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| 1.
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Sakamoto, Aiji ; Sugamoto, Yuka ; Tokunaga, Y. ; Yoshimuta, Tsuyoshi ; Hayashi, Kenshi ; Konno, Tetsuo ; Kawashiri, Masa-aki ; Takeda, Yoshiyu ; Yamagishi, Masakazu ; 林, 研至 ; 今野, 哲雄 ; 川尻, 剛照 ; 武田, 仁勇 ; 山岸, 正和
概要:
金沢大学医薬保健研究域医学系<br />Ephrin B1 and its cognate receptor, Eph receptor B2, key regulators of embryogenesis, are expressed
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in human atherosclerotic plaque and inhibit adult human monocyte chemotaxis. Few data exist, however, regarding the gene expression profiles of the ephrin (EFN) and Eph receptor (EPH) family of genes in atherosclerosis-related human cells. Gene expression profiles were determined of all 21 members of this gene family in atherosclerosis-related cells by reverse transcription-polymerase chain reaction analysis. The following 17 members were detected in adult human peripheral blood monocytes: EFNA1 and EFNA3 - EFNA5 (coding for ephrins A1 and A3 - A5); EPHA1, EPHA2, EPHA4 - EPHA6 and EPHA8 (coding for Eph receptors A1, A2, A4 - A6 and A8); EFNB1 and EFNB2 (coding for ephrins B1 and B2); and EPHB1 - EPHB4 and EPHB6 (coding for Eph receptors B1 - B4 and B6). THP-1 monocytic cells, Jurkat T cells and adult arterial endothelial cells also expressed multiple EFN and EPH genes. These results indicate that a wide variety of ephrins and Eph receptors might affect monocyte chemotaxis, contributing to the development of atherosclerosis. Their pathological significance requires further study. © 2011 Field House Publishing LLP.
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| 2.
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Funada, Akira ; Konno, Tetsuo ; Fujino, Noboru ; Muramoto, Akihiko ; Hayashi, Kenshi ; Tsubokawa, Toshinari ; Sakata, Kenji ; Kawashiri, Masa-aki ; Takeda, Yoshiyu ; Ino, Hidekazu ; Yamagishi, Masakazu ; 舟田, 晃 ; 今野, 哲雄 ; 藤野, 陽 ; 林, 研至 ; 坂田, 憲治 ; 川尻, 剛照 ; 武田, 仁勇 ; 井野, 秀一 ; 山岸, 正和
概要:
金沢大学医薬保健研究域医学系<br />Background: Although the renin - angiotensin system (RAS) can affect the development of left ventric
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ular (LV) hypertrophy, few data exist regarding the relationships between RAS polymorphisms and alteration of LV function. The effect of RAS polymorphisms on LV function in genotyped hypertrophic cardiomyopathy (HCM) was examined in the present study. Methods and Results: The study group comprised 126 carriers with sarcomere gene mutations from 49 HCM families (64 males, mean age 51±21 years). LV morphology and function were evaluated by echocardiography. In angiotensin-converting enzyme (ACE) insertion/deletion (I/D), the D allele (n=81) exhibited significantly larger LV end-systolic dimension (LVDs) (32±11 mm) and lower ejection fraction (56±15%) than those with the II genotype (28±7 mm and 62±12%, respectively, P<0.05; n=45). Although angiotensin II type 1 receptor (AT1-R) A/C1166 polymorphism did not affect echocardiographic parameters, the presence of the ACE D allele with the AT1-R C1166 allele (n=9) was associated with larger LVDs (37±17 mm) and lower ejection fraction (48±20%) compared with other genotypes (30±9 mm and 58±14%, respectively, P<0.05; n=117). Under these conditions, severe LV hypertrophy was frequently associated with LV wall thinning. Conclusions: The presence of both the ACE D and AT1-R C1166 allele is associated with LV dilation with systolic dysfunction in genotyped HCM. In addition to the severity of LV hypertrophy, screening for these RAS polymorphisms could contribute to further risk stratification of patients with HCM, although other genetic polymorphisms should be further examined.<br />出版者照会後に全文公開
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| 3.
