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While alcohol consumption is known to increase plasma high-density lipoprotein (HDL) cholesterol levels, its relationship with low-density lipoprotein (LDL) cholesterol levels is unclear. Aldehyde dehydrogenase 2 (ALDH2) is a rate-controlling enzyme in alcohol metabolism, but a large number of Japanese people have the inactive allele. Here, we conducted a Mendelian randomization analysis using the ALDH2 genotype to clarify a causal role of alcohol on circulating cholesterol levels and lipoprotein particle numbers.This study was conducted in three independent general Japanese populations (men, n = 2289; women, n = 1940; mean age 63.3 ± 11.2 years). Alcohol consumption was assessed using a questionnaire. Lipoprotein particle numbers were determined by nuclear magnetic resonance spectroscopy.Alcohol consumption increased linearly in proportion to the number of subjects carrying the enzymatically active *1 allele in men (p 0.001). The *1 allele was also positively associated with HDL cholesterol level (adjusted mean ± standard error, *1*1: 60 ± 0.5, *1*2: 56 ± 0.6, *2*2: 55 ± 1.3 mg/dl, p 0.001) and inversely associated with LDL cholesterol level (116 ± 0.9, 124 ± 1.1, 130 ± 2.6 mg/dl, p 0.001). The *1 allele was also positively associated with HDL particle numbers (per-allele: 2.60 ± 0.32 μmol/l, p 0.001) and inversely associated with LDL particle numbers (-67.8 ± 19.6 nmol/l, p = 0.001). Additional Mendelian randomization analysis failed to clarify the involvement of cholesteryl ester transfer protein in alcohol-related changes in lipoprotein cholesterol levels. No significant association was observed in women, presumably due to their small amount of alcohol intake.Alcohol consumption has a causal role in not only increasing HDL cholesterol levels but also decreasing LDL cholesterol levels and particle numbers.

IntroductionNordic walking, characterized by the use of two walking poles, is becoming increasingly popular. The aim of this study was to analyze the effects produced by a 12-week Nordic walking training program on functional abilities and metabolic profiles, specifically walk distance and insulin resistance, among elderly women.MethodsThe present study included 74 women (68 ± 7 years). The Nordic walking training program of 120 minutes per week was performed for 12 weeks. Before and at the end of the 12-week intervention, 6-minute walking distance (6MWD) and the homeostasis of the model assessment of insulin resistance (HOMA-IR) were measured.Results and conclusionsAfter the 12-week Nordic walking training program, 6MWD increased significantly (p

No long-term exercise training regimen with high adherence and effectiveness in middle-aged and older people is broadly available in the field. We assessed the adherence to, and effects of, our long-term training program comprising an interval walking training (IWT) and an information technology network system and the factors affecting adherence. Middle-aged and older men and women [ n = 696, aged 65 ± 7(SD) yr] underwent IWT. The subjects were instructed to repeat five or more sets of fast and slow walking for 3 min each at ≥70 and 40% peak aerobic capacity for walking (V̇o2peak), respectively, per day ≥4 days/wk for 22 mo. Adherence was assessed as training days accomplished relative to the target of 4 days/wk over 22 mo. The effects on the V̇o2peak and lifestyle-related disease score were evaluated every 6 mo. The independent factors affecting adherence were assessed by multiple-regression analysis after adjustment for baseline physical characteristics and other possible covariates, including vasopressin V1a receptor polymorphisms. The adherence over 22 mo averaged 70% and was highly correlated with a 13% reduction in the lifestyle-related disease score ( R2 = 0.94, P = 0.006) and with a 12% increase in V̇o2peak ( R2 = 0.94, P = 0.006). The major determinant of higher adherence was lower baseline body mass index (BMI) ( P < 0.0001) and male sex ( P < 0.0001). For men, in addition to BMI, nonsmokers ( P = 0.031) and V1a receptor polymorphisms ( P = 0.033) were independent determinants of higher adherence. Thus the long-term IWT program is an effective regimen. Moreover, baseline BMI and sex for all subjects, and smoking and V1a receptor polymorphisms for men, were associated with adherence.

