Okinaka Memorial Institute for Medical Research

Tokyo, Japan

Okinaka Memorial Institute for Medical Research

Tokyo, Japan
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Shingo A.S.,Okinaka Memorial Institute for Medical Research | Kanabayashi T.,Biopathology Institute | Kito S.,Chigasaki Tokushu kai Clinic | Murase T.,Okinaka Memorial Institute for Medical Research
Behavioural Brain Research | Year: 2013

We previously demonstrated that intracerebroventricular streptozotocin (STZ-icv) injection induced cognitive dysfunction and led to decreased expression levels of phospho-cyclic AMP responsive element binding protein (pCREB), Akt, and insulin degrading enzyme (IDE) and increased amyloid beta (Ab) deposition in the hippocampus. In the present study, we aimed to investigate whether treatment with an insulin analogue could prevent STZ-induced cognitive decline by reducing or eliminating these changes in the hippocampus. To test this hypothesis, we administrated a long-acting insulin analogue, detemir, into the third ventricle (3V) of STZ-treated rats and assessed cognitive outcomes using the Morris water maze (MWM), immunohistochemistry, and Golgi-Cox staining. Insulin injection successfully rescued STZ-induced cognitive decline, as evidenced by a marked elevation in learning ability. Detemir treatment also resulted in changes in hippocampal levels of IDE, insulin receptor (IR), Akt, somatostatin (SST), and Ab. The STZ-induced decrease of granule cell layer neurons was also recovered by detemir administration. These results provide evidence that 'brain diabetes' and Alzheimer-type dementia involve similar mechanisms and show that insulin may be a promising therapeutic agent to attenuate cognitive decline. © 2012 Elsevier B.V.


Nishioka H.,Toranomon Hospital | Nishioka H.,Okinaka Memorial Institute for Medical Research
Neurologia Medico-Chirurgica | Year: 2017

For the treatment of pituitary tumors, microscopic transsphenoidal surgery has been considered the “gold standard” since the late 1960s. Over the last two decades, however, a worldwide shift towards endoscopic endonasal surgery is in progress for many reasons. These include a wide panoramic view, improved illumination, an ability to look around anatomical corners using angled tip and, in addition, application to the extended approaches for parasellar tumors. Both endoscopic and microscopic approaches appear equally effective for nonfunctioning adenomas without significant suprasellar or lateral extensions, whereas the endoscopic approach may improve outcomes associated with the extent of resection and postoperative complications for larger tumors. Despite many theoretical benefits in the endoscopic surgery, remission rates of functioning adenomas do not substantially differ between the approaches in experienced hands. The endoscopic approach is a valid alternative to the microscopic approach for adenomas. The benefits will be more appreciated in the extended surgery for parasellar tumors. © 2017, Japan Neurosurgical Society. All rights reserved.


Shingo A.S.,Okinaka Memorial Institute for Medical Research | Kanabayashi T.,Biopathology Institute | Murase T.,Okinaka Memorial Institute for Medical Research | Kito S.,Doai kai Ozawa Hospital
Behavioural Brain Research | Year: 2012

Recent epidemiological studies have associated type 2 diabetes mellitus with an increased risk of developing Alzheimer's disease (AD). A dramatic decrease in glucose utilisation has been observed in the brains of AD patients, and this decrease has led to the hypothesis that the cognitive dysfunction in AD is associated with decreased central glucose metabolism [1], in addition to cholinergic deficit and elevated amyloid accumulation in the brain [2]. The aims of the present study were to examine the effects of intracerebral administration of streptozotocin (STZ) on cognitive performance in rats as observed by Morris water maze (MWM) task and to clarify the successive insulin-related neurochemical changes through immunohistochemical analysis of the hippocampus. Significant differences were observed in all the parameters of the MWM task (escape latency, path efficiency, average swimming speed and swim path) between STZ-3V-treated and control rats.Immunohistochemical analysis using hippocampal formations revealed significant decreases in phospho-cyclic AMP binding protein, Akt and insulin-degrading enzyme immunoreactivities and a significant increase in amyloid beta immunoreactivity. Our behavioural experiments confirmed that intraventricular administration of STZ led to cognitive impairment, which was ascertained by the changes in hippocampal immunohistochemical markers.In conclusion, we demonstrated that cognitive decline in diabetes was primarily due to impaired intracerebral insulin signalling in addition to arteriosclerotic cerebrovascular changes, which hitherto have been advocated as the main cause of diabetic dementia. © 2012 Elsevier B.V..


