[No Effect of the p.Arg230His Variant Of The VCL Protein on the Course of the Hypertrophic Cardiomyopathy In Russian Family Carrying The p.Gln1233Ter Pathogenic Variant In The MYBPC3 Gene].

Aim      To determine specific clinical characteristics caused by a combination of the rs397516037 pathogenic variant in the myosin-binding protein C (MTBPC3) and the rs749628307 polymorphic variant in the vinculin (VCL) gene in a Russian family of carriers and to evaluate the contribution of the rs749628307 polymorphic variant in the VCL gene to the development of hypertrophic cardiomyopathy (HCMP).Material and methods  The family under study included one healthy person and 3 patients with HCMP. A targeted analysis of proband's exome was performed. A structural alignment for both forms of the VCL protein, the canonical form and the form with p.Arg230His substitution, was performed.Results The pathogenic rs397516037 variant and the potentially pathogenic rs749628307 variant were detected in the proband and several family members. A possibly damaging variant rs749628307 was detected in the proband and several family members evaluated in this study. The structural alignment confirmed that the rs749628307 variant did not alter the protein structure significantly and could not cause an impairment or loss of the protein function.Conclusion      This study demonstrated that apparently the rs749628307 variant in the VCL gene does not affect the protein structure in a pathogenetically significant way, neither does it affect the severity and form of the clinical manifestations of HCMP; therefore, it cannot be considered as pathogenic.

Rearrangement of the Prefrontal Cortex Neural Activity in Both Hemispheres during Learning.

Neuronal activity of both right and left hemispheres of the rat prefrontal brain cortex was recorded in the two-ring maze during animal learning to operate in response to signals. At the beginning of learning, pairwise comparison of neural activity that accompanied correct and incorrect choice of the right and left sides showed significant differences in the left hemisphere and the lack of differences in the right one. With increasing percentage of correct choices during a session of learning, the differences in neuronal responses appeared in the right hemispheres and were reduced in the left one. The opposite trends in rearrangement of the total impulse activity are believed to be related to different roles of hemispheres in the construction of the internal behavioral model.

Evaluation of Individual Risk Factors of Alcohol Preference in Rats.

We evaluated individual risk factors of the development of alcohol preference in a model of voluntary alcohol consumption. Drinking behavior was estimated in the two-bottle test, and other behavioral features were studied in the open field test, test for social interaction, and marble burying test. The low adaptive capacity of an animal, which was manifested in a shorter time spent in the center of the open field, and low consumption of ethanol when the animal first tasted it were the leading factors of the subsequent preference of alcohol under the conditions of free choice.

Sucrose-enriched diet during maturation increases ethanol preference in rats.

In the present study we used a diet enriched with 10% sucrose, which was consumed by adolescent animals of the experimental group for one month. We found that consumption of sweet food during sexual maturation affected alcohol preference, anxiety, and locomotor and exploratory activity in the adult rats. Our data show that easily available tasty food during adolescence probably impairs the reward system and serves as a trigger of future alcohol preference.

Peptides semax and selank affect the behavior of rats with 6-OHDA induced PD-like parkinsonism.

Parkinson's disease (PD) is the second most common severe neurodegenerative disorder that is characterized by progressive degeneration of dopaminergic neurons (DA neurons) in the substantia nigra pars compacta (SNpc) region of the brain. In the present study, we investigated the effects of the synthetic regulatory peptides Semax (analog of an ACTH 4-10 fragment (ACTH4-10)) and Selank (analog of immunomodulatory taftsin) on behavior of rats with 6-hydroxidopamine (6-OHDA) induced PD-like parkinsonism. It was showed that both peptides did not affect motor activity of rats in elevated cross shaped maze and passive defensive behavior of the animals. At the same time, Selank decreased level of anxiety of rats with toxic damage of DA neurons in elevated cross shaped maze. Previously such effects of Selank were revealed in healthy rodents (rats and mice) with different models of psycho-emotional stress. Therefore, toxic damage of substantia nigra does not affect the response of the rat organism on this peptide.

[The evaluation of endogenous intoxication and level of proteins of acute phase in onco-urological patients depending on course of disease.]