The subjects comprised 230 men aged 77 ± 10 (range: 50–100) years and 279 women aged 81 ± 10 (50–101) years that visited the medical department. We examined the relationship between increased serum bilirubin and renal function evaluated by estimated glomerular filtration rate (eGFR) using CKD-EPI equations modified by a Japanese coefficient. Compared with the fourth quartile in serum bilirubin (1.01–1.97 mg/dL), the nonadjusted, age and gender-adjusted, and multivariate-adjusted odds ratios{95% confidence interval (CI)}of eGFR 2for the first quartile in serum bilirubin (0.13–0.50 mg/dL) were 2.08 (1.25–3.44), 1.82 (1.07–3.09), and 1.53 (0.83–2.81), respectively. Moreover, compared with the fourth quartile, nonadjusted, age and gender-adjusted, and multivariate-adjusted odds ratios (95% CI) of eGFR 2for the first quartile were 3.50 (1.95–6.23), 3.12 (1.72–5.65), and 3.53 (1.71–7.26), respectively. The data were further stratified by gender, age, medication (antihypertensive, antidyslipidemic, and antidiabetic agents), and prevalence of cardiovascular disease (CVD). The standardized coefficients for eGFR were significant in all the subgroups other than the prevalence of CVD, and there were significant interactions between the two groups regarding CVD. Our data demonstrated an independent positive association between serum bilirubin and eGFR among diabetic patients.

Background and Purpose— Arterial stiffness, a risk factor of brain small vessel diseases (SVD), causes hemodynamic changes. Mechanical stresses, circumferential wall tension (WT), and shear stress (SS) may change with arterial stiffness and be related to SVD. We investigated the associations between mechanical stresses and arterial stiffness and SVD. Methods— A total of 1296 subjects without apparent cardiovascular diseases were recruited. Brachial-to-ankle pulse wave velocity (baPWV) was measured as an arterial stiffness index. Silent lacunar infarction and deep subcortical white matter hyperintensity were evaluated as SVD indices. Circumferential WT and SS at peak systole and end diastole were measured at the common carotid artery. Second peak of systolic blood pressure was obtained from the radial waveform and used as a central systolic blood pressure substitute. Results— baPWV was associated positively with WT ( P P =0.0007) even after correction for confounding parameters including baPWV. SVD was associated with significantly higher WT ( P P P =0.0017) and end diastolic WT (odds ratio, 1.60; P =0.0038) were related to presence of silent lacunar infarction, whereas peak systolic (odds ratio, 0.95; P =0.014) and end diastolic SS (odds ratio, 0.94; P =0.014) were associated with presence of deep subcortical white matter hyperintensity grade >3. Regression lines between blood pressure and WT were significantly steeper in subjects with SVD than without SVD (β=0.02; P Conclusions— These findings indicate that SVD is phenotype-specifically associated with alterations in WT and SS independently of arterial stiffness.

Objective The relationship between plasma levels of adiponectin and cardiovascular events is inconclusive. We evaluated the clinical characteristics of people with high plasma adiponectin and high plasma leptin levels. Methods Thousand seven hundred participants recruited from visitors to the Anti-Aging Doc were divided into four groups by combining the bipartiles of plasma adiponectin and leptin levels in men and women separately: AL, high adiponectin and high leptin; Al, high adiponectin and low leptin; al, low adiponectin and low leptin; aL, low adiponectin and high leptin. Body composition, including visceral fat area and thigh muscle cross-sectional area (CSA), brachial-ankle pulse wave velocity (baPWV), periventricular hyperintensity, and urinary albumin excretion, were determined. Results Twenty percent of the studied population fell within the AL group. This group had a significantly higher visceral fat area than the Al group. Thigh muscle CSA was lowest in the AL group among groups. baPWV, brain white matter lesions, and albuminuria findings in the AL group were significantly higher than those of the Al group. Multiple and logistic regression analyses with confounding parameters further confirmed that plasma adiponectin was not an independent determinant for brain and renal small vessel-related disease. Conclusion These findings suggest that the plasma level of adiponectin alone is not enough for the risk stratification of cardiovascular disease. Leptin resistance associated with skeletal muscle loss in addition to obesity may need to be addressed to identify high risk people with high plasma adiponectin levels.

The electrocardiogram has several advantages in detecting cardiac arrhythmia-it is readily available, noninvasive and cost-efficient. Recent genome-wide association studies have identified single-nucleotide polymorphisms that are associated with electrocardiogram measures. We performed a genome-wide association study using Korea Association Resource data for the discovery phase (Phase 1, n = 6805) and two consecutive replication studies in Japanese populations (Phase 2, n = 2285; Phase 3, n = 5010) for QRS duration and PR interval. Three novel loci were identified: rs2483280 (PRDM16 locus) and rs335206 (PRDM6 locus) were associated with QRS duration, and rs17026156 (SLC8A1 locus) correlated with PR interval. PRDM16 was recently identified as a causative gene of left ventricular non-compaction and dilated cardiomyopathy in 1p36 deletion syndrome, which is characterized by heart failure, arrhythmia and sudden cardiac death. Thus, our finding that a PRDM16 SNP is linked to QRS duration strongly implicates PRDM16 in cardiac function. In addition, C allele of rs17026156 increases PR interval (beta ± SE, 2.39 ± 0.40 ms) and exists far more frequently in East Asians (0.46) than in Europeans and Africans (0.05 and 0.08, respectively).

