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Controversies concerning the association between obesity and acute myocardial infarction (AMI) are still ongoing in Japan. We investigated the association between obesity defined by body mass index of 25 kg/m(2) or higher and AMI by a case-control study using data from 1199 AMI cases and 4056 apparently healthy controls. The analysis was performed in age- and sex-matched samples of 621 case-control pairs younger than 80 years and in crude samples aged 40-79 years divided into 10-year age groups. Prevalence of obesity, diabetes, current smoking, hypertension, and hypercholesterolemia were compared between cases and controls, and a multivariable odds ratio (OR) of AMI was calculated for each risk factor in various age groups. The OR (95 % confidence interval (CI)) of AMI for obesity was 1.63 (1.23-2.17), P = 0.0008 in men younger than 80 years; 2.65 (1.41-5.00), P = 0.0025 in women younger than 80 years; 2.23 (1.46-3.41), P = 0.0002 in men aged 59 years or younger; 1.34 (0.90-2.01), P = 0.1510 in men aged 60-79 years; and 2.98 (1.56-5.71), P = 0.0010 in women aged 60-79 years using paired samples. The OR (95 % CI) of AMI for obesity was 4.92 (2.53-9.58), P < 0.0001 in men aged 40-49 years; 1.54 (1.07-2.21), P = 0.0197 in men aged 50-59 years; 1.07 (0.69-1.66), P = 0.7717 in men aged 60-69 years; 2.24 (1.20-4.20), P = 0.0118 in men aged 70-79 years; 2.48 (1.12-5.48), P = 0.0245 in women aged 60-69 years; and 3.05 (1.46-6.37), P = 0.0029 in women aged 70-79 years using crude samples. The association between obesity and AMI was age- and gender-dependent in a Japanese population.

To compare high-sensitivity C-reactive protein (hs-CRP) and white blood cell count (WBC) as a predictor of metabolic syndrome (MetS). Hazard ratios (HRs) adjusted for age, smoking, and other confounding covariates and areas under receiver operating characteristic curve (AUCs) of hs-CRP and WBC for developing MetS were calculated in 1,463 men and 920 women from a Japanese health screening population who were free from MetS, diabetes, histories of coronary heart disease, and stroke at baseline and followed through 3 years. The adjusted HRs (95% confidence interval-CI; p value) of MetS for each 1 SD increases in log hs-CRP, and log WBC were 1.345 (1.166-1.553; <0.001) and 1.406 (1.188-1.664; <0.001), respectively, in men and 1.388 (1.110-1.736; 0.004) and 1.358 (1.072-1.721; 0.011), respectively, in women. However, the HRs became nonsignificant after further adjusted for the components of MetS. The AUCs (95% CI; p value) of hs-CRP and WBC for predicting MetS were 0.616 (0.573-0.660; <0.001) and 0.613 (0.566-0.659; <0.001), respectively, in men and 0.636 (0.573-0.698; <0.001) and 0.606 (0.538-0.673; 0.003), respectively, in women. Hs-CRP and WBC equally predict development of MetS, but both are poor predictors of MetS in a Japanese health screening population where obesity is not prevailing.

Serum total bilirubin (TB) is a potent antioxidant and inversely associated with metabolic syndrome (MetS) in Asian populations. However, there has been no study which is aimed to investigate whether TB is a risk factor for MetS or not. We investigated cross-sectional and longitudinal associations between TB and MetS in 2,435 Japanese men and 1,436 Japanese women. The odds ratios [95 % confidence interval (CI)] of coexisting MetS for each 1 SD increase in log TB were 0.850 (0.754-0.958) (p = 0.008) in men and 0.809 (0.656-0.998) (p = 0.047) in women adjusted for sex, age, smoking, and other confounding covariates. Those for the third and fourth quartiles of TB compared with the lowest quartile were 0.720 (0.537-0.965) (p = 0.028) and 0.737 (0.530-1.052) (p = 0.095), respectively, in men and 0.822 (0.473-1.427) (p = 0.486) and 0.704 (0.362-1.369) (p = 0.301), respectively, in women. There was a tendency that TB and MetS changed inversely to each other. The similarly adjusted hazard ratios of developing MetS for each 1 SD increase in log TB and for the higher quartiles of TB compared with the lowest quartile were not significant either in men or in women. TB is inversely associated with MetS but not a risk factor for MetS in Japanese men and women.

Objective: The associations between atrial fibrillation (AF) or complete right bundle branch block (RBBB) and other laboratory tests have not been examined sufficiently in healthy populations., Methods: These associations were examined with multivariable logistic regression analyses using data from 6,381 apparently healthy subjects including 46 subjects with AF and 100 subjects with RBBB., Results: The mean age, body mass index (BMI), hemoglobin, the prevalence of male sex and a history of coronary heart disease (CHD) were significantly higher in subjects with AF or RBBB than without. The odds ratio (OR) (95% confidence interval (CI)) of AF was 1.62 (1.28-2.05) p<0.0001 for each 1 g/dL increment of hemoglobin and 1.07 (0.36-3.21) p=0.90 and 4.32 (1.29-14.43) p=0.017, respectively for the second and the third tertiles of hemoglobin compared with the first tertile after adjusting for sex, age, BMI, CHD, and other confounding covariates. The OR (95% CI) of RBBB was 1.53 (1.32-1.77) p<0.0001 for each 1 g/dL increment of hemoglobin and 2.53 (1.06-6.00) p=0.036, 3.10 (1.12-8.61) p=0.030, and 4.03 (0.91-17.82) p=0.066, respectively, for the second, third, and fourth quartiles of hemoglobin compared with the first quartile after adjusting for sex, age, BMI, CHD, and other confounding covariates., Conclusion: An increased blood levels of hemoglobin was independently associated with AF and RBBB after adjusting for sex, age, BMI, CHD, and other confounding covariates in apparently healthy subjects.

