CORRECTION OF PATHOLOGICAL CHANGES IN SALIVARY GLANDS OF ANIMALS WITH PACLITAXEL-INDUCED NEUROPATHY.

BACKGROUND: Paclitaxel is a highly effective chemotherapeutic agent used to treat breast, ovarian, and other cancers. At the same time, paclitaxel causes peripheral neuropathy as a side effect in 45%-70% of patients. AIM: The aim of the study was to investigate the effect of paclitaxel-induced peripheral neuropathy on the development of pathological changes in the salivary glands of animals and to explore the possibility of correction of the identified changes with vitamin B/ATP complex. MATERIALS AND METHODS: To simulate toxic neuropathy, animals were injected i/p with paclitaxel 2 mg/kg for 4 days. In order to correct the identified changes, rats were injected i/m with vitamin B/ATP complex (1 mg/ kg) for 9 days. In the homogenate of the submandibular salivary glands, α-amylase activity, total proteolytic activity, total antitryptic activity, the content of medium mass molecules, thiobarbituric acid reactive substances (TBARS), oxidatively modified proteins, and catalase activity were determined. RESULTS: A significant increase in the content of oxidatively modified proteins, medium mass molecules, and the content of TBARS and significant decrease in the activity of catalase and amylase were determined in the salivary glands of animals with toxic neuropathy compared to these parameters in intact animals. Administration of vitamin B/ATP complex for 9 days against the background of paclitaxel-induced neuropathy led to normalization of antitryptic activity and amylase activity, a significant decrease in the content of oxidatively modified proteins, medium mass molecules, and TBARS along with a significant increase in catalase activity in the salivary glands of animals compared to the untreated rats with neuropathy. CONCLUSION: Paclitaxel-induced neuropathy caused the development of pathological changes in the salivary glands of rats, which was evidenced by a carbonyl- oxidative stress and impaired protein synthetic function. The correction with vitamin B/ATP complex restored the protein-synthetic function and the proteinase-inhibitor balance, suppressed the oxidative stress and normalized free radical processes in the salivary glands of rats.

[Interferonogenic activity of the strain BH-3 duck hepatitis virus type I (Picornaviridae: Avihepatovirus: Avihepatovirus A)].

INTRODUCTION: Duck viral hepatitis type I (DVH-I) is a poorly studied contagious disease caused by RNA-containing duck (Anatinae) hepatitis virus type I (Picornaviridae: Avihepatovirus: Avihepatovirus A). This infection is widespread in many countries, including Russia, and causes significant damage to industrial duck breeding. The study of interferonogenic activity of its etiologic agent strains is of great importance in solving the problem of developing effective means to control the disease. MATERIAL AND METHODS: Strain BH-3 of duck hepatitis virus type I isolated from the liver of sick ducklings was used in the study. The strain was adapted to developing 10-12 day old duck embryos, to the cell culture of chicken and duck fibroblasts and deposited in the State Collection of Viruses of the D.I. Ivanovsky Institute of Virology of FSBI «National Research Centre for Epidemiology and Microbiology named after the honorary academician N.F. Gamaleya¼ of the Ministry of Health of Russia. Experiments were performed using the standard tissue culture method. RESULTS AND DISCUSSION: Data on the ability of the viral strain BH-3 to induce interferon (IFN) and its sensitivity to the action of exogenous interferon in the culture of duck fibroblasts are presented. It has been shown that the interferonogenic activity of this strain of the hepatitis virus is in direct proportion to the multiplicity of infection. The maximum induction of IFN (1 : 256 CEPD50) was observed at a dose of 1.0 TCD50/cell in 72-96 hrs after inoculation of the cell culture. Exogenous IFN at a dose of 1 : 128 completely suppressed the cytopathic effect and death of duck embryos infected with hepatitis virus at a dose of 100 TCD50/cell. CONCLUSION: The data obtained allow us to state that the vaccine strain BH-3 of duck hepatitis virus type I has a pronounced interferonogenic activity and sensitivity to the action of exogenous IFN. This may have implications for the development of effective therapeutic agents against DVH-I.

