Hiromi Ishibashi

Publications (164)617.76 Total impact

• Article: Development of the clinical practice guideline of primary biliary cirrhosis (PBC).

  Hiromi Ishibashi, Atsumasa Komori
  Nippon Shokakibyo Gakkai zasshi The Japanese journal of gastro-enterology 01/2013; 110(1):1-7.
• Article: Prediction of early HBeAg seroconversion by decreased titers of HBeAg in the serum combined with increased grades of lobular inflammation in the liver.

  Sung Kwan Bae, Hiroshi Yatsuhashi, Satoru Hashimoto, Yasuhide Motoyoshi, Eisuke Ozawa, Shinya Nagaoka, Seigo Abiru, Atsumasa Komori, Kiyoshi Migita, Minoru Nakamura, Masahiro Ito, Yuzo Miyakawa, Hiromi Ishibashi
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  ABSTRACT: Background: Hepatitis B e antigen (HBeAg) seroconversion is an important hallmark in the natural course of chronic hepatitis B. This study was designed to predict early HBeAg seroconversion within 1 year, by not only biochemical and virological markers, but also pathological parameters in patients with chronic hepatitis B. Material/Methods: In a retrospective cohort study, 234 patients with HBeAg were reviewed for demographic, biochemical, virological and pathological data at the time of liver biopsy. Then, the patients who accomplished HBeAg seroconversion within 1 year thereafter were compared with those who did not, for sorting out factors predictive of early HBeAg seroconversion. Results: Early HBeAg seroconversion occurred in 58 (24.8%) patients. In univariate analysis, factors predictive of early HBeAg seroconversion were: alanine aminotransferase (ALT) (p=0.002), IP-10 (p=0.029), HBsAg (p=0.003), HBeAg (p<0.001), HBV DNA (p=0.001), HBcrAg (p=0.001), core-promoter mutations (p=0.040), fibrosis (p=0.033) and lobular inflammation (p=0.002). In multivariate analysis, only serum HBeAg levels <100 Paul Ehrlich Institute (PEI) U/ml and grades of lobular inflammation ≥2 were independent factors for early HBeAg seroconversion (odds ratio 8.430 [95% confidence interval 4.173-17.032], p<0.001; and 4.330 [2.009-9.331], p<0.001; respectively). Conclusions: HBeAg levels < 100 PEIU/ml combined with grades of lobular inflammation ≥2 are useful for predicting early HBeAg seroconversion. In patients without liver biopsies, high ALT levels (≥200 IU/L) can substitute for lobular inflammation (grades ≥2).
  Medical science monitor: international medical journal of experimental and clinical research 12/2012; 18(12):CR698-705. · 1.70 Impact Factor
• Article: Familial Mediterranean Fever in Japan.

  Kiyoshi Migita, Ritei Uehara, Yoshikazu Nakamura, Michio Yasunami, Ayako Tsuchiya-Suzuki, Masahide Yazaki, Akinori Nakamura, Junya Masumoto, Akihiro Yachie, Hiroshi Furukawa, Hiromi Ishibashi, Hiroaki Ida, Kazuko Yamazaki, Atsushi Kawakami, Kazunaga Agematsu
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  ABSTRACT: Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease that is prevalent in Mediterranean populations. While it is considered a rare disease in the rest of world, a significant number of FMF patients have been reported in East Asia, including Japan. Our aim was to determine the prevalence of FMF in Japan and elucidate the clinical and genetic features of Japanese patients. A primary nationwide survey of FMF was conducted between January and December 2009. Hospitals specializing in pediatrics and hospitals with pediatric, internal medicine, and rheumatology/allergy departments were asked to report all patients with FMF during the survey year. The estimated total number of Japanese FMF patients was 292 (95% confidence interval, 187-398 people). We evaluated the clinical and genetic profiles of Japanese patients from the data obtained in a secondary survey of 134 FMF patients. High-grade fever was observed in 95.5%, chest pain (pleuritis symptoms) in 36.9%, abdominal pain (peritonitis symptoms) in 62.7%, and arthritis in 31.3%. Of the patients profiled, 25.4% of patients experienced their first attack before 10 years of age, 37.3% in their teens, and 37.3% after age 20 years. Colchicine was effective in 91.8% of patients at a relatively low dose (mean dose, 0.89 ± 0.45 mg/d). AA amyloidosis was confirmed in 5 patients (3.7%). Of the 126 patients studied, 109 (86.5%) were positive for 1 or more genetic mutations and 17 (13.5%) had no mutation detected. Common Mediterranean fever gene (MEFV) mutations were E148Q/M694I (19.8%) and M694I/normal (12.7%). The differences in the prevalence of peritonitis, pleuritis, and a family history of FMF were statistically significant between FMF patients with MEFV exon 10 mutations compared with those without exon 10 mutations.In conclusion, a significant number of patients with FMF exist in Japan. Although Japanese patients with FMF are clinically or genetically different from Mediterranean patients, the delay in diagnosis is an issue that should be resolved.
  Medicine 10/2012; · 4.35 Impact Factor
• Article: A novel animal model for in vivo study of liver cancer metastasis.

