Updated on 2022/12/01

写真a

 
SONE, Hirohito
 
Organization
Academic Assembly Institute of Medicine and Dentistry IGAKU KEIRETU Professor
Faculty of Medicine School of Medicine Professor
Graduate School of Medical and Dental Sciences Biological Functions and Medical Control Homeostatic Regulation and Developments Professor
Title
Professor
Contact information
メールアドレス
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Degree

  • MD, PhD, FACP ( 1997.3   University of Tsukuba )

Research Interests

  • 内科学

  • 予防医学・公衆衛生学

  • 身体運動科学・健康科学

  • 代謝内分泌・糖尿病・動脈硬化学

  • 栄養学・食品学

  • 健康診断医学・臨床検査医学

  • 肥満・脂質異常症・高血圧・メタボリックシンドローム

  • 人工知能(AI)

  • 疫学・臨床疫学・医療ビッグデータ解析学

  • 生活習慣病

  • 大規模臨床研究・臨床試験

Research Areas

  • Others / Others  / Laboratory medicine

  • Informatics / Life, health and medical informatics  / 医療ビッグデータ解析学

  • Life Science / Medical management and medical sociology  / 予防疫学、臨床疫学、臨床試験

  • Humanities & Social Sciences / Family and consumer sciences, and culture and living  / 栄養学、臨床栄養学、公衆栄養学、栄養疫学

  • Life Science / Genome biology  / バイオインフォマティクス、オミックス

  • Life Science / Hygiene and public health (laboratory)  / 地域医療学

  • Life Science / Nutrition science and health science  / 運動療法学、生涯スポーツ学

  • Life Science / Metabolism and endocrinology  / Endocrinilogy and Metabolism

  • Life Science / General internal medicine  / 総合診療学

  • Life Science / Hematology and medical oncology

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Research History (researchmap)

  • Niigata University   Graduate School of Medical and Dental Sciences Biological Functions and Medical Control Homeostatic Regulation and Developments   Professor

    2012.10

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  • Department of Endocrinology and Metabolism, University of Tsukuba Mito Medical Center   Professor

    2009.4 - 2012.8

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  • The Open University of Japan

    2008.4 - 2014.4

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  • Ochanomizu University   Associate Professor

    2006.4 - 2009.3

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  • The University of Tokyo   Faculty of Medicine

    2004.4

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  • Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Tsukuba   Lecturer

    1999.4 - 2006.3

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  • University of Michigan   Department of Endocrinology and Metabolism, School of Medicine of Endocrinology and Metabolism, School of Medicine

    1997.4 - 1999.3

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    Country:United States

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  • University of Tsukuba

    1996.4 - 1997.3

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  • Resident of Endocrinology and Metabolism, University of Tsukuba Hospital   Resident of Internal Medicine

    1990.6 - 1996.3

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Research History

  • Niigata University   Graduate School of Medical and Dental Sciences Biological Functions and Medical Control Homeostatic Regulation and Developments   Professor

    2012.9

  • Niigata University   Faculty of Medicine School of Medicine   Professor

    2012.9

Education

  • University of Tsukuba   School of Medicine

    1984.4 - 1990.3

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    Country: Japan

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Professional Memberships

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Committee Memberships

  • 日本医学会連合   COVID expert opinion 実務担当者会議委員  

    2020.12   

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  • 日本糖尿病・妊娠学会   副理事長  

    2020.11   

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    Committee type:Academic society

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  • 日本臨床運動療法学会   理事  

    2018.4   

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    Committee type:Academic society

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  • 日本糖尿病生活習慣病ヒューマンデータ学会   理事  

    2017.4   

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    Committee type:Academic society

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  • 日本内分泌学会   幹事  

    2016.4   

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    Committee type:Academic society

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  • 日本臨床栄養学会   理事  

    2016.4   

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    Committee type:Academic society

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  • 新潟県医師会   代議員  

    2016   

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  • 日本糖尿病眼学会   理事  

    2014.4   

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    Committee type:Academic society

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  • 日本公衆衛生学会   代議員  

    2014.4   

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    Committee type:Academic society

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  • 日本糖尿病・妊娠学会   常任理事  

    2014.4   

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    Committee type:Academic society

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  • 日本糖尿病学会   評議員  

    2013.4   

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    Committee type:Academic society

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  • 日本疫学会   理事  

    2013.4   

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    Committee type:Academic society

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  • 日本内科学会   評議員  

    2012.10   

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    Committee type:Academic society

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  • 厚生労働省 薬事・食品衛生審議会   委員  

    2011   

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    Committee type:Academic society

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  • 日本肥満学会   評議員  

    2010   

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    Committee type:Academic society

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  • 日本栄養・食糧学会   代議員・参与  

    2010   

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    Committee type:Academic society

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  • 日本臨床分子医学会   評議員  

    2010 - 2014   

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    Committee type:Academic society

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  • 日本栄養改善学会   評議員  

    2009.4   

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    Committee type:Academic society

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  • 日本病態栄養学会   評議員  

    2008.4   

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    Committee type:Academic society

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  • 日本未病システム学会   評議員  

    2008.4 - 2019.3   

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  • 日本生活習慣病(成人病)学会   評議員  

    2008 - 2020   

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    Committee type:Academic society

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  • 日本糖尿病合併症学会   評議員  

    2007.4   

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    Committee type:Academic society

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  • 日本動脈硬化学会   評議員  

    2002.4   

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    Committee type:Academic society

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Studying abroad experiences

  • Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan   Postdoctoral Research Fellow

    1997.4 - 1999.3

Qualification acquired

  • 日本内科学会 総合内科専門医・指導医

  • 日本糖尿病学会 専門医・指導医

  • 日本内分泌学会 専門医・指導医

  • 日本動脈硬化学会 専門医・指導医

  • 社会医学系専門医協会 社会医学系指導医

  • 日本臨床栄養学会 臨床栄養指導医

  • 日本成人病(生活習慣病)学会 管理指導医

  • 日本未病システム学会 未病医学認定医

  • 日本医師会 認定産業医

  • 日本医師会 認定健康スポーツ医

  • 日本スポーツ協会 認定スポーツドクター

  • Fellow of American College of Physicians (FACP)

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Papers

  • A 52-week randomized controlled trial of ipragliflozin or sitagliptin in type 2 diabetes combined with metformin: The N-ISM study. Reviewed International journal

    Masaru Kitazawa, Takashi Katagiri, Hiromi Suzuki, Satoshi Matsunaga, Mayuko H Yamada, Tomoo Ikarashi, Masahiko Yamamoto, Kazuo Furukawa, Midori Iwanaga, Mariko Hatta, Kazuya Fujihara, Takaho Yamada, Shiro Tanaka, Hirohito Sone

    Diabetes, obesity & metabolism   23 ( 3 )   811 - 821   2021.3

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)  

    AIM: To compare the long-term efficacy of sodium-glucose co-transporter-2 inhibitors and dipeptidyl peptidase-4 inhibitors as second-line drugs after metformin for patients not at high risk of atherosclerotic cardiovascular disease (ASCVD). MATERIALS AND METHODS: In a 52-week randomized open-label trial, we compared ipragliflozin and sitagliptin in Japanese patients diagnosed with type 2 diabetes, without prior ASCVD and treated with metformin. The primary endpoint was a glycated haemoglobin (HbA1c) reduction of ≥0.5% (5.5 mmol/mol) without weight gain at 52 weeks. RESULTS: Of a total of 111 patients (mean age 59.2 years, mean body mass index [BMI] 26.6 kg/m2 , 61.3% men), 54 patients received ipragliflozin and 57 received sitagliptin. After 52 weeks, achievement of the primary endpoint was not significantly different (37.0% and 40.3%; P = 0.72). HbA1c reduction rate at 24 weeks was greater for sitagliptin (56.1%) than for ipragliflozin (31.5%; P = 0.01). From 24 to 52 weeks, the HbA1c reduction with sitagliptin was attenuated, with no significant difference in HbA1c reduction after 52 weeks between sitagliptin (54.4%) and ipragliflozin (38.9%; P = 0.10). Improvements in BMI, C-peptide and high-density lipoprotein cholesterol were greater with ipragliflozin than with sitagliptin. Adverse events occurred in 17 patients with ipragliflozin and in 10 patients with sitagliptin (P = 0.11). CONCLUSION: The HbA1c-lowering effect at 24 weeks was greater with sitagliptin than with ipragliflozin, but with no difference in efficacy related to HbA1c and body weight at 52 weeks. However, some ASCVD risk factors improved with ipragliflozin.

    DOI: 10.1111/dom.14288

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  • A Prospective Cohort Study of Muscular and Performance Fitness and Risk of Hearing Loss: The Niigata Wellness Study. Reviewed International journal

    Ryoko Kawakami, Susumu S Sawada, Kiminori Kato, Yuko Gando, Haruki Momma, Hideaki Oike, Motohiko Miyachi, I-Min Lee, Steven N Blair, Minoru Tashiro, Chika Horikawa, Yasuhiro Matsubayashi, Takaho Yamada, Kazuya Fujihara, Hirohito Sone

    The American journal of medicine   134 ( 2 )   235 - 242   2021.2

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    Authorship:Corresponding author   Language:English   Publishing type:Research paper (scientific journal)  

    BACKGROUND: Several cross-sectional studies have linked higher physical fitness with better hearing sensitivity but have not established a causal relation; none have used a prospective design that is less susceptible to bias. We used a prospective cohort study to investigate the association between muscular and performance fitness and the incidence of hearing loss. METHODS: A total of 21,907 participants without hearing loss received physical fitness assessments between April 2001 and March 2002. Muscular and performance fitness index, an age- and sex-specific summed z-score based on grip strength, vertical jump height, single-leg balance, forward bending, and whole-body reaction time was calculated. Participants were classified into quartiles according to the muscular and performance fitness index and each physical fitness test. They were followed up for the development of hearing loss, assessed by pure-tone audiometry at annual health examinations between April 2002 and March 2008. Hazard ratios and 95% confidence intervals for hearing loss incidence were estimated using Cox proportional hazards regression models. RESULTS: During follow-up, 2765 participants developed hearing loss. The hazard ratios (95% confidence intervals) for developing hearing loss across the muscular and performance fitness index quartiles (lowest to highest) were 1.00 (reference), 0.88 (0.79-0.97), 0.83 (0.75-0.93), and 0.79 (0.71-0.88) (Ptrend <.001). Among the various physical fitness components, a clear dose-response association with hearing loss incidence was observed for vertical jump height and single-leg balance (Ptrend <.001 for both). CONCLUSION: Higher muscular and performance fitness is associated with a lower incidence of hearing loss.

    DOI: 10.1016/j.amjmed.2020.06.021

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  • Machine Learning Approach to Decision Making for Insulin Initiation in Japanese Patients With Type 2 Diabetes (JDDM 58): Model Development and Validation Study. Reviewed International journal

    Kazuya Fujihara, Yasuhiro Matsubayashi, Mayuko Harada Yamada, Masahiko Yamamoto, Toshihiro Iizuka, Kosuke Miyamura, Yoshinori Hasegawa, Hiroshi Maegawa, Satoru Kodama, Tatsuya Yamazaki, Hirohito Sone

    JMIR medical informatics   9 ( 1 )   e22148   2021.1

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    BACKGROUND: Applications of machine learning for the early detection of diseases for which a clear-cut diagnostic gold standard exists have been evaluated. However, little is known about the usefulness of machine learning approaches in the decision-making process for decisions such as insulin initiation by diabetes specialists for which no absolute standards exist in clinical settings. OBJECTIVE: The objectives of this study were to examine the ability of machine learning models to predict insulin initiation by specialists and whether the machine learning approach could support decision making by general physicians for insulin initiation in patients with type 2 diabetes. METHODS: Data from patients prescribed hypoglycemic agents from December 2009 to March 2015 were extracted from diabetes specialists' registries, resulting in a sample size of 4860 patients who had received initial monotherapy with either insulin (n=293) or noninsulin (n=4567). Neural network output was insulin initiation ranging from 0 to 1 with a cutoff of >0.5 for the dichotomous classification. Accuracy, recall, and area under the receiver operating characteristic curve (AUC) were calculated to compare the ability of machine learning models to make decisions regarding insulin initiation to the decision-making ability of logistic regression and general physicians. By comparing the decision-making ability of machine learning and logistic regression to that of general physicians, 7 cases were chosen based on patient information as the gold standard based on the agreement of 8 of the 9 specialists. RESULTS: The AUCs, accuracy, and recall of logistic regression were higher than those of machine learning (AUCs of 0.89-0.90 for logistic regression versus 0.67-0.74 for machine learning). When the examination was limited to cases receiving insulin, discrimination by machine learning was similar to that of logistic regression analysis (recall of 0.05-0.68 for logistic regression versus 0.11-0.52 for machine learning). Accuracies of logistic regression, a machine learning model (downsampling ratio of 1:8), and general physicians were 0.80, 0.70, and 0.66, respectively, for 43 randomly selected cases. For the 7 gold standard cases, the accuracies of logistic regression and the machine learning model were 1.00 and 0.86, respectively, with a downsampling ratio of 1:8, which were higher than the accuracy of general physicians (ie, 0.43). CONCLUSIONS: Although we found no superior performance of machine learning over logistic regression, machine learning had higher accuracy in prediction of insulin initiation than general physicians, defined by diabetes specialists' choice of the gold standard. Further study is needed before the use of machine learning-based decision support systems for insulin initiation can be incorporated into clinical practice.

    DOI: 10.2196/22148

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  • Leisure-time physical activity and incidence of objectively assessed hearing loss: The Niigata Wellness Study. International journal

    Ryoko Kawakami, Susumu S Sawada, Kiminori Kato, Yuko Gando, Haruki Momma, Hideaki Oike, Motohiko Miyachi, I-Min Lee, Minoru Tashiro, Chika Horikawa, Hajime Ishiguro, Yasuhiro Matsubayashi, Kazuya Fujihara, Hirohito Sone

    Scandinavian journal of medicine & science in sports   32 ( 2 )   435 - 445   2022.2

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    Previous cohort study reported that high physical activity was associated with a low risk of self-reported hearing loss in women. However, no studies have examined the association between physical activity and the development of hearing loss as measured using an objective assessment of hearing loss in men and women. Here, we used cohort data to examine the association between leisure-time physical activity and incidence of objectively assessed hearing loss in men and women. Participants included 27 537 Japanese adults aged 20-80 years without hearing loss, who completed a self-administered physical activity questionnaire between April 2001 and March 2002. The participants were followed up for the development of hearing loss as measured by audiometry between April 2002 and March 2008. During follow-up, 3691 participants developed hearing loss. Compared with the none physical activity group, multivariable adjusted hazard ratios (HRs) for developing hearing loss were 0.93 (95% confidence interval (CI), 0.86-1.01) and 0.87 (0.81-0.95) for the medium (<525 MET-min/week) and high (≥525 MET-min/week) physical activity groups, respectively (p for trend = 0.001). The magnitude of risk reduction was slightly greater in vigorous-intensity activity than in moderate-intensity activity (p for interaction = 0.01). Analysis by sound frequency showed that the amount of physical activity was inversely associated with high frequency hearing loss development (p for trend <0.001), but not with low frequency hearing loss development (p for trend = 0.19). Higher level of leisure-time physical activity was associated with lower incidence of hearing loss, particularly for vigorous-intensity activities and high sound frequencies.

    DOI: 10.1111/sms.14089

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  • Morphological and functional adaptation of pancreatic islet blood vessels to insulin resistance is impaired in diabetic db/db mice. International journal

    Yuka Okajima, Takashi Matsuzaka, Shun Miyazaki, Kaori Motomura, Hiroshi Ohno, Rahul Sharma, Takuya Shimura, Nurani Istiqamah, Song-Iee Han, Yuhei Mizunoe, Yoshinori Osaki, Hitoshi Iwasaki, Shigeru Yatoh, Hiroaki Suzuki, Hirohito Sone, Takafumi Miyamoto, Yuichi Aita, Yoshinori Takeuchi, Motohiro Sekiya, Naoya Yahagi, Yoshimi Nakagawa, Tsutomu Tomita, Hitoshi Shimano

    Biochimica et biophysica acta. Molecular basis of disease   1868 ( 4 )   166339 - 166339   2022.1

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    The pancreatic islet vasculature is of fundamental importance to the β-cell response to obesity-associated insulin resistance. To explore islet vascular alterations in the pathogenesis of type 2 diabetes, we evaluated two insulin resistance models: ob/ob mice, which sustain large β-cell mass and hyperinsulinemia, and db/db mice, which progress to diabetes due to secondary β-cell compensation failure for insulin secretion. Time-dependent changes in islet vasculature and blood flow were investigated using tomato lectin staining and in vivo live imaging. Marked islet capillary dilation was observed in ob/ob mice, but this adaptive change was blunted in db/db mice. Islet blood flow volume was augmented in ob/ob mice, whereas it was reduced in db/db mice. The protein concentrations of total and phosphorylated endothelial nitric oxide synthase (eNOS) at Ser1177 were increased in ob/ob islets, while they were diminished in db/db mice, indicating decreased eNOS activity. This was accompanied by an increased retention of advanced glycation end-products in db/db blood vessels. Amelioration of diabetes by Elovl6 deficiency involved a restoration of capillary dilation, blood flow, and eNOS phosphorylation in db/db islets. Our findings suggest that the disability of islet capillary dilation due to endothelial dysfunction impairs local islet blood flow, which may play a role in the loss of β-cell function and further exacerbate type 2 diabetes.

    DOI: 10.1016/j.bbadis.2022.166339

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  • Higher Iron Intake Is Independently Associated with Obesity in Younger Japanese Type-2 Diabetes Mellitus Patients. International journal

    Efrem d'Ávila Ferreira, Mariko Hatta, Yasunaga Takeda, Chika Horikawa, Mizuki Takeuchi, Noriko Kato, Hiroki Yokoyama, Yoshio Kurihara, Koichi Iwasaki, Kazuya Fujihara, Hiroshi Maegawa, Hirohito Sone

    Nutrients   14 ( 1 )   2022.1

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    We aimed to analyze the association between dietary iron intake and obesity assessed by BMI after adjustment for nutrient intake (macronutrients and fiber) and food groups. The study design was cross-sectional. Patients with type-2 diabetes (n = 1567; 63.1% males; mean age 62.3 ± 11.6 years) were included in the study. To assess diet, consumption of typical food groups was determined by a food frequency questionnaire. Obesity was defined as BMI ≥ 25 kg/m2. We performed a binary regression analysis between quartiles of iron intake and obesity by quartiles of age group. A direct linear association was found for the highest quartile of iron intake and obesity in the younger age group of 30 to 54 years (OR = 3.641, 95% CI = 1.020-12.990; p trend = 0.011). Multivariate analysis using food groups as opposed to nutrients revealed a positive trend for obesity in the younger age group after adjusting for lifestyle factors, energy intake and bean and vegetable intake (p trend = 0.023). In all participants, an inverse association was observed before adjustment by vegetable intake (OR = 0.453, 95% CI = 0.300-0.684; p trend = 0.001). Higher iron intake was associated with obesity independent of macronutrient and fiber intake but only in the youngest quartile of age group examined.

    DOI: 10.3390/nu14010211

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  • Predictive ability of current machine learning algorithms for type 2 diabetes mellitus: A meta-analysis.

    Satoru Kodama, Kazuya Fujihara, Chika Horikawa, Masaru Kitazawa, Midori Iwanaga, Kiminori Kato, Kenichi Watanabe, Yoshimi Nakagawa, Takashi Matsuzaka, Hitoshi Shimano, Hirohito Sone

    Journal of diabetes investigation   2021.12

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    AIMS/INTRODUCTION: Recently, an increasing number of cohort studies have suggested using machine learning (ML) to predict type 2 diabetes mellitus. However, its predictive ability remains inconclusive. This meta-analysis evaluated the current ability of ML algorithms for predicting incident type 2 diabetes mellitus. MATERIALS AND METHODS: We systematically searched longitudinal studies published from 1 January 1950 to 17 May 2020 using MEDLINE and EMBASE. Included studies had to compare ML's classification with the actual incidence of type 2 diabetes mellitus, and present data on the number of true positives, false positives, true negatives and false negatives. The dataset for these four values was pooled with a hierarchical summary receiver operating characteristic and a bivariate random effects model. RESULTS: There were 12 eligible studies. The pooled sensitivity, specificity, positive likelihood ratio and negative likelihood ratio were 0.81 (95% confidence interval [CI] 0.67-0.90), 0.82 [95% CI 0.74-0.88], 4.55 [95% CI 3.07-6.75] and 0.23 [95% CI 0.13-0.42], respectively. The area under the summarized receiver operating characteristic curve was 0.88 (95% CI 0.85-0.91). CONCLUSIONS: Current ML algorithms have sufficient ability to help clinicians determine whether individuals will develop type 2 diabetes mellitus in the future. However, persons should be cautious before changing their attitude toward future diabetes risk after learning the result of the diabetes prediction test using ML algorithms.

    DOI: 10.1111/jdi.13736

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  • Impact of prior cerebrovascular disease and glucose status on incident cerebrovascular disease in Japanese International journal

    Momoko Oe, Kazuya Fujihara, Mayuko Harada-Yamada, Taeko Osawa, Masaru Kitazawa, Yasuhiro Matsubayashi, Takaaki Sato, Yuta Yaguchi, Midori Iwanaga, Hiroyasu Seida, Takaho Yamada, Hirohito Sone

    Cardiovascular Diabetology   20 ( 1 )   174 - 174   2021.12

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Springer Science and Business Media LLC  

    <title>Abstract</title><sec>
    <title>Background</title>
    Although both a history of cerebrovascular disease (CVD) and glucose abnormality are risk factors for CVD, few large studies have examined their association with subsequent CVD in the same cohort. Thus, we compared the impact of prior CVD, glucose status, and their combinations on subsequent CVD using real-world data.


    </sec><sec>
    <title>Methods</title>
    This is a retrospective cohort study including 363,627 men aged 18–72 years followed for ≥ 3 years between 2008 and 2016. Participants were classified as normoglycemia, borderline glycemia, or diabetes defined by fasting plasma glucose, HbA1c, and antidiabetic drug prescription. Prior and subsequent CVD (i.e. ischemic stroke, transient ischemic attack, and non-traumatic intracerebral hemorrhage) were identified according to claims using ICD-10 codes, medical procedures, and questionnaires.


    </sec><sec>
    <title>Results</title>
    Participants’ mean age was 46.1 ± 9.3, and median follow up was 5.2 (4.2, 6.7) years. Cox regression analysis showed that prior CVD + conferred excess risk for CVD regardless of glucose status (normoglycemia: hazard ratio (HR), 8.77; 95% CI 6.96–11.05; borderline glycemia: HR, 7.40, 95% CI 5.97–9.17; diabetes: HR, 5.73, 95% CI 4.52–7.25). Compared with normoglycemia, borderline glycemia did not influence risk of CVD, whereas diabetes affected subsequent CVD in those with CVD- (HR, 1.50, 95% CI 1.34–1.68). In CVD-/diabetes, age, current smoking, systolic blood pressure, high-density lipoprotein cholesterol, and HbA1c were associated with risk of CVD, but only systolic blood pressure was related to CVD risk in CVD + /diabetes.


    </sec><sec>
    <title>Conclusions</title>
    Prior CVD had a greater impact on the risk of CVD than glucose tolerance and glycemic control. In participants with diabetes and prior CVD, systolic blood pressure was a stronger risk factor than HbA1c. Individualized treatment strategies should consider glucose tolerance status and prior CVD.


    </sec>

    DOI: 10.1186/s12933-021-01367-7

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    Other Link: https://link.springer.com/article/10.1186/s12933-021-01367-7/fulltext.html

  • Impact of Medication Adherence and Glycemic Control on the Risk of Micro- and Macrovascular Diseases in Patients with Diabetes. International journal

    Yuta Yaguchi, Kazuya Fujihara, Mayuko Harada Yamada, Yasuhiro Matsubayashi, Takaho Yamada, Midori Iwanaga, Masaru Kitazawa, Masahiko Yamamoto, Hiroyasu Seida, Satoru Kodama, Hirohito Sone

    The American journal of medicine   2021.11

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    PURPOSE: Our purpose in the research was to clarify the impact of medication adherence to oral hypoglycemic agents during a 1-year period and subsequent glycemic control on the risk of micro- and macrovascular diseases. METHODS: Examined was a nationwide claims database on 13,256 individuals with diabetic eye disease without requiring prior treatment, 7,862 without prior initiation of dialysis, 15,556 without prior coronary artery disease, 16,243 without prior cerebrovascular disease, and 19,386 without prior heart failure from 2008 to 2016 in Japan. Medication adherence was evaluated by the proportion of days covered. Patients were considered to have poor adherence if the proportion of days covered was <80%. Multivariate Cox regression model identified risks of micro- and macrovascular diseases. RESULTS: In each group, mean age was 53 to 54 years, HbA1c was 7.1% to 7.2%, and median follow-up period was 4.6 to 5.1 years, and the percentage of poor adherence was approximately 30%. During the study period, 532 treatment-requiring diabetic eye disease, 75 dialysis, 389 coronary artery disease, 316 cerebrovascular disease, and 144 heart failure events occurred. Multivariate Cox regression model revealed that the hazard ratio (95% confidence interval) of dialysis in the poor adherence group was 2.04 (1.27-3.30) compared with the good adherence group. The hazard ratios in the poor adherence/poor glycemic control group were 3.34 (2.63-4.24) for treatment-requiring diabetic eye disease, 4.23 (2.17-8.26) for dialysis, 1.69 (1.23-2.31) for coronary artery disease, and 2.08 (1.25-3.48) for heart failure compared with the good adherence/good glycemic control group. CONCLUSIONS: Poor medication adherence was an independent risk factor for the initiation of dialysis, suggesting that clinicians must pay close attention to these patients.

    DOI: 10.1016/j.amjmed.2021.10.018

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  • Comparing Associations of Dietary Energy Density and Energy Intake, Macronutrients with Obesity in Patients with Type 2 Diabetes (JDDM 63). International journal

    Yasunaga Takeda, Kazuya Fujihara, Rina Nedachi, Izumi Ikeda, Sakiko Yoshizawa Morikawa, Mariko Hatta, Chika Horikawa, Mitsutoshi Kato, Noriko Kato, Hiroki Yokoyama, Yoshio Kurihara, Kazuhiro Miyazawa, Hiroshi Maegawa, Hirohito Sone

    Nutrients   13 ( 9 )   2021.9

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    To investigate the association between dietary energy density (DED) and obesity in people with type 2 diabetes mellitus. Moreover, we compared the strength of the associations of DED with intake of energy and macronutrients in terms of obesity as well as nutritional factors that have long been used for medical nutritional therapy. Cross-sectionally investigated were 1615 outpatients with type 2 diabetes who attended 26 clinics nationwide with diabetes specialists. Odds ratios (ORs) were calculated for the association between obesity and DED, energy, and macronutrients by quintile categories and a 1 SD increment with adjustment for potential confounders. β coefficients were calculated for the association between body mass index (BMI) and each nutritional factor by 1 SD increments in nutritional values. Multi-adjusted OR for obesity between extreme quintiles of DED was 2.99 (95% confidence interval (95% CI): 2.01-3.12). Conversely, the ORs did not differ significantly according to the quintiles of other nutrient factors. Multi-adjusted β coefficient of BMI per 1 SD according to DED was far higher than those of other nutrient factors (β coefficient 0.65, 95% CI: 0.41-0.88). These findings indicated that DED in persons with type 2 diabetes was positively associated with BMI and the prevalence of obesity. DED was also much more potently associated with obesity and BMI than nutritional indicators such as intake of energy or macronutrients.

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  • Altered Microbiota by a High-Fat Diet Accelerates Lethal Myeloid Hematopoiesis Associated with Systemic Socs3 Deficiency International journal

    Kaori Cho, Takashi Ushiki, Hajime Ishiguro, Suguru Tamura, Masaya Araki, Tatsuya Suwabe, Takayuki Katagiri, Mari Watanabe, Yoko Fujimoto, Riuko Ohashi, Yoichi Ajioka, Ippei Shimizu, Shujiro Okuda, Masayoshi Masuko, Yoshimi Nakagawa, Hideyo Hirai, Warren S. Alexander, Hitoshi Shimano, Hirohito Sone

    iScience   24 ( 10 )   103117 - 103117   2021.9

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    The suppressors of cytokine signaling (SOCS) proteins are negative regulators of cytokine signaling required to prevent excessive cellular responses. In particular, SOCS3 is involved in the regulation of metabolic syndromes, such as obesity and diabetes, by suppressing leptin and insulin signals. SOCS3 also suppresses the inflammatory response associated with metabolic stress, but this specific role remains undefined. Wild-type mice on a high-fat diet (HFD) exhibited only fatty liver, whereas systemic deletion of SOCS3 resulted in excessive myeloid hematopoiesis and hepatic inflammation. In addition, depletion of the gut microbiota resulted in considerable improvement in excess granulopoiesis and splenomegaly, halting the progression of systemic inflammation in SOCS3KO mice on the HFD. This result suggests that intestinal dysbiosis is involved in inflammation associated with SOCS3KO. Although contributing to diet-induced obesity and fatty liver, SOCS3 is nevertheless critical to suppress excess myeloid hematopoiesis and severe systemic inflammation associated with intestinal dysbiosis on HFD.

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  • Carrot Consumption Frequency Associated with Reduced BMI and Obesity through the SNP Intermediary rs4445711 International journal

    Kazuya Fujihara, Shun Nogawa, Kenji Saito, Chika Horikawa, Yasunaga Takeda, Kaori Cho, Hajime Ishiguro, Satoru Kodama, Yoshimi Nakagawa, Takashi Matsuzaka, Hitoshi Shimano, Hirohito Sone

    Nutrients   13 ( 10 )   2021.9

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    It is unclear whether genetic interactions are involved in the association between vegetable intake and reduced body mass index (BMI) or obesity. We conducted a comprehensive search for single nucleotide polymorphisms (SNPs) which are associated with the interaction between vegetable intake frequency and BMI or obesity. We performed a genome-wide association analysis to evaluate the genetic interactions between self-reported intake of vegetables such as carrot, broccoli, spinach, other green vegetables (green pepper and green beans), pumpkin, and cabbage with BMI and obesity, which is defined as a BMI ≥ 25.0 kg/m2 in the Japanese population (n = 12,225). The mean BMI and prevalence of obesity was 23.9 ± 3.4 kg/m2 and 32.3% in men and 22.1 ± 3.8 kg/m2 and 17.3% in in women, respectively. A significant interaction was observed between rs4445711 and frequency of carrot intake on BMI (p = 4.5 × 10-8). This interaction was slightly attenuated after adjustment for age, sex, alcohol intake, smoking, physical activity and the frequency of total vegetable intake (p = 2.1 × 10-7). A significant interaction was also observed between rs4445711 and frequency of carrot intake on obesity (p = 2.5 × 10-8). No significant interactions that were the same as the interaction between frequency of carrot intake and rs4445711 were observed between the intake frequency of broccoli, spinach, other green vegetables, pumpkin or cabbage and BMI or obesity. The frequency of carrot consumption is implicated in reducing BMI by the intermediary of rs4445711. This novel genetic association may provide new clues to clarify the association between vegetable intake and BMI or obesity.

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  • Secular Trends in Dietary Intake over a 20-Year Period in People with Type 2 Diabetes in Japan: A Comparative Study of Two Nationwide Registries; Japan Diabetes Complications Study (JDCS) and Japan Diabetes Clinical Data Management Study (JDDM) International journal

    Mizuki Takeuchi, Chika Horikawa, Mariko Hatta, Yasunaga Takeda, Rina Nedachi, Izumi Ikeda, Sakiko Yoshizawa Morikawa, Noriko Kato, Hiroki Yokoyama, Rei Aida, Shiro Tanaka, Chiemi Kamada, Yukio Yoshimura, Toshiko Saito, Kazuya Fujihara, Atsushi Araki, Hirohito Sone

    Nutrients   13 ( 10 )   2021.9

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    BACKGROUND: In order to provide effective dietary guidance, it is necessary to consider dietary intake, which can change over time. This study analyzed changes in the diet of Japanese patients with type 2 diabetes over a 20-year period. METHODS: We compared the results of two dietary surveys that used the food frequency questionnaire format. The first was conducted in 1996 by the Japan Diabetes Complications Study (JDCS) (n = 1509; males 53.3%), and the second in 2014-2018 by the Japan Diabetes Clinical Data Management Study (JDDM) (n = 1145; males 65.6%). Both are nationwide representative registries of outpatients with type 2 diabetes in Japan. RESULTS: Over a 20-year period, both men and women with type 2 diabetes had a significant increase in body mass index (BMI). Nonetheless, there was only a small change in energy intake. Conversely, there was a significant increase in fat intake and thus in the fat-to-energy ratio. With regard to food groups, there was a significant increase in meat intake and a decrease in the intake of fish, soybeans/soy products, vegetables, and fruits, with a particularly significant decrease in vegetables. CONCLUSIONS: Even in Japan, an industrialized country with a stable socioeconomic environment, there were many significant changes in the dietary intake of patients with type 2 diabetes over the 20-year period.

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  • Developing a health economic model for Asians with type 2 diabetes based on the Japan Diabetes Complications Study and the Japanese Elderly Diabetes Intervention Trial. International journal

    Shiro Tanaka, Jakob Langer, Tim Morton, Nicki Hoskins, Lars Wilkinson, Sachiko Tanaka-Mizuno, Ryo Kawasaki, Tatsumi Moriya, Chika Horikawa, Rei Aida, Atsushi Araki, Kazuya Fujihara, Hirohito Sone

    BMJ open diabetes research & care   9 ( 1 )   2021.8

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    INTRODUCTION: Cost-effectiveness analyses are becoming increasingly important in Japan following the introduction of a health technology assessment scheme. The study objective was to develop an economic model to evaluate the cost-effectiveness of two interventions for type 2 diabetes in a Japanese population. RESEARCH DESIGN AND METHODS: The Japan Diabetes Complications Study/Japanese Elderly Diabetes Intervention Trial risk engine (JJRE) Cost-Effectiveness Model (JJCEM) was developed, incorporating validated risk equations in Japanese patients with type 2 diabetes from the JJRE. Weibull regression models were developed for progression of the model outcomes, and a targeted literature review was performed to inform default values for utilities and costs. To illustrate outcomes, two simulated analyses were performed in younger (aged 40 years) and older (aged 80 years) Japanese populations, comparing a hypothetical treatment with placebo. RESULTS: The model considers a population based on user-defined values for 11 baseline characteristic parameters and simulates rates of diabetic complications over a defined time horizon. Costs, quality-adjusted life years, and an incremental cost-effectiveness ratio are estimated. The model provides disaggregated results for two competing interventions, allowing visualization of the key drivers of cost and utility. A scatterplot of simulations and cost-effectiveness acceptability curve are generated for each analysis. CONCLUSIONS: This is the first cost-effectiveness model for East Asian patients with type 2 diabetes, developed using Japan-specific risk equations. This population constitutes the largest share of the global population with diabetes, making this model highly relevant. The model can be used to evaluate the cost-effectiveness of anti-diabetic interventions in patients with type 2 diabetes in Japan and other East Asian populations.

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  • Intensive oral care can reduce bloodstream infection with coagulase-negative staphylococci after neutrophil engraftment in allogeneic hematopoietic stem-cell transplantation. International journal

    Tatsuya Suwabe, Kyoko Fuse, Kouji Katsura, Marie Soga, Takayuki Katagiri, Yasuhiko Shibasaki, Miwako Narita, Hirohito Sone, Masayoshi Masuko

    Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer   30 ( 1 )   475 - 485   2021.7

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    PURPOSE: Bloodstream infection (BSI) is a major complication of allogeneic hematopoietic stem-cell transplantation (allo-SCT). There are several causes of BSI; in particular, severe oral mucositis (OM) can induce BSI due to coagulase-negative staphylococci (CoNS). The OM severity may be reduced with intensive oral care. Thus, we evaluated whether the type of oral care affects the BSI incidence eventually. METHOD: We performed retrospective analysis on 206 recipients who underwent allo-SCT from 2006 to 2017 at our institute. Intensive oral care by a dental specialist was performed for 111 recipients (intensive-care group) and self-oral care was performed by 95 recipients (self-care group). Incidence of BSI was assessed by type of the oral care, before neutrophil engraftment (pre-E-BSI) and after neutrophil engraftment (post-E-BSI) period until 180 days after allo-SCT. RESULT: A total of 112 BSI occurred in 90 of the 206 recipients and 120 bacteria were identified, with CoNS being the most prevalent. There was no significant difference in the incidence of pre-E-BSI between the self-care and intensive-care groups (30.8% and 30.6%, respectively; P = 0.508). Meanwhile, the incidence of post-E-BSI was significantly lower in the intensive-care group than in the self-care group (14.3% and 28.6%; P = 0.008). In addition, the intensive-care group had significantly lower incidence of post-E-BSI with CoNS than the self-care group (8.5% and 21.5%, respectively; P = 0.009). CONCLUSION: Intensive oral care through the period of allo-HCT can significantly reduce the post-E-BSI occurrence, especially due to CoNS.

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  • Central diabetes insipidus after syndrome of inappropriate antidiuretic hormone secretion with severe hyponatremia in a patient with Rathke's cleft cyst.

    Yudai Hinata, Nobumasa Ohara, Takeshi Komatsu, Yuki Sakurai, Yuichiro Yoneoka, Yasuhiro Seki, Katsuhiko Akiyama, Hirohito Sone

    Internal medicine (Tokyo, Japan)   61 ( 2 )   197 - 203   2021.7

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    A 49-year-old man developed severe hyponatremia associated with transient headache and was diagnosed with syndrome of inappropriate antidiuretic hormone secretion (SIADH). Fluid restriction and sodium supplementation corrected the hyponatremia. However, several days later, the patient exhibited hypernatremia with thirst and polyuria. A detailed examination indicated central diabetes insipidus (CDI) with an intrasellar cystic lesion indicative of Rathke's cleft cyst (RCC). A case of RCC exhibiting headache, hyponatremia, and subsequent hypernatremia has been reported. Our case shows that CDI may appear after SIADH in patients with RCC, especially in those with serum sodium levels that unexpectedly increase rapidly beyond the reference range.

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  • Meta-analytic research of the dose-response relationship between salt intake and risk of heart failure. Reviewed International journal

    Satoru Kodama, Chika Horikawa, Kazuya Fujihara, Mariko Hatta, Yasunaga Takeda, Rena Nedachi, Kiminori Kato, Kenichi Watanabe, Hirohito Sone

    Hypertension research : official journal of the Japanese Society of Hypertension   44 ( 7 )   885 - 887   2021.7

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  • Association of estimated plasma volume and weight loss after long-term administration and subsequent discontinuation of the sodium-glucose cotransporter-2 inhibitor tofogliflozin. International journal

    Yasuhiro Matsubayashi, Akihiro Yoshida, Hideki Suganami, Momoko Oe, Takaaki Sato, Yuta Yaguchi, Kazuya Fujihara, Takaho Yamada, Shiro Tanaka, Kohei Kaku, Hirohito Sone

    Diabetes, obesity & metabolism   23 ( 7 )   1660 - 1665   2021.7

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    Sodium-glucose cotransporter-2 inhibitors (SGLT2) are drugs that have been reported to have several effects through the regulation of plasma volume, for example, antihypertensive effects. This study aimed to clarify the impact of long-term administration and subsequent discontinuation of the SGLT2 inhibitor tofogliflozin on estimated plasma volume (ePV), brain natriuretic peptide (BNP) and the relationship between changes in ePV, BNP and body weight (BW). Data from 157 participants with type 2 diabetes receiving tofogliflozin monotherapy in a phase 3 study were analysed. Changes in variables or correlations among them during a 52-week administration and a 2-week post-treatment period were investigated. Percent change in ePV was calculated using the Strauss formula. Significant decreases in BW, ePV and ln-transformed BNP (ln-BNP) were noted by week 52. %ΔBW was not significantly correlated with %ΔePV and Δln-BNP, while %ΔePV was significantly correlated with Δln-BNP. Two weeks after discontinuation of tofogliflozin, BW, ePV and ln-BNP were significantly increased. %ΔBW was significantly correlated with %ΔePV and Δln-BNP. Furthermore, ePV and BNP were significantly higher than baseline levels.

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  • Author Correction: Meta-analytic research of the dose-response relationship between salt intake and risk of heart failure. International journal

    Satoru Kodama, Chika Horikawa, Kazuya Fujihara, Mariko Hatta, Yasunaga Takeda, Rena Nedachi, Kiminori Kato, Kenichi Watanabe, Hirohito Sone

    Hypertension research : official journal of the Japanese Society of Hypertension   44 ( 7 )   894 - 894   2021.7

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  • Starvation-induced transcription factor CREBH negatively governs body growth by controlling GH signaling. International journal

    Yoshimi Nakagawa, Kae Kumagai, Song-Iee Han, Yuhei Mizunoe, Masaya Araki, Seiya Mizuno, Hiroshi Ohno, Kazuya Matsuo, Yasunari Yamada, Jun-Dal Kim, Takafumi Miyamoto, Motohiro Sekiya, Morichika Konishi, Nobuyuki Itoh, Takashi Matsuzaka, Satoru Takahashi, Hirohito Sone, Hitoshi Shimano

    FASEB journal : official publication of the Federation of American Societies for Experimental Biology   35 ( 6 )   e21663   2021.6

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    cAMP responsive element-binding protein H (CREBH) is a hepatic transcription factor to be activated during fasting. We generated CREBH knock-in flox mice, and then generated liver-specific CREBH transgenic (CREBH L-Tg) mice in an active form. CREBH L-Tg mice showed a delay in growth in the postnatal stage. Plasma growth hormone (GH) levels were significantly increased in CREBH L-Tg mice, but plasma insulin-like growth factor 1 (IGF1) levels were significantly decreased, indicating GH resistance. In addition, CREBH overexpression significantly increased hepatic mRNA and plasma levels of FGF21, which is thought to be as one of the causes of growth delay. However, the additional ablation of FGF21 in CREBH L-Tg mice could not correct GH resistance at all. CREBH L-Tg mice sustained GH receptor (GHR) reduction and the increase of IGF binding protein 1 (IGFBP1) in the liver regardless of FGF21. As GHR is a first step in GH signaling, the reduction of GHR leads to impairment of GH signaling. These data suggest that CREBH negatively regulates growth in the postnatal growth stage via various pathways as an abundant energy response by antagonizing GH signaling.

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  • 同種造血幹細胞移植後の慢性GVHDとしての類上皮肉芽腫および多発筋炎

    諏訪部 達也, 布施 香子, 水戸部 正樹, 武田 ルイ, 米沢 穂高, 片桐 隆幸, 河本 啓介, 牛木 隆志, 柴崎 康彦, 瀧澤 淳, 成田 美和子, 曽根 博仁, 大島 孝一, 増子 正義

    臨床血液   62 ( 6 )   675 - 675   2021.6

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  • 陰茎・陰嚢病変を合併した精巣原発DLBCL

    水戸部 正樹, 武田 ルイ, 米沢 穂高, 田村 秀, 諏訪部 達也, 片桐 隆幸, 河本 啓介, 布施 香子, 柴崎 康彦, 増子 正義, 井上 佳菜子, 三好 寛明, 大島 孝一, 曽根 博仁, 瀧澤 淳

    臨床血液   62 ( 6 )   668 - 668   2021.6

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  • Associations of Systolic Blood Pressure and Diastolic Blood Pressure With the Incidence of Coronary Artery Disease or Cerebrovascular Disease According to Glucose Status. International journal

    Mayuko Harada Yamada, Kazuya Fujihara, Satoru Kodama, Takaaki Sato, Taeko Osawa, Yuta Yaguchi, Masahiko Yamamoto, Masaru Kitazawa, Yasuhiro Matsubayashi, Takaho Yamada, Hiroyasu Seida, Wataru Ogawa, Hirohito Sone

    Diabetes care   44 ( 9 )   2124 - 2131   2021.5

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    OBJECTIVE: To determine associations of systolic blood pressure (SBP) and diastolic blood pressure (DBP) with new-onset coronary artery disease (CAD) or cerebrovascular disease (CVD) according to glucose status. RESEARCH DESIGN AND METHODS: Examined was a nationwide claims database from 2008 to 2016 on 593,196 individuals. A Cox proportional hazards model identified risks of CAD and CVD events among five levels of SBP and DBP. RESULTS: During the study period 2,240 CAD and 3,207 CVD events occurred. Compared with SBP ≤119 mmHg, which was the lowest quintile of SBP, hazard ratios (95% CI) for CAD/CVD in the 4 higher quintiles (120-129, 130-139, 140-149, ≥150 mmHg) gradually increased from 2.10 (1.73-2.56)/1.46 (1.27-1.68) in quintile 2 to 3.21 (2.37-4.34)/4.76 (3.94-5.75) in quintile 5 for normoglycemia, from 1.39 (1.14-1.69)/1.70 (1.44-2.01) in quintile 2 to 2.52 (1.95-3.26)/4.12 (3.38-5.02) in quintile 5 for borderline glycemia, and from 1.50 (1.19-1.90)/1.72 (1.31-2.26) in quintile 2 to 2.52 (1.95-3.26)/3.54 (2.66-4.70) in quintile 5 for diabetes. A similar trend was observed for DBP across 4 quintiles (75-79, 80-84, 85-89, and ≥90 mmHg) compared with ≥74 mmHg, which was the lowest quintile. CONCLUSIONS: Results indicated that cardiovascular risks gradually increased with increases in SBP and DBP regardless of the presence of and degree of a glucose abnormality. Further interventional trials are required to apply findings from this cohort study to clinical practice.

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  • Accuracy of Japanese claims data in identifying diabetes-related complications. Reviewed International journal

    Kazuya Fujihara, Mayuko Yamada-Harada, Yasuhiro Matsubayashi, Masaru Kitazawa, Masahiko Yamamoto, Yuta Yaguchi, Hiroyasu Seida, Satoru Kodama, Kohei Akazawa, Hirohito Sone

    Pharmacoepidemiology and drug safety   30 ( 5 )   594 - 601   2021.5

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    PURPOSE: To evaluate the accuracy of various claims-based definitions of diabetes-related complications (coronary artery disease [CAD], heart failure, cerebrovascular disease and dialysis). METHODS: We evaluated data on 1379 inpatients who received care at the Niigata University Medical & Dental Hospital in September 2018. Manual electronic medical chart reviews were conducted for all patients with regard to diabetes-related complications and were used as the gold standard. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of each claims-based definition associated with diabetes-related complications based on Diagnosis Procedure Combination (DPC), International Classification of Diseases, Tenth Revision (ICD-10) codes, procedure codes and medication codes were calculated. RESULTS: DPC-based definitions had higher sensitivity, specificity, and PPV than ICD-10 code definitions for CAD and cerebrovascular disease, with sensitivity of 0.963-1.000 and 0.905-0.952, specificity of 1.000 and 1.000, and PPV of 1.000 and 1.000, respectively. Sensitivity, specificity, and PPV were high using procedure codes for CAD and dialysis, with sensitivity of 0.963 and 1.000, specificity of 1.000 and 1.000, and PPV of 1.000 and 1.000, respectively. DPC and/or ICD-10 codes + medication were better for heart failure than the ICD-10 code definition, with sensitivity of 0.933, specificity of 1.000, and PPV of 1.000. The PPVs were lower than 60% for all diabetes-related complications using ICD-10 codes only. CONCLUSION: The DPC-based definitions for CAD and cerebrovascular disease, procedure codes for CAD and dialysis, and DPC or ICD-10 codes with medication codes for heart failure could accurately identify these diabetes-related complications from claims databases.

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  • WT1-specific CD8 + cytotoxic T cells with the capacity for antigen-specific expansion accumulate in the bone marrow in MDS. Reviewed

    Tatsuya Suwabe, Yasuhiko Shibasaki, Hiroyuki Sato, Suguru Tamura, Takayuki Katagiri, Hiroki Nemoto, Takuya Kasami, Takashi Kozakai, Ayako Nanba, Toshiki Kitajima, Kyoko Fuse, Takashi Ushiki, Hirohito Sone, Miwako Narita, Masayoshi Masuko

    International journal of hematology   113 ( 5 )   723 - 734   2021.5

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    Wilms' tumor 1 (WT1) is a tumor-associated antigen and immunotherapy target in myelodysplastic syndrome (MDS). Further information is needed on the characteristics of WT1-specific CD8 + T cells to develop immunotherapeutic strategies for MDS. To clarify the frequency, distribution, and phenotype of WT1-specific CD8 + T cells, which occur innately in MDS patients, we analyzed paired peripheral blood (PB) and bone marrow (BM) samples from 39 patients with MDS or acute myeloid leukemia with myelodysplasia-related changes. The median frequency of WT1 tetramer-binding CD8 + T cells in the CD8 + T cell population was 0.11% in PB and 0.18% in BM. A further tetramer assay combined with mixed lymphocyte peptide culture (MLPC assay) was used to detect functional WT1-specific CD8 + T cells that could respond to the WT1 peptide. Functional WT1-specific CD8 + T cells were detected in BM in 61% of patients, which was significantly higher than in PB (23%, p = 0.001). The frequency of these cells estimated by the MLPC assay was tenfold higher in BM than in PB. The majority of WT1 tetramer-binding CD8 + T cells in BM had a unique phenotype with co-expression of CD39 and CXCR4. These findings will facilitate the development of novel immunotherapeutic strategies for MDS.

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  • 乾燥人フィブリノゲン製剤の継続輸注で着床・妊娠継続・出産をし得た先天性低フィブリノゲン血症

    関 義信, 牛木 隆志, 増子 正義, 瀧澤 淳, 曽根 博仁, 奥村 伸生

    日本血栓止血学会誌   32 ( 2 )   214 - 214   2021.5

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  • GB療法施行中にHigh-grade B-cell lymphoma with MYC and BCL2 rearrangementsで再燃したFollicular lymphoma(Grade 3A)の2症例

    水戸部 正樹, 本宮 奈津子, 武田 ルイ, 米沢 穂高, 鈴木 隆晴, 諏訪部 達也, 片桐 隆幸, 河本 啓介, 布施 香子, 柴崎 康彦, 増子 正義, 井上 佳菜子, 三好 寛明, 大島 孝一, 曽根 博仁, 瀧澤 淳

    日本リンパ網内系学会会誌   61   114 - 114   2021.5

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  • 腎障害を有する高悪性度B細胞リンパ腫症例にDA-EPOCH-Rを施行した1例

    水戸部 正樹, 河本 啓介, 鈴木 隆晴, 米沢 穂高, 田村 秀, 諏訪部 達也, 根本 洋樹, 布施 香子, 柴崎 康彦, 増子 正義, 三好 寛明, 大島 孝一, 曽根 博仁, 瀧澤 淳

    臨床血液   62 ( 5 )   532 - 532   2021.5

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  • ルキソルチニブ・ヒドロキシウレア併用療法が奏効した慢性好中球性白血病(CNL)の1例

    武田 ルイ, 布施 香子, 片桐 隆幸, 河本 啓介, 柴崎 康彦, 瀧澤 淳, 成田 美和子, 野本 信彦, 曽根 博仁, 増子 正義

    臨床血液   62 ( 5 )   529 - 530   2021.5

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  • 乾燥人フィブリノゲン製剤の継続輸注で着床・妊娠継続・出産をし得た先天性低フィブリノゲン血症

    関 義信, 牛木 隆志, 増子 正義, 瀧澤 淳, 曽根 博仁, 奥村 伸生

    日本血栓止血学会誌   32 ( 2 )   214 - 214   2021.5

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  • The Japanese Medical Science Federation COVID-19 Expert Opinion English Version.

    Masaomi Nangaku, Takashi Kadowaki, Hiroshi Yotsuyanagi, Norio Ohmagari, Moritoki Egi, Junichi Sasaki, Tetsuya Sakamoto, Yoshinori Hasegawa, Takashi Ogura, Shigeru Chiba, Koichi Node, Ryo Suzuki, Yasuhiro Yamaguchi, Atsuko Murashima, Norihiko Ikeda, Eriko Morishita, Kenji Yuzawa, Hiroyuki Moriuchi, Satoshi Hayakawa, Daisuke Nishi, Atsushi Irisawa, Toshiaki Miyamoto, Hidetaka Suzuki, Hirohito Sone, Yuuji Fujino

    JMA journal   4 ( 2 )   148 - 162   2021.4

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    In 2020, the COVID-19 pandemic has had unprecedented impacts on various aspects of the world. Each academic society has published a guide and/or guidelines on how to cope with COVID-19 separately. As the one and only nationwide association of academic societies that represent medical science in Japan, JMSF has decided to publish the expert opinion to help patients and care providers find specifically what they want. This expert opinion is a summary of recommendations by many academic societies and will be updated when necessary. Patients that each academic society targets differ even though they suffer from the same COVID-19, and recommendations can be different in a context-dependent manner. Readers are supposed to be flexible and adjustable when they use this expert opinion.

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  • Rates and risk factors for amputation in people with diabetes in Japan: a historical cohort study using a nationwide claims database. International journal

    Masanori Kaneko, Kazuya Fujihara, Mayuko Yamada Harada, Taeko Osawa, Masahiko Yamamoto, Masaru Kitazawa, Yasuhiro Matsubayashi, Takaho Yamada, Hiroyasu Seida, Satoru Kodama, Hirohito Sone

    Journal of foot and ankle research   14 ( 1 )   29 - 29   2021.4

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    BACKGROUND: The prevalence of diabetes is rising, and diabetes develops at a younger age in East Asia. Although lower limb amputation negatively affects quality of life and increases the risk of cardiovascular events, little is known about the rates and predictors of amputation among persons with diabetes from young adults to those in the "young-old" category (50-72 y). METHODS: We analyzed data from a nationwide claims database in Japan accumulated from 2008 to 2016 involving 17,288 people with diabetes aged 18-72 y (mean age 50.2 y, HbA1c 7.2%). Amputation occurrence was determined according to information from the claims database. Cox regression model identified variables related to lower limb amputation. RESULTS: The mean follow-up time was 5.3 years, during which time 16 amputations occurred (0.17/1000 person-years). Multivariate Cox regression analysis showed that age (hazard ratio [HR] 1.09 [95% confidence intervals] 1.02-1.16, p = 0.01) and HbA1c (HR 1.46 [1.17-1.81], p < 0.01) were independently associated with amputations. Compared with those aged < 60 years with HbA1c < 8.0%, the HR for amputation was 27.81 (6.54-118.23) in those aged ≥60 years and HbA1c ≥8.0%. CONCLUSIONS: Age and HbA1c were associated with amputations among diabetic individuals, and the rates of amputation were significantly greater in those ≥60 years old and with HbA1c ≥8.0%.

