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Uncoupling protein-2 (UCP2) is present in many tissues with relevance to fuel metabolism, and its expression is increased in fat and muscle in response to elevated circulating free fatty acids resulting from fasting and high fat feeding. We proposed a role for peroxisome proliferator-activated receptor-gamma (PPARgamma) as a mediator of these physiological changes in UCP2, because thiazolidinediones also increase expression of UCP2 in these cell types (). To determine the molecular basis for this regulation, we isolated the 7.3-kilobase promoter region of the mouse UCP2 gene. The -7.3-kilobase/+12-base pair fragment activates transcription of a reporter gene by 50-100-fold. Deletion and point mutation analysis, coupled with gel shift assays, indicate the presence of a 43-base pair enhancer (-86/-44) that is responsible for the majority of both basal and PPARgamma-dependent transcriptional activity. The distal (-86/-76) part of the enhancer specifically binds Sp1, Sp2, and Sp3 and is indistinguishable from a consensus Sp1 element in competition experiments. Point mutation in this sequence reduces basal activity by 75%. A second region (-74/-66) is identical to the sterol response element consensus and specifically binds ADD1/SREBP1. However, deletion of this sequence does not affect basal transcriptional activity or the response to PPARgamma. The proximal portion of the enhancer contains a direct repeat of two E-Box motifs, which contributes most strongly to basal and PPARgamma-dependent transcription of the UCP2 promoter. Deletion of this region results in a 10-20-fold reduction of transcriptional activity and complete loss of PPARgamma responsiveness. Point mutations in either E-Box, but not in the spacer region between them, eliminate the stimulatory response to PPARgamma. However, gel shift assays show that PPARgamma does not bind to this region. Taken together, these data indicate that PPARgamma activates the UCP2 gene indirectly by altering the activity or expression of other transcription factors that bind to the UCP2 promoter.

Both beta(2)- and beta(3)-adrenergic receptors (ARs) are able to activate the extracellular signal-regulated kinase (ERK) pathway. We previously showed that c-Src is required for ERK activation by beta(2)AR and that it is recruited to activated beta(2)AR through binding of the Src homology 3 (SH3) domain to proline-rich regions of the adapter protein beta-arrestin1. Despite the absence of sites for phosphorylation and beta-arrestin binding, ERK activation by beta(3)AR still requires c-Src. Agonist activation of beta(2)AR, but not beta(3)AR, led to redistribution of green fluorescent protein-tagged beta-arrestin to the plasma membrane. In beta-arrestin-deficient COS-7 cells, beta-agonist-dependent co-precipitation of c-Src with the beta(2)AR required exogenous beta-arrestin, but activated beta(3)AR co-precipitated c-Src in the absence or presence of beta-arrestin. ERK activation and Src co-precipitation with beta(3)AR also occurred in adipocytes in an agonist-dependent and pertussis toxin-sensitive manner. Protein interaction studies show that the beta(3)AR interacts directly with the SH3 domain of Src through proline-rich motifs (PXXP) in the third intracellular loop and the carboxyl terminus. ERK activation and Src co-precipitation were abolished in cells expressing point mutations in these PXXP motifs. Together, these data describe a novel mechanism of ERK activation by a G protein-coupled receptor in which the intracellular domains directly recruit c-Src.

On the base of clinical psychological and electrophysiological studies of 34 patients with primary manifestations of brain circulation insufficiency good tolerance and high efficiency of Tanakan course treatment (3 x 40 mg/day for 3 months) were showen. Tanakan decreased manifestations of clinical syndrome, improved psychological functions and electrophysiological parameters. Prospective study supported the stability of positive changes in the status of patients for 12 months after Tanakan course treatment.

