INTERLEUKIN 33 AND FIBROSIS: PATHOGENESIS UPDATED

Interleukin 33 (IL-33) is a member of the IL-1 family, which is widely expressed on all types of cells. IL-33 was identified as a functional ligand for the plasma membrane receptor complex, which is a heterodimer consisting of a membrane bound ST2 receptor (growth stimulating factor). IL-33 is involved in the development of immune response with predominant release of pro-inflammatory T helper type 2 cytokines. IL-33 is widely expressed on various structure-forming cells, such as epithelial, endothelial and smooth muscle cells. Increased expression of IL-33 is observed during necrosis of these cells (after tissue or cell damage), and it is released into extracellular space, and acts as an endogenous danger signal, sending a sort of warnings to neighboring cells and tissues. Recently, many studies have shown that IL-33 can participate in development and progression of fibrosis in various organs. However, it exerts anti-inflammatory effects upon development of other diseases. This review will discuss biological characteristics of IL-33 and a role of the IL-33/ST2 signaling pathway in the development of fibrosis

Interacting circular nanomagnets

Regular 2D rectangular lattices of permalloy nanoparticles (40 nm in diameter) were prepared by the method of the electron lithography. The magnetization curves were studied by Hall magnetometry with the compensation technique for different external field orientations at 4.2K and 77K. The shape of hysteresis curves indicates that there is magnetostatic interaction between the particles. The main peculiarity is the existence of remanent magnetization perpendicular to easy plain. By numerical simulation it is shown, that the character of the magnetization reversal is a result of the interplay of the interparticle interaction and the magnetization distribution within the particles (vortex or uniform).Comment: 16 pages, 8 figure

Magnetization curves for two-dimensional rectangular lattices of permalloy nanoparticles: experimental investigation and numerical simulation

Abstract This work is concerned with the behaviour of a regular 2D rectangular lattice of Ni 3 Fe nanoparticles, determined by the dipole interaction between them. The samples under study, prepared by electron-beam lithography, consisted of about 10 5 particles approximately 50 nm in size. The magnetization curves were studied by Hall magnetometry for different external magnetic field orientations at 4.2 K and 77 K. The results indicate a collective behaviour of the system. The magnetization curves depend on the external magnetic field direction and temperature; the system exhibits multistability. A model system of interacting 3D magnetic dipoles forming a rectangular lattice was numerically simulated by solving a system of stochastic Landau-Lifshitz equations. The multistability of the system and steps in the magnetization curves were obtained. It is shown analytically that the shape of the magnetization curves depends on the character of the interaction in the system

Thrombocyte aggregation activity in the conditions of intensive light deprivation

The aim of the research was to study the effect of photoperiodism disturbances on platelet aggregation activity. Material and methods. The experiment was conducted in two stages in 5 groups of male rats: the control group and four experimental groups. At the first stage, the animals were exposed to 24 h/day continuous light (24L:0D) for 10 and 21 days. In the second stage, animals after 10 and 21 days of round-the-clock lighting were returned to natural lighting for a period of 21 days to study the reversibility of changes. Animals were withdrawn from the experiment by intramuscular injection based on body weight of drugs for anesthesia (telazol, xylanite). Blood sampling was performed by puncture of the right heart. The functional activity of platelets was determined no later than 3 hours after the collection of blood. Results and discussion. The results of the experiment indicate a direct effect of light desynchronosis on the increase in platelet aggregation ability, while it was noted that the degree of increase in aggregation activity and reversibility of changes directly depend on the duration of round-the-clock lighting. So, a 10-day stay of animals in conditions of abnormal lighting leads to an increase in aggregation indices, which remain at a high level even when animals return to normal conditions. In animals that were under round-the-clock illumination for 21 days, a more pronounced increase in platelet aggregation values relative to animals on day 10 was noted. In this regard, it can be argued that circadian rhythm disturbances provoke the development of microvasculature disorders

CYTOKINE PROFILE IN VISCERAL OBESITY AND ADVERSE CARDIOVASCULAR PROGNOSIS OF MYOCARDIAL INFARCTION

Presence of myocardial infarction in patients with obesity can lead to an uncontrolled increase in proinflammatory cytokines and unfavorable course of the pathological process. Objective: to study the relationship of key inflammatory factors and the development of complications at different terms after myocardial infarction in patients with visceral obesity. The study involved 94 men with myocardial infarction. Visceral obesity was diagnosed by multi-slice computed tomography (LightspeedVCT 64 ,General Electric,USA). On the 1st and 12th day of hospitalization, we determined serum concentrations of interleukins (TNFα, IL-1β, IL-6, IL-8 IL-10 and IL-12), and C-reactive protein. Adverse cardiovascular events were documented during the next year. The most informative indicators were identified by a stepwise logistic regression analysis. In patients with myocardial infarction an imbalance of cytokine profile revealed, i.e., an increase in proinflammatory markers (TNFα, IL-1β, IL-6, IL-8, IL-12, CRP), along with decrease in IL-10, being more pronounced in cases of visceral obesity. Among the studied markers, closest relationship was observed between visceral obesity and serum concentrations of IL-6 and CRP. Over the year, adverse cardiovascular events proved to be more frequent in patients with visceral obesity. Post-infarction complication risk was associated with higher concentrations of IL-6, IL-12 and IL-10 deficiency. Hence, development of adverse cardiovascular events within a year after myocardial infarction is more typical to the patients with visceral obesity, and is accompanied by activation of proinflammatory cytokines and IL-10 deficiency

