Shiga Medical Center Research Institute

Moriyama, Japan

Shiga Medical Center Research Institute

Moriyama, Japan
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Baron J.-C.,University of Paris Pantheon Sorbonne | Yamauchi H.,Shiga Medical Center Research Institute | Fujioka M.,Nara Medical University | Endres M.,Charité - Medical University of Berlin
Journal of Cerebral Blood Flow and Metabolism | Year: 2014

As a sequel of brain ischemia, selective neuronal loss (SNL)-as opposed to pannecrosis (i.e. infarction)-is attracting growing interest, particularly because it is now detectable in vivo. In acute stroke, SNL may affect the salvaged penumbra and hamper functional recovery following reperfusion. Rodent occlusion models can generate SNL predominantly in the striatum or cortex, showing that it can affect behavior for weeks despite normal magnetic resonance imaging. In humans, SNL in the salvaged penumbra has been documented in vivo mainly using positron emission tomography and 11C-flumazenil, a neuronal tracer validated against immunohistochemistry in rodent stroke models. Cortical SNL has also been documented using this approach in chronic carotid disease in association with misery perfusion and behavioral deficits, suggesting that it can result from chronic or unstable hemodynamic compromise. Given these consequences, SNL may constitute a novel therapeutic target. Selective neuronal loss may also develop at sites remote from infarcts, representing secondary 'exofocal' phenomena akin to degeneration, potentially related to poststroke behavioral or mood impairments again amenable to therapy. Further work should aim to better characterize the time course, behavioral consequences-including the impact on neurological recovery and contribution to vascular cognitive impairment-association with possible causal processes such as microglial activation, and preventability of SNL. © 2014 ISCBFM. All rights reserved.


Harper K.M.,Yeshiva University | Hiramoto T.,Yeshiva University | Tanigaki K.,Shiga Medical Center Research Institute | Kang G.,Yeshiva University | And 3 more authors.
Human Molecular Genetics | Year: 2012

Social behavior dysfunction is a symptomatic element of schizophrenia and autism spectrum disorder (ASD). Although altered activities in numerous brain regions are associated with defective social cognition and perception, the causative relationship between these altered activities and social cognition and perception-and their genetic underpinnings-are not known in humans. To address these issues, we took advantage of the link between hemizygous deletion of human chromosome 22q11.2 and high rates of social behavior dysfunction, schizophrenia and ASD. We genetically manipulated Sept5, a 22q11.2 gene, and evaluated its role in social interaction in mice. Sept5 deficiency, against a high degree of homogeneity in a congenic genetic background, selectively impaired active affiliative social interaction in mice. Conversely, virally guided overexpression of Sept5 in the hippocampus or, to a lesser extent, the amygdala elevated levels of active affiliative social interaction in C57BL/6J mice. Congenic knockout mice and mice overexpressing Sept5 in the hippocampus or amygdala were indistinguishable from control mice in novelty and olfactory responses, anxiety or motor activity. Moreover, post-weaning individual housing, an environmental condition designed to reduce stress in male mice, selectively raised levels of Sept5 protein in the amygdala and increased active affiliative social interaction in C57BL/6J mice. These findings identify this 22q11.2 gene in the hippocampus and amygdala as a determinant of social interaction and suggest that defective social interaction seen in 22q11.2-associated schizophrenia and ASD can be genetically and environmentally modified by altering this 22q11.2 gene. © The Author 2012. Published by Oxford University Press. All rights reserved.


Takai S.,Osaka Medical College | Sakonjo H.,Shiga Medical Center Research Institute | Jin D.,Osaka Medical College
Journal of Pharmacological Sciences | Year: 2014

