PubMed Health⌕ Search

Biomedical subjects

S Shimoda

Publications and source records attributed to S Shimoda.

At least 19 recordsLinked to original sources
PubMed1999

A novel treatment of patients with chronic hepatitis C.

OBJECTIVES: Interferon alpha-2b therapy for Chronic Hepatitis C patients has been unsatisfactory. Recombinant Granulocyte Macrophage Colony-Stimulating Factor has been shown to have anti-viral effects in vivo and in vitro via cytokines release. Recently its effects on chronic hepatitis B and possibly chronic hepatitis C were reported. We, decided to conduct a pilot study to evaluate the anti-viral effects of recombinant human GM-CSF mono-therapy in patients with chronic hepatitis C and to assess its side effects. METHODS: A total of 10 patients (male/female: 5/5) (age: 34-60, mean: 45) seen in our center between 2/95 to 2/96 were randomly selected to receive recombinant human Granulocyte Macrophage Colony-Stimulating-Factor at 125 ug/m2 subcutaneously daily for two weeks followed by three times weekly for another 8 weeks. Biochemical (ALT) and viral (HCV-RNA) responses were measured prior to treatment and at weeks four and eight. Side effects were recorded. RESULTS: Six out of the ten patients treated had significant viral reduction but none became negative. Eight out the ten patients treated showed biochemical improvement and three out of the eight had normalized liver enzymes. Age, sex, stage of the disease did not influence the response but there seems to be a tendency for patients with higher pre-treatment viral level to respond virally. Side effects are minimal and well-tolerated. CONCLUSION: Recombinant human Granulocyte Macrophage Colony-Stimulating-Factor in the dose used has anti-viral effects in the majority of the chronic hepatitis C patients studied. Side effects are minimal and well tolerated. Further study with higher doses and longer duration is needed to prove its clinical efficacy in treating patients with chronic hepatitis C.

Adult↗
PubMed1998

Identification and precursor frequency analysis of a common T cell epitope motif in mitochondrial autoantigens in primary biliary cirrhosis.

The immunodominant antimitochondrial antibody response in patients with primary biliary cirrhosis (PBC) is directed against the E2 component of the pyruvate dehydrogenase complex (PDC-E2). Based on our earlier observations regarding peripheral blood mononuclear cell (PBMC) T cell epitopes, we reasoned that a comparative analysis of the precursor frequencies of PDC-E2 163-176-specific T cells isolated from PBMC, regional hepatic lymph nodes, and from the liver of PBC patients would provide insight regarding the role of T cells in PBC. Results showed a disease-specific 100-150-fold increase in the precursor frequency of PDC-E2 163-176-specific T cells in the hilar lymph nodes and liver when compared with PBMC from PBC patients. Interestingly, autoreactive T cells and autoantibodies from PBC patients both recognize the same dominant epitope. In addition, we demonstrated cross-reactivity of PDC-E2 peptide 163-176-specific T cell clones with PDC-E2 peptide 36-49 and OGDC-E2 peptide 100-113 thereby identifying a common T cell epitope "motif" ExETDK. The peptide 163-176-specific T cell clones also reacted with purified native PDC-E2, suggesting that this epitope is not a cryptic determinant. These data provide evidence for a major role for PDC-E2 peptide 163-176 and/or peptides bearing a similar motif in the pathogenesis of PBC.

Adult↗
PubMed1998

Enhanced, simplified glucose sensors: long-term clinical application of wearable artificial endocrine pancreas.

At present, 2 major problems should be solved before long-term application of the wearable artificial endocrine pancreas, the development of a reliable and stable glucose monitoring system and the development of a subcutaneous insulin infusion algorithm. With either a miniaturized extracorporeal glucose monitoring system based on microdialysis sampling method or a ferrocene-mediated needle-type glucose sensor covered with highly biocompatible membrane, poly(2-methacryloyloxyethyl phosphorylcholine-co-n-butyl methacrylate) (poly[MPC-co-BMA]) membrane, subcutaneous glucose concentrations could be monitored for 7 days without any in vivo calibrations, followed by 14 days with one point calibration. Considering the management and safety of the insulin delivery route, subcutaneous insulin infusion is obligatory. With the subcutaneous insulin infusion algorithm using a short acting insulin analogue (Insulin Lispro), near physiological glycemic control could be established in diabetic patients without showing any delayed hyperinsulinemia or hypoglycemia. The wearable artificial endocrine pancreas is now recognized as an excellent therapeutic tool for regulating blood glucose excursions physiologically in ambulatory diabetic patients on a long-term basis.

