Genetic determinants of virulence and drug resistance of <i>Mycobacterium avium</i> subsp. <i>hominissuis</i> — a causative agent of mycobacteriosis in humans

Among the members of the large group of non-tuberculous mycobacteria (comprising more than 180 species), M. avium subsp. hominissuis (MAH) is the most significant causative agent of pulmonary infection in immunocompetent individuals as well as disseminated infection in immunocompromised hosts, e.g. human immunodeficiency virus (HIV)-positive patients. Due to increased incidence rate of mycobacteriosis, especially in HIV infection, much still need to be learnt about the MAH genetic control and virulence mechanisms. Deciphering the genome contents of the M. avium strain 104 (isolated from an AIDS patient with disseminated MAH disease) allowed to compare genome sequences of M. avium strains to gain insights into genomic diversity associated with variable hosts and environments. Comparative genome analysis of MAH strains isolated from patients with pulmonary and disseminated forms of mycobacteri-osis revealed differences in the structure of the genome, affecting the key virulence genes. This review provides current data on the genetic determinants of MAH virulence associated with the initial phase of infection. Several mycobacterial virulence-associated gene families, such as mce (mammalian cell entry), mmp (mycobacterial membrane proteins), pe/ppe and esx expressed by MAH during human infection are thought to be crucial for adhesion, entry, survival, and reproduction inside host macrophages. The genetic mechanisms of MAH survival in human macrophage cell culture as well as mice exposed to toxic effects of reactive oxygen, nitric oxide, bactericidal proteins (cathelicidin) are discussed. The MAH survival in the latency-like state is important for pathogen dissemination. Some genetic and phenotypic features of MAH (absence of a cord factor, presence of plasmids, potential to “switch” morphological types of colonies) are compared with M. tuberculosis. In addition, we summarized current state of MAH drug discovery, a role of MAH intrinsic multidrug resistance, genetic control, as well as mechanisms underlying formation of resistance to various groups of antibiotics in MAH strains

PROFESSIONAL STANDARDS AS TOOLS TO SUPPORT THE DEVELOPMENT OF THE MODEL GRADUATE OF THE BASIC PROFESSIONAL EDUCATIONAL PROGRAMS OF HIGHER EDUCATION «THE TECHNOLOGY OF IMAGE IN THE INDUSTRY OF FASHION AND BEAUTY»

В статье рассматривается основные подходы к разработке модели выпускника основной профессиональной образовательной программы высшего образования «Технологии имиджа в идустрии моды и красоты»The article deals with the main approaches to the development of the model of the graduate of the basic professional educational program of higher education "technologies of image in the fashion and beauty industr

СHANGES OF IMMUNOREGULATORY INDEXES IN CHILDREN EXPOSED TO STRONTIUM

Evaluation of the immune system parameters can be used in order to assess capacity to adapt under conditions of increased external chemical load, including exposure to metals, which can exert either activating and inhibitory effects upon immune regulation parameters. The aim of this work was the analysis of immunoregulatory markers in a children’s population who consumed water with high strontium content (a sample from the Perm region). We carried out immunological evaluation of the children aged 7 to 12 years, living at a territory with a high strontium content in the drinking water. The comparison group included children from the conventionally clean region. We studied differential changes in cellular immunity (phagocytosis rates), humoral factors of immune defense (serum immunoglobulins), development of specific sensitization for strontium, as well as the processes of apoptosis triggering and regulation. A 3.68-fold increase in strontium levels was shown in fresh water within observation area, and the average  blood strontium content in the children of appropriate observation group was 1.55-fold higher than in children of the comparison group. At the same time, 1.2-fold increase in phagocytic activity determined as phagocytic number and phagocytic index was found, as compared to the control group. In 80% of the subjects, a reduction in serum IgG level was observed when compared to physiological norm, as well as a significant decrease in IgG and enhance in IgM production against the levels found in the comparison group. Wehave also shown an enhanced total sensitization in 55.0% of the observation group as shown by the total IgE test compared with normal age ranges, as well as excessive specific sensitization to strontium by 2.49 times, according to the IgG criterion. Disturbance in apoptosis triggering was associated with decreased number of CD95+ lymphocytes and TNFR1+ cells (2.8-fold compared to reference values), shifted balance in apoptogenic proteins, an average of 2.6-fold decrease in Bcl-2 expression, a 2.8-fold reduction of the p53 transcription factor expression relative to the reference interval. Thus, we have shown an ability of strontium excess in drinking water to influence the most important indices of immune regulation in pediatric population. These changes may serve as indices of populational health status under of external strontium exposure

