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Functional dysconnectivity in schizophrenia and affective disorders may be associated with myelin and oligodendrocyte abnormalities. Altered network integration involving the caudate nucleus (CN) and metabolic abnormalities in fronto-striatal-thalamic white matter tracts have been reported in schizophrenia and impaired patterns of cortico-caudate functional connectivity have been found in both bipolar disorder (BPD) and schizophrenia compared to healthy controls. Postmortem studies have found ultrastructural dystrophy and degeneration of oligodendrocytes and dysmyelination in the CN in schizophrenia and BPD. We aimed to test the hypothesis that oligodendrocyte density may be reduced in the CN in major psychiatric disorders and may thereby form the cellular basis for the functional dysconnectivity observed in these disorders. Optical disector was used to estimate the numerical density (Nv) of oligodendrocytes and oligodendrocyte clusters (OLC) in the CN of cases with schizophrenia, BPD and major depressive disorder (MDD) and in normal controls (15 cases per group). A significant reduction in the Nv of oligodendrocytes was found in schizophrenia and BPD as compared to the control group (p < 0.05), and the Nv of OLC was significantly lowered in schizophrenia and BPD compared to controls (p < 0.05). There were no significant differences between MDD and control groups. The Nv of OLC was significantly decreased in the left hemisphere in schizophrenia as compared to the left hemisphere of the control group (-52%, p < 0.01). The data indicates that a decreased density of oligodendrocytes and OLC could contribute to the altered functional connectivity of the CN in subjects with severe mental illnesses.

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Many hypotheses have been proposed for the pathogenesis of schizophrenia. The most common hypotheses of schizophrenia are dopaminergic, serotoninergic, glutamatergic. There are also assumptions about involvement of other neurochemical systems, in particular GABAergic, in the pathogenesis of schizophrenia. The available data on the damage of GABAergic interneurons, taking into account the results of postmortem, neuroimaging, molecule-genetic, electrophysiological studies in humans and fundamental studies in animals, are discussed. The author suggests that one of the pathophysiological mechanisms of the pathogenesis of schizophrenia may be a disturbance of myelination of GABAergic interneurons leading to a decrease in the number of intra- and interhemispheric coherent connections, and eventually to the development of symptoms of the disease.

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AIM: A deficit of cortical gray matter myelination in the frontal lobes has been reported in schizophrenia in neuroimaging studies. Previously the decrease in the numerical density (Nv) of oligodendrocytes (NvOl) in layers 3 and 5 in area 10 of the prefrontal cortex (PFC) has been reported in schizophrenia. Oligodendrocyte progenitors proliferate in the adult human brain and form oligodendrocyte clusters for functional-dependent adaptive myelination. We aimed to estimate the NvOl and Nv of oligodendrocyte clusters (NvOlC) in supra- and infragranular sublayers of the PFC in schizophrenia and healthy controls. MATERIAL AND METHODS: 17 chronic schizophrenia subjects and 20 healthy matched controls were studied in Nissl-stained sections in sublayers 3a- 3c and 5a of the PFC by stereological optical dissector method. RESULTS AND CONCLUSION: The NvOl and the NvOlC were significantly decreased in supra- (32%, p<0.02) and infragranular sublayers (50%, p<0.001) of the PFC in the schizophrenia group as compared to controls. The Nv OlC/Nv Ol ratio decreased significantly in the schizophrenia group only in sublayers 3a (p=0.015) and 5a (p<0.001). In the control group, the NvOlC was positively correlated with the NvOl in sublayers 3b, 3c and 5a (R≥0.59; p≤0.006). In the schizophrenia group, a significant correlation between the parameters was found only in sublayer 5a (R=0.8; p<0.001). The deficit of oligodendrocyte clusters might be associated with altered proliferation and/or maturation of oligodendrocyte progenitors in schizophrenia. Specific alterations of the Nv OlC/Nv Ol ratio might be due to different connectivity of supra- and infragranular sublayers of the PFC and their disturbances in schizophrenia.

