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212 results on '"Tatsuki Ichikawa"'

1. Elevated intestinal fatty acid-binding protein levels as a marker of portal hypertension and gastroesophageal varices in cirrhosis

Author

Satoshi Miuma, Hisamitsu Miyaaki, Naota Taura, Yasuko Kanda, Satoshi Matsuo, Kazuaki Tajima, Kosuke Takahashi, Yasuhiko Nakao, Masanori Fukushima, Masafumi Haraguchi, Ryu Sasaki, Eisuke Ozawa, Tatsuki Ichikawa, and Kazuhiko Nakao

Subjects
Medicine, Science
Abstract

Abstract We measured intestinal fatty acid-binding protein (I-FABP) levels, a useful marker of small intestinal mucosal injury, in patients with cirrhosis to determine their relationship with liver function and complications. This cross-sectional study included 71 patients with cirrhosis admitted for treatment of cirrhotic complications or hepatocellular carcinoma (cohort A) and 104 patients with cirrhosis who received direct-acting antiviral therapy for HCV (cohort B). I-FABP levels, measured by ELISA, were evaluated relative to hepatic reserve and compared with non-invasive scoring systems for diagnostic performance in cirrhotic complications. The median I-FABP level in both cohorts were significantly elevated in patients with reduced hepatic reserve (CTP grade A/BC cohort A, 2.33/3.17 ng/mL, p = 0.032; cohort B, 2.46/3.64 ng/mL, p = 0.008) and complications with gastroesophageal varices (GEV; GEV (-)/(+) cohort A, 1.66/3.67 ng/mL, p

Published
2024
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2. How mass disorder affects heat conduction in ternary amorphous alloys

Author

Tatsuki Ichikawa, Emi Minamitani, Yuzo Shigesato, Makoto Kashiwagi, and Takuma Shiga

Subjects
Physics, QC1-999
Abstract

Thermal management is critical in devices that use amorphous semiconductors. Recent studies have revealed how size and mass disorder affect heat conduction, but the effects of more-extreme mass and lattice disorder are also relevant. Here, we report modal analysis of simulated samples of amorphous silicon alloyed with atoms of different-mass silicon to yield a ternary amorphous material. Although we expected the material with high degrees of mass disorder to show dramatic changes in thermal conductivity as the composition of the material changed, the thermal conductivity instead changed monotonically. Thus, we find that no peculiar thermal transport properties appear in ternary amorphous alloys with high degrees of mass disorder. Furthermore, we find that while delocalized propagating modes (propagons) explain nearly 30% of the overall thermal conductivity independent of the composition, the contribution of delocalized non-propagating modes (diffusons) is sensitive to the composition and tends to be the dominant mechanism behind heat conduction in ternary amorphous alloys.

Published
2021
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3. Geranylgeranylacetone attenuates fibrogenic activity and induces apoptosis in cultured human hepatic stellate cells and reduces liver fibrosis in carbon tetrachloride-treated mice

Author

Takemasa Senoo, Ryu Sasaki, Yuko Akazawa, Tatsuki Ichikawa, Satoshi Miuma, Hisamitsu Miyaaki, Naota Taura, and Kazuhiko Nakao

Subjects
Geranylgeranylacetone, Hepatic stellate cells, Liver fibrosis, Apoptosis, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Abstract Background Geranylgeranylacetone (GGA), an anti-ulcer drug widely used in Japan, has attracted interest because of its various therapeutic effects. Therefore, we investigated the effects of GGA on human hepatic stellate cells (HSCs) in vitro and in a mouse model of liver fibrosis. Methods LX2, an immortalized human HSC line, was cultured and treated with GGA at concentrations up to 0.5 mM. After GGA treatment, changes in cellular morphology, apoptosis, and fibrosis-related gene expression were assessed. Male C57BL/6 J mouse model of carbon tetrachloride (CCl4)-induced liver fibrosis was treated with GGA. Liver fibrosis was evaluated using Sirius red staining and immunohistochemistry for α-smooth muscle actin (SMA). Results GGA decreased the density of LX2 and primary human hepatic stellate cells but not that of HepG2 cells (a human hepatoma cell line), which was employed as control. In addition, GGA decreased the expression of fibrogenic genes and increased that of C/EBP homologous protein (CHOP). It also induced endoplasmic reticulum (ER) stress and increased apoptosis. CHOP knockdown, however, failed to suppress the GGA-induced decrease in LX2 cell density, suggesting the involvement of additional molecules in ER stress–associated apoptosis. Expression of death receptor 5, mitogen-activated protein kinase, heat shock protein 70, and Akt, all of which affect the activity of stellate cells, was unchanged in relation to LX2 cell fibrogenic activity. In the mouse model of liver fibrosis, GGA decreased the extent of Sirius red staining and SMA expression. Conclusions GGA attenuated fibrogenic activity and induced apoptosis in cultured human HSCs, and suppressed liver fibrosis in mice, suggesting its potential as an agent for treating liver fibrosis.

Published
2018
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4. Serum Wisteria Floribunda Agglutinin-Positive Mac-2 Binding Protein Values Predict the Development of Hepatocellular Carcinoma among Patients with Chronic Hepatitis C after Sustained Virological Response.

Author

Ryu Sasaki, Kazumi Yamasaki, Seigo Abiru, Atsumasa Komori, Shinya Nagaoka, Akira Saeki, Satoru Hashimoto, Shigemune Bekki, Yuki Kugiyama, Atsushi Kuno, Masaaki Korenaga, Akira Togayachi, Makoto Ocho, Masashi Mizokami, Hisashi Narimatsu, Tatsuki Ichikawa, Kazuhiko Nakao, and Hiroshi Yatsuhashi

Subjects
Medicine, Science
Abstract

Measurement of Wisteria floribunda agglutinin-positive human Mac-2 binding protein (WFA+-M2BP) in serum was recently shown to be a noninvasive method to assess liver fibrosis. The aim of this study was to evaluate the utility of serum WFA+-M2BP values to predict the development of hepatocellular carcinoma (HCC) in patients who achieved a sustained virological response (SVR) by interferon treatment. For this purpose, we retrospectively analyzed 238 patients with SVR who were treated with interferon in our department. Serum WFA+-M2BP values were measured at pre-treatment (pre-Tx), post-treatment (24 weeks after completion of interferon; post-Tx), the time of HCC diagnosis, and the last clinical visit. Of 238 patients with SVR, HCC developed in 16 (6.8%) patients. The average follow-up period was 9.1 years. The cumulative incidence of HCC was 3.4% at 5 years and 7.5% at 10 years. The median pre-Tx and post-Tx WFA+-M2BP values were 1.69 (range: 0.28 to 12.04 cutoff index (COI)) and 0.80 (range: 0.17 to 5.29 COI), respectively. The WFA+-M2BP values decreased significantly after SVR (P < 0.001). The median post-Tx WFA+-M2BP value in patients who developed HCC was significantly higher than that in patients who did not (P < 0.01). Multivariate analysis disclosed that age (> 60 years), sex (male), pre-Tx platelet count (< 15.0×10(3)/μL), and post-Tx WFA+-M2BP (> 2.0 COI) were associated with the development of HCC after SVR. Conclusion: Post-Tx WFA+-M2BP (> 2.0 COI) is associated with the risk for development of HCC among patients with SVR. The WFA+-M2BP values could be a new predictor for HCC after SVR.

Published
2015
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5. Baseline Serum Cholesterol Is Associated with a Response to Pegylated Interferon Alfa-2b and Ribavirin Therapy for Chronic Hepatitis C Genotype 2

Author

Naota Taura, Tatsuki Ichikawa, Hisamitsu Miyaaki, Yoshiko Kadokawa, Takuya Tsutsumi, Shotaro Tsuruta, Yuji Kato, Osami Inoue, Noboru Kinoshita, Kazuo Ohba, Hiroyuki Kato, Kazuyuki Ohata, Junichi Masuda, Keisuke Hamasaki, Hiroshi Yatsuhashi, and Kazuhiko Nakao

Subjects
Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Background. HCV infection is associated with lipid disorders because this virus utilizes the host lipid metabolism to sustain its life cycle. Several studies have indicated that higher concentrations of serum cholesterol and LDL before treatment are important predictors of higher rates of sustained virological response (SVR). However, most of these studies involved patients infected with HCV genotype 1. Thus, we performed a multi-institutional clinical study to evaluate the impact of lipid profiles on SVR rates in patients with HCV genotype 2. Methods. A total of 100 chronic hepatitis C patients with HCV genotype 2 who received peg-IFN alfa-2b and ribavirin therapy were consecutively enrolled. The significance of age, sex, BMI, AST level, ALT level, WBC, hemoglobin, platelet count, gamma-glutamyltransferase, total cholesterol level (TC), LDL level, HCV RNA, and histological evaluation was examined for SVR using logistic regression analysis. Results. The 100 patients infected with HCV genotype 2 were divided into 2 groups, an SVR group and a non-SVR group. Characteristics of each group were subsequently compared. There was no significant difference in the level of HCV RNA, BMI, platelet, TG, or stage of fibrosis between the groups. However, there were significant differences in the levels of TC and LDL-C. In multivariate logistic regression analysis using baseline characteristics, high TC level was an independent and significant risk factor (relative risk 18.59, P=0.015) for SVR. Conclusion. Baseline serum total cholesterol levels should be considered when assessing the likelihood of sustained treatment response following the course of peg-IFN and ribavirin therapy in patients with chronic HCV genotype 2 infection.

Published
2012
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7. Infrared Thermography with High Accuracy in a Neonatal Incubator

Author

Keisuke Hamada, Eiji Hirakawa, Hidetsugu Asano, Hayato Hayashi, Takashi Mine, Tatsuki Ichikawa, and Yasuhiro Nagata

Subjects
Incubators, Infrared Rays, Thermography, Infant, Newborn, Biomedical Engineering, Humans, Reproducibility of Results, Skin Temperature, Body Temperature
Abstract

As the accuracy of body temperature measurement is especially critical in premature infants on admission to the neonatal intensive care unit (NICU), noninvasive measurement using infrared thermography (IRT) has not been widely adopted in the NICU due to a lack of evidence regarding its accuracy. We have established a new calibration method for IRT in an incubator, and evaluated its accuracy and reliability at different incubator settings using a variable-temperature blackbody furnace. This method improved the accuracy and reliability of IRT with an increase in percentage of data with mean absolute error (MAE) < 0.3 °C to 93.1% compared to 4.2% using the standard method. Two of three IRTs had MAE < 0.1 °C under all conditions examined. This method provided high accuracy not only for measurements at specific times but also for continuous monitoring. It will also contribute to avoiding the risk of neonates' skin trouble caused by attaching a thermistor. This study will facilitate the development of novel means of administering neonatal body temperature.

Published
2022
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8. Regular protocol liver biopsy is useful to adjust immunosuppressant dose after adult liver transplantation

Author

Shohei Narita, Satoshi Miuma, Sadayuki Okudaira, Yoshito Koga, Masanori Fukushima, Ryu Sasaki, Masafumi Haraguchi, Akihiko Soyama, Masaaki Hidaka, Hisamitsu Miyaaki, Mitsuru Futakuchi, Kazuhiro Nagai, Tatsuki Ichikawa, Susumu Eguchi, and Kazuhiko Nakao

Subjects
Transplantation
Abstract

Adjusting immunosuppression to minimal levels post-adult liver transplantation (LT) is critical; however, graft rejection has been reported in LT recipients with normal liver function evaluated by liver biopsy (LBx). Continual protocol liver biopsy (PLB) is performed regularly in LT recipients with normal liver function in some centers; however, its usefulness remains inadequately evaluated. This study aimed to assess retrospectively the usefulness of late PLB after adult LT.LBx evaluations of LT recipients with normal liver function and hepatitis B and C virus seronegativity were defined as PLB. The cases requiring immunosuppressive therapy for rejection findings based on Banff criteria were extracted from the PLBs, and pathological data collected before and after immunosuppressive dosage adjustment (based on modified histological activity index [HAI] score) were compared.Among 548 LBx cases, 213 LBx in 110 recipients fulfilled the inclusion criteria for PLB. Immunosuppressive therapy after PLB was intensified in 14 LBx (6.6%) recipients (12.7%); of these, nine had late-onset acute rejection, three had isolated perivenular inflammation, one had plasma cell-rich rejection, and one had early chronic rejection. Follow-up LBx after immunosuppressive dose adjustment showed improvement in the modified HAI score grading in 10 of 14 cases (71.4%). No clinical background and blood examination data, including those from the post-LT period, immunosuppressant trough level, or examination for de novo DSA, predicted rejection in PLB. Complications of PLB were found in only three cases.PLB is useful in the management of seemingly stable LT recipients, to discover subclinical rejection and allow for appropriate immunosuppressant dose adjustment.

Published
2022
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9. Treatment of Hepatitis C Virus Infection with Direct-acting Antiviral Agents Elevates the Serum Small-dense Low-density Lipoprotein Cholesterol Level

Author

Ryu Sasaki, Naoyuki Hino, Youichi Takahashi, Eisuke Ozawa, Hisamitsu Miyaaki, Masanori Fukushima, Takuya Honda, Satoshi Miuma, Makiko Koike, Masafumi Haraguchi, Kazuhiko Nakao, and Tatsuki Ichikawa

Subjects
Ledipasvir, hepatitis C virus, medicine.medical_specialty, Daclatasvir, Sofosbuvir, direct-acting antiviral agents, Hepatitis C virus, small dense low-density lipoprotein cholesterol, Hepacivirus, medicine.disease_cause, Gastroenterology, Antiviral Agents, chemistry.chemical_compound, Internal medicine, Internal Medicine, medicine, Humans, Retrospective Studies, business.industry, Ribavirin, Albumin, General Medicine, Hepatitis C, Chronic, Hepatitis C, chemistry, Asunaprevir, Original Article, Intramuscular fat, business, intramuscular fat deposition, medicine.drug
Abstract

Objective The low-density lipoprotein cholesterol (LDL) level is known to increase following the treatment of hepatitis C virus (HCV) infection using direct-acting antiviral agents (DAAs). This study aimed to investigate the changes in the lipid profiles, including small-dense LDL cholesterol (sdLDL), in HCV patients treated with DAAs. Patients We retrospectively assessed 67 HCV patients who achieved sustained virological response with DAA administration and were observed for more than 2 years, of whom 32 were on daclatasvir/asunaprevir, 14 were on sofosbuvir/ledipasvir, and 21 were on sofosbuvir/ribavirin. Methods We evaluated the lipid profiles, including sdLDL, every 6 months until 2 years after the start of treatment and analyzed the factors related to changes in the sdLDL level. Results The median sdLDL value at baseline was 12.8 mg/dL, which increased to 19.5 mg/dL at 6 months (p

Published
2021

10. Direct-acting Antivirals Improved the Quality of Life, Ameliorated Disease-related Symptoms, and Augmented Muscle Volume Three Years Later in Patients with Hepatitis C Virus

Author

Kazuhiko Nakao, Yasutaka Kuribayashi, Osamu Miyazaki, Mio Yamashima, Satoshi Miuma, Yasuhide Motoyoshi, Shinobu Yamamichi, Tatsuki Ichikawa, Keiji Kira, Ryouhei Uehara, Naota Taura, Hiroyuki Yajima, Yusuke Nakano, Hisamitsu Miyaaki, Makiko Koike, and Tetsurou Honda

Subjects
hepatitis C virus, Male, medicine.medical_specialty, Lumbar vertebrae, Disease, 030204 cardiovascular system & hematology, Chronic liver disease, Muscle Development, Antiviral Agents, 03 medical and health sciences, 0302 clinical medicine, Quality of life, Japan, Internal medicine, Internal Medicine, medicine, Humans, Restless legs syndrome, Muscle, Skeletal, Sleep disorder, direct-acting antiviral, business.industry, Skeletal muscle, disease-related symptom, General Medicine, skeletal muscle mass, Hepatitis C, Chronic, Middle Aged, medicine.disease, humanities, medicine.anatomical_structure, Cross-Sectional Studies, quality of life, Hepatocellular carcinoma, 030211 gastroenterology & hepatology, Original Article, Female, business, Immunosuppressive Agents, Follow-Up Studies
Abstract

Objective Patient-reported outcomes (PROs) are important measures of the quality of life (QOL) and symptoms in patients with hepatitis C virus (HCV). We evaluated the PROs at the beginning of direct-acting antiviral (DAA) treatment and three years later. A low QOL in patients with chronic liver disease suggested a low muscle mass. We compared the relationship between the QOL and muscle mass.Methods DAAs were administered to 100 patients with HCV infection. The PROs included the cirrhosis-related symptom score (CSS), presence of restless legs syndrome, Pittsburg sleep quality index (PSQI) to evaluate sleep disturbance, SF-36 to measure the QOL, and calculated body muscle mass (CBMM) measured at the beginning of treatment and three years later. Computed tomography (CT) was used to screen 82 patients for hepatocellular carcinoma at the beginning of treatment and three years later. Cross-sectional CT images of the third lumbar vertebrae were analyzed to evaluate the body composition.Results The general health perception (GHN) of SF-36 was better at three years after DAA administration than at the beginning. Changes in the GHN (dGHN) were related to an improved sleep quality on the PSQI and CSS and increased CBMM. The dGHN was positively related to changes in the skeletal muscle. The sleep quality, sleep latency, fatigue, and abdominal fullness were related to dGHN. Conclusion The QOL is related to sleep disturbance and several other symptoms. Furthermore, in patients with an increased muscle volume after DAA treatment, increased muscle mass is associated with an improvement in the QOL., Internal medicine, 59(21), pp.2653-2660; 2020

Published
2020

11. The linkage between medical student readiness for interprofessional learning and interest in community medicine

Author

Yuko Hamaguchi, Hiroki Ozawa, Ikuko Sagara, Ayako Nishino, Toru Yasutake, Yasuhiro Nagata, Tatsuki Ichikawa, Ikue Noguchi, Hiroyuki Ishii, Sumihisa Honda, Takashi Mine, Yuji Shiotani, Takahiro Maeda, Yusuke Matsuzaka, Sayaka Kuba, Kumiko Muta, and Alan Kawarai Lefor

Subjects
Medical education, Interprofessional Learning, Students, Medical, Attitude of Health Personnel, Interprofessional Relations, education, General Medicine, Linkage (mechanical), Interprofessional education, law.invention, Undergraduate curriculum, law, Community Medicine, Surveys and Questionnaires, ComputingMilieux_COMPUTERSANDEDUCATION, Humans, undergraduate curriculum, Cooperative Behavior, Psychology, medical education, Curriculum, Original Research
Abstract

Objectives: The purpose of this study is to investigate the relationship between medical student readiness for interprofessional learning and interest in community medicine prior to incorporating community-oriented interprofessional education into the curriculum. Methods: A questionnaire was administered to students at Nagasaki University School of Medicine in Japan during each of three consecutive years (N=2244). The Readiness for Interprofessional Learning Scale (RIPLS) was administered in addition to a questionnaire to evaluate interest in community medicine. The Kruskal-Wallis and Steel-Dwass tests were used to determine differences between school years. Correlation between the RIPLS score and interest in community medicine was evaluated with Spearman's rank correlation coefficient. Relationships between RIPLS score and demographic parameters, and interest in community medicine were evaluated with multiple linear regression analysis. Results: Eighty-four percent (1891/2244) of students responded. The RIPLS score was highest in school year 1, followed by year 6, year 5,year 3, and years 4 and 2. Interest in community medicine correlated with the RIPLS score (rs = 0.332, p < 0.001),but less in year 1 (rs = 0.125, p = 0.002) than in other years. RIPLS score was significantly associated with gender, age, school year, interest in community medicine, but not the year that the survey was conducted. Conclusions: Community-oriented interprofessional education has the potential to improve attitudes towards interprofessional learning. When introducing this promising education into the curriculum from year 1, attracting students' interest in community medicine should be considered., International journal of medical education, 11, pp.240-244; 2020

Published
2020

12. Calculated body muscle mass as a useful screening marker for low skeletal muscle mass and sarcopenia in chronic liver disease

Author

Osamu Miyazaki, Naoyuki Hino, Tatsuki Ichikawa, Ryousuke Hirata, Tetsurou Honda, Mio Yamashima, Ryouhei Uehara, Kazuhiko Nakao, Satoshi Miuma, Hiroyuki Yajima, Naota Taura, Shinobu Yamamichi, Hisamitsu Miyaaki, Yasuhide Motoyoshi, and Makiko Koike

Subjects
medicine.medical_specialty, Urology, Chronic liver disease, 03 medical and health sciences, Liver disease, Grip strength, chemistry.chemical_compound, 0302 clinical medicine, medicine, Creatinine, Hepatology, Receiver operating characteristic, biology, business.industry, Skeletal muscle, musculoskeletal system, medicine.disease, Infectious Diseases, medicine.anatomical_structure, Cystatin C, chemistry, 030220 oncology & carcinogenesis, Sarcopenia, biology.protein, 030211 gastroenterology & hepatology, business, human activities
Abstract

Aim Sarcopenia is a harmful condition in patients with chronic liver disease. However, the evaluation of body muscle mass requires expensive instrumentation. The sarcopenia index (SI): (creatinine / cystatin C × 100) has been reported to correlate with muscle volume. A calculated body muscle mass (CBMM) using creatinine, cystatin C, and bodyweight also correlates with muscle mass. We evaluated the applicability of using SIs and CBMMs as screening methods for sarcopenia. Methods Patients (n = 303) with liver damage were evaluated for creatinine, cystatin C, and grip strength (GS). All patients were evaluated using cross-sectional computed tomography images of the third lumbar vertebrae to determine their skeletal muscle (SM) mass. CBMMs and SIs were compared with SMs, GSs, and sarcopenia. Results Correlation coefficients (R) between SMI (SM / height2 [m2 ]) and CBMM, and between GS and CBMM were 0.643 and 0.723, respectively. Factors contributing to low GSs; low SM indices; and sarcopenia were age and SM; sex, age, GS, SI, and CBMM indices; and sex, bodyweight, and CBMM, respectively, in the multivariate logistic analyses. Receiver operating characteristic curve analysis between sarcopenia and CBMM showed an area under the receiver operating characteristic curve of 0.78504 in women and 0.86067 in men. Cut-off CBMM values for sarcopenia were 27.903 (sensitivity 0.73958) in women and 39.731 (sensitivity 0.7941) in men. Conclusions CBMMs and SIs are simple and minimally invasive screening methods in which low levels are indicative of sarcopenia in patients with liver disease.

