Evaluation of clinical efficacy of prostanoid therapy for Raynaud’s phenomenon in rheumatic diseases

Aim. On the basis of clinical manifestations of Raynaud’s phenomenon (RP) to determine the RP expression level and to evaluate the long-term efficacy of treatment of RP in patients with rheumatic diseases (RD) with iloprost and alprostadil. Methods. Treatment for indications with prostanoids (intravenous iloprost, alprostadil or their combinations) was administered to 40 patients with secondary RP in RD. During 3-year follow up, clinical instrumental parameters (frequency of attacks of Raynaud's, digital ulcers (DU) formation, pain intensity on visual analogue scale (VAS) were evaluated. The control group included 30 patients with RP in RD who did not receive prostanoid therapy. The method of factor analysis was used to determine the index of generalized expression of RP, on the basis of which the expression levels of the RP were determined. Results. The “expression of RP” scale revealed in the course of factor analysis as an indicator of generalized manifestation of RP, is the average value of two subscales, the first one of which consisted of four indices - “digital ulcer”, “digital pitting scars”, “phalange amputation” and “Raynaud's attack frequency”, and the second one included “intensity of pain”, “duration of illness”, “whitening of fingers”. Verification of the correlation revealed during the study of subscales, showed its reliability (r = 0.294, p = 0.053). The final expression of RP was 1.51 ± 0.86. The low level of RP expression had values up to 0.65, high - over 2.37. When included in the study, a high level of RP expression was defined in 16 (22.9 %) patients, medium - in 43 (61.4 %), low - in 11 (15.7 %). The use of iloprost in the treatment of RP was effective for healing of DU and a statistically significant decrease of the generalized expression of RP from 2.25 [1; 3] to 1.75 [1; 2] (p = 0.012) was observed. On alprostadil treatment, statistically significantly decreased frequency of attacks from multiple daily (more than once a day) to once a month and reduced numbness during RP attack were observed as well as a decrease of the level of generalized index of RP expression from 1.26 ± 0.71 to 0.97 ± 0.57 (р = 0.038). The combination of prostanoids had a contradictory clinical effect: the pain and frequency of RP attacks decreased, but the formation of DU and new cases of amputations of phalanges were registered, the treatment had no effect on the value of RP expression. Conclusion. Based on the clinical manifestations of RP, a generalized index of RP severity was identified and the levels of RP severity were determined. Treatment with iloprost and alprostadil has a significant effect on reducing the clinical manifestations of RP with a corresponding decrease in its severity

RESISTANCE TO THE BLAST AGENT AND THE MORPHOBIOLOGICALFEATURES OF GENOTYPES IN THE Oryza sativa L. COLLECTION FROM VARIOUS ECOLOGICAL AND GEOGRAPHICAL GROUPS IN CONDITIONS OF КUBAN ZONE OF RICE GROWING

The most common and harmful disease of the agricultural crop rice is a “burn” caused by the fungus Magnoporthe grisea (Hebert) Barr, the causative agent of rice blast. The important direction of modern domestic rice breeding is the development of high-yielding varieties resistant to blast. To solve the problem, it is important to search for sources and donors of resistance to the Krasnodar population of the pathogen among ecotypes of different ecological and geographical origin. Evaluation of the rice collection diversity for resistance to blast was carried out both on a natural background and on an infectious-provocative one. Immunological evaluation and phenotyping were carried out in 2015–2017 on 154 varieties of the Oryza sativa L. species from 7 ecological and geographical cultivation zones. Over the years of research, the range of variation in the intensity of the disease development in varieties was in the range from 1.1 to 77.8 %. The differences in the resistance of rice varieties to the pathogen between ecological groups and countries have been found. Most of the studied samples have shown medium resistance, there were isolated 51 resistant forms. Most often stable forms were found among the germplasm from China, Italy, the Philippines and Korea, and the unstable ones were from African countries, Japan, Primorye and Vietnam. Introduced samples resistant to the disease were identified and adapted to soil and climatic conditions and rice cultivation technologies of the Kuban, they were included in the breeding scheme for developing pathogen-resistant rice varieties with the extension of their genetic basis. The article presents data on the variation of morphological traits and the rate of development of plants of international varieties from 24 countries in the conditions of the south of Russia. The results of the comparison of germplasm of domestic and foreign varieties according to the degree of resistance to the pathogen in conditions of natural infection in the field experiment for five years are presented. As a result of the evaluation of plant resistance to the Krasnodar population of the pathogen, the effective genes for resistance to the pathogen for breeding programs of the south of Russia and the molecular genetic analysis of the rice collection variety were determined: Pi-1, Pi-z, Pi-ta, Pi-z5, Pi-9, Pi-5(t), Pi-t, Pi-19

