher concentration of the marker of oxidative stress 8-ON-deoxyguanosine and hypertriglyceridemia., Conclusion: The construction of a three-cluster model in patients at high vascular risk of the elderly age category showed the interaction of cardio-carotid comorbid background on the clinical diversity of systemic vascular lesions in MFA with the development of remodeling of the main arteries and disorders of intracardiac hemodynamics associated with laboratory changes in the assessment of the main parameters of dyslipidemia, apoptosis markers, oxidative stress.

Currently, the main pathogenetic method for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) is the treatment with recombinant monoclonal antibodies that block the C5 component of the complement system. Eculizumab is the first biotechnological drug, which is a monoclonal antibody, with proven clinical efficacy and safety for the treatment of patients with PNH, which is used in world clinical practice. In Russia, in the framework of the state program Development of the pharmaceutical and medical industry for 20132020 was developed Elizaria (JSC GENERIUM) the first biosimilar of the original drug eculizumab., Aim: To evaluate the pharmacokinetic and pharmacodynamic parameters, as well as safety and immunogenicity parameters of the drug Elizara in the induction phase of therapy in previously untreated patients with PNH., Materials and Methods: The study included 11 patients with PNH aged 26 to 75 years who had not previously received eculizumab. Each of the study participants was injected with the studied drug Elizaria at a dose of 600 mg intravenously once a week for 4 weeks., Results: During the clinical study, it was noted that the concentration of the studied drug significantly increased by the time the infusion was completed and then gradually decreased to a minimum at the end of the dosing interval. The average concentration of eculizumab 5 minutes before the administration of the study drug at all visits exceeded 35 g/ml, the minimum concentration sufficient to completely inhibit intravascular hemolysis in patients with PNH. The pharmacodynamic efficacy of the drug Elizaria was confirmed by a decrease in the concentration of the membrane-attack complex (MAC) after the first infusion of the drug was maintained at stable levels until visit 5. A persistent decrease in the level of MAC and a four-fold decrease in the average values of lactate dehydrogenase to visit 5 from 1286.4 to 280.9 U/l demonstrated a marked decrease in activity and stabilization of the hemolytic process against the background of the induction of therapy with Elizaria at a dose of 600 mg once a week and confirmed the effecacy of the study drug. Among the 9 adverse events, only 5 had a relationship with the studied drug, including one serious adverse event in the form of an allergic reaction, which, according to the researcher, had a possible cause-effect relationship with the infusion of the studied drug. In 2 patients, low-titer binding anti-drug antibodies were detected without neutralizing activity during treatment with the studied drug, which may indicate its low immunogenicity., Conclusion: The study evaluated the pharmacokinetic and pharmacodynamic properties of the drug Elizaria in the regimen of induction therapy in previously untreated patients with PNH, confirming its efficacy. The study demonstrated the safety and low immunogenicity of the study drug.

Respiratory syncytial virus (RSV) is one of the most common viral pathogens. It is especially dangerous for newborns and young children. In some cases it could lead to severe bronchiolitis, pneumonia with hospitalization or even a lethal outcome. Despite decades of investigation of RSV biology, effective and safe therapeutics are still under development. Certain natural peptides have been found to exhibit antiviral activity against respiratory viruses, but their implementation is limited by low stability in biological media. One of the current approaches to enhance the peptide therapeutic opportunities is chemical synthesis of peptide dendrimers with hyperbranched structures. Taking into account the recent data of bioactive cationic and helical regions of natural peptides and the structure features of nucleolin identified as an RSV cellular receptor, the main goal of this study was to design relatively short linear and dendrimeric cationic peptides and to test their antiviral activity against RSV. As a result 3 linear cationic peptides and 4 peptide dendrimers were synthesized and compared with known LL-37 (cathelicidin family) and anti-F0 monoclonal antibodies in terms of cytotoxicity and antiviral activity. Their affinity to the supposed molecular target - nucleolin (C23) - was estimated in silico by molecular docking analysis. Four synthesized peptides demonstrated a cytotoxic effect, two of them were even more cytotoxic than LL-37, which could be explained by a combination of a high amount of positive charge and amphipathicity. Contrariwise, non-hydrophobic dendrimer peptides did not exhibit cytotoxicity in mammalian cells in the studied concentration range. Two of the seven synthesized peptides, LTP (dendrimer) and SA-35 (linear), used in this study had a stronger antiviral effect than natural peptide LL-37, and three others showed slightly lower activity than anti-F0 monoclonal antibodies. The data obtained in this study suggest that evenly distributed positive charge, and low or medium amphipathicity play a key role in the antiviral activity of the studied peptides. Moreover, the calculated free energy values of the peptide/nucleolin complex for the most active peptides supported the idea that the peptide ability of nucleolin interaction promotes the anti-RSV properties of the molecules.

