Hall F.S.,Intramural Research Program |
Itokawa K.,Saitama Medical School |
Schmitt A.,University of Würzburg |
Moessner R.,University of Würzburg |
And 3 more authors.
Neuropharmacology | Year: 2014
Dopamine (DA) is accumulated and compartmentalized by the dopamine transporter (DAT; SLC3A6) and the vesicular monoamine transporter 2 (VMAT2; SLC18A2). These transporters work at the plasma and vesicular membranes of dopaminergic neurons, respectively, and thus regulate levels of DA in neuronal compartments that include the extravesicular cytoplasmic compartment. DA in this compartment has been hypothesized to contribute to oxidative damage that can reduce the function of dopaminergic neurons in aging brains and may contribute to reductions in dopaminergic neurochemical markers, locomotor behavior and responses to dopaminergic drugs that are found in aged animals. The studies reported here examined aged mice with heterozygous deletions of VMAT2 or of DAT, which each reduce transporter expression to about 50% of levels found in wild-type (WT) mice. Aged mice displayed reduced locomotor responses under a variety of circumstances, including in response to locomotor stimulants, as well as changes in monoamine levels and metabolites in a regionally dependent manner. Several effects of aging were more pronounced in heterozygous VMAT2 knockout (KO) mice, including aging induced reductions in locomotion and reduced locomotor responses to cocaine. By contrast, some effects of aging were reduced or not observed in heterozygous DAT KO mice. These findings support the idea that altered DAT and VMAT2 expression affect age-related changes in dopaminergic function. These effects are most likely mediated by alterations in DA compartmentalization, and might be hypothesized to be exacerbated by other factors that affect the metabolism of cytosolic DA. This article is part of the Special Issue entitled 'The Synaptic Basis of Neurodegenerative Disorders'.
Haller H.,Hannover Medical School |
Ito S.,Tohoku University |
Izzo Jr. J.L.,State University of New York at Buffalo |
Januszewicz A.,Institute of Cardiology |
And 8 more authors.
New England Journal of Medicine | Year: 2011
BACKGROUND: Microalbuminuria is an early predictor of diabetic nephropathy and premature cardiovascular disease. We investigated whether treatment with an angiotensin-receptor blocker (ARB) would delay or prevent the occurrence of microalbuminuria in patients with type 2 diabetes and normoalbuminuria. METHODS: In a randomized, double-blind, multicenter, controlled trial, we assigned 4447 patients with type 2 diabetes to receive olmesartan (at a dose of 40 mg once daily) or placebo for a median of 3.2 years. Additional antihypertensive drugs (except angio-tensin-converting-enzyme inhibitors or ARBs) were used as needed to lower blood pressure to less than 130/80 mm Hg. The primary outcome was the time to the first onset of microalbuminuria. The times to the onset of renal and cardiovascular events were analyzed as secondary end points. RESULTS: The target blood pressure (<130/80 mm Hg) was achieved in nearly 80% of the patients taking olmesartan and 71% taking placebo; blood pressure measured in the clinic was lower by 3.1/1.9 mm Hg in the olmesartan group than in the placebo group. Microalbuminuria developed in 8.2% of the patients in the olmesartan group (178 of 2160 patients who could be evaluated) and 9.8% in the placebo group (210 of 2139); the time to the onset of microalbuminuria was increased by 23% with olmesartan (hazard ratio for onset of microalbuminuria, 0.77; 95% confidence interval, 0.63 to 0.94; P = 0.01). The serum creatinine level doubled in 1% of the patients in each group. Slightly fewer patients in the olmesartan group than in the placebo group had nonfatal cardiovascular events - 81 of 2232 patients (3.6%) as compared with 91 of 2215 patients (4.1%) (P = 0.37) - but a greater number had fatal cardiovascular events - 15 patients (0.7%) as compared with 3 patients (0.1%) (P = 0.01), a difference that was attributable in part to a higher rate of death from cardiovascular causes in the olmesartan group than in the placebo group among patients with pre-existing coronary heart disease (11 of 564 patients [2.0%] vs. 1 of 540 [0.2%], P = 0.02). CONCLUSIONS: Olmesartan was associated with a delayed onset of microalbuminuria, even though blood-pressure control in both groups was excellent according to current standards. The higher rate of fatal cardiovascular events with olmesartan among patients with preexisting coronary heart disease is of concern. (Funded by Daiichi Sankyo; ClinicalTrials.gov number, NCT00185159.) Copyright © 2011 Massachusetts Medical Society.
