個人特性に基づいたアルツハイマー病の予後予測モデルの構築およびドネペジルによる治療効果の推定―８つのランダム化比較試験の個々の参加者データを用いたメタアナリシス―

京都大学新制・課程博士博士(社会健康医学)甲第24807号社医博第131号新制||社医||12(附属図書館)京都大学大学院医学研究科社会健康医学系専攻(主査)教授 中山 健夫, 教授 山本 洋介, 教授 髙橋 良輔学位規則第4条第1項該当Doctor of Public HealthKyoto UniversityDFA

Transplantable murine plasma cell leukemia with polyclonal gammopathy

A transplantable plasma cell leukemia cell line, designated as S27, was established from a 12-month-old female New Zealand Black mouse (NZB); serum showed polyclonal elevation of gamma globulin with agarose-agar gel electrophoresis. Immunoelectrophoretic analysis of the serum showed precipitation lines in the IgG1, IgG2a, IgG2b and IgM regions. The amount of serum immunoglobulin increased rapidly with tumor growth. S27 cells proliferating in the spleen contained simultaneously IgG1, IgG2a, IgG2b in the cytoplasm as revealed by indirect immunofluorescence. Membrane immunofluorescence revealed IgG1 on the tumor cell surface. S27 cells were transplantable to syngeneic NZB mice with inoculation of spleen cell suspension, and showed the same histological and immunological findings as those of the original mouse. These findings imply that a single clone of plasma cells has the capacity to produce more than one class of immunoglobulin.</p

Combination therapy with pemafibrate (K-877) and pitavastatin improves vascular endothelial dysfunction in dahl/salt-sensitive rats fed a high-salt and high-fat diet

Background Statins suppress the progression of atherosclerosis by reducing low-density lipoprotein (LDL) cholesterol levels. Pemafibrate (K-877), a novel selective peroxisome proliferator-activated receptor alpha modulator, is expected to reduce residual risk factors including high triglycerides (TGs) and low high-density lipoprotein (HDL) cholesterol during statin treatment. However, it is not known if statin therapy with add-on pemafibrate improves the progression of atherosclerosis. The aim of this study was to assess the effect of combination therapy with pitavastatin and pemafibrate on lipid profiles and endothelial dysfunction in hypertension and insulin resistance model rats. Methods Seven-week-old male Dahl salt-sensitive (DS) rats were divided into the following five treatment groups (normal diet (ND) plus vehicle, high-salt and high-fat diet (HD) plus vehicle, HD plus pitavastatin (0.3 mg/kg/day), HD plus pemafibrate (K-877) (0.5 mg/kg/day), and HD plus combination of pitavastatin and pemafibrate) and treated for 12 weeks. At 19 weeks, endothelium-dependent relaxation of the thoracic aorta in response to acetylcholine was evaluated. Results After feeding for 12 weeks, systolic blood pressure and plasma levels of total cholesterol were significantly higher in the HD-vehicle group compared with the ND-vehicle group. Combination therapy with pitavastatin and pemafibrate significantly reduced systolic blood pressure, TG levels, including total, chylomicron (CM), very LDL (VLDL), HDL-TG, and cholesterol levels, including total, CM, VLDL, and LDL-cholesterol, compared with vehicle treatment. Acetylcholine caused concentration-dependent relaxation of thoracic aorta rings that were pre-contracted with phenylephrine in all rats. Relaxation rates in the HD-vehicle group were significantly lower compared with the ND-vehicle group. Relaxation rates in the HD-combination of pitavastatin and pemafibrate group significantly increased compared with the HD-vehicle group, although neither medication alone ameliorated relaxation rates significantly. Western blotting experiments showed increased phosphorylated endothelial nitric oxide synthase protein expression in aortas from rats in the HD-pemafibrate group and the HD-combination group compared with the HD-vehicle group. However, the expression levels did not respond significantly to pitavastatin alone. Conclusions Combination therapy with pitavastatin and pemafibrate improved lipid profiles and endothelial dysfunction in hypertension and insulin resistance model rats. Pemafibrate as an add-on strategy to statins may be useful for preventing atherosclerosis progression

Enhancement of pacing function by HCN4 overexpression in human pluripotent stem cell-derived cardiomyocytes