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  • Physical Fitness and Dyslipidemia Among Japanese: A Cohort Study From the Niigata Wellness Study. Reviewed

    Haruki Momma, Kiminori Kato, Susumu S Sawada, Yuko Gando, Ryoko Kawakami, Motohiko Miyachi, Ryoichi Nagatomi, Minoru Tashiro, Yasuhiro Matsubayashi, Satoru Kodama, Midori Iwanaga, Kazuya Fujihara, Hirohito Sone

    Journal of epidemiology   31 ( 4 )   287 - 296   2021.4

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    BACKGROUND: Grip strength reflects systemic muscle strength and mass and is reportedly associated with various metabolic variables. However, its prognostic association with dyslipidemia is unknown. We examined the association of grip strength and other physical fitness markers with the incidence of dyslipidemia among Japanese adults. METHODS: A total of 16,149 Japanese (6,208 women) individuals aged 20-92 years who underwent a physical fitness test between April 2001 and March 2002 were included in this cohort study. Grip strength, vertical jump, single-leg balance with eyes closed, forward bending, and whole-body reaction time were evaluated at baseline. Dyslipidemia was annually determined based on fasting serum lipid profiles and self-reported dyslipidemia from April 2001 to March 2008. RESULTS: During the follow-up period, 4,458 (44.9%) men and 2,461 (39.6%) women developed dyslipidemia. A higher relative grip strength (grip strength/body mass index) was associated with a lower incidence of dyslipidemia among both men and women (P for trend <0.001). Compared with those for the first septile, the hazards ratios and 95% confidence intervals (CIs) for the seventh septile were 0.56 (95% CI, 0.50-0.63) for men and 0.69 (95% CI, 0.58-0.81) for women. Moreover, relative vertical jump (vertical jump strength/body mass index) was also inversely associated with the incidence of dyslipidemia among both men and women (P for trend <0.001). There was no association between other physical fitness and dyslipidemia among both men and women. CONCLUSION: Relative grip strength and vertical jump may be useful risk markers of the incidence of dyslipidemia.

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  • Distinct effects of chondroitin sulfate on hematopoietic cells and the stromal microenvironment in bone marrow hematopoiesis. Reviewed International journal

    Takayuki Katagiri, Shun Uemura, Takashi Ushiki, Yaeko Nakajima-Takagi, Motohiko Oshima, Tadahisa Mikami, Asami Kawasaki, Hajime Ishiguro, Tomoyuki Tanaka, Hirohito Sone, Hiroshi Kitagawa, Michihiro Igarashi, Atsushi Iwama, Masayoshi Masuko

    Experimental hematology   96   52 - 62   2021.4

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    The bone marrow (BM) microenvironment, known as the BM niche, regulates hematopoiesis but is also affected by interactions with hematopoietic cells. Recent evidence indicates that extracellular matrix components are involved in these interactions. Chondroitin sulfate (CS), a glycosaminoglycan, is a major component of the extracellular matrix; however, it is not known whether CS has a physiological role in hematopoiesis. Here, we analyzed the functions of CS in hematopoietic and niche cells. CSGalNAcT1, which encodes CS N-acetylgalactosaminyltransferase-1 (T1), a key enzyme in CS biosynthesis, was highly expressed in hematopoietic stem and progenitor cells (HSPCs) and endothelial cells (ECs), but not in mesenchymal stromal cells (MSCs) in BM. In T1 knockout (T1KO) mice, a greater number of HSPCs existed compared with the wild-type (WT), but HSPCs from T1KO mice showed significantly impaired repopulation in WT recipient mice on serial transplantation. RNA sequence analysis revealed the activation of IFN-α/β signaling and endoplasmic reticulum stress in T1KO HSPCs. In contrast, the number of WT HSPCs repopulated in T1KO recipient mice was larger than that in WT recipient mice after serial transplantation, indicating that the T1KO niche supports repopulation of HSPCs better than the WT niche. There was no obvious difference in the distribution of vasculature and MSCs between WT and T1KO BM, suggesting that CS loss alters vascular niche functions without affecting its structure. Our results revealed distinct roles of CS in hematopoietic cells and BM niche, indicating that crosstalk between these components is important to maintain homeostasis in BM.

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  • DA-EPOCH-R therapy for high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements in a patient with renal dysfunction. Reviewed

    Masaki Mitobe, Keisuke Kawamoto, Takaharu Suzuki, Tatsuya Suwabe, Yasuhiko Shibasaki, Masayoshi Masuko, Kanako Inoue, Hiroaki Miyoshi, Koichi Ohshima, Hirohito Sone, Jun Takizawa

    Journal of clinical and experimental hematopathology : JCEH   61 ( 1 )   42 - 47   2021.3

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    High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, also known as double-hit lymphoma, has been reported as refractory to R-CHOP therapy and requires more intensive regimens. However, intensive and safe regimens for patients with renal dysfunction are unknown. Herein, we report the successful use of DA-EPOCH-R therapy for double-hit lymphoma in a 64-year-old man with renal dysfunction. The patient had lymphoma-induced bilateral ureteral obstruction. Although renal dysfunction remained after removing the obstruction using R-CHOP therapy, we completed six cycles of DA-EPOCH-R therapy without any major adverse events. DA-EPOCH-R therapy may be a safe regimen for renal dysfunction patients.

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  • Dipeptidyl peptidase-4 inhibitor, anagliptin, alters hepatic insulin clearance in relation to the glycemic status in Japanese individuals with type 2 diabetes.

    Takahiro Abe, Yasuhiro Matsubayashi, Sayaka Muragishi, Akihiro Yoshida, Hideki Suganami, Kenichi Furusawa, Kazuya Fujihara, Shiro Tanaka, Kohei Kaku, Hirohito Sone

    Journal of diabetes investigation   12 ( 10 )   1805 - 1815   2021.3

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    AIMS/INTRODUCTION: This study investigated the impact of the dipeptidyl peptidase-4 inhibitor, anagliptin, on hepatic insulin clearance (HIC) in Japanese type 2 diabetes patients and explored its relationship to glycemic status. MATERIALS AND METHODS: Data on 765 participants in anagliptin phase 2 and 3 studies were analyzed. Adjusted changes in variables during 12 weeks of anagliptin therapy were compared with a placebo. HIC was calculated as the ratio, C-peptide area under the curve 0-120 min to insulin area under the curve 0-120 min, after a meal tolerance test. To explore the effects of baseline HIC levels on variables, participants receiving anagliptin were divided according to quartiles of baseline HIC. Furthermore, multivariate analysis investigated the association between baseline HIC levels and glycemic status. RESULTS: Anagliptin significantly reduced glycosylated hemoglobin levels (P < 0.001 vs placebo) and HIC levels (P < 0.01). Longer duration of diabetes, lower body mass index, higher glycosylated hemoglobin and lower insulin secretion capacity were observed with increases in baseline HIC levels. Improvements in glycosylated hemoglobin, glycoalbumin and 1,5-anhydroglucitol levels were greater in the relatively higher HIC group (baseline HIC levels ≥median) than in the lower HIC group (<median). CONCLUSIONS: Anagliptin affected HIC levels according to HIC baseline levels. Higher baseline HIC values might result in improved hyperglycemia through reduced HIC.

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  • Body flexibility and incident hypertension: The Niigata wellness study. Reviewed International journal

    Yuko Gando, Susumu S Sawada, Haruki Momma, Ryoko Kawakami, Motohiko Miyachi, I-Min Lee, Steven N Blair, Minoru Tashiro, Chika Horikawa, Yasuhiro Matsubayashi, Takaho Yamada, Kazuya Fujihara, Kiminori Kato, Hirohito Sone

    Scandinavian journal of medicine & science in sports   31 ( 3 )   702 - 709   2021.3

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    A high level of physical fitness, especially cardiorespiratory fitness, is associated with lower incidence of hypertension. However, the relationship between flexibility, which is a component of physical fitness, and the incidence of hypertension is unknown. The purpose of this study was to investigate the relationship between flexibility and the incidence of hypertension in a cohort study. A total of 22,972 (14,805 men and 8167 women; median age 49 years) normotensive participants were included in this study. Between April 2001 and March 2002, flexibility (standing forward bending) was measured using a standing trunk flexion meter. The participants were divided into quartiles of flexibility by sex and age group. Hypertension was defined as systolic blood pressure ≥ 140 mm Hg, diastolic blood pressure ≥ 90 mm Hg, or a self-reported history of previously diagnosed hypertension or current medication for hypertension at a health examination between April 2002 and March 2008. Hazard ratios and 95% confidence intervals (95% CI) for the incidence of hypertension were estimated using Cox proportional hazards models after adjusting for age, sex, body mass index, exercise habits, smoking status, and drinking status. During 102,948 person years of follow-up (median 5.6 years), 4235 participants developed hypertension. Compared with the lowest flexibility (quartile 1), hazard ratios and 95% CI were 0.96 (0.88 - 1.04) for quartile 2, 0.94 (0.86 - 1.03) for quartile 3, and 0.83 (0.76 - 0.91) for quartile 4. A high level of flexibility was associated with lower incidence of hypertension, independent of other confounding factors.

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  • Severity of hypertension as a predictor of initiation of dialysis among study participants with and without diabetes mellitus. Reviewed International journal

    Taeko Osawa, Kazuya Fujihara, Mayuko Harada Yamada, Masahiko Yamamoto, Masaru Kitazawa, Yasuhiro Matsubayashi, Midori Iwanaga, Takaho Yamada, Hiroyasu Seida, Satoru Kodama, Yoshimi Nakagawa, Hitoshi Shimano, Hirohito Sone

    Journal of investigative medicine : the official publication of the American Federation for Clinical Research   69 ( 3 )   724 - 729   2021.3

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    To determine associations between severity of hypertension and risk of starting dialysis in the presence or absence of diabetes mellitus (DM). A nationwide database with claims data on 258 874 people with and without DM aged 19-72 years in Japan was used to elucidate the impact of severity of hypertension on starting dialysis. Initiation of dialysis was determined from claims using International Classification of Diseases-10 codes and medical procedures. Using multivariate Cox modeling, we investigated the severity of hypertension to predict the initiation of dialysis with and without DM. Hypertension was significantly associated with the initiation of dialysis regardless of DM. The incidence of starting dialysis in those with systolic blood pressure (SBP) ≤119 mm Hg and DM (DM+) was almost the same as in those with SBP ≥150 mm Hg and absence of DM (DM-). In comparison with SBP ≤119 mm Hg, SBP ≥150 mm Hg significantly increased the risk of the initiation of dialysis about 2.5 times regardless of DM+ or DM-. Compared with DM- and SBP ≤119 mm Hg, the HR for DM+ and SBP ≥150 mm Hg was 6.88 (95% CI 3.66 to 12.9). Although the risks of hypertension differed only slightly regardless of the presence or absence of DM, risks for starting dialysis with DM+ and SBP ≤119 mm Hg were equivalent to DM- and SBP ≥150 mm Hg, indicating more strict blood pressure interventions in DM+ are needed to avoid dialysis. Future studies are required to clarify the cut-off SBP level to avoid initiation of dialysis considering the risks of strict control of blood pressure.

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  • Hepatocellular carcinoma development in diabetic patients: a nationwide survey in Japan

    Ryosuke Tateishi, Takeshi Matsumura, Takeshi Okanoue, Toshihide Shima, Koji Uchino, Naoto Fujiwara, Takafumi Senokuchi, Kazuyoshi Kon, Takayoshi Sasako, Makiko Taniai, Takumi Kawaguchi, Hiroshi Inoue, Hirotaka Watada, Naoto Kubota, Hitoshi Shimano, Shuichi Kaneko, Etsuko Hashimoto, Sumio Watanabe, Goshi Shiota, Kohjiro Ueki, Kosuke Kashiwabara, Yutaka Matsuyama, Hideo Tanaka, Masato Kasuga, Eiichi Araki, Kazuhiko Koike, Yoshiyasu Karino, Shuhei Hige, Masatomo Sekiguchi, Koji Ogawa, Hideaki Miyoshi, Kyu Yong Cho, Masaru Baba, Atsushi Inoue, Kazuobu Aso, Mitsuyoshi Okada, Yasuhiro Takikawa, Kei Endo, Yasushi Ishigaki, Hirobumi Togashi, Michiaki Unno, Takanori Morikawa, Hideki Katagiri, Shojiro Sawada, Hiromasa Ohira, Atsushi Takahashi, Michio Shimabukuro, Akihiro Kudo, Naomi Tanaka, Junko Mitsuhashi, Toshifumi Tokai, Yasushi Matsuzaki, Tadashi Ikegami, Masato Imai, Kou Nishikawa, Sadao Takahashi, Sumiko Nagoshi, Kosuke Maezawa, Masafumi Matsuda, Tetsuhiro Chiba, Masayuki Yokoyama, Koutaro Yokote, Yoko Hidetaka, Mitsuhiko Moriyama, Hitomi Nakamura, Midori Fujishiro, Tadakazu Hisamatsu, Kaori Nishikawa, Toshihiko Nouchi, Yuki Sakurai, Harumi Daikoku, Michinori Murayama, Yoshinori Saigusa, Takashi Matsui, Ryosuke Tateishi, Hidenari Nagai, Takanori Mukozu, Takahisa Hirose, Masahiko Miyagi, Hiroaki Sato, Akira Mizuki, Masanori Miura, Yuzuru Sato, Rena Kaneko, Kumiko Hamano, Hiroko Kato, Kentaro Kikuchi, Yusuke Kajiyama, Makoto Chuma, Hiroko Ito, Hiroshi Yasuda, Nobuyuki Matsumoto, Yasushi Tanaka, Yoshio Nagai, Kento Imajo, Yasuo Terauchi, Yuzuru Ito, Shuji Terai, Hirohito Sone, Satoshi Matsunaga

    Journal of Gastroenterology   56 ( 3 )   261 - 273   2021.3

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    Background: Although type 2 diabetes mellitus (T2DM) is a known risk factor for hepatocellular carcinoma (HCC) development, the annual incidence in diabetes patients is far below the threshold of efficient surveillance. This study aimed to elucidate the risk factors for HCC in diabetic patients and to determine the best criteria to identify surveillance candidates. Methods: The study included 239 patients with T2DM who were diagnosed with non-viral HCC between 2010 and 2015, with ≥ 5 years of follow-up at diabetes clinics of 81 teaching hospitals in Japan before HCC diagnosis, and 3277 non-HCC T2DM patients from a prospective cohort study, as controls. Clinical data at the time of and 5 years before HCC diagnosis were collected. Results: The mean patient age at HCC diagnosis was approximately 73 years, and 80% of the patients were male. The proportion of patients with insulin use increased, whereas the body mass index (BMI), proportion of patients with fatty liver, fasting glucose levels, and hemoglobin A1c (HbA1c) levels decreased significantly in 5 years. In the cohort study, 18 patients developed HCC during the mean follow-up period of 4.7 years with an annual incidence of 0.11%. Multivariate logistic regression analyses showed that the FIB-4 index was an outstanding predictor of HCC development along with male sex, presence of hypertension, lower HbA1c and albumin levels, and higher BMI and gamma-glutamyl transpeptidase levels. Receiver-operating characteristic analyses showed that a FIB-4 cut-off value of 3.61 could help identify high-risk patients, with a corresponding annual HCC incidence rate of 1.1%. Conclusion: A simple calculation of the FIB-4 index in diabetes clinics can be the first step toward surveillance of HCC with a non-viral etiology.

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  • Sodium Intake and Incidence of Diabetes Complications in Elderly Patients with Type 2 Diabetes-Analysis of Data from the Japanese Elderly Diabetes Intervention Study (J-EDIT). Reviewed International journal

    Chika Horikawa, Rei Aida, Shiro Tanaka, Chiemi Kamada, Sachiko Tanaka, Yukio Yoshimura, Remi Kodera, Kazuya Fujihara, Ryo Kawasaki, Tatsumi Moriya, Hidetoshi Yamashita, Hideki Ito, Hirohito Sone, Atsushi Araki

    Nutrients   13 ( 2 )   2021.2

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    This study investigates the associations between sodium intake and diabetes complications in a nationwide cohort of elderly Japanese patients with type 2 diabetes aged 65-85. Data from 912 individuals regarding their dietary intake at baseline is analyzed and assessed by the Food Frequency Questionnaire based on food groups. Primary outcomes are times to diabetic retinopathy, overt nephropathy, cardiovascular disease (CVD), and all-cause mortality during six years. We find that mean sodium intake in quartiles ranges from 2.5 g to 5.9 g/day. After adjustment for confounders, no significant associations are observed between sodium intake quartiles and incidence of diabetes complications and mortality, except for a significant trend for an increased risk of diabetic retinopathy (p = 0.039). Among patients whose vegetable intake was less than the average of 268.7 g, hazard ratios (HRs) for diabetic retinopathy in patients in the second, third, and fourth quartiles of sodium intake compared with the first quartile were 0.87 (95% CI, 0.31-2.41), 2.61 (1.00-6.83), and 3.70 (1.37-10.02), respectively. Findings indicate that high sodium intake under conditions of low vegetable intake is associated with an elevated incidence of diabetic retinopathy in elderly patients with type 2 diabetes.

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  • Ability of Current Machine Learning Algorithms to Predict and Detect Hypoglycemia in Patients With Diabetes Mellitus: Meta-analysis. Reviewed International journal

    Satoru Kodama, Kazuya Fujihara, Haruka Shiozaki, Chika Horikawa, Mayuko Harada Yamada, Takaaki Sato, Yuta Yaguchi, Masahiko Yamamoto, Masaru Kitazawa, Midori Iwanaga, Yasuhiro Matsubayashi, Hirohito Sone

    JMIR diabetes   6 ( 1 )   e22458   2021.1

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    BACKGROUND: Machine learning (ML) algorithms have been widely introduced to diabetes research including those for the identification of hypoglycemia. OBJECTIVE: The objective of this meta-analysis is to assess the current ability of ML algorithms to detect hypoglycemia (ie, alert to hypoglycemia coinciding with its symptoms) or predict hypoglycemia (ie, alert to hypoglycemia before its symptoms have occurred). METHODS: Electronic literature searches (from January 1, 1950, to September 14, 2020) were conducted using the Dialog platform that covers 96 databases of peer-reviewed literature. Included studies had to train the ML algorithm in order to build a model to detect or predict hypoglycemia and test its performance. The set of 2 × 2 data (ie, number of true positives, false positives, true negatives, and false negatives) was pooled with a hierarchical summary receiver operating characteristic model. RESULTS: A total of 33 studies (14 studies for detecting hypoglycemia and 19 studies for predicting hypoglycemia) were eligible. For detection of hypoglycemia, pooled estimates (95% CI) of sensitivity, specificity, positive likelihood ratio (PLR), and negative likelihood ratio (NLR) were 0.79 (0.75-0.83), 0.80 (0.64-0.91), 8.05 (4.79-13.51), and 0.18 (0.12-0.27), respectively. For prediction of hypoglycemia, pooled estimates (95% CI) were 0.80 (0.72-0.86) for sensitivity, 0.92 (0.87-0.96) for specificity, 10.42 (5.82-18.65) for PLR, and 0.22 (0.15-0.31) for NLR. CONCLUSIONS: Current ML algorithms have insufficient ability to detect ongoing hypoglycemia and considerate ability to predict impeding hypoglycemia in patients with diabetes mellitus using hypoglycemic drugs with regard to diagnostic tests in accordance with the Users' Guide to Medical Literature (PLR should be ≥5 and NLR should be ≤0.2 for moderate reliability). However, it should be emphasized that the clinical applicability of these ML algorithms should be evaluated according to patients' risk profiles such as for hypoglycemia and its associated complications (eg, arrhythmia, neuroglycopenia) as well as the average ability of the ML algorithms. Continued research is required to develop more accurate ML algorithms than those that currently exist and to enhance the feasibility of applying ML in clinical settings. TRIAL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews CRD42020163682; http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42020163682.

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  • Le Carbone prevents liver damage in non-alcoholic steatohepatitis-hepatocellular carcinoma mouse model via AMPKα-SIRT1 signaling pathway activation. Reviewed International journal

    Mst Rejina Afrin, Somasundaram Arumugam, Vigneshwaran Pitchaimani, Vengadeshprabhu Karuppagounder, Rajarajan Amirthalingam Thandavarayan, Meilei Harima, Chowdhury Faiz Hossain, Kenji Suzuki, Hirohito Sone, Yasuhiro Matsubayashi, Kenichi Watanabe

    Heliyon   7 ( 1 )   e05888   2021.1

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    Le Carbone (LC), a fiber-enriched activated charcoal dietary supplement, claimed to be effective against inflammation associated with colitis, trimethylaminuria, and sclerosis. The study aimed to investigate the underlying mechanisms of LC to protect liver damage and its progression in non-alcoholic steatohepatitis-hepatocellular carcinoma (NASH-HCC) mice. To induce this model, C57BL/6J male baby mice were injected with a low-dose of streptozotocin and fed with a high-fat diet (HFD) 32 during 4 weeks-16 weeks of age. The LC suspension was administered orally at a dose of 5 mg/mouse/day started at the age of 6 weeks and continued until 16 weeks of age along with HFD32 feeding. At the end of the experiment, serum and liver tissues were collected for the biochemical, histological, and molecular analysis. We found that LC suspension improved the histopathological changes, serum aminotransferases in NASH mice. The hepatic expression of metabolic proteins, p-AMPKα and sirtuin 1, and proteins responsible for β-oxidation of fatty acids, peroxisome proliferator-activated receptor (PPAR) γ coactivator-α, PPARα were significantly repressed in NASH mice. LC treatment markedly restored these expressions. LC treatment significantly reduced the hepatic proteins expressions of PPARγ, tissue inhibitor of metalloproteinases 4, p47phox, p-JNK, p-ERK1/2, glypican-3, and prothrombin in NASH mice. Our findings demonstrate that LC prevents the liver damage and progression of NASH, possibly by enhancing the AMPK-SIRT1 signaling pathway.

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  • Enterohepatic Transcription Factor CREB3L3 Protects Atherosclerosis via SREBP Competitive Inhibition. International journal

    Yoshimi Nakagawa, Yunong Wang, Song-Iee Han, Kanako Okuda, Asayo Oishi, Yuka Yagishita, Kae Kumagai, Hiroshi Ohno, Yoshinori Osaki, Yuhei Mizunoe, Masaya Araki, Yuki Murayama, Hitoshi Iwasaki, Morichika Konishi, Nobuyuki Itoh, Takashi Matsuzaka, Hirohito Sone, Nobuhiro Yamada, Hitoshi Shimano

    Cellular and molecular gastroenterology and hepatology   11 ( 4 )   949 - 971   2021

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    BACKGROUND & AIMS: cAMP responsive element-binding protein 3 like 3 (CREB3L3) is a membrane-bound transcription factor involved in the maintenance of lipid metabolism in the liver and small intestine. CREB3L3 controls hepatic triglyceride and glucose metabolism by activating plasma fibroblast growth factor 21 (FGF21) and lipoprotein lipase. In this study, we intended to clarify its effect on atherosclerosis. METHODS: CREB3L3-deficifient, liver-specific CREB3L3 knockout, intestine-specific CREB3L3 knockout, both liver- and intestine-specific CREB3L3 knockout, and liver CREB3L3 transgenic mice were crossed with LDLR-/- mice. These mice were fed with a Western diet to develop atherosclerosis. RESULTS: CREB3L3 ablation in LDLR-/- mice exacerbated hyperlipidemia with accumulation of remnant APOB-containing lipoprotein. This led to the development of enhanced aortic atheroma formation, the extent of which was additive between liver- and intestine-specific deletion. Conversely, hepatic nuclear CREB3L3 overexpression markedly suppressed atherosclerosis with amelioration of hyperlipidemia. CREB3L3 directly up-regulates anti-atherogenic FGF21 and APOA4. In contrast, it antagonizes hepatic sterol regulatory element-binding protein (SREBP)-mediated lipogenic and cholesterogenic genes and regulates intestinal liver X receptor-regulated genes involved in the transport of cholesterol. CREB3L3 deficiency results in the accumulation of nuclear SREBP proteins. Because both transcriptional factors share the cleavage system for nuclear transactivation, full-length CREB3L3 and SREBPs in the endoplasmic reticulum (ER) functionally inhibit each other. CREB3L3 promotes the formation of the SREBP-insulin induced gene 1 complex to suppress SREBPs for ER-Golgi transport, resulting in ER retention and inhibition of proteolytic activation at the Golgi and vice versa. CONCLUSIONS: CREB3L3 has multi-potent protective effects against atherosclerosis owing to new mechanistic interaction between CREB3L3 and SREBPs under atherogenic conditions.

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  • Skipping breakfast, late-night eating and current smoking are associated with medication adherence in Japanese patients with diabetes. Reviewed International journal

    Yuta Yaguchi, Kazuya Fujihara, Mayuko Harada Yamada, Yasuhiro Matsubayashi, Masaru Kitazawa, Taeko Osawa, Masahiko Yamamoto, Masanori Kaneko, Nauta Yamanaka, Hiroyasu Seida, Satoru Kodama, Hirohito Sone

    Primary care diabetes   14 ( 6 )   753 - 759   2020.12

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    AIMS: Little is known about the relationship between medication adherence for oral hypoglycemic agents (OHAs) and glycemic control after adjusting healthy adherer effect in large scale study. Thus, adjusting for health-related behaviors, we investigated the clinical variables associated with medication adherence and the relationship between medication adherence and glycemic control using a large claims database. METHODS: Analyzed were 8805 patients with diabetes whose medication records for OHA were available for at least 1year. Medication adherence was evaluated by the proportion of days covered (PDC). Multivariate logistic regression model was used to identify clinical variables significantly associated with non-adherence. Multiple regression analysis evaluated the relationship between PDC and HbA1c after adjusting for health-related behaviors. RESULTS: Mean PDC was 80.1% and 32.8% of patients were non-adherence. Logistic analysis indicated that older age and taking concomitant medications were significantly associated with adherence while skipping breakfast (odds ratio 0.66 [95% CI 0.57-0.76]), late-night eating (0.86 [0.75-0.98]), and current smoking (0.89 [0.80-0.99]) were significantly associated with non-adherence. CONCLUSIONS: Skipping breakfast, late-night eating and current smoking were significantly associated with medication adherence, suggesting that clinicians pay attention to those health-related behaviors to achieve good medication adherence.

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  • Marker chromosome is a strong poor prognosis factor after allogeneic HSCT for adverse-risk AML patients. Reviewed International journal

    Kyoko Fuse, Tomoyuki Tanaka, Yasuhiko Shibasaki, Tatsuo Furukawa, Miwako Narita, Hirohito Sone, Masayoshi Masuko

    European journal of haematology   105 ( 5 )   616 - 625   2020.11

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    INTRODUCTION: Chromosome analysis is necessary for the risk classification of acute myeloid leukemia (AML). Marker chromosome (MC) is a fragmented chromosome whose origin cannot be identified from other chromosomes and originates from marked genomic instability. Although AML with MC (MC+) has a poor prognosis even after intensive chemotherapy, its influence on the outcome after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is unclear. OBJECTIVE AND METHODS: We retrospectively analyzed 162 AML patients after allo-HSCT. To evaluate the significance of MC, we compared it with other chromosomal abnormalities. RESULT: Marker chromosome was detected in 14 (8.6%, MC+) patients (vs MC-, n = 158). The 2-year overall survival (OS) in MC+ vs MC- was 26.8% vs 62.2% (P = .0098). The 2-year cumulative incidence of relapse (CIR) in MC+ vs MC- was 80.4% vs 35.5% (P = .0004). Among adverse-risk AML (AD-AML, n = 36), AD-AML/MC+ (n = 11) demonstrated a poorer 2-year OS (9.1%, vs AD-AML/MC- n = 25, 58.3%, P = .0031) and higher 2-year CIR (89.6%, vs AD-AML/MC- 44.7%, P = .002). In multivariate analysis, MC (HR 3.08, 95% CI; 1.02-9.29, P = .046) and HCT-CI (HR 3.23, 95% CI; 1.00-10.4, P = .049) were independent risk factors for CIR among AD-AML. CONCLUSION: Our study suggests MC as a new independent factor for chromosome risk classification to further classify AD-AML.

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  • Network Meta-Analysis of Drug Therapies for Lowering Uric Acid and Mortality Risk in Patients with Heart Failure. Reviewed International journal

    Satoru Kodama, Kazuya Fujihara, Chika Horikawa, Mayuko Yamada, Takaaki Sato, Yuta Yaguchi, Masahiko Yamamoto, Masaru Kitazawa, Yasuhiro Matsubayashi, Takaho Yamada, Kenichi Watanabe, Hirohito Sone

    Cardiovascular drugs and therapy   35 ( 6 )   1217 - 1225   2020.10

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    PURPOSE: This network meta-analysis aimed to assess the current efficacy of decreasing the uric acid (UA) level with drugs to reduce mortality in patients with heart failure (HF). METHODS: Electronic literature searches using EMBASE and MEDLINE of studies published from 1 Jan 1950 to 26 Dec 2019 were conducted for randomized controlled trials or non-randomized cohort studies that included at least one group of patients who took UA-lowering drugs and with a study outcome of all-cause mortality. A random-effects network meta-analysis was performed within a frequentist framework. Hierarchy of treatments was expressed as the surface under the cumulative ranking curve (SUCRA) value, which is in proportion to mean rank (best is 100%). RESULTS: Nine studies, which included seven different types of groups, were eligible for analysis. The "untreated uricemia" group in which patients had hyperuricemia but without treatment had a significantly higher risk of mortality than the "no uricemia" group in which patients had no hyperuricemia (relative risk (RR)(95% confidence interval (CI), 1.43 (1.08-1.89)). The "start-allo" group wherein patients started to take allopurinol did not have a significantly lower risk of mortality than the "untreated uricemia" group (RR (95% CI), 0.68 (0.45-1.01)). However, in the "start-allo" group the SUCRA value was comparable to that in the "no uricemia" group (SUCRA: 65.4% for "start-allo"; 64.1% for "no uricemia"). CONCLUSIONS: Results suggested that allopurinol therapy was not associated with a significantly improved prognosis in terms of mortality but could potentially counteract the adverse effects associated with longstanding hyperuricemia in HF patients.

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  • A Prospective Cohort Study of Muscular and Performance Fitness and Incident Glaucoma: The Niigata Wellness Study. Reviewed International journal

    Ryoko Kawakami, Yuko Gando, Kiminori Kato, Susumu S Sawada, Haruki Momma, Motohiko Miyachi, I-Min Lee, Steven N Blair, Minoru Tashiro, Chika Horikawa, Yasuhiro Matsubayashi, Takaho Yamada, Kazuya Fujihara, Hirohito Sone

    Journal of physical activity & health   17 ( 11 )   1171 - 1178   2020.10

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    BACKGROUND: To examine the association between muscular and performance fitness (MPF) and the incidence of glaucoma. METHODS: A total of 27,051 glaucoma-free participants aged 20-87 years underwent physical fitness tests between April 2001 and March 2002. The MPF index was calculated using an age- and sex-specific summed z-score from grip strength, vertical jump, single-leg balance, forward bending, and whole-body reaction time. The participants were divided into quartiles according to the MPF index and each physical fitness test. Participants were followed up for the development of glaucoma, which was defined based on physician-diagnosed glaucoma at an annual health examination between April 2002 and March 2008. Hazard ratios for the incidence of glaucoma were estimated using Cox proportional hazards models. RESULTS: During follow-up, 303 participants developed glaucoma. Compared with the lowest MPF index group, hazard ratio (95% confidence interval) of developing glaucoma was 0.64 (0.46-0.89) for the highest MPF index group (P for trend = .001). Vertical jump and whole-body reaction time were associated with incident glaucoma (P for trend = .01 and <.001, respectively). There were no associations between the other physical fitness tests and the incidence of glaucoma. CONCLUSION: Higher MPF is associated with lower incidence of glaucoma.

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  • Diabetes mellitus and risk of new-onset and recurrent heart failure: a systematic review and meta-analysis. Reviewed International journal

    Satoru Kodama, Kazuya Fujihara, Chika Horikawa, Takaaki Sato, Midori Iwanaga, Takaho Yamada, Kiminori Kato, Kenichi Watanabe, Hitoshi Shimano, Tohru Izumi, Hirohito Sone

    ESC heart failure   7 ( 5 )   2146 - 2174   2020.10

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    Despite mounting evidence of the positive relationship between diabetes mellitus (DM) and heart failure (HF), the entire context of the magnitude of risk for HF in relation to DM remains insufficiently understood. The principal reason is because new-onset HF (HF occurring in participants without a history of HF) and recurrent HF (HF re-occurring in patients with a history of HF) are not discriminated. This meta-analysis aims to comprehensively and separately assess the risk of new-onset and recurrent HF depending on the presence or absence of DM. We systematically searched cohort studies that examined the relationship between DM and new-onset or recurrent HF using EMBASE and MEDLINE (from 1 Jan 1950 to 28 Jul 2019). The risk ratio (RR) for HF in individuals with DM compared with those without DM was pooled with a random-effects model. Seventy-four and 38 eligible studies presented data on RRs for new-onset and recurrent HF, respectively. For new-onset HF, the pooled RR [95% confidence interval (CI)] of 69 studies that examined HF as a whole [i.e. combining HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF)] was 2.14 (1.96-2.34). The large between-study heterogeneity (I2 = 99.7%, P < 0.001) was significantly explained by mean age [pooled RR (95% CI) 2.60 (2.38-2.84) for mean age < 60 years vs. pooled RR (95% CI) 1.95 (1.79-2.13) for mean age ≥ 60 years] (P < 0.001). Pooled RRs (95% CI) of seven and eight studies, respectively, that separately examined HFpEF and HFrEF risk were 2.22 (2.02-2.43) for HFpEF and 2.73 (2.71-2.75) for HFrEF. The risk magnitudes between HFpEF and HFrEF were not significantly different in studies that examined both HFpEF and HFrEF risks (P = 0.86). For recurrent HF, pooled RR (95% CI) of the 38 studies was 1.39 (1.33-1.45). The large between-study heterogeneity (I2 = 80.1%, P < 0.001) was significantly explained by the proportion of men [pooled RR (95% CI) 1.53 (1.40-1.68) for < 65% men vs. 1.32 (1.25-1.39) for ≥65% men (P = 0.01)] or the large pooled RR for studies of only participants with HFpEF [pooled RR (95% CI), 1.73 (1.32-2.26) (P = 0.002)]. Results indicate that DM is a significant risk factor for both new-onset and recurrent HF. It is suggested that the risk magnitude is large for new-onset HF especially in young populations and for recurrent HF especially in women or individuals with HFpEF. DM is associated with future HFpEF and HFrEF to the same extent.

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  • Association of treatment-achieved HbA1c with incidence of coronary artery disease and severe eye disease in diabetes patients Reviewed

    M. Harada, K. Fujihara, T. Osawa, M. Yamamoto, M. Kaneko, M. Ishizawa, Y. Matsubayashi, T. Yamada, N. Yamanaka, H. Seida, S. Kodama, W. Ogawa, H. Sone

    Diabetes & Metabolism   46 ( 4 )   331 - 334   2020.9

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  • Association of treatment-achieved HbA1c with incidence of coronary artery disease and severe eye disease in diabetes patients Reviewed

    M. Harada, K. Fujihara, T. Osawa, M. Yamamoto, M. Kaneko, M. Ishizawa, Y. Matsubayashi, T. Yamada, N. Yamanaka, H. Seida, S. Kodama, W. Ogawa, H. Sone

    Diabetes & Metabolism   46 ( 4 )   331 - 334   2020.9

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  • Applications of physical performance measures to routine diabetes care for frailty prevention concept: fundamental data with grip strength, gait speed, timed chair stand speed, standing balance, and knee extension strength. Reviewed International journal

    Hiroki Yokoyama, Toshihiko Shiraiwa, Mitsuyoshi Takahara, Masahiro Iwamoto, Nobuichi Kuribayashi, Takuo Nomura, Minoru Yamada, Hirohito Sone, Shin-Ichi Araki

    BMJ open diabetes research & care   8 ( 1 )   2020.9

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    INTRODUCTION: Progression of muscle strength weakening will lead to a poor physical performance and disability. While this is particularly important in patients with diabetes, the associations of reduced muscle strength measured by grip strength with clinical features and physical performance remain unclear. We investigated clinical features and physical performance measures in association with grip strength in elderly people with diabetes in a primary care setting. RESEARCH DESIGN AND METHODS: A cross-sectional study was conducted enrolling 634 male and 323 female Japanese patients with type 2 diabetes aged 60 years or older. First, grip strength was measured and the associations of gender-specific grip strength with clinical features were evaluated. Second, in patients with a grip strength below the gender-specific median, physical performance measures, including gait speed, timed chair stand speed, knee extension strength, standing balance, and short physical performance battery scores, were investigated. Patients with and without a low performance defined by Asian Working Group for Sarcopenia were compared in terms of clinical features and physical performance measures. RESULTS: Grip strength decreased according to aging and longer duration of diabetes and was independently related to body mass index, glycated hemoglobin A1c (HbA1c), serum albumin, albuminuria, neuropathy, and stroke in male patients, and to body mass index and albuminuria in female patients. The physical performance measures became worse proportionally to a decrease in the grip strength. Patients with a low performance exhibited a significantly older age, lower grip strength and serum albumin, higher albuminuria, and poorer physical performance measures than those without. CONCLUSIONS: Reduced grip strength was associated with glycemic exposure indicators of age-related duration, HbA1c, and vascular complications. The physical performance measures became worse with decreasing grip strength. Measurements of grip strength and physical performance in patients with diabetes may help promote intervention to prevent frailty in future studies.

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  • Family Support for Medical Nutritional Therapy and Dietary Intake among Japanese with Type 2 Diabetes (JDDM 56). Reviewed International journal

    Chika Horikawa, Mariko Hatta, Sakiko Yoshizawa Morikawa, Yasunaga Takeda, Mizuki Takeuchi, Kazuya Fujihara, Noriko Kato, Hiroki Yokoyama, Yoshio Kurihara, Koichi Iwasaki, Shiro Tanaka, Hiroshi Maegawa, Hirohito Sone

    Nutrients   12 ( 9 )   2020.8

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    The aim of this study was to investigate the association between habitual dietary intake for patients with diabetes and the content of family support for medical nutritional therapy (MNT). Analyzed were 289 Japanese with type 2 diabetes (men, 58.5%; mean age, 62.0 years; mean HbA1c, 53.4 mmol/mol) who completed the Food Frequency Questionnaire and Diabetes Family Behavior Checklist (DFBC). Relationships of mean values for food group intake to DFBC responses regarding MNT were examined using multivariate analysis of covariance. Positive response to "Praise for following diet" was associated with lower sweets intake (none: 60.1 g/day; ≥once monthly: 50.9 g/day, p = 0.038) and higher seasoning intake (none: 21.6 g/day, ≥once monthly: 24.1 g/day, p = 0.046). Energy intake was higher with positive responses to "Eat at the same time that you do" (none: 1636 kcal/day, ≥once monthly: 1818 kcal/day, p = 0.038). "Nags about not following diet" was associated with higher fish (none: 68.7 g/day, ≥once monthly: 78.7 g/day, p = 0.042) and salt intake (none: 8.3 g/day, ≥once monthly: 9.0 g/day, p = 0.014). Eating foods not part of the diabetic diet (none: 218.4 g/day, ≥once monthly: 246.9 g/day, p = 0.014) resulted in a higher vegetable intake. In females, significant differences in relationships in the overall analysis were reversed. Our results clarified relationships between types of family support of patients with type 2 diabetes and their dietary intake and the importance of sex differences for more effective MNT.

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  • Successful Treatment with Edoxaban for Disseminated Intravascular Coagulation in a Case of Aortic Dissection Complicated with Immune Thrombocytopenic Purpura. Reviewed

    Shun Uemura, Hironori Kobayashi, Yoshinobu Seki, Yuki Okoshi, Hirohito Sone, Nobuhiko Nomoto

    Internal medicine (Tokyo, Japan)   59 ( 16 )   2035 - 2039   2020.8

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    A 70-year-old woman was hospitalized for exacerbation of chronic idiopathic thrombocytopenic purpura (ITP) and disseminated intravascular coagulation (DIC) from old aortic dissection. Initially, we increased the dose of prednisolone for ITP. However, her bleeding tendency caused by DIC worsened despite the rapid recovery of her platelet count, and the required amount of fresh-frozen plasma for transfusion increased. The administration of edoxaban for atrial fibrillation led to the marked improvement of her DIC status without serious adverse events. This case suggests that a direct oral anticoagulant may be an effective treatment for DIC caused by aortic dissection.

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  • ガイドラインからみた糖尿病の食事療法における課題 高齢者糖尿病の食事療法

    荒木 厚, 大村 卓也, 山岡 巧弥, 田村 嘉章, 曽根 博仁

    糖尿病   63 ( Suppl.1 )   S - 83   2020.8

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  • 1型糖尿病に対して膵腎同時移植を施行し透析およびインスリンを離脱した1例

    岸 裕太郎, 竹内 亮, 山本 正彦, 松林 泰弘, 藤原 和哉, 岩永 みどり, 山田 高穂, 曽根 博仁, 三浦 宏平, 小林 隆, 若井 俊文

    糖尿病   63 ( 8 )   558 - 558   2020.8

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  • Brain adaptations of insulin signaling kinases, GLUT 3, p-BADser155 and nitrotyrosine expression in various hypoglycemic models of mice. Reviewed International journal

    Vigneshwaran Pitchaimani, Somasundaram Arumugam, Rajarajan Amirthalingam Thandavarayan, Vengadeshprabhu Karuppagounder, Mst Rejina Afrin, Remya Sreedhar, Meilei Harima, Masahiko Nakamura, Kenichi Watanabe, Satoru Kodama, Kazuya Fujihara, Hirohito Sone

    Neurochemistry international   137   104745 - 104745   2020.7

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    AIM AND OBJECTIVE: Insulin-induced moderate or severe hypoglycemia (MH or SH) impairs cognition and SH causes neuronal death. On the contrary, alternate day fasting (ADF) protects the brain during excitotoxic stress and improves cognitive function. Unlike the scenario in the periphery, insulin and its relationship towards brain glucose uptake and metabolism are considered to be less significant. Yet, the hypoglycemia associated brain metabolism is not clearly understood. The authors broadly investigated the brain metabolism in various hypoglycemic models such as insulin-induced MH, SH, SH with glucose reperfusion, 24 h fasting and ADF in the cortex or hippocampus of C57BL6/J mice. The authors analyzed the protein expression of insulin signaling kinases (plays a key role in neuronal survival and memory), Bcl-2 associated death promoter (p-BADser155) (dephosphorylation inhibits glucokinase activity and reduces glucose or increases ketone body metabolism in the brain), neuronal-specific glucose transporter 3 (GLUT 3) and nitrotyrosine (marker of nitric oxide which is involved in neuronal glucose uptake via GLUT 3) using western blotting analysis. RESULTS: Insulin-induced MH or SH differentially regulated the brain insulin signaling kinases. The expression of p-BADser155 decreased in all hypoglycemic models except the insulin-induced MH in hippocampus. The trended higher GLUT 3 and increased nitrotyrosine expression of insulin-induced SH were restored after glucose reperfusion. The trended higher or increased GLUT 3 and nitrotyrosine expression of ADF were positively correlated with serum beta-hydroxybutyrate levels. CONCLUSION: During hypoglycemia, it can be suggested that the brain might decrease glucose metabolism via glycolysis or prefer ketone body metabolism (except the insulin-induced MH in hippocampus) by modifying the p-BADser155 expression. In addition to the ketone body metabolism, the brain might adapt to uptake glucose in insulin-induced SH or ADF by modifying the GLUT 3 or nitrotyrosine expression.

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  • Hypertrophic pachymeningitis associated with myelodysplastic syndrome

    Akane Kaihatsu, Kyoko Fuse, Hirohito Sone, Masayoshi Masuko

    eJHaem   1 ( 1 )   12 - 13   2020.7

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  • Prevention of postprandial hypotension-related syncope by caffeine in a patient with long-standing diabetes mellitus. Reviewed

    Kazuo Furukawa, Tatsuro Suzuki, Hajime Ishiguro, Hiroshi Morikawa, Keiko Sonoda, Kenichi Iijima, Masahiro Ito, Osamu Hanyu, Hirohito Sone

    Endocrine journal   67 ( 6 )   585 - 592   2020.6

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    A 74-year-old man who had type 2 diabetes mellitus of a duration of 20 years was admitted for syncope after eating a high carbohydrate meal. Although he had had episodes of pallor or syncope after carbohydrate-rich meals, such as with large amounts of white rice, several times within a year and he had been taken to hospitals emergently, the etiology of these episodes had remained unclear despite his undergoing several studies. Studies did show severe orthostatic hypotension during the head-up tilt test and a decrease in the coefficient of variation of the R-R interval (CVR-R) on resting electrocardiogram, suggesting severe autonomic nervous dysfunction. Because of the episodes of syncope after eating a carbohydrate-rich meal, we investigated whether he had postprandial hypotension (PPH). The 75 g oral glucose tolerance test revealed a significant decrease in his postprandial blood pressure by about 40 mmHg, leading to the diagnosis of PPH. The carbohydrate-rich meal test induced syncope with systolic blood pressure under 40 mmHg. Then 150 mg caffeine was administered before a second carbohydrate-rich meal. The marked decline in postprandial blood pressure was suppressed and plasma noradrenaline levels were gradually increased over a period of 60 minutes. Caffeine could be useful for prevention of postprandial hypotension-related syncope.

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  • Association between Low Protein Intake and Mortality in Patients with Type 2 Diabetes. Reviewed International journal

    Takuya Yamaoka, Atsushi Araki, Yoshiaki Tamura, Shiro Tanaka, Kazuya Fujihara, Chika Horikawa, Rei Aida, Chiemi Kamada, Yukio Yoshimura, Tatsumi Moriya, Yasuo Ohashi, Yasuo Akanuma, Hideki Ito, Hirohito Sone

    Nutrients   12 ( 6 )   2020.6

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    The aim of this study was to investigate the association between protein intake and mortality risk in patients with type 2 diabetes. We analyzed a pooled data of 2494 diabetic patients from two prospective longitudinal studies. Nutritional intake was assessed using a Food Frequency Questionnaire at baseline. Protein intake per body weight (kg) per day was categorized into quartile groups. Adjusted hazard ratios (HRs) and 95% confidence interval (CI) were calculated using Cox regression analysis. During the six-year follow-up, there were 152 incidents of all-cause mortality. The HR for mortality in the lowest quartile of protein intake per body weight compared with the highest quartile was 2.26 (95% CI: 1.34-3.82, p = 0.002) after adjustment for covariates. Subgroup analyses revealed significant associations between low protein intake and mortality in patients aged over 75 years or under 65 years. After further adjustment of the total energy intake, a significant association between protein intake and mortality remained in patients aged ≥ 75 years, whereas the association was attenuated in those aged < 65 years. Our results suggest that adequate protein intake is necessary in older diabetic patients over 75 years, whereas with diabetes, whereas whole optimal total energy intake is required in younger patients with type 2 diabetes.

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  • Association of increased hepatic insulin clearance and change in serum triglycerides or β-hydroxybutyrate concentration via the sodium/glucose-cotransporter 2 inhibitor tofogliflozin. Reviewed International journal

    Yasuhiro Matsubayashi, Akihiro Yoshida, Hideki Suganami, Taeko Osawa, Kazuo Furukawa, Hiroshi Suzuki, Kazuya Fujihara, Shiro Tanaka, Kohei Kaku, Hirohito Sone

    Diabetes, obesity & metabolism   22 ( 6 )   947 - 956   2020.6

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    AIMS: Obesity and hepatic fat accumulation diminish hepatic insulin clearance, which can cause hyperinsulinaemia. Sodium/glucose-cotransporter 2 inhibitors (SGLT2-is) improve insulin resistance and hyperinsulinaemia by weight loss via increased urinary glucose excretion in type 2 diabetes. However, there are few reports of the influence of SGLT2-is on hepatic insulin clearance. We examined the impact of an SGLT2-i on hepatic insulin clearance and explored the clinical influence associated with changes in hepatic insulin clearance via an SGLT2-i and the mechanism of the effects of SGLT2-i. MATERIALS AND METHODS: Data were analysed from 419 patients with type 2 diabetes controlled by diet and exercise. Patients received a placebo or the SGLT2-i tofogliflozin (TOFO) (placebo: n = 56; TOFO: n = 363) orally once daily for ≥24 weeks. Hepatic insulin clearance was calculated from the ratio of areas under the curve (AUC) of C-peptide and insulin levels derived from oral meal tolerance test data (C-peptide AUC0-120 min /insulin AUC0-120 min : HICCIR ). The correlation of HICCIR via the SGLT2-i with other clinical variables was analysed using multivariate analysis. RESULTS: HICCIR was significantly increased via TOFO at week 24. Furthermore, with TOFO insulin and triglyceride (TG) levels were significantly reduced (P < 0.001) and β-hydroxybutyrate (BHB) was significantly elevated (P < 0.001). Changes in HICCIR were significantly correlated with changes in TG and BHB via TOFO. CONCLUSIONS: Increased HICCIR was significantly associated with reduced TG via TOFO and contributed to the greater increase in BHB compared with placebo in addition to the correction of hyperinsulinaemia.

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  • Vitamin B6 intake and incidence of diabetic retinopathy in Japanese patients with type 2 diabetes: analysis of data from the Japan Diabetes Complications Study (JDCS). Reviewed International journal

    Chika Horikawa, Rei Aida, Chiemi Kamada, Kazuya Fujihara, Shiro Tanaka, Sachiko Tanaka, Atsushi Araki, Yukio Yoshimura, Tatsumi Moriya, Yasuo Akanuma, Hirohito Sone

    European journal of nutrition   59 ( 4 )   1585 - 1594   2020.6

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    PURPOSE: Although vitamin B6 has been suspected to prevent the progression of diabetic retinopathy, evidence of this in patients with type 2 diabetes based on longitudinal studies is sparse. This study investigated the relationship between vitamin B6 intake and the incidence of diabetic retinopathy in Japanese patients with type 2 diabetes. METHODS: The study was part of an examination of a nationwide cohort of patients with type 2 diabetes aged 40-70 years with HbA1c ≥ 48 mmol/mol. After excluding nonresponders to a dietary survey using the Food Frequency Questionnaire based on food groups, 978 patients were analyzed. Primary outcome was the 8-year risk of a diabetic retinopathy event, and Cox regression analyses estimated hazard ratios (HRs) for retinopathy according to vitamin B6 intake adjusted for age, gender, body mass index, HbA1c, smoking, energy intake, and other confounders. RESULTS: Mean vitamin B6 intake in quartiles ranged from 1.1 to 1.6 mg/day, and half of the participants had vitamin B6 intake below the recommended daily dietary allowance according to dietary reference intakes in Japanese adults (men 1.4 mg/day; women 1.2 mg/day). After adjusting for confounders, HRs for diabetic retinopathy in the 2nd, 3rd, and 4th quartile groups of vitamin B6 intake compared with the 1st quartile group were 1.17 (95% confidence interval 0.81-1.69, p = 0.403), 0.88 (0.58-1.34, p = 0.550), and 0.50 (0.30-0.85, p = 0.010), respectively. CONCLUSIONS: Findings suggested that high vitamin B6 intake was associated with a lower incidence of diabetic retinopathy in Japanese with type 2 diabetes.

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  • Association of Higher Baseline BNP Levels with a Greater Reduction in Plasma Volume and Increase in Beta-Hydroxybutyrate via the SGLT2 Inhibitor Tofogliflozin in Type 2 Diabetes Reviewed

    Akihiro Yoshida, Yasuhiro Matsubayashi, Toshiaki Nojima, Hideki Suganami, Momoko Oe, Kazuya Fujihara, Shiro Tanaka, Kohei Kaku, Hirohito Sone

    DIABETES   69   2020.6

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  • Hepatocyte ELOVL Fatty Acid Elongase 6 Determines Ceramide Acyl-Chain Length and Hepatic Insulin Sensitivity in Mice. Reviewed International journal

    Takashi Matsuzaka, Motoko Kuba, Saori Koyasu, Yuta Yamamoto, Kaori Motomura, Sundaram Arulmozhiraja, Hiroshi Ohno, Rahul Sharma, Takuya Shimura, Yuka Okajima, Song-Iee Han, Yuichi Aita, Yuhei Mizunoe, Yoshinori Osaki, Hitoshi Iwasaki, Shigeru Yatoh, Hiroaki Suzuki, Hirohito Sone, Yoshinori Takeuchi, Naoya Yahagi, Takafumi Miyamoto, Motohiro Sekiya, Yoshimi Nakagawa, Masatsugu Ema, Satoru Takahashi, Hiroaki Tokiwa, Hitoshi Shimano

    Hepatology (Baltimore, Md.)   71 ( 5 )   1609 - 1625   2020.5

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    BACKGROUND AND AIMS: Dysfunctional hepatic lipid metabolism is a cause of nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disorder worldwide, and is closely associated with insulin resistance and type 2 diabetes. ELOVL fatty acid elongase 6 (Elovl6) is responsible for converting C16 saturated and monounsaturated fatty acids (FAs) into C18 species. We have previously shown that Elovl6 contributes to obesity-induced insulin resistance by modifying hepatic C16/C18-related FA composition. APPROACH AND RESULTS: To define the precise molecular mechanism by which hepatic Elovl6 affects energy homeostasis and metabolic disease, we generated liver-specific Elovl6 knockout (LKO) mice. Unexpectedly, LKO mice were not protected from high-fat diet-induced insulin resistance. Instead, LKO mice exhibited higher insulin sensitivity than controls when consuming a high-sucrose diet (HSD), which induces lipogenesis. Hepatic patatin-like phospholipase domain-containing protein 3 (Pnpla3) expression was down-regulated in LKO mice, and adenoviral Pnpla3 restoration reversed the enhancement in insulin sensitivity in HSD-fed LKO mice. Lipidomic analyses showed that the hepatic ceramide(d18:1/18:0) content was lower in LKO mice, which may explain the effect on insulin sensitivity. Ceramide(d18:1/18:0) enhances protein phosphatase 2A (PP2A) activity by interfering with the binding of PP2A to inhibitor 2 of PP2A, leading to Akt dephosphorylation. Its production involves the formation of an Elovl6-ceramide synthase 4 (CerS4) complex in the endoplasmic reticulum and a Pnpla3-CerS4 complex on lipid droplets. Consistent with this, liver-specific Elovl6 deletion in ob/ob mice reduced both hepatic ceramide(d18:1/18:0) and PP2A activity and ameliorated insulin resistance. CONCLUSIONS: Our study demonstrates the key role of hepatic Elovl6 in the regulation of the acyl-chain composition of ceramide and that C18:0-ceramide is a potent regulator of hepatic insulin signaling linked to Pnpla3-mediated NAFLD.

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  • Clinicopathological analysis of splenic red pulp low-grade B-cell lymphoma. Reviewed International journal

    Takaharu Suzuki, Hiroaki Miyoshi, Joji Shimono, Keisuke Kawamoto, Fumiko Arakawa, Takuya Furuta, Kyohei Yamada, Eriko Yanagida, Mai Takeuchi, Masao Seto, Hirohito Sone, Jun Takizawa, Koichi Ohshima

    Pathology international   70 ( 5 )   280 - 286   2020.5

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    Primary splenic low-grade B-cell lymphoma of the red pulp comprises hairy cell leukemia (HCL) and splenic B-cell lymphoma/leukemia, unclassifiable (SPLL-U). SPLL-U is a rare disease that includes subtypes of a hairy cell leukemia-variant (HCL-v), splenic diffuse red pulp small B-cell lymphoma (SDRPL) and other types that are known as narrow sense SPLL-U (SPLL-U-NS). Notably, limited information is available regarding the BRAF mutation (V600E) and cyclin D3 expression in subtypes of SPLL-U. Therefore, we performed a pathological analysis of the BRAF mutation (V600E) and characterized pathological features of SPLL-U. We reviewed the pathological findings of 12 SPLL-U cases. The 12 cases considered included two cases of HCL-v, six cases of SPLL-U-NS and four undetermined cases. The BRAF mutation (V600E) was detected in three cases, which were all SPLL-U-NS. Cases with the BRAF mutation (V600E) have increased levels of CD103 expression and decreased cyclin D3 and cyclin D1 expression compared with cases that lacked the BRAF mutation. These findings suggest that the BRAF mutation might play a significant role in SPLL-U. Therefore, the significance of the BRAF mutation should be evaluated via genomic or transcriptional analyses of a large cohort of SPLL-U patients.

