Shin-ichiro Ueda

Factors associated with serum high mobility group box 1 (HMGB1) levels in a general population

High mobility group box 1 (HMGB1), a nonhistone chromatin-associated protein, is implicated as a mediator of both infectious and non-infectious inflammatory conditions. Clinical research on this protein in humans just has begun; serum HMGB1 was reported to be elevated in a small number of critically ill patients suffering from sepsis. However, the kinetics, distribution and factors associated with circulating HMGB1 are unknown in a general population. In this study, we examined these issues in a large population of healthy subjects. Fasting blood samples were obtained from 626 subjects (237 males and 389 females). HMGB1 levels showed a skewed distribution with a mean of 1.65 +/- 0.04 ng/ml. Multiple stepwise regression analyses found that white blood cell (WBC) counts (P = .016) and the soluble form of receptor for advanced glycation end products (sRAGE; P < .001, inversely), which is also known to be a receptor for HMGB1, were independently associated with HMGB1 levels. We demonstrated for the first time that circulating HMGB1 levels were inversely associated with sRAGE levels in a general population. Because RAGE is involved in HMGB1 signaling, our present study suggests that sRAGE may capture and eliminate circulating HMGB1 in humans.

Administration of Pigment Epithelium-Derived Factor Inhibits Left Ventricular Remodeling and Improves Cardiac Function in Rats with Acute Myocardial Infarction

Oxidative stress and inflammation are involved in cardiac remodeling after acute myocardial infarction (AMI). We have found that pigment epithelium-derived factor (PEDF) inhibits vascular inflammation through its anti-oxidative properties. However, effects of PEDF on cardiac remodeling after AMI remain unknown. We investigated whether PEDF could inhibit left ventricular remodeling and improve cardiac function in rats with AMI. AMI was induced in 8-week-old Sprague-Dawley rats by ligation of the left ascending coronary artery. Rats were treated intravenously with vehicle or 10 μg PEDF/100 g b.wt. every day for up to 2 weeks after AMI. Each rat was followed until 16 weeks of age. PEDF levels in infarcted areas and serum were significantly decreased at 1 week after AMI and remained low during the observational periods. PEDF administration inhibited apoptotic cell death and oxidative stress generation around the infarcted areas at 2 and 8 weeks after AMI. Further, PEDF injection suppressed cardiac fibrosis by reducing transforming growth factor-β and type III collagen expression, improved left ventricular ejection fraction, ameliorated diastolic dysfunction, and inhibited the increase in left ventricular mass index at 8 weeks after AMI. The present study demonstrated that PEDF could inhibit tissue remodeling and improve cardiac function in AMI rats. Substitution of PEDF may be a novel therapeutic strategy for cardiac remodeling after AMI.

Administration of pigment epithelium-derived factor (PEDF) inhibits cold injury-induced brain edema in mice

Brain edema is the most life-threatening complication that occurs as a result of a number of insults to the brain. However, its therapeutic options are insufficiently effective. We have recently found that administration of pigment epithelium-derived factor (PEDF) inhibits retinal hyperpermeability in rats by counteracting biological effects of vascular endothelial growth factor (VEGF). In this study, we investigated whether PEDF could inhibit cold injury-induced brain edema in mice. Cold injury was induced by applying a pre-cooled metal probe on the parietal skull. VEGF and its receptor Flk-1 gene and/or protein expressions were up-regulated in the cold-injured brain. Cold injury induced brain edema, which was reduced by intraperitoneal injection of VEGF antibodies (Abs) or apocynin, an inhibitor of NADPH oxidase. PEDF mRNA and protein levels were up-regulated in response to cold injury. PEDF dose-dependently inhibited the brain edema, whose effect was neutralized by simultaneous treatments with anti-PEDF Abs. Although VEGF and Flk-1 gene and/or protein expressions were not suppressed by PEDF, PEDF or anti-VEGF Abs inhibited the cold injury-induced NADPH oxidase activity in the brain. Further, PEDF treatment inhibited activation of Rac-1, an essential component of NADPH oxidase in the cold-injured brain, while it did not affect mRNA levels of gp91phox, p22phox, or Rac-1. These results demonstrate that PEDF could inhibit the cold injury-induced brain edema by blocking the VEGF signaling to hyperpermeability through the suppression of NADPH oxidase via inhibition of Rac-1 activation. Our present study suggests that PEDF may be a novel therapeutic agent for the treatment of brain edema.

