Features of oxidative stress in alcoholism.

The review considers molecular mechanisms underlying formation and development of oxidative stress (OS) in patients with alcohol dependence. The major attention is paid to the effects of ethanol and its metabolite acetaldehyde associated with additional sources of generation of reactive oxygen species (ROS) in response to exogenous ethanol. The own results of studies of the in vitro effect of ethanol and acetaldehyde on the concentration of peripheral OS markers - products of oxidative modification of proteins (protein carbonyls), lipids (lipid peroxidation products), DNA (8-hydroxy-2-deoxyguanosine, 8-OHdG) in blood plasma are presented. The changes in these parameters and the activity of antioxidant enzymes (SOD, catalase) in patients with alcohol dependence were analyzed. Own and literature data indicate that at a certain stage of the disease OS can play a protective rather than pathogenic role in the body.

[Inflammatory markers in organic nonpsychotic disorders]. / Vospalitel'nye markery pri organicheskikh nepsikhoticheskikh rasstroistvakh.

OBJECTIVE: To determine the indicators of systemic inflammation in peripheral blood samples of patients with organic non-psychotic disorders. MATERIAL AND METHODS: The study included 60 patients, aged 56.9±7.7 years, with a disease duration of 7.3±5.55 years, with a verified ICD-10 diagnosis «Organic emotionally labile (asthenic) disorder¼ (F06.6) and «Organic Anxiety Disorder¼ (F06.4). Patients with organic asthenic disorder were divided into two groups according to the prevailing symptoms: 36 patients with asthenic-cephalgic syndrome (AC); 10 patients with astheno-dysthymic syndrome (AD); the third group (n=14) included patients with organic anxiety disorder (AND). The control group consisted of 65 people matched for age and sex with patients. The activity of leukocyte elastase (LE) and α1-proteinase inhibitor (α1-PI) was determined by the spectrophotometric method, the levels of aAB to S100b and MBP were determined by ELISA. The protease-inhibitory index (PII), i.e., the ratio of LE activity to α1-PI, was calculated. RESULTS: A significant increase in LE (235.4 [216.4; 258.1] nmol/min*ml, p<0.001), the functional activity of α1-PI (43.1 [38.7; 47.6] u/ml, p<0.001), the level of aAB to S100b (0.78 [0.70; 0.89] opt.units, p<0.05) and a decrease in PII (6.19 [5.32; 6.9], p<0.05) in the group of patients with organic non-mental disorders compared with controls were shown. Deviations from the normal values of immune markers of inflammation in blood samples were also found in various syndromes. Clustering of the total group of patients by LE activity made it possible to identify 2 immunotypes with a balanced and unbalanced inflammatory process, confirming the clinical diversity of the disease: 60% of patients with AC syndrome belong to the 1st cluster, in which the ratio of immune markers characterizes a balanced inflammatory process aimed at restoration of homeostasis; 80% of patients with organic AND belong to the second cluster, which characterizes low proteolytic activity and imbalance of inflammation, which is an unfavorable prognostic factor in terms of the further course of the disease and therapy. CONCLUSION: The results confirm the importance of the inflammatory link in the neuroprogression of organic non-psychotic disorders. The identified features of the immune response can serve as an additional paraclinical criterion for differential diagnosis and evaluation of the prognosis of the further development of the disease.

Cytokine Production in Whole Blood Cells Culture of Patients with Alcohol Dependence and Autologous Plasma Oxidative Stress Markers.

We studied spontaneous production of a spectrum of proinflammatory cytokines by cultured whole blood cells from men with alcohol dependence at the stage of withdrawal syndrome and oxidative stress markers (carbonylated proteins and TBA-reactive substances) in the plasma of these blood samples. Enhanced production of cytokines by blood cells and increased concentrations of oxidative stress markers in the autologous plasma were revealed in comparison with the corresponding parameters in the control (blood from healthy men). Direct correlations were found between the levels of spontaneous cytokine production by blood cells from subjects with alcohol dependence and the concentration of oxidized proteins and lipids in autologous plasma.

[Characteristic of innate and acquired immunity in adaptation disorders]. / Kharakteristika vrozhdennogo i priobretennogo immuniteta pri rasstroistvakh adaptatsii.

