Some aspects of treatment for cognitive impairments. Cyticolin: pharmacological characteristics, possible benefits, aspects of use

The paper reviews the data available in the literature on the pharmacokinetic and pharmacodynamic properties of cyticolin and its use in cognitive impairments (CIs).It assesses trials investigating the effect of cyticolin on cognitive functions, including its possible role in increasing Sirtuin 1 (SIRT1) expression. The results of the latest multicenter trials of the drug used to treat dementia syndrome are analyzed in elderly patients with clinical presentations of mental confusion (the VITA trial) and mild vascular CIs (the IDEALE trial).Cyticolin is able to potentiate neuroplasticity and is a natural precursor of phospholipids, mainly phosphotidylcholine that serves as a source of choline in the metabolic pathways of acetylcholine biosynthesis. The VITA and IDEALE have shown that the parenteral and oral administrations of cyticolin are effective and safe in the treatment of moderate vascular CIs and dementia with clinical presentations of mental confusion. Cyticolin therapy is used to reduce the risk of side effects and to delay of loss of the therapeutic effects of levodopa preparations. Cyticolin has been noted to have a positive effect on cognitive functions in patients with Alzheimer’s disease if it is used as an additional therapy

Diagnostically significant differences septic and aseptic instability of endoprosthesis components during arthroplasty of large joints

The purpose of the work is to analyze the results of laboratory, microbiological and instrumental studies to search for screening criteria for the difference between aseptic and septic instability of endoprosthesis components after knee and hip joint arthroplasty. The materials contained 146 cases of revision arthroplasty of the knee and hip joints, performed under the conditions of Federal State Budgetary Institution Federal Center of Traumatology, Orthopedics and endoprosthesis replacement of Ministry of Health of the Russian Federation (Cheboksary) for a 3-year period, including cases of aseptic instability - 69, septic instability-77. By methods for laboratory diagnosis were used to evaluate the blood levels of leukocytes, stab neutrophils, ESR, C-reactive protein (CRP), presepsin, procalcitonin, D-dimer, interleukin-6. Using ultrasound (ultrasonic) examination of the periprosthetic zone, the presence of fluid, granulation tissue in the joint cavity, altered lymph nodes was determined. Before the operation, the level of cytosis and cellular composition were determined in the synovial fluid; tissue bioptates, removed components of implants (after ULTRASONIC treatment) with sowing on the microflora were studied intraoperatively. Intraoperative tissue biopsies were used to make smears-prints on the glass, with gram staining, estimating the number of leukocytes and neutrophils in the field of vision. Results. Determination of indicators of ESR, presepsin and interleukin-6, the level of which goes beyond the generally recognized normal values in the presence of infection, can be recommended as a screening test in the diagnosis of the infectious nature of instability of the components of the endoprosthesis of large joints. The second stage of differential diagnosis of septic and aseptic instability can be the detection of lymphadenopathy. The third (final) stage of determining the infectious nature of instability is an invasive technique to determine the level of cytosis with the calculation of neutrophils in the synovial fluid.Цель работы - анализ результатов лабораторных, микробиологических и инструментальных исследований для поиска скрининг-критериев отличия асептической и септической нестабильности компонентов эндопротеза после артропластики коленных и тазобедренных суставов. Материалами послужили 146 случаев ревизионной артропластики коленных и тазобедренных суставов, выполненной в условиях Федерального государственного бюджетного учреждения «Федеральный центр травматологии, ортопедии и эндопротезирования» Министерства здравоохранения российской Федерации (г. Чебоксары) за 3-летний период, из них случаев асептической нестабильности - 69, септической нестабильности - 77. Методами лабораторной диагностики проводилась оценка содержания в крови лейкоцитов, палочкоядерных нейтрофилов, СОЭ, С-реактивного белка (СРБ), пресепсина, прокальцитонина, Д-димера, интерлейкина-6. С помощью ультразвукового (УЗ) исследования перипротезной зоны определяли наличие жидкости, грануляционной ткани в полости сустава, измененных лимфатических узлов. до операции в синовиальной жидкости определяли уровень цитоза и клеточный состав; интраоперационно исследовались тканевые биоптаты, удаленные компоненты имплантов (после УЗ обработки) с посевом на микрофлору. Из интраоперационных тканевых биоптатов делали мазки-отпечатки на стекле, с окрашиванием по Граму, оценивая количество лейкоцитов и нейтрофилов в поле зрения. результаты. Определение показателей СОЭ, пресепсина и интерлейкина-6, уровень которых выходит за пределы общепризнанных нормальных значений при наличии инфекции, может быть рекомендовано в качестве скрининг-теста при диагностике инфекционной природы нестабильности компонентов эндопротеза крупных суставов. Вторым этапом дифференциальной диагностики септической и асептической нестабильности может служить выявление лимфоаденопатии. третьим (заключительным) этапом определения инфекционной природы нестабильности является инвазивная методика с определением уровня цитоза с подсчетом нейтрофилов в синовиальной жидкости