Published
2020
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13. Corrigendum to ‘An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs’ [J Hepatol 2021;75(3):572–581]

Author

Heather J. Cordell, James J. Fryett, Kazuko Ueno, Rebecca Darlay, Yoshihiro Aiba, Yuki Hitomi, Minae Kawashima, Nao Nishida, Seik-Soon Khor, Olivier Gervais, Yosuke Kawai, Masao Nagasaki, Katsushi Tokunaga, Ruqi Tang, Yongyong Shi, Zhiqiang Li, Brian D. Juran, Elizabeth J. Atkinson, Alessio Gerussi, Marco Carbone, Rosanna Asselta, Angela Cheung, Mariza de Andrade, Aris Baras, Julie Horowitz, Manuel A.R. Ferreira, Dylan Sun, David E. Jones, Steven Flack, Ann Spicer, Victoria L. Mulcahy, Jinyoung Byun, Younghun Han, Richard N. Sandford, Konstantinos N. Lazaridis, Christopher I. Amos, Gideon M. Hirschfield, Michael F. Seldin, Pietro Invernizzi, Katherine A. Siminovitch, Xiong Ma, Minoru Nakamura, George F. Mells, Andrew Mason, Catherine Vincent, Gang Xie, Jinyi Zhang, Andrea Affronti, Piero L. Almasio, Domenico Alvaro, Pietro Andreone, Angelo Andriulli, Francesco Azzaroli, Pier Maria Battezzati, Antonio Benedetti, Maria Consiglia Bragazzi, Maurizia Brunetto, Savino Bruno, Vincenza Calvaruso, Vincenzo Cardinale, Giovanni Casella, Nora Cazzagon, Antonio Ciaccio, Barbara Coco, Agostino Colli, Guido Colloredo, Massimo Colombo, Silvia Colombo, Laura Cristoferi, Carmela Cursaro, Lory Saveria Crocè, Andrea Crosignani, Daphne D’Amato, Francesca Donato, Gianfranco Elia, Luca Fabris, Stefano Fagiuoli, Carlo Ferrari, Annarosa Floreani, Andrea Galli, Edoardo Giannini, Ignazio Grattagliano, Pietro Lampertico, Ana Lleo, Federica Malinverno, Clara Mancuso, Fabio Marra, Marco Marzioni, Sara Massironi, Alberto Mattalia, Luca Miele, Chiara Milani, Lorenzo Morini, Filomena Morisco, Luigi Muratori, Paolo Muratori, Grazia A. Niro, Sarah O’Donnell, Antonio Picciotto, Piero Portincasa, Cristina Rigamonti, Vincenzo Ronca, Floriano Rosina, Giancarlo Spinzi, Mario Strazzabosco, Mirko Tarocchi, Claudio Tiribelli, Pierluigi Toniutto, Luca Valenti, Maria Vinci, Massimo Zuin, Hitomi Nakamura, Seigo Abiru, Shinya Nagaoka, Atsumasa Komori, Hiroshi Yatsuhashi, Hiromi Ishibashi, Masahiro Ito, Kiyoshi Migita, Hiromasa Ohira, Shinji Katsushima, Atsushi Naganuma, Kazuhiro Sugi, Tatsuji Komatsu, Tomohiko Mannami, Kouki Matsushita, Kaname Yoshizawa, Fujio Makita, Toshiki Nikami, Hideo Nishimura, Hiroshi Kouno, Hirotaka Kouno, Hajime Ota, Takuya Komura, Yoko Nakamura, Masaaki Shimada, Noboru Hirashima, Toshiki Komeda, Keisuke Ario, Makoto Nakamuta, Tsutomu Yamashita, Kiyoshi Furuta, Masahiro Kikuchi, Noriaki Naeshiro, Hironao Takahashi, Yutaka Mano, Seiji Tsunematsu, Iwao Yabuuchi, Yusuke Shimada, Kazuhiko Yamauchi, Rie Sugimoto, Hironori Sakai, Eiji Mita, Masaharu Koda, Satoru Tsuruta, Hiroshi Kamitsukasa, Takeaki Sato, Naohiko Masaki, Tatsuro Kobata, Nobuyoshi Fukushima, Yukio Ohara, Toyokichi Muro, Eiichi Takesaki, Hitoshi Takaki, Tetsuo Yamamoto, Michio Kato, Yuko Nagaoki, Shigeki Hayashi, Jinya Ishida, Yukio Watanabe, Masakazu Kobayashi, Michiaki Koga, Takeo Saoshiro, Michiyasu Yagura, Keisuke Hirata, Atsushu Tanaka, Hajime Takikawa, Mikio Zeniya, Masanori Abe, Morikazu Onji, Shuichi Kaneko, Masao Honda, Kuniaki Arai, Teruko Arinaga-Hino, Etsuko Hashimoto, Makiko Taniai, Takeji Umemura, Satoru Joshita, Kazuhiko Nakao, Tatsuki Ichikawa, Hidetaka Shibata, Satoshi Yamagiwa, Masataka Seike, Koichi Honda, Shotaro Sakisaka, Yasuaki Takeyama, Masaru Harada, Michio Senju, Osamu Yokosuka, Tatsuo Kanda, Yoshiyuki Ueno, Kentaro Kikuchi, Hirotoshi Ebinuma, Takashi Himoto, Michio Yasunami, Kazumoto Murata, Masashi Mizokami, Kazuhito Kawata, Shinji Shimoda, Yasuhiro Miyake, Akinobu Takaki, Kazuhide Yamamoto, Katsuji Hirano, Takafumi Ichida, Akio Ido, Hirohito Tsubouchi, Kazuaki Chayama, Kenichi Harada, Yasuni Nakanuma, Yoshihiko Maehara, Akinobu Taketomi, Ken Shirabe, Yuji Soejima, Akira Mori, Shintaro Yagi, Shinji Uemoto, Egawa H, Tomohiro Tanaka, Noriyo Yamashiki, Sumito Tamura, Yasuhiro Sugawara, Norihiro Kokudo, Naga Chalasani, Vel Luketic, Joseph Odin, Kapil Chopra, Goncalo Abecasis, Michael Cantor, Giovanni Coppola, Aris Economides, Luca A. Lotta, John D. Overton, Jeffrey G. Reid, Alan Shuldiner, Christina Beechert, Caitlin Forsythe, Erin D. Fuller, Zhenhua Gu, Michael Lattari, Alexander Lopez, Thomas D. Schleicher, Maria Sotiropoulos Padilla, Karina Toledo, Louis Widom, Sarah E. Wolf, Manasi Pradhan, Kia Manoochehri, Ricardo H. Ulloa, Xiaodong Bai, Suganthi Balasubramanian, Leland Barnard, Andrew Blumenfeld, Gisu Eom, Lukas Habegger, Alicia Hawes, Shareef Khalid, Evan K. Maxwell, William Salerno, Jeffrey C. Staples, Marcus B. Jones, Lyndon J. Mitnaul, Richard Sturgess, Christopher Healey, Andrew Yeoman, Anton V.J. Gunasekera, Paul Kooner, Kapil Kapur, V. Sathyanarayana, Yiannis Kallis, Javaid Subhani, Rory Harvey, Roger McCorry, Paul Rooney, David Ramanaden, Richard Evans, Thiriloganathan Mathialahan, Jaber Gasem, Christopher Shorrock, Mahesh Bhalme, Paul Southern, Jeremy A. Tibble, David A. Gorard, Susan Jones, George Mells, Victoria Mulcahy, Brijesh Srivastava, Matthew R. Foxton, Carole E. Collins, David Elphick, Mazn Karmo, Francisco Porras-Perez, Michael Mendall, Tom Yapp, Minesh Patel, Roland Ede, Joanne Sayer, James Jupp, Neil Fisher, Martyn J. Carter, Konrad Koss, Jayshri Shah, Andrzej Piotrowicz, Glyn Scott, Charles Grimley, Ian R. Gooding, Simon Williams, Judith Tidbury, Guan Lim, Kuldeep Cheent, Sass Levi, Dina Mansour, Matilda Beckley, Coral Hollywood, Terry Wong, Richard Marley, John Ramage, Harriet M. Gordon, Jo Ridpath, Theodore Ngatchu, Vijay Paul Bob Grover, Ray G. Shidrawi, George Abouda, L. Corless, Mark Narain, Ian Rees, Ashley Brown, Simon Taylor-Robinson, Joy Wilkins, Leonie Grellier, Paul Banim, Debasish Das, Michael A. Heneghan, Howard Curtis, Helen C. Matthews, Faiyaz Mohammed, Mark Aldersley, Raj Srirajaskanthan, Giles Walker, Alistair McNair, Amar Sharif, Sambit Sen, George Bird, Martin I. Prince, Geeta Prasad, Paul Kitchen, Adrian Barnardo, Chirag Oza, Nurani N. Sivaramakrishnan, Prakash Gupta, Amir Shah, Chris D.J. Evans, Subrata Saha, Katharine Pollock, Peter Bramley, Ashis Mukhopadhya, Stephen T. Barclay, Natasha McDonald, Andrew J. Bathgate, Kelvin Palmer, John F. Dillon, Simon M. Rushbrook, Robert Przemioslo, Chris McDonald, Andrew Millar, Cheh Tai, Stephen Mitchell, Jane Metcalf, Syed Shaukat, Mary Ninkovic, Udi Shmueli, Andrew Davis, Asifabbas Naqvi, Tom J.W. Lee, Stephen Ryder, Jane Collier, Howard Klass, Matthew E. Cramp, Nichols Sharer, Richard Aspinall, Deb Ghosh, Andrew C. Douds, Jonathan Booth, Earl Williams, Hyder Hussaini, John Christie, Steven Mann, Douglas Thorburn, Aileen Marshall, Imran Patanwala, Aftab Ala, Julia Maltby, Ray Matthew, Chris Corbett, Sam Vyas, Saket Singhal, Dermot Gleeson, Sharat Misra, Jeff Butterworth, Keith George, Tim Harding, Andrew Douglass, Harriet Mitchison, Simon Panter, Jeremy Shearman, Gary Bray, Michael Roberts, Graham Butcher, Daniel Forton, Zahid Mahmood, Matthew Cowan, Debashis Das, Chin Lye Ch'ng, Mesbah Rahman, Gregory C.A. Whatley, Emma Wesley, Aditya Mandal, Sanjiv Jain, Stephen P. Pereira, Mark Wright, Palak Trivedi, Fiona H. Gordon, Esther Unitt, Altaf Palejwala, Andrew Austin, Vishwaraj Vemala, Allister Grant, Andrew D. Higham, Alison Brind, Ray Mathew, Mark Cox, Subramaniam Ramakrishnan, Alistair King, Simon Whalley, Jocelyn Fraser, S.J. Thomson, Andrew Bell, Voi Shim Wong, Richard Kia, Ian Gee, Richard Keld, Rupert Ransford, James Gotto, and Charles Millson

Subjects
Science & Technology, Hepatology, Gastroenterology & Hepatology, Italian PBC Study Group, Japan-PBC-GWAS Consortium, UK-PBC Consortium, Chinese PBC Consortium, 1103 Clinical Sciences, US PBC Consortium, Canadian PBC Consortium, Life Sciences & Biomedicine, PBC Consortia, 1117 Public Health and Health Services
Published
2021

14. Carotid Intima-media Thickness and Small Dense Low-density Lipoprotein Cholesterol Increase after One Year of Treatment with Direct-acting Antivirals in Patients with Hepatitis C Virus Infection

Author

Tatsuki Ichikawa, Yasuhide Motoyoshi, Syouhei Narita, Youichi Takahashi, Naoyuki Hino, Tetsurou Honda, Ryousuke Hirata, Satoshi Miuma, Satomi Toda, Ryouhei Uehara, Kazuhiko Nakao, Tomoko Hori, Hiroyuki Yajima, Naota Taura, and Hisamitsu Miyaaki

Subjects
Male, hepatitis C virus, Sustained Virologic Response, small dense low-density lipoprotein cholesterol, Hepacivirus, 030204 cardiovascular system & hematology, medicine.disease_cause, Carotid Intima-Media Thickness, Gastroenterology, Body Mass Index, chemistry.chemical_compound, 0302 clinical medicine, Risk Factors, Hyperlipidemia, Aged, 80 and over, General Medicine, Middle Aged, cardiovascular system, Original Article, Female, 030211 gastroenterology & hepatology, Adult, medicine.medical_specialty, Hepatitis C virus, Antiviral Agents, 03 medical and health sciences, Insulin resistance, Diabetes mellitus, Internal medicine, Internal Medicine, medicine, Humans, cardiovascular diseases, intima-media thickness, Triglycerides, direct-acting antivirals, Aged, Triglyceride, business.industry, Cholesterol, LDL, Hepatitis C, Chronic, Atherosclerosis, medicine.disease, Intima-media thickness, chemistry, Multivariate Analysis, Glycated hemoglobin, Insulin Resistance, business, Body mass index
Abstract

Objective Direct-acting antivirals (DAAs) for treating hepatitis C virus (HCV) infection exert a significantly high sustained viral response (SVR), and patients experience a rebound increase in low-density lipoprotein cholesterol (LDL) and total cholesterol levels. Carotid intima-media thickness (IMT) is a highly reproducible and non-invasive parameter for assessing the atherosclerotic process, and the small dense (sd) LDL level is useful for clinically evaluating the atherogenic risk. Methods A total of 48 patients with chronic HCV infection were treated with DAAs. All patients exhibited an SVR 24 weeks later. We compared the metabolic profiles of the patients, including the sdLDL and IMT values, at the start of DAA treatment with those after one year of treatment. We verified whether the HCV clearance after the administration of DAAs is associated with the development of atherosclerosis. Results The sdLDL, %sdLDL (sdLDL/LDL), and LDL values were exacerbated after a year of treatment;however, the triglyceride level, glycated hemoglobin level, insulin resistance, and body weight remained unaltered.The max-IMT was increased after a year compared to that at the start of treatment. Differences in the max-IMT (dmax-IMT) were greater in men than in women; however, no correlation was observed between the dmax-IMT and genotype, fibrosis, hypertension, hyperlipidemia, diabetes, obesity, and dialysis status. The %sdLDL at the start and a year later was positively correlated with the dmax-IMT. No correlation was observed among various factors including the LDL, triglyceride, body mass index, insulin resistance and dmax- IMT. In uni- and multivariate analyses, a significant correlation was observed between %sdLDL 16% at the start of treatment and the sex and dmax-IMT.Conclusion Because the sdLDL and IMT values were exacerbated after a year of DAA treatment, atherosclerosis must be evaluated in patients achieving an SVR., Internal medicine, 58(9), pp.1209-1215; 2019

Published
2019

15. Predictive factor of recurrence after endoscopic papillectomy for ampullary neoplasms

Author

Tatsuki Ichikawa, Hisamitsu Miyaaki, Takuji Yamao, Eisuke Ozawa, Ichiro Yasuda, Naohiro Komatsu, Kazuo Oba, Kazuhiko Nakao, Ken Ohnita, and Kosuke Takahashi

Subjects
medicine.medical_specialty, Ampulla of Vater, Multivariate analysis, Adenoma, Common Bile Duct Neoplasms, Resection, 03 medical and health sciences, Sphincterotomy, Endoscopic, 0302 clinical medicine, medicine, Humans, Pathological, Retrospective Studies, Univariate analysis, Hepatology, business.industry, Retrospective cohort study, medicine.disease, Predictive factor, Treatment Outcome, 030220 oncology & carcinogenesis, Adenocarcinoma, 030211 gastroenterology & hepatology, Surgery, Radiology, Neoplasm Recurrence, Local, business
Abstract

Background and aims Recurrence of ampullary neoplasms after endoscopic papillectomy (EP) has not been well elucidated. This study aimed to clarify the predictive factors for recurrences after EP. We also aimed to investigate the retreatment of the recurrent lesions and their outcomes. Methods This multicenter, retrospective cohort study included 96 patients with ampullary neoplasms who underwent EP at four tertiary centers between January 2000 and October 2018. Results The pathological diagnoses of resected specimens confirmed adenoma in 62 and adenocarcinoma in 34 patients (six Tis, 24 T1a, three T1b, one inconclusive). Complete resection was confirmed for 79 patients (82.3%). Recurrent lesions were observed in 13 patients (13.5%) during a median follow-up of 3 months (1-36 months) after EP. The predictive factors of recurrence were piecemeal resection, and non-negative horizontal or vertical margin in univariate analysis. Non-negative vertical margin was the only independent predictive factor of recurrence in the multivariate analysis. The recurrent lesions were treated endoscopically in 11 patients. Recurrence after the endoscopic retreatments was observed in one patient. Conclusions Complete resection with negative vertical margin is important factor in preventing the recurrence of ampullary neoplasms after EP. Endoscopic retreatments are also feasible for recurrent lesions.

Published
2021

16. Comparison of calculated body muscle mass and SARC-F as methods of screening for sarcopenia in patients with chronic liver disease

Author

Yasuhide Motoyoshi, Hisamitsu Miyaaki, Makiko Koike, Hiroyuki Yajima, Tatsuki Ichikawa, Yusuke Nakano, Osamu Miyazaki, Yasutaka Kuribayashi, Kazuhiko Nakao, Mio Yamashima, Ryouhei Uehara, Satoshi Miuma, Shinobu Yamamichi, Keiji Kira, Naota Taura, and Tetsurou Honda

Subjects
0301 basic medicine, medicine.medical_specialty, Body muscle mass, Lumbar vertebrae, Chronic liver disease, Gastroenterology, General Biochemistry, Genetics and Molecular Biology, sarcopenia, 03 medical and health sciences, Grip strength, 0302 clinical medicine, Internal medicine, medicine, In patient, General Pharmacology, Toxicology and Pharmaceutics, business.industry, General Neuroscience, Area under the curve, chronic liver disease, General Medicine, Articles, skeletal muscle mass, Hepatology, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, SARC-F, 030220 oncology & carcinogenesis, Sarcopenia, grip strength, CBMM, business
Abstract

A simple method is required to screen for sarcopenia in patients with chronic liver disease. In the present study, the value of the existing SARC-F questionnaire as well as calculated body muscle mass (CBMM) approaches were assessed for screening of sarcopenia. A total of 482 patients with chronic liver disease underwent CBMM, grip strength (GS) and SARC-F score assessments. Cross-sectional computed tomography images of the third lumbar vertebrae were analyzed to determine the skeletal muscle (SM) mass in 303 patients. Cutoff CBMM values for sarcopenia were