Central blood pressure (BP) has been shown to strongly associate with cardiovascular disease and outcome. Recent studies have demonstrated a relationship between changes in body size by exercise training and peripheral BP; however, the effect on changes in central BP is unknown. The aim of this study was to assess whether changes in body size are independently related to changes in central BP in the elderly. The subjects were 11 men (mean age, 68±6 years) and 84 women (68±7 years) from a rural village. Before and at the end of the 12-week training program, metabolic variables, and first peak radial systolic BP (SBP1) and second peak radial SBP (SBP2) as estimates of central SBP, were obtained. Radial augmentation index (AI) was calculated as follows: ((SBP2-diastolic BP (DBP))/(SBP1-DBP)) × 100 (%) and we used AI corrected at heart rate 75 per min (AI@75). After the 12-week training program, weight loss correlated strongly with reduction in brachial mean arterial pressure (MAP), radial SBP1, SBP2 and AI@75. After adjusting for confounding factors, weight loss was significantly and independently associated with each reduction in brachial MAP (β=0.34, P=0.001), radial SBP1 (β=0.31, P=0.002), SBP2 (β=0.37, P

Glycated hemoglobin A1c(HbA1c) is used as a measure of glycemic control and also as a diagnostic criterion for diabetes. To discover novel loci harboring common variants associated with HbA1cin East Asians, we conducted a meta-analysis of 13 genome-wide association studies (GWAS; N = 21,026). We replicated our findings in three additional studies comprising 11,576 individuals of East Asian ancestry. Ten variants showed associations that reached genome-wide significance in the discovery data set, of which nine (four novel variants at TMEM79 [ P value = 1.3 × 10-23], HBS1L/MYB [8.5 × 10-15], MYO9B [9.0 × 10-12], and CYBA [1.1 × 10-8] as well as five variants at loci that had been previously identified [CDKAL1, G6PC2/ ABCB11, GCK, ANK1, and FN3KI]) showed consistent evidence of association in replication data sets. These variants explained 1.76% of the variance in HbA1c. Several of these variants (TMEM79, HBS1L/MYB, CYBA, MYO9B, ANK1, and FN3K) showed no association with either blood glucose or type 2 diabetes. Among individuals with nondiabetic levels of fasting glucose (

Variants in the CDH13 gene have been identified as determinants of blood levels of adiponectin, an insulin-sensitizing adipokine. However, their association with other metabolic risk factors remains unclear. We examined variants at CDH13 in relation to total and high-molecular-weight (HMW) adiponectin using data from a genome-wide association study performed in 2,434 Singaporean Chinese with replication in up to 3,290 Japanese and 1,610 Koreans. The top signal rs4783244 in CDH13 showed strong associations with total adiponectin (standardized β [β] = −0.34, 95% CI −0.38 to −0.30, P = 2.0 × 10−70), HMW adiponectin (β = −0.40, 95% CI −0.43 to −0.36, P = 1.1 × 10−117), and the HMW-to-total adiponectin ratio (β = −0.44, 95% CI −0.49 to −0.40, P = 3.2 × 10−83). In the replication study, this single nucleotide polymorphism explained 4.1% of total and 6.5% of HMW adiponectin levels. No association was observed between rs4783244 and metabolic traits associated with insulin resistance before adjustment for HMW adiponectin levels. After adjustment for HMW adiponectin levels, the minor allele was associated with lower BMI (β = −0.15, 95% CI −0.19 to −0.11, P = 3.5 × 10−14), homeostasis model assessment-insulin resistance index (β = −0.16, 95% CI −0.20 to −0.12, P = 9.2 × 10−16), and triglycerides (β = −0.16, 95% CI −0.19 to −0.12, P = 1.3 × 10−16) and with higher HDL (β = 0.16, 95% CI 0.12 to 0.19, P = 2.1 × 10−17). CDH13 variants strongly influence plasma total and HMW adiponectin levels in East Asian populations but appear to alter adiponectin sensitivity, resulting in better metabolic health than expected based on circulating adiponectin levels.