160 patients over 60 years of age appealed to gerontologic unit of out-patient psychiatric clinic for the first time. The patients were divided into two main groups: with organic mental disorders (OMD) and with functional mental disorders (FMD) (79 and 81 patients, respectively). In the group of OMD the main form of disturbances were cases with dementia (74.4%) mainly of the Alzheimer's type, and cerebral vascular dementia. In 25.3% of the patients the cognitive disturbances didn't attain the level of dementia. In a group of patients with different forms of dementia a high frequency of comorbid mental pathology was observed (83%)--confusional states, delusions, depressive conditions as well as disturbed behavior (67.7%) that was one of the reasons for consulting a psychiatrist. In FMD group the prevailing pathology were depressions, both of the major (37.1%) and mild (34.6%) forms. The remaining cases were characterized by delusions (10.1%), anxiety-phobic (7.6%) states and somatoform disturbances (5.1%). Among the patients both of OMD and FMD groups it was possible to diagnose approximately 3-4 different somatic diseases; vascular and gastrointestinal disorders were met more frequently. The study of contribution of brain computer tomography (CT) to diagnosis of mental pathology (according to ICD-10), has demonstrated that in 30.8% of the cases it was decisive, in 41% it confirmed the clinical data and in 21.8% CT provide additional data (detecting latent cerebral vascular damage). And only in 6.4% of the cases CT fails to give definite information in diagnostically complicated cases. In 26.6% of the patients with FMD, CT of brain had detected symptoms of mild vascular pathology.

Transcription factors of the AP-1/ATF family, including c-Fos, c-Jun, and ATF-2, play an important role in the regulation of cell proliferation and differentiation, and changes in their levels and/or activities may contribute to oncogenesis. We analyzed the alterations of AP-1/ATF transcription factors upon immortalization and transformation in a panel of cell lines derived from rat embryo fibroblast (REF) cells. The tumorigenic E1A + cHa-ras cells are characterized by high and constitutive DNA binding activities of AP-1, in contrast to nontransformed cells and the E1A cells. The expression of c-fos and c-jun genes was affected differently by the oncogenic transformation. By using antibodies to c-Jun and c-Fos proteins in electrophoretic mobility shift assays (EMSA), we showed that E1A + cHa-ras transformants did not contain c-Fos under any condition of cell cultivation and growth factor stimulation, whereas c-Jun was constitutively upregulated. In the absence of c-fos gene expression, c-Fos protein appears to be replaced by proteins of Fos family (Fra-1) and ATF family (ATF-2 and ATFa). To determine the possible mechanisms of c-fos downregulation in E1A + cHa-ras transformants we have obtained populations of geneticin-resistant clones containing integrated reporter construct -711fos-CAT and its mutants in serum-responsive element (SRE) and cAMP-responsive element (CRE). Data obtained show that the mutations within the SRE lead to a manifold activation of fos-CAT expression. This allows to suggest that c-fos downregulation in E1A + cHa-ras transformants is provided by a negative control mediated through the SRE regulatory region. The profound differences in regulation and composition of transcription factors of the AP-1 family probably play a pivotal role in the transformation of REF cells by E1A and cHa-ras oncogenes.

Open study was performed concerning the efficiency of cerebrolysin in treatment of tardive dyskinesia and parkinsonism. 30 patients of middle (18-41 years) and old (60-82 years) age were examined by means of Extrapyramidal Symptom Rating Scale and Abnormal Involuntary Movement Scale. Cerebrolysin was administered intravenously by drops every other day in a dose of 5-10 ml during 28 days. Significant decrease of the severity of extrapyramidal symptoms (according to the Scales used) was observed by the end of the course of therapy. The number of the responders was 46.6%, of the partial responders--26.6%. Efficiency of cerebrolysin was the same both in the groups of patients with drug-induced parkinsonism (number of the responders--54.5%) and in patients with tardive dyskinesia (the responders' number--60%). The efficiency of cerebrolysin was lower in patients with combination of symptoms of parkinsonism and tardive dyskinesia as well as in ones with pronounced negative schizophrenic disorders in clinical picture. Efficacy of cerebrolysin was also the same in patients of both middle and old age. Its efficiency was equally high independently on the duration of extrapyramidal disorders' existence.

Evoked cortical activity in response to acoustic stimuli (oddball paradigm) was studied in patients with different paranoid disorders. The analysis covered the N150 negative wave and positive complex P300. In patients with paranoid schizophrenia and paranoid form of involutional psychosis cortical responses to the stimuli and cortex effects were not recorded. Such cognitive deficiency is believed to be typical for schizophrenia.

The effect of forbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA) on the growth of cultured human chronic promyelocytic leukemia (K562) cells has been studied using cells growing in a medium consisting of RPMI 1640 supplemented with 10% fetal serum and with or without retinoic acid. All the used concentrations of TPA (100.0, 10.0, 1.0 and 0.1 ng/ml) cause the expected inhibition of proliferation of these cells. Moreover, a block of proliferation of K562 cells became stronger after cotreatment with TPA and retinoic acid, although this acid itself did not have any effect on proliferation and differentiation of K562 cells.

