Hyperproduction Of Proinflammatory Cytokines Research Articles

SEPSIS-LIKE СИНДРОМ У НОВОРОЖДЕННОГО РЕБЕНКА ПРИ НАРУШЕНИИ ЦИКЛА ОБРАЗОВАНИЯ МОЧЕВИНЫ

Sepsis-like syndrome is a septic–like syndrome. The pathogenesis of Sepsis-like syndrome is based on the hyperproduction of proinflammatory cytokines. Hereditary metabolic disorders, including in violation of the urea formation cycle, can occur with the clinic of Sepsis-like syndrome. Ammonium easily penetrates the blood-brain barrier, causes neurotoxic effects, damages glial cells, increases osmolarity, which leads to cerebral edema. The symptoms are similar to hypoxic-ischemic lesions of the central nervous system, meningoencephalitis, intrauterine infections, which leads to a differential diagnostic search for causes and the need to exclude an infectious disease. The article presents a clinical case of a newborn with a Sepsis-like syndrome clinic. The girl was born from 2 births naturally at the age of 38 weeks. In the first day of life, there were signs of respiratory failure. She was on mixed feeding. From the 5th day of life, the deterioration of the condition caused by the syndrome of central nervous system depression, with an increase in depression of consciousness up to coma, the development of seizures. Differential diagnosis was performed with intrauterine infections, sepsis, as there was leukocytosis in the blood, increased ESR, ferritin, procalcitonin, and seeding from the cerebrospinal fluid of Micoplasma hominis. The presence of low urea content in the blood serum, up to its absence, made it possible to suspect hereditary metabolic diseases with a violation in the urea cycle. The conducted examinations revealed a total increase in the concentration of amino acids in the blood using the method of tandem mass spectrometry, metabolites in urine and hyperammonemia up to 354 mcg/dl. The newborn received antibacterial therapy, anticonvulsant therapy, sodium benzoate, and was transferred to a specialized therapeutic mixture "Nutrigen". Despite the therapy, neurological symptoms increased and the girl died at the age of 3 months. This clinical case showed the difficulties of differentiation. diagnosis of causes in the presence of Sepsis-like syndrome in newborn children.

Pathogenetic and clinical features of stroke associated with COVID-19

The novel coronavirus infection COVID-19 remains at the peak of current medical and social problems around the world. The incidence of the coronavirus infection remains at a fairly high level, despite new methods of diagnosis and treatment. The highest incidence of COVID-19 cases is observed among people with concomitant cardiovascular diseases. Such patients quite often develop COVID-19‑associated complications from various organs and systems, among which acute stroke is the most severe. The pathogenesis of stroke in COVID-19 is multifaceted. The key mechanisms for the development of acute cerebrovascular accidents in severe infections are the disruption of regulatory cortical and vegetative functions, hyperproduction of proinflammatory cytokines, and the disorder in the hemostasis system. This article analyzes current literature data on the features of the pathogenesis of stroke and its clinical course in patients with the novel coronavirus infection.

Shared features of pathogenetic aspects, autoimmunity and pharmacotherapy in coronavirus infection (COVID-19) and immunoinflammatory rheumatic diseases

The review is devoted to the relationship between the pathogenetic mechanisms of coronavirus infection (COVID-19) and immunoinflammatory rheumatic diseases (IRD). The current knowledge on the pathogenesis of COVID-19 is summarized, including the mechanisms of coagulopathy, hyperproduction of pro-inflammatory cytokines, and antiphospholipid antibodies that are common with IRD. The presence and clinical significance of detection of various autoantibodies in COVID-19, which probably play a pathogenetic role in immune dysregulation, were analyzed. Based on the data of recent studies, risk factors and features of the severe course of infection in patients with IRD are considered.