Objective: Both increased serum levels of low-density lipoprotein cholesterol (LDLC) and metabolic syndrome (MetS) are associated with obesity and have been established to be risk factors of cardiovascular disease. However, studies on the relationship between LDLC and MetS have been limited., Methods: Cross-sectional (n=3,871) and longitudinal (n=2,558) associations between LDLC and MetS were examined in a Japanese health screening population., Results: The odds ratio (OR) [95% confidence interval (CI)] of coexisting MetS for each one SD increase in the LDLC level was 1.25 [1.12-1.40] (p<0.001) adjusted for body mass index (BMI) and other confounding covariates and 1.12 [0.97-1.28] (p=0.119) adjusted for numerical values of the components of MetS and other confounding covariates. The similarly adjusted ORs [95% CIs] for the highest quartile of LDLC (Q4) compared with the lowest quartile (Q1) were 1.76 [1.22-2.54] (p=0.002) and 1.46 (0.93-2.30) (p=0.101), respectively. The hazard ratio (HR) [95% CI] for developing MetS for each one SD increase in the LDLC level was 1.24 [1.10-1.40] (p<0.001) adjusted for BMI and other confounding covariates and 1.19 [1.05-1.34] (p=0.006) adjusted for the pre-existing dichotomous five components of MetS and other confounding covariates. The similarly adjusted HRs [95% CIs] for developing MetS for Q4 compared with Q1 were 1.71 [1.17-2.51] (p=0.006) and 1.61 [1.08-2.40] (p=0.020), respectively., Conclusion: The LDLC level is associated with coexisting MetS and functions as a predictor of the development of MetS, independent of BMI or the pre-existing components of MetS, in a Japanese health screening population.

Objective: Although metabolic syndrome (MS) is considered to be a predictor of diabetes and cardiovascular disease, its value for predicting diabetes beyond the levels of fasting glucose (FG) and hemoglobin A1c (HbA1c) remains questionable. In this study, we evaluated the usefulness of MS and Japanese MS (JMS) as predictors of diabetes., Methods: This study is a longitudinal study using data for 2,034 subjects who visited our Medical Check-up Center in both 2008 and 2011 and were free from diabetes at baseline. The odds ratios (ORs) of developing diabetes in 2011 for MS and JMS were calculated after being adjusted for FG, age, sex and antihypertensive and antihyperlipidemic medication use, then further adjusted for HbA1c. The optimal cutoff points for FG, HbA1c and body mass index (BMI) to discriminate the development of diabetes and their sensitivities/specificities were obtained from receiver operating characteristic curves. These sensitivities/specificities were compared with the sensitivities/specificities of MS and JMS., Results: The ORs (95% confidence intervals (CIs)) of developing diabetes for MS and JMS were 1.36 (0.57-3.23) (p=0.484) and 3.23 (1.25-8.36) (p=0.016), respectively, after being adjusted for FG and 1.06 (0.39-2.86) (p=0.915) and 2.34 (0.79-6.95) (p=0.126), respectively, after being further adjusted for HbA1c. The sensitivities/specificities of FG, HbA1c, BMI, MS and JMS were 0.625/0.897, 0.828/0/919, 0.625/0.734, 0.375/0.911, and 0.375/0.941, respectively., Conclusion: MS and JMS were found to be poor predictors of diabetes in a Japanese health screening population.

Among the ongoing attempts to enhance cognitive performance, an emergent and yet underrepresented venue is brought by hemoencefalographic neurofeedback (HEG). This paper presents three related advances in HEG neurofeedback for cognitive enhancement: a) a new HEG protocol for cognitive enhancement, as well as b) the results of independent measures of biological efficacy (EEG brain maps) extracted in three phases, during a one year follow up case study; c) the results of the first controlled clinical trial of HEG, designed to assess the efficacy of the technique for cognitive enhancement of an adult and neurologically intact population. The new protocol was developed in the environment of a software that organizes digital signal algorithms in a flowchart format. Brain maps were produced through 10 brain recordings. The clinical trial used a working memory test as its independent measure of achievement. The main conclusion of this study is that the technique appears to be clinically promising. Approaches to cognitive performance from a metabolic viewpoint should be explored further. However, it is particularly important to note that, to our knowledge, this is the world's first controlled clinical study on the matter and it is still early for an ultimate evaluation of the technique.

The aim of this study was to investigate the association between leukocyte subtype counts and hyper-LDL cholesterolemia, hypertriglyceridemia, and hypo-HDL cholesterolemia. Logistic regressions using hyper-LDL cholesterolemia, hypertriglyceridemia, and hypo-HDL cholesterolemia as a dependent variable and total leukocyte, basophil, eosinophil, neutrophil, lymphocyte, and monocyte counts as an independent variable were calculated adjusting for age, body mass index (BMI), high-sensitivity C-reactive protein (hs-CRP), smoking, drinking, and physical activity in apparently healthy Japanese men (1,803) and women (1,150). The odds ratio (OR) of hyper-LDL cholesterolemia for total leukocyte, eosinophil, and lymphocyte counts, the OR of hypertriglyceridemia for total leukocyte, eosinophil, neutrophil, and lymphocyte counts, and the OR of hypo-HDL cholesterolemia for total leukocyte, neutrophil, and lymphocyte counts were significant in men, and the OR of hyper-LDL cholesterolemia, for lymphocyte count, and the OR of hypo-HDL cholesterolemia for eosinophil count were significant in women. Lymphocyte count was significantly associated with hyper-LDL cholesterolemia independently of hs-CRP in apparently healthy Japanese.

