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Seventy-five cirrhotic patients with hyperammonemia in ing number of patients with compensated or noncompenthe past or at the time of the study were randomly divided sated cirrhosis are managed in outpatient clinics over a long into two groups (treated with lactulose or nontreated) in 14 period. In these patients, prevention of the above complicahospitals in Japan. Thirty-six cirrhotic patients were diag-tions is necessary in long-term home care to improve the nosed as having subclinical hepatic encephalopathy (SHE), quality of life (QOL). and 39 were diagnosed as non-SHE. SHE was diagnosedIn hepatic encephalopathy, psychoneurological symptoms when the results of all three of the quantitative psychometric are clinically absent before the onset and during the interval tests used (number connection test, and symbol digit and period of encephalopathic episodes. However, subclinical heblock design tests of the Wechsler adult intelligence scale patic encephalopathy (SHE), in which behavior abnormali-[revised]) were abnormal as compared with age-matched ties and impairment in cognitive functions can be shown by normal values. The mean number of abnormal psychometric quantitative psychometric (neuropsychologic) tests, has been test results and the prevalence of SHE were used for a quanti-reported recently in cirrhotic patients who have no history tative evaluation of the efficacy of the lactulose treatment. of encephalopathy, and clinically appear to be free of encephTwenty-two of the SHE patients were treated with lactulose alopathy.1,2 Moreover, recent imaging analysis of the brain (45 mL/d) for 8 weeks, and the other 14 SHE patients did in cirrhotic patients with and without encephalopathy has not receive lactulose. In the SHE patients administered lactu-shown brain atrophy on computed tomography, 3 abnormal lose, the results of the quantitative psychometric evaluation regional cerebral blood flow on single photon emission comwere significantly improved at 4 and 8 weeks after the begin-puted tomography, 4 and high signals in the basal ganglia on ning of the lactulose administration. The SHE had disap-T1-weighted magnetic resonance imaging. Therefore, it is important for the long-term management it persisted in 11 (85%) of the untreated 13 patients. We of cirrhotic patients to understand the presence of these morconcluded that lactulose treatment in cirrhotic patients with phological changes and functional impairments of the brain, SHE is effective with respect to psychometric tests. (HEPA-and to pay attention to changes in daily behavior and sleep. TOLOGY 1997;26:1410-1414.)This approach would be useful for maintaining the compensated stage of cirrhosis over a long period and for reversing Because the treatment for complications of cirrhosis such as hepatic encephalopathy, jaundice, ascites, and gastrointes-the noncompensated cirrhosis to compensated cirrhosis. tinal bleeding has improved, the survival period of cirrhotic Lactulose has been used worldwide for the treatment of patients has been markedly prolonged. Th...

Ursodeoxycholic acid was recently recognized as an effective agent in the treatment of primary biliary cirrhosis. Experimental evidence supporting the usefulness of ursodeoxycholic acid as a potentially beneficial therapeutic agent for primary biliary cirrhosis has been reported from the biochemical and physiological aspects. In this study, we investigated the direct effects of ursodeoxycholic acid on immunoglobulin and cytokine production in vitro using plaque-forming cell assay and enzyme-linked immunosorbent assay. It was demonstrated that ursodeoxycholic acid suppressed the production of IgM, IgG and IgA induced by Staphylococcus aureus Cowan I in peripheral blood mononuclear cells derived from healthy subjects and patients with primary biliary cirrhosis and also in human B lymphoma cell lines. Furthermore, ursodeoxycholic acid suppressed interleukin-2 and interleukin-4 production induced by concanavalin A and interferon-gamma production induced by polyinosinic-polycytidylic acid, but it did not affect interleukin-1 and interleukin-6 production induced by lipopolysaccharide in peripheral blood mononuclear cells. In addition, ursodeoxycholic acid suppressed the concanavalin A-induced thymocyte proliferation mediated by interleukin-1. Cytotoxicity against lymphocytes was not observed at the concentrations of ursodeoxycholic acid used. These results suggest that the beneficial effect of ursodeoxycholic acid in primary biliary cirrhosis is mediated in part by immunosuppression.

The amount of TGF-beta contained in human whey was studied by the colony formation of NRK47F cells. It was noted that a factor inducing colony formation did exist in human whey, and its action was neutralized when anti-TGF-beta antibodies were introduced. This suggests that TGF-beta does exist in human whey. In colostrum, the total amount of TGF-beta was 1365.7 +/- 242.9 ng/ml, of which the active form comprised 728.1 +/- 248.7 ng/ml (n = 21). In late milk, the total TGF-beta was 952.5 +/- 212.6 ng/ml, with an active form of 178.7 +/- 157.3 ng/ml. Thus human milk contains a large amount of active TGF-beta. Furthermore, it was revealed by the reverse transcriptase polymerase chain reaction that mRNAs coding TGF-beta 1 and TGF-beta 2 exist in human milk cells. These results suggest that both TGF-beta 1 and TGF-beta 2 exist in human milk.

