マウス脂肪細胞における温度感受性Transient Receptor Potential Vanilloid (TRPV) チャネルに関する研究

学位の種別:課程博士University of Tokyo(東京大学

Relationship between chronotropic incompetence and β-blockers based on changes in chronotropic response during cardiopulmonary exercise testing

AbstractBackgroundChronotropic incompetence (CI), an attenuated heart rate (HR) response to exercise, is common in patients with cardiovascular disease. The aim of this study was to assess changes in the chronotropic response (CR) during cardiopulmonary exercise testing (CPET) in patients undergoing cardiac rehabilitation and investigate the effects of β-blockers.MethodsPatients undergoing cardiac rehabilitation performed CPET. Failure to achieve 80% of the age-predicted maximal HR (APMHR) defined CI. Values of the metabolic chronotropic relationship (MCR) were calculated from the ratio of the HR reserve to metabolic reserve at 4 stages, warm-up (MCR-Wu), anaerobic threshold (MCR-AT), respiratory compensation (MCR-Rc), and peak point (MCR-Pk), using the Wilkoff model. In patients who showed an increase in MCR at ≥3 of the 4 exercise stages, CR was considered to have improved.ResultsPatients with high BNP levels (≥80pg/ml) had a lower MCR at all stages compared with those with low BNP levels (<80pg/ml). Of the 80 patients, 47 showed an increase in both peak VO2 and AT, and of these 31 (66.0%) were taking β-blockers. Improvement in CR was observed in 30 of 47 patients with CI, and 70% of these were taking β-blockers. In patients not taking β-blockers, MCR-AT was lower than MCR-Rc, whereas in those taking β-blockers MCR-AT was higher than MCR-Rc.ConclusionsAn attenuated HR response may occur during the early stages of exercise. The HR response according to the presence or absence of β-blockers is clearly identifiable by comparing MCR-AT and MCR-Rc using the Wilkoff model

Connective Tissue Growth Factor Gene Expression in Tissue Sections From Localized Scleroderma, Keloid, and Other Fibrotic Skin Disorders

Connective tissue growth factor (CTGF) is a novel peptide that exhibits platelet-derived growth factor-like activities and is produced by skin fibroblasts after activation with transforming growth factor-β. Coordinate expression of transforming growth factor-β followed by CTGF during wound repair suggests a cascade process for control of tissue regeneration. We recently reported a significant correlation between CTGF mRNA expression and histologic sclerosis in systemic sclerosis. To confirm the relation between CTGF and skin fibrosis, we investigated CTGF gene expression in tissue sections from patients with localized scleroderma, keloid, and other sclerotic skin disorders using nonradioactive in situ hybridization. In localized scleroderma, the fibroblasts with positive signals for CTGF mRNA were scattered throughout the sclerotic lesions with no preferential distribution around the inflammatory cells or perivascular regions, whereas the adjacent nonaffected dermis was negative for CTGF mRNA. In keloid tissue, the fibroblasts positive for CTGF mRNA were diffusely distributed, especially in the peripheral expanding lesions. In scar tissue, however, the fibroblasts in the fibrotic lesions showed partially positive signals for CTGF mRNA. In eosinophilic fasciitis, nodular fasciitis, and Dupuytren's contracture, CTGF mRNA was also expressed partially in the fibroblasts of the fibrotic lesions. Our findings reinforce a correlation between CTGF gene expression and skin sclerosis and support the hypothesis that transforming growth factor-β plays an important role in the pathogenesis of fibrosis, as it is the only inducer for CTGF identified to date

A comparison of nephrotoxicity between patients with a solitary-functioning kidney and those with bilateral-functioning kidneys in cisplatin-based chemotherapy for advanced urothelial carcinoma: a Japanese retrospective multi-institutional study

BackgroundTo compare the prevalence of nephrotoxicity between patients with a solitary-functioning kidney versus those with bilateral-functioning kidneys during the administration of cisplatin-based chemotherapy for advanced urothelial carcinoma.MethodsWe retrospectively analyzed 244 advanced urothelial carcinoma patients treated with cisplatin-based chemotherapy between 2004 and 2010 at 17 institutes in Japan. The 24 h creatinine clearance, Cockcroft–Gault formula, and estimated glomerular filtration rate equation (eGFR), were compared before all chemotherapies. The urinary tract function status was determined based on the data of nephroureterectomy, hydronephrosis, and relief of upper urinary tract obstruction. A total of 244 patients were divided into four groups according to their urinary tract functioning status and eGFR results, including bilateral-functioning kidneys with pretreatment eGFR ≥60 mL/min/1.73 m2 group (n = 83, 34.0%); a solitary-functioning kidney with pretreatment eGFR ≥60 mL/min/1.73 m2 group (n = 36, 14.8%); bilateral-functioning kidneys with pretreatment eGFR  10% and 30% from baseline in the post-third-course of chemotherapy was significantly higher in patients with bilateral-functioning kidneys than in those with a solitary-functioning kidney, among patients with pretreatment eGFR  20% from baseline were significantly higher in patients with bilateral-functioning kidneys than those with a solitary-functioning kidney among patients with pretreatment eGFR < 60 mL/min/1.73 m2 (p = 0.034), whereas no significant difference was observed among patients with pretreatment eGFR ≥60 mL/min/1.73 m2.ConclusionsThe results suggest that cisplatin-based chemotherapy may have more nephrotoxicity in patients with bilateral-functioning kidneys than in those with a solitary-functioning kidney

