Репозиторий Университета

While deficient brain plasticity is a well-established pathophysiologic feature of depression, little is known about disorder-associated enhanced cognitive processing. Here, we studied a novel mouse paradigm that potentially models augmented learning of adverse memories during development of a depressive-like state. We used a modification of the classic two-day protocol of a mouse Porsolt test with an additional session occurring on Day 5 following the initial exposure. Unexpectedly, floating behaviour and brain glycogen synthase kinase-3 beta (GSK-3beta) mRNA levels, a factor of synaptic plasticity as well as a marker of distress and depression, were increased during the additional swimming session that was prevented by imipramine. Observed increases of GSK-3beta mRNA in prefrontal cortex during delayed testing session correlated with individual parameters of behavioural despair that was not found in the classic Porsolt test. Repeated swim exposure was accompanied by a lower pGSK-3beta/GSK-3beta ratio. A replacement of the second or the final swim sessions with exposure to the context of testing resulted in increased GSK-3beta mRNA level similar to the effects of swimming, while exclusion of the second testing prevented these changes. Together, our findings implicate the activation of brain GSK-3beta expression in enhanced contextual conditioning of adverse memories, which is associated with an individual susceptibility to a depressive syndrome.

Thiamine (vitamin B1) deficiency in the brain has been implicated in the development of dementia and symptoms of depression. Indirect evidence suggests that thiamine may contribute to these pathologies by controlling the activities of glycogen synthase kinase (GSK)-3β. While decreased GSK-3β activity appears to impair memory, increased GSK-3β activity is associated with the distressed/depressed state. However, hitherto direct evidence for the effects of thiamine on GSK-3β function has not been reported. Here, we administered thiamine or, the more bioavailable precursor, benfotiamine at 200 mg/kg/day for 2 weeks to C57BL/6J mice, to determine whether treatment might affect behaviours that are known to be sensitive to GSK-3β activity and whether such administration impacts on GSK-3β expression within the brain. The mice were tested in models of contextual conditioning and extinction, a 5-day rat exposure stress test, and a modified swim test with repeated testing. The tricyclic antidepressant imipramine (7.5 mg/kg/day), was administered as a positive control for the effects of thiamine or benfotiamine. As for imipramine, both compounds inhibited the upregulation of GSK-3β induced by predator stress or repeated swimming, and reduced floating scores and the predator stress-induced behavioural changes in anxiety and exploration. Coincident, thiamine and benfotiamine improved learning and extinction of contextual fear, and the acquisition of the step-down avoidance task. Our data indicate that thiamine and benfotiamine have antidepressant/anti-stress effects in naïve animals that are associated with reduced GSK-3β expression and conditioning of adverse memories. Thus thiamine and benfotiamine may modulate GSK-3β functions in a manner that is dependent on whether the contextual conditioning is adaptive or maladaptive.

Излагаются результаты анализа и систематизации интернет-ресурсов, используемых при подготовке врачей-специалистов по авиационной и космической медицине в системе высшего медицинского образования Российской Федерации. Представленный материал направлен на обеспечение успешности обучения с учетом требований, установленных Федеральным государственным образовательным стандартом по данной специальности.

Marine sponges contain a variety of low-molecular-weight compounds including guanidine alkaloids possessing different biological activities. Monanchomycalin B and urupocidin A were isolated from the marine sponge Monanchora pulchra. We found that they act as inhibitors of the TRPV1, TRPV2, and TRPV3 channels, but are inactive against the TRPA1 receptor. Monanchomycalin B is the most active among all published marine alkaloids (EC50 6.02, 2.84, and 3.25 μM for TRPV1, TRPV2, and TRPV3, correspondingly). Moreover, monanchomycalin B and urupocidin A are the first samples of marine alkaloids affecting the TRPV2 receptor. Two semi-synthetic urupocidin A derivatives were also obtained and tested against TRP (Transient Receptor Potential) receptors that allowed us to collect some data concerning the structure-activity relationship in this series of compounds. We showed that the removal of one of three side chains or double bonds in the other side chains in urupocidin A led to a decrease of the inhibitory activities. New ligands specific to the TRPV subfamily may be useful for the design of medicines as in the study of TRP channels biology.

1) Отделение сосудистой хирургии, Российский научный центр хирургии им. академика Б.В. Петровского,
2) Кафедра сердечно-сосудистой хирургии №1 им. академика Б.В. Петровского, Первый московский государственный медицинский университет им. И.М. Сеченова Минздрава РФ, Москва, Россия

Представлен обзор литературы, посвященный проблеме хирургического лечения больных с гемодинамически значимым стенозом внутренней сонной артерии и контрлатеральной окклюзией. Проведен обзор исследований, сравнивающих периоперационные и ранние послеоперационные исходы каротидной эндартерэктомии у пациентов с данной нозологией. Поиск литературы осуществлен с помощью баз данных Scopus, WebofScience, MedLine, РИНЦ.