  Shinsuke Fujiwara, Hikaru Fujioka, Chise Tateno, Ken Taniguchi, Masahiro Ito, Hiroshi Ohishi, Rie Utoh, Hiromi Ishibashi, Takashi Kanematsu, Katsutoshi Yoshizato
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  ABSTRACT: To establish an animal model with human hepatocyte-repopulated liver for the study of liver cancer metastasis. Cell transplantation into mouse livers was conducted using alpha-fetoprotein (AFP)-producing human gastric cancer cells (h-GCCs) and h-hepatocytes as donor cells in a transgenic mouse line expressing urokinase-type plasminogen activator (uPA) driven by the albumin enhancer/promoter crossed with a severe combined immunodeficient (SCID) mouse line (uPA/SCID mice). Host mice were divided into two groups (A and B). Group A mice were transplanted with h-GCCs alone, and group B mice were transplanted with h-GCCs and h-hepatocytes together. The replacement index (RI), which is the ratio of transplanted h-GCCs and h-hepatocytes that occupy the examined area of a histological section, was estimated by measuring h-AFP and h-albumin concentrations in sera, respectively, as well as by immunohistochemical analyses of h-AFP and human cytokeratin 18 in histological sections. The h-GCCs successfully engrafted, repopulated, and colonized the livers of mice in group A (RI = 22.0% ± 2.6%). These mice had moderately differentiated adenocarcinomatous lesions with disrupted glandular structures, which is a characteristics feature of gastric cancers. The serum h-AFP level reached 211.0 ± 142.2 g/mL (range, 7.1-324.2 g/mL). In group B mice, the h-GCCs and h-hepatocytes independently engrafted, repopulated the host liver, and developed colonies (RI = 12.0% ± 6.8% and 66.0% ± 12.3%, respectively). h-GCC colonies also showed typical adenocarcinomatous glandular structures around the h-hepatocyte-colonies. These mice survived for the full 56 day-study and did not exhibit any metastasis of h-GCCs in the extrahepatic regions during the observational period. The mice with an h-hepatocyte-repopulated liver possessed metastasized h-GCCs and therefore could be a useful humanized liver animal model for studying liver cancer metastasis in vivo. A novel animal model of human liver cancer metastasis was established using the uPA/SCID mouse line. This model could be useful for in vivo testing of anti-cancer drugs and for studying the mechanisms of human liver cancer metastasis.
  World Journal of Gastroenterology 08/2012; 18(29):3875-82. · 2.47 Impact Factor
• Article: HLA-DP gene polymorphisms and hepatitis B infection in the Japanese population.

  Kiyoshi Migita, Seigo Abiru, Masashi Ohtani, Yuka Jiuchi, Yumi Maeda, Sung Kwan Bae, Shigemune Bekki, Satoru Hashimoto, Kakharman Yesmembetov, Shinya Nagaoka, Minoru Nakamura, Atsumasa Komori, Tatsuki Ichikawa, Kazuhiko Nakao, Hiroshi Yatsuhashi, Hiromi Ishibashi, Michio Yasunami
  Translational research : the journal of laboratory and clinical medicine. 06/2012;
• Article: Serum amyloid A triggers the mosodium urate -mediated mature interleukin-1β production from human synovial fibroblasts.

  Kiyoshi Migita, Tomohiro Koga, Kenshi Satomura, Masahiro Izumi, Takafumi Torigoshi, Yumi Maeda, Yasumori Izumi, Yuka Jiuchi, Taiichiro Miyashita, Satoshi Yamasaki, Yoshihiro Aiba, Atsumasa Komori, Minoru Nakamura, Satoru Motokawa, Atsushi Kawakami, Tadashi Nakamura, Hiromi Ishibashi
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  ABSTRACT: Monosodium urate (MSU) has been shown to promote inflammasome activation and interleukin-1β (IL-1β) secretion in monocyte/macrophages, but the cellular pathway and nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation in synovial tissues, remain elusive. In this study, we investigated the effects of MSU on synovial fibroblasts to elucidate the process of MSU-mediated synovial inflammation. Human synovial fibroblasts were stimulated with MSU in the presence or absence of serum amyloid A (SAA). The cellular supernatants were analyzed by immunoblotting using anti-IL-1β or anti-caspase-1 antibodies. IL-1β or NLRP3 mRNA expressions were analyzed by real-time PCR or reverse transcription-PCR (RT-PCR) method. Neither SAA nor MSU stimulation resulted in IL-1β or interleukin-1α (IL-1α) secretions and pro-IL-1β processing in synovial fibroblasts. However, in SAA-primed synovial fibroblasts, MSU stimulation resulted in the activation of caspase-1 and production of active IL-1β and IL-1α. The effect of SAA on IL-1β induction was impaired in cells by silencing NLRP3 using siRNA or treating with caspase-1 inhibitor. In addition, SAA induced the secretion of cathepsin B and NLRP3 mRNA expression in synovial fibroblasts. Our data demonstrate that exposure of human synovial fibroblasts to SAA promotes MSU-mediated caspase-1 activation and IL-1β secretion in the absence of microbial stimulation. These findings provide insight into the molecular processes underlying the synovial inflammatory condition of gout.
  Arthritis research & therapy 05/2012; 14(3):R119. · 4.27 Impact Factor
• Article: Integrated fibrosis scoring by ultrasonography predicts the occurrence of hepatocellular carcinoma in patients with chronic hepatitis C virus infection