Background: Macrophages (Mф) can be M1/M2 polarized by Th1/2 signals, respectively. M2-like Mф are thought to be important in asthma pathogenesis, and M1-like in anti-infective immunity, however their roles in virus-induced asthma exacerbations are unknown. Our objectives were (i) to assess polarised Mф phenotype responses to rhinovirus (RV) infection in vitro and (ii) to assess Mф phenotypes in healthy subjects and people with asthma before and during experimental RV infection in vivo., Methods: We investigated characteristics of polarized/unpolarized human monocyte-derived Mф (MDM, from 3-6 independent donors) in vitro and evaluated frequencies of M1/M2-like bronchoalveolar lavage (BAL) Mф in experimental RV-induced asthma exacerbation in 7 healthy controls and 17 (at baseline) and 18 (at day 4 post infection) people with asthma., Findings: We observed in vitro: M1-like but not M2-like or unpolarized MDM are potent producers of type I and III interferons in response to RV infection (P<0.0001), and M1-like are more resistant to RV infection (P<0.05); compared to M1-like, M2-like MDM constitutively produced higher levels of CCL22/MDC (P = 0.007) and CCL17/TARC (P<0.0001); RV-infected M1-like MDM were characterized as CD14 + CD80 + CD197 + (P = 0.002 vs M2-like, P<0.0001 vs unpolarized MDM). In vivo we found reduced percentages of M1-like CD14 + CD80 + CD197 + BAL Mф in asthma during experimental RV16 infection compared to baseline (P = 0.024)., Interpretation: Human M1-like BAL Mф are likely important contributors to anti-viral immunity and their numbers are reduced in patients with allergic asthma during RV-induced asthma exacerbations. This mechanism may be one explanation why RV-triggered clinical and pathologic outcomes are more severe in allergic patients than in healthy subjects., Funding: ERC FP7 Advanced grant 233015, MRC Centre Grant G1000758, Asthma UK grant 08-048, NIHR Biomedical Research Centre funding scheme, NIHR BRC Centre grant P26095, the Predicta FP7 Collaborative Project grant 260895, RSF grant 19-15-00272, Megagrant No 14.W03.31.0024., Competing Interests: Declaration of Competing Interest Dr. Johnston reports personal fees from Therapeutic Frontiers, personal fees from Virtus Respiratory Research, personal fees from Myelo Therapeutics GmbH, personal fees from Concert Pharmaceuticals, personal fees from Bayer, personal fees from Synairgen, personal fees from Novartis, personal fees from Boehringer Ingelheim, personal fees from Chiesi, personal fees from Gerson Lehrman Group, personal fees from resTORbio, personal fees from Bioforce, personal fees from Materia Medical Holdings, personal fees from PrepBio Pharma, personal fees from Pulmotect, personal fees from Virion Health, personal fees from Lallemand Pharma, personal fees from AstraZeneca, outside the submitted work; In addition, Dr. Johnston has a patent Wark PA, Johnston SL, Holgate ST, Davies DE. Anti-virus therapy for respiratory diseases. UK patent application No. GB 0405634.7, 12 March 2004. with royalties paid, a patent Wark PA, Johnston SL, Holgate ST, Davies DE. Interferon-Beta for Anti-Virus Therapy for Respiratory Diseases. International Patent Application No. PCT/B05/50031, 12 March 2004. with royalties paid, and a patent Davies DE, Wark PA, Holgate ST, Johnston SL. Interferon Lambda therapy for the treatment of respiratory disease. UK patent application No. 6779645.9, granted 15th August 2012. licensed. Rudolf Valenta has received research grants from the Austrian Science Fund (FWF) and Viravaxx, Vienna, Austria and serves as a consultant for Viravaxx. The other authors do not have any conflict of interest., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To study conductive white matter pathways in patients with type 1 and type 2 diabetes with- and without cognitive impairment., Materials and Methods: The study included 85 patients with type 1 and 95 patients with type 2 diabetes who were divided into those who had normal cognitive functions and those with cognitive impairment. The groups were comparable in age and duration of the disease. Screening of cognitive functions was performed using the Montreal Scale for the Evaluation of Cognitive Function (MoCA-test). Brain MRI was performed on 1.5 Tesla system. All statistical analyses and data processing were performed using Statistica (Statsoft) software (version 10) on Windows 7/XP Pro operating systems., Results: The study revealed the prevalence of mild and moderate cognitive impairment in type 1 diabetes, medium and severe in type 2 diabetes, which were mainly manifested by memory, attention and optical-spatial disorders. Intergroup analysis of the brain tractography did not show any difference in the integrity of tracts in type 1 and type 2 diabetes, but the most significant risk factors of pathway impairment were identified. They include arterial hypertension (H=6.602833, p =0.0368), degree of polyneuropathy (H=15.30420, p =0.0005), degree of nephropathy (H=9.993923, p =0.0068), degree of retinopathy (H=8.445891, p =0.0376) for type 1 diabetes and age (H=7.381742, p =0.0607), (H=8.359127, p =0.0391) for type 2 diabetes. Cholesterol level contributes to the risk in both types (H=4.009380, p =0.0452; H=4.057357, p =0.0440; H=6.454558, p =0.0111). The corticospinal and commissural tracts are most susceptible to damage., Conclusions: There are no significant differences in axial cerebral tract diffusion in patients with type 1 and type 2 diabetes with- and without cognitive impairment. However, the most important risk factors for white matter structure damage, namely, arterial hypertension, diabetic complications, cholesterol levels and age, are verified.