This chapter focuses on large vessel vasculitis (LVV), encompassing Giant Cell Arteritis (GCA), Takayasu’s Arteritis (TA) and aortitis defined by the 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides [1]. We include Polymyalgia Rheumatica (PMR), which can occur with GCA and aortitis. Glucocorticoids (GC) are the mainstay treatment of large vessel vasculitides and PMR [2- 4]. However, the majority will have flares (>50%), remaining on GC for a minimum of 1- 3 years with their cumulative dose often resulting in side effects [5]. Furthermore, steroid resistance has been frequently recorded in a subset of patients. Relapse remains common despite use of GC and synthetic immunomodulators. We explore the use of biologic therapies and address the unmet need of patients who are resistant or intolerant to GC therapy, along with their use as steroid sparing agents. Having reviewed current literature and clinical trials we will focus our attention on when best to commence biologic therapy and who is most likely to benefit.

Abstract

Background and Aim

Non‐invasive markers are essential to assess the progression of chronic liver diseases to fibrosis/ cirrhosis and the effectiveness of therapeutic strategies. The aim of this study was to evaluate the ability of non‐invasive markers to identify significant fibrosis, severe fibrosis, and cirrhosis in patients with autoimmune hepatitis (AIH).

Methods

Seventy‐six patients with AIH were enrolled in the study and analyzed for the following parameters of liver fibrosis: Fibrosis 4 score (FIB‐4), aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio (AAR), AST to platelet count ratio (APRI), and platelet count to spleen diameter (PC/SD) ratio. All patients underwent liver biopsy. The diagnostic accuracy of tests was evaluated by the area under the receiver operating characteristic curve (AUROC).

Results

Among the 76 AIH patients, 55 (72.3%) had significant fibrosis (≥ F2), 37 (48.7%) had severe fibrosis (≥ F3), and 29 (38.2%) had cirrhosis (F4). PC/SD ratio (AUROC = 0.840) was superior to AAR (AUROC = 0.756), FIB‐4 (AUROC = 0.702), and APRI (AUROC = 0.626) in discriminating between mild and significant fibrosis (≥ F2). The AUROCs of PC/SD ratio, FIB‐4, AAR, and APRI were 0.884, 0.742, 0.731, and 0.707, respectively, for severe fibrosis (≥ F3); 0.968, 0.795, 0.744, and 0.723, respectively, for cirrhosis (F4). PC/SD ratio correctly identified 85.1% of patients with severe fibrosis, and 89.6% of patients with cirrhosis.

Conclusions

PC/SD ratio proved to be a simple non‐invasive tool to correctly identify AIH patients with severe fibrosis and cirrhosis, thereby reducing the need for a liver biopsy in these patients.

Background

The PGC-1α/PPAR axis has been proposed as a potential therapeutic target for several metabolic disorders. The aim was to evaluate the efficacy of the pan-PPAR agonist, bezafibrate, in tafazzin knockdown mice (TazKD), a mouse model of Barth syndrome that exhibits age-dependent dilated cardiomyopathy with left ventricular (LV) dysfunction.

Results

The effect of bezafibrate on cardiac function was evaluated by echocardiography in TazKD mice with or without beta-adrenergic stress. Adrenergic stress by chronic isoproterenol infusion exacerbates the cardiac phenotype in TazKD mice, significantly depressing LV systolic function by 4.5 months of age. Bezafibrate intake over 2 months substantially ameliorates the development of LV systolic dysfunction in isoproterenol-stressed TazKD mice. Without beta-adrenergic stress, TazKD mice develop dilated cardiomyopathy by 7 months of age. Prolonged treatment with suprapharmacological dose of bezafibrate (0.5% in rodent diet) over a 4-month period effectively prevented LV dilation in mice isoproterenol treatment. Bezafibrate increased mitochondrial biogenesis, however also promoted oxidative stress in cardiomyocytes. Surprisingly, improvement of systolic function in bezafibrate-treated mice was accompanied with simultaneous reduction of cardiolipin content and increase of monolysocardiolipin levels in cardiac muscle.

Conclusions

Thus, we demonstrate that bezafibrate has a potent therapeutic effect on preventing cardiac dysfunction in a mouse model of Barth syndrome with obvious implications for treating the human disease. Additional studies are needed to assess the potential benefits of PPAR agonists in humans with Barth syndrome.

