Surgical simulation and virtual reality: the coming revolution

The present study was designed to define whether maximal removal rate of indocyanine green (ICG Rmax), plasma cyclic 3',5'-adenosine monophosphate (cAMP) response to exogenous glucagon (peak to basal ratio of cAMP level: P/B cAMP) and plasma half-life of galactose (t1/2 galactose) can measure the hepatic functional reserve of fatty liver prepared in rats fed choline-deficient (9 weeks), 2% cholesterol (2 weeks) or 0.25% DL-ethionine (2 weeks) diet. Although changes in cholesterol and phospholipid values in serum during feeding periods differed among the models, histopathologic examinations in the liver of almost all animals revealed intermediate to severe fatty liver with or without fibrosis at each termination. ICG Rmax and P/B cAMP were significantly decreased in rats fed choline-deficient or DL-ethionine diet, implying reductions in hepatic functional mass and disturbances in hepatic cAMP production. Meanwhile, t1/2 galactose showed no change in any of the models, suggesting that glucose metabolisms in the models used may be preserved. These findings demonstrate that ICG Rmax and P/B cAMP can apply to measurement of hepatic surviving reserve of fatty liver with fibrosis.     

Experimental immunization with anti-rheumatic bacterial extract OM-89 induces T cell responses to heat shock protein (hsp)60 and hsp70; modulation of peripheral immunological tolerance as its possible mode of action in the treatment of rheumatoid arthritis (RA)

High intracellular 1,2,-sn-diacylglycerol (DAG) usually activates protein kinase C (PKC). In choline-deficient Fischer 344 rats, we previously showed that fatty liver was associated with elevated hepatic DAG and sustained activation of PKC. Steatosis is a sequelae of many liver toxins, and we wanted to determine whether fatty liver is always associated with accumulation of DAG with activation of PKC. Obese Zucker rats had 11-fold more triacylglycerol in their livers and 2-fold more DAG in their hepatic plasma membrane than did lean control Zucker rats. However, this increased diacylglycerol was not associated with translocation or activation of PKC in hepatic plasma membrane (activity in obese rats was 897 pmol/mg protein X min(-1) vs. 780 pmol/mg protein X min(-1) in lean rats). No differences in PKC isoform expression were detected between obese and lean rats. In additional studies, we found that choline deficiency in the Zucker rat did not result in activation of PKC in liver, unlike our earlier observations in the choline deficient Fischer rat. This dissociation between fatty liver, DAG accumulation and PKC activation in Zucker rats supports previous reports of abnormalities in PKC signaling in this strain of rats.     

Optical activity of a nucleotide-sensitive tryptophan in myosin subfragment 1 during ATP hydrolysis

Male rats of the Wistar strain were divided 4 groups, and give a liquid diet of control feed, bezafibrate (150 mg/kg), ethanol, and ethanol plus bezafibrate for 5 week. The effect of bezafibrate supplementation on rats fed ethanol was examined in terms of the fatty acid composition of the phospholipids in the erythrocyte membrane. In the phospholipids profiles of erythrocyte membranes, PI was significantly decreased. The decrease in PI caused by bezafibrate appeared to substantially affect the membrane and consequently lead to changes in the membrane anchor. In the fatty acid composition of the PC, C20: 4 was significantly decreased in the group receiving alcohol (p < 0.05) but increased in the groups receiving bezafibrate (p < 0.05). In the fatty acid composition of the PE, C16: 0 was significantly increased in the three groups when compared with the control, and C20: 4 was decreased in the alcohol group (p < 0.05). In the fatty acid of SM and PI, C20: 4 was decreased and C18: 0 increased in the alcohol group. In the PS, C14: 0 was increased in the alcohol group, and decreased in the alcohol plus bezafibrate group (p < 0.01). The levels of arachidonic acid in the total fatty acids that constituted the membrane phospholipids were decreased in the rats given ethanol (p < 0.05). However, arachidonic acid in the group of bezafibrate supplementation on rats fed ethanol were elevated in comparison with the alcohol group (p < 0.05). With decreasing arachidonic acid as a marker of alcohol tissue injury following chronic alcohol intake, the effects of bezafibrate supplementation appear to contribute to membrane fluidity by altering the biochemical flexibility of the membrane.     