OBJECTIVE: To determine factors of innate and acquired immunity in adaptation disorders with a predominance of asthenic or anxiety-depressive syndrome. MATERIAL AND METHODS: Twenty-five patients with ICD-10 diagnosis of «Adaptation Disorders¼ (F43.2), including 9 with asthenic syndrome and 16 with anxiety-depressive syndrome, were examined. The control group consisted of 23 healthy individuals. The relative number of lymphocyte phenotypes was determined by flow cytometry; the concentration of IgM, IgG, IgA, aAB to S100b and MBP - by ELISA; CIC level - by the method of selective precipitation with PEG-6000; phagocytic activity of neutrophils by a test system with melamine-formaldehyde latex; activities of leukocyte elastase (LE) and α1-proteinase inhibitor (α1-PI) by a spectrophotometric method. RESULTS: There were significant changes in the parameters of acquired immunity in the group with asthenic syndrome and those of innate immunity in the group with anxiety-depressive syndrome. An increase in α1-PI activity, in the total number of significant correlations between different immunological parameters, in the involvement of α1-PI in integration of acquired and innate immunity were observed in the anxiety-depressive group compared with the asthenic group. CONCLUSIONS: The peculiarities of stress response in patients with leading anxiety-depressive syndrome are the high activity of α1-PI, which, along with the strengthening of correlation intersystem associations and the involvement of this protein in the integration of acquired and innate immunity, allows us to consider α1-PI as a criterion that improves the accuracy of diagnosis of the nature of the course of adaptation disorders.

[Hormones of stress-response system in alcohol dependence: the ability to predict duration of remission]. / Gormony stress-realizuyushchei sistemy pri alkogol'noi zavisimosti: vozmozhnost' prognozirovaniya dlitel'nosti remissii.

OBJECTIVE: To determine the spectrum of hormones of the stress-realizing system in the time course of therapy of withdrawal syndrome and post-withdrawal state and analyze their possible relationships with the duration of therapeutic remission in patients with alcohol dependence. MATERIAL AND METHODS: The examination included 74 men admitted in the clinic at Mental Health Research Institute NRMC diagnosed as having «Mental and behavioral disorders due to use of alcohol¼ (dependence syndrome F10.21 and withdrawal state - F10.30) according to ICD-10. The control group included 35 men matched in age with patients. Concentration of cortisol, testosterone, and thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4) were determined by immunoenzyme method (IEM), in patients - at two points: point 1 - by day 3-5 of the admission in the clinic in the withdrawal syndrome state after alcohol detoxification; point 2 - by day 15-17 of the anti-alcohol therapy. RESULTS: In the general group of patients with alcohol dependence the elevation of the level of cortisol in comparison with control was established (pc<0,0001 at both points) and increase of concentration at point 2 (p=0,0253 to point 1). Concentration of testosterone at point 1 exceeded the level of control (pc=0,0203), at point 2 decreased up to control values and in relation to point 1 (p=0,0004). In relation to control the level of TSH in patients was decreased at point 1 (pc=0,0077); the concentration of fT3 and fT4 was reliably decreased at both points; concentration of fT4 decreased further in the process of the therapy of the post-withdrawal state (p=0,0003 to point 1). According to the duration of the last therapeutic remission, two groups of patients were formed: those with unstable remission (up to 6 months) and with the formed stable remission (1 year or more). A comparative analysis of the concentration of cortisol and testosterone in blood serum taken in patients at point 1 revealed a significant excess of testosterone in the group with unstable remission, both in relation to the control (pc=0,0239) and to the indicator in the group of patients with stable remission (p=0,0159). CONCLUSION: Dysfunctions in the spectrum of stress-realizing hormones in patients with alcohol dependence in the time course of the therapy for withdrawal syndrome and post-withdrawal state were revealed, the main of which are high level of cortisol, testosterone, reduction of secretion of free thyroxine and free triiodothyronine. Patients with unstable therapeutic remission are characterized by a high concentration of testosterone after alcohol detoxification, which allows us to consider testosterone as a biological criterion that can increase the accuracy of prediction of the duration of remission after anti-alcohol therapy.