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  • CREBH Improves Diet-Induced Obesity, Insulin Resistance, and Metabolic Disturbances by FGF21-Dependent and FGF21-Independent Mechanisms. Reviewed International journal

    Aoi Satoh, Song-Iee Han, Masaya Araki, Yoshimi Nakagawa, Hiroshi Ohno, Yuhei Mizunoe, Kae Kumagai, Yuki Murayama, Yoshinori Osaki, Hitoshi Iwasaki, Motohiro Sekiya, Morichika Konishi, Nobuyuki Itoh, Takashi Matsuzaka, Hirohito Sone, Hitoshi Shimano

    iScience   23 ( 3 )   100930 - 100930   2020.3

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    Mice overexpressing the nuclear form of CREBH mainly in the liver (CREBH-Tg) showed suppression of high-fat high-sucrose (HFHS) diet-induced obesity accompanied by an increase in plasma fibroblast growth factor 21 (FGF21) levels. CREBH overexpression induced browning in inguinal white adipose tissue (WAT) and whole-body energy expenditure, which was canceled in Fgf21-/- mice. Deficiency of FGF21 in CREBH-Tg mice mostly canceled the improvement of obesity, but the suppression of inflammation of epidermal WAT, amelioration of insulin resistance, and improvement of glucose metabolism still sustained. Kisspeptin 1 (Kiss1) was identified as a novel hormone target for CREBH to explain these FGF21-independent effects of CREBH. Knockdown of Kiss1 in HFHS-fed CREBH-Tg Fgf21-/- mice showed partially canceled improvement of glucose metabolism. Taken together, we propose that hepatic CREBH pleiotropically improves diet-induced obesity-mediated dysfunctions in peripheral tissues by improving systemic energy metabolism in FGF21-dependent and FGF21-independent mechanisms.

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  • Efficacy and safety of empagliflozin as add-on to insulin in Japanese patients with type 2 diabetes: A randomized, double-blind, placebo-controlled trial. Reviewed International journal

    Hirohito Sone, Tatsuroh Kaneko, Kosuke Shiki, Yoshifumi Tachibana, Egon Pfarr, Jisoo Lee, Naoko Tajima

    Diabetes, obesity & metabolism   22 ( 3 )   417 - 426   2020.3

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    AIM: To assess the efficacy and safety of empagliflozin as add-on to insulin in Japanese patients with type 2 diabetes (T2D). MATERIALS AND METHODS: This multicentre, double-blind, parallel-group study randomized Japanese patients with T2D insufficiently controlled with insulin (1:1:1) to empagliflozin 10 mg (n=89), empagliflozin 25 mg (n=90) or placebo (n=90) for 52 weeks. The primary endpoint was change from baseline in glycated haemoglobin (HbA1c) at 16 weeks. RESULTS: At 16 weeks, empagliflozin 10 mg and 25 mg significantly decreased HbA1c: adjusted mean difference -0.92% (95% confidence interval [CI] -1.11, -0.73) and -1.00% (95% CI -1.18, -0.82; both P<0.0001) compared with placebo. This difference was maintained up to 52 weeks: adjusted mean difference at 52 weeks -0.90% (95% CI -1.09, -0.70) and -0.96% (95% CI -1.15, -0.77; both P<0.0001). At 52 weeks, significant improvements in fasting plasma glucose (adjusted mean difference -27.62 mg/dL [95% CI -36.15, -19.08] and -31.99 mg/dL [95% CI -40.35, -23.62]) and in body weight (-1.78 kg [95% CI -2.46, -1.10] and -1.92 kg [95% CI -2.58, -1.25]) were also seen with empagliflozin 10 mg and 25 mg compared with placebo (all P<0.0001). At 52 weeks, the frequency of adverse events (AEs) and serious AEs was similar in the three treatment groups; confirmed hypoglycaemia was reported slightly more in participants in the empagliflozin 10 mg and 25 mg groups (23.3% and 22.2% vs 14.4%). All hypoglycaemic events were mild in severity; no episodes required assistance. CONCLUSIONS: In Japanese patients with insufficiently controlled T2D, adding empagliflozin 10 mg or 25 mg to insulin treatment was associated with clinically meaningful reductions in HbA1c at 16 weeks and was generally well tolerated.

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  • The Glasgow prognostic score divides high-risk hematopoietic cell transplantation-specific comorbidity index patients into stratified subgroups in allogeneic hematopoietic cell transplantation. Reviewed International journal

    Yasuhiko Shibasaki, Tatsuya Suwabe, Takayuki Katagiri, Kyoko Fuse, Miwako Narita, Hirohito Sone, Masayoshi Masuko

    Annals of hematology   99 ( 3 )   671 - 673   2020.3

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  • Combination of diabetes mellitus and lack of habitual physical activity is a risk factor for functional disability in Japanese. Reviewed International journal

    Kazuya Fujihara, Yasuhiro Matsubayashi, Mayuko Harada Yamada, Masaru Kitazawa, Masahiko Yamamoto, Masanori Kaneko, Satoru Kodama, Takuya Yahiro, Ayumu Tsutsui, Kiminori Kato, Hirohito Sone

    BMJ open diabetes research & care   8 ( 1 )   2020.1

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    OBJECTIVE: Declining healthy life expectancy due to functional disability is relevant and urgent because of its association with decreased quality of life and also for its enormous socioeconomic impact. The aim of this study is to examine the impact of diabetes, hypertension, dyslipidemia and physical activity habits on functional disability among community-dwelling Japanese adults. RESEARCH DESIGN AND METHODS: This is a population-based retrospective cohort study including 9673 people aged 39-98 years in Japan (4420, men). Functional disability was defined as a condition meeting Japan's new long-term care insurance certification requirements for the need of assistance in the activities of daily living whether by caregivers or assistive devices. Cox proportional-hazards regression model identified variables related to functional disability. RESULTS: Median follow-up was 3.7 years. During the study period, 165 disabilities occurred in the overall study population. Multivariate analysis showed that diabetes (HR 1.74 (95% CI 1.12 to 2.68)) and no physical activity habit (HR 1.83 (1.27 to 2.65)) presented increased risks for disability. HR for disability increased with the number of risk factors (HR of individuals with four conditions, 3.96 (1.59 to 9.99) vs individuals with none of those conditions as a reference). HR for disability among patients with diabetes with and without a physical activity habit was 1.68 (0.70 to 4.04) and 3.19 (1.79 to 5.70), respectively, compared with individuals without diabetes with a physical activity habit. CONCLUSIONS: The combination of diabetes and lack of habitual physical activity is predictive of functional disability in Japanese. Habitual physical activity attenuates the risk of functional disability in patients with diabetes.

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  • 副甲状腺癌の全身骨転移と鑑別が困難でありBrown腫瘍が疑われた一例

    山本 正彦, 種村 聡, 石黒 創, 松林 泰弘, 藤原 和哉, 岩永 みどり, 山田 貴穂, 曽根 博仁

    日本内分泌学会雑誌   95 ( 3 )   998 - 998   2020.1

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  • Weight and cardiometabolic risk among adolescents in Agano city, Japan: NICE EVIDENCE Study-Agano 1. Reviewed International journal

    Sakiko Yoshizawa Morikawa, Kazuya Fujihara, Yasunaga Takeda, Mariko Hatta, Chika Horikawa, Masahiro Ishizawa, Masahiko Yamamoto, Tomonobu Shiraishi, Hajime Ishiguro, Takaho Yamada, Yohei Ogawa, Hirohito Sone

    Asia Pacific journal of clinical nutrition   29 ( 4 )   856 - 866   2020

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    BACKGROUND AND OBJECTIVES: Pediatric obesity is associated with clustered cardiometabolic risk and the future incidence of cardiovascular disease. However, few studies have determined the effect of pediatric obesity in Asia, where obesity is less common than in Western countries. We aimed to clarify whether weight status including underweight and slightly overweight is associated with metabolic risk factors in Japanese adolescents. METHODS AND STUDY DESIGN: We performed a cross-sectional analysis of 2241 adolescents aged 13-14 years. Participants were classified as underweight, normal weight, slightly overweight, overweight, or obese according to the International Obesity Task Force. The clustered cardiometabolic risk (Z-CMR) was estimated by summing standardized sex-specific Z scores of mean arterial pressure (MAP), non-high-density lipoprotein cholesterol (non-HDLC), and HbA1c. RESULTS: Linear regression analysis showed that MAP, non-HDL-C, and Z-CMR were higher in the slightly overweight, overweight, and obese groups than in the normal weight group after adjusting for confounders. Compared with the normal weight group, the slightly overweight, overweight, and obese groups had higher prevalence of high BP [odds ratios (ORs): 1.38 (95% CI, 1.03, 1.85); 2.63 (1.77, 3.91); and 2.39 (1.57, 3.64), respectively]. Compared with the normal weight group, underweight boys, but not girls, had a lower prevalence of high Z-CMR [OR=0.20 (0.05, 0.84)]. CONCLUSIONS: Adolescents classified as slightly overweight had higher levels of BP, serum lipids, and clustered cardiometabolic risk than those classified as normal weight. This observation showed significant associations between weight status and cardiometabolic risk factors during adolescence even in East Asians.

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  • Association of Plasma Volume with Body Weight and BNP after Long-Term Administration and Subsequent Withdrawal of the SGLT2 Inhibitor Tofogliflozin

    Matsubayashi, Yasuhiro, Yoshida, Akihiro, Nojima, Toshiaki, Suganami, Hideki, Fujihara, Kazuya, Kaku, Kohei, Sone, Hirohito

    Diabetes   2020

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  • Medication Adherence (MA) Is an Independent Predictor for Glycemic Control Even after Adjustment for Lifestyle Confounders in Japanese Patients with Type 2 Diabetes

    Yaguchi, Yuta, Fujihara, Kazuya, Yamada, Mayuko H., Sato, Takaaki, Kitazawa, Masaru, Yamamoto, Masahiko, Seida, Hiroyasu, Yamanaka, Nauta, Matsubayashi, Yasuhiro, Sone, Hirohito

    Diabetes   2020

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  • Impact of Body Mass Index (BMI) and Waist Circumference (WC) on Coronary Artery Disease (CAD) in Japanese with and without Diabetes Mellitus (DM)

    Komatsu, Takeshi, Fujihara, Kazuya, Yamada, Mayuko H., Sato, Takaaki, Kitazawa, Masaru, Yamamoto, Masahiko, Seida, Hiroyasu, Yamanaka, Nauta, Matsubayashi, Yasuhiro, Yamada, Takaho, Sone, Hirohito

    Diabetes   2020

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  • Predictive Ability of Incident Type 2 Diabetes Mellitus (T2DM) Using Machine Learning Algorithms: A Meta-analysis

    Kodama, Satoru, Sato, Takaaki, Yamamoto, Masahiko, Ishiguro, Hajime, Iwanaga, Midori, Fujihara, Kazuya, Yamada, Takaho, Kato, Kiminori, Sone, Hirohito

    Diabetes   2020

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  • Association between Plasma Metabolites in the Urea Cycle and Diabetic Kidney Disease (DKD) in a Japanese Population

    Yamamoto, Masahiko, Harada, Sei, Okamura, Tomonori, Fujihara, Kazuya, Yaguchi, Yuta, Komatsu, Takeshi, Sato, Takaaki, Kitazawa, Masaru, Yamada, Mayuko H., Kaneko, Masanori, Osawa, Taeko, Matsubayashi, Yasuhiro, Yamada, Takaho, Kodama, Satoru, Sone, Hirohito, Takebayashi, Toru

    Diabetes   2020

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  • Ability for Detecting or Predicting Hypoglycemia with the Aid of Machine Learning Techniques: A Meta-analysis

    Kodama, Satoru, Yamada, Mayuko H., Yaguchi, Yuta, Kitazawa, Masaru, Kaneko, Masanori, Matsubayashi, Yasuhiro, Fujihara, Kazuya, Iwanaga, Midori, Kato, Kiminori, Sone, Hirohito

    Diabetes   2020

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  • Blood Pressure as Predictor of Coronary Artery Disease (CAD)/Cerebrovascular Disease (CVD) According to Glucose Tolerance Status (GTS): Implications for Updated Guidelines

    Yamada, Mayuko H., Fujihara, Kazuya, Yaguchi, Yuta, Osawa, Taeko, Kitazawa, Masaru, Matsubayashi, Yasuhiro, Iwanaga, Midori, Yamada, Takaho, Yamanaka, Nauta, Seida, Hiroyasu, Ogawa, Wataru, Sone, Hirohito

    Diabetes   2020

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  • Difference between Comprehensive Physical Fitness Age and Calendar Age Is a Potent Predictor of Incident Metabolic Syndrome (MetS)

    Sato, Takaaki, Fujihara, Kazuya, Yamada, Mayuko H., Yaguchi, Yuta, Kitazawa, Masaru, Matsubayashi, Yasuhiro, Iwanaga, Midori, Yamada, Takaho, Kato, Kiminori, Sone, Hirohito

    Diabetes   2020

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  • Low Level of and Decrease in Serum Amylase (AMY) Increases the Risk of Type 2 Diabetes Mellitus (T2DM)

    Ikeda, Izumi, Fujihara, Kazuya, Risa, Igarashi, Yamada, Mayuko H., Nedachi, Rina, Hatta, Mariko, Kodama, Satoru, Mori, Yasumichi, Matsubayashi, Yasuhiro, Arase, Yasuji, Sone, Hirohito, Yamamoto-Honda, Ritsuko

    Diabetes   2020

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  • Physical Fitness (PF), Weight Status, and Metabolic Risk in Japanese Adolescents

    Morikawa, Sakiko Y., Fujihara, Kazuya, Nedachi, Rina, Ikeda, Izumi, Takeda, Yasunaga, Takeuchi, Mizuki, Hatta, Mariko, Ishiguro, Hajime, Yamada, Takaho, Sone, Hirohito

    Diabetes   2020

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  • Randomized Controlled Trial of Ipragliflozin or Sitagliptin Combined with Metformin in Type 2 Diabetes: NISM Study

    Kitazawa, Masaru, Katagiri, Takashi, Suzuki, Hiromi, Matsunaga, Satoshi, Yamada, Mayuko H., Ikarashi, Tomoo, Yamamoto, Masahiko, Furukawa, Kazuo, Iwanaga, Midori, Hatta, Mariko, Fujihara, Kazuya, Yamada, Takaho, Tanaka, Shiro, Sone, Hirohito

    Diabetes   2020

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  • Association between Screen Time Including Smartphone Use and Obesity and Its Associated Lifestyles in School Children in Japan

    Ikeda, Izumi, Fujihara, Kazuya, Nedachi, Rina, Morikawa, Sakiko Y., Ishiguro, Hajime, Yamada, Mayuko H., Matsubayashi, Yasuhiro, Yamada, Takaho, Sone, Hirohito

    Diabetes   2020

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  • Isolated Adrenocorticotropic Hormone Deficiency Presenting with Severe Hyponatremia and Rhabdomyolysis: A Case Report and Literature Review. Reviewed International journal

    Takeshi Komatsu, Nobumasa Ohara, Naoko Hirota, Yuichiro Yoneoka, Takashi Tani, Keishi Terajima, Tetsutaro Ozawa, Hirohito Sone

    The American journal of case reports   20   1857 - 1863   2019.12

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    BACKGROUND Isolated adrenocorticotropic hormone deficiency (IAD) is a rare disorder characterized by central adrenal insufficiency (AI) but normal secretion of pituitary hormones other than adrenocorticotropic hormone. IAD usually presents with unspecific symptoms of AI, such as anorexia and fatigue, but some patients present with a variety of atypical manifestations. Rhabdomyolysis is a potentially life-threatening clinical syndrome caused by skeletal muscle injury with the release of muscle cell contents into the circulation. A wide variety of disorders can cause rhabdomyolysis. Herein, we report an unusual case of IAD presenting with hyponatremia and rhabdomyolysis. CASE REPORT A 67-year-old Japanese woman with a 2-month history of anorexia and fatigue was diagnosed with severe hyponatremia (serum sodium, 118 mEq/L) and rhabdomyolysis (serum creatine phosphokinase, 6968 IU/L), after 2 days of vomiting and muscle weakness. Physical and laboratory findings did not show dehydration or peripheral edema. Her rhabdomyolysis resolved with normalization of serum sodium levels during administration of sodium chloride. However, her anorexia and fatigue remained unresolved. After reducing the amount of sodium chloride administered, the patient still had hyponatremia. Detailed endocrinological examinations indicated IAD; her hyponatremia was associated with inappropriately high plasma arginine vasopressin levels. The patient received corticosteroid replacement therapy, which resolved her anorexia, fatigue, excessive arginine vasopressin, and hyponatremia. CONCLUSIONS This case highlights the importance of considering the possibility of central AI in patients with hyponatremia and excessive arginine vasopressin levels. In addition, rhabdomyolysis associated with hyponatremia can be an important manifestation of IAD.

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  • Risk of coronary artery disease according to glucose abnormality status and prior coronary artery disease in Japanese men. Reviewed International journal

    Masaru Kitazawa, Kazuya Fujihara, Taeko Osawa, Masahiko Yamamoto, Mayuko Harada Yamada, Masanori Kaneko, Yasuhiro Matsubayashi, Takaho Yamada, Nauta Yamanaka, Hiroyasu Seida, Hirohito Sone

    Metabolism: clinical and experimental   101   153991 - 153991   2019.12

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    OBJECTIVE: Although glucose abnormality status (GAS), prior coronary artery disease (CAD), and other traditional risk factors affect the incidence of subsequent CAD, their impact in the same cohort has been scantly studied. RESEARCH DESIGN AND METHODS: We analyzed data from a nationwide claims database in Japan that was accumulated during 2008-2016 involving 138,162 men aged 18-72 years. Participants were classified as having normoglycemia, borderline glycemia, or diabetes mellitus (DM) with prior CAD (CAD+) or without prior CAD (CAD-). Cox regression model identified variables related to the incidence of CAD. RESULTS: Among CAD-, management of traditional risks differed from those with and without subsequent CAD events. On the other hand, such differences were weaker in borderline glycemia and DM CAD+, and the influence of traditional risk factors on subsequent CAD was not observed. Cox regression model showed that borderline glycemia and DM confer approximately 1.2- and 2.8-fold excess risks of CAD, respectively, compared with CAD- with normoglycemia. CAD+ confers approximately a 5- to 8-fold increased risk. The impacts of DM and prior CAD additively reached a hazard ratio (HR) of 15.74 (95% confidence interval [CI]: 11.82-21.00). However, the HR in those with borderline glycemia and CAD+ was 7.20 (95% CI: 5.01-10.34), which was not different from those with normoglycemia and CAD+. CONCLUSION: Control status of traditional risk factors and impact on subsequent CAD differ among categories of glycemic status with and without prior CAD. Individualizing treatment strategies is needed in consideration of risk factors, such as GAS and CAD+.

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  • Relationship Between Number of Multiple Risk Factors and Coronary Artery Disease Risk With and Without Diabetes Mellitus. Reviewed International journal

    Mayuko Yamada-Harada, Kazuya Fujihara, Taeko Osawa, Masahiko Yamamoto, Masanori Kaneko, Masaru Kitazawa, Yasuhiro Matsubayashi, Takaho Yamada, Nauta Yamanaka, Hiroyasu Seida, Wataru Ogawa, Hirohito Sone

    The Journal of clinical endocrinology and metabolism   104 ( 11 )   5084 - 5090   2019.11

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    PURPOSE: To determine the degree of control of multiple risk factors under real-world conditions for coronary artery disease (CAD) according to the presence or absence of diabetes mellitus (DM) and to determine whether reaching multifactorial targets for blood pressure (BP), low-density lipoprotein-cholesterol (LDL-C), HbA1c, and current smoking is associated with lower risks for CAD. METHODS: We investigated the effects on subsequent CAD of the number of controlled risk factors among BP, LDL-C, HbA1c, and current smoking in a prospective cohort study using a nationwide claims database of 220,894 individuals in Japan. Cox regression examined risks over a 4.8-year follow-up. RESULTS: The largest percentage of participants had two risk factors at target in patients with DM (39.6%) and subjects without DM (36.4%). Compared with those who had two targets achieved, the risks of CAD among those who had any one and no target achieved were two and four times greater, respectively, regardless of the presence of DM. The effect of composite control was sufficient to bring CAD risk in patients with DM below that for subjects without DM with any two targets achieved, whereas the risk of CAD in the DM group with all four risk factors uncontrolled was 9.4 times more than in the non-DM group who had achieved two targets. CONCLUSIONS: These findings show that composite control of modifiable risk factors has a large effect in patients with and without DM. The effect was sufficient to bring CAD risk in patients with DM below that in the non-DM group who had two targets achieved.

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  • 2型糖尿病発症予防のための妊娠糖尿病妊婦への非薬物的強化介入の試み

    川崎 麻紀, 荒田 尚子, 和栗 雅子, 飯村 祐子, 山本 周美, 川嵜 有紀, 牧 尉太, 玉田 祥子, 青山 友子, 田中 茂穂, 秦 健一郎, 宮越 敬, 橋本 貢士, 杉山 隆, 安日 一郎, 曽根 博仁, 菊池 透, 瀧本 秀美, 安田 和基, 小川 佳宏, 大田 えりか, 井上 永介, 平松 祐司

    糖尿病と妊娠   19 ( 3 )   S - 96   2019.11

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  • Patient-based prediction algorithm of relapse after allo-HSCT for acute Leukemia and its usefulness in the decision-making process using a machine learning approach. Reviewed International journal

    Kyoko Fuse, Shun Uemura, Suguru Tamura, Tatsuya Suwabe, Takayuki Katagiri, Tomoyuki Tanaka, Takashi Ushiki, Yasuhiko Shibasaki, Naoko Sato, Toshio Yano, Takashi Kuroha, Shigeo Hashimoto, Tatsuo Furukawa, Miwako Narita, Hirohito Sone, Masayoshi Masuko

    Cancer medicine   8 ( 11 )   5058 - 5067   2019.9

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    Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapy for high-risk acute leukemia (AL), some patients still relapse. Since patients simultaneously have many prognostic factors, difficulties are associated with the construction of a patient-based prediction algorithm of relapse. The alternating decision tree (ADTree) is a successful classification method that combines decision trees with the predictive accuracy of boosting. It is a component of machine learning (ML) and has the capacity to simultaneously analyze multiple factors. Using ADTree, we attempted to construct a prediction model of leukemia relapse within 1 year of transplantation. With the model of training data (n = 148), prediction accuracy, the AUC of ROC, and the κ-statistic value were 78.4%, 0.746, and 0.508, respectively. The false positive rate (FPR) of the relapse prediction was as low as 0.134. In an evaluation of the model with validation data (n = 69), prediction accuracy, AUC, and FPR of the relapse prediction were similar at 71.0%, 0.667, and 0.216, respectively. These results suggest that the model is generalized and highly accurate. Furthermore, the output of ADTree may visualize the branch point of treatment. For example, the selection of donor types resulted in different relapse predictions. Therefore, clinicians may change treatment options by referring to the model, thereby improving outcomes. The present results indicate that ML, such as ADTree, will contribute to the decision-making process in the diversified allo-HSCT field and be useful for preventing the relapse of leukemia.

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  • Attenuation of Weight Loss Through Improved Antilipolytic Effect in Adipose Tissue Via the SGLT2 Inhibitor Tofogliflozin Reviewed International journal

    Akihiro Yoshida, Yasuhiro Matsubayashi, Toshiaki Nojima, Hideki Suganami, Takahiro Abe, Masahiro Ishizawa, Kazuya Fujihara, Shiro Tanaka, Kohei Kaku, Hirohito Sone

    JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM   104 ( 9 )   3647 - 3660   2019.9

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    Context: Although calorie loss from increased urinary glucose excretion continues after long-term treatment with sodium-glucose cotransporter 2 inhibitors (SGLT2is), the mechanisms of the attenuated weight loss due to SGLT2is are not well known.Objective: To examine the mechanism of the attenuated weight loss during long-term treatment with an SGLT2i, tofogliflozin, focusing on the antilipolytic effect of insulin on adipose tissue.Design and Participants: An integrated analysis was performed using data from two phase 3 studies of 52 weeks of tofogliflozin administration. The antilipolytic effect was evaluated using adipose tissue insulin resistance (Adipo-IR) calculated from the product of the levels of fasting insulin (f-IRI) and fasting free fatty acids (f-FFAs).Results: Data from 774 patients with type 2 diabetes (mean age, 58.5 years; glycosylated hemoglobin, 8.1%; body mass index, 25.6 kg/m(2); estimated glomerular filtration rate, 83.9 mUmin/1.73m(2); 66% men) were analyzed. Weight loss plateaued between weeks 24 and 52 after decreasing significantly. f-IRI levels decreased significantly from baseline to week 24, and the decrease was maintained until Week 52. f-FFA levels significantly increased, peaked at week 24, then declined from weeks 24 to 52. Adipo-IR levels declined progressively throughout the 52 weeks (-3.6 mmol/L.pmol/L and -6.2 mmol/L.pmol/L at weeks 24 and 52, respectively; P < 0.001 baseline vs weeks 24 and 52 and week 24 vs week 52). Higher baseline Adipo-IR levels were independently associated with greater weight loss at week 52.Conclusion: The improved antilipolytic effect in adipose tissue may attenuate progressive lipolysis, leading to attenuating future weight loss induced by an SGLT2i in patients with type 2 diabetes.

    DOI: 10.1210/jc.2018-02254

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  • Association between Helicobacter pylori infection, eradication and diabetes mellitus. Reviewed

    Masayuki Kato, Akiko Toda, Ritsuko Yamamoto-Honda, Yasuji Arase, Hirohito Sone

    Journal of diabetes investigation   10 ( 5 )   1341 - 1346   2019.9

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    AIMS/INTRODUCTION: It is suspected that Helicobacter pylori is associated with extradigestive diseases including diabetes. So far, a number of studies have examined the association between H. pylori and diabetes, and the results were conflicting. The aim of the present study was to examine the association between H. pylori infection, eradication and diabetes. MATERIALS AND METHODS: The present cross-sectional study was carried out using data from annual health checkups carried out at the Toranomon Hospital Health Management Center. The status of H. pylori infection, determined by serum antibodies and history of eradication, was categorized into three groups as "never," "current" and "past." The association between H. pylori infection and diabetes was examined using logistic regression. RESULTS: Of 21,634 participants, 6,530 (30.2%) had a current or past history of H. pylori infection, and 1,184 (5.5%) were identified as having diabetes. Multivariate adjusted odds ratios for diabetes compared with the "never" group were 1.36 (95% confidence interval 1.10-1.67) for the "current" group and 0.92 (95% confidence interval 0.79-1.07) for the "past" group. The association between H. pylori infection and diabetes was also observed among participants without a history of eradication. CONCLUSIONS: We found that current H. pylori infection was associated with an increased risk of diabetes, and the increased risk was not observed among participants after eradication. The results were concordant with the hypothesis that H. pylori infection increases the risk of diabetes. Further studies are necessary to validate the present results.

    DOI: 10.1111/jdi.13011

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  • 大血管障害 耐糖能状態及び心血管疾患既往の有無で層別化した、心血管疾患発症リスクの検討 Reviewed

    北澤 勝, 藤原 和哉, 山田 万祐子, 大澤 妙子, 山本 正彦, 矢口 雄大, 金子 正儀, 松林 泰弘, 山田 貴穂, 清田 浩康, 曽根 博仁

    糖尿病合併症   33 ( Suppl.1 )   242 - 242   2019.9

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  • 眼科処置を要する重症糖尿病性眼疾患発生リスクと血液学的因子の関係についての検討 Reviewed

    山本 正彦, 藤原 和哉, 大澤 妙子, 山田 万祐子, 石澤 正博, 石黒 創, 鈴木 浩史, 松林 泰弘, 児玉 暁, 長谷部 日, 曽根 博仁

    糖尿病合併症   33 ( Suppl.1 )   263 - 263   2019.9

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  • 大血管障害 糖尿病、非糖尿患者における血糖・血圧・脂質・喫煙の管理目標の達成状況と冠動脈疾患発症の関連 Reviewed

    山田 万祐子, 藤原 和哉, 大澤 妙子, 山本 正彦, 石澤 正博, 金子 正儀, 松林 泰弘, 清田 浩康, 山田 貴穂, 曽根 博仁

    糖尿病合併症   33 ( Suppl.1 )   241 - 241   2019.9

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  • 青少年期の体格と代謝指標の関連 Reviewed

    森川 咲子, 治田 麻理子, 平澤 玲子, 谷内 洋子, 堀川 千嘉, 曽根 博仁

    New Diet Therapy   35 ( 2 )   151 - 151   2019.9

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  • Effect of family-oriented diabetes programs on glycemic control: A meta-analysis. Reviewed International journal

    Satoru Kodama, Sakiko Morikawa, Chika Horikawa, Dai Ishii, Kazuya Fujihara, Masahiko Yamamoto, Taeko Osawa, Masaru Kitazawa, Takaho Yamada, Kiminori Kato, Shiro Tanaka, Hirohito Sone

    Family practice   36 ( 4 )   387 - 394   2019.7

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    BACKGROUND: Efficacy of programs for patients with diabetes mellitus (DM) that have promoted family members to help with patients' self-care activities has been largely inconsistent. This meta-analysis aims to assess the effect of family-oriented diabetes programs for glycemic control (GC). METHODS: Electronic literature searches were conducted for clinical trials with a parallel design wherein there were two groups according to whether family members were included (intervention group) or not included (control group) and changes in glycohemoglobin A1C (A1C) were assessed as a study outcome. Each effect size (i.e. difference in A1C change between the intervention and control group) was pooled with a random-effects model. RESULTS: There were 31 eligible trials consisting of 1466 and 1415 patients in the intervention and control groups, respectively. Pooled A1C change [95% confidence interval (CI)] was -0.45% (-0.64% to -0.26%). Limiting analyses to 21 trials targeted at patients with type 1 DM or 9 trials targeted at patients with type 2 DM, the pooled A1C changes (95% CI) were -0.35% (-0.55% to -0.14%) and -0.71% (-1.09% to -0.33%), respectively. CONCLUSION: This meta-analysis suggests that focusing on the family as well as the individual patient in self-management diabetes programs to improve the performance of self-care activities of patients with DM is effective in terms of proper GC.

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  • Blake's pouch cystに伴う水頭症の治療により若年性認知症の改善を認めた糖尿病の1例 Reviewed

    種村 聡, 山本 正彦, 石黒 創, 岩永 みどり, 松林 泰弘, 山田 貴穂, 藤原 和哉, 渡邊 賢一, 曽根 博仁

    糖尿病   62 ( 7 )   441 - 441   2019.7

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  • Overt Proteinuria, Moderately Reduced eGFR and Their Combination Are Predictive of Severe Diabetic Retinopathy or Diabetic Macular Edema in Diabetes. Reviewed International journal

    Masahiko Yamamoto, Kazuya Fujihara, Masahiro Ishizawa, Taeko Osawa, Masanori Kaneko, Hajime Ishiguro, Yasuhiro Matsubayashi, Hiroyasu Seida, Nauta Yamanaka, Shiro Tanaka, Satoru Kodama, Hiruma Hasebe, Hirohito Sone

    Investigative ophthalmology & visual science   60 ( 7 )   2685 - 2689   2019.6

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    Purpose: Since the combined effects of proteinuria and a moderately decreased eGFR on incident severe eye complications in patients with diabetes are still largely unknown, these associations were determined in a large historical cohort of Japanese patients with diabetes mellitus. Methods: We evaluated the effects of overt proteinuria (OP) (dipstick 1+ and over) and/or moderately reduced estimated glomerular filtration rate (eGFR) (MG) (baseline eGFR 30.0-54.9 mL/min/1.73 m2) on the incidence of treatment-required diabetic eye diseases (TRDED). We divided 7709 patients into four groups according to the presence or absence of OP and MG: no OP without MG (NP[MG-]), OP without MG (OP[MG-]), no OP with MG (NP[MG+]), and OP with MG (OP[MG+]). Multivariate Cox analyses were performed to calculate hazard ratios (HRs) with 95% confidence intervals for combinations of the presence and/or absence of OP and MG on the risk of developing TRDED. Results: During the median follow-up period of 5.6 years, 168 patients developed TRDED. HRs for OP and MG for incident TRDED were 1.91 (95% confidence interval, 1.27-2.87) and 1.90 (1.11-3.23), respectively. HRs for incident TRDED were 1.73 (1.11-2.69) and 5.57 (2.40-12.94) for OP(MG-) and OP(MG+), respectively, in comparison with NP(MG-). Conclusions: In Japanese patients with diabetes, OP and MG were separately as well as additionally associated with higher risks of TRDED. Results indicate the necessity of the simultaneous assessment of proteinuria and eGFR for appropriate evaluation of risks of severe eye complications in patients with diabetes.

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  • Combined Effects of Energy Intake and Physical Activity on Obesity in Japanese Patients with Type 2 Diabetes (JDDM 50): A Cross-Sectional Study. Reviewed International journal

    Mariko Hatta, Kazuya Fujihara, Sakiko Yoshizawa Morikawa, Yasutake Takeda, Dai Ishii, Chika Horikawa, Mitsutoshi Kato, Hiroki Yokoyama, Yoshio Kurihara, Koichi Iwasaki, Kazuhiro Miyazawa, Katsuya Yamazaki, Shiro Tanaka, Hiroshi Maegawa, Hirohito Sone

    Diabetes therapy : research, treatment and education of diabetes and related disorders   10 ( 3 )   1133 - 1138   2019.6

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    INTRODUCTION: The combined effects of energy intake (EI) and physical activity (PA) on obesity have been poorly investigated. We have investigated the combined effects of EI and PA quantitatively in Japanese men and women with type 2 diabetes. METHODS: Data on 1395 patients with type 2 diabetes who attended 25 diabetes clinics located throughout Japan, obtained by questionnaire, were analyzed. A logistic regression model was used to calculate the odds ratio for obesity. RESULTS: Multi-adjusted odds ratios for the top versus the bottom tertile of EI and the bottom versus the top tertile of PA were 1.39 (95% confidence interval [CI] 1.02-1.89) and 1.64 (95% CI 1.22-2.22), respectively. The combination of EI (kcal/day) ≥ 1967 and PA (metabolic equivalents [METs] h/week) ≤ 9.9 for men and of EI ≥ 1815 and PA ≤ 8.3 for women were significantly associated with obesity. CONCLUSIONS: The existence of "allowable maximum EI" and "required minimum PA" that is significantly associated with "not being obese" is implied, suggesting the need for lifestyle education for Japanese patients with type 2 diabetes.

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  • 450-P: Impact of Prior Coronary Artery Disease (CAD)/Cerebrovascular Disease (CVD) and Diabetes Mellitus (DM) on Incident CAD/CVD in Japanese Reviewed

    KAZUYA FUJIHARA, YASUHIRO MATSUBAYASHI, MAYUKO HARADA, TAEKO OSAWA, MASAHIKO YAMAMOTO, MASARU KITAZAWA, MASANORI KANEKO, HIROYASU SEIDA, NAUTA YAMANAKA, SATORU KODAMA, HIROHITO SONE

    Diabetes   68 ( Supplement 1 )   450 - P   2019.6

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    DOI: 10.2337/db19-450-p

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  • Enhanced Response in Serum Ketone Level in Men Compared with Women by Administration of SGLT2 Inhibitor Reviewed

    Akihiro Yoshida, Yasuhiro Matsubayashi, Toshiaki Nojima, Hideki Suganami, Kohei Kaku, Hirohito Sone

    DIABETES   68   2019.6

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    DOI: 10.2337/db19-1219-P

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  • Pulse Pressure is a Stronger Predictor Than Systolic Blood Pressure for Severe Eye Diseases in Diabetes Mellitus. Reviewed International journal

    Masahiko Yamamoto, Kazuya Fujihara, Masahiro Ishizawa, Taeko Osawa, Masanori Kaneko, Hajime Ishiguro, Yasuhiro Matsubayashi, Hiroyasu Seida, Nauta Yamanaka, Shiro Tanaka, Satoru Kodama, Hiruma Hasebe, Hirohito Sone

    Journal of the American Heart Association   8 ( 8 )   e010627   2019.4

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    Background Evidence of the role of systolic blood pressure ( SBP ) in development of severe diabetic retinopathy is not strong, although the adverse effect of low diastolic blood pressure has been a partial explanation. We assessed the predictive ability of incident severe diabetic retinopathy between pulse pressure ( PP ) which considers both SBP and diastolic blood pressure, compared with SBP . Methods and Results Eligible patients (12 242, 83% men) aged 19 to 72 years from a nationwide claims database were analyzed for a median observational 4.8-year period. Severe diabetic retinopathy was defined as vision-threatening treatment-required diabetic eye diseases. Multivariate Cox regression analysis revealed that hazard ratios (95% CI ) of treatment-required diabetic eye diseases for 1 increment of standard deviation and the top tertile compared with the bottom tertile were 1.39 (1.21-1.60) and 1.72 (1.17-2.51), respectively, for PP and 1.22 (1.05-1.41) and 1.43 (0.97-2.11), respectively, for SBP adjusted for age, sex, body mass index, hemoglobin A1c, fasting plasma glucose, lipids, and smoking status. In a model with SBP and PP simultaneously as covariates, the hazard ratios of only PP (hazard ratios [95% CI ], 1.57 [1.26-1.96]) but not SBP (0.85 [0.68-1.07]) were statistically significant. Delong test revealed a significant difference in the area under the receiver operating characteristic curve between PP and SBP (area under the receiver operating characteristic curve [95% CI ], 0.58 [0.54-0.63] versus 0.54 [0.50-0.59]; P=0.03). The strongest predictor remained as hemoglobin A1c (area under the receiver operating characteristic curve [95% CI ], 0.80 [0.77-0.84]). Conclusions After excluding the significant impact of glycemic control, PP in comparison with SBP is a better predictor of severe diabetic retinopathy, suggesting a role of diastolic blood pressure and arterial stiffness in pathology.

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  • Physical Fitness Tests and Type 2 Diabetes Among Japanese: A Longitudinal Study From the Niigata Wellness Study. Reviewed

    Haruki Momma, Susumu S Sawada, Kiminori Kato, Yuko Gando, Ryoko Kawakami, Motohiko Miyachi, Cong Huang, Ryoichi Nagatomi, Minoru Tashiro, Masahiro Ishizawa, Satoru Kodama, Midori Iwanaga, Kazuya Fujihara, Hirohito Sone

    Journal of epidemiology   29 ( 4 )   139 - 146   2019.4

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    BACKGROUND: Simple physical fitness test can be a useful potential predictor of type 2 diabetes (T2DM). We examined the association between performances on simple physical fitness tests and the incidence of T2DM. METHODS: This longitudinal study was conducted in 21,802 nondiabetic Japanese (6,649 women) aged 20 to 92 years, who underwent all physical fitness tests at baseline (April 2001 to March 2002). From April 2001 to March 2008, physical fitness tests, including grip strength, vertical jump, single-leg balance with eyes closed, forward bending, whole-body reaction time, and supine legs-up, were performed every year. Participants had physical fitness tests at least two times during the period. T2DM was also annually determined based on fasting blood glucose, glycated hemoglobin, and self-reported diabetes during the period. Discrete-time logit models were used to examine the influence of the serial level of each physical fitness test on the incidence of T2DM. RESULTS: During the entire study period, 972 participants developed diabetes. Lower relative grip strength (grip strength/body weight) and single-leg balance performance were associated with a higher incidence of T2DM. For relative grip strength, as compared with the fourth quartile group, the odds ratios for other groups ranged from 1.16 to 1.56 (P for trend < 0.001). For single-leg balance, the odds ratios ranged from 1.03 to 1.49 (P for trend < 0.001). CONCLUSION: The performance of a simple single-leg balance test as well as that of a grip strength test were negatively associated with the risk of T2DM among Japanese.

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  • Safety and effective salvage regimen comprising a novel combination of brentuximab vedotin, L-asparaginase, and dexamethasone for refractory anaplastic large cell lymphoma, anaplastic lymphoma kinase negative. Reviewed International journal

    Keisuke Kawamoto, Takaharu Suzuki, Takuya Kasami, Maiko Kiryu, Hirohito Sone, Hiroaki Miyoshi, Koichi Ohshima, Jun Takizawa

    Hematological oncology   37 ( 2 )   212 - 214   2019.4

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  • 糖尿病の有無別にみた血糖・血圧・脂質・喫煙の各管理目標達成状況が冠動脈疾患発症に及ぼす影響 Reviewed

    原田 万祐子, 藤原 和哉, 大澤 妙子, 石澤 正博, 山本 正彦, 金子 正儀, 松林 泰弘, 清田 浩康, 山田 貴穂, 小川 渉, 曽根 博仁

    糖尿病   62 ( Suppl.1 )   S - 285   2019.4

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  • 糖尿病の有無別にみた高血圧が透析導入に及ぼす影響の検討 Reviewed

    大澤 妙子, 藤原 和哉, 山本 正彦, 原田 万祐子, 北澤 勝, 金子 正儀, 石黒 創, 石澤 正博, 松林 泰弘, 清田 浩康, 山中 菜詩, 山田 貴穂, 曽根 博仁

    糖尿病   62 ( Suppl.1 )   S - 219   2019.4

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  • 糖尿病(DM)・冠動脈疾患(CAD)・脳血管疾患(CVD)の既往及び組み合わせがその後のリスクへ及ぼす影響の検討 Reviewed

    藤原 和哉, 松林 泰弘, 原田 万祐子, 大澤 妙子, 金子 正儀, 山本 正彦, 山田 高穂, 清田 浩康, 加藤 公則, 曽根 博仁

    糖尿病   62 ( Suppl.1 )   S - 254   2019.4

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  • 医療ビッグデータを用いた糖尿病患者の下肢切断に関するリスク因子の検討 Reviewed

    金子 正儀, 藤原 和哉, 原田 万祐子, 山本 正彦, 松林 泰弘, 北澤 勝, 石井 大, 清田 浩康, 曽根 博仁

    糖尿病   62 ( Suppl.1 )   S - 195   2019.4

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  • 2型糖尿病患者における食事エネルギー密度と食事パターンとの関連 Reviewed

    武田 安永, 藤原 和哉, 治田 麻理子, 森川 咲子, 堀川 千嘉, 石井 大, 根立 梨奈, 加藤 光敏, 横山 宏樹, 栗原 義夫, 宮澤 一裕, 岩崎 晧一, 川井 紘一, 朝長 修, 屋宜 宣治, 前川 聡, 曽根 博仁

    糖尿病   62 ( Suppl.1 )   S - 116   2019.4

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  • 耐糖能状態と心血管疾患既往の有無別に見たその後の心血管疾患発症リスク Reviewed

    北澤 勝, 藤原 和哉, 原田 万祐子, 大澤 妙子, 山本 正彦, 矢口 雄大, 金子 正儀, 松林 泰弘, 山田 貴穂, 清田 浩康, 曽根 博仁

    糖尿病   62 ( Suppl.1 )   S - 190   2019.4

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  • Higher pulse pressure predicts initiation of dialysis in Japanese patients with diabetes. Reviewed International journal

    Taeko Osawa, Kazuya Fujihara, Mayuko Harada, Masahiko Yamamoto, Masahiro Ishizawa, Hiroshi Suzuki, Hajime Ishiguro, Yasuhiro Matsubayashi, Hiroyasu Seida, Nauta Yamanaka, Shiro Tanaka, Hitoshi Shimano, Satoru Kodama, Hirohito Sone

    Diabetes/metabolism research and reviews   35 ( 3 )   e3120   2019.3

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    AIMS: To determine incidence and predictors of starting dialysis in patients with diabetes emphasizing blood pressure variables. METHODS: A nationwide database with claim data on 18 935 people (15 789 men and 3146 women) with diabetes mellitus aged 19 to 72 years in Japan was used to elucidate predictors for starting dialysis. Initiation of dialysis was determined from claims using ICD-10 codes and medical procedures. Using multivariate Cox modelling, interactions between glycaemic and blood pressure values were determined. RESULTS: During a median follow-up of 5.3 years, incidence of dialysis was 0.81 per 1000 person-years. Multivariate analysis of a model involving systolic and diastolic blood pressure (SBP and DBP) simultaneously as covariates showed that hazard ratios (HRs) for starting dialysis for each 1-SD elevation in SBP and DBP were 2.05 (95% confidence interval 1.58-2.64) and 0.66 (0.50-0.88), respectively, implying that pulse pressure (PP) was a promising predictor. For confirmation, a model involving SBP and PP simultaneously as covariates demonstrated that HRs for each 1-SD elevation in SBP and PP were 1.09 (0.81-1.48) and 1.54 (1.14-2.08), respectively, with PP the more potent predictor. Compared with HbA1c <8% and PP <60 mmHg, the HR for those with HbA1c ≥8% and PP ≥60 mmHg was 6.32 (3.42-11.7). CONCLUSIONS: In our historical cohort analysis, SBP and PP were independent predictors for starting dialysis. PP was the more potent, suggesting the contribution of increased arterial stiffness to the incidence of dialysis. Future studies are needed to conclude the independent influence of PP and HbA1c on dialysis considering other risk factors.

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  • Gemcitabine, Dexamethasone, and Cisplatin Regimen as an Effective Salvage Therapy for High-grade B-cell Lymphoma with MYC and BCL2 and/or BCL6 Rearrangements. Reviewed

    Masaki Mitobe, Keisuke Kawamoto, Takaharu Suzuki, Maiko Kiryu, Suguru Tamura, Ayako Nanba, Tatsuya Suwabe, Tomoyuki Tanaka, Kyoko Fuse, Yasuhiko Shibasaki, Masayoshi Masuko, Hiroaki Miyoshi, Koichi Ohshima, Hirohito Sone, Jun Takizawa

    Internal medicine (Tokyo, Japan)   58 ( 4 )   575 - 580   2019.2

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    A 61-year-old woman exhibited right inguinal lymphadenopathy and right lower limb edema approximately 1 month prior to hospitalization. She was diagnosed with high grade B-cell lymphoma, and a lymph node biopsy and fluorescence in situ hybridization indicated MYC, BCL2, and BCL6 rearrangements (triple-hit lymphoma). She had progressive disease that was CD20-negative after two courses of rituximab, cyclophosphamide, doxorubicin, vincristine, methotrexate/ifosfamide, etoposide, high-dose cytarabine (R-CODOX-M/IVAC) therapy. Subsequent etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin (EPOCH) therapy was not effective. However, after two cycles of gemcitabine, dexamethasone, and cisplatin (GDP) therapy, she achieved a complete response and was able to undergo autologous peripheral blood stem cell transplantation. GDP therapy may be effective as salvage therapy for chemotherapy-resistant triple-hit lymphoma.

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  • Meat intake and incidence of cardiovascular disease in Japanese patients with type 2 diabetes: analysis of the Japan Diabetes Complications Study (JDCS). Reviewed International journal

    Chika Horikawa, Chiemi Kamada, Shiro Tanaka, Sachiko Tanaka, Atsushi Araki, Hideki Ito, Satoshi Matsunaga, Kazuya Fujihara, Yukio Yoshimura, Yasuo Ohashi, Yasuo Akanuma, Hirohito Sone

    European journal of nutrition   58 ( 1 )   281 - 290   2019.2

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    PURPOSE: Excessive meat intake has been researched as a major cause of cardiovascular disease (CVD) among healthy adults, but data on this topic in Asian patients with diabetes are sparse. The quantity and variety of available meats vary widely between Asian and Western countries. As part of a nationwide cohort study we investigated the relationship between meat intake and incidence of CVD in Japanese patients with type 2 diabetes aged 40-70 years with HbA1c ≥ 6.5%. METHODS: Analyzed were 1353 responders to a baseline dietary survey assessed by the Food Frequency Questionnaire based on food groups. Primary outcome was the 8-year risk of a CVD event, including coronary heart disease (CHD) and stroke. Cox regression analyses estimated hazard ratios (HRs) for dietary intake adjusted for age, gender, body mass index, HbA1c, smoking, energy intake, and other confounders. RESULTS: Mean meat intake in quartiles ranged from 9.9 to 97.7 g/day. After adjusting for confounders, HRs of CHD in the 2nd, 3rd, and 4th quartiles for meat intake compared with the 1st quartile were 2.84 (95% confidence interval 1.29-6.24, p = 0.01), 3.02 (1.36-6.70, p < 0.01), and 2.99 (1.35-6.65, p = 0.01), respectively. In two groups according to meat intake, patients consuming ≥ 20 g/day of meat had a 2.94-fold higher risk of CHD than those consuming < 20 g/day (p < 0.01). There was no significant association of stroke with meat intake. CONCLUSIONS: An elevated incidence of CHD in Japanese patients with type 2 diabetes was associated with high meat intake.

    DOI: 10.1007/s00394-017-1592-y

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  • Anaplastic large cell lymphoma, with 1,25(OH) 2 D 3 -mediated hypercalcemia: A case report. Reviewed

    Masaki Mitobe, Keisuke Kawamoto, Takaharu Suzuki, Maiko Kiryu, Ayako Nanba, Tatsuya Suwabe, Tomoyuki Tanaka, Kyoko Fuse, Yasuhiko Shibasaki, Masayoshi Masuko, Hiroaki Miyoshi, Koichi Ohshima, Hirohito Sone, Jun Takizawa

    Journal of clinical and experimental hematopathology : JCEH   59 ( 1 )   22 - 28   2019

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    Hypercalcemia due to malignant tumors including malignant lymphomas is relatively common. Among cancer patients with hypercalcemia, humoral hypercalcemia of malignancy is the most common and accounts for about 80% of all cases with hypercalcemia. 1,25-dihydroxyvitamin D
    3
    (1,25(OH)
    2
    D
    3
    )-mediated hypercalcemia is relatively rare. Although malignant lymphoma has been also reported to cause 1,25(OH)
    2
    D
    3
    -mediated hypercalcemia, it is not known whether there is any association between 1,25(OH)
    2
    D
    3
    -mediated hypercalcemia and any specific histological type of malignant lymphoma. We herein report a case of an anaplastic large cell lymphoma (ALCL), anaplastic lymphoma kinase (ALK) -negative with 1,25(OH)
    2
    D
    3
    -mediated hypercalcemia, which has never been previously reported. An 80-year-old Japanese man was admitted to our department due to acute exacerbation of hypercalcemia. He was diagnosed with ALCL, ALK-negative. Serum 1,25(OH)
    2
    D
    3
    level was high and seemed to be associated with the lymphoma because the serum calcium and 1,25(OH)
    2
    D
    3
    levels improved in response to chemotherapy. Histological findings showed that many CD68 positive macrophages were observed in the microenvironment of tumor cells. Lymphoma cells or tumor microenvironmental cells may produce 1,25(OH)
    2
    D
    3
    because several previous reports showed the source of 1,25(OH)
    2
    D
    3
    can be either lymphoma or tumor microenvironmental cells. Moreover, because 1,25(OH)
    2
    D
    3
    -mediated hypercalcemia has been reported regardless of the specific histological type of lymphoma, tumor microenvironmental cells may be involved in this condition. However, we could not identify the source of 1,25(OH)
    2
    D
    3
    in this case. The association between 1,25(OH)
    2
    D
    3
    production and prognosis in malignant lymphomas is yet unknown; further studies are needed to elucidate the clinical characteristics of malignant lymphoma with 1,25(OH)
    2
    D
    3
    -mediated hypercalcemia.

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  • Glutamic Acid Decarboxylase Autoantibody-negative Slowly Progressive Type 1 Diabetes Mellitus: A Case Report and Literature Review. Reviewed

    Michi Kobayashi, Nobumasa Ohara, Yohei Ikeda, Ouki Nagano, Toshinori Takada, Makoto Kodama, Hirohito Sone

    Internal medicine (Tokyo, Japan)   57 ( 24 )   3581 - 3587   2018.12

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    A 59-year-old non-obese Japanese woman developed diabetes mellitus with a negative glutamic acid decarboxylase autoantibody (GADA) test result. Her hyperglycemia was initially well controlled by oral hypoglycemic agents; however, despite continued treatment the hyperglycemia gradually worsened. As she had endogenous insulin deficiency and tested positive for insulin autoantibody (IAA), insulin therapy was initiated. Few studies have investigated GADA-negative patients with slowly progressive type 1 diabetes mellitus (SPT1D). Our IAA-positive SPT1D patient progressed from the clinical onset of diabetes mellitus to starting insulin therapy relatively quickly (1.5 years), similarly to other previously reported non-obese patients with GADA-positive SPT1D.

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  • Cladribine treatment for Erdheim-Chester disease involving the central nervous system and concomitant polycythemia vera: A case report. Reviewed

    Suguru Tamura, Keisuke Kawamoto, Hiroaki Miyoshi, Takaharu Suzuki, Takayuki Katagiri, Takuya Kasami, Hiroki Nemoto, Shukuko Miyakoshi, Hironori Kobayashi, Yasuhiko Shibasaki, Masayoshi Masuko, Kengo Takeuchi, Koichi Ohshima, Hirohito Sone, Jun Takizawa

    Journal of clinical and experimental hematopathology : JCEH   58 ( 4 )   161 - 165   2018.12

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    Erdheim-Chester disease (ECD), a rare form of non-Langerhans cell histiocytosis, is characterized by the infiltration of foamy CD68+ and CD1a- histiocytes into multiple organ systems. Central nervous system (CNS) involvement has recently been reported to be a poor prognostic factor when treating ECD with interferon alpha. We report the case of a 66-year-old Japanese patient with ECD involving the CNS who harbored the BRAF V600E mutation and also concomitantly developed polycythemia vera with the JAK2 V617F mutation. We confirmed 2-chlorodeoxyadenosine (cladribine) therapy to be effective for the patient in this case.