Plasma and blood vessel endothelin-1 concentrations in hypertensive uremic rats treated with erythropoietin

The present study was designed to evaluate whether changes in plasma and blood vessel endothelin-1 (ET-1) concentrations may play a role in the enhanced blood pressure response to recombinant human erythropoietin (r-HuEPO) replacement therapy in uremia. Renal failure was induced by 5/6 nephrectomy (Nx). Uremic rats received either r-HuEPO (100 u s.c. three times a week) or the vehicle for 5 weeks. They were compared to control rats receiving the vehicle. Systolic blood pressure (tail cuff method), hematocrit, serum creatinine, plasma and tissue ET-1 were measured at the end of the protocol. Immunoreactive ET-1 (ir-ET-1) was determined by radioimmunoassay of acid-extracts from the plasma, thoracic aorta and mesenteric arterial bed. Creatinine increased about three fold in Nx animals. Blood pressure in control rats was 120+/-3 mmHg compared to 161 +/-6 mmHg in the Nx + vehicle group (p <0.01) and 199+/-9 mmHg in the Nx + r-HuEPO group (p <0.01 vs Nx + vehicle). Hematocrit in control rats was 41.3+/-0.4% vs 32.6+/-1.8% in the Nx + vehicle group (p <0.01) and 47.6+/-1.5% in the Nx + r-HuEPO group (p <0.01). Plasma ir-ET-1 levels were similar in the Nx + vehicle and Nx + r-HuEPO groups (7.9+/-1.0 and 7.8+/-0.8 pg/ml). In contrast, thoracic aorta ir-ET-1 content was significantly higher in the Nx + r-HuEPO group than in the Nx + vehicle group (20.3+/-2.9 vs 13.4+/-1.9 pg, p <0.05). Similar results were obtained in the mesenteric arterial bed. There were significant correlations between blood pressure and ir-ET-1 content in the thoracic aorta (r= 0.45, p<0.05) and in the mesenteric arterial bed (r= 0.41, p<0.05). Vascular ET-1 content but not plasma levels are increased in uremic rats treated with r-HuEPO suggesting an increase in blood vessel ET-1 production which may play a role in the pathogenesis of r-HuEPO-induced hypertension.     

Inhibition by piroxicam of oxidative DNA damage, liver cirrhosis and development of enzyme-altered nodules caused by a choline-deficient, L-amino acid-defined diet in rats

Previously, we have reported that aspirin, a cyclooxygenase (COX) inhibitor, can prevent the fibrosis, cirrhosis and generation of oxidative DNA damage, and the associated development of glutathione-S-transferase placental form (GST-P)-positive preneoplastic liver nodules, caused by a choline-deficient, L-amino acid-defined (CDAA) diet in rats. In the present study, in order to elucidate the role of COX pathway in liver lesion-induction by a CDAA diet, the modulatory effects of other distinct chemical classes of COX inhibitors were examined. A long-acting example, piroxicam (PIRO) (at doses of 0.01, 0.02, 0.04 and 0.06%) and the short-acting ibuprofen (IBU) (at doses of 0.02, 0.04 and 0.06%) and indomethacin (IND) (at doses of 0.005 and 0.008%) were administered in the CDAA diet to male F344 rats, and animals were killed after 12 and 30 weeks. In another experiment, IND was given in drinking water at doses of 0.001, 0.002 and 0.004%. None of the inhibitors affected the development of fatty liver caused by a CDAA diet, but PIRO at doses higher than 0.04%, strongly inhibited the development of GST-P-positive and neoplastic nodules as well as fibrosis, cirrhosis and formation of 8-hydroxydeoxyguanosine (8-OHdG) adducts. IBU at the highest dose also exhibited similar but much less pronounced inhibitory effects. With IND, there was only a tendency for inhibition with no clear dose-dependence. The results together with our previous findings, indicate that relatively strong COX inhibitors, acting irreversibly like aspirin or for extended periods like PIRO, can prevent the endogenous hepatocarcinogenesis associated with a CDAA diet, although not the development of a fatty liver, suggesting that an augmented COX pathway might play key roles in the causation of liver lesions in this model.     

