Repeated administration of ethambutol in therapeutic dose causes testes alteration and spermatogenesis disruption in Wistar rats.

Ethambutol (EMB) is conventionally used to treat tuberculosis and atypical Mycobacterium infections in combination with other antimycobacterial drugs. Eventually, EMB testicular toxicity has not been explored extensively yet. The aim of the study is to evaluate testicular toxicity of EMB. We explored the impact of EMB on male rats' fertility, testosterone level and germ cells state, testicular pro- and anti-oxidant status and DNA damage, as well as identified EMB effects on cytochrome P-450 2E1 (CYP2E1) both with computer simulation and in vivo. We demonstrated that EMB administration to male rats decreased in epididymal sperm count (19%) and fertility index (53%). These events were accompanied by reduction in serum testosterone content (1.6 times) and appearance of spermatogenic epithelium damages. It was also found in testes the intensification of lipid peroxidation, decrease in reduced glutathione content and changes in DNA fragmentation. Additionally, computer simulation showed direct interaction of EMB with CYP2E1 active site and heme. On the top of this, we demonstrated that level of testicular CYP2E1 messenger RNA in EMB-treated rats was increased 8.7 folds and p-nitrophenol hydroxylase activity in testes rose three folds. As this shows, EMB-caused CYP2E1 induction, oxidative stress, and apoptosis in the testes contribute to inhibition of steroidogenesis enzymes and spermatogenesis disruption.

[SURGICAL TREATMENT OF THE INJURED PERSONS WITH SPLENIC TRAUMA IN THE CLOSED COMBINED ABDOMINAL TRAUMA].

The results of treatment of the injured persons, suffering splenic injury, in closed com- bined abdominal trauma, depending on its severity and the splenic injury degree, are presented.

[Mechanism of hepatoprotective action of methionine and composition "Metovitan" against a background of antituberculosis drug administration to rats].

Oral administration of antituberculosis drugs to rats for 60 days in doses that are equivalent to clinical ones, causes changes in mRNA levels expression of liver cytochrome P-450 isoforms CYP3A2, CYP2C23, CYP2E1 and pro- and antioxidant state. Experimental composition "Metovitan" given with anti-TB drugs provided a correction of these abnormalities, that is evidenced by modulation of the level of CYP3A2, CYP2C23, CYP2E1 gene expression and antioxidant activity, inhibition of lipid peroxidation. "Metovitan" normalizes the enzymatic activity and content of total billirubin in the blood serum, shows high hepatoprotective properties, exceeding the efficiency of methionine.

[Optimization of animal model for investigation of pathogenesis of type 2 diabetes].

Diabetes mellitus is one of the three most common modem diseases. A number of animal models is used in investigations of the mechanisms of development of the disease. Most of these models replicate the symptoms of type 1 diabetes mellitus. The development of type 2 diabetes is caused by the insulin resistance, hyperglycemia, structural and functional disorders of the pancreatic cells. Investigation of pathogenesis of type 2 diabetes is complicated by the lack of adequate models of this disease. In this work, based on existing hyperglycemia model, we propose the model of metabolic syndrome as a precursor of type 2 diabetes. The development of metabolic syndrome symptoms was caused by 28 days long intramuscular injection of protamine sulfate to guinea pigs at a dose of 15 mg/kg along with keeping of animals on a high glucose diet. Increased blood glucose and cholesterol levels, reduction of glycogen in liver, the structural and functional damage and reduce in the number of functionally active beta-cells in the pancreas of the experimental animals were observed. The results confirm the development of the metabolic syndrome symptoms in experimental animals, which makes it possible to use such methodical approach in creation of promising type 2 diabetes model.

Epigenetic changes in the rat livers induced by pyrazinamide treatment.