[The main results of clinical trials of the efficacy, safety and pharmacokinetics of the perspective anti-tuberculosis drug makozinone (PBTZ169)].

Tuberculosis is a chronic infectious disease, usually localized in the respiratory system and representing one of the most important global social and biomedical health problems associated with the spread of therapy-resistant forms (multidrug-resistant and extensively drug-resistant tuberculosis). One of the most promising targets for the development of antimycobacterial drugs is the enzyme DprE1, which is involved in the synthesis of the cell wall of mycobacteria. In the series of DprE1 inhibitor drugs, the most advanced drug is PBTZ169 (INN maсozinone). Clinical trials (CT) of the efficacy and safety of macozinone are conducted by the pharmaceutical company LLC NEARMEDIC PLUS in the Russian Federation, and in other countries (Sponsors: Innovative Medicines for Tuberculosis Foundation, cole polytechnique fdrale de Lausanne and Bill and Melinda Gates Foundation). The publication describes results of completed I, IIa and Ib phases CT, conducted in the Russian Federation. AIM: The goal of phase I CT was to assess the safety, tolerability and pharmacokinetics (PK) of PBTZ169, 40 mg capsule, after single and multiple administration under fasting conditions in increasing doses in healthy volunteers. The goal of phase IIa CT was to study the efficacy (in terms of early bactericidal activity EBA), safety and PK of the drug PBTZ169, 80 mg capsules, in various doses, when used as monotherapy in patients with newly diagnosed respiratory tuberculosis with bacterial excretion and retained sensitivity to isoniazid and rifampicin. The purpose of phase Ib CT was to evaluate the safety, tolerability, PK of PBTZ169, 80 mg capsule, after single, double and multiple administration under fasting conditions in increasing doses, as well as the effect of food on its bioavailability in healthy volunteers. MATERIALS AND METHODS: The data of 100 healthy volunteers and 15 patients with newly diagnosed pulmonary tuberculosis, who received the study medication PBTZ169, capsules 40 mg and 80 mg, in the dose range 40 mg 1280 mg of PBTZ169, obtained during phase I, IIa and Ib CTs were analyzed. During I phases CTs, safety, tolerability, and PK of the drug after a single and multiple administration under fasting condition and after meals at rising doses were evaluated. The safety assessment included evaluation of AE/SAE, vital signs, ECG results, and laboratory tests results in the safety population. In the course of phase IIa CT, in addition to safety, tolerance, and PK evaluation, the efficacy of the drug (in terms of EBA) using sputum culture on agar with CFU/ml counting (main method) and quantitative PCR method (auxiliary method) was evaluated. RESULTS: During all CTs, a high safety and tolerability profile was shown, the main PK parameters of the drug and the efficacy were described. PBTZ169 demonstrated linear PK in the dosage range up to 640 mg after single and multiple administration, a statistically significant of EBA of the drug after monotherapy at the dose of 640 mg/day was demonstrate, and it was concluded that the preferred regimen of the drug PBTZ169 intake is administration after meals. Good tolerability and a favorable safety profile of the drug in the studied doses range were demonstrate during all the CTs. CONCLUSION: One of the most promising and currently studied drugs-inhibitors of DprE1, a new target for the cell wall of mycobacteria, is PBTZ169 or macozinone, which is being develop by the Russian pharmaceutical company NEARMEDIC PLUS ltd.

α-Galactosidase A/lysoGb3 ratio as a potential marker for Fabry disease in females.

Fabry disease (FD [MIM:301500]) is an X-linked lysosomal storage disorder caused by mutations in the GLA gene. Deficient activity of its product, lysosomal enzyme α-galactosidase A (α-Gal A), leads to excessive accumulation of glycosphingolipids in cells of multiple organs. The establishing of the diagnosis is challenge in female patients because of milder clinical manifestation and normal α-Gal A activity. The globotriaosylsphingosine (lysoGb3) is described as a more sensitive diagnostic biomarker for females with pathogenic mutation in the GLA gene. Thus, the aim of this study is to improve the biochemical diagnostic efficiency for FD in females. Here we report the α-Gal A/lysoGb3 ratio as the novel biochemical criteria for diagnosis of female patients with FD, using dried blood spots (DBS) as test samples. It showed 100% sensitivity in distinguishing our group of 35 female patients from control (n = 140). Whereas measurement of α-Gal A and lysoGb3 alone showed 8.6% and 74.4% respectively. A new approach of using the ratio of α-Gal A activity to lysoGb3 concentration in DBS may provide a more accurate screening tool for identification of FD females.

