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Biomedical subjects

S Kawata

Publications and source records attributed to S Kawata.

At least 73 records · Page 4Linked to original sources
PubMed1997

Recombinant interferon-alpha-2a for treatment of chronic hepatitis C: results of a multicenter randomized controlled dose study.

To compare the efficacy of low and relatively high dosages of recombinant interferon (IFN)-alpha-2a in Japanese patients with chronic hepatitis C, as well as to characterize the type of patients who will respond well to a low-dosage treatment, 88 patients with histologically proven chronic hepatitis C were randomly assigned to two treatment groups; one treated with IFN-alpha-2a 6 MU daily for 2 weeks followed by 6 MU three times weekly for 22 weeks (6-MU group), and another given the same initial treatment followed by 3 MU three times weekly for 22 weeks (3-MU group). The rate of sustained normalization of ALT 6 months after the cessation of treatment was 33% in the 3-MU group and 40% in the 6-MU group (p = 0.64). In addition, there was no difference in elimination of serum HCV-RNA 6 months after the cessation of treatment between the 3-MU group (26%) and 6-MU group (29%). Multivariate stepwise regression analysis revealed that serum HCV-RNA level (p = 0.0035) and platelet count (p = 0.0009) were independent variables useful in predicting a sustained response of ALT. The sustained response rate of ALT in patients with a serum HCV-RNA level less than 10(5) copies/ml and serum platelet level above 15 x 10(4)/microliter was 71%, whereas that in patients with a serum HCV-RNA level above 10(5) copies/ml and serum platelet level less than 15 x 10(4)/microliter was 12%. These results indicate that a high rate of sustained response to IFN therapy can be expected in chronic hepatitis C patients with a low serum level of HCV-RNA and a high level of platelets, even if treated with a low dose of IFN.

Antiviral Agents↗
PubMed1997

High concentration of glucose increases mitogenic responsiveness to heparin-binding epidermal growth factor-like growth factor in rat vascular smooth muscle cells.

The effect of a high extracellular glucose concentration on the mitogenic response of rat vascular smooth muscle cells (SMCs) to heparin-binding epidermal growth factor-like growth factor (HB-EGF) was investigated. The mitogenic effect of HB-EGF was significantly greater in SMCs cultured in high glucose (25 mmol/L) than in cells cultured in low glucose (5.5 mmol/L) or at high osmolarity (5.5 mmol/L glucose plus 19.5 mmol/L mannitol). The mitogenic effect of epidermal growth factor (EGF), which shares the EGF receptor with HB-EGF, was not affected by glucose concentration. The mitogenic effect of HB-EGF was greater when incubated with heparan sulfate (HS) isolated from SMCs cultured in high glucose than with HS from cells cultured in low glucose. HS synthesized by cells in high glucose was of smaller molecular size and less sulfated than HS synthesized by cells in low glucose. The abundance of mRNA encoding HS-N-deacetylase/N-sulfotransferase (HS-NdAc/NST), a regulatory enzyme in the biosynthesis of HS, was decreased by high glucose in a protein kinase C-independent manner. These observations suggest that the enhanced mitogenic response to HB-EGF in SMCs cultured in high glucose may be attributable to changes in cell-associated HS. Downregulation of HS-NdAc/NST gene expression by high glucose may be related to the altered HS biosynthesis.

Animals↗
PubMed1997

Chronic inflammatory demyelinating polyneuropathy accompanied by hepatocellular carcinoma.

We report a patient with chronic inflammatory demyelinating polyneuropathy (CIDP) accompanied by hepatocellular carcinoma (HCC). Due to the remarkable weakness in the lower limbs and loss of the position sense, he could not walk. On neurophysiological examination, he had impaired nerve conduction velocities. Biopsied nerve and muscle specimens demonstrated demyelination of nerve fibers and neurogenic degeneration of muscles. After steroid therapy he showed marked improvement in muscle strength and sensory function.

Anti-Inflammatory Agents↗
PubMed1997

Delayed gastric emptying during interferon-alpha therapy in patients with chronic hepatitis C: relief by cisapride.

