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Biomedical subjects

T Aikawa

Publications and source records attributed to T Aikawa.

At least 37 records · Page 2Linked to original sources
PubMed1997

Induction of osteogenic differentiation by hedgehog proteins.

In this study we asked whether members of the hedgehog gene family are involved in osteogenesis. C3H10T1/2 cells and MC3T3-E1 cells expressed the putative hedgehog receptor patched (Ptc) gene. Medium conditioned by chicken embryo fibroblast cultures expressing either Indian hedgehog or Sonic hedgehog stimulated alkaline phosphatase (APase) activity in cultures of the mouse mesenchymal cell line C3H10T1/2 and the osteoblastic cell line MC3T3-E1. These stimulatory effects were synergistically enhanced by bone morphogenetic protein-2 (BMP-2). Treatment with the amino-terminal portion of recombinant Sonic hedgehog proteins (rShh-N) up-regulated the expression of the Ptc gene within 12 h and increased production of APase in C3H10T1/2. rShh-N and BMP-2 also synergistically stimulated APase activity. rShh-N treatment did not affect the expression levels of Bmp-2, -4, -5, -6 and -7 genes. These findings indicate that hedgehog proteins directly act on osteogenic precursor cells and osteoblasts and stimulate osteogenic differentiation of these cells in co-operation with BMPs.

3T3 Cells↗
PubMed1997

The pharmacokinetics of glycyrrhizin and its restorative effect on hepatic function in patients with chronic hepatitis and in chronically carbon-tetrachloride-intoxicated rats.

The relationships between the pharmacokinetic behaviour of glycyrrhizin and its restorative effect for hepatic function were investigated in patients with chronic hepatitis and in rats chronically treated with carbon tetrachloride (CCl4-treated rats). In patients, the restorative effects in plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities were 62.2 +/- 7.4 and 64.4 +/- 7.5%, respectively, after daily 80 mg intravenous (i.v.) doses of glycyrrhizin for 2 weeks, and 63.1 +/- 19.1 and 68.7 +/- 15.2% after 120 mg doses. The present work suggests that the threshold plasma glycyrrhizin concentration for sufficient effect is near 5 micrograms mL-1. In rats, the total body clearance (Cltot) for glycrrhizin in the CCl4-treated rats after i.v. administration of glycyrrhizin (5 mg kg-1 dose) was three-tenths of that of the control, and the t1/2 for glycyrrhizin was 3.4-fold longer than that of the control. A good correlation was observed between Cltot and AST (r = -0.838) or ALT (r = -0.873) activity in both rats. When glycyrrhizin was administered intraperitoneally (i.p.) three times a week for 2 weeks, both the AST and ALT activities in the CCl4-treated rats showed a greater improvement than for a 10 mg kg-1 dose. Furthermore, the finding on the threshold plasma concentration in patients as above was also supported from the results of the experiments in rats.

Alanine Transaminase↗
PubMed1997

Cytotoxic T lymphocyte response and viral load in hepatitis C virus infection.

A cytotoxic T lymphocyte (CTL) response to the hepatitis C virus (HCV) nucleoprotein residues 88-96 that are the minimal and optimal epitope for human leukocyte antigen (HLA) B44-restricted CTLs was assessed in 27 HLA B44-positive patients with chronic HCV infection. Serum HCV RNA concentration and the amino acid sequence of the residues 81-100 were also determined. Three patients were infected with HCV with uncommon amino acid substitutions within the epitope. One was infected with HCV with an amino acid substitution in the flanking residues of the epitope. To stimulate CTLs in the peripheral blood, 9-mer peptides that corresponded to the residues 88-96 of the individual patients were synthesized and used. Seven of the 27 patients demonstrated a CTL response to the residues 88-96 with specific cytotoxic activities higher than 20%. The CTL activities were significantly higher in patients with a low titer of serum HCV RNA than in those with a high titer of serum HCV RNA (P = .0006). Some of the patients that demonstrated a CTL response to the residues 88-96 also demonstrated a CTL response to a newly identified HLA B44-restricted CTL epitope or a known HLA A11-restricted CTL epitope or both. No apparent association was observed between the CTL response and the stage of disease, or between the CTL response and the grade of necroinflammatory activity. The results suggest that the HLA B44-restricted CTLs together with other HCV-specific CTLs may inhibit the outgrowth of HCV and that high-titer infection with HCV may suppress the CTL responses.

Adult↗
PubMed1997

Response to interferon-alpha 2a in patients with e antigen-negative chronic hepatitis B.

