[The role of ω-3 polyunsaturated fatty acids in child development].

ω-3 polyunsaturated fatty acids (PUFAs) are incorporated in cell membranes and play an important role in the development and functioning of organs. Consolidation of data on the role of ω-3 PUFAs in child development may increase the professional's awareness, help to plan clinical studies, and develop recommendations for supplementation. The aim of the research was to analyze literature data on the effect of ω-3 PUFAs on the central nervous system, immune system, and vision in children. Material and methods. 86 literature sources have been analyzed, a keyword search was carried out in the PubMed, Scopus, Elsevier, eLibrary and Google Scholar databases. Results. ω-3 PUFAs (alpha-linolenic, docosahexaenoic and eicosapentaenoic acids) are not synthesized in the human organism, and should be obtained from food. The need for ω-3 PUFAs is especially high during periods of rapid growth (the first years of life and adolescence). ω-3 PUFAs play an important role in the anatomical and functional development of the brain, affecting the maturation and functioning of neurons, participating in the processes of neurogenesis, migration, synaptogenesis, and neurotransmission. The results of clinical studies on the effect of ω-3 PUFAs on the cognitive functions of healthy children and patients with attention deficit hyperactivity disorder are contradictory, which requ ires further research. PUFAs are substrates for the synthesis of bioactive compounds and take part in the control of acute and chronic inflammation, and also have a regulatory effect on immune cells. ω-3 PUFAs supplementation decreases the frequency and duration of acute respiratory viral infections in children. This indicates the potential effectiveness of ω-3 PUFAs in the prevention of acute respiratory viral infections. Сlinical studies demonstrated positive effects of ω-3 PUFAs on retinal development in premature infants. Conclusion. Adequate intake of ω-3 PUFAs is essential for the development and functioning of the central nervous system, immune system and vision in children. The body content of ω-3 PUFAs is closely related to the nutrition. In the Russian Federation, consumption of fish and other products containing ω-3 PUFAs is traditionally low. The majority of the Russian population has a deficiency in ω-3 PUFA consumption. With an unbalanced diet, supplementation of ω-3 PUFAs is necessary.

[Three-year follow-up study of clinical effectiveness of antiangiogenic therapy for neovascular age-related macular degeneration]. / Klinicheskaya effektivnost' antiangiogennoi terapii neovaskulyarnoi vozrastnoi makulyarnoi degeneratsii po rezul'tatam trekhletnego nablyudeniya.

PURPOSE: The study analyzes long-term (three years) clinical effectiveness of anti-VEGF treatment of neovascular age-related macular degeneration (nAMD) and attempts to identify the most clinically significant associations between the functional and structural parameters. MATERIAL AND METHODS: The study included 122 patients (122 eyes) diagnosed with nAMD, mean age -73.4±6.6 years old. Prospective follow-up lasted 144 weeks. All patients were treated with angiogenesis inhibitor (aflibercept 2 mg), and most of them (72.9%) - according to the Treat-and-Extend protocol. RESULTS: The average number of injections was 7.39±1.28, 4.63±0.97 and 4.06±0.81 during the first, second and third years of the follow-up, respectively. The mean baseline best-corrected visual acuity (BCVA) was 0.24±0.21. After three loading doses, BCVA increased to 0.33±0.26 (+0.09; 37.5%), by the end of follow-up BCVA was 0.35±0.27 (+0.11; 45.8%). Central retinal thickness (CRT) decreased from 314.89±88.07 µm to 234.4±42.8 µm (a 25.5% decrease) by the end of the follow-up. After three loading injections baseline functional and anatomical parameters had the most significant correlations (r≥0.7, p<0.05) with intraretinal fluid, ellipsoid zone integrity and the area of macular atrophy. CONCLUSIONS: Analysis of the morphological and functional outcomes by the end of the first year demonstrates the feasibility of preserving the results while reducing the number of visits and injections according to the Treat-and-Extend protocol. Achieving maximum improvement of functional parameters most significantly correlated with changes in such biomarkers as central retinal thickness, area of macular atrophy and integrity of the ellipsoid zone.