Animals↗
PubMed1997

Decreased production of nitric oxide by LPS-treated J774 macrophages in high-glucose medium.

We investigated the effect of high glucose levels on nitric oxide (NO) production by J774 macrophages treated with LPS. High concentrations of glucose inhibited the accumulation of nitrite, an indicator of NO production, and the steady state levels of inducible NO synthase mRNA were significantly reduced. While phorbol myrystate acetate mimicked the inhibition of NO production by glucose, the aldose reductase inhibitor ONO2235 did not alter NO production under normal or high glucose conditions. High glucose levels also prevented the increase in cellular levels of tetrahydrobiopterin, an essential cofactor of NO synthase. The reduction of inducible NO production by elevated glucose levels may therefore be involved in the pathophysiology of diabetes.

Aldehyde Reductase↗
PubMed1997

Analysis of T-cell receptor beta of the T-cell clones reactive to the human PDC-E2 163-176 peptide in the context of HLA-DR53 in patients with primary biliary cirrhosis.

T-cell-mediated autoimmune mechanisms are considered to be involved in the pathogenesis of primary biliary cirrhosis (PBC). In the previous study, we identified the immunodominant T-cell epitope on the E2 component of pyruvate dehydrogenase complex (PDC-E2) in patients with PBC who have HLA-DRB4*0101. In this report, we revealed that the frequency of the T cells reactive to the human PDC-E2 163-176 peptide is significantly increased in the peripheral blood of patients with PBC as compared with healthy subjects. We also confirmed that these T cells were all restricted with HLA-DRB4*01 (DR53) by using HLA-DR-transfected L cells. These results together with the evidence that the immunodominant B-cell epitope overlaps with the human T-cell epitope of the PDC-E2 antigen indicate that the T cells reactive to this epitope are closely associated with the pathogenesis of PBC at least in patients who have HLA-DR53. Therefore, we analyzed the T-cell receptor (TCR) Vbeta sequence of the five different T-cell clones and the three T-cell clones derived from three patients with PBC and healthy subjects, respectively, which are reactive to the human PDC-E2 163-176 peptide in the context of HLA-DR53. The Vbeta- and the Jbeta-gene usages were diverse among the T-cell clones (Vbeta11-Jbeta1.4, Vbeta8-Jbeta1.2, Vbeta12-Jbeta2.1, Vbeta10-Jbeta1.5, and Vbeta20-Jbeta2.1) in patients with PBC. By contrast, in the third complementarity determining region (CDR3), G was frequently found and GXG or GXS motif was identified in all T-cell clones. Moreover, RGXG motif was found in three clones generated from two patients. In healthy subjects, the Vbeta- and the Jbeta-gene usages were also diverse, and GXG and RGXG motif were found. These results indicate that the T cells may recognize the ligand (the human PDC-E2 163-176 peptide/HLA-DR53 complex) using the limited motif in the CDR3 region and that the design of CDR3-specific immunotherapy would be possible using these motifs.

Amino Acid Sequence↗
PubMed1997

The role of T cells in primary biliary cirrhosis.

While fervently studied by several laboratories, the role of T cells in the pathogenesis of primary biliary cirrhosis (PBC) still remains a mystery. The studies concerning cell phenotype, antigen specificity, and major histocompatibility complex (MHC)-T-cell receptor (TCR) interaction gathered thus far all address important aspects of this intriguing conundrum. However, the lack of an animal model and the genetic diversity of the human population with PBC make this task even more difficult. The possibilities regarding immune therapy resulting from such studies are of great importance. Future work concerning the T-cell epitopes--for both the pyruvate dehydrogenase complex (PDC), its related mitochondrial autoantigens, and any as yet unidentified PBC-specific autoantigens--may provide valuable information with regard to disease therapy. In addition, knowledge with regard to TCR usage and MHC association will help to clarify the pathogenic mechanisms of this enigmatic disease.

Antigen-Presenting Cells↗
PubMed1997

Induction of tetrahydrobiopterin synthesis in rat cardiac myocytes: impact on cytokine-induced NO generation.

