Evaluation of plasma peptides extraction methods by high-resolution mass spectrometry.

Monitoring of peptides offers a promising approach for the discovery of novel biomarkers, which might be valuable for detection, treatment and prevention of large variety of diseases. Development of highly effective methods for plasma peptide extraction remains an important task. In the current study, we applied different types of plasma peptide extraction approaches to reveal efficient methods which would provide the highest peptide yield. We used different combinations of plasma treatment with acetonitrile and/or urea/guanidine, protein precipitation by acetone, gel-filtration, ultrafiltration, and two types of solid phase extraction. The extracted peptides were analyzed by LC-MS/MS. The obtained results suggest that several methods, including differential solubilization, organic precipitation, as well as some variants of ultrafiltration and solid phase extraction, provide effective plasma peptide enrichment convenient for further LC-MS/MS analysis. Alas, most of the identified peptides were extracted by only one of the applied methods. Hence, it seems reasonable to consider several methods to increase the possibility of novel biomarker discovery.

[The Russian consensus on the diagnosis and treatment of chronic pancreatitis: Enzyme replacement therapy]. / Rossiiskii konsensus po diagnostike i lecheniiu khronicheskogo pankreatita: zamestitel'naia fermentnaia terapiia.

Pancreatology Club Professional Medical Community, 1A.S. Loginov Moscow Clinical Research and Practical Center, Moscow Healthcare Department, Moscow; 2A.I. Evdokimov Moscow State University of Medicine and Dentistry, Ministry of Health of Russia, Moscow; 3Kazan State Medical University, Ministry of Health of Russia, Kazan; 4Kazan (Volga) Federal University, Kazan; 5Far Eastern State Medical University, Ministry of Health of Russia, Khabarovsk; 6Morozov City Children's Clinical Hospital, Moscow Healthcare Department, Moscow; 7I.I. Mechnikov North-Western State Medical University, Ministry of Health of Russia, Saint Petersburg; 8Siberian State Medical University, Ministry of Health of Russia, Tomsk; 9M.F. Vladimirsky Moscow Regional Research Clinical Institute, Moscow; 10Maimonides State Classical Academy, Moscow; 11V.I. Razumovsky State Medical University, Ministry of Health of Russia, Saratov; 12I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, Moscow; 13S.M. Kirov Military Medical Academy, Ministry of Defense of Russia, Saint Petersburg; 14Surgut State Medical University, Ministry of Health of Russia, Surgut; 15City Clinical Hospital Five, Moscow Healthcare Department, Moscow; 16Nizhny Novgorod Medical Academy, Ministry of Health of Russia, Nizhny Novgorod; 17Territorial Clinical Hospital Two, Ministry of Health of the Krasnodar Territory, Krasnodar; 18Saint Petersburg State Pediatric Medical University, Ministry of Health of Russia, Saint Petersburg; 19Rostov State Medical University, Ministry of Health of Russia, Rostov-on-Don; 20Omsk Medical University, Ministry of Health of Russia, Omsk; 21Russian Medical Academy of Postgraduate Education, Ministry of Health of Russia, Moscow; 22Novosibirsk State Medical University, Ministry of Health of Russia, Novosibirsk; 23Stavropol State Medical University, Ministry of Health of Russia, Stavropol; 24Kemerovo State Medical University, Ministry of Health of Russia, Kemerovo; 25N.I. Pirogov Russian National Research Medical University, Ministry of Health of Russia, Moscow; 26A.M. Nikiforov All-Russian Center of Emergency and Radiation Medicine, Russian Ministry for Civil Defense, Emergencies and Elimination of Consequences of Natural Disasters, Saint Petersburg; 27Research Institute for Medical Problems of the North, Siberian Branch, Russian Academy of Sciences, Krasnoyarsk; 28S.P. Botkin City Clinical Hospital, Moscow Healthcare Department, Moscow; 29Tver State Medical University, Ministry of Health of Russia, Tver The Russian consensus on the diagnosis and treatment of chronic pancreatitis has been prepared on the initiative of the Russian Pancreatology Club to clarify and consolidate the opinions of Russian specialists (gastroenterologists, surgeons, and pediatricians) on the most significant problems of diagnosis and treatment of chronic pancreatitis. This article continues a series of publications explaining the most significant interdisciplinary consensus statements and deals with enzyme replacement therapy.