Противовоспалительный и регенеративный эффект подавления гипоксийного сигналинга на модели хронической обструктивной болезни легких

The aim of this study was to investigate anti-inflammatory and regenerative effects of inhibited activation of hypoxic signaling in COPD model using cyclooxygenase-2 (COX-2)-dependent pro-inflammatory cascade inhibition. Methods. COPD was modelled in rats by nitrogen dioxide (NO2, 30-40 mg×m–3) exposure for 90 days. Celecoxib was used as COX-2 inhibitor. The study group rats were given celecoxib (25 mg×kg–1) through an esophageal probe after 30 days of exposure. Control rats were given saline solution. The group 3 rats were intact. The rats were put out of the experience using cervical dislocation after 60 and 90 days of NO2 exposure. Bronchoalveolar lavage fluid (BALF) cytology was analyzed. COX-2, hypoxia-inducible factor-1α (HIF-1α), interleukin-17 (IL-17), and surfactant protein D (SP-D) were measured in BALF using ELISA method. Histological examination of the lung tissue was also performed. Results. 90-day exposure of NO2 resulted in 7.7-fold increase in BALF neutrophil count compared to that in intact rats. Pro-inflammatory mediators (СOX-2, HIF-1α, and IL-17) significantly increased and SP-D level decreased in BALF. Administration of celecoxib was accompanied by normalization of BALF cytology profile and decrease in COX-2, HIF-1α, and IL-17 levels in BALF; this could indicate a reduction in the hypoxic signaling activity and in inflammation. The growth of SP-D concentration could be considered as a result of the alveolar epithelium restoration. This was confirmed by histological examination of the lung tissue. Conclusion. COX-2 inhibition suppressed HIF-1α-signaling and decreased the lung inflammation. The results confirm a functional and regulatory relationship between HIF-1α and COX-2 signaling cascades that could be a therapeutic target for preventing the progression of inflammation and airway remodeling in COPD.Цель. Оценка противовоспалительного и регенеративного эффекта предотвращения активации гипоксийного сигналинга на модели хронической обструктивной болезни легких (ХОБЛ) путем ингибирования циклооксигеназы-2 (СОХ-2)-зависимого провоспалительного каскада. Материалы и методы. При помощи экспозиций диоксидом азота (NO2, 30–40 мг / м3) в течение 90 дней у крыс создана модель ХОБЛ. В качестве ингибитора СОХ-2 применялся целекоксиб. С 30-го дня крысам 1-й группы через пищеводный зонд вводился целекоксиб (25 мг / кг); животные 2-й группы (контроль) получали 0,9%-ный NaCl. Интактные крысы составили 3-ю группу. Животные выводились из опыта после 60 и 90 дней экспозиции NO2 путем цервикальной дислокации. При этом выполнялась цитография бронхоальвеолярной лаважной жидкости (БАЛЖ), определялось содержание COX-2, гипоксия-индуцибельного фактора-1a (HIF-1a), интерлейкина (IL)-17, сурфактантного протеина D (SP-D) методом ELISA. Выполнено гистологическое исследование легочной ткани. Результаты. Показано, что после 90-дневной экспозиции NO2 в БАЛЖ контрольных особей содержание нейтрофилов в 7,7 раза превышало интактное значение. Достоверно возрастало содержание провоспалительных медиаторов СОХ-2, HIF-1α, IL-17, а уровень SP-D снижался. Применение целекоксиба сопровождалось нормализацией цитологического профиля БАЛЖ и уменьшением содержания СОХ-2, HIF-1α, IL-17, что свидетельствовало о снижении активности гипоксийного сигналинга и воспалительного процесса. Значительно возрастала концентрация SP-D, что можно рассматривать как следствие восстановления морфологической структуры бронхоальвеолярного эпителия, о чем свидетельствовали данные гистологического исследования легочной ткани. Заключение. При ингибировании СОХ-2 отмечен супрессивный эффект на HIF-1α-сигналинг и уменьшение легочного воспаления. Полученные результаты подтверждают функционально-регуляторную связь HIF-1α и СОХ-2-сигнальных каскадов, которая может быть терапевтической мишенью для предотвращения прогрессирования воспаления и ремоделирования дыхательных путей при ХОБЛ

