The effect of 4-(3,7,11,15-tetramethyl-6,10,14-hexadecatrienoyl)morpholine (E-0712), a new synthetic compound, on liver injury induced by two hepatotoxins in rats was studied. Oral doses of E-0712 four times at 0, 6, 12 and 18 hr significantly attenuated elevated SGPT values and prolonged prothrombin time (PT) at 24, 36, 48, 60 and 72 hr in rats with a single s.c. dose of D-galactosamine in which SGPT values and PT reached the peak within 48 hr. In cases in which a dose of carbon tetrachloride (i.p.) produced peak SGPT values and PT within 36 hr attenuation occurred likewise at 24, 36 and 60 hr. In the control and E-0712-treated rats dosed with D-galactosamine or carbon tetrachloride, SGPT values were positively correlated with PT at 24 hr. In addition, morphological degrees of acidophilic body formation or centrizonal necrosis were significantly reduced by E-0712. These results suggest that E-0712 protects against liver injury, particularly hepatocellular necrosis, induced by D-galactosamine and carbon tetrachloride in rats.

Alanine Transaminase↗

PubMedDate not supplied

Anticalmodulin autoantibody in liver diseases: a new antibody against a cytoskeleton-related protein.

An ELISA has been developed for detection of auto-antibodies against calmodulin. There was a significantly increased frequency (63.1%) of autoantibodies against calmodulin in 103 patients with chronic liver diseases as compared to that (30%) of patients with systemic lupus erythematosus and to that (6.9%) of normal subjects (p less than 0.01). IgG autoantibodies against calmodulin were detected in the patients with acute hepatitis (37.9%), chronic liver disease (45.6%) and also in the patients with systemic lupus erythematosus (30%). IgM autoantibodies against calmodulin were frequently found in patients with liver cirrhosis (52.2%), primary biliary cirrhosis (50%) and autoimmune chronic active hepatitis (38.7%), but rarely in patients with acute hepatitis (13.8%), chronic persistent hepatitis (9.5%) and systemic lupus erythematosus (0%). IgA autoantibodies against calmodulin were frequently found in liver cirrhosis (33.3%), primary biliary cirrhosis (42.9%) and autoimmune chronic active hepatitis (53.6%), but rarely in chronic persistent hepatitis (15.8%), chronic active hepatitis (14.3%) and systemic lupus erythematosus (0%). The occurrences of autoantibodies against calmodulin correlated neither with those of antismooth muscle antibody, antinuclear antibody and antimitochondrial antibody, nor with serum IgG concentrations. Autoantibodies against calmodulin did not cross-react with troponin, myosin light chain, calf thymus DNA and actin. The titer of autoantibodies against calmodulin was decreased by absorption of serum with calmodulin and the liver plasma membrane fraction. The immunoblotting experiment revealed the binding of autoantibodies against calmodulin to calmodulin. IgG fraction from a patient with autoimmune chronic active hepatitis inhibited the activation of phosphodiesterase by calmodulin.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗

PubMedDate not supplied

IgM anti-HBc in anti-HBe positive chronic type B hepatitis with acute exacerbations.

IgM anti-HBc was measured by radioimmunoassay in serially collected serum samples during 20 acute exacerbations which developed in 14 patients with anti-HBe positive chronic type B hepatitis. IgM anti-HBc became positive in 12 of the 14 (86%) patients and in 18 of the 20 (90%) exacerbations, and elevation of IgM anti-HBc which was believed to be significant was also observed in the remaining two patients. In most of the patients who also had determinations of serum hepatitis B virus DNA, the hepatitis B virus DNA became positive. These results suggest that ALT elevation in anti-HBe positive chronic type B hepatitis is associated with active replication of hepatitis B virus. It is considered to be useful to measure IgM anti-HBc for the purpose of identifying the causes of ALT elevation in anti-HBe positive chronic type B hepatitis.

Adult↗

PubMedDate not supplied

The acquired vitamin K-dependent gamma-carboxylation deficiency in hepatocellular carcinoma involves not only prothrombin, but also protein C.