Female reproductive tract microbiome and early miscarriages

The review presents new data on the impact of the vaginal and uterine microbiome on the local immunity, including defense against sexually transmitted infections, and its association with other factors of miscarriage

EXPERIMENTAL MODELING OF APOPTOSIS UNDER CONDITIONS OF STABLE STRONTIUM EXPOSURE

Apoptosis is defined as a highly regulated form of programmed cell death with typical morphological and biochemical features. A variety of factors, including heavy metals, may influence the intensity of programmed cell death. The aim of the work was to simulate apoptosis in an in vitrosystem under the conditions of stable strontium exposure. The children’s population consuming drinking water with high strontium (Sr2+) content (n = 49) was observed. The level of lymphocyte apoptosis was determined with flow cytometry technique, by means of labeled annexin V-FITC conjugate (AnnV-FITC) and propidium iodide (PI) staining. AnnV-FITC+PI- cells were regarded as early apoptotic forms, whereas late apoptotic and/or necrotic cells were AnnV-FITC+PI+. The isolated leukocytes were incubated with Sr2+ at a concentration of 7.0 mg/l, the maximal permitted concentration (MPC) for water of aqueous objects, for 4 hours at 37 ºC. Expression of CD95 and p53 apoptosis markers was performed by flow cytometry using labeled monoclonal antibodies.In vitroexposure to strontium was associated with significantly decreased expression of apoptosisregulating factors, i.e., membrane marker CD95 and intracellular transcription protein p53, 1.56- and 1.68-fold, respectively. Meanwhile, we revealed a significantly (4.68-fold) decreased amounts of AnnV-FITC+PI--cells, as well as a statistically significant (1.35-fold) increase of the AnnV-FITC+PI+-cells. Moreover, the amounts of AnnV-FITC+ PI--lymphocytes in all samples were below the physiological ranges and control values. The number of samples with higher contents of AnnV-FITC+PI+-lymphocyte exceeding the established standards and control values, was 30.8%. Thus, it has been experimentally proven that strontium, at a concentration corresponding to MPC for water objects may significantly inhibit cell death along apoptotic pathways, with switching to necrotic cell death mechanisms, according to phosphatidylserine contents, as detected by annexin V binding test. The data have revealed an ability of strontium to have a significant effect upon the parameters of regulation and maintenance of cellular homeostasis, by influencing the apoptosis intensity, due to shifting a balance towards necrosis and reducing expression of apoptosis-regulating factors. The results of this study may be used in order to identify some marker indexes of immune disorders potentially induced by external influence of strontium upon human health under specific environmental factors

Видовое разнообразие нетуберкулезных микобактерий у больных микобактериозом на территориях Северо-Западного федерального округа России

