CRIMINAL LAW PROTECTION OF THE CIRCULATION OF MEDICINAL PRODUCTS ACCORDING TO THE LEGISLATION OF THE FEDERAL REPUBLIC OF GERMANY, THE REPUBLIC OF AUSTRIA AND THE SWISS CONFEDERATION.

The purpose of the article is to find out the scope of the criminal law protection of the circulation of medicinal products according to the legislation of the Federal Republic of Germany, the Republic of Austria, and the Swiss Confederation. The materials of the research were the legislation of the Federal Republic of Germany, the Republic of Austria, and the Swiss Confederation. Dialectical, axiological, comparative, and legal methods were applied during the research. Having studied the experience of the scope of criminal law protection of the circulation of medicinal products made it possible to conclude about the importance of having a certain legislative reference point that can help improve the criminal legislation of these and other countries and build a new model of the system of norms that ensure the criminal law protection of circulation of medicinal products. It has been concluded that in the criminal legislation of the Federal Republic of Germany, the Republic of Austria, and the Swiss Confederation there is an "aspiration" of the legislator to ensure the most complete scope of criminal law protection of circulation of medicinal products by creating their own specific systems. It has been proposed to single out separate groups of signs of criminal protection of pharmaceutical activity, since the scope of such protection is not the same in such countries (but has a lot in common). This may be a certain legislative guideline of the systematization of norms that ensure the circulation of medicinal products from the point of view of their criminal law protection.

Mitochondrion-targeted antioxidant SkQ1 prevents rapid animal death caused by highly diverse shocks.

The response to stress involves the activation of pathways leading either to protection from the stress origin, eventually resulting in development of stress resistance, or activation of the rapid death of the organism. Here we hypothesize that mitochondrial reactive oxygen species (mtROS) play a key role in stress-induced programmed death of the organism, which we called "phenoptosis" in 1997. We demonstrate that the synthetic mitochondria-targeted antioxidant SkQ1 (which specifically abolishes mtROS) prevents rapid death of mice caused by four mechanistically very different shocks: (a) bacterial lipopolysaccharide (LPS) shock, (b) shock in response to intravenous mitochondrial injection, (c) cold shock, and (d) toxic shock caused by the penetrating cation C12TPP. Importantly, under all these stresses mortality was associated with a strong elevation of the levels of pro-inflammatory cytokines and administration of SkQ1 was able to switch off the cytokine storms. Since the main effect of SkQ1 is the neutralization of mtROS, this study provides evidence for the role of mtROS in the activation of innate immune responses mediating stress-induced death of the organism. We propose that SkQ1 may be used clinically to support patients in critical conditions, such as septic shock, extensive trauma, cooling, and severe infection by bacteria or viruses.

[Retrospective analysis of the incidence rate of the population in the Republic of Tatarstan with diseases of the endocrine system].

Diseases of the endocrine system are an urgent medical and social problem in connection with their widespread prevalence and negative growth trend throughout the world; they often accompany other chronic diseases and can lead to disability. Aim: to study the trends in the structure and characteristics of the morbidity of the population in the Republic of Tatarstan with diseases of the endocrine system. The study was based on the materials of the official statistics in the Republic of Tatarstan for the period 2014-2019, the methods of descriptive statistics and linear regression analysis were used. The indicators of the primary morbidity and prevalence of the endocrine system diseases among various age groups in the Republic of Tatarstan were studied. The retrospective analysis of the incidence of the endocrine system diseases in the population in the Republic of Tatarstan indicates the formation of stable negative trends in the growth of the prevalence of thyroid diseases, diabetes and obesity among all the groups under study. There is an increase in the primary incidence and prevalence of thyroid diseases among children (growth rate in 2019 compared to 2014 of 198.6 and 50.1% respectively) and adolescents (growth rate of 244.9% and 114.3% respectively), as well as an increase in the prevalence of type 2 diabetes in these groups (growth rate of 500% and 269,2% respectively); an increase in both the primary incidence (growth rate of 200%) and the prevalence of hypothyroidism among children (growth rate of 183.5%), an increase in the prevalence of thyroiditis among adults (growth rate of 24.3%).The rate of increase in the primary incidence of obesity, over 6 years of observation, among children was 74.7%, among adolescents - 171.1%; among the adult population - 21.2%. To reverse negative trends in morbidity, we believe it is necessary to strengthen preventive work among all age groups to form healthy eating habits, maintain a normal body weight, take legislative decisions on mass prevention of iodine deficiency in endemic regions, as well as conduct some research aimed at assessing the impact of risk factors caused by the impact of endocrine disruptors on the health of the population of the Republic.