Sixty-eight consecutive patients with chronic hepatitis B received 702 million units of recombinant interferon-alpha 2a. Of the 24 patients negative for hepatitis B e antigen (HBeAg) in serum, the normalization of serum transaminase occurred in 14 (58%) at the completion of interferon therapy and in 13 (54%) at 12 months thereafter; it was normalized in 17 (39%) and 13 (30%), respectively, of the 44 HBeAg-positive patients. Of the HBeAg-negative patients, hepatitis B virus DNA was cleared from serum in six (25%) at the completion and in one (4%) at 12 months thereafter, in contrast to only one (2%, p < 0.05) and none of the HBeAg-positive patients, respectively. The 1896th nucleotide of G (G1896) for codon 28 for tryptophan or A (A1896) for the stop codon 28 in the precore region was determined by restriction fragment length polymorphism. The ten HBeAg-negative patients with A1896 only in the precore region had lower pretreatment levels of viral markers, which decreased more rapidly and extensively after interferon than in the 14 HBeAg-negative patients with a mixture of G1896 and A1896 or in the 44 HBeAg-positive patients. These results indicate that patients with HBeAg-negative chronic hepatitis B may respond better to interferon than HBeAg-positive patients, and that the precore mutant with the stop codon 28 may be sensitive to interferon.

Adult↗
PubMed1997

[Infection with hepatitis GB virus C in intravenous drug abusers with type C chronic liver diseases].

Hepatitis B virus(HBV), hepatitis C virus(HCV), and human immunodeficiency virus(HIV) infections are common among intravenous drug abusers, with a global distribution. The recently discovered hepatitis GB virus C(HGBV-C)/hepatitis G virus(HGV) has been linked to blood-borne non-A-E hepatitis. HGBV-C RNA was determined by the polymerase chain reaction with primers deduced from a helicase-like region in 189 patients with type C chronic liver diseases. Overall, HGBV-C RNA was detected in 22(11.6%) patients. The prevalence of HGBV-C RNA was estimated according to the suspected transmission routes(blood transfusion, intravenous drug abuse, tattooing and unknown) of HCV. 22.7-25.0% of type C hepatitis patients with a history of intravenous drug abuse were positive for HGBV-C RNA. These results indicate that HGBV-C is transmitted frequently in intravenous drug abusers coinfected with HCV.

Adult↗
PubMed1997

[A comparative study between low-dose and high-dose medroxyprogesterone acetate (MPA) in the treatment of advanced and recurrent breast cancer--in relation to dose, serum concentration and response. Osaka Breast Cancer Research Group].

A prospective randomized study was carried out to evaluate the effectiveness of MPA in the treatment of breast cancer by comparing low dose (600 mg/day) with high dose (1,200 mg/day) of MPA. In 35 evaluable cases, the response rate to treatment was 40.0% (8/20) with low dose MPA and 26.7% (4/15) with high dose MPA. There was no significant difference between the two groups. The serum MPA concentration measured by high-performance liquid chromatography (HPLC) assay was 23.2 +/- 17.6 ng/ml in the low-dose group and 89.5 +/- 56.7 ng/ml in the high-dose group. Intrapatient variability in serum MPA concentration was relatively stable, but interpatient variability was large. No correlation was found between the response rate and serum MPA concentration. The above results indicate that a low dose of MPA (600 mg/day) is a useful treatment with high effectiveness and safety in advanced and recurrent breast cancer patients. Though no exact data on the optimal serum concentration could not be obtained, it was obvious that a successful response cannot be expected from a serum MPA concentration of less than 17 ng/ml, which was the average serum concentration in NC and PD patients of the low-dose group.

Adult↗
PubMed1996

HLA DRB1 and DQB1 alleles and haplotypes influencing the progression of hepatitis C.