Evaluation of the effectiveness of the analgesic effect of selective and non-selective cyclooxygenase blockers in the composition of multimodal analgesia after knee joint endoprosthesis replacement

The purpose of the work is to compare the effectiveness of anesthesia with the use of a highly specific blocker COX-2 and a dedicated cyclo-oxygenase blocker COX-1 and COX-2 lornoxicam as part of multimodal analgesia in patients after primary knee replacement. The material was the cases of knee prosthesis (N=196) using multimodal analgesia; patients were divided into two groups, depending on the type of anesthesia, in accordance with the developed scheme of pharmacotherapy: I – receiving celecoxib (n=98) and II - lornoxicam (n=98). Methods for evaluating the effectiveness of anesthesia were the visual analogue scale (VAS), the KSS knee joint function evaluation scale before surgery and on the 5th day after it; analysis of the features of early verticalization, the patient's need for additional pain relief after surgery; costs of drug therapy are calculated. Results. Patients of both groups were comparable in age and average duration of hospitalization. The pain syndrome assessment on the VAS scale showed a higher efficacy of pain relief on days 1 and 5 in group II (4.1 ± 0.1 versus 3.5 ± 0.1 and 1.9 ± 0.04 versus 1.6 ± 0.1 points respectively) (p≤0.05). Evaluation of the functional activity of the prosthetic knee joint on the KSS scale did not reveal any differences between the groups. Of the features of early verticalization on the first day after surgery, a higher percentage of weakness in the legs (79.6%) and nausea (70.4%) was noted in group I, and a higher percentage of dizziness (15.3%) and hemodynamic disorders (6.1% of cases). The cost of providing basic pain therapy in group I was 2.4 times higher than in group II, with the same costs for additional anesthesia with solutions of paracetamol and narcotic analgesics. Conclusions. As part of multimodal analgesia, Lornoxicam showed a higher efficacy in relieving pain syndrome at a low cost of a course of treatment compared with celecoxib.Цель работы - сравнение эффективности обезболивания при использовании высокоспецифичного блокатора ЦОГ-2 целекоксиба и неспецифичного блокатора циклооксигеназы ЦОГ-1 и ЦОГ-2 лорноксикама в составе мультимодальной анальгезии у пациентов после первичного эндопротезирования коленного сустава. Материалом послужили случаи протезирования коленных суставов (N=196) с использованием мультимодальной анальгезии; в зависимости от типа обезболивания, в соответствии с разработанной схемой фармакотерапии, пациенты разделены на две группы: I - получающие целекоксиб (n=98) и II - лорноксикам (n=98). Методами оценки эффективности обезболивания являлись визуально-аналоговая шкала (ВАШ), шкала оценки функции коленного сустава KSS до операции и на 5 сутки после неё; анализ особенностей ранней вертикализации, потребности пациента в дополнительном обезболивании после операции; рассчитаны затраты на медикаментозную терапию. результаты. Пациенты обеих групп были сопоставимы по возрасту и средней длительности госпитализации. оценка болевого синдрома по шкале ВАШ показала более высокую эффективность купирования болевого синдрома на 1 и 5 сутки во II группе (4,1±0,1 против 3,5±0,1 и 1,9±0,04 против 1,6±0,1 балла соответственно) (p≤0,05). оценка функциональной активности протезированного коленного сустава по шкале KSS не выявила различий между группами. особенности ранней вертикализации в 1 сутки после операции: в I группе - более высокий процент слабости в ногах (79,6%) и тошноты (70,4%), во II - выше процент головокружения (15,3%) и нарушений гемодинамики (6,1% случаев). Затраты на обеспечение базовой обезболивающей терапии в I группе в 2,4 раза превысили показатель II группы, при равных затратах на дополнительное обезболивание растворами парацетамола и наркотических анальгетиков. Выводы. Лорноксикам в составе мультимодальной анальгезии показал более высокую эффективность купирования болевого синдрома при низкой стоимости курсового лечения по сравнению с целекоксибом