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  • 当科で経験した下垂体茎断裂症候群の1例 Reviewed

    佐藤 隆明, 金子 正儀, 福武 嶺一, 安楽 匠, 種村 聡, 今西 明, 矢口 雄大, 山本 正彦, 鈴木 達郎, 石黒 創, 松林 泰弘, 山田 貴穂, 岩永 みどり, 藤原 和哉, 曽根 博仁

    新潟医学会雑誌   132 ( 11-12 )   399 - 399   2018.12

  • Relationship between intake of fruit separately from vegetables and triglycerides - A meta-analysis. Reviewed International journal

    Satoru Kodama, Chika Horikawa, Kazuya Fujihara, Dai Ishii, Mariko Hatta, Yasunaga Takeda, Masaru Kitazawa, Yasuhiro Matsubayashi, Hitoshi Shimano, Kiminori Kato, Shiro Tanaka, Hirohito Sone

    Clinical nutrition ESPEN   27   53 - 58   2018.10

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    BACKGROUND & AIMS: High intake of fruit and vegetables is recommended for cardiovascular health. However, there have been persistent beliefs that fruits having high concentrations of fructose elevate the level of triglycerides (TG) in blood unlike vegetables. This meta-analysis aims to clarify the relationship between fruit intake and TG or hypertriglyceridemia. METHODS: Electronic literature searches were conducted for observational studies that investigated the relationship between fruit intake and hypertriglyceridemia or intervention studies that investigated the effect of increasing fruit intake on TG. Each effect size was pooled with an inverse-variance method. RESULTS: Five cross-sectional studies and only 2 intervention studies were eligible. The pooled odds ratio (OR) (95% confidence interval (CI)) of the 5 cross-sectional studies for the highest vs. the lowest fruit intake category was 0.79 (0.72-0.87). In these studies, the pooled OR for the highest vs. the lowest vegetable intake category was not significant (OR = 0.92; 95% CI, (0.82-1.03)). A linear dose-response association was observed between increases in fruit intake and ORs for hypertriglyceridemia; the OR (95% CI) for an incrementally increased intake of fruit by 1 serving/day was 0.91 (0.84-0.98). CONCLUSION: This meta-analysis suggests that high intake of fruit but not vegetables is inversely associated with hypertriglyceridemia. More trials are needed to clarify whether increasing fruit intake would reduce the level of TG and/or incident hypertriglyceridemia.

    DOI: 10.1016/j.clnesp.2018.07.001

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  • Network meta‐analysis of the relative efficacy of bariatric surgeries for diabetes remission Reviewed

    Kodama S, Fujihara K, Horikawa C, Harada M, Ishiguro H, Kaneko M, Furukawa K, Matsubayashi Y, Matsunaga S, Shimano H, Tanaka S, Kato K, Sone H

    Obesity reviews   19 ( 12 )   1621 - 1629   2018.9

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  • ステロイド糖尿病を合併し歯性感染から上顎の骨髄炎を発症した2型糖尿病の1例 Reviewed

    棚橋 怜生, 山本 正彦, 松林 泰弘, 松永 佐澄志, 山田 貴穂, 岩永 みどり, 藤原 和哉, 羽入 修, 曽根 博仁

    糖尿病   61 ( 9 )   644 - 644   2018.9

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  • 糖尿病重症視力障害発症とHbA1cの関連性についての検討 Reviewed

    山本 正彦, 藤原 和哉, 五十嵐 理沙, 石澤 正博, 松林 泰弘, 松永 佐澄志, 伊藤 知恵, 錦野 理絵, 山中 菜詩, 児玉 暁, 曽根 博仁

    日本糖尿病眼学会誌   22   134 - 134   2018.9

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  • Refinement of the Glasgow Prognostic Score as a pre-transplant risk assessment for allogeneic hematopoietic cell transplantation. Reviewed

    Yasuhiko Shibasaki, Tatsuya Suwabe, Takayuki Katagiri, Tomoyuki Tanaka, Takashi Ushiki, Kyoko Fuse, Naoko Sato, Toshio Yano, Takashi Kuroha, Shigeo Hashimoto, Miwako Narita, Tatsuo Furukawa, Hirohito Sone, Masayoshi Masuko

    International journal of hematology   108 ( 3 )   282 - 289   2018.9

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    The Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) is a widely used tool for pre-transplant risk assessment. Allogeneic hematopoietic cell transplantation (HCT) is performed on patients with diverse backgrounds, highlighting the need for other predictors to complement the HCT-CI and support bedside decision-making. There is a strong body of evidence supporting the use of pre-transplant serum ferritin (SF) in risk assessments of allogeneic HCT. We additionally found that the Glasgow Prognostic Score (GPS), which assesses inflammatory biomarkers and predicts survival of patients with solid organ malignancies, is a useful predictive marker for overall survival (OS) and non-relapse mortality (NRM) in allogeneic HCT, independent of HCT-CI and SF. In this study, we refined the GPS by adding pre-transplant SF to improve its prognostic ability and enable better stratification; we call this revised index the HCT-specific revised Glasgow Prognostic Score (HCT-GPS). We observed that the HCT-GPS more accurately predicted NRM and early-term OS than the GPS. Moreover, the HCT-GPS provides an independent prognostic factor adjusted for the HCT-CI and disease status, and stratifies patients into four risk groups by OS and NRM. Thus, the HCT-GPS is a useful index for predicting early-term complications after allogeneic HCT in patients with hematopoietic diseases.

    DOI: 10.1007/s12185-018-2463-x

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  • 糖尿病重症視力障害発症とHbA1cの関連性についての検討

    山本 正彦, 藤原 和哉, 五十嵐 理沙, 石澤 正博, 松林 泰弘, 松永 佐澄志, 伊藤 知恵, 錦野 理絵, 山中 菜詩, 児玉 暁, 曽根 博仁

    日本糖尿病眼学会誌   22   134 - 134   2018.9

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  • Expression of programmed death ligand 1 is associated with poor prognosis in myeloid sarcoma patients. Reviewed International journal

    Keisuke Kawamoto, Hiroaki Miyoshi, Takaharu Suzuki, Junichi Kiyasu, Shintaro Yokoyama, Yuya Sasaki, Hirohito Sone, Masao Seto, Jun Takizawa, Koichi Ohshima

    Hematological oncology   36 ( 3 )   591 - 599   2018.8

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    Myeloid sarcoma (MS) is a rare condition and is an extramedullary tumour of immature myeloid cells. It is now known that the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway suppresses the host antitumor responses and that these products are expressed on both tumour cells and tumour-infiltrating cells in various malignancies. However, little is known about the significance of PD-1/PD-L1 expression on tumour cells and tumour microenvironmental cells in MS. To investigate the clinicopathological significance of PD-1/PD-L1 expression in MS, we analyzed 98 patients by immunohistochemistry. Of these, 10.2% of cases had neoplastic tumour cells positive for PD-L1 (nPD-L1+ ). However, the rate of nPD-L1+ was <5% (range: 0.27 to 2.97%). On the other hand, PD-L1 expression on 1 or more of stromal cells in the tumour microenvironment (miPD-L1+ ) was observed in 37.8% of cases. Because all nPD-L1+ cases expressed PD-1 on less than 5% of tumour cells, we compared the miPD-L1+ and miPD-L1- groups. There was a correlation between miPD-L1+ status and the number of PD-1-expressing tumour -infiltrating lymphocytes (PD-1+ TILs; P = .0229). miPD-L1+ was found to be associated with poorer overall survival and progression-free survival (P = .00392, P = .00261, respectively). Multivariate analysis also confirmed miPD-L1+ to be an independent poor prognostic factor. In conclusion, our study indicated that the immunotherapy blocking the PD-1/PD-L1 pathway may improve the clinical outcome of MS.

    DOI: 10.1002/hon.2506

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  • Heterogeneity of intrahepatic iron deposition in transfusion-dependent iron overload patients with hematological malignancies. Reviewed International journal

    Hironori Kobayashi, Norihiko Yoshimura, Shun Uemura, Takayuki Katagiri, Tomoyuki Tanaka, Takashi Ushiki, Kyoko Fuse, Yasuhiko Shibasaki, Miwako Narita, Hirohito Sone, Masayoshi Masuko

    Leukemia research   70   41 - 44   2018.7

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    DOI: 10.1016/j.leukres.2018.05.005

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  • Transgenic Mice Overexpressing SREBP-1a in Male ob/ob Mice Exhibit Lipodystrophy and Exacerbate Insulin Resistance. Reviewed International journal

    Hiroshi Ohno, Takashi Matsuzaka, Nie Tang, Rahul Sharma, Kaori Motomura, Takuya Shimura, Aoi Satoh, Song-Iee Han, Yoshinori Takeuchi, Yuichi Aita, Hitoshi Iwasaki, Shigeru Yatoh, Hiroaki Suzuki, Motohiro Sekiya, Yoshimi Nakagawa, Hirohito Sone, Naoya Yahagi, Nobuhiro Yamada, Yoshikazu Higami, Hitoshi Shimano

    Endocrinology   159 ( 6 )   2308 - 2323   2018.6

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Oxford University Press  

    Sterol regulatory element-binding protein (SREBP)-1a is a key transcription factor that activates the expression of genes involved in the synthesis of fatty acids, triglycerides (TGs), and cholesterol. Transgenic mice that overexpress the nuclear form of SREBP-1a under the control of the phosphoenolpyruvate carboxykinase promoter (Tg-1a) were previously shown to display a lipodystrophic phenotype characterized by enlarged and fatty livers, diminished peripheral white adipose tissue (WAT), and insulin resistance. In the current study, we crossed these Tg-1a mice with genetically obese (ob/ob) mice (Tg-1a;ob/ob) and examined change in fat distribution between liver and adipose tissues in severe obesity and mechanism underlying the lipodystrophic phenotype in mice with Tg-1a. Tg-1a;ob/ob mice developed more severe steatohepatitis but had reduced WAT mass and body weight compared with ob/ob mice. The reduction of WAT mass in Tg-1a and Tg-1a;ob/ob mice was accompanied by enhanced lipogenesis and lipid uptake in the liver, reduced plasma lipid levels, impaired adipocyte differentiation, reduced food intake, enhanced energy expenditure, and extended macrophage infiltration and fibrosis in WAT. Despite the improved glucose tolerance, Tg-1a;ob/ob mice showed severe peripheral insulin resistance. Adenoviral hepatic expression of SREBP-1a mimicked these phenotypes. The "fat steal"-like lipodystrophy phenotype of the Tg-1a;ob/ob model demonstrates that hepatic SREBP-1a activation has a strong impact on the partition of TG accumulation, resulting in adipose-tissue remodeling by inflammation and fibrosis and insulin resistance.

    DOI: 10.1210/en.2017-03179

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  • Relationships among cardiorespiratory fitness, muscular fitness, and cardiometabolic risk factors in Japanese adolescents: Niigata screening for and preventing the development of non-communicable disease study-Agano (NICE EVIDENCE Study-Agano) 2. Reviewed International journal

    Sakiko Yoshizawa Morikawa, Kazuya Fujihara, Mariko Hatta, Taeko Osawa, Masahiro Ishizawa, Masahiko Yamamoto, Kazuo Furukawa, Hajime Ishiguro, Satoshi Matsunaga, Yohei Ogawa, Hitoshi Shimano, Hirohito Sone

    Pediatric diabetes   19 ( 4 )   593 - 602   2018.6

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    Authorship:Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:WILEY  

    OBJECTIVE: To examine the independent and combined associations of cardiorespiratory fitness (CRF) and muscular fitness (MF) with cardiometabolic risk factors in Japanese adolescents. METHODS: A cross-sectional study including 993 Japanese adolescents (aged 13-14 years) was undertaken. Height, body mass, blood pressure, lipid profile (non-fasting), and HbA1c were measured. The physical fitness (PF) test included measurements of CRF (20 m multistage shuttle run test), upper limb strength (hand grip strength), lower limb strength (standing long jump), and muscular endurance (sit-ups). The clustered cardiometabolic risk (CCMR) was estimated by summing standardized Z-scores of body mass index (BMI), mean arterial pressure (MAP), non-high-density lipoprotein cholesterol (non-HDL-C), and HbA1c. RESULTS: Linear regression analysis showed that all PF factors except for muscular endurance were inversely correlated with CCMR (P < .001). Among metabolic risk components, HbA1c was unrelated to PF, while non-HDL-C was inversely associated with CRF (B = -2.40; P < .001), upper limb strength (B = -1.77; P < .05), and lower limb strength (B = -1.53; P < .05) after adjustment for lifestyle factors. Logistic regression showed that the probability of having high CCMR (≥1SD) was synergistically higher in those with the lowest tertiles of both CRF and upper limb strength (P for interaction = .001); however, a substantially lower likelihood of having high CCMR was observed among individuals with the lowest tertile of upper limb strength but moderate CRF. CONCLUSIONS: Lower CRF and MF were significantly and synergistically associated with an unhealthier metabolic risk profile.

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  • 耐糖能及び肥満の有無別にみた代謝異常が冠動脈疾患発症に及ぼす影響の検討 Reviewed

    藤原 和哉, 松林 泰弘, 山本 正彦, 金子 正儀, 松永 佐澄志, 山田 貴穂, 清田 浩康, 山中 菜詩, 児玉 暁, 曽根 博仁

    日本動脈硬化学会総会プログラム・抄録集   50回   336 - 336   2018.6

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  • A distinct subtype of Epstein-Barr virus-positive T/NK-cell lymphoproliferative disorder: adult patients with chronic active Epstein-Barr virus infection-like features. Reviewed International journal

    Keisuke Kawamoto, Hiroaki Miyoshi, Takaharu Suzuki, Yasuji Kozai, Koji Kato, Masaharu Miyahara, Toshiaki Yujiri, Ilseung Choi, Katsumichi Fujimaki, Tsuyoshi Muta, Masaaki Kume, Sayaka Moriguchi, Shinobu Tamura, Takeharu Kato, Hiroyuki Tagawa, Junya Makiyama, Yuji Kanisawa, Yuya Sasaki, Daisuke Kurita, Kyohei Yamada, Joji Shimono, Hirohito Sone, Jun Takizawa, Masao Seto, Hiroshi Kimura, Koichi Ohshima

    Haematologica   103 ( 6 )   1018 - 1028   2018.6

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    The characteristics of adult patients with chronic active Epstein-Barr virus infection are poorly recognized, hindering early diagnosis and an improved prognosis. We studied 54 patients with adult-onset chronic active Epstein-Barr virus infection diagnosed between 2005 and 2015. Adult onset was defined as an estimated age of onset of 15 years or older. To characterize the clinical features of these adults, we compared them to those of 75 pediatric cases (estimated age of onset <15 years). We compared the prognosis of adult-onset chronic active Epstein-Barr virus infection with that of patients with nasal-type (n=37) and non-nasal-type (n=45) extranodal NK/T-cell lymphoma. The median estimated age of onset of these lymphomas was 39 years (range, 16-86 years). Compared to patients with pediatric-onset disease, those in whom the chronic active Epstein-Barr virus infection developed in adulthood had a significantly decreased incidence of fever (P=0.005), but greater frequency of skin lesions (P<0.001). Moreover, hypersensitivity to mosquito bites and the occurrence of hydroa vacciniforme were less frequent in patients with adult-onset disease (P<0.001 and P=0.0238, respectively). Thrombocytopenia, high Epstein-Barr virus nuclear antigen antibody titer, and the presence of hemophagocytic syndrome were associated with a poor prognosis (P=0.0087, P=0.0236, and P=0.0149, respectively). Allogeneic hematopoietic stem cell transplantation may improve survival (P=0.0289). Compared to pediatric-onset chronic active Epstein-Barr virus infection and extranodal NK/T-cell lymphoma, adult-onset chronic active Epstein-Barr virus infection had a poorer prognosis (P<0.001 and P=0.0484, respectively). Chronic active Epstein-Barr virus infection can develop in a wide age range, with clinical differences between adult-onset and pediatric-onset disease. Adult-onset chronic active Epstein-Barr virus infection is a disease with a poor prognosis. Further research will be needed.

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  • 眼科処置を要する重症糖尿病性眼疾患の発生リスクに対する腎症の影響についての検討 Reviewed

    山本 正彦, 藤原 和哉, 大澤 妙子, 原田 万祐子, 石黒 創, 石澤 正博, 岩永 みどり, 松永 佐澄志, 松林 泰弘, 清田 浩康, 山中 菜詩, 山田 貴穂, 曽根 博仁

    糖尿病   61 ( Suppl.1 )   S - 161   2018.4

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  • 糖尿病患者における脈圧が透析導入に及ぼす影響の検討 Reviewed

    大澤 妙子, 藤原 和哉, 山本 正彦, 原田 万由子, 石澤 正博, 清田 浩康, 山中 菜詩, 松林 泰弘, 松永 佐澄志, 山田 貴穂, 曽根 博仁

    糖尿病   61 ( Suppl.1 )   S - 160   2018.4

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  • 診断に難渋した再発性重症低血糖の原因特定に薬物血中濃度測定が有用であった一例 Reviewed

    三ツ間 友里恵, 山本 正彦, 橋本 浩平, 金子 正儀, 松林 泰弘, 松永 佐澄志, 山田 貴穂, 岩永 みどり, 藤原 和哉, 曽根 博仁

    糖尿病   61 ( Suppl.1 )   S - 181   2018.4

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  • 糖尿病治療薬別にみたHbA1cと冠動脈疾患(CAD)発症リスクとの関連 Reviewed

    原田 万祐子, 藤原 和哉, 大澤 妙子, 石澤 正博, 山本 正彦, 金子 正儀, 松林 泰弘, 松永 佐澄志, 山中 菜詩, 清田 浩康, 山田 貴穂, 曽根 博仁

    糖尿病   61 ( Suppl.1 )   S - 258   2018.4

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  • 耐糖能及び肥満の有無に関わらず代謝異常は冠動脈疾患発症リスクを増大させる Reviewed

    藤原 和哉, 松林 泰弘, 山本 正彦, 松永 佐澄志, 清田 浩康, 山中 菜詩, 児玉 暁, 曽根 博仁

    糖尿病   61 ( Suppl.1 )   S - 260   2018.4

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  • 指先穿刺による血糖およびHbA1c迅速測定をもちいた糖尿病啓発の取り組み Reviewed

    山田 貴穂, 石井 大, 武田 安永, 橋本 浩平, 三ツ間 友里恵, 張 かおり, 原田 万祐子, 白石 友信, 吉岡 大志, 山本 正彦, 大澤 妙子, 石黒 創, 金子 正儀, 鈴木 浩史, 松林 泰弘, 松永 佐澄志, 藤原 和哉, 岩永 みどり, 鈴木 亜希子, 羽入 修, 曽根 博仁

    糖尿病   61 ( Suppl.1 )   S - 377   2018.4

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  • 日本人2型糖尿病患者における、ビタミンB6摂取量と糖尿病網膜症発症との関係 JDCSによる報告 Reviewed

    堀川 千嘉, 相田 麗, 田中 司朗, 鎌田 智恵実, 田中 佐智子, 吉村 幸雄, 川崎 良, 山下 英俊, 大橋 靖雄, 井藤 英喜, 赤沼 安夫, 曽根 博仁

    糖尿病   61 ( Suppl.1 )   S - 141   2018.4

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  • 2型糖尿病患者における食事エネルギー密度と肥満との関連 JDDMにおける検討 Reviewed

    武田 安永, 藤原 和哉, 治田 麻理子, 森川 咲子, 堀川 千嘉, 石井 大, 加藤 光敏, 横山 宏樹, 栗原 義夫, 宮澤 一裕, 岩崎 晧一, 川井 紘一, 朝長 修, 屋宜 宣治, 前川 聡, 曽根 博仁

    糖尿病   61 ( Suppl.1 )   S - 265   2018.4

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  • 肥満境界型糖尿病患者に対する血糖自己測定と栄養指導媒体を用いた栄養教育の併用効果について Reviewed

    長谷川 美代, 堀川 千嘉, 田代 稔, 鈴木 沙織, 藤原 和哉, 北澤 勝, 加藤 公則, 曽根 博仁

    糖尿病   61 ( Suppl.1 )   S - 267   2018.4

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  • Cardiovascular Disease in Japanese Patients with Type 2 Diabetes Mellitus. Reviewed

    Kazuya Fujihara, Hirohito Sone

    Annals of vascular diseases   11 ( 1 )   2 - 14   2018.3

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    Individuals with diabetes have a two- to four-fold increased risk of coronary artery disease (CAD) and higher mortality rates than those without diabetes. Because not only microvascular but also macrovascular disease in patients with diabetes are known to predispose patients to a lower quality of life as well as lead to higher mortality rates, identifying and managing risk factors of CAD is of clinical relevance in diabetes care. A number of antihyperglycemic drugs are currently approved for the treatment of hyperglycemia in patients with type 2 diabetes mellitus (T2DM), with several new drugs having been developed during the last decade. Diabetes-related complications have been substantially reduced worldwide. However, in view of the current situation in which both the prevalence of obesity and glucose abnormality have increased worldwide, including Japan, diet and exercise remain the crucial means of treatment for patients with diabetes. Furthermore, predicting the development of CAD is essential. This review summarizes data from recent studies on cardiovascular disease in patients with T2DM, focusing on clinical trials and big data, including studies involving Japanese individuals.

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  • Predictors of the response of HbA1c and body weight after SGLT2 inhibition. Reviewed International journal

    T Abe, Y Matsubayashi, A Yoshida, H Suganami, T Nojima, T Osawa, M Ishizawa, M Yamamoto, K Fujihara, S Tanaka, K Kaku, H Sone

    Diabetes & metabolism   44 ( 2 )   172 - 174   2018.3

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    DOI: 10.1016/j.diabet.2017.10.003

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  • MAGI-1 expression is decreased in several types of human T-cell leukemia cell lines, including adult T-cell leukemia. Reviewed

    Takashi Kozakai, Masahiko Takahashi, Masaya Higuchi, Toshifumi Hara, Kousuke Saito, Yuetsu Tanaka, Masayoshi Masuko, Jun Takizawa, Hirohito Sone, Masahiro Fujii

    International journal of hematology   107 ( 3 )   337 - 344   2018.3

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    Membrane-associated guanylate kinase with inverted orientation protein 1 (MAGI-1) is a cytoplasmic scaffold protein that interacts with various signaling molecules; it negatively controls the cell growth of various types of cells and positively controls cell-cell interaction. In T cells, MAGI-1 has been shown to inhibit Akt activity through its interaction with PTEN and MEK1. In this study we found that MAGI-1 expression is decreased in multiple (9 out of 15) human T-cell leukemia cell lines, including adult T-cell leukemia (ATL), T-cell acute lymphoblastic leukemia and chronic T-cell lymphocytic leukemia. The overexpression of MAGI-1 protein in a MAGI-1-low ATL cell line reduced cellular growth. While the overexpression of MAGI-1 protein in a MAGI-1-low ATL cell line reduced the Akt and MEK activities, the knockdown of MAGI-1 in a MAGI-1-high ATL cell line augmented the Akt and MEK activities. Collectively, the findings of the present study suggest that the decreased expression of MAGI-1 in human T cells contributes to the development of several types of T-cell leukemia, partly through the stimulation of the Akt and MEK pathways.

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  • Role of fatty liver in the association between obesity and reduced hepatic insulin clearance. Reviewed International journal

    Y Matsubayashi, A Yoshida, H Suganami, H Ishiguro, M Yamamoto, K Fujihara, S Kodama, S Tanaka, K Kaku, H Sone

    Diabetes & metabolism   44 ( 2 )   135 - 142   2018.3

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    AIM: Hepatic insulin clearance (HIC) is important in regulating plasma insulin levels. Diminished HIC causes inappropriate hyperinsulinaemia, and both obesity and fatty liver (FL), which are known to decrease HIC, can be found either together in the same patient or on their own. The mechanism by which obesity reduces HIC is presumed to be mediated by FL. However, few reports have examined the role of FL in the relationship between obesity and HIC in type 2 diabetes (T2D) patients. Therefore, our study investigated the association of HIC with clinical factors, including insulin sensitivity indices, focusing on the presence or absence of FL and obesity in T2D patients. METHOD: Baseline data from 419 patients with T2D (279 men, 140 women; mean age: 57.6 years; body mass index: 25.5kg/m2) controlled by diet and exercise were analyzed. HIC was calculated from the ratio of fasting c-peptide to fasting insulin levels (HICCIR). Correlation analyses between HICCIR and clinical variables were performed using Pearson's product-moment correlation coefficients and single regression analysis in all participants and in those with obesity and FL either alone or in combination. RESULTS: HICCIR was significantly correlated with whole-body insulin sensitivity indices and influenced by FL, but only in the FL group was obesity independently influenced HIC level. HICCIR decreased in those with both FL and obesity compared with those with only one such complication. CONCLUSION: HICCIR may be used to evaluate whole-body insulin sensitivity in T2D. Also, compared with obesity, the influence of FL strongly contributed to a reduced HIC. TRIAL REGISTRATION NUMBER: These trials were registered by the Japan Pharmaceutical Information Centre clinical trials information (JapicCTI) as 101349 and 101351.

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  • Frequent expression of CD30 in extranodal NK/T-cell lymphoma: Potential therapeutic target for anti-CD30 antibody-based therapy. Reviewed International journal

    Keisuke Kawamoto, Hiroaki Miyoshi, Takaharu Suzuki, Yuya Sasaki, Kyohei Yamada, Eriko Yanagida, Reiji Muto, Maiko Kiryu, Hirohito Sone, Masao Seto, Koichi Ohshima, Jun Takizawa

    Hematological oncology   36 ( 1 )   166 - 173   2018.2

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    Extranodal NK/T-cell lymphoma, nasal type (ENKTL) is a subtype of non-Hodgkin lymphoma with a poor prognosis. Although first-line treatments for patients with localized ENKTL have been established, there is no gold standard treatment for patients with advanced ENKTL and refractory and/or relapsed disease. Anti-CD30 antibody-based therapy, including brentuximab vedotin (BV), has been shown to target malignant lymphomas with CD30 expression. In particular, this therapeutic agent has recently been suggested to be effective for Hodgkin lymphoma and mature T-cell lymphoma. However, the efficacy of BV toward ENKTL has not yet been established. Therefore, we investigated the expression of CD30 in a large cohort to evaluate BV as a potential treatment for ENKTL. In this study, 97 Japanese patients with newly diagnosed ENKTL between January 2007 and December 2015 were enrolled. Flow cytometry and immunohistochemistry were performed for the evaluation of CD30 expression. If the cut-off value of CD30 expression is 1% or more, there were 55 positive cases (56.5%). According to the localization of lesion, the frequency of CD30 expression was significantly higher in the non-nasal type than in the nasal type (P = .0394). No differences were observed in almost all clinical characteristics between CD30-positive cases and CD30-negative cases. In addition, the expression of CD30 was not a prognostic factor for either overall survival or progression-free survival. In conclusion, frequent expression of CD30 in ENKTL suggests anti-CD30 antibody-based therapy may be an effective treatment.

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  • Quantitative Relationship Between Cumulative Risk Alleles Based on Genome-Wide Association Studies and Type 2 Diabetes Mellitus: A Systematic Review and Meta-analysis. Reviewed

    Satoru Kodama, Kazuya Fujihara, Hajime Ishiguro, Chika Horikawa, Nobumasa Ohara, Yoko Yachi, Shiro Tanaka, Hitoshi Shimano, Kiminori Kato, Osamu Hanyu, Hirohito Sone

    Journal of epidemiology   28 ( 1 )   3 - 18   2018.1

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    Many epidemiological studies have assessed the genetic risk of having undiagnosed or of developing type 2 diabetes mellitus (T2DM) using several single nucleotide polymorphisms (SNPs) based on findings of genome-wide association studies (GWAS). However, the quantitative association of cumulative risk alleles (RAs) of such SNPs with T2DM risk has been unclear. The aim of this meta-analysis is to review the strength of the association between cumulative RAs and T2DM risk. Systematic literature searches were conducted for cross-sectional or longitudinal studies that examined odds ratios (ORs) for T2DM in relation to genetic profiles. Logarithm of the estimated OR (log OR) of T2DM for 1 increment in RAs carried (1-ΔRA) in each study was pooled using a random-effects model. There were 46 eligible studies that included 74,880 cases among 249,365 participants. In 32 studies with a cross-sectional design, the pooled OR for T2DM morbidity for 1-ΔRA was 1.16 (95% confidence interval [CI], 1.13-1.19). In 15 studies that had a longitudinal design, the OR for incident T2DM was 1.10 (95% CI, 1.08-1.13). There was large heterogeneity in the magnitude of log OR (P < 0.001 for both cross-sectional studies and longitudinal studies). The top 10 commonly used genes significantly explained the variance in the log OR (P = 0.04 for cross-sectional studies; P = 0.006 for longitudinal studies). The current meta-analysis indicated that carrying 1-ΔRA in T2DM-associated SNPs was associated with a modest risk of prevalent or incident T2DM, although the heterogeneity in the used genes among studies requires us to interpret the results with caution.

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  • 当科で経験した下垂体茎断裂症候群の1例 Reviewed

    佐藤隆明, 金子正儀, 福武嶺一, 安楽匠, 種村聡, 今西明, 矢口雄大, 山本正彦, 鈴木達郎, 石黒創, 松林泰弘, 山田貴穂, 岩永みどり, 藤原和哉, 曽根博仁

    新潟医学会雑誌   132 ( 11/12 )   399 - 399   2018

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  • Impact of body mass index and metabolic phenotypes on coronary artery disease according to glucose tolerance status. Reviewed International journal

    K Fujihara, Y Matsubayashi, M Yamamoto, T Osawa, M Ishizawa, M Kaneko, S Matsunaga, K Kato, H Seida, N Yamanaka, S Kodama, H Sone

    Diabetes & metabolism   43 ( 6 )   543 - 546   2017.12

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    OBJECTIVE: This study aimed to examine the impact of obesity, as defined by body mass index (BMI), and a metabolically unhealthy phenotype on the development of coronary artery disease (CAD) according to glucose tolerance status. METHODS: This population-based retrospective cohort study included 123,746 Japanese men aged 18-72years (normal glucose tolerance: 72,047; prediabetes: 39,633; diabetes: 12,066). Obesity was defined as a BMI≥25kg/m2. Metabolically unhealthy individuals were defined as those with one or more of the following conditions: hypertension, hypertriglyceridaemia and/or low HDL cholesterol. A Cox proportional hazards regression model identified variables related to CAD incidence. RESULTS: The prevalences of obese subjects with normal glucose tolerance, prediabetes and diabetes were 21%, 34% and 53%, whereas those for metabolically unhealthy people were 43%, 60% and 79%, respectively. Multivariate analysis showed that a metabolically unhealthy phenotype increases hazard ratios (HRs) for CAD compared with a metabolically healthy phenotype, regardless of glucose tolerance status (normal glucose tolerance: 1.98, 95% CI: 1.32-2.95; prediabetes: 2.91, 95% CI: 1.85-4.55; diabetes: 1.90, 95% CI: 1.18-3.06). HRs for CAD among metabolically unhealthy non-obese diabetes patients and obese diabetes patients with a metabolically unhealthy status were 6.14 (95% CI: 3.94-9.56) and 7.86 (95% CI: 5.21-11.9), respectively, compared with non-obese subjects with normal glucose tolerance and without a metabolically unhealthy status. CONCLUSION: A metabolically unhealthy state can associate with CAD independently of obesity across all glucose tolerance stages. Clinicians may need to consider those with at least one or more conditions indicating a metabolically unhealthy state as being at high risk for CAD regardless of glucose tolerance status.

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  • The Glasgow Prognostic Score as a pre-transplant risk assessment for allogeneic hematopoietic cell transplantation. Reviewed International journal

    Yasuhiko Shibasaki, Tatsuya Suwabe, Takayuki Katagiri, Tomoyuki Tanaka, Hironori Kobayashi, Kyoko Fuse, Takashi Ushiki, Naoko Sato, Toshio Yano, Takashi Kuroha, Shigeo Hashimoto, Miwako Narita, Tatsuo Furukawa, Hirohito Sone, Masayoshi Masuko

    Clinical transplantation   31 ( 11 )   2017.11

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    Evaluation methods, such as scoring systems for predicting complications in advance, are necessary for determining the adaptation of allogeneic hematopoietic cell transplantation (HCT) and selecting appropriate conditioning regimens. The Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI), which is based on functions of main organs, is a useful tool for pre-transplant risk assessments and has been widely applied in determining treatment strategies for patients with hematological diseases. However, as allogeneic HCT is performed on patients with diverse backgrounds, another factor, which reinforces the HCT-CI, is required to evaluate pre-transplant risk assessments. The Glasgow Prognostic Score (GPS), which assesses the combined C-reactive protein and albumin, was reported to predict survival of patients with solid-organ malignancies independently of receiving chemo/radiotherapy and stages of cancer. In this study, we applied the GPS for pre-transplant risk assessments for allogeneic HCT. The GPS successfully stratified the patients into three risk groups of overall survival (OS) and non-relapse mortality (NRM). Moreover, the GPS could predict outcomes independently of the HCT-CI for OS and NRM in multivariate analysis. The GPS is considered to be a useful tool and reinforces the HCT-CI for determining adaptation of allogeneic HCT for patients with hematopoietic neoplasms.

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  • Internal deletion of BCOR reveals a tumor suppressor function for BCOR in T lymphocyte malignancies. Reviewed International journal

    Tomoyuki Tanaka, Yaeko Nakajima-Takagi, Kazumasa Aoyama, Shiro Tara, Motohiko Oshima, Atsunori Saraya, Shuhei Koide, Sha Si, Ichiro Manabe, Masashi Sanada, Manabu Nakayama, Masayoshi Masuko, Hirohito Sone, Haruhiko Koseki, Atsushi Iwama

    The Journal of experimental medicine   214 ( 10 )   2901 - 2913   2017.10

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    Recurrent inactivating mutations have been identified in various hematological malignancies in the X-linked BCOR gene encoding BCL6 corepressor (BCOR); however, its tumor suppressor function remains largely uncharacterized. We generated mice missing Bcor exon 4, expressing a variant BCOR lacking the BCL6-binding domain. Although the deletion of exon 4 in male mice (BcorΔE4/y ) compromised the repopulating capacity of hematopoietic stem cells, BcorΔE4/y thymocytes had augmented proliferative capacity in culture and showed a strong propensity to induce acute T-cell lymphoblastic leukemia (T-ALL), mostly in a Notch-dependent manner. Myc, one of the critical NOTCH1 targets in T-ALL, was highly up-regulated in BcorΔE4/y T-ALL cells. Chromatin immunoprecipitation/DNA sequencing analysis revealed that BCOR was recruited to the Myc promoter and restrained its activation in thymocytes. BCOR also targeted other NOTCH1 targets and potentially antagonized their transcriptional activation. Bcl6-deficient thymocytes behaved in a manner similar to BcorΔE4/y thymocytes. Our results provide the first evidence of a tumor suppressor role for BCOR in the pathogenesis of T lymphocyte malignancies.

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  • Severe hypoglycaemia is a major predictor of incident diabetic retinopathy in Japanese patients with type 2 diabetes Reviewed

    S. Tanaka, R. Kawasaki, S. Tanaka-Mizuno, S. Iimuro, S. Matsunaga, T. Moriya, S. Ishibashi, S. Katayama, Y. Ohashi, Y. Akanuma, H. Sone, H. Yamashita

    DIABETES & METABOLISM   43 ( 5 )   424 - 429   2017.10

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    Aim. - Hypoglycaemia is a common complication in diabetes patients. However, its relationship with retinopathy has not been well documented in patients with type 2 diabetes (T2D). This study aimed to investigate the associations between hypoglycaemia and the incidence and progression of diabetic retinopathy (DR).
    Methods. - In this longitudinal cohort study, which was part of the Japan Diabetes Complications Study (JDCS), adult patients with T2D were recruited at 59 diabetes clinics across Japan. Their history of hypoglycaemia was assessed by standardized self-reported questionnaires. Severe hypoglycaemia was defined as having at least one episode with coma requiring an outpatients visit or hospitalization. Adjusted hazard ratios (HRs) for incidence and progression of DR over 8 years of follow-up were determined.
    Results. - Of 1221 patients without DR, 127 (10.4%) had experienced non-severe hypoglycaemia within the previous year, whereas 10 (0.8%) reported severe hypoglycaemia episodes. During the 8-year follow-up involving 8492 person-years, 329 patients developed DR. In 410 patients with prevalent DR, the adjusted HRs for incident DR were 4.35 (95% CI: 1.98-9.56; P &lt; 0.01) and, for progression of DR, 2.29 (95% CI: 0.45-11.78; P = 0.32) with severe hypoglycaemia.
    Conclusion. - Having a history of severe hypoglycaemia was one of the strongest predictors of incident DR in patients with T2D, with a fourfold increased risk. Identifying patients with greater risks of DR based on their history of hypoglycaemia may help to personalize risk evaluation in patients with diabetes. (C) 2017 Elsevier Masson SAS. All rights reserved.

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  • Comparative evaluation of torasemide and spironolactone on adverse cardiac remodeling in a rat model of dilated cardiomyopathy. Reviewed International journal

    Somasundaram Arumugam, Remya Sreedhar, Vengadeshprabhu Karuppagounder, Meilei Harima, Masahiko Nakamura, Hiroshi Suzuki, Hirohito Sone, Kenichi Watanabe

    Cardiovascular therapeutics   35 ( 5 )   2017.10

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    BACKGROUND: Chronic heart failure (CHF) involves fluid retention and volume overload, leading to impaired cardiac function. In these conditions, diuretic agents are most commonly used to treat edema and thereby reducing the volume load on the failing heart. There are several other beneficial effects of diuretics apart from their action on urinary excretion. METHODS: To identify the effects of diuretic agents on adverse cardiac remodeling in CHF, this study was carried out, where we have compared the effects of torasemide and spironolactone in a rat model of dilated cardiomyopathy induced by porcine cardiac myosin-mediated experimental autoimmune myocarditis. RESULTS: Cardiac protein expression levels of inflammation, endoplasmic reticulum stress, and fibrosis markers were upregulated in the hearts of CHF rats, while treatment with either torasemide or spironolactone has downregulated their expression. The effect produced by spironolactone on cardiac fibrosis markers was comparably lesser than torasemide. Further, immunohistochemical analysis and histopathological studies have provided evidence to confirm the beneficial effects of these drugs on adverse cardiac remodeling in rats with CHF. CONCLUSION: Torasemide treatment has benefits against adverse cardiac remodeling in CHF rats, which was better than the protection offered by spironolactone.

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  • Comprehensive risk management for the prevention of cerebro-cardiovascular diseases in Japan Reviewed

    Tamio Teramoto, Masayuki Yokode, Hiroyasu Iso, Akihiko Kitamura, Hiroki Shiomi, Tsuyoshi Kimura, Masayasu Matsumoto, Mami Iida, Jun Sasaki, Shigeru Inoue, Ryouichi Nagatomi, Tetsuo Shoji, Hidenori Arai, Hiromi Rakugi, Hirohito Sone, Shizuya Yamashita, Shigeru Mizyzaki

    CLINICAL AND EXPERIMENTAL NEPHROLOGY   21 ( 5 )   743 - 754   2017.10

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  • Functional dissection of hematopoietic stem cell populations with a stemness-monitoring system based on NS-GFP transgene expression. Reviewed International journal

    Mohamed A E Ali, Kyoko Fuse, Yuko Tadokoro, Takayuki Hoshii, Masaya Ueno, Masahiko Kobayashi, Naho Nomura, Ha Thi Vu, Hui Peng, Ahmed M Hegazy, Masayoshi Masuko, Hirohito Sone, Fumio Arai, Atsushi Tajima, Atsushi Hirao

    Scientific reports   7 ( 1 )   11442 - 11442   2017.9

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    Hematopoietic stem cells (HSCs) in a steady state can be efficiently purified by selecting for a combination of several cell surface markers; however, such markers do not consistently reflect HSC activity. In this study, we successfully enriched HSCs with a unique stemness-monitoring system using a transgenic mouse in which green florescence protein (GFP) is driven by the promoter/enhancer region of the nucleostemin (NS) gene. We found that the phenotypically defined long-term (LT)-HSC population exhibited the highest level of NS-GFP intensity, whereas NS-GFP intensity was strongly downregulated during differentiation in vitro and in vivo. Within the LT-HSC population, NS-GFPhigh cells exhibited significantly higher repopulating capacity than NS-GFPlow cells. Gene expression analysis revealed that nine genes, including Vwf and Cdkn1c (p57), are highly expressed in NS-GFPhigh cells and may represent a signature of HSCs, i.e., a stemness signature. When LT-HSCs suffered from remarkable stress, such as transplantation or irradiation, NS-GFP intensity was downregulated. Finally, we found that high levels of NS-GFP identified HSC-like cells even among CD34+ cells, which have been considered progenitor cells without long-term reconstitution ability. Thus, high NS-GFP expression represents stem cell characteristics in hematopoietic cells, making this system useful for identifying previously uncharacterized HSCs.

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  • Successful 5-azacytidine treatment of myeloid sarcoma and leukemia cutis associated with myelodysplastic syndrome: A case report and literature review. Reviewed International journal

    Takayuki Katagiri, Takashi Ushiki, Masayoshi Masuko, Tomoyuki Tanaka, Shukuko Miyakoshi, Kyoko Fuse, Yasuhiko Shibasaki, Jun Takizawa, Sadao Aoki, Hirohito Sone

    Medicine   96 ( 36 )   e7975   2017.9

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    RATIONALE: Myeloid sarcoma (MS) and leukemia cutis (LC) are extramedullary tumors comprising myeloid blasts. They can occur de novo or concurrently with hematological disorders, usually acute myeloid leukemia (AML). AML chemotherapy is generally the initial therapy for MS and LC, and hematopoietic stem cell transplantation (HSCT) can be considered as additional therapy. However, treatment for older patients who are unable to continue intensive chemotherapy is not currently standardized. PATIENT CONCERNS: A 71-year-old Japanese woman was diagnosed with multiple MSs associated with myelodysplastic syndrome (MDS), using bone marrow aspiration and lymph node biopsy. DIAGNOSES: Additionally, LC was diagnosed by skin biopsy. Extramedullary MS and LC lesions were formed by massive infiltration of myeloblastic cells. INTERVENTIONS: Twenty courses of 5-azacytidine (5-Aza) were administrated as maintenance therapy after induction therapy with daunorubicin and cytarabine. OUTCOMES: Myeloblasts decreased in the bone marrow and the LC disappeared after induction therapy. The MSs completely disappeared, except for the palatine tonsil lesion, after 5-Aza maintenance therapy. 5-Aza treatment provided long-term partial response for more than 21 months. LESSONS: 5-Aza was well tolerated and may be a good option for the treatment of MS and LC associated with MDS, especially in older patients who cannot receive HSCT.

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  • Association between all-cause mortality and severity of depressive symptoms in patients with type 2 diabetes: Analysis from the Japan Diabetes Complications Study (JDCS). Reviewed International journal

    Satoshi Matsunaga, Shiro Tanaka, Kazuya Fujihara, Chika Horikawa, Satoshi Iimuro, Masafumi Kitaoka, Asako Sato, Jiro Nakamura, Masakazu Haneda, Hitoshi Shimano, Yasuo Akanuma, Yasuo Ohashi, Hirohito Sone

    Journal of psychosomatic research   99   34 - 39   2017.8

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    OBJECTIVE: The aims of this study are to confirm whether the excess mortality caused by depressive symptoms is independent of severe hypoglycemia in patients with type 2 diabetes mellitus (T2DM) and to evaluate the association between all-cause mortality and degrees of severity of depressive symptoms in Japanese patients with T2DM. METHODS: A total of 1160 Japanese patients with T2DM were eligible for this analysis. Participants were followed prospectively for 3years and their depressive states were evaluated at baseline by the Center for Epidemiologic Studies Depression Scale (CES-D). Cox proportional hazards model was used to evaluate the relative risk of all-cause mortality and was adjusted by possible confounding factors, including severe hypoglycemia, all of which are known as risk factors for both depression and mortality. RESULTS: After adjustment for severe hypoglycemia, each 5-point increase in the CES-D score was significantly associated with excess all-cause mortality (hazard ratio 1.69 [95% CI 1.26-2.17]). The spline curve of HRs for mortality according to total CES-D scores showed that mortality risk was slightly increased at lower scores but was sharply elevated at higher scores. CONCLUSION: A high score on the CES-D at baseline was significantly associated with all-cause mortality in patients with T2DM after adjusting for confounders including severe hypoglycemia. However, only a small effect on mortality risk was found at relatively lower levels of depressive symptoms in this population. Further research is needed to confirm this relationship between the severity of depressive symptoms and mortality in patients with T2DM.

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  • Elovl6 Deficiency Improves Glycemic Control in Diabetic db/db Mice by Expanding beta-Cell Mass and Increasing Insulin Secretory Capacity Reviewed International journal

    Hui Zhao, Takashi Matsuzaka, Yuta Nakano, Kaori Motomura, Nie Tang, Tomotaka Yokoo, Yuka Okajima, Song-iee Han, Yoshinori Takeuchi, Yuichi Aita, Hitoshi Iwasaki, Shigeru Yatoh, Hiroaki Suzuki, Motohiro Sekiya, Naoya Yahagi, Yoshimi Nakagawa, Hirohito Sone, Nobuhiro Yamada, Hitoshi Shimano

    DIABETES   66 ( 7 )   1833 - 1846   2017.7

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    Dysfunctional fatty acid (FA) metabolism plays an important role in the pathogenesis of beta-cell dysfunction and loss of beta-cell mass in type 2 diabetes (T2D). Elovl6 is a microsomal enzyme that is responsible for converting C16 saturated and monounsaturated FAs into C18 species. We previously showed that Elovl6 played a critical role in the development of obesity-induced insulin resistance by modifying FA composition. To further define its role in T2D development, we assessed the effects of Elovl6 deletion in leptin receptor-deficient C57BL/KsJ db/db mice, a model of T2D. The db/db; Elovl6(-/-) mice had a markedly increased beta-cell mass with increased proliferation and decreased apoptosis, an adaptive increase in insulin, and improved glycemic control. db/db islets were characterized by a prominent elevation of oleate (C18: 1n-9), cell stress, and inflammation, which was completely suppressed by Elovl6 deletion. As a mechanistic ex vivo experiment, isolated islets from Elovl6(-/-) mice exhibited reduced susceptibility to palmitate-induced inflammation, endoplasmic reticulum stress, and beta-cell apoptosis. In contrast, oleate-treated islets resulted in impaired glucose-stimulated insulin secretion with suppressed related genes irrespective of the Elovl6 gene. Taken together, Elovl6 is a fundamental factor linking dysregulated lipid metabolism to beta-cell dysfunction, islet inflammation, and beta-cell apoptosis in T2D, highlighting oleate as the potential culprit of beta-cell lipotoxicity.

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  • Elovl6 Deficiency Improves Glycemic Control in Diabetic db/db Mice by Expanding β-Cell Mass and Increasing Insulin Secretory Capacity

    Zhao, Hui, Matsuzaka, Takashi, Nakano, Yuta, Motomura, Kaori, Tang, Nie, Yokoo, Tomotaka, Okajima, Yuka, Han, Song-Iee, Takeuchi, Yoshinori, Aita, Yuichi, Iwasaki, Hitoshi, Yatoh, Shigeru, Suzuki, Hiroaki, Sekiya, Motohiro, Yahagi, Naoya, Nakagawa, Yoshimi, Sone, Hirohito, Yamada, Nobuhiro, Shimano, Hitoshi

    Diabetes   66 ( 7 )   1833 - 1846   2017.7

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  • Impact of Obesity and Metabolic Phenotypes on Coronary Artery Disease (CAD) According to Glucose Tolerance Status Reviewed

    Kazuya Fujihara, Satoru Kodama, Masahiko Yamamoto, Satoshi Matsunaga, Yasuhiro Matsubayashi, Masahiro Ishizawa, Mieko Koishi, Chie Ito, Nauta Yamanaka, Kiminori Kato, Hirohito Sone

    DIABETES   66   A406 - A406   2017.6

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  • Advanced Glycation End Products Induce Brain-Derived Neurotrophic Factor Release from Human Platelets through the Src Family Kinases Activation Reviewed

    Kazuo Furukawa, Ichiro Fuse, Yuriko Iwakura, Hidekazu Sotoyama, Osamu Hanyu, Hiroyuki Nawa, Nobuyuki Takei, Hirohito Sone

    DIABETES   66   A123 - A123   2017.6

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  • Associations between Hypertension and End-Stage Renal Disease (ESRD) in People With and Without Diabetes Reviewed

    Atsushi Furuya, Kazuya Fujihara, Masahiro Ishizawa, Masahiko Yamamoto, Yasuhiro Matsubayashi, Satoshi Matsunaga, Chie Ito, Mieko Koishi, Nauta Yamanaka, Kiminori Kato, Satoru Kodama, Hirohito Sone

    DIABETES   66   A138 - A138   2017.6

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  • Impact of glucose tolerance status on the development of coronary artery disease among working-age men. Reviewed

    Fujihara K, Igarashi R, Yamamoto M, Ishizawa M, Matsubayasi Y, Matsunaga S, Kato K, Ito C, Koishi M, Yamanaka N, Kodama S, Sone H

    DIABETES & METABOLISM   43 ( 3 )   261 - 264   2017.6

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    Aims. To examine the impact of glucose tolerance status on the development of coronary artery disease (CAD) in working-age men in Japan.
    Methods. This population-based retrospective cohort study included 111,621 men aged 31-60 years [63,558 with normal glucose tolerance (NGT); 37,126 with prediabetes; 10,937 with diabetes]. The Cox proportional-hazards regression model was used to identify variables related to the incidence of CAD.
    Results. Multivariate analysis showed that, compared with NGT, diabetes increased the risk of CAD by 17.3 times (95% CI: 6.36-47.0) at ages 31-40 years, by 2.74 times (95% CI: 1.85-4.05) at ages 41-50 years and by 2.47 times (95% CI: 1.69-3.59) at ages 51-60 years. The HRs for CAD in men with diabetes aged 31-40 equaled that of men with NGT aged 51-60 [18.2 (7.15-46.4) and 19.4 (8.28-45.4), respectively].
    Conclusion. The impact of diabetes on CAD was markedly greater in men aged 31-40 years compared with those aged 41-60 years. (C) 2016 Elsevier Masson SAS. All rights reserved.

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  • Clinicopathological features of cryptococcal lymphadenitis and a review of literature. Reviewed

    Kawamoto K, Miyoshi H, Suzuki T, Muto R, Yamada K, Yanagida E, Koshino M, Sasaki Y, Takizawa J, Sone H, Sugita Y, Seto M, Ohshima K

    Journal of clinical and experimental hematopathology : JCEH   57 ( 1 )   26 - 30   2017.6

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    Cryptococcosis is an invasive fungal infection in immunocompromised patients. The clinicopathological characteristics of cryptococcal lymphadenitis are not well known. We analyzed three cases of cryptococcal lymphadenitis and compared their characteristics with those in previous reports. Two patients were human immunodeficiency virus (HIV) carriers, and one patient was a human T-cell leukemia virus type-1 (HTLV-1) carrier. The age of the HTLV-1 carrier with cryptococcosis was much higher than that of the HIV-1 carriers. CD4-positive cell counts in peripheral blood were 5.8/μL (Case 1) and 79.9/μL (Case 2) in the HIV carriers and 3285/μL in the HTLV-1 carrier (Case 3). According to flow cytometric analysis of the lymph nodes of Cases 1, 2, and 3, 50.0%, 87.1%, and 85.9%, respectively, of the T-cells were CD3; 9.8%, 16.3%, and 75.8%, respectively, were CD4; and 35.5%, 77.3%, and 10.2%, respectively, were CD8. Cryptococcus neoformans was detected in tissue culture in all patients. Although gelatinous lesions and numerous fungal cocci were observed in the two HIV patients, the granuloma formation was small. Gelatinous formation and granuloma formation were observed in the HTLV-1 carrier. Necrosis was observed in all cases. In previous reports, granuloma formation, epithelioid cells, and necrotic lesions were observed in most cases. Most of the patients were also immunosuppressed. However, no HTLV-1 carrier was detected. In conclusion, lymphadenopathy in a HTLV-1 carrier may suggest the presence of cryptococcal lymphadenitis. The frequency of cryptococcosis in HTVL-1 carriers may increase with increase in the long-term survival rate of HTLV-1 carriers.

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  • Potential protective effect of lactation against incidence of type 2 diabetes mellitus in women with previous gestational diabetes mellitus: A systematic review and meta-analysis. Reviewed International journal

    Tanase-Nakao K, Arata N, Kawasaki M, Yasuhi I, Sone H, Mori R, Ota E

    Diabetes/metabolism research and reviews   33 ( 4 )   2017.5

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    Lactation may protect women with previous gestational diabetes mellitus (GDM) from developing type 2 diabetes mellitus, but the results of existing studies are inconsistent, ranging from null to beneficial. We aimed to conduct a systematic review to gather available evidence. Databases MEDLINE, CINAHL, PubMed, and EMBASE were searched on December 15, 2015, without restriction of language or publication year. A manual search was also conducted. We included observational studies (cross-sectional, case-control, and cohort study) with information on lactation and type 2 diabetes mellitus incidence among women with previous GDM. We excluded case studies without control data. Data synthesis was conducted by random-effect meta-analysis. Fourteen reports of 9 studies were included. Overall risk of bias using RoBANS ranged from low to unclear. Longer lactation for more than 4 to 12 weeks postpartum had risk reduction of type 2 diabetes mellitus compared with shorter lactation (OR 0.77, 95% CI 0.01-55.86; OR 0.56, 95% CI 0.35-0.89; OR 0.22, 95% CI 0.13-0.36; type 2 diabetes mellitus evaluation time < 2 y, 2-5 y, and >5 y, respectively). Exclusive lactation for more than 6 to 9 weeks postpartum also had lower risk of type 2 diabetes mellitus compared with exclusive formula (OR 0.42, 95% CI 0.22-0.81). The findings support the evidence that longer and exclusive lactation may be beneficial for type 2 diabetes mellitus prevention in women with previous GDM. However, the evidence relies only on observational studies. Therefore, further studies are required to address the true causal effect.

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  • Comparison of clinicopathological characteristics between T-cell prolymphocytic leukemia and peripheral T-cell lymphoma, not otherwise specified. Reviewed International journal

    Kawamoto K, Miyoshi H, Yanagida E, Yoshida N, Kiyasu J, Kozai Y, Morikita T, Kato T, Suzushima H, Tamura S, Muta T, Kato K, Eto T, Seki R, Nagafuji K, Sone H, Takizawa J, Seto M, Ohshima K

    European journal of haematology   98 ( 5 )   459 - 466   2017.5

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    OBJECTIVES: T-cell prolymphocytic leukemia (T-PLL) is a very rare, aggressive T-cell neoplasm. Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is also a highly aggressive lymphoma. These two diseases can often be confused with each other; therefore, we aimed to determine the clinical and pathological differences between T-PLL and PTCL-NOS. METHODS: We analyzed 15 T-PLL and 91 PTCL-NOS patients and also compared clinical features between T-PLL and PTCL-NOS with leukemic presentation. Peripheral blood images and biopsy specimens were analyzed, and treatment responses were determined via imaging modalities. The clinicopathological characteristics were statistically compared. RESULTS: T-PLL cells were smaller in size than those of PTCL-NOS with leukemic presentation (P=.0068); moreover, PTCL-NOS cells with leukemic presentation were smaller than those of PTCL-NOS without leukemic presentation (P=.0017). Immunophenotypic patterns in T-PLL and PTCL-NOS were similar. Five-year overall survival rates of T-PLL and all PTCL-NOS patients were 57.5% and 36.8%, respectively. No significant differences were found in clinical manifestations or prognoses; T-PLL and PTCL-NOS with leukemic presentation had essentially equivalent characteristics. CONCLUSION: T-PLL and PTCL-NOS may share common biological and clinical characteristics in Japanese patients.