Kaneda H.,Okinaka Memorial Institute for Medical Research | Kaneda H.,Translational Research Informatics Center | Terashima M.,Toyohashi Heart Center | Yamaguchi H.,Tenyoukai Central Hospital
Current Atherosclerosis Reports | Year: 2012

New imaging techniques have been used to examine surrogate markers of atherosclerotic burden to determine the effects of pharmacologic intervention. In this review, we discuss the role of intravascular ultrasound (IVUS) in the determination of progression and regression of coronary artery disease. Several methodologic issues are discussed (selection of segments to analyze, measurement error, high drop out rate, and optimal IVUS variables). Usefulness of new IVUS-derived variables (plaque composition by radiofrequency analysis, deformability by palpography, and endothelial shear stress by three-dimensional coronary anatomy reconstructed from IVUS and angiography) will be determined. Based on comparisons between IVUS and clinical studies, IVUS variables seem to be a valid surrogate in studies using atorvastatin in patients with dyslipidemia. It remains unclear whether IVUS variables are valid surrogates for other drugs/diseases. As such, further studies are needed to determine whether IVUS can serve as an efficient surrogate for clinical events in coronary disease trials. © Springer Science+Business Media, LLC 2012.


News Article | December 15, 2016
Site: www.eurekalert.org

NEW YORK NY (December 15, 2016)--Gastric tumors are started by specialized cells in the stomach that signal nerves to make more acetylcholine, according to a study in mice. The multinational team of researchers who conducted the study also identified a substance called nerve growth factor that stimulates nerve development and, when blocked, inhibits stomach cancer development. The findings were published today in Cancer Cell. Previous studies have shown that nerves are abundant in the gastric tumor microenvironment. In an earlier paper, the researchers demonstrated that inhibiting signaling by the neurotransmitter acetylcholine, by severing the vagus nerve in the stomach or treating with Botulinum toxin, shrank or prevented the growth of gastric tumors in mouse models. "Nerves and acetylcholine clearly play a key role in regulating the development and growth of cancer cells, particularly cancer stem cells, in the gastric tumor microenvironment," said Timothy C. Wang, MD, the Dorothy L. and Daniel H. Silberberg Professor of Medicine at Columbia University Medical Center (CUMC) and senior author of the paper. "But little is known about what is driving cancer in the earliest stage of development, before the expansion of nerves in the microenvironment. We also wanted to find out where acetylcholine is coming from before the growth of nerves." Through a series of experiments in mouse models, the researchers determined that a neurotrophin (substance that triggers nerve growth) called nerve growth factor is highly expressed in gastric cancer cells. They also discovered that tuft cells--specialized cells found in the lining of the digestive tract that, like nerves, communicate with other cells--provide another source of acetylcholine for cancer cell growth, particularly during the formation of tumors. "We learned that tuft cells are increased during the earliest stage of gastric tumor development, making acetylcholine and stimulating the production of nerve growth factor within the lining of the stomach," said Dr. Wang. "As nerves grow in around the tumor, tuft cells decrease." In additional experiments, the scientists showed that overexpression of nerve growth factor in the mouse stomach drove tumorigenesis. Furthermore, administration of a nerve growth factor receptor inhibitor prevented stomach cancer in the mice. "Our study provides some insight into the cellular crosstalk that leads to the development of stomach cancer, and points to a viable therapeutic target for this type of cancer," said Dr. Wang. "Using our findings as a paradigm, additional studies can be done to identify the specific neurotrophins and neurotransmitters that are involved in tumor development in other areas of the body." The study is titled, "Nerve growth factor promotes gastric tumorigenesis through aberrant cholinergic signaling." The other contributors are: Yoku Hayakawa (University of Tokyo, Tokyo, Japan), Kosuke Sakitani (University of Tokyo), Mitsuru Konishi (University of Tokyo), Samuel Asfaha (University of Western Ontario, Ontario, Canada), Ryota Niikura (University of Tokyo), Hiroyuki Tomita (Gifu University Graduate School of Medicine, Gifu, Japan), Bernhard W. Renz (Hospital of the University of Munich, Munich, Germany), Yagnesh Taylor (CUMC), Marina Macchini (CUMC). Moritz Middlehoff (CUMC), Zhengyu Jiang (CUMC), Takayuki Tenaka (CUMC), Zinaida A. Dubeykovskaya (CUMC), Woosook Kim (CUMC), Xiaowei Chen (CUMC), Aleksandra M. Urbanska (CUMC), Karan Nagar (CUMC), Christoph B. Westphalen (Klinikum der Universität München, Munich, Germany), Michael Quante (Technische Universität München, Munich, Germany), Chyuan-Sheng Lin (CUMC), Michael D. Gershon (CUMC), Akira Hara (Gifu University Graduate School of Medicine), Chun-Mei Zhao (Norwegian University of Science and Technology, Trondheim. Norway), Duan Chen (Norwegian University of Science and Technology), Daniel L. Worthley (University of Aidelaide, Australia), and Kazuhiko Koike (University of Tokyo). The study was supported by grants from the National Institutes of Health (U54CA126513, R01CA093405, R01CA120979, and R01DK052778), the Clyde Wu Family Foundation, the Nakayama Cancer Research Institute, the Okinaka Memorial Institute for Medical Research, and the Project for Cancer Research and Therapeutic Evolution from the Japan Agency of Medical Research and Development. Y.H. and K.S. were supported by Japan Society for the Promotion of Science, and Y.H. and T.T. were supported by Uehara Memorial Foundation. The authors declare no conflicts of interest. Columbia University Medical Center provides international leadership in basic, preclinical, and clinical research; medical and health sciences education; and patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Columbia University Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest faculty medical practices in the Northeast. The campus that Columbia University Medical Center shares with its hospital partner, NewYork-Presbyterian, is now called the Columbia University Irving Medical Center. For more information, visit cumc.columbia.edu or columbiadoctors.org.


