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Biomedical subjects

T Saibara

Publications and source records attributed to T Saibara.

At least 55 records · Page 3Linked to original sources
PubMed1995

Exacerbation of primary biliary cirrhosis during interferon-alpha 2b therapy for chronic active hepatitis C.

A 60-year-old woman with chronic active hepatitis C was treated with 6 million units of rIFN-alpha 2b daily for two weeks and subsequently three times weekly for several months. Histological examination proved a severe form of chronic active hepatitis C unexpectedly complicated with primary biliary cirrhosis (PBC). Before treatment, levels of serum alkaline phosphatase (ALP) or gammaglutamyltranspeptidase (GGT) had remained within normal limits over six months, although anti-mitochondrial antibody (AMA) was shown to be positive. After eight weeks of therapy, the daily dose of rIFN was reduced to 3 million units because of a marked increase of ALP and GGT, although the serum alanine aminotransferase (ALT) was normalized. Four months later, IFN treatment was suspended because of continuous elevation of the ALP and GGT levels, and administration of ursodeoxycholic acid was substituted. Two months later, the ALP and GGT levels returned to the normal range, although ALT was not normalized and HCV-RNA remained positive. This is the first report case that demonstrates IFN treatment potentially exacerbates PBC associated with chronic active hepatitis C. It is important for treating physicians to keep this association in mind.

Biopsy↗
PubMed1995

The arterial ketone body ratio and serum alpha-fetoprotein level in patients with acute hepatic failure.

Hepatocyte regeneration is essential for recovery in acute hepatic failure, although it requires a large amount of energy. The ratio of acetoacetate to beta-hydroxybutyrate in arterial blood has been reported to reflect the cellular energy charge of hepatocytes, and we proposed that the recovery of the ratio in the early days of acute hepatic failure is essential for survival. However, there is no report on any marker of regeneration to confirm this hypothesis. In this study, we have assessed this ratio and the serum alpha-fetoprotein level sequentially in 26 patients with acute hepatic failure. Ten patients recovered and 16 died. The arterial blood ketone body ratio 3 days after the onset of hepatic encephalopathy of grade II or more was below 0.6 in 15 of the 16 nonsurvivors, whereas that in the 10 survivors was above 0.6. There was a positive correlation between the arterial blood ketone body ratio and the maximal concentration of alpha-fetoprotein (r = 0.465, p < 0.02 by Student's t-test). These data indicate that the arterial blood ketone body ratio is a marker for the capacity of the liver to regenerate and for the prognosis in patients with acute hepatic failure: effective hepatocyte regeneration may be impossible if these metabolic changes in acute hepatic failure impair the hepatocyte energy charge severely.

3-Hydroxybutyric Acid↗
PubMed1995

[Development of apoptosis induced by whole-body irradiation in murine liver].

Apoptosis is known to be induced by radiation. However, the correlation between radiation-induced apoptosis and radiation injury in tumors in vivo has been unclear. In this paper, we report the study of apoptosis induced by whole-body irradiation using an immunohistochemical technique to detect DNA fragmentation in murine liver. A dose of 7 Gy was employed as LD50/30. DNA fragmentation was observed 30 min after radiation, and it peaked between 1 and 6 hours. DNA fragmentation could be detected 48 hours after radiation in capillary endothelium. This study was able to reveal the development of radiation-induced apoptosis in the liver by detecting DNA fragmentation in situ.

Animals↗
PubMed1995

Selective inhibition of human TNF-alpha action by flecainide acetate, an antiarrhythmic drug.

It is now generally accepted that human tumor necrosis factor-alpha (hTNF-alpha) affects not only tumor cells but also normal cells, providing critical tissue damage. hTNF-alpha also enhanced the response of polymorphonuclear neutrophils (PMN) by its priming action and resulted in the increased generation of active oxygen which in turn may be responsible for the tissue injury. Seeking a conventional drug to attenuate the cytolytic activity of tumor necrosis factor (TNF-alpha) and thereby prevent excessive tissue injury, we focused on the cytolytic action of hTNF-alpha against L929 cells, which are sensitive to TNF-alpha, and found that flecainide acetate [N-(2-piperidylmethyl) 1,5-bis-(2,2,2-trifluoroethoxy) benzamide acetate] inhibited specifically the cytolytic action of hTNF-alpha against L929 cells. Flecainide acetate also specifically inhibited the priming action of hTNF-alpha which enhance the formylmethionyl-leucyl-phenylalanine (FMLP)-induced receptor-mediated superoxide (O.2-) generation of human peripheral polymorphonuclear neutrophils (hPMN). The ID50 values for hTNF-alpha induced cytotoxicity in L929 cells and hTNF-alpha primed FMLP-induced O.2- generation of hPMN were 30 and 50-60 microM, respectively. However, the drug does not inhibit the FMLP- or phorbol myristate acetate (PMA)-induced O.2- generation of nonprimed hPMN and has a weak cytotoxic effect on L929 cells. From these results, it is concluded that flecainide acetate suppressed specifically the action of hTNF-alpha.

