Early Postnatal Experience Modifies Activation of the Pituitary Testicular Complex in Male House Mice (Mus Musculus) Exposed to the Odor of Receptive Con- and Heterospecific Females.

For the first time, it was shown that activation of the pituitary-testicular complex in male house mice exposed to the odor of receptive females of their own and closely related species was modified under the influence of early postnatal experience and the maternal environment. We have confirmed associated formation of behavioral and physiological mechanisms of precopulatory isolation in early ontogenesis. The serum levels of free testosterone in males of closely related species M. spicilegus and M. m. wagneri differ, it is significantly lower in mound-building mice. In males fostered by a conspecific female, the level of free testosterone was significantly lower when exposed to a heterospecific female odor in comparison with a conspecific odor. The rearing of M. m. wagneri males by females of a closely related species led to a decrease in the testosterone response caused by exposure to female chemosignals (both con- and heterospecific) and to the absence of differences in the serum level of free testosterone when exposed to the odor of a female of their own or closely related species. These results indicate that the rearing conditions had a significant influence on the formation of hormonal mechanisms of reproductive isolation.

[Otorhinolaryngological symptoms of tumors of the pharyngeal process of the parotid saliva (clinical case with literature review)]. / Otorinolaringologicheskie simptomy opukholei glotochnogo otrostka okoloushnoi slyunoi zhelezy (klinicheskii sluchai s obzorom literatury).

The parotid gland is the largest salivary gland. Tumors of the salivary gland account for 5% in the structure of oncological morbidity, and up to 80% of tumors affect the large salivary glands with tumor localization in 20% of cases in the pharyngeal process of the parotid salivary gland. The main clinical sign of a tumor of the parotid salivary gland is the presence of a slowly growing mass in the area of the gland. Often, underestimation of the clinical symptoms of salivary gland tumors is the reason for the late diagnosis of this disease and the initial manifestations of the process remain unnoticed for a long time. In order to increase the efficiency of clinical diagnostics of salivary gland tumors, the staff of the Department of Maxillofacial Surgery, Otorhinolaryngology and Topographic Anatomy with Operative Surgery of the Burdenko Voronezh State Medical University studied the clinical and anatomical parallels of changes in the ENT organs in lesions of the pharyngeal process of the parotid salivary gland. Using the previously obtained results of interdisciplinary interaction of otorhinolaryngologists and maxillofacial surgeons made it possible to increase the efficiency of diagnosis and treatment of patients with tumors of the pharyngeal process of the parotid salivary gland.

Methodology for Conducting Post-Marketing Surveillance of Software as a Medical Device Based on Artificial Intelligence Technologies.

The aim of the study was to develop a methodology for conducting post-registration clinical monitoring of software as a medical device based on artificial intelligence technologies (SaMD-AI). Materials and Methods: The methodology of post-registration clinical monitoring is based on the requirements of regulatory legal acts issued by the Board of the Eurasian Economic Commission. To comply with these requirements, the monitoring involves submission of the review of adverse events reports, the review of developers' routine reports on the safety and efficiency of SaMD-AI, and the assessment of the system for collecting and analyzing developers' post-registration data on the safety and efficiency of medical devices. The methodology was developed with regard to the recommendations of the International Medical Device Regulators Forum and the documents issued by the Food and Drug Administration (USA). Field-testing of this methodology was carried out using SaMD-AI designed for diagnostic imaging. Results: The post-registration monitoring of SaMD-AI consists of three key stages: collecting user feedback, technical monitoring and clinical validation. Technical monitoring involves routine evaluation of SaMD-AI output data quality to detect and remove flaws in a timely manner, and to secure the product stability. Major outcomes include an ordered list of technical flaws in SaMD-AI and their classification using evidence from diagnostic imaging studies. The application of this methodology resulted in a gradual reduction in the number of studies with flaws due to timely improvements in artificial intelligence algorithms: the number of flaws decreased to 5% in various aspects during subsequent testing. Clinical validation confirmed that SaMD-AI is capable of producing clinically meaningful outputs related to its intended use within the functionality determined by the developer. The testing procedure and the baseline testing framework were established during the field testing. Conclusion: The developed methodology will ensure the safety and efficiency of SaMD-AI taking into account its specifics as intangible medical devices. The methodology presented in this paper can be used by SaMD-AI developers to plan and carry out the post-registration clinical monitoring.