The purpose of the study is to carry out a comparative analysis of endogenous intoxication and content of proteins of cute phase in patients with urinary bladder cancer with successful treatment and complicated course of disease. To evaluate level of endogenous intoxication in patients the analysis was applied concerning content of molecules of average mass and functional characteristics of albumin assessed by ratio of efficient and total concentration of albumin. The coefficient of intoxication was calculated reflecting balance between cumulation of toxic ligands in blood plasma and their binding. The analysis was implemented concerning indices of endogenous intoxication in patients with urinary bladder cancer prior to treatment, after complex treatment and in patients with main disease complicated by renal insufficiency and in patients with onco-urology of both localizations when post-operational period was complicated by development of gram-negative sepsis. The results of study of endotoxicosis in case of onco-urological pathology were compared against the level of acute-phase proteins: C-reactive protein and haptoglobin. In case of patients with muscular non-invasive urinary bladder cancer and patients with kidney cancer typically occurred decreasing of efficient concentration of albumin and its binding capacity against the background of increased level of endotoxins. In patients with urinary bladder cancer with chronic renal insufficiency alterations of all indices were expressed in a higher degree. The maximal derangement of capacity of albumin to bind products of endotoxicosis, increasing of level of molecules of average mass and multiple increasing of C-reactive protein were specific in patients with developed sepsis. The obtained data testifies the informativeness of analyzed indices for evaluation of condition of oncourological patients.

Recovery treatment of lower limbs trophic ulcers in patients with chronic venous insufficiency (review of literature).

Trophic ulcers are complications of chronic venous insufficiency in 15-18% of cases and appear in 1-2% of able- bodied population. The frequency increases with age up to 4-5% among the patients aged over 65, and radical removalof the disease can be achieved only in one tenth of the patients. With that, even healed trophic ulcers recur frequently: after surgery in 4,8-31,6% of cases (according to various authors), after conservative treatment in 15-100% of cases. Main treatment modalities for trophic ulcers are medical and surgical. Recent researches necessitate including physical therapy methods into the treatment complex, as combined techniques that enable to improve results of various treatment variants.

[Complementary methods of rehabilitation in borderline mental disorders].

The article covers treatment results of 417 patients (186 males and 231 females) aged 18 to 71 years, with borderline mental disorders. Findings are that using specified complementary methods, more when treatment complex is applied, causes better psycho-emotional state in patients with borderline mental disorders, that is supported by results of medical diagnostic tests including psychometry tests (abridged minnesota multiphasic personality inventory, Beck depression inventory, Spielberger-Hanin, test "feeling, activity, mood").

[Combined treatment of palmoplantar syndrome in patients under antitumor therapy].

Observation covered 12 patients under various antitumor medications. Group 1 was formed of patients with developed palmoplantar syndrome varying in severity, who received complex treatment including IR-therapy and local antioxidant medication. Group 2 included patients without palmoplantar syndrome, who received preventive treatment with IR-therapy. All patients of group 1 demonstrated lower severity of palmoplantar syndrome manifestations. In group 2, 80% of the patients avoided palmoplantar syndrome development, and 20% of the patients had light course of the syndrome manifestations. Patients at high risk of palmoplantar syndrome under antitumor therapy are recommended to undergo IR-therapy and local antioxidant medication.

[Approaches to phototherapy in children with chronic dermatosis (review of literature)].

The article covers main aspects of phototherapy and photochemotherapy in treatment of skin diseases in children, risks of such methods usage, prophylactic and therapeutic measures, and precaution means for such treatment in pediatrics.

[MODIFIED INTRAVESICAL CHEMOTHERAPY OF BLADDER CANCER].

This paper gives an account of an experimental and clinical application of super-low frequency scanning magnetic field in patients with noninvasive bladder cancer treated with adjuvant intravesical gemcitabine chemotherapy. Treatment of isolated bladder cancer cells incubated with gemcitabine by this physical factor increased the permeability of cell membranes to the chemotherapy drug. This effect was demonstrated by increased fluorescence intensity of cancer cells. Clinical application of this combination therapy technology showed 2,8-fold increase of disease-free survival interval compared to early recurrences in the control group. These results indicate the potential of biophysical mechanisms to increase chemotherapy effectiveness.

[Analysis of mutations in patients with suspected autosomal dominant form of the Parkinson disease].