Drug-induced liver injury, including drug-induced hepatotoxicity during the treatment of tuberculosis infection, is a major health problem with increasingly significant challenges to modern hepatology. Therefore, the assessment and monitoring of the hepatotoxicity of antituberculosis drugs for prevention of liver injury are great concerns during disease treatment. The recently emerged data showing the ability of toxicants, including pharmaceutical agents, to alter cellular epigenetic status, open a unique opportunity for early detection of drug hepatotoxicity. Here we report that treatment of male Wistar rats with antituberculosis drug pyrazinamide at doses of 250, 500 or 1000 mg/kg/day body weight for 45 days leads to an early and sustained decrease in cytosine DNA methylation, progressive hypomethylation of long interspersed nucleotide elements (LINE-1), and aberrant promoter hypermethylation of placental form glutathione-S-transferase (GSTP) and p16(INK4A) genes in livers of pyrazinamide-treated rats, while serum levels of bilirubin and activity of aminotransferases changed modestly. The early occurrence of these epigenetic alterations and their association with progression of liver injury specific pathological changes indicate that alterations in DNA methylation may be useful predictive markers for the assessment of drug hepatotoxicity.

[Gene protective effect of the short-chain derivative of Vitamin E under the action of alkylating compounds]. / Genoprotektorna dlia korotkolantsiugovogo pokhinogo vitaminu E za umov dii alkiliuchikh spoluk.

The gene protective effect of the short chain derivative of vitamin E was investigated in rats intoxicated with embichin and cyclophosphamide. Prophylactic administration of tocopherol derivative for 14 days promotes reduction of the genome and chromosome disturbances in marrow cells caused by this compounds. Correcting influence of tocopherol derivative depends on chemical structure and biologic peculiarities of the alkylating compound.

[Erythrocyte membrane fatty acids in ischemic heart disease]. / Zhyrni kysloty membran erytrotsytiv za ishemichnoï khvoroby sertsia.

The erythrocyte ghosts fatty acid composition of 27 patients with coronary artery disease (CAD) and 6 healthy people were investigated. Patients suffering from CAD were divided in two groups. The first group was matched by 18 patients with CAD and essential hypertension (EH) and 9 patients with CAD without EH. Significant decrease of the levels of some saturated fatty acids such as palmitic, stearic and begenic acids in the erythrocyte ghosts of the patients with CAD without EH was established among the major changes of the erythrocyte ghosts fatty acid composition. At the same time the amount, of arachidonic acid increased by 74% and docosahexaenoic acid--by 5.7 times. The content of miristic, palmitic and stearic acids was also diminished in patients with CAD and EH. The percent of arachidonic acid was elevated by 51% and docosatrienic acid--by 94%. It is notable that the quantity of docosahexaenoic acid did not change markedly if copmare to healthy people but was fallen for 5 times if compare to patients with CAD without EH. It was suggested that the lack of adaptive changes in erythrocyte ghosts omega-3 fatty acids of patients with CAD and EH was an important factor which could rise the risk of heart attack development.

[Correcting influence of vitamin E short chain derivatives on lipid peroxidation, liver cell membrane, and chromatin structure when rats are exposed to embichin]. / Korihiuchyi vplyv korotkolantsiuhovoho pokhidnoho vitaminu E na stan protsesiv POL ta strukturuu membran i khromatynu klityn pechinky shchuriv za diï embikhinu.

Embikhin causes activation of LPO processes in endoplasmic reticulum and in nuclear chromatine fractions of rat liver cells. The latter is accompanied by the impairment of repressive and active nuclear chromatine fractions structure. Derivate of vitamin E in these conditions renders correcting action on parameters of lipid peroxidation in the investigated subcellular structures, testifying its positive influence on the cell heredity apparatus state. The normalizing action of tocopherol derivative on cytochromes P450 and b5 levels is shown.

[Antioxidant effectiveness of short-chain alpha-tocopherol acetate in acute paracetamol poisoning in rats]. / Antioksydantna efektyvnist' pokhidnoho alpha-tokoferolatsetatu z ukorochnym bichnym lantsiuhom za umov hostroho otruiennia shchuriv paratsetamolom.

In the experiments in vivo on white rats possibility of paracetamol hepatotoxic effects correction with synthetic short-chain alpha-tocopherol derivative and pharmacopeial preparation of vitamin E has been studied. Levels of superoxide anion generation in liver mitochondria fraction, catalase activity and reduced glutathione, serum aminotransferase and alcaline phosphatase activities and liver subcellular fractions lipid contents were investigated. It was shown that the short-chain vitamin E derivative and pharmacopeial preparation had a membranotropic effect, normalizing free and total cholesterol levels in liver mitochondria fraction and decreasing serum aminotransferase activity level. Investigated compounds also decreased levels of superoxide anions generation, increased catalase activity and level of reduced glutathione in liver. Antioxidative properties of this derivative and pharmacopeial preparation were demonstrated both at the primary (dienes, trienes) and at final steps of lipid peroxidation (TBA-products formation). This antioxidative activity of alpha-tocopherol acetate and its derivative depended on the structure of chromane cycle but not on the length of side chain.

