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Biomedical subjects

S Kakizaki

Publications and source records attributed to S Kakizaki.

At least 19 recordsLinked to original sources
PubMed2006

Endoscopic submucosal dissection for early gastric cancers and large flat adenomas.

BACKGROUND AND STUDY AIM: Endoscopic submucosal dissection (ESD) is a new diagnostic and treatment technique for early gastric cancer (EGC). The present study aims to identify the technical feasibility, operation time, and complications associated with ESD. METHODS: We reviewed the patients who underwent ESD for EGCs at Maebashi Red Cross Hospital. RESULTS: There were 160 patients with 171 EGCs treated by ESD. The mean age was 71.4 +/- 8.9 years (median 72). The rate for one-piece resection with tumor-free margins was 94.2 % (161/171), and was 93.2 % (82/88) for large lesions (> 20 mm) and 92.1 % (35/38) for ulcerative lesions. The median operation time was 80 min (range 10-600 min). Evidence of immediate bleeding was found in 2.9 % (5/171), delayed bleeding was seen in 7.6 % (13/171), and perforation was observed in 3.5 % (6/171) of the lesions. All patients with complications, including perforation, were successfully treated endoscopically. There were no local or distant metastases in the lesions which met our indication criteria for ESD. CONCLUSION: The present study shows the technical feasibility of ESD, which provides the capability of one-piece resection even in large and ulcerative lesions.

Adenoma↗
PubMed2002

A ligand for peroxisome proliferator activated receptor gamma inhibits cell growth and induces apoptosis in human liver cancer cells.

BACKGROUND AND AIMS: Induction of apoptosis of cancer cells through ligands of nuclear hormone receptors (NHRs) is a new approach in cancer therapy. Recently, one of the NHRs, peroxisome proliferator activated receptor gamma (PPARgamma), has been shown to influence cell growth in certain cancer cells although its effect on hepatocellular carcinoma (HCC) has not been analysed. METHODS: Experiments were conducted using three human liver cancer cell lines, PLC/PRF/5, Hep G2 and HuH-7, in vitro. These cells were exposed to troglitazone, a synthetic ligand for PPARgamma, and the effects on cell growth were analysed. RESULTS: Expression of PPARgamma mRNA was detected in all three liver cancer cell lines. Activation of PPARgamma by troglitazone caused a marked growth inhibition in a dose dependent manner in three hepatoma cell lines. The DNA fragmentation ELISA assay and Hoechst 33258 staining revealed that the growth inhibitory effect by adding troglitazone was due to apoptosis of PLC/PRF/5, which strongly expressed PPARgamma. Troglitazone also induced activation of the cell death protease, caspase 3, but not caspase 8, in PLC/PRF/5 cells. However, expression levels of antiapoptotic factor bcl-2 and apoptosis inducing factor bax were not affected. CONCLUSION: Our study showed that PPARgamma was expressed in human liver cancer cells and that the ligand for PPARgamma, troglitazone, inhibited the growth of these cells by inducing apoptosis through caspase 3 activation, indicating that troglitazone could be potentially useful as an apoptosis inducer for the treatment of HCC.

Antineoplastic Agents↗
PubMed2001

Effect of alpha-tocopherol on hepatocarcinogenesis in transforming growth factor-alpha (TGF-alpha) transgenic mice treated with diethylnitrosamine.