The Parkinson disease (PD) is a severe neurological disorder. Diverse genetic systems and environmental factors are involved in the pathogenesis of this disease. However, despite extensive research into the disease, its causes are not fully elucidated, and the exact spectrum of genes and mutations involved in the development of hereditary forms of PD has not been fully clarified yet. The present work is devoted to the analysis of mutations that lead to the development of monogenic forms of PD in patients with suspected autosomal dominant form of PD using Multiplex Ligation-dependent Probe Amplification (MLPA). We have identified several mutations (G2019S in LRRK2, heterozygous deletions of 2-3, 3-4 exons and heterozygous duplication of 2-4 exons in PARK2, deletion of 3 exon in PARK7) that lead to the development of PD in only 7 people out of 70 (18.4%), which suggests the need for further search of new mutations, for example, using exome sequencing. In the future it will help to develop the molecular genetic tests for early preclinical diagnosis and risk evaluation of the development of PD, and to understand better the causes and mechanisms of this disease.

Expression analysis of genes of ubiquitin-proteasome protein degradation system in MPTP-induced mice models of early stages of Parkinson's disease.

Parkinson's disease (PD) is the second most common severe neurodegenerative disorder that is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) region of the brain. However, causes and mechanisms of the development of this disorder are still not fully understood. At the same time, it is well known that dysfunction of the ubiquitin-proteasome protein degradation system (UPPDS) is one of the major mechanisms of the pathogenesis of PD. In this study we have investigated alterations in expression of Uchl3, Ubr7, Ube3c, Usp19, Usp39, Ube2k, Ube2d3, Ube2m, Ube2g1 genes, which are directly involved in the functioning of the UPPDS, using the real-time PCR in mice with the MPTP-induced pre-symptomatic and early symptomatic stages of PD. We have revealed reduction of expression of all genes studied in the striatum of brain in mice with the MPTP-induced pre-symptomatic and early symptomatic stages of PD and the majority of genes in the substantia nigra: Uchl3, Ubr7, Ube3c, Usp39, Ube2k, Ube2d3, Ube2g1 at pre-symptomatic stage and Uchl3, Ube3c, Usp39, Ube2k, Ube2m at early symptomatic stage of PD. Decreasing transcript levels of the genes studied may indicate decrease in the efficiency of the UPPDS on the whole which in turn may lead to the accumulation of abnormal proteins and toxic protein aggregates and subsequent death of the neurons. Thus, our findings appear to indicate that a violation of this system can play an important role in the development of pathogenic processes that occur at the earliest stages of the disease.

[Pharmacological action on emotional sphere with phenazepam and caffeine changes preference of ethanol in Wistar male rats].

Earlier we have shown that essential for formation of preference to alcohol is not that much the initial anxiety level, but rather direction of its change in the process of forced alcoholization. The goal of this work was study of effect of change in the anxiety level on formation of action on the emotional sphere. Out of four groups, for 4 months of experiment, the 1st group had access only to the 10 % ethanol solution; the 2nd group--to the 10% ethanol with addition of 0.4 g/l caffeine; the 3rd - to 10% ethanol with 0.5 mg/l phenazepam; the 4th (control)--only to water. The anxiety level and behavioral parameters were estimated prior to the experiment and after each 5 weeks with aid of the test "the open field". Preference of ethanol was determined with aid of the test "the two-glass sample" before the experiment and each 4 weeks. In experimental groups of rats the long-term consumption of ethanol, of ethanol with caffeine, and of ethanol with phenazepam led to an increase in preference of alcohol as compared with control. A decrease of motor activity at the period of forced alcoholization was found to correlate positively with the low level of preference of alcohol. The rats consuming ethanol with caffeine and sensitive to action of the psychostimulator enhancing anxiety formed faster the preference to alcohol. In rats not sensitive to action of caffeine the preference to alcohol was not formed. Rats sensitive to the sedative action of phenazepam were less anxious and subsequently did not prefer alcohol. In rats not sensitive to phenazepam, anxiety was enhanced and preference to alcohol was formed.

[Modeling of schizophrenia with Levodopa + Carbidopa].

Animal experimental modeling of mental disorders helps revealing mechanisms of the diseases and identifying effective methods of their treatment. The aim this study was to develop a new model of schizophrenia by oral Levodopa + Carbidopa (LC) administration. It was found that introduction of LC to rats induced a significant reduction of emotional reactions, hypersensitivity to a sound, a decreased exploratory activity and stereotype behavior, locomotor hyperactivity in some rats. It is concluded that LC introduction to rats may be used as an alternative dopaminergic animal model of schizophrenia.