Mutations of the VCORC1 Gene of Resistance to Anticoagulants in Synanthropic Rodents in Urbanized Areas of Russia.

This is the first study to analyze the variability of two exons (the 1st and 3rd) of the VCORC1 gene in Russian populations of mice and rats, namely, 125 Mus musculus and 19 Rattus norvegicus captured in 13 settlements. Previously, it has been shown that a number of mutations in these exons in the countries of Western Europe are associated with resistance to anticoagulants in synanthropic rodents. We did not find such mutations in house mice in Russia. However, in the first exon, two previously unknown mutations were identified that could potentially have such an effect (Lys58Arg and Ser31Trp). In three districts of Moscow, Norway rats were found carrying in the third exon a previously known resistance mutation (Tyr139Ser) in the heterozygous state. The results are discussed in connection with the intensity of the use of anticoagulants in the settlements of Russia and the mutation rate of the VCORC1 gene.

[A clinical observation of laryngeal ossifying fibromyxoid tumor]. / Nablyudenie ossifitsiruyushchei fibromiksoidnoi opukholi gortani.

A rare observation of ossifying fibromyxoid tumor of the larynx in a 23-year-old young man is presented. Surgical intervention, performed in two stages, provided a positive result. With dynamic observation of this patient for three years, continued growth and tumor recurrence were not observed. Due to the fact that ossifying fibromyxoid tumor is rare, differs in the complexity of differential diagnosis and an uncertain prognosis of the course of the disease, registration and dispensary observation of patients with this pathology is necessary.

[Prostate cancer and atherosclerosis].

Prostate cancer (PCa) remains a relevant public health concern and one of the main causes of morbidity and mortality worldwide. Coronary artery disease (CAD) with the underlying coronary artery atherosclerosis is the leading cause of global death. The interaction between modifiable and non-modifiable risk factors for these pathological conditions is discussed in the review. Elevated serum cholesterol, a known risk factor for CAD, can be associated with both development and progression of PCa. From this perspective, patients with atherosclerosis may represent a potential target group for PCa screening. Alternatively, patients with PCa should undergo examination for concomitant cardiovascular diseases as well as their risk factors. Statins are supposed to be potentially beneficial in treating atherosclerosis in men and reducing the risk of PCa development and progression.

[On the 100th anniversary of the Department of Otorhinolaryngology of Burdenko Voronezh State Medical University]. / K 100-letiyu kafedry otorinolaringologii Voronezhskogo gosudarstvennogo meditsinskogo universiteta im. N.N. Burdenko.

The article is dedicated to the 100th anniversary of the Department of Otorhinolaryngology of Burdenko Voronezh State Medical University.

Removal of the Tumor Thrombus from the Right Atrium without Extracorporeal Circulation: Emphasis on the Displacement of the Tumor Apex.

OBJECTIVES: To assess the outcomes of cavoatrial tumor thrombus removal using the liver transplantation technique for thrombectomy, a retrospective study was conducted. MATERIALS AND METHODS: Five patients with atrial tumor thrombi who underwent piggy-back mobilization of the liver, surgical access to the right atrium from the abdominal cavity, and external manual repositioning of the thrombus apex below the diaphragm (milking maneuver) were included into the study. Extracorporeal circulation was used in none of the cases. The average length of the atrial component of the tumor was 20.0 ± 11.7 mm (10 to 35 mm), and the width was 14.8 ± 8.5 mm (10 to 30 mm). In this work, the features of patients and surgical interventions as well as perioperative complications and mortality were analyzed. RESULTS: External manual repositioning of the tumor thrombus apex below the diaphragm was successfully performed in all patients. Tumor thrombi with the length of the atrial part up to 1.5 cm were removed through the extrapericardial approach. For evacuation of the thrombi with the large atrial part (3.0 cm or more), a transpericardial surgical approach was required. Specific complications associated with the access to the right atrium from the abdominal cavity (paresis of the right phrenic nerve, pneumothorax, and mediastinitis) were not detected in any case. The average clamping time of the supradiaphragmatic inferior vena cava (IVC) was 6.3 ± 4.6 min. The volume of intraoperative blood loss varied from 2500 to 5600 ml (an average of 3675 ± 1398.5 ml). CONCLUSION: Our work represents the initial experience in the liver transplantation technique for thrombectomy in distinct and well-selected patients with atrial tumor thrombi. The effectiveness of this approach needs further study. The video presentation of our research took place in March 2019 at the 34th Annual EAU Congress in Barcelona.