[Cluster analysis of inflammatory markers in disorders of adaptation]. / Klasternyi analiz vospalitel'nykh markerov pri rasstroistvakh adaptatsii.

AIM: To determine immunophenotypes of patients with adaptation disorders using cluster analysis. The level of inflammatory markers such as leukocyte elastase (LE) enzyme activity and functional activity of α1-protease inhibitor (α1-PI) were used as a classifying attribute (characteristic). MATERIAL AND METHODS: The results of evaluation of enzymatic activity of LE and functional activity of α1-PI in 40 patients with adaptation disorders (ICD-10 F43.2) were subjected to cluster analysis. The control group included 23 age- and sex-matched healthy controls. RESULTS: Several algorithms of cluster analysis allow to identify three immunophenotypes in the group of patients with adaptation disorders. Immunophenotypes differed significantly by ratios of LE and α1-PI activity, which were mostly driven by different LE activity. Cluster 1 with the relatively low LE activity and high background α1-PI, is of particular interest because it may reflect the disturbed interaction between the various links of immune response. CONCLUSION: The obtained results of cluster analysis confirm the hypothesis about the existence of three immunophenotypes in the patients with adaptation disorders, which indicates that a phenotypically similar pattern can be determined by different spectra of immune indices.

[Inflammatory factors and immunophenotypes in adjustment disorders]. / Faktory vospaleniia i immunofenotipy pri rasstroistvakh adaptatsii.

AIM: To identify inflammatory and autoimmune markers (enzymatic activity of leukocyte elastase (LE), functional α1-proteinase inhibitor (α1-PI), the level of autoantibodies to neurospecific antigens S100b and myelin basic protein (MBP)) as well as phagocytic activity of blood neutrophils of patients with disorders of adaptation, to determine certain immunophenotypes and analyze their possible relationships with disease characteristics. MATERIAL AND METHODS: The study included 40 patients with adaptation disorders, mostly women. Diagnostic evaluation and clinical qualification of patients was carried out in accordance with ICD-10: 'Adjustment disorder' (F43.2). The control group consisted of 23 individuals matched for age and sex with patients. The activity of LE and α1-PI was determined by spectrophotometry, and the levels of autoantibodies to S100b and MBP by ELISA, phagocytic activity by the absorptive capacity of neutrophils of peripheral blood of melamine-formaldehyde latex particles. RESULTS: In the total group of patients with adaptation disorders, increased enzymatic activity of LE and functional α1-PI was shown compared to controls (p<0.001 and p<0.0001, respectively). There were no differences in the level of autoantibodies to neuroantigens, and changes in phagocytic index (PhN) compared with the control, however the tendency to reduction of phagocytic number (PhN) was observed. Patients were stratified by leading psychopathological symptoms (predominance of asthenic-depressive or anxious-depressive symptoms, polymorphic symptomatology) and by immunophenotype: (A) inflammatory markers - in the range of control values, (B) - the increase compared to the control activity of both LE and α1-PI, (C) preferential increase in the activity of α1-PI only. The frequency of these immunophenotypes was similar within each of the clinical subgroups. CONCLUSION: The results suggest the involvement of inflammation in the pathogenesis of adjustment disorders due to stress factors. Various immunological variants differed by proportion of inflammatory markers were not associated with clinical symptoms.

[An effect of quetiapine on the immune system of patients with schizophrenia]. / Vliyanie kvetiapina na nekotorye pokazateli immuniteta u bol'nykh shizofreniei.

AIM: To study an effect of the atypical antipsychotic quetiapine on the immune system of patients with schizophrenia with account for treatment efficacy. MATERIAL AND METHODS: Quetiapine was administered to 27 patients diagnosed with residual schizophrenia (F20.5) for 6 weeks in dose 200-400 mg/day; dynamic of clinical symptoms was evaluated with PANSS и CGI scales before administration of quetiapine and by week 6 of the treatment. Along with clinical assessments, immune indices were determined. RESULTS: At the end of week 6 of treatment, statistically significant changes of PANSS psychopathological symptoms were noted. According to CGI scale, patients were divided into group 1 with high treatment efficacy (n=17) and group 2 with the low efficacy (n=10). Significant between-group differences before treatment were as follows: the decreased number of lymphocytes of CD3+- CD16+-phenotypes, increased number of HLADR+-lymphocytes and IgA level in group 2. The quetiapine therapy led to the positive dynamic of phagocytosis indices, CD16+-lymphocytes, decrease in the level of IgA. CONCLUSION: Possible predictors of treatment efficacy were found including the number of mature T (CD3+) lymphocytes, CD16+ natural killers, HLADR+ lymphocytes and IgA concentrations.

