CORRELATION OF PLASMA AND BRAIN AMINO ACID AND PUTATIVE NEUROTRANSMITTER ALTERATIONS DURING ACUTE HEPATIC COMA IN THE RAT

During acute hepatic coma following two-stage hepatic devascularization in the rat, profound changes occurred in plasma and whole-brain amino acids and putative neurotransmitters. Brain ammonia, glutamine and GABA were increased, aspartate was decreased, while glutamate was unchanged. An increase in brain tryptophan was accompanied by a similar increase in plasma unbound tryptophan but decreased plasma total tryptophan. These changes occurred in the presence of high plasma levels of the other neutral amino acids, including the branched chain amino acids. Plasma insulin was unchanged while glucagon levels rose, resulting in a decreased insulin to glucagon ratio. These results suggest that while plasma unbound tryptophan may influence brain tryptophan levels, altered plasma concentrations of neutral amino acids which compete with tryptophan for transport into the brain do not contribute to the increase in brain tryptophan observed during acute hepatic coma.     

The study of some mechanisms of injurious effects of low-frequency noises

Low-frequency noise has been shown to cause certain functional changes in the organism of laboratory animals that manifest in changes of the state of the regulatory systems and metabolic disturbances at cellular and subcellular levels. The obtained data support the hypothesis of the mechanism of injurious effect of this physical factor including two basically correlated ways, i.e. the central mechanism associated with overexcitation of the hypotalamohypophysis-adrenal system and mediating the homeostatic parameters of the body, and the local one which is determined by a direct effect of low-frequency noise on highly organized structure of membraneous and genetic apparatus of cells.     

The dose-dependent action of naloxone on systemic and portal circulation in acute blood loss in rats

Using the method of contact luminescent biomicroscopy of the liver and the intestine coupled with the ultrasonic measurement of systemic blood pressure, blood flow velocity in the portal vein and hepatic artery it has been established that in rats with acute decompensatory hemorrhage naloxone increases blood pressure and improves the state of protal macro and microcirculation only after i. v. injection of large dose (5 mg/kg). Naloxone does not influence the dynamics of acute compensatory hemorrhage and the development of the posthemorrhagic microcirculatory disturbances (local microstases, microthromboses, erythrocyte aggregation).     

Circadian time-dependent hepatic and renal toxicities to valproic acid in mice

This study aims to investigate whether hepatic and renal valproic acid (VPA) toxicities varied according to the dosing time in the 24-h scale in mice. VPA was administered by i.p. route to different groups of animals at four different circadian stages (1, 7, 13, and 19 h after light onset (HALO)). Biochemical study and histopathological examinations on liver and kidney sections were performed. The results showed that the hepatic and renal toxicity induced by VPA was time related. Animals treated at 19 HALO showed vacuolar degenerative changes, congestions, and inflammatory areas on liver parenchyma. Lesions within proximal tubules were observed in the kidney in groups treated at 19 HALO. The largest increases in alanine aminotransferase, alkaline phosphatase and plasma creatinine activities were also observed at 19 HALO. The obtained data indicate that the optimal hepatic and renal tolerance is observed when VPA was injected in the middle of the light-rest span of mice.     

Elevated plasma homocysteine in older shift-workers: a potential risk factor for cardiovascular morbidity

There is evidence supporting an association between shift work and cardiovascular morbidity, but the underlying mechanisms are unknown. The present paper investigated the levels of cardiovascular biochemical risk factors in shift-workers both with (n=26) and without (n=103) sleep complaints, and in day-workers (n=173) working in the same plant. Blood samples were taken in the morning after an overnight fast and analyzed for homocysteine, C-reactive protein, and lipid profile. Biochemical data were compared among groups after stratifying workers by age (i.e., <40 and > or = 40 yrs). Shift-workers who complained about sleep disturbances and who were > or = 40 years of age had significantly higher levels of homocysteine than did their younger counterparts - shift-workers who did not complain of sleep disturbances and day-workers. There were no other between-group differences in any of the biochemical variables. The results of this investigation demonstrate an association between sleep disturbances in older shift-workers and mild hyperhomocysteinemia. The elevated homocysteine levels may play a role in the increased rates of cardiovascular morbidity in shift-workers, and they may have practical implications regarding the nutrition of shift-workers.     