  Tetsuya Nishiura, Hideaki Watanabe, Koji Yano, Masahiro Ito, Seigo Abiru, Toshifumi Fujimoto, Atsumasa Komori, Hiroshi Yatsuhashi, Yojiro Matsuoka, Hiromi Ishibashi
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  ABSTRACT: PurposeThis study was performed to elucidate whether evaluating the liver surface, edge, and texture by high-resolution ultrasonography is useful for predicting the occurrence of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV)-associated chronic liver diseases (CLDs) MethodsThe integrated fibrosis stage (a comprehensive value of scores for liver edge, surface, and texture) of 337 patients with HCV-associated CLDs was evaluated, at entry, by ultrasonography (US), as a US score. The patients were followed up prospectively (mean observation period was 16.4months; range 2.8–36.2months) for the occurrence of HCC by US or helical CT at 3-month intervals. A total of 140 patients received interferon therapy, and the occurrence of HCC was compared between those with and without interferon therapy ResultsThe annual incidence of HCC was 1.1, 5.5, and 10.2% in low, middle, and high US score groups, respectively. Univariate analysis showed that age, serum levels of total bilirubin, alpha-fetoprotein (AFP), platelet count, albumin, total cholesterol, and the US score were associated with HCC occurrence in the patients. A multivariate proportional hazard model revealed that only the middle and high US scores (p=0.0922, hazard ratio 4.006, 95% CI 0.796–20.153 and p=0.008, hazard ratio 7.991, 95% CI 1.721–37.10, respectively) and elevated AFP (p=0.031, hazard ratio 2.774, CI 1.097–7.014) were independently associated with HCC occurrence. Our US scoring based on evaluation of the liver surface, edge, and texture was clearly and strongly associated with the occurrence of HCC in patients with HCV-associated CLDs, and with the higher occurrence rate of HCC in patients with higher US scores ConclusionThus, US is a good tool for evaluating the fibrosis stage of the liver, and may therefore be useful in designing an optimum follow-up interval for each patient with HCV-associated CLD. KeywordsHepatocellular carcinoma-Hepatitis C virus-Fibrosis-High and low-frequency probe-US score
  Journal of Medical Ultrasonics 04/2012; 38(1):13-19. · 0.33 Impact Factor
• Article: Long-term outcomes of add-on adefovir dipivoxil therapy to ongoing lamivudine in patients with lamivudine-resistant chronic hepatitis B.

  Takashi Toyama, Hisashi Ishida, Hiromi Ishibashi, Hiroshi Yatsuhashi, Makoto Nakamuta, Masaaki Shimada, Hajime Ohta, Takeaki Satoh, Michio Kato, Taizo Hijioka, Hirotsugu Takano, Toshiki Komeda, Michiyasu Yagura, Hiroshi Mano, Yukio Watanabe, Masakazu Kobayashi, Eiji Mita
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  ABSTRACT: Aim:  Add-on adefovir dipivoxil (ADV) therapy has been a standard rescue treatment for patients with lamivudine (LAM)-resistant chronic hepatitis B, but the overall benefits of long-term add-on ADV therapy are still limited. The aim of this study was to evaluate the long-term efficiency of add-on ADV treatment and to explore predictive factors associated with it. Methods:  A total of 158 patients with LAM-resistant chronic hepatitis B were included in this retrospective, multicenter, nationwide study in Japan. After confirming LAM resistance, ADV was added to LAM treatment. Three types of events were considered as outcomes: virological response, hepatitis B e antigen (HBeAg) clearance and alanine aminotransferase (ALT) normalization. Virological response was defined as serum hepatitis B virus (HBV) DNA levels of less than 3 log copies/mL. Baseline factors contributing to these outcomes were examined by univariate and multivariate analyses. Results:  The median total duration of ADV treatment was 41 months (range, 6-84). The rate of virological response was 90.8% at 4 years of treatment; HBeAg clearance and ALT normalization were achieved by 34.0% and 82.7%, respectively, at the end of follow up. Each outcome had different predictive factors: baseline HBV DNA and albumin level were predictive factors for virological response, history of interferon therapy and ALT level for HBeAg clearance, and sex and baseline albumin level for ALT normalization. Conclusion:  Long-term add-on ADV treatment was highly effective in LAM-resistant chronic hepatitis B patients in terms of virological and biochemical responses. Lower HBV replication and lower albumin level at baseline led to better outcomes.
  Hepatology Research 04/2012; · 2.20 Impact Factor
• Article: Serum amyloid A (SAA) induces pentraxin 3 (PTX3) production in rheumatoid synoviocytes.