This article discusses the role of some pathogenetical factors in the main morphological variants of vascular dementia and their correlation with certain clinical parameters. On the basis of computer-tomographical (CT) studies of 62 patients with dementia, it was possible to distinguish three groups of patients, according to the type of parenchymatous brain lesions: (1) 14 patients with "pure" leukoaraiosis (LA); (2) 23 patients with ischemic foci (IF), and (3) 25 patients with a combination of LA and IF. A comparative study of these groups confirmed the concept that in the development of LA and dementia related to it, a special role is being attributed to such factors as arterial hypertension and aging.

Computed tomography was used to study the prevalence rates of various types of intracranial pathology, hydrocephalus (HDC) and cortical atrophy (CA) in patients with late dementia (LD) and to comparatively assess the informative value of tomographic methods of cerebral morphometry. Computed tomographic data were obtained from 432 patients with LD. Despite the type of dementia, the authors revealed intracranial abnormalities of various etiology in 24.5%, postischemic foci being prevalent. Tumors, arachnoidal cysts, and chronic subdural hematomas were more infrequently diagnosed (in 2.6% of cases). HDC and CA were detected in 81.5 and 82.2% of patients with LD, respectively.

In 186 patients with obstructive jaundice admitted to the clinic for diagnosis of its cause, the ultrasound scanning with duodenoscopy was employed. This permitted to establish the cause of jaundice in 84.9% of the patients and to choose proper therapeutic tactics at the shortest time after hospitalization. In 80% of the patients, an obstacle for bile outflow was liquidated by means of endoscopy. When it was not possible to established the cause of jaundice by the findings of ultrasound scanning and duodenoscopy, percutaneous transhepatic cholangiography was performed, which has proved to be successful in 5.9% of cases. Use of the given methods for diagnosis permitted to define the optimal therapeutic tactics in patients with obstructive jaundice, to reduce the lethality.

Regulation of c-fos protooncogene activity in rat embryonal fibroblasts (REF), E1Aad5-immortalized REF cells, and E1Aad5 + cHa-ras transformed REF cells has been investigated. The analysis of regulation of fos-promoter activity was done by means of transient and stable transfection of fos-CAT plasmid into immortalized and transformed cells. In parallel, the regulation of cellular c-fos as well as c-jun and c-myc genes expression has been studied. It has been found that in E1Aad5 + cHa-ras-transformed cells the expression of c-fos promoter has a constitutive, non-inducible character while in REF cells and cells immortalized by E1Aad5 the fos-promoter can be regulated by serum growth factors, EGF, and TPA.

Hemosorption was included in the complex treatment of 30 patients (age: 25-50 years) suffering of rheumatoid arthritis. It was found that the most sensitive laboratory tests of treatment efficacy were erythrocyte sedimentation rate, reduction of the level of gammaglobulins. Clinical improvement was pronounced as result of hemosorption treatment.

Paranoid and hallucination syndromes were studied in 71 cases of senile non-dementia psychoses located at the patients' house. Two major variants were singled out: paranoid and hallucinatory (the latter subdivided into patterns with or without the persecution delusion, and physical affection delusion). Paranoid variant was shown to be based upon a special transformation of visual perception with formation of delusions of penetration of a "stranger" into the patients' home. Hallucinatory variants were based predominantly on primitive physically-straining hallucinations with protopathic meaning. As the paranoid syndrome increased in severity, the space of its projection onto housing place expanded. It is suggested that housing conditions themselves could influence the psychopathology of housing paranoid.

Spectral signs of genetically conditioned convulsibility of rats of the Krushinskiĭ-Molodkina (KM) strain were determined when studying the background electrical brain activity. These signs were: an increase of the delta-activity power in motor and visual cortical zones; considerable increase of the hippocampal potential power; weakening of the caudate nucleus potential power. Spectra of biopotentials being approximated by theoretical spectral function, model parameters simulating physiological characteristics of neural networks were estimated (an inverse problem of modelling). Spectral signs of convulsibility were shown to reflect changes in properties of the neural network. On the basis of calculations it is supposed that genetically determined convulsibility of KM rats results from weakening of inhibitory functions of the caudate nucleus as well as from increased excitability (reactivity) of hippocampal and neocortical neurons.