Biological activity of interferons in the novel coronavirus infection COVID-19

The immunopathogenesis of the novel coronavirus infection COVID-19 is usually associated with the development of imbalance in the immune response to its causative agent, SARS-CoV-2 virus (Coronaviridae: Coronavirinae: Betacoronavirus: Sarbecovirus). This is manifested, in particular, by interferons' (IFNs) deficiency at the beginning of the disease followed by hyperproduction of pro-inflammatory cytokines. The virus causes a decrease in IFN types I (α/β) and III (λ) levels; changes in IFN type II (γ) are less studied. In this regard, it is relevant to assess the functional bioactive IFN (interferon status) in COVID-19. The aim of the study was to assess the antiviral potential of the body by testing the biologically active IFNs in COVID-19. We used biological serum samples of COVID-19 patients taken in the acute phase (110 patients on the 1-5 days of the disease) and during rehabilitation (47 patients during 1-3 months after the disease onset). Assessment of interferon status was performed according to the technique developed by the authors and described earlier. The IFN status of patients with COVID-19 in the acute period and in the phase of post-infection rehabilitation was studied вduring the observation period. It was found that SARS-CoV-2 causes a pronounced inhibition of biological activity of IFN types I and II compared to the reference values by more than 20 and 7 times, respectively. During the post-COVID period, incomplete recovery of the IFN system activity was registered, which proceeded very slowly. No cases of reaching physiological indicators of interferon status were identified during the observation period. The obtained data on deficiency of the functional biologically active IFN confirm the hypothesis about the predominant role of impaired IFN production of different types in the immunopathogenesis of the novel coronavirus infection.

Оценка факторов риска в течении ревматоидного артрита и анкилозирующего спондилита

The purpose — to study individual risk factors and their influence on the course of rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Material and methods. Patients with RA and AS took part in the research; the group of comparison was practically healthy people. We evaluated clinical condition and laboratory indicators (the level of cytokines, lymphocyte subpopulation, rheumatoid factor, antibodies to the cyclic citrullinated peptide, S-reactive protein, proinflammatory cytokines, monocyte-macrophage protein, vascular endothelial factor, and cell cycle analysis). The obtained data were processed with Statistics 7.0 software. The results were considered to be statistically reliable at р < 0.05. Results. Hyper production of proinflammatory cytokines was marked in sick patients compared with healthy ones. The analysis of peripheral blood lymphocytes in patients showed their excess in comparison to healthy people. The assessment of lymphocytes ability for blast transformation defined the lymphocytes activation with the growth of cells at apoptosis stage (G1-phase); with the decrease in the proportion of resting cells (GO-phase) in patients, the activation coefficient was significantly growing. More apoptosis activation markers were found in the group of RA patients. Changes in apoptosis were revealed with the decreased proportion of lymphocytes in unstimulated cultures of patients; at the same time, the amount of cells in apoptosis increased four times in the examined patients compared to the healthy ones. Conclusions. In patients with RA and AS, changes of the factors of the immune system wee noted as the amount of pro-inflammatory cytokines IL—1β, IL-6, TNF—α and the concentration of MSR-1, VEGF, SPB, RF increased. The enhancement of cellular apoptosis is due to the increase of the apoptosis inducer — CD95+9(FaS) lymphocytes, TNF- α, the growth of cells at pre-synthetic stage of apoptosis G1-phase and the activation coefficient.

Ювенильный артрит: этиология, патогенез, современные аспекты (обзор литературы)

