Papers - SONE, Hirohito

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: The challenge ahead

William H. Goodson, Leroy Lowe, David O. Carpenter, Michael Gilbertson, Abdul Manaf Ali, Adela Lopez de Cerain Salsamendi, Ahmed Lasfar, Amancio Carnero, Amaya Azqueta, Amedeo Amedei, Amelia K. Charles, Andrew R. Collins, Andrew Ward, Anna C. Salzberg, Annamaria Colacci, Ann-Karin Olsen, Arthur Berg, Barry J. Barclay, Binhua P. Zhou, Carmen Blanco-Aparicio, Carolyn J. Baglole, Chenfang Dong, Chiara Mondello, Chia-Wen Hsu, Christian C. Naus, Clement Yedjou, Colleen S. Curran, Dale W. Laird, Daniel C. Koch, Danielle J. Carlin, Dean W. Felsher, Debasish Roy, Dustin G. Brown, Edward Ratovitski, Elizabeth P. Ryan, Emanuela Corsini, Emilio Rojas, Eun-Yi Moon, Ezio Laconi, Fabio Marongiu, Fahd Al-Mulla, Ferdinando Chiaradonna, Firouz Darroudi, Francis L. Martin, Frederik J. Van Schooten, Gary S. Goldberg, Gerard Wagemaker, Gladys Nangami, Gloria M. Calaf, Graeme Williams, Gregory T. Wolf, Gudrun Koppen, Gunnar Brunborg, H. Kim Lyerly, Harini Krishnan, Hasiah Ab Hamid, Hemad Yasaei, Hideko Sone, Hiroshi Kondoh, Hosni K. Salem, Hsue-Yin Hsu, Hyun Ho Park, Igor Koturbash, Isabelle R. Miousse, A. Ivana Scovassi, James E. Klaunig, Jan Vondráček, Jayadev Raju, Jesse Roman, John Pierce Wise, Jonathan R. Whitfield, Jordan Woodrick, Joseph A. Christopher, Josiah Ochieng, Juan Fernando Martinez-Leal, Judith Weisz, Julia Kravchenko, Jun Sun, Kalan R. Prudhomme, Kannan Badri Narayanan, Karine A. Cohen-Solal, Kim Moorwood, Laetitia Gonzalez, Laura Soucek, Le Jian, Leandro S. D'Abronzo, Liang-Tzung Lin, Lin Li, Linda Gulliver, Lisa J. McCawley, Lorenzo Memeo, Louis Vermeulen, Luc Leyns, Luoping Zhang, Mahara Valverde, Mahin Khatami, Maria Fiammetta Romano, Marion Chapellier, Marc A. Williams, Mark Wade, Masoud H. Manjili, Matilde Lleonart, Menghang Xia, Michael J. Gonzalez, Michalis V. Karamouzis, Micheline Kirsch-Volders, Monica Vaccari, Nancy B. Kuemmerle, Neetu Singh, Nichola Cruickshanks, Nicole Kleinstreuer, Nik Van Larebeke, Nuzhat Ahmed, Olugbemiga Ogunkua, P. K. Krishnakumar, Pankaj Vadgama, Paola A. Marignani, Paramita M. Ghosh, Patricia Ostrosky-Wegman, Patricia Thompson, Paul Dent, Petr Heneberg, Philippa Darbre, Po Sing Leung, Pratima Nangia-Makker, Qiang Shawn Cheng, R. Brooks Robey, Rabeah Al-Temaimi, Rabindra Roy, Rafaela Andrade-Vieira, Ranjeet K. Sinha, Rekha Mehta, Renza Vento, Riccardo Di Fiore, Richard Ponce-Cusi, Rita Dornetshuber-Fleiss, Rita Nahta, Robert C. Castellino, Roberta Palorini, Roslida Abd Hamid, Sabine A.S. Langie, Sakina Eltom, Samira A. Brooks, Sandra Ryeom, Sandra S. Wise, Sarah N. Bay, Shelley A. Harris, Silvana Papagerakis, Simona Romano, Sofia Pavanello, Staffan Eriksson, Stefano Forte, Stephanie C. Casey, Sudjit Luanpitpong, Tae-Jin Lee, Takemi Otsuki, Tao Chen, Thierry Massfelder, Thomas Sanderson, Tiziana Guarnieri, Tove Hultman, Valérian Dormoy, Valerie Odero-Marah, Venkata Sabbisetti, Veronique Maguer-Satta, W. Kimryn Rathmell, Wilhelm Engström, William K. Decker, William H. Bisson, Yon Rojanasakul, Yunus Luqmani, Zhenbang Chen, Zhiwei Hu

Carcinogenesis   36   S254 - S296   2015.6

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

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/ mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.