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  • Comparative effects of torasemide and furosemide on gap junction proteins and cardiac fibrosis in a rat model of dilated cardiomyopathy. Reviewed International journal

    Watanabe K, Sreedhar R, Thandavarayan RA, Karuppagounder V, Giridharan VV, Antony S, Harima M, Nakamura M, Suzuki K, Suzuki H, Sone H, Arumugam S

    BioFactors (Oxford, England)   43 ( 2 )   187 - 194   2017.3

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    Cardiac fibrosis is the major hallmark of adverse cardiac remodeling in chronic heart failure (CHF) and its therapeutic targeting might help against cardiac dysfunction during chronic conditions. Diuretic agents are potentially useful in these cases, but their effects on the cardiac fibrosis pathogenesis are yet to be identified. This study was designed to identify and compare the effects of diuretic drugs torasemide and furosemide on cardiac fibrosis in a rat model of dilated cardiomyopathy induced by porcine cardiac myosin mediated experimental autoimmune myocarditis. Gap junction proteins, connexin-43 and N-cadherin, expressions were downregulated in the hearts of CHF rats, while torasemide treatment has upregulated their expression. Western blotting and immunohistochemical analysis for various cardiac fibrosis related proteins as well as histopathological studies have shown that both drugs have potential anti-fibrotic effects. Among them, torasemide has superior efficacy in offering protection against adverse cardiac remodeling in the selected rat model of dilated cardiomyopathy. In conclusion, torasemide treatment has potential anti-fibrotic effect in the hearts of CHF rats, possibly via improving the gap junction proteins expression and thereby improving the cell-cell interaction in the heart. © 2016 BioFactors, 43(2):187-194, 2017.

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  • Carbohydrate intake during early pregnancy is inversely associated with abnormal glucose challenge test results in Japanese pregnant women. Reviewed International journal

    Tajima R, Yachi Y, Tanaka Y, Kawasaki YA, Nishibata I, Hirose AS, Horikawa C, Kodama S, Iida K, Sone H

    Diabetes/metabolism research and reviews   33 ( 6 )   2017.3

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    BACKGROUND: In East Asian countries, which have a high prevalence of underweight individuals, there is little information about the association between dietary factors and abnormal glucose tolerance during pregnancy. We examined the association between carbohydrate intake and moderately abnormal glucose tolerance in Japanese pregnant women. METHODS: We conducted a prospective study on 325 Japanese pregnant women without a diagnosis of diabetes mellitus prior to pregnancy. Dietary carbohydrate intake (% of total energy intake) was assessed using a 3-day dietary record during weeks 8-15 of pregnancy. Glucose tolerance was assessed by the 50 g glucose challenge test (GCT) during weeks 24-28 of pregnancy. A positive GCT result was defined by a 1-hour plasma concentration ≥ 7.8 mmol/L. Odds ratios of a positive GCT were calculated for the top and middle tertile categories of carbohydrate intake using the bottom category as reference. RESULTS: Mean (standard deviation) body mass index at the first prenatal visit was 19.7 (1.9) kg/m2 , and 95 women were underweight. Seventy-four women had positive GCT results. Carbohydrate intake was negatively associated with a positive GCT result after adjusting for age, parity, body mass index at first prenatal visit, family history of diabetes mellitus, rate of gestational weight gain, energy intake, and dietary fiber intake (odds ratio for top category: 0.46 [95% CI, 0.23-0.93]). CONCLUSIONS: These findings suggest that high carbohydrate intake was negatively associated with moderately abnormal glucose tolerance in a population with a high prevalence of underweight individuals.

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  • Dietary salt intake and diabetes complications in patients with diabetes: An overview. Reviewed

    Chika Horikawa, Hirohito Sone

    Journal of general and family medicine   18 ( 1 )   16 - 20   2017.3

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    Dietary salt restriction is an essential constituent of diabetes care in preventing or slowing the development of diabetes complications, and many diabetes management guidelines include recommendations for dietary salt intake. However, descriptions of guidelines for salt intake are sometimes confined to studies of participants without diabetes or small short-term studies of patients with diabetes. However, in response to such situations, recent longitudinal studies of patients with diabetes have reported an association between dietary salt intake and diabetes complications. Thus, this review summarizes important points in the current situation regarding guidelines on salt intake and the latest findings and future issues on dietary salt intake for diabetes care focusing on (i) the current status and issues regarding the leading guidelines for dietary salt intake for diabetes care in various regions worldwide, and (ii) findings on salt intake from recent longitudinal studies of patients with diabetes whose dietary salt intake was restricted.

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  • Patients with type 2 diabetes having higher glomerular filtration rate showed rapid renal function decline followed by impaired glomerular filtration rate: Japan Diabetes Complications Study. Reviewed International journal

    Moriya T, Tanaka S, Sone H, Ishibashi S, Matsunaga S, Ohashi Y, Akanuma Y, Haneda M, Katayama S

    Journal of diabetes and its complications   31 ( 2 )   473 - 478   2017.2

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    AIMS: The Japan Diabetes Complications Study (JDCS), a nation-wide, multicenter, prospective study of patients with type 2 diabetes, reported that hemoglobin A1c (HbA1c), systolic blood pressure, and smoking were risk factors for the onset of macroalbuminuria. This study explored the risk factors for glomerular filtration rate (GFR) decline in the JDCS patients. METHODS: We examined the 1407 JDCS patients (667 women, mean age 59years, 974 normoalbuminuria, 433 microalbuminuria) whose urinary albumin-to-creatinine ratio (UACR) and estimated GFR (eGFR) were determined at baseline with an 8-year follow-up. We divided all the patients into four groups according to baseline eGFR: G1 (120≤eGFR), G2 (90≤eGFR<120), G3 (60≤eGFR<90), G4 (eGFR<60). RESULTS: The eGFRs in groups G1 and G2 decreased at follow-up compared to those at the baseline. The risk of annual eGFR decline rate≥3ml/min/1.73m2 (rapid decliners) increased as the baseline eGFR increased. Advanced age, high HbA1c, and UACR, or diabetic retinopathy at baseline were risk factors for the rapid decliners. Especially the G1 group had a significant risk for the rapid decliners. The frequency of the patients with GFR<60ml/min/1.73m2 at the follow-up amounted to 31.1% in the rapid decliners, which was higher than 12% in the non-rapid decliners. CONCLUSIONS: In normo- and microalbuminuric patients with type 2 diabetes, extra careful attention should be paid to patients with eGFR ≥120ml/min/1.73m2 to detect cases with rapidly decreased GFR under the normal range.

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  • Is the Proportion of Carbohydrate Intake Associated with the Incidence of Diabetes Complications?-An Analysis of the Japan Diabetes Complications Study. Reviewed International journal

    Horikawa C, Yoshimura Y, Kamada C, Tanaka S, Tanaka S, Matsunaga S, Hanyu O, Araki A, Ito H, Tanaka A, Ohashi Y, Akanuma Y, Sone H

    Nutrients   9 ( 2 )   2017.2

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    The appropriate proportions of macronutritional intake have been controversial in medical nutritional therapy for diabetes, and evidence of the effects of carbohydrate consumption on diabetes complications in prospective settings is sparse. We investigated the relationships between proportions of carbohydrate intake as the % of total energy and diabetes complications in a nationwide cohort of Japanese patients with type 2 diabetes aged 40-70 years with hemoglobin A1c ≥6.5%. The analysis was of 1516 responders to a baseline dietary survey assessed by the Food Frequency Questionnaire based on food groups. Primary outcomes were times to overt nephropathy, diabetic retinopathy, and cardiovascular disease (CVD) after 8 years. Hazard ratios (HRs) for proportions of carbohydrate intake were estimated by Cox regression adjusted for confounders. High carbohydrate intake was significantly related to higher intakes of grain, fruits, and sweets/snacks and lower intakes of soybean and soy products, vegetables, seaweed, meat and processed meat, fish and processed fish, eggs, milk and dairy products, oil, and alcoholic beverages. During the eight-year follow-up, there were 81, 275, and 129 events of overt nephropathy, diabetic retinopathy, and CVD, respectively. After adjustment for confounders, HRs for complications in patients with carbohydrate intake in the second or third tertiles (51.0%-56.4% and ≥56.5%, respectively) compared with carbohydrate intake in the first tertile (<50.9%, referent) were analyzed. No significant associations were shown in the second and third tertiles relative to first tertile (overt nephropathy: 1.05 (95% Confidence Interval, 0.54-2.06) and 0.98 (0.40-2.44); diabetic retinopathy: 1.30 (0.90-1.88) and 1.30 (0.78-2.15); and CVD: 0.95 (0.55-1.63) and 1.37 (0.69-2.72)). By exploring potentially nonlinear relationships, trends for the incidence of diabetes complications according to proportions of carbohydrate intake were not clearly shown. Findings suggested that proportions of carbohydrate intake were not associated with the incidence of diabetes complications among type 2 diabetes patients in Japan.

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  • Advanced glycation end products induce brain-derived neurotrophic factor release from human platelets through the Src-family kinase activation. Reviewed International journal

    Furukawa K, Fuse I, Iwakura Y, Sotoyama H, Hanyu O, Nawa H, Sone H, Takei N

    Cardiovascular diabetology   16 ( 1 )   20 - 20   2017.2

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    BACKGROUND: Brain-derived neurotrophic factor (BDNF) exerts beneficial effects not only on diabetic neuropathies but also on cardiovascular injury. There is argument regarding the levels of serum BDNF in patients with diabetes mellitus (DM). Because BDNF in peripheral blood is rich in platelets, this may represent dysregulation of BDNF release from platelets. Here we focused on advanced glycation end products (AGEs), which are elevated in patients with DM and have adverse effects on cardiovascular functions. The aim of this study is to elucidate the role of AGEs in the regulation of BDNF release from human platelets. METHODS: Platelets collected from peripheral blood of healthy volunteers were incubated with various concentrations of AGE (glycated-BSA) at 37 °C for 5 min with or without BAPTA-AM, a cell permeable Ca2+ chelator, or PP2, a potent inhibitor of Src family kinases (SFKs). Released and cellular BDNF were measured by ELISA and calculated. Phosphorylation of Src and Syk, a downstream kinase of SFKs, in stimulated platelets was examined by Western blotting and immunoprecipitation. RESULTS: AGE induced BDNF release from human platelets in a dose-dependent manner, which was dependent on intracellular Ca2+ and SFKs. We found that AGE induced phosphorylation of Src and Syk. CONCLUSIONS: AGE induces BDNF release from human platelets through the activation of the Src-Syk-(possibly phospholipase C)-Ca2+ pathway. Considering the toxic action of AGEs and the protective roles of BDNF, it can be hypothesized that AGE-induced BDNF release is a biological defense system in the early phase of diabetes. Chronic elevation of AGEs may induce depletion or downregulation of BDNF in platelets during the progression of DM.

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  • Comparison of baseline characteristics and clinical course in Japanese patients with type 2 diabetes among whom different types of oral hypoglycemic agents were chosen by diabetes specialists as initial monotherapy (JDDM 42). Reviewed International journal

    Fujihara K, Igarashi R, Matsunaga S, Matsubayashi Y, Yamada T, Yokoyama H, Tanaka S, Shimano H, Maegawa H, Yamazaki K, Kawai K, Sone H

    Medicine   96 ( 7 )   e6122   2017.2

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    Little is known about the relationships between patient factors and the antihyperglycemic agents that have been prescribed as initial therapy by diabetes specialists for patients with type 2 diabetes. Moreover, there has been little clarification of the subsequent usage patterns and related factors that influenced the continuation or discontinuation of the drug or the addition of another drug. To provide information on these issues, we evaluated the clinical characteristics of Japanese patients with type 2 diabetes for whom different types of oral hypoglycemic agents (i.e., either sulfonylureas, biguanides, or DPP-4 inhibitors (DPP-4Is)) were chosen as initial monotherapy by diabetes specialists and evaluated subsequent usage patterns.Prescription data on 3 different antidiabetic agents from December 2009 to March 2015 from diabetes specialists' patient registries were used to identify variables at baseline related to initial prescriptions; also, the addition of another hypoglycemic drug or discontinuation of the initial therapy was evaluated 1 year after the initial prescription. Analyzed were data on 2666 patients who received initial monotherapy with either a sulfonylurea (305 patients), biguanide (951 patients), or DPP-4I (1410 patients). Patients administered sulfonylureas were older, had a lower body mass index (BMI), longer duration of diabetes, and worse glycemic control than recipients of biguanides. Use of biguanides was related to younger age, short duration of diabetes, and obesity but was negatively associated with poor glycemic control. Older age but neither obesity nor poor glycemic control was associated with DPP-4Is. In all 3 groups a high HbA1c value was related to adding another hypoglycemic agent to the initial therapy. Moreover, adding another drug to a DPP-4I was related to a younger age and higher BMI.Patients' age, duration of diabetes, obesity, and glycemic control at baseline influenced the choice of hypoglycemic agents. Selection of a biguanide differs greatly from that of a sulfonylurea or DPP-4I with regard to age and obesity.

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  • Unstable bodyweight and incident type 2 diabetes mellitus: A meta-analysis. Reviewed

    Kodama S, Fujihara K, Ishiguro H, Horikawa C, Ohara N, Yachi Y, Tanaka S, Shimano H, Kato K, Hanyu O, Sone H

    Journal of diabetes investigation   8 ( 4 )   501 - 509   2017.1

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    AIMS/INTRODUCTION: The present meta-analysis aimed to clarify the association of unstable bodyweight with the risk of type 2 diabetes mellitus, an association that has been controversial among longitudinal studies. MATERIALS AND METHODS: An electronic literature search using EMBASE and MEDLINE was followed up to 31 August 2016. The relative risks (RRs) of type 2 diabetes mellitus in individuals with unstable bodyweight were pooled using the inverse variance method. RESULTS: Eight studies were eligible for the meta-analysis. The median duration of measurements of weight change and follow-up years for ascertaining type 2 diabetes mellitus were 13.5 and 9.4 years, respectively. The pooled RR for the least vs most stable category was 1.33 (95% confidence interval 1.12-1.57). Between-study heterogeneity was statistically significant (P = 0.048). Whether type 2 diabetes mellitus was ascertained by blood testing explained 66.0% of the variance in the logarithm of RR (P = 0.02). In three studies in which blood testing was carried out, type 2 diabetes mellitus risk was not significant (RR 1.06, 95% confidence interval 0.91-1.25). Furthermore, publication bias that inflated type 2 diabetes mellitus risk was statistically detected by Egger's test (P = 0.09). CONCLUSIONS: Unstable bodyweight might be modestly associated with the elevated risk of type 2 diabetes mellitus; although serious biases, such as diagnostic suspicion bias and publication bias, made it difficult to assess this association.

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  • Prevalence of non-communicable diseases and number of comorbidities according to differences in household income levels in Japan: Analysis from National Health and Nutrition Survey. Reviewed

    Horikawa C, Murayama N, Ota A, Tsuruta M, Matsunaga S, Fujihara K, Hanyu O, Sone H

    Food and nutrition Sciences   7 ( 1 )   19 - 30   2017.1

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  • Successful umbilical cord blood hematopoietic stem cell transplantation in a patient with adult T-cell leukemia/lymphoma initially achieving complete remission with anti-CC chemokine receptor 4 antibody combined chemotherapy. Reviewed

    Suwabe T, Shibasaki Y, Kaihatsu A, Katagiri T, Miyakoshi S, Fuse K, Kobayashi H, Ushiki T, Moriyama M, Takizawa J, Narita M, Sone H, Masuko M

    [Rinsho ketsueki] The Japanese journal of clinical hematology   58 ( 1 )   32 - 36   2017

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    A 62-year-old man with CHOP refractory adult T-cell leukemia/lymphoma (ATLL) received anti-CC chemokine receptor 4 antibody (mogamulizumab) combined with CHOP and achieved complete remission. At 71 days after the final administration of mogamulizumab, he received umbilical cord blood transplantation (CBT) using reduced intensity conditioning. Umbilical cord blood engraftment was confirmed on day16. Grade II acute graft-versus-host disease (GVHD) was diagnosed on day60 and was controlled by administration of methylprednisolone. There was no evidence of relapse at 9 months after CBT. Ratios of regulatory T cells in CD4 positive T cells were remarkably low during all of these periods. Since mogamulizumab reduces regulatory T cells, the frequency and severity of acute GVHD were reported to be increased in patients administered mogamulizumab before allogenic stem cell transplantation. Further experiences are needed for selecting optimal donor sources, the portability period and GVHD prophylaxis for patients using mogamulizumab before allogeneic stem cell transplantation.

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  • Peripheral T-cell lymphoma, not otherwise specified: a retrospective single-center analysis. Reviewed

    Takaharu Suzuki, Keisuke Kawamoto, Suguru Tamura, Shun Uemura, Akane Kaihatsu, Hiroki Nemoto, Hironori Kobayashi, Takashi Ushiki, Kyoko Fuse, Yasuhiko Shibazaki, Masato Moriyama, Masayoshi Masuko, Miwako Narita, Hirohito Sone, Sadao Aoki, Naoya Nakamura, Koichi Oshima, Jun Takizawa

    [Rinsho ketsueki] The Japanese journal of clinical hematology   58 ( 8 )   905 - 911   2017

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    We retrospectively analyzed clinical and pathological features, treatments, and prognoses in 28 patients with newly diagnosed peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) in Niigata University Medical and Dental Hospital. Of them, 16 were males and 12 were females, and their median age was 62.5 (range, 26-88) years. The International Prognostic Index was high-intermediate/high in 68% of patients. Twelve patients were treated with CHOP/THP-COP and nine with third-generation chemotherapy regimens. At a median follow-up period of 30 (range: 1-164) months, the 2-year overall survival and progression-free survival rates were 61% and 44%, respectively. Further investigation of novel agents for treating PTCL-NOS is warranted.

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  • [Myelodysplastic syndrome with refractory hemorrhage due to reduced platelet aggregation activity]. Reviewed

    Tanaka T, Kozakai T, Kitajima T, Fuse K, Kobayashi H, Ushiki T, Shibazaki Y, Moriyama M, Takizawa J, Sone H, Fuse I, Masuko M

    [Rinsho ketsueki] The Japanese journal of clinical hematology   58 ( 12 )   2402 - 2405   2017

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    <p>A 75-year-old woman suffered a cat bite 10 months after myelodysplastic syndrome (MDS) diagnosis. She visited our hospital because the internal bleeding of the wound did not improve. Although the wound was treated, the bleeding did not stop. She was hospitalized for emergency medical treatment because the bleeding volume exceeded 200 m<i>l</i>. Although her platelet count was normal, the platelet function test showed a decrease in collagen and arachidonic acid aggregation. After platelet transfusion, her bleeding stopped. Patients with MDS may potentially have platelet dysfunction. In the case of bleeding without thrombocytopenia, a platelet function test should be performed and treatment intervention, such as platelet transfusion, should be considered.</p>

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  • Aggregation is a critical cause of poor transfer into the brain tissue of intravenously administered cationic PAMAM dendrimer nanoparticles. Reviewed

    Kurokawa Y, Sone H, Win-Shwe TT, Zeng Y, Kimura H, Koyama Y, Yagi Y, Matsui Y, Yamazaki M, Hirano S

    2017

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  • Development and evaluation of the Japanese version of the Audit of Diabetes-Dependent Quality of Life for patients with diabetes. Reviewed

    Ayumi Sugawara Hirose, Kazuya Fujihara, Flaminia Miyamasu, Shigeru Iwakabe, Misa Shimpo, Yoriko Heianza, Chika Horikawa, Yoko Yachi, Hirohito Sone

    Diabetology international   7 ( 4 )   384 - 390   2016.12

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    Objectives: Our objective was to undertake linguistic validation and cultural adaptation of the Japanese version of the Audit of Diabetes-Dependent Quality of Life (JP-ADDQoL) and to evaluate its psychometric properties when completed by Japanese patients with diabetes. Methods: We followed the standard linguistic validation procedure and subsequently evaluated the reliability (internal consistency) and construct validity (exploratory and confirmatory factor analyses) of the translated version by surveying 239 Japanese patients with diabetes. Results: We translated 19 items for the JP-ADDQoL. The internal consistency was excellent (Cronbach's alpha = 0.933). In the exploratory factor analysis, four factors were extracted, and most of the items in all four factors had high loadings. Forced one-factor analysis revealed all factor loadings other than those for sex life to be >0.40 (sex life: 0.398). Confirmatory factor analysis indicated an acceptable fit for the JP-ADDQoL. Conclusions: The JP-ADDQoL showed adequate reliability and acceptable validity. Examining not only the impact of diabetes on a specific domain of life but also its importance for each patient leads to more accurate and individualized measurement of the patient's QoL.

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  • CREB3L3 controls fatty acid oxidation and ketogenesis in synergy with PPARα. Reviewed International journal

    Nakagawa Y, Satoh A, Tezuka H, Han SI, Takei K, Iwasaki H, Yatoh S, Yahagi N, Suzuki H, Iwasaki Y, Sone H, Matsuzaka T, Yamada N, Shimano H

    Scientific reports   6   39182 - 39182   2016.12

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    CREB3L3 is involved in fatty acid oxidation and ketogenesis in a mutual manner with PPARα. To evaluate relative contribution, a combination of knockout and transgenic mice was investigated. On a ketogenic-diet (KD) that highlights capability of hepatic ketogenesis, Creb3l3-/- mice exhibited reduction of expression of genes for fatty oxidation and ketogenesis comparable to Ppara-/- mice. Most of the genes were further suppressed in double knockout mice indicating independent contribution of hepatic CREB3L3. During fasting, dependency of ketogenesis on CREB3L3 is lesser extents than Ppara-/- mice suggesting importance of adipose PPARα for supply of FFA and hyperlipidemia in Creb3l3-/- mice. In conclusion CREB3L3 plays a crucial role in hepatic adaptation to energy starvation via two pathways: direct related gene regulation and an auto-loop activation of PPARα. Furthermore, as KD-fed Creb3l3-/- mice exhibited severe fatty liver, activating inflammation, CREB3L3 could be a therapeutic target for NAFLD.

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  • Intestinal CREBH overexpression prevents high-cholesterol diet-induced hypercholesterolemia by reducing Npc1l1 expression. Reviewed International journal

    Kikuchi T, Orihara K, Oikawa F, Han SI, Kuba M, Okuda K, Satoh A, Osaki Y, Takeuchi Y, Aita Y, Matsuzaka T, Iwasaki H, Yatoh S, Sekiya M, Yahagi N, Suzuki H, Sone H, Nakagawa Y, Yamada N, Shimano H

    Molecular metabolism   5 ( 11 )   1092 - 1102   2016.11

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    OBJECTIVE: The transcription factor cyclic AMP-responsive element-binding protein H (CREBH, encoded by Creb3l3) is highly expressed in the liver and small intestine. Hepatic CREBH contributes to glucose and triglyceride metabolism by regulating fibroblast growth factor 21 (Fgf21) expression. However, the intestinal CREBH function remains unknown. METHODS: To investigate the influence of intestinal CREBH on cholesterol metabolism, we compared plasma, bile, fecal, and tissue cholesterol levels between wild-type (WT) mice and mice overexpressing active human CREBH mainly in the small intestine (CREBH Tg mice) under different dietary conditions. RESULTS: Plasma cholesterol, hepatic lipid, and cholesterol crystal formation in the gallbladder were lower in CREBH Tg mice fed a lithogenic diet (LD) than in LD-fed WTs, while fecal cholesterol output was higher in the former. These results suggest that intestinal CREBH overexpression suppresses cholesterol absorption, leading to reduced plasma cholesterol, limited hepatic supply, and greater excretion. The expression of Niemann-Pick C1-like 1 (Npc1l1), a rate-limiting transporter mediating intestinal cholesterol absorption, was reduced in the small intestine of CREBH Tg mice. Adenosine triphosphate-binding cassette transporter A1 (Abca1), Abcg5/8, and scavenger receptor class B, member 1 (Srb1) expression levels were also reduced in CREBH Tg mice. Promoter assays revealed that CREBH directly regulates Npc1l1 expression. Conversely, CREBH null mice exhibited higher intestinal Npc1l1 expression, elevated plasma and hepatic cholesterol, and lower fecal output. CONCLUSION: Intestinal CREBH regulates dietary cholesterol flow from the small intestine by controlling the expression of multiple intestinal transporters. We propose that intestinal CREBH could be a therapeutic target for hypercholesterolemia.

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  • Clinicopathological, Cytogenetic, and Prognostic Analysis of 131 Myeloid Sarcoma Patients. Reviewed International journal

    Kawamoto K, Miyoshi H, Yoshida N, Takizawa J, Sone H, Ohshima K

    The American journal of surgical pathology   40 ( 11 )   1473 - 1483   2016.11

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    Myeloid sarcoma (MS) is an extramedullary tumor of immature myeloid cells. We analyzed 131 patients with MS, including: (1) de novo MS; (2) MS with concomitant acute myeloid leukemia (AML); (3) MS following myelodysplastic syndrome, myeloproliferative neoplasm, or chronic myelogenous leukemia; and (4) MS as a recurrence of AML. The most common development site was the lymph node. Testicular lesions were statistically more frequent in MS as a recurrence of AML than in other types of MS (P=0.0183). MS tended to lack myeloid markers (myeloperoxidase was present in 63.2%, CD68 in 51.3%, CD13 in 48.7%, and CD33 in 48.7% of patients) and express T-cell markers such as CD3 (20.7%) and CD5 (34.2%). All T-cell marker-positive MS cases were negative for the αβ and γδ T-cell receptors on immunohistochemistry. Underlying myelodysplastic syndrome or myeloproliferative neoplasm was a poor prognostic factor (vs. de novo MS: P=0.0383; vs. MS with concomitant AML: P=0.0143). However, there was no statistical difference in prognosis between de novo MS and MS with concomitant AML (P=0.288). There were no significant differences in prognosis between the prognoses of T-cell marker-positive and T-cell marker-negative MS cases. In addition, CXCR4 expression was a poor prognostic factor in MS (P=0.0229). This study involves the largest MS cohort to date and expands the clinical and pathologic knowledge of the disease.

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  • Quantitative assessment of genetic testing for type 2 diabetes mellitus based on findings of genome-wide association studies. Reviewed International journal

    Satoru Kodama, Kazuya Fujihara, Hajime Ishiguro, Chika Horikawa, Nobumasa Ohara, Yoko Yachi, Shiro Tanaka, Hitoshi Shimano, Kiminori Kato, Osamu Hanyu, Hirohito Sone

    Annals of epidemiology   26 ( 11 )   816 - 818   2016.11

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  • Utility of nonblood-based risk assessment for predicting type 2 diabetes mellitus: A meta-analysis Reviewed International journal

    Sakiko Yoshizawa, Satoru Kodama, Kazuya Fujihara, Hajime Ishiguro, Masahiro Ishizawa, Yasuhiro Matsubayashi, Satoshi Matsunaga, Takaho Yamada, Hitoshi Shimano, Kiminori Kato, Osamu Hanyu, Hirohito Sone

    PREVENTIVE MEDICINE   91   180 - 187   2016.10

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    Objective. Nonblood-based risk assessment for type 2 diabetes mellitus (T2DM) that depends on data based on a questionnaire and anthropometry is expected to avoid unnecessary diagnostic testing and overdiagnosis due to blood testing. This meta-analysis aims to assess the predictive ability of nonblood-based risk assessment for future incident T2DM.Methods. Electronic literature search was conducted using EMBASE and MEDLINE (from January 1, 1997 to October 1, 2014). Included studies had to use at least 3 predictors for T2DM risk assessment and allow reproduction of 2 x 2 contingency table data (i.e., true positive, true negative, false positive, false negative) to be pooled with a bivariate random-effects model and hierarchical summary receiver-operating characteristic model. Considering the importance of excluding individuals with a low likelihood of T2DM from diagnostic blood testing, we especially focused on specificity and LR-.Results. Eighteen eligible studies consisting of 184,011 participants and 7038 cases were identified. The pooled estimates (95% confidence interval) were as follows: sensitivity = 0.73 (0.66-0.79), specificity = 0.66 (0.59-0.73), LR+ = 2.13 (1.81-2.50), and LR- = 0.41 (0.34-0.50).Conclusions. Nonblood-based assessment of risk of T2DM could produce acceptable results although the feasibility of such a screener needs to be determined in future studies. (C) 2016 Elsevier Inc. All rights reserved.

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  • Association of eating three meals irregularly with changes in BMI and weight among young Japanese men and women: A 2-year follow-up. Reviewed International journal

    Yoko Ibe, Happei Miyakawa, Yasuko Fuse-Nagase, Ayumi Sugawara Hirose, Reiko Hirasawa, Yoko Yachi, Kazuya Fujihara, Kazuto Kobayashi, Hitoshi Shimano, Hirohito Sone

    Physiology & behavior   163   81 - 87   2016.9

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    OBJECTIVE: Epidemiological longitudinal investigations of the association between not eating three meals regularly and changes in BMI and weight are scarce. The aim of this study was to investigate whether or not regularly eating three meals was associated with changes in BMI and weight in young Japanese men and women. METHODS: Study participants were 1241 men and 897 women aged 19.0±1.2 and 18.8±0.8years, respectively, who underwent health checkups at a university in Japan in 2001 as the baseline and subsequently in 2003. Weight and height were measured at baseline and 2years later. Whether an individual ate three meals regularly was determined by a self-report questionnaire in 2001. RESULTS: During the 2-year follow-up, the BMI gain was 0.347 for men and 0.067 for women. In the logistic regression analysis, for men, eating three meals irregularly was significantly associated with a 4% BMI gain (OR 1.60, CI 1.11-2.30), 6% BMI gain (OR 1.72, CI 1.12-2.63), 4kg weight gain (OR 2.01, CI 1.29-3.13), 6kg weight gain (OR 1.86, CI 1.02-3.37), and incidence of obesity (BMI ≧ 25)(OR 2.96, CI 1.22-7.17). For women, eating three meals irregularly was significantly associated with a 4% BMI loss (OR 1.99, CI 1.01-3.94), 6% BMI loss (OR 2.79, CI 1.29-6.03), 4kg weight loss (OR 3.85, CI 1.62-9.12), 6kg weight loss (OR 7.65, CI 2.06-28.46), and the incidence of underweight (OR 3.95, CI 1.32-11.89). CONCLUSIONS: The current results suggested that eating three meals irregularly was associated with subsequent BMI and weight gains for men and subsequent BMI and weight losses for women; both groups were around 20years of age. Self-reported eating behavior in this study might be used to screen and evaluate young Japanese men and women at high risk for changes in BMI and weight in a practical clinical setting.

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  • Impact of individual components and their combinations within a family history of hypertension on the incidence of hypertension: Toranomon hospital health management center study 22. Reviewed International journal

    Risa Igarashi, Kazuya Fujihara, Yoriko Heianza, Masahiro Ishizawa, Satoru Kodama, Kazumi Saito, Shigeko Hara, Osamu Hanyu, Ritsuko Honda, Hiroshi Tsuji, Yasuji Arase, Hirohito Sone

    Medicine   95 ( 38 )   e4564   2016.9

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    Although a family history (FH) of hypertension is a risk factor for the development of hypertension, only a few studies have investigated in detail the impact of individual components of an FH on incident hypertension. We investigated the impact of individual components and their combinations on the presence or development of hypertension considering obesity, smoking habits, physical activity, and other metabolic parameters.Studied were 12,222 Japanese individuals without hypertension (n = 9,766) and with hypertension (n = 2,456) at the baseline examination. The presence or incidence of hypertension during 5 years after a baseline examination was assessed by the presence of systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg or a self-reported history of clinician-diagnosed hypertension. In this prospective study, the odds ratio for incident hypertension was 1.39 (95% confidence interval [CI], 1.22, 1.59) for individuals with any FH of hypertension compared with those without such an FH. Individuals with an FH of hypertension in both parents and one or more grandparents had an odds ratio of 3.05 (95% CI 1.74, 5.36) for hypertension compared with those without an FH of hypertension. FH was associated with incident hypertension independently of other modifiable risk factors such as obesity, smoking, physical inactivity, hyperglycemia, hyperuricemia, and hypertriglyceridemia.A parental history of hypertension was an essential component within an FH for incident hypertension. FH of hypertension over two generations with both parents affected was the most important risk factor for incident hypertension. Although an FH is not a modifiable risk factor, modifying other risk factors could contribute to reducing the risk of hypertension even among individuals with a family history of hypertension.

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  • Maximum BMI and microvascular complications in a cohort of Japanese patients with type 2 diabetes: the Japan Diabetes Complications Study Reviewed

    Shiro Tanaka, Sachiko Tanaka, Satoshi Iimuro, Shun Ishibashi, Hidetoshi Yamashita, Tatsumi Moriya, Shigehiro Katayama, Yasuo Akanuma, Yasuo Ohashi, Nobuhiro Yamada, Atsushi Araki, Hideki Ito, Hirohito Sone

    JOURNAL OF DIABETES AND ITS COMPLICATIONS   30 ( 5 )   790 - 797   2016.7

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    Aims: The aim of this study was to examine the associations between possible indices of obesity based on information on weight history and the incidence of microvascular complications.
    Methods: A cohort of individuals with type 2 diabetes from 59 institutes in Japan was followed for 8 years. Patients were classified into three categories according to weight at entrance and past maximum weight: normal (BMI at baseline &lt;25 kg/m(2) and maximum BMI &lt;25 kg/m(2)), past obesity (BMI at baseline &lt;25 kg/m2 and maximum BMI &gt;= 25 kg/m(2)), and current obesity (BMI at baseline 25 kg/m(2)) groups. The outcomes were diabetic retinopathy and overt nephropathy.
    Results: BMI at maximum and baseline of the 1809 patients was 26.5 +/- 3.5 and 23.1 +/- 3.0 kg/m(2) (p &lt; 0.01), respectively (23.0 +/- 1.6 and 20.6 +/- 1.9 kg/m(2) for normal, 27.4 +/- 2.0 and 22.8 +/- 1.4 kg/m(2) for past obesity, and 30.1 +/- 2.9 and 27.0 +/- 1.8 kg/m(2) for current obesity). The hazard ratios of past and current obesity compared to normal were 1.92 (95% CI, 1.08-3.41; p = 0.03) and 221 (1.16-4.22; p = 0.02), respectively, for overt nephropathy and 138 (1.05-1.83; p = 0.02) and 1.64 (1.18-2.28; p &lt; 0.01), respectively, for diabetic retinopathy after adjustment for confounders.
    Conclusions: Past obesity as well as current obesity were associated with increased risks of microvascular complications. Further identification of high-risk populations may be possible by classifying normal weight patients by past obesity. (C) 2016 Elsevier Inc. All rights reserved.

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  • Cluster-randomized trial to improve the quality of diabetes management: The study for the efficacy assessment of the standard diabetes manual (SEAS-DM). Reviewed

    Hiroshi Noto, Yukio Tanizawa, Toru Aizawa, Hirohito Sone, Narihito Yoshioka, Yasuo Terauchi, Nobuya Inagaki, Mitsuhiko Noda

    Journal of diabetes investigation   7 ( 4 )   539 - 43   2016.7

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    AIMS/INTRODUCTION: 'The Standard Diabetes Manual' has been developed by clinical researchers from multiple major institutions in Japan, such as the National Center for Global Health and Medicine, as a comprehensive disease management program, including collaboration between primary care physicians (PCPs) and specialist services. The present study evaluated the efficacy of the manual as a quality improvement strategy in diabetes care by PCPs. MATERIALS AND METHODS: A total of 42 PCPs in eight domestic districts of the Japan Medical Association were allocated to either the intervention group or the control group in a cluster-randomized design. The PCPs in both groups were provided with a copy of the Diabetes Treatment Guide published by the Japan Diabetes Society, and the PCPs in the intervention group additionally received a copy of the manual and a 30-min relevant seminar at the inception of the intervention. The primary end-point was the adherence to the following performances as quality indicators: evaluation of retinopathy, and urinary albumin excretion measurements and serum creatinine measurements, as recommended by the Japan Medical Association. RESULTS: A total of 416 patients were enrolled by 36 PCPs. During the 1-year follow-up period, the proportion of PCPs who adhered to recommendation-concordant measurements of urinary albumin excretion was significantly higher in the intervention group than in the control group (adherence: 17.9% vs 5.3%, P = 0.016). The other parameters were not statistically different between the two groups. CONCLUSIONS: Implementation of 'The Standard Diabetes Manual' potentially leads to an improved quality of diabetes management by PCPs.

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  • Hyperlipidemia and hepatitis in liver-specific CREB3L3 knockout mice generated using a one-step CRISPR/Cas9 system. Reviewed International journal

    Yoshimi Nakagawa, Fusaka Oikawa, Seiya Mizuno, Hiroshi Ohno, Yuka Yagishita, Aoi Satoh, Yoshinori Osaki, Kenta Takei, Takuya Kikuchi, Song-Iee Han, Takashi Matsuzaka, Hitoshi Iwasaki, Kazuto Kobayashi, Shigeru Yatoh, Naoya Yahagi, Masaaki Isaka, Hiroaki Suzuki, Hirohito Sone, Satoru Takahashi, Nobuhiro Yamada, Hitoshi Shimano

    Scientific reports   6   27857 - 27857   2016.6

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    cAMP responsive element binding protein 3-like 3 (CREB3L3), a transcription factor expressed in the liver and small intestine, governs fasting-response energy homeostasis. Tissue-specific CREB3L3 knockout mice have not been generated till date. To our knowledge, this is the first study using the one-step CRISPR/Cas9 system to generate CREB3L3 floxed mice and subsequently obtain liver- and small intestine-specific Creb3l3 knockout (LKO and IKO, respectively) mice. While LKO mice as well as global KO mice developed hypertriglyceridemia, LKO mice exhibited hypercholesterolemia in contrast to hypocholesterolemia in global KO mice. LKO mice demonstrated up-regulation of hepatic Srebf2 and its corresponding target genes. No phenotypic differences were observed between IKO and floxed mice. Severe liver injury was observed in LKO mice fed a methionine-choline deficient diet, a model for non-alcoholic steatohepatitis. These results provide new evidence regarding the hepatic CREB3L3 role in plasma triglyceride metabolism and hepatic and intestinal CREB3L3 contributions to cholesterol metabolism.

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  • MYC translocation and/or BCL 2 protein expression are associated with poor prognosis in diffuse large B-cell lymphoma Reviewed

    Keisuke Kawamoto, Hiroaki Miyoshi, Noriaki Yoshida, Naoya Nakamura, Koichi Ohshima, Hirohito Sone, Jun Takizawa

    CANCER SCIENCE   107 ( 6 )   853 - 861   2016.6

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    Genomic alterations and protein expression levels have been established as prognostic factors for survival in patients with diffuse large B-cell lymphoma (DLBCL). In particular, double-hit DLBCL (DHL), which exhibits translocations in MYC and BCL2 and/or BCL6, is known to be associated with a poor prognosis. However, the clinical significance of gene alterations and protein expression levels for MYC, B-cell lymphoma (BCL)2, and BCL6 are unclear. In this study, we analyzed 61 adult patients diagnosed with DLBCL without DHL, who were treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone, or similar regimens. There were no differences in the distribution of MYC expression rates among the different MYC gene statuses. In log-rank tests, MYC translocation was a prognostic factor for overall survival (OS; P = 0.011), whereas BCL2 and BCL6 translocation were not prognostic indicators (P = 0.999 and P = 0.925, respectively). Although the expression levels of MYC and BCL6 were not significantly associated with OS, the expression of BCL2 was a prognostic factor for OS (P = 0.027). Furthermore, copy number gains in the MYC, BCL2, and BCL6 genes did not affect OS. MYC translocation (hazard ratio, 4.769; range, 1.518-14.98; P = 0.007) and BCL2 protein expression (hazard ratio, 3.072; range, 1.002-9.413; P = 0.049) were independent prognostic factors for survival in multivariate analyses. In conclusion, MYC translocation and BCL2 expression may need to be investigated at the initial diagnosis to predict prognosis in patients with DLBCL.

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  • Body Mass Index (BMI), Waist Circumference (WC) and Waist Height Ratio (WHtR) Cutoff Values, and the Impact of Their Combinations on Future Diabetes among Japanese Individuals Reviewed

    Risa Igarashi, Kazuya Fujihara, Yoriko Heianza, Masahiro Ishizawa, Megumi Tsuruta, Mariko Hatta, Sakiko Yoshizawa, Chika Hirikawa, Satoshi Matsunaga, Osamu Hanyu, Satoru Kodama, Koji Sato, Kiminori Kato, Hirohito Sone

    DIABETES   65   A519 - A520   2016.6

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  • The Dinakara equation for adjusting DLCO for hemoglobin in the HCT-CI is superior to the Cotes equation for predicting high-risk patients in allogeneic hematopoietic stem cell transplantation Reviewed

    Yasuhiko Shibasaki, Takayuki Katagiri, Hironori Kobayashi, Takashi Ushiki, Miwako Narita, Hirohito Sone, Tatsuo Furukawa, Masayoshi Masuko

    AMERICAN JOURNAL OF HEMATOLOGY   91 ( 5 )   E296 - E297   2016.5

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  • [Features of Japanese diabetic macroangiopathy]. Reviewed

    Masanori Kaneko, Kazuo Furukawa, Hirohito Sone

    Nihon rinsho. Japanese journal of clinical medicine   74 Suppl 2   22 - 6   2016.4

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  • [The 43rd Scientific Meeting: Perspectives of Internal Medicine; Genetic predisposition and related life-style underlying metabolic disorders; 2. Genetic and Environmental Susceptibility; 3) Epidemiology and large-scale clinical data analysis in metabolic diseases]. Reviewed

    Hirohito Sone

    Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine   105 ( 3 )   383 - 90   2016.3

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  • Comparison of lipid parameters to predict cardiovascular events in Japanese mild-to-moderate hypercholesterolemic patients with and without type 2 diabetes: Subanalysis of the MEGA study Reviewed

    Hirohito Sone, Tomoko Nakagami, Rimei Nishimura, Naoko Tajima

    DIABETES RESEARCH AND CLINICAL PRACTICE   113   14 - 22   2016.3

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    Aims: To determine whether specific lipid parameters are better predictors of cardiovascular disease (CVD) in Japanese mild-to-moderate hypercholesterolemic patients with and without diabetes.
    Methods: Mildly or moderately hypercholesterolemic patients with no history of CVD received diet therapy or diet therapy plus pravastatin. In this post-hoc subanalysis, 5-year data from 3170 patients (668 diabetes, 2502 non-diabetes) on diet therapy alone were used to compare lipid parameters as predictors of CVD. We examined the data by tertiles, using hazard ratio (HR) per one-standard deviation (SD) increment (decrease for high-density lipoprotein cholesterol, HDL-C), chi(2) value, receiver operating characteristic curve analysis, and spline analysis.
    Results: In mild-to-moderate hypercholesterolemic patients with diabetes, increased total cholesterol (TC)/HDL-C, low-density lipoprotein cholesterol (LDL-C)/HDL-C and decreased HDL-C were strongly associated with increased incidence of CVD (tertile analysis). In non-diabetes, increased non-HDL-C, and LDL-C/HDL-C were significantly associated with increased incidence of CVD. A one-SD decrease in HDL-C and a one-SD increment in non-HDL-C, TC/HDL-C, and LDL-C/HDL-C were significantly associated with increased HRs for CVD in both diabetes and non-diabetes. Linear CVD risk increases were found for non-HDL-C in diabetes and for non-HDL-C and HDL-C in non-diabetes (spline analysis).
    Conclusions: In mild-to-moderate hypercholesterolemia, CVD risk prediction by stratifications of single or combination of traditional lipid parameter values illustrates various patterns. Parameters including HDL-C are better predictors of cardiovascular risk than only using TC or LDL-C alone. Non-HDL-C could be the most useful lipid parameter to assess CVD risk, considering it is easy to calculate and less affected by food intake. (C) 2016 The Authors. Published by Elsevier Ireland Ltd.

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  • Assessment of kidney dysfunction with cystatin C- and creatinine-based estimated glomerular filtration rate and predicting type 2 diabetes: Toranomon Hospital Health Management Center Study 21 Reviewed

    Yoriko Heianza, Shigeko Hara, Kazumi Saito, Hiroshi Tsuji, Shiro Tanaka, Satoru Kodama, Tetsuro Kobayashi, Yasuji Arase, Hirohito Sone

    DIABETES RESEARCH AND CLINICAL PRACTICE   113   60 - 68   2016.3

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    Objective: Whether early stages of kidney dysfunction assessed by the estimated glomerular filtration rate from cystatin C measurements (eGFRCysC) rather than from creatinine measurements (eGFRCr) would more precisely reflect the risk of developing type 2 diabetes (T2D) has not been clarified. We compared the risk of developing T2D associated with renal dysfunction indicated by eGFRCysC or eGFRCr measurements.
    Methods: Studied were 2131 Japanese individuals without diabetes. Hazard ratios (HRs) for the development of T2D over 3-5 y were calculated across categories of eGFRCysC and eGFRCr, respectively.
    Results: Reduced levels of eGFRCysC were associated with a step-wise increase in the cumulative incidence rate of T2D (p = 0.007). In comparison with the eGFRCysC &gt;85th percentile group (&gt;= 117.4 ml/min/1.73 m(2)), the lowest group, which was the eGFRCysC &lt;15th percentile group (&lt;86.2 ml/min/1.73 m(2)), had an adjusted HR of 2.30 (95% CI 1.13, 4.68) for T2D. Compared with the eGFRCr &gt;85th percentile group, the lowest eGFRCr group (&lt;15th percentile) had an HR of 1.19 (0.63, 2.24) for T2D. However, individuals with eGFRCr &lt;60 ml/min/1.73 m(2) had a significantly increased risk of T2D. Clustering of both low eGFRCysC and low eGFRCr further elevated the HR for T2D compared with the presence of either.
    Conclusions: Although eGFRCr in ranges indicating chronic kidney disease reflected an elevated risk of developing diabetes, earlier stages of kidney dysfunction indicated by reduced eGFRCysC, which could not be captured by reduced eGFRCr, would be a marker for an elevated risk of developing T2D. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

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  • Comparison of clinical characteristics in patients with type 2 diabetes among whom different antihyperglycemic agents were prescribed as monotherapy or combination therapy by diabetes specialists. Reviewed

    Kazuya Fujihara, Osamu Hanyu, Yoriko Heianza, Akiko Suzuki, Takaho Yamada, Hiroki Yokoyama, Shiro Tanaka, Hiroaki Yagyu, Hitoshi Shimano, Atsunori Kashiwagi, Katuya Yamazaki, Koichi Kawai, Hirohito Sone

    Journal of diabetes investigation   7 ( 2 )   260 - 9   2016.3

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    AIMS/INTRODUCTION: We compared clinical characteristics in patients with type 2 diabetes for whom different antihyperglycemic agents were prescribed as monotherapy or combination therapy by diabetes specialists in Japan. MATERIALS AND METHODS: Prescription data for 2005, 2008 and 2011 from diabetes specialists' patient registries identified variables related to prescription of different antihyperglycemic agents. RESULTS: A total of 33,251 prescriptions in 2005, 25,119 in 2008 and 20,631 in 2011 were analyzed. Prescribing insulin was related to younger age, long duration of diabetes and glycated hemoglobin (HbA1c) ≥8.0%, but was negatively associated with obesity. Prescribing sulfonylureas was related to older age and long duration of diabetes, but not to obesity. Use of biguanides was related to younger age, short duration of diabetes and obesity, but was negatively associated with HbA1c ≥8.0%. A short duration of diabetes and HbA1c ≥8.0% were associated with use of a DPP-4 inhibitor, but not with obesity. Prescribing GLP-1 receptor agonists was related to younger age, obesity and HbA1c ≥8.0%. Odds ratios for each antihyperglycemic combination therapy were determined based on the characteristics of each included antihyperglycemic agent. CONCLUSIONS: These results could be expected to reflect in part the consensus of diabetes specialists, and might provide guidance regarding pharmacotherapy in the clinical setting.

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  • Meta-analytic research on the relationship between cumulative risk alleles and risk of type 2 diabetes mellitus. Reviewed International journal

    Satoru Kodama, Kazuya Fujihara, Hajime Ishiguro, Chika Horikawa, Nobumasa Ohara, Yoko Yachi, Shiro Tanaka, Hitoshi Shimano, Kiminori Kato, Osamu Hanyu, Hirohito Sone

    Diabetes/metabolism research and reviews   32 ( 2 )   178 - 86   2016.2

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    BACKGROUND: Our aim is to examine the dose-response association between cumulative genetic risk and actual risk of type 2 diabetes mellitus (T2DM) and the influence of adjustment for covariates on T2DM risk through a comprehensive meta-analysis of observational studies. METHODS: Electronic literature search using EMBASE and MEDLINE (from 2003 to 2014) was conducted for cross-sectional or longitudinal studies that presented the odds ratio (OR) for T2DM in each group with categories based on the total number of risk alleles (RAs) carried (RAtotal ) using at least two single-nucleotide polymorphisms. Spline regression model was used to determine the shape of the relationship between the difference from the referent group of each study in RAtotal (ΔRAtotal ) and the natural logarithms of ORs (log OR) for T2DM. RESULTS: Sixty-five eligible studies that included 68 267 cases among 182 603 participants were analysed. In both crude and adjusted ORs, defined by adjusting the risk for at least two confounders among age, gender and body mass index, the slope of the log OR for T2DM became less steep as the ΔRAtotal increased. In the analysis limited to 14 cross-sectional and four longitudinal studies presenting both crude and adjusted ORs, regression curves of both ORs in relation to ΔRAtotal were almost identical. CONCLUSION: Using only single-nucleotide polymorphisms for T2DM screening was of limited value. However, when genotypic T2DM risk was considered independently from risk in relation to covariates, it was suggested that genetic profiles might have a supplementary role related to conventional T2DM risk factors in identifying individuals at high risk of T2DM. Copyright © 2015 John Wiley & Sons, Ltd.

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  • In Search of the Ideal Resistance Training Program to Improve Glycemic Control and its Indication for Patients with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis Reviewed

    Hajime Ishiguro, Satoru Kodama, Chika Horikawa, Kazuya Fujihara, Ayumi Sugawara Hirose, Reiko Hirasawa, Yoko Yachi, Nobumasa Ohara, Hitoshi Shimano, Osamu Hanyu, Hirohito Sone

    SPORTS MEDICINE   46 ( 1 )   67 - 77   2016.1

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    Background Resistance training (RT) is effective for glycemic control in type 2 diabetes mellitus (T2DM) patients. However, the characteristics of an RT program that will maximize its effect and those of patients that will especially benefit from RT are unknown.
    Objective The objectives of this systematic review were to identify via a comprehensive meta-analysis the characteristics of an RT program for patients with T2DM that might increase the patients' improvement in glycemic control and the characteristics of patients that will benefit from RT. Data Sources Electronic-based literature searches of MEDLINE and EMBASE entries from 1 January 1966 to 25 August 2014 were conducted to identify clinical trials examining the effect of RT on glycemic control among patients with T2DM. Study keywords were text words and thesaurus terms related to RT and T2DM.
    Study Selection Studies were included if they (1) were clinical trials consisting of two groups with and without RT exercise intervention; (2) had an intervention period of at least 5 weeks; (3) clarified that all patients had T2DM; and (4) reported or made it possible to estimate the effect size [i.e., change in glycosylated hemoglobin (HbA1c) in the RT group minus that in the control group] and its corresponding standard error.
    Study Appraisal and Synthesis Methods The effect size in each study was pooled with a random-effects model. Analyses were stratified by several key characteristics of the patients and RT exercise programs; meta-regression analysis was then used to detect a difference in the effect size among strata within each factor. Linear regression analyses were added by entering each of the following profiles: patients' baseline characteristics [mean baseline age, body mass index (BMI), and HbA1c levels] and exercise characteristics (total sets per week, total sets per bout of exercise, frequency, and intensity).
    Results There were 23 eligible studies comprising 954 patients with T2DM. The pooled effect size (95 % confidence interval) was -0.34 % (-0.53 to -0.16). A program with multiple sets (&gt;= 21 vs. &lt;21) per one RT bout was associated with a large effect size (P = 0.03); however, the linear correlation between the number of sets and effect size was not significant (P = 0.56). A larger effect size was observed in studies with participants with diabetes of a relatively short duration (&lt;6 vs. &gt;= 6 years; P = 0.04) or a high baseline HbA(1c) [&gt;= 7.5 % (58 mmol/mol) vs. &lt;7.5 %; P = 0.01] while a smaller effect size was observed in studies with a particularly high mean baseline BMI value (&gt;= 32 vs. &lt;32 kg/m(2); P = 0.03). Linear regression analyses predicted that each increment of 1 % in the baseline HbA(1c) would enlarge the effect size by 0.036 %, while each increment of 1 kg/m(2) in the baseline BMI decreased it by 0.070 % in the range between 22.3 and 38.8 kg/m(2).
    Conclusion In terms of glycemic control, RT could be recommended in the early stage of T2DM, especially for patients with relatively poor glycemic control. More benefit would be elicited in less obese patients within a limited range of the BMI. A substantial amount of exercise might be required to stimulate post-exercise glucose uptake, although the dose-dependency was not specifically clarified.

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  • Rapid Normalization of High Glutamic Acid Decarboxylase Autoantibody Titers and Preserved Endogenous Insulin Secretion in a Patient with Diabetes Mellitus: A Case Report and Literature Review Reviewed

    Nobumasa Ohara, Masanori Kaneko, Tatsuo Furukawa, Tadashi Koike, Hirohito Sone, Shoichiro Tanaka, Kenzo Kaneko, Kyuzi Kamoi

    INTERNAL MEDICINE   55 ( 5 )   485 - 489   2016

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    A 59-year-old Japanese woman developed diabetes mellitus without ketoacidosis in the presence of glutamic acid decarboxylase autoantibody (GADA) (24.7 U/mL). After the amelioration of her hyperglycemia, the patient had a relatively preserved serum C-peptide level. Her endogenous insulin secretion capacity remained almost unchanged during 5 years of insulin therapy. The patient's GADA titers normalized within 15 months. The islet-related autoantibodies, including GADA, are believed to be produced following the autoimmune destruction of pancreatic beta cells and are predictive markers of type 1 diabetes mellitus. Therefore, the transient appearance of GADA in our patient may have reflected pancreatic autoimmune processes that terminated without progression to insulin deficiency.

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  • Different Effects of Eicosapentaenoic and Docosahexaenoic Acids on Atherogenic High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease in Mice. Reviewed International journal

    Noriko Suzuki-Kemuriyama, Takashi Matsuzaka, Motoko Kuba, Hiroshi Ohno, Song-Iee Han, Yoshinori Takeuchi, Masaaki Isaka, Kazuto Kobayashi, Hitoshi Iwasaki, Shigeru Yatoh, Hiroaki Suzuki, Katsuhiro Miyajima, Dai Nakae, Naoya Yahagi, Yoshimi Nakagawa, Hirohito Sone, Nobuhiro Yamada, Hitoshi Shimano

    PloS one   11 ( 6 )   e0157580   2016

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    Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of metabolic syndrome, can progress to steatohepatitis (NASH) and advanced liver damage, such as that from liver cirrhosis and cancer. Recent studies have shown the benefits of consuming n-3 polyunsaturated fatty acids (PUFAs) for the treatment of NAFLD. In the present study, we investigated and compared the effects of the major n-3 PUFAs-eicosapentaenoic acid (EPA, C20:5) and docosahexaenoic acid (DHA, C22:6)-in preventing atherogenic high-fat (AHF) diet-induced NAFLD. Mice were fed the AHF diet supplemented with or without EPA or DHA for four weeks. Both EPA and DHA reduced the pathological features of AHF diet-induced NASH pathologies such as hepatic lobular inflammation and elevated serum transaminase activity. Intriguingly, EPA had a greater hepatic triacylglycerol (TG)-reducing effect than DHA. In contrast, DHA had a greater suppressive effect than EPA on AHF diet-induced hepatic inflammation and ROS generation, but no difference in fibrosis. Both EPA and DHA could be effective for treatment of NAFLD and NASH. Meanwhile, the two major n-3 polyunsaturated fatty acids might differ in a relative contribution to pathological intermediate steps towards liver fibrosis.