Objective: To develop a model for the prognosis of cognitive impairment in patients with type 1 diabetes mellitus based on data from proton magnetic resonance spectroscopy., Materials and Methods: Patients with type 1 diabetes mellitus and individuals without diabetes were examined (control group). All participants were evaluated for carbohydrate metabolism, underwent neuropsychological testing (MoCa test), proton magnetic resonance spectroscopy of the brain. Statistical processing of the results was performed using the IBM SPSS Statistics 20.0 program. The predictive model is calculated using discriminant analysis., Results: Based on the data of proton magnetic resonance spectroscopy, a predictive model for the development of cognitive impairment in patients with type 1 diabetes mellitus was obtained using discriminant analysis., Conclusions: The method for the early diagnosis of cognitive impairment allows predicting the development of cognitive dysfunction in patients with type 1 diabetes in the early stages and can be used in clinical practice to assess the effectiveness of preventive therapy for cognitive impairment.

Cytokines of the interleukin-1 (IL-1) family play an important role in the realization of the protective functions of innate immunity and are the key mediators involved in the pathogenesis of a wide range of diseases, including various manifestations of allergy. The IL-1 family includes more than 11 members. However, the functions of many of them remain to be elucidated. Recently, new members of the IL-1 family have been discovered. In 2000, several independent research groups reported the discovery of a new interleukin of this family, which was named IL-37, or IL-1F7 (according to the new nomenclature). IL-37 was assigned to the IL-1 family based on its structural similarity with other members of this family. The study of its biological properties showed that its activity changes in inflammatory diseases, such as rheumatoid arthritis, psoriasis, as well as allergic diseases (allergic rhinitis, bronchial asthma, and atopic dermatitis). However, unlike most members of the IL-1 family, IL-37 acts as a negative regulator of inflammation. Activation of IL-37 suppresses inflammation, resulting in the suppression of inflammatory cytokines and chemokines, which in turn prevents infiltration of pro-inflammatory cells, mainly eosinophils and neutrophils. The exact molecular and cellular mechanisms of the anti-inflammatory effect of IL-37 in the development of allergic diseases (AD) have not been fully studied. This review summarizes and analyzes the accumulated experimental data on the role of IL-37 in the pathogenesis of AD, such as allergic rhinitis, bronchial asthma, and atopic dermatitis., (Copyright ® 2019 National Research University Higher School of Economics.)