BACKGROUND: Patients receiving interferon-alpha often experience symptoms such as upper abdominal discomfort, anorexia, and nausea, which suggest a delay in gastric emptying. Reduction of the dosages of interferon-alpha or even interruption of the treatment is sometimes required because of these symptoms. The present study was designed to investigate the effect of interferon-alpha on gastric emptying and to evaluate the effects of cisapride on gastric emptying and upper abdominal symptoms during interferon-alpha therapy. METHODS: Gastric emptying in 14 patients with chronic hepatitis C was estimated by the sulfamethizole capsule method before and 1 and 2 weeks after the beginning of interferon-alpha (6 million U/day) therapy. RESULTS: Before therapy none of the patients complained of upper abdominal symptoms, and all had normal gastric emptying. Interferon treatment delayed gastric emptying in 12 of the patients and induced discomfort and anorexia in 9 of the patients. The administration of cisapride reversed the delayed gastric emptying in six of seven patients and relieved abdominal discomfort and anorexia. CONCLUSIONS: These findings indicate that interferon-alpha delays gastric emptying and suggest that cisapride administration corrects the delayed gastric emptying and relieves the abdominal symptoms associated with interferon-alpha therapy.

Antiviral Agents↗
PubMed1997

[Evaluation of intra-arterial infusion chemotherapy for liver metastasis from gastric cancer].

We evaluated the result of intra-arterial infusion chemotherapy on liver metastasis from gastric cancer. Of 92 cases of metastatic liver tumor, 17 cases received intra-arterial infusion chemotherapy after primary resection. For comparison, we assigned the 17 cases to two groups according to the infused agents. One group was treated with the combination therapy of 5-FU, epirubicin and MMC (FEM group: n = 7), and another with other antineoplastic agents (non-FEM group: n = 10). In the FEM group, the response rate, 1-year survival rate and 50% survival period were 33.3%, 51.4%, 430 days, respectively, while those of the non-FEM group were 10.0%, 10.0%. 147 days. Although there was no significant difference (p = 0.0951), improvements in survival rate and survival period were observed. This implies the possibility that intra-arterial infusion chemotherapy, especially the combination therapy of FEM, is an effective treatment for liver metastasis from gastric cancer.

Aged↗
PubMed1997

[Complication due to arterial infusion chemotherapy for liver metastasis from colorectal cancer].

OBJECTIVES: Arterial infusion chemotherapy is considered to be an extremely effective treatment for liver metastasis from colorectal cancer in terms of its tumor reduction and preventing recurrence in residual liver after resection. However, there still remain some unclear points as to the influence on hepatic artery and bile duct when this treatment is used over the long term. We report some conclusions obtained by examining cases of hepatic arterial occlusion (stenosis) and biliary complication who received this treatment. MATERIALS AND METHODS: Thirty-six cases who received this treatment over 3 months were the objects of this study, with the aim of direct effect against metastatic focus (21 cases) and prevention of recurrence in residual liver (15 cases). The ages were from 27 to 81; 22 cases were male and 14 were female. Indwelling routes of catheter were gastroduodenal artery (GDA) in 28 cases and femoral artery (FA) in 8 cases. Intermittent high-dose infusion (WHF: 5-FU 1,000 mg/m2/5 hrs qw) was adopted as the method. RESULTS: Hepatic arterial occlusion or stenosis was observed in 12 cases (GDA: 10; FA: 2). There seemed to be no correlation with the total dosage of 5-FU or the number of administrations. Even when hepatic arterial occlusion or stenosis occurred, no change was observed in liver function, and there no death was caused by this. However, CT showed a low-density area followed by atrophy in the right lobe in one case with right hepatic arterial stenosis, despite normal portal blood flow. Of the 6 cases which developed obstructive jaundice, 4 were due to the increase of metastatic focus or lymph nodes, and 1 case without dilatation of bile duct died from suspected sclerosing cholangitis. In this case, ALP had been increasing since 1 month before the onset of jaundice. Another case which developed biloma accompanied by the increase of serum bilirubin improved by discontinuance of chemotherapy. CONCLUSION: Since arterial infusion chemotherapy for liver metastasis from colorectal cancer causes hepatic arterial occlusion (stenosis) at a high rate, early detection of abnormalities by liver function test and imaging diagnosis which leads to early treatment is important.