High fidelity of biological systems is frequently achieved by duplication of the essential intracellular machineries or, removal of the entire cell, which becomes unnecessary or even harmful in altered physiological environments. Carefully controlled removal of these cells, without damaging normal cells, requires precise signaling, and is critical to maintaining homeostasis. This review describes how two anionic phospholipids - phosphatidylserine (PS) and cardiolipin (CL) - residing in distinct compartments of the cell, signal removal of "the unnecessary" using several uniform principles. One of these principles is realized by collapse of inherent transmembrane asymmetry and the externalization of the signal on the outer membrane surface - mitochondria for CL and the plasma membrane for PS - to trigger mitophagy and phagocytosis, respectively. Release from damaged cells of intracellular structures with externalized CL or externalized PS triggers their elimination by phagocytosis. Another of these principles is realized by oxidation of polyunsaturated species of CL and PS. Highly specific oxidation of CL by cytochrome c serves as a signal for mitochondria-dependent apoptosis, while oxidation of externalized PS improves its effectiveness to trigger phagocytosis of effete cells.Copyright © 2016 Elsevier Inc. All rights reserved.

Background: The evaluation of brown adipose tissue (BAT) and its role in metabolism and obesity remains an important topic in the recent literature. This study evaluated the influence of the BAT triglyceride content measured by proton magnetic resonance (MR) spectroscopy in patients with type 2 diabetes mellitus (DM2) and prediabetes on insulin sensitivity. Methods: A total of 25 patients with DM2 and prediabetes (45.9 ± 10.1 years old, body mass index [BMI] of 31.6 ± 5.4 kg/m²) underwent anthropometric measurements (BMI), insulin sensitivity analysis (M value during euglycemic hyperinsulinemic clamp and homeostasis model assessment of insulin resistance), proton MR spectroscopy, and blood tests (total cholesterol, low-density lipoproteins, high-density lipoproteins, and triglycerides). The relationship between the triglyceride content in the supraclavicular fat depot and insulin sensitivity, anthropometric measurements, and blood test results was assessed. Results: The triglyceride content in the supraclavicular fat depot varied between 79.2% and 97.1% (mean: 92.6% ± 4.2%). The triglyceride content in the subcutaneous white adipose tissue of the neck was significantly higher (85.3%–99.3%; mean: 95.5% ± 2.9%; P = 0.0007). The triglyceride content in the supraclavicular fat depot exhibited a significantly moderate correlation with the BMI (r = 0.64; P = 0.0009). A significant weak negative correlation between the supraclavicular fat content and M value was revealed (r = −0.44; P = 0.002). Patients with high insulin resistance (IR) had a higher triglyceride content in the supraclavicular fat depot than patients with normal and lower IR (94.3% ± 2.0% vs. 90.4% ± 5.2%; P = 0.02). Conclusions: Reducing the BAT content in the supraclavicular fat depot can influence the development of IR in patients with DM2 and prediabetes.
(PDF) The Relationship Between Brown Adipose Tissue Content in Supraclavicular Fat Depots and Insulin Sensitivity in Patients with Type 2 Diabetes Mellitus and Prediabetes. Available from: https://www.researchgate.net/publication/313146757_The_Relationship_Between_Brown_Adipose_Tissue_Content_in_Supraclavicular_Fat_Depots_and_Insulin_Sensitivity_in_Patients_with_Type_2_Diabetes_Mellitus_and_Prediabetes [accessed Dec 18 2018].

Среди хронических диффузных заболеваний печени наиболее распространены алкогольная болезнь печени и хронический гепатит С, и именно их прогрессирование наиболее часто приводит к формированию цирроза печени (ЦП) [1, 2]. Ежегодно от причин, связанных с употреблением алкоголем, умирают 2,5 млн человек, среди которых 320 тыс. в возрасте от 15 до 29 лет [3]. Длительное течение заболевания печени вне зависимости от этиологии приводит к формированию последовательных стадий фиброза. На конечной стадии происходят рассечение ткани печени фиброзными септами и образование узлов регенерации в печени, окруженных широкими полями фиброзной ткани, что служит основным морфологическим критерием ЦП [4, 5]. Клинически принято выделять компенсированный и декомпенсированный Ц.П. Пациент с ЦП и компенсированной функцией печени часто не предъявляет жалоб и не обращается к врачу, при объективном осмотре не всегда можно выявить признаки заболевания. У таких больных ЦП диагностируется, как правило, при случайном обследовании, когда проводится анализ крови, позволяющий косвенно предположить патологию печени [6, 7]. В настоящее время все пациенты с ЦП рассматриваются как группа, разнородная по прогнозу, который во многом определяется степенью портальной гипертензии (ПГ). В норме давление в системе воротной вены не превышает 5 мм рт.ст. При увеличении этого показателя более 10 мм рт.ст. происходит формирование варикозно-расширенных вен пищевода — ВРВП (развивается клинически значимая ПГ) [8]. Одновременно с увеличением давления в воротной вене возрастает риск смерти пациента. У пациентов с ЦП и давлением в портальной системе менее 10 мм рт.ст. составляет меньше 2%, но при повышении давления до 20 мм рт.ст. он в течение года превышает 70% [9]. «Золотым стандартом» измерения давления в воротной вене является определение внутрипеченочного градиента давления. При проведении этой процедуры баллонный катетер под ультразвуковым и рентгенологическим контролем вводится в правую яремную вену и в последующем проводится в правую печеночную вену. Градиент давления определяется разницей между давлением, измеренным свободным катетером, и давлением заклинивания. Использование метода ограничено его инвазивностью, стоимостью, необходимостью специальной техники и квалифицированных специалистов [10]. Эластометрия—метод, разработанный для неинвазивной диагностики фиброза печени у пациентов с диффузными заболеваниями печени [11]. В последние годы проведены исследования, оценивающие возможность использования данного метода в ранней диагностике клинически значимой П.Г. Исследования продемонстрировали возможность использования эластометрии печени или селезенки у пациентов с ЦП вирусной (вирус гепатита С — HCV) этиологии [12, 13]. Однако диагностическая точность этого метода недостаточно изучена у пациентов c ЦП другой этиологии [14].

