The main effect of arginase inhibition after administration of L-norvaline is a decrease in BP. At the same time, norvaline causes various side effects in normotensive and hypertensive animals. In our experiments, L-norvaline was administered intraperitoneally (30 mg/kg) for 7 days to normotensive WAG rats (Wistar Albino Glaxo) and hypertensive ISIAH rats (Inherited, Stress-Induced Arterial Hypertension). In ISIAH rats, BP decrease was accompanied by an increase in diuresis, while in WAG rats, diuresis remained unchanged or little changed. At the same time, hypertensive rats demonstrated an increase of catecholamine content in the adrenal glands, while in normotensive animals, it was decreased. The differences in the effects of norvaline can be associated with different mechanisms of BP maintenance in normotensive and hypertensive animals. Normally, BP is maintained by the regulatory influences of the nitric oxide system. In hypertension, this system is weakened, and the hypotensive effects are probably achieved via increased diuresis.

Недавно была обнаружена ассоциация полиморфизмов гена SIRT1, кодирующего сиртуин-1 (фермент, обладающий деацетилазной или АДФ-рибозилтрансферазной активностью, в частности, деацетилирующий транскрипционные факторы, вовлеченные в регуляцию стресса), с тревогой и депрессией, однако его роль в механизмах развития депрессии остается малоизученной. В работе проведен анализ фармакологических эффектов ресвератрола, (активатор SIRT1 – 40 мг/кг, 4 недели, внутрибрюшинно) и никотинамида (ингибитора SIRT1 – 500 мг/кг, 4 недели, внутрибрюшинно) на проявления депрессивно-подобного поведения у мышей, вызванные хроническим непредсказуемым стрессом (ХНС). Ресвератрол снижал двигательную активность в тесте «Открытое поле» вне зависимости от ХНС, не влиял на социальное поведение и продолжительность неподвижности в тесте «Принудительное плавание» («поведенческое отчаяние»). В то время как никотинамид оказывал антидепрессивное действие в тесте «Принудительное плавание», не влияя на двигательную активность, но подавлял социальную мотивацию у животных, подверженных ХНС. Эффекты никотинамида — фармакологического блокатора SIRT1 оказались более выражены в условиях хронического стресса, чем влияние активатора SIRT1, ресвератрола. Актуальны дальнейшие исследования роли SIRT1 в молекулярно-генетических депрессогенных механизмах, вызванных стрессом.

In a parallel placebo-controlled study, we examined the effect of repetitive transcranial magnetic stimulation (rTMS) on serum concentrations of cortisol and dehydroepiandrosteron sulfate (DHEAS), and their relationships with clinical symptoms in men and women with Parkinson's disease. A 20-day course of real rTMS reduced the UPDRS and UPDRS III scores in patients with Parkinson's disease in comparison with the basal parameters (before rTMS), regardless of their sex. The level of cortisol did not change in men and women; at the same time, the content of DHEAS in men increased and before rTMS negatively correlated with the UPDRS scores. Sham rTMS had no effects on clinical parameters or hormonal levels. Possible mechanisms of sex-dependent differences in the effect of rTMS on the level of the neurosteroid hormone DHEAS are discussed.

Депрессия - многофакторное психическое расстройство, являющееся одной из основных причин инвалидности и приводящее к самоубийству в 15% случаев. Активный поиск генетической компоненты депрессии выявил ряд генов-кандидатов, ассоциированных с депрессией. Недавние исследования продемонстрировали ассоциацию ряда полиморфных вариантов гена SIRT1 с депрессией. В то же время остается неизученной специфика распределения полиморфных вариантов в гене SIRT1 в различных популяциях, что может быть существенным при анализе ассоциаций. Нами была изучена структура кодирующей часть гена SIRT1 в популяциях якутов, тувинцев и жителей Новосибирска. В зависимости от этнической группы наблюдалось изменение частот встречаемости полиморфных вариантов. Depression is a multifactorial mental disorder that is one of the main causes of disability and leads to suicide in 15% of cases. An active search for the genetic component of depression has identified a number of candidate genes that correlate with depression. Recent studies have demonstrated the association of a number of polymorphic variants of the SIRT1 gene with depression. At the same time, the specificity of the distribution of polymorphic variants in the SIRT1 gene among different populations remains unexplored, which may be significant in the analysis of associations. We have studied the structure of the coding part of the SIRT1 gene in the populations of Yakuts, Tuvans, and residents of Novosibirsk. Depending on the ethnic group, there was a change in the frequency of occurrence of polymorphic variants.