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Kometani, Mitsuhiro ; Yoneda, Takashi ; Demura, Masashi ; Koide, Hiroshi ; Nishimoto, Koshiro ; Mukai, Kuniaki ; Gomez-Sanchez, Celso E. ; Akagi, Tadayuki ; Yokota, Takashi ; Horike, Shin-ichi ; Karashima, Shigehiro ; Miyamori, Isamu ; Yamagishi, Masakazu ; Takeda, Yoshiyu ; 米田, 隆 ; 赤木, 紀之 ; 横田, 崇 ; 堀家, 慎一 ; 唐島, 成宙 ; 宮森, 勇 ; 山岸, 正和 ; 武田, 仁勇
概要:
金沢大学医薬保健研究域医学系<br />Adrenocortical hormone excess, due to primary aldosteronism (PA) or hypercortisolemia, causes hypert
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ension and cardiovascular complications. In PA, hypomethylation of aldosterone synthase (CYP11B2) is associated with aldosterone overproduction. However, in hypercortisolemia, the role of DNA methylation of 11β-hydroxylase (CYP11B1), which catalyzes cortisol biosynthesis and is highly homologous to CYP11B2, is unclear. The aims of our study were to determine whether the CYP11B1 expression was regulated through DNA methylation in hypercortisolemia with cortisol-producing adenoma (CPA), and to investigate a possible relationship between DNA methylation and somatic mutations identified in CPA. Methylation analysis showed that the CYP11B1 promoter was significantly less methylated in CPA than in adjacent unaffected adrenal tissue and white blood cells. Furthermore, in CPA with somatic mutations in either the catalytic subunit of protein kinase A (PRKACA) or the guanine nucleotide-binding protein subunit alpha (GNAS) gene, the CYP11B1 promoter was significantly hypomethylated. In addition, DNA methylation reduced CYP11B1 promoter activity using a reporter assay. Our study results suggest that DNA methylation at the CYP11B1 promoter plays a role in the regulation of CYP11B1 expression and cortisol production in CPA, and that somatic mutations associated with CPA reduce DNA methylation at the CYP11B1 promoter. © 2017 The Author(s).
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4. Insulin Secretion and Risk for Future Diabetes in Subjects with a Nonpositive Insulinogenic Index
Aono, Daisuke ; Oka, Rie ; Kometani, Mitsuhiro ; Takeda, Yoshimichi ; Karashima, Shigehiro ; Yoshimura, Kenichi ; Takeda, Yoshiyu ; Yoneda, Takashi ; 青野, 大輔 ; 大家, 理恵 ; 米谷, 充弘 ; 武田, 仁裕 ; 唐島, 成宙 ; 吉村, 健一 ; 武田, 仁勇 ; 米田, 隆
概要:
金沢大学附属病院代謝内科<br />Aim. To characterize subjects with a nonpositive insulinogenic index and longitudinally observe change
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s in their glucose tolerance. Subjects and Methods. A historical cohort study was conducted using data from the medical checkups of public school workers. Indices of insulin secretion and insulin sensitivity derived from oral glucose tolerance test (OGTT) and the incidences of diabetes and impaired glucose tolerance (IGT) were compared among subgroups of subjects with different insulinogenic index (change in insulin/change in glucose over the first 30 min on the OGTT). Results. Of the 1464 nondiabetic subjects at baseline, 72 (4.9%) subjects had a nonpositive insulinogenic index: 42 of those subjects had a nonpositive glucose response (ΔGlu0–30 ≤ 0) and 30 had a nonpositive insulin response (ΔIns0–30 ≤ 0). Compared with subjects who had normal glucose tolerance (NGT) with insulinogenic index ≥ 0.4, subjects with a nonpositive glucose response had a higher first-phase Stumvoll and lower incidences of diabetes and IGT based on a log-rank test (), whereas subjects with a nonpositive insulin response had lower indices of insulin secretion and a higher incidence of diabetes (). Conclusions. These results demonstrate that in the first 30 min on the OGTT, subjects with a nonpositive insulinogenic index due to a nonpositive glucose response (ΔGlu0–30 ≤ 0) had a lower risk for future diabetes and that subjects with nonpositive insulin response (ΔIns0–30 ≤ 0) had a higher risk for future one.
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| 5.