Evolution of climate, glaciation and subglacial environments of Antarctica from the deep ice core and Lake Vostok water sample studies (Key results of implementation of the Russian Science Foundation project, 2014–2016)

Work on the project focused on the following five areas: 1)  field works in Antarctica at Vostok and Concordia stations; 2)  experimental and theoretical studies in the field of ice core and paleoclimate research; 3) experimental and theoretical works related to the exploration of subglacial Lake Vostok; 4) development of technology and drilling equipment for deep ice coring and exploration of subglacial lakes; 5) upgrading the analytical instrumentation in the Climate and Environmental Research Laboratory (CERL) of the Arctic and Antarctic Research Institute. The main achievements in the field of ice core and paleoclimate research include 1) further elaboration of a new method of ice core dating, which is based on the link between air content of ice and local insolation, 2) investigation of the possible applications of the 17O-excess measurements in ice core to the paleoclimate research, 3)  a better understanding of the mechanisms of the formation of relief-related variations in the isotopic content of an ice core drilled in the area of Antarctic megadunes, and 4) obtaining the first reliable data set on the variations of the 17O-excess in the Vostok core corresponding to marine isotope stage 11. As part of our studies of subglacial Lake Vostok, we have obtained a large body of new experimental data from the new ice core recovered from the 5G-3 borehole to the surface of the subglacial lake. Stacked profiles of isotopic composition, gas content and the size and orientation of the ice crystals in the lake ice have been composed from the data of three replicate cores from boreholes 5G-1, 5G-2 and 5G-3. The study reveals that the concentration of gases in the lake water beneath Vostok is unexpectedly low. A clear signature of the melt water in the surface layer of the lake, which is subject to refreezing on the icy ceiling of Lake Vostok, has been discerned in the three different properties of the accreted ice (the ice texture, the isotopic and gas content of the ice). These sets of data indicate in concert that poor mixing of the melt (and hydrothermal) water with the resident lake water and pronounced spatial and/or temporal variability of local hydrological conditions are likely to be the characteristics of the southern end of the lake. A considerable part of the funding allocated by the RSF to this project was used for upgrading the analytical instrumentation for ice core studies in the CERL of AARI. Using this grant, we purchased and started working with the Picarro L-2140i, a new-generation laser mass analyzer, and set the upgraded mass spectrometer Delta V Plus into operation. The new equipment was used to carry out research planned as part of the project, including the setting up and carrying out of new measurements of 17О in ice cores

Rapid selection of BRCA1-proficient tumor cells during neoadjuvant therapy for ovarian cancer in BRCA1 mutation carriers

Ovarian carcinomas (OC) often demonstrate rapid tumor shrinkage upon neoadjuvant chemotherapy (NACT). However, complete pathologic responses are very rare and the mechanisms underlying the emergence of residual tumor disease remain elusive. We hypothesized that the change of somatic BRCA1 status may contribute to this process. The loss-of-heterozygosity (LOH) at the BRCA1 locus was determined for 23 paired tumor samples obtained from BRCA1 germ-line mutation carriers before and after NACT. We observed a somatic loss of the wild-type BRCAI allele in 74% (17/23) of OCs before NACT. However, a retention of the wild-type BRCA1 copy resulting in a reversion of LOH status was detected in 65% (11/17) of those patients after NACT. Furthermore, we tested 3 of these reversion samples for LOH at intragenic BRCA1single nucleotide polymorphisms (SNPs) and confirmed a complete restoration of the SNP heterozygosity in all instances. The neoadjuvant chemotherapy for BRCA1-associated OC is accompanied by a rapid expansion of pre-existing BRCA1-proficient tumor clones suggesting that continuation of the same therapy after NACT and surgery may not be justified even in patients initially experiencing a rapid tumor regression. (C) 2017 Elsevier B.V. All rights reserved.Peer reviewe

