Clinical features of hepatocellular carcinoma that occur after sustained virological response to interferon for chronic hepatitis C

Background and Aim: This study investigated the clinical features of hepatocellular carcinoma in patients with sustained virological response to interferon for hepatitis C viral (HCV) infection. Methods: A total of 7715 patients with HCV infection were treated with interferon and followed up for more than 1 year after withdrawal of interferon in 64 Japanese hospitals and clinics between July 1988 and August 2001. Sustained virological response was obtained in 2515 (32.6%) patients. Of these 2515 patients, clinical data were collected for 38 patients in whom hepatocellular carcinoma developed. Sustained virological response was defined as HCV RNA negativity more than 6 months after the termination of interferon. Results: All patients were HCV RNA negative at the time of diagnosis of hepatocellular carcinoma. The median period until the detection of hepatocellular carcinoma was 4.7 years (range 1.4–9.0 years). There were significant improvements in hepatic function including serum albumin, aspartate aminotransferase, alanine aminotransferase, indocyanine green test, platelet count and histological activity grade in comparison with those before interferon therapy and at the onset of hepatocellular carcinoma. The maximum tumor size in patients without medical follow‐up for 1 year or more (median: 60 mm) was significantly larger than in patients who were periodically followed up for 6 months or less (median: 25 mm) (P = 0.002). Conclusions: The present findings emphasize the importance of regular medical follow up of patients with HCV infection, as even patients showing a sustained virological response to interferon and in whom hepatic function has improved have the potential to develop hepatocellular carcinoma.     

Melatonin treatment for rhythm disorder

Abstract We tried melatonin treatment in two patients with non-24 h sleep-wake syndrome, who did not respond to treatments by vitamin B₁₂, bright light therapy, or hypnotics. In one patient, melatonin 5–10 mg improved difficulty in falling asleep and in waking, although it failed to improve the sleep-wake rhythm. In another patient, melatonin 3 mg successfully changed the sleep-wake rhythm from free-running pattern to delayed sleep phase pattern. However, melatonin re-administration after a 4-month drug-free interval failed to improve his free-running sleep-wake rhythm. These results suggest that melatonin acted as a sleep inducer in one patient and as a phase setter in the other, although the effect on the latter patient was transient.     

A Ro/SS-A auto-antibody positive mother's infant revealed congenital complete atrioventricular block,followed by insulin dependent diabetes mellitus and multiple organ failure

We experienced a congenital complete atrioventricular block infant who was born from a Ro/SS-A antibody positive mother. Ro/SS-A antibody was also found in this baby which was presumed to be mediated by the maternal placenta. Temporary cardiac pacing was required at birth and pacemaker implantation was performed at 9 months. At 11 months of age, the baby fell into shock and experienced multiple organ failure because of diabetes mellitus-induced coma. The association between congenital complete heart block and the Ro/SS-A antibody is well known. However, the accompaniment of insulin-dependent diabetes mellitus has not been reported previously. As the Ro/SS-A antigen appears in the cytoplasm of many tissues, the possibility of an association between Ro/SS-A antibody and diabetes mellitus is difficult to deny. We report this rare case to draw attention to the possibility that babies who are born from an Ro/SS-A antibody positive mother may develop diabetes mellitus as well as congenital complete heart block.     

Abnormal cardiac histology in severe intrauterine growth retardation infants

Four infants with severe intrauterine growth retardation (IUGR) weighing less than 1000 g at birth developed heart failure and died in our unit, where heart failure of IUGR infants is the main reason of death in extremely low birth-weight infants. The causes of their heart failure are one of the main themes in current neonatal medicine. The subjects of this study were four small for gestational age infants; all died due to heart failure 5 to 10 days after birth. Microscopic specimens of hearts from autopsies were evaluated with respect to the following characteristics: thickness of myocardial fibers, maturation of nuclei, presence of dysgenesis or necrosis in myocardium, and amount of glycogen in the heart. Neither dysgenesis nor infarction of the heart was found but hypoplasia in myocardial fibers and decreased glycogen levels were observed. Maturation delay in myocytes' nuclei did not appear to be severe. We conclude that these infants' hearts failed to adapt to postnatal hemodynamic changes because of inadequate myocardial function and inadequate glycogen reserves.     