Published
2021

17. X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis

Author

S. Abiru, John F. Dillon, Yasuhiro Miyake, Piero Portincasa, Giancarlo Spinzi, R. Harvey, T. Ngatchu, Agostino Colli, M. Taniai, K. Flahive, Masanori Abe, B. Hoeroldt, S. Holder, Howard Curtis, María Isabel Colombo, C. MacNicol, Gang Xie, Andrew Chilton, H. Hussaini, Cristina Rigamonti, M. Kato, Shintaro Yagi, G. Abouda, D. Tyrer, Chris D. Evans, Christopher I. Amos, K. Koss, Kazuaki Chayama, P. Premchand, K. Migita, Simon Panter, Marco Marzioni, Silvia Colombo, Konstantinos N. Lazaridis, M. Yagura, Ashley Brown, D. Gocher, Domenico Alvaro, K. Murata, Mark Wright, Piero Luigi Almasio, C. Healey, A. Ciaccio, N. Wheatley, Vincenzo Cardinale, T. Delahooke, Chiara Milani, T. Shewan, W. Stableforth, S. Levi, Mark L. Green, James V. Jones, Y. Baird, Aftab Ala, Burroughs Ak, D. Williams, K. Ario, P. Sanghi, Hemant Gupta, P. Southern, L. Farrington, M. Hamilton, Andrew D. Higham, I. Yabuuchi, H. Yatsuhashi, Lorenzo Morini, T. Yamamoto, Douglas Thorburn, M. Carnahan, N. Nishida, Susan Slininger, M. Koga, K. Honda, Annarosa Floreani, Andrew Douglass, K. Netherton, M. Yasunami, Hirohito Tsubouchi, F. Donato, K. Walker, U. Shmueli, Paolo Muratori, Ray Mathew, J. Maiden, E. Dungca, Subramaniam Ramakrishnan, S. Vyas, Helen Sweeting, Subrata Saha, T. Komeda, T. Komatsu, H. J. Lee, Maria Consiglia Bragazzi, T. Komura, C. Thomas, C. Shallcross, C. Duggan, J. Kordula, F. Muscariu, Lourdes Cumlat, Imran Patanwala, Giulia Cardamone, L. Morgan, J. Brighton, Masao Honda, H. Nakamura, David Jones, Raj Srirajaskanthan, M. E. Gershwin, T. Muro, L. Stafford, N. Fukushima, Graham P. Butcher, Andrea Crosignani, George Lipscomb, K. Hirata, Y. Nagaoki, S. Mann, Paul G. Richardson, David A Elphick, M. Mupudzi, Y. Ohara, E. Grieve, Gayle Clifford, Claudio Tiribelli, M. Quinn, G. Van Duyvenvoorde, E. Archer, Tatsuki Ichikawa, J. Maltby, T. Arinaga-Hino, Simon Williams, A. King, Yasuni Nakanuma, H. Doyle, A. Brind, Nora Cazzagon, H. Ota, Daphne D’Amato, K. Hogben, H. Wooldridge, J. Wilkins, Shuichi Kaneko, L. Hankey, Gordon Wood, Andrew Fraser, K. Martin, A. Naqvi, M. Ninkovic, M. Patel, Yoshihiko Maehara, Kapil Kapur, I. Amey, Vincenza Calvaruso, Kenichi Harada, T. Yamashita, James Neuberger, N. Taylor, T. Lee, J. Featherstone, C. Lawlor, K. Seward, Satoshi Yamagiwa, Andrea Galli, L. Tan, Kentaro Kikuchi, K. Furuta, Mark A. Ainsworth, Hiromasa Ohira, Esther Unitt, Yosuke Kawai, N. Lancaster, D. Simpson, R. Shidrawi, I. Salam, A.J. Bell, Pietro Andreone, J. Ishida, Voi Shim Wong, N Fisher, Andrew C. Douds, R. Penn, Matthew Foxton, A. Watson, Andrew Mason, S. Walsh, Hiromi Ishibashi, Daniel M. Forton, Giovanni Casella, H. Takaki, K. Yamauchi, Pietro Lampertico, Osamu Yokosuka, M. Koda, M. Davies, H. Mitchison, P. Gyawali, G. Bird, M. Hughes, L. Jones, C. Hamilton, A. Hynes, R. Galaska, Fabio Marra, Debasish Das, C. Cowley, A. Fouracres, Yasuhiko Sugawara, E. Mita, T. Saoshiro, Akinobu Taketomi, Robert P. Myers, R. Przemioslo, F. Wright, L. Hobson, L. Currie, J. Allison, J. Hails, Noriyo Yamashiki, Massimo Zuin, C. Grimley, Alessio Gerussi, S. Besley, Stefano Duga, A. Piotrowicz, H. Kouno, L. Dali-kemmery, H. Sakai, M. Mizokami, Stefano Fagiuoli, Amy Davis, Pier Maria Battezzati, Masao Nagasaki, Luigi Muratori, A. Mori, S. Desmennu, S. Jones, R. Abrahams, Keith George, F. Makita, J. Brown, D. Gorard, Satoru Joshita, M. Mills, Pierluigi Toniutto, S. Campbell, J. Butterworth, S. Dyer, Filomena Morisco, Norihiro Kokudo, T. Yapp, C. Shorrock, Floriano Rosina, E. Walker, Shinji Uemoto, H. Takahashi, Simon M. Rushbrook, K. Amor, E. Marshall, J. Browning, S. Batham, Luca Fabris, Paul R. Banim, Meenakshi Narain, M. Harada, Dermot Gleeson, N. Hirashima, M. Kikuchi, T. Nikami, Gideon M. Hirschfield, Carlo Ferrari, G. Prasad, O. Chirag, Katsushi Tokunaga, M. Nasseri, Rosanna Asselta, Y. Lu, Ken Shirabe, D. Sirdefield, George F. Mells, K. Sugi, R. Ayres, G. Whatley, A. Singhal, M. Leoni, N. Sivaramakrishnan, T. Harding, Rupert Ransford, Anton V J Gunasekera, C. Mulvaney-Jones, D. Ramanaden, M. Mendall, Muhammad F. Dawwas, Dave Jones, Luca Valenti, Earl J. Williams, Markus Gess, Peter Bramley, A. McNair, E. Hashimoto, P. Townshend, C. Ford, Mario Strazzabosco, Luca Miele, Matthew J Brookes, J. Colley, Mark Wilkinson, H. Dewhurst, Charles Millson, E. Shpuza, Shinji Shimoda, T. Himoto, P. Kitchen, M. Nakamuta, Hiroaki Nishimura, Martin Lombard, Kevork M. Peltekian, M. Pitcher, G. Lim, L. Graves, C. Palmer, S. Lord, S. Katsushima, S. Tripoli, Andrew Austin, N. White, B. Grover, S. Congreave, M. Prince, Rebecca Jones, K. Hirano, A. Shepherd, Y. Mano, Michael A. Heneghan, Richard Sandford, L. O'Donohoe, Marco Carbone, S. A. Rolls, Patrick Goggin, M. L. Cowan, M. Crossey, A. Loftus, K. Young, Mesbah Rahman, Cameron N. Ghent, E. Nambela, M. Xiong, L. Grellier, Sunil Dolwani, Antonio Picciotto, Gill Watts, Alberto Mattalia, Elvezia Maria Paraboschi, J. Orpe, Takeji Umemura, Yuki Hitomi, Fiona H. Gordon, Shotaro Sakisaka, A. Dias, Chin Lye Ch'ng, M. Carter, A. Mandal, Yufang Shi, Takafumi Ichida, N. Masaki, M. Oblak, S. Nagaoka, Kevin Yoong, O. Gervais, Minoru Nakamura, Kazuhiko Nakao, S. Taylor-Robinson, L. Kent, Sushma Saksena, A. Affronti, K. Boulton, R. Ede, H. Pateman, K. Yoshizawa, G. Bray, H. Ebinuma, Yeng Ang, Akio Ido, John Ramage, Richard Sturgess, C. Gray, E. Durant, M. Hayes, A. Saeed, J. Keggans, J. Gitahi, T. Valliani, Edoardo G. Giannini, C. Foale, A. Palegwala, Lory Saveria Crocè, K. Matsushita, S. Shaukat, J. Mclindon, S. Pearson, A. Barnardo, A. Wright, Mirko Tarocchi, R Marley, M. Kent, C. Dickson, A. Gibbins, J. Whiteman, S. Singhal, Richard Aspinall, M. Ito, Laura Cristoferi, Maurizia Rossana Brunetto, J. Booth, A. Bathgate, Morikazu Onji, A. Grant, A. Paton, Y. Aiba, P. Chan, J. Sayer, S. Whalley, T. Mathialahan, J. Gotto, T. Kanda, B. Williams, K. Elliott, P. Raymode, Akinobu Takaki, V. Silvestre, I. Gee, C. Hovell, Graham R. Foster, D. Cotterill, G. Stansfield, Grazia Anna Niro, J. Conder, Yoshiyuki Ueno, A. Shah, Jane Metcalf, S. Hayashi, T. Sato, S. Jain, J. Subhani, Donatella Barisani, A. McKay, Kuniaki Arai, Jeremy Shearman, Torao Tanaka, S. Glenn, S. E. O'Donnell, Federica Malinverno, Denise O'Donnell, R. Casey, N. Sharer, J. Bowles, J. Kendall, Maria Cristina Vinci, Antonio Benedetti, George MacFaul, K. Houghton, Vincenzo Ronca, P. Desousa, B. Holbrook, F. Ali, B. Longhurst, Atsushi Tanaka, Marek Czajkowski, R. Tang, Kazuhide Yamamoto, Y. Watanabe, Graeme J.M. Alexander, R. Cloudsdale, F. Hines, M. Karmo, Brian D. Juran, I. Gooding, Y. Takeyama, J. Fraser, A. Mukhopadhya, Sumihito Tamura, Hajime Takikawa, R. Damant, E. Wilhelmsen, M. Kobayashi, J. Tregonning, V. Lambourne, D. Clement, D. Braim, M. Shimada, S. Sen, Shaun Greer, C. Innes, E. Gunter, C. Brown, H. Klass, A. Komori, Andy Li, H. Fairlamb, N. Ncube, Yoshinori Shimada, M. Harrison, S. Marriott, I. Grattagliano, Savino Bruno, A. Naganuma, Xiangjun Gu, Michael F. Seldin, S. Thornthwaite, Peter R. Mills, Katherine A. Siminovitch, X. Liu, Masataka Seike, J. Curtis, Carmela Cursaro, Z. Li, Mikio Zeniya, K. Warner, B. Bird, Jane Collier, Bridget Gunson, S. Tsuruta, E. Tanqueray, Richard Evans, H. Kamitsukasa, R. Sugimoto, Jeremy Tibble, D. Neal, S. Ducker, Francesco Azzaroli, K. Spurdle, K. Ocker, M. Senju, C. Collins, Y. Nakamura, Matthew E. Cramp, Yuji Soejima, I. Drake, K. Ueno, T. Mannami, Clara Mancuso, M. Kawashima, M. Cox, S. S. Kohn, H. Shibata, Stephen D. Ryder, Christopher Macdonald, J. Ridpath, Stephen P. Pereira, L. March, Barbara Coco, J. Morrison, A. Broad, J. Verheyden, Angelo Andriulli, N. Higuchi, J. Musselwhite, R. Bishop, Gwen Baxter, Richard A. Miller, Guido Colloredo, A. Eastick, I. Rees, Deb Ghosh, L. Winter, Sara Massironi, R. McCorry, Gianfranco Elia, T. Kobata, N. Naeshiro, K. Pollock, J. Gasem, S. Gallagher, K. Jing, S. Misra, B. Shinder, Harriet Gordon, E. Takesaki, J. Sadeghian, S. Tsunematsu, Ana Lleo, M. Aldersley, Elizabeth J. Atkinson, Pietro Invernizzi, Heather J. Cordell, Asselta, R., Paraboschi, E. M., Gerussi, A., Cordell, H. J., Mells, G. F., Sandford, R. N., Jones, D. E., Nakamura, M., Ueno, K., Hitomi, Y., Kawashima, M., Nishida, N., Tokunaga, K., Nagasaki, M., Tanaka, A., Tang, R., Li, Z., Shi, Y., Liu, X., Xiong, M., Hirschfield, G., Siminovitch, K. A., Walker, E., Xie, G., Mason, A., Myers, R., Peltekian, K., Ghent, C., Atkinson, E., Juran, B., Lazaridis, K., Lu, Y., Gu, X., Jing, K., Amos, C., Affronti, A., Brunetto, M., Coco, B., Spinzi, G., Elia, G., Ferrari, C., Lleo, A., Muratori, L., Muratori, P., Portincasa, P., Colli, A., Bruno, S., Colloredo, G., Azzaroli, F., Andreone, P., Bragazzi, M., Alvaro, D., Cardinale, V., Cazzagon, N., Rigamonti, C., Floreani, A., Rosina, F., Ciaccio, A., Cristoferi, L., D'Amato, D., Malinverno, F., Mancuso, C., Massironi, S., Milani, C., O'Donnell, S. E., Ronca, V., Barisani, D., Lampertico, P., Donato, F., Fagiuoli, S., Almasio, P. L., Giannini, E., Cursaro, C., Colombo, M., Valenti, L., Miele, L., Andriulli, A., Niro, G. A., Grattagliano, I., Morini, L., Casella, G., Vinci, M., Battezzati, P. M., Crosignani, A., Zuin, M., Mattalia, A., Calvaruso, V., Colombo, S., Benedetti, A., Marzioni, M., Galli, A., Marra, F., Tarocchi, M., Picciotto, A., Morisco, F., Fabris, L., Croce, L. S., Tiribelli, C., Toniutto, P., Strazzabosco, M., Ch'Ng, C. L., Rahman, M., Yapp, T., Sturgess, R., Healey, C., Czajkowski, M., Gunasekera, A., Gyawali, P., Premchand, P., Kapur, K., Marley, R., Foster, G., Watson, A., Dias, A., Subhani, J., Harvey, R., Mccorry, R., Ramanaden, D., Gasem, J., Evans, R., Mathialahan, T., Shorrock, C., Lipscomb, G., Southern, P., Tibble, J., Gorard, D., Palegwala, A., Jones, S., Dawwas, M., Alexander, G., Dolwani, S., Prince, M., Foxton, M., Elphick, D., Mitchison, H., Gooding, I., Karmo, M., Saksena, S., Mendall, M., Patel, M., Ede, R., Austin, A., Sayer, J., Hankey, L., Hovell, C., Fisher, N., Carter, M., Koss, K., Piotrowicz, A., Grimley, C., Neal, D., Lim, G., Levi, S., Ala, A., Broad, A., Saeed, A., Wood, G., Brown, J., Wilkinson, M., Gordon, H., Ramage, J., Ridpath, J., Ngatchu, T., Grover, B., Shaukat, S., Shidrawi, R., Abouda, G., Ali, F., Rees, I., Salam, I., Narain, M., Brown, A., Taylor-Robinson, S., Williams, S., Grellier, L., Banim, P., Das, D., Chilton, A., Heneghan, M., Curtis, H., Gess, M., Drake, I., Aldersley, M., Davies, M., Jones, R., Mcnair, A., Srirajaskanthan, R., Pitcher, M., Sen, S., Bird, G., Barnardo, A., Kitchen, P., Yoong, K., Chirag, O., Sivaramakrishnan, N., Macfaul, G., Jones, D., Shah, A., Evans, C., Saha, S., Pollock, K., Bramley, P., Mukhopadhya, A., Fraser, A., Mills, P., Shallcross, C., Campbell, S., Bathgate, A., Shepherd, A., Dillon, J., Rushbrook, S., Przemioslo, R., Macdonald, C., Metcalf, J., Shmueli, U., Davis, A., Naqvi, A., Lee, T., Ryder, S. D., Collier, J., Klass, H., Ninkovic, M., Cramp, M., Sharer, N., Aspinall, R., Goggin, P., Ghosh, D., Douds, A., Hoeroldt, B., Booth, J., Williams, E., Hussaini, H., Stableforth, W., Ayres, R., Thorburn, D., Marshall, E., Burroughs, A., Mann, S., Lombard, M., Richardson, P., Patanwala, I., Maltby, J., Brookes, M., Mathew, R., Vyas, S., Singhal, S., Gleeson, D., Misra, S., Butterworth, J., George, K., Harding, T., Douglass, A., Panter, S., Shearman, J., Bray, G., Butcher, G., Forton, D., Mclindon, J., Cowan, M., Whatley, G., Mandal, A., Gupta, H., Sanghi, P., Jain, S., Pereira, S., Prasad, G., Watts, G., Wright, M., Neuberger, J., Gordon, F., Unitt, E., Grant, A., Delahooke, T., Higham, A., Brind, A., Cox, M., Ramakrishnan, S., King, A., Collins, C., Whalley, S., Li, A., Fraser, J., Bell, A., Wong, V. 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E., Seldin, M. F., Invernizzi, P., Asselta R., Paraboschi E.M., Gerussi A., Cordell H.J., Mells G.F., Sandford R.N., Jones D.E., Nakamura M., Ueno K., Hitomi Y., Kawashima M., Nishida N., Tokunaga K., Nagasaki M., Tanaka A., Tang R., Li Z., Shi Y., Liu X., Xiong M., Hirschfield G., Siminovitch K.A., Walker E., Xie G., Mason A., Myers R., Peltekian K., Ghent C., Atkinson E., Juran B., Lazaridis K., Lu Y., Gu X., Jing K., Amos C., Affronti A., Brunetto M., Coco B., Spinzi G., Elia G., Ferrari C., Lleo A., Muratori L., Muratori P., Portincasa P., Colli A., Bruno S., Colloredo G., Azzaroli F., Andreone P., Bragazzi M., Alvaro D., Cardinale V., Cazzagon N., Rigamonti C., Floreani A., Rosina F., Ciaccio A., Cristoferi L., D'Amato D., Malinverno F., Mancuso C., Massironi S., Milani C., O'Donnell S.E., Ronca V., Barisani D., Lampertico P., Donato F., Fagiuoli S., Almasio P.L., Giannini E., Cursaro C., Colombo M., Valenti L., Miele L., Andriulli A., Niro G.A., Grattagliano I., Morini L., Casella G., Vinci M., Battezzati P.M., Crosignani A., Zuin M., Mattalia A., Calvaruso V., Colombo S., Benedetti A., Marzioni M., Galli A., Marra F., Tarocchi M., Picciotto A., Morisco F., Fabris L., Croce L.S., Tiribelli C., Toniutto P., Strazzabosco M., Ch'ng C.L., Rahman M., Yapp T., Sturgess R., Healey C., Czajkowski M., Gunasekera A., Gyawali P., Premchand P., Kapur K., Marley R., Foster G., Watson A., Dias A., Subhani J., Harvey R., McCorry R., Ramanaden D., Gasem J., Evans R., Mathialahan T., Shorrock C., Lipscomb G., Southern P., Tibble J., Gorard D., Palegwala A., Jones S., Dawwas M., Alexander G., Dolwani S., Prince M., Foxton M., Elphick D., Mitchison H., Gooding I., Karmo M., Saksena S., Mendall M., Patel M., Ede R., Austin A., Sayer J., Hankey L., Hovell C., Fisher N., Carter M., Koss K., Piotrowicz A., Grimley C., Neal D., Lim G., Levi S., Ala A., Broad A., Saeed A., Wood G., Brown J., Wilkinson M., Gordon H., Ramage J., Ridpath J., Ngatchu T., Grover B., Shaukat S., Shidrawi R., Abouda G., Ali 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Sadeghian J., Williams B., Rolls S.-A., Hynes A., Duggan C., Crossey M., Stansfield G., MacNicol C., Wilkins J., Wilhelmsen E., Raymode P., Lee H.-J., Durant E., Bishop R., Ncube N., Tripoli S., Casey R., Cowley C., Miller R., Houghton K., Ducker S., Wright F., Bird B., Baxter G., Keggans J., Hughes M., Grieve E., Young K., Williams D., Ocker K., Hines F., Martin K., Innes C., Valliani T., Fairlamb H., Thornthwaite S., Eastick A., Tanqueray E., Morrison J., Holbrook B., Browning J., Walker K., Congreave S., Verheyden J., Slininger S., Stafford L., O'Donnell D., Ainsworth M., Lord S., Kent L., March L., Dickson C., Simpson D., Longhurst B., Hayes M., Shpuza E., White N., Besley S., Pearson S., Wright A., Jones L., Gunter E., Dewhurst H., Fouracres A., Farrington L., Graves L., Marriott S., Leoni M., Tyrer D., Dali-kemmery L., Lambourne V., Green M., Sirdefield D., Amor K., Colley J., Shinder B., Jones J., Mills M., Carnahan M., Taylor N., Boulton K., Tregonning J., Brown C., Clifford G., Archer E., Hamilton M., Curtis J., Shewan T., Walsh S., Warner K., Netherton K., Mupudzi M., Gunson B., Gitahi J., Gocher D., Batham S., Pateman H., Desmennu S., Conder J., Clement D., Gallagher S., Orpe J., Chan P., Currie L., O'Donohoe L., Oblak M., Morgan L., Quinn M., Amey I., Baird Y., Cotterill D., Cumlat L., Winter L., Greer S., Spurdle K., Allison J., Dyer S., Sweeting H., Kordula J., Aiba Y., Nakamura H., Abiru S., Nagaoka S., Komori A., Yatsuhashi H., Ishibashi H., Ito M., Kawai Y., Kohn S.-S., Gervais O., Migita K., Katsushima S., Naganuma A., Sugi K., Komatsu T., Mannami T., Matsushita K., Yoshizawa K., Makita F., Nikami T., Nishimura H., Kouno H., Ota H., Komura T., Nakamura Y., Shimada M., Hirashima N., Komeda T., Ario K., Nakamuta M., Yamashita T., Furuta K., Kikuchi M., Naeshiro N., Takahashi H., Mano Y., Tsunematsu S., Yabuuchi I., Shimada Y., Yamauchi K., Sugimoto R., Sakai H., Mita E., Koda M., Tsuruta S., Kamitsukasa H., Sato T., Masaki N., Kobata T., Fukushima N., Higuchi N., Ohara Y., Muro T., Takesaki E., Takaki H., Yamamoto T., Kato M., Nagaoki Y., Hayashi S., Ishida J., Watanabe Y., Kobayashi M., Koga M., Saoshiro T., Yagura M., Hirata K., Takikawa H., Ohira H., Zeniya M., Abe M., Onji M., Kaneko S., Honda M., Arai K., Arinaga-Hino T., Hashimoto E., Taniai M., Umemura T., Joshita S., Nakao K., Ichikawa T., Shibata H., Yamagiwa S., Seike M., Honda K., Sakisaka S., Takeyama Y., Harada M., Senju M., Yokosuka O., Kanda T., Ueno Y., Kikuchi K., Ebinuma H., Himoto T., Yasunami M., Murata K., Mizokami M., Shimoda S., Miyake Y., Takaki A., Yamamoto K., Hirano K., Ichida T., Ido A., Tsubouchi H., Chayama K., Harada K., Nakanuma Y., Maehara Y., Taketomi A., Shirabe K., Soejima Y., Mori A., Yagi S., Uemoto S., Tanaka T., Yamashiki N., Tamura S., Sugawara Y., Kokudo N., Carbone M., Cardamone G., Duga S., Gershwin M.E., Seldin M.F., Invernizzi P., Asselta, R, Paraboschi, E, Gerussi, A, Cordell, H, Mells, G, Sandford, R, Jones, D, Nakamura, M, Ueno, K, Hitomi, Y, Kawashima, M, Nishida, N, Tokunaga, K, Nagasaki, M, Tanaka, A, Tang, R, Li, Z, Shi, Y, Liu, X, Xiong, M, Hirschfield, G, Siminovitch, K, Walker, E, Xie, G, Mason, A, Myers, R, Peltekian, K, Ghent, C, Atkinson, E, Juran, B, Lazaridis, K, Lu, Y, Gu, X, Jing, K, Amos, C, Affronti, A, Brunetto, M, Coco, B, Spinzi, G, Elia, G, Ferrari, C, Lleo, A, Muratori, L, Muratori, P, Portincasa, P, Colli, A, Bruno, S, Colloredo, G, Azzaroli, F, Andreone, P, Bragazzi, M, Alvaro, D, Cardinale, V, Cazzagon, N, Rigamonti, C, Floreani, A, Rosina, F, Ciaccio, A, Cristoferi, L, D'Amato, D, Malinverno, F, Mancuso, C, Massironi, S, Milani, C, O'Donnell, S, Ronca, V, Barisani, D, Lampertico, P, Donato, F, Fagiuoli, S, Almasio, P, Giannini, E, Cursaro, C, Colombo, M, Valenti, L, Miele, L, Andriulli, A, Niro, G, Grattagliano, I, Morini, L, Casella, G, Vinci, M, Battezzati, P, Crosignani, A, Zuin, M, Mattalia, A, Calvaruso, V, Colombo, S, Benedetti, A, Marzioni, M, Galli, A, Marra, F, Tarocchi, M, Picciotto, A, Morisco, F, Fabris, L, Croce, L, Tiribelli, C, Toniutto, P, Strazzabosco, M, Ch'Ng, C, Rahman, M, Yapp, T, Sturgess, R, Healey, C, Czajkowski, M, Gunasekera, A, Gyawali, P, Premchand, P, Kapur, K, Marley, R, Foster, G, Watson, A, Dias, A, Subhani, J, Harvey, R, Mccorry, R, Ramanaden, D, Gasem, J, Evans, R, Mathialahan, T, Shorrock, C, Lipscomb, G, Southern, P, Tibble, J, Gorard, D, Palegwala, A, Jones, S, Dawwas, M, Alexander, G, Dolwani, S, Prince, M, Foxton, M, Elphick, D, Mitchison, H, Gooding, I, Karmo, M, Saksena, S, Mendall, M, Patel, M, Ede, R, Austin, A, Sayer, J, Hankey, L, Hovell, C, Fisher, N, Carter, M, Koss, K, Piotrowicz, A, Grimley, C, Neal, D, Lim, G, Levi, S, Ala, A, Broad, A, Saeed, A, Wood, G, Brown, J, Wilkinson, M, Gordon, H, Ramage, J, Ridpath, J, Ngatchu, T, Grover, B, Shaukat, S, Shidrawi, R, Abouda, G, Ali, F, Rees, I, Salam, I, Narain, M, Brown, A, Taylor-Robinson, S, Williams, S, Grellier, L, Banim, P, Das, D, Chilton, A, Heneghan, M, Curtis, H, Gess, M, Drake, I, Aldersley, M, Davies, M, Jones, R, Mcnair, A, Srirajaskanthan, R, Pitcher, M, Sen, S, Bird, G, Barnardo, A, Kitchen, P, Yoong, K, Chirag, O, Sivaramakrishnan, N, Macfaul, G, Shah, A, Evans, C, Saha, S, Pollock, K, Bramley, P, Mukhopadhya, A, Fraser, A, Mills, P, Shallcross, C, Campbell, S, Bathgate, A, Shepherd, A, Dillon, J, Rushbrook, S, Przemioslo, R, Macdonald, C, Metcalf, J, Shmueli, U, Davis, A, Naqvi, A, Lee, T, Ryder, S, Collier, J, Klass, H, Ninkovic, M, Cramp, M, Sharer, N, Aspinall, R, Goggin, P, Ghosh, D, Douds, A, Hoeroldt, B, Booth, J, Williams, E, Hussaini, H, Stableforth, W, Ayres, R, Thorburn, D, Marshall, E, Burroughs, A, Mann, S, Lombard, M, Richardson, P, Patanwala, I, Maltby, J, Brookes, M, Mathew, R, Vyas, S, Singhal, S, Gleeson, D, Misra, S, Butterworth, J, George, K, Harding, T, Douglass, A, Panter, S, Shearman, J, Bray, G, Butcher, G, Forton, D, Mclindon, J, Cowan, M, Whatley, G, Mandal, A, Gupta, H, Sanghi, P, Jain, S, Pereira, S, Prasad, G, Watts, G, Wright, M, Neuberger, J, Gordon, F, Unitt, E, Grant, A, Delahooke, T, Higham, A, Brind, A, Cox, M, Ramakrishnan, S, King, A, Collins, C, Whalley, S, Li, A, Fraser, J, Bell, A, Wong, V, Singhal, A, Gee, I, Ang, Y, Ransford, R, Gotto, J, Millson, C, Bowles, J, Thomas, C, Harrison, M, Galaska, R, Kendall, J, Whiteman, J, Lawlor, C, Gray, C, Elliott, K, Mulvaney-Jones, C, Hobson, L, Van Duyvenvoorde, G, Loftus, A, Seward, K, Penn, R, Maiden, J, Damant, R, Hails, J, Cloudsdale, R, Silvestre, V, Glenn, S, Dungca, E, Wheatley, N, Doyle, H, Kent, M, Hamilton, C, Braim, D, Wooldridge, H, Abrahams, R, Paton, A, Lancaster, N, Gibbins, A, Hogben, K, Desousa, P, Muscariu, F, Musselwhite, J, Mckay, A, Tan, L, Foale, C, Brighton, J, Flahive, K, Nambela, E, Townshend, P, Ford, C, Holder, S, Palmer, C, Featherstone, J, Nasseri, M, Sadeghian, J, Williams, B, Rolls, S, Hynes, A, Duggan, C, Crossey, M, Stansfield, G, Macnicol, C, Wilkins, J, Wilhelmsen, E, Raymode, P, Lee, H, Durant, E, Bishop, R, Ncube, N, Tripoli, S, Casey, R, Cowley, C, Miller, R, Houghton, K, Ducker, S, Wright, F, Bird, B, Baxter, G, Keggans, J, Hughes, M, Grieve, E, Young, K, Williams, D, Ocker, K, Hines, F, Martin, K, Innes, C, Valliani, T, Fairlamb, H, Thornthwaite, S, Eastick, A, Tanqueray, E, Morrison, J, Holbrook, B, Browning, J, Walker, K, Congreave, S, Verheyden, J, Slininger, S, Stafford, L, O'Donnell, D, Ainsworth, M, Lord, S, Kent, L, March, L, Dickson, C, Simpson, D, Longhurst, B, Hayes, M, Shpuza, E, White, N, Besley, S, Pearson, S, Wright, A, Jones, L, Gunter, E, Dewhurst, H, Fouracres, A, Farrington, L, Graves, L, Marriott, S, Leoni, M, Tyrer, D, Dali-kemmery, L, Lambourne, V, Green, M, Sirdefield, D, Amor, K, Colley, J, Shinder, B, Jones, J, Mills, M, Carnahan, M, Taylor, N, Boulton, K, Tregonning, J, Brown, C, Clifford, G, Archer, E, Hamilton, M, Curtis, J, Shewan, T, Walsh, S, Warner, K, Netherton, K, Mupudzi, M, Gunson, B, Gitahi, J, Gocher, D, Batham, S, Pateman, H, Desmennu, S, Conder, J, Clement, D, Gallagher, S, Orpe, J, Chan, P, Currie, L, O'Donohoe, L, Oblak, M, Morgan, L, Quinn, M, Amey, I, Baird, Y, Cotterill, D, Cumlat, L, Winter, L, Greer, S, Spurdle, K, Allison, J, Dyer, S, Sweeting, H, Kordula, J, Aiba, Y, Nakamura, H, Abiru, S, Nagaoka, S, Komori, A, Yatsuhashi, H, Ishibashi, H, Ito, M, Kawai, Y, Kohn, S, Gervais, O, Migita, K, Katsushima, S, Naganuma, A, Sugi, K, Komatsu, T, Mannami, T, Matsushita, K, Yoshizawa, K, Makita, F, Nikami, T, Nishimura, H, Kouno, H, Ota, H, Komura, T, Nakamura, Y, Shimada, M, Hirashima, N, Komeda, T, Ario, K, Nakamuta, M, Yamashita, T, Furuta, K, Kikuchi, M, Naeshiro, N, Takahashi, H, Mano, Y, Tsunematsu, S, Yabuuchi, I, Shimada, Y, Yamauchi, K, Sugimoto, R, Sakai, H, Mita, E, Koda, M, Tsuruta, S, Kamitsukasa, H, Sato, T, Masaki, N, Kobata, T, Fukushima, N, Higuchi, N, Ohara, Y, Muro, T, Takesaki, E, Takaki, H, Yamamoto, T, Kato, M, Nagaoki, Y, Hayashi, S, Ishida, J, Watanabe, Y, Kobayashi, M, Koga, M, Saoshiro, T, Yagura, M, Hirata, K, Takikawa, H, Ohira, H, Zeniya, M, Abe, M, Onji, M, Kaneko, S, Honda, M, Arai, K, Arinaga-Hino, T, Hashimoto, E, Taniai, M, Umemura, T, Joshita, S, Nakao, K, Ichikawa, T, Shibata, H, Yamagiwa, S, Seike, M, Honda, K, Sakisaka, S, Takeyama, Y, Harada, M, Senju, M, Yokosuka, O, Kanda, T, Ueno, Y, Kikuchi, K, Ebinuma, H, Himoto, T, Yasunami, M, Murata, K, Mizokami, M, Shimoda, S, Miyake, Y, Takaki, A, Yamamoto, K, Hirano, K, Ichida, T, Ido, A, Tsubouchi, H, Chayama, K, Harada, K, Nakanuma, Y, Maehara, Y, Taketomi, A, Shirabe, K, Soejima, Y, Mori, A, Yagi, S, Uemoto, S, Tanaka, T, Yamashiki, N, Tamura, S, Sugawara, Y, Kokudo, N, Carbone, M, Cardamone, G, Duga, S, Gershwin, M, Seldin, M, Invernizzi, P, Asselta R, Paraboschi EM, Gerussi A, Cordell HJ, Mells GF, Sandford RN, Jones DE, Nakamura M, Ueno K, Hitomi Y, Kawashima M, Nishida N, Tokunaga K, Nagasaki M, Tanaka A, Tang R, Li Z, Shi Y, Liu X, Xiong M, Hirschfield G, Siminovitch KA, Canadian-US PBC Consortium, Italian PBC Genetics Study Group, UK-PBC Consortium, Japan PBC-GWAS Consortium, Carbone M, Cardamone G, Duga S, Gershwin ME, Seldin MF, Invernizzi P, and LiveR North

