SYNOPSIS AND PROSPECTS OF AUTOIMMUNOLOGY DEVELOPMENT WORLDWIDE (AFTER THE MATERIALS OF THE 11th INTERNATIONAL CONGRESS IN LISBON, MAY 16-20, 2018). PROCEEDING I: FIRST ACADEMY OF AUTOIMMUNITY

A review article is an aftermath of the 11th International Congress on Autoimmunity and First Academy of Autoimmunity, happened 14th to 20th May, 2018 in Lisbon. The first part of paper discusses the formation, main problems and prospects for the development of Autoimmunology as a new integral branch of fundamental and clinical Medicine engaged in the research, diagnosis, treatment and prevention of autoimmune diseases of various organs and systems, totally circa 90 of them. A summary of all lectures conducted during the Academy of Autoimmunity is given, including a discussion of the newest and controversial aspects of the development of the modern concepts of the immune system, autoimmunity and autoimmune pathology. Article reviews data on the current problems of Immunology associated with the use of large databases of clinical and laboratory findings and extrapolation of animal experimentation data to humans. The newest ideas about congenital immunity, including the populations of innate lymphoid cells, on the role of various groups of receptors of the innate immunity system, on the participation of the mechanisms of innate immunity in pathogenesis of autoimmune disorders are highlighted. Modern concepts of antigen presentation are offered, including classification of dendritic cells, alternative pathways of macrophage activation, as well as on costimulatory and inhibitory interactions of ligands and receptors of lymphocytes and antigen-presenting cells. The latest data about the subpopulations of T lymphocytes and their role, including the functions of Tfh cells and the relationships of these subpopulations with various immune responses are highlighted. Influence of microbiota on T cell subpopulations is discussed. The main regularities of the phenomenon of immunological memory are formulated. The questions of antibody production and B lymphocyte functions are considered taking into account recently discovered mechanisms of intracellular penetration of immunoglobulins and details of affinity maturation of lymphoid clones. The new therapeutic approaches in the treatment of autoimmune diseases associated with influences on B and T lymphocytes are described. Mechanisms of central and peripheral autotolerance have been highlighted, taking into account data on the function of the AIRE gene and T regulators. The role of T regulators in placentation is considered. The role of interleukin-2 and its recombinant analogues in immune interactions is interpreted in a new way, taking into account not only their immunostimulating, but, under certain conditions, immunosuppressive potential also. Considerable attention has been paid to the inhibitory receptors of T lymphocytes and to immuno-biotherapeutic effects on them. The history and current status of Oncoimmunology and the use of blockers of inhibitory T lymphocyte receptors in Oncology, including the side effects of treatment with check-point inhibitors, are briefly discussed. Information was given on the held on 21-23 September 2018 2nd Academy of Autoimmunity in St. Petersburg

COMPARATIVE CHARACTERISTICS OF IMMUNOLOGICAL RECONSTRUCTION OF WHITE MICE IMMUNIZED BY CELL WALL OF DIFFERENT SUBSPECIES OF FRANCISELLA TULARENSIS

At present, development of effective vaccines of new generation is an actual problem, in particular concerning the tularemia causative agent. It determines the need to search antigen determinants with high immunogenic activity. Some authors demonstrate that outer membrane proteins of Francisella tularensis possess immunological activity. This fact gave occasion to isolation and comprehensive study of F tularensis cellular envelopes as a perspective component in vaccine engineering. The influence of cell walls of F. tularensis was studied for morphological changes in immunocompetent organs of experimental animals. Cell walls were obtained from three virulence strains of living cultures: F. tularensis subsp. mediaasiatica А-61, F. tularensis subsp. nearctica В-399 A-Cole, F. tularensis subsp. holarctica 306 and vaccine strain F. tularensis subsp. holarctica 15 (extracted by Research Institute of Epidemiology and Hygiene). Cell walls of different subspecies of F. tularensis stimulate the production of antibody forming cells and cell proliferation more in T-dependent zones of lymph nodes and spleen. It has been determined that these antigen preparations do not cause stress reaction of the experimental animal organisms. Basing on the findings, we made a conclusion that there is a need for further detailed investigation of immunogenic properties of CE F. tularensis subsp. holarctica 306, F. tularensis subsp. mediasiatica А-61 and F. tularensis subsp. tularensis B-399 A-Cole as perspective components in development of tularemia vaccines

