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| 1.
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Nomura, Akihiro ; Tada, Hayato ; Nohara, Atsushi ; Kawashiri, Masa-aki ; Yamagishi, Masakazu ; 野村, 章洋 ; 多田, 隼人 ; 野原, 淳 ; 川尻, 剛照 ; 山岸, 正和
概要:
金沢大学附属病院先端医療開発センター<br />Aim: Sitosterolemia is an extremely rare, autosomal recessive disease characterized by high plas
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ma cholesterols and plant sterols because of increased absorption of dietary cholesterols and sterols from the intestine, and decreased excretion from biliary tract. Previous study indicated that sitosterolemic patients might be vulnerable to post-prandial hyperlipidemia, including high remnant-like lipoprotein particles (RLP) level. Here we evaluate whether a loading dietary fat increases a post-prandial RLP cholesterol level in sitosterolemic patients compared to heterozygous familial hypercholesterolemic patients (FH).\nMethods: We recruit total of 20 patients: 5 patients with homozygous sitosterolemia, 5 patients with heterozygous sitosterolemia, and 10 patients with heterozygous FH as controls from May 2015 to March 2018 at Kanazawa University Hospital, Japan. All patients receive Oral Fat Tolerance Test (OFTT) cream (50 g/body surface area square meter, orally only once, and the cream includes 34% of fat, 74 mg of cholesterol, and rich in palmitic and oleic acids. The primary endpoint is the change of a RLP cholesterol level after OFTT cream loading between sitosterolemia and FH. We measure them at baseline, and 2, 4, and 6 hours after the oral fat loading.\nResults: This is the first study to evaluate whether sitosterolemia patients have a higher post-prandial RLP cholesterol level compared to heterozygous FH patients.\nConclusion: The result may become an additional evidence to restrict dietary cholesterols for sitosterolemia. This study is registered at University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN ID: UMIN000020330).<br />This article distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License.
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| 2.
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Tada, Hayato ; Kawashiri, Masa-aki ; Nohara, Atsushi ; Inazu, Akihiro ; Kobayashi, Junji ; Yasuda, Kenji ; Mabuchi, Hiroshi ; Yamagishi, Masakazu ; Hayashi, Kenshi ; 多田, 隼人 ; 川尻, 剛照 ; 野原, 淳 ; 稲津, 明広 ; 小林, 淳二 ; 馬淵, 宏 ; 山岸, 正和 ; 林, 研至
概要:
金沢大学附属病院循環器内科<br />Aim: The Japan Atherosclerosis Society (JAS) guidelines for the prevention of atherosclerotic disease
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s 2012 (JAS2012) proposed lipid management targets; however, less data is available regarding the attainment rates of each target in community-based settings. Therefore, we assessed the attainment rates of lipid management targets among subjects who underwent Japanese specific health checkups.\nMethods: A total of 85,716 subjects (male=29,282, 34.2%) aged 40–74 years who underwent specific health checkups from 2012 to 2014 in Kanazawa city, Japan, were included in this study. We evaluated the attainment rates of the lipid management targets according to the JAS2012 guideline and investigated the clinical characteristics of the subjects without achieving the targets.\nResults: The target for LDL cholesterol (LDL-C) was the least attained in all risk categories, 89, 72, 50, and 34% for category I, II, III, and secondary prevention, respectively, in 2014. In addition, these rates inversely correlated with the grade of risk categories (p-value for trends ＜0.001). Attainment rate of the LDL-C target in the suspected chronic kidney disease (CKD) group was significantly lower than in the groups with diabetes, stroke, or absolute risk in category III (49.2, 60.3, 63.5, 54.4%, respectively, p-value ＜0.001 for each). Moreover, the attainment rate of the LDL-C target was significantly lower in subjects that did not receive lipid-lowering therapy than in those who received it in the secondary prevention (27.7 and 40.6%, respectively, p-value ＜0.001).\nConclusions: Lipid management is inadequate in community-based settings, particularly, in subjects with CKD and secondary prevention.<br />This article distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License.