To clarify the role of dipeptidyl peptidase-4 (DPP-4) inhibition in vascular tissues, we compared the effects of the poorly tissue-penetrative DPP-4 inhibitor sitagliptin to the highly tissue-penetrative DPP-4 inhibitor linagliptin in Zucker diabetic fatty (ZDF) rats. Six-week-old ZDF rats were orally treated with placebo, sitagliptin (10 mg/kg), or linagliptin (3 mg/kg) for 4 weeks. Sitagliptin and linagliptin produced equivalent decreases in blood glucose concentrations and increased plasma insulin concentrations during oral glucose tolerance tests after the first and the last treatments. In isolated arteries, acetylcholine-induced vascular relaxation was significantly augmented by sitagliptin and linagliptin, with significantly stronger relaxation observed with linagliptin compared to sitagliptin. Vascular DPP-4 activity was attenuated by these drugs, with linagliptin producing significant greater attenuation than sitagliptin. Vascular malondialdehide levels were significantly lower with linagliptin compared to sitagliptin. Significantly greater attenuation of vascular gene expressions of p22phoxand monocyte chemoattractant protein-1 by linagliptin, compared with sitagliptin, was also observed. In conclusion, the superior vascular protection by linagliptin compared with sitagliptin was unrelated to the regulation of circulating glucose and insulin levels, and the stronger vascular DPP-4 inhibition by linagliptin may contribute to the mechanism of vascular protection. © The Japanese Pharmacological Society.


Takai A.,Kyoto University | Marusawa H.,Kyoto University | Minaki Y.,Kyoto University | Watanabe T.,Kyoto University | And 4 more authors.
Oncogene | Year: 2012

Inflammatory bowel disease (IBD) is an important etiologic factor in the development of colorectal cancer. However, the mechanism underlying carcinogenesis through chronic inflammation is still unknown. Activation-induced cytidine deaminase (AID) is induced by the inflammation and involved in various human carcinogenesis via its mutagenic activity. In the current study, we investigated whether the inflammation/AID axis plays an integral role in the development of colitis-associated cancers. Inflammation in the cecum was more severe than that in other colonic regions, and endogenous AID expression was enhanced most prominently in the inflamed cecal mucosa of interleukin (IL)-10 -/- mice. Blockade of tumor necrosis factor (TNF)-α and IL-12 significantly suppressed AID expression. Although proinflammatory cytokine expression was comparable between IL-10 -/-AID +/+ and IL-10 -/-AID -/- mice, sequencing analyses revealed a significantly lower incidence of somatic mutations in Trp53 gene in the colonic mucosa of IL-10 -/-AID -/- than IL-10 -/-AID +/+ mice. Colon cancers spontaneously developed in the cecum in 6 of 22 (27.2%) IL-10 -/-AID +/+ mice. In contrast, none of the IL-10 -/-AID +/+ mice developed cancers except only one case of neoplasia in the distal colon. These findings suggest that the proinflammatory cytokine-induced aberrant production of AID links colonic inflammation to an enhanced genetic susceptibility to oncogenic mutagenesis. Targeting AID could be a novel strategy to prevent colitis-associated colon carcinogenesis irrespective of ongoing colonic inflammation. © 2012 Macmillan Publishers Limited All rights reserved.


Matsumoto Y.,Kyoto University | Marusawa H.,Kyoto University | Kinoshita K.,Shiga Medical Center Research Institute | Niwa Y.,Shiga Medical Center Research Institute | And 2 more authors.
Gastroenterology | Year: 2010

Background & Aims The DNA/RNA editing enzyme activation-induced cytidine deaminase (AID) is mutagenic and has been implicated in human tumorigenesis. Helicobacter pylori infection of gastric epithelial cells leads to aberrant expression of AID and somatic gene mutations. We investigated whether AID induces genetic aberrations at specific chromosomal loci that encode tumor-related proteins in gastric epithelial cells. Methods Human gastric epithelial cell lines that express activated AID and gastric cells from AID transgenic mice were examined for DNA copy number changes and nucleotide alterations. Copy number aberrations in stomach cells of H pyloriinfected mice and gastric tissues (normal and tumor) from H pyloripositive patients were also analyzed. Results In human gastric cells, aberrant AID activity induced copy number changes at various chromosomal loci. In AID-expressing cells and gastric mucosa of AID transgenic mice, point mutations and reductions in copy number were observed frequently in the tumor suppressor genes CDKN2A and CDKN2B. Oral infection of wild-type mice with H pylori reduced the copy number of the Cdkn2b-Cdkn2a locus, whereas no such changes were observed in the gastric mucosa of H pyloriinfected AID-deficient mice. In human samples, the relative copy numbers of CDKN2A and CDKN2B were reduced in a subset of gastric cancer tissues compared with the surrounding noncancerous region. Conclusions H pylori infection leads to aberrant expression of AID and might be a mechanism of the accumulation of submicroscopic deletions and somatic mutations in gastric epithelial cells. AID-mediated genotoxic effects appear to occur frequently at the CDKN2b-CDKN2a locus and contribute to malignant transformation of the gastric mucosa. © 2010 AGA Institute.