To examine the potentially chemopreventive effects of alpha-tocopherol on hepatocarcinogenesis, we fed the transgenic mice line MT42, which overexpresses transforming growth factor-alpha (TGF-alpha) and which has been established as having a high incidence of liver tumor, with different concentrations of alpha-tocopherol and examined the hepatic tumorigenesis of these mice. At 3 weeks of age, MT42 male mice received a single intraperitoneal injection of diethylnitrosamine (DEN), 5 mg/kg body weight, to initiate the formation of liver tumors. The mice were divided into three groups: group A, control diet (20 mg/kg of alpha-tocopherylacetate); group B, deficient diet (less than 1 mg/kg); group C, supplemented diet (500 mg/kg). Neoplastic change was determined at 40 weeks of age. The incidence of adenomas (p < 0.05), the maximum tumor size (p < 0.01), the mean relative liver weight (p < 0.01), and the proliferating cell nuclear antigen (PCNA) labeling indices of the non-tumor sites (p < 0.01) of group B were significantly higher than those of group C. No toxic effects of alpha-tocopherol were found. Alpha-tocopherol-deficient diet accelerated the hepatocarcinogenesis of TGF-alpha transgenic mice treated with DEN. At best, these data demonstrate that alpha-tocopherol-deficiency is not beneficial for prevention of hepatocarcinogenesis in this model. Alpha-tocopherol may be useful for the chemoprevention for liver cancer.

Alkylating Agents↗
PubMed2001

Zinc supplementation enhances the response to interferon therapy in patients with chronic hepatitis C.

We evaluated the synergistic effect of zinc supplementation on the response to interferon (IFN) therapy in patients with intractable chronic hepatitis C in a pilot study using natural IFN-alpha with or without zinc. No clinical differences were observed between patients treated with IFN alone (n=40) and IFN with polaprezinc (IFN + Zn, n=35). All patients were positive for HCV genotype Ib and had more than 105 copies of the virus/mL serum. Ten million units of natural IFN-alpha was administered daily for 4 weeks followed by the same dose every other day for 20 weeks. In the IFN + Zn group, patients received an additional dose of 150 mg/day polaprezinc orally throughout the 24-week IFN course. No additional side-effects of polaprezinc were noted but four out of 40 IFN alone treatment and three out of 35 IFN + Zn group withdrew because of side-effects. Complete response (CR) was defined as negative HCV RNA in the serum on PCR and normal aminotransferase level 6 months after therapy. Incomplete response (IR) was normal liver enzyme and positive serum HCV RNA. Both of them were evaluated at the 6 months after the completion of the treatment. Patients with higher levels of serum HCV (more than 5 x 105 copies/mL) had little response in both treatment groups. Patients with moderate amount of HCV (105 to 4.99 x 105/mL) showed high response rates in combination group (CR: 11/27, 40.7%; CR + IR 15/27, 64.3%), better than IFN alone (CR: 2/15, 18.2%; CR + IR: 2/15, 18.2%). Serum zinc levels were higher in patients with IFN + Zn group than in the IFN group. Our results indicate that zinc supplementation enhances the response to interferon therapy in patients with intractable chronic hepatitis C.

Adult↗
PubMed2001

The phenobarbital response enhancer module in the human bilirubin UDP-glucuronosyltransferase UGT1A1 gene and regulation by the nuclear receptor CAR.

The UDP-glucuronosyltransferase, UGT1A1, is the critical enzyme responsible for detoxification of the potentially neurotoxic bilirubin by conjugating it with glucuronic acid. For decades, phenobarbital (PB) treatment for hyperbilirubinemia has been known to increase expression of the UGT1A1 gene in liver. We have now delineated the PB response activity to a 290-bp distal enhancer sequence (-3483/-3194) of the UGT1A1 gene. The enhancer contains 3 putative nuclear receptor motifs, and it was activated by the nuclear orphan receptor, human constitutive active receptor (hCAR), in cotransfected HepG2 cells. Bacterially expressed hCAR, acting as a heterodimer with in vitro-translated retinoid X receptor (RXRalpha), only bound to 1 of the 3 NR motifs, named gtNR1 in a gel-shift assay. Consistently, mutations of the gtNR1 site significantly decreased the activation by hCAR of the 290-bp DNA in transfection assays. Moreover, the 290-bp DNA was effectively activated in mouse primary hepatocytes in response to PB, offering an excellent clinical test for the examination of the responsiveness of the UGT1A1 to PB in the human population, particularly individuals with hyperbilirubinemia.

Base Sequence↗
PubMed2000

Iron enhances hepatitis C virus replication in cultured human hepatocytes.