Subjects
Canadian-US PBC Consortium, 0301 basic medicine, Male, Linkage disequilibrium, Genome-wide association study, Disease, PBC, Settore MED/03 - GENETICA MEDICA, Linkage Disequilibrium, 0302 clinical medicine, UK-PBC Consortium, Genotype, Mitochondrial Precursor Protein Import Complex Proteins, Italian PBC Genetics Study Group, Odds Ratio, X-Wide Association Study, Japan PBC-GWAS Consortium, X chromosome, Genetics, Liver Cirrhosis, Biliary, Gastroenterology, Forkhead Transcription Factors, DNA-Binding Proteins, Shal Potassium Channels, 030211 gastroenterology & hepatology, Female, Adult, Monosaccharide Transport Proteins, Superenhancer, Locus (genetics), Single-nucleotide polymorphism, Biology, Protein Serine-Threonine Kinases, Polymorphism, Single Nucleotide, Article, White People, 03 medical and health sciences, Asian People, Proto-Oncogene Proteins, Endopeptidases, Humans, Cell Lineage, Genetic Predisposition to Disease, Meta-analysi, Genetic association, Chromosomes, Human, X, Gastroenterology & Hepatology, Hepatology, 1103 Clinical Sciences, Meta-analysis, 030104 developmental biology, Genetic Loci, 1114 Paediatrics and Reproductive Medicine, 1109 Neurosciences, Carrier Proteins, Genome-Wide Association Study
Abstract

Background & aims: Genome-wide association studies in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually dimorphic complex autoimmune disease. Methods: We performed a chrX-wide association study, including genotype data from 5 genome-wide association studies (from Italy, United Kingdom, Canada, China, and Japan; 5244 case patients and 11,875 control individuals). Results: Single-marker association analyses found approximately 100 loci displaying P < 5 × 10-4, with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 × 10-6; odds ratio [OR], 1.39; 95% confidence interval [CI], 1.028-1.88; Japanese cohort). Although the transethnic meta-analysis evidenced only a suggestive signal (rs2239452, mapping within the PIM2 gene; OR, 1.17; 95% CI, 1.09-1.26; P = 9.93 × 10-8), the population-specific meta-analysis showed a genome-wide significant locus in East Asian individuals pointing to the same region (rs7059064, mapping within the GRIPAP1 gene; P = 6.2 × 10-9; OR, 1.33; 95% CI, 1.21-1.46). Indeed, rs7059064 tags a unique linkage disequilibrium block including 7 genes: TIMM17B, PQBP1, PIM2, SLC35A2, OTUD5, KCND1, and GRIPAP1, as well as a superenhancer (GH0XJ048933 within OTUD5) targeting all these genes. GH0XJ048933 is also predicted to target FOXP3, the main T-regulatory cell lineage specification factor. Consistently, OTUD5 and FOXP3 RNA levels were up-regulated in PBC case patients (1.75- and 1.64-fold, respectively). Conclusions: This work represents the first comprehensive study, to our knowledge, of the chrX contribution to the genetics of an autoimmune liver disease and shows a novel PBC-related genome-wide significant locus.