[Influence of Adamantilbromphenylamine on Parameters of Immunity and Symptoms of Asthenia in Patients with Non-Psychotic Mental Disorders].

OBJECTIVE: Our aim was to assess effect of antiasthenic drug adamantilbromphenylamine on the immune system and symptoms of asthenia in patients with non-psychotic mental disorders and to reveal possible criteria for prediction of treatment efficiency. METHODS: Uncontrolled study with interrupted time series was carried out. According to efficiency of treatment patients were divided into two groups (group 1 (n=21)--very much improved and much improved; group 2 (n=9)--minimally improved). Adamantilbromphenylamine was administered to patients as a monotherapy 100 mg a day for 28 days. Examination was conducted before and after therapy. Severity of asthenic symptoms according to MFI-20 scale was identified; cellular and humoral immunity parameters, mitogen-induced production of interleukins (IL) 1ß and IL 4 by immunocompetent cells of patients were assessed. RESULTS: 30 patients with non-psychotic mental disorders with predominance of asthenic symptomatology in clinical picture of the disease were examined. Before therapy every proband had over 60 points across 5 items of MFI-20 scale. As compared with control decrease of number of lymphocytes of CD3+-, HLA-DR+, CD16+-phenotypes; increase in the ratio of CD4+/CD8+; concentration of serum IgM; phagocytic activity of neutrophils were revealed. In the end of therapy in group 1, sum total of points of asthenia decreased up to 26(23-37) (p<0.001); in group 2--up to 57(47-61). Only in group 1 positive dynamic of immune parameters was revealed. It was shown that baseline level of proinflammatory cytokine IL 1ß in group with apparent therapeutic effect of the drug was reliably lower, than in group with minimal improvement (p=0.005). These differences remained also after course of therapy (p=0.042). CONCLUSION: Interrelationship of clinical-immunological effect of adamantilbromphenylamine has been revealed; intensity of production of IL 1ß may be considered as a criterion of prognosis of efficiency of treatment with adamantilbromphenylamine in patients with non-psychotic mental disorders.

Association of Cytokine Production with Hormone Level and Sensory Responses during the Formation of Psychoactive Drug Addiction in Men.

We performed immunophysiological examination of 144 men aged 17-25 years, patients with psychoactive substance dependence, episodic psychoactive drug users, and conditionally healthy individuals. Associations of proinflammatory cytokine production with age, sex, hormone levels, and olfactory and nociceptive indices were revealed in cases of psychoactive drug use and formation of addiction. Predictive models based on the use of androstenone aversion, pressure algometry testing, and immunological parameters were proposed.

[Association between pathological olfaction, immunological abnormalities and predisposition to substance use].

OBJECTIVE: To reveal olfactory parameters of substance addiction formation through evaluation of predictive capability of olfactometry combined with laboratory-immunological methods. MATERIAL AND METHODS: Authors examined 156 people of both sexes aged 18-25 years. Three comparison groups with different attitudes towards psychoactive substances were formed as follows: people who do not use psychoactive substances (controls), episodic consumers (group at risk) and people with dependence syndrome. RESULTS: The occurrence of olfactory abnormalities in the anamnesis has immunological, psychological and behavioral correlates and is associated with earlier age of onset of substance consumption. The severity of aversive reactions to the test odorant is reduced already in the stage of episodic substance use and is associated with clinical signs of immune deficiency, suppression of cellular immunity and an increase in blood cortisol levels in substance abusers. CONCLUSION: Diagnostic and predictive modeling in the field of biological and clinical science of drug addiction is possible based on immunological and olfactory parameters.

[Autoantibodies to glutamate and GABA in opiate addiction].