Background: Apart from the severity of myocardial infarction and coronary artery disease, several predictors of in-hospital death (In-HD) are suggested in patients with acute myocardial infarction (AMI)., Methods: We investigated predictors of In-HD and ventricular rupture (VR) including ventricular septal rupture (VSR) and free wall rupture (FWR) with stepwise multivariable logistic regressions in 1,042 patients admitted to our Cardiovascular Center within 48 hours from symptom onset for the first attack of AMI., Results: In-HD, VSR, and FWR were observed in 78 cases (7.5%), 14 cases of which 13 cases were In-HD, and 13 cases of which 6 cases were In-HD, respectively. Apart from the disease severity, age and renal dysfunction (RD) defined by estimated glomerular filtration rate of lower than 60 mL/min/ 1.73 m 2 were independent positive predictors of In-HD (the odds ratios (ORs) (95% confidence interval (CI)): 1.04 (1.01 - 1.06) P = 0.0069 and 5.75 (3.12 - 10.59) P < 0.0001, respectively) and hypercholesterolemia was an independent negative predictor for In-HD (OR (95% CI): 0.34 (0.17 - 0.67) P = 0.0017). After including the categories of coronary disease, ventricular rupture, and ejection fraction in predictors, RD remained an independent predictor of In-HD (OR (95% CI): 6.65 (2.67 - 16.60) P < 0.0001). Age (OR (95% CI): 1.07 (1.02 - 1.12) P = 0.0064), RD (OR (95% CI): 2.77 (1.18 - 6.49) P = 0.019), and diabetes (OR (95% CI): 2.52 (1.12 - 5.71) P = 0.026) were independent predictors of VR., Conclusions: RD was an independent predictor of In-HD and VR in patients with initial AMI.

Chagas disease is a zoonosis caused by the flagellated parasite Trypanosoma cruzi and transmitted by triatomine insects to several mammalian species acting as reservoir hosts. In the present study, we assess T. cruzi-prevalence, survivorship and T. cruzi-infection rate of the endemic rodent Octodon degus from a hyper-endemic area of Chagas disease in Chile. Parasite detection is performed by PCR assays on blood samples of individuals captured in austral summer of 2010, and on non-infected individuals recaptured in 2011 as well as on new captures. Results show a high infection level in this species (up to 70%). Infected O. degus have the same chance of surviving to the next reproductive season as uninfected individuals, irrespective of sex. We suggest that O. degus, an abundant long-lived rodent with high dispersal capability, could be considered an important native reservoir of T. cruzi in the wild transmission cycle of Chagas disease in Chile., (Copyright © 2011 Elsevier B.V. All rights reserved.)

In late twentieth century, Ruderman and Reaven showed that insulin resistance might be fundamental to metabolic syndrome (MetS) which means a constellation of obesity-related metabolic derangements predisposing to type 2 diabetes and cardiovascular disease. In 2001, user-friendly National Cholesterol Education Program (NCEP) criteria of MetS were proposed. In 2005, the International Diabetes Federation (IDF) and the Examination Committee for Criteria of Metabolic Syndrome in Japan issued different criteria of MetS where abdominal obesity is a necessary component. In 2009, IDF, National Heart, Lung, and Blood Institute, American Heart Association, World Heart Federation, International Atherosclerosis Society, and International Association for the Study of Obesity jointly adopted the revised NCEP criteria, where abdominal obesity is not a necessary component, as worldwide criteria of MetS. In 2010, WHO Expert Consultation warned that MetS is a concept that focuses attention on complex multifactorial health problems but has limited practical utility as a management tool. In animal studies, adipose tissue inflammation characterized by an increased number of crown-like structures in adipose tissue, rather than obesity per se, was shown to be a fundamental mechanism of metabolic derangements.

Backgrounds: The association between cigarette smoking and hypertension is controversial. The aim of this study is to investigate the association between smoking and incident hypertension., Methods: This is a post-hoc five-year follow-up study in a general Japanese population. Logistic regressions were performed using incident hypertension as an outcome and smoking status as an independent predictor adjusting for sex, age, body mass index (BMI), total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, fasting plasma glucose (FPG), drinking status, and diabetes in 1,297 subjects without hypertension at baseline., Results: The incidence of hypertension was 16.9% vs. 27.6% (smokers vs. nonsmokers, P = 0.01) in men and 0.0% vs. 16.9% (smokers vs. nonsmokers, P = 0.03) in women. The odds ratio (OR) (95% confidence interval (CI)) of incident hypertension was 0.38 (0.19 - 0.76) (P = 0.006) for smokers at baseline, 0.33 (0.16 - 0.68) (P = 0.003) for continuing smokers, and 2.11 (0.33 - 13.45) (P = 0.4) for ex-smokers. Age (OR = 1.52, P < 0.0001), BMI (OR = 1.46, P < 0.0001), and FPG (OR = 1.23, P = 0.007) were other independent predictors of incident hypertension., Conclusions: Smoking was a possible significant negative predictor of incident hypertension in a general Japanese population.