BACKGROUND: Iron overload in the presence of increasing concentrations of iron is one of the indicators of poor response to interferon therapy in chronic hepatitis C. In order to analyze the effect of iron on hepatitis C virus (HCV) replication, we measured replication in an HCV-infected cell line. METHODS AND RESULTS: Cells from a non-neoplastic HCV-infected human hepatocyte line (PH5CH8) susceptible to HCV infection and supportive of HCV replication were used in this study. The replication of HCV RNA was measured by reverse transcription-nested polymerase chain reaction (RT-nested PCR). PH5CH8 cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. PH5CH8 cells were incubated with 0, 1, 10, 50, and 100 microM of FeSO4 at 37 degrees C with 5% CO2. Forty-eight hours after iron supplementation, the quantity of HCV RNA in the cells incubated in 50 and 100 microM of FeSO4 was approximately ten times that of the cells with no iron supplementation. Similar changes were observed beginning at 12 h from supplementation with FeSO4 and continued for at least 72 h after supplementation. MTT assay indicated that iron did not have cytotoxic effects on the PH5CH8 cells. CONCLUSION: Iron enhances HCV replication in a hepatocyte cell line. The results suggest that iron deposition in hepatocytes could facilitate HCV infection in the liver.

Cell Line, Transformed↗
PubMed2000

Role of serum soluble Fas/soluble Fas ligand and TNF-alpha on response to interferon-alpha therapy in chronic hepatitis C.

AIMS/BACKGROUND: To determine the relationship between host factors and host response to interferon (IFN) therapy, serum soluble Fas (sFas), soluble Fas ligand (sFas ligand), and tumor necrosis factor-alpha (TNF-alpha) were analyzed in 41 patients with chronic hepatitis C (CH-C) treated with IFN-alpha. METHODS: Serum levels of sFas, sFas ligand, and TNF-alpha were measured at 0, 4, and 24 weeks of IFN therapy. RESULTS: Eighteen patients were complete responders (CR) and 23 patients were non-responders (NR). Serum levels of sFas and TNF-alpha in patients with CHC were significantly higher than those in healthy controls (p<0.01 and p<0.01, respectively). Serum sFas ligand levels were significantly lower in CH-C patients than in healthy controls (p<0.01). Before IFN therapy, serum levels of sFas in NR were significantly higher than those in CR (p<0.05). At 4 weeks of IFN therapy, serum levels of sFas of CR were significantly elevated compared with levels before IFN therapy (p<0.05). Serum levels of sFas correlated with the histological activity of the liver (p<0.05) and alanine aminotransferase (p<0.05). None of the three parameters, serum sFas, sFas ligand, or TNF-alpha levels, correlated with each other, with HCV-RNA genotype or with serum HCV-RNA load. Multiple logistic regression analysis showed that serum sFas levels before IFN therapy were a contributive factor to predict efficacy of IFN therapy. CONCLUSIONS: Serum sFas/sFas ligand and TNF-alpha play a possible role in pathogenesis of CH-C and also in IFN therapy. Serum sFas levels before IFN therapy may be one of the host-related factors used for evaluating the response of CH-C patients to IFN therapy.

Adult↗
PubMed2000

Estrogen activation of the nuclear orphan receptor CAR (constitutive active receptor) in induction of the mouse Cyp2b10 gene.

The nuclear orphan receptor CAR (constitutively active receptor or constitutive androstane receptor) can be activated in response to xenochemical exposure, such as activation by phenobarbital of a response element called NR1 found in the CYP2B gene. Here various steroids were screened for potential endogenous chemicals that may activate CAR, using the NR1 enhancer and Cyp2b10 induction in transfected HepG2 cell and/or in mouse primary hepatocytes as the experimental criteria. 17beta-Estradiol and estrone activated NR1, whereas estriol, estetrol, estradiol sulfate, and the synthetic estrogen diethylstilbestrol did not. On the other hand, progesterone and androgens repressed NR1 activity in HepG2 cells, and the repressed NR1 activity was fully restored by estradiol. Moreover, estrogen treatment elicited nuclear accumulation of CAR in the mouse livers, as well as primary hepatocytes, and induced the endogenous Cyp2b10 gene. Ovariectomy did not affect either the basal or induced level of CAR in the nucleus of the female livers, while castration slightly increased the basal and greatly increased the induced levels in the liver nucleus of male mice. Thus, endogenous estrogen appears not to regulate CAR in female mice, whereas endogenous androgen may be the repressive factor in male mice. Estrogen at pharmacological levels is an effective activator of CAR in both female and male mice, suggesting a biological and/or toxicological role of this receptor in estrogen metabolism. In addition to mouse CAR, estrogens activated rat CAR, whereas human CAR did not respond well to the estrogens under the experimental conditions.