Inhibitory effect of ursodeoxycholic acid on the progression of chronic hepatic disorders with special reference to increases in blood flow

Ursodeoxycholic acid (UDCA), which is commonly used as a cholesterol-gallstone-dissolving agent, is now expected to be effective not only for primary biliary cirrhosis but for chronic active hepatitis as well. In this study, we administered 0.1% ethionine-added, choline-deficient diet for 8 weeks to male Sprague-Dawley rats to prepare an animal model of chronic hepatic disorders. At the same time, UDCA (50 mg/kg/day) was administered orally to these animals, and its effects on the liver, including effects on hepatic blood flow determined with a laser Doppler blood flow meter, were evaluated. Hepatic blood flow increased significantly in the UDCA group compared with the untreated groups. Transaminase levels decreased significantly in the UDCA group compared with the untreated group. Histologic differences were noted between the UDCA and untreated groups in histopathologic examinations of the liver, with liver cirrhosis or early liver cirrhosis being present in the untreated group, compared with only chronic active hepatitis in the UDCA group. These findings suggest that UDCA is able to prevent or inhibit the progression of chronic hepatic disorders, an effect that may be due in part to increases in hepatic blood flow.     

Peroxisome proliferator-activated receptor-gamma agonist, rosiglitazone, protects against nephropathy and pancreatic islet abnormalities in Zucker fatty rats

Rosiglitazone (BRL 49653), a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist and potent insulin action-enhancing agent, was given in the diet (50 micromol/kg of diet) to male Zucker rats ages 6-7 weeks for 9 months (prevention group). In this treatment mode, rosiglitazone prolonged the time to onset of proteinuria from 3 to 6 months and markedly reduced the rate of its subsequent progression. Progression was also retarded when treatment was commenced (intervention group) after proteinuria had become established (4 months; ages 24-25 weeks). In either treatment mode, rosiglitazone normalized urinary N-acetyl-beta-D-glucosaminidase activity, a marker for renal proximal tubular damage, and ameliorated the rise in systolic blood pressure that occurred coincidentally with the development of proteinuria in Zucker fatty control rats. The renal protective action of rosiglitazone was verified morphologically. Thus in the prevention group there was an absence of the various indexes of chronic nephropathy that were prominent in the Zucker fatty control group, namely, glomerulosclerosis, dilated tubules containing proteinaceous casts, a loss of functional microvilli on the tubular epithelium, and varying degrees of chronic interstitial nephritis. An intermediate pathology was observed in the intervention group. Also, pancreatic islet hyperplasia, ultrastructural evidence of beta-cell work hypertrophy, and derangement of alpha-cell distribution within the islet were prominent features of Zucker fatty control rats, but these adaptive changes were ameliorated (intervention group) or prevented (prevention group) by rosiglitazone treatment. These data demonstrate that treatment of Zucker fatty rats with rosiglitazone produced substantial protection over a prolonged period against the development and progression of renal injury and the adaptive changes to pancreatic islet morphology caused by sustained hyperinsulinemia.     