DOI： 10.1093/carcin/bgv039

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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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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

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.

DOI： 10.1016/j.leukres.2015.03.021

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

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.

DOI： 10.1111/dme.12646

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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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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

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 > G) homozygous risk genotype (TT genotype) was observed in the participants. The frequency of TGF-beta 1 SNP (29C > 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 > T) may be used as one of the risk indicators for severe periodontitis in Japanese diabetic patients.

DOI： 10.1007/s10266-014-0171-4

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

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.

DOI： 10.1111/jdi.12308

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

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.

DOI： 10.1038/jhh.2014.77

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

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.

DOI： 10.1111/jdi.12274

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

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.

DOI： 10.1111/hepr.12343

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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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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SAGE PUBLICATIONS INC  

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 < .01, respectively) and AFG plus high TGs (HR, 2.87 and 3.87; P < .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.

DOI： 10.1177/1074248414537706

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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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Language：English   Publisher：Elsevier  

DOI： 10.1016/j.jns.2014.11.029

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Cardioprotective Food Function as Underpinning Strategy for Disease Prevention <i>Dietary Antioxidants in Diabetic Cardiac Complications</i>

Hirohito Sone

Clinical Aspects of Functional Foods and Nutraceuticals   2015

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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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Language：English   Publishing type：Research paper (scientific journal)   Publisher：HINDAWI PUBLISHING CORPORATION  

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.

DOI： 10.1155/2015/507245

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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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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

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.

DOI： 10.2169/internalmedicine.54.5022

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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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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

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.

DOI： 10.2169/internalmedicine.54.2332

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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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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer-Verlag Tokyo  

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.

DOI： 10.1007/s13340-014-0166-y

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Current situation of exercise therapy in patients with diabetes mellitus in Japan (report no. 2): A nationwide survey to patients using the questionnaires

Yuzo Sato, Hirohito Sone, Masashi Kobayashi, Ryuzo Kawamori, Yoshihito Atsumi, Yoshiharu Oshida, Shiro Tanaka, Susumu Suzuki, Shigeru Makita, Isao Ohsawa, Yoshifumi Tamura, Tomoyuki Watanabe

Journal of the Japan Diabetes Society   58 ( 11 )   850 - 859   2015

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japan Diabetes Society  

To investigate the actual situation and problems of exercise therapy for patients with diabetes mellitus in Japan, we conducted nationwide surveys for diabetic patients. The subjects were 5,100 patients with diabetes mellitus. Data from 4,176 patients (81.9 %) who responded to the questionnaire were analyzed. The HbA1c level of the exercise therapy group was significantly lower than that in the non-exercise therapy group. Approximately 30 % of diabetic patients did not receive exercise guidance, while 10 % of the patients did not receive dietary guidance
52 % of the diabetic patients received exercise guidance by physicians, while 64 % of the patients received dietary guidance by registered dieticians. Only half of the diabetic patients performed regular physical exercise. The results of the current surveys showed that there were significant differences between exercise guidance and dietary guidance, such as the frequency and education systems. To solve the lack of exercise guidebook for physicians, the members of this committee published "A Teaching Manual for Therapeutic Exercise in Diabetes Mellitus" (Nankodo). We recommend the establishment of an exercise therapy guideline for patients with diabetes mellitus conducted by the Japan Diabetes Society in the near future.

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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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Language：English   Publisher：AMER SOC HEMATOLOGY  

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

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.

DOI： 10.1016/j.ijcard.2014.10.093

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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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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：BMJ PUBLISHING GROUP  

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.

DOI： 10.1136/jech-2014-204054

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

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.

DOI： 10.1210/jc.2014-1855

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