The objective of the study: to analyze the structure and trends in non-tuberculous mycobacteria (NTBM) population causing diseases in the North-Western Federal District of the Russian Federation.Subjects and methods. 745 clinical NTBM strains were identified. All clinical strains of NTBM were isolated by culture from clinical samples (sputum, bronchial washings, bronchoalveolar lavage fluid, pus, stool, urine, surgical and biopsy specimens, and venous blood in case of sepsis). In 23 cases, NTBM were detected post mortem. Mycobacteria were cultured on solid media or by the automated system of Bactec MGIT 960 BD USA. Species of re-cultured mycobacteria were identified using the test system of GenoType® Mycobacterium CM/AS (Hain Lifescience, Germany).Results. Analysis of the structure of the NTBM population isolated from patients with mycobacteriosis in the North-West of Russia, for the period of 2012-2018 showed overall dominance of M. avium (56.4%). However, certain NTBM species were found to be prevailing in some regions: M. lentiflavum and M. gordonae dominated in the Komi Republic and Arkhangelsk respectively. Unlike other regions of Russia, in the North-Western region, there was a consistently low level of detection of M. кansasii and M. xenopi. For the last 12 years in Saint Petersburg and Leningrad region, the variety NTBM in patients with different immune status has been growing but the portion of M. avium remains to be stably high exceeding 50%.Цель исследования: анализ структуры и тенденций популяции нетуберкулезных микобактерий (НТМБ), вызывающих заболевания, на территориях Северо-Западного федерального округа Российской Федерации.Материалы и методы. Проведена идентификация 745 клинических штаммов НТМБ. Все клинические штаммы НТМБ выделены при культивировании клинического материала (мокрота, промывные воды бронхов, жидкость бронхоальвеолярного лаважа, гной, кал, моча, операционный и биопсированный материал, венозная кровь при септических состояниях). В 23 случаях НТМБ выявлены посмертно. Культивирование микобактерий осуществляли на плотных питательных средах или в автоматизированной системе Bactec MGIT 960 BD USA. Видовую идентификацию рекультивированных штаммов микобактерий осуществляли с использованием тест-системы для идентификации НТМБ GenoType® Mycobacterium CM/AS (Hain Lifescience, Германия).Результаты исследования. Анализ структуры популяции НТМБ, выделенных от больных микобактериозом на Северо-Западе России, за период 2012-2018 гг. показал в целом доминирование вида M. avium (56,4%). Однако выявлены территориальные особенности видового разнообразия НТМБ: в Республике Коми и Архангельской области преобладали M. lentiflavum и M. gordonae соответственно. В отличие от других регионов России, на территории Северо-Запада отмечен стабильно низкий̆ уровень выявляемости M. кansasii и M. xenopi. В Санкт-Петербурге и Ленинградской области в течение последних 12 лет отмечено увеличение разнообразия НТМБ у пациентов с разным иммунным статусом, но доля M. avium остается стабильно высокой, превышая 50%

Клинические особенности анкилозирующего спондилита у пациентов с вторичным АА-амилоидозом

Renal AA amyloidosis is the most severe type of renal pathology in patients with ankylosing spondylitis (AS). The characteristic symptoms of AA amyloidosis in rheumatic diseases do not often occur for years, making it difficult to diagnose it early and to start adequate therapy.Objective: to identify the clinical features of AS complicated by secondary AA amyloidosis.Patients and methods. The investigation enrolled 9 patients with AS (according to the 1984 modified New York criteria) and histologically confirmed secondary AA amyloidosis (Group 1). A comparison group included 216 AS patients without amyloidosis (Group 2).Results and discussion. In Group 1 patients, the age at the onset of AS was significantly less and the disease duration was 4 times longer than those in Group 2. All the patients with AA amyloidosis had enthesitis and arthritis, including those of the hip joints. The scores of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the Ankylosing Spondylitis Disease Activity Score with C-reactive protein (ASDAS-CRP), and the acute phase inflammation index CRP were higher in Group 1 than in Group 2.Conclusion. The clinical feature of AS complicated by secondary AA-amyloidosis is the long duration of the disease and the high frequency of juvenile onset, non-axial manifestations (arthritis, coxitis and enteritis), as well as the high activity of systemic inflammation.Почечный АА-амилоидоз – самый тяжелый тип патологии почек у пациентов с анкилозирующим спондилитом (АС). Нередко характерные симптомы АА-амилоидоза при ревматических заболеваниях не проявляются годами, затрудняя его раннюю диагностику и начало адекватной терапии.Цель исследования – выявление особенностей клинической картины АС, осложненного вторичным АА-амилоидозом.Пациенты и методы. В исследование включено 9 больных АС (согласно модифицированным Нью-Йоркским критериям, 1984) с гистологически подтвержденным вторичным АА-амилоидозом (1-я группа). Во 2-ю группу (группа сравнения) вошли 216 пациентов с АС без амилоидоза.Результаты и обсуждение. У пациентов 1-й группы возраст дебюта АС был значительно меньше, а длительность болезни – в 4 раза больше, чем у больных 2-й группы. Все больные с АА-амилоидозом имели энтезит и артрит, в том числе тазобедренных суставов. Индексы BASDAI и ASDAS-СРБ, а также острофазовый показатель воспаления – СРБ – у пациентов с АА-амилоидозом были выше, чем в группе сравнения.Заключение. Особенностью клинической картины АС, осложненного вторичным АА-амилоидозом, являются большая длительность заболевания и высокая частота ювенильного начала, внеаксиальных проявлений (артрит, коксит и энтезит), а также высокая активность системного воспаления

Опыт эффективного использования ингибиторов интерлейкина 6 у больных анкилозирующим спондилитом со вторичным амилоидозом