The sustainability of the information lies in the system's guarantee that anelectronic record will be returned in an intelligible manner throughout its retentionperiod. Part of the documentary memory of our society created and preserved ondigital media is already compromised, and the costs of restoring electronic recordsare very high. In addition, the fragility of the media and technological obsolescencemust be addressed.

OBJECTIVE:To evaluate therapeutic effects of navigational dual-target high-frequency rTMS over the primary motor (M1, bilateral) and the left dorsolateral prefrontal cortex (DLPFC) on clinical dynamics of Parkinson's disease (PD) symptoms in a parallel placebo-controlled study.MATERIAL AND METHODS:The study included 46 patients randomized into equal therapeutic and placebo rTMS groups. Navigational therapeutic and placebo10 Hz rTMS was applied over the M1 and DLPFC areas (20 daily sessions, for 3 weeks). Assessment of the dynamics of clinical symptoms was performed using the MDS UPDRS scale (Parts I-IV) before the first session, immediately after 20 sessions, and 4-6 weeks after the rTMS course. Non-motor and mental symptoms were assessed using the Hamilton Depression Rating Scale (HDRS-17), Beck depression inventory (BDI-II), Depression, Anxiety and Stress (DASS-21) scales and the Mini Mental State Examination (MMSE).RESULTS:Significant therapeutic effects of rTMS compared to placebo were established: a greater decrease in overall score on the MDS-UPDRS scale (parts I-IV), a decrease in the severity of non-motor (part I) and motor symptoms (part III, with a large therapeutic effect for the symptoms of rigidity, bradykinesia and postural instability), as well as the severity of motor complications of dopamine replacement therapy (part IV). The effects of rTMS on motor symptoms persisted 4 weeks after the end of the stimulation course. It is also important to note significant positive dynamics in both rTMS and placebo groups in the form of comparable reduction in the severity of everyday motor symptoms (MDS-UPDRS part II), improvement of the total scores on MMSE, HDRS, BDI-II, DASS-21.CONCLUSIONS:The dual-target high-frequency rTMS over the primary motor cortex (bilateral) and the left dorsolateral prefrontal cortex has positive therapeutic effects on the motor and affective symptoms of Parkinson's disease, which are significantly stronger than that of the placebo stimulation.

An enhanced vasoconstrictor activity of cutaneous arteries participates in the reduction of skin blood flow induced by cooling stimulation. Raynaud's phenomenon, which is characterized by intense cooling-induced constriction of cutaneous arteries, is more common in women during the period from menarche to menopause. We thus investigated the effect of 17β-estradiol (E2) on cooling-induced reduction of plantar skin blood flow (PSBF) in mouse in vivo. Ovariectomized female ddY mice, anaesthetized with pentobarbital, were treated with tetrodotoxin for eliminating the sympathetic nerve tone and artificially ventilated. The PSBF was measured by laser Doppler flowmetry. Cooling air temperature around the foot from 25 to 20, 15, or 10 °C decreased the PSBF in a temperature-dependent manner, which was suppressed by the specific α2C-adrenoceptor antagonist MK-912. When E2 was intravenously administered as a bolus followed by a constant infusion for 10 min just before the cooling stimulation, the cooling-induced reduction of PSBF was facilitated by E2 in a dose-dependent manner. The facilitatory effect of E2 was not induced after the treatment with MK-912. Similar facilitatory effect was induced by an intravenous application of G-1, an agonist of G protein-coupled estrogen receptor (GPER, also termed GPR30). Moreover, the facilitatory effect of E2 was abolished by the GPER antagonist G15. These results suggest that acute administration of E2 leads to the facilitation of cooling-induced, α2C-adrenoceptor-mediated reduction of skin blood flow via the activation of the non-genomic estrogen receptor GPER.