Pompe disease is classified into infantile-, childhood- and adult-onset forms based on onset age and the degree of organ involvement. Differing from the infantile-onset form which is characterized by marked organ involvement, the childhood-onset form usually presents with muscle weakness and elevation of serum creatine kinase (CK), mimicking those of progressive muscular dystrophy. We report our successful early diagnosis and initiation of enzyme replacement therapy (ERT) in a young girl with childhood-onset Pompe disease before the development of skeletal muscle symptoms. She was referred to our hospital at the age of 2 years 4 months because of hyperCKemia detected incidentally. She was active and lacked developmental delay and muscle weakness; however, hepatomegaly was noted. The combination of high-density changes in the liver and skeletal muscle on computed tomography (CT) images was suggestive of glycogen storage disorder, especially childhood-onset Pompe disease. Low alpha-glucosidase (GAA) activity on dried blood spots facilitated the diagnostic process, and genetic analysis of GAA allowed a definitive diagnosis, without performing muscle biopsy. We promptly started ERT at the age of 2 years 6 months. After 1 year, she still had not developed any skeletal muscle symptoms, and serum CK level was almost normal. Since the efficacy of ERT is thought to depend on the extent of muscle damage at its commencement, we expect that ERT may have prevented the manifestation of skeletal muscle involvement in this patient., (Copyright © 2011 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Pompe disease is classified into infantile and late-onset (childhood and adult) forms based on onset age and degree of organ involvement. While benefits of enzyme replacement therapy (ERT) for the infantile form have been confirmed, efficacy for late-onset forms reportedly varies. We report close monitoring of initial ERT, focusing especially on the first year, in a 12-year-old boy with childhood-onset Pompe disease. At age 10, he started ERT at 20 mg/kg every other week. Respiratory and motor functions were evaluated at each infusion, and by skeletal muscle computed tomography (CT) and cardiac echography every 4 months. He gained the ability to climb stairs without a rail and % vital capacity improved just 1.5 months after starting ERT. Grip power, manual muscle testing (MMT) and the timed and 6-min walking distance tests (6MWT) improved promptly, paralleling improvements in clinical symptoms. However, this steady improvement stopped around 8 months, with deterioration to the initial level by about 24 months. Antibody against recombinant human alpha-glucosidase was very low at 15 months; therefore, the lack of treatment response did not completely correspond to antibody production. On the other hand, cardiac wall thickening worsened after 4 months, then improved to better than baseline after 8 months, and this improvement was well maintained. Among our set parameters, the timed test results corresponded better to his changing clinical course than did grip power, MMT or 6-min walking test results., (Copyright © 2011 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Background/aims: The relationship between serum total bilirubin (TB) and estimated glomerular filtration rate (eGFR) is controversial and there is no report on the association between TB and end-stage kidney disease (ESKD)., Methods: We examined the cross-sectional association between TB and eGFR and investigated whether TB can predict ESKD with multivariable logistic regression adjusted for age, sex, and baseline eGFR using hospital-based data., Results: The geometric mean TB of patients with eGFR ≥ 90 mL/min/1.73 m2 (S1), 8960 mL/min/1.73 m2 (S2), 59-30 mL/min/1.73 m2 (S3), 29-15 mL/min/1.73 m2 (S4), and < 15 mL/min/1.73 m2 (S5 = ESKD) was 0.55 mg/dL, 0.59 mg/dL, 0.56 mg/dL, 0.47 mg/dL, and 0.36 mg/dL (all p<0.0001 except for S1 vs. S3 where p=0.3726), respectively excluding patients with hyperbilirubinemia (TB > 1.24 mg/dL). The odds ratio (95% confidence interval) of incident ESKD for each 0.1 mg/dL increase in TB and hypobilirubinemia defined as TB ≤ 0.34 mg/dL were 0.92 (0.80-1.07) (p=0.2804) and 3.51 (1.56-7.88) (p=0.0023), respectively in patients with baseline eGFR ≥ 15 mL/min/1.73 m2 and 0.59 (0.37-0.95) (p=0.0283) and 6.03 (1.63-22.30) (p=0.0071), respectively in patients with baseline eGFR 29-15 mL/min/1.73 m2., Conclusions: Hypobilirubinemia might be a possible risk factor of ESKD., (Copyright © 2012 S. Karger AG, Basel.)

Background: Increased risks of acute pancreatitis in patients with type 2 diabetes mellitus have been reported recently in several countries. We aimed to estimate the risks of acute pancreatitis in Japanese patients with diabetes mellitus., Methods/findings: We examined a large-scale hospital administrative database consisting of one million patients in 16 secondary medical care hospitals, from 2003 to 2010. The incidence rates of acute pancreatitis were estimated with cohort design; the odds ratios associated with diabetes mellitus and other comorbid risk factors were estimated with separate case-control analyses. In cohort analysis, the incidence of acute pancreatitis was higher in 14,707 diabetic patients than in 186,032 non-diabetic patients (4.75 vs. 1.65 per 1,000 patient-years) and increased in male patients and as age advanced. The adjusted odds ratio of acute pancreatitis in patients with diabetes mellitus was 1.86 (P<0.001) compared with non-diabetic patients in case-control analysis from 1,372 cases and 5,469 matched controls, which is consistent with the ones reported in previous studies. Alcoholism and gallstones were associated with a large increase in the risk of acute pancreatitis (adjusted odds ratio 13.40 and 14.29, respectively, P<0.001), although dyslipidemia was associated with significant risk reduction (adjusted odds ratio 0.62, P<0.001)., Conclusions: This observational study ascertained the elevated incidence rates and risk of acute pancreatitis in Japanese patients with diabetes. The risk estimates in Japanese patients with diabetes were in agreement with the ones reported in previous studies, and the elevated risk of acute pancreatitis in patients with diabetes would be generalized in different locations/populations.

Bilirubin is a potent antioxidant, and serum total bilirubin (TB) is reported to be negatively associated with cardiovascular disease (CVD). There has been no report on the association between TB and CVD prevalence in Japanese. The aim of the study is to examine the association between TB and CVD prevalence in a Japanese health screening population. Prevalence of CVD was studied in 3,375 Japanese men and 2,069 Japanese women. Odds ratios (ORs) of each higher quintile of TB using the lowest quintile as the reference in men and of each higher tertile of TB using the lowest tertile as the reference in women were calculated for coronary heart disease (CHD) and stroke adjusting for age, liver function tests, smoking, physical activity, and alcohol consumption. The ORs [95% confidence intervals (CIs)] for CHD and stroke of the 2nd, 3rd, 4th, and 5th quintiles of TB were 0.63 (0.37-1.07) and 0.49 (0.24-1.00), 0.45 (0.22-0.90) and 0.65 (0.28-1.51), 0.69 (0.39-1.20) and 0.37 (0.15-0.87), and 0.61 (0.34-1.09) and 0.40 (0.18-0.92), respectively in men. The ORs (95% CIs) for CHD and stroke of the 2nd and 3rd tertiles of TB were 1.32 (0.49-3.54) and 0.35 (0.13-0.93), and 1.26 (0.44-3.62) and 0.34 (0.13-0.93), [corrected] respectively in women. Low TB was associated with the higher prevalence of CHD and stroke in men and with the higher prevalence of stroke in women among a Japanese health screening population.