Impaired fasting glucose (IFG) in diabetes is a risk factor for arterial stiffness and cardiovascular disease (CVD), but the impact of a slightly high-normal glucose level remains controversial. We investigated whether slightly high-normal fasting plasma glucose (FPG) was independently associated with arterial stiffness in non-diabetic community-dwelling persons. We recruited 114 men aged 69 ± 9 years (range 40–89) and 208 women aged 68 ± 7 years (range 36–84) during their annual health examination in a single community. Arterial stiffness was evaluated by the mean of the right and left brachial–ankle pulse wave velocity (ba-PWV). Age-adjusted ba-PWV increased significantly from the lowest to the highest FPG group ( p < 0.001). Multiple linear regression analyses for ba-PWV revealed that FPG levels (β=0.154, p < 0.001) were independently and significantly associated with ba-PWV. The multivariate-adjusted ba-PWV value of the high-normal glucose group (Group 3: 95–100 mg/dL) was significantly higher than that of the lowest normal glucose group (Group 1: 52–89 mg/dL) ( p=0.021), and the ba-PWV value in the IFG group (Group 4: 101–125 mg/dL) was significantly higher than those of the normal glucose groups (Group 1

Metabolic syndrome (MetS) is associated with an increased risk of major cardiovascular events. In women, increased uric acid (UA) levels are associated with MetS and its components. High-sensitivity C-reactive protein (hsCRP) levels are also associated with MetS, and hsCRP levels could be modulated by UA. We investigated whether combining UA and hsCRP levels are independently associated with MetS and insulin resistance in Japanese community-dwelling women. From a single community, we recruited 1,097 women (63 ± 12 years) during their annual health examination, and examined the cross-sectional relationship between UA, hsCRP, and MetS and insulin resistance, which was evaluated by homeostasis of minimal assessment of insulin resistance. Of these subjects, 218 women (19.9 %) had MetS. Multiple linear regression analysis was performed to evaluate the contribution of each confounding factor for MetS and insulin resistance, both UA and hsCRP as well as age and alcohol consumption, were independently and significantly associated with MetS and insulin resistance. The adjusted-odds ratios (95 % confidence interval) for MetS across tertiles of UA and hsCRP were 1.00, 1.45 (0.95–2.22), and 2.61 (1.74–3.93), and 1.00, 1.80 (1.18–2.74), and 3.23 (2.15–4.85), respectively. In addition, the combination increased UA, and hsCRP was also a significant and independent determinant for MetS and insulin resistance. In direction associations, we also observed a synergistic effect between these two molecules (F = 2.76, P = 0.027). These results suggested that combined assessment of UA and hsCRP levels provides incremental information for risk stratification of patients with MetS, independent of other confounding factors in community-dwelling women.

Serum uric acid (SUA) levels are strongly correlated with aging, gender, renal function, obesity, and metabolic abnormality; however, whether SUA has a causative role in elevated blood pressure (BP) is still a matter of debate. From a single community, we recruited 1177 eligible women (mean age, 61±13 years) during their annual health examination. All subjects were divided into two groups according to their age (participants aged ≥55 years and those aged

Resistin is an adipokine secreted from adipocytes in mice. We previously reported that a single nucleotide polymorphism (SNP) –420 (rs1862513) in the human resistin gene (RETN), is correlated with plasma resistin. Decorin is a multifunctional proteoglycan, and its isoform, lacking 14 amino acids from the N terminal region of mature core decorin, recently was identified as a resistin receptor in mice. To examine whether SNPs in the vicinity of the human decorin gene (DCN) are associated with plasma resistin, we cross-sectionally analyzed six tag SNPs selected around DCN in the same linkage disequilibrium block in 2,078 community-dwelling Japanese subjects. Plasma resistin was associated with the rs7139228, rs7956537, rs516115, and rs3138167 genotypes in DCN. A multiple regression analysis revealed that the genotype of rs7308752 (G/G) or rs516115 (C/C) was associated with decreased plasma resistin after adjusted for age, sex, BMI, and the RETN SNP rs1862513. The effect of rs7139228 and rs1862513 seemed to be additive without synergistic interaction. Therefore, plasma resistin was associated with some tag SNPs around DCN in the general Japanese population. The possibility that human decorin is a human resistin receptor should be pursued.

BACKGROUND: Elevated hematocrit levels have been suggested to be an independent determinant of insulin resistance and type 2 diabetes. To clarify the diagnostic significance of hematocrit level, we investigated the association with hemodynamic profiles, insulin resistance and insulin sensitivity, arterial properties, and asymptomatic cerebrovascular damage in a general Japanese population. METHODS: This study included 1, 978 participants from two independent cohorts. Insulin sensitivity was assessed by the oral 75 g glucose tolerance test. Carotid ultrasonography was performed to evaluate atherosclerosis and wall shear stress. Periventricular hyperintensity and lacunar infarction were assessed by brain magnetic resonance imaging. RESULTS: Hematocrit quartile showed a stepwise association with insulin sensitivity (Q1: 2.2 ± 0.7, Q2: 2.0 ± 0.7, Q3: 1.9 ± 0.7, Q4: 1.8 ± 0.6, p < 0.001) and insulin resistance (1.0 ± 0.6, 1.2 ± 0.7, 1.3 ± 0.8, 1.5 ± 1.0, p < 0.001). Multiple linear regression analysis adjusted for possible covariates identified hematocrit as an independent determinant of insulin sensitivity (β = −0.074, p = 0.019) and insulin resistance (β = 0.115, p < 0.001). However, this association was lost after further adjustment for visceral fat area and plasma alanine aminotransferase level. Further, no significant association was observed between hematocrit and carotid intima-media thickness (p = 0.306) where as wall shear stress was inversely associated with the carotid atherosclerosis (r = −0.250, p < 0.001). In contrast, a low hematocrit level was independently associated with periventricular hyperintensity (odds ratio 0.87 (95% CI 0.80–0.95), p = 0.001). CONCLUSION: Hematocrit was positively associated with insulin resistance and insulin sensitivity. This association was epiphenomenon of visceral and hepatic adiposity. Conversely, low hematocrit was a significant risk factor for periventricular hyperintensity independent of insulin resistance.