Adult↗
PubMed1996

Localization of heparin-binding epidermal growth factor-like growth factor in human coronary arteries. Possible roles of HB-EGF in the formation of coronary atherosclerosis.

BACKGROUND: Heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) is a newly identified member of the EGF family. Our previous in vitro studies showed that HB-EGF is a potent mitogen and chemoattractant for vascular smooth muscle cells (SMCs), suggesting the role of HB-EGF in the pathogenesis of atherosclerosis. The purposes of the present study were to investigate the localization of HB-EGF in both normal and atherosclerotic human coronary arteries and to elucidate the possible roles of this growth factor in the formation of atherosclerotic lesions. METHODS AND RESULTS: The immunohistochemical localization of HB-EGF, SMCs, macrophages, and EGF receptors (EGFRs) was examined in human coronary arteries obtained at autopsy. The medial SMCs of coronary arteries in neonates, infants, and children consistently synthesized HB-EGF protein. In normal adults, however, the relative number of HB-EGF-positive medial SMCs decreased gradually with age after about 30 years of age. In nonatherosclerotic coronary arteries with diffuse intimal thickening, SMCs of the intima, especially those located in the area of the medial side of the intima, were strongly positive for HB-EGF protein. In atherosclerotic plaques of coronary arteries with eccentric intimal thickening, both SMCs and macrophages in and around the core lesions, in addition to the intimal and medial SMCs located adjacent to the plaque, produced HB-EGF protein. A strong immunostaining of EGFRs was observed in these SMCs, suggesting a close association of HB-EGF and EGFR expression. CONCLUSIONS: These data suggest that HB-EGF might play important roles in the migration of SMCs from the media to the intima, the proliferation of intimal SMCs, and the interaction between SMCs and macrophages in the process of coronary atherogenesis.

Adult↗
PubMed1996

Induction of macrophage colony-stimulating factor receptor (c-fms) expression in vascular medial smooth muscle cells treated with heparin binding epidermal growth factor-like growth factor.

Vascular smooth muscle cells migrate, proliferate, and transform to foam cells during the atherosclerotic process. We have reported that smooth muscle cells derived from the intima of atherosclerotic lesions express the proto-oncogene c-fms and a scavenger receptor, which are not normally expressed in normal medial smooth muscle cells. In the present study, we demonstrated that heparin binding epidermal growth factor-like growth factor (HB-EGF) induced the expression of c-fms and the scavenger receptor in normal human medial smooth muscle cells to the level observed in the intima. The expression of c-fms was partially inhibited by a protein kinase C inhibitor, suggesting that HB-EGF induces c-fms via pathways that are both dependent on and independent of protein kinase C. By contrast, most of the scavenger receptor induction by HB-EGF was suppressed by protein kinase C inhibitors. These results indicate that two characteristic genes of monocyte-derived macrophages were induced by HB-EGF via different mechanisms. The alteration of gene expression in response to HB-EGF may play an important role in the phenotypic change of smooth muscle cells to macrophage-like foam cells during the atherosclerotic process.

Blotting, Western↗
PubMed1996

The effect of hepatitis B virus X gene expression on response to growth inhibition by transforming growth factor-beta 1.

Hepatitis B virus X protein (HBx protein), which seems to be involved in hepatocarcinogenesis, was studied for its effect on cell growth regulation. We examined the response to growth inhibition of transforming growth factor beta 1 (TGF-beta 1) in HBx gene-introduced cells. HBx gene in pRc/CMV was transfected to mink lung epithelial cells (Mv1Lu cells) and a stable transformant was obtained. The inhibition rates of [3H] thymidine incorporation by addition of TGF-beta 1 (0.08 ng/ml) to parent cells and pRc/CMV-transfected cells were 34% and 26%, respectively. However, the inhibition rates in the HBx gene-transfected cells were 3-8%. The amount of TGF-beta type II receptor on the surface of HBx gene-transfected cells was about half of that on the parent or pRc/CMV-transfected cells. Our results indicated that expression of HBx gene reduces the response to growth inhibition by TGF-beta 1.