  Kenshi Satomura, Takafumi Torigoshi, Tomohiro Koga, Yumi Maeda, Yasumori Izumi, Yuka Jiuchi, Taiichiro Miyashita, Satoshi Yamasaki, Atsushi Kawakami, Yoshihiro Aiba, Minoru Nakamura, Atsumasa Komori, Junji Sato, Hiromi Ishibashi, Satoru Motokawa, Kiyoshi Migita
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  ABSTRACT: OBJECTIVE: Pentraxin 3 (PTX3) is an acute-phase reactant that is involved in amplification of the inflammatory response and innate immunity. In the present study, we evaluated the relationship between PTX3 and serum amyloid A (SAA), another acute-phase reactant, in rheumatoid synoviocytes. METHODS: PTX3 mRNA expression was examined by reverse transcription polymerase chain reaction, and PTX3 protein was measured by enzyme-linked immunosorbent assay. RESULTS: SAA induced PTX3 mRNA and PTX3 protein expression in rheumatoid synoviocytes. SAA-induced PTX3 expression was attenuated when rheumatoid synoviocytes were nucleofected with N-formyl peptide receptor ligand-1 (FPRL-1)-specific siRNA, suggesting the involvement of FPRL-1. Furthermore, SAA-induced PTX3 expression was inhibited by NF-κB or mitogen-activated protein kinase-specific inhibitors. Neither soluble TNF receptor (etanercept) nor recombinant IL-1 receptor antagonist affected PTX3 production by SAA-stimulated synoviocytes, suggesting that SAA directly induces PTX3. CONCLUSION: Our data suggest that SAA plays a role in the proinflammatory and immune responses in rheumatoid synovium by inducing PTX3. We provide the first evidence that the acute-phase reactant SAA, which is produced systemically by hepatocytes, perpetuates the rheumatoid inflammatory processes by inducing another proinflammatory molecule, PTX3, locally in rheumatoid synovial tissues.
  Modern Rheumatology 03/2012; · 1.58 Impact Factor
• Article: Concurrent systemic AA amyloidosis can discriminate primary sclerosing cholangitis from IgG4-associated cholangitis.

  Takehiro Kato, Atsumasa Komori, Sung-Kwan Bae, Kiyoshi Migita, Masahiro Ito, Yasuhide Motoyoshi, Seigo Abiru, Hiromi Ishibashi
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  ABSTRACT: Chronic hepatobiliary inflammatory diseases are not widely acknowledged as underlying disorders of systemic AA amyloidosis, except epidemic schistosomiasis. Among them, primary sclerosing cholangitis (PSC) might initiate amyloid A protein deposition in diverse tissues, giving rise to systemic amyloidosis, due to a progressive and unresolved inflammatory process, and its possible association with inflammatory bowel diseases. Nevertheless, only one such case has been reported in the literature to date. We report a 69-year-old Japanese woman with cirrhosis who was diagnosed with PSC complicated with systemic AA amyloidosis, without any evidence of other inflammatory disorders. As a result of cholestasis in conjunction with biliary strictures and increased serum IgG4, the presence of IgG4(+) plasma cells was examined systemically, resulting in unexpected documentation of Congo-red-positive amyloid deposits, but not IgG4(+) plasma cells, in the liver, stomach and salivary glands. Elevated serum IgG4 is the hallmark of IgG4-related disease, including IgG4-associated cholangitis, but it has also been demonstrated in certain patients with PSC. Amyloid A deposits in multiple organs associated with an indolent clinical course that progresses over many years might have a diagnostic value in discriminating PSC from IgG4-associated cholangitis.
  World Journal of Gastroenterology 01/2012; 18(2):192-6. · 2.47 Impact Factor
• Article: Pathogenesis of biliary tract injury in primary biliary cirrhosis.

