Genetic Variants Associated with Bronchial Asthma Specific to the Population of the Russian Federation.

Bronchial asthma (BA) is a disease that still lacks an exhaustive treatment protocol. In this regard, the global medical community pays special attention to the genetic prerequisites for the occurrence of this disease. Therefore, the search for the genetic polymorphisms underlying bronchial asthma has expanded considerably. As the present study progressed, a significant amount of scientific medical literature was analyzed and 167 genes reported to be associated with the development of bronchial asthma were identified. A group of participants (n = 7,303) who had voluntarily provided their biomaterial (venous blood) to be used in the research conducted by the Federal Medical Biological Agency of Russia was formed to subsequently perform a bioinformatic verification of known associations and search for new ones. This group of participants was divided into four cohorts, including two sex-distinct cohorts of individuals with a history of asthma and two sex-distinct cohorts of apparently healthy individuals. A search for polymorphisms was made in each cohort among the selected genes, and genetic variants were identified whose difference in occurrence in the different cohorts was statistically significant (significance level less than 0.0001). The study revealed 11 polymorphisms that affect the development of asthma: four genetic variants (rs869106717, rs1461555098, rs189649077, and rs1199362453), which are more common in men with bronchial asthma compared to apparently healthy men; five genetic variants (rs1923038536, rs181066119, rs143247175, rs140597386, and rs762042586), which are more common in women with bronchial asthma compared to apparently healthy women; and two genetic variants (rs1219244986 and rs2291651) that are rare in women with a history of asthma.

Hypogonadism and its treatment following ischaemic stroke in men with type 2 diabetes mellitus.

Premature mortality in Russia is a major socio-economic problem, especially from acute cerebrovascular diseases which constitute 21.4% of the total mortality and is a considerable contributor to chronic disability. Risk of vascular catastrophe is higher in males than females, thought, in part, due to anti-atherosclerotic effects of oestrogens in females whilst an associated age-related deficiency of testosterone is observed in men. Clinical symptoms such as high blood pressure, changes in lipid profile, insulin resistance, obesity, and blood coagulation factors often accompany declining testosterone in males and reduced total testosterone is considered a cardiovascular risk factor. In the present study, the prevalence of hypogonadism in men who had suffered ischaemic stroke was evaluated along with the efficacy of testosterone undecanoate injections (TU) in patients with testosterone deficiency and type-2 diabetes (T2DM) in the acute phase of hemispheric ischaemic stroke. Hypogonadism was present in 66.3% of patients with ischaemic stroke, 50% with T2DM, and 26.3% without T2DM, respectively. TU treatment, at both the 2 and 5-year observation points, demonstrated significant improvements in biochemical, physical, and mental parameters. This supports that testosterone deficiency is a contributing factor in ischaemic events and that long-term testosterone therapy could play an important role in patient recovery.

[Results of implementation of a 'Complex of measures to improve medical care for patients with stroke in the Russian Federation']. / Rezul'taty realizatsii 'Kompleksa meropriiatii po sovershenstvovaniiu meditsinskoi pomoshchi patsientam s ostrymi narusheniiami mozgovogo krovoobrashcheniia v Rossiiskoi Federatsii'.

Vascular diseases of the brain and heart are the main cause of death and disability of the population of the Russian Federation. The social and economic burden of acute cerebral circulation disorders necessitated the development of a national program for the care of patients with acute vascular diseases. As a result of the implementation of a set of measures to improve medical care for patients with stroke over the past decade, the regions of the Russian Federation managed to create an 'insult network', equip the departments with high-tech diagnostic and therapeutic equipment, and train medical personnel. Due to the implementation of modern methods of treatment of stroke, the rates of disability and mortality from stroke have decreased.

Gamma-Carbolines Derivatives As Promising Agents for the Development of Pathogenic Therapy for Proteinopathy.