An α-glucosidase inhibitor, acarbose treatment decreases serum levels of glyceraldehyde-derived advanced glycation end products (AGEs) in patients with type 2 diabetes

Diabetes is a major risk factor for cardiovascular disease (CVD) morbidity and mortality, and the incidence of CVD is 2–4 times greater in diabetic patients than in a general population [1]. There is a growing body of evidence that postprandial hyperglycemia plays an important role in the development and progression of CVD [2, 3]. Indeed, the DECODE study revealed that 2-h postload hyperglycemia was associated with an increased risk of mortality from CVD, independent of fasting plasma glucose [2]. Further, the Diabetes Intervention Study identified postprandial hyperglycemia to be an independent risk factor for myocardial infarction and all-cause mortality [3]. Since postprandial hyperglycemia is associated with endothelial dysfunction and increased intima-media thickness (IMT) of the common carotid arteries [4], postprandial hyperglycemia is a therapeutic target for preventing CVD in type 2 diabetes. Acarbose, an a-glucosidase inhibitor, which delays the absorption of carbohydrate from the small intestine, reduces postprandial hyperglycemia in patients with type 2 diabetes [4]. Recently, acarbose treatment was reported to slow the progression of IMT of the carotid arteries and to reduce the incidence of CVD in patients with impaired glucose tolerance or type 2 diabetes [4], thus suggesting that acarbose treatment could inhibit the development and progression of CVD by suppressing postprandial hyperglycemia. We have previously shown that glyceraldehyde can rapidly react with amino groups of proteins to form glyceraldehyde-derived advanced glycation end products (AGEs) in vivo, which evoke vascular inflammation and oxidative stress generation, thereby being implicated in accelerated atherosclerosis in diabetes [5, 6]. Further, recently, we found that serum levels of glyceraldehydederived AGEs rather than HbA1c could reflect cumulative postprandial hyperglycemia in type 2 diabetic rats [7]. These observations led us to speculate that acarbose treatment reduced serum levels of glyceraldehyde-derived AGEs, which could contribute to its cardioprotective properties in vivo. To address this issue, we investigated the effects of acarbose on anthropometric and metabolic variables, including glyceraldehyde-derived AGE levels in oral hypoglycemic agent (OHA)-naive type 2 diabetic patients. The study protocol was approved by our institutional ethics committee, and informed consent was obtained from all patients. Thirteen OHA-naive Japanese type 2 diabetic patients (mean age of 63.6 ± 2.4 years, 10 males and 3 females) without microangiopathy, coronary artery disease or any active inflammatory disease were enrolled for the present study. The patients were treated with 50 mg acarbose three times a day for 12 weeks. Blood pressure (BP) was measured in the sitting position using an upright M. Tsunosue N. Mashiko Y. Ohta Y. Matsuo K. Ueda M. Ninomiya S. Tanaka M. Hoshiko Y. Yoshiyama YY Research Group, Yanagawa-Yamato, Japan

Longest Survivor of Pulmonary Atresia With Ventricular Septal Defect Well-Developed Major Aortopulmonary Collateral Arteries Demonstrated by Multidetector Computed Tomography

A 59-year-old woman was admitted because of cyanosis and dyspnea on exertion and at rest. In her childhood, she was suspected of having ventricular septal defect (VSD), but she refused to undergo cardiac catheterization and operation. Dyspnea on exertion gradually developed after adolescence. On admission, chest roentgenography demonstrated enlarged cardiac silhouette with elevated cardiac apex, a right aortic arch, and enlargement of the main pulmonary arteries and their major branches with increased pulmonary arterial vascularity (Figure 1). Echocardiography revealed a large VSD which lay beneath the dilated aorta that overrides the interventricular septum, hypertrophied right ventricle, and the blind outflow tract of the right ventricle …

Low-density lipoprotein levels are one of the independent determinants of circulating levels of advanced glycation end products in nondiabetic subjects.

Nonenzymatic modification of proteins by reducing sugars leads to the formation of advanced glycation end products (AGEs), whose process has been reported to progress under diabetes. Recently, diet has been found to be a major environmental source of proinflammatory AGEs in humans. Further, fats or meat‐derived products processed by high heat such as broiling have been shown to contain more AGEs than carbohydrates boiled for longer periods. Since circulating levels of low‐density lipoprotein cholesterol (LDL‐C) are also regulated by dietary cholesterol, it is conceivable that intake of cholesterol‐rich foods could regulate serum levels of AGEs in humans. In this study, we investigated whether LDL‐C levels are one of the independent determinants of circulating AGEs levels in a nondiabetic general population.

Miliary Tuberculosis Noticed by the Efficacy of Levofloxacin Monotherapy

1 Department of Infection Control and Prevention, Kurume University School of Medicine 2 Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine 3 Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine 4 Coronary Care Unit, Advanced Emergency Medical Service Center, Kurume University School of Medicine 5 Department of Pathology, Kurume University School of Medicine