c-Jun N-terminal kinase (JNK) is a critical mitogen activated protein kinase (MAPK) implicated in inflammatory processes, with IQ-1S (11H-indeno[1,2-b]quinoxalin-11-one oxime sodium salt) being a high-affinity JNK inhibitor with pronounced anti-inflammatory properties. Here, we studied direct effects of IQ-1S on phenotypical and cytokine-producing characteristics of activated human monocytes/macrophages and T cells in vitro. Purified monocyte/macrophage cells were activated by bacterial lipopolysaccharide (LPS, 1 μg/ml) for 24 h, while T cells were activated by particles conjugated with antibodies (Abs) against human CD2, CD3, and CD28 for 48 h. Treatment with IQ-1S (0.5–25 μМ) in the presence of LPS reduced percentages of CD197 (CCR7)-positive cells in macrophage cultures, without affecting CD16+ (FcγRIII, low-affinity Fc-receptor), CD119+ (interferon-γ receptor 1), and CD124+ (IL-4 receptor α-subunit) cells. In addition, IQ-1S reduced production of tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, and IL-10 in macrophage cultures. In activated T cell cultures, IQ-1S decreased CD25+ cell numbers in both CD4-positive and CD4-negative T cell compartments. Central memory СD45RA−/СD197+ and effector memory СD45RA−/СD197- T cells were more sensitive to IQ-1S-mediated suppression, as compared to naïve СD45RA+/СD197+ and terminally-differentiated effector СD45RA+/СD197- T cells. IQ-1S also suppressed T-cell cytokine production (IL-2, interferon-ɣ, IL-4, and IL-10). Collectively, the results suggest that both human macrophage and T cells could be immediate cell targets for IQ-1S-based anti-inflammatory immunotherapy. IQ-1S-mediated suppressive effects were unlikely to be associated with macrophage/T helper polariation.

PD is a neurodegenerative disease characterized with loss of dopamine neurons and associated with neuroinflamation and unbalanced in HPA-axis. We investigated the content of cortisol and DEAS - hormones of HPA-axis in patients with PD after applying rTMS. Feng S.F. et al. (2012) showed that rTMS improves the balance of HPA axis hormones during depression, which is one of the non-motor manifestations of PD. PD patients were randomized into groups with active rTMS (13 men, 11 women) and sham rTMS (10 men, 15 women).The 10Hz rTMS was performed sequentially over 2 targets: the primary motor cortex and the DLPFC daily for 20 days. Outcome measures included the indicators of MDS-UPDRS (Part 3) scale, content of cоrtisol and DEAS in the peripheral blood.The Motor Examination Part scores demonstrated clinically meaningful improvement only in the active treatment group (p < 0.01). The content of the DEAS in this group was negatively correlated with indicators of scales of clinical manifestations, stress and anxiety (p < 0.05). In this group an increase of content of DEAS in the peripheral blood of men was found (p < 0.01, Wald-Wolfowitz Runs Test). Thus, the rTMS increases the levels of a wellknown neuroprotective hormone and a modulator of DA activity DEAS only in men.

The risk of metabolic disorders, including type 2 diabetes and cardiovascular diseases, is increased in depression, there is a decrease in life expectancy by 8-10 years. Pharmacotherapy is the first-line method in the treatment of depression. However, pharmaceutical-related side-effects and resistance to antidepressant pharmacotherapy create serious problems in treatment. Regular exercise not only weakens the symptoms of depression, increases aerobic capacity and muscle strength, but also has a positive effect on comorbid diseases. The purpose of this review is to answer the question, on which parameters of exercise the antidepressant effect depends. The review highlights the results of clinical studies of different types of exercises, intensities and modalities for the treatment of depression over the past 10 years. Because of the contradictory results of the studies, it is impossible to make final conclusions regarding the parameters of exercise. It is possible to say with high probability that in the treatment of depression, moderate and intense aerobic exercises with elements of strength exercises and a variety of coordination exercises more often lead to a positive effect than monotonous exercises with low intensity. It is possible that regular patient adherence to the prescribed exercise regimen is more important than the specific exercise type.

The aim of the study was to investigate the characteristics of the individual balance of the activity of brain defensive and reinforcing systems in patients with major depressive disorder. Material and methods. In 41 patients with major depressive disorder and 32 healthy subjects, we investigated visual evoked potentials in the emotional Oddball paradigm in perception of high and low arousal motivational signals of reward and threat. Results and discussion. It was established that reduced amplitude of the neuronal response in the perception of high arousal motivational signals of reward and, in a less degree, threat, is associated with an indicator of the clinical severity of depression. It supports the model of emotion context insensitivity in depression. However, a more pronounced reduce in the neuronal response to stimuli of reward may indicate a prevailing deficiency of the reinforcement system. Thus, the late positive potential magnitude of visual evoked potentials for high arousal motivational signals of reward and threat can be viewed as a promising objective neurobiological marker for monitoring the dynamics of the disturbed individual balance of the defensive and reinforcing brain systems in major depressive disorder patients which can become an important tool of personalized prevention and treatment strategy.