Features of COVID-19 course in patients with obesity and dysglycemia

Aim. To study the features of coronavirus disease 2019 (COVID-19) in patients with different severity of carbohydrate metabolism disorders (CMDs), taking into account the possible role of obesity in the acceleration of clinical and laboratory disorders.Material and methods. There were 137 consecutive patients admitted to the infectious disease hospital for COVID-19patients. Three 3 groups were formed: group 1 — 42 patients with concomitant type 2 diabetes (T2D); group 2 — 13 patients with concomitant prediabetes; group 3 — 82 patients without concomitant CMDs.Results. Patients with T2D tended to have a more severe disease course according to the SMRT-CO algorithm (p=0,089), which was associated with the longest hospital stay (p=0,038), the most pronounced (p=0,011) and prolonged (p=0,0001) decrease in oxygen saturation, the maximum percentage of lung injury at the beginning (p=0,094) and at the end (p=0,007) of hospitalization, the greater need for intensive care unit (p=0,050), as well as the highest increase in C-reactive protein and fibrinogen (hypercoagulability and systemic inflammation were noted in all groups). Patients with prediabetes in terms of COVID-19 severity occupied an intermediate position between those with T2D and without CMDs; at the same time, they most often needed the prescription of biological preparations (p=0,001). In the first and second groups, there were larger, compared with the control, proportions of obese people (61,9%, 53,8% and 30,5%, respectively, p=0,003). Prediabetes group had a strong correlation between the severity of viral pneumonitis according to SMRT-CO and the presence of obesity (R=0,69, p=0,009).Conclusion. In patients with impaired carbohydrate metabolism of any severity, COVID-19 is more severe. At the same time, persons with overt T2D are prone to the most severe COVID-19 course, while patients with prediabetes in terms of disease severity occupy an intermediate position between them and those without CMDs. Obesity is a strong risk factor for severe COVID-19 among patients with initial CMDs (prediabetes), which is partly mediated by prior liver dysfunction associated with the metabolic syndrome. The increase in proinflammatory changes and hypercoagulability is associated with COVID-19 severity in patients with and without CMDs. These disorders had the greatest severity and persistence in patients with T2D

Results of the study of the immunogenic activity of cell envelopes of Francisella tularensis different subspicies (Report 2)

The effect of cell envelopes preparations of four subspecies of Francisella tularensis, derived from urea lysates of tularemia microbe on cytokine production by immunocompetent cells of experimental animals has been studied. Stimulating influence of F. tularensis cell envelopes preparations on cytokine synthesis on the 7th day after inoculation was shown. The results showed that the cell envelopes of different subspecies F. tularensis have different stimulatory effect on the production of proinflammatory cytokines and growth factors GM-CSF and G-CSF, further defining the immune system of host.The results allow to consider cell envelopes preparations of F. tularensis as constituent component in the development of subunit vaccines

Single step process for the synthesis of carbon nanotubes and metal/alloy-filled multiwalled carbon nanotubes

A single-step approach for the synthesis of multi-walled nanotubes (MWNT) filled with nanowires of Ni/ternary Zr based hydrogen storage alloy has been illustrated. We also demonstrate the generation of CO-free hydrogen by methane decomposition over alloy hydride catalyst. The present work also highlights the formation of single-walled nanotubes (SWNT) and MWNTs at varying process conditions. These carbon nanostructures have been characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), high resolution TEM (HRTEM), Energy dispersive X-ray analysis (EDX) and Raman spectroscopy. This new approach overcomes the existing multi-step process limitation, with possible impact on the development of future fuel cell, nano-battery and hydrogen sensor technologies

Применение двух форм ингаляционного бесфреонового беклометазона дипропионата у больных бронхиальной астмой