The role of resistin in the pathophysiology of insulin resistance in human is controversial and different in men and women. Thus, the discrepancy among previous reports may be resolved by gender-specific analysis of a large number of participants.From a single community, we recruited 746 men (mean age, 60±14 years) and 1033 women (63±12 years) during their annual health examination. We investigated whether plasma resistin levels are associated with insulin resistance evaluated by homeostasis of model assessment of insulin resistance (HOMA-IR) according to gender.Resistin levels were significantly correlated with HOMA-IR in men, but not in women. Analysis of covariance showed that two regression lines were significantly different (F=9.941, P=0.002). Multiple linear regression analyses for resistin showed that the resistin levels (β=0.124, P0.001) were independently and significantly associated with HOMA-IR as well as body mass index (BMI), alcohol consumption, smoking status, uric acid, γ-glutamyltransferase (GGT), and high molecular weight (HMW) adiponectin only in men and not in women. The interaction between gender and resistin level (F=11.50, P0.001) was also a significant and independent determinant for HOMA-IR as well as gender, BMI, alcohol consumption, smoking status, uric acid, GGT, HMW adiponectin, and resistin.These results suggest that plasma resistin levels are associated with insulin resistance in older Japanese men.

Background: HMG-CoA-reductase (statin) therapy to reduce low-density lipoprotein cholesterol (LDL-C) levels in patients with coronary heart disease can substantially improve outcomes; however, the benefits of statins in stroke patients, particularly for secondary stroke prevention, remain poorly under stood. Moreover, the degree of decrease in LDL-C that is required to prevent the recurrence of stroke is unknown. Objective: To determine whether the on-treatment LDL-C/high-density lipoprotein cholesterol ratio (LDL-C/HDL-C) is a predictive marker of stroke recurrence in patients with acute ischaemic stroke, and whether medical management of the LDL-C/HDL-C ratio would be of strategic significance for stroke prevention. Methods: A total of 137 dyslipidaemic patients who had suffered acute ischaemic stroke were enrolled and treated with rosuvastatin 2.5 mg within 24 hours of onset. Blood pressure and serum lipids were assessed at baseline and after 1 month of treatment with rosuvastatin. Fatal and non-fatal stroke events were recorded during a follow-up period of 36 months. We used univariate and multivariate analyses, as well as Kaplan-Meier analysis, to assess the predictive value of various parameters and to identify factors independently associated with stroke recurrence. Results: During a mean follow-up of 34.9 ± 0.8 months, there were ten cases of stroke recurrence. Age, chronic kidney disease (CKD) at baseline, and an on-treatment LDL-C/HDL-C ratio >2 after 1 month of rosuvastatin treatment were predictors of stroke recurrence in univariate analyses. Stepwise regression analysis showed that CKD (standardized adjusted odds ratio [OR] 6.55; 95% confidence interval [CI] 1.12, 36.43; p = 0.030) and on-treatment LDL-C/HDL-C ratio >2 (standardized adjusted OR 9.70; 95% CI 1.70, 55.33; p = 0.011) were independent risk factors for stroke recurrence. Post hoc analysis indicated that more intensive lipid control, to an LDL-C/HDL-C ratio ≤1.5, may reduce the risk of stroke recurrence. Conclusion: These results suggest that the use of statin therapy to achieve an on-treatment LDL-C/HDL-C ratio ≤2 is a suitable treatment strategy in patients having suffered acute ischaemic stroke. Further studies are required to confirm the clinical benefits of reducing the on-treatment LDL-C/HDL-C ratio to ≤1.5.