RatDEGdb: a knowledge base of differentially expressed genes in the rat as a model object in biomedical research.

The animal models used in biomedical research cover virtually every human disease. RatDEGdb, a knowledge base of the differentially expressed genes (DEGs) of the rat as a model object in biomedical research is a collection of published data on gene expression in rat strains simulating arterial hypertension, age-related diseases, psychopathological conditions and other human afflictions. The current release contains information on 25,101 DEGs representing 14,320 unique rat genes that change transcription levels in 21 tissues of 10 genetic rat strains used as models of 11 human diseases based on 45 original scientific papers. RatDEGdb is novel in that, unlike any other biomedical database, it offers the manually curated annotations of DEGs in model rats with the use of independent clinical data on equal changes in the expression of homologous genes revealed in people with pathologies. The rat DEGs put in RatDEGdb were annotated with equal changes in the expression of their human homologs in affected people. In its current release, RatDEGdb contains 94,873 such annotations for 321 human genes in 836 diseases based on 959 original scientific papers found in the current PubMed. RatDEGdb may be interesting first of all to human geneticists, molecular biologists, clinical physicians, genetic advisors as well as experts in biopharmaceutics, bioinformatics and personalized genomics. RatDEGdb is publicly available at https://www.sysbio.ru/RatDEGdb.

[Prognosis criteria of optical coherence tomography angiography for the long-term efficacy of anti-VEGF therapy of neovascular age-related macular degeneration]. / Prognosticheskie kriterii opticheskoi kogerentnoi tomografii-angiografii v otsenke dolgosrochnoi effektivnosti anti-VEGF-terapii neovaskulyarnoi vozrastnoi makulyarnoi degeneratsii setchatki.

PURPOSE: The study aimed to determine the most significant optical coherence tomography angiography (OCTA) parameters in terms of predicting anti-VEGF therapy effectiveness during long-term (3-year) follow-up of patients with neovascular age-related macular degeneration (nAMD). MATERIAL AND METHODS: The study included 122 patients (122 eyes) with mean age of 73.4±6.6 years who were diagnosed with nAMD. Subgroup analysis included 50 patients (50 eyes) with detailed OCT angiography examination of macular neovascularization (MNV) characteristics and their changes in the course of the follow-up, which lasted 144 weeks. All patients were treated by angiogenesis inhibitor (aflibercept 2 mg), most of them - according to Treat-and-Extend protocol. RESULTS: Treatment response (either 'good' or 'partial') was achieved in all patients, and the proportion of the response types was similar in both types 1 and 2 MNV. Key OCTA parameters associated with the number of injections, as well as morphological and functional response (best-corrected visual acuity, retinal neuroepithelium and pigment epithelium detachment), were vascular network area and MNV area assessed at baseline and three months after treatment initiation. Both of these parameters were closely related in both MNV types during the follow-up. Key parameter with maximum number of clinically significant correlations ('very high' strength, p<0.05) in eyes with 'good' response was MNV area, in eyes with 'partial' response - vascular density and greatest vascular caliber. CONCLUSIONS: Vascular network area and MNV area assessed at baseline and after three loading doses were determined as the most significant OCTA characteristics for predicting the number of injections and treatment response based on functional and morphological parameters. MNV area was found to be the most clinically significant marker in 'good' response, vascular density and greatest vascular caliber - in 'partial' response.

[New findings on pathogenetic mechanisms in the development of age-related macular degeneration]. / Novye dannye o patogeneticheskikh mekhanizmakh razvitiya vozrastnoi makulyarnoi degeneratsii.