The aim of this study was to compare clinical efficiency of Freon-free ultra-fine metered dose aerosol of beclomethasone dipropionate (BDP) (Beclason ECO) and Easy-Breath system (Beclason ECO EB), or an inhaler with larger BDP particles (Beclojet). Methods. The study involved 120 moderate to severe asthma (BA) patients (the average age, 50 yrs; the mean length of the disease, 12 to 13 yrs). More than 75 % of the Beclason and Beclojet group patients have received inhaled steroids when starting the study (the mean doses, 542 ± 308 and 641 ± 379 mcg daily, respectively). The patients have been treated with Beclason ECO 500 mcg daily or Beclojet 1 000 mcg daily (moderate BA), Beclason ECO EB 750 mcg daily or Beclojet 1 500 mcg daily (severe BA) for 12 wks. Results. FEV1 increased by 18 and 20 % in Beclason ECO / Beclason ECO EB group and Beclojet group, correspondingly; FVC increased by the 11 and 21 %, and FEF25–75 grew by 26 and 24 % correspondingly by the end of the study. Daytime symptoms improved by 1.6 and 1.3 scores in the Beclason ECO / Beclason ECO EB patients and Beclojet patients correspondingly and nighttime symptoms improved by 1.0 score in both the groups. The need in beta-2-agonists reduced during the study by 3.1 and 3.4 doses daily correspondingly in the groups. Quality of life improved in both the groups, the difference between the groups was not significant. The inhaled drugs were well-tolerated, rate of unwanted events was low and quite similar in both the groups. Therefore, the freon-free ultra-fine aerosols of BDP (Beclason ECO and Beclason ECO EB) have the comparable clinical efficiency with freon-free non-ultra-fine aerosol (Beclojet) in the dose ratio 2 : 1.Цель исследования — изучение клинической эффективности применения в 2 раза меньшей дозы бесфреонового ультрамелкодиспесного беклометазона дипропионата (БДП) в обычном дозированном аэрозольном ингаляторе (Беклазон ЭКО) и в форме ингалятора Легкое Дыхание (Беклазон ЭКО ЛД) по сравнению с немелкодисперсным аналогом (Беклоджет). Методы. В исследование были включены 120 больных бронхиальной астмой (БА) тяжелого и среднетяжелого течения (средний возраст — около 50 лет, средняя длительность заболевания — 12–13 лет). Свыше 75 % больных на момент включения в исследование принимали иГКС (средняя доза — 542 ± 308 и 641 ± 379 мкг / сут. в группах больных, принимающих Беклоджет и Беклазон). Больные в течение 12 нед. получали терапию Беклазоном или Беклоджетом (среднетяжелая астма — Беклазон ЭКО 500 мкг / сут. либо Беклоджет 1 000 мкг /сут.; тяжелая астма — Беклазон ЭКО ЛД 750 мкг / сут. либо Беклоджет 1 500 мкг / сут.). Результаты. К концу исследования ОФВ1 вырос в среднем на 18 и 20 % в группах Беклазона ЭКО / Беклазона ЭКО ЛД и Беклоджета, ФЖЕЛ — на 11 и 21 %, МОС25–75% — на 26 и 24 % соответственно. Выраженность дневных симптомов уменьшилась в среднем на 1,6 и 1,3 балла в группах Беклазона ЭКО / Беклазона ЭКО ЛД и Беклоджета, выраженность ночных симптомов — на 1,0 и 1,0 балла соответственно. Во время исследования в обеих группах больных значительно сократилось число ингаляций β2-агонистов короткого действия — в среднем на 3,1 и 3,4 инг. в сутки. Отмечено значительное клинически значимое улучшение качества жизни у больных сравниваемых групп, при этом различий отмечено не было. Сравниваемые препараты хорошо переносились больными, число побочных эффектов было невелико и практически не различалось между группами больных. Выводы. Препараты бесфреонового БДП в виде ультра-мелкодисперсной формы (ингаляторы Беклазон ЭКО и Беклазон ЭКО ЛД) по своей клинической эффективности сравнимы с препаратами бесфреонового немелкодисперсного БДП (Беклоджет) при соотношении доз БДП 2 : 1

