Yusuke Uemura

Prevalence of restless legs syndrome in a rural community in Japan

To assess the prevalence and clinical significance of restless legs syndrome (RLS) in a Japanese population, we carried out a community‐based survey in a rural area of Japan. We sent questionnaires requesting information on demographics, the Center for Epidemiological Studies Depression scale, the Short Form‐8, the Pittsburgh Sleep Quality Index, the National Institutes of Health/International RLS Study Group (IRLSSG) consensus questionnaire, and the IRLSSG severity scale for RLS (IRLS) to 5,528 eligible adult residents in the town of Daisen in the Tottori prefecture of Japan. Next, we performed telephone interviews to identify subjects with probable RLS. Of the 2,812 subjects (51.1%) who gave complete answers on the IRLSSG questionnaire, 50 (1.8%) were judged as RLS positive. The prevalence of RLS was significantly higher in women than in men, and significantly lower in individuals 60 years of age or older. Multiple logistic regression analysis revealed that the existence of RLS was significantly associated with depression, lowered mental quality of life, and sleep disturbances. The prevalence of RLS in adult Japanese populations may be lower than that reported in Caucasian populations. However, in a group of Japanese subjects, RLS had a significant impact on daytime functioning as well as subjective sleep quality.

Utility of the REM sleep behavior disorder screening questionnaire (RBDSQ) in Parkinson's disease patients.

OBJECTIVE We evaluated the usefulness of the REM sleep behavior disorder (RBD) screening questionnaire (RBDSQ) among patients with Parkinsons disease (PD). METHODS Forty-five patients with PD were evaluated (22 male and 23 female, 72.9±9.1 years old). After patients completed the RBDSQ, we conducted interviews regarding RBD symptoms and performed polysomnographic examinations on the subjects. We then compared RBDSQ scores among the following groups: PD with RBD (n=19), PD without RBD (n=26), and idiopathic RBD (n=31, 22 male and 9 female, 67.8±6.5 years old), and estimated the cut-off score for an RBD diagnosis. RESULTS RBDSQ scores in PD with RBD and idiopathic RBD groups were similar and higher than those in the PD without RBD group (PD with RBD: 7.2±1.9, idiopathic RBD: 7.9±2.8, PD without RBD: 2.9±1.6). Cronbachs α for RBDSQ sub-scores was 0.73, suggesting a fair internal consistency. A receiver-operator characteristics curve revealed that a total score of 6 points on the RBDSQ represented the best cut-off value for detecting RBD (sensitivity=0.842, specificity=0.962). CONCLUSION RBDSQ could be a useful tool for the screening of RBD in PD patients.

CTRP9 Protein Protects against Myocardial Injury following Ischemia-Reperfusion through AMP-activated Protein Kinase (AMPK)-dependent Mechanism

Background: The functional role of the fat-derived plasma protein CTRP9 in ischemic heart disease is unknown. Results: Systemic delivery of CTRP9 reduces myocardial infarct size and apoptosis following ischemia-reperfusion in mice. CTRP9 protects cardiomyocyte from apoptosis through activation of AMP-activated protein kinase (AMPK). Conclusion: CTRP9 prevents acute cardiac ischemic injury via an AMPK-dependent mechanism. Significance: CTRP9 represents a novel target molecule for manipulation of myocardial ischemic injury. Ischemic heart disease is the major cause of death in Western countries. CTRP9 (C1q/TNF-related protein 9) is a fat-derived plasma protein that has salutary effects on glucose metabolism and vascular function. However, the functional role of CTRP9 in ischemic heart disease has not been clarified. Here, we examined the regulation of CTRP9 in response to acute cardiac injury and investigated whether CTRP9 modulates cardiac damage after ischemia and reperfusion. Myocardial ischemia-reperfusion injury resulted in reduced plasma CTRP9 levels and increased plasma free fatty acid levels, which were accompanied by a decrease in CTRP9 expression and an increase in NADPH oxidase component expression in fat tissue. Treatment of cultured adipocytes with palmitic acid or hydrogen peroxide reduced CTRP9 expression. Systemic administration of CTRP9 to wild-type mice, before the induction of ischemia or at the time of reperfusion, led to a reduction in myocardial infarct size following ischemia-reperfusion. Administration of CTRP9 also attenuated myocyte apoptosis in ischemic heart, which was accompanied by increased phosphorylation of AMP-activated protein kinase (AMPK). Treatment of cardiac myocytes with CTRP9 protein reduced apoptosis in response to hypoxia/reoxygenation and stimulated AMPK phosphorylation. Blockade of AMPK activity reversed the suppressive actions of CTRP9 on cardiomyocyte apoptosis. Knockdown of adiponectin receptor 1 diminished CTRP9-induced increases in AMPK phosphorylation and survival of cardiac myocytes. Our data suggest that CTRP9 protects against acute cardiac injury following ischemia-reperfusion via an AMPK-dependent mechanism.