[Case of a Сombination of Lupus Erythematosus, Antiphospholipid Syndrome and Myocardial Infarction].

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease of unknown etiology characterized by a wide range of clinical manifestations with damage to various organs and systems of the body. There are bad prognostic factors for SLE: damage to the heart, kidney, central nervous system, the development of hematological crises and secondary antiphospholipid syndrome. A number of authors consider systemic lupus erythematosus a "new" risk factor for atherosclerosis. The overall risk of myocardial infarction (MI) in patients with SLE is 10 times higher than in the general population. The article presents clinical case report of the development of myocardial infarction in a woman with SLE, receiving therapy for secondary antiphospholipid syndrome.

[Antiviral effect of «Kagocel¼ substance in vitro on influenza viruses H1N1, H1N1pdm09 and H3N2.]

INTRODUCTION: Active circulation of pandemic influenza and new variants of influenza H3N2 strains requires monitoring of antiviral efficacy of drugs permitted for influenza therapy in the Russian Federation. PURPOSE: Assessment of antiviral efficacy of «Kagocel¼ substance against influenza viruses H1N1, H1N1pdm09 and H3N2 in vitro. MATERIAL AND METHODS: Cytotoxic effect of «Kagocel¼ substance on MDCK cells had been determined by stained with MTS. Antiviral efficacy of «Kagocel¼ substance against influenza infection has been studied in vitro in the culture of MDCK cells infected with influenza virus strains: A/Puerto Rico/8/34 (H1N1), А/California/7/2009 (H1N1)pdm09, А/Hong Kong/1/68 (H3N2) and А/ Hong Kong/4801/2014 (H3N2). The antiviral activity of «Kagocel¼ substance was tested by its effect on the infectious titer of the influenza viruses and on its impact on the expression level of viral antigens in the enzyme immunoassay test system. RESULTS: «Kagocel¼ substance had low toxicity for MDCK cells. «Kagocel¼ inhibited the infection titer of influenza virus strains A/Puerto Rico/8/34 (H1N1), А/California/7/2009 (H1N1)pdm09, А/Hong Kong/1/68 (H3N2) and А/ Hong Kong /4801/2014 (H3N2) in the MDCK cell culture with equal efficacy. Study of the impact of «Kagocel¼ substance on the expression level of viral antigens by ELISA also revealed its antiviral efficacy for all tested strains. Dose dependence was observed from concentration of substance and from infective dose of virus. DISCUSSION: Effective suppression of the reproduction of influenza virus strains A(H1N1), A(Н1N1)pdm09 and A(H3N2) in the different sublines of MDCK cells with «Kagocel¼ was shown by the different methods. These results give the possibility to suggest that along with the ability to induce interferons, «Kagocel¼ can impact on the reproduction of influenza virus, but the further research is needed. CONCLUSION: «Kagocel¼ substance effectively inhibits the reproduction of influenza virus strains A(H1N1), A(Н1N1)pdm09 and A(H3N2) in vitro. At the same time, the selectivity index is quite high.

THE KINETICS OF THE INACTIVATION OF THE HEPATITIS VIRUS TYPE I (AVIHEPATOVIRUS, PICORNAVIRIDAE).

Experimental data on the kinetics of the inactivation of the vaccine strain of the duckling hepatitis virus of the type I with increased temperature and aminoethyl ethylenimine are presented. It was shown that the vaccine strain 3M-UNIIP of the hepatitis virus of ducklings of type I was comparatively thermostable at 56°C and sensitive to the action of aminoethyl ethylenimine; the time of complete inactivation of the virus at a final concentration of 0.1% at 37°C was 24 h. The obtained results suggest that aminoethyl ethylenimine can be used as an inactivator in manufacturing inactivated vaccine against viral hepatitis of ducklings of type I.