  Hiromi Ishibashi, Shinji Shimoda
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  ABSTRACT: Primary biliary cirrhosis (PBC) is histologically characterized by chronic nonsuppurative destructive cholangitis (CNSDC) associated with destruction of small bile ducts. The pathogenesis of PBC, predominance of female, or the reason why biliary duct is selectively involved, however, remains unknown. Infectious or non-infectious noxious insults such as xenobiotic chemicals may precipitate in the individual having a genetic background of PBC. Activation of innate immune response seems to be a key event in early PBC, leading to the autoimmune injury of small intrahepatic bile duct. Biliary epithelial cells possess an innate immune system consisting of the Toll-like receptor (TLR) family and recognize pathogen-associated molecular patterns (PAMPs). In PBC, dysregulated biliary innate immunity, namely hyper-responsiveness to PAMPs, is associated with the pathogenesis of cholangiopathy. Moreover, the targeted biliary epithelial cells (BEC) may play an active role in the perpetuation of autoimmunity by attracting immune cells via chemokine secretion. Biliary innate immune responses induce the production of two chemokines, CX3CL1 (fractalkine) and several Th1 shift chemokines, causing the migration of inflammatory cells including NK cells. TLR 4 ligand-stimulated NK cells destroy autologous BECs in the presence of interferon alpha (IFN-α) synthesized by TLR 3 ligand-stimulated monocytes. These findings give new insights in the pathogenesis of this mysterious disease, PBC.
  Japanese Journal of Clinical Immunology 01/2012; 35(6):455-62.
• Article: Vitamin D binding protein-macrophage activating factor inhibits HCC in SCID mice.

  Koichi Nonaka, Shinya Onizuka, Hiromi Ishibashi, Yoshihiro Uto, Hitoshi Hori, Toshiyuki Nakayama, Nariaki Matsuura, Takashi Kanematsu, Hikaru Fujioka
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  ABSTRACT: A high incidence of recurrence after treatment is the most serious problem in hepatocellular carcinoma (HCC). Therefore, a new strategy for the treatment of the disease is needed. The aim of the present study was to investigate whether vitamin D binding protein-macrophage activating factor (DBP-maf) is able to inhibit the growth of HCC. The effects of DBP-maf on endothelial cells and macrophage were evaluated by WST-1 assay and phagocytosis assay, respectively. Human HCC cells (HepG2) were implanted into the dorsum of severe combined immunodeficiency (SCID) mice. These mice were divided into control and DBP-maf treatment groups (n = 10/group). The mice in the treatment group received 40 ng/kg/d of DBP-maf for 21 d. DBP-maf showed anti-proliferative activity against endothelial cells and also activated phagocytosis by macrophages. DBP-maf inhibited the growth of HCC cells (treatment group: 126 ± 18mm(3), untreated group: 1691.5 ± 546.9mm(3), P = 0.0077). Histologic examinations of the tumors revealed the microvessel density was reduced and more macrophage infiltration was demonstrated in the tumor of mice in the treatment group. DBP-maf has at least two novel functions, namely, an anti-angiogenic activity and tumor killing activity through the activation of macrophages. DBP-maf may therefore represent a new strategy for the treatment of HCC.
  Journal of Surgical Research 01/2012; 172(1):116-22. · 2.25 Impact Factor
• Article: [Fostering future gastroenterology specialists -initiatives and challenges of medical gastroenterology-].

  Hiromi Ishibashi, Toshiyuki Matsui, Yuichiro Eguchi, Hisamitsu Miyaaki, Takashi Nagahama, Shintaro Abe, Ryukichi Kumashiro, Jun Hayashi, Atsumasa Komori, Kikuo Kanda, Mikio Yamanishi, Kazuhiro Mizukami, Tetsuya Koga, Tadashi Nishimaki, Michio Sata
  Nippon Shokakibyo Gakkai zasshi The Japanese journal of gastro-enterology 01/2012; 109(1):19-29.
• Article: Hepatocellular carcinoma and survival in patients with autoimmune hepatitis (Japanese National Hospital Organization-autoimmune hepatitis prospective study).