[European Registry on the management of Helicobacter pylori infection (Hp-EuReg protocol): The first results of Russian centers].

AIM: To assess the clinical practice of diagnosis and treatment in patients with Helicobacter pylori infection and to compare this practice with the international guidelines in the European Registry on the management of Helicobacter pylori infection, Hp-EuReg protocol), a multicenter prospective observational study initiated by the European Helicobacter and Microbiota Study Group. MATERIALs AND METHODS: The data of 813 patients infected with H. pylori and entered in the Hp-EuReg register by the Russian centers in 2013-2015 were analyzed. RESULTS: The most common methods for the primary diagnosis of H. pylori infection are histology (40.3%), rapid urease test (35.7%), and serology (17.2%). The duration of H. pylori eradication therapy was 7, 10, and 14 days in 18.0, 49.3, and 25.1%, respectively. To monitor the effectiveness of treatment, the investigators used a histological examination (34%), a urea breath test (27.3%), H. pylori stool antigen (22.8%), and a rapid urease test (16.3%). A serological test was carried out in 2.5% of the cases. No monitoring was done in 13.5% of the patients. The average eradication efficiency was 82.6%. If the therapy was ineffective, 80% of physicians did not intend to prescribe a new cycle of treatment. CONCLUSION: Significant differences were found between clinical practice and the current guidelines.

[COMPARATIVE STUDY OF DE-NOL AND NOVOBISMOL IN REGIMENS ERADICATION IN PATIENTS WITH H. PYLORI--ASSOCIATED DISEASES].

AIMS: The aim of this study is to assess efficacy and safety of reinforced H. pylori eradication therapy. METHODS: During 2013-2014, 40 outpatients were examined. The study included men and women 18-65 y.o. They have been devided in to 2 group by randomized choice (20 patients in each group). Patients were treated with the reinforced H. pylori eradication therapy: PPI (40 mg,/q12h), clarithromycin (500mg/q12h), amoxicillin (1000 mg/q12h), bismuth subcitrate (240 mg/q12h) for 10 days. The first group given bismuth subcitrate--De-Nol, the second group given Novobismol. Eradication was confirmed by a 13C-urea breath test and monoclonal stool antigen test 6-8 weeks after therapy. RESULTS: A total of 34 patients underwent eradication treatment. Two were lost to follow-up (one patient in each group), four patients (two patients in each group) did not complete treatment due to adverse events. The eradication rates were 97.1% (95% CI, 88.9% -100.0%) by per-protocol (PP) and 82.5% (95% CI, 69.4% - 92.5%) by intention-to-treat (ITT) in the two groups. The ITT analyses resulted in rates of 85% (95% CI, 66.5-96.9) for the 10-d reinforced therapy with DeNol and was 80% (95% CI: 60.2-94.1) for the 10-d reinforced therapy with Novobismol (P = 0.68), while the PP analyses resulted in 100% (95% CI, 94.5-100.0) and 94.1% (95% CI: 78.3-99.9), respectively (P = 0.31). CONCLUSION: The reinforced H. pylori eradication therapy (10-day high-dose PPI bismuth-containing standard triple therapy) achieves a significantly high eradication rates in patients with H. pylori - associated diseases. Both drugs (De- Nol and Novobismol) are both effective and safe for the first-line eradication of H. pylori.

[Pseudomembranous colitis: pathogenesis, prevention, treatment].

The article reviews a pathogenesis of Pseudomembranous colitis. Questions of prevention and treatment of Clostridium difficile--associated diarrhea are shown by the Evidence-based medicine. There is an accent on the rational prescription of antibiotics.

Morphological changes in salivary glands of neonatal rats after intra-abdominal hypertension.