选择性贲门周围血管离断术治疗门静脉高压症的临床价值

目的：探讨选择性断流术与传统断流术在门静脉高压症手术治疗中的疗效。方法：分析我院从2007 年10 月至2013 年10 月行传统断流术52 例患者与行选择性断流术的34例患者的临床资料,对两组进行回顾性对比分析。结果：选择性断流术术后近 期脾窝积液、发热以及随访期间再出血、门静脉高压性胃病(portal hypertensive gastropathy,PHG)发生率明显减低(P<0.05),食管胃 底静脉曲张程度明显减轻（P<0.05）,肝性脑病发生率未增加(P>0.05)。结论：选择性断流术可以明显改善断流术后再出血和PHG 发病率高的问题,降低术后并发症的发生,近期疗效显著。但术后6-12 月,食管旁静脉均基本闭塞,远期疗效还有待于进一步研 究。     

Hemodynamic parameters in a surgical devascularization model of fulminant hepatic failure in the minipig

Animal models of fulminant hepatic failure (FHF) are important for studying the pathophysiology of this process and for evaluation of the efficacy of artificial and bioartificial liver support systems. In experiments, hemodynamic parameters were monitored in a group of minipigs with FHF induced by surgical devascularization, and compared with those in a control group. During the experiment, animals were analgosedated and were on mechanical lung ventilation. Crystalloid and colloidal solutions were administered and norepinephrine in continuous infusion was applied if mean arterial pressure (MAP) decreased below 60 mm Hg despite adequate intravascular volumes. An increase in heart rate, and decreases in MAP and systemic vascular resistance, compared with the baseline, occurred in the FHF group from 6 h after surgery. A comparison of FHF and control groups revealed no significant differences in systemic vascular resistance and MAP until after 12 h after surgery (systemic vascular resistance index: 953 FHF vs. 1658 controls; p < 0.05; MAP: 58.1 FHF vs. 76 controls; p < 0.05). No significant differences in CI were seen between the FHF group and controls. FHF animals survived for about 13 h after surgery, i.e. a period, which we consider long enough to test a support device. The parameters are believed to be quite adequate, as we were able to maintain satisfactory hemodynamic stability in all experimental animals with induced acute hepatic failure.     

Elevated Plasma Homocysteine in Older Shift‐Workers: A Potential Risk Factor for Cardiovascular Morbidity

There is evidence supporting an association between shift work and cardiovascular morbidity, but the underlying mechanisms are unknown. The present paper investigated the levels of cardiovascular biochemical risk factors in shift‐workers both with (n=26) and without (n=103) sleep complaints, and in day‐workers (n=173) working in the same plant. Blood samples were taken in the morning after an overnight fast and analyzed for homocysteine, C‐reactive protein, and lipid profile. Biochemical data were compared among groups after stratifying workers by age (i.e., <40 and ≥40 yrs). Shift‐workers who complained about sleep disturbances and who were ≥40 years of age had significantly higher levels of homocysteine than did their younger counterparts—shift‐workers who did not complain of sleep disturbances and day‐workers. There were no other between‐group differences in any of the biochemical variables. The results of this investigation demonstrate an association between sleep disturbances in older shift‐workers and mild hyperhomocysteinemia. The elevated homocysteine levels may play a role in the increased rates of cardiovascular morbidity in shift‐workers, and they may have practical implications regarding the nutrition of shift‐workers.     

脾切除及贲门周围血管离断术对肝硬化门静脉高压患者肝脏血流动力学的影响及其术后门静脉血栓形成的因素分析

目的:探讨脾切除及贲门周围血管离断术对肝硬化门静脉高压患者肝脏血流动力学的影响,并分析患者术后门静脉血栓形成的危险因素。方法:选择2016年1月-2017年12月在我院进行脾切除及贲门周围血管离断术的96例肝硬化门静脉高压患者,于术前、术后1d、3d、7d采用彩色多普勒超声对患者的肝脏血流动力学指标进行动态监测。统计术后7d内患者门静脉血栓的发生率,并将患者分为血栓组(n=28)和无血栓组(n=68),对两组患者的一般资料、手术指标、彩色多普勒超声监测指标等进行单因素分析,并采用Logistic多因素回归分析门静脉血栓形成的危险因素。结果:患者在术前、术后1d、3d、7d时的门静脉内径、最大流速、血流量呈逐渐降低的趋势,肝动脉内径、最大流速、血流量呈逐渐升高的趋势,且各时间点间两两比较差异有统计学意义(P0.05)。术后7d内有28例患者出现门静脉血栓,发生率为29.17%。血栓组和无血栓组患者在性别、年龄、体质量指数、手术时间、术前门静脉流速比较差异无统计学意义(P0.05);血栓组患者Child-Pugh分级为B级比例、术中出血量、脾质量、腹水量、术前门静脉内径均高于无血栓组,术后门静脉内径、术后门静脉流速均低于无血栓组(P0.05)。经Logistic多因素回归分析显示,患者术后门静脉内径、术后门静脉流速是门静脉血栓形成的危险因素(P0.05)。结论:行脾切除及贲门周围血管离断术的肝硬化门静脉高压患者术后进行肝脏血流动力学监测,有助于患者术后的疗效判断,且术后门静脉内径、术后门静脉流速是门静脉血栓形成的危险因素。     