Ineffectiveness of interleukin 6 inhibitors (iIL6), tocilizumab (TCZ) and sarilimumab in ankylosing spondylitis (AS) was shown in randomized clinical trials. However, there is ample evidence that IL6 is actively involved in the pathogenesis of this disease. In addition, the efficacy of iIL6 in patients with secondary AA-amyloidosis was established.Objective: to analyze the results of TCZ administration in AS, complicated by secondary AA-amyloidosis.Patients and methods. The analysis included 6 patients with AS with secondary AA-amyloidosis. All patients were HLA-B27 positive male. The average age of patients was 44±9.2 years, the average age of the disease onset was 16.3±7.9 years, the average duration of AS was 26.0±7.5 years. All 6 patients had pathomorphologic confirmed secondary AA-amyloidosis: all had kidney affection, 5 patients also had gastrointestinal tract affection and 2 had heart affection. As a first biological drug TCZ was prescribed in 2 patients, and 4 patients had previously received one or more inhibitors of tumor necrosis factor α. The average duration of TCZ treatment was 27.6 [3.0; 36.0] months.Results and discussion. During TCZ therapy, the level of CRP (M±σ) significantly decreased: from 81.1±74.5 to 1.2±0.8 mg/L (p&lt;0.05), as well as daily proteinuria (Me [25th ; 75th percentile]): from 1.8 [1.0; 2.1] to 0.2 [0.1; 0.3] g/day (p&lt;0.05) and AS activity indices – BASDAI (M±σ): from 6.2±1.6 to 3.3±0.9 (p&lt;0.05 ); ASDAS-CRP (M±σ) from 4.6±1.1 to 2.04±0.7 (p&lt;0.05). Positive dynamics was also noted in relation to a decrease in the number of patients with inflammatory back pain, arthritis and coxitis. A case of clinical and laboratory remission of AS on TCZ treatment is described. Conclusion. The presented data show that in certain clinical situations iIL6 can be highly effective in AS.В рандомизированных клинических исследованиях, в которых изучалась эффективность ингибиторов интерлейкина 6 (иИЛ6) тоцилизумаба (ТЦЗ) и сарилимумаба при анкилозирующем спондилите (АС), показана их неэффективность. Однако имеются многочисленные данные о том, что ИЛ6 активно участвует в патогенезе данного заболевания. Кроме того, установлена эффективность иИЛ6 у пациентов со вторичным АА-амилоидозом.Цель исследования – проанализировать результаты назначения ТЦЗ при АС, осложненном вторичным АА-амилоидозом. Пациенты и методы. В анализ включено 6 больных АС со вторичным АА-амилоидозом. Все пациенты были мужского пола, позитивные по HLA-B27. Средний возраст больных составил 44±9,2 года, средний возраст дебюта болезни – 16,3±7,9 года, средняя длительность АС – 26,0±7,5 года. Все 6 пациентов имели гистологически подтвержденный вторичный АА-амилоидоз: у всех отмечалось поражение почек, у 5 – также поражение желудочно-кишечного тракта и у 2 – сердца. В качестве первого биологического препарата ТЦЗ был назначен 2 больным, а 4 пациента ранее уже получали один или более ингибитор фактора некроза опухоли α. Средняя длительность лечения ТЦЗ составила 27,6 [3,0; 36,0] мес.Результаты и обсуждение. На фоне терапии ТЦЗ значимо снизились как уровень СРБ (М±σ): с 81,1±74,5 до 1,2±0,8 мг/л (р&lt;0,05) и суточной протеинурии (Ме [25-й; 75-й перцентили]): с 1,8 [1,0; 2,1] до 0,2 [0,1; 0,3] г/сут (р&lt;0,05), так и индексы активности АС – BASDAI (М±σ): с 6,2±1,6 до 3,3±0,9 (р&lt;0,05); ASDAS-СРБ (М±σ) с 4,6±1,1 до 2,04±0,7 (р&lt;0,05). Положительная динамика отмечена и в отношении уменьшения числа больных с воспалительной болью в спине, артритами и кокситом. Описан клинический случай применения ТЦЗ с развитием клинико-лабораторной ремиссии АС.Заключение. Представленные данные показывают, что в определенных клинических ситуациях иИЛ6 могут быть высокоэффективны при АС