Immunogenic lipid markers of atherosclerosis in type 2 diabetic patients on program haemodialysis.

AIM: Determination of desialized apolipoprotein-B-100 (apoB-100) and lipoprotein-containing circulating immune complexes in patients with chronic kidney disease (CKD) in program hemodialysis with type 2 diabetes mellitus. MATERIALS AND METHODS: We examined 81 patients with CKD (50 men / 31 women) treated with program hemodialysis, of which 36 (17/19) with type 2 diabetes mellitus, 45 (33/12) non-diabetic patients. The levels of total cholesterol, triglycerides and desialylated apoB-100 in blood plasma and lipoprotein-containing circulating immune complexes. A color duplex scan of brachiocephalic arteries was used to assess the extent of development of atherosclerosis with the determination of the thickness of the intima-medial complex. RESULTS: Patients with diabetes had high values of total cholesterol, triglycerides (p<0.05). Duplex scan of brachiocephalic arteries showed an increase in the thickness of intima-medial complex in all patients for program hemodialysis, however, in patients with diabetes, the thickness was 13% higher (p<0.05). In patients with diabetes, plaques with stenosis up to 50% prevail, compared with non-diabetic patients, p<0.05. The incidence was significantly higher for desialized apoB-100 by 46% in patients with diabetes on hemodialysis compared non-diabetic patients (p<0.05). An increase in the level of lipoprotein-containing circulating immune complexes by 39%, (p<0.05) in patients with diabetes mellitus was observed, compared with patients non-diabetic patients. The correlation between desialized apoB-100 and duplex scan of brachiocephalic arteries parameters (r=0.325), as well as between the cholesterol level and stenosis up to 50% (r=0.465) in patients with diabetes mellitus, was found to be of medium strength. The patients with diabetes and CKD, myocardial infarction developed 79% more often than in patients without diabetes (p<0.05). Thus, immunogenic lipid markers of atherosclerosis can be considered both as mechanical factors of atherogenesis and diagnostic and prognostic characteristics in type 2 diabetic patients with impaired renal function and chronic renal insufficiency. CONCLUSION: Accelerated development of atherosclerosis with diabetes and CKD, confirmed with the help of duplex scan of brachiocephalic arteries, may be associated with an increase in the level of modified low density lipoprotein.

Influence of autophagy on the genesis and development of atherosclerosis and its risk factors. / Vliianie autofagii na vozniknovenie i razvitie ateroskleroza i ego faktorov riska.

Autophagy is a highly conservative process of degeneration during which intracellular components including soluble macromolecules (e. g., nucleic acids, proteins, carbohydrates and lipids) and dysfunctional organelles (e. g., mitochondria, peroxisomes, and the endoplasmatic reticulum) are degraded by a lysosome. Autophagy serves as a dynamic system of recycling proving cells with energy and building components. Because of it in cells of an organism new proteins and membranes can form contributing to survival of the individual under starvation conditions. Autophagy plays an important role in the genesis and development of multifactorial pathogenesis including atherosclerosis and its risk factors. The present article examines both a pathogenic and protective role of autophagy in such pathological processes. The article can be useful to molecular biologists and biochemists, as well as to professionals involved in the problems of atherosclerosis and cardiovascular diseases.

Phytoestrogen-Rich Natural Preparation for Treatment of Climacteric Syndrome and Atherosclerosis Prevention in Perimenopausal Women.