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蘇馬, 由衣 ; 大家, 理恵 ; 藤井, 寿美枝 ; 伊藤, 直子 ; 米谷, 充弘 ; 唐島, 成宙 ; 武田, 仁勇 ; 米田, 隆 ; 浅野, 昭道 ; Soma, Yui ; Oka, Rie ; Fujii, Sumie ; Ito, Naoko ; Kometani, Mitsuhiro ; Karashima, Shigehiro ; Takeda, Yoshiyu ; Yoneda, Takashi ; Asano, Akimichi
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金沢大学附属病院代謝内科<br />Aim: The Japan Diabetes Society (JDS)/Japan Geriatrics Society (JGS) Joint Committee reported 'Glycemi
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c Targets for Elderly Patients with Diabetes' in 2016. Based on this recommendation, we aimed to clarify 1) the achievement status of glycemic targets in the elderly and 2) the presence of hypoglycemia in real life among elderly individuals with an HbA1c below the lower limit.Subjects and Methods: [Analysis I] In 326 elderly with diabetes ≥65 years of age visiting the outpatient department specializing in diabetes, the proportions of patients with HbA1c values below the lower limit and the use of drugs potentially associated with severe hypoglycemia (e.g. insulin formulations, sulfonylureas, glinides) were investigated. [Analysis II] Of the patients with HbA1c values below the lower limit, seven were tested for hypoglycemia in real life using a continuous glucose monitoring system (CGM).Results: [Analysis I] Among the 326 subjects, 235 (72.1%) were using drugs potentially associated with severe hypoglycemia, and 63 (19.3%) had an HbA1c value below the lower limit. [Analysis II] In the seven patients examined using CGM, hypoglycemia was detected in five, all of whom were unaware.Conclusions: A considerable number of elderly patients were taking drugs associated with hypoglycemic risks and had an HbA1c value below the lower limit, some of whom actually had hypoglycemia as detected by CGM. Using tools such as CGM, preventive measures against hypoglycemia should be taken.<br />目的：「高齢者糖尿病の治療向上のための日本糖尿病学会と日本老年医学会の合同委員会」は2016年5月に「高齢者糖尿病の血糖コントロール目標（HbA1c値）」ガイドラインを発表した．本ガイドラインに基づいて，1）糖尿病専門外来に通院する高齢者におけるHbA1c目標達成状況，2）HbA1c下限値未満の高齢者での実生活での低血糖の有無について明らかにしたいと考えた．対象と方法：【分析I】K病院糖尿病専門外来通院中の65歳以上の高齢糖尿病患者326人を対象として，“重症低血糖が危惧される薬剤（インスリン，SU薬，グリニド薬）”使用中の患者の割合，及びHbA1c下限値未満の割合を調査した．【分析II】分析IのHbA1c下限値未満の患者のうち7名において持続的血糖モニタリング（CGM）で実生活での低血糖がないかを検査した．結果：【分析I】研究対象者326人のうち，“重症低血糖が危惧される薬剤”使用中の割合は235人（72.1％）であり，このうち63人（19.3％）がHbA1c下限値未満であった．【分析II】HbA1c下限値未満であった63人のうち7名にCGMを施行したところ，5例に低血糖が検出され，いずれも自覚症状を欠いていた．結論：K病院糖尿病専門外来通院中の高齢糖尿病患者において，低血糖が危惧される薬剤を使用し，HbA1c下限値未満の患者が相当数見られ，一部はCGMで実際に低血糖が確認された．CGMなどのツールを用いて，実生活での低血糖に対する予防策を講じつつ投薬管理にあたる必要がある．<br />出版者照会後に全文公開
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| 6.
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Demura, Masashi ; Demura, Yoshiki ; Ameshima, Shingo ; Ishizaki, Takeshi ; Sasaki, Masato ; Miyamori, Isamu ; Yamagishi, Masakazu ; Takeda, Yoshiyu ; Bulun, Serdar E.