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| 3.
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Imamura, S. ; Kobayashi, Junji ; Sakasegawa, S. ; Nohara, Atsushi ; Nakajima, Kenichi ; Kawashiri, Masa-aki ; Inazu, Akihiro ; Yamagishi, Masakazu ; Koizumi, Junji ; Mabuchi, Hiroshi ; 小林, 淳二 ; 野原, 淳 ; 中嶋, 憲一 ; 川尻, 剛照 ; 稲津, 明広 ; 山岸, 正和 ; 小泉, 順二 ; 馬渕, 宏
概要:
金沢大学医薬保健研究域医学系<br />The objective of this study was to establish a hepatic lipase (HL) assay method that can be applied
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to automatic clinical analyzers. Seventy-four hyperlipidemic subjects (men/women 45/29) were recruited. Lipase activity was assayed measuring the increase in absorbance at 546 nm due to quinonediimine dye production. Reaction mixture R-1 contained 50 mM Tris-HCl (pH 9.5), 0.5 mM glycerol-1,2-dioleate, 0.4% (unless otherwise noted) polyoxyethylenenonylphenylether, 3 mM ATP, 3 mM MgCl2, 1.5 mM CaCl2, monoacylglycerol-specific lipase, glycerol kinase, glycerol-3-phosphate oxidase, 0.075% N,N-bis-(4-sulfobutyl)-3-methylaniline-2 Na, peroxidase, ascorbic acid oxidase. Reaction mixture R-2 contained 50 mM Tris-HCl (pH9.5), 0.15% 4-aminoantypirine. Automated assay for activity was performed with a Model 7080 Hitachi analyzer. In the lipase assay, 160 μl of R-1 was incubated at 37°C with 3 μl of samples for 5 min, and 80 μl of R-2 was added. Within-run coefficient of variations was 0.9-1.0%. Calibration curve of lipase activity was linear (r = 0.999) between 0 and 320 U/l. Analytical recoveries of purified HL added to plasma were 96.6-99.8%. HL activity in postheparin plasma measured in this method had a closer correlation with HL mass by a sandwich ELISA (r = 0.888, P , 0.0001) than those in the conventional method using [ 14C-]triolein (r = 0.730, P < 0.0001). This assay method for HL activity can be applied to an automatic clinical analyzer. Copyright © 2007 by the American Society for Biochemistry and Molecular Biology, Inc.
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Tada, Hayato ; Kawashiri, Masa-aki ; Nohara, Atsushi ; Inazu, Akihiro ; Kobayashi, Junji ; Mabuchi, Hiroshi ; Yamagishi, Masakazu ; 多田, 隼人 ; 川尻, 剛照 ; 野原, 淳 ; 稲津, 明広 ; 小林, 淳二 ; 馬渕, 宏 ; 山岸, 正和
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金沢大学医薬保健研究域医学系<br />Autosomal recessive hypercholesterolemia (ARH) is an extremely rare inherited disorder, the cause of
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which is mutations in the low-density lipoprotein (LDL) receptor adaptor protein 1 (LDLRAP1) gene. Only 36 families with 14 different mutations have been reported in the literature to date. The clinical phenotype of ARH is milder than that of homozygous familial hypercholesterolemia (FH) caused by LDL receptor gene mutations. Recently, the lipoprotein metabolism of ARH was investigated in both humans and mice by several investigators, including ourselves. Based on these findings the preserved clearance of LDL receptor-dependent very-LDL (VLDL) may be a possible mechanism underlying the responsiveness to statins and the milder phenotype of ARH. Although ARH has been described as being “recessive,” several studies, including ours, have indicated that a heterozygous carrier status of the LDLRAP1 gene is associated with mild hypercholesterolemia and exacerbates the phenotype of FH resulting from LDL receptor gene mutations. This review summarizes current understanding regarding ARH and its causative gene, LDLRAP1, and attempts to provide new insight into novel pharmacological targets for treating dyslipidemic patients. © Journal of Atherosclerosis and Thrombosis. All right received.<br />出版者照会後に全文公開
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| 5.