  Kiyoshi Migita, Yukio Watanabe, Yuka Jiuchi, Yoko Nakamura, Akira Saito, Michiyasu Yagura, Hajime Ohta, Masaaki Shimada, Eiji Mita, Taizo Hijioka, [......], Eiichi Takezaki, Toyokichi Muro, Hironori Sakai, Makoto Nakamuta, Seigo Abiru, Atsumasa Komori, Masahiro Ito, Hiroshi Yatsuhashi, Minoru Nakamura, Hiromi Ishibashi
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  ABSTRACT: Although the outcome of autoimmune hepatitis (AIH) is generally good, the natural course and likelihood of progression to cirrhosis or hepatocellular carcinoma (HCC) remain undefined, and may vary by region and population structure. Our aims were to evaluate risk factors that contribute to poor outcome and particularly development of HCC in a prospective multicentric cohort study of AIH. The study group comprised 193 Japanese patients with AIH who were prospectively followed up at annual intervals between 1995 and 2008. The mean follow-up period was 8.0 ± 4.5 years. Twenty-one (10.9%) patients had cirrhosis at presentation and a further 15 (7.8%) developed cirrhosis during the follow-up period. Survival rates were 94.2% at 10 years and 89.3% at 15 years. HCC was diagnosed in seven of the 193 patients. The presence of cirrhosis at presentation was a risk factor for HCC according to a Cox proportional hazard model, and the HCC-free survival rate was significantly lower in those with cirrhosis compared to those without cirrhosis according to Kaplan-Meier analysis. Although the outcome of AIH is as good if not better among Japanese than for other populations, there was an increased risk of HCC in these patients. Cirrhosis at presentation was predictive of development of HCC in AIH in Japan.
  Liver international: official journal of the International Association for the Study of the Liver 12/2011; 32(5):837-44. · 3.82 Impact Factor
• Article: Early dynamics of viremia in patients with genotype 1b chronic hepatitis C: Peg-IFNalpha2a shows earlier viral decline than peg-IFNalpha2b in combination therapy with ribavirin.

  Tatsuya Fujino, Makoto Nakamuta, Yoko Aoyagi, Motoyuki Kohjima, Takeaki Satoh, Mika Fukuda, Hiromi Ishibashi, Hiroshi Yatsuhashi, Munechika Enjoji
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  ABSTRACT: We aimed to assess differences in early viral dynamics following treatment with either peg-IFNalpha2a or peg-IFNalpha2b in combination with ribavirin in patients with chronic genotype 1b HCV infection. Sixty-one patients in the peg-IFNalpha2a + ribavirin treatment (group alpha2a) and 88 patients in the peg-IFNalpha2b + ribavirin treatment (group alpha2b) were retrospectively analyzed. The early dynamics of HCV RNA over 12 weeks were evaluated. Sustained virological response (SVR) was defined as undetectable HCV RNA at week 24 after end of therapy. First- (day 0-1) and second-phase (day 1-28) viral decline rates were calculated in accordance with theoretical formulae. Baseline HCV RNA concentrations were almost similar between the 2 groups. In group alpha2a, viral decline was significantly greater than in group alpha2b at weeks 4, 8, and 12. In group alpha2a, viral decline was significantly greater in SVR patients than in non-SVR patients at week 2, whereas significantly greater viral decline in SVR patients was found during weeks 1-12 in group alpha2b. The first-phase viral decline rate was significantly larger in group alpha2a than in group alpha2b (1.31 ± 0.84 vs. 0.70 ± 0.97 log IU/mL/day; p < 0.0001). Within SVR patients, first-phase viral decline rate was significantly larger in group α2a compared with group alpha2b (1.45 ± 0.85 vs. 0.78 ± 1.0 log IU/mL/day; p < 0.0001). Second-phase viral decline rate was comparable between the groups. Peg-IFNalpha2a showed earlier viral decline than peg-IFNalpha2b and the difference was obvious, especially in the first-phase viral decline.
  Medical science monitor: international medical journal of experimental and clinical research 12/2011; 17(12):CR687-91. · 1.70 Impact Factor
• Article: Hepatitis B virus strains of subgenotype A2 with an identical sequence spreading rapidly from the capital region to all over Japan in patients with acute hepatitis B.

  Yoko Tamada, Hiroshi Yatsuhashi, Naohiko Masaki, Makoto Nakamuta, Eiji Mita, Tatsuji Komatsu, Yukio Watanabe, Toyokichi Muro, Masaaki Shimada, Taizo Hijioka, Takeaki Satoh, Yutaka Mano, Toshiki Komeda, Masahiko Takahashi, Hiroshi Kohno, Hajime Ota, Shigeki Hayashi, Yuzo Miyakawa, Seigo Abiru, Hiromi Ishibashi
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  ABSTRACT: To examine recent trends of acute infection with hepatitis B virus (HBV) in Japan by nationwide surveillance and phylogenetic analyses. During 1991 through 2009, a sentinel surveillance was conducted in 28 national hospitals in a prospective cohort study. Genotypes of HBV were determined in 547 patients with acute hepatitis B. Nucleotide sequences in the preS1/S2/S gene of genotype A and B isolates were determined for phylogenetic analyses. HBV genotype A was detected in 137 (25% (accompanied by genotype G in one)) patients, B in 48 (9%), C in 359 (66%), and other genotypes in the remaining three (0.5%). HBV persisted in five with genotype A including the one accompanied by genotype G; another was co-infected with HIV type 1. The genotype was A in 4.8% of patients during 1991-1996, 29.3% during 1997-2002, and 50.0% during 2003-2008 in the capital region, as against 6.5%, 8.5% and 33.1%, respectively, in other regions. Of the 114 genotype A isolates, 13 (11.4%) were subgenotype A1, and 101 (88.6%) were A2, whereas of the 43 genotype B isolates, 10 (23.3%) were subgenotype B1, 28 (65.1%) were B2, two (4.7%) were B3, and three (7.0%) were B4. Sequences of 65 (64%) isolates of A2 were identical, as were three (23%) of A1, and five (18%) of B2, but none of the B1, B3 and B4 isolates shared a sequence. Acute infection with HBV of genotype A, subgenotype A2 in particular, appear to be increasing, mainly through sexual contact, and spreading from the capital region to other regions in Japan nationwide. Infection persisted in 4% of the patients with genotype A, and HBV strains with an identical sequence prevailed in subgenotype A2 infections. This study indicates the need for universal vaccination of young people to prevent increases in HBV infection in Japan.
  Gut 11/2011; 61(5):765-73. · 10.11 Impact Factor
• Source