В статье даны современные представления об этиологии, наследственной предрасположенности, иммунопатогенезе ювенильного ревматоидного артрита (ЮРА), одного из наиболее частых и самых инвалидизирующих ревматических заболеваний, встречающихся у детей. Этиология заболевания в настоящее время окончательно не расшифрована, существует лишь ряд более или менее обоснованных гипотез. Среди предрасполагающих факторов важную роль отводят персистирующим вирусам. Артротропные персистирующие вирусы — вирусы Коксаки, Эпштейна — Барр, цитомегаловирус, вирусы герпеса, парвовирусы, обладающие тропизмом к тканям суставов, способны длительно в них персистировать и вызывать иммунное воспаление на фоне иммунологических дефектов. Также имеются данные о связи ЮРА с инфекцией, вызванной Mycoplasma pneumoniaе и Chlamydоphila pneumoniaе. В возникновении и развитии ЮРА играет роль генетическая предрасположенность и особенности иммунной системы. Имеются сведения об ассоциации генов гистосовместимости HLA с ЮРА в целом и с отдельными вариантами заболевания. HLA А2, DR5, DR8 являются маркерами олигоартрита у девочек, имеющих увеит, с серопозитивностью по антинуклеарному фактору. HLA В27 — маркер риска развития ЮРА у мальчиков с олигоартритом или ограниченным полиартритом, с преимущественным поражением суставов нижних конечностей, с наличием энтезопатий в школьном или подростковом возрасте. HLA DR4, DR5, DRВ1-04 являются маркерами ЮРА у девочек с поражением мелких симметричных суставов кистей, серопозитивных по ревматоидному фактору, с дебютом заболевания в старшем школьном возрасте. Основу патогенеза ЮРА составляют дефекты Т- и В-клеточных иммунных реакций, приводящие к гиперпродукции провоспалительных цитокинов. Гиперпродукция провоспалительных цитокинов лежит в основе повреждения синовиальной оболочки сустава, хряща, а также в основе развития системных проявлений болезни. Среди большого количества провоспалительных цитокинов центральное место в развитии заболевания занимает фактор некроза опухоли α (ФНО-α), интерлейкины — ИЛ-6, ИЛ-1β. ФНО-α приводит к развитию хронического воспаления, деструкции хряща и кости. ИЛ-6 принадлежит исключительная роль в генезе системного варианта заболевания. С его гиперпродукцией связывают такие внесуставные проявления болезни, как лихорадка, гипохромная анемия, тромбоцитоз. ИЛ-6 стимулирует продукцию гепатоцитами острофазовых белков, играет роль в развитии ряда осложнений, таких как остеопороз и амилоидоз. Состояние цитокиновой сети при различных вариантах ЮРА до конца не изучено. Некоторые авторы указывают на максимальное повышение ИЛ-6 и ИЛ-1 при системном варианте заболевания. Значительное повышение ФНО-α выявлено у пациентов с полиартикулярным вариантом ЮРА, особенно с высокими значениями ревматоидного фактора. Уровень провоспалительных цитокинов коррелирует с активностью воспаления и отражает тяжесть заболевания, определяет дальнейший прогноз. В основе развития ревматических заболеваний у детей существенную роль играет не абсолютное количество образования тех или иных цитокинов, а дисбаланс про- и противовоспалительных цитокинов. Данный дисбаланс может возникнуть под действием повреждающего фактора: бактериальной или вирусной инфекции, переохлаждения, инсоляции, профилактических прививок, травмы суставов, неблагоприятных экологических факторов, хронических психоэмоциональных стрессов. Но у большинства детей после ликвидации действия повреждающего фактора восстанавливается нормальное соотношение цитокинов, а у детей с генетической предрасположенностью дисбаланс сохраняется, что ведет к развитию ревматической патологии.

Indexes of innate and adaptive immunity in the patients with SARS-CoV-2 infection

The main pathogenetic mechanisms of the SARS-CoV-2 infection include imbalance of immune response and impaired cytokine regulation involving insufficient interferon synthesis at the onset of the disease, and subsequent hyperproduction of proinflammatory cytokines resulting in marked inflammation and damage of pulmonary parenchyma. Our objective was to perform monitoring of cytokine content, determination of antibodies, immune cells, and inflammatory biomarkers in the patients who had coronavirus infection caused by COVID-19, during the disease and over the convalescence period. The study included sixty patients at the age of 18 y.o. and older with severe and moderate course of disease caused by COVID-19. The diagnosis was verified in accordance with provisional instructional guidelines of the Ministry of Healthcare of the Russian Federation “Prevention, diagnosis and treatment of novel coronavirus infection (COVID-19)” version 11 (17.05.2021). The study involved analysis of medical documents, evaluation of differential white blood cell count, T cell subpopulations, C-reactive ptrotein (CRP) levels, interleukin-6 (IL-6), interferon gamma (IFNγ), tumor necrosis factor-alpha (TNFα), as well as IgM and IgG antibodies against SARS-CoV-2.Statistical processing of data was performed by Statistica 13 program with critical significance level p 0.05, correlations were analyzed using Spearman rank correlation coefficient, multidimensional correlation analysis with creation of pleiads, according to V.P. Terentyev’s method (1959), and Shapiro–Wilk testing for normality of data distributions. The sample size made it possible to evaluate the results at a significance of 95-99%. These studies have yielded the results concerning specific changes of the inflammatory biomarkers at different stages of disease, persistent changes in quantitative and qualitative characteristics of immune cells and cytokine levels, correlations between immunological indicators and severity of clinical course, and degree of damage to pulmonary parenchyma. During the period of significant clinical presentations, the patients with severe course of disease exhibited leukopenia with low proportion of lymphocytes, and maintenance of CRP and ESR at high levels for longer terms, including early recovery. Levels and changes in amounts of IgG and IgM antibodies to SАRS-CoV-2 varied in accordance with clinical severity and duration of convalescence period. During the recovery period, an imbalance of regulatory T cell subpopulations and low levels of IFNγ were observed. The stable impairment of structural and functional characteristics of immune cells and aberrant production of cytokines during the disease caused by SARS-CoV-2 may serve as a pre-requisite for monitoring immunological indices in search for personalized immunotropic therapy.