Protein C, one of the vitamin K-dependent plasma proteins synthesized in the liver, was measured immunologically in normal subjects (n = 20), patients with hepatocellular carcinoma (n = 60), liver cirrhosis (n = 60), acute hepatitis (n = 16), chronic hepatitis (n = 19), malignant neoplasms other than hepatocellular carcinoma (n = 35) and patients on warfarin treatment (n = 20). We also assayed gamma-carboxyglutamic acid-complete (carboxylated) protein C in these population by using a monoclonal antibody directed against human protein C, JTC-1, which recognizes the gamma-carboxyglutamic acid domain-related conformational change induced by metal ions. We demonstrated that the plasma of patients with hepatocellular carcinoma contains considerable amounts of gamma-carboxyglutamic acid-incomplete protein C, evidenced by the significantly reduced protein C:gamma-carboxyglutamic acid/protein C:antigen ratios in hepatocellular carcinoma as compared to those seen in normal controls, other liver diseases and other malignant neoplasms (p less than 0.01). In two patients with hepatocellular carcinoma with the reduced protein C:gamma-carboxyglutamic acid/protein C:antigen ratios, successful treatment (transcatheter hepatic arterial embolization or lipiodolization of antitumor agent) led to the very rapid normalization of the ratios. Intravenous administration of vitamin K, however, induced no such effects in three other patients with hepatocellular carcinoma with the abnormality. We conclude that the impaired vitamin K-dependent gamma-carboxylation observed in patients with hepatocellular carcinoma involves not only prothrombin, but also protein C, and that the impairment is not due to vitamin K deficiency.

1-Carboxyglutamic Acid↗

PubMedDate not supplied

Decreased collagen accumulation by a prolyl hydroxylase inhibitor in pig serum-induced fibrotic rat liver.

Hepatic fibrosis was induced in rats by repeated i.p. injections of pig serum. The hepatic hydroxyproline content increased to 2.1 times the normal control level at 6 weeks and to 3.2 times at 10 weeks. When P-1894B, an inhibitor of prolyl hydroxylase, was administered, there was a dose-dependent inhibition of the increase to nearly normal control levels at 6 and 10 weeks. There was also by histology a dose-dependent reduction in the degree of hepatic fibrosis. Hepatocellular damage was minimal and its extent did not vary with the degree of fibrosis or the treatment. P-1894B dose dependently reduced the hydroxylation of peptidyl proline in the fibrotic liver. These data suggest that P-1894B inhibited hepatic fibrogenesis by direct action on collagen but not by protection against hepatocellular damage leading to collagen formation. A prolyl hydroxylase inhibitor may be a candidate for use in treatment of hepatic fibrosis.

Animals↗

PubMedDate not supplied

Embolization of portal-systemic shunts in cirrhotic patients with chronic recurrent hepatic encephalopathy.

PURPOSE: To evaluate the efficacy of embolization of portal-systemic shunts in cirrhotic patients with chronic recurrent hepatic encephalopathy (CRHE). METHODS: Seven cirrhotic patients with CRHE refractory to medical treatment (3 men and 4 women, mean age 66 years) were studied. Five patients had splenorenal shunts, 1 had a gastrorenal shunt, and 1 had an intrahepatic portal vein-hepatic vein shunt. Shunt embolization was performed using stainless steel coils, with a percutaneous transhepatic portal vein approach in 4 patients and a transrenal vein approach in 3 patients. RESULTS: After embolization, the shunt disappeared in 4 patients on either ultrasound pulsed Doppler monitoring or portography. Complications observed in the 7 patients were fever, transient pleural effusion, ascites, and mild esophageal varices. For 3-6 months after embolization, the 4 patients whose shunts disappeared showed minimal or no reappearance of a shunt, and had no recurrence of encephalopathy. The serum ammonia levels decreased and electroencephalograms also improved. One of the 4 patients, who developed mild esophageal varices, required no treatment. Treatment was effective in 3 of the 4 patients (75%) who underwent embolization via a transhepatic portal vein. CONCLUSION: Transvascular embolization of shunts improved the outcome in 4 of 7 patients. The most effective embolization was achieved via the percutaneous transhepatic portal vein approach.

Aged↗

PubMedDate not supplied

Functional organization of the parvocellular red nucleus in the cat.