Geochemistry of Vein Calcites Hosted in the Troodos Pillow Lavas and Their Implications for the Timing and Physicochemical Environment of Fracturing, Fluid Circulation, and Vein Mineral Growth

Calcite veins hosted in pillow lavas of the Late Cretaceous Troodos suprasubduction zone ophiolite provide insights into the timing and physicochemical environment of postmagmatic fracturing and fluid circulation through oceanic crust. This study presents rare earth element and yttrium (REE+Y) concentrations, δ13C, δ18O, 87Sr/86Sr, and clumped isotopic (Δ47) compositions of vein calcites in order to investigate their fluid sources, formation temperatures, and precipitation ages. These geochemical data are combined with microtextural analyses. Intersections of 87Sr/86Sr ratios of vein calcites with the Sr isotope seawater curve suggest two distinct calcite veining phases. Major calcite veining within an interval of ~10 Myr after crust formation is characterized by microtextures that point to extensional fracturing related to crack and sealing, host rock brecciation, and advective fluid flow. These vein calcites show REE+Y characteristics, 87Sr/86Sr ratios, and clumped isotopic compositions indicative of precipitation from seawater at <50 °C. Extended fluid residence times intensified fluid‐rock interactions and lowered Y/Ho ratios of some blocky vein calcites, whereas crack and sealing resulted in pristine seawater signatures. Low 87Sr/86Sr ratios of localized high‐temperature blocky vein calcites point to the involvement of hydrothermal fluids. These calcites show Mn‐controlled oscillatory growth zonations that probably developed in a closed system out of equilibrium. Later calcite veining (<75 Ma) may have coincided with rotation and/or uplift of the Troodos ophiolite. Microtextures of these vein calcites indicate fluid diffusion and fracture‐independent crystallization pressure‐driven veining. Their variably modified seawater signatures resulted from diffusion‐related fluid interaction with hydrothermal sediments

Молекулярный фенотип клеток крови, ассоциированный с прогрессированием трижды негативного рака молочной железы

Introduction. triple negative breast cancer is an aggressive clinical phenotype characterized by poor prognosis. immune system plays an important role in the development, treatment response, and progression of solid tumor. The search for immune-related markers associated with the prediction of treatment efficacy and disease prognosis, and based on the use of high-resolution molecular techniques, is a promising area of research, the results of which can be translated into clinical practice. Case description. The molecular profile of blood mononuclear cells in a 48-year-old female patient with histologically proven triple negative breast cancer (estrogen Receptor – 0; progesteron Receptor – 0; Her2/neu – 0; gata-3 – 0, androgen Receptor – 0 and Ki67 – 70 %) was described. The patient did not response to neoadjuvant chemotherapy with 4 cycles of paclitaxel + carboplatin followed by 2 cycles of adriamycin + cyclophosphamide. The patient underwent surgery. disease progression (pelvic bone metastases) occurred 2 months after surgery. The features of blood lymphocytes and monocytes associated with a lack of response to neoadjuvant chemotherapy and disease progression were described.Conclusion. This clinical case demonstrates that sequencing of peripheral blood mononuclear cells can be used as a method for identifying predictive markers of therapy efficacy and developing personalized treatments for patients with triple negative breast cancer.Актуальность. Трижды негативный подтип рака молочной железы характеризуется агрессивным течением и неблагоприятным прогнозом. Компоненты иммунной системы как непосредственные участники патогенеза играют роль в развитии, ответе на терапию и прогрессировании этой нозологии. Поиск маркеров иммунных клеток, ассоциированных с предсказанием эффективности лечения и прогнозом заболевания, основанный на применении молекулярных методов высокого разрешения, является перспективным направлением поискового исследования, результаты которого можно транслировать в клиническую практику. Описание клинического случая. Представлен первый опыт описания молекулярного профиля мононуклеарных клеток крови пациентки с трижды негативным раком молочной железы. Опухоль: инвазивная карцинома неспецифического типа с экспрессией: estrogen Receptor – 0; progesteron Receptor – 0; Her2/neu – 0; gata-3 – 0, androgen Receptor – 0, Ki67 – 70 % опухолевых клеток. Отмечено отсутствие ответа на неоадъювантную химиотерапию по схеме: 4 цикла «паклитаксел + + карбоплатин», с последующими 2 курсами АС (адриамицин + циклофосфан). Пациентке проведено оперативное лечение, через 2 мес после которого выявлены метастазы в кости таза. У пациентки описаны особенности лимфоцитов и моноцитов крови, которые могут быть ассоциированы с отсутствием ответа на неоадъювантную химиотерапию и прогрессированием заболевания.Заключение. Представленное клиническое наблюдение показывает, что метод секвенирования мононуклеарных клеток периферической крови можно использовать в качестве поискового для обнаружения предиктивных маркеров эффективности терапии и создания персонифицированной системы лечения пациенток с трижды негативным раком молочной железы