Animals↗
PubMed1996

Expression of heparin-binding EGF-like growth factor in rat liver injured by carbon tetrachloride or D-galactosamine.

We reported recently that heparin-binding EGF-like growth factor (HB-EGF), a member of the EGF family, is a new hepatotrophic factor for the regeneration of rat liver after partial hepatectomy. The current study examined changes in the amount of HB-EGF mRNA in liver injured by hepatotoxins. The level of HB-EGF mRNA was very low in normal rat liver, but increased markedly in the liver of rats injured by CCl4, showing two peaks, the first at 6 h and the second at 36 h. Western blot analysis showed that HB-EGF protein in the liver of CCl4-treated rats (at 6 h) was increased about 3.4-fold above normal. The level of HB-EGF mRNA also increased markedly in the liver of rats treated with D-galactosamine, showing a major peak at 18 h, and a smaller one at 6 h. These results indicate that HB-EGF may play a role in the regeneration of the liver following hepatotoxic injury.

Animals↗
PubMed1996

Inhibition of cell growth of human hepatoma cell line (Hep G2) by a farnesyl protein transferase inhibitor: a preferential suppression of ras farnesylation.

So far, treatment with anti-cancer agents has failed to achieve satisfactory results in hepatocellular carcinoma. In the process of hepatocarcinogenesis, ras has been shown to play a role. ras requires a farnesyl moiety for activation. It has been found that UCFI-C (manumycin), an antibiotic, inhibits farnesyl protein transferase, an enzyme that catalyzes farnesylation. Therefore, we investigated the effects of UCFI-C on cell growth, prenylation of cellular proteins including ras and Rapl, MAP kinase activity, activities of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, and synthesis of cholesterol in a ras-activated human hepatoma cell line, Hep G2. Treatment with varying concentrations of UCF1-C(10-30 microM for 24 and 72 hr resulted in a time- and dose-dependent inhibition of cell numbers. 3H-Thymidine incorporation was also inhibited in a dose-dependent manner, with 50% inhibition after 44 hr being observed at a concentration of 17 microM. UCFI-C dose-dependently inhibited ras farnesylation and MAP kinase activity, but did not decrease Rap 1++ geranylgeranylation or prenylation of 21-to 26-kDa proteins. Neither the activities of 3-hydroxy-3-methylglutaryl-coenzyme A reductase nor cholesterol synthesis were inhibited. These results suggest that UCFI-C antagonizes the growth of Hep G2 via the suppression of ras farnesylation and could be a lead for the development of new anti-cancer agents blocking the function of oncogenic ras associated with human cancer, including hepatocellular carcinoma.

Alkyl and Aryl Transferases↗
PubMed1996

Regulation of heparin-binding EGF-like growth factor expression by phorbol ester in a human hepatoma-derived cell line.

Heparin-binding EGF-like growth factor (HB-EGF) is a recently identified potent mitogen for smooth muscle cells and fibroblasts. HB-EGF has been shown to be an EGF receptor ligand, and also to stimulate epithelial cell growth. A human hepatoma-derived cell line, Mahlavu, was analyzed for the production of HB-EGF mRNA and active HB-EGF protein. It was found that the cell line synthesized very low or undetectable basal level of HB-EGF mRNA. However, the addition of 12-O-tetradecanoylphorbol-13-acetate (TPA) led to a rapid and transient rise in HB-EGF mRNA level. HB-EGF in Mahlavu cells appears to be regulated by a protein kinase C (PKC) pathway, since PKC inhibitors, H7, staurosporin, and calphostin C, abrogated the induction of HB-EGF mRNA by TPA. Unlike vascular smooth muscle cells, induction of HB-EGF gene transcription by TPA was blocked completely by incubation with cycloheximide, suggesting that protein synthesis may be a prerequisite for HB-EGF gene transcription in Mahlavu cells. Mahlavu cells were also found to release a bioactive HB-EGF-like protein into conditioned medium which stimulates DNA synthesis in EP170.7 cells. This activity was neutralized by an anti-HB-EGF antibody. These results indicate that HB-EGF gene transcription is regulated via a PKC pathway, resulting in secretion of active HB-EGF into the culture medium of hepatoma-derived Mahlavu cells.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1996

Islet-infiltrating t lymphocytes in insulin-dependent diabetic patients express CD80 (B7-1) and CD86 (B7-2).