Because tetra-hydrobiopterin (BH4) is an essential cofactor for nitric oxide (NO) formation, we investigated whether BH4 synthesis is required for cytokine-induced NO production in cultured rat cardiac myocytes. The total biopterin content of untreated cardiac myocytes was below our limit of detection. However, treatment with interleukin-1 alpha (IL-1 alpha) + interferon-gamma (IFN-gamma) caused a significant rise in biopterin levels and induced NO synthesis. 2,4-Diamino-6-hydroxypyrimidine (DAHP), a selective inhibitor of GTP cyclohydrolase I (the rate-limiting enzyme for de novo BH4 synthesis), completely abolished the elevation in biopterin levels induced by IL-1 alpha + IFN-gamma. DAHP also caused a concentration-dependent inhibition of (IL-1 alpha + IFN-gamma)-induced NO synthesis. Similarly, N-acetylserotonin, an inhibitor of the BH4 synthetic enzyme sepiapterin reductase, blocked increases in biopterin levels as well as NO synthesis induced by IL-1 alpha + IFN-gamma. Sepiapterin, substrate for BH4 synthesis via the pterin salvage pathway, prevented this inhibition by DAHP or N-acetylserotonin, and this effect was blocked by methotrexate. Sepiapterin and, to a lesser extent, BH4 dose dependently enhanced (IL-1 alpha + IFN-gamma)-induced NO synthesis, suggesting that the concentration of BH4 limits the rate of NO production. Inducible NO synthase mRNA and GTP cyclohydrolase I mRNA were induced by IL-1 alpha + IFN-gamma in parallel. We thus demonstrate that BH4 synthesis is an absolute requirement for induction of NO synthesis by cytokines in cardiac myocytes.

Animals↗
PubMed1997

Closed-loop subcutaneous insulin infusion algorithm with a short-acting insulin analog for long-term clinical application of a wearable artificial endocrine pancreas.

Considering the management and safety of the insulin delivery route when a wearable artificial endocrine pancreas is applied to ambulatory diabetic patients on a long-term basis, we developed a s.c. insulin infusion algorithm by analyzing the dynamics of a s.c. injected short-acting insulin analog (Insulin Lispro) by a three-compartment model. Principally the insulin infusion algorithm was developed as a transfer function with the first-order delay in both proportional and derivative actions to blood glucose concentrations. The parameters for this algorithm were calculated to simulate a physiological plasma insulin profile as closely as possible. By applying this algorithm with regular insulin, diabetic patients showed a 2 h postprandial hyperglycemia and a delayed hyperinsulinemia, followed by hypoglycemic episodes 4-5 h after oral glucose load, just as observed in the computer simulation study. However, using Insulin Lispro, a near-physiological glycemic control (postprandial blood glucose of 153.1 +/- 8.3 mg/100 ml at 60 min and 90.3 +/- 7.1 mg/100 ml at 180 min, respectively) could be achieved without showing any delayed hyperinsulinemia or hypoglycemia. Daily glycemic excursions were also controlled near-physiologically and although the daily insulin requirement (731.7 +/- 160.5 mU/kg/day) was slightly higher, it was not significantly different from that with i.v. insulin infusion (622.3 +/- 142.6 mU/kg/day). These results indicate that the application of s.c. insulin infusion algorithm with Insulin Lispro is feasible for long-term glycemic control with a wearable artificial endocrine pancreas in ambulatory diabetic patients.

Adult↗
PubMed1996

Ursodeoxycholic acid inhibits the induction of nitric oxide synthase.

Ursodeoxycholic acid was recently recognized as an effective agent in the treatment of primary biliary cirrhosis. Since the beneficial effect of ursodeoxycholic acid therapy appears to be mediated in part by an immune mechanism, we evaluated the effects of ursodeoxycholic acid on the synthesis of nitric oxide (NO), elevated production of which could be important in the pathogenesis of autoimmunity. Ursodeoxycholic acid (0.1-1000 microM) inhibited NO production by bacterial lipopolysaccharide-activated J774 macrophages in a concentration-dependent fashion, but the cytotoxicity was also evident at higher concentrations (250 and 1000 microM). Ursodeoxycholic acid did not have any effect on the activity of NO synthase that had already been induced. Treatment with lipopolysaccharide led to a significant expression of NO synthase mRNA that was significantly reduced by ursodeoxycholic acid. Findings indicated that ursodeoxycholic acid inhibited NO synthesis by inhibiting the induction of NO synthase, rather than its catalytic activity. Ursodeoxycholic acid therapy may exert a beneficial effect, in part, by attenuating the production of NO.

Animals↗
PubMed1996

Molecular scanning of the insulin receptor substrate-1 (IRS-1) gene in Japanese patients with NIDDM: identification of five novel polymorphisms.

