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Iwata, Yasunori ; Wada, Takashi ; Yokoyama, Hitoshi ; Toyama, Tadashi ; Kitajima, Shinji ; Okumura, Toshiya ; Hara, Akinori ; Yamahana, Junya ; Nakaya, Izaya ; Kobayashi, Motoo ; Kitagawa, Kiyoki ; Kokubo, Satoshi ; Yoshimoto, Keiichi ; Shimizu, Kazuaki ; Sakai, Norihiko ; Furuichi, Kengo ; Koshino, Yoshitaka ; Takaeda, Chikako ; Takeda, Shinichi ; Takasawa, Kazuya ; Ohta, Satoshi ; Takaeda, Masayoshi ; Kaneko, Shuichi
出版情報: Internal Medicine.  46  pp.447-452,  2007-04-08.  日本内科学会
URL: http://hdl.handle.net/2297/6249
概要: 金沢大学保健管理センター<br />金沢大学大学院医学系研究科<br />金沢大学附属病院<br />Background: In hemodialysis patients, adynamic bone disease has been reported to be closely associated with low levels of parathyroid hormone (PTH) due to exposure to high levels of serum calcium following the administration of calcium carbonate (CaCO3) or vitamin D agents. This study was conducted to clarify the therapeutic effect of a non-calcemic phosphate binder, sevelamer hydrochloride (sevelamer), for hypoparathyroidism in hemodialysis patients with or without diabetes mellitus. Methods: Based on entry criteria, 40 Japanese chronic hemodialysis patients (22 males and 18 females with a mean age of 60.6, 14 diabetic patients and 26 non-diabetic patients) were switched from CaCO3 to sevelamer for 48 weeks. Serum calcium, phosphate, intact (i) PTH and PTH-(1-84) were analyzed. Bone remodeling activity was evaluated by determining intact osteocalcine (iOC), bone-specific alkaline phosphatase (BAP). Results: The switch from CaCO3 to sevelamer significantly decreased the serum levels of calcium, resulting in the elevation of iPTH levels from 31±18 pg/mL to 95±96 pg/mL by 48 weeks. In contrast, serum phosphate levels remained similar to those in patients with CaCO3 treatment. Concomitantly, the levels of BAP and iOC were elevated. Further, these beneficial effects on bone turnover were observed in both diabetic and non-diabetic patients. Conclusion: Sevelamer reduced the calcium concentration and thereby increased PTH levels, resulting in the improvement of markers of bone turnover. The administration of sevelamer is of therapeutic benefit for the improvement of bone remodeling activity even in hemodialysis patients with diabetes. © 2007 The Japanese Society of Internal Medicine. 続きを見る
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Takamura, Toshinari ; Shimizu, Akiko ; Komura, Takuya ; Ando, Hitoshi ; Zen, Yoh ; Minato, Hiroshi ; Matsushita, Eiki ; Kaneko, Shuichi
出版情報: Internal Medicine.  46  pp.579-581,  2007-05-01.  日本内科学会
URL: http://hdl.handle.net/2297/6609
概要: 金沢大学大学院医学系研究科環境社会医学<br />A 53-year-old postmenopausal woman, who had a family history of cryptogenic liver cirrhosis, wa s diagnosed with osteoporosis, and started on the selective estrogen receptor modulator (SERM) raloxifene 60 mg/day orally. She developed marked liver dysfunction. Her body mass index (BNU) was 26.5. Her blood chemistry indicated AST 342 IU/L, ALT 356 IU/L, and hyaluronic acid 255 ng/mL. An oral glucose tolerance test showed impaired glucose tolerance with marked insulin resistance. Histologically, we diagnosed this case as having pre-cirrhotic nonalcoholic steatohepatitis (NASH). This is the first histologically confirmed case of NASH that was aggravated by raloxifene. © 2007 The Japanese Society of Internal Medicine. 続きを見る
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Koike, Nobuhiko ; Takamura, Toshinari ; Kaneko, Shuichi
出版情報: Life Sciences.  80  pp.1721-1728,  2007-04-01.  Elsevier
URL: http://hdl.handle.net/2297/3863
概要: 大学院医学系研究科環境社会医学<br />Diabetic nephropathy is a major complication of diabetes leading to end-stage renal disease, which requires hemodialysis. Although the mechanism by which it progresses is largely unknown, the role of hyperglycemia-derived oxidative stress has recently been the focus of attention as the cause of diabetic complications. Constituent cells of the renal glomeruli have the capacity to release reactive oxygen species (ROS) upon stimulation of NADPH oxidase activated by protein kinase C (PKC). Hyperglycemia and insulin resistance in the diabetic state are often associated with activation of PKC and tumor necrosis factor (TNF)-α, respectively. The aim of this study is to clarify the signaling pathway leading to ROS production by PKC and TNF-α in rat glomeruli. Isolated rat glomeruli were stimulated with phorbol 12-myristate 13-acetate (PMA) and TNF-α, and the amount of ROS was measured using a chemiluminescence method. Stimulation with PMA (10 ng/ml) generated ROS with a peak value of 136 ± 