Omentin Prevents Myocardial Ischemic Injury Through AMP-Activated Protein Kinase- and Akt-Dependent Mechanisms

OBJECTIVES This study examined the impact of omentin on myocardial injury in a mouse model of ischemia/reperfusion (I/R) and explored its underlying mechanisms. BACKGROUND Obesity is a major risk factor for ischemic heart disease. Omentin is a circulating adipokine that is down-regulated by obesity. METHODS In patients who underwent successful reperfusion treatment after acute myocardial infarction, cardiac function and perfusion defect were assessed by using scintigraphic images. Mice were subjected to myocardial ischemia followed by reperfusion. RESULTS This study found that high levels of plasma omentin were associated with improvement of heart damage and function after reperfusion therapy in patients with acute myocardial infarction. Systemic administration of human omentin to mice led to a reduction in myocardial infarct size and apoptosis after I/R, which was accompanied by enhanced phosphorylation of AMP-activated protein kinase (AMPK) and Akt in the ischemic heart. Fat-specific overexpression of human omentin also resulted in reduction of infarct size after I/R. Blockade of AMPK or Akt activity reversed omentin-induced inhibition of myocardial ischemic damage and apoptosis in mice. In cultured cardiomyocytes, omentin suppressed hypoxia/reoxygenation-induced apoptosis, which was blocked by inactivation of AMPK or Akt. CONCLUSIONS Our data indicate that omentin functions as an adipokine that ameliorates acute ischemic injury in the heart by suppressing myocyte apoptosis through both AMPK- and Akt-dependent mechanisms.

Adipose-derived factor CTRP9 attenuates vascular smooth muscle cell proliferation and neointimal formation

Obesity is closely associated with the progression of vascular disorders, including atherosclerosis and postangioplasty restenosis. C1q/TNF‐related protein (CTRP) 9 is an adipocytokine that is down‐regulated in obese mice. Here we investigated whether CTRP9 modulates neointimal hyperplasia and vascular smooth muscle cell (VSMC) proliferation in vivo and in vitro. Left femoral arteries of wild‐type (WT) mice were injured by a steel wire. An adenoviral vector expressing CTRP9 (Ad‐CTRP9) or β‐galactosidase as a control was intravenously injected into WT mice 3 d before vascular injury. Delivery of Ad‐CTRP9 significantly attenuated the neointimal thickening and the number of bromode‐oxyuridine‐positive proliferating cells in the injured arteries compared with that of control. Treatment of VSMCs with CTRP9 protein attenuated the proliferative and chemotactic activities induced by growth factors including platelet‐derived growth factor (PDGF)‐BB, and suppressed PDGF‐BB‐stimulated phosphorylation of ERK. CTRP9 treatment dose‐dependently increased cAMP levels in VSMCs. Blockade of cAMP‐PKA pathway reversed the inhibitory effect of CTRP9 on DNA synthesis and ERK phosphorylation in response to PDGF‐BB. The present data indicate that CTRP9 functions to attenuate neointimal formation following vascular injury through its ability to inhibit VSMC growth via cAMP‐dependent mechanism, suggesting that the therapeutic approaches to enhance CTRP9 production could be valuable for prevention of vascular restenosis after angioplasty.—Uemura, Y., Shibata, R., Ohashi, K., Enomoto, T., Kambara, T., Yamamoto, T., Ogura, Y., Yuasa, D., Joki, Y., Matsuo, K., Miyabe, M., Kataoka, Y., Murohara, T., Ouchi, N. Adipose‐derived factor CTRP9 attenuates vascular smooth muscle cell proliferation and neointimal formation. FASEB J. 27, 25–33 (2013). www.fasebj.org

Relationship between 123I-MIBG scintigrams and REM sleep behavior disorder in Parkinson’s disease

BACKGROUND Uptake of (123)I-labeled meta-iodobenzylguanidine (MIBG) in myocardial scintigrams has been shown to be as low in patients with idiopathic RBD as in Parkinsons disease (PD) patients. AIM FOR STUDY: To clarify whether the existence of RBD accelerates autonomic dysfunction in PD, we investigated the association between MIBG scintigraphic findings and RBD measures among non-dementia PD patients. SUBJECTS & METHODS We conducted clinical interviews to assess REM sleep behavior disorder (RBD) symptoms, and performed polysomnograms (PSG) recordings and MIBG scintigrams on 49 PD patients. The patients were divided into three groups (PD with clinical RBD, PD with subclinical RBD, and PD with normal REM sleep). RESULTS PD patients with clinical RBD had reduced MIBG uptake as determined by heart-to-mediastinum ratios of the delayed image compared to those with subclinical RBD and those with normal REM sleep. Multiple linear regression analysis revealed that only the existence of RBD symptoms was significantly associated with reduced MIBG uptake among PD patients without dementia after adjusting for demographic and PD symptom-related variables. CONCLUSION PD patients with clinical RBD might suffer from a wider α-synuclein pathology, including reduced cardiac sympathetic ganglia function as reflected by a lowered MIBG uptake.

Prevalence of dementia in the rural island town of Ama-cho, Japan.