Current Methods for the Isolation and Cultivation of Microglia (Review).

The role and morphological features of microglia (M1 and M2 microglia, "stellate", "amoeboid", giant, round-shaped, rod-shaped, dysfunctional, etc.) in vivo under physiological conditions and during the development of neurodegenerative diseases have been described. Various methods and techniques of microglia isolation from adult (density gradient isolation, use of "magnetic beads", from mesenchymal bone marrow progenitor cells) and newborn (obtaining from a mixed glial culture, density gradient isolation) animals have been considered, including microglia isolation from the cerebral cortex or hippocampus. Various methods of cell cultivation have been shown, including obtaining two-dimensional and three-dimensional cell cultures (on scaffolds, hydrogels, nanofibers), co-cultures on slice cultures of the hippocampus, as well as changes in microglia during cultivation.

[Hygienic characteristics of actual nutrition of the working population Samara Region].

The article presents the data of a retrospective analysis of the average per capita consumption of food by the population of the Samara region in comparison with the all-Russian indicators and recommended values of consumption in the period from 2010 to 2015, as well as the analysis of the actual nutrition of different groups of the working-age population of the Samara region in 2015 (2154 people aged 18 up to 62 years of age, 1179 of them women, 975 men) using the method of 24-hour reproduction of food and the frequency method with quantitative assessment of consumed products, in comparison with the dynamics of the prevalence of alimentary-dependent diseases. Estimation of parameters of nutritional status was also conducted on blood level of cholesterol and glucose, bioelectrical impedance analysis of body composition (n=514). It was found that 48.2% of the subjects had normal body weight, 38.1% -overweight, 13.7% - obesity. The analysis of actual consumption revealed an unfavorable trend of increasing consumption of fats, as well as sugar from 2010 to 2015, while the consumption of vegetables, fruits and berries was lowed compared to the national indicators and recommended consumption values. The analysis of actual nutrition allowed to make a conclusion about severe violations of the relationships between nutrients in the diet of all surveyed populations, characterized by the excess intake of fat (45% of the energy diet value), including saturated fatty acids, and added sugar (13% calories). In the diet of 82% of the respondents the content of vitamins B1 and B2 did not reach the recommended level, niacin - 37%, vitamin A - 47%, vitamin C - 68%, calcium and iron - 14%. With an increase in BMI, there was an increase in blood level of cholesterol and glucose (r=0.24 and r=0.26, respectively, p<0.05), both in men and women. In individuals with excess fat and added sugar in the diet, increased fat body component (r=0.17, p<0.05) and lowered content of skeletal muscle mass (r=0.25, p<0.05) were observed. The revealed unfavorable trend of nutritional and metabolic disorders, against the background of increased consumption of fats, added sugar, indicates the need for an integrated approach to the correction of diet at both individual and population levels.

Effects of Mitochondrial Antioxidant SkQ1 on Biochemical and Behavioral Parameters in a Parkinsonism Model in Mice.

According to one hypothesis, Parkinson's disease pathogenesis is largely caused by dopamine catabolism that is catalyzed on mitochondrial membranes by monoamine oxidase. Reactive oxygen species are formed as a byproduct of these reactions, which can lead to mitochondrial damage followed by cell degeneration and death. In this study, we investigated the effects of administration of the mitochondrial antioxidant SkQ1 on biochemical, immunohistochemical, and behavioral parameters in a Parkinson-like condition caused by protoxin MPTP injections in C57BL/6 mice. SkQ1 administration increased dopamine quantity and decreased signs of sensory-motor deficiency as well as destruction of dopaminergic neurons in the substantia nigra and ventral tegmental area in mice with the Parkinson-like condition.