1.2 cpm/mg protein (mean ± SEM). The PKC inhibitor H-7, the NADPH oxidase inhibitor diphenylene iodonium and the phosphatidylinositol-3 (PI-3) kinase inhibitor wortmannin inhibited PMA-induced ROS production by 100%, 100% and 80%, respectively. In addition, TNF-α stimulated ROS production (283 ± 5.8/mg protein/20 min). The phosphodiesterase inhibitor cilostazol activates protein kinase A and is reported to improve albuminuria in diabetic rats. Cilostazol (100 μg/ml) inhibited PMA, and TNF-α-induced ROS production by 78 ± 1.8, and 19 ± 2.7%, respectively. The effects of cilostazol were not additive with wortmannin. Cilostazol arrests oxidative stress induced by PKC activation by inhibiting the PI-3 kinase-dependent pathway, and may thus prevent the development of diabetic nephropathy. © 2007 Elsevier Inc. All rights reserved. 続きを見る
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Ota, Tsuguhito ; Takamura, Toshinari ; Kaneko, Shuichi
出版情報: New England Journal of Medicine.  356  pp.1067-1069,  2007-03-08.  Massachusetts Medical Society
URL: http://hdl.handle.net/2297/9927
概要: 金沢大学医薬保健研究域医学系
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Takamura, Toshinari ; Shimizu, Akiko ; Ando, Hitoshi ; Kaneko, Shuichi
出版情報: Journal Diabetologia.  50  pp.229-230,  2007-01-01.  Springer
URL: http://hdl.handle.net/2297/3792
概要: 金沢大学大学院医学系研究科環境社会医学
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Sakurai, Masaru ; Takamura, Toshinari ; Ota, Tsuguhito ; Ando, Hitoshi ; Akahori, Hiroshi ; Kaji, Kyosuke ; Sasaki, Motoko ; Nakanuma, Yasuni ; Miura, Katsuyuki ; Kaneko, Shuichi
出版情報: Journal of Gastroenterology.  42  pp.312-317,  2007-04-01.  Springer Verlag
URL: http://hdl.handle.net/2297/5487
概要: 金子, 周一<br />金沢大学大学院医学系研究科環境社会医学<br />Background: To address the hypothesis that liver steatosis causes systemic insulin resistance, we sought to determine the liver histological feature that most strongly contributes to insulin resistance in patients with nonalcoholic fatty liver disease (NAFLD). Methods: Liver biopsy specimens were obtained from 131 patients with clinically suspected NAFLD. The stage, grade of nonalcoholic steatohepatitis (NASH), and level of steatosis were scored and analyzed in relation to the homeostasis model assessment of insulin resistance (HOMA-IR) and the metabolic clearance rate (MCR), measured using the glucose clamp method. Results: In the univariate analysis, the degree of hepatic steatosis (r = 0.458, P < 0.001), stage (r = 0.360, P < 0.001), and grade (r = 0.349, P < 0.01) of NASH were significantly correlated with the HOMA-IR. Multiple regression analysis adjusting for age, sex, body mass index, and each histological score showed that steatosis was significantly and independently associated with HOMA-IR (coefficient = 1.42, P < 0.001), but not with the stage (coefficient = 0.33, P = 0.307) or grade (coefficient = 0.67, P = 0.134) of NASH. Similar independent relationships were observed between steatosis and MCR, but the relationship was weaker (coefficient = -0.98, P = 0.076). Conclusions: Steatosis of the liver, but not the stage or the grade of NASH, is associated with insulin resistance in patients with NAFLD. © Springer-Verlag Tokyo 2007. 続きを見る
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Hayakawa, Tetsuo ; Takamura, Toshinari ; Abe, Toshio ; Kaneko, Shuichi
出版情報: Metabolism: Clinical and Experimental.  56  pp.44-48,  2007-01-01.  Elsevier BV
URL: http://hdl.handle.net/2297/3469
概要: 金沢大学大学院医学系研究科環境社会医学<br />A C825T polymorphism of the gene encoding the G-protein β3 subunit (GNB3) is associated with in creased intracellular signal transduction. We know that this C825T polymorphism may influence hypertension and obesity. In whites, the C825T polymorphism has been reported to induce hypertension, obesity, and diabetic nephropathy. Thus, we investigated how genetic variation in the GNB3 gene is associated with hypertension, obesity, insulin resistance, diabetes, diabetic complications, and diabetic therapies in 427 Japanese subjects with type 2 diabetes mellitus and in 368 Japanese subjects who underwent general health examinations. The frequency of the GNB3 gene polymorphism was 0.48 and 0.47 in subjects with diabetes and in those who had general health examinations, respectively. The amount of hyperlipidemia of the CT allele was significantly lower than the amount in the CC allele in the Japanese subjects with diabetes. Our results suggest that the C825T polymorphism influences lipid metabolism and is not associated with hypertension, obesity, insulin resistance, diabetes, diabetic complications, or diabetic therapies. © 2007. 続きを見る