Alcadeins (Alcs) constitute a family of neuronal type I membrane proteins (α, β, γ) that share identical localization and function to the amyloid-β protein precursor (AβPP) in the brain. Alcs are proteolyzed in neurons through successive cleavages via secretases, resulting in non-aggregative p3-Alc, where p3 corresponds to the AβPP-fragment. We found p3-Alcα detected in human plasma reflected the pathological process of amyloid-β accumulation in Alzheimer's disease (AD) patients and therefore investigated the utility of p3-Alcα as a plasma biomarker in AD. We measured p3-Alcα plasma levels in 83 sporadic-AD, 18 mild cognitive impaired (MCI), and 24 control subjects using the sandwich-ELISA system. Pooled samples with previously published data (171 AD and 45 controls) were also analyzed. The plasma p3-Alcα concentrations in patients with AD and MCI were significantly higher compared with control subjects (224.7 ± 40.4, 223.3 ± 53.9, and 189.1 ± 32.9 pg/ml, respectively; p = 0.0012). In AD patients, the plasma p3-Alcα concentration significantly correlated with age (r = 0.23, p = 0.037) and serum creatinine levels (r = 0.23, p = 0.0012). Even after adjusting for confounding factors of age, gender, renal function, and ApoE-ε4, high plasma p3-Alcα levels were correlated with significant AD risk, with an odds ratio 1.47 (95% confidence interval: 1.18-1.93, p = 0.0019) for every 10 pg/ml increase. Pooled analysis further confirmed these findings. Increased plasma p3-Alcα, evident in the early stages of cognitive impairment, suggests that Alc metabolites are useful plasma biomarkers of AD.

The Millennium Genome Project for Hypertension was started in 2000 to identify genetic variants conferring susceptibility to hypertension, with the aim of furthering the understanding of the pathogenesis of this condition and realizing genome-based personalized medical care. Two different approaches were launched, genome-wide association analysis using single-nucleotide polymorphisms (SNPs) and microsatellite markers, and systematic candidate gene analysis, under the hypothesis that common variants have an important role in the etiology of common diseases. These multilateral approaches identified ATP2B1 as a gene responsible for hypertension in not only Japanese but also Caucasians. The high blood pressure susceptibility conferred by certain alleles of ATP2B1 has been widely replicated in various populations. Ex vivo mRNA expression analysis in umbilical artery smooth muscle cells indicated that reduced expression of this gene associated with the risk allele may be an underlying mechanism relating the ATP2B1 variant to hypertension. However, the effect size of a SNP was too small to clarify the entire picture of the genetic basis of hypertension. Further, dense genome analysis with accurate phenotype data may be required.

We reported previously that ATP2B1 was one of the genes for hypertension receptivity in a large-scale Japanese population, which has been replicated recently in Europeans and Koreans. ATP2B1 encodes the plasma membrane calcium ATPase isoform 1, which plays a critical role in intracellular calcium homeostasis. In addition, it is suggested that ATP2B1 plays a major role in vascular smooth muscle contraction. Because the ATP2B1 knockout (KO) mouse is embryo-lethal, we generated mice with vascular smooth muscle cell-specific KO of ATP2B1 using the Cre-loxP system to clarify the relationship between ATP2B1 and hypertension. The KO mice expressed significantly lower levels of ATP2B1 mRNA and protein in the aorta compared with control mice. KO mice showed significantly higher systolic blood pressure as measured by tail-cuff method and radiotelemetric method. Similar to ATP2B1, the expression of the Na + -Ca 2+ exchanger isoform 1 mRNA was decreased in vascular smooth muscle cells of KO mice. However, ATP2B4 expression was increased in KO mice. The cultured vascular smooth muscle cells of KO mice showed increased intracellular calcium concentration not only in basal condition but also in phenylephrine-stimulated condition. Furthermore, phenylephrine-induced vasoconstriction was significantly increased in vascular rings of the femoral artery of KO mice. These results suggest that ATP2B1 plays important roles in the regulation of blood pressure through alteration of calcium handling and vasoconstriction in vascular smooth muscle cells.

The aim of this article was that high-density lipoprotein cholesterol (HDL-C) reduces blood vessel injury through its antioxidant and anti-inflammatory functions. However, the effect of HDL-C on blood pressure may be controversial. Therefore, the aim of this study was to address whether HDL-C level is associated with blood pressure, and we examined cross-sectional data from community-dwelling persons. A total of 859 men [58 ± 15 (mean ± standard deviation); 20-89 (range) (years) and 1,169 women (61 ± 13; 19-88 years)] participants not on medication for hypertension were recruited from a single community at the time of their annual health examination. We examined the relationship between cardiovascular risk factors and blood pressure status. Multiple linear regression analysis using systolic blood pressure (SBP) and diastolic blood pressure (DBP) as an objective variable showed that HDL-C was significantly and independently associated with both SBP (β = 0.138), and DBP (β = 0.144). Compared to normotensive participants with the lowest quartile of HDL-C, multivariate-adjusted odds ratio (OR) for pre-hypertension was 1.72 (1.22-2.45) for the second quartile, 1.51 (1.07-2.15) for the third quartile, and 1.52 (1.04-2.22) for the highest quartile. Moreover, compared with normotensive participants with the lowest quartile, the multivariate-adjusted ORs for hypertension were 2.37 (1.63-3.45), 2.24 (1.54-3.28), 3.15 (2.10-4.74), respectively. There were no interactions between the two groups stratified by gender, age, BMI, drinking status, TG, FPG, and medication. Therefore, we concluded that HDL-C levels were positively associated with blood pressure in Japanese dwelling-community persons.