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Tada, Hayato ; Nohara, Atsushi ; Kawashiri, Masa-aki ; Inazu, Akihiro ; Mabuchi, Hiroshi ; Yamagishi, Masakazu ; 多田, 隼人 ; 野原, 淳 ; 川尻, 剛照 ; 稲津, 明広 ; 馬渕, 宏 ; 山岸, 正和
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金沢大学医薬保健研究域医学系<br />We herein report a case of marked transient hypercholesterolemia in a man receiving low-dose mitotan
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e as adjuvant chemotherapy for adrenocortical carcinoma.A 58-year-old man without any clinical symptoms or history of hypercholesterolemia was admitted to our hospital to treat an adrenocortical carcinoma detected on general screening using computed tomography. He reported no chest symptom and did not exhibit any established risk factors for coronary artery disease, such as diabetes, obesity, hypertension or relevant family history, with the exception of current smoking, on admission. A stress electrocardiogram showed negative findings. The left adrenal tumor as well as left kidney, spleen and distal portion of the pancreas were subsequently resected using radical surgery. The histopathological findings confirmed the preoperative diagnosis of adrenocortical carcinoma. After the operation, treatment with low-dose mitotane (1g/day) was introduced as adjuvant chemotherapy. Interestingly, the patient developed marked hyper-LDL cholesterolemia at a level equivalent to that of familial hypercholesterolemia (LDL cholesterol level ~ 300 mg/ dL) following the introduction of mitotane, without evidence of primary or secondary hypercholesterolemia due to other causes. A coronary angiogram performed to assess the new-onset angina revealed three-vessel disease, which was later revascularized via percutaneous coronary intervention eight months after the start of mitotane therapy. The cholesterol level normalized with the suspension of mitotane. This case suggests that mitotane can cause severe hypercholesterolemia, potentially resulting in coronary atherosclerosis. © 2014, Japan Atherosclerosis Society. All rights reserved.<br />出版者照会後に全文公開
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| 6.
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Tsuji, Shigetsugu ; Nohara, Atsushi ; Hayashi, Yoshiaki ; Yoshida, Isao ; Oka, Rie ; Moriuchi, Tadashi ; Higashita, Tomomi ; Miyamoto, Susumu ; Suzuki, Ayako ; Okada, Toshihide ; Yamagishi, Masakazu ; 野原, 淳 ; 山岸, 正和
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金沢大学医薬保健研究域医学系<br />Aim: The role of gastrectomy in glycemic control has been established in the current era of bariatri
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c surgery for obesity. Gastrectomy in obese patients is associated with increased levels of high-density lipoprotein cholesterol (HDL-C). However, limited data on the effects of gastrectomy in nonobese patients are available. We herein investigated the long-term plasma lipid changes in nonobese patients who had undergone gastrectomy. Methods: Patients were enrolled as part of routine healthcare examinations from 1984 to 2003. Preoperative and postoperative data from patients who had undergone curative gastrectomy were analyzed for up to 10 years postoperatively. Three age- and sex-matched controls were assigned to each case. Results: Sixty-four nonobese patients without diabetes mellitus or a history of having taken lipidlowering drugs who underwent curative gastrectomy during the study period were enrolled (60 subtotal gastrectomies, four total gastrectomies). The median follow-up period was 7.6 years. The mean body mass index was 9.6% lower one year after gastrectomy (p<0.01), then plateaued with a slight recovery. Intriguingly, the preoperative HDL-C level was 21% higher one year after gastrectomy (p<0.01), increased by another 30% six years after gastrectomy and remained at this level for the rest of the follow-up period. No significant changes in the HDL-C level were observed in the controls. The degree of HDL-C elevation was consistently significant, irrespective of the baseline triglyceride level, HDL-C level or body weight. Conclusions: Gastrectomy in nonobese patients was associated with consistent and distinct longterm HDL-C elevations and body mass index reductions. © 2015 Japan Atherosclerosis Society.<br />出版者照会後に全文公開
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| 7.