Гломерулярные поражения почек у детей с ювенильным ревматоидным артритом (обзор литературы)

Обзор литературы посвящен описанию различных форм гломерулонефрита (ГН) у детей с полиартикулярной и системной формами ювенильного ревматоидного артрита (ЮРА). В доступной литературе представлен 21 клинический случай развития ГН, а именно: ANCA-ассоциированный ГН, мезангиопролиферативный ГН, в том числе IgA- и IgМ-нефропатия, мембранозная нефропатия, фокально-сегментарный гломерулосклероз, болезнь минимальных изменений, экстракапиллярный ГН. Механизм гломерулярных поражений при ЮРА объясняется гиперпродукцией провоспалительных цитокинов, а также нефротоксическим действием базисных противовоспалительных лекарственных средств. Подробно проанализированы клинические проявления и эффективность проводимой терапии каждого варианта ГН у детей с ЮРА. Больше всего публикаций посвящено ANCA-ассоциированному ГН, который развился у пациентов с торпидным течением и высокой степенью активности полиартикулярной и системной форм ЮРА. Особенностью ANCA-ассоциированного ГН явилось наличие гиперкреатининемии и практически в половине случаев— развитие терминальной почечной недостаточности, несмотря на проводимую иммунодепрессивную терапию. Единичные случаи других вариантов ГН описаны более 10 лет назад. Клинически отмечались протеинурия и реже— нефротический синдром, что стало основанием для прижизненного морфологического исследования почек. Иммунодепрессивная терапия была эффективной при мезангиопролиферативном ГН и болезни минимальных изменений. Во всех случаях при фокально-сегментарном гломерулосклерозе, экстракапиллярном ГН отмечено формирование терминальной почечной недостаточности. Благоприятный прогноз оказался у детей с мембранозной нефропатией, индуцированной препаратами, после отмены последних. Представлены публикации с положительным терапевтическим эффектом применения генно-инженерных биологических препаратов при ANCA-ассоциированном ГН, IgМ-нефропатии, гормонорезистентном варианте болезни минимальных изменений у детей с ЮРА.

Does thyroid dysfunction influence inflammatory mediators in experimental periodontitis?

Objective. The aim of the present study was to investigate the presence of inflammatory mediators in rats with only periodontitis and periodontitis in a setting of hyper- and hypo-thyroidism and to analyze the correlative linkages between inflammatory mediators and thyroid hormones. Methods. White male 12-14 weeks old inbred rats (n=48) weighing 180-200 g were employed in the experiment. They were randomly divided into the following groups: Group I - control group, Group II - group with a model of periodontitis, Group III - group with a periodontitis in a setting of hyperthyroidism, and Group IV - group with periodontitis in a setting of hypothyroidism. The presence of tumor-necrosis factor-α (TNF-α) and interleukins IL-1β and IL-10 in the periodontal homogenate supernatant was studied by a solid-phase enzyme-linked immunosorbent assay. Results. It was shown that experimental lipopolysaccharide (LPS)-induced periodontitis is accompanied by hyperproduction of pro-inflammatory cytokines (TNF-α, IL-1β) and reduction of anti-inflammatory cytokines (IL-10), whereas TNF-α underwent to maximum changes. Thyroid dysfunction exacerbates cytokine imbalance and severity of inflammation in experimental LPS-induced periodontitis, especially pronounced at hyperthyroidism, as evidenced by the predominance of TNF-α and IL-1β levels in the periodontal homogenate supernatant by 38.5% (р<0.01) and 75.6% (p<0.001), respectively, hyperthyroid over the euthyroid, and by 20.1% (p<0.05) and 24.1% (p<0.05), respectively, over the hypothyroid rats. Conclusions. Thyroid dysfunction, especially hyperthyroidism, may play an important role in the pro-inflammatory response in periodontitis. Hyperproduction of inflammatory mediators in thyroid dysfunction can induce a noticeable damage in the whole apparatus of the periodontium, thereby causing progression of periodontitis.

COVID-19 related stroke

The COVID-19 pandemic had a significant impact on both the incidence of acute cerebral circulatory disorders and the structure of mortality. SARS-CoV-2 increases the risk of both ischemic and hemorrhagic stroke. The key pathogenetic links underlying the development of cerebral stroke in COVID-19 are impaired functioning of angiotensin 2 receptors, accompanied by the accumulation of excess angiotensin 2, endothelial dysfunction, hypercoagulation, hyperproduction of proinflammatory cytokines and oxidative storm. In patients with stroke and COVID-19, the severity of the lesion is associated with a dual mechanism of ischemia - systemic and cerebral. The possibilities of medical correction of systemic disorders associated with coronavirus infection, as well as local ones caused by ischemic or hemorrhagic brain damage, are limited. Substances with antioxidant activity could potentially be effective in patients with stroke and COVID-1.