Since the insulin receptor substrate-1 (IRS-1) is the major substrate of the insulin receptor tyrosine kinase and has been shown to activate phosphatidylinositol (PI) 3-kinase and promote GLUT4 translocation, the IRS-1 gene is a potential candidate for development of non-insulin-dependent diabetes mellitus (NIDDM). In this study, we have identified IRS-1 gene polymorphisms, evaluated their frequencies in Japanese subjects, and analysed the contribution of these polymorphisms to the development of NIDDM. The entire coding region of the IRS-1 gene of 94 subjects (47 NIDDM and 47 control subjects) was screened by polymerase chain reaction-single stranded conformation polymorphism (PCR-SSCP) analysis. Seven SSCP polymorphisms were identified. These corresponded to two previously identified polymorphisms [Gly971 --> Arg (GGG --> AGG) and Ala804 (GCA --> GCG)] as well as five novel polymorphisms [Pro190 --> Arg (CCC --> CGC), Met209 --> Thr (ATG --> ACG), Ser809 --> Phe (TCT --> TTT), Leu142 (CTT --> CTC), and Gly625 (GGC --> GGT)]. Although the prevalence of each of these polymorphisms was not statistically different between NIDDM and control subjects, the prevalence of the four IRS-1 polymorphisms with an amino acid substitution together was significantly higher in NIDDM than in control subjects (23.4 vs 8.5%, p < 0.05), and two substitutions (Met 209 --> Thr and Ser809 --> Phe) were found only in NIDDM patients. Equilibrium glucose infusion rates during a euglycaemic clamp in NIDDM and control subjects with the IRS-1 polymorphisms decreased by 29.5 and 22.0%, respectively on the average when compared to those in comparable groups without polymorphisms, although they were not statistically significant. Thus, IRS-1 polymorphisms may contribute in part to the insulin resistance and development of NIDDM in Japanese subjects; however, they do not account for the major part of the decrease in insulin-stimulated glucose uptake which is observed in subjects with clinically apparent NIDDM.

Amino Acid Sequence↗
PubMed1996

Up-regulation of rat adrenomedullin gene expression by endotoxin: relation to nitric oxide synthesis.

The effect of bacterial endotoxin (LPS) on adrenomedullin (AM) gene expression was investigated in cultured rat aortic vascular smooth muscle (VSM) cells and in tissues from anesthetized rats. The addition of LPS together with interferon-gamma to VSM cells resulted in a marked increase in the abundance of AM mRNA as well as the appearance of mRNA for the inducible isoform of nitric oxide (NO) synthase (iNOS). Intravenous injection of LPS into rats also increased AM mRNA abundance and induced iNOS mRNA in lung, heart, liver, and kidney. AM significantly enhanced NO synthesis evoked by LPS and interferon-gamma in cultured VSM cells. These data suggest that AM may contribute to circulatory failure during endotoxin shock, in part, by modulating NO synthesis.

Adrenomedullin↗
PubMed1996

Nitric oxide inhibits cell growth in cultured human thyrocytes.

Effect of NO induced by interleukin-1 (IL-1) or IL-1/interferon- gamma (IL-1/IFN-gamma) was investigated on cell growth using primary cultures of human thyrocytes. Cytokine-induced NO production was associated not only with an increase in cyclic GMP (cGMP) formation but also with an inhibition of cell growth determined by bromo-deoxyuridine (Br-dU) incorporation into DNA. When NO synthesis was blocked by NG-monomethyl-L-arginine (L-MMA), cGMP formation was prevented in parallel with NO production and inversely a restoration of cell growth was evident. S-nitroso-N-acetyl-penicillamine, a NO donor, but not a cell permeable cGMP analog, 8-bromo-cGMP, inhibited cell growth in a dose-dependent manner. The present findings strongly indicate that endogenous NO produced by the cytokine treatment as well as exogenous NO, has a cGMP-independent inhibitory action on human thyrocyte growth.

Cell Division↗
PubMed1996

Effect of cycloheximide on the expression of LPS-inducible iNOS, IFN-beta, and IRF-1 genes in J774 macrophages.

The effect of cycloheximide (CHX) on the gene expression for inducible NO synthase (iNOS), interferon (IFN)-beta, and IFN regulatory factor (IRF)-1 was examined in LPS-stimulated J774 macrophages. LPS caused increased expression of mRNAs specific for iNOS, IFN-beta, and IRF-1 with different kinetics. Addition of CHX resulted in inhibition of the LPS-induced iNOS gene expression and parallel decrease in NO production. In contrast, expression of IFN-beta and IRF-1 genes in response to LPS was potentiated in the presence of CHX. These results indicate that de novo protein synthesis is not required for IFN-beta and IRF-1 gene expression and that ongoing protein synthesis including IFN-beta and IRF-1 may be involved in the induction process of iNOS in mouse macrophages.

Animals↗