PLASMA AND BRAIN TRYPTOPHAN CHANGES IN EXPERIMENTAL ACUTE HEPATIC FAILURE

An experimental model for acute hepatic failure in man was obtained in pigs by hepatic devascularization. After operation, liver function was grossly impaired, movements became inco-ordinated and coma ensued. Most animals died 5½–8½ h after operation. Plasma unesteritied fatty acid and free (but not total) tryptophan concentrations rose markedly after operation and correlated significantly with each other. Brain tryptophan concentration increased and correlated significantly with plasma free tryptophan concentration. Increased tryptophan was found in the four brain regions studied (hypothalamus, thalamus, caudate and cortex) and was associated with raised 5-hydroxytryptamine turnover as indicated by raised 5-hydroxyindolylacetic acid concentration. Results are discussed in relation to altered tryptophan metabolism in human hepatic coma and to investigations of the influence of plasma unesterified fatty acid and free tryptophan changes on brain tryptophan metabolism in the rat.     

Ultrastructural alterations in extrinsic eye muscles induced by vincristine.

A comparative morphological analysis of the effects of vincristine on particular types of muscle fibres of the eye and selected trunk muscles of the mouse was performed. Great resistance of the mouse organism to the action of sublethal doses of vincristine has been found. Degenerative changes of great intensity (atrophy of myofibrils, disturbances of the Z line) and the appearance of new changes, not mentioned hitherto among the vincristine myopathies (megamitochondria, intermembranous inclusions, glycogen in mitochondria and very large vacuoles) were observed in the trunk muscles of mice. The eye muscles are seem to be more resistant to the action of vincristine. The intensity of changes in the eye muscles was connected with the types of muscle fibres. Red fibres, rich in mitochondria, underwent relatively greatest changes, whereas the smallest changes were found in tonic fibres, poor in mitochondria and sarcotubular system, i.e. these structures from which spheromembranous bodies, most characteristic of the pathogenic effects of vincristine arise.     

Comparative study of intravital microcirculation and hemorheological changes following burn injury of different severity in rats

It was shown in experiments on rats that burn injury is followed by microcirculatory disturbances, hemoconcentration and increasing blood viscosity that is especially pronounced in the vessels with low blood pressure. The microcirculatory changes in the mesentery correlated with the in vitro investigated dynamic viscosity and blood composition. The disturbances were more pronounced after severe burn followed by a mortal shock than after moderate burn without fatal consequences. This investigation confirms great importance of hemorheological changes and microcirculatory disturbances in the early period of burn disease.     

Combined administration of N-acetylcysteine and monoisoamyl DMSA on tissue oxidative stress during arsenic chelation therapy

The present study deals with the therapeutic potential of combined administration of N-acetylcysteine (NAC) along with monoisoamyl DMSA (MiADMSA) against chronic arsenic poisoning in guinea pigs. Animal were exposed to 50 ppm arsenic in drinking water for 8 mo and subsequently treated for 5 consecutive days with 100 mg/kg NAC (orally) and MiADMSA (intraperitoneally), individually or in combination (50 mg/kg each). Arsenic exposure produced a significant depletion of blood δ-aminolevulinic acid dehydrate (ALAD) activity, increased the blood zinc protoporphyrin (ZPP) level, and reduced blood and liver glutathione (GSH) levels in guinea pigs. Hepatic oxidized glutathione (GSSG) and thiobarbituric acid reactive substance (TBARS) levels showed a marked increase, whereas hepatic alkaline phosphatase (ALP) activity decreased and acid phosphatase (ACP) activity increased on arsenic exposure. Significant depletion of liver transaminase activities on arsenic exposure suggests organ injury. Administration of MiADMSA, alone and in combination with NAC after arsenic exposure, was able to significantly enhance hepatic GSH and to reduce GSSG and TBARS levels compared to the arsenic control. Biochemical variables indicative of liver injury generally remained insensitive to any of these treatments. The recoveries in parameters indicative of oxidative stress were more marked in guinea pigs treated with combined administration of NAC and MiADMSA than monotherapy. Interestingly, there was a more pronounced depletion of arsenic from blood and tissues after combined treatment with NAC plus MiADMSA than MiADMSA. Blood and tissues copper, zinc, iron, and calcium concentrations showed a significant increase after arsenic exposure, which showed improvement, particularly after combined administration of MiADMSA and NAC. Based on these data, a proposal can be made that greater effectiveness in chelation treatment against chronic arsenic poisoning (i.e., turnover in the oxidative stress and removed of arsenic from the system) could be achieved by combined administration of an antioxidant (preferably having a thiol moiety) with MiADMSA.     