Nakanishi K.,Okinaka Memorial Institute for Medical Research | Nakanishi K.,Fuji Toranomon Hospital | Saitoh S.,Toranomon Hospital
Diabetes Care | Year: 2011

OBJECTIVE - This study clarified characteristics of interferon-associated type 1 diabetes. RESEARCH DESIGNANDMETHODS - The study compared 12 patients with interferon-associated type 1 diabetes with 128 patients with type 1A diabetes with respect to clinical characteristics, and with 10 patients without diabetes despite interferon therapy and 136 normal controlswith respect to HLA allele distributions. RESULTS - Patients with interferon-associated type 1 diabetes retained higher levels of fasting serum C peptide as well as GAD65 antibodies than those with type 1A diabetes until 2 to 4 years after onset. HLA-A*2402 was increased among patientswith interferon-associated type 1 diabetes compared with those without diabetes, despite interferon therapy (odds ratio [OR] 4.00 [95%CI 1.09-17.26]). The haplotype of DRB1*1302- DQA1*0102-DQB1*0604 was increased in these two groups combined compared with normal controls (OR 5.64 [95% CI 2.67-11.81]). CONCLUSIONS - Interferon-associated type 1 diabetes is characterized clinically by high titers of GAD65 antibodies and preserved β-cell function, and genetically by addition of HLA-A* 2402 to DRB1*1302-DQA1*0102- DQB1*0604. © 2011 by the American Diabetes Association.


Araoka H.,Toranomon Hospital | Araoka H.,Okinaka Memorial Institute for Medical Research | Baba M.,Toranomon Hospital | Kimura M.,Toranomon Hospital | And 4 more authors.
Journal of Clinical Microbiology | Year: 2014

The aim of this study was to clarify the clinical characteristics of patients with Helicobacter cinaedi bacteremia and the time required for blood cultures to become positive. The medical records of all patients with H. cinaedi bacteremia at Toranomon Hospital and Toranomon Hospital Kajigaya between March 2009 and March 2013 were retrospectively reviewed. Sixty-three patients, 34 men and 29 women with a median age of 67 years (range, 37 to 88 years), were diagnosed with H. cinaedi bacteremia. A total of 51,272 sets of blood cultures were obtained during the study period, of which 5,769 sets of blood cultures were positive for some organism and 126 sets were H. cinaedi positive. The time required for blood cultures to become positive for H. cinaedi was≤5 days in 69 sets (55%) and>5 days in 57 sets (45%). Most patients had an underlying disease, including chronic kidney disease (21 cases), solid tumor (19 cases), hematological malignancy (13 cases), diabetes mellitus (8 cases), chronic liver disease (6 cases), and postorthopedic surgery (3 cases). Only 1 patient had no apparent underlying disease. The clinical symptoms included cellulitis in 24 cases, colitis in 7 cases, and fever only in 27 cases, including 7 cases of febrile neutropenia. The 30-day mortality rate of H. cinaedi bacteremia was 6.3%. In conclusion, most cases of H. cinaedi bacteremia occurred in immunocompromised patients. We might have overlooked nearly half of the H. cinaedi bacteremia cases if the duration of monitored blood culture samples had been within 5 days. Therefore, when clinicians suspect H. cinaedi bacteremia, the observation period for blood cultures should be extended. Copyright © 2014, American Society for Microbiology. All Rights Reserved.