Some HLA class II alleles and haplotypes were examined by restriction fragment length polymorphism of corresponding DNA fragments amplified by the polymerase chain reaction in 117 patients with chronic hepatitis C in Japan. The prevalence rates were compared between patients and 1216 controls and in 67 patients with liver cirrhosis, of whom 20 had hepatocellular carcinoma and 50 patients with chronic hepatitis who did not have cirrhosis or hepatocellular carcinoma. Notably, DRB1*0405 (49% [95% confidence range 38-60%] vs. 26% [16-40%]; P < 0.05, relative risk [rr] = 2.8) and DQB1*0401 (43% [33-54%] vs. 22% [13-34%]; P < 0.05, rr = 2.1) were detected more frequently in patients with cirrhosis than in those without cirrhosis. By contrast, DRB1*0901 (11% [6-19%] vs. 28% [18-40%]; P < 0.05; rr = 0.3) and DQB1*0303 (11% [6-19%] vs. 36% [25-49%]; P < 0.01; rr = 0.2) were detected less frequently in patients with cirrhosis than those without cirrhosis. Accordingly, the DRB1*0405-DQB1*0401 haplotype was more common (43% [33-54%] vs. 22% [13-34%]; P < 0.05; rr = 2.7), while the DRB1*0901-DQB1*0303 haplotype was less common (9% [4-17%] vs. 28% [18-40%]; P < 0.05; rr = 0.3) in patients with cirrhosis than in those without cirrhosis. These results suggest that there would be HLA class II alleles and haplotypes which may be associated with an accelerated or slower progression of chronic hepatitis C towards cirrhosis and eventually to hepatocellular carcinoma.

Alleles↗
PubMed1996

Establishment of bone morphogenetic protein 2 responsive chondrogenic cell line.

A clonal cell line named RMD-1 was established from the skeletal muscle of a 20-day fetal rat. RMD-1 represents a morphologically homogeneous population of undifferentiated mesenchymal cells, expressing alpha-smooth muscle actin and type I collagen, but no cartilage-associated genes. When cultured in agarose gel containing 100 ng/ml of recombinant human bone morphogenetic protein 2 (rhBMP-2; BMP-2), RMD-1 cells formed colonies and showed chondrocyte-like features as assessed by their ultrastructure, metachromatic staining with toluidine blue, and the production of large hydrodynamic-size proteoglycans. RMD-1 cells also differentiated into chondrocytes when the cells were plated at high density (over 2.5 x 10(5) cells/cm2) on type I collagen and incubated in medium containing 0.5% fetal bovine serum and 100 ng/ml of BMP-2. This chondrogenic differentiation was evidenced by a distinct morphological change into spherical cells, an increase in the levels of sulfated glycosaminoglycans, a decrease in type I collagen mRNA and the expression of cartilage-associated genes, including type II collagen, type IX collagen, aggrecan and alkaline phosphatase. In the presence of ascorbic acid and 10% serum, RMD-1 cells increased in size and expressed type X collagen as well as high alkaline phosphatase activity, then induced matrix mineralization. Thus, RMD-1 is a unique cell line that can differentiate from undifferentiated mesenchymal cells into hypertrophic chondrocytes.

Actins↗
PubMed1996

Multivariate analysis of risk factors for hepatocellular carcinoma in patients with hepatitis C virus-related liver cirrhosis.

To elucidate the risk factors for hepatocellular carcinoma (HCC) in hepatitis C virus (HCV)-related liver cirrhosis (LC), we examined 204 cirrhotic patients negative for hepatitis B surface antigen and positive for HCV antibodies. The independent influence of various clinical characteristics in these patients was analyzed by multiple logistic regression, and the risk factors for HCC were identified. Multiple logistic regression analysis identified and ranked the following four risk factors: male sex (P < 0.001), habitual heavy drinking (P < 0.005), hepatitis B virus antibody positivity (anti-HBs and/or anti-HBc, P < 0.05), and age greater than 60 years (P < 0.05). The odds ratio of HCC was 4.20 (95% confidence interval; CI, 1.80-9.78) in male patients, 3.27 (95% CI, 1.46-7.30) in habitual heavy drinkers, 2.01 (95% CI, 1.01-3.99) in patients positive for hepatitis B virus antibodies, and 2.06 (95% CI, 1.00-4.23) in patients older than 60 years. The cumulative occurrence rates of HCC after blood transfusion were significantly higher in habitual heavy drinkers (4.8%, 49.4%, and 74.7% at 10, 20, and 30 years, respectively) than in non-drinkers (0%, 21.0%, and 23.3% at 10, 20, and 30 years, respectively, P < 0.0003). The mean interval for progression to LC after blood transfusion was significantly shorter in the habitual heavy drinkers than in the non-drinkers (22.4 +/- 4.4 years vs 28.4 +/- 3.9 years; P < 0.0003). This multivariate analysis revealed that habitual heavy drinking and hepatitis B virus antibody positivity are significant risk factors for HCC in HCV-related liver cirrhosis.

Age Factors↗
PubMed1996

Cold activation of complement in sera from patients with persistent hepatitis C virus infection on interferon therapy.