Embolization of the hepatic artery in cases of atypical anatomical structural variants in patients with malignant liver tumors

Therapeutic embolization of the hepatic artery was performed in 60 patients with nonresectable malignant liver tumors. Atypical topographical anatomical variants of the arterial system of the liver were revealed in 10 of them (16.7%). In 8 patients two hepatic vessels, one coming out of the celiac artery, the other--out of the upper mesenterial or left gastric artery supplied a tumor with blood. In three of them one vessel was embolized, in five patients both arteries were embolized. The blocking of the entire blood flow of a tumor brought about a positive clinical effect in all the patients. Embolization of one blood-supplying artery alone led to no improvement. A conclusion was made of a necessity to achieve arterial devascularization of the entire tumor tissue area during intravascular therapy.     

Age aspects of receptor-effector reactions and the regulation of adenylate cyclase activity

The present-day notions on the trends and mechanisms of changes in the activity of the cyclic nucleotide system are considered in the age aspect. Their role in disturbances of the neurohumoral regulation processes at the molecular level is discussed. Biochemical mechanisms of changes in the receptor-effector reactions are analyzed. An analysis of these changes is very important for elucidating general regularities of the cyclase system functioning with disturbances of biochemical regulation at the membrane and cell levels.     

General anesthesia and hepatic circulation

This article describes hepatic circulatory disturbances associated with anesthesia and surgical intervention. The material is presented in three parts: part 1 describes the effects of general anesthetics on the hepatic circulation; part 2 deals with different factors related to surgical procedures and anesthesia; and part 3 analyzes the role of hepatic circulatory disturbances and hepatic oxygen deprivation in anesthesia-induced hepatotoxicity. The analysis of available data suggests that general anesthesia affects the splanchnic and hepatic circulation in various directions and to different degrees. The majority of anesthetics decreases portal blood flow in association with a decrease in cardiac output. However, hepatic arterial blood flow can be preserved, decreased, or increased. The increase in hepatic arterial blood flow, when it occurs, is usually not enough to compensate for a decrease in portal blood flow and therefore total hepatic blood flow is usually decreased during anesthesia. This decrease in total hepatic blood flow has certain pharmacokinetic implications, namely a decrease in clearance of endogenous and exogenous substances with a high hepatic extraction ratio. On the other hand, a reduction in the hepatic oxygen supply might play a certain role in liver dysfunction occurring perioperatively. Surgical procedures-preparations combined with anesthesia have a very complex effect on the splanchnic and hepatic circulation. Within this complex, the surgical procedure-preparation plays the main role in developing circulatory disturbances, while anesthesia plays only a modifying role. Hepatic oxygen deprivation may play an important role in anesthesia-induced hepatotoxicity in different experimental models.     

The dose dependence of the development of compensatory-restorative body reactions to irradiation. The EPR method]

The study deals with the mechanism of organism's adaptive responses to the effect of radiation in widely ranging dose. Post-irradiation metabolic changes were evaluated in canine blood as well as in murine blood, spleen, bone marrow and liver using the EPR spectroscopy. It was shown that the dynamics of changes in transferrin and ceruloplasmin pools and ribonucleotide reductase activity were phase-dependent with the maxima at the 2nd, 6th and 10-12th days after irradiation. Such dynamics was observed at various irradiation doses applied. The data allow us to suggest that the nonspecific compensatory--adaptive reactions of organisms develop as the response to irradiation. The dose-response function of the reaction intensity was found to be linear. The shape of the dose-response curve indicates that the minimum response of organism depends on the dose linearly up to 3.2 Gy (for dogs) as well as the maximum one. However, in the case of low-dose irradiation (0.25 or 0.5 Gy) there were deviations of maximum responses from the linearity, i.e. the amplification of the amplitude of compensatory adaptive reactions. These effect were shown to be dependent upon initial individual characteristics of animal blood and to be related to the "depressed" or "activated" state of organism prior to irradiation. The ribonucleotide reductase activity was measured in bone marrow and spleen of animals by the EPR method. The nature of non-repairable DNA damage is discussed in view of the inactivation of ribonucleotide reductase.     