[Variability of Fragments of Nuclear Brca1 Gene, Exon 11, and Mitochondrial Cox1 Gene in House Mice Mus musculus].

To clarify genetic differences between subspecies of the house mouse Mus musculus, their distribution, and hybridization, we first conducted a comparative analysis of variability of nucleotide sequences of fragments of the nuclear gene Brca1, exon 11 (2331 bp), and mitochondrial gene Cox1 (1260 bp) in 40 house mice from West and East Europe, Transcaucasia, Siberia, and Central and South Asia. Brca1 genotypes were divided into five main groups, which differed in a number of fixed substitutions. Genotypes of each group are characteristic for the certain geographical region and the following subspecies: M. m. musculus, M. m. domesticus, M. m. castaneus, and M. m. wagneri together with M. m. gansuensis; a fifth group corresponds to an unidentified subspecies or a distinct genetic form of M. musculus from India (Sikkim State). Besides the homozygous specimens, we revealed mice, which were heterozygous for all diagnostic loci simultaneously; these specimens were determined as hybrid. Hybrid mice were mainly found in the zones of contact of subspecies, but in some cases, quite far from one of the parent subspecies (possibly, due to transportation). In two hybrid mice (from Bakhtiari Province of Iran and Transbaikalia of Russia), unique Brca1 haplotypes were detected. It cannot be ruled out that, at least partly, they may be characteristic of the M. m. bactrianus and M. m. gansuensis subspecies, respectively. Thus, the results of the study showed that the nuclear Brca1 gene is a promising molecular genetic marker for the analysis of variability, differentiation, and hybridization of house mice as well for subspecific identification of M. musculus specimens. Despite more rapid evolution of the Cox1 gene, it is not well suited for discrimination of M. m. musculus, M. m. wagneri, M. m. gansuensis specimens and Transcaucasian representatives of M. m. domesticus due to introgression and long-term maintenance of foreign mitochondrial DNA in populations. However, Cox1 gene analysis (along with the diagnostics of animals by nuclear DNA) may be useful for estimation of population differences in M. m. castaneus and M. m. domesticus subspecies.

Measurement of the angular dependence of the spontaneous Raman scattering in anisotropic crystalline materials using spherical samples: Potassium dihydrogen phosphate as a case example.

A specialized experimental configuration was developed to allow for more-accurate characterization of the spontaneous Raman scattering properties in anisotropic materials. This need stems from the challenges, arising from the complexity of light propagation, in obtaining accurate measurements of the angular dependence of the Raman scattering cross section in birefringent materials. The nonlinear optical material KH2PO4 (KDP) is used as a model medium. This study is motivated by the need to improve our understanding and management of transverse stimulated Raman scattering in KDP crystals and its deuterated analog, DKDP, typically used for frequency conversion and polarization control in large-aperture laser systems. Key to this experimental platform is the use of high-quality spherical samples that enable one to measure the Raman scattering cross section in a wide range of geometries using only a single sample. The effect of polarization rotation of both the pump light and the collected Raman signal must be carefully considered in data analysis and can give rise to artifacts, which can, in part, be mitigated by reducing the input and collection cone angles.

[Dynamics of free-radical oxidation in suppurative otitis media]. / Dinamika svobodno-radikal'nogo okisleniia pri gnoino-vospalitel'nykh zabolevaniiakh srednego ukha.

The dynamics of indicators of free-radical oxidation in various purulent-inflammatory diseases of the middle ear in 280 patients was studied. Significant violations of the processes of free radical oxidation in the serum of blood were taken for the patients, the degree of which depends entirely on the severity and nature of the inflammation. A complex treatment with the use of antioxidant therapy in 280 patients was carried out. Positive results were obtained, confirmed by clinical and laboratory indicators. The pathogenetic significance and dependence of the course of purulent-inflammatory diseases of the middle ear on the processes of free radical oxidation was established, which was reflected in the determination of the duration of treatment of various forms of both acute and chronic otitis media.