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  • Fulminant Type 1 Diabetes Mellitus Associated with Coxsackie Virus Type A2 Infection: A Case Report and Literature Review Reviewed

    Nobumasa Ohara, Masanori Kaneko, Takeaki Nishibori, Kazuhiro Sato, Tatsuo Furukawa, Tadashi Koike, Hirohito Sone, Kenzo Kaneko, Kyuzi Kamoi

    INTERNAL MEDICINE   55 ( 6 )   643 - 646   2016

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    A 65-year-old Japanese man presented to our hospital in June 2013 with a 6-day history of fever and fatigue, a 24-h history of thirst, and polyuria. His temperature was 37.8 degrees C and he was alert. However, laboratory tests revealed severe hyperglycemia, undetectable C-peptide levels, and diabetic ketoacidosis. Serum antibody testing confirmed a Coxsackie virus A2 infection. A variety of viral infections are reported to be involved in the development of fulminant type 1 diabetes mellitus (FT1D). Our patient is the first reported case of FT1D associated with Coxsackie virus A2 infection and supports the etiological role of common viral infections in FT1D.

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  • Fibromyalgia in a Patient with Cushing's Disease Accompanied by Central Hypothyroidism Reviewed

    Nobumasa Ohara, Shinichi Katada, Takaho Yamada, Naomi Mezaki, Hiroshi Suzuki, Akiko Suzuki, Osamu Hanyu, Yuichiro Yoneoka, Izumi Kawachi, Takayoshi Shimohata, Akiyoshi Kakita, Masatoyo Nishizawa, Hirohito Sone

    INTERNAL MEDICINE   55 ( 21 )   3185 - 3190   2016

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    A 39-year-old woman with a 3-year history of a rounded face developed widespread myalgia. Detailed examinations revealed no disorders that could explain the pain other than concomitant Cushing's disease and central hypothyroidism. Both the hypercortisolemia and hypothyroidism completely resolved after the patient underwent surgery to treat Cushing's disease, but she continued to experience unresolved myalgia and met the diagnostic criteria for fibromyalgia. Few studies have so far investigated patients with fibromyalgia associated with Cushing's syndrome. In our case, the hypothyroidism caused by Cushing's disease probably played an important role in triggering and exacerbating fibromyalgia. This highlights the need to examine the endocrine function in patients with muscle pain.

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  • A case of hypoglycemia attributable to atypical antipsychotic drugs Reviewed

    Hajime Ishiguro, Osamu Hanyu, Satoshi Houya, Kazuaki Morohashi, Ganji Kuroiwa, Osamu Kuwabara, Tsukasa Nakamaru, Katsuya Fuse, Kouji Sato, Hirohito Sone

    Diabetology International   6 ( 4 )   341 - 346   2015.12

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    We report a 55-year-old Japanese man who presented with symptomatic hypoglycemia attributable to atypical antipsychotic drugs (APD). He had been taking olanzapine, quetiapine, and paliperidone. One morning, his consciousness level dropped without inducement and his blood glucose was low. His symptoms improved after intravenous glucose infusion. These episodes reoccurred a few times, but ceased after APD were stopped. Physical examination did not find any organic disease that might cause hypoglycemia. Hyperglycemia, dyslipidemia, and body weight gain are well-documented side-effects of APD, but hypoglycemia is rare. There are a variety of hypotheses on how APD cause hypoglycemia: (1) Weight gain and dyslipidemia caused by APD might increase insulin resistance, meaning that excess insulin is secreted, causing hypoglycemia. (2) The quantity of basal insulin secreted by pancreatic beta cells might be enhanced by APD, which might cause hypoglycemia. (3) APD might work as an antagonist of muscarinic receptors such that insulin secretion might continue even after the glucose level has returned to normal, which might cause hypoglycemia. However, the mechanism is not fully understood and more research is needed.

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  • Fatal tracheal aspergillosis during rituximab combined chemotherapy for diffuse large B-cell lymphoma that developed after lung transplantation Reviewed

    K. Kawamoto, Y. Shibasaki, S. Sato, H. Nemoto, J. Takizawa, M. Narita, M. Tsuchida, H. Sone, M. Masuko

    Transplant Infectious Disease   17 ( 6 )   872 - 875   2015.12

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    Invasive tracheal aspergillosis (ITA) is an infection that is unique to patients who have undergone lung transplantation (LT). Although the activity of this disease often appears on imaging, we encountered a case of ITA that became exacerbated, despite few computed tomography (CT) findings, during rituximab combined chemotherapy for diffuse large B-cell lymphoma. ITA developed during immunosuppressive therapy after LT. Because CT findings may show false-negative results, bronchoscopy is recommended for such cases.

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  • Absence of Elovl6 attenuates steatohepatitis but promotes gallstone formation in a lithogenic diet-fed Ldlr(-/-) mouse model Reviewed

    Motoko Kuba, Takashi Matsuzaka, Rie Matsumori, Ryo Saito, Naoko Kaga, Hikari Taka, Kei Ikehata, Naduki Okada, Takuya Kikuchi, Hiroshi Ohno, Song-Iee Han, Yoshinori Takeuchi, Kazuto Kobayashi, Hitoshi Iwasaki, Shigeru Yatoh, Hiroaki Suzuki, Hirohito Sone, Naoya Yahagi, Yoji Arakawa, Tsutomu Fujimura, Yoshimi Nakagawa, Nobuhiro Yamada, Hitoshi Shimano

    SCIENTIFIC REPORTS   5   17604   2015.12

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    Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD) that can develop into liver cirrhosis and cancer. Elongation of very long chain fatty acids (ELOVL) family member 6 (Elovl6) is a microsomal enzyme that regulates the elongation of C12-16 saturated and monounsaturated fatty acids (FAs). We have previously shown that Elovl6 plays an important role in the development of hepatic insulin resistance and NASH by modifying FA composition. Recent studies have linked altered hepatic cholesterol homeostasis and cholesterol accumulation to the pathogenesis of NASH. In the present study, we further investigated the role of Elovl6 in the progression of lithogenic diet (LD)-induced steatohepatitis. We showed that the absence of Elovl6 suppresses hepatic lipid accumulation, plasma total cholesterol and total bile acid (BA) levels in LDL receptor-deficient (Ldlr(-/-)) mice challenged with a LD. The absence of Elovl6 also decreases hepatic inflammation, oxidative stress and liver injury, but increases the formation of cholesterol crystals in the less dilated gallbladder. These findings suggest that Elovl6-mediated changes in hepatic FA composition, especially oleic acid (C18:1n-9), control handling of hepatic cholesterol and BA, which protects against hepatotoxicity and steatohepatitis, but promotes gallstone formation in LD-fed Ldlr(-/-) mice.

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  • [Clinical and pathophysiological features of Japanese patients with type 2 diabetes mellitus and their risk factors for diabetic complication]. Reviewed

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    Nihon rinsho. Japanese journal of clinical medicine   73 ( 12 )   1979 - 1987   2015.12

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  • Clinical Significance of MYC, BCL2 and BCL6 Rearrangement and Protein Expression in GCB and Non-GCB Type Diffuse Large B-Cell Lymphoma Invited Reviewed

    Keisuke Kawamoto, Jun Takizawa, Hiroaki Miyoshi, Noriaki Yoshida, Yasuhiko Shibasaki, Masayoshi Masuko, Hirohito Sone, Naoya Nakamura, Koichi Ohshima

    BLOOD   126 ( 23 )   2015.12

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  • Risk factors associated with abnormal cognition in Japanese outpatients with diabetes, hypertension or dyslipidemia Reviewed

    Hiroki Yokoyama, Mayumi Ogawa, Jun Honjo, Shinichiro Okizaki, Daishiro Yamada, Ryushi Shudo, Hitoshi Shimizu, Hirohito Sone, Masakazu Haneda

    DIABETOLOGY INTERNATIONAL   6 ( 4 )   268 - 274   2015.12

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    Aims According to the recent increase in life expectancy in patients with diabetes, the incidence of dementia with diabetes is increasing drastically in Japan. However, the number of studies on the prevalence of abnormal cognition and the associated risk factors in a large number of outpatients with diabetes in a primary care setting is very limited.Methods The Mini-Mental State Examination (MMSE) test was performed in 1,449 outpatients aged >= 50 years with diabetes, hypertension or dyslipidemia (126 without and 1,323 with diabetes). Prevalence of abnormal cognition defined as an MMSE score <24 and the associated risk factors were explored.Results Prevalence of abnormal cognition was 5.8 % in total, and was 8.3 % in outpatients aged >= 65 years with diabetes. Logistic regression analysis after adjustment for age, sex, BMI and smoking indicated that abnormal cognition was associated with lower serum albumin and higher uric acid levels in all subjects. In subjects with diabetes, in addition to the associations with serum albumin and uric acid levels, lower renal function, retinopathy, use of insulin and a-glucosidase inhibitor, and non-use of pioglitazone and metformin were significantly associated with abnormal cognition independent of the effect of duration of diabetes, hypertension, dyslipidemia, and history of coronary heart disease and stroke.Conclusions Because of the higher prevalence of abnormal cognition in aged outpatients with diabetes found in primary care practice and significant associations with serum albumin, uric acid, renal function, retinopathy and antidiabetic drugs, there is a need for early diagnosis and strategies against dementia.

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  • Skeletal muscle-specific HMG-CoA reductase knockout mice exhibit rhabdomyolysis: A model for statin-induced myopathy Reviewed

    Yoshinori Osaki, Yoshimi Nakagawa, Shoko Miyahara, Hitoshi Iwasaki, Akiko Ishii, Takashi Matsuzaka, Kazuto Kobayashi, Shigeru Yatoh, Akimitsu Takahashi, Naoya Yahagi, Hiroaki Suzuki, Hirohito Sone, Ken Ohashi, Shun Ishibashi, Nobuhiro Yamada, Hitoshi Shimano

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   466 ( 3 )   536 - 540   2015.10

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    HMG-CoA reductase (HMGCR) catalyzes the conversion of HMG-CoA to mevalonic acid (MVA); this is the rate-limiting enzyme of the mevalonate pathway that synthesizes cholesterol. Statins, HMGCR inhibitors, are widely used as cholesterol-reducing drugs. However, statin-induced myopathy is the most adverse side effect of statins. To eludicate the mechanisms underlying statin the myotoxicity and HMGCR function in the skeletal muscle, we developed the skeletal muscle-specific HMGCR knockout mice. Knockout mice exhibited postnatal myopathy with elevated serum creatine kinase levels and necrosis. Myopathy in knockout mice was completely rescued by the oral administration of MVA. These results suggest that skeletal muscle toxicity caused by statins is dependent on the deficiencies of HMGCR enzyme activity and downstream metabolites of the mevalonate pathway in skeletal muscles rather than the liver or other organs. (C) 2015 Elsevier Inc. All rights reserved.

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  • Prevalence of resistant hypertension and associated factors in Japanese subjects with type 2 diabetes

    H. Yokoyama, S. Araki, S. Watanabe, J. Honjo, S. Okizaki, D. Yamada, R. Shudo, H. Shimizu, H. Sone, M. Haneda

    DIABETES RESEARCH AND CLINICAL PRACTICE   110 ( 1 )   18 - 25   2015.10

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    Objective: The prevalence of treatment resistant hypertension (RH) depends on methods used for blood pressure (BP) measurements, goals of BP, and therapeutic efforts in terms of medication and adherence. We focused on diabetic subjects and explored the prevalence of RH in primary care practice.
    Methods: In 1737 subjects with type 2 diabetes who continued regular visits, office BP was evaluated by multiple measurements over one year. RH was defined as using more than four antihypertensive drugs or failure to achieve the goal with three antihypertensive drugs from different classes. The RH prevalence was investigated with BP goals &lt;130/80 and 140/90 mmHg.
    Results: The percentage of subjects who achieved BP goals &lt;130/80 and 140/90 were 70.5% and 93.8% with adherence to medication &gt;= 95%, and the corresponding prevalence rates of RH in treated subjects were 28.4% and 21.8%, respectively. Factors independently associated with RH were age (odds ratio 1.02 [95% CI 1.01-1.04]), body mass index (1.10 [1.06-1.13]), variability in systolic BP (1.06 [1.02-1.09]), triglycerides (2.86 [1.34-6.11]), macroalbuminuria (3.33 [2.03-5.48]), estimated glomerular filtration rate (0.98 [0.97-0.99]), retinopathy (1.91 [1.39-2.61]), and family history of hypertension (1.85 [1.23-2.21]). Worsening albuminuria and glomerular filtration rate enhanced the prevalence of RH in a graded manner.
    Conclusion: Careful estimation of office BP values over one year with a high achievement of BP goals and adequate adherence revealed that the prevalence of RH in type 2 diabetes is high. RH was characterized by accumulation of cardiovascular genetic and environmental risks. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

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  • Impact of population aging on trends in diabetes prevalence: A meta-regression analysis of 160,000 Japanese adults Reviewed

    Hadrien Charvat, Atsushi Goto, Maki Goto, Machiko Inoue, Yoriko Heianza, Yasuji Arase, Hirohito Sone, Tomoko Nakagami, Xin Song, Qing Qiao, Jaakko Tuomilehto, Shoichiro Tsugane, Mitsuhiko Noda, Manami Inoue

    JOURNAL OF DIABETES INVESTIGATION   6 ( 5 )   533 - 542   2015.9

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    Aims/IntroductionTo provide age- and sex-specific trends, age-standardized trends, and projections of diabetes prevalence through the year 2030 in the Japanese adult population.
    Materials and MethodsIn the present meta-regression analysis, we included 161,087 adults from six studies and nine national health surveys carried out between 1988 and 2011 in Japan. We assessed the prevalence of diabetes using a recorded history of diabetes or, for the population of individuals without known diabetes, either a glycated hemoglobin level of 6.5% (48mmol/mol) or the 1999 World Health Organization criteria (i.e., a fasting plasma glucose level of 126mg/dL and/or 2-h glucose level of 200mg/dL in the 75-g oral glucose tolerance test).
    ResultsFor both sexes, prevalence appeared to remain unchanged over the years in all age categories except for men aged 70years or older, in whom a significant increase in prevalence with time was observed. Age-standardized diabetes prevalence estimates based on the Japanese population of the corresponding year showed marked increasing trends: diabetes prevalence was 6.1% among women (95% confidence interval [CI] 5.5-6.7), 9.9% (95% CI 9.2-10.6) among men, and 7.9% (95% CI 7.5-8.4) among the total population in 2010, and was expected to rise by 2030 to 6.7% (95% CI 5.2-9.2), 13.1% (95% CI 10.9-16.7) and 9.8% (95% CI 8.5-12.0), respectively. In contrast, the age-standardized diabetes prevalence using a fixed population appeared to remain unchanged.
    ConclusionsThis large-scale meta-regression analysis shows that a substantial increase in diabetes prevalence is expected in Japan during the next few decades, mainly as a result of the aging of the adult population.

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  • Pioglitazone treatment and cardiovascular event and death in subjects with type 2 diabetes without established cardiovascular disease (JDDM 36)

    H. Yokoyama, S. Araki, K. Kawai, K. Hirao, M. Oishi, K. Sugimoto, H. Sone, H. Maegawa, A. Kashiwagi

    DIABETES RESEARCH AND CLINICAL PRACTICE   109 ( 3 )   485 - 492   2015.9

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    Aims: The protective association of pioglitazone with cardiovascular events and death was investigated over 6-years in large-scale type 2 diabetic subjects without established cardiovascular disease in a primary care setting.
    Methods: A six-year observational cohort study including 2864 subjects with type 2 diabetes without established cardiovascular disease was performed. The primary endpoint was a composite of first occurrence of cardiovascular disease or death. The effect of pioglitazone use at a baseline year with a Cox proportional hazard model and the time-dependent use in each one-year examination interval with a pooled logistic regression model were analyzed.
    Results: Baseline use of pioglitazone (n = 493) did not show a statistically protective effect on the primary endpoint (n = 175), although it tended to reduce the risk (adjusted hazard ratio 0.67 [95% CI: 0.43-1.05]). However, pooled logistic regression analysis indicated a significant protective association of pioglitazone with the primary endpoint (0.58 [0.38 to 0.87] and cardiovascular disease (0.54 [0.33-0.88]), independent of concurrent levels of blood glucose, blood pressure, lipids, albuminuria, and renal function. In particular, this protective association was observed in those with diabetic nephropathy regardless of the daily dose of pioglitazone. Among a total of 898 subjects who took pioglitazone during the period, 43% experienced a discontinuation at least once; however, serious adverse effects were rare.
    Conclusions: This observational study indicated a protective association of pioglitazone with cardiovascular disease and death in type 2 diabetic subjects without established vascular disease, particularly those with nephropathy. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

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  • Possible Involvement of Lung Cells Harboring an Abnormal Karyotype in the Pathogenesis of Pulmonary Alveolar Proteinosis Associated with Myelodysplastic Syndrome. Reviewed

    Moriyama M, Yano T, Furukawa T, Takada T, Ushiki T, Masuko M, Takizawa J, Sone H, Tazawa R, Saijo Y, Ishii H, Nakata K

    Annals of the American Thoracic Society   12 ( 8 )   1251 - 1253   2015.8

  • The association of level of reduction of Wilms' tumor gene 1 mRNA transcript in bone marrow and outcome in acute myeloid leukemia patients Reviewed

    Yasuhiko Shibasaki, Yoshinobu Seki, Tomoyuki Tanaka, Syukuko Miyakoshi, Kyoko Fuse, Takashi Kozakai, Hironori Kobayashi, Takashi Ushiki, Takashi Abe, Toshio Yano, Masato Moriyama, Takashi Kuroha, Noriatsu Isahai, Jun Takizawa, Miwako Narita, Satoru Koyama, Tatsuo Furukawa, Hirohito Sone, Masayoshi Masuko

    LEUKEMIA RESEARCH   39 ( 6 )   667 - 671   2015.6

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    We focused on the level of reduction of Wilms' tumor gene 1 (WT1) mRNA in bone marrow as minimal residual disease during chemotherapies in adult acute myeloid leukemia (AML) patients. Forty-eight patients were enrolled in this study. Log levels of reduction of WT1 mRNA transcript after induction therapy compared with those at diagnosis were associated with disease-free survival (DFS) (P = 0.0066) and overall survival (OS) (P = 0.0074) in patients who achieved complete remission. Also log levels of reduction of WT1 mRNA transcript after final consolidation therapy compared with those at diagnosis were associated with DFS (P = 0.015) and OS (P = 0.012). By multivariate analysis, log levels of reduction of WT1 mRNA transcript after induction therapy and after final consolidation therapy compared with those at diagnosis were extracted as risk factors for outcome. Our results suggest that early and deep reduction of tumor burden may be important for the outcome of AML patients. In addition, it may be useful for the decision to proceed with allogeneic SCT as post-remission therapy. (C) 2015 Elsevier Ltd. All rights reserved.

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  • Risk of the development of Type 2 diabetes in relation to overall obesity, abdominal obesity and the clustering of metabolic abnormalities in Japanese individuals: does metabolically healthy overweight really exist? The Niigata Wellness Study Reviewed

    Y. Heianza, K. Kato, S. Kodama, N. Ohara, A. Suzuki, S. Tanaka, O. Hanyu, K. Sato, H. Sone

    DIABETIC MEDICINE   32 ( 5 )   665 - 672   2015.5

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    AimsWe investigated the risk of developing diabetes across various metabolic phenotypes by considering the presence of overall adiposity or abdominal adiposity and the number of metabolic abnormalities and aimed to clarify whether a healthy overweight' phenotype, that is, overweight with no metabolic abnormalities, was protective of the development of diabetes.
    MethodsWe studied 29564 Japanese individuals without diabetes. The 5-year incidence of diabetes was assessed according to a combination of either overweight (BMI25.0kg/m(2)) or abdominal obesity (waist circumference 90cm in men and 80cm in women) and the number of metabolic factors present (hypertension, elevated triglyceride concentration, low HDL cholesterol concentration and impaired fasting glucose).
    ResultsA total of 1188 individuals developed diabetes. Compared with normal weight individuals with none of the four metabolic abnormalities, in overweight individuals with none of the four abnormalities there was an odds ratio (OR) of 2.32 [95% confidence interval (CI) 1.50, 3.59] for diabetes; having any one metabolic abnormality increased the risk of developing diabetes among normal weight individuals [OR 3.23 (2.55, 4.10)] and overweight individuals [OR 5.00 (3.77, 6.63)]. Among overweight individuals, the presence of impaired fasting glucose alone substantially elevated the risk of diabetes by 8.98-fold (5.52, 14.6) in comparison with the absence of the four metabolic factors.
    ConclusionsBeing healthy overweight' was associated with a higher OR of developing future diabetes among Japanese individuals than normal weight individuals with no metabolic abnormalities, and being overweight with one or more abnormalities had a further elevated OR compared with healthy overweight' people.
    What's new
    Japanese men and women who were healthy overweight', that is, overweight with none of the four metabolic abnormalities, were at risk of developing diabetes in comparison with those who were metabolically healthy and of normal weight. Each additional metabolic abnormality (hypertension, elevated triglycerides, low HDL cholesterol and impaired fasting glucose) increased the risk of developing Type2 diabetes in all four groups of people: overweight, abdominal adiposity, normal weight and normal abdominal adiposity.

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  • Correlation between SNP genotypes and periodontitis in Japanese type II diabetic patients: a preliminary study Reviewed

    Teerasak Damrongrungruang, Hiroshi Ogawa, Sayaka Hori-Matsumoto, Kumiko Minagawa, Osamu Hanyu, Hirohito Sone, Hideo Miyazaki

    ODONTOLOGY   103 ( 2 )   233 - 240   2015.5

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    The present study aims to investigate the correlation between SNP genotype patterns and periodontitis severity in Japanese type II diabetic patients. A cross-sectional study in 43 Japanese diabetic patients with periodontitis was performed. Blood samples were drawn for single nucleotide polymorphism (SNP) analyses and periodontal index (probing pocket depth and clinical attachment level) was subsequently recorded. Twelve functional genes with SNPs that had been shown to be associated with diabetes and/or inflammation were genotyped using a nuclease-mediated SNP-specific ligation method. Subjects with two or more sites with clinical attachment level a parts per thousand yen6 mm and who additionally had one or more sites with pocket depth a parts per thousand yen5 mm were classified as having severe periodontitis. Proportions of risk genotypes/non-risk genotypes between severe and non-severe periodontitis were subsequently compared. A high frequency (21/43 participants, 49 %) of adiponectin gene polymorphism (ADIPOQ 45T &gt; G) homozygous risk genotype (TT genotype) was observed in the participants. The frequency of TGF-beta 1 SNP (29C &gt; T) risk genotype (TT genotype) in severe periodontitis (34 %, n = 11) was significantly higher than in non-severe periodontitis (0 %, n = 0) (p = 0.04). Our study suggests that TGF-beta 1 SNPs (29C &gt; T) may be used as one of the risk indicators for severe periodontitis in Japanese diabetic patients.

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  • Trajectory of body mass index before the development of type 2 diabetes in Japanese men: Toranomon Hospital Health Management Center Study 15 Reviewed

    Yoriko Heianza, Yasuji Arase, Satoru Kodama, Hiroshi Tsuji, Shiro Tanaka, Kazumi Saito, Shigeko Hara, Hirohito Sone

    Journal of Diabetes Investigation   6 ( 3 )   289 - 294   2015.5

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    Aims/IntroductionWe aimed to investigate the long-term trajectory of general adiposity assessed by the body mass index (BMI) before the onset of type2 diabetes in Japanese individuals.
    Materials and MethodsWe retrospectively examined data on 1,553 Japanese men without diabetes. Mean BMI and incident cases of diabetes (diabetes indicated by fasting glucose concentrations 7.0mmol/L, a self-reported history of clinician-diagnosed diabetes, or glycated hemoglobin 6.5% (48mmol/mol) were assessed on an annual basis over a 10-year period after the baseline examination.
    ResultsMean (standard deviation) BMI at the time of diagnosis was 24.4kg/m(2) (3.1kg/m(2)) among cases of diabetes (n=191). An increasingly high BMI was associated with the early stage of the disease development, such as an 8- to 10-year prediagnosis period; individuals who developed diabetes experienced a prolonged and stable elevated BMI of 24.4kg/m(2) over the 8years before the diagnosis of diabetes. The mean BMI among the non-cases of diabetes did not exceed 23.2kg/m(2) throughout the period.
    ConclusionsThese results suggested that Japanese men who eventually developed diabetes during the 10-year observation period were not characterized as obese, but had stable high-normal BMIs before the onset of diabetes. Previous evidence showed that values for glycemic markers rapidly increased before the development of diabetes; however, the present study showed a slight gain in BMI in the earlier stage of the natural history of diabetes followed by a prolonged period of overweight.

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  • Fasting glucose and HbA1c levels as risk factors for the development of hypertension in Japanese individuals: Toranomon hospital health management center study 16 (TOPICS 16) Reviewed

    Y. Heianza, Y. Arase, S. Kodama, S. D. Hsieh, H. Tsuji, K. Saito, S. Hara, H. Sone

    Journal of Human Hypertension   29 ( 4 )   254 - 259   2015.4

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    We investigated the effect of elevated concentrations of fasting plasma glucose (FPG) or hemoglobin A1c (HbA1c) on the risk of development of hypertension among apparently healthy Japanese. Studied were 9584 individuals without known diabetes and hypertension. During a 5-year follow-up period, 1098 individuals developed hypertension. Elevated concentrations of FPG, rather than of HbA1c, were significantly predictive of future hypertension. Compared with the lowest quartile category of FPG (&lt
    4.9 mmol l-1), the second (4.9-&lt
    5.2 mmol l-1), third (5.2-&lt
    5.6 mmol l-1) and highest (≥ 5.6 mmol l-1) quartile categories had age-, sex- and body mass index-adjusted odds ratios (95% confidence interval) of 1.35 (1.10, 1.66), 1.39 (1.13, 1.71) and 1.85 (1.51, 2.28) for hypertension, respectively. In the highest quartile of FPG, the multivariate-adjusted OR was 1.37 (1.10, 1.70) compared with the lowest quartile. Results of these adjusted models showed no significant association across quartile categories of HbA1c concentrations and an increased risk of developing hypertension. The joint effect of hyperglycemia and overweight, older age or prehypertension resulted in further elevated ORs for hypertension than the absence of such an association. Higher FPG levels rather than HbA1c were strongly predictive of future hypertension among Japanese. Hyperglycemia along with older age, overweight and prehypertension contributed to identifying individuals at increased risk of developing hypertension.

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  • Simple self-reported behavioral or psychological characteristics as risk factors for future type 2 diabetes in Japanese individuals: Toranomon Hospital Health Management Center Study 14 Reviewed

    Yoriko Heianza, Yasuji Arase, Satoru Kodama, Hiroshi Tsuji, Kazuya Fujihara, Kazumi Saito, Shigeko Hara, Hirohito Sone

    JOURNAL OF DIABETES INVESTIGATION   6 ( 2 )   236 - 241   2015.3

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    Aims/IntroductionDepression, anger, sleep disorders and cognitive impairment are regarded as presenting a high risk for diabetes. We investigated whether responses to single statements on a self-report questionnaire on the presence of each of these four factors were associated with the development of type 2 diabetes.
    Materials and MethodsWe investigated 3,211 Japanese individuals without diabetes. Cumulative incidence rate and hazard ratios (HRs) for future type 2 diabetes over 7-13years were evaluated according to the presence of lack of perseverance, anger, memory loss or sleep disorders.
    ResultsResults of Cox regression analysis showed that lack of perseverance (age- and sex-adjusted HR 1.41, 95% confidence interval 1.07-1.84), anger, (HR 1.51, 95% confidence interval 1.07-2.12) or memory loss (HR 1.47, 95% confidence interval 1.14-1.90) was predictive of the development of diabetes. Even after adjustment for metabolic factors including glycemic measurements, anger was significantly associated with an increased risk of future diabetes. Individuals with both anger and memory loss had a 1.94-fold (95% confidence interval 1.19-3.15) increased risk of type2 diabetes than those without those two symptoms.
    ConclusionsResponses to a simple self-report questionnaire as to whether individuals were aware of anger or memory loss were associated with the development of type2 diabetes independent of traditional risk factors for diabetes in this cohort of Japanese individuals.

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  • The Combination of Elevated Triglycerides and Abnormal Fasting Glucose Increases Risk of Cerebral Infarction in Patients With Mild to Moderate Hypercholesterolemia: A Post Hoc Analysis of the MEGA Study Reviewed

    Tomoko Nakagami, Rimei Nishimura, Hirohito Sone, Naoko Tajima

    JOURNAL OF CARDIOVASCULAR PHARMACOLOGY AND THERAPEUTICS   20 ( 2 )   169 - 173   2015.3

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    Background: While triglycerides (TGs) and diabetes increase the risk of cardiovascular disease (CVD), their combined effects have not been quantified. We explored the combined effect of elevated TGs and glucose on CVD in a post hoc analysis of the large-scale Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Study. Material and Methods: In the MEGA Study, 8214 patients with mild to moderate hypercholesterolemia were randomly allocated to the diet alone group or diet plus pravastatin group and followed for 5 years. Of those, 7832 patients included in the intention-to-treat analysis were stratified into 4 groups: abnormal fasting glucose (AFG) plus high TGs, high TGs alone, AFG alone, and normal fasting glucose plus normal TGs (reference). Cox proportional hazard models were used to compare the incidence of and mortality from CVD in the 4 groups.
    Results: Incidence of CVD and coronary heart disease was significantly higher in the groups with AFG alone (hazard ratio [HR], 2.02 and 3.38; P &lt; .01, respectively) and AFG plus high TGs (HR, 2.87 and 3.87; P &lt; .01, respectively) than the reference group. A similar relation was found in models adjusting for high-density lipoprotein cholesterol (HDL-C). Although the incidence of cerebral infarction was significantly higher only in the group with AFG plus high TGs (HR, 2.16; P = .01), it was marginally significantly higher than the reference group after adjustment for HDL-C (HR, 1.86; P = .06). Diet plus pravastatin treatment reduced the risk of cerebral infarction by 66% in the group with AFG plus high TGs (P = .03).
    Conclusions: Our findings contribute to the formulation of the hypothesis that patients with hypercholesterolemia having AFG plus high TGs have an increased risk of cerebral infarction. These are compatible with the result from the main study that patients with hypercholesterolemia randomized to diet plus pravastatin had a reduced risk of cerebral infarction.

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  • Potential impact of joint association of alanine aminotransferase and gamma-glutamyltransferase on insulin resistance in Japan: The Toranomon Hospital Health Management Center Study 19 (TOPICS 19) Reviewed

    Yasuji Arase, Yoriko Heianza, Shigeko Hara, Yuki Ohmoto-Sekine, Kazuhisa Amakawa, Hiroshi Tsuji, Kyoko Ogawa, Kazumi Saito, Satoru Kodama, Kenji Ikeda, Hiromitsu Kumada, Tetsuro Kobayashi, Hirohito Sone

    HEPATOLOGY RESEARCH   45 ( 3 )   247 - 258   2015.3

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    AimTo investigate the potential impact of joint association of alanine aminotransferase (ALT) and -glutamyltransferase (GGT) on insulin resistance and -cell dysfunction in healthy Japanese individuals with a normal range of liver enzymes.
    MethodsThis study included 1010 individuals (545 men and 465 women) aged 20-89 years who underwent an oral glucose tolerance test for health screening. Participants were divided into four groups on the basis of median values for ALT and GGT: (i) both ALT and GGT low (both-low); (ii) ALT high and GGT low (ALT-high); (iii) ALT low and GGT high (GGT-high); and (iv) both ALT and GGT high (both-high). Logistic regression analysis was used to investigate the relationship between liver enzyme and insulin dynamics, such as Homeostasis Model of Assessment - Insulin Resistance (HOMA-IR) and insulinogenic index (IGI). The insulin resistance was defined when HOMA-IR was 2.5 or more. IGI of less than 0.4 was considered to be decreased early-phase insulin secretion.
    ResultsMean values of HOMA-IR in men was 1.5 in the both-low group, 1.8 in ALT-high, 1.8 in GGT-high and 2.8 in both-high. The mean HOMA-IR in women was 1.3 in the both-low group, 1.3 in ALT-high, 1.6 in GGT-high and 2.0 in both-high. HOMA-IR in the both-high group was significantly higher than that in the both-low group regardless of the difference of sex. Multivariate analysis showed that insulin resistance occurred when the patient had high liver enzymes.
    ConclusionCombining the two liver function markers would be effective for identifying individuals with insulin resistance.

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  • Reply to: Relationship between leptin and blood pressure in patients with multiple system atrophy Reviewed

    Tetsutaro Ozawa, Hirohito Sone, Masatoyo Nishizawa

    Journal of the Neurological Sciences   348 ( 1-2 )   285   2015.1

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  • Circulating Malondialdehyde-Modified LDL-Related Variables and Coronary Artery Stenosis in Asymptomatic Patients with Type 2 Diabetes Reviewed

    Kazuya Fujihara, Hiroaki Suzuki, Akira Sato, Satoru Kodama, Yoriko Heianza, Kazumi Saito, Hitoshi Iwasaki, Kazuto Kobayashi, Shigeru Yatoh, Akimitsu Takahashi, Naoya Yahagi, Hiroaki Yagyu, Hirohito Sone, Hitoshi Shimano

    JOURNAL OF DIABETES RESEARCH   2015   507245   2015

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    Aims. To elucidate the levels of malondialdehyde-modified LDL (MDA-LDL)-related variables for predicting coronary artery stenosis (CAS) by coronary CT angiography (CCTA) in asymptomatic patients with type 2 diabetes (T2DM). Methods. Enrolled were 36 Japanese patients with T2DM who underwent CCTA and in whom MDA-LDL levels were measured. Definition of CAS was luminal narrowing of &gt;= 50%. Trends through tertiles of each MDA-LDL-related variable were analyzed with a general linear model. The ability of each MDA-LDL-related variable to predict CAS was compared to areas under the curve (AUCs) in receiver operating characteristic curve (ROC) analysis. Results. Seventeen patients had CAS. Each MDA-IDL-related variable was an independent predictor of CAS (P = 0.039 for MDALDL, P = 0.013 for MDA-LDL/LDL-C, P = 0.047 for MDA-LDL/HDL-C, and P = 0.013 for (MDA-LDULDL-C)/HDL-C). AUCs of MDA-LDL, MDA-LDL/LDL-C, MDA-LDL/HDL-C, and (MDA-LDULDLC)/HDL-C were 0.675 (95% CI 0.496-0.854), 0.765 (0.602-0.927), 0.752 (0.592-0.913), and 0.799 (0.643-0.955), respectively, for predicting CAS. Trends throughout the tertiles showed significant associations between N4DA-LDL/LDL-C, N4DA-LDL/41DL-C, or (MDALDL/LDL-C)/41DL-C and CAS (P 0.003 for MDA-LDL/LDL-C, P=0.042 for MDA-LDULIDL-C, and P 0.001 for (MDA-LDULDL-C)/HDL-C). Conclusions. Data suggest that measurements of MDA-LDL/LDL-C, MDA-LDL/HDLC, and (MakLDULDL-C)/HDL-C are useful for predicting CAS.

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  • Type 1 Diabetes Mellitus and Isolated Adrenocorticotropin Deficiency Manifested by Parkinsonism: A Case Report and Literature Review Reviewed

    Nobumasa Ohara, Naoyuki Kojima, Takashi Sato, Tomoo Ikarashi, Hirohito Sone, Yutaka Oki, Kyuzi Kamoi, Masao Hara, Hideo Sasaki

    INTERNAL MEDICINE   54 ( 20 )   2629 - 2635   2015

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    A 67-year-old woman developed isolated adrenocorticotropin deficiency (IAD), which manifested as lethargy, a 20-kg body weight loss, hypoglycemia, and parkinsonism, and began corticosteroid replacement. Her symptoms resolved rapidly, and her weight returned to normal within six months. However, she then developed slowly progressive type 1 diabetes mellitus (T1D) with co-existing Hashimoto thyroiditis, and commenced insulin therapy. To our knowledge, this is the first reported case of parkinsonism associated with IAD. In addition, because diabetes mellitus, including T1D, could be latent in patients with untreated IAD, careful assessment of glucose metabolism is needed after commencing corticosteroid replacement until weight regain is achieved.

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  • Late Onset Post-Transfusion Hepatitis E Developing during Chemotherapy for Acute Promyelocytic Leukemia Reviewed

    Kyoko Fuse, Yuichi Matsuyama, Masato Moriyama, Shukuko Miyakoshi, Yasuhiko Shibasaki, Jun Takizawa, Tatsuo Furukawa, Ichiro Fuse, Hiro Matsumura, Shigeharu Uchida, Yoshifumi Takahashi, Kenya Kamimura, Hiroyuki Abe, Takeshi Suda, Yutaka Aoyagi, Hirohito Sone, Masayoshi Masuko

    INTERNAL MEDICINE   54 ( 6 )   657 - 661   2015

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    We herein report the case of a leukemia patient who developed hepatitis E seven months after undergoing a transfusion with contaminated blood products. The latency period in this case was significantly longer than that of typical hepatitis E. Recently, chronic infection with hepatitis E virus (HEV) genotype 3 has been reported in immunocompromised patients. There is a possibility that our patient was unable to eliminate the virus due to immunosuppression following chemotherapy and the administration of steroids. The prevalence of HEV in healthy Japanese individuals is relatively high and constitutes a critical source of infection via transfusion. Hepatitis E is an important post-transfusion infection, and immunocompromised patients may exhibit a long latency period before developing the disease.

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  • The factors that affect exercise therapy for patients with type 2 diabetes in Japan: a nationwide survey Reviewed

    S. Arakawa, T. Watanabe, H. Sone, Y. Tamura, M. Kobayashi, R. Kawamori, Y. Atsumi, Y. Oshida, S. Tanaka, S. Suzuki, S. Makita, I. Ohsawa, Yuzo Sato

    Diabetology International   6 ( 1 )   19 - 25   2015

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    Purpose: This study was performed to investigate important factors of exercise therapies for diabetes patients in Japan. Methods: Subjects were 5,100 patients with type 2 diabetes mellitus. Data from 3,685 patients (88.2 % effective answer rate) who answered the question whether they are performing exercise therapy or not by the questionnaire were analyzed. We used multiple logistic regression analysis to assess the factors associated with exercise therapy in diabetes patients. Results: Exercise and non-exercise therapy groups had 1,926 and 1,759 patients, respectively. The HbA1c level of the exercise therapy group was significantly lower than that in the non-exercise therapy group. The multivariate odds ratios (ORs) of possible factors affecting the exercise therapy group adjusted for age, gender, BMI and living area were as follows: frequency of exercise therapy guidance [OR = 1.89, 95 % confidence interval = 1.40–2.56
    reference group (ref.): no exercise therapy guidance], detailed exercise prescription such as type (1.32, 1.08–1.61), frequency (1.60, 1.24–2.06) and duration (1.63, 1.32–2.01
    ref.: no exercise prescription), patients who enjoy physical exercise (4.85, 2.97–7.93
    ref.: patients who dislike physical exercise) and high level of physical activity (2.31, 1.77–3.03
    ref.: low level of physical activity). Conclusion: The results of the current study showed that, concerning exercise therapy education, it is important to maintain the motivation of the patients to participate in exercise therapies, to increase the frequency of guidance, and to provide more detailed exercise prescription such as frequency and duration.

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  • Imaging of Body Iron Stores in Transfusion-Dependent Patients By Liver Dual-Energy CT Reviewed

    Hironori Kobayashi, Norihiko Yoshimura, Takashi Ushiki, Yasuhiko Shibasaki, Masato Moriyama, Jun Takizawa, Miwako Narita, Hirohito Sone, Masayoshi Masuko

    BLOOD   124 ( 21 )   2014.12

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  • Efficacy of HMG-CoA reductase inhibitors in the prevention of cerebrovascular attack in 1016 patients older than 75 years among 4014 type 2 diabetic individuals Reviewed

    Toshio Hayashi, Kiyoshi Kubota, Seinosuke Kawashima, Hirohito Sone, Hiroshi Watanabe, Takashi Ohrui, Koutaro Yokote, Minoru Takemoto, Atsushi Araki, Mitsuhiko Noda, Hiroshi Noto, Ichiro Sakuma, Masao Yoshizumi, Koichiro Ina, Hideki Nomura

    INTERNATIONAL JOURNAL OF CARDIOLOGY   177 ( 3 )   860 - 866   2014.12

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    Background/objectives: HMG-CoA reductase inhibitors (statins) reduce ischemic heart disease (IHD) in middle-aged diabetic individuals, and LDL-cholesterol (LDL-C) is a risk factor. However, their preventive effects on cerebrovascular attack (CVA) have not been identified in elderly, especially in elderly &gt;= 75 years (late elderly), who account for approximately 30% of diabetic individuals in Japan. Randomized controlled studies of statins for late elderly are difficult to carry out, because many co-morbidities in elderly disrupt randomized controlled conditions.
    Methods: We performed a prospective cohort study (Japan Cholesterol and Diabetes Mellitus Study) with 5.5 years of follow-up since 2004. A total of 4014 type 2 diabetic patients without previous IHD or CVA (n = 1936 women; age = 67.4 +/- 9.5 years; = 75 years: n = 1016) were enrolled, while 405 patients were registered as sub-cohort patients. We recorded detailed information on medications and laboratory data after every change in medication in patients of sub-cohort and suffered from IHD or CVA. We subdivided statin-users into prevalent, new and non-users.
    Results: A total of 104 CVAs occurred during 5.5-years. Plasma HDL-C level was inversely correlated with CVA in patients &gt;= 65 years. In case-control study, among patients who were not prescribed statins, CVA increased in age-dependent manner. CVA incidence was lower in prevalent and new statin-users than in non-users (hazard ratio [HR]: 0.46, 0.523), especially in late elderly (HR: 0.51, 0.21). Statins reduced CVAs mainly due to a direct effect and partially due to the effects of HDL-C and glucose metabolism. No significant differences were observed between statins.
    Conclusion: Statins prevented CVA in middle-aged, elderly and late elderly diabetic patients via a direct effect. This study is the first to demonstrate the usefulness of observational studies for statistically analyzing agents' effects on late elderly. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

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  • Impact on short-term glycaemic control of initiating diabetes care versus leaving diabetes untreated among individuals with newly screening-detected diabetes in Japan Reviewed

    Yoriko Heianza, Akiko Suzuki, Kazuya Fujihara, Shiro Tanaka, Satoru Kodama, Osamu Hanyu, Hirohito Sone

    JOURNAL OF EPIDEMIOLOGY AND COMMUNITY HEALTH   68 ( 12 )   1189 - 1195   2014.12

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    Background The impact of early initiation of diabetes care soon after the identification of hyperglycaemia rather than leaving diabetes untreated on changes in glycaemic control has not been fully clarified. We aimed to quantify the effect of initiating and continuing diabetes care compared with not starting management of diabetes on short-term changes in glycaemic control among the Japanese with newly screening-detected diabetes.
    Methods We retrospectively reviewed data from a nationwide claims database to assess histories of physician-diagnosed diabetes or hyperglycaemia, as well as the use of antidiabetic agents, blood testing for hyperglycaemia or dietary advice among individuals without a history of diabetes care. Changes in glycated haemoglobin (HbA1c) concentrations were evaluated using baseline data and data from a health examination during the following year.
    Results Among 1393 individuals with newly screening-detected diabetes, 62% (n=864) did not initiate diabetes management during the follow-up period; 49.2% (n=425) of the untreated group had poor glycaemic control (HbA1c =7%) at the baseline examination. Only 38% (n=529) began diabetes management in medical settings. Individuals who remained untreated had a 1.87 (95% CI 1.38 to 2.52) or 1.63 (1.10 to 2.41) times higher risk of absolute increases in HbA1c &gt;= 0.5% or &gt;= 1%, respectively, compared with the treated patients, a difference that was significant. Making more frequent clinic visits especially after the first visit was dose-dependently associated with improved HbA1c levels compared with no diabetes management.
    Conclusions In comparison with a lack of management of diabetes, immediately initiating and continuing diabetes care after identification of hyperglycaemia in a screening setting would contribute to clinically meaningful, improved glycaemic control in the Japanese.

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  • Body Mass Index and Mortality Among Japanese Patients With Type 2 Diabetes: Pooled Analysis of the Japan Diabetes Complications Study and the Japanese Elderly Diabetes Intervention Trial Reviewed

    Shiro Tanaka, Sachiko Tanaka, Satoshi Iimuro, Yasuo Akanuma, Yasuo Ohashi, Nobuhiro Yamada, Atsushi Araki, Hideki Ito, Hirohito Sone

    JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM   99 ( 12 )   E2692 - E2696   2014.12

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    Context: Previous studies on the association between body mass index (BMI) and mortality in diabetes do not necessarily provide a comprehensive view in terms of the global population because of the exclusion of individuals with a BMI less than 18.5 kg/m(2).
    Objective: The objective of the study was to examine the association between BMI and mortality.
    Design, Setting, and Participants: We analyzed pooled data from 2 cohorts of 2620 Japanese patients with type 2 diabetes followed up for 6.3 years. Patients with a history of cardiovascular disease or cancer were excluded.
    Main Outcome Measure: The end point was all-cause mortality. Hazard ratios were estimated by Cox regression adjusted for age, smoking, leisure-time physical activity, and other confounders.
    Results: An analysis using BMI categories of 14.4-18.5 (5.2%), 18.5-22.4 (37.3%), 22.5-24.9 (31.0%), and 25.0-37.5 kg/m(2) (26.6%) revealed no significant trend in mortality among patients with a BMI of 18.5 kg/m(2) or greater (trend P = .69). In contrast, the hazard ratio of patients with a BMI less than 18.5 kg/m(2) vs 22.5-24.9 kg/m(2) was 2.58 (95% confidence interval 1.38-4.84; P = .01). Exclusion of deaths in the first 4 years of follow-up decreased the hazard ratio only slightly.
    Conclusions: The lowest mortality rate was observed among patients with a BMI of 18.5-24.9 kg/m2, and obesity hadnobenefits regarding mortality. Further research is needed in lean patients, especially among aging populations in East Asia.

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  • Hepatic CREB3L3 Controls Whole-Body Energy Homeostasis and Improves Obesity and Diabetes Reviewed

    Yoshimi Nakagawa, Aoi Satoh, Sachiko Yabe, Mika Furusawa, Naoko Tokushige, Hitomi Tezuka, Motoki Mikami, Wakiko Iwata, Akiko Shingyouchi, Takashi Matsuzaka, Shiori Kiwata, Yuri Fujimoto, Hidehisa Shimizu, Hirosuke Danno, Takashi Yamamoto, Kiyoaki Ishii, Tadayoshi Karasawa, Yoshinori Takeuchi, Hitoshi Iwasaki, Masako Shimada, Yasushi Kawakami, Osamu Urayama, Hirohito Sone, Kazuhiro Takekoshi, Kazuto Kobayashi, Shigeru Yatoh, Akimitsu Takahashi, Naoya Yahagi, Hiroaki Suzuki, Nobuhiro Yamada, Hitoshi Shimano

    ENDOCRINOLOGY   155 ( 12 )   4706 - 4719   2014.12

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    Transcriptional regulation of metabolic genes in the liver is the key to maintaining systemic energy homeostasis during starvation. The membrane-bound transcription factor cAMP-responsive element-binding protein 3-like 3 (CREB3L3) has been reported to be activated during fasting and to regulate triglyceride metabolism. Here, we show that CREB3L3 confers a wide spectrum of metabolic responses to starvation in vivo. Adenoviral and transgenic overexpression of nuclear CREB3L3 induced systemic lipolysis, hepatic ketogenesis, and insulin sensitivity with increased energy expenditure, leading to marked reduction in body weight, plasma lipid levels, and glucose levels. CREB3L3 overexpression activated gene expression levels and plasma levels of antidiabetic hormones, including fibroblast growth factor 21 and IGF-binding protein 2. Amelioration of diabetes by hepatic activation of CREB3L3 was also observed in several types of diabetic obese mice. Nuclear CREB3L3 mutually activates the peroxisome proliferator-activated receptor(PPAR) alpha promoter in an autoloop fashion and is crucial for the ligand transactivation of PPAR alpha by interacting with its transcriptional regulator, peroxisome proliferator-activated receptor gamma coactivator-1 alpha. CREB3L3 directly and indirectly controls fibroblast growth factor 21 expression and its plasma level, which contributes at least partially to the catabolic effects of CREB3L3 on systemic energy homeostasis in the entire body. Therefore, CREB3L3 is a therapeutic target for obesity and diabetes.

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  • Log Reduction Levels of WT1 mRNA Expression in BM after Chemotherapies Are Predictive Markers of Good Prognosis in AML Patients Achieved CR after Induction Therapy Reviewed

    Yasuhiko Shibasaki, Yoshinobu Seki, Tomoyuki Tanaka, Syukuko Miyakoshi, Kyoko Fuse, Takashi Kozakai, Hironori Kobayashi, Takashi Ushiki, Takashi Abe, Toshio Yano, Masato Moriyama, Takashi Kuroha, Noriatsu Isahai, Jun Takizawa, Miwako Narita, Satoru Koyama, Tatsuo Furukawa, Hirohito Sone, Masayoshi Masuko

    BLOOD   124 ( 21 )   2014.12

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  • High cholesterol intake is associated with elevated risk of type 2 diabetes mellitus - A meta-analysis(1-4) Reviewed

    Ryoko Tajima, Satoru Kodama, Miho Hirata, Chika Horikawa, Kazuya Fujihara, Yoko Yachi, Sakiko Yoshizawa, Kaoruko Tada Iida, Hirohito Sone

    CLINICAL NUTRITION   33 ( 6 )   946 - 950   2014.12

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    Background & aims: Some foods rich in cholesterol are associated with high risk of type 2 diabetes (T2D). To confirm the association between dietary cholesterol intake and T2D risk, we performed a meta-analysis of observational studies.
    Methods: We searched for longitudinal studies that provided data on the relative risk (RR) for T2D in relation to the cholesterol intake level using MEDLINE (from 1950 for July 10, 2013) and EMBASE (from 1974 to July 10, 2013). The RR for the highest vs. lowest cholesterol intake category or for an increment of 100 mg/day in cholesterol consumption was pooled with an inverse-variance method.
    Results: Five studies met the inclusion criteria. Compared with the lowest category, the highest category had a significantly higher association with T2D risk (RR [95% confidence interval (CI)], 1.25 [1.16-1.36]). The pooled RR for a 100-mg/day increment was also significant (RR [95% CI], 1.11 [1.06-1.15]).
    Conclusion: Current meta-analysis suggested that high intake of cholesterol was positively associated with future T2D risk. (C) 2014 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

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  • The circulating level of leptin and blood pressure in patients with multiple system atrophy Reviewed

    Tetsutaro Ozawa, Jun Tokunaga, Musashi Arakawa, Atsushi Ishikawa, Ryoko Takeuchi, Akio Yokoseki, Hirohito Sone, Masatoyo Nishizawa

    JOURNAL OF THE NEUROLOGICAL SCIENCES   347 ( 1-2 )   349 - 351   2014.12

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    Patients with multiple system atrophy (MSA) frequently exhibit orthostatic hypotension (OH). Leptin, an adipose-derived hormone, contributes to the sympathetic control of blood pressure (BP), and loss of leptin may cause OH. We aimed to clarify the relationship between leptin and OH in MSA. Serum leptin levels were measured in 36 patients with MSA, 25 patients with other atypical parkinsonian disorders (APDs), including progressive supranuclear palsy-Richardson syndrome and corticobasal syndrome, and 26 control subjects. Blood samples were obtained after fasting for 12 h. In MSA patients, baseline BP was measured in the recumbent position after a 3-min rest, and orthostatic changes in BP were evaluated after 0-3 min of standing. Serum leptin levels did not differ significantly between MSA patients (5.9 +/- 0.8 ng/ml), other APD patients (5.2 +/- 0.8 ng/ml), and controls (6.1 +/- 1.3 ng/ml; P = 0.8). In MSA patients, serum leptin levels correlated significantly with body mass index ( P = 0.01), but not baseline BPs (systolic BP, P = 0.20; diastolic BP, P = 0.44) or orthostatic drop in BP (systolic BP, P = 0.13; diastolic BP, P = 0.58). Our observations indicated that the circulating level of leptin was preserved, and OH occurred independent of the leptin level in MSA patients. (C) 2014 Elsevier B.V. All rights reserved.

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  • Stability and Changes in Metabolically Healthy Overweight or Obesity and Risk of Future Diabetes: Niigata Wellness Study Reviewed

    Yoriko Heianza, Kiminori Kato, Satoru Kodama, Akiko Suzuki, Shiro Tanaka, Osamu Hanyu, Koji Sato, Hirohito Sone

    OBESITY   22 ( 11 )   2420 - 2425   2014.11

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    ObjectiveStability and changes in obesity and metabolic health status from a baseline period and longitudinally investigated their impact on predicting future diabetes were assessed.
    MethodsStudied were 27,478 Japanese individuals without diabetes. Metabolically healthy (MH) was indicated by having 1 among impaired fasting glucose, hypertension, hypertriglyceridemia and low HDL cholesterol concentration. Metabolically abnormal (MA) was indicated by having 2 of those metabolic abnormalities. A cut-off value of BMI 25.0 defined overweight or obesity (O) or normal weight (NW). Hazard ratio (HR) for diabetes for a 6-year period was investigated after changes in phenotypes were assessed during the previous 2 years.
    ResultsCompared with maintaining MH-NW, transitioning to MH-O from MH-NW resulted in a multivariate-adjusted HR of 1.96 (95% CI: 1.18, 3.25) for diabetes. With a stable MH-O the HR for diabetes was 2.59 (2.00, 3.34) while change from MH-O to MH-NW resulted in an HR of 1.30 (0.61, 2.76). Transitioning to MA-O from MH-O was associated with an HR of 7.09 (5.41, 9.30). With a stable MA-O the risk of diabetes was substantially elevated with an HR of 12.5 (10.5, 14.9).
    ConclusionsExamining the transitory nature of apparently benign or unhealthy obese phenotypes was effective for differentiating high-risk individuals for future diabetes.