Pompe disease is caused by a deficiency of acid alpha-glucosidase (GAA) that results in glycogen accumulation, primarily in muscle. Newborn screening (NBS) for Pompe disease has been initiated in Taiwan and is reportedly successful. However, the comparatively high frequency of pseudodeficiency allele makes NBS for Pompe disease complicated in Taiwan. To investigate the feasibility of NBS for Pompe disease in Japan, we obtained dried blood spots (DBSs) from 496 healthy Japanese controls, 29 Japanese patients with Pompe disease, and five obligate carriers, and assayed GAA activity under the following conditions: (1) total GAA measured at pH 3.8, (2) GAA measured at pH 3.8 in the presence of acarbose, and (3) neutral glucosidase activity (NAG) measured at pH 7.0 without acarbose. The % inhibition and NAG/GAA ratio were calculated. For screening, samples with GAA<8% of the normal mean, % inhibition>60%, and NAG/GAA ratio>30 were considered to be positive. Two false positive cases (0.3%) were found, one was a healthy homozygote of pseudodeficiency allele (c.1726G>A). The low false-positive rate suggests that NBS for Pompe disease is feasible in Japan., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Heme oxygenase (HO) catalyzes the O(2)-dependent degradation of heme to biliverdin IXα, carbon monoxide (CO), and free ferrous iron through a multistep mechanism. Electrons required for HO catalysis in mammals are provided by NADPH-cytochrome P450 reductase. Recently, Kim et al. reported for the first time that HO, especially inducible HO-1, appears in caveolae and showed that caveolin-1, a principal isoform of the caveolin family, physically interacts with HO-1 [ Jung , N. H. et al. ( 2003 ) IUBMB Life 55 , 525 - 532 ; Kim , H. P. et al. ( 2004 ) FASEB J. 18 , 1080 - 1089 ]. In the present study, we confirmed by immunoprecipitation experiments that rat HO-1 and rat caveolin-1 (residues 1-101) directly interact with each other and that the HO-1 activity is inhibited by caveolin-1 (1-101). The 82-101 residues of caveolin-1 (CAV(82-101)), called the caveolin scaffolding domain, play essential roles in caveolin-related protein-protein interactions. The HO-1 activity is also inhibited by CAV(82-101) in a competitive manner with hemin, and a hemin titration experiment showed that CAV(82-101) interferes with hemin binding to HO-1. The enzyme kinetics and surface plasmon resonance experiments gave comparable K(i) and K(D) values of 5.2 and 1.0 μM for CAV(82-101), respectively, with respect to the interaction with HO-1. These observations indicated that CAV(82-101) and hemin share a common binding site within the HO-1 protein. The identified caveolin binding motif (FLLNIELF) of rat HO-1 is incomplete compared to the proposed consensus sequence. The affinity between HO-1 and CAV(82-101), however, was almost completely or remarkably eliminated by replacement of Phe(207) and/or Phe(214) with Ala, indicating that HO-1 binds to caveolin-1 via this motif. Among the peptide fragments derived from CAV(82-101), i.e., CAV(82-91), CAV(87-96), CAV(92-101), and CAV(97-101), CAV(92-101) and CAV(97-101) are able to inhibit the HO-1 activity to a similar extent; thus, the five-amino acid sequence (residues 97-101) is considered to be a minimum sequence for binding to HO-1.

The aims are to examine whether changes in body weight (dBW) are associated with changes in cardiovascular risk factors in Japanese men without abdominal obesity (waist circumference (WC) < 85 cm) and which anthropometric index, dBW or changes in WC (dWC), is more strongly associated with changes in cardiovascular risk factors in men without abdominal obesity. It is a retrospective study in 692 Japanese men without abdominal obesity who took annual health screening tests consecutively over one year. Standardized linear regression coefficients (SRCs) of dBW and dWC were calculated for changes in systolic blood pressure (dSBP), diastolic blood pressure (dDBP), fasting plasma glucose (dFPG), triglycerides (dTG), HDL cholesterol (dHDL), and high-sensitivity C-reactive protein (dCRP). The SRCs of dBW for dFPG and dHDL were significant in all men and in men with each risk factor corresponding to the component of metabolic syndrome (MetS). The SRCs of dWC for dTG and dCRP were significant in all men but not in men with each risk factor corresponding to the MetS component. In conclusions, dBW were significantly associated with dFPG and dHDL in Japanese men without abdominal obesity. Therefore, abdominal obesity should not be considered as a necessary component of MetS in Japanese men. dBW may be more useful than dWC as a marker of changes in cardiovascular risk factors in lifestyle intervention programs.

Background: Serum total bilirubin (TB) is a potent antioxidant and may be a negative risk factor of cardiovascular disease. In non-diabetic adults, hemoglobin A(1c) (HbA(1c)), but not fasting plasma glucose, is an independent risk factor of cardiovascular disease., Methods and Results: Linear regression using TB as a dependent variable and cardiovascular risk factors, including HbA(1c), as independent variables, linear regression using HbA(1c) as a dependent variable and other cardiovascular risk factors, including TB, as independent variables, and logistic regression using the highest decile (≥ 5.4%) of HbA(1c) as a dependent variable and TB and other cardiovascular risk factors as independent variables were performed for 893 apparently healthy male smokers, 1,607 male nonsmokers, and 1,680 women. The standardized regression coefficient of HbA(1c) for TB and that of TB for HbA(1c) was -0.12 (P = 0.007) and -0.06 (P = 0.02), respectively, in the smokers, -0.20 (P < 0.0001) and -0.07 (P < 0.0001), respectively, in the nonsmokers, and -0.21 (P < 0.0001) and -0.14 (P < 0.0001), respectively, in the women. The odds ratio of 1 SD increment in TB for HbA(1c) ≥ 5.4% was not significant in the smokers, 0.67 (P = 0.002) in the nonsmokers, and 0.55 (P<0.0001) in the women., Conclusions: Bilirubin was negatively associated with HbA(1c) independently of other cardiovascular risk factors in apparently healthy Japanese men and women. The association was weak in male smokers.