Age-related macular degeneration (AMD) is a complex multifactorial disease that occurs due to disfunction and degeneration of retinal pigment epithelium (RPE) and choriocapillaris, as well as death of photoreceptors. The exact pathogenetic mechanism remains uncertain. The aging process is the main and the clearest risk factor of AMD. In the development of this condition, a special role belongs to the secretory phenotype of aging spreading from one cell to another and mediated by the secretion and release of growth factors, cytokines, chemokines, proteases, and other molecules. Another major contributor is oxidative stress caused by violations in the recirculation of vitamin A in the vision cycle and accompanied by accumulation of lipofuscin, which mediates the formation of iron-based oxidants that are toxic for mitochondria. Furthermore, prolonged oxidative stress and constant light exposure induce the development of inflammation in the retina. Accumulation of metabolic products and cellular defects with age can induce an inflammatory reaction that amplifies the damage. The inflammatory processes including innate immune response, activation of microglia and parainflammation that occur locally in the vascular membrane, pigment epithelium and neuroretina are very significant contributors to the age-related changes, their progression, and the development of advanced stages of AMD. Various growth factors play a special role in the development of choroidal neovascularization (CNV). Vascular endothelial growth factor A (VEGF-A) has traditionally been considered the main factor of neoangiogenesis and, consequently, the main therapeutic target, but in recent years various studies have determined the role of other factors - VEGF-B, C, D, PGF, Gal-1, angiopoietins. This article describes the main underlying mechanisms in the development of choroidal neovascularization including retinal aging, impaired metabolic activity, mitochondrial dysfunction, inflammatory reactions and genetic variations, as well as the role of various growth factors.

[Leukocyte telomere length and response to antiangiogenic therapy in patients with neovascular age-related macular degeneration.]

Age-related macular degeneration (AMD) is becoming the leading cause of vision loss in people over 60 years of age. The neovascular form of AMD (nVMD) is characterized by choroidal neovascularization (CNV), the main trigger of which is vascular endothelial growth factor (VEGF), the inhibition of which is the current standard of treatment. Significant variability of response to anti-VEGF therapy determines the relevance of the search for biological markers - prognostic criteria of treatment response. We analyzed the response of 110 nVMD patients to anti-VEGF therapy depending on the functional and anatomical parameters of the retina (according to optical coherence tomography, OCT) and leukocyte telomere length (LTL, was assessed by quantitative PCR). Positive dynamics of best corrected visual acuity (BCVA) was observed in 100% of eyes. The central retinal thickness (CRT) decreased after the 3rd injection to 265 [234-306] µm, by the end of the observation period - to 211 [190-262] µm. The retention of activity of the subretinal neovascular membrane (SNM) at the end of the observation period correlated with lower values of the initial BCVA and high values of the initial CRT. An association of LTL with response to treatment was revealed: in patients with higher LTL the active form of SNM was more often switched to inactive after three injections, while with lower LTL, the activity of SNM was more often preserved, which determined the need for more intravitreal injections.

Autophagy as a Target for the Retinoprotective Effects of the Mitochondria-Targeted Antioxidant SkQ1.

Age-related macular degeneration (AMD) is a complex neurodegenerative disease, a main cause of vision loss in elderly people. The pathogenesis of dry AMD, the most common form of AMD (~ 80% cases), involves degenerative changes in the retinal pigment epithelium (RPE), which are closely associated with the age-associated impairments in autophagy. Reversion of these degenerative changes is considered as a promising approach for the treatment of this incurable disease. The purpose of our study was to assess the relationship between previously identified retinoprotective effects of the mitochondrial antioxidant plastoquinonyl-decyl-triphenylphosphonium (SkQ1) and its influence on the autophagy process in senescence-accelerated OXYS rats characterized by the development of AMD-like retinopathy (Wistar rats were used as a control). The treatment with SkQ1 (250 nmol/kg body weight) during the period of active disease progression (from 12 to 18 months of age) completely prevented progression of clinical manifestations of retinopathy in the OXYS rats, suppressed atrophic changes in the RPE cells and activated autophagy in the retina, which was evidenced by a significant decrease in the content of the multifunctional adapter protein p62/Sqstm1 and increase in the level of the Beclin1 gene mRNA. In general, the results obtained earlier and in the present study have shown that SkQ1 is a promising agent for prevention and suppression of AMD.