The present study evaluated the risks and benefits of phytoestrogen treatment in healthy perimenopausal women in relation to the dynamics of climacteric syndrome and progression of atherosclerosis. Study participants were treated with placebo or phytoestrogen-rich natural preparation Karinat based on grape (Vitis vinifera) seeds, green tea (Camellia sinensis) leaves, hop (Hunulus lupulus) cone powder and garlic (Allium sativum) powder. The dynamics of climacteric syndrome was evaluated by Kupperman Index and Utian Quality of Life Scale. Atherosclerosis progression was evaluated by measuring carotid intima-media thickness. Significant changes of climacteric syndrome's severity in both Karinat and placebo groups (p = 0.005 and p = 0.001) were obtained after 24 months of follow-up. Detailed analysis of Kupperman Index suggested that Karinat possessed a significant effect on nervousness (p = 0.010), weakness (p = 0.020) and formication (p = 0.010). A significant improvement of medical (p = 0.070) and emotional (p = 0.060) components of Kupperman Index and Utian Quality of Life Scale was also observed in Karinat group. However, difference in carotid intima-media thickness between the two groups was not statistically significant at follow-up. A slight positive effect of phytoestrogens on climacteric syndrome manifestations was demonstrated in this study. Karinat can be used for alleviation of climacteric syndrome and cardiovascular disease prevention in perimenopausal women. Copyright © 2017 John Wiley & Sons, Ltd.

[Macrophage activation in atherosclerosis. Message 2. Effects of factors on macrophage activation].

In atherosclerosis, macrophages demonstrate phenotypic plasticity to rapidly adjust to changing microenvironmental conditions. In the plaque, serum lipids, serum lipoproteins and various pro- or anti-inflammatory stimuli such as cytokines, chemokines and small bioactive molecules could greatly influence the macrophage phenotype inducing switch towards more proinflammatory or anti-inflammatory properties. Dynamic plasticity of macrophages is achieved by up-regulation and down-regulation of overlapping set of transcription factors that drive macrophage polarization. Understanding of mechanisms of macrophage plasticity and resolving functional characteristics of distinct macrophage phenotypes should help in the development of new strategies for treatment of chronic inflammation in cardiovascular disease.

[ROLE OF SEROTONIN IN THE REGULATION OF RESPIRATION AND BILE SECRETORY FUNCTION OF THE LIVER].

In acute experiments on laboratory male rats we have shown that serotonin (10 mkg/kg, intraportal) increased the oxygen consumption of by liver on 28.8% (P < 0.001) and reduced oxygen tension levels on 19.3% (P < 0.001). The action of serotonin on tissue respiration in liver realized through 5-HT(2) receptors because previous blockade by ketanserin (3 mg/kg) led to remove the effects of exogenous serotonin and inhibition of the action of endogenous autacoid. Serotonin reduced the amount of secreted bile on 13.5% (P < 0.05), and increases the concentration of conjugated bile acids and decreases the content of free cholate, indicating enhanced conjugation with taurine and glycine in the liver cells. However, serotonin didn't stimulate synthesis of primary bile acids. Introduction of serotonin in the conditions of 5-HT2 receptors blockade by ketanserin also led to speed decrease of bile secretion, but in this case stimulating effect of autacoid on bile acid conjugation with taurine and glycine wasn't manifested and content of free cholate wasn't reduced.

[AMPUTATION OR EXARTICULATION OF TOES IN PATIENTS WITH DIABETIC FOOT SYNDROME].

The results of surgical treatment of 127 patients, suffering diabetic foot syndrome, were analyzed. In 82 patients (1st group) a radical toe extirpation was accomplished; in 45 (2nd group)--a phalangopreserving operations (amputaion of toe, necrectomy, sequestrectomy, the abscess opening) were done. The reoperation rate in patients of the 1st group have constituted 6.1%, the wound suppuration -3.6%, in a 2nd group satisfactory results were achieved in 26.7% of patients, and in the rest of them--reoperations were done for the pathological process progression.

[Changes of y neuron formation in cat visual system during early postnatal ontogenesis under the influence of binocular rhythmic light stimulation].

To examine the effect of an artificial rhythmic light stimulation on the development of structural and functional organization of Y neurons of cat visual system in the ontogenesis, the distribution of the neurons immunopositive to SMI-32 antibodies was studied in lateral geniculate nucleus (LGN) and posteromedial suprasylvian area (PMLS). Laminar distribution of SMI-32-positive neurons and neuronal body profile area were analyzed in intact animals (n = 4) and in kittens (n = 4) grown under conditions of rhythmic light stimulation with 15 Hz frequency for 4 months. In light-stimulated animals, changes in laminar distribution of immunopositive neurons were detected in both LGN (decline in the percentage of the immunopositive cells in C(M) layer) and in PMLS area (decrease in cell count in layer V). Morphometric analysis has shown the significant reduction of cell body profile area in immunopositive neurons in light-stimulated kittens only in layers III and V of PMLS area. The data obtained suggest that Y channel functional disturbances in light-stimulated animals are caused by the structural and metabolic changes detected in Y neurons.