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AIM: Oligodendrocyte abnormalities are thought to be one of the key cellular pathologies involved in disturbances of neuronal connectivity in schizophrenia. MATERIAL AND METHODS: The density of oligodendrocytes in layer III of the prefrontal cortex, BA10, in schizophrenia (n=20) was compared to controls (n=20) using optical dissector method. MANCOVA was applied for group comparisons. RESULTS AND CONCLUSION: The density of oligodendrocytes was significantly lower in each sublayers of layer III (≤20% p≤0.05) in the schizophrenia group as compared to the control group. The deficit of oligodendrocytes in the prefrontal cortex in schizophrenia may be of developmental origin or the result of alterations in the neural tissue of the brain during disease course.

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Treatment of congestive heart failure (CHF) remains one of the challenging problems in cardiology. In recent years, the method of multifrequency bio-impendancemetry is used in patients with CHF for the assessment of water imbalance and determination of its severity. The aim of the study was to determine the diagnostic capabilities of bio-impendancemetry in evaluation of the early manifestations of CHF. The study included 92 healthy individuals, and 335 patients who were hospitalized in the cardiology department with NYHA I-II functional class (FC) of chronic CHF. The echocardiography, rheography and biochemical examination were performed for determination of FC of CHF. Procedures were repeated at day 5 of hospitalization, 6-minute walk test was performed to assess physical tolerance and objectification of the functional status of patients with CHF. 45 patients had signs of CHF FC III-IV, therefore, they were excluded from the study. Analysis of endpoints was conducted by telephone survey in 1 year after discharge from the hospital. The results of the comparison of the predictive value of different methods for diagnosing CHF showed maximum sensitivity for brain natriuretic peptide (BNP) which was 82%, specificity was 88%. The 6-minute walk test showed the lowest values of sensitivity and specificity (sensitivity 67%, specificity 72%) as well as leg impedance at low frequencies (LF) (sensitivity 69%, specificity 74%). The values for the leg impedance at high frequencies (HF) were as follows: sensitivity 68%, specificity 97%. High predictive value of a positive result (PPV) was shown in phase angle (91%) and BNP (91%). Left ventricle ejection fraction(LVEF) measurements had the lowest PPV (72%).

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AIM: To specify a possible role of oligodendrocyte deficit in the development of interhemispheric asymmetry. MATERIAL AND METHODS: Perineuronal oligodendrocytes were counted in layer III, Broadmann area 39, in Nissl-stained sections in both hemispheres of post-mortem brain samples of patients with schizophrenia and controls (healthy people). RESULTS AND CONCLUSION: The left-hemispheric asymmetry of perineuronal oligodendrocytes was found in the control group. A decrease of this parameter by 22% and the absence of the interhemispheric asymmetry were noted in patients with schizophrenia. It has been concluded that perineuronal oligodendrocyte deficit in the inferior parietal cortex in schizophrenia can contribute significantly to disturbed interhemispheric asymmetry of this brain structure.

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OBJECTIVE: To study effects of blood serum (BS) from schizophrenia patients under olanzapine monotherapy on astrocytes in the human fetal brain organotypic culture. MATERIAL AND METHODS: Authors studied the human fetal brain organotypic culture after the application of BS from 20 normals and 33 patients (ICD-10 schizophrenia, paranoid type, F20.02; F20.22) taken before and after 8 and 28 weeks of olanzapine treatment. A qualitative electron microscopic study of glial cells, neurons and neuropil as well as morphometric study of the ultrastructure of astrocytes were performed. RESULTS: Authors found no effects of BS from the patients with schizophrenia on neurons and synaptic contacts. The qualitative and morphometric studies revealed different effects of BS from the patients on the astrocyte ultrastructure before and after olanzapine treatment. The application of BS from untreated schizophrenia patients induced dystrophic alterations of astrocytes, BS from patients who received olanzapine during 8 weeks did not influence the astrocyte ultrastructure. After 28 weeks of olanzapine treatment,a hypertrophy of astrocytes (an increase (р≤0.05) of the area of cells and the number of mitochondria (p=0,015) and unaltered volume density of mitochondria) was found as compared to normal control cultures. CONCLUSION: BS from patients with schizophrenia before and after olanzapine treatment induced opposite types of ultrastructural changes of astrocytes in the human fetal brain organotypic culture. The differences might be due to the previously reported changes of the level of circulating immune complexes and interleukins in blood serum of schizophrenia patients and due to the effects of olanzapine on these parameters.