OBJECTIVE: Given the overall prevalence of elevated Intra-abdominal pressure (IAP), along with earlier detection and appropriate therapy of Intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS), a significant reduction in patient morbidity and mortality is currently achieved by modern medicine. This article assesses the long-term degree of salivary gland damage in rats depending on the severity of experimental IAH during the neonatal period. MATERIALS AND METHODS: To simulate IAH, newborn rats, under the control of intravesical manometry, were injected into the abdominal cavity with bulking collagen filler in the amount necessary to create a given level of IAP. RESULTS: As shown by the results obtained, rats exposed to intra-abdominal hypertension for ten days had pathological changes in their salivary glands within 120 days. The severity of sialadenitis revealed a correlation with the severity of IAH. Some rats had individual reactions expressed in relative resistance to their organs' abnormalities under hypoxia. CONCLUSIONS: It was concluded that children with severe IAH history might need the disease prevention of the CNS, kidneys, digestive, and respiratory systems and oral diseases, particularly diseases involving the salivary glands. Future research is supposed to investigate further the IAH effect on various organs and tissues, including the dentofacial system.

Diagnosis of Schizophrenia Based on the Data of Various Modalities: Biomarkers and Machine Learning Techniques (Review).

Schizophrenia is a socially significant mental disorder resulting frequently in severe forms of disability. Diagnosis, choice of treatment tactics, and rehabilitation in clinical psychiatry are mainly based on the assessment of behavioral patterns, socio-demographic data, and other investigations such as clinical observations and neuropsychological testing including examination of patients by the psychiatrist, self-reports, and questionnaires. In many respects, these data are subjective and therefore a large number of works have appeared in recent years devoted to the search for objective characteristics (indices, biomarkers) of the processes going on in the human body and reflected in the behavioral and psychoneurological patterns of patients. Such biomarkers are based on the results of instrumental and laboratory studies (neuroimaging, electro-physiological, biochemical, immunological, genetic, and others) and are successfully being used in neurosciences for understanding the mechanisms of the emergence and development of nervous system pathologies. Presently, with the advent of new effective neuroimaging, laboratory, and other methods of investigation and also with the development of modern methods of data analysis, machine learning, and artificial intelligence, a great number of scientific and clinical studies is being conducted devoted to the search for the markers which have diagnostic and prognostic value and may be used in clinical practice to objectivize the processes of establishing and clarifying the diagnosis, choosing and optimizing treatment and rehabilitation tactics, predicting the course and outcome of the disease. This review presents the analysis of the works which describe the correlates between the diagnosis of schizophrenia, established by health professionals, various manifestations of the psychiatric disorder (its subtype, variant of the course, severity degree, observed symptoms, etc.), and objectively measured characteristics/quantitative indicators (anatomical, functional, immunological, genetic, and others) obtained during instrumental and laboratory examinations of patients. A considerable part of these works has been devoted to correlates/biomarkers of schizophrenia based on the data of structural and functional (at rest and under cognitive load) MRI, EEG, tractography, and immunological data. The found correlates/biomarkers reflect anatomic disorders in the specific brain regions, impairment of functional activity of brain regions and their interconnections, specific microstructure of the brain white matter and the levels of connectivity between the tracts of various structures, alterations of electrical activity in various parts of the brain in different EEG spectral ranges, as well as changes in the innate and adaptive links of immunity. Current methods of data analysis and machine learning to search for schizophrenia biomarkers using the data of diverse modalities and their application during building and interpretation of predictive diagnostic models of schizophrenia have been considered in the present review.

[Neuropsychiatric symptoms in patients with mild cognitive impairment]. / Neiropsikhiatricheskie simptomy u patsientov s myagkim kognitivnym snizheniem.

OBJECTIVE: To study the prevalence of neuropsychiatric symptoms (NPS) in patients with mild cognitive impairment (MCI) who asked for help in memory clinics. MATERIAL AND METHODS: We analysed data on 729 patients with MCI (average age 76.6 years, average MMSE score 25.3), who underwent a course of cognitive neurorehabilitation in a specialized department - a memory clinic. A Russian version of Neuropsychiatric Inventory (NPI) was used. We compared the indicators for the main psychometric scales for the diagnosis of MCI in comparison with the dynamics of NPS. RESULTS: The prevalence rates for NPS differed in part from those reported in the literature. The most common symptom was anxiety (54.7%) and irritability (56.5%), while euphoria, as well as delusions and hallucinations were not detected. All disorders significantly reduced at the end of the rehabilitation program. CONCLUSION: MCI influences the level of functioning and social interaction in older patients and mediates the quality of life. Thus, given the increase in life expectancy, it is necessary to introduce new methods of examination applicable in the practice of psychiatrists to diagnose and rehabilitate such patients. NPS turned out to be widespread in MCI, but may reduce during the course of complex neurorehabilitation.