  Available from: Mikio Zeniya

  Article: Primary biliary cirrhosis - Autoimmune hepatitis overlap syndrome: A rationale for corticosteroids use based on a nation-wide retrospective study in Japan.

  Atsushi Tanaka, Kenichi Harada, Hirotoshi Ebinuma, Atsumasa Komori, Junko Yokokawa, Kaname Yoshizawa, Masanori Abe, Yasuhiro Miyake, Kentaro Kikuchi, Hiromasa Ohira, Mikio Zeniya, Kazuhide Yamamoto, Hiromi Ishibashi, Morikazu Onji, Yasuni Nakanuma, Hirohito Tsubouchi, Hajime Takikawa
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  ABSTRACT: Aims:  Primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH) may simultaneously coexist in some patients, designated as PBC-AIH overlap syndrome. Previous studies suggest that combination therapy of ursodeoxycholic acid (UDCA) and corticosteroids may be effective. In the current study, we aimed to describe clinical features of these cases and to propose a rationale for combination treatment in PBC-AIH overlap. Methods:  We enrolled patients with PBC-AIH overlap from eight referral centers for liver diseases in Japan, and clinical, biochemical and immunological features were examined. Liver histology of all patients at diagnosis were analyzed altogether in detail. Eighty-nine and 44 patients with PBC and AIH alone were included and served as controls. Results:  We identified 33 patients with PBC-AIH overlap. The mean follow-up period was 6.1 years. On liver histology, the HA (hepatitis activity) score was significantly higher than the CA (cholangitis activity) score (P < 0.001). At the end of the follow-up period, corticosteroids were used in 23 patients (72%), and neither liver-related death nor liver transplantation had been noted. The sensitivity and specificity of the simplified AIH scoring system for prediction of patients who required corticosteroids during clinical course was 92% and 75% in the training set (n = 17), and 91% and 80% in the validation set (n = 16) of overlap. Only 3% of PBC patients were diagnosed as having indication for corticosteroid use. Conclusion:  In PBC-AIH overlap, AIH-like features are dominant in liver histology. The simplified AIH scoring system could predict patients who needed corticosteroids with a higher specificity.
  Hepatology Research 09/2011; 41(9):877-886. · 2.20 Impact Factor
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  Available from: PubMed Central

  Article: Inhibitory effects of the JAK inhibitor CP690,550 on human CD4(+) T lymphocyte cytokine production.

  Kiyoshi Migita, Taiichiro Miyashita, Yasumori Izumi, Tomohiro Koga, Atsumasa Komori, Yumi Maeda, Yuka Jiuchi, Yoshihiro Aiba, Satoshi Yamasaki, Atsushi Kawakami, Minoru Nakamura, Hiromi Ishibashi
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  ABSTRACT: The new JAK3 inhibitor, CP690,550, has shown efficacy in the treatment of rheumatoid arthritis. The present study was undertaken to assess the effects of CP690,550 on cytokine production and cellular signaling in human CD4(+) T cells. CD4(+) T cells produced IL-2, IL-4, IL-17, IL-22 and IFN-γ in following stimulation with a CD3 antibody. At the optimal concentration, CP690,550 almost completely inhibited the production of IL-4, IL-17, IL-22 and IFN-γ from these activated CD4(+) T cells, but only had marginal effects on IL-2 production. Moreover CP690,550 inhibited anti-CD3-induced phosphorylation of STAT1, STAT3, STAT4, STAT5, and STAT6, but not the TCR-associated phosphorylation of ZAP-70. Therefore, CP690,550-mediated modification of the JAK/STAT pathway may be a new immunosuppressive strategy in the treatment of autoimmune diseases.
  BMC Immunology 08/2011; 12:51. · 2.53 Impact Factor
• Article: Influence of Janus kinase inhibition on interleukin 6-mediated induction of acute-phase serum amyloid A in rheumatoid synovium.