Background: With the striking increase in the number of elderly people in Japan, dementia has not only become a medical but also a social issue. Methods: We studied the prevalence of dementing disorders in a rural island town of Japan (Ama-cho), using a door-to-door 2-phase design. Results: Of the 120 persons screened as having cognitive impairment, 104 people were diagnosed as having dementia. The prevalence (cases/100 persons aged 65 years and older) was 11.0 for all types of dementia, 7.0 for Alzheimer’s disease, 1.7 for vascular dementia, 0.53 for dementia with Lewy bodies, 0.74 for Parkinson’s disease dementia, 0.21 for progressive supranuclear palsy, 0.11 for frontotemporal lobar degeneration and 0.74 for other dementia. The overall prevalence was higher in women for Alzheimer’s disease and Parkinson’s disease dementia, and in men, for vascular dementia and dementia with Lewy bodies. Conclusion: We confirmed the overall prevalence of dementia in the elderly population aged 65 years and older to be 11.0. This finding is higher compared with previous reports in Japan.

FGF21 attenuates pathological myocardial remodeling following myocardial infarction through the adiponectin-dependent mechanism

Ischemic heart disease is one of the leading causes of death. Fibroblast growth factor 21 (FGF21) is a circulating factor with an anti-diabetic property. Skeletal muscle is an important source of FGF21 production. Here, we investigated whether skeletal muscle-derived FGF21 modulates cardiac remodeling in a murine model of myocardial infarction. Myocardial infarction was produced in C57BL/6J wild-type (WT) mice by the permanent ligation of the left anterior descending coronary artery (LAD). Adenoviral vectors expressing FGF21 (Ad-FGF21) or control β-galactosidase were intramuscularly injected into mice at 3 days before permanent LAD ligation. Intramuscular injection of Ad-FGF21 increased plasma FGF21 levels in WT mice compared with control. Treatment of WT mice with Ad-FGF21 led to improvement of left ventricular systolic dysfunction and dilatation at 2 weeks after LAD ligation. Ad-FGF21 administration to WT mice also led to enhancement of capillary density in the infarct border zone, and reduction of myocyte apoptosis in the remote zone, which were accompanied by decreased expression of pro-inflammatory cytokines. Furthermore, treatment of WT mice with Ad-FGF21 increased plasma levels of adiponectin, which is a cardioprotective adipokine. The beneficial effects of Ad-FGF21 on cardiac dysfunction and inflammatory response after myocardial infarction were diminished in adiponectin-knockout mice. These data suggest that muscle-derived FGF21 ameliorates adverse cardiac remodeling after myocardial infarction, at least in part, through an adiponectin-dependent mechanism.

Comparison of the clinical features of rapid eye movement sleep behavior disorder in patients with Parkinson's disease and multiple system atrophy

Aims:  The aim of this study was to evaluate differences in the clinical presentation and polysomnographic characteristics of rapid eye movement sleep behavior disorder (RBD) between patients with Parkinsons disease (PD) and those with multiple system atrophy (MSA).

Atorvastatin 10 mg plus ezetimibe 10 mg compared with atorvastatin 20 mg: Impact on the lipid profile in Japanese patients with abnormal glucose tolerance and coronary artery disease

BACKGROUND Oxidized low-density lipoprotein (LDL) cholesterol is a sensitive lipid marker for predicting atherosclerosis. Ezetimibe and statins are reported to decrease both LDL cholesterol and oxidized LDL cholesterol. This prospective randomized open-label crossover study compared combination therapy with atorvastatin plus ezetimibe versus high-dose atorvastatin monotherapy. Changes in serum lipids, including malondialdehyde-modified LDL (MDA-LDL) as a representative form of oxidized LDL cholesterol, and glucose metabolism were assessed. METHODS AND RESULTS The subjects were 39 Japanese patients with coronary artery disease and type 2 diabetes or impaired glucose tolerance who were taking 10 mg/day of atorvastatin (30 men and 9 women with a mean age of 67.8 years). They were randomized to a group that first received add-on ezetimibe (10 mg/day) or a group that first received atorvastatin monotherapy at a higher dose of 20 mg/day. Both treatments were given for 12 weeks each in a crossover fashion. Add-on ezetimibe significantly decreased MDA-LDL (109.0 ± 31.9 mg/dl to 87.7 ± 29.4 mg/dl, p=0.0009), while up-titration of atorvastatin did not. The decrease with add-on ezetimibe was significantly greater than with up-titration of atorvastatin (p=0.0006). Total cholesterol and LDL cholesterol were significantly decreased by both treatments, but the percent reduction with add-on ezetimibe was significantly greater (p<0.05). High-density lipoprotein cholesterol was significantly increased by both treatments and there was no significant difference between them. The apolipoprotein B/apolipoprotein A-I ratio and remnant-like particle cholesterol were only significantly decreased by add-on ezetimibe. Both treatments caused similar elevation of hemoglobin A(1c). CONCLUSION In Japanese patients with type 2 diabetes or impaired glucose tolerance and coronary artery disease, adding ezetimibe (10 mg/day) to atorvastatin (10 mg/day) significantly improved the lipid profile compared with atorvastatin monotherapy at 20 mg/day.