Anterior eye segment damage in coronavirus infection (COVID-19)

Conjunctivitis may appear as the first symptom of the coronavirus infection (COVID-19). In isolated cases, the lesion of the conjunctiva evokes a systemic infectious process. Currently, the conjunctiva is not considered as an area of long-term reproduction of coronavirus, and its damage is caused by hyperproduction of pro-inflammatory cytokines (especially IL-6); development of iridocyclitis and keratoconjunctivitis is also possible. Most often, local corticosteroids are used to treat these processes, although their use requires caution due to the risk of activating secondary infection (herpetic bacterial, fungal), which often develops as a result of immunodeficiency caused both by COVID-19 and the massive corticosteroid and antibiotic therapy employed when the course of the disease is severe. The severe condition of patients, the lung ventilation, and the prone position all contribute to corneal erosions, exposure keratopathy, pseudomonas aeruginosa keratitis and angle-closure glaucoma attacks. The risk of transmission of coronavirus infection during keratoplasty is estimated as minimal.

ОСОБЕННОСТИ ЦИТОКИНОВОГО ПРОФИЛЯ У ОЖОГОВЫХ ПАЦИЕНТОВ

Introduction. Currently, more and more attention is paid to burn injury as one of the most significant medical and social problems. Treatment of burn injury is performed by autotransplantation of the skin flap. The efficiency of using this method is from 70 to 90%. A significant reason for the failure of skin flap transplantation in burn disease is the lack of objective methods for assessing the patient's condition on the eve of free autodermoplasty surgery. Assessment of the levels of both Pro-and anti-inflammatory cytokines in burned patients is not included in the algorithm of examination and monitoring of the status of these patients. The aim of the study: to study the levels of pro — and anti-inflammatory cytokines to expand the algorithm of laboratory examination in preparing patients for free autodermoplasty.Materials and methods. The levels of IL-6, IL-8, and IL-10 in the peripheral blood of 50 patients with burn injury compared to healthy individuals were studied by enzyme immunoassay. Results. The serum content of all studied cytokines was significantly increased upon admission to the hospital in all burn patients compared to healthy individuals. A particularly pronounced increase was observed in patients with a fatal outcome. The results of autodermoplasty correlated with the severity of hyperproduction of proinflammatory cytokines on the eve of surgery. Conclusion. A justification for the addition of the algorithm for laboratory examination of burned patients by determining cytokines-interleukins 6, 8 and 10. Monitoring the level of cytokines in burn injury is appropriate for objectifying the choice of the timing of surgery, which will help reduce the mortality rate and increase the effectiveness of free autodermoplasty.

The effect of hyperlipidemia on the local content of cytokines in the zone of implantation of synthetic materials

Relevance. Abdominal plastic with the use of synthetic materials is a universally recognized method of treating ventral hernias. However, using implants, surgeons have faced the problem of tissue biocompatibility.&#x0D; The aim of the study was to evaluate the effect of synthetic implants from polypropylene mesh ("Esfil") and polytetrafluoroethylene ("Ecoflon") on local production of cytokines in experimental hyperlipidemia.&#x0D; Materials and methods. The work was performed on male Wistar rats weighing 250 ± 50 grams (n=54). The method of Meshcherskaya K.A. (1966) was used for the development of hyperlipidemia. The diet consisted of adding to the food of cholesterol powder 1%, 20% margarine and 2.5 IU of vitamin D per kg of body weight of rats for 6 months. The plastic of the anterior abdominal wall was performed by 8 month old animals using the Onlay method using the implants "Esfil" and "Ecoflon". The control group was rats with prosthetics of the abdominal wall on a normal diet. The material of the study was blood plasma and biopsy specimens of the muscle-aponeurotic rumen of the anterior abdominal wall of rats.&#x0D; Results. It was noticed in the course of the experimental study that the implants used in the reconstruction of the anterior abdominal wall have individual features of the effect on the local production of cytokines. "Ecoflon" has a more pronounced reactogenicity, manifested by hyperproduction of pro-inflammatory cytokines from 10 to 30 days. "Esfil" is characterized by less pronounced influence on local pro-inflammatory activity of cells in dynamics after alloplasty, in comparison with the use of "Ecoflon". Hyperlipidemia leads to a decrease in local production, both of pro-inflammatory and anti-inflammatory cytokines.