Androgens↗
PubMed2000

Histological change after interferon therapy in chronic hepatitis C in view of iron deposition in the liver.

We examined the efficacy of interferon (IFN) therapy for chronic hepatitis C (CHC) in view of the change of liver histology and iron staining before and after IFN therapy. Enrolled in this study were 109 patients with CHC who completed IFN treatment and were followed for at least 1 yr after the end of IFN therapy. Serum iron, unsaturated-iron-binding capacity (UIBC), and total-iron-binding capacity (TIBC) were assessed before IFN therapy. Knodell's histological activity index (HAI) score and iron staining were examined in 55 patients in whom liver biopsy was performed at two points: before and. 1 yr after IFN therapy. Serum iron levels before IFN therapy did not correlate with the response to IFN. The HAI score significantly decreased after IFN therapy in complete responders (p < 0.01) and biochemical responders (p < 0.01). Three factors in the HAI, periportal necrosis, intralobular necrosis, and portal inflammation, but not fibrosis, were significantly decreased in complete responders (p < 0.01) and biochemical responders (p < 0.01). Of 55 patients, 23 (41.8%) were positive for iron staining before IFN therapy and 14 of 55 (25.5%) after IFN therapy. The positive rate for iron staining tended to decrease after IFN therapy, not correlating to the response to IFN, but the change was not statistically significant. In conclusion, the histological improvement by IFN therapy was mostly seen in necroinflammatory changes but not in fibrosis at least 1 yr after IFN, and iron staining tended to decrease after IFN therapy.

Adult↗
PubMed2000

Preliminary study of combination therapy with interferon-alpha and zinc in chronic hepatitis C patients with genotype 1b.

We have evaluated the efficacy of interferon-alpha (IFN-alpha) plus zinc therapy in hepatitis C patients with genotype 1b, poor responders for IFN alone. Ten patients were injected with 10 MU of IFN-alpha every day for 4 wk, followed by three times a week for 20 wk (control group). Nine patients took 300 mg of zinc sulfate a day orally during IFN-alpha therapy (zinc sulfate group), and 15 patients took IFN-alpha and 150 mg of polaprezinc (polaprezinc group). On the d 8 of IFN therapy, circadian zinc levels in serum elevated significantly in the polaprezinc group compared to the zinc sulfate group or control group. Serum ALT levels normalized in 73.3% of the polaprezinc group, 55.6% of the zinc sulfate group, and 40.0% of the control group at 6 mo after the end of IFN therapy. Sustained eradication for the hepatitis C virus RNA judged at the end of the 6-mo follow-up period was higher in the polaprezinc group than in the zinc sulfate group (53.3% vs 11.1%, p < 0.05) or the control group (20.0%). No clinical side effects of zinc were observed at the dose used. The data suggest that polaprezinc is expected to increase the therapeutic response of IFN-alpha for chronic hepatitis C with genotype 1b.

Carnosine↗
PubMed1999

HLA antigens in patients with interferon-alpha-induced autoimmune thyroid disorders in chronic hepatitis C.