[Platelet hemostatic changes in patients with chronic alcoholism stage II in rest and exercise]. / Izmenenie trombotsitarnogo zvena gemostaza u bol'nykh khronicheskim alkogolizmom II stadii v pokoe i pri fizicheskoi nagruzke.

Platelet hemostasis was studied in 23 patients with chronic alcoholism (CA) stage II at rest and under muscular exercise. At rest, the patients had elevated spontaneous aggregation of platelets and more active start of adrenaline and ristomycin aggregation. Exercise stimulated spontaneous platelet aggregation, enhances adrenaline and ristomycin aggregation. According to adrenalin test 32% of the examinees had platelet dysfunction. According to ristomycin aggregation, vascular endothelium was impaired in 95.7%of the patients. Thus, it is evident that CA stage II patients develop disorder of platelet hemostasis and vascular endothelium. Such patients are at high risk of thrombogenesis.

[Thrombocytic hemostasis in patients with severe craniocerebral trauma]. / Trombotsitarnyi gemostaz u bol'nykh s tiazheloi cherepno-mozgovoi travmoi.

Platelet vascular hemostasis was assessed in 32 patients with slight craniocerebral injuries (SCCI) (Glasgow coma score 14-15) (group 1) on days 1, 3, 5, and 7 and in 84 patients (score 3-8) (group 2) in the same terms and on days 9, 14, and 21 after the injury. Under study were platelet count, spontaneous platelet aggregation and that induced by ADP, adrenalin, and ristomicin. Moderate disorders of platelet vascular hemostasis were revealed in all the patients; they were most of all expressed on day 5 and were mainly due to moderate disorders of the athrombogenicity of the vascular endothelium. The injury caused a manifest dysfunction of platelets connected with the developing disseminated intravascular blood coagulation and, specifically, with injury to the vascular endothelium. Spontaneous aggregation of platelets was the maximum on day 5 and coincided in time with an increase in Willebrand factor-dependent ristomicin-induced platelet aggregation (Willebrand factor is a marker of injury to the vascular endothelium). An increase of ristomicin-induced platelet aggregation was more often observed in the patients who died than in the survivors, and in those developing the respiratory distress syndrome (stages II-IV) and that combined with pneumonia.

[The possible mechanisms of a fibrinolytic disorder in patients with severe craniocerebral trauma]. / O vozmozhnykh mekhanizmakh narusheniia fibrinoliza u bol'nykh s tiazheloi cherepno-mozgovoi travmoi.

Fibrinolysis components were studied in 32 patients with slight and 38 ones with grave craniocerebral injuries on days 1, 3, 5, and 7 after the injury. No expressed disorders of blood fibrinolytic activity were revealed in patients with slight injuries. Grave craniocerebral injuries were associated with disorders of the plasmin system. Depression of the external and internal mechanisms of fibrinolysis were the most manifest starting from day 3 and caused by a number of factors characteristic of the developing disseminated intravascular blood coagulation syndrome and, possibly, by impaired regulation of the plasmin system by the central nervous system.

[Diagnosis and treatment of DIC syndrome in patients with severe craniocerebral trauma]. / Diagnostika i lechenie DVS-sindroma u bol'nykh s tiazheloi cherepno-mozgovoi travmoi.

The hemostasis parameters are compared in 32 patients with slight (14-15 Glasgow score) and 114 with grave craniocerebral injury (3 to 7 Glasgow score) on days 1, 3, 5, and 7 after the injury. Assessment of hemostasiograms revealed a regular development of disseminated intravascular blood coagulation (DIC) in patients with grave craniocerebral injury, whereas in patients with slight injury the changes in the hemostasis system were compensatory. Early (starting from day 1) addition of anticoagulants, disaggregants, and fresh-frozen plasma to treatment protocols are advisable for patients with grave craniocerebral injuries.