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金沢大学医薬保健研究域医学系<br />In humans, aromatase (CYP19) gene expression is regulated via alternative promoters. Activation of e
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ach promoter gives rise to a CYP19 mRNA species with a unique 5′-untranslated region. Inhibition of aromatase has been reported to downregulate lung tumor growth. The genetic basis for CYP19 gene expression and aromatase activity in lung cancer remains poorly understood. We analyzed tissues from 15 patients with non-small cell lung cancer (NSCLC) to evaluate CYP19 promoter usage and promoter-specific aromatase mRNA levels in NSCLC tumor tissues and adjacent non-malignant tissues. CYP19 promoter usage was determined by multiplex RT-PCR and aromatase mRNA levels were measured with real-time RT-PCR. In non-malignant tissues, aromatase mRNA was primarily derived from activation of CYP19 promoter I.4. Although promoter I.4 usage was also dominant in tumor tissues, I.4 activation was significantly lower compared with adjacent non-malignant tissues. Activity of promoters I.3, I.1 and I.7 was significantly higher in tumor tissues compared with non-malignant tissues. In 4 of 15 cases of non-small cell lung cancer, switching from CYP19 promoter I.4 to the alternative promoters II, I.1 or I.7 was observed. In 9 cases, there were significantly higher levels of aromatase mRNA in lung tumor tissues compared with adjacent non-malignant tissues. These findings suggest aberrant activation of alternative CYP19 promoters that may lead to upregulation of local aromatase expression in some cases of NSCLC. Further studies are needed to examine the impact of alternative CYP19 promoter usage on local estrogen levels and lung tumor growth. © 2011 Elsevier Ireland Ltd. All rights reserved.
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| 7.
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Demura, Masashi ; Wang, Fen ; Yoneda, Takashi ; Karashima, Shigehiro ; Mori, Shunsuke ; Oe, Masashi ; Kometani, Mitsuhiro ; Sawamura, Toshitaka ; Cheng, Yuan ; Maeda, Yuji ; Namiki, Mikio ; Ino, Hidekazu ; Fujino, Noboru ; Uchiyama, Katsuharu ; Tsubokawa, Toshinari ; Yamagishi, Masakazu ; Nakamura, Yasuhiro ; Ono, Katsuhiko ; Sasano, Hironobu ; Demura, Yoshiki ; Takeda, Yoshiyu
概要:
金沢大学医薬保健研究域医学系<br />Objective: Nuclear receptors are involved in a wide variety of functions, including aldosteronogenes
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is. Nuclear receptor families NR4A [nerve growth factor-induced clone B (NGFIB), Nur-related factor 1 (NURR1) and neuron-derived orphan receptor 1 (NOR1)] and NR2F [chicken ovalbumin upstream promoter-transcription factor 1 (COUP-TFI), COUP-TFII and NR2F6) activate, whereas NR5A1 [steroidogenic factor 1 (SF1)] represses CYP11B2 (aldosterone synthase) gene transcription. The present study was undertaken to elucidate the mechanism of differential regulation of nuclear receptors between cardiovascular and adrenal tissues. Methods: We collected tissues of artery (n = 9), cardiomyopathy muscle (n = 9), heart muscle (noncardiomyopathy) (n = 6), adrenal gland (n = 9) and aldosterone-producing adenoma (APA) (n = 9). 5′-rapid amplification of cDNA ends (RACE) identified transcription start sites. Multiplex reverse-transcription PCR (RT-PCR) determined use of alternative noncoding exons 1 (ANEs). Results: In adrenocortical H295R cells, angiotensin II, KCl or cAMP, all stimulated CYP11B2 transcription and NR4A was upregulated, whereas NR2F and NR5A1 were downregulated. 5′-RACE and RT-PCR revealed four ANEs of NGFIB (NR4A1), three of NURR1 (NR4A2), two of NOR1 (NR4A3) and two of SF1 (NR5A1) in cardiovascular and adrenal tissues. Quantitative multiplex RT-PCR showed NR4A and NR5A1 differentially employed multiple ANEs in a tissue-specific manner. The use of ANEs of NGFIB and NURR1 was significantly different between APA and artery. Changes in use of ANEs of NGFIB and NOR1 were observed between cardiomyopathy and noncardiomyopathy. The NR4A mRNA levels in artery were high compared with cardiac and adrenal tissues, whereas the NR5A1 mRNA level in adrenal tissues was extremely high compared with cardiovascular tissues. Conclusion: NR4A and NR5A1 genes are complex in terms of alternative promoter use. The use of ANEs may be associated with the pathophysiology of the heart and adrenal gland. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.
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| 8.