Rat embryonal fibroblasts of the second passage have been immortalized or transformed with the E1A region of the human adenovirus type 5 and the cloned c-Ha-ras oncogene. Several cell lines obtained greatly differ according to the criteria of the transformed phenotype: saturation cell density, the ability to be cloned on a substrate and in soft agar, the ability to give tumors in nude mice. We have transiently transfected these immortalized and transformed cell lines with CAT-plasmids containing the CAT gene under the control of promoters of the "cell-cycle dependent" genes (human hsp70 and protooncogene c-fos). The results showed that the expression of hsp-CAT and fos-CAT plasmids differed in great extent depending on whether the cells were immortalized (E1Aad5) or transformed (E1Aad5+Ha-ras). The role of cellular genes and cellular transcription factors influencing the expression of transiently transfected CAT-plasmids has been discussed.

Rats of the Krushinskiĭ-Molodkina (KM) strain genetically predisposed to audiogenic seizures were repeatedly injected camphor for 4-5 months in gradually increasing doses (beginning from those below the seizure threshold up to those above it). As a result of "adaptation" to the convulsant action rats endured without seizures camphor doses 1.5-3 times higher than seizure threshold ones. Parallel with this "adaptation" the motor cortex of KM rats accumulated properties peculiar to the epileptic focus: spontaneous epileptiform spikes were recorded there after the camphor application. Estimation of the neural network parameters from spectra of the motor cortex biopotentials using the network model has shown a decrease of a parameter reflecting efficacy of the recurrent inhibition mechanisms. It is supposed that development of compensatory processes making rats able to avoid generalized camphor seizures are related to an increase of inhibitory functions of the caudate nucleus and weakening of the hippocampal excitability.

A total of 84 senile patients with malignant schizophrenia were examined. These pateints could be divided into 3 groups: with adolescent schizophrenia (with an onset of the disease before 24 years); with schizophrenia in middle age (with an onset of the disease from 25--35 years); with late schizophrenia (with an onset from 40--61 years). It was established, that the clinical and age-associated differences between the groups are distinct only in the initial and manifest stages of the disease. In the terminal period of the disease seen in senescence, there is a complete smoothening of the specific traits of each group, which is due to a formation of a deep defect infrequently associated with pseudosenile traits.

On the basis of a study of 51 patients with schizophrenia older than 60 years of age with catatonic outcome states the author accomplished differentiation of these conditiones with consideration of the character of the catatonic symptoms, as well as of the whole structure of the state. It was demonstrated that in the elderly the most diverse of the described in literature catatonic outcome states may be encountered. A significant percentage of the studied cases was with outcome states, prevalence of speech disorders and certain restoration of adaptation.

Selective attention was studied by registering cortical evoked potentials to acoustic stimuli in mental patients and mentally healthy subjects of old age. Disorder of selective attention in the patients was manifested in an impaired ability of the higher portions of the central nervous system to differentiate between essential and non-essential external stimuli as well as in a weakened inhibition of irrelevant information.

The resting EEGs of several brain structures (motor and visual cortex, caudate nucleus and intralaminar thalamic nuclei) were submitted to spectral and coherence computer analyses in two rat strains. Genetically predisposed to convulsive state KM rats were shown to differ from nonpredisposed Wistar rats in EEG spectral properties. KM rats EEG pattern was characterized by increase of low frequencies (1-2 Hz) power and decrease of faster activity (5-12 Hz) power in cortical spectrograms as well as by decrease of caudate nucleus EEG absolute power. The coherence value between cortical or subcortical structures at below 4 Hz was intensified in KM rats. Reinforcement of cortical auto-oscillating properties manifested by ECoG synchronization in cortical-thalamic resonance interaction as well as weakening of striatal inhibitory system may constitute neurophysiological mechanisms of enhanced convulsive readiness. The probable role of mediator imbalance in these mechanisms is discussed.

On the basis of examining 86 senile schizophrenics with defective initial conditions two groups of such conditions were specified: 1) defect conditions retaining the structure specific for schizophrenia (apathic defect, apathic mental deficiency and its variant with pseudosenile disturbances); 2) defect conditions, approaching by their manifestations to the picture of psychic disintegration associated with senile dementia. The psychopathological structure of the first group of defect conditions primarily reflects the degree of the schizophrenia progression. Their time course in old age was limited to insignificant age-related modifications and decompensation. Deficit conditions in the second group develop the more frequently, the closer to old age the period of the maximum activity of the schizophrenic process and the older the patients.