Animals↗
PubMed1995

Hepatic sinusoidal endothelial cells can store and metabolize serum immunoglobulin.

Sinusoidal inclusion-containing endothelial cells in the liver were investigated with particular interest in their capacity of metabolizing immunoglobulin. Formalin-fixed deparaffinized liver specimens were used for immunohistochemistry, and pronase digestion was proved to be effective for antigen retrieval of immunoglobulin. The inclusions in sinusoidal endothelial cells were strongly immunostained with anti-immunoglobulin (Ig)G, IgA, and IgM antibodies in predigested sections. The complements were not identified immunohistochemically in the inclusions even after pronase treatment. Two women with autoimmune liver disease, who initially represented high levels of serum gamma globulin and abundant inclusion-containing endothelial cells, were studied. The subsequent biopsy after effective corticosteroid therapy demonstrated significant histological improvement as well as the disappearance of inclusion-containing endothelial cells (ICECs). During and after treatment, their serum gamma globulin levels were drastically reduced. In conclusion, the hepatic sinusoidal endothelial cells can take up serum immunoglobulin, probably through a receptor-mediated pathway, and its excessive storage results in the formation of cytoplasmic inclusions that are easily recognized by a light microscope. The stored immunoglobulin may be degraded in the cytoplasm, and the inclusions would disappear in association with the reduction of sinusoidal gamma globulin content. In other words, the intralobular density of inclusion-containing endothelial cells is a morphological predictor for the serum gamma globulin level.

Adrenal Cortex Hormones↗
PubMed1994

Immunological significances of invariant chain from the aspect of its structural homology with the cystatin family.

The primary structure of p31 of invariant chain (Ii-chain) shows about 50% homology with those of the cystatin family which are endogenous cysteine protease inhibitors. The binding domains between Ii-chain and HLA-DR-7 were estimated from the structural homology between cystatin and Ii-chain and also between cathepsins and DR-7, respectively. The QL64-71 and GS76-88 of Ii-chain were estimated to be the binding domains with GG45-51 and VS57-63 of HLA-DR7, respectively. The purified human Ii-chain from spleen is capable of forming four molecular forms from monomer to tetramer by redox-potential dependent disulfide bond formation. The Ii-chain inhibits cathepsin L and H competitively as a dimer and the K(i) value for cathepsin L was 4.1 x 10(-8) M, but cathepsin B was not inhibited at all. The Ii-chain showed mainly a dimer (60 kDa) under the assay condition of cathepsins with cysteine and was not degraded by these cathepsins. The Ii-chain may play an important role in the regulation of antigenic peptide presentation to MHC class II.

Amino Acid Sequence↗
PubMed1994

Hitherto unrecognized arterioles within hepatocellular carcinoma.

The distribution of blood vessels in human hepatocellular carcinoma was studied with the anti-a-smooth muscle actin monoclonal antibody by light and electron microscopy, and with morphometric analysis. a-Smooth muscle actin-positive arterioles were never observed in lobules or pseudolobules of non-cancerous areas, but were frequently seen within hepatocellular carcinomas. Morphometric analysis revealed that most of these arterioles measured between 10 and 25 microns in diameter. The morphology of intratumoural arterioles differed considerably from that of conventional arteries in the portal tracts of the non-cancerous area. The presence of abundant intratumoural arterioles can explain the angiographic hypervascularity of hepatocellular carcinoma and provides a pathological basis for its susceptibility to hypoxia and for arterial embolization as a therapeutic strategy.

Adult↗
PubMed1994

Immunoelectron microscopic observations on Leu-7 positive cells in virus-related chronic liver diseases.