Published
2021

18. An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs

Author

Heather J. Cordell, James J. Fryett, Kazuko Ueno, Rebecca Darlay, Yoshihiro Aiba, Yuki Hitomi, Minae Kawashima, Nao Nishida, Seik-Soon Khor, Olivier Gervais, Yosuke Kawai, Masao Nagasaki, Katsushi Tokunaga, Ruqi Tang, Yongyong Shi, Zhiqiang Li, Brian D. Juran, Elizabeth J. Atkinson, Alessio Gerussi, Marco Carbone, Rosanna Asselta, Angela Cheung, Mariza de Andrade, Aris Baras, Julie Horowitz, Manuel A.R. Ferreira, Dylan Sun, David E. Jones, Steven Flack, Ann Spicer, Victoria L. Mulcahy, Jinyoung Byan, Younghun Han, Richard N. Sandford, Konstantinos N. Lazaridis, Christopher I. Amos, Gideon M. Hirschfield, Michael F. Seldin, Pietro Invernizzi, Katherine A. Siminovitch, Xiong Ma, Minoru Nakamura, George F. Mells, Andrew Mason, Catherine Vincent, Gang Xie, Jinyi Zhang, Andrea Affronti, Piero L. Almasio, Domenico Alvaro, Pietro Andreone, Angelo Andriulli, Francesco Azzaroli, Pier Maria Battezzati, Antonio Benedetti, MariaConsiglia Bragazzi, Maurizia Brunetto, Savino Bruno, Vincenza Calvaruso, Vincenzo Cardinale, Giovanni Casella, Nora Cazzagon, Antonio Ciaccio, Barbara Coco, Agostino Colli, Guido Colloredo, Massimo Colombo, Silvia Colombo, Laura Cristoferi, Carmela Cursaro, Lory Saveria Crocè, Andrea Crosignani, Daphne D’Amato, Francesca Donato, Gianfranco Elia, Luca Fabris, Stefano Fagiuoli, Carlo Ferrari, Annarosa Floreani, Andrea Galli, Edoardo Giannini, Ignazio Grattagliano, Pietro Lampertico, Ana Lleo, Federica Malinverno, Clara Mancuso, Fabio Marra, Marco Marzioni, Sara Massironi, Alberto Mattalia, Luca Miele, Chiara Milani, Lorenzo Morini, Filomena Morisco, Luigi Muratori, Paolo Muratori, Grazia A. Niro, Sarah O’Donnell, Antonio Picciotto, Piero Portincasa, Cristina Rigamonti, Vincenzo Ronca, Floriano Rosina, Giancarlo Spinzi, Mario Strazzabosco, Mirko Tarocchi, Claudio Tiribelli, Pierluigi Toniutto, Luca Valenti, Maria Vinci, Massimo Zuin, Hitomi Nakamura, Seigo Abiru, Shinya Nagaoka, Atsumasa Komori, Hiroshi Yatsuhashi, Hiromi Ishibashi, Masahiro Ito, Kiyoshi Migita, Hiromasa Ohira, Shinji Katsushima, Atsushi Naganuma, Kazuhiro Sugi, Tatsuji Komatsu, Tomohiko Mannami, Kouki Matsushita, Kaname Yoshizawa, Fujio Makita, Toshiki Nikami, Hideo Nishimura, Hiroshi Kouno, Hirotaka Kouno, Hajime Ota, Takuya Komura, Yoko Nakamura, Masaaki Shimada, Noboru Hirashima, Toshiki Komeda, Keisuke Ario, Makoto Nakamuta, Tsutomu Yamashita, Kiyoshi Furuta, Masahiro Kikuchi, Noriaki Naeshiro, Hironao Takahashi, Yutaka Mano, Seiji Tsunematsu, Iwao Yabuuchi, Yusuke Shimada, Kazuhiko Yamauchi, Rie Sugimoto, Hironori Sakai, Eiji Mita, Masaharu Koda, Satoru Tsuruta, Hiroshi Kamitsukasa, Takeaki Sato, Naohiko Masaki, Tatsuro Kobata, Nobuyoshi Fukushima, Yukio Ohara, Toyokichi Muro, Eiichi Takesaki, Hitoshi Takaki, Tetsuo Yamamoto, Michio Kato, Yuko Nagaoki, Shigeki Hayashi, Jinya Ishida, Yukio Watanabe, Masakazu Kobayashi, Michiaki Koga, Takeo Saoshiro, Michiyasu Yagura, Keisuke Hirata, Atsushu Tanaka, Hajime Takikawa, Mikio Zeniya, Masanori Abe, Morikazu Onji, Shuichi Kaneko, Masao Honda, Kuniaki Arai, Teruko Arinaga-Hino, Etsuko Hashimoto, Makiko Taniai, Takeji Umemura, Satoru Joshita, Kazuhiko Nakao, Tatsuki Ichikawa, Hidetaka Shibata, Satoshi Yamagiwa, Masataka Seike, Koichi Honda, Shotaro Sakisaka, Yasuaki Takeyama, Masaru Harada, Michio Senju, Osamu Yokosuka, Tatsuo Kanda, Yoshiyuki Ueno, Kentaro Kikuchi, Hirotoshi Ebinuma, Takashi Himoto, Michio Yasunami, Kazumoto Murata, Masashi Mizokami, Kazuhito Kawata, Shinji Shimoda, Yasuhiro Miyake, Akinobu Takaki, Kazuhide Yamamoto, Katsuji Hirano, Takafumi Ichida, Akio Ido, Hirohito Tsubouchi, Kazuaki Chayama, Kenichi Harada, Yasuni Nakanuma, Yoshihiko Maehara, Akinobu Taketomi, Ken Shirabe, Yuji Soejima, Akira Mori, Shintaro Yagi, Shinji Uemoto, Egawa H, Tomohiro Tanaka, Noriyo Yamashiki, Sumito Tamura, Yasuhiro Sugawara, Norihiro Kokudo, Naga Chalasani, Vel Luketic, Joseph Odin, Kapil Chopra, Goncalo Abecasis, Michael Cantor, Giovanni Coppola, Aris Economides, Luca A. Lotta, John D. Overton, Jeffrey G. Reid, Alan Shuldiner, Christina Beechert, Caitlin Forsythe, Erin D. Fuller, Zhenhua Gu, Michael Lattari, Alexander Lopez, Thomas D. Schleicher, Maria Sotiropoulos Padilla, Karina Toledo, Louis Widom, Sarah E. Wolf, Manasi Pradhan, Kia Manoochehri, Ricardo H. Ulloa, Xiaodong Bai, Suganthi Balasubramanian, Leland Barnard, Andrew Blumenfeld, Gisu Eom, Lukas Habegger, Alicia Hawes, Shareef Khalid, Evan K. Maxwell, William Salerno, Jeffrey C. Staples, Marcus B. Jones, Lyndon J. Mitnaul, Richard Sturgess, Christopher Healey, Andrew Yeoman, Anton VJ. Gunasekera, Paul Kooner, Kapil Kapur, V. Sathyanarayana, Yiannis Kallis, Javaid Subhani, Rory Harvey, Roger McCorry, Paul Rooney, David Ramanaden, Richard Evans, Thiriloganathan Mathialahan, Jaber Gasem, Christopher Shorrock, Mahesh Bhalme, Paul Southern, Jeremy A. Tibble, David A. Gorard, Susan Jones, George Mells, Victoria Mulcahy, Brijesh Srivastava, Matthew R. Foxton, Carole E. Collins, David Elphick, Mazn Karmo, Francisco Porras-Perez, Michael Mendall, Tom Yapp, Minesh Patel, Roland Ede, Joanne Sayer, James Jupp, Neil Fisher, Martyn J. Carter, Konrad Koss, Jayshri Shah, Andrzej Piotrowicz, Glyn Scott, Charles Grimley, Ian R. Gooding, Simon Williams, Judith Tidbury, Guan Lim, Kuldeep Cheent, Sass Levi, Dina Mansour, Matilda Beckley, Coral Hollywood, Terry Wong, Richard Marley, John Ramage, Harriet M. Gordon, Jo Ridpath, Theodore Ngatchu, Vijay Paul Bob Grover, Ray G. Shidrawi, George Abouda, L. Corless, Mark Narain, Ian Rees, Ashley Brown, Simon Taylor-Robinson, Joy Wilkins, Leonie Grellier, Paul Banim, Debasish Das, Michael A. Heneghan, Howard Curtis, Helen C. Matthews, Faiyaz Mohammed, Mark Aldersley, Raj Srirajaskanthan, Giles Walker, Alistair McNair, Amar Sharif, Sambit Sen, George Bird, Martin I. Prince, Geeta Prasad, Paul Kitchen, Adrian Barnardo, Chirag Oza, Nurani N. Sivaramakrishnan, Prakash Gupta, Amir Shah, Chris DJ. Evans, Subrata Saha, Katharine Pollock, Peter Bramley, Ashis Mukhopadhya, Stephen T. Barclay, Natasha McDonald, Andrew J. Bathgate, Kelvin Palmer, John F. Dillon, Simon M. Rushbrook, Robert Przemioslo, Chris McDonald, Andrew Millar, Cheh Tai, Stephen Mitchell, Jane Metcalf, Syed Shaukat, Mary Ninkovic, Udi Shmueli, Andrew Davis, Asifabbas Naqvi, Tom JW. Lee, Stephen Ryder, Jane Collier, Howard Klass, Matthew E. Cramp, Nichols Sharer, Richard Aspinall, Deb Ghosh, Andrew C. Douds, Jonathan Booth, Earl Williams, Hyder Hussaini, John Christie, Steven Mann, Douglas Thorburn, Aileen Marshall, Imran Patanwala, Aftab Ala, Julia Maltby, Ray Matthew, Chris Corbett, Sam Vyas, Saket Singhal, Dermot Gleeson, Sharat Misra, Jeff Butterworth, Keith George, Tim Harding, Andrew Douglass, Harriet Mitchison, Simon Panter, Jeremy Shearman, Gary Bray, Michael Roberts, Graham Butcher, Daniel Forton, Zahid Mahmood, Matthew Cowan, Debashis Das, Chin Lye Ch’ng, Mesbah Rahman, Gregory C.A. Whatley, Emma Wesley, Aditya Mandal, Sanjiv Jain, Stephen P. Pereira, Mark Wright, Palak Trivedi, Fiona H. Gordon, Esther Unitt, Altaf Palejwala, Andrew Austin, Vishwaraj Vemala, Allister Grant, Andrew D. Higham, Alison Brind, Ray Mathew, Mark Cox, Subramaniam Ramakrishnan, Alistair King, Simon Whalley, Jocelyn Fraser, S.J. Thomson, Andrew Bell, Voi Shim Wong, Richard Kia, Ian Gee, Richard Keld, Rupert Ransford, James Gotto, Charles Millson, Cordell, H. J., Fryett, J. J., Ueno, K., Darlay, R., Aiba, Y., Hitomi, Y., Kawashima, M., Nishida, N., Khor, S. -S., Gervais, O., Kawai, Y., Nagasaki, M., Tokunaga, K., Tang, R., Shi, Y., Li, Z., Juran, B. D., Atkinson, E. J., Gerussi, A., Carbone, M., Asselta, R., Cheung, A., de Andrade, M., Baras, A., Horowitz, J., Ferreira, M. A. R., Sun, D., Jones, D. E., Flack, S., Spicer, A., Mulcahy, V. L., Byan, J., Han, Y., Sandford, R. N., Lazaridis, K. N., Amos, C. I., Hirschfield, G. M., Seldin, M. F., Invernizzi, P., Siminovitch, K. A., Ma, X., Nakamura, M., Mells, G. F., Mason, A., Vincent, C., Xie, G., Zhang, J., Affronti, A., Almasio, P. L., Alvaro, D., Andreone, P., Andriulli, A., Azzaroli, F., Battezzati, P. M., Benedetti, A., Bragazzi, M., Brunetto, M., Bruno, S., Calvaruso, V., Cardinale, V., Casella, G., Cazzagon, N., Ciaccio, A., Coco, B., Colli, A., Colloredo, G., Colombo, M., Colombo, S., Cristoferi, L., Cursaro, C., Croce, L. S., Crosignani, A., D'Amato, D., Donato, F., Elia, G., Fabris, L., Fagiuoli, S., Ferrari, C., Floreani, A., Galli, A., Giannini, E., Grattagliano, I., Lampertico, P., Lleo, A., Malinverno, F., Mancuso, C., Marra, F., Marzioni, M., Massironi, S., Mattalia, A., Miele, L., Milani, C., Morini, L., Morisco, F., Muratori, L., Muratori, P., Niro, G. A., O'Donnell, S., Picciotto, A., Portincasa, P., Rigamonti, C., Ronca, V., Rosina, F., Spinzi, G., Strazzabosco, M., Tarocchi, M., Tiribelli, C., Toniutto, P., Valenti, L., Vinci, M., Zuin, M., Nakamura, H., Abiru, S., Nagaoka, S., Komori, A., Yatsuhashi, H., Ishibashi, H., Ito, M., Migita, K., Ohira, H., Katsushima, S., Naganuma, A., Sugi, K., Komatsu, T., Mannami, T., Matsushita, K., Yoshizawa, K., Makita, F., Nikami, T., Nishimura, H., Kouno, H., Ota, H., Komura, T., Nakamura, Y., Shimada, M., Hirashima, N., Komeda, T., Ario, K., Nakamuta, M., Yamashita, T., Furuta, K., Kikuchi, M., Naeshiro, N., Takahashi, H., Mano, Y., Tsunematsu, S., Yabuuchi, I., Shimada, Y., Yamauchi, K., Sugimoto, R., Sakai, H., Mita, E., Koda, M., Tsuruta, S., Kamitsukasa, H., Sato, T., Masaki, N., Kobata, T., Fukushima, N., Ohara, Y., Muro, T., Takesaki, E., Takaki, H., Yamamoto, T., Kato, M., Nagaoki, Y., Hayashi, S., Ishida, J., Watanabe, Y., Kobayashi, M., Koga, M., Saoshiro, T., Yagura, M., Hirata, K., Tanaka, A., Takikawa, H., Zeniya, M., Abe, M., Onji, M., Kaneko, S., Honda, M., Arai, K., Arinaga-Hino, T., Hashimoto, E., Taniai, M., Umemura, T., Joshita, S., Nakao, K., Ichikawa, T., Shibata, H., Yamagiwa, S., Seike, M., Honda, K., Sakisaka, S., Takeyama, Y., Harada, M., Senju, M., Yokosuka, O., Kanda, T., Ueno, Y., Kikuchi, K., Ebinuma, H., Himoto, T., Yasunami, M., Murata, K., Mizokami, M., Kawata, K., Shimoda, S., Miyake, Y., Takaki, A., Yamamoto, K., Hirano, K., Ichida, T., Ido, A., Tsubouchi, H., Chayama, K., Harada, K., Nakanuma, Y., Maehara, Y., Taketomi, A., Shirabe, K., Soejima, Y., Mori, A., Yagi, S., Uemoto, S., H, E., Tanaka, T., Yamashiki, N., Tamura, S., Sugawara, Y., Kokudo, N., Chalasani, N., Luketic, V., Odin, J., Chopra, K., Abecasis, G., Cantor, M., Coppola, G., Economides, A., Lotta, L. A., Overton, J. D., Reid, J. G., Shuldiner, A., Beechert, C., Forsythe, C., Fuller, E. D., Gu, Z., Lattari, M., Lopez, A., Schleicher, T. D., Padilla, M. S., Toledo, K., Widom, L., Wolf, S. E., Pradhan, M., Manoochehri, K., Ulloa, R. H., Bai, X., Balasubramanian, S., Barnard, L., Blumenfeld, A., Eom, G., Habegger, L., Hawes, A., Khalid, S., Maxwell, E. K., Salerno, W., Staples, J. C., Jones, M. B., Mitnaul, L. J., Sturgess, R., Healey, C., Yeoman, A., Gunasekera, A. V., Kooner, P., Kapur, K., Sathyanarayana, V., Kallis, Y., Subhani, J., Harvey, R., Mccorry, R., Rooney, P., Ramanaden, D., Evans, R., Mathialahan, T., Gasem, J., Shorrock, C., Bhalme, M., Southern, P., Tibble, J. A., Gorard, D. A., Jones, S., Mells, G., Mulcahy, V., Srivastava, B., Foxton, M. R., Collins, C. E., Elphick, D., Karmo, M., Porras-Perez, F., Mendall, M., Yapp, T., Patel, M., Ede, R., Sayer, J., Jupp, J., Fisher, N., Carter, M. J., Koss, K., Shah, J., Piotrowicz, A., Scott, G., Grimley, C., Gooding, I. R., Williams, S., Tidbury, J., Lim, G., Cheent, K., Levi, S., Mansour, D., Beckley, M., Hollywood, C., Wong, T., Marley, R., Ramage, J., Gordon, H. M., Ridpath, J., Ngatchu, T., Bob Grover, V. P., Shidrawi, R. G., Abouda, G., Corless, L., Narain, M., Rees, I., Brown, A., Taylor-Robinson, S., Wilkins, J., Grellier, L., Banim, P., Das, D., Heneghan, M. A., Curtis, H., Matthews, H. C., Mohammed, F., Aldersley, M., Srirajaskanthan, R., Walker, G., Mcnair, A., Sharif, A., Sen, S., Bird, G., Prince, M. I., Prasad, G., Kitchen, P., Barnardo, A., Oza, C., Sivaramakrishnan, N. N., Gupta, P., Shah, A., Evans, C. D., Saha, S., Pollock, K., Bramley, P., Mukhopadhya, A., Barclay, S. T., Mcdonald, N., Bathgate, A. J., Palmer, K., Dillon, J. F., Rushbrook, S. M., Przemioslo, R., Mcdonald, C., Millar, A., Tai, C., Mitchell, S., Metcalf, J., Shaukat, S., Ninkovic, M., Shmueli, U., Davis, A., Naqvi, A., Lee, T. J., Ryder, S., Collier, J., Klass, H., Cramp, M. E., Sharer, N., Aspinall, R., Ghosh, D., Douds, A. C., Booth, J., Williams, E., Hussaini, H., Christie, J., Mann, S., Thorburn, D., Marshall, A., Patanwala, I., Ala, A., Maltby, J., Matthew, R., Corbett, C., Vyas, S., Singhal, S., Gleeson, D., Misra, S., Butterworth, J., George, K., Harding, T., Douglass, A., Mitchison, H., Panter, S., Shearman, J., Bray, G., Roberts, M., Butcher, G., Forton, D., Mahmood, Z., Cowan, M., Ch'Ng, C. L., Rahman, M., Whatley, G. C. A., Wesley, E., Mandal, A., Jain, S., Pereira, S. P., Wright, M., Trivedi, P., Gordon, F. H., Unitt, E., Palejwala, A., Austin, A., Vemala, V., Grant, A., Higham, A. D., Brind, A., Mathew, R., Cox, M., Ramakrishnan, S., King, A., Whalley, S., Fraser, J., Thomson, S. J., Bell, A., Wong, V. S., Kia, R., Gee, I., Keld, R., Ransford, R., Gotto, J., Millson, C., Cordell H.J., Fryett J.J., Ueno K., Darlay R., Aiba Y., Hitomi Y., Kawashima M., Nishida N., Khor S.-S., Gervais O., Kawai Y., Nagasaki M., Tokunaga K., Tang R., Shi Y., Li Z., Juran B.D., Atkinson E.J., Gerussi A., Carbone M., Asselta R., Cheung A., de Andrade M., Baras A., Horowitz J., Ferreira M.A.R., Sun D., Jones D.E., Flack S., Spicer A., Mulcahy V.L., Byan J., Han Y., Sandford R.N., Lazaridis K.N., Amos C.I., Hirschfield G.M., Seldin M.F., Invernizzi P., Siminovitch K.A., Ma X., Nakamura M., Mells G.F., Mason A., Vincent C., Xie G., Zhang J., Affronti A., Almasio P.L., Alvaro D., Andreone P., Andriulli A., Azzaroli F., Battezzati P.M., Benedetti A., Bragazzi M., Brunetto M., Bruno S., Calvaruso V., Cardinale V., Casella G., Cazzagon N., Ciaccio A., Coco B., Colli A., Colloredo G., Colombo M., Colombo S., Cristoferi L., Cursaro C., Croce L.S., Crosignani A., D'Amato D., Donato F., Elia G., Fabris L., Fagiuoli S., Ferrari C., Floreani A., Galli A., Giannini E., Grattagliano I., Lampertico P., Lleo A., Malinverno F., Mancuso C., Marra F., Marzioni M., Massironi S., Mattalia A., Miele L., Milani C., Morini L., Morisco F., Muratori L., Muratori P., Niro G.A., O'Donnell S., Picciotto A., Portincasa P., Rigamonti C., Ronca V., Rosina F., Spinzi G., Strazzabosco M., Tarocchi M., Tiribelli C., Toniutto P., Valenti L., Vinci M., Zuin M., Nakamura H., Abiru S., Nagaoka S., Komori A., Yatsuhashi H., Ishibashi H., Ito M., Migita K., Ohira H., Katsushima S., Naganuma A., Sugi K., Komatsu T., Mannami T., Matsushita K., Yoshizawa K., Makita F., Nikami T., Nishimura H., Kouno H., Ota H., Komura T., Nakamura Y., Shimada M., Hirashima N., Komeda T., Ario K., Nakamuta M., Yamashita T., Furuta K., Kikuchi M., Naeshiro N., Takahashi H., Mano Y., Tsunematsu S., Yabuuchi I., Shimada Y., Yamauchi K., Sugimoto R., Sakai H., Mita E., Koda M., Tsuruta S., Kamitsukasa H., Sato T., Masaki N., Kobata T., Fukushima N., Ohara Y., Muro T., Takesaki E., Takaki H., Yamamoto T., Kato M., Nagaoki Y., Hayashi S., Ishida J., Watanabe Y., Kobayashi M., Koga M., Saoshiro T., Yagura M., Hirata K., Tanaka A., Takikawa H., Zeniya M., Abe M., Onji M., Kaneko S., Honda M., Arai K., Arinaga-Hino T., Hashimoto E., Taniai M., Umemura T., Joshita S., Nakao K., Ichikawa T., Shibata H., Yamagiwa S., Seike M., Honda K., Sakisaka S., Takeyama Y., Harada M., Senju M., Yokosuka O., Kanda T., Ueno Y., Kikuchi K., Ebinuma H., Himoto T., Yasunami M., Murata K., Mizokami M., Kawata K., Shimoda S., Miyake Y., Takaki A., Yamamoto K., Hirano K., Ichida T., Ido A., Tsubouchi H., Chayama K., Harada K., Nakanuma Y., Maehara Y., Taketomi A., Shirabe K., Soejima Y., Mori A., Yagi S., Uemoto S., H E., Tanaka T., Yamashiki N., Tamura S., Sugawara Y., Kokudo N., Chalasani N., Luketic V., Odin J., Chopra K., Abecasis G., Cantor M., Coppola G., Economides A., Lotta L.A., Overton J.D., Reid J.G., Shuldiner A., Beechert C., Forsythe C., Fuller E.D., Gu Z., Lattari M., Lopez A., Schleicher T.D., Padilla M.S., Toledo K., Widom L., Wolf S.E., Pradhan M., Manoochehri K., Ulloa R.H., Bai X., Balasubramanian S., Barnard L., Blumenfeld A., Eom G., Habegger L., Hawes A., Khalid S., Maxwell E.K., Salerno W., Staples J.C., Jones M.B., Mitnaul L.J., Sturgess R., Healey C., Yeoman A., Gunasekera A.V., Kooner P., Kapur K., Sathyanarayana V., Kallis Y., Subhani J., Harvey R., McCorry R., Rooney P., Ramanaden D., Evans R., Mathialahan T., Gasem J., Shorrock C., Bhalme M., Southern P., Tibble J.A., Gorard D.A., Jones S., Mells G., Mulcahy V., Srivastava B., Foxton M.R., Collins C.E., Elphick D., Karmo M., Porras-Perez F., Mendall M., Yapp T., Patel M., Ede R., Sayer J., Jupp J., Fisher N., Carter M.J., Koss K., Shah J., Piotrowicz A., Scott G., Grimley C., Gooding I.R., Williams S., Tidbury J., Lim G., Cheent K., Levi S., Mansour D., Beckley M., Hollywood C., Wong T., Marley R., Ramage J., Gordon H.M., Ridpath J., Ngatchu T., Bob Grover V.P., Shidrawi R.G., Abouda G., Corless L., Narain M., Rees I., Brown A., Taylor-Robinson S., Wilkins J., Grellier L., Banim P., Das D., Heneghan M.A., Curtis H., Matthews H.C., Mohammed F., Aldersley M., Srirajaskanthan R., Walker G., McNair A., Sharif A., Sen S., Bird G., Prince M.I., Prasad G., Kitchen P., Barnardo A., Oza C., Sivaramakrishnan N.N., Gupta P., Shah A., Evans C.D., Saha S., Pollock K., Bramley P., Mukhopadhya A., Barclay S.T., McDonald N., Bathgate A.J., Palmer K., Dillon J.F., Rushbrook S.M., Przemioslo R., McDonald C., Millar A., Tai C., Mitchell S., Metcalf J., Shaukat S., Ninkovic M., Shmueli U., Davis A., Naqvi A., Lee T.J., Ryder S., Collier J., Klass H., Cramp M.E., Sharer N., Aspinall R., Ghosh D., Douds A.C., Booth J., Williams E., Hussaini H., Christie J., Mann S., Thorburn D., Marshall A., Patanwala I., Ala A., Maltby J., Matthew R., Corbett C., Vyas S., Singhal S., Gleeson D., Misra S., Butterworth J., George K., Harding T., Douglass A., Mitchison H., Panter S., Shearman J., Bray G., Roberts M., Butcher G., Forton D., Mahmood Z., Cowan M., Ch'ng C.L., Rahman M., Whatley G.C.A., Wesley E., Mandal A., Jain S., Pereira S.P., Wright M., Trivedi P., Gordon F.H., Unitt E., Palejwala A., Austin A., Vemala V., Grant A., Higham A.D., Brind A., Mathew R., Cox M., Ramakrishnan S., King A., Whalley S., Fraser J., Thomson S.J., Bell A., Wong V.S., Kia R., Gee I., Keld R., Ransford R., Gotto J., Millson C., Medical Research Council (MRC), LiveR North, Cordell, H, Fryett, J, Ueno, K, Darlay, R, Aiba, Y, Hitomi, Y, Kawashima, M, Nishida, N, Khor, S, Gervais, O, Kawai, Y, Nagasaki, M, Tokunaga, K, Tang, R, Shi, Y, Li, Z, Juran, B, Atkinson, E, Gerussi, A, Carbone, M, Asselta, R, Cheung, A, de Andrade, M, Baras, A, Horowitz, J, Ferreira, M, Sun, D, Jones, D, Flack, S, Spicer, A, Mulcahy, V, Byan, J, Han, Y, Sandford, R, Lazaridis, K, Amos, C, Hirschfield, G, Seldin, M, Invernizzi, P, Siminovitch, K, Ma, X, Nakamura, M, Mells, G, Mason, A, Vincent, C, Xie, G, Zhang, J, Affronti, A, Almasio, P, Alvaro, D, Andreone, P, Andriulli, A, Azzaroli, F, Battezzati, P, Benedetti, A, Bragazzi, M, Brunetto, M, Bruno, S, Calvaruso, V, Cardinale, V, Casella, G, Cazzagon, N, Ciaccio, A, Coco, B, Colli, A, Colloredo, G, Colombo, M, Colombo, S, Cristoferi, L, Cursaro, C, Croce, L, Crosignani, A, D'Amato, D, Donato, F, Elia, G, Fabris, L, Fagiuoli, S, Ferrari, C, Floreani, A, Galli, A, Giannini, E, Grattagliano, I, Lampertico, P, Lleo, A, Malinverno, F, Mancuso, C, Marra, F, Marzioni, M, Massironi, S, Mattalia, A, Miele, L, Milani, C, Morini, L, Morisco, F, Muratori, L, Muratori, P, Niro, G, O'Donnell, S, Picciotto, A, Portincasa, P, Rigamonti, C, Ronca, V, Rosina, F, Spinzi, G, Strazzabosco, M, Tarocchi, M, Tiribelli, C, Toniutto, P, Valenti, L, Vinci, M, Zuin, M, Nakamura, H, Abiru, S, Nagaoka, S, Komori, A, Yatsuhashi, H, Ishibashi, H, Ito, M, Migita, K, Ohira, H, Katsushima, S, Naganuma, A, Sugi, K, Komatsu, T, Mannami, T, Matsushita, K, Yoshizawa, K, Makita, F, Nikami, T, Nishimura, H, Kouno, H, Ota, H, Komura, T, Nakamura, Y, Shimada, M, Hirashima, N, Komeda, T, Ario, K, Nakamuta, M, Yamashita, T, Furuta, K, Kikuchi, M, Naeshiro, N, Takahashi, H, Mano, Y, Tsunematsu, S, Yabuuchi, I, Shimada, Y, Yamauchi, K, Sugimoto, R, Sakai, H, Mita, E, Koda, M, Tsuruta, S, Kamitsukasa, H, Sato, T, Masaki, N, Kobata, T, Fukushima, N, Ohara, Y, Muro, T, Takesaki, E, Takaki, H, Yamamoto, T, Kato, M, Nagaoki, Y, Hayashi, S, Ishida, J, Watanabe, Y, Kobayashi, M, Koga, M, Saoshiro, T, Yagura, M, Hirata, K, Tanaka, A, Takikawa, H, Zeniya, M, Abe, M, Onji, M, Kaneko, S, Honda, M, Arai, K, Arinaga-Hino, T, Hashimoto, E, Taniai, M, Umemura, T, Joshita, S, Nakao, K, Ichikawa, T, Shibata, H, Yamagiwa, S, Seike, M, Honda, K, Sakisaka, S, Takeyama, Y, Harada, M, Senju, M, Yokosuka, O, Kanda, T, Ueno, Y, Kikuchi, K, Ebinuma, H, Himoto, T, Yasunami, M, Murata, K, Mizokami, M, Kawata, K, Shimoda, S, Miyake, Y, Takaki, A, Yamamoto, K, Hirano, K, Ichida, T, Ido, A, Tsubouchi, H, Chayama, K, Harada, K, Nakanuma, Y, Maehara, Y, Taketomi, A, Shirabe, K, Soejima, Y, Mori, A, Yagi, S, Uemoto, S, H, E, Tanaka, T, Yamashiki, N, Tamura, S, Sugawara, Y, Kokudo, N, Chalasani, N, Luketic, V, Odin, J, Chopra, K, Abecasis, G, Cantor, M, Coppola, G, Economides, A, Lotta, L, Overton, J, Reid, J, Shuldiner, A, Beechert, C, Forsythe, C, Fuller, E, Gu, Z, Lattari, M, Lopez, A, Schleicher, T, Padilla, M, Toledo, K, Widom, L, Wolf, S, Pradhan, M, Manoochehri, K, Ulloa, R, Bai, X, Balasubramanian, S, Barnard, L, Blumenfeld, A, Eom, G, Habegger, L, Hawes, A, Khalid, S, Maxwell, E, Salerno, W, Staples, J, Jones, M, Mitnaul, L, Sturgess, R, Healey, C, Yeoman, A, Gunasekera, A, Kooner, P, Kapur, K, Sathyanarayana, V, Kallis, Y, Subhani, J, Harvey, R, Mccorry, R, Rooney, P, Ramanaden, D, Evans, R, Mathialahan, T, Gasem, J, Shorrock, C, Bhalme, M, Southern, P, Tibble, J, Gorard, D, Jones, S, Srivastava, B, Foxton, M, Collins, C, Elphick, D, Karmo, M, Porras-Perez, F, Mendall, M, Yapp, T, Patel, M, Ede, R, Sayer, J, Jupp, J, Fisher, N, Carter, M, Koss, K, Shah, J, Piotrowicz, A, Scott, G, Grimley, C, Gooding, I, Williams, S, Tidbury, J, Lim, G, Cheent, K, Levi, S, Mansour, D, Beckley, M, Hollywood, C, Wong, T, Marley, R, Ramage, J, Gordon, H, Ridpath, J, Ngatchu, T, Bob Grover, V, Shidrawi, R, Abouda, G, Corless, L, Narain, M, Rees, I, Brown, A, Taylor-Robinson, S, Wilkins, J, Grellier, L, Banim, P, Das, D, Heneghan, M, Curtis, H, Matthews, H, Mohammed, F, Aldersley, M, Srirajaskanthan, R, Walker, G, Mcnair, A, Sharif, A, Sen, S, Bird, G, Prince, M, Prasad, G, Kitchen, P, Barnardo, A, Oza, C, Sivaramakrishnan, N, Gupta, P, Shah, A, Evans, C, Saha, S, Pollock, K, Bramley, P, Mukhopadhya, A, Barclay, S, Mcdonald, N, Bathgate, A, Palmer, K, Dillon, J, Rushbrook, S, Przemioslo, R, Mcdonald, C, Millar, A, Tai, C, Mitchell, S, Metcalf, J, Shaukat, S, Ninkovic, M, Shmueli, U, Davis, A, Naqvi, A, Lee, T, Ryder, S, Collier, J, Klass, H, Cramp, M, Sharer, N, Aspinall, R, Ghosh, D, Douds, A, Booth, J, Williams, E, Hussaini, H, Christie, J, Mann, S, Thorburn, D, Marshall, A, Patanwala, I, Ala, A, Maltby, J, Matthew, R, Corbett, C, Vyas, S, Singhal, S, Gleeson, D, Misra, S, Butterworth, J, George, K, Harding, T, Douglass, A, Mitchison, H, Panter, S, Shearman, J, Bray, G, Roberts, M, Butcher, G, Forton, D, Mahmood, Z, Cowan, M, Ch'Ng, C, Rahman, M, Whatley, G, Wesley, E, Mandal, A, Jain, S, Pereira, S, Wright, M, Trivedi, P, Gordon, F, Unitt, E, Palejwala, A, Austin, A, Vemala, V, Grant, A, Higham, A, Brind, A, Mathew, R, Cox, M, Ramakrishnan, S, King, A, Whalley, S, Fraser, J, Thomson, S, Bell, A, Wong, V, Kia, R, Gee, I, Keld, R, Ransford, R, Gotto, J, Millson, C, Cordell HJ, Fryett JJ, Ueno K, Darlay R, Aiba Y, Hitomi Y, Kawashima M, Nishida N, Khor SS, Gervais O, Kawai Y, Nagasaki M, Tokunaga K, Tang R, Shi Y, Li Z, Juran BD, Atkinson EJ, Gerussi A, Carbone M, Asselta R, Cheung A, de Andrade M, Baras A, Horowitz J, Ferreira MAR, Sun D, Jones DE, Flack S, Spicer A, Mulcahy VL, Byan J, Han Y, Sandford RN, Lazaridis KN, Amos CI, Hirschfield GM, Seldin MF, Invernizzi P, Siminovitch KA, Ma X, Nakamura M, Mells GF, PBC Consortia, Canadian PBC Consortium, Chinese PBC Consortium, Italian PBC Study Group, Japan-PBC-GWAS Consortium, US PBC Consortium, UK-PBC Consortium, and Calvaruso V. .