Objective: to study clinical and cluster features of cardiovascular burdening taking into account the comorbid polymorbid background in patients of middle age (45-60 years) with the presence of multifocal atherosclerosis (MFA)., Materials and Methods: Patients were examined in the Regional Vascular Center of Ufa (RVCU). Depending on the predominant localization of lesions in the vascular bed patients were divided into 3 clusters by the method of hierarchical analysis of categorical variables according to the clinical manifestation of atherosclerotic lesions of the heart, brain and lower limb arteries confirmed by coronary angiography, ultrasound Doppleroscopy of main arteries of the head and lower extremities. Ninety-six patients had predominant lesions in the heart (1st cluster), 96 - in carotid arteries (2nd cluster), and 96 patients had ischemia of lower extremities (3rd cluster). Examination during hospitalization in RVCU included when indicated echocardiography, magnetic resonance imaging of the chest and abdomen, ultrasound studies of abdomen, kidney, and pelvis., Results: According to data obtained the following conditions were most often observed in different combinations and with varying degrees of severity of clinical manifestation.Claster 1. Clinical manifestation of atherosclerotic heart disease mainly due to stage III hypertension, history of myocardial infarction were combined with pneumonia, chronic obstructive pulmonary disease with the outcome in pneumosclerosis and emphysema, as well as the presence of cholecysto-cardial syndrome, chronic gastritis, chronic cholecysto-pancreatitis, abdominal ischemic syndrome, rheumatoid arthritis, diabetes mellitus, and chronic pyelonephritis.Claster 2. Hemodynamically significant lesions of brachiocephalic arteries mainly with acute ischemic disturbance of cerebral circulation were combined with bronchial asthma, (the development of which was associated with prolonged persistent eosinophilic inflammation), worsening of chronic kidney disease with urolithiasis, angionephropathy and iron deficiency anemia, as well as the presence of dorsopathy associated with stenotic atherosclerosis of brain vessels.Claster 3.Hemodynamic ischemia with clinical manifestation of vascular lesions of lower extremities was accompanied by type 2 diabetes, chronic cholecysto-pancreatitis, erosive and ulcerative lesions in the stomach and duodenum, polyosteoarthrosis, abdominal-ischemic syndrome. Type 2 diabetes prevailed in patients with occlusion of right posterior tibial artery and trophic ulcer of the right foot., Conclusion: Interdependence of comorbid and polymorbid background and cardiovascular burdening changes their clinical picture and course, increases number of complications and their severity.

Background: Mouse models of allergic asthma play a crucial role in exploring of asthma pathogenesis and testing of novel anti-inflammatory drugs. Widely used acute asthma models usually developed with adjuvant (aluminum hydroxide (alum)) do not reproduce one of the main asthma feature - airway remodeling while chronic asthma model mimic the pathophysiology of human disease. Moreover, the use of alum causes distress in experimental animals and impedes the test of adjuvant-containing drugs. In this study, we aimed to develop a chronic adjuvant-free asthma model with pronounced asthmatic phenotype., Methods: Female BALB/c mice were divided into 3 groups. The first group was sensitized with intraperitoneal injections of ovalbumin (OVA) emulsified in aluminum hydroxide on days 0, 14, 28 followed by two stages of intranasally challenge with OVA on days 41-43 and 62-64. The second group was subcutaneously sensitized with the same dose of OVA without adjuvant and challenged on the same days. The third group (negative control) included mice which did not received any kind of treatment (i.e. sensitization and challenge). Serum levels of OVA-specific IgE, IgG2a and IgG1 antibodies were detected by ELISA. Airway hyper-responsiveness was measured by non-invasive plethysmography on days 44 and 65. Bronchoalveolar lavage fluids (BALF) sampled in all groups on days 45 and 66 were analyzed by light microscopy. The left lung was removed for histological analysis. The IL-4 and IFNγ mRNA expression in BALF cells was evaluated by RT-PCR., Results: The OVA-specific IgE antibody response was two-fold increased in mice from adjuvant-free group compared to the adjuvant group that reflects reorientation of immune response towards Th2 phenotype. At the same time, the level of OVA-specific IgG1 and IgG2a antibodies was increased in the adjuvant group. Airway hyperresponsiveness to methacholine in mice of both experimental groups was two-fold higher than in control. Analysis of cell composition in BAL has shown a significant increase in eosinophil count in both experimental groups that indicate the development of allergic inflammation. Lung histology revealed airway remodeling in both experimental groups including goblet cell hyperplasia/metaplasia, thickening of airway walls, collagen deposition in the wall of distal airways. Additionally, the tendency to develop hypertrophy of bronchial smooth muscle layer was observed. Study of gene expression in BAL cells revealed the increase of IL-4 level in both adjuvant and adjuvant-free groups while IFNγ expression in both experimental groups was similar to control group., Conclusion: We have developed a chronic adjuvant-free mouse asthma model which possesses all necessary features of the disease including airway remodeling and is more suitable for pre-clinical evaluation of novel therapeutic approaches including adjuvant-containing drugs., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The study of potential mechanisms of cognitive impairments associated with gene expression in patients with diabetes mellitus (DM) is becoming increasingly important due to the increase in the prevalence of dementia in this category of patients. DM is associated with the alteration of neurogenesis, and the variability of glycemia causes the changes in plasma and mitochondria, promotes the formation of free radicals, oxidative stress, activation of apoptosis of neurons, circulation of proinflammatory agents and other pathological factors. The association between diabetes and cognitive impairment is largely mediated by both neurodegeneration markers and cerebrovascular diseases. However, the literature presents conflicting results on the risk and frequency of cognitive impairment in patients with type 1 and 2 diabetes. This is probably explained by limitations and variations of the studies, but also by the contribution of genetic polymorphisms to the development of cognitive impairment in patients with diabetes. This review describes rare genetic markers of cognitive disorders in type 1 and type 2 diabetes as well as their relationship with various parameters of carbohydrate metabolism and clinical manifestations of cognitive disorders.