Blood serum from 129 patients with opium addiction at different stages of the disease and 63 donors (control group) was examined for the presence of autoantibodies to the exciting and inhibitory amino acids glutamate and GABA. It was shown enhanced production of autoantibodies to glutamate and GABA. Dependence of the level and frequency of detec- tion of autoantibodies to glutamate and GABA on the stage of the disease was revealed.

Ratio of antibodies to neurotransmitters in the serum of students, occasional drug users.

The survey included volunteer students of secondary and higher educational institutions. Two groups have been formed based on the results of clinical and laboratory studies. Group 1 comprised students occasionally using cannabinoids and amphetamines (risk group for psychoactive substances addiction) and group 2 included students who do not use drugs. The serum level of autoantibodies to norepinephrine, dopamine, and serotonin was reduced in the risk group.

Neurophysiological patterns of search and creative behavior in patients with psychoactive substance-induced disorders.

The correlation between search and creative behavior with parameters of bioelectric brain activity was observed in patients with addictive disorders. The prevalence of α- and θ-activities in the parietal-temporal-occipital areas of the cortex and increased θ-activity in the right hemisphere in addiction patients with high search and creative activities were associated with enhanced high-frequency activity in these brain areas. These changes can reflect the formation of a focus of pathologically increased excitation related to the pathogenic mechanisms of addictive disorders.

[Antibodies to neurotransmitters as possible neuroimmune risk markers of formation dependence to psychoactive substances].

In the sera of patients with opioid addiction has been found elevated levels of autoantibodies to the neurotransmitters dopamine, norepinephrine and serotonin in comparison with a control group of healthy people of the same age. In the group of patients with acute withdrawal was showed a reduction of antibody to dopamine, noradrenaline and serotonin in the blood serum when compared with patients in the period of postabstinent disorders. In the group of patients with risk for the formation of substance dependence in serum was observed decrease in autoantibodies to dopamine and norepinephrine compared with the control group.

[Effect of antipsychotic amisulpride on immune reactivity].

The effect of atypical antipsychotic solian (amisulpride), binding predominantly to dopamine D2/D3-receptors, on the immune reactivity has been studied in mice of the CBA strain with different psychoemotional states (aggressive and submissive behavior). In addition, the effect of solian on the expression of various CD-markers of lymphocytes in has been analyzed in vitro for patients with schizophrenia diagnosis. Chronic (10 days) administration of solian in mice at a dose of 5.0 mg/kg resulted in a significant suppression of the immune response to T-dependent antigen (sheep red blood cells). This effect was manifested in animals with both psychoemotional states, but was more expressed in aggressive animals. In the in vitro system, solian produced opposite effects on the expression of surface CD receptors in lymphocytes of patients with schizophrenia. It is suggested that solian does not only affects immune function through D2 receptors of the brain, but also directly influences immunocompetent cells.

[EEG features during olfactory stimulation in drug dependence persons].

Power spectra analysis EEG was used for baseline interval and during olfactory stimulation in drug dependence and healthy persons. Intergroup differences of EEG spectra were related with enhancement of cortex biopotential power in narcological patients at parietal and temporal sites. Interhemispheres features of frequency bands contribution in EEG spectra were identified. Increased biopotential power in drug dependence persons was observed at left temporal hemisphere in high-frequency bands in baseline interval and during olfactory stimulation. Increased power of alpha activity was typical for right temporal hemisphere in narcological patients as compare to healthy persons. Detected neurophysiological patterns may be related with psychological and behavioral features of addictive disorders.

[Clinical and experimental research of immunomodulatory effect of amisulpride].

Study of immunomodulatory effect of atypical antipsychotic amisulpride has revealed a positive clinical effect after 6-week therapy of schizophrenic patients regarding both positive and negative symptoms. A decrease in activity of humoral immunity factors (B lymphocytes, immunoglobulins, HLADR(+)-cells) identified among schizophrenic patients in the process of amisulpride therapy can be attributed to a positive effect optimizing the ratio Th1/Th2. Amisulpride when used under experimental conditions produced a suppression of IgM-immune response in mice of the C57BL/6J strain. This effect was more expressed in animals with aggressive behavior pattern.