[RECOGNITION OF ADULTS EMOTIONAL STATE OF TYPICALLY DEVELOPING CHILDREN AND CHILDREN WITH AUTISM SPECTRUM DISORDERS].

The goal of the study was the definition of adult's possibilities of recognition the emotional state of typically developing (TD) and children with autism spectrum disorders (ASD), by facial expression, vocalizations and speech signals. Participants in the study were children with ASD (F 84.0 according to ICD-10), aged 5-16 years (n = 25) and typically developing (TD) children aged 4-7 years (n = 60). The analysis of child behavior, vocalizations and speech was performed for the purpose of stimulus selection. The peculiarities of emotion state recognition of TD children and ASD children by adults (n = 514) were revealed. It is shown that the emotional states of ASD children are better recognized by the features of vocalizations and speech than by facial expression. This finding is promising in terms of development of children with methods for assessing the characteristics of their voices, and to create an automatic speech recognition system for the purpose of teaching children with atypical development.

[Risk assessment from exposure to chemical contaminants in food].

There was investigated the impact of chemical substances contained in the public health foodstuffs in eight regions of the Republic of Tatarstan on 11 product groups: meat and meat products, fish and fish products, milk and dairy products, bread and bakery products, sugar and confectionery products, vegetables and melons (excluding potatoes), potatoes, fruits and berries, vegetable oil, eggs and egg products, salt. In total there were analyzed more than 240 thousand samples offood raw materials andfood products over the period offrom 2006 to 2014. The study took place on 27 priority chemicals, including thirteen carcinogens (benzo (a) pyrene, DDT, hexachlorobenzene, hexachloran, heptachlor, alpha-lindane, beta-lindane, lindane, cadmium, arsenic, lead, derivatives of 2,4-D acid, cypermethrin). Exposition load is calculated by the 50 (median), and 90 percentiles of the content ofpollutants in food products. There were calculated carcinogenic risks, HQ coefficients and HI indices for chronic non-cancer exposure. High values of the total cancer risk (3.31*10 at the median level of 1.49*10+ at the 90 percentile) are associated with the exposure to tohexachlorane and alpha-lindane seem to be alarming (from 1.73*10 to 9.68*10) with the effect of lindane, cadmium and lead with dominant contribution to the total risk in the use of meat and meat products, milk and dairy products. The warning value of Hazard ratios (HQ 1.1-3) at 90-percentile were shown on nitrate, lead, beta-lindane, high (HQ >3), for DDT and its metabolites, lindane and arsenic, with the dominant contribution to the exposure of vegetables and melons (excluding potatoes), potato, milk and milk products.

[Monitoring and assessment contamination of toxic elements food in Tatarstan monitoring and evaluation of contamination by toxic elements of food products in the territory of the Republic of Tatarstan].

Actual consumption of toxic elements in the body of an adult human in the Republic of Tatarstan (during the period of the study of the production in 2008-2012) amounts for lead: 0.68 mg/week for cadmium: 0.18 mg/day, arsenic: 0.68 mg/day, mercury: 0.21 mg/week (per 1 kg body weight) or respectively: 22.81%, 18.0%, 13.69%, 4.27% of the allowable levels of the chemical load. We have performed calculations with account of the balance of food resources per capita per year in the Republic of Tatarstan. This analysis showed that the main dietary sources of income for cadmium there are milk and dairy products (48.32%), bakery products (16.07%), meat and meat products (13.22%); for lead there are bakely products (26.85%), potatoes (24.36%), milk and dairy products (23.94%), meat and meat products (7.55%); for mercury there are milk and dairy products (53.72%), meat and meat products (16.82%), potatoes (10.92%); fish and fish products (4.74%); for arsenic there are milk and dairy products (72.51%), meat and meat products (12.8%), bakery products (3.05% ,); fish and fish products (2.23%). It is important to know not only what products are the most contaminated, but what place in the structure of the nutrition they take.

Plant cell death caused by fungal, bacterial, and viral elicitors: protective effect of mitochondria-targeted quinones.