Оценка предсказательной значимости рецептора сосудистого эндотелиального фактора роста VEGFR-2 у больных тройным негативным раком молочной железы

The identification of informative biomarkers that are able to predict prognosis and treatment response may be particularly important in triple negative breast cancer.The aim of the study was to investigate the relationship between vascular endothelial growth factor receptor VEGFR-2 expression and KDR gene polymorphisms with the efficacy of neoadjuvant chemotherapy (NAC) in patients with triple negative breast cancer.Methods. The study included 70 patients with triple negative operable breast cancer (T1–3N0–3M0), who had received 2–4 cycles of FAC and CAX regimens. The pathologic complete response (pCR) to treatment was determined by RECIST. VEGFR-2 expression level was evaluated using immunohistochemistry. Genotypes for KDR (rs2071559, rs2305948) were detected by a Real-time PCR.Results. The pCR rate was significantly associated with young age at diagnosis (≤50 years) (p=0.0044), a high level of Ki67 expression (≥20) (p=0.0322) and with CAX regimen (p=0.0246). Additionally, all patients with pCR had the lack of VEGFR-2 expression in tumor tissue after surgery (p=0.0000). The presence of the VEGFR-2 expression (negative or positive) in tumor tissue before NAC was associated with KDR rs2071559 (r=−0.297; p=0.0273). A significant correlation between the KDR rs2071559 and VEGFR-2 expression level (less than 70, 70% or more) in the tumor tissue before NAC was found (r=−0.314; p=0.0297). Multivariate logistic regression analysis showed that the young age of the patients (≤50 years), the lack of VEGFR-2 expression after surgery and CAX regimen were significant predictors of NAC.Conclusion. The VEGFR-2 expression level in tumor tissue and KDR gene polymorphism can be considered as new additional molecular predictive markers of pathologic complete response to NAC in triple negative breast cancer patients.Введение. Поиск информативных молекулярно-генетических маркеров тройного негативного рака молочной железы, обладающих высокой предсказательной значимостью в отношении ответа опухоли на проводимую терапию, является актуальной научной задачей.Целью исследования явилось изучение взаимосвязи экспрессии рецепторов сосудистого эндотелиального фактора роста VEGFR-2 и полиморфных вариантов гена KDR с эффективностью неоадъювантной химиотерапии (НАХТ) у больных тройным негативным раком молочной железы.Методы. В исследование включено 70 больных операбельным тройным негативным раком молочной железы (T1–3N0–3M0), получавших 2–4 курса НАХТ по схемам FAC и CAX. Оценка эффективности НАХТ осуществлялась по шкале RECIST. Уровень экспрессии VEGFR-2 оценивался иммуногистохимическим методом. Изучение полиморфных вариантов гена KDR (rs2071559, rs2305948) проведено с помощью ПЦР в режиме реального времени.Результаты. Показано, что достижение полных морфологических регрессий на фоне проведения НАХТ ассоциировано с возрастом до 50 лет (р=0,0044) и высоким уровнем экспрессии Ki67 (≥20) (р=0,0322). Отмечено, что у пациентов, получавших лечение по схеме CAX, эффективность НАХТ была значимо выше по сравнению с группой больных, получавших FAC режим (р=0,0246). Кроме того, все случаи полной морфологической регрессии были ассоциированы с отсутствием экспрессии VEGFR-2 в опухолевой ткани после оперативного лечения (р=0,0000). Наличие экспрессии VEGFR-2 (негативной или позитивной) в опухолевой ткани до лечения сопряжено с полиморфизмом гена KDR rs2071559 (r=−0,297; p=0,0273). Выявлена значимая корреляционная связь между KDR rs2071559 и уровнем экспрессии VEGFR-2 (менее 70, 70 % и более) в опухолевой ткани до лечения (r=−0,314; p=0,0297). Результаты многофакторного логистического регрессионного анализа свидетельствуют, что молодой возраст пациенток (≤50 лет), отсутствие экспрессии VEGFR-2 после операции и схема CAX являются статистически значимыми предикторами эффективности НАХТ.Заключение. Уровень экспрессии VEGFR-2 в опухолевой ткани и полиморфные варианты гена KDR могут рассматриваться в качестве новых дополнительных предсказательных молекулярных критериев у больных тройным негативным раком молочной железы при проведении НАХТ