[Topical drugs for the treatment of non-streptococcal acute tonsillopharyngitis in children: results of a multicenter study]. / Topicheskie preparaty dlya lecheniya nestreptokokkovogo ostrogo tonzillofaringita u detei: rezul'taty mnogotsentrovogo issledovaniya.

INTRODUCTION: Acute tonsillopharyngitis (ATP) is a very common disease in children. In non-streptococcal ATP, systemic antibiotics are usually not indicated, but topical antimicrobial therapy is advisable. OBJECTIVE: To evaluate the effectiveness of the combination of cetylpyridinium chloride with gramicidin C in the form of a spray in children with ATP in a prospective multicenter non-interventional study.Patients and methods. The study included 94 patients aged 6-15 years with non-streptococcal ATP. A standard examination, assessment of the pain intensity in the throat using a visual analogue scale, assessment of the pain frequency during swallowing and a score assessment of objective manifestations were carried out. Sixty-eight patients of the main group received a combination of cetylpyridinium chloride with gramicidin C (Grammidin for children) in the form of a spray, 26 patients of the control group received throat irrigation with saline solution (based on sea water) for 7 days. Therapy was assessed after 1 day (by phone), 4 and 8 days (by examination). RESULTS: The groups of patients did not differ significantly in terms of demographic indicators and initial clinical manifestations. Body temperature initially did not differ, but was significantly lower in the main group after 1 (p=0.003) and 4 (p=0.04) days. The sore throat pain intensity decrease in the main group significantly exceeded this indicator in the control group after 1 (p<0.001) and 4 (p <0.001) days. Initially, swallowing pain was observed in all patients, after 4 days the complaint was significantly less frequent in the main group (p<0.001). The total assessment of objective data was significantly lower in the main group after 4 (p<0.001) and 8 (p<0.001) days. No adverse effects of pharmacotherapy were observed. CONCLUSIONS: The study showed high efficacy and safety of the cetylpyridinium chloride and gramicidin C (in the form of a spray) combination for non-streptococcal ATP in children aged 6-15 years.

p38 MAPK-dependent alphaB-crystallin phosphorylation in Alzheimer's disease-like pathology in OXYS rats.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder. Development of AD is closely related to alterations of proteostasis including the deposition of amyloid beta (Aß) and hyperphosphorylated tau in the brain. Molecular chaperones such as αB-crystallin (CryaB) can prevent aggregation of proteins and enable their correct refolding. The p38 mitogen-activated protein kinase signaling (MAPK) pathway regulates CryaB activity through phosphorylation of CryaB. Here, we examined CryaB and phospho-(p-)Ser59-CryaB protein amounts in the prefrontal cortex of the senescence-accelerated OXYS rats at different stages of the development of AD-like pathology and in Wistar rats (control). We compared this result with the changes in the expression of genes involved in the p38 MAPK signaling pathway in the prefrontal cortex of both rat strains. Manifestation and progression of AD-like pathology in OXYS rats were accompanied by an increased level of detergent-insoluble p-Ser59-CryaB in the brain cortex, while the CryaB amount did not change. p-Ser59-CryaB was absent in the detergent-soluble protein fraction of the cortex in both rat strains. Immunostaining of brain slices revealed notable colocalization of p-Ser59-CryaB with Aß in 18-month-old OXYS rats. According to RNA sequencing data, the development of AD-like pathology in OXYS rats is accompanied in the cortex by up- and downregulation of genes involved in p38 MAPK signaling. In general, we demonstrated that the manifestation AD-like pathology in OXYS rats occurs against the background of activation of p38 MAPK-dependent CryaB phosphorylation and alterations of the p38 MAPK signaling pathway. The increased p-Ser59-CryaB amount and its colocalization with Aß can be considered a response to the accumulation of protein aggregates and may be an important part of an endogenous mechanism of AD development.

[Assessment of mitochondria-associated genes for single nucleotide polymorphisms linked to the development of hypertrophic cardiomyopathy in the senescence-accelerated OXYS rats.]

