IMMUNOSUPPRESSIVE EFFECTS OF ARGININE DEIMINASE FROM STREPTOCOCCUS PYOGENES

Many pathogens use metabolic pathway of arginine for successful dissemination. Bacterial arginine deiminase hydrolyzes arginine to form one molecule of ammonia and two molecules of ATP. The activity of the enzyme contributes to the improvement of survival of pathogenic bacteria in conditions of low pH at the site of infection or in phagolysosome, as well as in anaerobic conditions, and also leads to deficiency of arginine. Metabolism of arginine plays an important role in regulating the functions of immune system cells in mammals. Arginine is a substrate of enzymes NOS and arginase. Arginine depletion, potentially contributs to immunosuppression. The review analyzed the literature data on the effect of streptococcal arginine deiminase on the metabolism of arginine eukaryotic cells, and discusses immunosuppressive action of the enzyme

Assessing cytokine status of patients with chronic endometritis combined with endometrial hyperplastic processes in reproductive period

The goal of our study was to examine local and serum cytokine level involved in regulating inflammation in patients with chronic endometritis combined with endometrial hyperplastic processes. On admission, all patients underwent hysteroscopy with separate diagnostic curettage followed by histological examination of samples isolated from the uterine and cervical canal mucosa. Such manipulations were indicated due to abnormal uterine bleeding as well as suspected endometrial pathology based on ultrasound examination. According to the histological examination data of the endometrial samples, all patients were divided into two groups: group I contained 45 women with CE combined with PEG without atypia; group II — 38 patients with morphologically verified CEE combined with AEG without atypia. Level of IL-1P, IL-2, IL-6, IFNy, TNFa in biological fluids (aspirate from the uterus; serum) was measured by using enzyme-linked immunosorbent assay. We found that in both groups (91.1% and 89.6%, respectively) the vast majority of patients was hospitalized due to abnormal uterine bleeding. Oligomenorrhea alternated with intermenstrual bleeding (66.7% and 71.2%, respectively) and dominated in pattern of menstrual cycle disorders in the examined patients, whereas 11 (24.4%) and 7 (18.4%) patients from group I and II, respectively, were noted to suffer from severe menstrual bleeding. Overall, analyzing the data on cytokine level both in the uterine aspirate and serum evidences about ongoing inflammatory process found at examination time point. Upon that, such process was not only local, but also exhibited signs of a systemic inflammatory response. The data on cytokine level in the uterine aspirate from patients with CE coupled to PGE or CGE without atypia point at local inflammatory process characterized by significantly increased concentration of IL-ф, IL-2, IL-6, TNFa and IFNy. At the same time, higher level of IL-ф and IFNy in patients from group II might indicates that degree of morphological changes in the endometrium could affect the level of local cytokine production. Thus, the data obtained evidence that immune changes in chronic endometritis combined with non-atypical endometrial hyperplastic processes mostly occur locally. In this regard, measuring cytokine concentration in the uterine aspirate is a diagnostic predictor and serves as a sign for monitoring therapeutic effectiveness of therapy in this cohort of patients

Influence of streptococcal arginine deiminase on the leukocyte infiltration in murine air pouch model

Numerous pathogens express arginine deiminase, an enzyme that catalyzes the hydrolysis of L-arginine in a chain of biochemical reactions aimed at the synthesis of ATP in bacterial cells. L-arginine is a semi-essential, proteinogenic amino acid that plays an important role in regulating the functions of the immune system cells in mammals. Depletion of L-arginine may cause a weakening of the immune reaction. In order to improve the conditions of dissemination, many pathogens use a strategy of L-arginine depletion in the microenvironment of host cells. Bacterial arginine deiminase can be a pathogenicity factor aimed for dysregulating the processes of inflammation and immune response. In general, the effect of arginine deiminase on immune cells may result into disturbed production of regulatory proinflammatory molecules, such as NO, and related substances, inhibition of activation, migration and differentiation of individual leukocyte subsets. The aim of this study was to investigate the effect of arginine deiminase on the formation of inflammatory infiltrate in murine air pouch model of streptococcal infection. Materials and methods: The study was performed using S. pyogenes M49-16 expressing arginine deiminase and its isogenic mutant S. pyogenes M49-16delArcA with inactivated arginine deiminase gene. The flow cytometry analysis of the inflammatory infiltrate leukocytes subpopulation in mice infected with the original strain of S. pyogenes M49-16 and its isogenic mutant S. pyogenes M49-16delArcA at different periods of infection was performed. It was shown that the inflammation reached its peak 6 hours after streptococcal inoculation, being more pronounced in mice infected with the mutant strain. Тhis finding was affirmed by a simultaneous and more pronounced increase in the absolute numbers of all leukocyte subsets in the focus of inflammation in this group of mice when compared to mice infected with original bacterial strain. Despite the decrease in the absolute number of all leukocyte types in the inflammatory infiltrate in both groups of mice for 24 hours, this trend was more pronounced in the group of mice infected with mutant microbial strain. Comparison of the inflammatory infiltrates developing in mice infected with original versus mutant strains showed that arginine deiminase may be a pathogenicity factor leading to dysregulation of protective immune response, due to impaired migration of white blood cells to the site of infection