Neuro-Immune Aspects of Schizophrenia with Severe Negative Symptoms: New Diagnostic Markers of Disease Phenotype.

The aim of the study was to analyze the immune-inflammatory profile of patients with paranoid schizophrenia and relate it to the severity of negative symptoms and the MRI data in order to identify biomarkers of schizophrenia severity, search for new approaches to therapy, and control its effectiveness. Materials and Methods: The main group included 51 patients with paranoid schizophrenia, the control group - 30 healthy subjects. Patients underwent MRI scans and immunological studies, which included an assessment of natural and adaptive immunity, the systemic level of key pro-inflammatory and anti-inflammatory cytokines, and other markers of inflammation. Results: Disorders of immunity and immunoinflammatory profile in patients with paranoid schizophrenia with severe negative symptoms were revealed for the first time: in the presence of severe negative symptoms (>15 points according to the NSA-4 scale), the levels of humoral immunity factors, cytokines IL-10 and IL-12p40 and neurotrophin NGF were increased as well as the markers of systemic inflammation. Morphometric changes in the brain, typical for patients with schizophrenia, and also specific for patients with severe negative symptoms, were determined. The data analysis revealed correlations between the immune changes with structural changes in some of the brain areas, including the frontal cortex and hippocampus. Associations were found between the levels of anti-inflammatory IL-10, IL-12p40 cytokines and morphometric parameters of the brain, specific only for schizophrenic patients with severe negative symptoms. Conclusion: The interdisciplinary approach, combining brain morphometry with in-depth immunological and clinical studies, made it possible to determine neurobiological, immune, and neurocognitive markers of paranoid schizophrenia with severe negative symptoms. The results are important for further deciphering the pathogenesis of schizophrenia and its subtypes, as well as for the search for new approaches to the treatment of severe forms of the disease.

[Antioxidant status of blood plasma of acutely psychotic patients and its correlation with Nrf2 activation]. / Antioksidantnyi status plazmy krovi patsientov s ostrym psikhozom i ego svyaz' s aktivatsiei transkriptsionnogo faktora Nrf2.

OBJECTIVE: To study the correlation between the blood plasma antioxidant profile and the transcriptional activity of the Nrf2 gene in acute psychosis in patients with schizophrenia and alcoholism. MATERIAL AND METHODS: The study included 40 patients with the first episode of the paranoid form of schizophrenia, 33 patients with schizophrenic psychosis who had previously received therapy, 22 patients with first-time acute alcohol psychosis, and 25 healthy volunteers. The level of Nrf2 in peripheral blood mononuclear cells was estimated by flow cytometry, and the antioxidant profile of blood plasma was estimated with chemiluminometry. RESULTS: The total and «thiol¼ antioxidant capacity were reduced in patients with initially diagnosed schizophrenic psychosis and alcoholic psychosis. In patients after treatment, the total antioxidant capacity was higher compared to previously untreated patients. The level of Nrf2 protein in mononuclear cells in patients with the first psychotic episode was significantly lower than in patients with alcoholism and lower than in the control group. In patients with alcoholic psychosis, Nrf2 level was correlated with both the total antioxidant capacity due to uric acid and the «thiol¼ antioxidant capacity; in patients with psychosis in schizophrenia, Nrf2 level was correlated only with the «thiol¼ antioxidant capacity. CONCLUSIONS: The correlation between the total and «thiol¼ antioxidant capacity and the level of Nrf2 in mononuclear cells of patients with alcohol delirium indicates the undamaged state of the regulation. The absence of a correlation between the total antioxidant capacity and the level of Nrf2 in patients with schizophrenia indicates a disturbance of the activation of the Nrf2 pathway due to, possibly, a part associated with the participation of uric acid.

[Lanzoptol efficacy at gastroesophageal reflux disease: results of multicenter study leader].