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Oka, Rie ; Yamada, Takayoshi ; Nakanishi, Chiaki ; Konno, Tetsuo ; Kawashiri, Masa-aki ; Hayashi, Kenshi ; Nohara, Atsushi ; Inazu, Akihiro ; Yamagishi, Masakazu ; 大家, 理恵 ; 八木, 邦公 ; 今野, 哲雄 ; 川尻, 剛照 ; 林, 研至 ; 野原, 淳 ; 稲津, 明広 ; 山岸, 正和
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金沢大学医薬保健研究域医学系<br />Aim: The commonly observed relationship between increased visceral adiposity and metabolic abnormali
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ties may be partly mediated by a concomitant increase in liver fat content. We evaluated the independent association between the level of alanine aminotransferase (ALT) as a surrogate marker of the liver fat content and the incidence of metabolic abnormalities after adjusting for the amount of visceral adipose tissue (AT). Methods: The subjects included 1,118 Japanese individuals (44% women) who underwent computed tomography to assess the amount of visceral AT on medical checkups. Cross-sectional associations between the serum ALT, visceral AT and metabolic risk factors were examined. Results: The ALT level and visceral AT were found to show a significant correlation (r =0.41 in men and r =0.36 in women, p<0.001). In a multivariable linear regression analysis, the ALT level and visceral AT were found to be independently associated with blood pressure in men and triglycerides and 2-hour post-challenge glucose in both genders (p<0.01), whereas only visceral AT was found to be associated with HDL-cholesterol (p<0.01). When the participants were classified into four subgroups based on the 75th percentiles of ALT and visceral AT, the low-ALT/high-visceral AT group, but not the high-ALT/low-visceral AT group, had a significantly higher odds ratio for low HDL-cholesterol among both genders (p<0.05) and for hypertriglyceridemia in men only (p<0.05). Meanwhile, the high-ALT/low-visceral AT group, but not the low-ALT/high-visceral AT group, had a significantly higher odds ratio for IGT among women (p<0.05). Conclusions: Although the ALT level and visceral AT were found to be independently associated with most metabolic risk factors, visceral AT had a dominant association with dyslipidemia in both genders, while the ALT level appeared to have a closer association with IGT in women.<br />出版者照会後に全文公開
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Mabuchi, Hiroshi ; Nohara, Atsushi ; Noguchi, Tohru ; Kobayashi, Junji ; Kawashiri, Masaaki ; Tada, Hayato ; Nakanishi, Chiaki ; Mori, Mika ; Yamagishi, Masakazu ; Inazu, Akihiro ; Koizumi, Junji ; Hokuriku FH Study Group
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金沢大学医学系研究科<br />Aim: Familial hypercholesterolemia (FH) is caused by mutations of FH genes, i.e. LDL-receptor (LDLR), PC
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SK9 and apolipoprotein B (ApoB) gene. We evaluated the usefulness of DNA analysis for the diagnosis of homozygous FH (homo-FH), and studied the frequency of FH in the Hokuriku district of Japan. Methods: Twenty-five homo-FH patients were recruited. LDLR mutations were identified using the Invader assay method. Mutations in PCSK9 were detected by PCR-SSCP followed by direct sequence analysis. Results: We confirmed 15 true homozygotes and 10 compound heterozygotes for LDLR mutations. Three types of double heterozygotes for LDLR and PCSK9 were found. No FH patients due to ApoB mutations were found. The incidences of homo-FH and hetero-FH in the Hokuriku district were 1/171,167 and 1/208, respectively. Conclusions: Our observations underlined the value of FH gene analysis in diagnosing homo-FH and confirmed extraordinarily high frequency of FH in the Hokuriku district of Japan. © 2010 Elsevier Ireland Ltd.