Neural Substrate of Cold-Seeking Behavior in Endotoxin Shock

Systemic inflammation is a leading cause of hospital death. Mild systemic inflammation is accompanied by warmth-seeking behavior (and fever), whereas severe inflammation is associated with cold-seeking behavior (and hypothermia). Both behaviors are adaptive. Which brain structures mediate which behavior is unknown. The involvement of hypothalamic structures, namely, the preoptic area (POA), paraventricular nucleus (PVH), or dorsomedial nucleus (DMH), in thermoregulatory behaviors associated with endotoxin (lipopolysaccharide [LPS])-induced systemic inflammation was studied in rats. The rats were allowed to select their thermal environment by freely moving in a thermogradient apparatus. A low intravenous dose of Escherichia coli LPS (10 µg/kg) caused warmth-seeking behavior, whereas a high, shock-inducing dose (5,000 µg/kg) caused cold-seeking behavior. Bilateral electrocoagulation of the PVH or DMH, but not of the POA, prevented this cold-seeking response. Lesioning the DMH with ibotenic acid, an excitotoxin that destroys neuronal bodies but spares fibers of passage, also prevented LPS-induced cold-seeking behavior; lesioning the PVH with ibotenate did not affect it. Lesion of no structure affected cold-seeking behavior induced by heat exposure or by pharmacological stimulation of the transient receptor potential (TRP) vanilloid-1 channel (“warmth receptor”). Nor did any lesion affect warmth-seeking behavior induced by a low dose of LPS, cold exposure, or pharmacological stimulation of the TRP melastatin-8 (“cold receptor”). We conclude that LPS-induced cold-seeking response is mediated by neuronal bodies located in the DMH and neural fibers passing through the PVH. These are the first two landmarks on the map of the circuitry of cold-seeking behavior associated with endotoxin shock

Эффективность и безопасность применения бовгиалуронидазы азоксимера (Лонгидаза) у пациентов с постковидным синдромом: результаты открытого проспективного контролируемого сравнительного многоцентрового клинического исследования DISSOLVE