Uncontrolled protein aggregation, accompanied by the formation of specific inclusions, is a major component of the pathogenesis of many common neurodegenerative diseases known as proteinopathies. The intermediate products of this aggregation are toxic to neurons and may be lethal. The development strategy of pathogenic therapy for proteinopathy is based on the design of drugs capable of both inhibiting proteinopathy progression and increasing the survival of affected neurons. The results of a decade-long research effort at leading Russian and international laboratories have demonstrated that Dimebon (Latrepirdine), as well as a number of its derivatives from a gamma-carboline group, show a strong neuroprotective effect and can modulate the course of a neurodegenerative process in both in vitro and in vivo model systems. The accumulated data indicate that gamma-carbolines are promising compounds for the development of pathogenic therapy for proteinopathies.

[The FUS protein: Physiological functions and a role in amyotrophic lateral sclerosis].

Certain forms of amyotrophic lateral sclerosis (ALS) are associated with an altered compartmentalization of FUS and its aggregation in the cytoplasm of motoneurons. FUS is a DNA/RNA-binding protein that is involved in DNA repair and the regulation of transcription, splicing, RNA transport, and local translation. Two theories have been proposed to explain the mechanism of the pathophysiological process in ALS. The theories attribute degeneration of motor neurons to either loss or gain of FUS function. The review describes the main physiological functions of FUS and considers evidence for each of the theories of ALS pathogenesis.

[Dimebon delays the onset of symptoms of FUS-proteinopathy in transgenic mice]. / Otsrochennyi debiut simptomaticheskoi stadii FUS-proteinopatii u transgennykh myshei pod deistviem dimebona.

AIM: To evaluate an effect of dimebon on the onset of symptomatic stage in FUS.1-513 transgenic mice - a new genetic model of neurodegeneration, and to study the dynamics of disease progression in the terminal stage. MATERIAL AND METHODS: The study was carried out on males of line FUS1-513 with the contribution of genes from CD1 strains. Mice of the experimental group (n=28) received dimebon with water in the concentration of 70 mcg/ml starting from the 35th day of life. The control group (n=25) did not receive the drug. Age, body mass of animals at the start of symptomatic stage and duration of symptomatic stage were assessed. RESULTS: Application of dimebon can delay the onset of the manifestation of clinical symptoms of the neurodegenerative process in the experimental group (127.6±4.6 days) compared to the control group (110.6±4.2 days). The body mass was similar in both groups. CONCLUSION: Dimebon leads to an increase in the duration of presymptomatic stage and delays the manifestation of clinical symptoms. The changes in the dynamics of the pathological process in the symptomatic stage are not detected.

Detection of autoantibodies to potentially amyloidogenic protein, gamma-synuclein, in the serum of patients with amyotrophic lateral sclerosis and cerebral circulatory disorders.

In this study, we analyzed serum for the presence of antibodies to gamma-synuclein in patients with amyotrophic lateral sclerosis (ALS) compared to the control group of patients with other neurological diseases and healthy control donors. As a result, antibodies against gamma-synuclein are not an ALS-specific feature and have been identified in patients with ALS as well as in the control group patients. Patients with the impaired cerebral circulation showed increased incidence of autoantibodies to gamma-synuclein, yet the difference lacks statistical representativeness due to limited sample size.

[Effects of ischemia on the expression of neurotrophins and their receptors in rat brain structures outside the lesion site, including on the opposite hemisphere].

Neurotrophins stimulate the regeneration of neural tissue after lesions. It is also known that the sources of neurogenesis and cerebral function recovery are predominantly located in subcortical brain structures. The effects of ischemia on the expression of genes that encode neurotrophins (Bdnf, Ngf, Nt-3) and their receptors (TrkB, TrkA, TrkC, p75) in brain structures outside the lesion site were studied 3, 24, and 72 h after irreversible unilateral occlusion of the middle cerebral artery in rats. Changes in the mRNA expression of these genes were assessed by relative quantification using real-time RT-PCR. Sham surgery was found to stimulate the expression of genes that encode neurotrophins (Bdnf, Ngf) and their receptor (p75). It has been shown that ischemia influenced the expression of neurotrophins (Bdnf, Ngf, Nt-3) and their receptors (TrkB, TrkA, TrkC, p75) in brain structures outside the lesion focus, including the contralateral hemisphere. The downregulation of Bdnf and TrkB transcripts and Ngf and TrkA upregulation in the contralateral cortex on the first day of ischemia obviously reflected stress response. On day 3, Nt-3 transcription increased in all investigated structures outside the lesion focus. In the contralateral hemisphere, relative levels of TrkA and TrkC mRNA expression increased, while p75 expression decreased. Presumably, the observed changes in gene transcription serve to facilitate neuroplasticity and neural tissue regeneration.