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  • Role of sleep duration as a risk factor for Type 2 diabetes among adults of different ages in Japan: the Niigata Wellness Study Reviewed

    Y. Heianza, K. Kato, K. Fujihara, S. Tanaka, S. Kodama, O. Hanyu, K. Sato, H. Sone

    DIABETIC MEDICINE   31 ( 11 )   1363 - 1367   2014.11

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    AimTo compare the role of short sleep duration as a risk factor for diabetes among adults of different ages.
    MethodsThe study enrolled 38987 Japanese individuals without diabetes, and the 8-year risk of developing diabetes attributable to different sleep durations (&lt;5.5h, 5.5 to &lt;6.5h, 6.5 to &lt;7.0h, 7.0-7.5h, &gt;7.5-8.0h, or &gt;8.0h) was assessed among individuals aged 45, 46-59 or 60years.
    ResultsDuring the 8-year follow-up period, 2085 individuals developed diabetes. Overall, individuals with a short sleep duration of &lt;5.5h or 5.5 to &lt;6.5h had, respectively, a 1.53-fold (95% CI 1.19, 1.97) or 1.25-fold (95% CI 1.10, 1.42) increased risk of diabetes as compared with those who had 7.0-7.5h of sleep. A sleep duration of &lt;5.5h or 5.5 to &lt;6.5h was predictive of the development of diabetes among individuals aged 45years, but not among those aged 60years. With increasing age, the effect of short sleep duration on the risk of diabetes was attenuated.
    ConclusionsShort sleep duration was predictive of diabetes among young or middle-aged Japanese adults but not among elderly individuals after age was considered. Managing habitual short sleep and the possible reasons for having such short sleep duration could be particularly important for young or middle-aged adults in the development of future diabetes.

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  • High risk of failing eradication of Helicobacter pylori in patients with diabetes: A meta-analysis Reviewed

    Chika Horikawa, Saroru Kodama, Kazuya Fujihara, Reiko Hirasawa, Yoko Yachi, Akiko Suzuki, Osamu Hanyu, Hitoshi Shimano, Hirohito Sone

    DIABETES RESEARCH AND CLINICAL PRACTICE   106 ( 1 )   81 - 87   2014.10

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    Aims: Eradication of Helicobacter pylori (HP) is an effective approach to improve intestinal symptoms and prevent gastric cancer. However, there has been concern that the presence of diabetes reduces the effectiveness of antibiotics. We performed this meta-analysis to investigate the effect of diabetes on the risk of failing eradication in patients with diabetes.
    Methods: An electronic literature search was conducted using Biosis, MEDLINE, Embase, PASCAL, and SciSearch through November 30, 2012. Selected studies had to provide data on the number of individuals who received treatment for HP infection and on the failure of HP eradication in groups with and without diabetes. Two authors independently extracted relevant data.
    Results: Data were obtained from 8 eligible studies (693 total participants including 273 participants with diabetes). Overall, the pooled risk ratio (RR) of failing HP eradication for diabetic patients compared with non-diabetic participants was 2.19 [95% CI, 1.65-2.90] (P &lt; 0.001). Excluding the 2 studies that used a non-standard protocol for HP eradication, individuals with diabetes had a higher risk of failure of eradication compared to those without diabetes (RR = 2.31 [95% CI, 1.72-3.11]).
    Conclusions: Current meta-analysis confirmed the higher risk of HP eradication failure in individuals with diabetes compared with those without diabetes, suggesting the necessity of prolonging treatment or developing a new regimen for HP eradication in patients with diabetes. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

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  • Dietary Sodium Intake and Incidence of Diabetes Complications in Japanese Patients with Type 2 Diabetes: Analysis of the Japan Diabetes Complications Study (JDCS) Reviewed

    Chika Horikawa, Yukio Yoshimura, Chiemi Kamada, Shiro Tanaka, Sachiko Tanaka, Osamu Hanyu, Atsushi Araki, Hideki Ito, Akira Tanaka, Yasuo Ohashi, Yasuo Akanuma, Nobuhiro Yamada, Hirohito Sone

    JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM   99 ( 10 )   3635 - 3643   2014.10

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    Context: Many guidelines recommend that patients with type 2 diabetes should reduce their dietary sodium intake. However, the relationship between dietary sodium intake and incidence of diabetic complications in patients with type 2 diabetes has not been explored.
    Objective: Our objective was to investigate the relationship between dietary sodium intake and incidence of diabetes complications.
    Participants: The study was of a nationwide cohort of patients with type 2 diabetes aged 40 to 70 years with hemoglobin A1c (HbA1c) &gt;= 6.5%.
    Main Outcome Measures: After excluding nonresponders to a dietary survey, 1588 patients were analyzed. Baseline dietary intake was assessed by the Food Frequency Questionnaire based on food groups. Primary outcomes were times to cardiovascular disease (CVD), overt nephropathy, diabetic retinopathy, and all-cause mortality.
    Results: Mean daily dietary sodium intake in quartiles ranged from 2.8 to 5.9 g. After adjustment for confounders, hazard ratios for CVD in patients in the second, third, and fourth quartiles of sodium intake compared with the first quartile were 1.70 (95% confidence interval, 0.98-2.94), 1.47 (0.82-2.62), and 2.07 (1.21-3.90), respectively (trend P &lt; .01). In addition, among patients who had HbA1c &gt;= 9.0%, the hazard ratio for CVD in patients in the top vs bottom quartile of sodium in take was dramatically elevated compared with patients with HbA1c &lt;9.0% (1.16 [0.56-2.39] and 9.91 [2.66-36.87], interaction P &lt; .01). Overt nephropathy, diabetic retinopathy, and all-cause mortality were not significantly associated with sodium intake.
    Conclusions: Findings suggested that high dietary sodium intake is associated with elevated incidence of CVD in patients with type 2 diabetes and that there is a synergistic effect between HbA1c values and dietary sodium intake for the development of CVD.

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  • Importance of high-density lipoprotein cholesterol levels in elderly diabetic individuals with type IIb dyslipidemia: A 2-year survey of cardiovascular events Reviewed

    Koichiro Ina, Toshio Hayashi, Atsushi Araki, Seinosuke Kawashima, Hirohito Sone, Hiroshi Watanabe, Takashi Ohrui, Koutaro Yokote, Minoru Takemoto, Kiyoshi Kubota, Mitsuhiko Noda, Hiroshi Noto, Qun-Fang Ding, Jie Zhang, Ze-Yun Yu, Byung-Koo Yoon, Hideki Nomura, Masafumi Kuzuya

    GERIATRICS & GERONTOLOGY INTERNATIONAL   14 ( 4 )   806 - 810   2014.10

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    AimThe risk factors for ischemic heart disease (IHD) or cerebrovascular accident (CVA) in elderly diabetic individuals with type IIb dyslipidemia are not fully known. Therefore, we investigated the relationship between lipid levels and IHD and CVA in diabetic individuals with type IIb dyslipidemia.
    MethodThe Japan Cholesterol and Diabetes Mellitus Study is a prospective cohort study of 4014 type 2 diabetic patients (1936 women; age 67.49.5 years). The primary end-points were the onset of IHD or CVA. Lipid and glucose levels, and other factors were investigated in relation to the occurrence of IHD or CVA. A total of 462 participants were included in the group of patients with type IIb dyslipidemia.
    ResultsThe 462 diabetic participants with type IIb dyslipidemia were divided into those who were aged &lt;65 years, 65-74 years and &gt;75 years (n=168, 190 and 104, respectively). High-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol/HDL-C were significantly associated with the risk of cardiovascular events in diabetic individuals with type IIb dyslipidemia who were aged &lt;65 years, and HDL-C and diastolic blood pressure was significantly associated with cardiovascular events in patients aged 65-74 years. Non-HDL-C was not significantly associated with the risk of cardiovascular events. Multiple regression analysis showed that lower HDL-C was significantly associated with the risk of cardiovascular events in diabetic individuals with type IIb dyslipidemia who were aged &lt;65 years and 65-74 years.
    ConclusionsLower HDL-C was an important risk factor for cardiovascular events in diabetic individuals with type IIb dyslipidemia who were aged &lt;75 years. Geriatr Gerontol Int 2014; 14: 806-810.

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  • A possible link between BDNF and mTOR in control of food intake Reviewed

    Nobuyuki Takei, Kazuo Furukawa, Osamu Hanyu, Hirohito Sone, Hiroyuki Nawa

    FRONTIERS IN PSYCHOLOGY   5   1093   2014.9

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    Food intake is intricately regulated by glucose, amino acids, hormones, neuropeptides, and trophic factors through a neural circuit in the hypothalamus. Brain-derived neurotrophic factor (BDNF), the most prominent neurotrophic factor in the brain, regulates differentiation, maturation, and synaptic plasticity throughout life. Among its many roles, BDNF exerts an anorexigenic function in the brain. However, the intracellular signaling induced by BDNF to control food intake is not fully understood. One candidate for the molecule involved in transducing the anorexigenic activity of BDNF is the mammalian target of rapamycin (mTOR). mTOR senses extracellular amino acids, glucose, growth factors, and neurotransmitters, and regulates anabolic reactions response to these signals. Activated mTOR increases protein and lipid synthesis and inhibits protein degradation. In the hypothalamus, mTOR activation is thought to reduce food intake. Here we summarize recent findings regarding BDNF- and mTOR-mediated feeding control, and propose a link between these molecules in eating behavior.

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  • Fasting mediated increase in p-BAD(ser155) and p-AKT(ser473) in the prefrontal cortex of mice Reviewed

    Vigneshwaran Pitchaimani, Somasundaram Arumugam, Rajarajan Amirthalingam Thandavarayan, Vengadeshprabhu Karuppagounder, Remya Sreedhar, Rejina Afrin, Meilei Harima, Hiroshi Suzuki, Shizuka Miyashita, Mayumi Nomoto, Hirohito Sone, Kenji Suzuki, Kenichi Watanabe

    NEUROSCIENCE LETTERS   579   134 - 139   2014.9

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    BAD-deficient mice and fasting have several common functional roles in seizures, beta-hydroxybutyrate (BHB) uptake in brain and alteration in counterregulatory hormonal regulation during hypoglycemia. Neuronal specific insulin receptor knockout (NIRKO) mice display impaired counterregulatory hormonal responses during hypoglycemia. In this study we investigated the fasting mediated expression of p-BAD(ser155) and p-AKT(ser473) in different regions of brain (prefrontal cortex, hippocampus, midbrain and hypothalamus). Fasting specifically increases p-BAD(ser155) and p-AKT(ser473) in prefrontal cortex and decreases in other regions of brain. Our results suggest that fasting may increase the uptake BHB by decreasing p-BAD(ser155) in the brain during hypoglycemia except prefrontal cortex and it uncovers specific functional area of p-BAD(ser155) and p-AKT(ser473) that may regulates counter regulatory hormonal response. Overall in support with previous findings, fasting mediated hypoglycemia activates prefrontal cortex insulin signaling which influences the hypothalamic paraventricular nucleus mediated activation of sympathoadrenal hormonal responses. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

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  • Second trimester postload glucose level as an important predictor of low birth weight infants: Tanaka Women's Clinic Study Reviewed

    Yoko Yachi, Yasuhiro Tanaka, Izumi Nishibata, Sakiko Yoshizawa, Kazuya Fujihara, Satoru Kodama, Akiko Suzuki, Osamu Hanyu, Hirohito Sone

    DIABETES RESEARCH AND CLINICAL PRACTICE   105 ( 3 )   E16 - E19   2014.9

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    Authorship:Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:ELSEVIER IRELAND LTD  

    Although it is well known that the maternal prepregnancy BMI is a strong contributor to fetal growth, our results showed that a low postload glucose level, although within normal range, independent of maternal BMI was strongly associated with an increased risk of low birth weight births among Japanese mothers. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

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  • Activation of the Leukemia Plasmacytoid Dendritic Cell Line PMDC05 by Toho-1, a Novel IDO Inhibitor Reviewed

    Akie Yamahira, Miwako Narita, Minami Iwabuchi, Takayoshi Uchiyama, Shunpei Iwaya, Rie Ohiwa, Yoshinori Nishizawa, Takafumi Suzuki, Yusaku Yokoyama, Shigeo Hashimoto, Jun Takizawa, Hirohito Sone, Masuhiro Takahashi

    ANTICANCER RESEARCH   34 ( 8 )   4021 - 4028   2014.8

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    Background/Aim: Indoleamine-2,3-dioxygenase (IDO) is a rate-limiting enzyme for tryptophan metabolism and plays an immunosuppressive role. Antigen-presenting cells, when activated, increase the expression of IDO, which results in the suppression of subsequent immune reaction. A novel IDO inhibitor, Toho-1, was explored for its applicability to immunotherapy. Materials and Methods: We investigated the effects of Toho-1 on antigen presentation and antigen-specific cytotoxic T-lymphocyte-inducing ability of leukemia plasmacytoid dendritic cell line PMDC05, which was established in our laboratory. Results: While antigen presentation-associated molecules in PMDC05 cells were increased by stimulation with lipopolysaccharide and interferon-gamma, IDO mRNA and protein expression were also enhanced. Such treatment of PMDC05 cells in combination with Toho-1 enhanced the antigen-presenting and CTL-inducing ability of PMDC05 cells. Conclusion: These findings suggest the ability of Toho-1 to potentiate antigen-presenting cells and its applicability in immunotherapy of cancer.

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  • Role of Body Mass Index History in Predicting Risk of the Development of Hypertension in Japanese Individuals Toranomon Hospital Health Management Center Study 18 (TOPICS 18) Reviewed

    Yoriko Heianza, Satoru Kodama, Yasuji Arase, Shiun Dong Hsieh, Sakiko Yoshizawa, Hiroshi Tsuji, Kazumi Saito, Shiro Tanaka, Shigeko Hara, Hirohito Sone

    HYPERTENSION   64 ( 2 )   247 - +   2014.8

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    It has not been clarified whether overall adiposity in early adulthood or at the lifetime maximum weight would confer a residual risk of hypertension after considering the risk associated with current adiposity. Studied were 6121 Japanese without hypertension. The risk of developing hypertension 4 years after a baseline examination was investigated using the body mass index in the early 20s, at the lifetime maximum, or at the baseline examination. An elevated body mass index at baseline or at the maximum rather than in the early 20s was strongly associated with future hypertension. Compared with individuals with low body mass index both at baseline and in the early 20s, those with an elevated body mass index at the baseline alone had an odds ratio of 1.89 (95% confidence interval, 1.58-2.27) and those with an elevated body mass index both at baseline and in the early 20s had the highest odds ratio of 2.26 (1.76-2.89). Individuals with an elevated body mass index both at baseline and at the maximum had a 2.26-fold (1.87-2.72) increased risk of hypertension compared with those without the 2 factors. An elevated body mass index at the baseline examination weakened the favorable influence of a low body mass index in early adulthood on developing hypertension. Adding information on body mass index in early adulthood or at the maximum in addition to that at the baseline examination contributed to differentiating the risk of hypertension among Japanese, particularly among those with an elevated overall adiposity at present.

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  • Cohort Profile: The Japan Diabetes Complications Study: a long-term follow-up of a randomised lifestyle intervention study of type 2 diabetes Reviewed

    Shiro Tanaka, Sachiko Tanaka, Satoshi Iimuro, Hidetoshi Yamashita, Shigehiro Katayama, Yasuo Ohashi, Yasuo Akanuma, Nobuhiro Yamada, Hirohito Sone

    INTERNATIONAL JOURNAL OF EPIDEMIOLOGY   43 ( 4 )   1054 - 1062   2014.8

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    The Japan Diabetes Complications Study, a randomised lifestyle intervention study of type 2 diabetes conducted at 59 institutes throughout Japan that enrolled 2033 eligible patients from January 1995 to March 1996, was directed at: (i) determining the incidence and progression rates of complications of diabetes; (ii) exploring clinical risk factors for complications of diabetes; and (iii) determining the association between lifestyle factors, including diet and physical activity, and complications of diabetes, in addition to comparing, in a randomised manner, the effects on type 2 diabetes of an extensive lifestyle intervention and conventional treatment. The protocol for the study originally specified four study populations according to primary outcomes, consisting of: (1) a macroangiopathy group (N = 1771); (ii) a nephropathy group (N = 1607); (iii) a retinopathy-incident group (N = 1221); and (iv) a retinopathy-progression group (N = 410). The primary outcomes were: (i) development of retinopathy; (ii) progression of retinopathy; (iii) development of overt nephropathy; and (iv) occurrence of macroangiopathic events including proven coronary heart disease and stroke. The study was originally planned to follow patients for 8 years, and an extended follow-up is ongoing. Information about primary outcomes, laboratory tests, and other clinical variables for each patient was collected at a central data centre through an annual report from each investigator. Additionally, extensive lifestyle surveys were conducted at baseline and 5 years after the beginning of the study intervention in both the intervention and conventional treatment groups. A description of the occurrence of complications of diabetes and of all-cause mortality, provided in this paper, demonstrated a clear gender-based difference in cardiovascular disease and all-cause mortality. The data set of the study is not freely available, but collaborative ideas are welcome. Potential collaborators should discuss ideas informally with the principal investigator by e-mail.

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  • Metabolically Healthy Obesity, Presence or Absence of Fatty Liver, and Risk of Type 2 Diabetes in Japanese Individuals: Toranomon Hospital Health Management Center Study 20 (TOPICS 20) Reviewed

    Yoriko Heianza, Yasuji Arase, Hiroshi Tsuji, Kazuya Fujihara, Kazumi Saito, Shiun Dong Hsieh, Shiro Tanaka, Satoru Kodama, Shigeko Hara, Hirohito Sone

    JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM   99 ( 8 )   2952 - 2960   2014.8

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    Objective: We investigated whether the metabolically healthy obese (MHO) phenotype was associated with an increased risk of the development of diabetes. If so, we aimed to determine what factors could explain this finding.
    Design, Setting, and Participants: Studied were 8090 Japanese individuals without diabetes. Metabolic health status was assessed by common clinical markers: blood pressure, triglycerides, high-density lipoprotein-cholesterol, and fasting glucose concentrations. The cutoff value for obesity or normal weight (NW) was a body mass index of 25.0 kg/m(2).
    Results: The 5-year incidence rate of diabetes was 1.2% (n = 58 of 4749) in metabolically healthy NW (MHNW) individuals, 2.8% (n = 20 of 719) in MHO individuals, 6.0% (n = 102 of 1709) in metabolically abnormalNWindividuals, and 10.3%(n = 94 of 913) in metabolically abnormal obese individuals. Although MHO individuals had no or one metabolic factor, 47.8% had ultrasonographic fatty liver (FL). The MHO group had a significantly increased risk of diabetes compared with the MHNW group [multivariate adjusted odds ratio (OR) 2.23 (95% confidence interval [CI] 1.33, 3.75)], but this risk was attenuated after adjustment for FL. Compared with the MHNW/non-FL group, the risk of diabetes in the MHO/non-FL group was not significantly elevated [OR 1.01 (95% CI 0.35, 2.88)]. However, the MHO/FL and MHNW/FL groups had similarly elevated risks of diabetes [OR 4.09 (95% CI 2.20, 7.60) and 3.16 (1.78, 5.62), respectively].
    Conclusions: Almost half of the MHO participants had FL, which partially explained the increased risk of diabetes among the obese phenotypes. The presence of FL should be evaluated to assess whether an individual was actually in a metabolically benign state for the prediction of diabetes.

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  • [Successful treatment with bortezomib in a patient with systemic primary AL amyloidosis manifesting severe gastrointestinal bleeding]. Reviewed

    Ida T, Hayashi K, Ida T, Hirano S, Nakamura F, Sone H, Fujiwara M

    [Rinsho ketsueki] The Japanese journal of clinical hematology   55 ( 7 )   808 - 814   2014.7

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    We present a systemic primary AL amyloidosis patient with severe gastrointestinal bleeding for whom treatment with bortezomib and dexamethasone was very effective. An 83-year-old woman was admitted to our hospital suffering from multiple gastric ulcers with bleeding. She had monoclonal protein (IgG, λ) in her serum. Systemic primary AL amyloidosis was diagnosed. She was also suspected of having amyloid deposition in cardiac muscle, as well as her bladder and intestinal mucosa. However, we were unable to carry out other invasive examinations due to her bleeding tendency. She was treated with bortezomib and dexamethasone. Her bleeding tendency gradually diminished. After one year, the bleeding tendency had completely resolved. However, she still had amyloid deposition in her gastric mucosa and skin.

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  • Ablation of Elovl6 protects pancreatic islets from high-fat diet-induced impairment of insulin secretion Reviewed

    Nie Tang, Takashi Matsuzaka, Marii Suzuki, Yuta Nakano, Hui Zao, Tomotaka Yokoo, Noriko Suzuki-Kemuriyama, Motoko Kuba, Yuka Okajima, Yoshinori Takeuchi, Kazuto Kobayashi, Hitoshi Iwasaki, Shigeru Yatoh, Akimitsu Takahashi, Hiroaki Suzuki, Hirohito Sone, Masako Shimada, Yoshimi Nakagawa, Naoya Yahagi, Nobuhiro Yamada, Hitoshi Shimano

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   450 ( 1 )   318 - 323   2014.7

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    ELOVL family member 6, elongation of very long-chain fatty acids (Elovl6) is a microsomal enzyme that regulates the elongation of C12-16 saturated and monounsaturated fatty acids and is related to the development of obesity-induced insulin resistance via the modification of the fatty acid composition. In this study, we investigated the role of systemic Elovl6 in the pancreatic islet and beta-cell function. Elovl6 is expressed in both islets and beta-cell lines. In mice fed with chow, islets of the Elovl6(-/-) mice displayed normal architecture and beta-cell mass compared with those of the wild-type mice. However, when fed a high-fat, high-sucrose (HFHS) diet, the islet hypertrophy in response to insulin resistance observed in normal mice was attenuated and glucose-stimulated insulin secretion (GSIS) increased in the islets of Elovl6(-/-) mice compared with those of the wild-type mice. Enhanced GSIS in the HFHS Elovl6-/- islets was associated with an increased ATP/ADP ratio and the suppression of ATF-3 expression. Our findings suggest that Elovl6 could be involved in insulin secretory capacity per beta-cell and diabetes. (C) 2014 Elsevier Inc. All rights reserved.

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  • Commentary on the United Kingdom Prospective Diabetes Study outcomes model 2: Need for long-term follow up and quality of life data in Asian patients Reviewed

    Shiro Tanaka, Sachiko Tanaka, Hirohito Sone

    JOURNAL OF DIABETES INVESTIGATION   5 ( 3 )   281 - 283   2014.5

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    Authorship:Corresponding author   Language:English   Publisher:WILEY-BLACKWELL  

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  • Meta-Analysis of the Quantitative Relation Between Pulse Pressure and Mean Arterial Pressure and Cardiovascular Risk in Patients With Diabetes Mellitus Reviewed

    Satoru Kodama, Chika Horikawa, Kazuya Fujihara, Sakiko Yoshizawa, Yoko Yachi, Shiro Tanaka, Nobumasa Ohara, Satoshi Matsunaga, Takaho Yamada, Osamu Hanyu, Hirohito Sone

    AMERICAN JOURNAL OF CARDIOLOGY   113 ( 6 )   1058 - 1065   2014.3

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    Results of epidemiologic studies that investigated the significance of pulse pressure (PP) and mean arterial pressure (MAP) in terms of risk of cardiovascular disease (CVD) in patients with diabetes mellitus are inconsistent. We performed a quantitative meta-analysis to estimate CVD risk in relation to PP or MAP. Electronic literature search was conducted for prospective studies providing data on CVD risk for an increment in baseline MAP or PP in patients with diabetes mellitus. The pooled CVD risk for a 10-mm Hg increase in each blood pressure (BP) index was estimated with a random-effects model. There were 17 eligible studies consisting of 52,647 patients and 5,112 CVD cases. The pooled relative risk (95% confidence interval) of CVD for an increment of 10 mm Hg was 1.10 (1.04 to 1.16) for PP and 1.09 (0.98 to 1.21) for MAP. Significant between-study heterogeneity was observed (I-2 [p value]; 76.5% [p &lt; 0.001] for PP, 67.8% [p = 0.005] for MAP). In studies concurrently investigating CVD risk for the 4 indexes (i.e., PP, MAP, systolic BP, and diastolic BP), the pooled relative risk (95% confidence interval) was 1.17 (1.09 to 1.26) for PP, 1.11 (1.06 to 1.15) for MAP, 1.14 (1.06 to 1.22) for systolic BP, and 1.06 (0.94 to 1.19) for diastolic BP. In conclusion, the current meta-analysis suggested that PP was the strongest indicator among the 4 commonly used BP indexes. However, the large heterogeneity urged cautious interpretation of the study results. (c) 2014 Elsevier Inc. All rights reserved.

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  • Dietary intake in Japanese patients with type 2 diabetes: Analysis from Japan Diabetes Complications Study Reviewed

    Chika Horikawa, Yukio Yoshimura, Chiemi Kamada, Shiro Tanaka, Sachiko Tanaka, Akane Takahashi, Osamu Hanyu, Atsushi Araki, Hideki Ito, Akira Tanaka, Yasuo Ohashi, Yasuo Akanuma, Nobuhiro Yamada, Hirohito Sone

    JOURNAL OF DIABETES INVESTIGATION   5 ( 2 )   176 - 187   2014.3

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    Aims/IntroductionThough there are many differences in dietary habits and in the metabolic basis between Western and Asian people, the actual dietary intake in Asian patients with diabetes has not been investigated in a nationwide setting, unlike in Western countries. We aimed to clarify dietary intake among Japanese individuals with type 2 diabetes, and identify differences in dietary intake between Japanese and Western diabetic patients.
    Materials and MethodsNutritional and food intakes were surveyed and analyzed in 1,516 patients with type 2 diabetes aged 40-70years from outpatient clinics in 59 university and general hospitals using the food frequency questionnaire based on food groups (FFQg).
    ResultsMean energy intake for all participants was 1737412kcal/day, and mean proportions of total protein, fat, and carbohydrate comprising total energy intake were 15.7, 27.6 and 53.6%, respectively. They consumed a low-fat energy-restricted diet' compared with Western diabetic patients, and the proportion of fat consumption was within the suggested range that has been traditionally recommended in Western countries. As a protein source, consumption of fish (100g) and soybean products (71g) was larger than that of meat (50g) and eggs (29g). These results imply that dietary content and food patterns among Japanese patients with type 2 diabetes are quite close to those reported as suitable for prevention of obesity, type 2 diabetes, cardiovascular disease, and total mortality in Europe and America.
    ConclusionsA large difference was shown between dietary intake by Japanese and Western patients. These differences are important to establish ethnic-specific medical nutrition therapy for diabetes.

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  • Quantitative relationship between body weight gain in adulthood and incident type 2 diabetes: a meta-analysis Reviewed

    S. Kodama, C. Horikawa, K. Fujihara, S. Yoshizawa, Y. Yachi, S. Tanaka, N. Ohara, S. Matsunaga, T. Yamada, O. Hanyu, H. Sone

    OBESITY REVIEWS   15 ( 3 )   202 - 214   2014.3

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    This meta-analysis quantified the risk of type 2 diabetes mellitus (T2DM) preceded by body weight (BW) gain in the general population. Systematic literature searches retrieved 15 eligible studies. The BW gain was divided into early weight-gain, which was defined as BW gain from early adulthood (18-24 years of age) to cohort entry (&gt;= 25 years of age), and late weight-gain, which was defined as BW gain from cohort entry. The pooled relative risk (RR; 95% confidence interval [CI]) of T2DM for an increment of BW gain standardized into a 5-kg m(-2) increment in the body mass index (BMI) was 3.07 (2.49-2.79) for early weight-gain and 2.12 (1.74-2.58) for late weight-gain. When limiting analysis to studies that concurrently examined T2DM risk for current BMI (defined in both groups as BMI at cohort entry), a larger magnitude of T2DM risk was revealed for early weight-gain compared with current BMI (RR [95% CI], 3.38 [2.20-5.18] vs. 2.39 [1.58-3.62]), while there was little difference between late weight-gain (RR [95% CI], 2.21 [1.91-2.56]) and current BMI (RR [95% CI], 2.47 [1.97-3.30]). The meta-analysis suggested that BW gain was a quantifiable predictor of T2DM, as well as current obesity in adults. Particularly, BW gain in early rather than middle-to-late adulthood played an important role in developing T2DM.

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  • Efficacy of Habitual Exercise for Improving Lipid Profiles Depends on the PPRA gamma Genotype in Japanese Males Reviewed

    Yasuko Sone, Reiko Hirasawa, Ikuyo Ichi, Tomoko Isbikawa, Satoru Kodama, Hirohito Sone, Shigenobu Egawa, Kazuo Kawahara, Yuzuru Otsuka, Yoko Fujiwara

    JOURNAL OF NUTRITIONAL SCIENCE AND VITAMINOLOGY   60 ( 1 )   66 - 70   2014.2

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    Peroxisome proliferator-activated receptor gamma (PPAR gamma) responds to thiazolidinedione derivatives, which are ligands of PPAR gamma, and affects insulin resistance. Recently, a PPAR gamma study reported that in high-fat-diet-induced obesity, the phosphorylation of PPAR gamma prevented the transcription of specific PPAR gamma targets that have anti-obesity effects. We previously reported that genetic variants of the fatty acid desaturase were associated with plasma lipid profiles and could contribute to dyslipidemia in Japanese males. The aim of this study was to investigate the anti-obesity effects of PPAR gamma variants on lipid profiles. One hundred and thirty-eight (138) Japanese males participated in the study. Their serum lipid markers and the fatty acid composition of their red blood cell (RBC) membranes were determined. The stearoyl-CoA desaturase 1 (SCD1) indices were represented as the fatty acid product : precursor ratios. The participants were genotyped for the single-nucleotide polymorphism rs2938392 in the PPAR gamma gene. The participants' fitness habits were also surveyed by questionnaire. The effects of habitual exercise on the measured lipid parameters were compared in each genotype group. No association between the genotypes in the PPAR gamma gene and the biochemical data was found. However, the serum triglyceride levels and the SCD1 indices in RBC membranes were significantly higher in the participants who carried the major rs2938392 allele (A/A) and did not habitually exercise than in those who did exercise. These findings indicate that the risk for detrimental lipid profiles in the absence of habitual exercise depends on the PPAR gamma genotype in Japanese males.

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  • Hypertension increases urinary excretion of immunoglobulin G, ceruloplasmin and transferrin in normoalbuminuric patients with type 2 diabetes mellitus Reviewed

    Nobumasa Ohara, Osamu Hanyu, Satoshi Hirayama, Osamu Nakagawa, Yoshifusa Aizawa, Seiki Ito, Hirohito Sone

    JOURNAL OF HYPERTENSION   32 ( 2 )   432 - 438   2014.2

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    Objective:Increased urinary excretion of certain plasma proteins, such as immunoglobulin G (IgG), ceruloplasmin and transferrin, with different molecular radii of 55 angstrom or less and different isoelectric points have been reported to precede development of microalbuminuria in patients who have diabetes mellitus with hypertension. We examined how hypertension affects these urinary proteins in a diabetic state.Methods:Excretion of IgG, ceruloplasmin, transferrin, albumin, 2-macroglobulin with a large molecular radius of 88 angstrom and N-acetylglucosaminidase in first-morning urine samples were measured in normoalbuminuric patients (urinary albumin-to-creatinine ratio&lt;15mg/g) with hypertension and nondiabetes mellitus (group hypertension, n=32), type 2 diabetes mellitus and normotension (group diabetes mellitus, n=52) and type 2 diabetes mellitus and hypertension (group Both, n=45), and in age-matched controls (n=72).Results:Urinary IgG, ceruloplasmin, transferrin, albumin and N-acetylglucosaminidase and estimated glomerular filtration rate (eGFR) were significantly elevated in groups diabetes mellitus and Both compared with controls. Furthermore, urinary IgG, ceruloplasmin and transferrin in group Both were significantly higher than those in group diabetes mellitus. These exhibited a positive and relatively strong association with eGFR compared with controls. No significant difference in urinary albumin or N-acetylglucosaminidase was found between the two diabetic groups. In contrast, group hypertension had elevated urinary transferrin without any changes in the other compounds. Urinary 2-macroglobulin did not differ among the four groups.Conclusion:These findings suggest that normoalbuminuric diabetic patients without hypertension have both glomerular hemodynamic changes such as increased intraglomerular hydraulic pressure and altered proximal tubules, and that hypertension increases intraglomerular hydraulic pressure. Increased urinary IgG, ceruloplasmin and transferrin may reflect an increase in intraglomerular hydraulic pressure.

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  • Manifestations of Fulminant CD8 T-cell Post-transplant Lymphoproliferative Disorder Following the Administration of Rituximab for Lymphadenopathy with a High Level of Epstein-Barr Virus (EBV) Replication after Allogeneic Hematopoietic Stem Cell Transplantation Reviewed

    Tomoyuki Tanaka, Jun Takizawa, Shukuko Miyakoshi, Takashi Kozakai, Kyoko Fuse, Yasuhiko Shibasaki, Masato Moriyama, Koichi Ohshima, Ken Toba, Tatsuo Furukawa, Hirohito Sone, Masayoshi Masuko

    INTERNAL MEDICINE   53 ( 18 )   2115 - 2119   2014

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    We herein report the case of a 22-year-old woman with severe aplastic anemia who underwent allogeneic hematopoietic stem cell transplantation (HSCT). After HSCT, the Epstein-Barr virus (EBV)-DNA load in the peripheral blood gradually increased, and the patient presented with a fever and lymphadenopathy on day 56 post-HSCT. Although we administered rituximab, her clinical condition worsened. After rituximab treatment, CD8 T-cells emerged and became dominant in the peripheral blood, some of which were positive on an EBV-specific tetramer analysis. However, an open biopsy of the lymphadenopathy lesions revealed the CD8 T-cells to be infected with EBV, exhibiting proliferation with oligoclonality. The patient ultimately died of multiple organ failure on day 99 post-HSCT.

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  • Weight Loss Maintenance for 2 Years after a 6-Month Randomised Controlled Trial Comparing Education-Only and Group-Based Support in Japanese Adults Reviewed

    Yoshio Nakata, Masafumi Okada, Koichi Hashimoto, Yoshinori Harada, Hirohito Sone, Kiyoji Tanaka

    OBESITY FACTS   7 ( 6 )   376 - 387   2014

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    Objective: Our previous study, a 6-month randomised controlled trial, demonstrated that a group based support promoted weight loss as compared to an education only intervention. The purpose of this study was to examine weight loss maintenance for 2 years. Methods: Originally, 188 overweight Japanese adults, aged 40-65 years, were randomly assigned to 3 groups: control, education only or group based support. After the 6-month intervention, 125 participants in the education-only and the group-based support groups were followed up for 2 years. The primary outcome was the amount of weight lost. The participants were retrospectively grouped into quartiles of percent weight loss for secondary analyses. Results: At the end of follow-up, the amount of weight lost in the education only and the group based support groups was the same (3.3 kg). Secondary analyses using data of those who completed the study (n = 100) revealed that the participants in the highest quartile of percent weight loss significantly increased their step counts and moderate-to-vigorous physical activity compared with the lowest quartile. No significant differences were observed in the energy intake among the four groups. Conclusion: The effects of group based support disappear within 2 years. Increasing physical activity may be a crucial factor for successful maintenance of weight loss. (C) 2014 S. Karger GmbH, Freiburg

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  • Utility of the Triglyceride Level for Predicting Incident Diabetes Mellitus According to the Fasting Status and Body Mass Index Category: The Ibaraki Prefectural Health Study Reviewed

    Kazuya Fujihara, Ayumi Sugawara, Yoriko Heianza, Toshimi Sairenchi, Fujiko Irie, Hiroyasu Iso, Mikio Doi, Hitoshi Shimano, Hiroshi Watanabe, Hirohito Sone, Hitoshi Ota

    JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS   21 ( 11 )   1152 - 1169   2014

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    Aim: The levels of lipids, especially triglycerides (TG), and obesity are associated with diabetes mellitus (DM). Although typically measured in fasting individuals, non-fasting lipid measurements play an important role in predicting future DM. This study compared the predictive efficacy of lipid variables according to the fasting status and body mass index (BMI) category.
    Methods: Data were collected for 39,196 nondiabetic men and 87,980 nondiabetic women 40-79 years of age who underwent health checkups in Ibaraki-Prefecture, Japan in 1993 and were followed through 2007. The hazard ratios (HRs) for DM in relation to sex, the fasting status and BMI were estimated using a Cox proportional hazards model.
    Results: A total of 8,867 participants, 4,012 men and 4,855 women, developed DM during a mean follow-up of 5.5 years. TG was found to be an independent predictor of incident DM in both fasting and non-fasting men and non-fasting women. The multivariable-adjusted HR for DM according to the TG quartile (Q) 4 vs. Q1 was 1.18 (95% confidence interval (CI): 1.05, 1.34) in the non-fasting men with a normal BMI (18.5-24.9). This trend was also observed in the non-fasting women with a normal BMI. That is, the multivariable-adjusted HRs for DM for TG Q2, Q3 and Q4 compared with Q1 were 1.07 (95% CI: 0.94, 1.23), 1.17 (95% CI: 1.03, 1.34) and 1.48 (95% CI: 1.30, 1.69), respectively.
    Conclusions: The fasting and non-fasting TG levels in men and non-fasting TG levels in women are predictive of future DM among those with a normal BMI. Clinicians must pay attention to those individuals at high risk for DM.

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  • Association of Helicobacter pylori Infection with Glycemic Control in Patients with Diabetes: A Meta-Analysis Reviewed

    Chika Horikawa, Satoru Kodama, Kazuya Fujihara, Yoko Yachi, Shiro Tanaka, Akiko Suzuki, Osamu Hanyu, Hitoshi Shimano, Hirohito Sone

    JOURNAL OF DIABETES RESEARCH   2014   250620   2014

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    Objective. To assess the association between Helicobacter pylori (HP) infection and glycemic control in patients with diabetes through a meta-analytic approach. Research Design and Methods. Electronic literature searches were conducted for cross-sectional studies that examined the hemoglobin A1c (A1C) level by whether patients with diabetes were or were not carriers of HP. Mean differences in A1C between groups with and without HP infection were pooled with a random-effects model. Results. Thirteen eligible studies were included in this meta-analysis. Overall, the HP carriers did not have significantly higher A1C levels compared with HP noncarriers (mean difference (95% CI), 0.19% (-0.18 to 0.46), P = 0.16). When the analysis was limited to studies targeting patients with type 1 diabetes, there was also no significant difference in A1C (0.69% (-0.31 to 1.68), P = 0.18). Conclusions. There was insufficient evidence that HP infection worsened glycemic control in patients with diabetes.

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  • Reversible brain atrophy and cognitive impairment in an adolescent Japanese patient with primary adrenal Cushing's syndrome. Reviewed International journal

    Nobumasa Ohara, Hiroshi Suzuki, Akiko Suzuki, Masanori Kaneko, Masahiro Ishizawa, Kazuo Furukawa, Takahiro Abe, Yasuhiro Matsubayashi, Takaho Yamada, Osamu Hanyu, Takayoshi Shimohata, Hirohito Sone

    Neuropsychiatric disease and treatment   10   1763 - 7   2014

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    Endogenous Cushing's syndrome is an endocrine disease resulting from chronic exposure to excessive glucocorticoids produced in the adrenal cortex. Although the ultimate outcome remains uncertain, functional and morphological brain changes are not uncommon in patients with this syndrome, and generally persist even after resolution of hypercortisolemia. We present an adolescent patient with Cushing's syndrome who exhibited cognitive impairment with brain atrophy. A 19-year-old Japanese male visited a local hospital following 5 days of behavioral abnormalities, such as money wasting or nighttime wandering. He had hypertension and a 1-year history of a rounded face. Magnetic resonance imaging (MRI) revealed apparently diffuse brain atrophy. Because of high random plasma cortisol levels (28.7 μg/dL) at 10 AM, he was referred to our hospital in August 2011. Endocrinological testing showed adrenocorticotropic hormone-independent hypercortisolemia, and abdominal computed tomography demonstrated a 2.7 cm tumor in the left adrenal gland. The patient underwent left adrenalectomy in September 2011, and the diagnosis of cortisol-secreting adenoma was confirmed histologically. His hypertension and Cushingoid features regressed. Behavioral abnormalities were no longer observed, and he was classified as cured of his cognitive disturbance caused by Cushing's syndrome in February 2012. MRI performed 8 months after surgery revealed reversal of brain atrophy, and his subsequent course has been uneventful. In summary, the young age at onset and the short duration of Cushing's syndrome probably contributed to the rapid recovery of both cognitive dysfunction and brain atrophy in our patient. Cushing's syndrome should be considered as a possible etiological factor in patients with cognitive impairment and brain atrophy that is atypical for their age.

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  • Early Diagnosis of Hepatic Intravascular Lymphoma: A Case Report and Literature Review Reviewed

    Hiroyuki Abe, Kenya Kamimura, Maiko Mamizu, Yasuhiko Shibazaki, Takanobu Ishiguro, Shin-ichi Katada, Yu-ki Nishiyama, Yoshifumi Takahashi, Yu-ya Hatano, Ken-ichi Mizuno, Yukari Watanabe, Aiko Nagashima, Jun Takizawa, Manabu Takeuchi, Hirokazu Kawai, Minoru Nomoto, Hirohito Sone, Masatoyo Nishizawa, Yutaka Aoyagi

    INTERNAL MEDICINE   53 ( 6 )   587 - 593   2014

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    Hepatic intravascular large B-cell lymphoma (IVL) is a rare disease entity that involves invasion into various organs. Due to the aggressive behavior and poor prognosis of the disease and the difficulty in making an early diagnosis, some cases are diagnosed at autopsy. Early suspicion and the use of imaging studies and liver biopsies are key for diagnosing IVL; however, no reports have described the results of imaging studies due to the limited number of cases. We herein report the results of imaging studies of hepatic IVL, including the findings PET-CT, dynamic-CT, EOB-MRI and CEUS. These results may help physicians to make an early diagnosis and improve the prognosis.

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  • Comparison of the Framingham Risk Score, UK Prospective Diabetes Study (UKPDS) Risk Engine, Japanese Atherosclerosis Longitudinal Study-Existing Cohorts Combine (JALS-ECC) and Maximum Carotid Intima-Media Thickness for Predicting Coronary Artery Stenosis in Patients with Asymptomatic Type 2 Diabetes Reviewed

    Kazuya Fujihara, Hiroaki Suzuki, Akira Sato, Tomoko Ishizu, Satoru Kodama, Yoriko Heianza, Kazumi Saito, Hitoshi Iwasaki, Kazuto Kobayashi, Shigeru Yatoh, Akimitsu Takahashi, Naoya Yahagi, Hirohito Sone, Hitoshi Shimano

    JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS   21 ( 8 )   799 - 815   2014

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    Aims: To compare the efficacy of Framingham Risk Score (FRS), UK Prospective Diabetes Study (UKPDS) risk engine, a risk score based on the Japanese Atherosclerosis Longitudinal Study-Existing Cohorts Combine (JALS-ECC), the maximum intima-media thickness (max-IMT) determined on coronary computed tomography angiography (CCTA) and their combination in asymptomatic patients with type 2 diabetes.
    Methods: A total of 116 Japanese patients with type 2 diabetes underwent CCTA. The risk of coronary heart disease was calculated according to the FRS, UKPDS and JALS-ECC. We evaluated the reclassification of coronary artery stenosis (CAS) based on the risk score categories after adding each IMT related variable.
    Results: Sixty-eight patients had CAS. The areas under the curves (AUCs) in the receiver operating characteristic curve analyses of FRS, UKPDS and JALS-ECC were 0.763 (95% confidence interval [CI]: 0.674-0.853), 0.785 (95% CI: 0.703-0.868) and 0.767 (95% CI: 0.681-0.853), respectively. The AUCs for FRS, UKPDS and JALS-ECC combined with the max-IMT were 0.788 (95% CI: 0.705-0.872), 0.800 (95% CI: 0.720-0.879) and 0.786 (95% CI: 0.703-0.869), respectively. Combining the max-IMT with the risk scores improved the identification of subjects with stenotic lesions, in particular, those in the first, second and third tertiles of the FRS, first and second tertiles of the UKPDS and first and second tertiles of the JALS-ECC (P=0.054, P=0.056, P=0.015, P=0.082, P=0.060, P=0.007, and P=0.080, respectively). The net reclassification improvement increased following the addition of a max-IMT of &gt;= 1.9 mm (32.4% in FRS, 19.9% in UKPDS and 51.7% in JALS-ECC).
    Conclusions: These data suggest that combining a risk score with the max-IMT improves the prediction of CAS in comparison with the risk score alone.

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  • Relationship between a Low Ankle Brachial Index and All-Cause Death and Cardiovascular Events in Subjects with and without Diabetes Reviewed

    Hiroki Yokoyama, Hirohito Sone, Jun Honjo, Shinichiro Okizaki, Daishiro Yamada, Ryushi Shudo, Hitoshi Shimizu, Tatsumi Moriya, Masakazu Haneda

    JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS   21 ( 6 )   574 - 581   2014

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    Aims: The association between a low ankle brachial index (ABI) and mortality and vascular morbidity in Japanese individuals with diabetes and the independence of this association from other risk factors have not yet been examined in the primary care setting among a large number of patients.Methods: An observational prospective cohort study was performed among 3,004 Japanese individuals (2,598 patients with diabetes) to examine all-cause death and cardiovascular disease (CVD) in relation to low ABI (< 0.9) values and other risk factors.Results: Low ABI values were found in 127 subjects (4.2%) and was associated with smoking, diabetes, hypertension, pulse pressure, glycosylated hemoglobin A(1C), lipid profiles, glomerular filtration rate, uric acid and prevalent CVD at baseline. Over 13,242 person-years, 93 deaths and 117 cases of CVD occurred. In a multivariate Cox regression analysis, the hazard ratio for low-normal ABI values was 3.97 (95% CI, 2.29 to 6.88) for all-cause death and 2.86 (95% CI, 1.83-4.49) for fatal and non-fatal CVD and all-cause death. Similar hazard ratios were found when the subjects were confined to those with diabetes. All risk analyses indicated that age, a low ABI, diabetes, a history of CVD and smoking remained significantly and independently predictive of CVD and all-cause death.Conclusions: A low ABI exhibits significant cross-sectional associations with conventional risk factors and further more with the glomerular filtration rate, uric acid level and presence of prevalent CVD at baseline, and a low ABI independently predicts subsequent death and cardiovascular events. These findings support the concept that a low ABI is an integrated marker of an excess risk of death and cardiovascular events, independent of conventional risk factors.

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  • Comparison of different aspects of BMI history to identify undiagnosed diabetes in Japanese men and women: Toranomon hospital health management center study 12 (TOPICS 12) Reviewed

    S. Yoshizawa, Y. Heianza, Y. Arase, K. Saito, S. D. Hsieh, H. Tsuji, O. Hanyu, A. Suzuki, S. Tanaka, S. Kodama, H. Shimano, S. Hara, H. Sone

    Diabetic Medicine   31 ( 11 )   1378 - 1386   2014

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    Aims: To examine current BMI and various aspects of BMI history as pre-screening tools for undiagnosed diabetes in Japanese individuals. Methods: This cross-sectional study included 16 226 men and 7026 women aged 30-75 years without a self-reported history of clinician-diagnosed diabetes. We estimated the probability of having undiagnosed diabetes (fasting glucose ≥ 7.0 mmol/l and/or HbA&lt
    inf&gt
    1c&lt
    /inf&gt
    ≥ 48 mmol/mol (≥ 6.5%) for the following variables: current BMI, BMI in the early 20s (BMI&lt
    inf&gt
    20y&lt
    /inf&gt
    ), lifetime maximum BMI (BMI&lt
    inf&gt
    max&lt
    /inf&gt
    ), change between BMI in the early 20s and current BMI (ΔBMI&lt
    inf&gt
    20y-cur&lt
    /inf&gt
    ), change between BMI in the early 20s and maximum BMI (ΔBMI&lt
    inf&gt
    20y-max&lt
    /inf&gt
    ), and change between lifetime maximum and current BMI (ΔBMI&lt
    inf&gt
    max-cur&lt
    /inf&gt
    ). Results: The prevalence of undiagnosed diabetes was 3.3% (771/23252) among participants. BMI&lt
    inf&gt
    max&lt
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    , ΔBMI&lt
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    20y-max&lt
    /inf&gt
    and current BMI (1-sd increments) were more strongly associated with diabetes than the other factors (multivariate odds ratio 1.58 [95% CI 1.47-1.70] in men and 1.65 [95% CI 1.43-1.90] in women for BMI&lt
    inf&gt
    max&lt
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    multivariate odds ratio 1.47 [95% CI 1.37-1.58] in men and 1.61 [95% CI 1.41-1.84] in women for ΔBMI&lt
    inf&gt
    20y-max&lt
    /inf&gt

    multivariate odds ratio 1.47 [95% CI 1.36-1.58] in men and 1.63 [95% CI 1.40-1.89] in women for current BMI). The probability of having diabetes was markedly higher in those with both the highest tertile of BMI&lt
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    max&lt
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    and greatest ΔBMI&lt
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    20y-max&lt
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    however, a substantially lower likelihood of diabetes was observed among individuals with the lowest and middle tertiles of current BMI (&lt
    24.62 kg/m&lt
    sup&gt
    2&lt
    /sup&gt
    in men and &lt
    22.54 kg/m&lt
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    2&lt
    /sup&gt
    in women). Conclusions: Lifetime maximum BMI and BMI changes from early adulthood were strongly associated with undiagnosed diabetes. Adding BMI history to people's current BMI would improve the identification of individuals with a markedly higher probability of having undiagnosed diabetes.

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  • Quality and accuracy of Internet information concerning a healthy diet Reviewed

    Reiko Hirasawa, Yoko Yachi, Sakiko Yoshizawa, Chika Horikawa, Yoriko Heianza, Ayumi Sugawara, Yasuko Sone, Kazuo Kondo, Hitoshi Shimano, Kazumi Saito, Satoru Kodama, Hirohito Sone

    INTERNATIONAL JOURNAL OF FOOD SCIENCES AND NUTRITION   64 ( 8 )   1007 - 1013   2013.12

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    The Internet is used by many consumers interested in healthy living. The aim of the present study was to explore the variations among Internet information concerning a healthy diet and to evaluate the potential for misleading information. To conduct a descriptive analysis, the search term "healthy diet'' was entered into three search engines and the first 100 results were examined. Of the evaluated 48 websites, 5, 26 and 11, respectively, gave references, date when information was updated and cautioned users. For assessment of accuracy, six dietary guidelines were used as references and the website was scored according to the number of recommended dietary features that matched the guidelines. Websites that specified their objectives scored significantly higher when matched with each guideline than the websites that did not state four guidelines (p&lt;0.05). Internet information on a "healthy diet'' was likely to only partially follow recommendations of the guidelines.

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  • Intakes of Dietary Fiber, Vegetables, and Fruits and Incidence of Cardiovascular Disease in Japanese Patients With Type 2 Diabetes Reviewed

    Shiro Tanaka, Yukio Yoshimura, Chiemi Kamada, Sachiko Tanaka, Chika Horikawa, Ryota Okumura, Hideki Ito, Yasuo Ohashi, Yasuo Akanuma, Nobuhiro Yamada, Hirohito Sone

    DIABETES CARE   36 ( 12 )   3916 - 3922   2013.12

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    OBJECTIVEFoods rich in fiber, such as vegetables and fruits, prevent cardiovascular disease (CVD) among healthy adults, but such data in patients with diabetes are sparse. We investigated this association in a cohort with type 2 diabetes aged 40-70 years whose HbA(1c) values were 6.5% in Japan Diabetes Society values.RESEARCH DESIGN AND METHODSIn this cohort study, 1,414 patients were analyzed after exclusion of patients with history of CVDs and nonresponders to a dietary survey. Primary outcomes were times to stroke and coronary heart disease (CHD). Hazard ratios (HRs) of dietary intake were estimated by Cox regression adjusted for systolic blood pressure, lipids, energy intake, and other confounders.RESULTSMean daily dietary fiber in quartiles ranged from 8.7 to 21.8 g, and mean energy intake ranged from 1,442.3 to 2,058.9 kcal. Mean daily intake of vegetables and fruits in quartiles ranged from 228.7 to 721.4 g. During the follow-up of a median of 8.1 years, 68 strokes and 96 CHDs were observed. HRs for stroke in the fourth quartile vs. the first quartile were 0.39 (95% CI 0.12-1.29, P = 0.12) for dietary fiber and 0.35 (0.13-0.96, P = 0.04) for vegetables and fruits. There were no significant associations with CHD. The HR per 1-g increase was smaller for soluble dietary fiber (0.48 [95% CI 0.30-0.79], P &lt; 0.01) than for total (0.82 [0.73-0.93], P &lt; 0.01) and insoluble (0.79 [0.68-0.93], P &lt; 0.01) dietary fiber.CONCLUSIONSIncreased dietary fiber, particularly soluble fiber, and vegetables and fruits were associated with lower incident stroke but not CHD in patients with type 2 diabetes.

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  • Effect of postmenopausal status and age at menopause on type 2 diabetes and prediabetes in Japanese individuals: Toranomon Hospital Health Management Center study 17 (TOPICS 17) Reviewed

    Yoriko Heianza, Yasuji Arase, Satoru Kodama, Shiun Dong Hsieh, Hiroshi Tsuji, Kazumi Saito, Hitoshi Shimano, Shigeko Hara, Hirohito Sone

    Diabetes Care   36 ( 12 )   4007 - 4014   2013.12

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    Objective-Findings on the effect of menopause or age at menopause on the presence of hyperglycemia are controversial, and why women after menopause have a higher probability of having hyperglycemia than men in the same age range remains unknown. Research design and methods-We reviewed data on 29,189 men, 6,308 premenopausalwomen, and 4,570 postmenopausal women in Japan. Odds ratios (ORs) for diabetes or prediabetes indicated by American Diabetes Association criteria were calculated for men and for pre- and postmenopausal women. Results-Compared with premenopausal women, women after natural menopause had an age-adjusted OR of 1.40 (95% CI 1.03-1.89) for diabetes, and women after menopause by surgical or other causes had an age-adjusted OR of 1.59 (1.07-2.37). The age-adjusted OR in men was 4.02 (3.15-5.14). Compared with premenopausal nondiabetic women, postmenopausal nondiabetic women had a significantly elevated OR of 1.33 (1.20-1.48) for prediabetes
    nondiabetic men had an OR of 1.93 (1.77-2.10) independently of age and demographic and metabolic factors. Even among women aged &lt
    50 years, postmenopausal status was significantly associated with an elevated OR (1.50 [1.18-1.91]) for dysglycemia (either diabetes or prediabetes). Postmenopausal women aged ≥50 years had a particularly elevated OR for dysglycemia, regardless of age at menopause. Conclusions-The postmenopausal state was significantly associated with the presence of dysglycemia independently of normal aging, although the increased probability in postmenopausal women did not equal that in men. Among women, menopause and older age might additively influence the elevated probability of dysglycemia. © 2013 by the American Diabetes Association.