Hypertrophic cardiomyopathy (HС) is a heterogeneous myocardial disease with a wide range of clinical manifestations and risk of development increasing with age along with myocardial changes characteristic of aging. The contribution of genetic component to the development of HC is obvious, however, the etiology and pathogenesis of this disease remains unclear in 50% of cases. The aim of the present study was to search for single nucleotide polymorphisms (SNPs) in mitochondria-associated genes that can contribute to the development of myocardial hypertrophy using RNA-Seq data from senescence-accelerated OXYS rats. Here we revealed SNPs with a possible negative effect on the function of the protein product in mitochondria-associated genes Fbxl4 and Slc25a32, mutations in which were not previously associated with HC. Alterations in the expression of these genes in the myocardium of OXYS rats at different stages of the development of pathological changes indicate that the revealed SNPs can contribute to the development of HC. Thus, SNPs in the Fbxl4 and Slc25a32 genes, as well as the genes themselves, can be considered promising molecular targets in the studies of the contribution of mitochondrial dysfunction to the development of myocardial hypertrophy.

[Application of mathematical modeling methods in the evaluation of severity of ischemic stroke in patients with arterial hypertension]. / Primenenie metodov matematicheskogo modelirovaniia v otsenke tiazhesti ishemicheskogo insul'ta u patsientov s arterial'noi gipertenziei.

AIM: To study the possibility of applying methods of mathematical modeling in assessing the severity of ischemic stroke in patients with arterial hypertension. MATERIAL AND METHODS: The study included 80 patients with ischemic stroke. Blood pressure was measured. Transcutaneous polarography was used to measure the oxygen tension in tissues. Measurements of gas composition of the blood and thickness of the intima-media complex were performed. The level of stable metabolites of nitric oxide in the blood was determined. Measurement of endothelin-1 in the blood was performed by enzyme immunoassay. NIHSS scale was administered to assess the neurological status. Patients were divided into 3 groups according to the degree of neurological deficit. The control group consisted of 10 people without signs of vascular pathology. RESULTS: An increase in the neurological deficit was accompanied by an increase in the level of endothelin-1, a decrease in the level of stable metabolites of nitric oxide, and a reduction in tissue oxygenation. Discriminative functions were developed for each group of patients using discriminant analysis based on the data obtained in the study. The most statistically significant were two signs: the level of systolic blood pressure and the content of stable metabolites of nitric oxide in the blood. CONCLUSION: Thus, the imbalance in the indices of endothelium-dependent mechanisms of vascular tone regulation reflect the severity of the condition in ischemic stroke. The method of discriminant analysis allows the creation of sufficiently reliable mathematical models that can have practical significance, and can be used as a method of clarifying the severity of the condition in the acute period of ischemic stroke.

VEGF and PEDF levels in the rat retina: effects of aging and AMD-like retinopathy.

Age-related macular degeneration (AMD) is the leading cause of vision loss among the elderly. By clinical signs, there are two forms of AMD: the atrophic or dry (~ 90% of all cases) and wet or neovascular AMD (~10% of cases). Anti-vascular endothelial growth factor (VEGF) intravitreal agents are the only successful treatment for wet AMD. However, there are emerging signals that anti-VEGF treatment can potentially increase development of atrophic AMD. There is neither a treatment of the dry AMD due poor understanding of the pathogenesis and retina aging process in general. We have shown previously that senescence-accelerated OXYS rats are a suitable model of dry AMD. Signs of retinopathy in OXYS rats manifest themselves by age 3 months against the background of a decline in the number of retinal pigment epithelium (RPE) cells and an alteration of choroidal microcirculation. Herein, we compared retinal expression of proteins VEGF and PEDF (pigment epithelium-derived factor) between OXYS and Wistar rats (control). The amount of the VEGF protein increased with age in the retina of both rat strains from 3 months of age. From age 3 to 24 months, this parameter was significantly lower in OXYS rats than in Wistar rats. PEDF protein concentration was significant lower in the OXYS retina only at the age of 3 months. We can conclude that development of retinopathy in OXYS rats takes place at reduced concentrations of VEGF and PEDF. Because RPE cells control the VEGF-PEDF balance, an RPE-targeted approach is a logical choice for AMD treatment and for decreasing adverse effects of anti-VEGF treatment.