Results of multicenter study "Efficacy of Lansoptol (lansoprazole, KRKA) and its influence on the Dynamics of GERD symptoms" (LIEDER) are presented. The impact of 56-days treatment with lansoprazole 30 mg once daily on symptoms relief, a quality of life of 121 patients with gastroesophageal reflux disease (GERD) and healing of esophageal lesions of 30 patients with reflux esophagitis were investigated. Rapid acid inhibition effect of first dose of lansoptol was shown by 48-hr pH-monitoring. At the first day of the treatment 43.1% of patients reported decreasing of intensity of heartburn and 36.5%--of regurgitation. It were shown that the treatment with lansoptol provided symptoms relief in 25% patients at day 3, in 50% of patients at day 5 and in 75% at day 8 for heartburn, and at days 2, 6 and 9--for regurgitation. It was conducted improvement of quality of life. Healing rate of esophagitis at 28 day was 83.3%.

[Features of the immune profile of schizophrenic patients with catatonic syndrome]. / Osobennosti immunnogo profilya bol'nykh shizofreniei s katatonicheskim sindromom.

OBJECTIVE: An analysis of inflammatory and autoimmune markers in schizophrenic patients with- and without catatonic symptoms in comparison to healthy controls. MATERIAL AND METHODS: A sample of 170 patients with paranoid schizophrenia was stratified by the presence of catatonic symptoms in the structure of psychosis (66 patients with catatonia and 104 patients without catatonia), inclusion threshold was >10 points on the Bush-Francis catatonia scale. The examination was carried out in the early days of inpatient treatment using psychopathological, psychometric and immunological methods. RESULTS: Quantitative and qualitative differences in the spectrum of immune indicators in both groups of patients are revealed. A higher level of the immune system activation is found in the group with catatonic symptoms that indicates a worsening of the pathological process. A specific feature of the immunological profile of catatonic syndrome in schizophrenia is a decrease in ratio between leukocyte elastase and a1-proteinase inhibitor (leukocyte-inhibitory index) accompanied by the increase of other inflammatory markers that, presumably, indicates the deterioration of the phagocyte component of the inflammatory response. CONCLUSION: The results suggest that the decrease in leukocyte-inhibitory index is a potential biomarker of catatonic syndrome in schizophrenia.

Thermo- and pH-sensitive glycosaminoglycans derivatives obtained by controlled grafting of poly(N-isopropylacrylamide).

Poly(N-isopropyl acrylamide) grafted heparin and chondroitin sulfate were synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization. The copolymers were characterized by NMR, IR, SEC, DLS, SLS and NTA methods. High grafting densities were reached for both glycosaminoglycans. The temperature, pH and polymer concentration affected the low critical solution temperatures values. The increased pNIPAAm chain length, grafting density and concentration led to the sharp phase transition at 35 °C. Spherical nanogels were formed around this temperature. Terminal dodecyl trithiocarbonate groups of the copolymers were reduced to thiols that allowed formation of sensitive nanogels with sharp phase transitions induced by pNIPAAm chains. The copolymers showed no toxicity to the ocular cells and they provided the prolonged release of dexamethasone phosphate at 37 °C. These copolymers are interesting alternatives for ocular drug delivery.

Proteome data of serum samples from patients with schizophrenia.

Schizophrenia is a complex chronic disease. The molecular determinants and neuropathology of schizophrenia are multifaceted; an important role in the pathogenesis is played by the dysregulation of molecular and epigenetic mechanisms. However, the molecular mechanisms of the development of the disease have not yet been studied. An important task is the accumulation and systematization of "OMICS"-knowledge of the molecular profiles (transcriptome, proteome, metabolome) of blood specific to pathology. Thereby the development and improvement of mass spectrometric methods for the detection of biological molecules has become increasingly important in biomedical research. In the field of applied problems in biomedical research, the most prevalent issue involves the identification of serological protein markers associated with the development of schizophrenia, which account for the diseases that cause the a life-shortening illness, disability, decreased of functioning and quality of life and wellbeing or health status. OMICS approaches are designed to detect genes (genomics), mRNA (transcriptomics), proteins (proteomics) and metabolites (metabolomics) in a specific biological sample. We report the proteomic datasets on the serum samples from patients with schizophrenia (series "SCZ") and healthy volunteers (series "CNT"). Data were acquired using shotgun ultra-high resolution mass spectrometry.

Copy number variations of satellite III (1q12) and ribosomal repeats in health and schizophrenia.