ЗАВОЗНОЙ ОСТРЫЙ ОПИСТОРХОЗ В МОСКВЕ: ПРОБЛЕМЫ КЛИНИЧЕСКОЙ И ЛАБОРАТОРНОЙ ДИАГНОСТИКИ И ПРОФИЛАКТИКИ

We describe the human acute opisthorchiasis outbreaks in Moscow region acquired from eating raw Leuciscus idus, Abramis brama and Aspius aspius in 10 patiens: 5 delivered fish from Tyumen and Sverdlovsk regions and 5 – from fish during their travelling to Tomsk and Astrakhan regions. Although, 18 people had identical history of consumption raw fish 10 had clinical symptoms of which the most frequent one was febrile eosinophilic syndrome. Other 8 people had no clinical symptoms. Eggs of O.felineus were found in 10 patients. Due to risk of cholangiocarcinoma in patients infected with O.felineus we recommend one day of praziquantel 25 mg/kg TID. Although opisthorchiasis is not frequently reported in Moscow region, it should be considered in cases of unexplained acute febrile eosinophilic syndrome with cholestasis, especially when patients confirm the ingestion of raw fish.Проанализировано 10 случаев острой стадии описторхоза у больных, проживающих в Московском регионе, которые заразились при употреблении в пищу рыбы, присланной из Тюменской и Свердловской областей (5 чел.) и при употреблении рыбы во время краткосрочного пребывания в Томской и Астраханской областях (5 чел.). У всех больных имелись клинические симптомы острой стадии, наиболее типичными из которых являлись лихорадка, эозинофилия и холестаз. У 8 лиц, употреблявших в пищу зараженную рыбу, признаки заболевания отсутствовали. Хотя у всех 18 лиц, находившихся под наблюдением, был одинаковый пищевой анамнез, причины различий между лицами, у которых развилась острая стадия, и теми, у которых не было клинических проявлений инвазии, не установлены. Яйца O. felineus в фекалиях были выявлены у всех 10 больных. Основным фактором заражения человека O. felineus в Московском регионе явилась рыба (лещи (Abramis brama) и язи (Leuciscus idus)), которая была прислана из эндемичных очагов. В связи с отсутствием яиц O. felineus в фекалиях в начальном периоде острой стадии инвазии принципиально важным является тщательный сбор пищевого анамнеза, свидетельствующий об употреблении в пищу соленой и вяленой рыбы карповых пород. Пищевой анамнез, а также типичная клиническая симптоматика (лихорадка, боли в правом подреберье), повышение уровня лейкоцитов, эозинофилов и ферментов печени, указывающие на холестаз, должны служить основанием для проведения более тщательного медицинского обследования с целью подтверждения диагноза описторхоза и проведения лечения празиквантелем

Проблемні питання визначення правової природи і структури правовідносин інтелектуальної власності, що виникають у мережі Інтернет

Харитонова О. І., Ульянова Г. О., Кирилюк А. В., Симонян Ю. Ю., Бааджи Н. П., Позова Д. Д., Григор'янц Г. І., Бурова Л. І., Мартинюк І. В. Проблемні питання визначення правової природи і структури правовідносин інтелектуальної власності, що виникають у мережі Інтернет / О. І. Харитонова, Г. О.Ульянова, А. В. Кирилюк, Ю. Ю. Симонян, Н. П. Бааджи, Д. Д. Позова, Г. І. Григор'янц, Л. І. Бурова, І. В. Мартинюк // Наукові праці Національного університету «Одеська юридична академія». Т. 17 / голов. ред. М. В. Афанасьєва ; МОН України, НУ «ОЮА». – Одеса : Юрид. л-ра, 2015. – C. 159-200.Сьогодні під впливом науково-технічного прогресу значно розширилось коло суспільних відносин. Виникає така категорія правовідносин, як «правовідносини в мережі Інтернет». Постає питання правового регулювання таких відносин, суб'єктного складу, змісту та з приводу чого вони виникають. Саме ці питання розкриті в даній статті

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.