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Karashima, Shigehiro ; Yoneda, Takashi ; Kometani, Mitsuhiro ; Ohe, Masashi ; Mori, Shunsuke ; Sawamura, Toshitaka ; Furukawa, Kenji ; Seta, Takashi ; Yamagishi, Masakazu ; Takeda, Yoshiyu
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The mineralocorticoid receptor (MR) is expressed in the kidneys and in adipose tissue, and primary aldosteronism (PA) is
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associated with metabolic syndrome. This study assessed the effects of MR blockade by eplerenone (EPL) and spironolactone (SPL) on blood pressure (BP) and metabolic factors in patients with PA. Fifty-four patients with PA were treated with one of two MRAs, EPL (25-100 mg daily, n=27) or SPL (12.5-100 mg daily, n=27) for 12 months. Visceral (VAT) and subcutaneous adipose tissue were quantified using CT and FatScan imaging analysis software. Body mass index, homeostasis model assessment-insulin resistance (HOMA-IR), serum creatinine, potassium and lipids, urinary albumin excretion (UAE) and plasma aldosterone concentration (PAC) and plasma renin activity (PRA) were measured before and after treatment. EPL and SPL decreased BP and increased serum potassium levels to similar degrees. PAC and PRA did not differ between the two groups. Although treatment with the MRAs did not change HOMA-IR or serum lipids, they significantly decreased UAE and VAT (P<0.05). These results suggest that EPL and SPL are effective and safe for the treatment of PA. The long-term metabolic and renal effects of these MRAs should be further investigated. © 2016 The Japanese Society of Hypertension. All rights reserved.<br />Embargo Period 6 months
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| 9.
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Kometani, Mitsuhiro ; Yoneda, Takashi ; Demura, Masashi ; Karashima, Shigehiro ; Mori, Shunsuke ; Oe, Masashi ; Sawamura, Toshitaka ; Okuda, Rika ; Yamagishi, Masakazu ; Takeda, Yoshiyu
概要:
Primary aldosteronism (PA) is a major cause of secondary hypertension, divided into two subtypes: unilateral and bilater
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al. Unilateral PA (u-PA) is surgically-curable. Medical treatment with mineralocorticoid receptors antagonists is recommended as a second-line treatment when the patients are not candidate for surgical treatment. The present case was a 39-year-old woman with u-PA, who had refused surgery, had suffered from adverse effects of medical treatment. She was treated with transcatheter adrenal arterial embolization (TAAE). Her blood pressure had been well controlled without progression of cardiorenovascular damage for 12 years. TAAE can be the third treatment option for u-PA patients. © 2016 The Japanese Society of Internal Medicine.
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10. Difference between Fasting and Nonfasting Triglyceridemia: the Influence of Waist Circumference.
Oka, Rie ; Kobayashi, Junji ; Miura, Katsuyuki ; Nagasawa, Shinya ; Moriuchi, Tadashi ; Hifumi, Senshu ; Miyamoto, Susumu ; Kawashiri, Masa-aki ; Nohara, Atsushi ; Inazu, Akihiro ; Takeda, Yoshiyu ; Mabuchi, Hiroshi ; Yagi, Kunimasa ; Yamagishi, Masakazu ; 小林, 淳二 ; 川尻, 剛照 ; 野原, 淳 ; 稲津, 明広 ; 武田, 仁勇 ; 馬渕, 宏 ; 八木, 邦公 ; 山岸, 正和
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Aim: Postprandial hypertriglyceridemia is recognized as an independent risk factor for cardiovascular disease. The aim o
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f this study was to identify differences between fasting and postprandial TG levels, focusing on the influence of waist circumference. Methods: Subjects included 1,505 men and 798 women aged 3865 years who were not taking medications for diabetes or dyslipidemia. Fasting TG levels were measured after an overnight fast, and postprandial TG levels were measured 2 hours after a standardized rice-based lunch (total 740 kcal, 20 g fat, 30 g protein, and 110 g carbohydrates) in the afternoon on the same day. Results: Fasting and postprandial TG levels were highly correlated in both men (r=0.86, p<0.001) and women (r=0.84, p<0.001). Waist circumference was positively correlated with fasting TG (r=0.38 in men and r=0.36 in women) and postprandial TG (r=0.42 in men and r=0.45 in women), respectively. On multiple regression analyses, the association of waist circumference with postprandial TG was still significant (standardized β=0.10 in men and standardized β=0.15 in women, p<0.001) after the inclusion of HbA1c, age, high-density-lipoprotein (HDL)-cholesterol, alcohol consumption, and fasting TG in the regression model. Conclusion: Postprandial TG has a better relation with waist circumference than fasting TG.<br />出版者照会後に全文公開
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