EFFECTS OF SEED SAPONINS OF THEA SINENSIS L. (RYOKUCHA SAPONIN) ON ALCOHOL ABSORPTION AND METABOLISM

We evaluated the effects of the seed saponins of Thea sinensisL. on alcohol absorption and metabolism in rats and mice. Anethanolic extract from the seeds of T. sinensis was orally administeredto the rats 1 hr before or 0.5 hr after administration of ethanol(2 g/kg), and the blood ethanol assayed 0.5, 1, 2, 3, and 4hr after ethanol administration. The ethanol level decreasedafter both pie- and post- administration of the extract. Theextract was further purified to obtain a saponin fraction whichwas orally administered to mice 1 hr before ethanol administration.Blood, liver, and stomach were obtained 0, 1, 3, and 6 hr afterethanol administration, and the ethanol, acetaldehyde, acetate,and acetone concentrations in each specimen were measured byhead space gas chromatography. The saponin fraction decreasedthe ethanol levels in the blood and liver but increased thatin the stomach five-fold over the control level, suggestinginhibition of alcohol absorption. The ethanol disappearancetime from the blood was shortened, suggesting the promotionof alcohol disappearance. The acetate and acetone levels wereunaffected. However, the acetaldehyde level decreased in theblood, liver, and stomach. The decreases in the ethanol andacetaldhyde levels in the liver suggested the protective effectsof the seed saponins on the liver. The saponins did not directlyinhibit hepalic alcohol dehydrogenase activity. The seed saponinsof T. sinensis seem to suppress alcohol absorption by slowinggastric emptying and by inhibiting absorption across the cellmembranes of the digestive tract.     

Modification by Nickel of Instrumental Thermoregulatory Behavior in Rats1

Modification by Nickel of Instrumental Thermoregulatory Behaviorin Rats. WATANABE, C, WEISS, B., COX, C, AND ZIRIAX, J. (1990).Fundam. Appl. Toxicol. 14, 578–588. The effects of NiCl₂on the colonic temperature and thermoregulatory behavior (TRB)of rats were examined. TRB was evaluated in an instrumental(operant) setting in which rats were required to press a leverto obtain convectional heat (SEEK) or to avoid heat (ESCAPE).Orthogonal polynomial regression was used to describe the responsepatterns in both the SEEK and ESCAPE situations. Two milligramsper kilogram of Ni (ip) caused rapid, transient hypothermiaat an ambient temperature of 21°C. When given access toheat reinforcement, rats responded for heat at a lower rateimmediately after 2 or 5 mg/kg of Ni (up to 5–15 min)than after saline. Subsequently, response rates rose 30 minor more after Ni injection. A converse pattern was found withthe heat escape situation. These observations, confirmed bytwo contrasting procedures, indicate that the changes were thermoregulatoryin nature and cannot be explained by nonspecific sup-pressiveor excitatory effects of Ni. They further suggest that Ni-inducedhypothermia results from an altered body temperature set point.The subsequent reversal in behavior probably arises from a directaction of Ni on autonomic effector mechanisms. The origin andbiological significance of these findings require further investigation.Physical requirements and response topography are discussedas critical variables in the interpretation of experiments requiringsimilar responses under different ambient temperatures.     

A Comparison of the Fate of Inhaled Methyl Chloroform (1,1,1-Trichloroethane) Following Single or Repeated Exposure in Rats and Mice

A Comparison of the Fate of Inhaled Methyl Chloroform (1,1,1-Trichloroethane)Following Single or Repeated Exposure in Rats and Mice. Schumann,A.M., Fox, T.R. and Watanabe, P.G. (1982). Fundam. Appl. Toxicol.2:27–32. Male Fischer 344 rats and B6C3F1 mice were exposedby inhalation to 1500 ppm of methyl chloroform (MC) 6 hours/day,5 days/week for approximately 16 months. On the last day ofrepeated exposure ¹⁴C-labeled MC was used. The fate of the ¹⁴C-MCin the repeatedly exposed animals was compared to a group ofrats and mice which had been exposed concurrently for 16 monthsto chamber air (age-matched controls) prior to receiving thesingle 6 hour exposure to 1500 ppm of ¹⁴C-MC. The routes ofexcretion and tissue concentration of ¹⁴C activity were similarbetween the singly and repeatedly exposed rats and mice. Themajor route of elimination of MC was exhalation of the parentchemical In the expired air and constituted approximately 97%of the total recovered radioactivity in rats and 92–94%in mice. The remaining radioactivity (3.9%) was recovered asmetabolized MC in the expired air (¹⁴CO₂) and as nonvolatileradioactivity in the urine, feces, carcass and cage wash. Micewere found to eliminate MC more rapidly via the pulmonary routeand to biotransform approximately 5-fold more MC on a body weightbasis than rats. Repeated exposure to MC did not significantlyaffect the disposition of MC compared to the singly exposedrats and mice. Thus even after long-term repeated exposure toMC, its biotransformation remains limited. Comparison of theresults of the present study to those obtained previously inyoung-adult rats and mice indicates that alterations in thepharmacokinetics of ¹⁴C-MC (increased body burden and decreasedrate of pulmonary elimination) occur with age but not priorrepeated exposure to MC.