OBJECTIVE: Earlier we studied the copy number variations (CNVs) of ribosomal repeat (rDNA) and the satellite III fragment (1q12) (f-SatIII) in the cells of schizophrenia patients (SZ) and healthy controls (HC). In the present study we pursued two main objectives: (1) to confirm the increased rDNA and decreased f-SatIII content in the genomes of enlarged SZ and HC samples and (2) to compare the rDNA and f-SatIII content in the same DNA samples of SZ and HC individuals. METHODS: We determined the rDNA CN and f-SatIII content in the genomes of leukocytes of 1770 subjects [HC (N = 814) and SZ (N = 956)]. Non-radioactive quantitative hybridization method (NQH) was applied for analysis of the various combinations of the two repeats sizes in SZ and HC groups. RESULTS: f-SatIII in human leukocytes (N = 1556) varies between 5.7 and 44.7 pg/ng DNA. RDNA CN varies between 200 and 896 (N = 1770). SZ group significantly differ from the HC group by lower f-SatIII content and by rDNA abundance. The f-SatIII and rDNA CN are not randomly combined in the genome. Higher rDNA CN values are associated with higher f-SatIII index values in SZ and HC. The f-SatIII variation interval in SZ group increases significantly in the subgroup with the high rDNA CN index values (>300 copies). CONCLUSION: Schizophrenia patients' genomes contain low number of f-SatIII copies corresponding with a large ribosomal repeats CN. A scheme is proposed to explain the low f-SatIII content in SZ group against the background of high rDNA CN.

[Network analysis of cognitive, oculomotor and speech parameters in schizophrenia]. / Setevoi analiz kognitivnykh, glazodvigatel'nykh i rechevykh pokazatelei pri shizofrenii.

OBJECTIVE: To determine the network connections between clinical, cognitive, speech and oculographic parameters in patients with schizophrenia. MATERIAL AND METHODS: The study included 104 patients with schizophrenia and schizophrenia spectrum disorders and 70 healthy subjects. Clinical assessment of the patients was performed using a number of scales: PANSS, CDSS, YMRS, SAS and BAS. Basic cognitive functions were assessed by BACS. Eye movements were recorded using the SMI RED-500 non-invasive eye tracking system. Several experimental paradigms were used - free viewing of animal images with subsequent description of these images, performing progressive saccades in the experimental Go/NoGo scheme, and performing anti-saccades. RESULTS: The severity of clinical symptoms, cognitive impairments, oculomotor parameters and characteristics of speech structure of written speech are largely independent, although not completely isolated from each other. Cognitive and oculomotor parameters have the largest number of connections. In this case, the results of cognitive tests are the central element of the «network¼ that connects other groups. CONCLUSION: Further development of the approach should be aimed at studying the influence of node changes on the structure of the network that would potentially allows the identification of the most effective points of application of therapeutic and rehabilitation programs.

[The relationship between inflammation, cognitive disorders and neuroimaging data in schizophrenia]. / Svyaz' mezhdu vospaleniem, kognitivnymi narusheniyami i dannymi neirovizualizatsii pri shizofrenii.

OBJECTIVE: To search for the relationship between the results of functional imaging, immunological parameters and laboratory markers of inflammation in schizophrenia, taking into account cognitive impairment in patients, and to consider the possibility of using a multidisciplinary approach to diagnosis, treatment and prognosis of schizophrenia. MATERIAL AND METHODS: The study included 25 patients with schizophrenia and 13 healthy volunteers. Psychiatric scales were administered to evaluate the patient's condition. The main indicators of humoral immunity, the level of markers of inflammation, key pro-inflammatory and anti-inflammatory cytokines, and growth factor VEGF were determined by ELISA. Brain MRI was performed. All calculated tractographic data are included in the connection database to study the effect of immunological markers and the degree of severity of cognitive impairment. RESULTS AND CONCLUSION: Levels of markers of systemic inflammation and growth factor VEGF-A as well as the activation of humoral immunity are increased in patients with schizophrenia compared with controls. For the first time, the relationship of immunological parameters with the coefficient of quantitative anisotropy in the area of the corpus callosum in schizophrenia was revealed. The results indicate the possible value of indicators of the activation of the humoral immune response and systemic inflammation as markers of neurophysiological changes and cognitive dysfunction in schizophrenia.