Subjects
Liver Cirrhosis, ALSPAC, ERN RARE-LIVER, Genomic co-localization, Network-based in silico drug efficacy screening, UK-PBC, 0301 basic medicine, Candidate gene, Genome-Wide Association Study, Humans, Liver Cirrhosis, Biliary, Italian PBC Study Group, LD SCORE REGRESSION, Japan-PBC-GWAS Consortium, Genome-wide association study, Locus (genetics), Disease, SUSCEPTIBILITY, PBC, Chronic liver disease, Bioinformatics, GENETIC ASSOCIATION, 1117 Public Health and Health Services, 03 medical and health sciences, 0302 clinical medicine, UK-PBC Consortium, Genotype, Medicine, Genetic association, Science & Technology, Gastroenterology & Hepatology, Hepatology, business.industry, Biliary, Chinese PBC Consortium, 1103 Clinical Sciences, medicine.disease, PBC Consortia, 030104 developmental biology, Meta-analysis, ERN RARE LIVER, 030211 gastroenterology & hepatology, US PBC Consortium, Canadian PBC Consortium, business, Life Sciences & Biomedicine, Human
Abstract

[BACKGROUND & AIMS] Primary biliary cholangitis (PBC) is a chronic liver disease in which autoimmune destruction of the small intra-hepatic bile ducts eventually leads to cirrhosis. Many patients have inadequate response to licensed medications, motivating the search for novel therapies. Previous genome-wide association studies (GWAS) and meta-analyses (GWMA) of PBC have identified numerous risk loci for this condition, providing insight into its aetiology. We undertook the largest GWMA of PBC to date, aiming to identify additional risk loci and prioritise candidate genes for in silico drug efficacy screening. [METHODS] We combined new and existing genotype data for 10, 516 cases and 20, 772 controls from five European and two East Asian cohorts. [RESULTS] We identified 56 genome-wide significant loci (20 novel) including 46 in European, 13 in Asian, and 41 in combined cohorts; and a 57th genome-wide significant locus (also novel) in conditional analysis of the European cohorts. Candidate genes at newly identified loci include FCRL3, INAVA, PRDM1, IRF7, CCR6, CD226, and IL12RB1, each having key roles in immunity. Pathway analysis reiterated the likely importance of pattern recognition receptor and TNF signalling, Jak-STAT signalling, and differentiation of TH1 and TH17 cells in the pathogenesis of this disease. Drug efficacy screening identified several medications predicted to be therapeutic in PBC, some well-established in the treatment of other autoimmune disorders. [CONCLUSIONS] This study has identified additional risk loci for PBC, provided a hierarchy of agents that could be trialled in this condition, and emphasised the value of genetic and genomic approaches to drug discovery in complex disorders. [Lay summary] Primary biliary cholangitis (PBC) is a chronic liver disease that eventually leads to cirrhosis. In this study, we analysed genetic information from 10, 516 people with PBC and 20, 772 healthy individuals recruited in Canada, China, Italy, Japan, UK, or USA. We identified several genetic regions associated with PBC. Each of these regions contains several genes. For each region, we used diverse sources of evidence to help us choose the gene most likely to be involved in causing PBC. We used these ‘candidate genes’ to help us identify medications that are currently used for treatment of other conditions, which might also be useful for treatment of PBC., 原発性胆汁性胆管炎のゲノムワイド関連解析 --国際メタ解析による新規疾患感受性遺伝子と治療薬候補の同定--. 京都大学プレスリリース. 2021-06-28.

Published
2021

19. Geranylgeranylacetone decreases the production of hepatitis B virus-related antigen by comprehensive downregulation of mRNA transcription activity

Author

Hisamitsu Miyaaki, Masanori Fukushima, Kazuo Yamamoto, Masafumi Haraguchi, Yasuko Kanda, Yuko Akazawa, Kazuhiko Nakao, Yasuhiko Nakao, Ryu Sasaki, Satoshi Miuma, and Tatsuki Ichikawa

Subjects
Hepatitis B virus, Down-Regulation, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Antigen, Enhancer binding, medicine, Humans, RNA, Messenger, Enhancer, Hepatitis B Surface Antigens, Hepatology, business.industry, Gastroenterology, virus diseases, Promoter, cccDNA, Molecular biology, digestive system diseases, Hepatocyte nuclear factors, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Hepatocyte, 030211 gastroenterology & hepatology, Diterpenes, business, Transcription Factors
Abstract

Background and aim Elimination of hepatitis B virus (HBV) is infrequently achieved with current therapies. Therefore, more effective anti-HBV therapy is needed. We previously reported that geranylgeranylacetone (GGA) showed anti-hepatitis C virus activity in human hepatoma cells. In this study, we examined the anti-HBV activity of GGA. Methods We used HepG2.2.15.7 cells, PXB cells infected with HBV, Huh7 cells transfected with linear HBV, and PLC/PRF/5 cells as HBV-infected hepatocyte models. After GGA treatment, HBV-related antigen was measured by chemiluminescent immunoassay. HBV-related mRNA was examined by Northern blot. cccDNA and endoplasmic reticulum stress markers were measured by real-time polymerase chain reaction. The activities of HBV promoters and enhancer regions were examined using luciferase vectors. Results After GGA treatment, hepatitis B surface antigen and hepatitis B e antigen secretion was decreased in all HBV-infected hepatocyte models. HBV-related mRNA was also decreased by GGA treatment, although cccDNA levels were not affected. Additionally, the activity of HBV S1 and S2 promoter region and Enhancer 1/Enhancer 2/core promoter region was reduced by GGA treatment. The mRNA expression of the main transcription factors, hepatocyte nuclear factor 3 and 4 and CCAAT/enhancer binding protein, was also decreased. Further, the expression levels of endoplasmic reticulum stress markers were increased by GGA treatment, which reflected the change in HBV-related antigen secretion. Conclusions Geranylgeranylacetone treatment reduces HBV-related protein levels by suppressing comprehensive downregulation of HBV promoter and enhancer activity, which might be caused by decreased hepatic transcription factor expression. GGA treatment may enhance anti-HBV effects in combination with other therapies.

Published
2020

20. Evaluating the Role of Hepatobiliary Phase of Gadoxetic Acid-Enhanced Magnetic Resonance Imaging in Predicting Treatment Impact of Lenvatinib and Atezolizumab plus Bevacizumab on Unresectable Hepatocellular Carcinoma

Author

Ryu Sasaki, Kazuyoshi Nagata, Masanori Fukushima, Masafumi Haraguchi, Satoshi Miuma, Hisamitsu Miyaaki, Akihiko Soyama, Masaaki Hidaka, Susumu Eguchi, Masaya Shigeno, Mio Yamashima, Shinobu Yamamichi, Tatsuki Ichikawa, Yuki Kugiyama, Hiroshi Yatsuhashi, and Kazuhiko Nakao

Subjects
atezolizumab, bevacizumab, biomarkers, hepatocellular carcinoma, catenins, lenvatinib, Cancer Research, Oncology, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Background: Atezolizumab plus bevacizumab therapy has high response rates in patients with unresectable hepatocellular carcinoma (HCC). The hepatobiliary phase of gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI) has been reported to be useful as an imaging biomarker for detecting β-catenin mutations. We evaluated whether the pretreatment of the hepatobiliary phase of EOB-MRI could predict the therapeutic effect of lenvatinib and atezolizumab plus bevacizumab. Methods: This study included 68 patients (lenvatinib group (n = 33) and atezolizumab plus bevacizumab group (n = 35)). The visual assessment and relative enhancement ratio (RER) of the largest HCC lesions were evaluated using the hepatobiliary phase of EOB-MRI. Results: The hyperintensity type (RER ≥ 0.9) was 18.2% in the lenvatinib group and 20.0% in the atezolizumab plus bevacizumab group. In the lenvatinib group, progression-free survival (PFS) was not different between the heterogeneous and homogenous types (p = 0.688) or between the hyperintensity and hypointensity types (p = 0.757). In the atezolizumab plus bevacizumab group, the heterogeneous type had significantly shorter PFS than the homogenous type (p = 0.007), and the hyperintensity type had significantly shorter PFS than the hypointensity type (p = 0.012). Conclusions: The hepatobiliary phase of EOB-MRI was useful for predicting the therapeutic effect of atezolizumab plus bevacizumab therapy on unresectable HCC.

Published
2022
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21. Hepatitis B virus reactivation in patients with rheumatoid arthritis: A single-center study

Author

Yukitaka Ueki, Natsumi Nagao, Yasuhiro Kamo, Hisamitsu Miyaaki, Toshihisa Matsuzaki, Tatsuki Ichikawa, Ikuko Tokimura, S. Tsuji, Naota Taura, Kazuhiko Nakao, Hidetoshi Oda, Kaoru Terada, Toshiyuki Aramaki, Katsumi Eguchi, Shinichi Iwatsu, Atsushi Kawakami, and Noboru Kinoshita

Subjects
Adult, Male, Hepatitis B virus, Single Center, medicine.disease_cause, Arthritis, Rheumatoid, 03 medical and health sciences, 0302 clinical medicine, Japan, Rheumatology, medicine, Humans, In patient, 030203 arthritis & rheumatology, Nucleoside analogue, business.industry, virus diseases, Middle Aged, Hepatitis B, medicine.disease, digestive system diseases, Rheumatoid arthritis, Practice Guidelines as Topic, Immunology, Female, Virus Activation, 030211 gastroenterology & hepatology, business, medicine.drug
Abstract

This study aimed to investigate the frequency of hepatitis B virus (HBV) reactivation in patients with rheumatoid arthritis (RA) and to verify the guidelines relating to HBV reactivation in Japan.We retrospectively investigated 1351 RA patients who were treated with antirheumatic drugs at our hospital.Fifty patients (3.7%; 50/1351) were determined to be HBV carriers and 360 patients (26.7%; 360/1351) had resolved infections. HBV reactivation occurred in six cases (1.7%: 6/360) with resolved infections, of whom, two cases (0.6%; 2/360) developed de novo HBV infections. Eleven of the patients who were HBV carriers received a nucleoside analogue (NA) prophylactically. In all of the cases, the HBV-DNA levels became undetectable and the patients' liver function normalized. Sixteen patients, who had lower titers of the HBV surface antigen and undetectable HBV-DNA levels, did not show HBV reactivation in the absence of NA therapy.The results from this study suggest that HBV reactivation might not be so frequent among RA patients, and that reliable indicators for prescribing a NA should be clarified for RA patients.

Published
2018
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22. Significance of hepatitis B virus core-related antigen and covalently closed circular DNA levels as markers of hepatitis B virus re-infection after liver transplantation

Author

Matsuzaki, Toshihisa, Tatsuki, Ichikawa, Otani, Masashi, Akiyama, Motohisa, Ozawa, Eisuke, Miuma, Satoshi, Miyaaki, Hisamitsu, Taura, Naota, Hayashi, Tomayoshi, Okudaira, Sadayuki, Takatsuki, Mitsuhisa, Isomoto, Hajime, Takeshima, Fuminao, Eguchi, Susumu, and Nakao, Kazuhiko

Published
2013
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23. Change in tartrate‑resistant acid phosphatase isoform 5b levels, a marker of bone metabolism, in patients with chronic hepatitis B treated with tenofovir alafenamide

Author

Shinobu Yamamichi, Tatsuki Ichikawa, Satoshi Miuma, Takuma Okamura, Kazuhiko Nakao, Yasuhide Motoyoshi, Osamu Miyazaki, Yusuke Nakano, Tetsurou Honda, Makiko Koike, Naota Taura, Mio Yamashima, Hisamitsu Miyaaki, Yasutaka Kuribayashi, Tomonari Ikeda, and Hiroyuki Yajima

Subjects
Oncogene, business.industry, General Neuroscience, Cell, Cancer, General Medicine, Articles, Cell cycle, medicine.disease, Molecular medicine, Tenofovir alafenamide, General Biochemistry, Genetics and Molecular Biology, medicine.anatomical_structure, Apoptosis, Cancer research, medicine, tartrate-resistant acid phosphatase isoform 5b, tenofovir alafenamide, General Pharmacology, Toxicology and Pharmaceutics, tartrate‑resistant acid phosphatase isoform 5b, business, bone mineral density, hepatitis B virus, Tartrate-resistant acid phosphatase
Abstract

Hepatitis B virus (HBV) infection is associated with the risk of osteoporosis and bone mineral density (BMD) loss. Tenofovir alafenamide (TAF) is associated with a slightly lower degree of BMD loss compared with tenofovir disoproxil, without loss of the excellent anti‑HBV effects. The aim of the present study was to verify the effect of bone metabolism in patients with HBV treated with TAF. A total of 87 patients were treated with TAF. Of these, 32 patients were treatment naïve, and 55 patients were treated with entecavir (ETV) for at least 1 year, after which ETV was switched to TAF. At the start of TAF and after 1 year, BMD in the lumbar and neck of the femur, tartrate‑resistant acid phosphatase isoform 5b (TRACP‑5b) levels as a marker of bone metabolism and serum inorganic phosphorus (P) were compared to estimate bone metabolism. Serum creatinine (Cr), cystatin C, urine protein and β2 microglobulin levels were evaluated to estimate kidney function. Treatment with TAF for 1 year decreased TRACP‑5b levels, particularly in patients with bone disease, except for a minimal significant change (MSC; decrease of 12.4%) in TRACP‑5b levels. The change in rate of TRACP‑5b levels were positively associated with changes in P, Cr‑estimated glomerular filtration rate and TRACP‑5b levels at the start of TAF. Logistic regression analysis showed that increased BMD in the lumbar region contributed to the switch from ETV to TAF. TAF induced a decrease in TRACP‑5b levels in patients with HBV. Bone disease was a contributing factor for MSC. Since TRACP‑5b can be used as a marker of bone metabolism and fractures, TAF may exhibit potential in preventing fractures in patients with HBV., Biomedical Reports, 16(1), art. no. 6; 2022

Published
2021

24. Hemodialysis Patient with Diffuse Liver Calcification After Septic Shock

Author

Hiroshi Mukae, Takashi Harada, Tatsuki Ichikawa, Kosei Yamaguchi, Kanako Hayashi, Kenji Sawase, Takahiro Takazono, Hideshi Tomura, Satoshi Funakoshi, Tayo Kawazu, Tomoya Nishino, and Mineaki Kitamura

Subjects
medicine.medical_specialty, medicine.medical_treatment, Gastroenterology, Calcification, Sepsis, Liver disease, Ectopic calcification, Calcification, Physiologic, Calcinosis, Renal Dialysis, Internal medicine, medicine, Humans, Renal Insufficiency, Physiologic, Aged, 80 and over, business.industry, Septic shock, Liver Diseases, General Medicine, Articles, medicine.disease, Shock, Septic, Shock (circulatory), Female, Hemodialysis, medicine.symptom, business
Abstract

BACKGROUND: Calcification in arteries is sometimes observed in patients undergoing hemodialysis; however, ectopic calcification in other organs is uncommon. In particular, diffuse liver calcification is very rare. We report a case of rapidly developing diffuse liver calcification in a patient undergoing hemodialysis. CASE REPORT: An 82-year-old woman started hemodialysis because of diabetic nephropathy, and her renal function worsened due to acute coronary syndrome. Percutaneous coronary intervention was conducted, and she was referred to our hospital. However, she subsequently contracted various infections, including a urinary tract infection and pneumonia. On day 43 of hospitalization, she developed septic shock and liver dysfunction due to catheter-induced infection. Although she did not have any medical history of liver disease, hypoperfusion of the liver resulted in liver dysfunction, and a computed tomography scan conducted 3 months later showed diffuse calcification in her liver. Despite recovering from septic shock, she ultimately died of multiple organ failure 21 months after admission to our hospital. CONCLUSIONS: Diffuse liver calcification is extremely rare; however, it can be observed in patients undergoing hemodialysis who experience liver hypoperfusion. The precise mechanisms underlying this disorder remain unknown, but a critically ill status and specific characteristics of hemodialysis patients may play important roles in liver calcification., American Journal of Case Reports, 22, art. no. e933386; 2021

Published
2021

25. Intrahepatic MicroRNA Profile of Liver Transplant Recipients with Hepatitis C Virus Co-Infected with Human Immunodeficiency Virus

Author

Tatsuki Ichikawa, Norihiro Kokudo, Masaaki Hidaka, Susumu Eguchi, Hisamitsu Miyaaki, Shinji Uemoto, Mitsuhisa Takatsuki, Akihiko Soyama, Yukihiro Inomata, Hideki Ohdan, and Kazuhiko Nakao

Subjects
Adult, 0301 basic medicine, Hepatitis, Viral, Human, Microarray, medicine.medical_treatment, Hepatitis C virus, HIV Infections, Liver transplantation, medicine.disease_cause, Hepatitis, End Stage Liver Disease, 03 medical and health sciences, 0302 clinical medicine, Immune system, Humans, Medicine, Viral, Original Paper, Transplantation, Coinfection, business.industry, Microarray analysis techniques, Gene Expression Profiling, virus diseases, General Medicine, Middle Aged, medicine.disease, Hepatitis C, Virology, Transplant Recipients, digestive system diseases, Liver Transplantation, Gene expression profiling, MicroRNAs, 030104 developmental biology, Liver, Liver cirrhosis, Hepatitis C antibodies, 030211 gastroenterology & hepatology, business, Human
Abstract

Background: In patients with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) co-infection, HIV can modulate HCV replication and immune response as well as accelerate liver fibrosis. The role of miRNA in HIV/HCV co-infection is not fully elucidated. The aim of this study was to examine the differential expression of miRNAs in the liver. Material/Methods: Thirteen patients who had undergone a liver transplant (7 HCV-infected and 6 HIV/HCV-co-infected patients) were examined using a miRNA array containing 1347 human miRNAs. To confirm the microarray results, data for 20 patients (10 HCV-infected and 10 HIV/HCV-co-infected) were validated using real-time polymerase chain reaction probing for miR101b, miR149, and miR200c. This miRNA was selected based on microarray results and its biological significance in liver fibrosis. Results: Microarray analysis revealed 22 miRNAs that were differentially expressed in the HIV/HCV-co-infected group compared to the HCV-infected group (p, Annals of Transplantation, 22, pp.701-706; 2017

Published
2017

26. Clarification of interspousal transmission of the hepatitis C virus (HCV) using genetic analysis of the HCV core and NS5A region

Author

Ayako Mine, Tatsuki Ichikawa, Junji Irie, Ryohei Uehara, Eriko Ikeda, Rikako Kinoshita, Satoshi Miuma, Yoichi Takahashi, Yasuhide Motoyoshi, Tetsuro Honda, and Hiroshi Akahoshi

Subjects
0301 basic medicine, Hcv core, Hepatology, Transmission (medicine), business.industry, Hepatitis C virus, medicine.disease_cause, Genetic analysis, Virology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine, 030211 gastroenterology & hepatology, NS5A, business
Published
2017
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27. Indices calculated by serum creatinine and cystatin C as predictors of liver damage, muscle strength and sarcopenia in liver disease

Author

Shinobu Yamamichi, Tatsuki Ichikawa, Naoyuki Hino, Ryousuke Hirata, Kazuhiko Nakao, Hisamitsu Miyaaki, Naota Taura, Hiroyuki Yajima, Yasuhide Motoyoshi, Youichi Takahashi, Satoshi Miuma, Makiko Koike, Ryouhei Uehara, Mio Yamashima, and Tetsurou Honda

Subjects
0301 basic medicine, medicine.medical_specialty, Urology, Renal function, Liver function, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Liver disease, Grip strength, chemistry.chemical_compound, 0302 clinical medicine, medicine, Estimated glomerular filtration rate, Cystatin C, General Pharmacology, Toxicology and Pharmaceutics, Creatinine, biology, Muscle strength, business.industry, General Neuroscience, Skeletal muscle, General Medicine, Articles, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, chemistry, 030220 oncology & carcinogenesis, Sarcopenia, biology.protein, business
Abstract

Serum creatinine (Cr)-based glomerular filtration rate (CrGFR) is overestimated in liver disease. The present study evaluated whether the difference in CrGFR and cystatin C (CysC) GFR (dGFR) is significant in liver disease. The Cr-to-CysC ratio and sarcopenia index (SI) have been reported to correlate with muscle volume. An estimated total body muscle mass with Cr, CysC and calculated body muscle mass (CBMM) has also been reported to correlate with muscle mass. The applicability of dGFR, SI and CBMM for liver disease were evaluated. A total of 313 patients with liver damage were evaluated for Child-Pugh score, albumin-bilirubin (ALBI) score, model for end-stage liver disease, fibrosis-4, Cr, CysC, Cr-based estimated GFR (CreGFR), CysCGFR and grip strength. Of the 313 patients, 199 were evaluated using cross-sectional computed tomography (CT) of the third lumbar vertebra to determine the skeletal muscle (SM) mass. dGFR, CBMM and SI were compared to liver damage, muscle strength and muscle mass. In the 313 patients, dGFR was correlated with age, ALBI and grip strength; CBMM was correlated with body mass index (BMI) and grip strength; and SI was correlated with BMI and grip strength. In patients evaluated with CT, the correlation coefficients for CBMM and SI with SM were 0.804 and 0.293, respectively. Thus, CBMM and SI were associated with sarcopenia. The relationship between dGFR and ALBI does not differ with different grades of CrGFR-based chronic kidney disease (CKD). dGFR is a marker of liver damage and muscle strength regardless of CKD. CBMM and SI are markers for sarcopenia in liver disease., Biomedical Reports, 12(3), pp.89-98; 2020

Published
2019

28. Deep sequence analysis of NS5A resistance-associated substitution changes in patients reinfected with the hepatitis C virus after liver transplantation

Author

Satoshi Miuma, Tatsuki Ichikawa, Hidetaka Shibata, Hisamitsu Miyaaki, Takayuki Wada, Shinobu Yamamichi, Taro Yamamoto, Naota Taura, Hiroshi Masumoto, Yasuko Kanda, and Kazuhiko Nakao

Subjects
Hepatology, Genotype, Sequence analysis, Hepatitis C virus, medicine.medical_treatment, Substitution (logic), Hepacivirus, Liver transplantation, Biology, Viral Nonstructural Proteins, medicine.disease_cause, Virology, Antiviral Agents, Hepatitis C, Liver Transplantation, Infectious Diseases, Amino Acid Substitution, Reinfection, Drug Resistance, Viral, medicine, Humans, In patient, NS5A, Sequence Analysis
Published
2019

29. Bacteroides in colonic mucosa-associated microbiota affects the development of minimal hepatic encephalopathy in patients with cirrhosis

Author

Tatsuki Ichikawa, Hiroshi Masumoto, Hisamitsu Miyaaki, Satoshi Miuma, Yasuko Kanda, Naota Taura, Kazuhiko Nakao, Masafumi Haraguchi, Masanori Fukushima, and Ryu Sasaki

Subjects
Liver Cirrhosis, Male, medicine.medical_specialty, Cirrhosis, Colon, Gut flora, Neuropsychological Tests, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Reaction Time, Medicine, Bacteroides, Humans, Risk factor, Intestinal Mucosa, Hepatic encephalopathy, Hepatology, medicine.diagnostic_test, biology, business.industry, Microbiota, food and beverages, Neuropsychological test, Middle Aged, biology.organism_classification, medicine.disease, Bacteroides Infections, 030220 oncology & carcinogenesis, Hepatic Encephalopathy, 030211 gastroenterology & hepatology, Female, Liver function, business, human activities
Abstract

Gut microbiota has been associated with liver cirrhosis and, possibly, hepatic encephalopathy. However, only a few studies have examined the link between mucosa-associated microbiota (MAM) and minimal hepatic encephalopathy (MHE). Our aim was to investigate this relationship. Twenty-four patients with cirrhosis underwent colon biopsies at our institution, between January 2014 and April 2015. Patterns of microbial colonization were examined using 16S rRNA gene sequences. MHE was diagnosed using the Neuropsychological Test. Ten (41.7%) of the 24 patients were diagnosed as having MHE. There was no significant difference in the diversity of gut microbiota by sampling locations between those with and without MHE. However, the diversity of the gut microbiota and the proportion of the genus Bacteroides decreased as a function of declining liver function. We divided patients into those with the highest proportion of the genus Bacteroides (Bacteroides-dominant group; n = 9) and into a Bacteroides non-dominant group (n = 15). In the Bacteroides-dominant group, only 1 patient (11.1%) was diagnosed as having MHE, with the incidence rate of MHE being significantly lower in the Bacteroides-dominant group than in the non-dominant group (p = 0.019). The Child–Pugh score (p = 0.05) and use of proton-pump inhibitors (p = 0.015) were negatively correlated to the proportion of Bacteroides. Furthermore, the proportion of the family Clostridiaceae was significantly higher in the Bacteroides-dominant group than in the non-dominant group (p = 0.078). The decrease in microbial diversity and genus Bacteroides in MAM is a risk factor for MHE in patients with liver cirrhosis.