Potential value of saline-induced Pd/Pa ratio in patients with coronary artery stenosis

BackgroundFractional flow reserve (FFR) is the current gold standard for identifying myocardial ischemia in individuals with coronary artery stenosis. However, FFR is not penetrated as much worldwide due to time consumption, costs associated with adenosine, FFR-related discomfort, and complications. Resting physiological indexes may be widely accepted alternatives to FFR, while the discrepancies with FFR were found in up to 20% of lesions. The saline-induced Pd/Pa ratio (SPR) is a new simplified option for evaluating coronary stenosis. However, the clinical implication of SPR remains unclear.ObjectivesIn the present study, we aimed to compare the accuracies of SPR and resting full-cycle ratio (RFR) and to investigate the incremental value of SPR in clinical practice.MethodsIn this multicenter prospective study, 112 coronary lesions (105 patients) were evaluated by SPR, RFR, and FFR.ResultsThe overall median age was 71 years, and 84.8% were men. SPR was correlated more strongly with FFR than with RFR (r = 0.874 vs. 0.713, respectively; p &lt; 0.001). Using FFR &lt; 0.80 as the reference standard variable, the area under the receiver-operating characteristic (ROC) curve for SPR was superior to that of RFR (0.932 vs. 0.840, respectively; p = 0.009).ConclusionSaline-induced Pd/Pa ratio predicted FFR more accurately than RFR. SPR could be an alternative method for evaluating coronary artery stenosis and further investigation including elucidation of the mechanism of SPR is needed (225 words)

Demonstration for Inactivation of Zooplankton by Irradiation with a Pulsed Intense Relativistic Electron Beam

Zooplankton contained in water have been successfully inactivated by irradiation with a pulsed intense relativistic electron beam (PIREB). A treatment chamber is filled with a solution of 3-wt% salt in water containing Artemia larvae as zooplankton samples and is irradiated using the PIREB (2 MeV, 0.4 kA, 140 ns). We found that up to 24% of the Artemia are inactivated by firing 10 shots of PIREB irradiation. Ships such as cargo ships use ballast water to stabilize their hulls during navigation. The ballast water is carried around the world and is dumped at a port of call, causing an undesirable propagation of microbes, bacilli and eggs and larvae of marine organisms and the growth of marine plankton in ocean ecosystems. To conserve the ocean environment, a convention was adopted by the International Maritime Organization in 2004 In the present study, we propose a new method of treatment which uses irradiation by a pulsed intense relativistic electron beam (PIREB). In this method, chemicals and/or additives are unnecessary for treatment. The purpose of this paper is to investigate the properties of PIREB injection into ballast water and the effects of irradiation by the PIREB on zooplankton. The PIREB with a kinetic energy of up to 2 MeV is generated using a field-emission foilless electron-beam diode, in which a hollow cathode and a ring anode are set at the first acceleration cell of the pulsed power generator ETIGO-II

Prevalence and Antigen Specificity of Anti-Histone Antibodies in Patients with Polymyositis/Dermatomyositis

Anti-histone antibodies have been detected in the sera of patients with various autoimmune diseases. The existence of anti-histone antibodies in patients with polymyositis/dermatomyositis, however, has not been reported. We found anti-histone antibodies in eight (17%) of 46 sera from patients with polymyositis/dermatomyositis by an enzyme-linked immunosorbent assay. One serum was positive for both IgG anti-histone antibodies and IgM anti-histone antibodies. Six sera were positive only for IgG anti-histone antibodies. One serum was positive only for IgM anti-histone antibodies. An indirect immunofluorescence analysis using HEp-2 cells as the substrate showed that all sera positive for anti-histone antibodies produced homogeneous nuclear fluorescence. This immunofluorescence pattern disappeared after absorption of anti-histone activity with total histones. An immunoblotting analysis demonstrated that the anti-histone antibodies were predominantly directed against histone H1 in all seven sera with IgG anti-histone antibodies. Weak reactivity with H2B and H4 were also found in three sera from the patients with polymyositis/dermatomyositis. Sera from two patients with polymyositis/dermatomyositis displayed anti-H2A and H3 activity. One of the two sera showed IgM anti-histone antibodies in the enzyme-linked immunosorbent assay reacted with H1, H2A, H2B, H3, and H4, whereas the other serum reacted with no fractions of total histones. The activity of anti-histone antibodies disappeared in immunoblotting after absorption with total histones. All of the patients with anti-histone antibodies were free from lung fibrosis or internal malignancies. Thus, our data indicate that the presence of anti-histone antibodies is classified as one of the serologic abnormalities observed in polymyositis/dermatomyositis