ИНФАРКТ МИОКАРДА ВТОРОГО ТИПА: СОВРЕМЕННЫЕ ОСОБЕННОСТИ ДИАГНОСТИКИ И ЛЕЧЕНИЯ

Aim. To determine the frequency of detection of patients with myocardial infarction (MI) type 2 and their features in real clinical practice.Methods. A prospective study of 204 patients diagnosed with acute coronary syndrome (ACS) was performed. Diagnosis of ACS at admission followed by a confirmed diagnosis of MI during the hospital period according to the Fourth Universal Definition of MI. The following were analyzed: anthropometric parameters, clinical and anamnestic characteristics of patients, results of laboratory research methods, determination of biochemical markers of myocardial necrosis, results of instrumental diagnostic methods and coronary angiography. The annual follow-up stage was carried out in the form of a telephone survey of patients with a follow-up of dynamic features during the year after ACS (presence of endpoints: repeated coronary events, death, repeated hospitalizations, adherence to medical recommendations, therapy taken by the patient).Results. Type 2 MI was diagnosed in 22 (10.8%) cases. The results of coronary angiography demonstrated the absence of coronary artery (CA) in 16 (72.7%) patients of this group or the presence of stenoses of less than 50% without indications of the presence of thrombosis. Chronic occlusion of the infarct-unrelated coronary artery was found in 6 (27.3%) patients. Patients with type 2 MI were comparable in age with the group of patients with type 1 MI. Differences were female predominance (p = 0.029), fewer smokers (p = 0.037) and more frequent history of atrial fibrillation (AF) (p = 0.003). The most frequent provoking factors of type 2 MI were determined: sinus tachycardia in 3 (13.6%) patients, flutter paroxysm or AF with tachysystole for the ventricles in 4 cases (18.2%).Conclusion. A less favorable course of the disease was found in patients with type 1 MI. A feature of the post-infarction period in this case was the greatest number of recurrent MI and deaths during the year compared with patients after type 2 MI, which were characterized by a predominance of women, a smaller number of smokers and people with dyslipidemia, as well as a more frequent indication of the presence of AF.Основные положенияВыявлены особенности отдаленного постинфарктного периода у больных инфарктом миокарда 2-го типа в виде благоприятного течения при сравнении с больными ИМ 1-го типа. Определены различия клинико-анамнестических данных пациентов с ИМ 1-го и 2-го типа. Аннотация:Цель. Определить частоту выявления пациентов с инфарктом миокарда (ИМ) 2-го типа и их особенностей в реальной клинической практике.Материалы и методы. Проведено проспективное исследование 204 пациентов с диагнозом «острый коронарный синдром (ОКС)». В исследование вошли лица с установленным при поступлении ОКС и последующим диагнозом ИМ, подтвержденным в госпитальном периоде согласно Четвертому универсальному определению ИМ. Проанализированы антропометрические показатели, клинико-анамнестические характеристики пациентов, результаты лабораторных методов исследования, биохимические маркеры некроза миокарда, результаты инструментальных методов диагностики и коронароангиографии. Годовой этап наблюдения осуществлялся в виде телефонного опроса пациентов с целью отслеживания динамических особенностей в течение года после перенесенного ОКС (наличия конечных точек: повторных коронарных событий, летального исхода, повторных госпитализаций по причине кардиальных и внекардиальных событий; приверженности врачебным рекомендациям и принимаемой терапии).Результаты. Диагноз ИМ 2-го типа установлен в 22 (10,8%) случаях. Результаты коронарографии продемонстрировали отсутствие поражения коронарных артерий у 16 (72,7%) больных этой группы или наличие стенозов менее 50% без указаний на тромбоз. Хроническая окклюзия инфаркт-несвязанной коронарной артерии обнаружена у 6 (27,3%) пациентов. Пациенты с ИМ 2-го типа оказались сопоставимы по возрасту с группой больных ИМ 1-го типа. Отличия заключались в преобладании лиц женского пола (p = 0,029), меньшем количестве курящих пациентов (p = 0,037) и более частом указании на наличие фибрилляции предсердий в анамнезе (p = 0,003). Определены факторы, наиболее часто провоцирующие ИМ 2-го типа: синусовая тахикардия – у 3 (13,6%) пациентов, пароксизм трепетания или фибрилляции предсердий с тахисистолией желудочков – в 4 (18,2%) случаях.Заключение. Выявлено менее благоприятное течение заболевания у пациентов, перенесших ИМ 1-го типа. Особенностью постинфарктного периода в данном случае стало наибольшее количество повторных ИМ и летальных исходов в течение года по сравнению с пациентами после ИМ 2-го типа, которые характеризовались преобладанием женщин, меньшим количеством курящих и лиц, имеющих дислипидемию, а также более частым указанием на наличие фибрилляции предсердий