[Soluble receptors for tumor necrosis factor and lipid metabolism as potential prognostic factors in patients with prostate cancer].

There was investigated the relationship of lipid metabolism, humoral immunity, high sensitivity C-reactive protein and soluble receptors for TNF-alpha with the presence, severity and prognosis of the disease in 85 patients with morphologically verified diagnosis of prostate cancer. Connection with the dynamics of change in PSA as a major predictor of the disease was observed for concentration sRI and sRII to TNF, PSA baseline, total cholesterol and LDL-cholesterol. During follow-up the relative risk of poor prognosis increased by 3 times, and death-in 8.7 times with increasing concentrations of soluble receptors for TNF. The concentration of soluble receptors for TNF may serve as an additional predictor of the presence and clinical course of disease in patients with prostate cancer.

[Cardiovascular risk factors in psoriatic and rheumatoid arthritis].

AIM: To study the role of conventional and new factors of cardiovascular risk in development of atherosclerosis in patients with rheumatoid arthritis (RA) and psoriatic arthritis (PA). MATERIAL AND METHODS: Sixty patients with psoriatic arthritis, 414 RA patients and 79 healthy controls entered the trial. All of them had no manifestations of cardiovascular diseases. Screening was made of the leading risk factors of cardiovascular diseases and cardiovascular complications, thickness of the complex intima-media (TIM) of the carotid arteries, vascular wall stiffness were measured, vasoregulatory function of the endothelium, markers of endothelial damage were examined. RESULTS: Patients with psoriatic and rheumatoid arthritis were found to have increased TIM of the carotid arteries, high incidence of atherosclerotic plaques, increased stiffness, damage of the vascular wall, affected endothelial vasoregulation. These alterations were associated with high arthritis activity, systemic manifestations, seropositivity by rheumatoid factor (in RA), presence of entesitis, uveitis and dactilitis (in psoriatic arthritis), dislipidemia, arterial hypertension (AH). CONCLUSION: To determine cardiovascular risk in patients with arthritis, it is necessary to consider not only standard risk factors (dislipidemia and AH), but also severity of systemic inflammation, arterial stiffness, endothelial damage and ability of the vascular wall to relax reflecting endothelial dysfunction.

[Development of primary visual cortex connections with the motion processing center: the role of visual environment].

Development of axonal connections between cat primary visual area 17 and visual motion processing center was studied to investigate cortico-cortical connection plasticity in ontogenesis as affected by an experimental modification of visual environment (flickering light stimulation). By using a retrograde axonal labeling by horseradish peroxidase, a distribution of initial neurons in area 17 that send afferent projections to PMLS (posterior medial part of lateral suprasylvian sulcus) was analyzed. Sixteen 5-week-old and 12-14-week-old kittens, than were reared in normal visual environment or were subjected to a flickering light of 15 Hz frequency, were examined. It was shown that session stimulation by flickering light led to an impairment of normal development of regular organization of the connections between these visual areas including the decrease of labeled surface area and labeled initial neuron density in area 17. The data obtained elucidate the structural bases of cortical mechanisms that underlie motion processing disturbances in kittens stimulated by a flickering light.

[ A method for detection and quantitative analysis of two-dimensional patterns of labeled neuron distribution in the cerebral cortex].

The aim of the present investigation was to elaborate an algorithm for labeled neuron 2-D pattern reconstruction and its analysis. Using the study of cat cortico-cortical connections between the areas 17, 18 and posteromedial lateral suprasylvian area as an example, it was shown that proposed algorithm is adequate for present aims of initial neuron pattern reconstruction and analysis, and that it can be applied as a working algorithm for highly specialized computer program elaboration.