Chitosan (partially deacetylated chitin), a component of fungal cell walls, caused epidermal cell (EC) death in the leaves of pea (Pisum sativum L.) and tobacco Nicotiana tabacum or Nicotiana benthamiana detected by destruction of cell nuclei. The mitochondria-targeted quinone SkQ1 prevented the destruction of EC nuclei induced by chitosan. Chitosan increased and SkQ1 suppressed the activity of protein kinases in N. benthamiana and P. sativum and eliminated the effect of chitosan. Chitosan induced the generation of reactive oxygen species (ROS) in the guard cells (GC) of pea plants. Treatment with chitosan or H2O2 did not cause destruction of GC nuclei; however, it resulted in disruption of the permeability barrier of the plasma membrane detected by propidium iodide fluorescence. Treatment with bacterial lipopolysaccharide but not peptidoglycan caused destruction of pea EC nuclei, which was prevented by SkQ1. Leaves of tobacco plants containing the N gene responsible for resistance to tobacco mosaic virus (TMV) were infiltrated with Agrobacterium tumefaciens cells. These cells contained a genetic construct with the gene of the helicase domain of TMV replicase (p50); its protein product p50 is a target for the N-gene product. As a result, the hypersensitive response (HR) was initiated. The HR manifested itself in the death of leaves and was suppressed by SkQ3. Treatment of tobacco epidermal peels with the A. tumefaciens cells for the p50 gene expression stimulated the destruction of EC nuclei, which was inhibited by SkQ1 or SkQ3. The p50-lacking A. tumefaciens cells did not induce the destruction of EC nuclei. The protective effect of mitochondria-targeted antioxidants SkQ1 and SkQ3 demonstrates the involvement of mitochondria and their ROS in programmed cell death caused by pathogen elicitors.

[Early neonatal mortality in the Russian Federation in 2010].

The paper analyzes the data of the Federal State Statistics Service on early neonatal mortality in the Russian Federation as a whole and its federal districts in 2010. There was a steady decline (ranging from 6.52 to 2.75%) in the mean early neonatal mortality rates in the Russian Federation in 2000-2010. In 2010, there were low, moderate, and high early neonatal mortality rates in 59 (71.1%), 20 (24.1%), 4 (4.8%) federal subjects, respectively. Most neonatal deaths were noted within the first 24 hours of life. According to the Federal State Statistics Service data, the commonest cause of early neonatal death in Russia is respiratory distress (103.2 deaths per 100,000 live births), hyaline membrane disease in particular. Among the causes of neonatal death, maternal diseases unrelated to pregnancy are indicated most commonly (in 22.7% of cases).

Effect of mitochondria-targeted antioxidant SkQ1 on programmed cell death induced by viral proteins in tobacco plants.

Programmed cell death (PCD) is the main defense mechanism in plants to fight various pathogens including viruses. The best-studied example of virus-induced PCD in plants is Tobacco mosaic virus (TMV)-elicited hypersensitive response in tobacco plants containing the N resistance gene. It was previously reported that the animal mitochondrial protein Bcl-xL, which lacks a homolog in plants, effectively suppresses plant PCD induced by TMV p50 - the elicitor of hypersensitive response in Nicotiana tabacum carrying the N gene. Our studies show that the mitochondria-targeted antioxidant SkQ1 effectively suppresses p50-induced PCD in tobacco plants. On the other hand, SkQ1 did not affect Poa semilatent virus TGB3-induced endoplasmic reticulum stress, which is followed by PCD, in Nicotiana benthamiana epidermal cells. These data suggest that mitochondria-targeted antioxidant SkQ1 can be used to study molecular mechanisms of PCD suppression in plants.

[Stillbirth rates in the subjects of the Russian Federation in 2010].

The paper analyzes the 2010 Russian State Statistics Service data on stillbirth rates in the Russian Federation and its subjects. There was a steady decline in the mean stillbirth rate (from 6.8 to 4.67 per thousand) in the Russian Federation in 2000-2010. In 2010, the rate was low in 10 (12%) subjects, moderate in 42 (50.6%), and high in 31 (37.4%). The reduction in the proportion of intranatal stillbirth is naturally accompanied by the increase in its antenatal component. According to the data of the Russian State Statistics Service, the most common cause of stillbirth is intrauterine hypoxia and birth asphyxia: 391.9 per 100,000 born alive and dead. The most frequent maternal cause was notified to be placental pathology: 209 per 100,000 born alive and dead.