Yamauchi H.,Kyoto University | Nishii R.,Shiga Medical Center Research Institute | Higashi T.,Shiga Medical Center Research Institute | Kagawa S.,Shiga Medical Center Research Institute | Fukuyama H.,Kyoto University
Journal of Cerebral Blood Flow and Metabolism | Year: 2011

In atherosclerotic internal carotid artery (ICA) or middle cerebral artery (MCA) disease, hemodynamic compromise may cause selective neuronal damage manifested as loss of central benzodiazepine receptors (BZRs) in the normal-appearing cerebral cortex, without overt episode of stroke. To investigate the association of decreases in cortical BZRs with hemodynamic compromise and the effect of angiotensin receptor blockers (ARBs) on these receptors in patients whose atherosclerotic ICA or MCA disease is asymptomatic, we measured BZRs using positron emission tomography and 11 C-flumazenil in 79 patients with asymptomatic atherosclerotic ICA or MCA disease and no cortical infarction. Three-dimensional stereotactic surface projections were used to calculate the BZR index, a measure of abnormally decreased BZRs in the cerebral cortex within the MCA distribution. Multiple regression analysis showed this index to be positively correlated with the value of oxygen extraction fraction, with the presence of silent subcortical infarcts, and with the presence of ischemic heart disease, whereas it was negatively correlated with the treatment of hypertension with ARBs. In asymptomatic atherosclerotic ICA or MCA disease, hemodynamic compromise is associated with selective neuronal damage manifested as decreases in cortical BZRs in the noninfarcted cerebral cortex, whereas ARBs are associated with preservation of cortical BZRs. © 2011 ISCBFM All rights reserved.


Higashi T.,Shiga Medical Center Research Institute | Kudo T.,Nagasaki University | Kinuya S.,Kanazawa University
Annals of Nuclear Medicine | Year: 2012

Radioactive iodine (RAI, 131I) has been used as a therapeutic agent for differentiated thyroid cancer (DTC) with over 50 years of history. Recently, it is now attracting attention in medical fields as one of the molecular targeting therapies, which is known as targeted radionuclide therapy. Radioactive iodine therapy (RIT) for DTC, however, is now at stake in Japan, because Japan is confronting several problems, including the recent occurrence of the Great East Japan Disaster (GEJD) in March 2011. RIT for DTC is strictly limited in Japan and requires hospitalization. Because of strict regulations, severe lack of medical facilities for RIT has become one of the most important medical problems, which results in prolonged waiting time for Japanese patients with DTC, including those with distant metastasis, who wish to receive RIT immediately. This situation is also due to various other factors, such as prolonged economic recession, super-aging society, and subsequent rapidly changing medical environment. In addition, due to the experience of atomic bombings in Hiroshima and Nagasaki, Japanese people have strong feeling of "radiophobia". There is fear that GEJD and related radiation contamination may worsen this feeling, which might be reflected in more severe regulation of RIT. To overcome these difficulties, it is essential to collect and disclose all information about the circumstances around this therapy in Japan. In this review, we would like to look at this therapy through several lenses, including historical, cultural, medical, and socio-economic points of view. We believe that clarifying the problems is sure to lead to the resolution of this complicated situation. We have also included several recommendations for future improvements. © 2011 The Japanese Society of Nuclear Medicine.