Changes in Retinal Glial Cells with Age and during Development of Age-Related Macular Degeneration.

Age is the major risk factor in the age-related macular degeneration (AMD) which is a complex multifactor neurodegenerative disease of the retina and the main cause of irreversible vision loss in people over 60 years old. The major role in AMD pathogenesis belongs to structure-functional changes in the retinal pigment epithelium cells, while the onset and progression of AMD are commonly believed to be caused by the immune system dysfunctions. The role of retinal glial cells (Muller cells, astrocytes, and microglia) in AMD pathogenesis is studied much less. These cells maintain neurons and retinal vessels through the synthesis of neurotrophic and angiogenic factors, as well as perform supporting, separating, trophic, secretory, and immune functions. It is known that retinal glia experiences morphological and functional changes with age. Age-related impairments in the functional activity of glial cells are closely related to the changes in the expression of trophic factors that affect the status of all cell types in the retina. In this review, we summarized available literature data on the role of retinal macro- and microglia and on the contribution of these cells to AMD pathogenesis.

Mitochondria with Morphology Characteristic for Alzheimer's Disease Patients Are Found in the Brain of OXYS Rats.

Growing evidence suggests that mitochondrial dysfunction is closely linked to the pathogenesis of sporadic Alzheimer's disease (AD). One of the key contributors to various aspects of AD pathogenesis, along with metabolic dysfunction, is mitochondrial dynamics, involving balance between fusion and fission, which regulates mitochondrial number and morphology in response to changes in cellular energy demand. Recently, Zhang et al. ((2016) Sci. Rep., 6, 18725) described a previously unknown mitochondrial phenotype manifesting as elongated chain-linked mitochondria termed "mitochondria-on-a-string" (MOAS) in brain tissue from AD patients and mouse models of AD. The authors associated this phenotype with fission arrest, but implications of MOAS formation in AD pathogenesis remain to be understood. Here we analyze the presence and number of MOAS in the brain of OXYS rats simulating key signs of sporadic AD. Using electron microscopy, we found MOAS in OXYS prefrontal cortex neuropil in all stages of AD-like pathology, including manifestation (5-month-old rats) and progression (12-18-month-old rats). The most pronounced elevation of MOAS content (8-fold) in OXYS rats compared to Wistar controls was found at the preclinical stage (20 days) on the background of decreased numbers of non-MOAS elongated mitochondria. From the age of 20 days through 18 months, the percentage of MOAS-containing neuronal processes increased from 1.7 to 8.3% in Wistar and from 13.9 to 16% in OXYS rats. Our results support the importance of the disruption of mitochondrial dynamics in AD pathogenesis and corroborate the existence of a causal link between impaired mitochondrial dynamics and formation of the distinctive phenotype of "mitochondria-on-a-sting".

Isolation and characterization of H5Nx highly pathogenic avian influenza viruses of clade 2.3.4.4 in Russia.

In 2016-2017, several subtypes of the highly pathogenic avian influenza (HPAI) virus were isolated on the territory of Russia. In the autumn of 2016, during the avian influenza virus surveillance in the territory of the Kamchatka region of Russia the HPAI A(H5N5) influenza virus was isolated. Then, during 2016-2017, multiple outbreaks among wild birds and poultry caused by HPAI A(H5N8) avian influenza virus were recorded in European part of Russia. At the end of 2017, an outbreak among poultry caused by HPAI A(H5N2) influenza virus was recorded in the European part of Russia. Phylogenetic analysis of HA of the A(H5N5), A(H5N8), A(H5N2) showed the strains belong to the clade 2.3.4.4 b. All isolated strains were antigenically closely related to candidate vaccine viruses of clade 2.3.4.4 and showed high virulence in mice. Genetic analysis revealed presence of genetic markers potentially related to high virulence in mice in all studied viruses.