POLYMORPHISM GENES OF DETOXIFICATION SYSTEM AND IMMUNEDEPENDENT MECHANISMS IN THE DEVELOPMENT OF GENITAL ENDOMETRIOSIS

Endometriosis is one of the most mysterious and unresolved problem in modern gynecology, taking the third place in the structure of gynecological diseases. In the genesis of endometriosis important role belongs to the metabolism genes, which are characterized by a large variability of molecular structure of DNA. It is proved that implantation of endometrial cells and their proliferation is provided, if a woman abuses humoral and cellular immunity.The aim of our study was to determine the role of polymorphisms genes of detoxification system and immunedependent mechanisms in the development of endometriosis.Material and methods. Surveyed 102 patients with internal genital endometriosis. The polymerase chain reaction investigated the frequency of polymorphic variants of genes GSTT1 and GSTM1. DNA extraction from peripheral blood was perfomed using the test system «AmpliSens». Determination of interleukins levels in serum was perfomed by the method monoparentale analysis using the test-ystems for IFA.Results of the study and their discussion. The results of the conducted researches have allowed to establish that genital endometriosis is significantly associated with deleting polymorphisms genes of detoxication system. Also, it was found that patients with internal endometriosis there is a hyperproduction of proinflammatory cytokines and tumor necrosis factor-α.Conclusions. Research factors of immune regulation, and gene deletions of the glutation-S-transferase is a promising for future research in terms of studying them as a potential marker for noninvasive diagnosis of endometriosis.

Deletion of adenosine A2A receptor blocks the beneficial effects of Lactobacillus reuteri on Treg-deficiency-induced autoimmunity

Abstract The lack of Foxp3+ regulatory T cells (Tregs) causes a lethal, CD4+T cell-driven autoimmune disease in scurfy (SF) mice and humans characterized by immunodysregulation, polyendocrinopathy, enteropathy, with X-linked inheritance (or IPEX syndrome). We observed that adenosine 2A receptor (A2A) activation limits inflammation and tissue damage, and that Lactobacillus reuteri DSM 17938 (LR) modulates the abnormal fecal microbial community associated with the disease, stimulating the production of bioactive metabolites, especially inosine by activating A2A expressed on T cells. To conclusively provide evidence of a central role of A2A in the actions of LR, we generated A2A null SF mice (SF·A2A−/−). Male mice were given daily by gavage culture media (MRS) or LR in MRS (107CFU/day), starting at d8 to d22 for plasma and tissue analysis or long-term survival We found that A2A receptor deletion in SF mice did not affect early life events, the development of a lymphoproliferative disorder, or hyper-production of proinflammatory cytokines. LR treatment prolonged survival and reduced multi-organ inflammation in SF mice. In marked contrast, A2A receptor deletion reversed the effect of LR in prolonging lifespan in SF mice and negated the effects of LR on inflammation in the liver and lungs of SF mice. A2A deletion also inhibited LR-mediated reduction of TH1/TH2 cells and reversed the effect of LR on plasma pro-inflammatory cytokines. In conclusion, (a) the absence of the A2A receptor does not affect the development of disease in SF mice, and (b) the A2A receptor plays a critical role in immunomodulation produced by LR treatment. Lactobacillus reuteri and A2A receptor activation may have a role in other Treg dysfunction-mediated autoimmune diseases.

PATHOGENETIC SUBSTANTIATION OF COMPREHENSIVE TREATMENT OF PATIENTS WITH CHRONIC PANCREATITIS COMBINED WITH OSTEOARTHROSIS AND OBESITY CONCERNING THE CORRECTION OF THE DISORDERS IN THE PROTEINASE INHIBITOR SYSTEM AND METABOLISM OF THE CONNECTIVE TISSUE COM