Aim: Vascular aging is known to be a major determinant of life expectancy. Recently, perceived age was reported to be a better predictor for mortality than chronological age. Based on these findings, we investigated whether or not perceived age was related to atherosclerosis in a general population. Methods: The participants were 273 individuals aged ≥50 years who participated in the Skin-doc in Anti-Aging Doc program. Facial photos were taken under a shadowless lamp from three directions (antero-posterior, and 60° right and left oblique projection) using a high-resolution digital camera. Perceived age was assessed either by 19 professional nurses in the geriatric ward or using facial identification program software. Carotid intima-media thickness (IMT), radial augmentation index (AI) and brachial-ankle pulse wave velocity (baPWV) were measured as indices for atherosclerosis. Results: The perceived age difference (expressed as the difference between perceived age and chronological age), when estimated either by nurses or software, was significantly and negatively associated with chronological age. Subjects who were evaluated by nurses to be younger than their chronological age had significantly lower carotid IMT after adjustment for chronological age. Conversely, carotid IMT was an independent and negative determinant of looking young, as perceived by nurses. Similar observations were also made between perceived age using facial identification software and carotid IMT. Radial AI and baPWV were not associated with perceived age. Conclusion: These findings show that carotid atherosclerosis is related to perceived age. This association might underlie previous findings showing that perceived age predicts life expectancy. Geriatr Gerontol Int 2012; ••: ••–••.

SummaryLonger lifespans have been accompanied by an increasing number of older people suffering from impaired cognitive function (dementia) including Alzheimer's disease (AD) and vascular dementia (VaD). Some studies have suggested that hypertension in old age correlates with the pathogenesis of dementia. Since hypertension is potentially reversible, a number of randomized trials have examined whether antihypertensive treatment may help to prevent dementia. We review five studies, all using subjects aged 60 years or older, which investigated different antihypertensive pharmacological treatments and found conflicting results regarding impact on dementia. At the same time, other studies have suggested that hypotension in older people, especially those with low diastolic blood pressure, are also at higher risk for developing dementia. Four studies are reviewed here, but none is able to determine unequivocally if hypotension is a cause or a consequence of dementia in old age.

INTRODUCTION. Serum high molecular weight (HMW) adiponectin, an adipocytokine, which is a protein secreted specifically by adipose tissue, improves insulin sensitivity and plays an important role in the development of metabolic syndrome and cardiovascular disease (CVD). Pulse wave velocity (PWV) is a noninvasive method of measuring arterial stiffness for the assessment of CVD in high-risk populations. We investigated whether serum HMW adiponectin is independently associated with arterial stiffness when evaluated using PWV. METHODS. We randomly recruited 99 men aged 69 ± 9 (mean ± standard deviation) years and 170 women aged 68 ± 7 years during their annual health examination in a single community. Peripheral arterial stiffness was evaluated by mean PWV determined at three points: from the heart to the carotid artery, to the brachial artery, and to the ankle. RESULTS AND CONCLUSIONS. Age-adjusted PWV in all sites other than the heart to the carotid artery decreased progressively with increased serum HMW adiponectin. Age-adjusted mean PWV significantly decreased from the lowest to the highest serum HMW adiponectin group. Multiple linear regression analyses for mean PWV revealed that decreased serum HMW adiponectin levels were significantly associated with increased mean PWV as well as age, BMI, SBP, DBP, prevalence of antihypertensive medication, and eGFR. Inclusion of serum HMW adiponectin into the model further increased the coefficient of determination (R(2)). Multivariate-adjusted mean PWV was significantly lowest in the highest serum HMW adiponectin group.

It was recently reported that GCKR rs780094 was associated with fasting plasma glucose (FPG) and triglyceride (TG) levels in various ethnic populations (A allele for low FPG and high TG). An association between GCKR rs780094 and type 2 diabetes mellitus (T2DM) (A allele for low risk) has also been reported. We examined the association between GCKR rs780094 and T2DM in Japanese subjects by analyzing 488 cases and 398 controls. A meta-analysis was performed involving two previous association studies. We also analyzed the association between the single-nucleotide polymorphism and clinical parameters in the general Japanese population (n=1854). In the case-control study, the A allele of GCKR rs780094 was associated with a reduced risk of T2DM (odds ratio=0.711 (95% confidence interval=0.589-0.859), P=4.2 × 10(-4)). A meta-analysis confirmed the association of GCKR rs780094 with T2DM susceptibility. In the general Japanese population, subjects with the A/A genotype had lower levels of FPG, fasting plasma insulin and homeostasis model assessment of insulin resistance than those with the G/G genotype. Conversely, subjects with the A/A genotype had higher levels of TG than those with the G/G genotype. We replicated GCKR rs780094 as a marker of T2DM susceptibility in Japanese subjects. This suggests that GCKR rs780094 is a common variant for T2DM susceptibility in various ethnic groups.