Desynchronous (low voltage fast activity), synchronous (high voltage slow waves) as well as convulsive brain activities were stimulated by a computer model of neuronal population. Network excitatory and inhibitory elements possessed fundamental dynamic properties of real neurones. Being independent both of the excitability of elements and of external influence efficacy, synchronous (desynchronous) network activity resulted from the increase (decrease) of the average power of "neuronal" interconnections which imitated mutual and recurrent excitation and inhibition. The inhibition efficacy being reduced as compared with excitation, synchronization of elements became intensified. As a consequence, the rhythmic activity amplitude increased and the appearance of self-sustained oscillations simulating convulsive activity was facilitated. The probable mechanism of EEG activation by virtue of the reduction of mutual and recurrent excitation and inhibition efficacy as well as the significance of inhibitory mechanism deficiency for epileptogenesis are discussed.

On the basis of a study of 217 patients with terminal schizophrenic states in old age the author found it possible to distinguish 2 forms of such conditions: psychotic and deficient. The psychotic forms were expressed in syndromological polymorphic psychoses, which most frequently reflected the form of the process development and which is senescence often enough undergone pathoplastical changes. The deficiency forms were presented by apathic dementia, while the connection with the previous form of development was lost. In many cases in old age there was worsening of the states with a senile-like change of the clinical picture.

Ecmnestic disturbances were revealed in 170 out of 260 schizophrenic patients who have lived up to the old age. In all the patients the disease took an unfavourable course (paranoid and malignant schizophrenia). The ecmnestic disturbances appeared to be rather diverse in their contents, and were encountered in the structure of various psychopathological manifestations both productive and deficient. Two types of the ecmnestic disturbances were differentiated, and namely, ecmnesia of delay and ecmnesia of regression of the psychic development. The role of the age factor in the formation of each type of those disturbances is demonstrated.

The authors investigated the impact of single CT investigation of senile dementia patients. CT was assessed visually. Investigated were 214 patients (23 with senile dementia, 29 with Alzheimer disease, 14 with Pick disease, 90 with vasculogenic dementia, 58 with other forms of dementia). The overall high efficiency of CT was shown in diagnosis of senile dementia. Depending on peculiar clinico-morphological relations different patterns of CT contribution to dementia diagnosis are determined: its verification, detection of concomitant (clinically latent) pathology, establishment of an alternative diagnosis, reduction of the number of diagnostic hypotheses, correction of a diagnostic error.

On the basis of neuronal network a linearized model of power spectrum of the network stable activity was calculated with the approximation of external input by "white" noise. The power spectrum function obtained was used for approximation of the power spectra of the rats motor cortex potentials by the least squares method. As a result the network parameters modelling excitatory and inhibitory cellular and synaptic mechanisms were calculated for two rat strains differing in seizure readiness. As a result of calculations genetically predisposed to seizures KM rats were assumed to differ from unpredisposed to seizures Wistar rats in the increase of efficacy of neuronal interactions (excitatory and inhibitory) as a consequence of the enhanced neuronal "reactivity".

Under examination there were 100 patients with paranoid schizophrenia who had reached an old age. In all the patients signs of delusion reduction were observed at the late stages of the disease. It was shown that most delusional disorders tended to transform into residual ones and to become peculiar manifestations of the derangement. Against this background it was actual delusional experiences that persisted most frequently. More and more place in their structure took psychopathological elements that reflected various aspects of the ageing of the patients' psychosis.

The authors studied 62 patients with late schizophrenia with the predominance of elementary misperceptions. The main variants of such psychoses with auditory, olfactory and tactile perceptive disturbances have been identified. The authors also ascertained common typological signs distinguishing these psychoses from the classical paranoids of late age. A possible role of the age and environmental factors in the formation of the above psychoses is considered.

Brain rhythmic activity model on the basis of space uniform neuronal network consisting of excitatory and inhibitory elements was examined. Network activity description by "lump approximation" was compared with simulation model computation. Lump approximation parameters dependence on the properties of neurons and synapses as well as conditions of the transition between network activity types which imitate desynchronous (low voltage fast activity) and synchronous (high voltage slow waves) brain activities were obtained.

Thirty-eight patients with late mentally deteriorating processes were studied. Using a standardized neuropsychological method, the authors have outlined four major variants of neuropsychological syndromes characteristic of damage to definite zones of the brain. Comparison of these data with the results of clinical and computer-aided tomographic examination showed that the neuropsychological approach is an adequate method in the combined study of senile dementia.