Background The number of patients with bradyarrhythmia and the number of patients with cardiac pacemakers are increasing with the aging population and the increase in the number of patients with heart diseases. Some patients in whom a cardiac pacemaker has been implanted experience problems such as pacemaker infection and inconvenience due to electromagnetic interference. We have reported that overexpression of HCN channels producing a pacemaker current in mouse embryonic stem cell-derived cardiomyocytes showed enhanced pacing function in vitro and in vivo. The aim of this study was to determine whether HCN4 overexpression in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) can strengthen the pacing function of the cells. Methods Human HCN4 was transduced in the AAVS1 locus of human induced pluripotent stem cells by nucleofection and HCN4-overexpressing iPSC-CMs were generated. Gene expression profiles, frequencies of spontaneous contraction and pacing abilities of HCN4-overexpressing and non-overexpressing iPSC-CMs in vitro were compared. Results HCN4-overexpressing iPSC-CMs showed higher spontaneous contraction rates than those of non-overexpressing iPSC-CMs. They responded to an HCN channel blocker and beta adrenergic stimulation. The pacing rates against parent iPSC line-derived cardiomyocytes were also higher in HCN4-overexpressing iPSC-CMs than in non-overexpressing iPSC-CMs. Conclusions Overexpression of HCN4 showed enhancement of I-f current, spontaneous firing and pacing function in iPSC-CMs. These data suggest this transgenic cell line may be useful as a cardiac pacemaker

Feature extraction from images of endoscopic large intestine

The 14th Korea-Japan Joint Workshop on Frontiers of Computer Vision (FCV2008), Poster ; Place : Beppu, Oita, Japan ; Date : January 23-26, 200

A consideration for condition analysis with pit pattern of endoscope image

MIRU 2007 第10回 画像の認識・理解シンポジウム ポスター資料 ; 開催場所 : 広島市立大学, 広島 ; 開催日時:2007年7月30日～8月1

Prognostic value of non-alcoholic fatty liver disease for predicting cardiovascular events in patients with diabetes mellitus with suspected coronary artery disease: a prospective cohort study

Background Risk stratification of cardiovascular events in patients with type 2 diabetes mellitus (T2DM) has not been established. Coronary artery calcium score (CACS) and non-alcoholic fatty liver disease (NAFLD) are independently associated with cardiovascular events in T2DM patients. This study examined the incremental prognostic value of NAFLD assessed by non-enhanced computed tomography (CT) in addition to CACS and Framingham risk score (FRS) for cardiovascular events in T2DM patients. Methods This prospective pilot study included 529 T2DM outpatients with no history of cardiovascular disease who underwent CACS measurement because of suspected coronary artery disease. NAFLD was defined on CT images as a liver:spleen attenuation ratio  Results Among 529 patients (61% men, mean age 65 years), NAFLD was identified in 143 (27%). Forty-four cardiovascular events were documented during a median follow-up of 4.4 years. In multivariate Cox regression analysis, NAFLD, CACS, and FRS were associated with cardiovascular events (hazard ratios and 95% confidence intervals 5.43, 2.82–10.44, p  Conclusions NAFLD assessed by CT, in addition to CACS and FRS, could be useful for identifying T2DM patients at higher risk of cardiovascular events

Pemafibrate Prevents Rupture of Angiotensin II-Induced Abdominal Aortic Aneurysms

Background: Abdominal aortic aneurysm (AAA) is a life-threatening disease that lacks effective preventive therapies. This study aimed to evaluate the effect of pemafibrate, a selective peroxisome proliferator-activated receptor alpha (PPAR alpha) agonist, on AAA formation and rupture. Methods: Experimental AAA was induced by subcutaneous angiotensin II (AngII) infusion in ApoE(-)(/)(-) mice for 4 weeks. Pemafibrate (0.1 mg/kg/day) was administered orally. Dihydroethidium staining was used to evaluate the reactive oxygen species (ROS). Results: The size of the AngII-induced AAA did not differ between pemafibrate- and vehicle-treated groups. However, a decreased mortality rate due to AAA rupture was observed in pemafibrate-treated mice. Pemafibrate ameliorated AngII-induced ROS and reduced the mRNA expression of interleukin-6 and tumor necrosis factor-alpha in the aortic wall. Gelatin zymography analysis demonstrated significant inhibition of matrix metalloproteinase-2 activity by pemafibrate. AngII-induced ROS production in human vascular smooth muscle cells was inhibited by pre-treatment with pemafibrate and was accompanied by an increase in catalase activity. Small interfering RNA-mediated knockdown of catalase or PPAR alpha significantly attenuated the anti-oxidative effect of pemafibrate. Conclusion: Pemafibrate prevented AAA rupture in a murine model, concomitant with reduced ROS, inflammation, and extracellular matrix degradation in the aortic wall. The protective effect against AAA rupture was partly mediated by the anti-oxidative effect of catalase induced by pemafibrate in the smooth muscle cells