The relationship of a neonatal care center, a pediatric neurology division and a rehabilitation center for disabled children]

In alloxan-induced diabetic rats (Wistar, females, age 3-4 months of postnatal life) the large spectrum of fatty acids in blood serum, brain cortex, medulla oblongata and liver was studied. The fatty acids, using gas chromatography, were detected as methyl esters and the methods were published previously (Smídová and al. 1994). Alloxan (Merck) administered i.p., 140 mg/kg body weight, caused immediately elevation (three times) of blood sugar levels. On the 13th day the rats were killed. The results are as follows: a) In blood serum alloxan diabetes of cca two weeks duration caused a significantly increased participation of saturated FA and decreased participation of both polyunsaturated FA (n-3 and n-6). b) In brain cortex no differences between controls and diabetic rats in the indicated groups of FA were found. c) In the medulla oblongata an increased participation of polyunsaturated fatty acids n-6 was established. d) In hepatic tissue the increased participation of saturated FA as well as a decreased participation of FA n-6 was described. Analysing the main groups of FA we found especially in n-3 and n-6 FA several significant changes in single FA (a smaller pool of arachidonic acid in blood serum as well as in liver, decreased participation of docosahexaenoic acid in the brain cortex, etc.). The purpose and possible consequences of such changes are discussed.     

Effectiveness of relative low-dose interferon treatment for patients with chronic hepatitis C

To demonstrate effectiveness by relative low-dose of interferon treatment for patients with chronic hepatitis C, we investigated the histological activity index (HAI) score of liver tissue, hepatitis C virus (HCV) genotype by polymerase chain reaction (PCR) with type-specific primers, HCV RNA levels by competitive PCR, serum aminotransferase, sex, age, history of blood transfusion and history of hepatitis in patients with chronic hepatitis C prior to treatment. Twenty-two patients were treated with human lymphoblastoid interferon (3 MU daily, 2 weeks, 3 MU thrice a week, 6 weeks, 1.5 MU thrice a week, 16 weeks) for 24 weeks, of whom 10 (45.5%) were responders within a 6 month follow-up. HAI score before treatment was significantly lower in responders than in a combined group of relapse patients and nonresponders (7.5 +/- 3.4 vs. 12.0 +/- 3.1, p < 0.01). The prevalence of responders in patients with genotypes III and IV was significantly higher than in those with genotype II (85.7% vs. 21.4%, p < 0.05). HCV RNA level (logarithmic transformed copy per 50 microliter of serum) was significantly lower in responders than in a combined group of relapse patients and nonresponders (4.8 +/- 1.2 vs. 5.7 +/- 0.8, p < 0.05). In case of other pretreatment factors, there were no significant differences between responders and a combined group relapse patients and nonresponders. Thus severe histological changes in the liver, HCV genotype II and high HCV RNA levels are markers of unfavorable effects of interferon treatment for patients with chronic hepatitis C.     

Differential accumulation and release of long-chain n-3 fatty acids from liver, muscle, and adipose tissue triacylglycerols

Eicosapentaenoic acid (EPA, 20:5n-3) is less efficiently accumulated in tissue triacylglycerols (TAGs) during fish oil feeding than docosahexaneoic acid (DHA, 22:6n-3) or docosapentaenoic acid (DPA, 22:5n-3), and EPA is preferentially released from the TAG of isolated adipocytes in vitro and adipose tissue in vivo during fasting compared with DHA or DPA. It is not known if this preferential release occurs in vivo under nonfasting conditions or if it is limited to adipose tissue. Accordingly, we have carried out experiments to study the turnover of EPA, DHA, and DPA in the TAG of adipose tissue, liver, and skeletal muscle. Weanling rats were fed diets containing fish oil for 6 weeks and then switched to diets containing only corn oil as the dietary fat for 8 weeks. The fatty acid composition and mass in epididymal fat pads, omental fat, liver, and soleus muscle TAGs were determined weekly for the first 10 weeks and at weeks 12 and 14. Subsequent to the change to the corn oil diet, EPA (20:5n-3), DPA (22:5n-3), and DHA (22:6n-3), which had accumulated during fish oil feeding, were lost from the tissue TAG pools of each tissue examined. After 8 weeks on the corn oil diet, less than 10% of the accumulated EPA, DPA, and DHA remained in the liver and muscle. The loss of EPA, DPA, and DHA from epididymal fat pad was slower. In each tissue, EPA was lost more rapidly than DPA or DHA. This selective loss of EPA relative to DHA or DPA may explain the previously reported underrepresentation of EPA compared with DHA or DPA in tissue TAG.     