Suzuki H.,Saitama Medical School
Advances in peritoneal dialysis. Conference on Peritoneal Dialysis | Year: 2010
We previously reported that the level of low-density lipoprotein cholesterol (LDL-C) was higher in patients receiving continuous ambulatory peritoneal dialysis (CAPD) than in patients on hemodialysis (HD). One of the problems associated with reaching the LDL-C target during statin treatment of patients on CAPD is the emergence of laboratory or clinical side effects. The present study evaluated the efficacy and tolerability of daily combined treatment with ezetimibe 10 mg and simvastatin 10 mg in patients receiving CAPD. Our study enrolled 12 CAPD patients who were experiencing adverse effects from statin therapy. Their existing statin therapy was suspended for 1 month ("washout period"), and the patients were then shifted to treatment with the ezetimibe-simvastatin combination. The patients were again monitored for adverse events such as asthenia and myalgia during the subsequent 12 months. Body mass index and levels of glycated hemoglobin, fasting plasma glucose, total cholesterol, LDL-C, triglycerides, alanine amino-transferase, aspartate aminotransferase, and creatinine phosphokinase were also assessed. The combination of ezetimibe and low-dose simvastatin significantly reduced levels of total cholesterol (by a mean of 27%), triglycerides (by 9%), and LDL-C (by 33%) and increased levels of high-density lipoprotein cholesterol (by 15%). In 11 patients (92%), the target LDL-C level of less than 100 mg/dL was reached. No significant change in weekly creatinine clearance occurred, and no serious adverse effects were observed. No patient developed muscle pain or weakness, and no increase in creatinine kinase was found. Residual renal function declined, although not significantly when compared with initial values. In conclusion, the present study suggests that combined ezetimibe and low-dose statin treatment is a promising approach for safe and effective primary treatment of dyslipidemia in CAPD patients.
Fujiwara K.,Saitama Medical School |
Kurosaki A.,Saitama Medical School |
Hasegawa K.,Saitama Medical School
Current Oncology Reports | Year: 2013
The aim of neoadjuvant chemotherapy is to reduce the tumor volume or spread of the disease before the main treatment, and it could possibly make the main procedures easier or less invasive. Although the standard therapeutic strategy for advanced ovarian cancer is a maximum primary debulking surgery followed by chemotherapy, a European Organisation for Research and Treatment of Cancer (EORTC) prospective randomized trial demonstrated that neoadjuvant chemotherapy followed by interval debulking surgery was not inferior to the standard procedure. This study raised a number of controversies, particularly regarding the quality of debulking surgery. To solve the questions, we need to wait for the results of two additional ongoing randomized trials. However, the results of those two trials must be carefully assessed, because the quality of debulking surgery would significantly affect survival, and may make the interpretation of the trial results more confusing and difficult. © 2013 Springer Science+Business Media New York.
Hosoda Y.,Kyoto University |
Uji A.,Kyoto University |
Hangai M.,Saitama Medical School |
Morooka S.,Kyoto University |
And 2 more authors.