Introduction. The incidence of the co-morbid course of chronic pancreatitis (CP) and obesity has recently increased significantly both in Ukraine and all over the world, especially in individuals being in the second half of their adulthood and in the elderly ones. This combination of interdependent diseases is often complemented by osteoarthrosis (OA) of the large joints, which is characterized by severe, rapidly progressing course. The basis CP and OA progression, among various mechanisms of pathogenesis, is the proteinase-inhibitor imbalance, which leads to proteolytic damage and destruction of acinar epithelium and cartilage tissue, polymorphocyte infiltration of the tissue of the pancreas and synovial epithelium (reactive synovitis) under the influence of increased expression and activation of cellular adhesion factors, hyperproduction of proinflammatory cytokines, growth factors of anabolic action, acidosis, hypoxia, etc.Objective. Тo identify the mechanisms of mutual aggravation of chronic pancreatitis and osteoarthrosis of large joints in obese patients on the basis of the study of protein and carbohydrate-protein components of the extracellular matrix of the proteinase inhibitor system, to increase the efficiency of comprehensive treatment for this polymorbidity.Materials and methods. Тhe study involved 90 patients with CP, aged 45 to 63 years old , 22 of whom had normal body weight (1group 1), 27 patients with CP suffered from the first degree obesity (group 2), 41 patients had CP with comorbid first degree obesity and І-ІІ stage osteoarthritis of the of the hip and knee joints (group 3).To evaluate the effectiveness of the proposed treatment, the patients of group 3 were divided into two subgroups: 3A and 3B. Group 3А (21 individuals) received basic treatment of CP exacerbation: a hypocaloric diet with elimination of extractive foods, antisecretory (proton pump inhibitor), antispasmodic (mebeverine hydrochloride) for 1 month, multienzyme (kreon10-20 thousand units) preparations, L-carnitine (solution) 1.0 (10 ml) twice a day for 90 days. Group 3B (20 people), in addition to the above therapy, received the drinking form of L-carnitine 1.0 (10 ml) twice a day and L-glutathione (hepaval) 250 mg twice a day for 90 days.Results. Тhe proposed therapy contributed to the normalization of proteinase inhibitor homeostasis. Without proteinase inhibitors in the basic therapy the complex application of L-carnitine and L-glutathione contributed to a reliable decrease in the intensity of azole albumin lysis in patients of both groups: 1.2 and 1.6 times, respectively (p &lt;0.05), due to significant inhibition of hyperproduction of proteinase inhibitors: the content of α2- macroglobulins in the blood dropped by 1.6 and 2.2 times (p &lt;0.05) with normalization of the values.Conclusions. Patients with chronic pancreatitis, comorbid obesity and osteoarthrosis of large joints were studied during their therapy, the mechanisms of mutual aggravation were identified: hyperproduction of the extracellular matrix components, acute phase proteins, an increased degradation of fucoglycoproteins and proteinase-inhibitor imbalance.The integrated therapy of patients with CP and obesity which includes antioxidant (L-glutathione) and a metabolism stabilizer (L-carnitine) against the basic treatment resulted in the balance of the processes of synthesis and decomposition of collagen and glycoproteins, proteinase-inhibitor system homeostasis, collagenolysis enhancement with the achievement of the balance in the metabolism of the connective tissue components, homeostasis of hydrogen sulfide, which underlies the achievement of stable remission of CP and OA, reducing the risk of their progression.

THE ROLE OF LABORATORY BIOMARKERS IN MONITORING THE EFFECTIVENESS OF TREATMENT WITH INHIBITORS OF TUMOR NECROSIS FACTOR а IN RHEUMATOID ARTHRITIS

Currently there are several biological therapy drugs used in the treatment of rheumatoid arthritis (RA), in connection with which there was a problem of choosing a drug. Materials and methods. 18 patients with rheumatoid arthritis, who received combination therapy with methotrexate and infliximab were examined. All patients before the start of treatment with infliximab and after 30 weeks were determined in the blood serum of TNF-α, IL-1, IL-2, IL-6. Results and conclusions. Hyperproduction of proinflammatory cytokines again confirms their participation in the development and progression of the RA. Increased levels of TNF-α, IL-1, IL-2 are more likely associated with a moderate effect of the conducted gene therapy at minimal and medium therapeutic dosages.

The effectiveness of complex prevention of tooth loss in patients with duodenal ulcer in conditions of non-removable dental prosthesis

68 patients with duodenal ulcer (DU) with fixed metal and metal-ceramic dentures were examined, the significant changes in metabolism of the periodontal extracellular matrix (ECM) components were established, hyperproduction of proinflammatory cytokines (TNF-α, IL-1) and lack of TGF-β1 with anabolic action in the blood, accompanied by intense oxidative stress (OS) and depletion of the factors of antioxidant protection (AOP), which are the basis of progressive teeth loss. Complex therapy of patients with DU including L-glutathione and nemoliks NW (biovafleks, bosvelliya Serrat, Curcumin C3) helps to restore metabolic processes of ECM components, which provide the probable increase of synthesis intensity of collagen, glycosaminoglycans and glycoproteins on the background of a possible reduction in intensity of collagenolysis and fukoglycoproteins degradation. This therapy helps to reduce the blood content of proinflammatory cytokines (TNF-α, IL-1) and to recover of the TGF-β1 pool with anabolic action in the blood, to reduce the intensity of the OS, to increase AOP factors, which is active prevention of the further tooth loss and the need for prosthetics.