[Clinical course of cutaneous melanoma of the head and neck, and the factors affecting patient survival].

It was found that melanomas of the skin of the head and neck, compared to the trunk and limbs, were characterized by a greater proportion of men, an older average age of the patients, high frequency spindle cell tumors, more frequent synchronous distant metastasis and worse survival. Melanomas, which are localized on the skin of the neck and scalp, have similar aggressive clinical course and are characterized by worse overall and disease-free survival than skin melanomas on the trunk and limbs. However, melanomas of the skin on the ear and face proceed more favorably as compared to skin melanomas of the scalp and neck. Multivariate regression analysis using Cox models showed that the melanoma of the head and neck Breslow tumor thickness was the strongest predictor of overall survival. For skin melanomas of the neck and scalp Breslow tumor thickness was the only significant independent factor for overall survival. In melanoma, skin and ear predictors of survival are: sex, age and tumor thickness. In skin melanomas of the face and ear predictors of survival were sex, age and tumor thickness.

[Current concepts of perinatal ischemic injury in the brain neurovascular unit: molecular targets for neuroprotection].

Perinatal hypoxic-ischemic brain injury is a relevant medical and social problem. Among many pathological processes in the neonatal period perinatal hypoxic-ischemic injury is a major cause of further hemorrhage, necrotic and atrophic changes in the brain. This review presents recent data on the basic mechanisms of the hypoxic-ischemic brain injury along the concept of neurovascular unit (neurons, astrocytes, endothelial cells, pericytes) with the focus on alterations in cell-to-cell communication. Pathological changes caused by ischemia-hypoxia are considered within two phases of injury (ischemic phase and reperfusion phase). The review highlights changes in each individual component of the neurovascular unit and their interactions. Molecular targets for pharmacological improvement of intercellular communication within neurovascular unit as a therapeutic strategy in perinatal brain injury are discussed.

[Risk assessment of carcinogenic and non-carcinogenic effects in the use of food].

Application of methodology for assessing the risk of diseases associated with consumption of contaminated foods, is aimed at predicting possible changes in the future and helps to create a framework for the prevention of negative effects on public health. The purpose of the study is assessment of health risks formed under the influence of chemical contaminants that pollute the food. Exponential average daily dose of receipt of chemicals in the body, non-carcinogenic and carcinogenic risks were calculated.

New viral vector for superproduction of epitopes of vaccine proteins in plants.

The novel viral vectors PVX-CP AltMV and PVXdt-CP AltMV are superexpressors of the capsid protein (CP). These viral vectors were constructed on the basis of the potato virus X (PVX) genome andAlternantheramosaic virus (AltMV) CP gene. The expression, based on the hybrid viral vectors, is genetically safe, since the systemic transport and formation of infective viral particles are blocked. CP AltMV can self-assemble into virus-like particles (VLPs) in the absence of genomic RNA. The vectors can be used for the presentation of foreign peptides (including epitopes of human pathogens) on the surface of the VLP. The N-terminal extracellular domain (M2e) of the influenza virus A M2 protein and its truncated variant (ΔM2e) were used as model heterologous peptides for the construction of the chimeric CP AltMV. Chimeric CP AltMV retains its ability to self-assemble into VLP. The epitopes of the M2 influenza virus protein were not eliminated during the process of accumulation, polymerization and purification of chimeric VLP AltMV, providing evidence of the stability of chimeric VLP with C-terminal heterologous epitopes. It appears that VLP produced by the vectors PVX-CP AltMV and PVXdt-CP AltMV can be used in the field of biotechnology for the presentation of the epitopes of vaccine proteins on their surfaces. The chimeric VLP AltMV with the presented foreign epitopes can be used as candidate vaccines.

Perinatal hypoxic-ischemic brain injury affects the glutamatergic signal transduction coupled with neuronal ADP-ribosyl cyclase activity.

Agonists of glutamate ionotropic (NMDA) and metabotropic receptors (mGluRI and mGluRIII) had the regulatory effect on ADP-ribosyl cyclase/CD38 activity in cerebellar granular cells of newborn rats. Perinatal hypoxic-ischemic brain injury was followed by dysregulation of this mechanism.