The new line of genetically modified mice with constitutive knockout of the gene alpha synuclein to study pathogenetic aspects of differential loss of dopaminergic neurons .

The purpose: This study investigated the role of alpha-synuclein in the development of dopaminergic neurons. Methods: In this study a new SNCA knockout mouse line has been used to model the deficiency of alpha-synuclein function. In the knockout and control mice the dynamics of the formation of two distinct populations of dopaminergic neurons differently affected in patients with PD was studied by the comparative morphometric analysis. Results: Here, we revealed a prominent modulating effect of alpha-synuclein on the developing DA neurons in substantia nigra (SN) which is the most affected region in PD patients. Yet, alpha-synuclein had no effect on the formation of DA neurons in ventral tegmental area which is much less susceptible to degeneration in PD patients. Conclusion: The new line of knockout mice is a convenient model for studying pathophysiologic aspects of selective impairment of DA neurons.

[Characteristics of immune response and inflammatory reaction in atherothrombotic stroke and myocardial infarction]. / Osobennosti immunnogo otveta i vospalitel'noi reaktsii pri aterotromboticheskom insul'te i infarkte miokarda.

AIM: To study characteristics of ischemic tissue damage basing on the assessment of the correlations between markers of immune response, inflammation and apoptosis in patients with myocardial infarction (MI) and atherothrombotic stroke (AS). MATERIAL AND METHODS: Concentrations of matrix metalloproteinase-9 (MMP-9), immune complexes with cryogenic properties, soluble Fas-ligand, tumor necrosis factor alpha, interleukin-10 measured with ELISA as well as the activity of spontaneous apoptosis of mononuclear cells and surface expression of Toll-like receptors-4 and intracellular heat shock proteins measured with flow cytofluorometry were determined in the blood of 93 patients with the first AS and 94 patients with MI without concomitant inflammation in the 1st and 7th day of the disease. RESULTS AND CONCLUSION: Increased levels of the markers of immune response, inflammation, apoptosis and destruction of the extracellular matrix were identified at the beginning of MI and AS. The results provide the evidence that similar mechanisms may be involved in ischemic tissue damage. Multivariate analysis conducterd by of principal component analysis correlation matrix revealed the specificity of the relationships between all of these markers. This is the completely new approach to assessin the role and importance of defined parameters in the acute period of the myocardial ischemia and brain.

[A mice model of amyotrophic lateral sclerosis expressing mutant human FUS protein].

UNLABELLED: BACKGROUND AND ОBJECTIVE: Loss of conformation and function of sufficient number of proteins with high aggregation capacity plays an important role in the pathogenesis of many neurodegenerative disorders (NDD). Due to a recent discovery of new array of proteins with the capacity to form aggregates of nonamyloid type, new NDD models as well as a new level of understanding in vivo models which are already exist is needed. DNA/RN A binding proteins - FUS and TDP-43 play a crucial role in the pathogenesis of some forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. The objective of the study was to develop a new ALS transgenic model. MATERIAL AND METHODS: In cell culture experiments, we studied mutant FUS proteins capable to form intracellular deposits morphologically similar to those observed in the autopsy material of ALS patients. RESULTS AND CONCLUSION: We created a transgenic mice line, in which a pathogenic form of human FUS protein was expressed in the nervous system. That led to the aggregation of FUS protein in spinal cord and motor neurons with the following degeneration and development of a phenotype, similar to the human ALS disease phenotype, in young grown-up animals. This neurodegenerative phenotype corresponds to a great number of clinical manifestations of human ALS and is an adequate transgenic model of the disease.