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AIM: Experimental verification of the hypothesis about the possible involvement of the mosaic genome variations (mosaic aneuploidy) in the pathogenesis of a number of mental illnesses, including schizophrenia and autism: a genetic study of the level of mosaic genome variations in cells of the brain autopsy tissues in healthy controls and schizophrenia. MATERIAL AND METHODS: Autopsy brain tissues of 15 unaffected controls and 15 patients with schizophrenia were analyzed by molecular cytogenetic methods to determine the frequency of chromosomal mutations (the mosaic aneuploidy) in neural human cells. The original collection of chromosome-enumeration DNA probes to autosomes 1, 9, 15, 16, 18 and the sex chromosomes X and Y was used for the interphase cytogenetic analysis of chromosomes in the cells of the brain. RESULTS AND CONCLUSION: The frequency of low-level aneuploidy per individual chromosome was 0.54% (median - 0.53%; 95% confidence interval (CI) CI - 0.41-1.13%) in controls and 1.66% (median - 1.55%; 95% CI -1.32-2.12%) in schizophrenia (p=0.000013). Thus, the three-fold increase in aneuploidy frequency in the brain in schizophrenia was detected. It is suggested that mosaic aneuploidy, as a significant biological marker of genomic instability, may lead to genеtic imbalance and abnormal functional activity of neural cells and neural networks in schizophrenia.

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AIM: To detect cytotoxic effects of blood serum (BS) from schizophrenia patients on astrocytes and neurons in the human fetal brain organotypic culture. MATERIAL AND METHODS: Authors studied the human fetal brain organotypic culture after the application of BS from 20 healthy donors and 33 untreated patients with attack-like progressive schizophrenia (ICD-10: schizophrenia, paranoid type, F20.02; F20.22). The numerical density of degenerating cells was estimated by the optical dissector method in Nissl stained sections. A qualitative electron microscopic study of glial cells, neurons and neuropil as well as morphometric study of the ultrastructure of astrocytes were performed. RESULTS: Authors found no significant effect of BS from patients with schizophrenia on the numerical density of degenerating cells as compared to BS from healthy donors. The qualitative study detected ultrastructural alterations in astrocytes and microglial cells but not in neurons. The morphometric study of astrocytes demonstrated a decrease of the area of astrocytes, their nuclei (р<0.001) and cytoplasm (р<0.05), reduced number of mitochondria (р<0.05) and increase in the number and volume fraction of lypofuscin inclusions (р<0.01). CONCLUSION: The application of BS from untreated schizophrenia patients does not influence the cell survival in human fetal brain organotypic culture and the ultrastructure of neurons and neuropil but induces the hypotrophy of astrocytes and increase in the number of lypofuscin inclusions. The data suggest that astrocytes are specific target for the damage effect of BS from schizophrenia patients.

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To study the spatial organization of oligodendrocytes and pyramidal neurons in the frontal limbic cortex of patients with schizophrenia and healthy controls, the authors used a method of two-dimensional automated analysis of images. The decrease in the minimal distance between the oligodendrocyte and the nearest neuron by 20% and in the mean and maximal distances between neurons and the nearest oligodendrocytes by 10% and 9%, respectively, was found in the layer III in patients with schizophrenia. Therefore, this method allows to characterize the spatial organization of neurons and glia in the brain cortex not only in the normal brain but also in mental pathology.

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A U.S./Russian collaboration of accelerator scientists was directed to the development of high averaged-current (∼1 mA) and high-quality (emittance ∼15 πmm mrad; energy spread ∼0.1%) 1.75 MeV proton beams to produce active interrogation beams that could be applied to counterterrorism. Several accelerator technologies were investigated. These included an electrostatic tandem accelerator of novel design, a compact cyclotron, and a storage ring with energy compensation and electron cooling. Production targets capable of withstanding the beam power levels were designed, fabricated, and tested. The cyclotron/storage-ring system was theoretically studied and computationally designed, and the electrostatic vacuum tandem accelerator at BINP was demonstrated for its potential in active interrogation of explosives and special nuclear materials.