Insulin-dependent diabetes mellitus (IDDM) results mainly from T cell mediated pancreatic beta cell destruction. To fully activate antigen specific T cells, current evidence suggests that two signals are required. One signal is delivered via the antigen specific T cell receptor (TCR) when engaged by major histocompatibility complex presented antigen (MHC:Ag), the other via the T cell's CD28 when engaged by CD80/86. Recent studies have demonstrated that transgenic mice expressing CD80 on their pancreatic beta cells are susceptible to autoimmune beta cell destruction. To further explore whether CD80/86 expression plays a role in IDDM pathogenesis, we analysed pancreatic biopsy specimens from 16 recent-onset IDDM patients (13 men and 3 women; age 29.7 +/- 8.8 years) for CD80/86 expression. While no biopsy revealed any islet cell specific CD80 or CD86 expression, biopsies from six of the nine patients with insulitis revealed both CD80 and CD86 expression on the islet infiltrating cells. Triple immunofluorescent staining for CD80/86, CD3, and glucagon revealed that the CD80/86-positive cells were also CD3-positive. Of the CD3-positive cells, 19.4% expressed CD80 and 21.7% expressed CD86. CD80 and CD86-positive cells were similarly distributed throughout the inflamed islets. These data suggest that CD28 engagement with CD80/86 may play a pathogenic role in the beta cell destruction underlying IDDM.

Adult↗
PubMed1996

Efficacy of ursodeoxycholic acid therapy in chronic viral hepatitis C with high serum gamma-glutamyltranspeptidase levels.

We administered ursodeoxycholic acid (UDCA) orally, at a daily dose of 600 mg, for 4 months to 36 patients with chronic viral hepatitis C. Another 36 patients with chronic viral hepatitis C, treated with placebo for 4 months, served as controls. None of the patients were alcoholics and none suffering from autoimmune hepatitis. Of the 36 patients in the UDCA-treated group, 13 had high levels of serum gamma-glutamyltranspeptidase (GGT), i.e., exceeding 150 U/l (normal < 50 U/l). Histological examination of liver biopsy specimens obtained from 10 patients in this group before treatment suggested that damage of the interlobular bile ducts was prominent in patients with higher levels of serum GGT. After 1 month of UDCA treatment, significant decreases in the levels of serum GGT, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were observed (P < 0.05 for GGT and AST), and the decreases continued for the 4-month treatment period. The reduction of GGT levels was the most prominent change in the liver function indices; the percent change in the GGT level was -25.2 +/- 4.4 (mean percent change +/- SE) at 1 month and -38.0 +/- 5.0 at 4 months. A significant correlation was observed between the serum delta GGT level (GGT value before treatment minus value after 3 months of treatment) and the total score for morphological injury of the bile ducts (P < 0.05). These results suggested that UDCA has the potential to reverse hepatocellular damage in patients with chronic viral hepatitis C, in whom high GGT levels may be due, in part, to a damaged interlobular bile duct. UDCA may be useful for the treatment of chronic viral hepatitis C, especially in patients exhibiting a high level of GGT.

Administration, Oral↗
PubMed1996

Dominant TCR alpha-chain clonotypes and interferon-gamma are expressed in the pancreas of patients with recent-onset insulin-dependent diabetes mellitus.