[Effect of tripeptide Pro-Gly-Pro on rat brain transcriptome in focal ischemia].

Biologically active regulatory peptide, tripeptide Pro-Gly-Pro (PGP) was used as C-terminal fragment for peptide drugs Semax and Selank. In recent years the independent effects of PGP were observed. The question was raised, whether PGP contributes to the effects ofpeptide drugs containing PGP as a fragment. The genome-wide analysis was performed to investigate the influence of PGP on the transcriptome of ischemic rat brain cortex tissues. The gene expression alterations caused by the action of the tripeptide PGP were compared with the gene expression of the control group "ischemia" at 3 and 24 h after permanent occlusion of left middle cerebral artery. The altered expression was detected for 29 genes at 3 h and 57--at 24 h. The proteins encoded by these genes have variety of functions: cytokines, transport proteins, transcription factors, transmembrane receptors, etc. Biological processes, which are related to the genes with altered expression, were distinguished. The influence of PGP on the diversity of biological processes in different systems of the organism is demonstrated for the first time. The process "Immune response" was the most statistically notable at 24 h after occlusion. The expression of the immune system genes was predominately down regulated.

[The effect of semax and its C-end peptide PGP on Vegfa gene expression in the rat brain during incomplete global ischemia].

Vascular endothelial growth factor (VEGFA) is a hypoxia-inducible signal glycoprotein. VEGFA causes vascular endothelial cell growth and proliferation, that leads to the regeneration of vascular network in brain regions damaged by ischemia. However, this protein is involved in processes of inflammation and edema in early stages of ischemia. Synthetic peptide semax shows neuroprotective and anti-inflammatory properties and is actively used in the treatment of ischemia.We have previously shown that semax reduces vascular injury and activates the mRNA synthesis of neurotrophins and their receptors under global cerebral ischemia in rats. Here we have analyzed the effects of semax and its C-terminal Pro-Gly-Pro tripeptide upon Vegfa mRNA expression in different rat brain regions after common carotid artery occlusion. The animals were decapitated 30 min, 1, 2, 4, 8, 12, 24 h after the operation. It was shown that ischemia increases levels of Vegfa mRNA in the rat brain of animals (4 h after the occlusion--in the cerebellum, cerebral cortex and hippocampus, 8 h--in the cortex and hippocampus, and 24 h in the cortex). Semax treatment reduces Vegfa mRNA levels in the frontal cortex (4, 8 and 12 h after the occlusion) and hippocampus of ischemic rats (2 and 4 h). Effect of PGP on the Vegfa gene expression was almost negligible. Our results showed that semax prevents activating effect ofhypoxia on the Vegfa gene expression in early stages of global ischemia. Furthermore, increase in the level of mRNA Vegfa in the hippocampus (24 h after occlusion) perhaps reflects neuroprotective properties of this drug.

[Comparative analysis of associations of polymorphic genes F2, F5, GP1BA and ACE with the risk of stroke development in Russian and Ukrainian populations].

The comparative analysis of the associations between G20210A polymorphism of F2 gene, G1691A polymorphism of F5 gene, -5T/C polymorphism of gene GP1BA, I/D polymorphism of gene ACE and the risk of development of the stroke in two ethnical samplings--Russian and Ukrainian populations--was conducted. It was shown that the patients of the Russian population with genotype DD have a higher level of the risk of ischemic stroke development (OR = 1.4, 95% CI [1.05; 1.78], p = 0.02), whereas genotypes I/I and I/D are associated with the lower level of risk of ischemic stroke (OR = 0.7, 95% CI [0.56; 0.95], p = 0.02). In the Ukrainian ethnical sampling, differences in distribution of genotypes and alleles frequencies between patients with stroke and healthy persons upon given polymorphic locus are not significant, and I/D polymorphism of gene ACE is not associated with the risk of development of the stroke (OR = 0.8, 95% CI [0.48; 1.32], p = 0.45). The G20210A polymorphism of gene F2, G1691A polymorphism of gene F5, -5T/C polymorphism of gene GP1BA are not associated with the risk of stroke in two ethnical samplings.