[Perspectives of the use of pharmacogenetic tests in neurology and psychiatry]. / Perspektivy primeneniia farmakogeneticheskikh testov v psikhiatrii i nevrologii.

The review is devoted to the analysis of the current state of pharmacogenetic research and their use in psychiatric practice. The main genes responsible for the pharmacodynamics and pharmacokinetics of drugs used in psychiatry are listed. Foreign pharmacogenetic clinical recommendations and progress on their implementation in medical practice in various countries of Europe and the USA are analyzed. The need to create Russian clinical guidelines on pharmacogenomics to improve the effectiveness of patient care and to implement a personalized approach to therapy is discussed.

Accumulation of Circulating Cell-Free CpG-Enriched Ribosomal DNA Fragments on the Background of High Endonuclease Activity of Blood Plasma in Schizophrenic Patients.

INTRODUCTION: Schizophrenia (SZ) increases the level of cell death, leading to an increase in the concentration of circulating cell-free DNA (cfDNA). Ribosomal DNA (rDNA) contains many unmethylated CpG motifs that stimulate TLR9-MyD88-NF-κB signaling and the synthesis of proinflammatory cytokines. The number of rDNA copies in the genomes of SZ patients is increased; therefore, we expect that the concentration of cell-free rDNA in the plasma of the SZ patients also increases. This may be one of the explanations of the proinflammatory cytokine increase that is often observed in SZ. The major research question is what is the rDNA copy number in cfDNA (cf-rDNA CN) and its putative role in schizophrenia? Materials and Methods. We determined cfDNA concentration (RNase A/proteinase K/solvent extraction; fluorescent dye PicoGreen) and endonuclease activity (NA) of blood plasma (radial diffusion method) in the untreated male SZ group (N = 100) and in the male healthy control group (HC) (N = 96). Blood leukocyte DNA and cfDNA rDNA CN were determined with nonradioactive quantitative hybridization techniques. Plasma concentration of cf-rDNA was calculated. RESULTS: In the subjects from the SZ group, the mean cfDNA plasma concentration was twofold higher and NA of the plasma was fourfold higher than those in the healthy controls. rDNA CN in the blood leukocyte genome and in the cfDNA samples in the SZ group was significantly higher than that in the HC group. cf-rDNA concentration was threefold higher in the SZ group. CONCLUSION: Despite the abnormally high endonuclease activity in the blood plasma of SZ patients, the circulating cfDNA concentration is increased. Fragments of cf-rDNA accumulate in the blood plasma of SZ patients. Potentially, SZ patients' cfDNA should be a strong stimulating factor for the TLR9-MyD88-NF-κB signaling pathway.

[A role of the immune system in the pathogenesis of schizophrenia]. / Rol' immunnoi sistemy v patogeneze shizofrenii.

The review addresses immunological aspects of schizophrenia, a multifactor disease caused by genetic factors, innate disorders of the central nervous system (CNS), including the consequences of perinatal hypoxia and infections, and adverse environmental influences. Neuroinflammation as a part of the pathophysiology of schizophrenia is characterized by the higher transcription of CNS inflammatory mediators, excessive activation of microglia, inhibition of glutamatergic receptors that leads to the decrease in the number of cortical synapses and neuronal apoptosis. The authors discuss a role of genetic polymorphisms of cytokine genes, complement system components etc. The literature data on the changes in systemic immune response and imbalance in Th1/Th2 adaptive immune responses are analyzed as well. Some papers showed higher levels of proinflammatory mediators in CSF and blood of patients with schizophrenia that indicated the involvement of blood brain barrier (BBB) dysfunction. The authors present the recent data on BBB dysfunction in schizophrenia and its role in the pathogenesis of the disease, autoimmunity in patients comparing it with immune activation and genetic predisposition. An important and arguable issues about a role of parasite and viral infections in the pathogenesis of schizophrenia, initiation of immune responses and direct impacts on the brain, an influence of antipsychotic treatment on immunity are discussed. In author's opinion, conflicting results of genetic and immunological studies of schizophrenia may be explained by different methodological approaches to selection of patients and healthy controls and the differences in schizophrenia classification.