Fatty acid composition in maternal milk and plasma during supplementation with cod liver oil

OBJECTIVE: We investigated how cod liver oil influences the amount of essential fatty acids in mothers' breast milk. DESIGN AND INTERVENTION: Lactating mothers (n =22) were randomized into four groups 3-8 weeks after parturition. They were supplemented for 14 days with 0, 2.5, 5 and 10 ml cod liver oil (7.7 g eicosapentaenoic acid (EPA, 20:5n-3), 10.2 g docosahexaenoic acid (DHA, 22:6n-3) and 22.9 g n-3 fatty acids in total per 100 ml). RESULTS: In maternal plasma phospholipids there was an increase in the content of EPA and DHA in the group supplemented with 10 ml cod liver oil daily (P < or = 0.05). DHA concentrations in breast milk pre-supplementation ranged from 0.15 to 1.56 wt% and increased in all supplemented groups (P< or =0.05). The concentration of EPA in breast milk increased in the groups supplemented with 5 or 10 ml cod liver oil (P< or =0.05), whereas the concentration of arachidonic acid (AA, 20:4n-6) did not change in any of the supplemented groups. Total intake of DHA adjusted to body mass index (BMI), correlated to DHA concentrations in plasma (r = 0.49, P = 0.02) and breast milk (r = 0.45, P = 0.04). The concentration of tocopherol did not change during the supplementation period, neither in plasma nor in breast milk. CONCLUSION: Dietary intake of DHA is reflected in the concentration of DHA in breast milk, without affecting the concentration of AA or tocopherol.     

Low doses of eicosapentaenoic acid, docosahexaenoic acid, and hypolipidemic eicosapentaenoic acid derivatives have no effect on lipid peroxidation in plasma

It was of interest to investigate the influence of both high doses of eicosapentaenoic acid (EPA) and low doses of 2- or 3-methylated EPA on the antioxidant status, as they all cause hypolipidemia, but the dose required is quite different. We fed low doses (250 mg/d/kg body wt) of different EPA derivatives or high doses (1500 mg/d/kg body wt) of EPA and DHA to rats for 5 and 7 d, respectively. The most potent hypolipidemic EPA derivative, 2,2-dimethyl-EPA, did not change the malondialdehyde content in liver or plasma. Plasma vitamin E decreased only after supplementation of those EPA derivatives that caused the greatest increase in the fatty acyl-CoA oxidase activity. Fatty acyl-CoA oxidase activity increased after administration of both EPA and DHA at high doses. High doses of EPA and DHA decreased plasma vitamin E content, whereas only DHA elevated lipid peroxidation. In liver, however, both EPA and DHA increased lipid peroxidation, but the hepatic level of vitamin E was unchanged. The glutathione-requiring enzymes and the glutathione level were unaffected, and no significant changes in the activities of xanthine oxidase and superoxide dismutase were observed in either low- or high-dose experiments. In conclusion, increased peroxisomal beta-oxidation in combination with high amounts of polyunsaturated fatty acids caused elevated lipid peroxidation. At low doses of polyunsaturated fatty acids, lipid peroxidation was unchanged, in spite of increased peroxisomal beta-oxidation, indicating that polyunsaturation is the most important factor for lipid peroxidation.     

Prevention by inhibitors of arachidonic acid cascade of liver carcinogenesis, cirrhosis and oxidative DNA damage caused by a choline-deficient, L-amino acid-defined diet in rats