In order to clarify the nature of T lymphocytes infiltrating the pancreatic islets of patients with insulin-dependent diabetes mellitus (IDDM), we analysed T cell receptor (TCR) gene transcripts expressed in pancreatic biopsy specimens of patients with recent-onset IDDM. We also investigated the expression of cytokines (interferon-gamma: IFN-gamma; tumour necrosis factor-alpha: TNF-alpha; interleukin-4: IL-4; interleukin-6: IL-6) in the same specimens. The TCR V beta repertoire was not restricted either in the pancreas or the peripheral lymphocytes of IDDM patients. In contrast, the TCR V alpha repertoire was restricted in the pancreas, but not in the peripheral blood lymphocytes, of IDDM patients. The sequence analysis of the complementarity-determining region 3 (CDR3) of the TCR alpha revealed the presence of dominant clonality in alpha chains of T cells in the patients. IFN-gamma mRNA was highly expressed in the pancreas of IDDM patients, while IL-4 mRNA was deficient. A lower level of expression of IL-6 mRNA was detected in the IDDM pancreas than in the control tissue. These results indicate that T cells bearing a distinct TCR alpha chain are selectively retained and activated within the pancreas of recent-onset IDDM.

Adolescent↗
PubMed1996

High levels of transforming growth factor beta 1 in patients with colorectal cancer: association with disease progression.

BACKGROUND & AIMS: Contribution of transforming growth factor beta 1 (TGF-beta 1) to tumor progression has been suggested. However, little is known about the role of TGF-beta 1 in colorectal cancer. Plasma TGF-beta 1 levels and its expression were analyzed in patients with colorectal cancer. METHODS: Plasma TGF-beta 1 levels were measured in 22 patients with colorectal cancer using a TGF-beta 1 enzyme-linked immunosorbent assay. Expression of TGF-beta 1 messenger RNA and immunohistochemical distribution of the protein in colorectal cancer tissues were examined. RESULTS: Plasma TGF-beta 1 levels in patients with colorectal cancer (14.8 +/- 8.4 ng/mL) were significantly higher than in normal controls (1.9 +/- 1.4; n = 22) (P < 0.001). After curative surgical resection, plasma TGF-beta 1 levels decreased in examined patients from 11.9 +/- 6.7 to 3.8 +/- 1.2 ng/mL (P < 0.01). TGF-beta 1 messenger RNA was about 2 1/2 times more abundant in colorectal cancer tissues than in control (P < 0.01). TGF-beta 1 was detected in the cytoplasm of colorectal cancer cells immunohistochemically. Both TGF-beta 1 messenger RNA expression in colorectal adenocarcinoma tissues and its plasma levels were associated with tumor stage of Dukes' classification (P < 0.05). CONCLUSIONS: These results suggest that plasma TGF-beta 1 levels may reflect overexpression of the gene in colon cancer tissues and are associated with disease progression.

Adenocarcinoma↗
PubMed1996

Hepatic cholesterol metabolism in patients with cholesterol gallstones: enhanced intracellular transport of cholesterol.

BACKGROUND & AIMS: Alterations of hepatic cholesterol metabolism in patients with cholesterol gallstones are still controversial. This study investigated whether hepatic cholesterol metabolism is altered in Japanese patients with cholesterol gallstones. METHODS: In this systematic study of 24 middle-aged nonobese and nondiabetic Japanese patients who had cholesterol gallstones and were undergoing elective cholecystectomy, an analysis of three regulatory enzymes in the cholesterol metabolism, as well as cytosolic total and free cholesterol levels and sterol carrier protein 2/nonspecific lipid transfer protein (SCP2/nsLTP) levels, was conducted using liver biopsy samples obtained during surgery. RESULTS: The activities of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, cholesterol 7 alpha-hydroxylase, and acyl-CoA/cholesterol acyltransferase were not significantly different between patients and controls. Nevertheless, patients with gallstones showed tendencies for elevated HMG-CoA reductase activity and protein content and decreased cholesterol 7 alpha-hydroxylase activities. As anticipated, serum levels of 7 alpha-hydroxycholesterol and squalene paralleled these findings. The patients with gallstones also had significantly increased cytosolic total and free cholesterol levels (P < 0.001), which correlated strongly with increased cytosolic levels of SCP2/nsLTP (r = 0.80, P < 0.001 and r = 0.81, P < 0.001, respectively). CONCLUSIONS: The results suggest that intracellular cholesterol transport is enhanced in patients with cholesterol gallstones.

Adult↗