We investigated the liver biopsies of 78 patients with hepatitis virus-related chronic liver diseases (B type; 14 patients, C type; 64 patients) by immunoelectron microscopy with the Leu-7 monoclonal antibody in order to determine the association of NK/K cells in virus-related chronic liver diseases. Most Leu-7 positive cells in the liver had the Pit cell morphology but a few Pit cells were Leu-7 negative. A few Leu-7 positive cells had neither Pit cell nor typical T cell morphology. No ultrastructural difference was observed in Leu-7 positive cells between hepatitis B virus- and hepatitis C virus-related chronic liver diseases. Regardless of virus type and hepatitis activity, the fine morphology of extravascular Leu-7 positive cells differed considerably from intravascular cells. Leu-7 positive cells were regularly seen in the cellular infiltrates but the ratio of Leu-7 positive cells/whole infiltrates was low. There was no correlation between the inflammatory activity of the disease and the level of Leu-7 positive cell infiltration. A virus aetiology (hepatitis-C or hepatitis-B) did not affect Leu-7 positive cell infiltration. We conclude that NK cells play only a small role in the pathogenesis of hepatitis B virus or hepatitis C virus-related hepatocytolysis, during the chronic stage.

Adult↗
PubMed1994

Immunohistochemical identification of Ito cells and their myofibroblastic transformation in adult human liver.

To identify Ito cells in normal and pathological adult human livers, immunohistochemical studies were performed by the avidin-biotin-peroxidase complex method using monoclonal antibodies for alpha-smooth muscle actin (ASMA), desmin, and vimentin. Fifty one needle biopsies, 7 surgically resected specimens, and 5 autopsy specimens were studied. In the normal adult liver vascular smooth muscle cells and pericytes, together with perisinusoidal cells with thin cytoplasmic processes were positive for ASMA. These latter cells formed a loose and discontinuous layer along the sinusoidal walls. Immunoelectron microscopy showed that the ASMA-positive perisinusoidal cells were Ito cells containing fat droplets. The other sinusoidal lining cells were negative for ASMA. In chronic liver disease, ASMA-positive Ito cells showed an increase in number, size, and the intensity of immunostaining in areas of piece-meal necrosis), and formed a continuous cellular network. These cells were dendritic in shape with irregularly elongated cytoplasmic processes and contained an increased amount of microfilaments, in association with loss of the characteristic fat droplets. Thus, their ultrastructural features corresponded to those of myofibroblastic cells. Ito cells showed no staining for desmin in both normal and pathological livers. These results indicate that immunohistochemistry using an anti-ASMA antibody is a sensitive and reliable method for the identification of both normal and transformed Ito cells in adult human livers.

Actins↗
PubMed1994

Mechanism and regulation of antigen processing by cathepsin B.

Cellular and humoral immune responses to vaccines of hepatitis B and rabies as antigens were suppressed by specific inhibitors of cathepsin B, anti-cathepsin B antibody and the specific substrate of cathepsin B. The antigenic peptides of these vaccines are processed by cathepsin B and the fragments are capable of binding with the desetope of MHC class II, beta-chain, because one of the active sites of cathepsin B (14, 15) VN217-222 shares high homology with a part of the desetope, VN57-62, of MHC class II, beta-chain. Rechallenge of the synthesized antigenic peptides of these vaccine molecules shows a strong proliferative response to the splenocyte primed by these vaccines. However, the response to these antigenic peptides was not inhibited by cathepsin B inhibitors. These findings suggest that cathepsin B inhibitors do not inhibit any other processes of immune responses than the proteolytic processing of antigens. Some investigators reported recently that the Ii-chain is degraded by purified cathepsin B in vitro (23-25). However, we showed that the suppression of these immune responses by cathepsin B inhibitors is not due to the inhibition of invariant chain degradation. We found that the invariant chain shares about 40% homology with the cystatin family which are the endogenous inhibitors of cysteine proteases (23, 24). Therefore, the Ii-chain is one of the members of the cystatin superfamily and may participate in the regulation of presentation of antigenic peptides and also antigen processing by cathepsin B.

Amino Acid Sequence↗
PubMed1994

Alpha-smooth muscle actin-positive perisinusoidal stromal cells in human hepatocellular carcinoma.

The purpose of this study is to clarify the morphological characteristics and functional significance of the perisinusoidal stromal cells in hepatocellular carcinoma. The liver specimens surgically resected from 24 patients with hepatocellular carcinoma were studied by electron microscopy and immunohistochemistry using monoclonal antibodies against alpha-smooth muscle actin, vimentin and desmin. In the tissue space between endothelial cells and trabeculae of cancer cells, the stromal cells were frequently found. They were strongly positive for alpha-smooth muscle actin, weakly and less frequently positive for vimentin but negative for desmin. They varied in shape, size and distribution, stretching cytoplasmic processes and occasionally surrounding the trabeculae of cancer cells. They contained considerable amounts of microfilaments that were positive for alpha-smooth muscle actin and condensed in cell periphery. Along the cell membrane, the short dense areas and pinocytotic vesicles were seen. The external lamina incompletely invested the stromal cells. They were always surrounded by amorphous material. In the granulation tissue and fibrotic areas around necrotic cancer tissue, they were increased in size and number. On the other hand, immunohistochemically and ultrastructurally, they closely resembled the Ito cells in the piecemeal necrosis that showed myofibroblastic transformation. These results suggest that the perisinusoidal stromal cells in nonnecrotic cancer tissue produce the extracellular matrix in the tissue space and maintain the cancerous trabecular structure. After necrosis of cancer tissue, they may become activated and actively participate in the fibrosis.