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  • [Stroke in the elderly people with diabetes mellitus]. Reviewed

    Minagawa S, Hanyu O, Sone H

    Nihon rinsho. Japanese journal of clinical medicine   71 ( 11 )   1948 - 1953   2013.11

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  • Use of high-normal levels of haemoglobin A(1C) and fasting plasma glucose for diabetes screening and for prediction: a meta-analysis. Reviewed International journal

    Satoru Kodama, Chika Horikawa, Kazuya Fujihara, Reiko Hirasawa, Yoko Yachi, Sakiko Yoshizawa, Shiro Tanaka, Yasuko Sone, Hitoshi Shimano, Kaoruko Tada Iida, Kazumi Saito, Hirohito Sone

    Diabetes/metabolism research and reviews   29 ( 8 )   680 - 92   2013.11

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    BACKGROUND: Using high-normal levels of haemoglobin A1C (Abnormal-A1C ) or fasting plasma glucose (FPG) (Abnormal-FPG) for diabetes screening are expected to improve the ability to detect persons with or at high risk of diabetes. We assessed the diagnostic and predictive capacity for diabetes of Abnormal-A1C and Abnormal-FPG. We compared these to the combined use of the two measures to the single use of either measurement. METHODS: We analysed 31 eligible cross-sectional or cohort studies that assessed diagnostic or predictive ability, respectively, by using lower A1C and FPG cutoff values than recommended by current diabetes criteria. Positive and negative likelihood ratios (LR+ and LR-) were calculated to assess the ability to confirm or exclude diabetes, respectively, on the basis of a bivariate random-effects model. RESULTS: With both Abnormal-A1C and Abnormal-FPG, the pooled LR+ was above 4 for diagnosing diabetes and above 3 for predicting diabetes. However, the pooled LR- for predicting diabetes was higher with Abnormal-A1C (0.48) and Abnormal-FPG (0.49) in comparison with that for diagnosing diabetes (0.27, Abnormal-A1C ; 0.28, Abnormal-FPG). In eight studies that assessed the predictive ability of the combination of A1C and FPG, using either Abnormal-A1C or Abnormal-FPG could lower LR- to 0.17 from 0.43 for only Abnormal-A1C and from 0.38 for only Abnormal-FPG. Accordingly, LR+ was also lowered to 2.37 from 3.36 for only Abnormal-A1C and from 3.84 for only-Abnormal-FPG. CONCLUSION: The use of the two blood glucose tests had insufficient capacity to identify subjects at high risk for diabetes but had considerable capacity to identify undiagnosed diabetes.

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  • Efficacy and safety in sitagliptin therapy for diabetes complicated by non-alcoholic fatty liver disease Reviewed

    Yasuji Arase, Yusuke Kawamura, Yuya Seko, Mariko Kobayashi, Fumitaka Suzuki, Yoshiyuki Suzuki, Norio Akuta, Masahiro Kobayashi, Hitomi Sezaki, Satoshi Saito, Tetsuya Hosaka, Kenji Ikeda, Hiromitsu Kumada, Yuki Ohmoto-Sekine, Shiun Dong Hsieh, Kazuhisa Amakawa, Kyoko Ogawa, Naoki Matsumoto, Akiko Iwao, Hiroshi Tsuji, Shigeko Hara, Yasumichi Mori, Minoru Okubo, Hirohito Sone, Tetsuro Kobayashi

    HEPATOLOGY RESEARCH   43 ( 11 )   1163 - 1168   2013.11

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    AimThe aim of this case-control study was to assess the efficacy and safety of dipeptidyl peptidase-4 inhibitor (sitagliptin) for type 2 diabetes mellitus (T2DM) with non-alcoholic fatty liver disease (NAFLD).
    MethodsTwenty NAFLD patients with T2DM treated by sitagliptin were retrospectively enrolled as the sitagliptin group. These patients were given sitagliptin between January 2010 and July 2011. Another 20 NAFLD patients with T2DM treated only with diet and exercise for 48weeks were selected as the control group. Serum levels of fasting plasma glucose (FPG), hemoglobin A1C (HbA1c), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured before and 12, 24, 36 and 48weeks after the initiation of treatment.
    ResultsIn the sitagliptin group, average HbA1c levels decreased approximately 0.7% at 48weeks after the initiation of sitagliptin. Next, average FPG levels decreased approximately 15mg/dL at 48weeks after the initiation of sitagliptin. The serum levels of HbA1c and FPG in the sitagliptin group decreased with statistical significance compared to those in the control group (P&lt;0.05). All the patients could take sitagliptin of 50mg/day without reduction necessitated by sitagliptin-related side-effects. There were no significant changes of average AST and ALT levels during follow up of 48weeks in both sitagliptin and control groups.
    ConclusionOur results indicate sitagliptin is effective and safe for the treatment of T2DM complicated with NAFLD.

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  • Diabetic Cardiomyopathy and Oxidative Stress Reviewed

    Somasundaram Arumugam, Vengadeshprabhu Karuppagounder, Rajarajan A. Thandavarayan, Vigneshwaran Pitchaimani, Hirohito Sone, Kenichi Watanabe

    Diabetes: Oxidative Stress and Dietary Antioxidants   25 - 32   2013.11

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    Diabetes mellitus (DM) is the most common metabolic disorder associated with high mortality, which is mostly due to its cardiovascular complications. Diabetic cardiomyopathy (CM) is characterized by abnormal ventricular function in the absence of DM-associated risk factors such as obesity, hypertension, hypercholesterolemia, or coronary artery disease. Oxidative stress plays a pivotal role in the development of diabetic CM, in which chronic hyperglycemia plays a major role. As this develops, the endogenous antioxidant system becomes suppressed and so cannot counter-balance the increased oxidative stress. The metabolic abnormalities of DM cause mitochondrial superoxide overproduction, which further enhances the production of other reactive species, including nitric oxide, hydroxyl radical, hydrogen peroxide and peroxy nitrite, causing aggravation of the myocardial damage. In addition, free-radical-mediated platelet activation in the narrowed arteries culminates in acute myocardial infarction and stroke, indirectly affecting cardiac function. This chapter focuses on various aspects of the oxidative stress induced by reactive species during the pathogenesis of diabetic CM. © 2014 Elsevier Inc. All rights reserved.

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  • Association of living alone with the presence of undiagnosed diabetes in Japanese men: The role of modifiable risk factors for diabetes: Toranomon hospital health management center study 13 (TOPICS 13) Reviewed

    Y. Heianza, Y. Arase, S. Kodama, S. D. Hsieh, H. Tsuji, K. Saito, H. Shimano, S. Hara, H. Sone

    Diabetic Medicine   30 ( 11 )   1355 - 1359   2013.11

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    Aims: To investigate whether living alone was associated with the presence of undiagnosed diabetes and whether this association could be attenuated by modifiable lifestyle habits. Methods: This cross-sectional study included 6400 Japanese men without a history of diagnosed diabetes. Individuals with currently undiagnosed diabetes were identified through fasting glucose concentration ≥7.0 mmol/l or HbA1c concentration ≥ 48 mmol/mol (≥ 6.5%). Effect modification was examined using body mass index, hypertension, history of dyslipidaemia, drinking habits, smoking habits, physical activity, vegetable intake, emotional stress and depressed mood. Results: Men who lived alone (n = 1098) had a significantly elevated odds ratio for having undiagnosed diabetes in an age-adjusted model (odds ratio 1.45, 95% CI 1.07, 1.96
    P = 0.018). After adjustment for lifestyle factors, the association was slightly attenuated (odds ratio 1.40, 95% CI 1.02, 1.91
    P = 0.036). After further adjustment for all factors mentioned above, living alone was still marginally significantly associated with the presence of undiagnosed diabetes (odds ratio 1.38, 95% CI 1.003, 1.90
    P = 0.048). A significant association of living alone with the presence of undetected diabetes was particularly observed among men who were overweight, currently smoked and were physically inactive, or had any one of those three factors. Conclusions: The association between undiagnosed diabetes and living alone can be partially influenced by modifiable lifestyle factors. Men who lived alone, especially those who did not engage in favourable lifestyle habits, were more likely to have undiagnosed diabetes. Such individuals have a higher probability of having undetected diabetic hyperglycaemia and would need to undergo glucose tests to identify the disease. © 2013 The Authors. Diabetic Medicine © 2013 Diabetes UK.

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  • [Cutting-edge of medicine; clinical epidemiology regarding clinical and pathophysiological features of Japanese patients with type 2 diabetes mellitus]. Reviewed

    Sone H, Akanuma Y, Yamada N

    Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine   102 ( 10 )   2714 - 2722   2013.10

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  • Association Between Remission of Macroalbuminuria and Preservation of Renal Function in Patients With Type 2 Diabetes With Overt Proteinuria Reviewed

    Hiroki Yokoyama, Shin-ichi Araki, Jun Honjo, Shinichiro Okizaki, Daishiro Yamada, Ryushi Shudo, Hitoshi Shimizu, Hirohito Sone, Tatsumi Moriya, Masakazu Haneda

    DIABETES CARE   36 ( 10 )   3227 - 3233   2013.10

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    OBJECTIVEStudies on the rate of remission of macroalbuminuria in patients with type 2 diabetes mellitus (T2DM) and the effects of reduction in albuminuria on renal prognosis in a primary care setting are absolutely lacking.RESEARCH DESIGN AND METHODSA total of 211 T2DM patients with albuminuria 300 mg/g were enrolled in a prospective observational study (mean of 4.5 years). The incidence of patients with remission of macroalbuminuria at every 1-year study time point after starting intensified diabetes treatment and the factors associated with remission were evaluated. The association of reduction in albuminuria with renal events (doubling of serum creatinine and end-stage renal disease) was also investigated.RESULTSDuring the 5-year study period, remission to microalbuminuria occurred in 116 patients and the 5-year cumulative incidence was 58.3%. Notably, most cases (82.8%) obtained remission at the 1-year study time point. The remission rate increased with achieving therapeutic targets for blood pressure and blood glucose. Remission and reduction in albuminuria of 50% were associated with preservation of renal function. In particular, patients who obtained both remission and 50% reduction at the 1-year study time point exhibited a significantly reduced risk for renal events as compared with those with no remission and no reduction (adjusted hazard ratio 0.30 [95% CI 0.12-0.76]).CONCLUSIONSRemission of macroalbuminuria occurs frequently and is associated with the preservation of renal function in T2DM patients. The initial adequate diabetes treatment aimed at reducing albuminuria may lead to improved renal prognosis in the primary care setting.

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  • TFE3 Controls Lipid Metabolism in Adipose Tissue of Male Mice by Suppressing Lipolysis and Thermogenesis Reviewed

    Yuri Fujimoto, Yoshimi Nakagawa, Aoi Satoh, Kanako Okuda, Akiko Shingyouchi, Ayano Naka, Takashi Matsuzaka, Hitoshi Iwasaki, Kazuto Kobayashi, Naoya Yahagi, Masako Shimada, Shigeru Yatoh, Hiroaki Suzuki, Satomi Yogosawa, Tetsuro Izumi, Hirohito Sone, Osamu Urayama, Nobuhiro Yamada, Hitoshi Shimano

    ENDOCRINOLOGY   154 ( 10 )   3577 - 3588   2013.10

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    Transcription factor E3 (TFE3) is a transcription factor that binds to E-box motifs and promotes energy metabolism-related genes. We previously reported that TFE3 directly binds to the insulin receptor substrate-2 promoter in the liver, resulting in increased insulin response. However, the role of TFE3 in other tissues remains unclear. In this study, we generated adipose-specific TFE3 transgenic (aP2-TFE3 Tg) mice. These mice had a higher weight of white adipose tissue (WAT) and brown adipose tissue than wild-type (WT) mice under fasting conditions. Lipase activity in the WAT in these mice was lower than that in the WT mice. Them RNA level of adipose triglyceride lipase (ATGL), the rate-limiting enzyme for adipocyte lipolysis, was significantly decreased in aP2-TFE3 Tg mice. The expression of Foxo1, which directly activates ATG Lexpression, was also suppressed in transgenic mice. Promoter analysis confirmed that TFE3 suppressed promoter activities of the ATGL gene. In contrast, G0S2 and Perilipin1, which attenuate ATGL activity, were higher in transgenic mice than in WT mice. These results indicated that the decrease in lipase activity in adipose tissues was due to a decrease in ATGL expression and suppression of ATGL activity. We also showed that thermogenesis was suppressed in aP2-TFE3 Tg mice. The decrease in lipolysis in WAT of aP2-TFE3 Tg mice inhibited the supply of fatty acids to brown adipose tissue, resulting in the inhibition of the expression of thermogenesis-related genes such as UCP1. Our data provide new evidence that TFE3 regulates lipid metabolism by controlling the gene expression related to lipolysis and thermogenesis in adipose tissue.

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  • Diabetic Retinopathy and Microalbuminuria Can Predict Macroalbuminuria and Renal Function Decline in Japanese Type 2 Diabetic Patients: Japan Diabetes Complications Study Reviewed

    Tatsumi Moriya, Shiro Tanaka, Ryo Kawasaki, Yasuo Ohashi, Yasuo Akanuma, Nobuhiro Yamada, Hirohito Sone, Hidetoshi Yamashita, Shigehiro Katayama

    DIABETES CARE   36 ( 9 )   2803 - 2809   2013.9

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    OBJECTIVE To examine the interactive relationship between diabetic retinopathy (DR) and diabetic nephropathy (DN) in type 2 diabetic patients and to elucidate the role of DR and microalbuminuria on the onset of macroalbuminuria and renal function decline.RESEARCH DESIGN AND METHODS We explored the effects of DR and microalbuminuria on the progression of DN from normoalbuminuria and low microalbuminuria (&lt;150 mg/gCr) to macroalbuminuria or renal function decline in the Japan Diabetes Complications Study (JDCS), which is a nationwide randomized controlled study of type 2 diabetic patients focusing on lifestyle modification. Patients were divided into four groups according to presence or absence of DR and MA: normoalbuminuria without DR [NA(DR-)] (n = 773), normoalbuminuria with DR [NA(DR+)] (n = 279), microalbuminuria without DR [MA(DR-)] (n = 277), and microalbuminuria with DR [MA(DR+)] (n = 146). Basal urinary albumin-to-creatinine ratio and DR status were determined at baseline and followed for a median of 8.0 years.RESULTS Annual incidence rates of macroalbuminuria were 1.6/1,000 person-years (9 incidences), 3.9/1,000 person-years (8 incidences), 18.4/1,000 person-years (34 incidences), and 22.1/1,000 person-years (22 incidences) in the four groups, respectively. Multivariate-adjusted hazard ratios of the progression to macroalbuminuria were 2.48 (95% CI 0.94-6.50; P = 0.07), 10.40 (4.91-22.03; P &lt; 0.01), and 11.55 (5.24-25.45; P &lt; 0.01) in NA(DR+), MA(DR-), and MA(DR+), respectively, in comparison with NA(DR-). Decline in estimated glomerular filtration rate (GFR) per year was two to three times faster in MA(DR+) (-1.92 mL/min/1.73 m(2)/year) than in the other groups.CONCLUSIONS In normo- and low microalbuminuric Japanese type 2 diabetic patients, presence of microalbuminuria at baseline was associated with higher risk of macroalbuminuria in 8 years. Patients with microalbuminuria and DR showed the fastest GFR decline. Albuminuria and DR should be considered as risk factors of renal prognosis in type 2 diabetic patients. An open sharing of information will benefit both ophthalmologists and diabetologists.

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  • Direct effect of dasatinib on proliferation and cytotoxicity of natural killer cells in in vitro study Reviewed

    Takayoshi Uchiyama, Naoya Sato, Miwako Narita, Akie Yamahira, Minami Iwabuchi, Tatsuo Furukawa, Hirohito Sone, Masuhiro Takahashi

    HEMATOLOGICAL ONCOLOGY   31 ( 3 )   156 - 163   2013.9

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    Lymphocytosis predominantly due to natural killer (NK) cells has been reported in nearly a half of chronic myelogenous leukemia (CML) patients who were being treated with dasatinib. Besides, dasatinib-treated patients with lymphocytosis have a better prognosis than patients without lymphocytosis. In order to elucidate the effects of dasatinib on the proliferation of lymphocyte subset, dasatinib was added to the culture of peripheral blood mononuclear cells with IL-2 (lymphokine-activated killer culture) or a low dose of IL-2 with zoledronate ( T-cell culture). In both culture conditions, NK cells were increased in both percentage and absolute number in the culture with dasatinib compared with control culture without dasatinib. The increase of NK cells was dose dependent of dasatinib in the range of 2-25nM. NK cell cytotoxicity of cultured cells with dasatinib was demonstrated to be superior to control cells without dasatinib in cytotoxicity assay using EGFP-transfected K562 cells as target cells. The present study suggested that lymphocytosis in dasatinib-treated CML patients is at least partly associated with a direct effect of dasatinib to stimulate the proliferation of NK cells. Favourable prognosis in patients with dasatinib-induced lymphocytosis might be associated with the effects of dasatinib to potentiate NK cytotoxicity in vivo. Copyright (c) 2012 John Wiley & Sons, Ltd.

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  • Body Weight Change and Type 2 Diabetes Reviewed

    Satoru Kodama, Chika Horikawa, Sakiko Yoshizawa, Kazuya Fujihara, Yoko Yachi, Shiro Tanaka, Akiko Suzuki, Osamu Hanyu, Hiroaki Yagyu, Hirohito Sone

    EPIDEMIOLOGY   24 ( 5 )   778 - 779   2013.9

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  • Molecular understanding of curcumin in diabetic nephropathy Reviewed

    Vivian Soetikno, Kenji Suzuki, Punniyakoti T. Veeraveedu, Somasundaram Arumugam, Arun P. Lakshmanan, Hirohito Sone, Kenichi Watanabe

    Drug Discovery Today   18 ( 15-16 )   756 - 763   2013.8

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    Diabetic nephropathy is characterized by a plethora of signaling abnormalities. Recent trials have suggested that intensive glucose-lowering treatment leads to hypoglycemic events, which can be dangerous. Curcumin is the active ingredient of turmeric, which has been widely used in many countries for centuries to treat numerous diseases. The preventive and therapeutic properties of curcumin are associated with its antioxidant and anti-inflammatory properties. Here, we highlight the renoprotective role of curcumin in diabetes mellitus (DM) with an emphasis on the molecular basis of this effect. We also briefly discuss the numerous approaches that have been undertaken to improve the pharmacokinetics of curcumin. © 2013 Elsevier Ltd. All rights reserved.

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  • Genetic Variants of the Fatty Acid Desaturase Gene Cluster Are Associated with Plasma LDL Cholesterol Levels in Japanese Males Reviewed

    Yasuko Sone, Toshimi Kido, Tomomi Ainuki, Mariko Sonoda, Ikuyo Ichi, Satoru Kodama, Hirohito Sone, Kazuo Kondo, Yutaka Morita, Shigenobu Egawa, Kazuo Kawahara, Yuzuru Otsuka, Yoko Fujiwara

    JOURNAL OF NUTRITIONAL SCIENCE AND VITAMINOLOGY   59 ( 4 )   325 - 335   2013.8

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    Fatty acid (FA) compositions in tissues are related to metabolic disorders, and consequently the appropriate management of underlying FA compositions in tissues is considered to be important. However, the relationship among the serum lipid profiles, the FA composition of the red blood cell (RBC) membranes and genetic variations in the fatty acid desaturase (FADS) genes in Japanese men is unclear. In this study, the subjects recruited were 137 Japanese men, 40 to 60 y old, who had a regular health checkup. Their serum lipid profile and the relative FA composition of the RBC membranes were measured. They were genotyped for the single nucleotide polymorphisms (SNPs) rs174553, rs174546, rs99780 and rs174583 in FADS gene. Multiple regression analysis was conducted to detect the relationship among hyperlipidemia, the FA composition of the RBC and the FADS genotypes. As a result, the homozygous genotype for the minor alleles in rs174553, rs174546, rs99780 were found to be associated with lower low-density lipoprotein cholesterol (LDL-C) levels and a lower LDL-C/total-cholesterol ratio. The homozygous genotype for the minor alleles reduced the risk of high LDL-C level (R-2=0.50, beta=-0.20, p=0.009), whereas, the arachidonic acid (AA) levels in the carriers of the homozygous genotype for the minor alleles tended to be lower compared with the carriers of the major alleles. However, no significant differences were observed in any FA level among the three genotypes for four SNPs. These results indicate that the appropriate management of serum LDL-C levels depending on genetic predisposition in FADS genotypes should be encouraged.

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  • Importance of high-density lipoprotein cholesterol control during pravastatin treatment in hypercholesterolemic Japanese with type 2 diabetes mellitus: A post hoc analysis of MEGA study Reviewed

    Rimei Nishimura, Hirohito Sone, Tomoko Nakagami, Naoko Tajima

    DIABETES RESEARCH AND CLINICAL PRACTICE   100 ( 2 )   E31 - E33   2013.5

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    To investigate the role of HDL-C in cardiovascular risk reduction, we evaluated using data from a diabetic population in a large clinical trial with pravastatin. A significant risk reduction in CVD was found only in diabetic patients who had both a reduction in LDL-C and an increase in HDL-C. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

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  • Leisure-time physical activity is a significant predictor of stroke and total mortality in Japanese patients with type 2 diabetes: Analysis from the Japan Diabetes Complications Study (JDCS) Reviewed

    H. Sone, S. Tanaka, S. Tanaka, S. Suzuki, H. Seino, O. Hanyu, A. Sato, T. Toyonaga, K. Okita, S. Ishibashi, S. Kodama, Y. Akanuma, N. Yamada

    Diabetologia   56 ( 5 )   1021 - 1030   2013.5

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    Aims/hypothesis: Our aim was to clarify the association between leisure-time physical activity (LTPA) and cardiovascular events and total mortality in a nationwide cohort of Japanese diabetic patients. Methods: Eligible patients (1,702) with type 2 diabetes (mean age, 58.5 years
    47% women) from 59 institutes were followed for a median of 8.05 years. A comprehensive lifestyle survey including LTPA and occupation was performed using standardised questionnaires. Outcome was occurrence of coronary heart disease (CHD), stroke and total mortality. The adjusted HR and 95% CI were calculated by Cox regression analysis. Results: A significant reduction in HR in patients in the top (≥15.4 metabolic equivalents [MET] h/week) vs the bottom tertile (≤3.7 MET h/week) of LTPA, adjusted by age, sex and diabetes duration, was observed in stroke (HR 0.55, 95% CI 0.32, 0.94) and total mortality (HR 0.49, 95% CI 0.26, 0.91) but not in CHD (HR 0.77, 95% CI 0.48, 1.25). The HR for stroke became borderline significant or nonsignificant after adjustment for lifestyle or clinical variables including diet or serum lipids. The significantly reduced total mortality by LTPA was independent of these variables and seemed not to be, at least mainly, attributed to reduced cardiovascular disease. Conclusions/interpretation: In Japanese persons with type 2 diabetes, LTPA of 15.4 MET h/week or more was associated with a significantly lower risk of stroke partly through ameliorating combinations of cardiovascular risk factors. It was also associated with significantly reduced total mortality but independently of cardiovascular risk factors or events. These findings, implying differences from Western diabetic populations, should be considered in the clinical management of East Asians with diabetes. © 2013 Springer-Verlag Berlin Heidelberg.

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  • Predicting Macro- and Microvascular Complications in Type 2 Diabetes Reviewed

    Shiro Tanaka, Sachiko Tanaka, Satoshi Iimuro, Hidetoshi Yamashita, Shigehiro Katayama, Yasuo Akanuma, Nobuhiro Yamada, Atsushi Araki, Hideki Ito, Hirohito Sone, Yasuo Ohashi

    DIABETES CARE   36 ( 5 )   1193 - 1199   2013.5

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    OBJECTIVE-To develop and validate a risk engine that calculates the risks of macro- and microvascular complications in type 2 diabetes.
    RESEARCH DESIGN AND METHODS-We analyzed pooled data from two clinical trials on 1,748 Japanese type 2 diabetic patients without diabetes complications other than mild diabetic retinopathy with a median follow-up of 7.2 years. End points were coronary heart disease (CHD), stroke, noncardiovascular mortality, overt nephropathy defined by persistent proteinuria, and progression of retinopathy. We fit a multistate Cox regression model to derive an algorithm for prediction. The predictive accuracy of the calculated 5-year risks was cross-validated.
    RESULTS-Sex, age, HbA(1c), years after diagnosis, BMI, systolic blood pressure, non-HDL cholesterol, albumin-to-creatinine ratio, atrial fibrillation, current smoker, and leisure-time physical activity were risk factors for macro- and microvascular complications and were incorporated into the risk engine. The observed-to-predicted (O/P) ratios for each event were between 0.93 and 1.08, and Hosmer-Lemeshow tests showed no significant deviations between observed and predicted events. In contrast, the UK Prospective Diabetes Study (UKPDS) risk engine overestimated CHD risk (O/P ratios: 0.30 for CHD and 0.72 for stroke). C statistics in our Japanese patients were high for CHD, noncardiovascular mortality, and overt nephropathy (0.725, 0.696, and 0.767) but moderate for stroke and progression of retinopathy (0.636 and 0.614). By combining macro- and microvascular risks, the classification of low- and high-risk patients was improved by a net reclassification improvement of 5.7% (P = 0.02).
    CONCLUSIONS-The risk engine accurately predicts macro- and microvascular complications and would provide helpful information in risk classification and health economic simulations.

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  • Two authors reply Reviewed

    Satoru Kodama, Hirohito Sone

    American Journal of Epidemiology   177 ( 8 )   863   2013.4

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  • [Effect of smoking on diabetes mellitus and dyslipidemia (effect of smoking on glucose and lipid metabolism)]. Reviewed

    Saito K, Sone H

    Nihon rinsho. Japanese journal of clinical medicine   71 ( 3 )   443 - 448   2013.3

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  • Comparison of Education-Only versus Group-Based Intervention in Promoting Weight Loss: A Randomised Controlled Trial (vol 4, pg 222, 2011)

    Nakata, Yoshio, Okada, Masafumi, Hashimoto, Koichi, Harada, Yoshinori, Sone, Hirohito, Tanaka, Kiyoji

    OBESITY FACTS   6 ( 1 )   89 - 90   2013.3

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  • Development of a Screening Score for Undiagnosed Diabetes and Its Application in Estimating Absolute Risk of Future Type 2 Diabetes in Japan: Toranomon Hospital Health Management Center Study 10 (TOPICS 10) Reviewed

    Yoriko Heianza, Yasuji Arase, Kazumi Saito, Shiun Dong Hsieh, Hiroshi Tsuji, Satoru Kodama, Shiro Tanaka, Yasuo Ohashi, Hitoshi Shimano, Nobuhiro Yamada, Shigeko Hara, Hirohito Sone

    JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM   98 ( 3 )   1051 - 1060   2013.3

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    Objective: The objective of the study was to develop a screening score for undiagnosed diabetes by eliciting information on noninvasive clinical markers and to assess its effectiveness for identifying the presence of diabetes and predicting future diabetes.
    Design, Setting, and Participants: A screening score was cross-sectionally developed for 33 335 Japanese individuals aged 18-88 years without known diabetes who underwent a health examination. We validated its utility and compared it with existing screening tools in an independent population (n = 7477). After initial assessment of the instrument, 7332 nondiabetic individuals were followed up for a mean 4.0 years.
    Results: Prevalence of undiagnosed diabetes (fasting plasma glucose &gt;= 7.0 mmol/L or glycated hemoglobin &gt;= 6.5%) was 2.9% (n = 965). Diabetes score included age, sex, family history of diabetes, current smoking habit, body mass index, and hypertension with an area under the receiver-operating characteristics curve of 0.771. Screening with 8 or more points yielded a sensitivity of 72.7% and a specificity of 68.1%. In the validation cohort, the area under the receiver-operating characteristics curve was 0.806. The developed score with 8 or more points had better positive predictive value (9.6%) and positive likelihood ratio (2.52) compared with existing tools (positive predictive value, from 6.9% to 9.4%; positive likelihood ratio, from 1.77 to 2.46) in which each tool's highest combination of sensitivity and specificity was observed. The 4-year cumulative risk of developing diabetes gradually escalated in association with higher screening scores at the initial examination.
    Conclusions: Our algorism could serve as a self-assessment tool for undiagnosed diabetic patients needing timely medical care and as a prognostic tool for individuals without present diabetes who must be closely followed up to prevent future diabetes. (J Clin Endocrinol Metab 98: 1051-1060, 2013)

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  • Fruit Intake and Incident Diabetic Retinopathy with Type 2 Diabetes Reviewed

    Shiro Tanaka, Yukio Yoshimura, Ryo Kawasaki, Chiemi Kamada, Sachiko Tanaka, Chika Horikawa, Yasuo Ohashi, Atsushi Araki, Hideki Ito, Yasuo Akanuma, Nobuhiro Yamada, Hidetoshi Yamashita, Hirohito Sone

    EPIDEMIOLOGY   24 ( 2 )   204 - 211   2013.3

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    Background: Antioxidants and dietary fiber are postulated to have preventive effects on diabetic retinopathy, but evidence is lacking. We investigated this association in a cohort with type 2 diabetes 40-70 years of age with hemoglobin (Hb)A(1C) 6.5%, originally part of the Japan Diabetes Complications Study.
    Methods: After excluding people who did not respond to a dietary survey and patients with diabetic retinopathy or a major ocular disease at baseline, we analyzed 978 patients. Baseline dietary intake was assessed by a food frequency questionnaire based on food groups and 24-hour dietary records. Primary outcome was incident diabetic retinopathy determined using international severity scales.
    Results: Mean fruit intake in quartiles ranged from 23 to 253 g/day, with increasing trends across quartiles of fruit intake for vitamin C, vitamin E, carotene, retinol equivalent, dietary fiber, potassium, and sodium. Mean energy intake ranged from 1644 to 1863 kcal/day, and fat intake was approximately 25%. HbA(1C), body mass index, triglycerides, and systolic blood pressure were well controlled. During the 8-year follow-up, the numbers of incident cases of diabetic retinopathy from the first through the fourth quartiles of fruit intake were 83, 74, 69, and 59. Multivariate-adjusted hazard ratios for the second, third, and fourth quartiles of fruit intake compared with the first quartile were 0.66 (95% confidence interval = 0.46-0.92), 0.59 (0.41-0.85), and 0.48 (0.32-0.71) (test for trend, P &lt; 0.01). There was no substantial effect modification by age, sex, HbA(1C), diabetes duration, overweight, smoking, and hypertension. Risk for diabetic retinopathy declined with increased intake of fruits and vegetables, vitamin C, and carotene.
    Conclusion: Increased fruit intake in ranges commonly consumed was associated with reduced incident diabetic retinopathy among patients adhering to a low-fat energy-restricted diet. (Epidemiology 2013;24: 204-211)

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  • Role of alcohol drinking pattern in type 2 diabetes in Japanese men: the Toranomon Hospital Health Management Center Study 11 (TOPICS 11) Reviewed

    Yoriko Heianza, Yasuji Arase, Kazumi Saito, Hiroshi Tsuji, Kazuya Fujihara, Shiun Dong Hsieh, Satoru Kodama, Hitoshi Shimano, Nobuhiro Yamada, Shigeko Hara, Hirohito Sone

    AMERICAN JOURNAL OF CLINICAL NUTRITION   97 ( 3 )   561 - 568   2013.3

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    Background: Findings of past studies on the effect of drinking patterns on diabetes risk have been inconsistent.
    Objective: We aimed to investigate the role of drinking frequency and usual quantity consumed in the development of type 2 diabetes.
    Design: Enrolled were 1650 Japanese men without diabetes (diabetes: fasting plasma glucose &gt;= 7.0 mmol/L, glycated hemoglobin &gt;= 6.5%, or self-reported clinician-diagnosed diabetes). Average alcohol consumption and 12 combinations of frequency and usual quantity per drinking occasion were assessed at the baseline examination. The absolute risk and HR for the development of diabetes were calculated.
    Results: During a mean follow-up period of 10.2 y, 216 individuals developed diabetes. Lifetime abstainers (n = 153) had a relatively low incidence of diabetes (9.1/1000 person-years), similar to moderate consumers (99-160 g ethanol/wk; 9.0/1000 person-years). Increasingly higher quantities of alcohol usually consumed per occasion increased the risk of diabetes regardless of drinking frequency. The lowest incidence rate of diabetes (8.5/1000 person-years) was associated with the consumption of &lt;1 drink (&lt;23 g ethanol) per occasion over &gt;= 6 times/wk. Binge drinking (&gt;= 3 drinks per occasion) significantly increased the risk of future diabetes regardless of frequency (HR: 1.79; 95% CI: 1.17, 2.74) compared with &lt;1 drink per occasion.
    Conclusions: Among current drinkers, a drinking pattern of &lt;1 drink per occasion regularly over 6 times within a week was associated with the lowest risk of developing diabetes. Usual quantity per drinking occasion was a more important determinant than was weekly drinking frequency in the association between alcohol consumption and risk of diabetes in Japanese men. Am J Clin Nutr 2013;97:561-8.

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  • Risk of Cardiovascular Diseases Is Increased Even with Mild Diabetic Retinopathy The Japan Diabetes Complications Study Reviewed

    Ryo Kawasaki, Shiro Tanaka, Sachiko Tanaka, Sachi Abe, Hirohito Sone, Koutaro Yokote, Shun Ishibashi, Shigehiro Katayama, Yasuo Ohashi, Yasuo Akanuma, Nobuhiro Yamada, Hidetoshi Yamashita

    OPHTHALMOLOGY   120 ( 3 )   574 - 582   2013.3

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    Objective: Diabetic retinopathy (DR) is linked to cardiovascular risk in diabetic patients. This study examined whether mild-stage DR is associated with risk of coronary heart disease (CHD) and stroke in type 2 diabetic patients of the Japan Diabetes Complications Study (JDCS).
    Design: Prospective cohort study.
    Participants: In the JDCS, there were 2033 Japanese persons with type 2 diabetes free of cardiovascular diseases at baseline.
    Methods: Diabetic retinopathy was ascertained from clinical and photographic grading (70%) following the international clinical diabetic retinopathy and diabetic macular edema disease severity scales. Incident CHD and stroke were followed up prospectively annually up to 8 years.
    Main Outcome Measures: Eight-year incidence of CHD and stroke compared between persons with or without DR.
    Results: After adjusting for traditional cardiovascular risk factors, persons with mild to moderate nonproliferative DR had a higher risk of CHD (hazard ratio [HR], 1.69; 95% confidence interval [CI], 1.17-2.97) and stroke (HR, 2.69; 95% CI, 1.03-4.86). Presence of retinal hemorrhages or microaneurysms was associated with risk of CHD (HR, 1.63; 95% CI, 1.04-2.56) but was not associated with stroke (P = 0.06). Presence of cotton-wool spots was associated with risk of incident stroke (HR, 2.39; 95% CI, 1.35-4.24) but was not associated with CHD (P = 0.66). When information about DR was added in the prediction models for CHD and stroke based on traditional cardiovascular risk factors, the area under the receiver operating curve improved from 0.682 to 0.692 and 0.640 to 0.677, and 9% and 13% of persons were reclassified correctly for CHD and stroke, respectively.
    Conclusions: Type 2 diabetic patients with even a mild stage of DR, such as dot hemorrhages, are already at higher risk of CHD and stroke independent of traditional risk factors.
    Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2013;120:574-582 (C) 2013 by the American Academy of Ophthalmology.

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  • The hyperglycemia stimulated myocardial endoplasmic reticulum (ER) stress contributes to diabetic cardiomyopathy in the transgenic-non-obese type 2 diabetic rats: A differential role of unfolded protein response (UPR) signaling proteins Reviewed

    Arun Prasath Lakshmanan, Meilei Harima, Kenji Suzuki, Vivian Soetikno, Masaki Nagata, Takashi Nakamura, Toshihiro Takahashi, Hirohito Sone, Hiroshi Kawachi, Kenichi Watanabe

    INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY   45 ( 2 )   438 - 447   2013.2

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    It has been well demonstrated that excessive blood glucose level could be detrimental to the myocardial function through the variety of mechanisms, of which endoplasmic reticulum stress (ERS) could play an unprecedented role through the activation of unfolded protein response (UPR). Recently, reports are coming out with the evidences that UPR signaling proteins are regulated differentially depend on the experimental conditions and cell types. In addition, ERS has been proposed to be closely associated with the regulation of lipogenesis. Therefore, in this study we tried to find out the expressions of myocardial UPR signaling proteins as well as proteins involved in lipid and glucose metabolism in non-obese type 2 diabetic mellitus (DM) condition using Spontaneous Diabetic Toni (SDT) rat. We have found the significant up-regulation of oxidative, nitrosative and ERS marker proteins in the myocardium of the SDT rats, in comparison to its normal (Sprague-Dawley - SD) rats. In addition, the sub-arm-of UPR signaling proteins, such as p-PERK, p-eIF2 alpha, ATF6, CHOP/GADD153, TRAF2, apoptotic signaling proteins, such as BAD, cytochrome C, cleaved caspase-7 and -12, were significantly up-regulated in the SDT rats, in comparison to the SD rats. Interestingly, there were no significant changes in the phosphorylation of IRE-1 alpha, and XBP-1 protein expression. In addition, the proteins involved in lipid and glucose metabolisms, such as PPAR alpha, PPAR gamma, CPT1, PGC-1 alpha except GLUT4, and the proteins involved in insulin signaling, such as p-Akt and p-PI3K were shown significant attenuation in its expressions in the SDT rats, when compared with the SD rats. Taken together, it is suggested that the activation of PERK and ATF6 pathway are the major determinant rather than the IRE-1 alpha-XBP1 pathway for the ERS-mediated metabolic dysfunction, which might eventually leads to diabetic cardiomyopathy in non-obese type 2 DM. (c) 2012 Elsevier Ltd. All rights reserved.

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  • Association Between Physical Activity and Risk of All-Cause Mortality and Cardiovascular Disease in Patients With Diabetes A meta-analysis Reviewed

    Satoru Kodama, Shiro Tanaka, Yoriko Heianza, Kazuya Fujihara, Chika Horikawa, Hitoshi Shimano, Kazumi Saito, Nobuhiro Yamada, Yasuo Ohashi, Hirohito Sone

    DIABETES CARE   36 ( 2 )   471 - 479   2013.2

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    OBJECTIVE-The association between habitual physical activity (PA) and lowered risk of all-cause mortality (ACM) and cardiovascular disease (CVD) has been suggested in patients with diabetes. This meta-analysis summarizes the risk reduction in relation to PA, focusing on clarifying dose-response associations.
    RESEARCH DESIGN AND METHODS-Electronic literature searches were conducted for cohort studies that examined relative risk (RR) of ACM or CVD in relation to PA in patients with diabetes. For the qualitative assessment, RR for the highest versus the lowest PA category in each study was pooled with a random-effects model. We added linear and spline regression analyses to assess the quantitative relationship between increases in PA and ACM and CVD risk.
    RESULTS-There were 17 eligible studies. Qualitatively, the highest PA category had a lower RR [95% CI] for ACM (0.61 [0.52-0.70]) and CVD (0.71 [0.60-0.84]) than the lowest PA category. The linear regression model indicated a high goodness of fit for the risk of ACM (adjusted R-2 = 0.44, P = 0.001) and CVD (adjusted R-2 = 0.51, P = 0.001), with the result that a 1 MET-h/day incrementally higher PA was associated with 9.5% (5.0-13.8%) and 7.9% (4.3-11.4%) reductions in ACM and CVD risk, respectively. The spline regression model was not significantly different from the linear model in goodness of fit (P = 0.14 for ACM risk; P = 0.60 for CVD risk).
    CONCLUSIONS-More PA was associated with a larger reduction in future ACM and CVD risk in patients with diabetes. Nevertheless, any amount of habitual PA was better than inactivity. Diabetes Care 36:471-479, 2013

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  • Metabolic predictors of ischemic heart disease and cerebrovascular attack in elderly diabetic individuals: Difference in risk by age Reviewed

    Toshio Hayashi, Atsushi Araki, Seinosuke Kawashima, Hirohito Sone, Hiroshi Watanabe, Takashi Ohrui, Koutaro Yokote, Minoru Takemoto, Kiyoshi Kubota, Mitsuhiko Noda, Hiroshi Noto, Koichiro Ina, Hideki Nomura

    Cardiovascular Diabetology   12 ( 1 )   10   2013.1

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    Background: High LDL-cholesterol (LDL-C) and glucose levels are risk factors for ischemic heart disease (IHD) in middle-aged diabetic individuals
    however, the risk among the elderly, especially the very elderly, is not well known. The aim of this study was to identify factors that predict IHD and cerebrovascular attack (CVA) in the elderly and to investigate their differences by age.Methods: We performed a prospective cohort study (Japan Cholesterol and Diabetes Mellitus Study) with 5.5 years of follow-up. A total of 4,014 patients with type 2 diabetes and without previous IHD or CVA (1,936 women
    age 67.4 ± 9.5 years, median 70 years
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    65 years old, n = 1,261
    65 to 74 years old, n = 1,731
    and ≥ 75 years old, n = 1,016) were recruited on a consecutive outpatient basis from 40 hospitals throughout Japan. Lipids, glucose, and other factors related to IHD or CVA risk, such as blood pressure (BP), were investigated using the multivariate Cox hazard model.Results: One hundred fifty-three cases of IHD and 104 CVAs (7.8 and 5.7/1,000 people per year, respectively) occurred over 5.5 years. Lower HDL-cholesterol (HDL-C) and female gender were correlated with IHD in patients ≥75 years old (hazard ratio (HR):0.629, P &lt
    0.01 and 1.132, P &lt
    0.05, respectively). In contrast, systolic BP (SBP), HbA1C, LDL-C and non-HDL-C were correlated with IHD in subjects &lt
    65 years old (P &lt
    0.05), and the LDL-C/HDL-C ratio was correlated with IHD in all subjects. HDL-C was correlated with CVA in patients ≥75 years old (HR: 0.536, P &lt
    0.01). Kaplan-Meier estimator curves showed that IHD occurred more frequently in patients &lt
    65 years old in the highest quartile of the LDL-C/HDL-C ratio. In patients ≥75 years old, IHD and CVA were both the most frequent among those with the lowest HDL-C levels.Conclusions: IHD and CVA in late elderly diabetic patients were predicted by HDL-C. LDL-C, HbA1C, SBP and non-HDL-C are risk factors for IHD in the non-elderly. The LDL-C/HDL-C ratio may represent the effects of both LDL-C and HDL-C. These age-dependent differences in risk are important for developing individualized strategies to prevent atherosclerotic disease.Trial registration: UMIN-CTR, UMIN00000516. © 2013 Hayashi et al
    licensee BioMed Central Ltd.

    DOI: 10.1186/1475-2840-12-10

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  • Diabetes and Risk of Hearing Impairment in Adults: A Meta-Analysis Reviewed

    Chika Horikawa, Satoru Kodama, Shiro Tanaka, Kazuya Fujihara, Reiko Hirasawa, Yoko Yachi, Hitoshi Shimano, Nobuhiro Yamada, Kazumi Saito, Hirohito Sone

    JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM   98 ( 1 )   51 - 58   2013.1

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    Context: Recently, several studies have investigated the relationship between diabetes and hearing impairment, but results were inconsistent.
    Objective: Our objective was to compare the prevalence of hearing impairment between diabetic and nondiabetic adults. Data Sources : We performed a systematic literature search using MEDLINE (1950 to May 30, 2011) and EMBASE (1974 to May 30, 2011).
    Study Selection: Cross-sectional studies were included if data on numbers of hearing-impaired and non-hearing-impaired cases with diabetes were presented. Hearing impairment was limited to that assessed by pure-tone audiometry that included at least 2 kHz of frequency range and was defined as progressive, chronic, sensorineural, or without specified cause.
    Data Extraction: Two authors independently extracted relevant data. Odd ratios (ORs) of hearing impairment related to diabetes calculated in each study were pooled with the random-effects model.
    Data Synthesis: Data were obtained from 13 eligible studies (20,194 participants and 7,377 cases). Overall pooled OR (95% confidence interval) of hearing impairment for diabetic participants compared with nondiabetic participants was 2.15 (1.72-2.68). OR was higher in younger participants (mean age, &lt;= 60 yr) than in those over 60 yr among which the OR remained significant (2.61 and 1.58, P = 0.008). The strength of the association between diabetes and prevalence of hearing impairment was not significantly influenced by whether participants were matched for age and gender (P = 0.68) or whether participants chronically exposed to noisy environments were excluded (P = 0.19).
    Conclusions: Current meta-analysis suggests that the higher prevalence of hearing impairment in diabetic patients compared with nondiabetic patients was consistent regardless of age. (J Clin Endocrinol Metab 98: 51-58, 2013)

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  • Nutrition education in Japanese medical schools: A follow-up survey Reviewed

    Hideo Orimo, Takahiro Ueno, Hiroshi Yoshida, Hirohito Sone, Akira Tanaka, Hiroshige Itakura

    Asia Pacific Journal of Clinical Nutrition   22 ( 1 )   144 - 149   2013.1

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    A questionnaire survey was used to determine the status of nutrition education in Japanese medical schools in 2009. A similar survey was conducted in 2004, at which time nutritional education was determined to be inadequate in Japanese medical schools. The current questionnaire was sent to the directors of Centers for Medical Education of 80 medical schools, who represented all medical schools in Japan. Sixty-seven medical schools (83.8%) responded, of which 25 schools (37.3%) offered dedicated nutrition courses and 36 schools (53.7%) did not offer dedicated nutrition courses but offered something related to nutrition in other courses
    six schools (9.0%) did not offer any nutrition education. Overall, 61 schools (91.0%) offered at least some nutritional topics in their undergraduate education. Nevertheless, only 11 schools (16.4%) seem to dedicate more than 5 hours to substantial nutrition education as judged by their syllabi. Although the mean length of the course was 11 hours, substantial nutrition education accounted for only 4.2 hours. Of the 25 medical schools that offered dedicated nutrition courses, seven schools offered the nutrition course as a stand-alone course and 18 schools offered it as an integrated course. In conclusion, the status of nutrition education in Japan has improved slightly but is still inadequate.

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  • TFE3 inhibits myoblast differentiation in C2C12 cells via down-regulating gene expression of myogenin Reviewed

    Ayano Naka, Kaoruko Tada Iida, Yoshimi Nakagawa, Hitoshi Iwasaki, Yoshinori Takeuchi, Aoi Satoh, Takashi Matsuzaka, Kiyo-aki Ishii, Kazuto Kobayashi, Shigeru Yatoh, Masako Shimada, Naoya Yahagi, Hiroaki Suzuki, Hirohito Sone, Nobuhiro Yamada, Hitoshi Shimano

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   430 ( 2 )   664 - 669   2013.1

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    Transcription factor E3 (TFE3) belongs to a basic-helix-loop-helix family, and is involved in the biology of osteoclasts, melanocytes and their malignancies. We previously reported the metabolic effects of TFE3 on insulin in the liver and skeletal muscles in animal models. In the present study, we explored a novel role for TFE3 in a skeletal muscle cell line. When TFE3 was overexpressed in C2C12 myoblasts by adenovirus before induction of differentiation, myogenic differentiation of C2C12 cells was significantly inhibited. Adenovirus-mediated TFE3 overexpression also suppressed the gene expression of muscle regulatory factors (MRFs), such as MyoD and myogenin, during C2C12 differentiation. In contrast, knockdown of TFE3 using adenovirus encoding short-hairpin RNAi specific for TFE3 dramatically promoted myoblast differentiation associated with significantly increased expression of MRFs. Consistent with these findings, promoter analyses via luciferase reporter assay and electrophoretic mobility shift assay suggestid that TFE3 negatively regulated myogenin promoter activity by direct binding to an E-box, E2, in the myogenin promoter. These findings indicated that TFE3 has a regulatory role in myoblast differentiation, and that transcriptional suppression of myogenin expression may be part of the mechanism of action. (C) 2012 Elsevier Inc. All rights reserved.

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  • Low BMI at age 20years predicts gestational diabetes independent of BMI in early pregnancy in Japan: Tanaka Women's Clinic Study Reviewed

    Y. Yachi, Y. Tanaka, I. Nishibata, A. Sugawara, S. Kodama, K. Saito, H. Sone

    Diabetic Medicine   30 ( 1 )   70 - 73   2013.1

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    Aims Maternal obesity and weight gain since early adulthood are known predictors of gestational diabetes in Western countries. However, their impact has not been evaluated well in Asia, where mean BMI levels are generally lower than in Western countries. We therefore examined the associations of BMI at age 20years and BMI change since age 20years with the risk of gestational diabetes in Japanese pregnant women. Methods Six hundred and twenty-four consecutive pregnant women without recognized diabetes before pregnancy, whose initial obstetric clinic visit was before 13weeks' gestation, were prospectively observed. Weight at age 20years was self-reported. Baseline height and weight measurements were obtained at the initial obstetric visit. Multivariate logistic regression analysis estimated the risk of incident gestational diabetes for BMI change since 20years and BMI at age 20years. Results Twenty-eight women developed incident gestational diabetes. By multivariate logistic regression analysis that adjusted for maternal age, parity and baseline BMI, we observed a statistically significant inverse association between BMI at age 20years and incidence of gestational diabetes (odds ratio 0.68, 95% CI 0.51-0.92). Similarly, when we assessed the association of BMI change since age 20years, adjusted for maternal age and parity, BMI change was associated with an increased risk of gestational diabetes (odds ratio 1.26, 95%CI 1.03-1.53). When we focused on the threshold of risk of gestational diabetes, women with BMI at 20years of less than 18kg/m2 had a 6.30-fold (2.26-17.59) greater risk than women with both BMI at age 20years of 18kg/m2 or more and BMI change since age 20years of less than 1.85. Conclusions Both low BMI at age 20years and BMI change since age 20years were significantly associated with increased risk of incident gestational diabetes. © 2012 Diabetes UK.

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  • The Relationship between Diabetic Neuropathy and Sleep Apnea Syndrome: A Meta-Analysis. Reviewed International journal

    Kazuya Fujihara, Satoru Kodama, Chika Horikawa, Sakiko Yoshizawa, Ayumi Sugawara, Reiko Hirasawa, Hitoshi Shimano, Yoko Yachi, Akiko Suzuki, Osamu Hanyu, Hirohito Sone

    Sleep disorders   2013   150371 - 150371   2013

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    Aims. High prevalence of sleep apnea syndrome (SAS) has been reported in patients with diabetes. However, whether diabetic neuropathy (DN) contributes to this high prevalence is controversial. Our aim of this study is to compare the prevalence of SAS between patients with and without DN. Methods. Systematic literature searches were conducted for cross-sectional studies that reported the number of patients with DN and SAS using MEDLINE (from 1966 to Nov 5, 2012) and EMBASE (from 1974 to Nov 5, 2012). Odds ratios (ORs) of SAS related to DN were pooled with the Mantel-Haenszel method. Results. Data were obtained from 5 eligible studies (including 6 data sets, 880 participants, and 429 cases). Overall, the pooled OR of SAS in patients with DN compared with that in non-DN patients was significant (OR (95% CI), -1.95 (1.03-3.70)). The pooled OR of SAS was 1.90 (0.97-3.71) in patients with type 2 diabetes. Excluding data on patients with type 1 diabetes, a higher OR was observed in younger patients (mean age <60 years) than in those ≥60 years among whom the OR remained significant (3.82; 95% CI, 2.24-6.51 and 1.17; 95% CI, 0.81-1.68). Conclusions. Current meta-analysis suggested the association of some elements of neuropathy with SAS in type 2 diabetes. Further investigations are needed to clarify whether the association is also true for patients with type 1 diabetes.

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  • Carotid artery plaque and LDL-to-HDL cholesterol ratio predict atherosclerotic status in coronary arteries in asymptomatic patients with type 2 diabetes mellitus Reviewed

    Kazuya Fujihara, Hiroaki Suzuki, Akira Sato, Satoru Kodama, Yoriko Heianza, Kazumi Saito, Hitoshi Iwasaki, Kazuto Kobayashi, Shigeru Yatoh, Akimitsu Takahashi, Nobuhiro Yamada, Hirohito Sone, Hitoshi Shimano

    Journal of Atherosclerosis and Thrombosis   20 ( 5 )   452 - 464   2013

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    Aims: To investigate the clinical predictors of coronary atherosclerosis and to assess the utility of maximum-IMT for predicting coronary atherosclerosis in asymptomatic type 2 diabetic patients. Methods: One hundred one Japanese patients with type 2 diabetes underwent computed tomography coronary angiography. Definitions of coronary artery stenosis and vulnerable coronary plaque were luminal narrowing of ≥50% and any coronary plaque with positive vessel remodeling and low attenuation, respectively. Carotid intima-media thickness (IMT) was assessed using B-mode ultrasound. Results: Of the 101 patients, 40 had coronary artery stenosis without vulnerable coronary plaque, 7 had vulnerable coronary plaque without coronary artery stenosis, and 23 had coronary artery stenosis with vulnerable coronary plaque. Male sex (p= 0.031), duration of diabetes (p= 0.024), systolic blood pressure (SBP) (p=0.039), and the LDL/HDL ratio (LDL/HDL) (p=0.013) were independent predictors of coronary artery stenosis and the LDL/HDL (p=0.042) independently predicted vulnerable coronary plaque by logistic regression analyses. Areas under the curves in receiver operating characteristic curve analysis of the maximum-IMT, LDL/HDL, and these two parameters combined were 0.711 (95% CI 0.601-0.820), 0.618 (0.508-0.728), and 0.732 (0.632-0.831), respectively, for predicting coronary artery stenosis and 0.655 (0.537-0.773), 0.629 (0.504-0.754), and 0.710 (0.601- 0.818), respectively, for predicting vulnerable coronary plaque. Conclusions: Male sex, duration of diabetes, elevated SBP, and LDL/HDL were independent predictors of coronary artery stenosis. LDL/HDL was an independent predictor of vulnerable coronary plaque. Maximum-IMT predicted both coronary stenosis and vulnerable coronary plaque. Adding LDL/HDL improved the prediction of coronary artery stenosis and vulnerable coronary plaque.

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  • Elovl6 Promotes Nonalcoholic Steatohepatitis Reviewed

    Takashi Matsuzaka, Ayaka Atsumi, Rie Matsumori, Tang Nie, Haruna Shinozaki, Noriko Suzuki-Kemuriyama, Motoko Kuba, Yoshimi Nakagawa, Kiyoaki Ishii, Masako Shimada, Kazuto Kobayashi, Shigeru Yatoh, Akimitsu Takahashi, Kazuhiro Takekoshi, Hirohito Sone, Naoya Yahagi, Hiroaki Suzuki, Soichiro Murata, Makoto Nakamuta, Nobuhiro Yamada, Hitoshi Shimano

    HEPATOLOGY   56 ( 6 )   2199 - 2208   2012.12

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    Nonalcoholic steatohepatitis (NASH) is associated with obesity and type 2 diabetes, and an increased risk for liver cirrhosis and cancer. ELOVL family member 6, elongation of very long chain fatty acids (Elovl6), is a microsomal enzyme that regulates the elongation of C12-16 saturated and monounsaturated fatty acids (FAs). We have shown previously that Elovl6 is a major target for sterol regulatory element binding proteins in the liver and that it plays a critical role in the development of obesity-induced insulin resistance by modifying FA composition. To further investigate the role of Elovl6 in the development of NASH and its underlying mechanism, we used three independent mouse models with loss or gain of function of Elovl6, and human liver samples isolated from patients with NASH. Our results demonstrate that (1) Elovl6 is a critical modulator for atherogenic high-fat diet-induced inflammation, oxidative stress, and fibrosis in the liver; (2) Elovl6 expression is positively correlated with severity of hepatosteatosis and liver injury in NASH patients; and (3) deletion of Elovl6 reduces palmitate-induced activation of the NLR family pyrin domain-containing 3 inflammasome; this could be at least one of the underlying mechanisms by which Elovl6 modulates the progress of NASH. Conclusion: Hepatic long-chain fatty acid composition is a novel determinant in NASH development, and Elovl6 could be a potential therapeutic target for the prevention and treatment of NASH. (HEPATOLOGY 2012;56:2199-2208)

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