Effects of inhibitors of arachidonic acid (AA) cascade on the development of fatty liver, cirrhosis, glutathione S-transferase placental form (GST-P)-positive preneoplastic nodules, neoplastic nodules and generation of 8-hydroxydeoxyguanosine (8-OHdG), caused by a choline-deficient, L-amino acid-defined (CDAA) diet, were examined in Fischer 344 male rats by feeding CDAA diet supplemented with the inhibitors for 12 and 30 weeks. None of the inhibitors affected fatty liver. Among cyclooxygenase (COX) inhibitors, an irreversibly acting acetylsalicylic acid and a long-acting piroxicam, and to a much lesser extent the short-acting ibuprofen but not indomethacin, inhibited the development of cirrhosis, GST-P-positive and neoplastic nodules and generation of 8-OHdG. A phospholipase A2 inhibitor p-bromophenacylbromide (BPB) also exerted similar but lesser extent of inhibitory effects. Lipoxygenase inhibitors quercetin and nordihydroguiaretic acid inhibited GST-P-positive nodules but not cirrhosis or 8-OHdG. Present results suggest that perturbed AA cascade, particularly augmented COX pathway, might play key roles in the causation of liver lesions in the CDAA diet model.     

Effects of rilmenidine on rats made insulin resistant and hypertensive by a high fructose diet

This study was aimed to determine the effects of rilmenidine, an hypertensive drug, in an animal model of hypertension associated with insulin resistance, i.e. rats fed on a high fructose diet. Wistar rats were fed during four weeks either on a standard diet (S) or on a high fructose diet (F, 34.5% de fructose). In half of the F groups, rilmenidine (1 mg/kg/day) was added to the drinking water during the two last weeks of the diet (FR). Arterial blood pressure as well as insulin efficiency were determined at the end of the four weeks. Body weight gain was higher in F than in S rats (66 +/- 8 g versus 45 +/- 8 g; p < 0.05), this was prevented by rilmenidine treatment (32 +/- 2 g). Arterial systolic blood pressure was increased in F rats (162 +/- 2 vs 155 +/- 2 mmHg; p < 0.05), rilmenidine brought this value back to normal (149 +/- 3 mmHg). During the euglycemic hyperinsulinemic clamp, glucose utilization was lower (10 +/- 1 vs 14 +/- 1.5 mg/min/kg; p < 0.05) and hepatic glucose production higher (1 +/- 0.01 vs 0 mg/min/kg; p < 0.01) in F than in S rats. These changes in insulin action were totally abolished by rilmenidine. These data demonstrate that rilmenidine can ameliorate the deleterious effects of a high fructose diet, i.e. weight gain, hypertension and resistance to the effects of insulin Rilmenidine could represent a potential therapeutic agent for the treatment of hypertension associated with metabolic disorders such as syndrom X and obesity.     

Comparative costs of family planning services and hospital-based maternity care in Turkey

The effect of dietary fats on the chemical composition and enzyme activities has been studied in intestinal brush border membranes (BBM) or rats. Animals were given commercial rat pellet diet (RP) or semisynthetic diet rich in either saturated [coconut oil (CCO))] or polyunsaturated [n-6, corn oil (CO) or n-3, fish oil (FO)] fat at the 10% level for 5 weeks. The membrane cholesterol/phospholipid ratio was augmented in CO- or RP-fed rats. There was an increase in level of saturated fatty acids in BBM from CCO- or FO-fed animals. n-3 polyunsaturated fatty acid content was raised in FO-fed rats, while the proportion of linoleic acid and arachidonic acid was enhanced in animals given a CO diet. Membrane fluidity was in the order of CCO < RP = CO < FO. The membrane hexose content was high (p < 0.05) in the CCO group. Hexosamines were elevated (p < 0.05) in CCO- or FO-fed rat brush borders. Membrane fucose was unaltered, while sialic acid content was elevated in CO- (p < 0.05) and FO- (p < 0.01) fed vs. CCO-fed rats. Lectin binding to brush borders corroborated these findings. The activities of alkaline phosphatase, sucrase and lactase were augmented (p < 0.001) in CCO-fed animals. Leucine-aminopeptidase and sucrase activities were depressed by FO feeding. The activities of PNP-beta-glycosidases were the highest in FO-fed rats. These results indicate that dietary fat quality markedly affects microvillus membrane lipid composition, glycosylation and enzyme functions in rat intestine.     