Novel allosteric mechanism of p53 activation by small molecules for targeted anticancer therapy

Given the immense significance of p53 restoration for anti-cancer therapy and that p53-activating molecules are in clinical trials, elucidation of the mechanisms of action of p53-activating molecules is of the utmost importance. Here we report a discovery of a novel allosteric modulation of p53 by small molecules, which is an unexpected turn in the p53 story. We identified a structural element involved in allosteric regulation of p53, whose targeting by small molecules RITA, PpIX and licofelone blocks the binding of two p53 inhibitors, MDM2 and MDMX, thereby restoring p53 function. Deletion and mutation analysis followed by molecular modeling and its thorough validation, identified the key p53 residues S33 and S37 targeted by RITA and PpIX. We propose that the binding of small molecules to the identified site in p53 induces a conformational trap preventing p53 from the interaction with MDM2 and MDMX. These results point to a high potential of allosteric activators as targeted drugs. Our study provides a basis for the development of therapeutics with a novel mechanism of action, thus extending the p53 pharmacopeia

Эволюция климата, оледенения и подледниковой среды Антарктиды по данным исследований ледяных кернов и проб воды озера Восток (Основные итоги работ по проекту РНФ, 2014–2016 гг.)

Work on the project focused on the following five areas: 1)  field works in Antarctica at Vostok and Concordia stations; 2)  experimental and theoretical studies in the field of ice core and paleoclimate research; 3) experimental and theoretical works related to the exploration of subglacial Lake Vostok; 4) development of technology and drilling equipment for deep ice coring and exploration of subglacial lakes; 5) upgrading the analytical instrumentation in the Climate and Environmental Research Laboratory (CERL) of the Arctic and Antarctic Research Institute. The main achievements in the field of ice core and paleoclimate research include 1) further elaboration of a new method of ice core dating, which is based on the link between air content of ice and local insolation, 2) investigation of the possible applications of the 17O-excess measurements in ice core to the paleoclimate research, 3)  a better understanding of the mechanisms of the formation of relief-related variations in the isotopic content of an ice core drilled in the area of Antarctic megadunes, and 4) obtaining the first reliable data set on the variations of the 17O-excess in the Vostok core corresponding to marine isotope stage 11. As part of our studies of subglacial Lake Vostok, we have obtained a large body of new experimental data from the new ice core recovered from the 5G-3 borehole to the surface of the subglacial lake. Stacked profiles of isotopic composition, gas content and the size and orientation of the ice crystals in the lake ice have been composed from the data of three replicate cores from boreholes 5G-1, 5G-2 and 5G-3. The study reveals that the concentration of gases in the lake water beneath Vostok is unexpectedly low. A clear signature of the melt water in the surface layer of the lake, which is subject to refreezing on the icy ceiling of Lake Vostok, has been discerned in the three different properties of the accreted ice (the ice texture, the isotopic and gas content of the ice). These sets of data indicate in concert that poor mixing of the melt (and hydrothermal) water with the resident lake water and pronounced spatial and/or temporal variability of local hydrological conditions are likely to be the characteristics of the southern end of the lake. A considerable part of the funding allocated by the RSF to this project was used for upgrading the analytical instrumentation for ice core studies in the CERL of AARI. Using this grant, we purchased and started working with the Picarro L-2140i, a new-generation laser mass analyzer, and set the upgraded mass spectrometer Delta V Plus into operation. The new equipment was used to carry out research planned as part of the project, including the setting up and carrying out of new measurements of 17О in ice cores.Изложены основные результаты работ, выполненных Лабораторией изменений климата и окружающей среды ААНИИ по проекту Российского научного фонда в 2014–2016 гг. Показано, что поддержка фонда способствовала получению научных результатов международного уровня в двух приоритетных направлениях антарктических исследований  – реконструкции палеоклимата по ледяным кернам и изучении подледниковой среды Антарктиды