[The status and means for improvement of the rheumatology service in Ukraine]. / Stan ta shliakhy udoskonalennia revmatolohichnoï sluzhby v Ukraïni.

Morbidity, prevalence, temporary loss of capacity for work and invalidity due to rheumatic diseases for the last 5 years in the Ukraine are analysed. Ways of further improvement of rheumatological service are determined. Aspects of coordinated approach to the solution of urgent rheumatological problems on the part of doctors working in different fields of medicine are discussed.

[The effect of finoptin on platelet aggregation, blood coagulability and fibrinolysis in patients with ischemic heart disease during physical exercise]. / Vliianie finoptina na agregatsiiu trombotsitov, svertyvaemoct' krovi i fibrinoliz u bol'nykh ishimicheskoi bolezn'iu serdtsa pri fizicheskoi nagruzke.

Exercise platelet aggregation, blood coagulability, and fibrinolysis were examined in patients prior myocardial infarction 2-3 months following the disease. Seventy patients of whom 35 had received placebo and 35 finoptin prior to exercise were studied. The platelet aggregation, blood coagulability, and fibrinolysis were explored before and after bicycle ergometric test. Following exercise, the patients on placebo showed higher platelet aggregation, blood coagulability and lower fibrinolysis, whereas those on finoption exhibited a lower increase in platelet aggregation and blood coagulability and activated fibrinolysis.

[The coagulating and anticoagulating blood systems and thrombocyte aggregation in healthy subjects and patients with ischemic heart disease at rest and under physical loading]. / Svertyvaiushchaia, protivosvertyvaiushchaia sistemy krovi i agregatsiia trombotsitov u zdorovykh lits i bol'nykh ishemicheskoi bolezn'iu serdtsa v pokoe i pri fizicheskoi nagruzke.

A study was made of hemostasis, fibrinolysis and platelet aggregation at rest and exercise in 32 healthy persons and 35 patients suffering from coronary heart disease (CHD) with a history of myocardial infarction that had occurred 2-3 months before. It has been discovered as a result that in healthy persons at exercise, the blood coagulation system and fibrinolysis are activated, the level of antithrombin-III rises and initial platelet aggregation decreases. In patients with CHD at exercise, hypercoagulation, deceleration of fibrinolysis, and the decline of the level of AT-III are detectable, with platelet aggregation being enhanced.

[The personality characteristics of normal pregnant women and in pathology]. / Lichnostnye osobennosti beremennykh v norme i pri patologii.

Altogether 357 pregnant women were examined for the personality traits using a method of an all-round study of the personality. In 96 women (group I), the course of gestation appeared favourable, whereas in 134 women, it was complicated by late gestosis (group II), and in 127 women, by threatening premature delivery (group III). The personality traits of the group I women turned out to keep within the limits of the "conditional norm" in the presence of moderate anxiety. For the p pregnant women belonging to groups II and III, the general "register syndrome" was defined as a psychogenic-neurotic one. The differences in the personality types were established in these groups. The late gestosis group was characterized by the autistic-rigid mode of reacting whereas that with the threatening premature delivery by the anxious-phobic type of reacting.

[Ammonia release and binding processes and the activity of acid proteinase and glycolysis enzymes in the dynamics of experimental toxic adrenal encephalopathy]. / Protsessy osvobozhdeniia i sviazyvaniia ammiaka, aktivnost' kisloi proteinazy i fermentov glikoliza v dinamike éksperimental'noi toksiko-adrenalovoi éntsefalopatii.

The content of ammonium, glutamine, glutamate, aspartate and GABA, glutamine synthetase activity, acid proteinase, hexonase, phosphohexoisomerase and dehydrogenase glucose-6-phosphate were studied in dog brain homogenates after individual injections of Bacillus coli endotoxin (10 micrograms/kg) and adrenaline (75 micrograms/kg) into veins and their combined injections into the carotid artery. Isolated injections of endotoxin and adrenaline were shown to cause transient metabolic compensatory changes. Combined injections caused stable progressing brain metabolic disorders. It is suggested that neurochemical changes influence endogenous development of toxic adrenal encephalopathy.