Published
2019

30. Changes in serum LDL, PCSK9 and microRNA‑122 in patients with chronic HCV infection receiving Daclatasvir/Asunaprevir

Author

Hiroyuki Yajima, Kazuhiko Nakao, Seina Sasaki, Tatsuki Ichikawa, Hiroshi Akahoshi, Yasuhide Motoyoshi, Satoshi Miuma, Tetsurou Honda, Ryouhei Uehara, Hisaya Tanaka, Hisamitsu Miyaaki, Junpei Nakamura, Naoyuki Hino, Youichi Takahashi, Naota Taura, and Syouhei Narita

Subjects
0301 basic medicine, MicroRNA122, medicine.medical_specialty, Daclatasvir, Hepatitis C virus, Protein convertase subtilisin/kexin 9, medicine.disease_cause, Gastroenterology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, microRNA, medicine, Hepatitis Cvirus, General Pharmacology, Toxicology and Pharmaceutics, medicine.diagnostic_test, business.industry, General Neuroscience, PCSK9, Articles, General Medicine, 030104 developmental biology, chemistry, 030220 oncology & carcinogenesis, Low-density lipoprotein, Low?density lipoprotein, Asunaprevir, Direct acting anti?virals, Lipid profile, business, Lipoprotein, medicine.drug
Abstract

The present study evaluated the changes in lipid profile, and the associations between serum protein convertase subtilisin/kexin 9 (PCSK9),microRNA (miR)122 and low?density lipoprotein variation following treatment of hepatitis C virus (HCV) genotype 1b infection with Daclatasvir/Asunaprevir. A total of 39 patients with HCV genotype 1b infection with chronic hepatitis received a 24?week treatment regimen of Daclatasvir/Asunaprevir. Laboratory data were obtained for each subject every 4 weeks during treatment and every 12 weeks after treatment.Serum miR122 and PCSK9 were measured at the start of treatment (week 0), end of treatment (week 24), 4 weeks after the end of treatment (week 28),12 weeks after the end of treatment (week 36) and 28 weeks after the end of treatment (week 52). LDL was increased at week 4 after the start of treatment to week 52. The increased LDL/HDL ratio at week 52 compared with week 4 was also associated with relative miR122 at week 52 At week 4,PCSK9?active form (A) was lower than that at other time points, and PCSK9?inactive form (I) exhibited the greatest increase. At week 52,PCSK9?A was higher than that during treatment, but PCSK9?I level at week 52 did not markedly differ from that any time point except for week 4. Relative miR122 at week 4 was associated with increased PCSK9?A at weeks 36 and 52 from the start of DAA. In summary, treatment of HCV with Daclatasvir/Asunaprevir resulted in elevated LDL, and relative miR122 and PCSK9?A levels in serum appeared to have some association with LDL increase., Biomedical Reports, 10(3), pp.156-164; 2019

Published
2019
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31. POGLUT1, the putative effector gene driven by rs2293370 in primary biliary cholangitis susceptibility locus chromosome 3q13.33

Author

Takeaki Sato, Hironori Sakai, Tatsuki Ichikawa, Atsushi Naganuma, Atsushi Tanaka, Tatsuo Kanda, Hirotoshi Ebinuma, Masataka Seike, Hidetaka Shibata, Tatsuji Komatsu, Mikio Zeniya, Shinji Uemoto, Toshiki Nikami, Yoko Nakamura, Osamu Yokosuka, Yoshiyuki Ueno, Masaru Harada, Masao Nagasaki, Keisuke Ario, Yuki Hitomi, Haruhiro Yamashita, Yutaka Mano, Michio Senju, Makiko Taniai, Kazuhiko Yamauchi, Satoshi Yamagiwa, Makoto Nakamuta, Fujio Makita, Kazuhiro Sugi, Kouki Matsushita, Kiyoshi Migita, Masahiro Ito, Noriaki Naeshiro, Hajime Takikawa, Kaname Kojima, Noboru Hirashima, Norihiro Kokudo, Shinji Katsushima, Shinya Nagaoka, Hironao Takahashi, Kuniaki Arai, Kazumoto Murata, Etsuko Hashimoto, Masanori Abe, Tsutomu Yamashita, Naohiko Masaki, Minoru Nakamura, Hiroshi Kouno, Atsumasa Komori, Kiyoshi Furuta, Shinji Shimoda, Kaname Yoshizawa, Yoshihiko Maehara, Iwao Yabuuchi, Seigo Abiru, Shotaro Sakisaka, Rie Sugimoto, Hideo Nishimura, Takashi Himoto, Yasuaki Takeyama, Yosuke Kawai, Hiromasa Ohira, Satoru Joshita, Yusuke Shimada, Katsushi Tokunaga, Masahiro Kikuchi, Minae Kawashima, Masao Honda, Hiroshi Kamitsukasa, Toshiki Komeda, Yoshihiro Aiba, Eiji Mita, Hajime Ohta, Nao Nishida, Kazuhiko Nakao, Hiroshi Yatsuhashi, Takeji Umemura, Masaharu Koda, Seiji Tsunematsu, Hirotaka Kouno, Teruko Arinaga-Hino, Kazuko Ueno, Masaaki Shimada, Hitomi Nakamura, Shuichi Kaneko, and Akinobu Takaki

Subjects
0301 basic medicine, Adult, Male, In silico, lcsh:Medicine, Genome-wide association study, Locus (genetics), Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, Pathogenesis, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Japan, SNP, Humans, lcsh:Science, Gene, Aged, Genetics, Aged, 80 and over, Multidisciplinary, Effector, Liver Cirrhosis, Biliary, lcsh:R, Middle Aged, 030104 developmental biology, Glucosyltransferases, lcsh:Q, Female, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Article, Scientific reports.9 :102(2019)

Published
2019

32. How mass disorder affects heat conduction in ternary amorphous alloys

Author

Makoto Kashiwagi, Takuma Shiga, Emi Minamitani, Tatsuki Ichikawa, and Yuzo Shigesato

Subjects
010302 applied physics, Amorphous silicon, Amorphous metal, Materials science, Condensed matter physics, Silicon, Physics, QC1-999, technology, industry, and agriculture, General Physics and Astronomy, chemistry.chemical_element, 02 engineering and technology, 021001 nanoscience & nanotechnology, Thermal conduction, equipment and supplies, 01 natural sciences, Amorphous solid, Delocalized electron, chemistry.chemical_compound, Thermal conductivity, chemistry, 0103 physical sciences, 0210 nano-technology, Ternary operation
Abstract

Thermal management is critical in devices that use amorphous semiconductors. Recent studies have revealed how size and mass disorder affect heat conduction, but the effects of more-extreme mass and lattice disorder are also relevant. Here, we report modal analysis of simulated samples of amorphous silicon alloyed with atoms of different-mass silicon to yield a ternary amorphous material. Although we expected the material with high degrees of mass disorder to show dramatic changes in thermal conductivity as the composition of the material changed, the thermal conductivity instead changed monotonically. Thus, we find that no peculiar thermal transport properties appear in ternary amorphous alloys with high degrees of mass disorder. Furthermore, we find that while delocalized propagating modes (propagons) explain nearly 30% of the overall thermal conductivity independent of the composition, the contribution of delocalized non-propagating modes (diffusons) is sensitive to the composition and tends to be the dominant mechanism behind heat conduction in ternary amorphous alloys.

Published
2021

33. Hemodialysis Patient with Diffuse Liver Calcification After Septic Shock.

Author

Kanako Hayashi, Mineaki Kitamura, Hideshi Tomura, Kosei Yamaguchi, Tayo Kawazu, Kenji Sawase, Takashi Harada, Tatsuki Ichikawa, Takahiro Takazono, Satoshi Funakoshi, Hiroshi Mukae, and Tomoya Nishino

Subjects
SEPTIC shock, HEMODIALYSIS patients, DIABETIC nephropathies, COMPUTED tomography, CALCIFICATION, ARTERIAL calcification, URINARY tract infections
Abstract

Objective: Rare coexistence of disease or pathology Background: Calcification in arteries is sometimes observed in patients undergoing hemodialysis; however, ectopic calcification in other organs is uncommon. In particular, diffuse liver calcification is very rare. We report a case of rapidly developing diffuse liver calcification in a patient undergoing hemodialysis. Case Report: An 82-year-old woman started hemodialysis because of diabetic nephropathy, and her renal function worsened due to acute coronary syndrome. Percutaneous coronary intervention was conducted, and she was referred to our hospital. However, she subsequently contracted various infections, including a urinary tract infection and pneumonia. On day 43 of hospitalization, she developed septic shock and liver dysfunction due to catheter-induced infection. Although she did not have any medical history of liver disease, hypoperfusion of the liver resulted in liver dysfunction, and a computed tomography scan conducted 3 months later showed diffuse calcification in her liver. Despite recovering from septic shock, she ultimately died of multiple organ failure 21 months after admission to our hospital. Conclusions: Diffuse liver calcification is extremely rare; however, it can be observed in patients undergoing hemodialysis who experience liver hypoperfusion. The precise mechanisms underlying this disorder remain unknown, but a critically ill status and specific characteristics of hemodialysis patients may play important roles in liver calcification. [ABSTRACT FROM AUTHOR]

Published
2021
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34. Prevalence of Restless Legs Syndrome in Patients with Inflammatory Bowel Disease

Author

Naota Taura, Tatsuki Ichikawa, Hidetaka Shibata, Fuminao Takeshima, Satoshi Miuma, Yuko Akazawa, Ikuko Takahara, Toshihisa Matsuzaki, Kazuhiko Nakao, and Hisamitsu Miyaaki

Subjects
Adult, Male, Sleep Wake Disorders, medicine.medical_specialty, Physiology, Statistics as Topic, Population, Gastroenterology, Inflammatory bowel disease, Pittsburgh Sleep Quality Index, 03 medical and health sciences, Sex Factors, 0302 clinical medicine, Crohn Disease, Japan, Quality of life, Restless Legs Syndrome, Internal medicine, mental disorders, Prevalence, medicine, Humans, Restless legs syndrome, education, Sleep disorder, Crohn's disease, education.field_of_study, business.industry, Middle Aged, medicine.disease, Ulcerative colitis, C-Reactive Protein, Quality of Life, Colitis, Ulcerative, Female, 030211 gastroenterology & hepatology, business, 030217 neurology & neurosurgery
Abstract

There has been increased interest in sleep disorders in patients with inflammatory bowel disease (IBD). Studies in North America and Europe reported that the prevalence of restless legs syndrome (RLS) is much higher in patients with Crohn’s disease (CD) than in the general population. The aim of this study was to reveal the prevalence and clinical features of RLS in Japanese patients with IBD and investigate the influence of RLS on sleep quality and quality of life (QOL). The study included 80 outpatients with IBD who visited Nagasaki University Hospital between December 2012 and July 2014. All patients completed the international RLS study group rating scale, a validated measure of the presence of RLS. Sleep quality was assessed using the Japanese version of the Pittsburgh Sleep Quality Index (PSQI), and health-related QOL was assessed using the Japanese version of the 36-item short form healthy profile (SF-36) version 2. The prevalence of RLS in patients with IBD was 20%, including rates of 21.7% in patients with ulcerative colitis (UC) and 17.6% in patients with CD. Among patients with CD, the proportion of women and serum level of CRP were higher in the RLS group than in the non-RLS group. Among those with UC, there were no differences in clinical characteristics between the RLS and non-RLS groups. Patients in the RLS group slept significantly less well than those in the non-RLS group (PSQI > 5; 62.5 vs. 34.4%, P

Published
2016
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35. Elevated Fasting Plasma Glucose before Liver Transplantation is Associated with Lower Post-Transplant Survival

Author

Tatsuki Ichikawa, Emi Katsura, Hisamitsu Miyaaki, Fuminao Takeshima, Hidetaka Shibata, Takuya Honda, Akihiko Soyama, Susumu Eguchi, Naota Taura, Satoshi Miuma, Masaaki Hidaka, and Kazuhiko Nakao

Subjects
Liver Cirrhosis, Adult, Blood Glucose, Male, medicine.medical_specialty, Cirrhosis, medicine.medical_treatment, Liver transplantation, Gastroenterology, Impaired glucose tolerance, Diabetes Complications, 03 medical and health sciences, 0302 clinical medicine, Clinical Research, Risk Factors, Diabetes mellitus, Internal medicine, medicine, Diabetes Mellitus, Humans, Aged, Univariate analysis, business.industry, Microangiopathy, Graft Survival, General Medicine, Fasting, Glucose Tolerance Test, Middle Aged, medicine.disease, Prognosis, Liver Transplantation, Transplantation, Postprandial, Treatment Outcome, Diabetes Mellitus, Type 2, 030220 oncology & carcinogenesis, Hyperglycemia, 030211 gastroenterology & hepatology, Female, business, Biomarkers
Abstract

BACKGROUND The risk of liver cirrhosis is higher among individuals with diabetes mellitus, and a cirrhotic patient with diabetes may have a poorer prognosis after liver transplantation compared to a patient without diabetes. Thus, we evaluated whether fasting plasma glucose prior to receiving a liver transplant was a prognostic factor for post-transplant survival. MATERIAL AND METHODS Ninety-one patients received a living donor liver transplant between November 2005 and December 2012. Patients were considered diabetic if they were prescribed diabetes medications or had impaired glucose tolerance as measured by an oral glucose tolerance test. Each patient was monitored through December 31, 2013, to evaluate prognosis. RESULTS Fasting plasma glucose of at least 100 mg/dL significantly decreased survival following transplant (52% in the high FPG group compared to 78% in the control group, p=0.04), while postprandial hyperglycemia had no effect on survival. Additionally, overall mortality and the incidence of vascular disease were significantly higher among patients with uncontrolled plasma glucose. Impaired fasting plasma glucose was significantly and inversely associated with overall survival in the univariate and multivariate analyses, while creatinine (at least 1 mg/dL) was inversely associated with survival in the univariate analysis. CONCLUSIONS Elevated fasting plasma glucose prior to liver transplantation was inversely associated with post-transplant survival. This effect may be due to underlying microangiopathy as a result of uncontrolled diabetes before transplantation. Our data demonstrated the importance of controlled blood glucose prior to liver transplantation.

Published
2016

36. β-cell function prior to liver transplantation contributes to post-operative diabetes

Author

Kazuhiko Nakao, Tatsuki Ichikawa, Hidetaka Shibata, Mitsuhisa Takatsuki, Akihiko Soyama, Susumu Eguchi, Takuya Honda, Naota Taura, Masaaki Hidaka, Satoshi Miuma, and Hisamitsu Miyaaki

Subjects
medicine.medical_specialty, Cirrhosis, General Neuroscience, Incidence (epidemiology), medicine.medical_treatment, Cancer, Articles, General Medicine, 030230 surgery, Biology, Liver transplantation, medicine.disease, Gastroenterology, Molecular medicine, General Biochemistry, Genetics and Molecular Biology, Impaired glucose tolerance, Transplantation, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Diabetes mellitus, Immunology, medicine, 030211 gastroenterology & hepatology, General Pharmacology, Toxicology and Pharmaceutics
Abstract

Liver cirrhosis and diabetes mellitus (DM) are closely associated. The present study aimed to determine whether liver transplantation (LT) may prevent/cure DM in patients with cirrhosis and whether the degree of glucose tolerance prior to transplantation is associated with the onset of DM after transplantation. Seventy-three patients who received a living donor LT at Nagasaki University Hospital (Nagasaki, Japan) between November 2005 and December 2012 were recruited. Among them, patients were considered diabetic if they had been prescribed diabetes medications or had impaired glucose tolerance, as evidenced by an oral glucose tolerance test (OGTT). Patients were followed up until December 31, 2013 to evaluate glucose tolerance. Patients who had developed DM 2 years after transplantation were found to be older and the incidence of diabetes prior to transplantation (n=73) was higher than in those who did not. Multivariate analysis revealed that DM requiring treatment prior to transplantation was the only independent factor for DM developed at 2 years after transplantation. OGTT results showed that in patients with poor insulin sensitivity indices prior to transplantation (n=45), improvements were seen at 2 years after transplantation, while β-cell function and insulinogenic index had decreased, which may have been the cause of DM after transplantation. In conclusion, the pre-operative β-cell function determined by an OGTT may be a useful predictive tool for the recurrence of DM after LT.

Published
2016
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37. Geranylgeranylacetone attenuates fibrogenic activity and induces apoptosis in cultured human hepatic stellate cells and reduces liver fibrosis in carbon tetrachloride-treated mice

Author

Ryu Sasaki, Tatsuki Ichikawa, Hisamitsu Miyaaki, Satoshi Miuma, Naota Taura, Takemasa Senoo, Kazuhiko Nakao, and Yuko Akazawa

Subjects
Male, 0301 basic medicine, Liver fibrosis, Cell, Cell Count, Apoptosis, CCL4, Endoplasmic Reticulum, Liver Cirrhosis, Experimental, Cell Line, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Hepatic stellate cells, Animals, Humans, Medicine, lcsh:RC799-869, Protein kinase A, Carbon Tetrachloride, Sirius Red, Protein kinase B, business.industry, Gastroenterology, Hep G2 Cells, General Medicine, Molecular biology, Hsp70, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, chemistry, 030220 oncology & carcinogenesis, Geranylgeranylacetone, Hepatic stellate cell, lcsh:Diseases of the digestive system. Gastroenterology, Diterpenes, business, Transcription Factor CHOP, Research Article
Abstract

Background: Geranylgeranylacetone (GGA), an anti-ulcer drug widely used in Japan, has attracted interest because of its various therapeutic effects. Therefore, we investigated the effects of GGA on human hepatic stellate cells (HSCs) in vitro and in a mouse model of liver fibrosis. Methods: LX2, an immortalized human HSC line, was cultured and treated with GGA at concentrations up to 0.5 mM. After GGA treatment, changes in cellular morphology, apoptosis, and fibrosis-related gene expression were assessed. Male C57BL/6 J mouse model of carbon tetrachloride (CCl4)-induced liver fibrosis was treated with GGA. Liver fibrosis was evaluated using Sirius red staining and immunohistochemistry for α-smooth muscle actin (SMA). Results: GGA decreased the density of LX2 and primary human hepatic stellate cells but not that of HepG2 cells (a human hepatoma cell line), which was employed as control. In addition, GGA decreased the expression of fibrogenic genes and increased that of C/EBP homologous protein (CHOP). It also induced endoplasmic reticulum (ER) stress and increased apoptosis. CHOP knockdown, however, failed to suppress the GGA-induced decrease in LX2 cell density, suggesting the involvement of additional molecules in ER stress-associated apoptosis. Expression of death receptor 5, mitogen-activated protein kinase, heat shock protein 70, and Akt, all of which affect the activity of stellate cells, was unchanged in relation to LX2 cell fibrogenic activity. In the mouse model of liver fibrosis, GGA decreased the extent of Sirius red staining and SMA expression. Conclusions: GGA attenuated fibrogenic activity and induced apoptosis in cultured human HSCs, and suppressed liver fibrosis in mice, suggesting its potential as an agent for treating liver fibrosis., BMC Gastroenterology, 18, 34; 2018

Published
2018
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38. Clinical Characteristics of Patients with Gastroesophageal Reflux Disease Refractory to Proton Pump Inhibitors and the Effects of Switching to 20 mg Esomeprazole on Reflux Symptoms and Quality of Life

Author

Naota Taura, Ken Ohnita, Tatsuki Ichikawa, Kayoko Matsushima, Kazuhiko Nakao, Naoyuki Yamaguchi, Fuminao Takeshima, Yuko Akazawa, Keiichi Hashiguchi, Hajime Isomoto, Ken Shiozawa, Hitomi Minami, Ken Tanigawa, and Yasunori Onitsuka

Subjects
Adult, Male, Abdominal pain, medicine.medical_specialty, medicine.drug_class, Proton-pump inhibitor, Severity of Illness Index, Gastroenterology, Esomeprazole, Refractory, Quality of life, Clinical Research, Surveys and Questionnaires, Internal medicine, medicine, Humans, Prospective Studies, Aged, Aged, 80 and over, business.industry, Heartburn, Proton Pump Inhibitors, General Medicine, Middle Aged, medicine.disease, Indigestion, digestive system diseases, humanities, Treatment Outcome, Gastroesophageal Reflux, Quality of Life, GERD, Female, medicine.symptom, business, medicine.drug
Abstract

Background: Refractory gastroesophageal reflux disease (GERD) may deteriorate patient quality of life (QOL) despite proton pump inhibitor (PPI) therapy. Material/Methods: Nineteen Japanese institutions were surveyed to determine the clinical characteristics and QOL of patients with refractory GERD. Those patients treated with a conventional PPI were switched to 20 mg esomeprazole for 4 weeks. Symptoms and QOL were assessed using Global Overall Symptom and Gastrointestinal Symptom Rating Scale (GSRS) questionnaires at baseline and at 2 and/or 4 weeks of esomeprazole treatment. Results: Of 120 patients who completed the survey, 58 (48.3%) had refractory GERD. Of these, 69.0% were aged >65 years, 79.3% were prescribed a PPI at a standard or high dose, and 22.4% were prescribed a PPI together with another drug. After switching to esomeprazole, patients reported significant improvements in heartburn, acid regurgitation, and excessive belching at 2 weeks using a symptom diary, as well as the total score, reflux, ab dominal pain, and indigestion, which were assessed using the GSRS at 4 weeks. Conclusions: About half of Japanese patients with GERD may be refractory to conventional PPIs. Their reflux-related symp toms are often severe and may impair QOL. Switching to esomeprazole could be used to improve their symptoms and QOL., Medical Science Monitor, 21, pp.4111-4121; 2015

Published
2015
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39. Impact of Donor and Recipient Single Nucleotide Polymorphisms in Living Liver Donor Transplantation for Hepatitis C

Author

Tatsuki Ichikawa, Hisamitsu Miyaaki, Naota Taura, Takuya Honda, M. Takatsuki, Hidetaka Shibata, Masaaki Hidaka, A. Soyama, Susumu Eguchi, Kazuhiko Nakao, and Satoshi Miuma

Subjects
Liver Cirrhosis, Male, medicine.medical_specialty, Genotype, Hepatitis C virus, medicine.medical_treatment, Hepacivirus, Single-nucleotide polymorphism, Liver transplantation, medicine.disease_cause, Polymorphism, Single Nucleotide, Gastroenterology, Cohort Studies, Fibrosis, Internal medicine, Living Donors, Humans, Medicine, Transplantation, biology, business.industry, Donor selection, Patient Selection, Membrane Proteins, Lipase, Hepatitis C, Middle Aged, medicine.disease, biology.organism_classification, Liver Transplantation, Immunology, Disease Progression, Female, Surgery, business
Abstract

Recently, several studies have shown that specific single nucleotide polymorphisms (SNPs) affect liver fibrosis progression in patients with hepatitis C virus (HCV) infection. In this study, we examined the impact of donor and recipient SNPs on the progression of fibrosis after liver transplantation for HCV infection.This cohort study enrolled 43 patients with HCV infection who underwent liver transplantation at our hospital. We evaluated 5 genotypes (rs4374383, rs2629751, rs9380516, rs8099917, and rs738409) that have been reported to be significant predictors of fibrosis in HCV infection using a Taqman assay.Liver fibrosis (stage ≥ F1, New Inuyama classification) was detected at 1 year after liver transplantation in 30 cases (70%). The rs2629751 non-AA-genotype was found to be significantly associated with fibrosis progression at 1 year after liver transplantation (AA:GG or GA = 46%:88%, P.05). The primary outcome was stage ≥F2 (portoportal septa) or liver-related mortality in 22 patients. The time to stage ≥F2 fibrosis or liver-related mortality was significantly different only in terms of the donor rs2629751 genotype (AA:GG or GA = 5.5 ± 0.6 years:3.6 ± 0.7 years, P = .025).The rs2629751 genotype may be an important predictor of posttransplant outcome in HCV-infected patients. This result might be useful in donor selection for liver transplantation in HCV-infected patients and may guide therapeutic decisions regarding early antiviral treatment.