American Journal of Ophthalmology | Year: 2014
Purpose To investigate the correlation between choroidal and retinal lesions in eyes with acute Vogt-Koyanagi-Harada disease (VKH) using optical coherence tomography (OCT) by using a new parameter, retinal pigment epithelium (RPE) undulation index, which quantitatively describes choroidal deformations. Design Retrospective, observational, cross-sectional study. Methods Spectral-domain OCT (SD OCT) and swept-source OCT images from a consecutive series of 42 eyes in 22 patients with acute VKH who underwent steroid therapy and 20 healthy eyes in 20 volunteers were analyzed retrospectively. Correlations between best-corrected visual acuity (BCVA), axial length change, and OCT parameters were examined. The RPE undulation index was defined as RPE line length to the total scan length ratio on a foveal-centered scan in the SD OCT image. Results Eyes with acute VKH showed increased RPE undulation index, choroidal thickness, and retinal thickness compared to normal subjects, which were reduced following steroidal treatment (P <.0001, P =.0003, and P <.0001, respectively). RPE undulation index was related to choroidal thickness (r = 0.624, P =.0043), retinal thickness (r = 0.483, P =.0028), and BCVA (r = 0.588, P =.0002). Meanwhile, no statistically significant relationship was observed between choroidal thickness and retinal thickness. Axial length changes were significantly correlated with both choroidal thickness (r = 0.842, P <.0001) and RPE undulation index (r = 0.600, P =.0139). Conclusions This study demonstrated that the choroid was diffusely undulated and bulged inward in eyes with acute VKH. Correlations between RPE undulation index and choroid morphology, retinal thickness, and poor BCVA suggest that choroidal folding, quantified by RPE undulation index, is useful in assessing VKH disease severity. © 2014 by elsevier inc. all rights reserved.
Hashiguchi M.,Tokyo Medical University |
Hashiguchi T.,Saitama Medical School
International Review of Cell and Molecular Biology | Year: 2013
The microtubule (MT)-associated protein tau attaches to neuronal MT networks and regulates their integrity. The phosphorylation state of tau alters its binding activity. MT integrity is maintained by the phosphorylation state of tau, which is under the control of the kinase-phosphatase balance. This control requires the proper regulation of topographical and temporal characteristics of tau kinases and phosphatases. The tau phosphorylation protein complex (TPPC) anchors tau kinases and phosphatases via scaffold proteins, tau effectors, and tau itself. Targeting these proteins in TPPC fulfills the topographical requirements for maintaining MT functions. The switching of tau kinase activity determines the order of the kinase action. The combined action of kinases is temporally modulated; reversal of the time order of events results in a differential state of tau phosphorylation. Elucidation of protein-protein interaction in the regulation of tau phosphorylation will shed light on the physiology and pathology of tau phosphorylation. © 2013 Elsevier Inc.
Horinaga M.,Saitama Medical School
Urology | Year: 2010
Objectives: To evaluate the antitumor effect of the coincident administration of intravesical gemcitabine (Gem) plus bacillus Calmette-Gurin (BCG) in an orthotopic bladder cancer model. Methods: We evaluated the cytotoxic effect of gemcitabine against MBT-2 cells in vitro. Orthotopic tumors were established by implanting MBT-2 cells into the bladder of syngeneic female C3H mice. Intravesical Gem administration was evaluated at various doses: 0 mg (control); 1, 2, 4, and 8 mg (n = 8 for each group). Next, a comparative evaluation of tumor growth among the control, Gem-alone, BCG-alone, and combined Gem + BCG groups was performed (n = 16 for each group). Therapy was administered at 3-day intervals starting on day 5 and repeated 6 times. To evaluate the proliferative activity among the groups, Ki-67 immunostaining of the tumor was performed. Results: Gemcitabine exhibited a dose-dependent antitumor effect. Of the 8 mice in each group treated with a dose of 0, 1, 2, 4, or 8 mg of Gem, 1, 4, 4, 4, 5, and 4 mice failed to develop tumors and survived, respectively. The combination of Gem + BCG (54.1 ± 9.4 days) provided a significant survival advantage compared with BCG-alone (39.0 ± 16.4 days) (P = .02). Ki-67 expression, representing tumor proliferation, was significantly lower in the combined Gem + BCG group than in the BCG-alone group (P <.01). Conclusions: Our results suggest that intravesical Gem + BCG treatment induces an enhanced antitumor effect against bladder tumors. © 2010 Elsevier Inc. All Rights Reserved.