BACKGROUND/AIMS: To determine the immunological predisposition to autoimmune thyroid disorders induced by interferon-alpha therapy, human leukocyte antigen (HLA) was analyzed in patients with chronic hepatitis C who developed autoimmune thyroid disorders during or after treatment with interferon-alpha. METHODS: Four hundred and thirty-nine patients with chronic hepatitis C (278 males and 161 females, aged 20-73 years) were treated with interferon-alpha (natural-alpha, 169; alpha-2a, 82; alpha-2b, 188) for 24 weeks. RESULTS: Seventeen of 439 (3.9%) patients developed symptomatic autoimmune thyroid disorders; these included nine cases of hyperthyroidism and eight cases of hypothyroidism. The incidence of HLA-A2, B46 and Cw7 increased in patients with interferon-alpha-induced autoimmune thyroid disorders. Especially, the incidence of HLA-A2 (15/17; 88.2%) was significantly higher than that observed in the general population in Japan (corrected p-value (p(c)): p(c)<0.003). The odds ratios for the relative risk of the autoimmune thyroid disorders were A2, 10.6 [95% confidence interval, 2.4-46.5]; B46, 4.8 [1.6-14.0]; and Cw7, 3.0 [1.1-7.9]. CONCLUSIONS: Our study revealed that HLA-A2 is highly linked to the autoimmune thyroid disorders induced by interferon-alpha-therapy in patients with chronic hepatitis C.

Adult↗
PubMed1999

Evaluation of twice-daily administration of interferon-beta for chronic hepatitis C.

To improve the efficacy of interferon (IFN) in the treatment of chronic hepatitis C, administration of IFN-beta twice per day was evaluated. Thirty-eight patients with chronic hepatitis C (26 males and 12 females, aged 25-67 years) were included. Patients were treated with a new protocol that included twice-daily treatment with IFN-beta. Three million units (MU) of IFN-beta was administered twice daily every day for 4 weeks followed by 10 MU of IFN-alpha2b, every day for 2 weeks and then three times a week for 18 weeks (total IFN-beta, 148 MU; IFN-alpha2b, 680 MU). Complete responders (CR) were defined by alanine aminotransferase levels that normalized within 6 months after completion of IFN therapy and remained normal for more than 6 months, and by serum hepatitis C virus (HCV) RNA levels that became negative as determined using the Amplicor assay. Twenty-one of 38 (55.3%) patients were CR. Nine of 21 (42.9%) patients with HCV serotype 1 were responders compared with nine of 12 (75.0%) patients with HCV serotype 2. In patients with an HCV titre greater than 1 million equivalents ml-1 (1 MEq ml-1), nine of 24 (37.5%) responded, and in patients with HCV titres less than 1 MEq ml-1, 12 of 14 (85.7%) responded. In patients with HCV serotype 1 and greater than 1 MEq ml-1 HCV RNA, four of 15 (26.7%) responded to IFN. Two-thirds (66.7%) of the patients who became negative for HCV RNA after 2 weeks of therapy responded, while 72.7% of those with positive HCV RNA after 2 weeks of therapy were non-responders. Proteinuria was frequently observed as an adverse effect of twice-daily administration of IFN-beta. The combination of twice-daily administration of IFN-beta for 4 weeks followed by IFN-alpha showed a high response rate in patients with chronic hepatitis C, but in patients with both serotype 1 and a high titre of HCV RNA, response rates were still low. Thus, the HCV RNA titre 2 weeks after starting therapy with IFN was useful for predicting the eventual response to IFN.

Adult↗
PubMed1999

Faropenem enhances superoxide anion production by human neutrophils in vitro.

Neutrophils are important cellular components in the defence against infections and many studies in vitro have shown that some antibiotics affect neutrophil function. We examined the effect of faropenem, a new oral penem antibiotic on neutrophil killing function by determining the generation of superoxide anion in vitro. The production of superoxide anion was measured by chemiluminescence amplified by a Cypridina luciferin analogue in the presence of N-formyl-Met-Leu-Phe (fMLP). Faropenem significantly enhanced chemiluminescence in a dose-dependent manner. The effect of faropenem was maximal at 5 min of incubation time and continued for at least 30 min. The effect of faropenem was also observed when neutrophils were stimulated by a calcium ionophore (ionomycin), while the effect of faropenem did not change in the presence of 12-O-tetra-decanoylphorbolmyristate acetate. Cytosol Ca2+ concentration ([Ca2+]i) monitored with Fura-2 increased in response to fMLP, however, faropenem did not influence the response of [Ca2+]i to fMLP. Our results suggest that faropenem enhanced the generation of superoxide anion by neutrophils, probably at the site where cytosol Ca2+ regulates NADPH oxidase. Faropenem might be potentially advantageous in the treatment of infections because a synergic interaction of antibodies and cytocidal neutrophils is necessary for the early eradication of the pathogenic bacteria.