Post-COVID syndrome develops after COVID-19 (COronaVIrus Disease 2019) and leads to cumulative effects in the form of shortness of breath and impaired lung function. Notably, patients with airway inflammation and COVID-19 were found to have increased concentrations of hyaluronic acid (HA). Since bovhyaluronidase azoximer (Longidase®) catalyzes the hydrolysis of HA, this drug has the potential to reduce HA levels and improve lung function in patients with post-COVID syndrome.The aim of the DISSOLVE trial, which was conducted early in the pandemic, was to investigate the efficacy and safety of bovhyaluronidase azoximer in patients with symptoms associated with post-COVID syndrome.Methods. An open, prospective, controlled, comparative, multicenter clinical trial (NCT04645368) included adult patients (n = 160) who had post-COVID syndrome. Patients in the treatment group (n = 81) received bovhyaluronidase azoximer, and individuals in the control group (n = 79) were followed up without intervention. The study included physical examination, evaluation of forced vital capacity (FVC), assessment of dyspnea with the Modified Medical Research Council Dyspnea Scale (mMRC), 6-minute walking test, and pulse oximetry. These indicators were measured on 3 visits, at days 1 (baseline), 75, and 180. In addition, the number of patients who experienced adverse events and serious adverse events were recorded.Results. Baseline patient characteristics in the treatment group and the control group were similar. In the treatment group, there was a statistically significant reduction in residual pulmonary abnormalities after visit 2 (day 75) and visit 3 (day 180). In addition, FVC, pulse oximetry values, and functional exercise tolerance increased statistically significantly at days 75 and 180 compared to baseline. The mMRC scores for dyspnea decreased statistically significantly in the treatment group over 75 days. The safety profile of the drug was reported to be favorable throughout the study. Conclusion. Treatment with bovhyaluronidase azoximer in patients with post-COVID syndrome showed improvement in FVC, pulse oximetry, functional exercise tolerance, and mMRC dyspnea.Постковидный синдром (ПКС) после перенесенного COVID-19 (COronaVIrus Disease 2019) – это состояние, которое развивается у пациентов, переболевших COVID-19 и приводит к кумулятивным эффектам в виде одышки и нарушения функции легких. Примечательно, что у пациентов с воспалением дыхательных путей и COVID-19 обнаружены более высокие концентрации гиалуроновой кислоты (ГК). Поскольку бовгиалуронидаза азоксимер (Лонгидаза®) катализирует гидролиз ГК, при назначении данного препарата потенциально можно ожидать снижение концентрации ГК и улучшения функции легких у пациентов с ПКС.Целью исследования DISSOLVE, которое проводилось на начальной стадии пандемии, явилось изучение эффективности и безопасности применения бовгиалуронидазы азоксимера у пациентов с симптомами, связанными с ПКС.Материалы и методы. В открытом проспективном контролируемом сравнительном многоцентровом клиническом исследовании (NCT04645368) принимали участие взрослые пациенты (n = 160), у которых выявлен ПКС. Пациенты, составившие группу лечения (n = 81), получали бовгиалуронидазу азоксимер, лица, составившие группы контроля (n = 79), наблюдались динамически. В рамках исследования выполнялось физикальное обследование, проводилась оценка показателей форсированной жизненной емкости легких (ФЖЕЛ), одышки по шкале модифицированного вопросника Британского медицинского исследовательского совета (Modified Medical Research Council Dyspnea Scale – mMRC), дистанции, пройденной при выполнении 6-минутного шагового теста, и пульсоксиметрии. Эти показатели измерялись в рамках 3 визитов: в 1-й (исходный уровень), 75-й и 180-й дни. Кроме того, регистрировалось число пациентов, у которых наблюдались нежелательные явления (НЯ) и серьезные НЯ.Результаты. Исходные характеристики у пациентов группы лечения и контрольной группы были сходными. В группе лечения отмечено статистически значимое снижение остаточных легочных изменений после визита 2 (75-й день) и визита 3 (180-й день); кроме того, показатели ФЖЕЛ, пульсоксиметрии и переносимости функциональных физических нагрузок статистически значимо увеличились на 75-й и 180-й дни относительно исходного уровня. Показатели одышки по шкале mMRC в группе лечения статистически значимо снизились в течение 75 дней. Профиль безопасности препарата отмечался как благоприятный на протяжении всего исследования.Заключение. При терапии бовгиалуронидазой азоксимером у пациентов с ПКС отмечено улучшение показателей ФЖЕЛ, пульсоксиметрии, переносимости функциональных физических нагрузок и оценки одышки по mMRC

Severe plastic deformation for producing superfunctional ultrafine-grained and heterostructured materials: An interdisciplinary review

Ultrafine-grained and heterostructured materials are currently of high interest due to their superior mechanical and functional properties. Severe plastic deformation (SPD) is one of the most effective methods to produce such materials with unique microstructure-property relationships. In this review paper, after summarizing the recent progress in developing various SPD methods for processing bulk, surface and powder of materials, the main structural and microstructural features of SPD-processed materials are explained including lattice defects, grain boundaries and phase transformations. The properties and potential applications of SPD-processed materials are then reviewed in detail including tensile properties, creep, superplasticity, hydrogen embrittlement resistance, electrical conductivity, magnetic properties, optical properties, solar energy harvesting, photocatalysis, electrocatalysis, hydrolysis, hydrogen storage, hydrogen production, CO2 conversion, corrosion resistance and biocompatibility. It is shown that achieving such properties is not limited to pure metals and conventional metallic alloys, and a wide range of materials are currently processed by SPD, including high-entropy alloys, glasses, semiconductors, ceramics and polymers. It is particularly emphasized that SPD has moved from a simple metal processing tool to a powerful means for the discovery and synthesis of new superfunctional metallic and nonmetallic materials. The article ends by declaring that the borders of SPD have been extended from materials science and it has become an interdisciplinary tool to address scientific questions such as the mechanisms of geological and astronomical phenomena and the origin of life