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Oishi, Naoki ; Shilagardi, Khurts ; Nakamoto, Yasunari ; Honda, Masao ; Kaneko, Shuichi ; Murakami, Seishi
出版情報: Cancer Science.  98  pp.1540-1548,  2007-01-01.  Japanese Cancer Association / Blackwell Publishing Ltd
URL: http://hdl.handle.net/2297/45958
概要: 医薬保健研究域医学系<br />Chronic infection with hepatitis B virus (HBV) is a major risk factor for hepatocellular carcinoma. The HBV X protein (HBx) is thought to have oncogenic potential, although the molecular mechanism remains obscure. Pathological roles of HBx in the carcinogenic process have been examined using rodent systems and no report is available on the oncogenic roles of HBx in human cells in vitro. We therefore examined the effect of HBx on immortalization and transformation in human primary cells. We found that HBx could overcome active RAS-induced senescence in human immortalized cells and that these cells could form colonies in soft agar and tumors in nude mice. HBx alone, however, could contribute to neither immortalization nor transformation of these cells. In a population doubling analysis, an N-terminal truncated mutant of HBx, HBx-D1 (amino acids 51-154), which harbors the coactivation domain, could overcome active RAS-induced cellular senescence, but these cells failed to exhibit colonigenic and tumorigenic abilities, probably due to the low expression level of the protein. By scanning a HBx expression library of the clustered-alanine substitution mutants, the N-terminal domain was found to be critical for overcoming active RAS-induced senescence by stabilizing full-length HBx. These results strongly suggest that HBx can contribute to carcinogenesis by overcoming active oncogene-induced senescence. © 2007 Japanese Cancer Association. 続きを見る
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Wada, Takashi ; Sakai, Norihiko ; Matsushima, Kouji ; Kaneko, Shuichi
出版情報: Kidney International.  72  pp.269-273,  2007-08-01.  Nature Publishing Group
URL: http://hdl.handle.net/2297/6933
概要: 金沢大学医学部附属病院血液浄化療法部<br />Fibrocytes are supposed to be a circulating connective tissue cell progenitor, which consists of a novel population of peripheral blood cells. This distinct population of blood-borne cells shares markers of leukocytes as well as mesenchymal cells. Accumulating evidence indicates that fibrosis is characteristic of progressive chronic kidney diseases of any etiologies, resulting in kidney failure. We have uncovered that CCR7-positive fibrocytes migrate into the kidney in response to secondary lymphoid tissue chemokine (SLC/CCL21) and contribute to kidney fibrosis induced by unilateral ureteral obstruction in mice. In addition, the blockade of CCL21/CCR7 signaling by anti-CCL21 antibodies reduced kidney fibrosis, which was confirmed by a decrease in fibrosis in CCR7-null mice with concomitant reduction in macrophage recruitment along with reduced renal transcripts of monocyte chemoattractant protein-1 (MCP-1/CCL2). These findings suggest that fibrocytes dependent on CCL21/CCR7 signaling pathways contribute to the pathogenesis of kidney fibrosis, thereby providing that regulating fibrocytes may provide a novel therapeutic benefit for kidney fibrosis. © 2007 International Society of Nephrology. 続きを見る
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Wada, Taizo ; Maeba, Hideaki ; Ikawa, Yasuhiro ; Hashida, Yoko ; Okumura, Akiko ; Shibata, Fumie ; Tone, Yumi ; Inoue, Masayuki ; Koizumi, Shoichi ; Takatori, Hajime ; Sakai, Yoshio ; Kaneko, Shuichi ; Yachie, Akihiro
出版情報: International Journal of Hematology.  85  pp.191-194,  2007-04-01.  日本血液学会 = Japanese Society of Hematology
URL: http://hdl.handle.net/2297/16857
概要: 金沢大学附属病院小児科<br />Reactive plasmacytosis is a transient expansion of plasma cell progenitors and precursors. This rare co ndition has been reported to occur mainly in infections and tumors. We describe a case of acute hepatitis A presenting with marked peripheral blood plasmacytosis. Plasma cells made up 27.5% of the mononuclear cells and had the immunophenotype CD10-CD19 +CD20-CD21-CD23-CD34 -CD38++HLA-DR+. Although the level of interleukin 6 was not increased, the presence of activated T-cells with an inverted CD4/CD8 ratio and high levels of soluble interleukin 2 receptor and neopterin indicated a marked immune response to acute hepatitis A. The patient's plasma cells had almost disappeared from the blood by hospital day 16. This report may represent the first described case of reactive peripheral blood plasmacytosis in acute hepatitis A. © 2007 The Japanese Society of Hematology. 続きを見る