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The distribution coefficient (Kd) of tuberculostatic rifabutin in a liposome/water system at pH 6.4 and 7.4 has been determined by the fluorescence quenching method. Large unilamellar vesicles composed of phosphatidylcholine alone or its combination with cholesterol or cardiolipin were used. The fluorescent probe anthrylphosphatidylcholine, which contains the anthryl moiety in the hydrophobic part, was incorporated into large unilamellar vesicles. The Kd values calculated with the use of dynamic quenching theory (Stern-Volmer model), were comparable for phosphatidylcholine and its combination with cholesterol at both pH. The value of lgKd (24-2.6) demonstrates the hydrophobicity of the rifabutin molecule. After the introduction of negatively charged cholesterol, Kd increases more than tenfold at pH 6.4. At pH 7.4, a second phosphate group of cholesterol undergoes ionization, and Kd of rifabutin gains an additional increase. The results obtained demonstrate a strong influence of electrostatic forces on rifabutin-model membranes interaction.

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Autopsy samples from the prefrontal cortex were obtained from 22 schizophrenic cases and 22 normal controls. Capillaries and oligodendrocytes were viewed in paraffin sections stained with a Luxol-fast blue + cresyl violet. Electron microscopy was applied to study the ultrastructure of oligodendrocytes. Numerical density of pericapillary oligodendrocytes was measured in layer V of Broadmann's area 10. Subjects with schizophrenia had a significantly lower (-20,8%) numerical density of pericapillary oligodendrocytes compared to controls. The analysis for schizophrenic subgroups with predominantly positive or predominantly negative symptoms revealed a significant decrease in the numerical density of pericapillary oligodendrocytes only in the latter one (-29,4%). The numerical density of pericapillary oligodendrocytes in cases with predominantly positive symptoms also decreased (-8,3%) but not differed significantly from the controls. Electron microscopy revealed the prominent ultrastructural dystrophic and degenerative alterations of pericapillary oligodendrocytes in the prefrontal cortex in schizophrenic brains. The present study points out that the population of pericapillary oligodendrocytes is involved in the pathogenesis of schizophrenia. Damage and loss of pericapillary oligodendrocytes might lead to disruption of the blood-brain barrier and as a result to dysregulation of metabolic trafficking across the blood-brain barrier in the prefrontal cortex in schizophrenia.

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The aim of the present work was to produce organotypic cultures of human embryo brain tissues, as needed for investigation of the effects of serum factors on mental diseases and their pharmacological treatment. Cultures were made using slices of medulla oblongata from human embryos aged 9-10 weeks, obtained from medical abortions. Free-floating slices were cultured using a modified roller method for four weeks. Light and electron microscopy, along with immunocytochemistry, demonstrated that cultured slices showed differentiation and growth of neurons, astro- and microgliocytes, with formation of the synaptic contacts and glioneuronal interactions typical of organotypic cultures. However, along with differentiated neurons and glial cells, there was some persistence of undifferentiated cellular elements with signs of stem cells and neuron and gliocyte precursor cells. These experiments showed that organotypic roller cultivation of free-floating slices of human embryo brain tissue can be used to study the processes of neuron and gliocyte development, the mechanisms of neurotoxicity and neuroprotection using a variety of morphological (including stereological) and biochemical study methods.

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Rifabutin solubility within pH 3.0 to 11.0 was determined. Potentiometry, spectrophotometry and computation revealed ionization of three groups with pKa 3.5, 6.5 and 9.5 in the rifabutin molecule. On the basis of the pKa values of certain fragments of the rifabutin molecule computed by the ACD/pKa programme they were related to ionization of the following groups: imidazole residue nitrogen, aromatic hydoxyl and piperidin nitrogen respectively. Interaction of rifabutin with model membranes, i. e. large unilamellar vesicules was studied. At lower pH of the medium, entrapment of rifabutin to the large unilamellar vesicules increased that was evident of satisfactory correlation with the decrease in the rifabutin distribution coefficient in the system multilamellar vesicules/water under the experimental conditions.

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Liposomal and free rifabutin were separated by the method of gel filtration. The percents of rifabutin bound to liposomes of different phospholipid composition were measured. The presence of negatively charged phospholipids increased the degree of binding. Binding decreased with increasing the ionic strength. Incubation of rifabutin with liposomes containing anthryl phosphatidylcholine was accompanied by fluorescence quenching. Activity of rifabutin depended on the phospholipid composition of liposomes. Our results indicate that binding of rifabutin is associated with electrostatic and hydrophobic interactions.

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