Enhanced tonic GABAA inhibition in typical absence epilepsy

The cellular mechanisms underlying typical absence seizures, which characterize various idiopathic generalized epilepsies, are not fully understood, but impaired GABAergic inhibition remains an attractive hypothesis. In contrast, we show here that extrasynaptic GABAA receptor–dependent ‘tonic’ inhibition is increased in thalamocortical neurons from diverse genetic and pharmacological models of absence seizures. Increased tonic inhibition is due to compromised GABA uptake by the GABA transporter GAT–1 in the genetic models tested, and GAT–1 is critical in governing seizure genesis. Extrasynaptic GABAA receptors are a requirement for seizures in two of the best characterized models of absence epilepsy, and the selective activation of thalamic extrasynaptic GABAA receptors is sufficient to elicit both electrographic and behavioural correlates of seizures in normal animals. These results identify an apparently common cellular pathology in typical absence seizures that may have epileptogenic significance, and highlight novel therapeutic targets for the treatment of absence epilepsy.peer-reviewe

Management of Work and Procedure for the Laboratory Diagnostics of Infectious Diseases during the Winter XXII Olympics and XI Paralympics, 2014

Analyzed is the management system for laboratory diagnostics of infectious diseases during the XXII Olympics and XI Paralympics, 2014 in Sochi. Reviewed is piece of work, executed in the pre-Olympic period as regards provision of laboratory facilities deployed for clinical material investigation, development of normative and regulatory documentation which considers peculiarities of the situation, identification of diagnostic capacities of the laboratories, and forecasting of the probable volume of laboratory studies by reference to various groups of infections. Put forward is the procedure for arrangement of work at the different stages of laboratory diagnostics, cooperation and response in case of emergency situation in the sphere of sanitary-epidemiological welfare of the population. Discussed is the role of geo-information system and current means of monitoring over epidemiological situation in the participating states and in the region of the Olympics in laboratory support organization