α2-Adrenoceptor signaling in cardiomyocytes of spontaneously hypertensive rats starts to impair already at early age.

α2-Adrenoceptors (α2-AR) found in the cardiomyocyte's sarcolemma represent a very important negative feedback for control of myocardial contractility by endogenous catecholamines. Earlier, we showed that the endogenous neurotransmitter agmatine in micromolar concentrations via α2-AR activates the nitric oxide (NO) synthesis, enhancing the Ca2+ pumping into sarcoplasmic reticulum (SR). In the millimolar doses it inhibits Ca2+ sequestration by SR Ca2+ ATPase (SERCA), acting through the first type of imidazoline receptors. Here, we study the functional activity of agmatine, as well as a specific α2-agonist, guanabenz, in respect to spontaneous Ca2+-transients in SHR cardiomyocytes of the early age (2-2.5 months), and adulthood animals (8-9 months). α2-mediated cardioprotective effect was almost twofold decreased in SHR cardiac cells compared to normotensive rats of the corresponding age, despite the fact that both α2A- and α2B-AR protein levels were significantly increased in SHR cardiomyocytes. NO-mediated facilitation of SERCA activity is substantially reduced in SHR cardiomyocytes vs. normotensive rats. These data suggest that the SHR phenotype starting from early age shows signs of the impaired sarcolemmal α2-AR signaling, which can aggravate the development of this cardiovascular pathology.

[Non-Central Influences of α2-Adrenergic and Imidazoline Agonist Interactions in Isolated ardiomyocytes Cardiac Cells].

AIM: to investigate the functional interaction of α2-adrenergic and imidazoline receptors recently identified on the sarcolemma of isolated cardiomyocytes for regulation of the intracellular calcium and the production of the signal molecule of nitric oxide (NO). MATERIALS AND METHODS: experiments were performed on isolated left ventricular cardiomyocytes of Wistar rats. Potential-dependent Ca2+-currents were measured from the whole-cell by the patch-clamp method in "perforated-patch" configuration. The intracellular calcium and the production of nitric oxide were estimated from the changes in fluorescence intensity of the Ca2+-specific and NO-sensitive dyes at fluorescent or confocal microscope. RESULTS: It has been shown that α2­adrenergic and imidazoline receptor agonists inhibit L-type Ca2+-currents by themselves, but their effects do not develop against each other's background. The blockade of key effector molecules: protein kinase B (Akt kinase) for α2­adrenergic receptors, and protein kinase C for imidazoline receptors causes the action of agonists to become additive. Both the selective α2­agonist, guanabenz, and the specific agonist of the first type imidazoline receptors, rilmenidine, show an additional inhibition of Ca2+-currents against the basal background already reduced by the activation of one of the two receptor systems. Wherein rilmenidine increases the level of free  Ca2+ in the cytosol, and guanabenz, on the contrary, decreases it. The action of guanabenz does not develop against the background of rilmenidine, although it, in turn, effectively increases the intracellular level of calcium in guanabenz-pretreated cardiac cells. Activation of α2­adrenergic receptors leads to significant stimulation of the endothelial isoform of NO-synthase, and as a result to an increase in the NO level. Activation of imidazoline receptors itself does not affect NO synthesis but it prevents the production of NO induced by α2­agonists. CONCLUSION: obtained data make it possible to formulate a number of useful recommendations for clinical practice, and also to clarify the non-central peripheral effects arising from the activation of α2­adrenergic or imidazoline systems under conditions of endogenous hyperactivation on of the two systems.

Synergism of myocardial ß-adrenoceptor blockade and I1-imidazoline receptor-driven signaling: Kinase-phosphatase switching.