Nakanishi K.,Toranomon Hospital | Nakanishi K.,Okinaka Memorial Institute for Medical Research | Shima Y.,Kyorin University
Diabetes Care | Year: 2010

OBJECTIVE - To identify type 1 diabetes-susceptible HLA DR-DQ haplotypes using tag single nucleotide polymorphisms (SNPs) and to estimate the disease risk using these tag SNPs. RESEARCH DESIGN AND METHODS- Five tag SNPs were typed in a total of 211 Japanese subjects including 201 patients with type 1 diabetes who had already been typed for HLA-DRB1, -DQA1, and -DQB1 alleles and 300 control subjects. RESULTS- Tag SNP rs2395185 captured haplotypes involving all DR4 specificities and DR9 specificity with a sensitivity of 98.5% and specificity of 94.9%. Using the T allele of rs2395185, we obtained an odds ratio (95% CI) of 2.87 (2.21-3.74) for type 1 diabetes. In addition, rs3129888 captured haplotypes involving HLA-DRB1*0802 with a sensitivity of 92.3% and specificity of 98.9%. CONCLUSIONS- Typing of two tag SNPs (rs2395185 and rs3129888) may be useful for the screening of Japanese subjects at genetic risk of type 1 diabetes. © 2010 by the American Diabetes Association.


Sakurai R.,University of Tokyo | Koo B.-K.,Seoul National University | Kaneda H.,Okinaka Memorial Institute for Medical Research | Bonneau H.N.,Highlands Consulting Inc. | Nagai R.,University of Tokyo
International Journal of Cardiology | Year: 2013

Background: The effects of cilostazol added to aspirin and clopidogrel (triple antiplatelet therapy: TAT) on clinical outcomes after drug-eluting stent (DES) implantation are unknown. Methods: We conducted a meta-analysis of randomized controlled trials (RCTs) comparing TAT with aspirin and clopidogrel (dual antiplatelet therapy: DAT) in DES patients. Clinical end points were target lesion (TLR) and/or vessel (TVR) revascularization, death, myocardial infarction (MI), stent thrombosis (ST), bleeding, rash, gastrointestinal (GI) side effects, and drug discontinuation. We calculated the pooled estimate based on a fixed-effects model using Peto odds ratio (OR) for rare events. If heterogeneity was observed across an individual RCT, an analysis based on a random-effects model was performed. Results: Eight RCTs were included in this meta-analysis, involving 3590 patients (TAT:DAT = 1800:1790). Up to 24 months, TAT showed a significant reduction in TLR (OR: 0.58, 95% confidence interval (CI): 0.43 to 0.78, p < 0.001) and TVR (OR: 0.58, 95% CI: 0.40 to 0.83, p = 0.003) compared with DAT. The incidence of death, MI, ST, or overall or major bleeding was comparable between the 2 groups, whereas the proportion of rash (OR: 2.50, 95% CI: 1.52 to 4.10, p < 0.001), GI side effects (OR: 3.14, 95% CI: 1.79 to 5.50, p < 0.001), or drug discontinuation (OR: 6.81, 95% CI: 2.12 to 21.86, p < 0.001) was higher in TAT than DAT. Conclusions: In this meta-analysis, TAT was associated with significantly effective outcomes for TLR and TVR without any increase in major adverse events but was associated with tolerance issues compared with DAT after DES implantation. © 2012 Elsevier Ireland Ltd.


Terashima M.,Toyohashi Heart Center | Kaneda H.,Okinaka Memorial Institute for Medical Research | Suzuki T.,Toyohashi Heart Center
Korean Journal of Internal Medicine | Year: 2012

Optical coherence tomography (OCT) is an optical analog of intravascular ultrasound (IVUS) that can be used to examine the coronary arteries and has 10-fold higher resolution than IVUS. Based on polarization properties, OCT can differentiate tissue characteristics (fibrous, calcified, or lipid-rich plaque) and identify thin-cap fibroatheroma. Because of the strong attenuation of light by blood, OCT systems required the removal of blood during OCT examinations. A recently developed frequency-domain OCT system has a faster frame rate and pullback speed, making the OCT procedure more user-friendly and not requiring proximal balloon occlusion. During percutaneous coronary intervention (PCI), OCT can provide detailed information (dissection, tissue prolapse, thrombi, and incomplete stent apposition [ISA]). At follow-up examinations after stent implantation, stent strut coverage and ISA can be assessed. Several OCT studies have demonstrated delayed neointimal coverage following drug-eluting stent (DES) implantation vs. bare metal stent (BMS) placement. While newer DESs promote more favorable vascular healing, the clinical implications remain unknown. Recent OCT studies have provided insights into restenotic tissue characteristics; DES restenotic morphologies differ from those with BMSs. OCT is a novel, promising imaging modality; with more in-depth assessments of its use, it may impact clinical outcomes in patients with symptomatic coronary artery disease. © 2012 The Korean Association of Internal Medicine.

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