Molecular and Cellular Mechanisms of Sporadic Alzheimer's Disease: Studies on Rodent Models in vivo.

In this review, recent data are presented on molecular and cellular mechanisms of pathogenesis of the most widespread (about 95%) sporadic forms of Alzheimer's disease obtained on in vivo rodent models. Although none of the available models can fully reproduce the human disease, several key molecular mechanisms (such as dysfunction of neurotransmitter systems, especially of the acetylcholinergic system, ß-amyloid toxicity, oxidative stress, neuroinflammation, mitochondrial dysfunction, disturbances in neurotrophic systems) are confirmed with different models. Injection models, olfactory bulbectomy, and senescence accelerated OXYS rats are reviewed in detail. These three approaches to in vivo modeling of sporadic Alzheimer's disease have demonstrated a considerable similarity in molecular and cellular mechanisms of pathology development. Studies on these models provide complementary data, and each model possesses its specific advantages. A general analysis of the data reported for the three models provides a multifaceted and the currently most complete molecular picture of sporadic Alzheimer's disease. This is highly relevant also from the practical viewpoint because it creates a basis for elaboration and preclinical studies of means for treatment of this disease.

Impact of Changes in Neurotrophic Supplementation on Development of Alzheimer's Disease-Like Pathology in Oxys Rats.

Alzheimer's disease (AD) is the most common type of age-related dementia. The development of neurodegeneration in AD is closely related to alterations in neurotrophic supplementation of the brain, which may be caused either by disorder of neurotrophin metabolism or by modification of its availability due to changes in the microenvironment of neurons. The underlying mechanisms are not fully understood. In this work, we used senescence-accelerated OXYS rats as a unique model of the sporadic form of AD to examine the relationship of development of AD signs and changes in neurotrophic supplementation of the cortex. Based on comparative analysis of the transcriptome of the frontal cerebral cortex of OXYS and Wistar (control) rats, genes of a neurotrophin signaling pathway with different mRNA levels in the period prior to the development of AD-like pathology in OXYS rats (20 days) and in the period of its active manifestation (5 months) and progression (18 months) were identified. The most significant changes in mRNA levels in the cortex of OXYS rats occurred in the period from 5 to 18 months of age. These genes were associated with neurogenesis, neuronal differentiation, synaptic plasticity, and immune response. The results were compared to changes in the levels of brain-derived neurotrophic factor (BDNF), its receptors TrkB and p75NTR, as well as with patterns of their colocalization, which reveal the balance of proneurotrophins and mature neurotrophins and their receptors. We found that alterations in neurotrophic balance indicating increased apoptosis precede the development of AD-like pathology in OXYS rats. Manifestation of AD-like pathology occurs against a background of activation of compensatory and regenerative processes including increased neurotrophic supplementation. Active progression of AD-like pathology in OXYS rats is accompanied by the suppression of activity of the neurotrophin system. Thus, the results confirm the importance of the neurotrophin system as a potential target for development of new approaches to slow age-related alterations in brain and AD development.

[Age-related changes of water transport by corneal endothelial cells in rats.]

Senescence-associated alterations in structure and function of cornea make it more sensitive to traumas and disease. Trauma of cornea leads to edema and vision impairment and only corneal transplantation remains the effective for vision correction. Role of aquaporins for cornea endothelium function, as well as age-related changes of their activity, are not entirely understood. Herein, we studied changes with age the water permeability (Pf) of the plasma membranes of the corneal endothelial cells and the level of expression in them of the mRNA genes of the water channels of the aquaporins AQP1 and AQP3 in Wistar and senescence-accelerated OXYS rats. From the age of 3 to 18 months, Pf in Wistar rats increased, in OXYS - decreased and was twice lower than in Wistar rats. The expression of aqp1 mRNA (studied by RT-PCR) in the endothelium was the same in Wistar and OXYS rats at the age of 3 months. By the age of 18 months, it increased only in Wistar rats and became twice higher than in OXYS rats. The expression of aqp3 mRNA in the endothelium of 3-month-old OXYS rats was half that of Wistar rats and did not change with age, while in Wistar rats it decreased and at 18 months was 4 times lower than in 3 months. We supposed that increased water permeability of endothelial cells in Wistar rats is adaptive and compensates for the decrease in endothelial cell density with age, while the accelerated aging of OXYS rats abolishes this compensation.