The experiments were performed on cats under pentobarbital anesthesia. The following results were obtained. (1) Most of the neurons in the rostral part of the red nucleus (RN) were activated by stimulation of the parietal association cortex (P) and the lateral cerebellar nucleus (CN). A number of the neurons were regarded as rubro-olivary since they responded antidromically to inferior olive (IO) stimulation. (2) Stimulation of the P as well as the frontal motor cortex activated IO neurons. A longer and more variable latency in P-induced responses indicated the existence of an indirect connection from the P to the IO. The recording sites for P-induced responses were located in the rostral region of the IO, giving off projection fibers to the cerebellar hemispheral part. After horseradish peroxidase (HRP) injection through recording microelectrodes into the IO where P-induced responses were recorded, small cells labeled retrogradely with HRP were found distributed in the rostral part of the RN. (3) Effects of stimulus to or lesion of the rostral part of the RN revealed that the climbing fiber responses to P stimulation were conveyed through the rubro-olivary pathway originating in the rostral part of the RN. (4) Following HRP injection through recording electrodes into the rostral part of the RN where P-induced responses were recorded, retrogradely labeled cells were seen and located in the P and CN. From these findings, the rostral part of the RN investigated in this study could be regarded as the rubral parvocellular part. The present study suggests that the latero (dentato-)-rubro-olivo-cerebellar circuit forms an internal feedback loop and the P acts on this loop.

Animals↗

PubMedDate not supplied

Formation, characterization, and toxicity of the glutathione and cysteine conjugates of toxic heptapeptide microcystins.

Microcystins LR, YR, and RR, cyclic heptapeptide hepatotoxins produced by cyanobacteria, were synthetically converted into glutathione (GSH) and cysteine (Cys) conjugates. Fast atom bombardment mass spectra showed [M + H]+ ions corresponding to GSH and Cys conjugates of microcystins LR, YR, and RR for the obtained compounds. 1H NMR spectral analyses revealed that two singlet signals of olefinic protons of N-methyldehydroalanine (Mdha) in microcystins disappeared in the conjugates, confirming that thiols of GSH and Cys added nucleophilically to the alpha, beta-unsaturated carbonyl of the Mdha moiety. On examination of the 50% lethal dose (LD50) with intravenous injection using mice, both GSH and Cys conjugates showed reduction in toxicity compared with microcystins, but their toxicity still remained. Microcystin LR and its GSH conjugate were separated and identified in a standard mixture by using a frit-fast atom bombardment liquid chromatography/mass spectrometry (Frit-FAB LC/MS) method. Obtained conjugates in the present study would be important compounds as the standard samples for study of metabolism of microcystins, and the Frit-FAB LC/MS method would be applicable to mass spectrometric identification of metabolites of microcystins.

Animals↗

PubMedDate not supplied

Detection of anti-interferon-alpha 2a antibodies in chronic liver disease.

The occurrence of antibodies to interferon-alpha 2a (anti-IFN-alpha 2a) to recombinant human IFN-alpha 2a was examined in chronic liver disease by a sensitive enzyme-linked immunosorbent assay (ELISA). Naturally occurring IgG and/or IgM anti-IFN-alpha 2a were found in one of 12 cases of chronic persistent hepatitis, four of 18 cases of chronic active hepatitis (CAH), two of 12 cases of liver cirrhosis, six of seven cases of primary biliary cirrhosis, nine of 11 cases of auto-immune CAH and none of 21 normal control subjects. Fifteen patients with viral CAH were treated with recombinant IFN-alpha 2a. Two of them were positive prior to receipt of IFN-alpha 2a and their titres increased after the therapy. Two patients became positive for anti-IFN-alpha 2a after the therapy. Absorption experiments revealed that anti-IFN-alpha 2a cross-reacted with native human leucocyte IFN-alpha and recombinant IFN-alpha 2b but not with recombinant IFN-beta and -gamma. The immunoblotting experiment confirmed the binding of antibodies to IFN. The results of anti-IFN-alpha 2a obtained by antiviral, cytopathic effect assay were in good agreement with those of IgG anti-IFN-alpha 2a, but not with those of IgM antibodies obtained by the ELISA. The ELISA described in the present study is a simple, sensitive and quantitative assay for anti-IFN-alpha 2a. It should be useful in assessing sub-specificities of anti-IFN and provide valuable information to predict the effect of IFN therapy and to elucidate the immunological abnormality in liver disease.

Antibodies↗