MicroRNAs: possible role in pathogenesis of Parkinson's disease.

Parkinson's disease is one of the most common human neurodegenerative disorders caused by the loss of dopaminergic neurons from the substantia nigra pars compacta of human brain. However, causes and mechanisms of the progression of the disease are not yet fully clarified. To date, investigation of the role of miRNAs in norm and pathology is one of the most intriguing and actively developing areas in molecular biology. MiRNAs regulate expression of a variety of genes and can be implicated in pathogenesis of various diseases. Possible role of miRNAs in pathogenesis of Parkinson's disease is discussed in this review.

[Prolonged release of chlorambucil and etoposide from poly-3-oxybutyrate-based microspheres].

Microspheres were obtained on the basis of poly(3-oxibutyrate) (POB) with the inclusion of the Chlorambucil and Etoposide cytostatic drugs in a polymer matrix, and the morphology, kinetics of drug release from microspheres, and the interaction between microspheres and tumor cells in vitro were studied. Data on the kinetics of drug release suggests that a prolonged release occurs by drug diffusion from the polymer matrix at the initial stage and at the expense of hydrolytic degradation of the polymer at a later stage. A study of the biocompatibility and biological activity of biopolymeric microspheres showed that chlorambucil operates actively and strongly inhibits the growth of cultured cells for a short time (24 h). Etoposide acts weaker (the percentage of cell growth suppression during 48 h does not exceed 50%), but subsequently it has a basis for the creation of new dosage forms with prolonged action of Etoposide and chlorambucil for cancer therapy.

[Expression of GSK3B gene in peripheral blood in patient with Parkinson's disease].

Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder characterized by the degeneration of dopaminergic neurons. Detecting changes in gene expression in untreated de novo patients with PD is important for understanding disease pathogenesis and for identifying biomarkers for preclinical stage of PD. In this study we investigate expression of gene of Glycogen synthase kinase-3 beta (GSK3B) in the peripheral blood of different groups of patients with neurological diseases using reverse transcription reaction and real-time polymerase chain reaction (PCR). Our results suggest that the expression levels of GSK3B can't serve as a biomarker for early stages of PD.

[Analysis of single nucleotide polymorphism rs415430 in the WNT3 gene in the Russian population with the Parkinson disease].

The Parkinson disease (PD) is the second most common progressive neurodegenerative disorder that arises due to degeneration of dopaminergic neurons. The causes of this disease are still unknown, but a number of genes involved in pathogenesis of familial and sporadic forms of PD has been identified. According to recent data of genome wide association studies (GWAS), single nucleotide polymorphisms (SNPs) in these genes (including MAPT locus) may play an important role in the development of PD. Therefore, we analyzed distribution of genotype frequencies of SNP rs415430 in the WNT3 gene in the Russian patients with sporadic PD and in the Russian population controls (OR = 0.84, Confidence Interval (95% CI) 0.58-1.23, p = 0.39). It was concluded that SNP rs415430 in the WNT3 gene was not associated with the risk of development of PD.

[Effect of individual peculiarities on formation of preference of ethanol in female and male Wistar rats].

Individual characteristics of animal behavior can serve a prognostic parameter of predisposition to use of alcohol. The goal of the work was to study dynamics of formation of preference of alcohol at early stages in the process of forced alcoholization in male and female rats as well as the accompanying changes in behavior parameters. For 3 months, the rats were submitted to the forced alcoholization with 10 % ethanol. Each week the rats were tested in the "two-glass trial". Individual peculiarities of all animals were evaluated prior to, after 6 weeks, and after the end of the experiment with aid of the "open field test" and "Suok-test". Results showed that the male rats demonstrating by the end of the experiment the significantly higher level of the alcohol preference, at the initial stages of the forced alcoholization demonstrated the significantly lower preference as compared with the remaining ones. These rats also showed the lower levels of the motor and exploratory activities before alcoholization as compared with control. On the contrary, the individuals that by the end of the experiment did not differ from control by the level of the alcohol preference demonstrated prior to alcoholization in the "Suok-test" the higher anxiety level. In female groups, no statistically significant differences were observed both in parameters of the motor and exploratory activities and in the anxiety level in both tests. Thus, in male rats, the prognostic parameter predicting formation of the abuse can serve the degree of alcohol preference at the initial stages.