Published
2015
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40. A case of liver cirrhosis type C complicated with acute onset idiopathic thrombocytopenic purpura which was possible to undergo living donor liver transplantation by multidisciplinary therapy

Author

Naota Taura, Junichi Tokumitsu, Tatsuki Ichikawa, Kazuhiko Nakao, Hidetaka Shibata, Hisamitsu Miyaaki, Susumu Eguchi, Masafumi Haraguchi, Masaaki Hidaka, Mitsuhisa Takatsuki, and Satoshi Miuma

Subjects
medicine.medical_specialty, Acute onset, Cirrhosis, Hepatology, business.industry, medicine, Living donor liver transplantation, business, medicine.disease, Thrombocytopenic purpura, Surgery
Published
2015
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41. Hepatitis C virus‐related symptoms, but not quality of life, were improved by treatment with direct‐acting antivirals

Author

Tatsuki Ichikawa, Satomi Nakamura, Youichi Takahashi, Naota Taura, Seina Sasaki, Syouhei Narita, Ryouhei Uehara, Tetsurou Honda, Yasuhide Motoyoshi, Hiroyuki Yajima, Hisamitsu Miyaaki, Naoyuki Hino, Satoshi Miuma, Hiroshi Akahoshi, Junpei Nakamura, Hisaya Tanaka, and Kazuhiko Nakao

Subjects
Ledipasvir, medicine.medical_specialty, Daclatasvir, Hepatology, Sofosbuvir, business.industry, Epworth Sleepiness Scale, Ribavirin, humanities, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Infectious Diseases, chemistry, Quality of life, 030220 oncology & carcinogenesis, Internal medicine, Physical therapy, Medicine, Asunaprevir, 030211 gastroenterology & hepatology, business, Adverse effect, medicine.drug
Abstract

AIM Direct-acting antivirals (DAAs) for the treatment of hepatitis C virus (HCV) infection have a significantly high sustained virologic response rate after a short treatment course and do not have any severe adverse effects. Patient-reported outcomes (PROs) have become increasingly important to assess the total impact of a chronic disease. We aimed to evaluate the changes in symptoms of patients with HCV infection treated with DAAs by using PROs. METHODS A total of 107 patients with chronic HCV infection were treated with DAAs. Daclatasvir/asunaprevir or sofosbuvir/ledipasvir was used for HCV 1B infection, and sofosbuvir/ribavirin for HCV 2A/2B infection. The PROs measured at the start of treatment and 1 year after the start of treatment were cirrhosis-related symptom score (CSS), presence of restless legs syndrome (RLS), Epworth sleepiness scale (ESS), Pittsburg sleep quality index (PSQI), Kessler 6 score (K-6), and the SF-36 to measure quality of life (QOL). All patients had a sustained virologic response rate of 24. RESULTS The CSS, PSQI, K-6, and RLS scores were improved 1 year after beginning treatment. However, QOL had not recovered. Changes in total CSS were correlated with HCV genotype, sex, hypertensive drug use, serum low-density lipoprotein, and ESS at the start of treatment and RLS 1 year after the start of treatment. The factors that contributed to worsening of CSS were HCV genotype 2B and RLS 1 year after the start of treatment. CONCLUSION Treatment with DAAs eliminated HCV-RNA and improved most symptoms, but QOL did not recover.

Published
2017
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42. Incidence of and risk factors for bile duct stones after living donor liver transplantation: An analysis of 100 patients

Author

Tatsuki Ichikawa, Hidetaka Shibata, Takemasa Senoo, Satoshi Miuma, Naota Taura, Kazuhiko Nakao, Akihiko Soyama, Masaaki Hidaka, Susumu Eguchi, Hisamitsu Miyaaki, Mitsuhisa Takatsuki, and Takuya Honda

Subjects
medicine.medical_specialty, Univariate analysis, Hepatology, business.industry, Bile duct, Medical record, Incidence (epidemiology), medicine.medical_treatment, Odds ratio, Liver transplantation, medicine.disease, Gastroenterology, Surgery, Sepsis, Infectious Diseases, medicine.anatomical_structure, Internal medicine, Medicine, business, Complication
Abstract

Aim Although bile duct stone (BDS) is one of the biliary complications of liver transplantation, analytical studies, particularly on living donor liver transplantation (LDLT) cases, are rare. This study aimed to clarify the incidence of and risk factors for BDS following LDLT. Methods We retrospectively reviewed the medical records of 100 patients who underwent LDLT at our institute from August 2000 to May 2012, and analyzed their clinical characteristics and risk factors for BDS. Results Of these, 10 patients (10.0%) developed BDS during the observation period. The median follow-up period to BDS diagnosis was 45.5 months (range, 5–84) after LDLT. Univariate analysis revealed male sex, right lobe graft and bile duct strictures as factors that significantly correlated with BDS formation. Multivariate analysis revealed bile duct strictures (odds ratio, 7.17; P = 0.011) and right lobe graft (odds ratio, 10.20; P = 0.040) to be independent risk factors for BDS formation. One patient with BDS and biliary strictures succumbed to sepsis from cholangitis. Conclusion In the present study, right lobe graft and bile duct strictures are independent risk factors for BDS formation after LDLT. More careful observation and monitoring are required in the patients with high-risk factors.

Published
2014
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43. Significance of miRNA-122 in chronic hepatitis C patients with serotype 1 on interferon therapy

Author

Shinjirou Uchida, Tatsuki Ichikawa, Naota Taura, Hidetaka Shibata, Fuminao Takeshima, Tohei Yamaguchi, Takuya Honda, Hajime Isomoto, Kazuhiko Nakao, Yasuhiro Kamo, and Hisamitsu Miyaaki

Subjects
Hepatology, medicine.diagnostic_test, Combination therapy, business.industry, Ribavirin, Single-nucleotide polymorphism, Virus, chemistry.chemical_compound, Infectious Diseases, chemistry, Interferon, Liver biopsy, Immunology, microRNA, Medicine, SNP, business, medicine.drug
Abstract

Aim Peginterferon (PEG IFN) and ribavirin combination therapy is a curative treatment for chronic hepatitis C virus (HCV) infection, and virological response to IFN therapy has been strongly associated with genetic variation in IL28B single nucleotide polymorphisms (SNP). Recently, miRNA122 (miR-122), which is the most abundant miRNA in the liver, has been reported to be important for the replication of HCV RNA. Therefore, we investigated the correlation of miR-122 expression with virological response to IFN and other clinical data. Methods A total of 51 patients with HCV infection who were treated with IFN therapy at Nagasaki University Hospital from 2006 to 2011 were included in this study. We investigated the correlation of miR-122 expression in liver biopsy specimens with virological response to IFN therapy and other predictors of response, including IL28 SNP. Results miR-122 expression did not correlate with IL28 SNP. However, a significant difference was observed in miR-122 expression between patients who showed a sustained virological response (SVR) and those who did not (P

Published
2014
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44. Antitumor function of microRNA-122 against hepatocellular carcinoma

Author

Kazuhiko Nakao, Hisamitsu Miyaaki, and Tatsuki Ichikawa

Subjects
Gene isoform, Regulation of gene expression, Carcinoma, Hepatocellular, medicine.drug_class, Liver Neoplasms, Histone deacetylase inhibitor, Gastroenterology, Down-Regulation, Gene Expression, Biology, PKM2, Gene Expression Regulation, Neoplastic, Mice, MicroRNAs, Hepatocyte nuclear factors, Cell Transformation, Neoplastic, Gene expression, Serum response factor, medicine, Cancer research, Animals, Humans, Transcription factor
Abstract

MicroRNA-122 (miR-122), a highly abundant and liver-specific miRNA, acts as a tumor suppressor against hepatocellular carcinoma (HCC). Decreased expression of miR-122 in HCC is frequently observed and is associated with poor differentiation, larger tumor size, metastasis and invasion, and poor prognosis. Mutant mice with knockout (KO) of the miR-122 locus developed steatohepatitis due to increased triglyceride (TG) synthesis and decreased TG secretion from hepatocytes, and eventually developed HCC. Exogenic miR-122 introduction into miR-122 KO mice inhibited the development of HCC. Target genes of miR-122, including cyclin G1, a disintegrin and metalloprotease (ADAM)10, serum response factor, insulin-like growth factor-1 receptor, ADAM17, transcription factor CUTL1, the embryonic isoform of pyruvate kinase (Pkm2), Wnt1, pituitary tumor-transforming gene 1 binding factor, Cut-like homeobox 1, and c-myc, are involved in hepatocarcinogenesis, epithelial mesenchymal transition, and angiogenesis. MiR-122 expression is regulated by liver-enriched transcription factors such as hepatocyte nuclear factor (HNF)1α, HNF3β, HNF4α, HNF6, and CCAAT/enhancer-binding protein (C/EBP)α. A positive feedback loop exists between C/EBPα and miR-122 and between HNF6 and miR-122, whereas a negative feedback loop exists between c-myc and miR-122. Since cotreatment of 5-Aza-Cd and histone deacetylase inhibitor restored miR-122 expression in HCC cells, epigenetic modulation of miR-122 expression is involved in the suppression of miR-122 in HCC. Several experiments suggest that increasing miR-122 levels in HCC with or without antitumor agents may be a promising strategy for HCC treatment.

Published
2014
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45. Estimation of Visceral Fat and Fatty Liver Disease Using Ultrasound in Patients with Diabetes

Author

Shigeru Kohno, Tatsuki Ichikawa, Fuminao Takeshima, Yasunori Onitsuka, and Kazuhiko Nakao

Subjects
Male, medicine.medical_specialty, Intra-Abdominal Fat, Biguanides, Type 2 diabetes, Gastroenterology, Body Mass Index, Japan, Fatty liver disease, Non-alcoholic Fatty Liver Disease, Diabetes mellitus, Internal medicine, Prevalence, Internal Medicine, medicine, Humans, Obesity, Aged, Ultrasonography, Metabolic Syndrome, Preperitoneal fat thickness, business.industry, Fatty liver, General Medicine, medicine.disease, Logistic Models, Endocrinology, Diabetes Mellitus, Type 2, Diet, Western, Body Composition, Thiazolidines, Female, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Waist Circumference, Steatohepatitis, Metabolic syndrome, business, Body mass index
Abstract

Objective Fatty liver disease is the most commonly encountered form of chronic liver dysfunction in routine medical care and is closely associated with type 2 diabetes. We aimed to elucidate how the use of new medications affects the incidence of fatty liver disease and amount of visceral fat, both of which are associated with diabetes. Methods Abdominal ultrasonography was performed to assess the preperitoneal fat thickness (PFT) and presence of fatty liver. The PFT, body mass index (BMI) and waist circumference were used to investigate the rate and development of fatty liver disease in each group. A multivariate analysis with multiple logistic regression was performed using the PFT and presence of fatty liver disease as dependent variables. Patients We evaluated 202 patients treated at the Onitsuka Clinic. The subjects were divided into three subgroups (non-diabetic and diabetic with or without treatment with antidiabetic medications). Results Positive correlations between the PFT, BMI, and waist circumference were observed. No increases in the prevalence of fatty liver disease were observed in the medicated diabetic group, even when the PFT levels were high. A multivariate analysis with multiple logistic regression revealed that visceral fat accumulation was inhibited in women and those taking statins or thiazolidines and aggravated in men and those with obesity or an increased waist circumference. Obesity was an aggravating factor for fatty liver disease, and biguanides were useful as counteractants. Conclusion Measuring the PFT is effective for screening metabolic syndrome and evaluating diabetes, dyslipidemia and hypertension associated with fatty liver disease. Clinically, fatty liver progression to non-alcoholic steatohepatitis (NASH) may be prevented by tackling obesity and administering appropriate medications., Internal Medicine, 53(6), pp.545-553; 2014

Published
2014
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46. The linkage between medical student readiness for interprofessional learning and interest in community medicine.

Author

Yusuke Matsuzaka, Yuko Hamaguchi, Ayako Nishino, Kumiko Muta, Ikuko Sagara, Hiroyuki Ishii, Ikue Noguchi, Sayaka Kuba, Yuji Shiotani, Takashi Mine, Tatsuki Ichikawa, Hiroki Ozawa, Toru Yasutake, Lefor, Alan Kawarai, Sumihisa Honda, Takahiro Maeda, and Yasuhiro Nagata

Abstract

Objectives: The purpose of this study is to investigate the relationship between medical student readiness for interprofessional learning and interest in community medicine prior to incorporating community-oriented interprofessional education into the curriculum. Methods: A questionnaire was administered to students at Nagasaki University School of Medicine in Japan during each of three consecutive years (N=2244). The Readiness for Interprofessional Learning Scale (RIPLS) was administered in addition to a questionnaire to evaluate interest in community medicine. The Kruskal-Wallis and Steel-Dwass tests were used to determine differences between school years. Correlation between the RIPLS score and interest in community medicine was evaluated with Spearman's rank correlation coefficient. Relationships between RIPLS score and demographic parameters, and interest in community medicine were evaluated with multiple linear regression analysis. Results: Eighty-four percent (1891/2244) of students responded. The RIPLS score was highest in school year 1, followed by year 6, year 5, year 3, and years 4 and 2. Interest in community medicine correlated with the RIPLS score (rs = 0.332, p < 0.001), but less in year 1 (rs = 0.125, p = 0.002) than in other years. RIPLS score was significantly associated with gender, age, school year, interest in community medicine, but not the year that the survey was conducted. Conclusions: Community-oriented interprofessional education has the potential to improve attitudes towards interprofessional learning. When introducing this promising education into the curriculum from year 1, attracting students' interest in community medicine should be considered. [ABSTRACT FROM AUTHOR]

Published
2020
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47. Characteristics of gastrointestinal symptoms and function following endoscopic submucosal dissection and treatment of the gastrointestinal symptoms using rikkunshito

Author

Tatsuki Ichikawa, Kazuhiko Nakao, Hajime Isomoto, Ryohei Uehara, Saburo Shikuwa, Naoyuki Yamaguchi, Fuminao Takeshima, Hitomi Minami, and Ken Ohnita

Subjects
Cancer Research, medicine.medical_specialty, Abdominal pain, Constipation, Gastric emptying, business.industry, medicine.drug_class, Incidence (epidemiology), Healthy subjects, Proton-pump inhibitor, General Medicine, Endoscopic submucosal dissection, Articles, Gastroenterology, Indigestion, Immunology and Microbiology (miscellaneous), Rikkunshito, Internal medicine, Medicine, medicine.symptom, business, Gastric cancer
Abstract

The aim of the present study was to investigate the gastrointestinal (GI) symptoms and gastric emptying following endoscopic submucosal dissection (ESD), as well as to evaluate a novel treatment strategy using rikkunshito, a traditional Japanese herbal medicine. GI symptoms and gastric emptying were evaluated 6-8 days after ESD as part of the Step I study. In the Step 1 study, the Gastrointestinal Symptom Rating Scale (GSRS) scores of the two groups after 4 and 8 weeks of treatment with either a proton pump inhibitor (PPI; PPI monotreatment group, n=5) or a PPI plus rikkunshito (PPI + rikkunshito group, n=8) were compared against baseline values. Abdominal pain and constipation occurred in the majority of patients after ESD. The mean T-max 6-8 days after gastric emptying was 75.4±13.6 min, which was significantly longer compared with that reported in healthy subjects (43.9±10.3 min). In the Step 2 study, the total GSRS score was significantly improved only in the PPI + rikkunshito group after 8 weeks of treatment. In conclusion, ESD affects gastric emptying and is associated with an increased incidence of upper GI symptoms such as abdominal pain and indigestion. Rikkunshito may be useful as a novel supporting therapeutic drug for the treatment of GI symptoms in patients who have undergone ESD., Experimental and Therapeutic Medicine, 6(5), pp.1083-1088; 2013

Published
2013

48. Two difficulty diagnosis cases of severe veno-occlusive disease

Author

Mitsuhisa Takatsuki, Tatsuki Ichikawa, Akihiko Soyama, Sadayuki Okudaira, Hisamitsu Miyaaki, Naota Taura, Osamu Nakashima, Hidetaka Shibata, Shinobu Yamamichi, Shotaro Turuta, Masayoshi Kage, Taro Akashi, Kazuhiko Nakao, Masaaki Hidaka, Takuya Honda, and Susumu Eguchi

Subjects
Pediatrics, medicine.medical_specialty, business.industry, medicine.medical_treatment, liver failure, Liver failure, Autopsy, Case Report, General Medicine, Disease, Liver transplantation, medicine.disease, stem cell transplantation, Community hospital, Transplantation, Liver disease, surgical procedures, operative, Medicine, Veno-Occlusive Disease, business, veno-occlusive disease
Abstract

Backgroud The occurrence of Hepatic veno-occlusive disease (VOD) is rale liver disease. However, severe VOD is often lethal and one of the most common causes of death following stem cell transplantation (SCT). Case Reports: Case 1 was a 30-year-old woman who was diagnosed as Budd-Chiari syndrome with liver failure. She was admitted to our department to undergo liver transplantation. Four days after admission, she underwent liver transplantation. Her liver explant showed VOD. Case 2 was a 74-year-old woman who was admitted to a community hospital for further examination. Her condition continued to deteriorate with liver failure, and she died 39 days after admission. Liver autopsy also showed VOD. Either of the patients had difficulty in diagnose as VOD. Neither of the patients had a history of SCT. Conclusions: VOD should be considered as a cause of acute hepatic failure, even if the patient has no history of SCT.

Published
2013

49. Recent topics on α-fetoprotein

Author

Tatsuki Ichikawa and Kazuhiko Nakao

Subjects
Sorafenib, Hepatology, business.industry, medicine.medical_treatment, digestive, oral, and skin physiology, Fibrosis stage, Promoter, Liver transplantation, medicine.disease, digestive system diseases, Infectious Diseases, medicine.anatomical_structure, Hepatocellular carcinoma, Hepatocyte, embryonic structures, Immunology, medicine, Cancer research, Risk factor, business, neoplasms, Cyclin, medicine.drug
Abstract

Zinc-fingers and homeoboxes 2 (ZHX2) and zinc-finger and BTB domain containing 20 (ZBTB20) repress the postnatal expression of α-fetoprotein (AFP) by interacting with the AFP gene promoter regions. ZHX2 inhibits the expression of AFP and cyclins A and E. ZBTB20 is negatively regulated by CUX1, which promotes cell-cycle progression, suggesting that AFP reactivation is closely linked to hepatocyte proliferation. A slight elevation in the serum AFP level often occurs in patients with chronic hepatitis C in the absence of hepatocellular carcinoma (HCC) and is an independent risk factor for HCC development to complement the fibrosis stage. In addition, the sustained elevation of AFP after interferon therapy is a risk factor of HCC development. AFP levels are clinically useful in predicting the outcomes of liver transplantation and sorafenib therapy for HCC patients. A low preoperative AFP level is a predictor of long-term survival and is associated with a low recurrence rate of HCC after liver transplantation. AFP response (≥20% decrease in AFP during 6-8 weeks of treatment) rather than radiological outcomes is a significant prognostic factor for survival in sorafenib-treated HCC patients. Highly sensitive Lens culinaris agglutinin-reactive AFP (AFP-L3) is 5-10 times more sensitive than conventional AFP-L3, and useful for early detection of HCC in patients with total AFP below 20 ng/mL.

Published
2013
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50. Glucose fluctuations reduce quality of sleep and of life in patients with liver cirrhosis

Author

Eisuke Ozawa, Tatsuki Ichikawa, Fuminao Takeshima, Satoshi Miuma, Takuya Honda, Hidetaka Shibata, Kazuhiko Nakao, Hisamitsu Miyaaki, Naota Taura, and Masafumi Haraguchi

Subjects
Adult, Blood Glucose, Glycation End Products, Advanced, Liver Cirrhosis, Male, Sleep Wake Disorders, medicine.medical_specialty, Cirrhosis, medicine.medical_treatment, Liver transplantation, Chronic liver disease, Gastroenterology, Pittsburgh Sleep Quality Index, 03 medical and health sciences, 0302 clinical medicine, Quality of life, Risk Factors, Internal medicine, Medicine, Humans, Glycated Serum Albumin, Risk factor, Serum Albumin, Aged, Glycated Hemoglobin, Sleep disorder, Hepatology, business.industry, Middle Aged, medicine.disease, Endocrinology, Quality of Life, Regression Analysis, 030211 gastroenterology & hepatology, Female, business, 030217 neurology & neurosurgery
Abstract

Sleep disturbance and decreased health-related quality of life (HRQOL) are significant complaints in patients with liver cirrhosis. Although the etiology of these complications is unclear, we propose that glucose intolerance may be a predisposing factor. Therefore, our aim was to investigate the relationship between glucose intolerance and these complications. We assessed continuous glucose monitoring in 43 patients with chronic liver disease. Among these patients, 36 completed the Pittsburgh Sleep Quality Index (PSQI), the 36-Item Short-form Health Survey (SF-36), and the Neuropsychological Test (NPT). We also assessed the change in glucose fluctuations between preoperative periods and 1 year after liver transplantation in 13 patients. Standard deviation (SD) of blood glucose was 24.15 ± 13.52. SD values correlated to glucose metabolism measures, including HbA1c and glycoalbumin. SD values also correlated to markers of liver fibrosis, including type IV collagen. Twenty-one patients (58.3 %) were classified as “poor” sleepers, with a global PSQI score ≥6. Glucose fluctuations correlated with the global PSQI score (r = 0.456, p = 0.008) and the SF-36 score (r = 0.434, p = 0.013). Multivariate regression analysis identified SD values as an independent risk factor for sleep disturbance (r = 0.12, p = 0.039) and decreased HRQOL (r = −0.32, p = 0.024). SD values did not correlate with the NPT. SD values were also improved in 11 (84.6 %) patients 1 year after liver transplantation. Abnormal glucose fluctuations are a risk factor for sleep disturbance and decrease of HRQOL in patients with cirrhosis.

Published
2016

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