Effect of hemosorption on the ultrastructure of hepatocytes in toxic liver damage

Extracorporeal perfusion of toxic blood via carbonic sorbents is an effective method for correcting severe disturbances of hemostasis. Ultrastructural alterations in hepatic cells were studied in experimental toxic liver injury before and after hemosorption. It was established that after hemosorption the processes of intracellular regeneration were significantly activated in the liver parenchyma. The number of crysts in the mitochondria increased as did the electronic density of the matrix. At the same time the number of lysosomes rose as well. However, in persistent unresolved cholestasis, destructive alterations in the hepatic tissue progressed despite the performance of hemosorption.     

Effects of positive end-expiratory pressure on hepatic blood flow and performance

Positive end-expiratory pressure (PEEP) may impair extrapulmonary organ function. However, the effects of PEEP on the liver are unclear. We tested the hypothesis that at a constant cardiac output (CO), PEEP does not induce changes in hepatic blood flow (QL) and parenchymal performance. In splenectomized, close-chested canine preparations (group I, n = 6), QL was derived as hepatic outflow using electromagnetic flow probes (QLemf), and hepatic performance was defined by extraction and clearance of indocyanine green (ICG). In a noninvasive model (group II, n = 7), the effects of PEEP on hepatic performance alone were similarly analyzed. Measurements were taken during intermittent positive-pressure ventilation (IPPV1), after addition of 10 cmH2O PEEP to IPPV (PEEP1), during continued PEEP but after return of CO to IPPV1 levels by intravascular volume infusions (PEEP2), and after removal of both PEEP and excess blood volume (IPPV2). Phasic inspiratory decreases in QLemf present during positive-pressure ventilation were not increased during either PEEP1 or PEEP2. Mean QLemf decreased proportionately with CO during PEEP1 (P less than 0.05), but was restored to IPPV1 levels in a parallel fashion with CO during PEEP2. The ICG pharmacokinetic responses to PEEP were complex, with differential effects on extraction and clearance. Despite this, hepatic performance was not imparied in either group. we conclude that global QL reductions during PEEP are proportional to PEEP-induced decreases in CO and are preventable by returning CO to pre-PEEP levels by intravascular volume infusions. However, covarying changes in blood volume and hepatic outflow resistance may independently modulate hepatic function.     

Relationship between endothelin and thromboxane A2 in rat liver microcirculation.

In our previous study, we determined changes in hepatic blood flow using a Laser Doppler blood flow meter after i.v. injection of endothelin-1 (ET-1) or endothelin-3 (ET-3) at 2 nmol/kg in rats and found that ET-3 caused greater decreases in blood flow than ET-1. In the present study, we determined how the arachidonic acid cascade, mainly thromboxane A2 (TXA2), is related to ET-1 and ET-3 using indomethacin (INDO), which inhibits the biosynthesis of prostaglandin (PG), and OKY-046, a selective inhibitor of TXA2 synthesis. In the first series of experiments, ET-1 and ET-3 were administered after inhibiting the biosynthesis of PG by s.c. injection of 2 mg/kg of INDO. While INDO failed to inhibit the slight decrease in hepatic blood flow induced by ET-1, it significantly inhibited the marked decrease in hepatic blood flow elicited by ET-3. In the next series of experiments, ET-1 and ET-3 were administered after administration of 20 mg/kg of OKY-046. OKY-046 showed no effects in animals treated with ET-1, as in those pre-treated with INDO, while it significantly inhibited the decreases in hepatic blood flow induced by ET-3. These findings suggest that ET-1 decreases hepatic blood flow due to its direct effects although to a lesser extent than ET-3, while ET-3 does so due not only to its direct effects but also to TXA2-mediated effects. It is therefore likely that in addition to ET family peptides, PG-mediated mechanisms are involved in the regulation of hepatic microcirculation by ETs.