Carnitine contents in remnant liver, kidney, and skeletal muscle after partial hepatectomy in rats: randomized trial

Carnitine, an important carrier of free fatty acid that is transported into mitochondria for beta-oxidation, was thought to be one of the key factors in the regulation of liver regeneration. If the carnitine content is insufficient in the hepatocyte, it might impair the energy substrate's transport and the energy charge required for cell regeneration. The purpose of this study is to evaluate the changes of carnitine content in remnant liver, kidney, and skeletal muscle simultaneously after partial hepatectomy in rats. Partial hepatectomy with resection of the median and left lateral lobes was performed on male Wistar rats. Rats with a sham operation comprised a control group. This study was an experimental randomized trial. Ten rats from each group were sacrificed before the operation and at 6, 24, 48, and 72 hours after the operation. The carnitine content, as total and free forms, in remnant liver, kidney, and skeletal muscle were quantified by high-performance liquid chromatography. The carnitine contents in the remnant liver increased significantly at 6, 24, and 48 hours after partial hepatectomy (p < 0.01). The increase of total carnitine content was more obvious than that of the free form. In contrast, the decreasing concentrations of total carnitine and free carnitine in the kidney were significant (p < 0.01). In skeletal muscle the total carnitine content decreased to a small extent, and it was observed only at 6 hours after partial hepatectomy (p < 0.05). It is suggested that remnant liver promoted the generation of carnitine, whereas kidney and skeletal muscle released their stored carnitine at an early stage after partial hepatectomy. As a result, the influx of the carnitine into hepatocytes increased at the regenerative stage. The carnitine content of remnant liver is sufficient during the early posthepatectomy stage.     

Liver metastasis rare in colorectal cancer patients with fatty liver

BACKGROUND/AIMS: As no reports in terms of the relationship between fatty liver and liver metastasis of colorectal cancer clinicopathological analysis of colorectal cancer patients with fatty were found a liver was carried out. PATIENTS AND METHODS: Among 839 patients with single colorectal carcinoma who underwent operations at our department between 1985 and 1994, 121 patients were designated as fatty liver using ultrasonography (FL group). The remaining 718 non-fatty liver patients with colorectal cancer (NFL group) were compared to the FL group regarding clinicopathological aspects. RESULTS: (1) There were only two patients who had liver metastasis in the FL group (1.7%), while the NFL group included 115 patients with liver metastasis (16.0%) (p < 0.01). (2) The five-year survival rate of the FL group was 95.7%, which was significantly higher than that in the NFL group (9.8%) (p < 0.001). (3) In the multivariate analysis, the fatty liver was identified as an independent prognostic factor. CONCLUSIONS: The FL group had a much better prognosis compared to the NFL group. Especially, liver metastasis was extremely rare in the FL group. We believe that these results will lead to the clarification of the liver metastasis mechanism.     

Comparative changes in the liver of female Fischer-344 rats after short-term feeding of a semipurified or a semisynthetic L-amino acid-defined choline-deficient diet

Groups of female Fischer-344 rats were fed a semipurified choline-deficient (CD) diet, or a semisynthetic L-amino acid-defined choline-deficient (CDAA) diet, for up to 12 wk and effects of the 2 diets on the liver were compared. Steatosis was diffuse and more severe throughout in rats fed the CDAA diet than in rats fed the CD diet. Greater elevations in serum aspartate and alanine aminotransferase activities were also present in the former rats, along with higher 2-bromodeoxyuridine labeling indices in the liver. Discrete amounts of 8-hydroxyguanine were detected in liver DNA, but were not significantly different in rats fed the 2 diets, or from those present in a group of control rats killed at 0 time. Glutathione S- transferase placental form-positive focal lesions were not observed in any of the rats. The results show that the CDAA diet causes more severe degrees of steatosis and liver cell death and proliferation than the CD diet, raising the possibility that it may, in contrast to the CD diet, result in the eventual induction of hepatocellular carcinomas in female Fischer-344 rats.     