The loss of haemolytic activity in sera during storage at low temperature (the cold activation of complement) was observed in 136 of 184 (74%) patients with chronic liver disease associated with hepatitis C virus (HCV) infection. This was more frequent than observed in the three of 40 (8%) patients with chronic hepatitis B (P < 0.001) or none in 43 normal controls (P < 0.001). Of 103 patients with chronic hepatitis C who had completed a full course of recombinant interferon-alpha 2a therapy (total dose: 516 x 10(6) U), 40 responded completely and 21 responded partially, as judged by the normalization or decrease of alanine aminotransferase levels 6 months after the completion of therapy; 42 patients did not respond at all. The cold activation of complement persisted in five (13%) complete responders, less often than in 33 (79%) non-responders (P < 0.001). At the completion of interferon therapy, the cold activation of complement persisted in 12 of 54 patients despite the normalization of alanine aminotransferase. Spontaneous exacerbation of hepatitis occurred in seven of 12 (58%) patients with cold activation, which was more frequent than in the four of 42 patients (10%) without it (P < 0.01). The cold activation of complement disappeared along with the loss of HCV-RNA in five of six responders during the 6 month period after the completion of interferon therapy, while both cold activation and HCV-RNA persisted in all eight non-responders. These results indicate that the cold activation of complement may be useful as a marker of HCV viraemia for monitoring the response to interferon in patients with HCV infection.

Adult↗
PubMed1996

Expression of S-100 protein and glial fibrillary acidic protein in cultured submandibular gland epithelial cells and salivary gland tissues. Histogenetic implication for salivary gland tumors.

S-100 protein and glial fibrillary acidic protein (GFAP) were studied in human salivary gland tissues and human cultured submandibular gland epithelial cells. Immunohistochemically, ductal cells in normal salivary gland tissues were positive for S-100 protein and GFAP, but myoepithelial cells were uniformly negative. Immunocytochemically, cultured submandibular gland ductal cells were positive for S-100 protein and GFAP. By immunoblotting analysis of the cultured cell lysates, a 6.5-kd S-100 protein was detected. This band corresponded to S-100 protein purified from bovine brain. The cultured submandibular gland cells expressed 49- and 54-kd GFAP polypeptides. These results have important implications for the histogenesis of salivary gland tumors.

Animals↗
PubMed1996

The role of previous hepatitis B virus infection and heavy smoking in hepatitis C virus-related hepatocellular carcinoma.

OBJECTIVE: Worldwide epidemiological studies have demonstrated that hepatitis C virus (HCV) probably is a causative agent of hepatocellular carcinoma (HCC). However, there are no available reports that clearly identify the risk factors for the development of HCC in HCV-related chronic liver disease (CLD). The aim of the present study is to explore the risk factors for hepatocarcinogenesis in HCV-related CLD. METHODS: We prospectively observed 412 patients with anti-HCV-positive CLD but without co-infection of hepatitis B virus (232 patients with chronic hepatitis and 180 with liver cirrhosis) for between 0.5 and 15.8 yr (median: 4.9 yr). Risk factors for hepatocarcinogenesis were identified with a Cox proportional-hazard model. RESULTS: Sixty-three patients (15.3%) developed HCC during the observation period; the cumulative occurrence rates at the end of the 5th, 10th, and 15th yr was 3.7%, 12.1%, and 12.1%, respectively, for chronic hepatitis patients and 23.3%, 49.4%, and 90.7%, respectively, for 180 cirrhotic patients. The Cox proportional-hazard model showed that the risk of hepatocarcinogenesis increased almost 5-fold in cirrhotic patients (risk ratio, 5.14; 95% confidence interval, 2.52-10.46, p = 0.0001), 2-fold in patients with positive antibodies against hepatitis B surface antigen and/or antibodies against hepatitis B core antigen (risk ratio, 2.14; 95% confidence interval, 1.13-4.07, p = 0.0201), and 2.5-fold in heavy smokers (risk ratio, 2.46; 95% confidence interval, 1.11-5.49, p = 0.0276). CONCLUSION: These epidemiological results indicate that previous infection with hepatitis B virus and heavy smoking (in addition to liver cirrhosis, a known risk factor) play important roles as risk factors for carcinogenesis in HCV-related CLD.

Adult↗
PubMed1996

Core promoter mutations of hepatitis B virus for the response to interferon in e antigen-positive chronic hepatitis B.