Характеристика пациентов с первичной цилиарной дискинезией

Primary ciliary dyskinesia (PCD) (Online Mendelian Inheritance in Man - OMIM - #242650) is a rare hereditary disease, which is based on a defect in the ultrastructure of the cilia epithelium of the respiratory tract which leads to the motor function disorder. Data about health characteristics of patients with PCD in the Russian Federation are incomplete.The aim of the study was to investigate the clinical, laboratory, and instrumental characteristics of patients with PCD.Methods. The data of 90 patients (22 adults (24.4%) and 68 children (75.6%)) from several medical centers were studied. The following methods were used: medical history, spirometry, microbiological examination of the respiratory tract, video microscopic analysis of the functional activity of the nasal mucosa ciliated epithelium, transmission electron microscopy of the ciliated epithelium, and DNA testing.Results. The median age at diagnosis was 17.0 years for adults and 5.0 years for children. Kartagener syndrome was detected in 23 (27%) people, including 6 (26.0%) adults. Hearing loss was noted in 5 (26.3%) adult patients and 15 (26.8%) children. Light microscopy of the ciliated epithelium was performed in 14 (82.3%) children and 3 (17.7%) adults. In 12 patients, cilia motor activity was not registered at each of the magnifications (x 100, x 400, x 1,000). Transmission electron microscopy showed that absence ofinternal and external dynein handles (51%) and absence of internal dynein handles (17.9%) were the most common disorders. DNA testing was performed in 55 (61.2%) patients: 16 (29.1%) adults and 38 (70.9%) children. The most common genetic variants were found in the DNAH5 and HYDIN genes. Lung function was reduced in both adults and children, but a significant decrease was noted in adult patients. P. aeruginosa predominated in the culture and accounted for 21.3% (intermittent detection in 13.2%, persistent detection in 9%). It has increased resistance to antibiotics.Conclusion. The results correlate with the European data. Infection caused by P. aeruginosa with the increased resistance to antibiotics was prevalent in patienths with PCD.Первичная цилиарная дискинезия (ПЦД) (код по медицинской базе данных известных заболеваний с генетическим компонентом и генов, ответственных за их развитие, «Менделевское наследование у человека» (Online Mendelian Inheritance in Man — OMIM — #242650) — редкое наследственное заболевание, основу которого составляет дефект ультраструктуры ресничек эпителия респираторного тракта и аналогичных им структур, что приводит к нарушению их двигательной функции. В Российской Федерации информации о характеристиках здоровья пациентов с ПЦД недостаточно.Целью исследования являлось изучение клинико-лабораторной и инструментальной характеристики пациентов с ПЦД.Материалы и методы. Изучены данные пациентов (n = 90: 22 (24,4 %) взрослых и 68 (75,6 %) детей) из нескольких медицинских центров. При обследовании использовались анамнестический метод, спирометрия, микробиологическое исследование дыхательного тракта, видеомикроскопический анализ функциональной активности реснитчатого эпителия слизистой оболочки носа, трансмиссионная электронная микроскопия реснитчатого эпителия, ДНК-диагностика.Результаты. Медиана возраста установления диагноза у взрослых составила 17,0 лет, среди детей — 5,0 лет. Синдром Картагенера выявлен у 23 (27 %) больных, из них 6 (26,0 %) взрослых. В анамнезе пациентов преобладали рецидивирующие бронхиты, пневмонии, отиты. Снижение слуха отмечено у 5 (26,3 %) взрослых пациентов и 15 (26,8 %) детей. Световая микроскопия реснитчатого эпителия выполнена у 14 (82,3 %) детей и 3 (17,7 %) взрослых. У 12 (3 взрослых и 9 детей) пациентов двигательной активности ресничек на каждом из увеличений микроскопа (к 100, к 400, х 1 000) не зарегистрировано. При трансмиссионной электронной микроскопии чаще встречалось полное отсутствие наружных и внутренних динеиновых ручек (51 %) и внутренних динеиновых ручек (17,9 %). Молекулярногенетическое исследование выполнено у 55 (61,2 %) пациентов (16 (29,1 %) взрослых и 38 (70,9 %) детей). Наиболее часто встречались генетические варианты в генах DNAH5 и HYDIN. Функция легких была снижена как у взрослых, так и у детей, но в значительной степени снижение отмечено у взрослых пациентов. В микробиологических посевах превалирует Pseudomonas aeruginosa — 21,3 % (интер-миттирующий высев — у 13,2 %, хронический высев — у 9 %), обладающая повышенной резистентностью к антибактериальным препаратам (АБП).Заключение. Полученные результаты коррелируют с европейскими данными. У пациентов с ПЦД обнаружено преобладание инфекции, вызванной P. aeruginosa, характеризуемой повышенной резистентностью к АБП