Effects of dietary iron deficiency on inductions of putative preneoplastic lesions and oxidative alterations in the livers of rats by a choline-deficient L-amino acid defined (CDAA) diet were examined. Male Fischer 344 rats, 4 weeks old, were used with a total experimental period of 16 weeks, consisting of 4-week pretreatment and 12-week treatment periods (periods A and B respectively). During period A, a choline-supplemented L-amino acid defined (CSAA) or an iron-deficient CSAA diet was administered, and the CDAA or an iron-deficient CDAA diet was fed in period B. Formation of 8-hydroxydeoxyguanosine (8OHdG), a DNA adduct generated by activated oxygen species, in DNA and lipid peroxidation in liver cell membranes were sequentially determined after the beginning of period B. At the end of the experiment, development of gamma-glutamyltransferase (GGT) and glutathione S-transferase placental form (GSTP) positive liver lesions were quantitatively analysed. In the animals fed the CDAA diet, formation of 8OHdG and lipid peroxidation increased with time, and GGT and GSTP positive liver lesions developed. Formation of 8OHdG, lipid peroxidation and the numbers of induced enzyme-altered liver lesions were all reduced in rats fed the iron-deficient CSAA diet in period A and/or the iron-deficient CDAA diet in period B. The present results indicate that iron plays an important role in induction of preneoplastic liver lesions in rats caused by exposure to the CDAA diet possibly in connection with its known catalytic role in generation of highly reactive activated oxygen species.

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In the field of gene therapy using retroviral vectors, it appears impossible to introduce a foreign gene into all target cells. Therefore adjacent cell killing, the socalled bystander effect, caused by genetically modified cells provides therapeutic advantages for gene therapy against cancers. We retrovirally transduced the herpes simplex virus thymidine kinase (HSV-tk) gene into murine and rat hepatocellular carcinoma (HCC) cells. These HSV-tk gene-transduced HCC cells were cocultured with the corresponding parental cells in the presence of ganciclovir, at a concentration not at all cytotoxic to the parental cells. When parental HCC cells were cocultured with their HSV-tk gene-transduced counterparts at a high density at which most cells were in contact with one another, they were markedly eliminated. Conversely, when cocultured at a low density at which none of the cells were in contact, a weak but statistically significant bystander effect was observed. Addition of lysates of HSV-tk gene-transduced cells in the presence of ganciclovir did not cause and killing of parental cells. Furthermore, media conditioned by transduced cells with ganciclovir exhibited weak cytotoxic effects on parental cells. These results indicate that cell-cell contact plays a major causative role in the bystander effect and that minor contributors to this phenomenon are some cytotoxic substance released from transduced cells. Importantly, the bystander effect was induced in vivo as well as in vitro. When mixtures of transduced and untransduced HCC cells were implanted into the flank region of mice, intraperitoneal ganciclovir administration considerably inhibited tumor development, indicating the feasibility of gene therapy with HSV-tk gene and ganciclovir against HCC.

We developed segmental Lp-TAE, which is transcatheter hepatic sub-subsegmental, subsegmental, or segmental chemoembolization using Lipiodol introduced into the tumor-bearing hepatic sub-subsegment, subsegment, or segment as the target area. A total of 98 patients with nonresectable hepatocellular carcinoma (HCC) undergoing segmental Lp-TAE (Seg-Lp-TAE) were studied, and the relationship between the CT pattern observed after Seg-Lp-TAE (Seg-Lp-CT) and the therapeutic results obtained in those patients was evaluated. Seg-Lp-CT was classified into four types (type I, homogeneous; type II, defective; type III, inhomogeneous; and type IV, only slight accumulation, if any) according to the Lipiodol accumulation pattern observed after Seg-Lp-TAE. The cumulative nonrecurrence rates of type I were higher than those of types II-IV. The cumulative survival rates of type Ia, in which Lp accumulation is also seen around the main tumor, were the highest (93.8% at 1 year, 85.9% at 2 years, 85.9% at 3 years, and 57.3% at 4 years). The cumulative survival rates achieved with Seg-Lp-TAE were 89.2% at 1 year, 69.4% at 2 years, 58.9% at 3 years, 44.0% at 4 years, and 30.2% at 5 years, which were higher than those achieved with conventional Lp-TAE. Seg-Lp-TAE is very useful in the treatment of HCC limited to one sub-subsegment, subsegment, or segment, and it is important to choose sub-subsegmental, subsegmental, or segmental Lp-TAE on the basis of the size and site of the tumor as well as the type and the number of feeding arteries.