OBJECTIVES: Mutations in the precore region are not always detected in hepatitis B virus (HBV) from patients with chronic hepatitis B who respond to interferon and lose hepatitis B e antigen (HBeAg) from serum. The other mutations may also be responsible for the loss of HBeAg and response. METHODS: Forty six consecutive patients with HBeAg-positive chronic hepatitis B received recombinant-alpha 2 a interferon (total dose: 702 MU). The mutation for stop codon 28 in the precore region was determined by restriction fragment length polymorphism, and mutations in the core promoter were searched for in five HBV DNA clones propagated from each patient. RESULTS: HBeAg was cleared at 6 months after interferon in 11 (61%) of 18 patients with the precore mutation and in 12 (43%) of 28 without it. Of these 28 patients, 19 with mutations in the core promoter in all five HBV DNA clones lost HBeAg more frequently than the remaining nine who had at least one clone among the five that lacked such mutations (58 vs 11%, p < 0.05). CONCLUSIONS: HBeAg-positive patients infected with HBV variants having mutations for an HBeAg-negative phenotype would respond better to interferon by clearing HBeAg from serum. Such mutations may not necessarily be in the precore region but also in the core promoter, which would interfere with the synthesis and secretion of HBeAg either at the translation or transcription level.

Adult↗
PubMed1995

The relationship between pharmacokinetic behaviour of glycyrrhizin and hepatic function in patients with acute hepatitis and liver cirrhosis.

The pharmacokinetic behavior of glycyrrhizin in four patients with acute hepatitis (hepatitis group) and six patients with liver cirrhosis (cirrhosis group) receiving chronically an IV administration of a 120 mg dose once a day or once every other day of glycyrrhizin was investigated. The plasma concentration of glycyrrhizin declined monoexponentially in both groups. The elimination half-life (t1/2) for glycyrrhizin in the hepatitis and cirrhosis groups varied significantly in the range of 2.7-7.6 h and 6.2-40.1 h, and the total body clearance (CLtot) in the range of 2.8-23.2 mL h-1 kg-1 and 1.4-12.9 mL h-1 kg-1, respectively. The t1/2 for glycyrrhizin in the hepatitis and the cirrhosis groups was about twice and eight times that in normal subjects, respectively, as reported previously, and CLtot values were about 0.7 and 0.23 times that in normal subjects, respectively. There was significant correlation between the CLtot and hepatic function (aspartate aminotransferase and alanine aminotransferase in serum) in both patient groups. With improvement of the liver function, the CLtot for glycyrrhizin increased from 2.8 ml h-1 kg-1 to 11.4 mL h-1 kg-1, and the t1/2 shortened from 7.6 h to 3.4 h. These findings indicated that the variation of pharmacokinetic behaviour of glycyrrhizin in both groups was closely related to the extent of the liver function.

Adult↗
PubMed1995

Corticosterone secretion in response to serotonin and ACTH by perfused adrenal of normal and athymic nude mice.

Adrenocortical secretory responses to chemical mediators and ACTH in CD1 ICR nu/nu (athymic) mice were compared with those in CD1 ICR (normal) mice. The bilateral adrenals of normal or athymic mice were perfused in situ with artificial medium equilibrated by 95% O2 + 5% CO2. Infusion of serotonin induced the secretory response of corticosterone significantly at 10 nM and markedly at 100 nM and the response at 1000 or 10000 nM declined as compared with that at 100nM in normal mice. Total corticosterone secretion in response to 100 or 1000 nM serotonin in athymic mice was about one fourth that in normal mice, respectively. Corticosterone responses to ACTH at the range of 10 to 300 pg/ml in athymic mice were comparable to those in normal mice. Infusion of histamine, platelet activating factor(PAF), or compound 48/80 did not induce significant corticosterone response in both normal and athymic mice. The data suggest that the congenital defect of the thymus and/or hair causes the hyporesponsiveness of adrenocortical cells to serotonin although the adrenal cortex of athymic mice is able to perform its function in response to ACTH.

Adrenal Cortex↗
PubMed1995

HCV RNA monitoring for tailored regimens of interferon therapy in hepatitis C.

Sustained non-viraemia is prerequisite for a virological cure of hepatitis C virus (HCV) disease. We monitored serum HCV RNA in our patients during interferon therapy and for 6 months of follow-up. The rate of sustained responders (RNA-negative at the end of follow-up) differed significantly by whether or not RNA became sero-negative within 24 weeks of the initiation of therapy (71% vs 7%); and also by whether or not the RNA-seronegativity lasted for 12 weeks during therapy (88% vs 11%). Thus, by monitoring viraemia in individual patients, we can tailor the duration of therapy and minimize waste of interferon.

Follow-Up Studies↗