Obesity is associated with hypertension. However, it is controversial which obesity index, body mass index (BMI) or waist circumference (WC), is more strongly associated with hypertension. We compared the cross-sectional associations of BMI and WC with hypertension. Logistic regressions using hypertension as a dependent variable and age, BMI, WC, fasting plasma glucose, triglycerides, high-density lipoprotein cholesterol, smoking status, drinking status, and physical activity as independent variables were performed using data from apparently healthy 1,803 Japanese men aged 49.9 ± 9.0 and 1,150 women aged 49.5 ± 9.0 excluding subjects with a history of cardiovascular disease, or with antidiabetic, antihypertensive and/or antihyperlipidemic medications. The odds ratio [95% confidence interval] of 1 kg/m² increase in BMI and that of 1 cm increase in WC for diagnosing hypertension were 1.23 [1.11-1.36] (p < 0.0001) and 0.99 [0.95-1.02] (p = 0.4) in men and 1.35 [1.16-1.58] (p < 0.0001) and 0.97 [0.91-1.03] (p = 0.4) in women, respectively. Thus, BMI, but not WC, was independently associated with hypertension in apparently healthy Japanese men and women.

Recent genetic studies have revealed that several epidemiological factors affect Mycobacterium avium complex (MAC) infection in pig populations. However, mechanisms underlying the spread of MAC infection among hog farms have not been clarified. In consideration of this situation, we cross-sectionally investigated the mechanisms underlying the spread of MAC on the island of Okinawa. Pigs slaughtered (n=706,763) and 331 hog farms on Okinawa were surveyed during the years 2002-2004. Two outbreaks of MAC infection were occurred in several farms during survey period. Bacteria were isolated from randomly selected pigs and genotype of isolates was determined by using genetic finger printing methods with the insertion sequence (IS) 1245 restriction fragment length polymorphism (RFLP). Most isolates had large numbers of IS1245 copies, while strains with low copy numbers of IS1245 and isolates without IS1245 were seen in few farms. MACs strains were repeatedly isolated from pigs of the affected farms during the survey period. Those farms with an identical pig rearing systems showed synchronic changes in the prevalence of MAC infection. An industrial farm without an outbreak had an independent pig flow, but maintained distinct MAC strains. Multivariate analysis did not reveal independent factors for the prevalence of the MAC infection. These findings suggest that there were three clusters distinguished genetically in the main island of Okinawa, which were potentially spread by common pig flow. However, the outbreaks occurred because of unspecified conditions on each farm environment., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Background: Cutoff points for high-sensitivity C-reactive protein (hs-CRP) as a component of metabolic syndrome (MetS) in Japanese have been proposed as 0.40-0.45 mg/L for men and 0.25-0.35 mg/L for women. However, there are some concerns about the reproducibility of hs-CRP., Methods and Results: Reproducibility of hs-CRP as a component of MetS was examined using receiver-operating characteristic (ROC) curves for diagnosing MetS in 1,274 men and 673 women whose serum levels of hs-CRP were measured twice at annual health screening tests. The Spearman's correlation coefficient between baseline hs-CRP and hs-CRP at the next year's test was 0.68 in men and 0.71 in women. The area under the ROC curves of baseline hs-CRP, hs-CRP at the next year's test, and the mean of the 2 hs-CRP tests for diagnosing baseline MetS were 0.71, 0.71, and 0.72, respectively, in men and 0.75, 0.74, and 0.74, respectively, in women. Optimal cutoff points of baseline hs-CRP, hs-CRP at the next year's test, and the mean of 2 tests for diagnosing baseline MetS were all 0.40 mg/L in men and 0.35 mg/L in women., Conclusions: The serum level of hs-CRP was stable enough for use as a measure of the inflammatory component of MetS, and the optimal cutoff point of hs-CRP was 0.40 mg/L for men and 0.35 mg/L for women in a Japanese health-screening population.

Objective: To compare two systemic inflammatory markers, high-sensitivity C-reactive protein (hs-CRP) and white blood cell count (WBC), as a component of metabolic syndrome (MetS)., Methods: Data of hs-CRP and WBC from 2,185 Japanese men and 1,383 Japanese women were examined using receiver operating characteristic (ROC) curve for diagnosing MetS and Spearman's correlation coefficients., Results: The area under ROC curve (AUC) of hs-CRP was 0.71 in men and 0.74 in women. The AUC of WBC was 0.65 in men and 0.69 in women. The optimal cutoff point (sensitivity; specificity) of hs-CRP was 0.40 mg/L (0.69; 0.65) in men and 0.35 mg/L (0.67; 0.72) in women. The optimal cutoff point (sensitivity; specificity) of WBC was 5,600/L(-6) (0.61; 0.61) in men and 5,000/L(-6) (0.65; 0.63) in women. Correlations between obesity parameters, blood pressure, and liver function tests were stronger with hs-CRP than with WBC. But, no correlation between MetS-related risk factors was stronger with WBC than with hs-CRP., Conclusion: Hs-CRP is superior to WBC as an inflammatory component of MetS in Japanese. However, WBC may be useful when hs-CRP is not available because WBC is routinely measured in clinical practice.

Background: Low-density lipoprotein (LDL) cholesterol and chronic kidney disease (CKD) are both well-known risk factors for cardiovascular disease. However, few studies have examined the associations between LDL cholesterol and CKD., Methods: In the present study, we investigated the associations between LDL cholesterol and CKD using medical check-up data from 2,449 Japanese men and 1,448 Japanese women. Metabolic syndrome (MetS) was defined according to the revised National Cholesterol Education Program (NCEP) criteria for Japanese people. CKD was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2) and/or proteinuria., Results: Blood levels of LDL cholesterol were higher in CKD subjects than in non-CKD subjects only in men and the frequency of antihyperlipidemic medication and MetS was higher in CKD subjects than in non-CKD subjects, regardless of gender. The frequency of CKD was significantly higher in male subjects with the highest quartile of LDL cholesterol than in those with the lowest quartile of LDL cholesterol. LDL cholesterol levels were significantly higher in subjects with eGFR corresponding to CKD stages 2 and 3 than in those with eGFR corresponding to CKD stage 1 both in men and women. LDL cholesterol was independently associated with CKD, eGFR <60 mL/min/1.73 m(2), and proteinuria in Japanese men, but not in women., Conclusion: LDL cholesterol is cross-sectionally associated with preclinical CKD in Japanese men.