Recently identified imidazoline receptors of the first type (I1Rs) on the cardiomyocyte's sarcolemma open a new field in calcium signaling research. In particular, it is interesting to investigate their functional interaction with other well-known systems, such as ß-adrenergic receptors. Here we investigated the effects of I1Rs activation on L-type voltage-gated Ca2+-currents under catecholaminergic stress induced by the application of ß-agonist, isoproterenol. Pharmacological agonist of I1Rs (I1-agonist), rilmenidine, and the putative endogenous I1-ligand, agmatine, have been shown to effectively reduce Ca2+-currents potentiated by isoproterenol. Inhibitory analysis shows that the ability to suppress voltage-gated Ca2+-currents by rilmenidine and agmatine is fully preserved in the presence of the protein kinase A blocker (PKA), which indicates a PKA-independent mechanism of their action. The blockade of NO synthase isoforms with 7NI does not affect the intrinsic effects of agmatine and rilmenidine, which suggests NO-independent signaling pathways triggered by I1Rs. A nonspecific serine/threonine protein phosphatase (STPP) inhibitor, calyculin A, abrogates effects of rilmenidine or agmatine on the isoproterenol-induced Ca2+-currents. Direct measurements of phosphatase activity in the myocardial tissues showed that activation of the I1Rs leads to stimulation of STPP, which could be responsible for the I1-agonist influences. Obtained data clarify peripheral effects that occur during activation of the I1Rs under endogenous catecholaminergic stress, and can be used in clinical practice for more precise control of heart contractility in some cardiovascular pathologies.

[The association of gamma-synuclein autoantibodies with the polymorphism in exon 4 of the coding gene]. / Sviaz' nalichiia autoantitel k gamma-sinukleinu s polimorfizmom v 4-m ékzone kodiruiushchego gena.

AIM: To analyze the polymorphism in exon 4 of the gamma-synuclein gene (SNCG) in patients with autoantibodies against the gamma-synuclein protein. MATERIAL AND METHODS: To identify autoantibodies against gamma-synuclein, the serum from patients with chronic cerebral ischemia and cervical osteochondrosis was used. All patients were women of the Slavic ethnic group, mean age 61±5 years. The isolated genomic DNA was used to determine the point mutation in exon 4 by the restriction endonuclease HphI and subsequent sequencing of the resulting fragments to confirm the results. RESULTS AND CONCLUSION: Antibodies against gamma-synuclein were identified in 2 patients with chronic cerebral ischemia and 3 with cervical osteochondrosis. All five patients had a T to A substitution at position 371, which was detected by the restriction endonuclease HphI resulting in a hydrolysis of the amplicon and the formation of two fragments. The subsequent sequencing of exon 4 of the SNCG revealed no other mutations and confirmed the T to A substitution. This single nucleotide polymorphism results in the amino acid substitution of glutamic acid to valine at position 110 (out of 127), changing its physicochemical properties and the ability to form aggregates as well as post-translational modifications. The obtained results provide grounds for further association studies of SNCG polymorphism in patients with various diseases of the nervous system.

[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.

[STANDARD TRANSCUTANEOUS AND ULTRA-MINI TRANSCUTANEOUS NEPHROLITHOTRIPSY IN TREATMENT OF NEPHROLITHIASIS].

Comparative analysis of two variants of transcutaneous nephrolithotripsy (TCNLT) in 45 patients, suffering nephrolithiasis, was performed. In 17 patients (the first group) the ultra-mini (UM) TCNLT, using tubus 11Сh, was done, and in 28 patients (the second group) ­ TCNLT, using a standard tubus 24Сh. The operation duration in the first group have had constituted (86.2 ± 16.3) min at average, and in the second group ­ (51 ± 13.6) min. The method of UМ TCNLT is a secure, miniinvasive, owing low rate of morbidity, comparing with a standard procedure, but with equal efficacy, concerning the «stone free¼ status (accordingly, 95.3 and 96.5%) in patients when calculi's diameter up to 2 sm. Тubus 11Ch guarantees lesser risk of hemorrhagic complications occurrence, permits to conduct UM TCNLT without nephrostomic draining of the renal calyx and pelvis system more confidently.

[ОPTIMIZATION OF EXAMINATION ALGORITHM FOR PATIENTS BEFORE AND AFTER OPERATIVE INTERVENTION FOR HYDRONEPHROSIS].

Algorithm of the patients examination, suffering hydronephrosis, caused by obstruction of different etiology, was optimized, what permitted, using qualification of rational volume and sequence of diagnostic methods, owing high sensitivity and specificity, as well as morphological diagnostic coefficients (parenchymal­stromal, dysbalance of collagens) and the risk criterion for recurrence occurrence, to estimate renal structure­ functional state, to determine the disease stage, its course severity and to substantiate a volume and duration of preoperative preparation needed, the operative intervention kind and postoperative management of the patients.