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| 9.
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Noguchi, Tohru ; Kobayashi, Junji ; Yagi, Kunimasa ; Nohara, Atsushi ; Yamaaki, Naoto ; Sugihara, Masako ; Ito, Naoko ; Oka, Rie ; Kawashiri, Masaaki ; Tada, Hayato ; Takata, Mutsuko ; Inazu, Akihiro ; Yamagishi, Masakazu ; Mabuchi, Hiroshi
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金沢大学医学系研究科<br />Background: Bezafibrate and fenofibrate show different binding properties against peroxisome proliferato
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r-activated receptor subtypes, which could cause different clinical effects on circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) levels and on various metabolic markers. Methods: An open, randomized, four-phased crossover study using 400 mg of bezafibrate or 200 mg of fenofibrate was performed. Study subjects were 14 dyslipidemia with impaired glucose tolerance or type 2 diabetes mellitus (61 ± 16 years, body mass index (BMI) 26 ± 3 kg/m2, total cholesterol (TC) 219 ± 53 mg/dL, triglyceride (TG) 183 ± 83 mg/dL, high-density lipoprotein-cholesterol (HDL-C) 46 ± 8 mg/dL, fasting plasma glucose 133 ± 31 mg/dL and HbA1c 6.2 ± 0.8%). Subjects were given either bezafibrate or fenofibrate for 8 weeks, discontinued for 4 weeks and then switched to the other fibrate for 8 weeks. Circulating PCSK9 levels and other metabolic parameters, including adiponectin, leptin and urine 8-hydroxy-2′-deoxyguanosine (8-OHdG) were measured at 0, 8, 12 and 20 weeks. Results: Plasma PCSK9 concentrations were significantly increased (+39.7% for bezafibrate and +66.8% for fenofibrate, p < 0.001) in all patients except for one subject when treated with bezafibrate. Both bezafibrate and fenofibrate caused reductions in TG (-38.3%, p < 0.001 vs. -32.9%, p < 0.01) and increases in HDL-C (+18.0%, p < 0.001 vs. +11.7%, p < 0.001). Fenofibrate significantly reduced serum cholesterol levels (TC, -11.2%, p < 0.01; non-HDL-C, -17.3%, p < 0.01; apolipoprotein B, -15.1%, p < 0.01), whereas bezafibrate significantly improved glucose tolerance (insulin, -17.0%, p < 0.05) and metabolic markers (γ-GTP, -38.9%, p < 0.01; adiponectin, +15.4%, p < 0.05; urine 8-OHdG/Cre, -9.5%, p < 0.05). Conclusion: Both bezafibrate and fenofibrate increased plasma PCSK9 concentrations. The addition of a PCSK9 inhibitor to each fibrate therapy may achieve beneficial cholesterol lowering along with desirable effects of respective fibrates. © 2011 Elsevier Ireland Ltd. All rights reserved.
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Nozue, Tsuyoshi ; Higashikata, Toshinori ; Inazu, Akihiro ; Kawashiri, Masa-aki ; Nohara, Atsushi ; Kobayashi, Junji ; Koizumi, Junji ; Yamagishi, Masakazu ; Mabuchi, Hiroshi
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Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive sterol storage disease caused by a mutated sterol 27-
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hydroxylase (CYP27A1) gene. We analyzed the CYP27A1 gene in two Japanese CTX patients. The CYP27A1 gene was amplified by PCR and screened by PCR-SSCP. The nucleotide sequence was analyzed to confirm mutations. Case 1 was a compound heterozygote for Arg104Gln in exon 2 and Arg441Gln in exon 8. To our knowledge, this is the first report in which the Arg104Gln mutation is identified in CTX patients. Probably case 2 would be a compound heterozygote for Arg441Trp in exon 8 and a mutation that was not identified. © 2010 The Japanese Society of Internal Medicine.
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