Objective: To compare body mass index (BMI), waist circumference (WC), and percent body fat (%BF) as markers for the clustering of metabolic risk factors in Japanese., Methods: Age-adjusted correlation coefficients (Rs) were calculated between the three anthropometric markers of obesity and metabolic risk factors in 2,444 men and 1,442 women among Japanese. Areas under receiver operating characteristic curves (AUCs) of BMI, WC, and %BF were calculated for diagnosing the clustering of 1 or more, 2 or more, 3 or more, and 4 risk factors among increased blood pressure, impaired fasting glucose, increased triglycerides, and decreased HDL cholesterol and for the clustering of 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, and 6 risk factors among the upper four risk factors as well as increased high-sensitivity C-reactive protein and increased LDL cholesterol., Results: The Rs were not significantly different among BMI, WC, and %BF except for the difference between the R of BMI (0.217) and that of %BF (0.283) with LDL cholesterol in men (p=0.014). The AUCs of BMI, WC, and %BF for diagnosing any of the risk factor clustering patterns defined above were not significantly different in both men and women., Conclusion: The AUCs for diagnosing the clustering of metabolic risk factors were not significantly different among BMI, WC, and %BF.

Objectives: A lower vital capacity (VC) has been reported to be an independent predictor of diabetes in Western countries. The aim of this study was to examine the relationships between VC and diabetes and between VC and metabolic syndrome (MS) in Japanese individuals., Methods: Stepwise multiple linear regressions with fasting glucose as a dependent variable and age, metabolic risk factors, and percentage vital capacity (%VC) as independent variables were performed using data obtained from 1651 men and 957 women. Area under the receiver operating characteristic curve (AUC) of -%VC for diagnosing diabetes, MS, and Japanese MS (JMS) were calculated, and stepwise logistic regressions using diabetes, MS, and JMS as dependent variables were performed., Results: Percentage vital capacity was independently associated with fasting glucose in men, but not in women. The AUC of -%VC for diagnosing diabetes, MS, and JMS were 0.647, 0.606, and 0.598, respectively (all p < 0.0001) in men and 0.639 (p = 0.065), 0.513 (p = 0.732), and 0.668 (p = 0.01), respectively, in women. Age, waist circumference (WC), and %VC in men and WC and %VC in women were independently associated with diabetes. Age and %VC in men and only age in women were independently associated with MS, and age and %VC in both men and women were independently associated with JMS., Conclusions: Among a representative Japanese population, a lower VC was significantly associated with diabetes and MS in men, but the relationships were not conclusive in women.

Background: Autonomic dysfunction is thought to be an important mechanism of metabolic syndrome (MetS), but there has not been a study on the direct association between MetS and heart rate (HR) in Japanese., Methods and Results: The association between MetS and HR was examined using medical check-up data from 1,880 men and 1,079 women. HR was significantly higher in MetS subjects than in non-MetS subjects in both men and women (P<0.0001 in men, P<0.001 in women). The prevalence of MetS increased linearly through the quartiles of HR in both men and women. HR was significantly correlated with MetS-related risk factors other than uric acid in men and other than uric acid, body mass index, waist circumference, and high-density lipoprotein cholesterol in women., Conclusions: The prevalence of MetS increased linearly with the increase in HR among Japanese men and women, and HR was significantly correlated with MetS-related risk factors.

Aims: The aim of the present study was to examine the cross-sectional relationship between vital capacity and diabetes, metabolic syndrome (MS), and high-sensitivity C-reactive protein (hs-CRP) among Japanese men., Methods: Medical check-up data of 1353 men were examined. Spearman's correlation coefficients between respiratory function and MS-related risk factors were calculated excluding subjects with hypoglycemic medication. The prevalence of diabetes and MS were compared between subjects with the lowest and the highest quartiles of % vital capacity (%VC). Area under receiver operating characteristic curve (AUC) were calculated for risk factors excluding fasting glucose. Logistic regression using diabetes as a dependent variable and %VC and MS-related risk factors excluding fasting glucose as independent variables was performed., Results: %VC was significantly correlated with some components of MS and hs-CRP. The prevalence of diabetes, MS, and MS components other than blood pressure were significantly lower in the highest quartile than in the lowest quartile of %VC. AUC of -%VC was highest among MS-related risk factors excluding fasting glucose though statistically not significant. %VC was an independent marker of diabetes in the multivariable logistic regression analysis., Conclusions: Vital capacity was an independent marker of diabetes and associated with MS and hs-CRP in Japanese men.

To investigate the feasibility of newborn screening for glycogen storage disease type II (GSDII; Pompe disease or acid maltase deficiency) in the Japanese population, we assayed the acid alpha-glucosidase activity in dried blood spots from 715 Japanese newborns and 18 previously diagnosed patients using a fluorometric procedure. The enzyme activity of apparently healthy newborns showed a bimodal distribution. The median activity of the minor group (31 individuals, 4.3% of the samples) was 6.5 times lower than that of the major group. Four of the 715 control samples (0.56%) fell in the patient range. We then analyzed genomic DNA, extracted from the same blood spots, for the occurrence of two sequence variants, c.1726G>A and c.2065G>A, known to cause "pseudodeficiency". This analysis revealed that 27 of 28 individuals homozygous for c.[1726A; 2065A] belonged to the minor group. One c.[1726A; 2065A] homozygote had just slightly higher activity. Twelve of the 18 patients with GSDII either had one (9 cases) or two (3 cases) c.[1726A; 2065A] alleles. The frequency of this allele was double in the patient compared to the control group (0.42 vs 0.19) at the expense of a lower frequency of the c.[1726G; 2065G] and c.[1726G; 2065A] alleles (0.58 vs 0.71 and 0 vs 0.1). These findings illustrate that c.[1726A; 2065A] homozygosity among apparently healthy individuals (3.9 per 100) complicates newborn screening for GSDII in Japan, and further that one or more pathogenic mutations are associated with the c.[1726A; 2065A] allele.