Цель настоящего исследования — установить диагностическую точность измерений плотности печени (ПП) и плотности селезенки (ПС) у пациентов с компенсированным алкогольным ЦП в диагностике ПГ.

Перестройка последних лет в медицинском образовании нашей страны не может не затронуть и систему подготовки студентов — будущих специалистов хирургического профиля. Поэтому поиск таких студентов с целью более ранней отработки ими основных практических навыков представляет важную задачу

A novel bioactive peptide named τ-AnmTx Ueq 12-1 (short name Ueq 12-1) was isolated and characterized from the sea anemone Urticina eques. Ueq 12-1 is unique among the variety of known sea anemone peptides in terms of its primary and spatial structure. It consists of 45 amino acids including 10 cysteine residues with an unusual distribution and represents a new group of sea anemone peptides. The 3D structure of Ueq 12-1, determined by NMR spectroscopy, represents a new disulfide-stabilized fold partly similar to the defensin-like fold. Ueq 12-1 showed the dual activity of both a moderate antibacterial activity against Gram-positive bacteria and a potentiating activity on the transient receptor potential ankyrin 1 (TRPA1). Ueq 12-1 is a unique peptide potentiator of the TRPA1 receptor that produces analgesic and anti-inflammatory effects in vivo. The antinociceptive properties allow us to consider Ueq 12-1 as a potential analgesic drug lead with antibacterial properties.

Представлен опыт коллектива кафедры болезней уха, горла и носа Первого МГМУ им. И.М. Сеченова по обучению сту
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дентов в студенческом научном кружке. Выделены основные причины, по которым студенты, обучающиеся на старших
курсах, должны быть ориентированы на выполнение научно-исследовательской работы в рамках работы в студенческом
научном кружке. Особенно подчеркивается роль студенческого научного кружка в формировании ценностных ориента
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ций личности будущего врача в целом. Также представлен опыт последних лет по проведению межвузовских студенче
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ских олимпиад по оториноларингологии.

Обзор посвящен строению и функции вомероназальной системы, а также оценке ее влияния на сексуальную сферу. Особое внимание уделено роли феромонов и их влиянию на поведение человека и животных. Проанализированы данные, касающиеся функции вомероназального органа после хирургических вмешательств в полости носа.

Autophagy is an evolutionary conserved intracellular catabolic process of vital importance to cell and tissue homeostasis. Autophagy is implicated in the pathogenesis of atherosclerosis but participating cells, molecular mechanisms and functional outcomes have not been fully elucidated. T-cadherin, an atypical glycosylphosphatidylinositol-anchored member of the cadherin superfamily of adhesion molecules, is upregulated on smooth muscle cells (SMCs)¹ in atherosclerotic lesions. Here, using rat and murine aortic SMCs as experimental models, we surveyed the ability of T-cadherin to regulate autophagy in SMCs during serum-starvation stress. Ectopic upregulation of T-cadherin in SMCs resulted in augmented autophagy characterized by increased autophagic flux, LC3-II abundance and autophagosome formation. Analysis of signal transduction pathway effectors and use of specific pharmacological inhibitors demonstrated that T-cadherin-associated enhancement of the autophagic response to serum-deprivation was dependent on MEK1/2/Erk1/2 activation and independent of PI3K/Akt/mTORC1, reactive oxygen species or endoplasmic reticulum stress. T-cadherin upregulation on SMCs conferred a survival advantage during prolonged serum-starvation which was sensitive to inhibition of MEK1/2/Erk1/2 by PD98059 or UO126 and to blockade of autophagy by chloroquine. Loss of T-cadherin expression in SMCs diminished autophagy responsiveness and compromised survival under conditions of serum-starvation. Overall our findings have identified T-cadherin as a novel positive regulator of autophagy and survival in SMCs.