  Kiyoshi Migita, Tomohiro Koga, Atsumasa Komori, Takafumi Torigoshi, Yumi Maeda, Yasumori Izumi, Junji Sato, Yuka Jiuchi, Taiichiro Miyashita, Satoshi Yamasaki, Atsushi Kawakami, Minoru Nakamura, Satoru Motokawa, Hiromi Ishibashi
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  ABSTRACT: Inhibition of intracellular signal transduction is considered to be a therapeutic target for chronic inflammation. The new Janus kinase (JAK)3 inhibitor CP690,550 has shown efficacy in the treatment of rheumatoid arthritis (RA). We investigated the influence of JAK/STAT inhibition using CP690,550 on the induction of acute-phase serum amyloid A (SAA), which is triggered by interleukin 6 (IL-6) stimulation in rheumatoid fibroblast-like synoviocytes (RA-FLS). IL-6-stimulated gene expression of the acute-phase serum amyloid A genes (A-SAA; encoded by SAA1+SAA2) and SAA4 was analyzed by reverse transcriptase-polymerase chain reaction. The intracellular signaling pathway mediating the effects of CP690,550 on IL-6-stimulated JAK/STAT activation was assessed by measuring the phosphorylation levels using Western blots. IL-6 trans-signaling induced A-SAA messenger RNA (mRNA) expression in RA-FLS. By contrast IL-6 stimulation did not affect SAA4 mRNA expression, which is expressed constitutively in RA-FLS. IL-6 stimulation elicited rapid phosphorylation of JAK2 and STAT3, which was blunted by CP690,550. CP690,550 abrogated IL-6-mediated A-SAA mRNA expression in RA-FLS. Similarly, CP690,550 inhibited IL-6-mediated A-SAA mRNA expression in human hepatocytes. Our data indicated that CP690,550 blocked IL-6-induced JAK2/STAT3 activation, as well as the induction of A-SAA. Inhibition of IL-6-mediated proinflammatory signaling pathways by CP690,550 may represent a new antiinflammatory therapeutic strategy for RA and AA amyloidosis.
  The Journal of Rheumatology 08/2011; 38(11):2309-17. · 3.69 Impact Factor
• Article: Genetic polymorphisms in CTLA4 and SLC4A2 are differentially associated with the pathogenesis of primary biliary cirrhosis in Japanese patients.

  Yoshihiro Aiba, Minoru Nakamura, Satoru Joshita, Tatsuo Inamine, Atsumasa Komori, Kaname Yoshizawa, Takeji Umemura, Hitomi Horie, Kiyoshi Migita, Hiroshi Yatsuhashi, [......], Toshiki Komeda, Masaaki Shimada, Naohiko Masaki, Tatsuji Komatsu, Michiyasu Yagura, Kazuhiro Sugi, Michiaki Koga, Kazuhiro Tsukamoto, Eiji Tanaka, Hiromi Ishibashi
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  ABSTRACT: Anti-gp210 and anti-centromere antibodies are different risk factors for the progression of primary biliary cirrhosis (PBC). In order to dissect the genetic basis for the production of these autoantibodies, as well as the development and progression of PBC in Japanese patients, we examined single nucleotide polymorphisms (SNPs) in cytotoxic T-lymphocyte antigen 4 (CTLA4) and solute carrier family 4 anion exchanger, member 2 (SLC4A2), which have been associated with the pathogenesis of PBC in Caucasian patients. Four SNPs for both CTLA4 and SLC4A2 were genotyped, using the polymerase chain reaction-restriction fragment length polymorphism method and TaqMan assay, in 450 Japanese PBC patients and 371 sex-matched healthy controls. The CTLA4 rs231775, rs3087243, and rs231725 SNPs were significantly associated with PBC susceptibility. The CTLA4 rs231725 SNP was significantly associated with progression to late-stage disease. The CTLA-4 haplotype 1 (rs231775 G, rs231777 C, rs3087243 G, rs231725 A; GCGA) was a risk factor for PBC susceptibility but a protective factor for PBC progression. Conversely, the CTLA-4 haplotype 2 (ACAG) was a protective and risk factor, respectively, for PBC susceptibility and progression. In addition, the CTLA4 rs231777 SNP and haplotype 3 (ATGG) was significantly associated with anti-gp210 antibody production, while SLC4A2 haplotype 4 (rs2069443 A, rs2303933 G, rs2303937 A, rs2303941 T; AGAT) and haplotype 3 (AAGC) were significantly associated with PBC susceptibility and anti-centromere antibody production, respectively. CTLA4 and SLC4A2 genetic polymorphisms are differentially associated with PBC development and progression, as well as anti-gp210 or anti-centromere antibody production, in Japanese PBC patients.
  Journal of Gastroenterology 05/2011; 46(10):1203-12. · 4.16 Impact Factor