Background: High-sensitivity C-reactive protein (hs-CRP) is an independent risk factor of diabetes and cardiovascular disease, and is proposed as a component of metabolic syndrome (MetS). An optimal cut point of hs-CRP as a component of MetS was previously reported as 0.65 mg/L based on data from a small-sized study., Methods and Results: Medical check-up data of 1,062 men and 647 women whose plasma levels of hs-CRP were <10 mg/L were examined using a receiver-operating characteristic (ROC) curve for diagnosing MetS, which was defined by revised NCEP criteria for Japanese. An optimal cut point was defined as the point on a ROC curve nearest to the point where both sensitivity and specificity were 1. The area under the ROC curve of hs-CRP was 0.74 (95% confidence interval (CI) 0.70-0.79) in men and 0.73 (95%CI 0.66-0.79) in women. The optimal cut point of hs-CRP and its sensitivity-specificity were, respectively, 0.45 mg/L and 0.67-0.72 in men and 0.25 mg/L and 0.71-0.62 in women., Conclusions: Among Japanese patients, a tentative cut point of hs-CRP as a component of MetS may be 0.45 mg/L in men and 0.25 mg/L in women. However, standardization of the measurement of hs-CRP is required.

Interferons-alpha/beta, which are produced upon viral infection, are key soluble factors for the establishment of an antiviral state, but are also produced at low levels in the absence of infection. Herein, we demonstrate that a weak signal by these constitutively produced IFN-alpha/beta show a preventive role in cellular transformation. Ifnar1-deficient (Ifnar1(-/-)) MEF, which are devoid of IFN-alpha/beta signal, undergo a spontaneous transformation during long-term cell culture. Similar to Irf1(-/-) MEF, primary Ifnar1(-/-) MEF become tumorigenic in nude mice by the expression of activated c-Ha-Ras oncoprotein. However, Ifnar1(-/-) MEF do not show any abnormal growth properties. A similar observation is made in Ifnb(-/-) MEF that fail to produce constitutive IFN-alpha/beta, whereas such a transforming property is not found in MEF that lack any of the IFN receptor downstream molecules including Stat1, IRF9 and IRF1. Furthermore, Ifnar1(-/-) mice develop chemically-induced skin papilloma more severely than wild-type mice. In addition, the expression levels of IFNAR1 mRNA are significantly decreased in human gastric cancer tissues. These results suggest a cell-intrinsic role of the weak signal by constitutively produced IFN-alpha/beta to prevent cells from transformation, which may be mediated by a hitherto-unknown pathway(s) downstream of the IFN-alpha/beta receptor.

Background: Gamma glutamyltransferase (GGT) or alanine aminotransferase (ALT) is reported to be an independent risk factor of diabetes and cardiovascular disease and proposed as a component of metabolic syndrome (MS). However, there are few studies examining the direct association between MS and GGT or ALT in Japanese men and women., Methods: Direct associations between GGT or ALT and MS defined by revised NCEP criteria for Japanese and between GGT or ALT and Japanese MS (JMS) defined by the Examination Committee for the Criteria of Metabolic Syndrome were examined using medical check-up data from 1,880 men and 1,079 women., Results: The prevalence of MS and JMS was significantly higher in subjects with the highest quartile of GGT or ALT than the subjects with the lowest quartile of GGT or ALT (p<0.0001 in men and p<0.0001 for MS and p<0.001 for JMS in women). The optimal cutoff points of GGT and ALT for diagnosing MS or JMS were 42 U/L or 41 U/L, respectively for GGT and both 25 U/L for ALT in men and 21 U/L or 23 U/L, respectively for GGT and 20 U/L or 25 U/L, respectively for ALT in women., Conclusion: The prevalence of MS and JMS increases with the increase in blood levels of GGT or ALT even through the normal range of GGT or ALT in Japanese men and women.

Objective: LDL cholesterol is not usually considered as a component of metabolic syndrome (MetS) but rather it is associated with MetS components., Methods: Data from 2,449 men and 1,448 women were examined using receiver operating characteristic (ROC) curve for diagnosing MetS and correlation coefficients., Results: Blood levels of LDL cholesterol increased more steeply in women than in men as the number of MetS components increased. The area under ROC curve (AUC) and its 95% confidence interval (CI) of LDL cholesterol for diagnosing MetS were 0.57 and 0.53-0.60 in men and 0.66 and 0.61-0.71 in women. The optimal cut-off point (sensitivity; specificity) of LDL cholesterol was 127 mg/dL (0.50; 0.60) in men and 125 mg/dL (0.64; 0.61) in women. Correlations between LDL cholesterol and systolic blood pressure, diastolic blood pressure, gamma glutamyltransferase, and hemoglobin A1c were stronger in women than in men even after adjustment for age. The correlation between LDL cholesterol and blood pressure was significant in women, but not in men, even after adjusting for age., Conclusion: LDL cholesterol was more strongly associated with MetS in Japanese women than in men. The correlation between LDL cholesterol and blood pressure was significant in women, but not in men.

Background: The relationships between uric acid and metabolic syndrome (MetS) and diabetes, as well as the gender differences in these relationships are controversial., Methods: Medical check-up data from 2,449 Japanese men and 1,448 Japanese women were examined. The prevalence of MetS and diabetes was calculated by the quartiles of serum levels of uric acid. Correlation coefficients between uric acid and MetS-related risk factors were calculated and compared between men and women., Results: The prevalence of MetS in the 3rd quartile (Q3) of uric acid was significantly higher than that in the 1st (lowest) quartile (Q1) and the prevalence of MetS in the 4th quartile (Q4) was significantly higher than that in Q1, the 2nd quartile (Q2), and Q3 in men. The prevalence of MetS in Q4 was significantly higher than that in Q1, Q2, and Q3 in women. The prevalence of diabetes in Q3 was significantly lower than that in Q1 and the prevalence of diabetes in Q4 was significantly lower than that in Q1 and Q2 in men. The prevalence of diabetes was not significantly different among the quartiles of uric acid in women. The age-adjusted correlation coefficient between uric acid and fasting glucose was not significant in men., Conclusion: Uric acid is positively associated with metabolic syndrome but negatively associated with diabetes in Japanese men.