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Prevalence of electrocardiographic changes in Kemerovo region according to the data of the ESSE-RF study

Aim. To study the prevalence of ECG changes associated with gender and age according to the program ESSE-RF, Kemerovo.Material and methods. The object of the study is a random sampling of male and female population aged 25-64, Kemerovo. The standard 12-leads ECG was captured in 1623 people. Coding was carried out according to the Minnesota code. The average age of the respondents was 49 years (37; 57), men, 47 years (36; 56), women, 50 years (38; 57), (p=0,004).Results. The ECGs changes were recorded in 265 people (16,3%), in 124 men (17,8%) and 141 women (15,2%) (p=0,159). Heart rhythm disturbances were revealed in 108 people (6,7%), intraventricular conduction disturbances in 147 (9%). The most frequently recorded changes in the T wave (in 11,2% of the subjects), ST segment changes take the second place (in 5,1%), the pathological Q wave was registered less frequently (in 2,5%). In men, the ECG signs of LV hypertrophy, rhythm disturbances, the pathological Q wave were more often detected. In the group of the 50-64-year-olds, the pathological Q wave, changes in ST segment and T wave, rhythm and conduction disturbances were detected significantly more often as well as the greater prevalence of risk factors of ischemic heart disease.Conclusion. Detection of ECG changes is an important stage in the formation of a risk group at the development and progression of the cardiovascular pathology

Visceral adiposity index in patients with coronary artery disease, obesity and type 2 diabetes

Aim. To assess visceral adiposity index (VAI) in patients with coronary artery disease (CAD) and overweight or obesity, as well as to determine its relationship with lipid and carbohydrate metabolism parameters and inflammatory markers, depending on the presence of carbohydrate metabolism disorders (CMD).Material and methods. The study included 95 patients with CAD and overweight (body mass index (BMI) >25 kg/m2) or obesity (BMI >30 kg/m2), of which 59 patients had type 2 diabetes (T2D) and 36 were without CMD. All patients were assessed for obesity; VAI was calculated. Following laboratory parameters were evaluated: glucose, glycated hemoglobin, C-reactive protein, adiponectin, lipid panel. In patients without history of CMD, an oral glucose tolerance test was performed.Results. Compared with patients without CMD, subjects with T2D had significantly higher values of BMI, waist circumference, as well as the body fat percentage, area and volume of visceral adipose tissue estimated by computed tomography. Analysis of lipid profile, C-reactive protein and adiponectin levels did not reveal significant differences between the groups. VAI also did not significantly differ in both groups. VAI had the most correlations with clinical and metabolic parameters in both patients with T2D and without CMD. Other methods for assessing obesity were less correlated with laboratory parameters in both groups. Only VAI significantly correlated with adiponectin in both groups.Conclusion. The obtained correlations between VAI and clinical and metabolic parameters confirm the practicability of using it to determine adipose tissue dysfunction in patients with/without CMD. The effect of increased VAI on the cardiovascular risk in high-risk patients requires further study

Two Novel Mutations Associated With Ataxia-Telangiectasia Identified Using an Ion AmpliSeq Inherited Disease Panel

Ataxia-telangiectasia (A-T), or Louis-Bar syndrome, is a rare neurodegenerative disorder associated with immunodeficiency. For families with at least one affected child, timely A-T genotyping during any subsequent pregnancy allows the parents to make an informed decision about whether to continue to term when the fetus is affected. Mutations in the ATM gene, which is 150 kb long, give rise to A-T; more than 600 pathogenic variants in ATM have been characterized since 1990 and new mutations continue to be discovered annually. Therefore, limiting genetic screening to previously known SNPs by PCR or hybridization with microarrays may not identify the specific pathogenic genotype in ATM for a given A-T family. However, recent developments in next-generation sequencing technology offer prompt high-throughput full-length sequencing of genomic fragments of interest. This allows the identification of the whole spectrum of mutations in a gene, including any novel ones. We report two A-T families with affected children and current pregnancies. Both families are consanguineous and originate from Caucasian regions of Russia and Azerbaijan. Before our study, no ATM mutations had been identified in the older children of these families. We used ion semiconductor sequencing and an Ion AmpliSeq™ Inherited Disease Panel to perform complete ATM gene sequencing in a single member of each family. Then we compared the experimentally determined genotype with the affected/normal phenotype distribution in the whole family to provide unambiguous evidence of pathogenic mutations responsible for A-T. A single novel SNP was allocated to each family. In the first case, we found a mononucleotide deletion, and in the second, a mononucleotide insertion. Both mutations lead to truncation of the ATM protein product. Identification of the pathogenic mutation in each family was performed in a timely fashion, allowing the fetuses to be tested and diagnosed. The parents chose to continue with both pregnancies as both fetuses had a healthy genotype and thus were not at risk of A-T