Thrombosis with outflow obstruction delays thrombolysis and results in chronic wall thickening of rat veins

PURPOSE: An in vivo model of acute deep venous thrombosis was developed in rats to assess the role of venous thrombosis and outflow obstruction in recanalization and development of secondary wall changes. METHODS: The left femoral veins of male Sprague-Dawley rats were thrombosed either by means of proximal ligation (obstruction, group A, n = 38) or by means of temporary 24-hour occlusion with a microvascular clamp (unobstructed, group B, n = 20). Right femoral veins served as controls. The rats were killed at intervals over 5 weeks. Wall thickness was compared among groups by means of counting of cells on representative sections through the midvein area. Thrombi were indirectly quantitated with a radiolabeled fibrinogen assay in a parallel series of rats. RESULTS: Control veins showed no evidence of cellular or structural changes. Early thrombus extension was seen in group A (peak at day 4) followed by recanalization after 2 weeks. Group A veins had marked wall thickening (27 +/- 7 vs 6 +/- 2 cells, p < 0.01, peak at 10 days) consisting of smooth muscle-type, neointimal, and medial cellular proliferations. Within 2 to 3 weeks, local neovascular channels had grown to bypass the outflow obstruction, and resumption of normal cephalad flow was seen. At the same time neointimal proliferation regressed, but medial cellular growth persisted, resulting in chronic wall thickening (11 +/- 3 vs 5 +/- 1 cells, p < 0.01, after 21 days). In contrast, group B veins exhibited no thrombus extension, had significantly less wall thickening (13 +/- 2 vs 5 +/- 1 cells, p < 0.01, peak at 4 days), and did not induce growth of local collateral blood vessels. Within 2 weeks, group B veins regained normal appearance and resumed normal flow. CONCLUSIONS: Thrombosis of rat femoral veins without chronic obstruction results in rapid lysis of thrombus and transient proliferative changes. In contrast, thrombosis with chronic outflow obstruction results in delayed recanalization, early extension of thrombus, and development of vigorous and persistent proliferative cellular responses. Thrombus-induced chronic wall thickening may be an important factor in development of postthrombotic venous insufficiency.     

Inhibitory effect of the non-steroidal anti-inflammatory drugs, indomethacin and piroxicam on 2-acetylaminofluorene-induced hepatocarcinogenesis in male ACI/N rats

The modifying effects of the non-steroidal anti-inflammatory drugs, indomethacin (IMC) and piroxicam (PC) on hepatocarcinogenesis induced by 2-acetylaminofluorene (AAF) were investigated in male ACI/N rats. Rats were divided into 6 groups: group 1 was fed a diet containing 200 ppm AAF for 16 weeks, starting at 6 weeks of age; group 2 was fed an AAF together with 130 ppm PC-containing diet; group 3 received an AAF diet and IMC (10 ppm) in their drinking water; group 4 was fed a PC diet alone; group 5 was given IMC alone; and group 6 served as controls. The PC diet, or the drinking water containing IMC, was given to the rats starting at 5 weeks of age until 1 week after the carcinogen exposure. At termination of the experiment (week 36), the incidences of iron-excluding altered liver cell foci (24.2 +/- 5.2/cm2) and liver cell tumors (1/10, 10%), and the tumor multiplicity (0.10/rat) in rats of group 2 were significantly smaller than those of group 1 (foci incidence, 42.6 +/- 6.7/cm2; tumor incidence, 10/10, 100%; and multiplicity, 4.00/rat) (P < 0.05). Similarly, the incidence of iron-excluding hepatocellular foci (27.4 < 1.2/cm2) and liver cell tumors (1/10, 10%) and the tumor multiplicity (0.10/rat) in rats of group 3 were significantly lower than those of group 1 (P < 0.05). There were no liver cell lesions (foci and neoplasms) in rats of groups 4, 5 and 6. Thus, PC and IMC inhibited the hepatocarcinogenesis induced by AAF when administered concurrently with the carcinogen and the results may indicate possible involvement of altered arachidonic metabolism in the initiation phase of AAF-induced liver carcinogenesis.