[Clinical characteristics of post-stroke anxiety disorders].

Authors studied 198 patients with first-ever cerebral stroke. Affective disorders, including depression, generalized anxiety disorder (GAD) and phobias, were identified in 71.2% of patients. The study demonstrated that the anxiety syndrome developed in the post-stroke period may be regarded as relatively independent. Some post-stroke anxiety disorders had different risk and pathogenetic factors. GAD is associated with young age and phobias are associated with female sex and inherited predisposition. In contrast to post stroke depression, anxiety-phobic disorders develop more frequently in patients with mild stroke.

[The balance of markers of regulation vascular tone and fibrinogen in the prognosis of hemorrhagic transformation and fatal outcome in the acute period of ischemic stroke].

The markers of regulation vascular tone, such as rennin, endothelin-1, and C-type natriuretic peptide, are of great value for prognosis of hemorrhagic transformation and fatal outcome of ischemic stroke. A change in the vascular tone in case of hemorrhagic transformation at the affected site precedes activation of the coagulation component of hemostasis as a mechanism preventing blood loss and increasing fibrinogen level. This work was aimed to study the balance of the above markers and fibrinogen in the prognosis of hemorrhagic transformation and fatal outcome in the acute period of ischemic stroke. It included 62 patients receiving no thrombolytic therapy. It was shown that symptomatic hemorrhagic transformation was associated with elevated rennin levels without a marked fall in the level of C-type natriuretic peptide and asymptomatic hemorrhagic transformation with elevated endothelin-1 levels and decreased concentration of natriuretic peptide. Fibrinogen level on day 4 of the observation proved to be a reliable predictor of negative prognosis. Asymptomatic hemorrhagic transformation without fatal outcome was associated with systemic and local vasoconstriction and inhibition of local vasodilation. Symptomatic hemorrhagic transformation with the fatal outcome was accompanied by dysregulation of vascular tone in the form of activation of systemic and local vasoconstriction, insufficient inhibition of local vasodilation and compensatory reaction in the form of activation of hemostatic mechanisms manifest as elevated fibrinogen levels on day 4. The lethal outcome without hemorrhagic transformation was associated with systemic vasoconstriction, activation of local vasodilation and vasoconstriction leading to local "biochemical paralysis" of vascular tone regulation.

[A complex study of the movement biomechanics in patients with post-stroke hemiparesis].

The authors present results of a pilot study on biomechanics of non-cyclic movements of the human consequent verticalization in the ontogenesis of patients with post-stroke hemiparesis (10 patients in the acute stage of cerebral stroke) and 10 healthy volunteers without neurologic and orthopedic pathology. Some movements of therapeutic exercises Balance (a model of ontogenetic kinesitherapy) have been selected for the study. Cinematic parameters have been recorded using a system of motion 3D video analysis, a kinematic model was build in accordance to standard protocols. The skin (native and straightened) electromyogram (EMG) was recorded synchronously with kinematic data using 16-channel electromyography from the following pairs of muscles: mm. sternocleido-mastoideus, trapezius (горизонтальная порция), biceps brachii, triceps brachii, rectus femoris, adductor magnus. Major differences in the EMG picture between patients and controls were: 1) the EMG "monotony" with the involvement of multiple additional muscles in locomotions with the prevalence of the peculiar "tonic" muscle activity (low amplitudes without distinct peaks), stretching along the whole cycle of movement. In controls, EMG demonstrated variability and had mostly "phasic" character with distinct 1 or 2 peaks; 2) the asymmetry of EMG profile in symmetric movements. i.e. when performed simultaneously from the right and from the left sides. The latter feature may be considered as predictive because it was never found in healthy people. It allows to identify objectively weak muscles even in the absence of visible parethis during the routine neurological examination.