Fatal Cases of Seasonal Influenza in Russia in 2015-2016.

The influenza epidemic in 2015-2016 in Russia is characterized by a sharp increase of influenza cases (beginning from the second week of 2016) with increased fatalities. Influenza was confirmed in 20 fatal cases registered among children (0-10 years), in 5 cases among pregnant women, and in 173 cases among elderly people (60 years and older). Two hundred and ninety nine people died from influenza were patients with some chronic problems. The overwhelming majority among the deceased (more than 98%) were not vaccinated against influenza. We isolated 109 influenza A(H1N1)pdm09 and one A(H3N2) virus strains from 501 autopsy material samples. The antigenic features of the strains were similar to the vaccine strains. A phylogenic analysis of hemagglutinin revealed that influenza A(H1N1)pdm09 virus strains belonged to 6B genetic group that had two main dominant subgroups during the 2015-2016 season. In Russia strains of the first group predominated. We registered an increased proportion of strains with D222G mutation in receptor-binding site. A herd immunity analysis carried out immediately prior to the epidemic showed that 34.4% blood sera samples collected in different regions of Russia were positive to A/California/07/09(H1N1)pdm09. We came to a conclusion that public awareness enhancement is necessary to reduce unreasonable refusals of vaccination.

The influence of changes in expression of redox-sensitive genes on the development of retinopathy in rats.

Age-related macular degeneration (AMD) is a complex multifactorial disease of the elderly, with unclear pathogenesis; AMD is the leading cause of blindness. One of the destructive processes in AMD is oxidative stress, which leads to an imbalance in the processes responsible for production and detoxification of reactive oxygen species. The aryl hydrocarbon receptor (AhR) signaling pathway can participate in the development of oxidative stress, but the main regulator of antioxidant defense is nuclear factor, erythroid derived 2 (Nrf2). AhR-dependent oxidative stress can be attenuated by activation of Nrf2, and defects in the Nrf2 signaling pathway can increase sensitivity of the cell to oxidative stress. Our aim was to determine the role of the pro-oxidant (AhR-dependent) and antioxidant (Nrf2-dependent) systems in the pathogenesis of AMD using rats of OXYS strain and of OXYSb substrain with signs of AMD-like retinopathy of varying severity. We compared the retinal levels of mRNA expression of Nrf2- and AhR-dependent redox-sensitive systems between 1-, 3-, and 12- month-old senescence-accelerated OXYS rats (have been shown to be a valid experimental model of AMD) and the rat substrain OXYSb, which shows low morbidity of AMD. We uncovered interstrain differences in the expression of Nrf2 and Nrf2-dependent genes (glutathione S-reductase [Gsr] and heme oxygenase 1 [Hmox1]), in the expression of AhR-dependent genes (cytochrome P450 1A2 [Cyp1a2] and cytochrome P450 1B1 [Cyp1b1]), and in the NADPH-quinone oxidoreductase (Nqo1) expression, which is controlled by both AhR and Nrf2. Binding of AhR and Nrf2 proteins to the regulatory regions of AhR and Nrf2 genes, respectively, was detected by chromatin immunoprecipitation in the retina of 1-, 3-, and 12-month-old OXYS, OXYSb, and Wistar (control) rats. We compared the strength of DNA-protein interactions of AhR and Nrf2 with regulatory sequences and found that the level of autoupregulation of the AhR gene was higher in the retina of 1-month-old OXYSb rats in comparison with OXYS rats. An imbalance between pro-oxidant (AhR-dependent) and antioxidant (Nrf2-dependent) systems may play a crucial role in the onset and/or progression of AMD.