Aim: The two-year study of the efficacy of Ifnb-1B (infibeta) in patients with relapsing-remitting (RRS) and secondary progressive multiple sclerosis (SPMS) in the Moscow region with the criteria NEDA-3., Material and Methods: Three hundred patients, 81 men and 219 women, aged from 18 to 67 years, including 227 with RRS and 73 with SPMS, were studied. The duration of disease was from 0.5 to 39 years, the level of neurological deficit on EDSS scale was from 1 to 6.5 points. All patients received infibeta., Results and Conclusion: During the treatment with infibeta, the chance of exacerbation decreased by an average of 39.4 times (OR 39.4 95% CI; 16.6-122.7) during the first year, by 35.3 times (OR 35.3; 95% CI 13.5-131,2) during the second year. A statistically significant decrease in the probability of exacerbation is also confirmed in the conditional logistic regression model (p<0.001). MRI revealed the signs of exacerbation and progression of the disease only in 11.5% of patients; 54.9% of the patients met the criteria NEDA-3. The highest efficacy of infibeta is noted in patients with RRS, more than 3 / 4 of them responded to therapy with the absence of both clinical and MRI signs of exacerbation and increase in neurodegeneration. Thus, a good clinical result is achieved in patients with RRS and SPMS treated with infibeta. When using the NEDA-3 criteria, a positive result is achieved in more than half of patients.

Development of efficient biodegradable, environmentally responsive, biocompatible and non-toxic delivery system is needed for efficient gene delivery. As well known, properties of the vehicle are determined by the structure of carrier components. The aim of the current study was to estimate in vitro transfection efficacy of aliphatic di-, tri- and tetrapeptide-based cationic lipoplexes loaded with siRNA in function of a number of cationic groups using 2D (monolayer culture) and 3D (multicellular tumor spheroids) in vitro models. Physicochemical properties and cytotoxicity of the liposomes were found to be dependent upon a number of amino acid derivatives in an amphiphilic polar head. Uptake of liposomes loaded with nucleic acid (lipoplexes) and their localization in HEK293T cells was studied by confocal microscopy. The liposomes based on lipotripeptides had the highest transfection efficiency which was 20-fold higher than those fabricated from lipotetrapeptides., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Aim: To analyze the relationship between the markers of cognitive impairment and the variability of glycaemia in patients with DM type 1., Material and Methods: Patients with DM type 1 and people without DM (the control group) were examined. Neuropsychological testing (MoCA-test), brain MRI and proton magnetic resonance spectroscopy of the brain, as well as parameters of carbohydrate metabolism (fasting blood glucose, glycated hemoglobin and glycemic variability coefficients) were used., Results and Conclusion: Data on the decrease in the overall performance of the MoCA-test (in particular, on assignments to memory and attention domains), atrophic changes in the cerebral cortex and violations of the content of the main metabolites of brain cells in patients with DM type 1 in comparison with the control group were obtained. A number of positive and negative correlations between these disorders and coefficients of glycemic variability were found in patients with DM type 1. The results suggest a significant negative effect of high levels of glycaemia variability on cognitive functions in patients with DM type 1.