Anti-Bacterial Agents↗
PubMed1999

Prevalence of hepatitis G virus in liver disease.

The prevalence of hepatitis G virus (HGV) in liver disease of non-A, -B, -C viral hepatitis, hepatitis B and hepatitis C was determined. Two of 44 patients (4.5%) with liver injury without any hepatitis A, B or C marker were positive for HGV. One of five cases of hepatocellular carcinoma was positive for HGV. One of three cases with fulminant hepatitis was positive for HGV. This case was negative at the onset of fulminant hepatitis and became positive after plasmapheresis. No patient with acute (n=8) or chronic (n=5) hepatitis or liver cirrhosis (n=8) was positive for HGV in non-A, -B, -C liver disease. One of 30 patients with various HBV-positive liver diseases and nine (17.3) of 52 patients with type C liver disease were positive for HGV. In patients with hepatitis C, four (28.6%) of 14 HGV-co-infected patients were complicated with diabetes mellitus compared with four (10.5%) of 38 single hepatitis C virus (HCV)-infected patients (not significant). In 12 HGV-positive patients, eight of 10 (80%) had a history of blood transfusion. In HCV-positive patients, co-infection with HGV was not a risk factor in patients with diabetes mellitus as a complication. HGV appeared to cause non-A, -B, -C hepatitis rarely, and its main route of infection was blood transfusion.

Adolescent↗
PubMed1999

[Autoimmune thyroid disease induced by interferon therapy].

Interferon therapy, widely used in chronic viral hepatitis and in various malignant diseases, has been known to induce autoimmune phenomena, the most frequent being autoimmune thyroid disease. We have studied the human leukocyte antigen (HLA) in patients who developed autoimmune thyroid dysfunction after interferon-alpha therapy for chronic hepatitis C. Seventeen of 439 patients (3.9%) developed symptomatic autoimmune thyroid dysfunction after interferon-alpha therapy, including nine cases of hyperthyroidism and eight cases of hypothyroidism. The incidence of HLA-A2 in those patients was significantly higher than that in general population in Japan. The present results suggest that HLA-A2 is associated with interferon-alpha therapy-induced autoimmune thyroid dysfunction in patients with chronic hepatitis C.

Autoimmune Diseases↗
PubMed1998

Survival of patient with late onset hepatic failure by living-related liver transplantation from maternal donor with incompatible blood type.

A 14-year-old girl with blood type B with late onset hepatic failure (LOHF) of unknown cause has survived through living-related liver transplantation (LRLT). No hepatitis virus, including HAV, HBV, HCV, and HGV, was positive at the onset of LOHF. Autoimmune hepatitis was thought to be the cause because of positive results for serum anti-nuclear antibody at 80 times dilution and elevated gamma-globulin, but treatment with glucocorticoid did not suppress the progressive hepatic failure. Supportive therapy, including pulse therapy with 1g methylprednisolone for 3 days, ursodesoxycholic acid, branched-chain amino acid, and azathioprine did not resolve the hepatic failure. She was treated by repeated plasmapheresis and plasma absorption for 10 months, and then received the left lobe of her mother's liver. (Her mother's blood type was AB). The patient had been well, being treated with tacrolimus and prednisolone, although the serum titer of anti-blood type B antibody was high just after LRLT and mild liver dysfunction continued for more than 3 years after LRLT. Follow-up biopsy 3 years after LRLT revealed chronic hepatitis and progression to liver cirrhosis. Re-transplantation is now under consideration; the patient is now aged 19 years.

ABO Blood-Group System↗