Actins↗
PubMed1994

Plasma exchange and the arterial blood ketone body ratio in patients with acute hepatic failure.

Hepatocyte regeneration in acute hepatic failure is essential for recovery, but requires a large amount of energy. One problem with plasma exchange as supportive therapy in these cases is that massive citrate infusion has an adverse effect on the hepatic energy charge, which may be a serious risk in these patients. The ratio of acetoacetate to beta-hydroxybutyrate in arterial blood has been reported to reflect the cellular energy charge of hepatocytes. In this study, this ratio was assessed before and after plasma exchange in 19 patients with acute hepatic failure. Eight patients recovered and 11 died. The arterial blood ketone body ratio was below 0.6 in all 11 nonsurvivors. It fell to below 0.4 in 10 of them during the first plasma exchange session, and remained below 0.4 for over 12 h in seven of them. On the other hand, the arterial blood ketone body ratio returned to above 0.6 in four of eight surviving patients within 12 h after the first plasma exchange and remained below 0.4 for over 12 h only in two of eight patients. These data indicate that plasma exchange may cause suppression of the arterial ketone body ratio in patients with severe acute hepatic failure. These metabolic changes impair liver metabolism and may make effective hepatocyte regeneration impossible.

3-Hydroxybutyric Acid↗
PubMed1994

DNA typing of HLA class II genes; DRB1*0803 increases the susceptibility of Japanese to primary biliary cirrhosis.

The association between human leukocyte antigens and primary biliary cirrhosis is controversial, but major histocompatibility complex class II antigen DR8 was recently reported to be associated with increased susceptibility for primary biliary cirrhosis in some Caucasians and Japanese. Accordingly, we performed DNA typing of HLA class II genes in Japanese patients with primary biliary cirrhosis. The genotypes of HLA DRB1, DRB3-5, DQA and DQB were determined by polymerase chain reaction and subsequent hybridization with sequence specific oligonucleotides in 31 primary biliary cirrhosis patients and 215 racially matched local controls. DR8 was found in 24 of the 31 primary biliary cirrhosis patients and was highly concentrated in DRB1*0803. The gene frequency of DRB1*0803 was significantly increased in the patients (35.5% vs 7.4%, relative risk = 6.84, p < 0.0001). DQA1*0103 and DQB1*0601 were also increased in the primary biliary cirrhosis patients, in relation to linkage disequilibrium with DRB1*0803 on the same haplotype. In contrast, DQA1*0102 showed a significantly lower frequency in the primary biliary cirrhosis patients (p < 0.05). These data suggest that DRB1*0803 is one of the HLA class II genes related to an increased risk of primary biliary cirrhosis in Japanese individuals.

Adult↗
PubMed1994

The arterial blood ketone body ratio as a possible marker of multi-organ failure in patients with alcoholic hepatitis.

The arterial blood ketone body ratio (AKBR: acetoacetate/3-hydroxybutyrate) within 48 h of admission is reported to be an excellent prognostic indicator for acute hepatic failure. In this study, we assessed the AKBR in 63 patients receiving supportive medical therapy for alcoholic hepatitis, in order to investigate its efficacy for predicting complications and the prognosis. Twelve patients (19%) died and 51 patients (81%) survived. Hepatic encephalopathy, severe coagulopathy, and renal failure were the critical complications (P < 0.01), and the AKBR at 72 h of hospitalization was closely correlated with these complications (P < 0.01), although they could not be predicted in any other way during the early admission period. The AKBR of normal individuals ranged from 1.0 to 2.1 (1.54 +/- 0.26, mean +/- SD), so an AKBR > 1.0 (mean-2SD) was defined as normal. The AKBR value at 48 and 72 h of hospitalization showed a significant difference between survivors and non-survivors (P < 0.01). All survivors showed an increase of the AKBR to above 0.7 at 72 h, with subsequent maintenance of the ratio over 1.0, while eight of the 12 non-survivors had sustained suppression of the AKBR below 0.7 at 72 h. Seven of these eight patients subsequently developed multiple organ failure. These findings suggest that the AKBR could be a possible marker of potentially fatal complications and a poor prognosis in patients with alcoholic hepatitis.

Acetoacetates↗