Yamauchi H.,Shiga Medical Center Research Institute | Higashi T.,Shiga Medical Center Research Institute | Kagawa S.,Shiga Medical Center Research Institute | Kishibe Y.,Shiga Medical Center Research Institute | Takahashi M.,Shiga Medical Center Research Institute
Journal of Neurology, Neurosurgery and Psychiatry | Year: 2013

Objective: Blood pressure (BP) lowering may increase stroke risk in patients with symptomatic major cerebral artery disease and impaired perfusion. To investigate the relationships among BP, impaired perfusion and stroke risk. Methods: We retrospectively analysed data from 130 non-disabled, medically treated patients with either symptomatic extracranial carotid occlusion or intracranial stenosis or occlusion of the carotid artery or middle cerebral arteries. All patients had baseline haemodynamic measurements with 15O-gas positron emission tomography and were followed for 2 years or until stroke recurrence or death. Results: There was a negative linear relationship between systolic BP (SBP) and risk of stroke in the territory of the diseased artery. The 2-year incidence of ischaemic stroke in the territory in patients with normal SBP (<130 mm Hg, 5/32 patients) was significantly higher than in patients with high SBP (2/98, p<0.005). Multivariate analysis revealed that normal SBP and impaired perfusion were independently associated with increased risk of stroke in the previously affected territory, while risk of stroke elsewhere was positively correlated with SBP. Overall, high total stroke risk was observed at lower BP in patients with impaired perfusion and at higher BPs in patients without (interaction, p<0.01). Overall, the relationship between SBP and total stroke recurrence was J-shaped. Conclusions: Impaired perfusion modified the relationship between blood pressure and stroke risk, although this study had limitations including the retrospective analysis, the potentially biased sample, the small number of critical events and the fact that BP was measured only as a snapshot in clinic.


Yamauchi H.,Shiga Medical Center Research Institute
Neurologia Medico-Chirurgica | Year: 2015

In patients with atherosclerotic internal carotid artery or middle cerebral artery occlusive disease, chronic reduction in cerebral perfusion pressure (chronic hemodynamic compromise) increases the risk of ischemic stroke and can be detected by directly measuring hemodynamic parameters. However, strategies for selecting treatments based on hemodynamic measurements have not been clearly established. Bypass surgery has been proven to improve hemodynamic compromise. However, the benefit of bypass surgery for reducing the stroke risk in patients with hemodynamic compromise is controversial. The results of the two randomized controlled trials were inconsistent. Hypertension is a major risk factor for stroke, and antihypertensive therapy provides general benefit to patients with symptomatic atherosclerotic major cerebral artery disease. However, the benefit of strict control of blood pressure for reducing the stroke risk in patients with hemodynamic compromise is a matter of debate. The results of the two observational studies were different. We must establish strategies for selecting treatments based on hemodynamic measurements in atherosclerotic major cerebral artery disease. © 2015, Japan Neurosurgical Society. All rights reserved.


Nagahama Y.,Shiga Medical Center Research Institute | Okina T.,Shiga Medical Center Research Institute | Suzuki N.,Shiga Medical Center Research Institute
Journal of Neurology, Neurosurgery and Psychiatry | Year: 2015

Introduction: To examine whether imitation of gestures provided useful information to diagnose early dementia in elderly patients. Methods: Imitation of finger and hand gestures was evaluated in patients with mild dementia; 74 patients had dementia with Lewy bodies (DLB), 100 with Alzheimer's disease (AD) and 52 with subcortical vascular dementia (SVaD). Results: Significantly, more patients with DLB (32.4%) compared with patients with AD (5%) or SVaD (11.5%) had an impaired ability to imitate finger gestures bilaterally. Also, significantly, more patients with DLB (36.5%) compared with patients with AD (5%) or SVaD (15.4%) had lower mean scores of both hands. In contrast, impairment of the imitation of bimanual gestures was comparable among the three patient groups (DLB 50%, AD 42%, SVaD 42.3%). Discussion: Our study revealed that imitation of bimanual gestures was impaired non-specifically in about half of the patients with mild dementia, whereas imitation of finger gestures was significantly more impaired in patients with early DLB than in those with AD or SVaD. Although the sensitivity was not high, the imitation tasks may provide additional information for diagnosis of mild dementia, especially for DLB. © 2015, BMJ Publishing Group. All rights reserved.

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