Adenosine A2A Receptor Deletion Blocks the Beneficial Effects of Lactobacillus reuteri in Regulatory T-Deficient Scurfy Mice

The lack of a functional Foxp3 transcription factor and regulatory T (Treg) cells causes lethal, CD4+ T cell-driven autoimmune diseases in scurfy (SF) mice and humans. Recent studies have shown that adenosine A2A receptor activation limits inflammation and tissue damage, thereby playing an anti-inflammatory role. However, the role of the adenosine A2A receptor in the development of disease in SF mice remains unclear. Using a genetic approach, we found that adenosine A2A receptor deletion in SF mice (SF) does not affect early life events, the development of a lymphoproliferative disorder, or hyper-production of pro-inflammatory cytokines seen in the Treg-deficiency state. As shown previously, Lactobacillus reuteri DSM 17938 treatment prolonged survival and reduced multiorgan inflammation in SF mice. In marked contrast, A2A receptor deletion completely blocked these beneficial effects of L. reuteri in SF mice. Altogether, these results suggest that although absence of the adenosine A2A receptor does not affect the development of disease in SF mice, it plays a critical role in the immunomodulation by L. reuteri in Treg-deficiency disease. The adenosine A2A receptor and its activation may have a role in treating other Treg dysfunction-mediated autoimmune diseases.

ОСОБЛИВОСТІ ОБМІНУ ВУГЛЕВОДНО-БІЛКОВИХ КОМПОНЕНТІВ СПОЛУЧНОЇ ТКАНИНИ ПАРОДОНТА ТА ЇХ ЦИТОКІНОВОЇ РЕГУЛЯЦІЇ У ХВОРИХ НА ВИРАЗКОВУ ХВОРОБУ ДВАНАДЦЯТИПАЛОЇ КИШКИ ЗАЛЕЖНО ВІД ВИДУ НЕЗНІМНИХ ЗУБНИХ ПРОТЕЗІВ

Мета роботи – встановити вплив незнімних металевих, металокерамічних та керамічних протезів на стан білково-вуглеводних компонентів сполучної тканини пародонта та стан їх цитокінової регуляції у крові хворих на виразкову хворобу (ВХ) дванадцятипалої кишки (ДПК).Матеріали і методи. Обстежено 147 хворих на ВХ ДПК у фазі рубцювання виразки, у тому числі 43 особи із дефектами зубного ряду без зубних протезів (1 група), 35 осіб із незнімними металевими зубними протезами (2 група), 42 – із незнімними металокерамічними протезами (3 група), 27 – із незнімними керамічними протезами (4 група). Використовували клінічні, біохімічні та імуноферментні методи дослідження.Результати досліджень. У хворих на ВХ ДПК без протезів зубного ряду виявлено істотні зміни метаболізму компонентів позаклітинного матриксу (ПКМ) пародонта: вірогідне зниження інтенсивності синтезу колагену, глікозаміногліканів, глікопротеїнів, фібронектину на тлі підвищення інтенсивності процесів колагенолізу та деградації фукоглікопротеїнів. Наявність металовмісних незнімних зубних протезів призвела до істотного поглиблення даного дисбалансу внаслідок підвищення активності колагеназ та еластази ПКМ, гіперпродукції прозапальних цитокінів (TNF-α, IL-1) та недостатності вмісту в крові факторів росту (TGF-β1) анаболічної дії, які у сильній взаємозалежності корелюють із інтенсивністю реакцій ана- та катаболізму колагену, еластину, вмістом у крові глікозаміногліканів, фукоглікопротеїнів, фібронектину.Висновки. Наявність металовмісних незнімних зубних протезів у хворих на ВХ ДПК сприяє зниженню синтезу колагену та підвищенню колагенолізу внаслідок зростання активності колагеназ та еластази ПКМ, що супроводжується вірогідно вищою гіперпродукцією прозапальних цитокінів (TNF-α, IL-1) на тлі недостатності вмісту в крові факторів росту (TGF-β1), які істотно перевищують показники хворих на ВХ без зубних протезів та за наявності незнімних керамічних протезів.