Urano T.,University of Tokyo |
Shiraki M.,Saitama Medical School |
Ouchi Y.,University of Tokyo |
Inoue S.,University of Tokyo |
Inoue S.,Saitama Medical School
Journal of Clinical Endocrinology and Metabolism | Year: 2012
Context: Wnt/β-catenin signaling is related to the pathogenesis of osteoporosis, diabetes, and metabolic diseases. Sclerostin is an inhibitor of Wnt/β-catenin signaling. However, there are few data regarding the relationship between sclerostin levels and metabolic disease. Objective: This study aimed to identify the relationship between serum sclerostin levels, body composition markers, and the markers of metabolic disease. Design, Setting, and Patients: The present study is a cross-sectional study. We measured serum sclerostin levels in 352 Japanese postmenopausal women and analyzed the relationship of these levels with bone mineral density, abdominal fat mass, and biochemical markers. The mean (SD) age of the subjects was 65.5 (9.3) yr. Results: Serum sclerostin levels were positively correlated with percentages of abdominal and gynoid fat. We also analyzed the association between serum sclerostin levels and biochemical markers related to metabolic diseases. Multivariate analysis revealed that the serum sclerostin levels were significantly correlated with the levels of low-density lipoprotein cholesterol and homocysteine. Conclusions: The circulating sclerostin levels were associated with fat mass. The circulating sclerostin levels were also correlated with low-density lipoprotein cholesterol and homocysteine. Copyright © 2012 by The Endocrine Society.
Sano H.,Saitama Medical School |
Ogawa R.,Saitama Medical School
Dermatology | Year: 2013
Objective: To assess the relationship between nail configuration and mechanical force, the nail morphology and pinch strengths of the paralyzed and non-paralyzed sides of patients with hemiplegia were measured. Methods: Study 1: Analysis of nail configuration. Both thumb nails of 100 subjects with hemiplegia and 100 healthy volunteers (400 thumb nails) were enrolled. The left and right thumb nails were compared in terms of configuration, namely the curve index (defined as nail height/width). Study 2: Measurement of pinch strength. In 10 subjects with hemiplegia and 10 healthy volunteers, the pinch strengths of both sides were compared. Results: Study 1: In the subjects with hemiplegia, the palsy side had a significantly higher curve index than the non-palsy side (32.7 ± 8.3 vs. 24.4 ± 6.5%). The two sides of the healthy volunteers did not differ significantly in terms of the curve index. Study 2: In all hemiplegia cases, the non-palsy side had a higher pinch strength. The differences were statistically significant (4.40 ± 1.90 vs. 0.05 ± 0.16 kg). In the healthy volunteers, the dominant and non-dominant sides did not differ significantly. Conclusion: Mechanical forces may affect the nail configuration and could participate in the pathophysiology of nail deformities. © 2013 S. Karger AG, Basel.
Suzuki H.,Saitama Medical School
Advances in peritoneal dialysis. Conference on Peritoneal Dialysis | Year: 2010
The number of elderly patients requiring dialysis therapy has been increasing in developed countries. Among elderly patients on dialysis, the incidence of death from cardiovascular complications has increased. Our objective was to study whether the presence of abnormal cardiac function at the initiation of peritoneal dialysis (PD) affects the prognosis of patients over the age of 75 years on PD therapy. A retrospective analysis of 46 patients more than 75 years of age who started PD therapy (average age: 79.4 +/- 3.5 years; 26 women, 20 men) collected demographic and comorbidity data. Survival was defined as time from the initiation of PD therapy. In 12 patients, ejection fraction measured by echocardiography was less than 50% ("abnormal EF" group); in 34 patients, ejection fraction was more than 50% ("normal EF" group). In the abnormal EF group, 9 patients (75%) survived 12 months; in the normal EF group, 26 patients (76%) survived that long. However, at 24 months, only 2 patients (16%) in the abnormal EF group and 18 patients (52%) in the normal EF group were still alive. Survival was significantly longer in the normal EF group (p < 0.0019). With the exception of serum albumin, other parameters such as age, serum creatinine, and hemoglobin were not significantly difference between the two groups at the initiation of dialysis therapy. Our study demonstrated that cardiac performance at the initiation of PD therapy predicts prognosis in PD patients more than 75 years of age.