Constrictive pericarditis (CP) is an uncommon disease characterized by clinical signs of right-sided heart failure subsequent to loss of pericardial compliance. Although pericardiectomy is the accepted treatment for improving cardiac hemodynamics in CP, some patients fail to improve after pericardiectomy. We herein report a case of CP that showed some physical and hemodynamic features with a constrictive pattern that persisted despite the improvement in heart failure symptoms after pericardiectomy. A 61-year-old man was diagnosed with CP 7 months after the onset of symptoms of shortness of breath and edema in the legs. The waffle procedure was performed using an ultrasonic scalpel. Post-operative cardiac catheterization demonstrated a dip-and-plateau pattern in both right ventricular (RV) and left ventricular (LV) pressures, but the RV and LV end-diastolic pressures improved. Moreover, Doppler echocardiography showed an improvement in the change in mitral and tricuspid early velocities with respiration. Decrease in intraoperative right atrial pressure and respiratory variability in LV and RV inflow on echocardiography are important predictors of improvement in post-operative heart failure symptoms.Learning objective: Decrease in intraoperative right atrial pressure and respiratory variability in left ventricular and right ventricular inflow on post-operative echocardiography are important predictors of improvement in heart failure symptoms even if some hemodynamic features characterizing constrictive pericarditis (dip and plateau pattern, Friedreich's sign) persist.>

КЛЕТОЧНО-МОЛЕКУЛЯРНЫЕ ОСОБЕННОСТИ ВОСПАЛЕНИЯ И ВЫЖИВАЕМОСТЬ БОЛЬНЫХ ПРОФЕССИОНАЛЬНОЙ ХРОНИЧЕСКОЙ ОБСТРУКТИВНОЙ

This literature review considers meta-analyzes, systematic reviews and original research over the last decade addressing a comprehensive analysis of the antidepressant effect of targeted physical exercise and physical activity in general. Exercise is a promising non-pharmacological treatment for depression, showing effects that are comparable or may even exceed other first-line treatments of depression. The article introduces modern ideas about the mechanisms of depression and mechanisms of exercise effects on depression manifestations. The structures of the central nervous system, changing with the effective exercise-based treatment of depression, are indicated. Physical activity stimulates the secretion of growth factors, maintenance of angio-, synapto-, and neurogenesis. The regulation of antioxidant protection of neuronal mitochondria, a decrease in pro-inflammatory reactions and stress reactivity are also observed in response to regular exercise. Physical activity has a multimodal effect that stimulates biochemical pathways and restores neuronal structures disturbed in depression.

There is an unmet need to develop noninvasive biomarkers to stratify patients in drug-radiotherapy trials. In this pilot study we investigated lung cancer radiotherapy response and toxicity blood biomarkers and correlated findings with tumor volume and proliferation imaging.Blood samples were collected before and during (day 21) radiotherapy. Twenty-six cell-death, hypoxia, angiogenesis, inflammation, proliferation, invasion, and tumor-burden biomarkers were evaluated. Clinical and laboratory data were collected. Univariate analysis was performed on small-cell and non–small-cell lung cancer (NSCLC) whereas multivariate analysis focused on NSCLC.Blood samples from 78 patients were analyzed. Sixty-one (78.2%) harbored NSCLC, 48 (61.5%) received sequential chemoradiotherapy. Of tested baseline biomarkers, undetectable interleukin (IL)-1b (hazard ratio [HR], 4.02; 95% confidence interval [CI], 2.04-7.93; P < .001) was the only significant survival covariate. Of routinely collected laboratory tests, high baseline neutrophil count was a significant survival covariate (HR, 1.07; 95% CI, 1.02-1.11; P = .017). Baseline IL-1b and neutrophil count were prognostic for survival in a multivariate model. The addition of day-21 cytokeratin-19 antigen modestly improved this model's survival prediction (concordance probability, 0.75-0.78). Chemotherapy (P < .001) and baseline keratinocyte growth factor (P = .019) predicted acute esophagitis, but only chemotherapy remained significant after Bonferroni correction. Baseline angioprotein-1 and hepatocyte growth factor showed a direct correlation with tumor volume whereas changes in vascular cell adhesion molecule 1 showed significant correlations with 18F-fluorothymidine (FLT) positron emission tomography (PET).Select biomarkers are prognostic after radiotherapy in this lung cancer series. The correlation between circulating biomarkers and 18F-FLT PET is shown, to our knowledge for the first time, highlighting their potential role as imaging surrogates.

We analyzed variability of the expression of three reference genes in biopsy samples of the olfactory epithelium obtained from healthy volunteers. The expression of B2M, HPRT1, and CASC3 genes was analyzed by real-time PCR. The pairs of genes B2M-HPRT1 and B2M-CASC3 were found to possess minimum individual variability of expression and can be reliable candidates for the reference genes in analysis of gene expression in neural cells.