Cibenzoline, a Class I antiarrhythmic agent, can attenuate the left ventricular pressure gradient (LVPG) in patients with hypertrophic obstructive cardiomyopathy (HOCM). An association between the insertion/deletion polymorphism of the angiotensin-converting enzyme (ACE) gene and the progression of left ventricular hypertrophy in patients with hypertrophic cardiomyopathy has been reported. The aim of this study was to investigate the pharmacogenetic interactions between the ACE insertion/deletion polymorphism and the response to cibenzoline in patients with HOCM. Twenty-four patients with HOCM participated in this study. The LVPG and left ventricular function were measured by echocardiography before and 2 hours after administration of a single oral dose of 200 mg cibenzoline. The ACE insertion/deletion polymorphism was genotyped. The frequencies of the genotypes D/D, D/I, and I/I were 16%, 42%, and 42%, respectively. Before administration of cibenzoline, the LVPG was higher in patients with the D allele than in those without it (105 +/- 47 mm Hg versus 64 +/- 24 mm Hg, P = 0.0195). After administration of cibenzoline, the LVPG significantly decreased to 41 +/- 27 mm Hg in those with the D allele (P = 0.0001) and to 33 +/- 24 mm Hg in those without it (P = 0.0003). The LVPG in patients with the D allele was significantly decreased by cibenzoline when compared with patients without the allele (64 +/- 45 mm Hg versus 31 +/- 17 mm Hg, P = 0.038). Patients with HOCM with the ACE D allele had a high LVPG. Cibenzoline was more effective in patients with HOCM with the ACE D allele.

Aim: Aging shifts body composition to comprising more fat and less muscle. Sarcopenia, particularly in the knee extensors, and obesity, particularly visceral obesity, either alone or in combination, may exacerbate age-related physical disability. We investigated the association between age-related quadriceps (Qc) sarcopenia and visceral obesity, as measured by cross-sectional area (CSA), on postural instability. Methods: Mid-thigh muscle CSA and abdominal visceral and subcutaneous fat area at the level of the umbilicus were assessed from computed tomography (CT) images in 410 apparently healthy independent middle-aged to elderly subjects attending the medical check-up program in Ehime University Hospital. Static postural instability using a posturograph and one-leg standing time with eyes open were assessed. Results: Both abdominal visceral fat area and Qc muscle CSA corrected by body weight (BW) were associated with static postural instability, in addition to age and sex, while BW-corrected Qc muscle CSA predicted a short one-leg standing time. The combination of Qc sarcopenia, defined as greater than 1 standard deviation below the mean of a young group (age

Habitual exercise training, including a high-intensity interval walking programme, improves cardiorespiratory fitness and alleviates lifestyle-related diseases, such as obesity, hypertension and dyslipidaemia. However, the extent of improvement has been shown to differ substantially among individuals for various exercise regimens. A body of literature has demonstrated that gene polymorphisms could account for the inter-individual variability in the improvement of risk factors for lifestyle-related diseases following exercise training. However, the fractions of the variability explained by the polymorphisms are small (∼5%). Also, it is likely that the effects of gene polymorphisms differ with exercise regimens and subject characteristics. These observations suggest the necessity for further studies to exhaustively identify such gene polymorphisms. More importantly, the physiological and molecular genetic mechanisms by which gene polymorphisms interact with exercise to influence the improvements of risk factors for lifestyle-related diseases differentially remain to be clarified. A better understanding of these issues should lead to more effective integration of exercise to optimize the treatment and management of individuals with lifestyle-related diseases.

Summary Objective The Ala allele of the Pro12Ala polymorphism (rs1801282) of peroxisome proliferator-activated receptor γ (PPARγ) is protective against type 2 diabetes (T2DM). Resistin, secreted from adipocytes, causes insulin resistance in rodents. Resistin gene expression is reduced by the PPARγ ligand. We previously reported that subjects with the G/G genotype of a resistin gene single nucleotide polymorphism (SNP) at –420 (rs1862513) had the highest circulating resistin levels, followed by C/G and C/C. The aim of this study was to determine the relationship among PPARγ Pro12Ala polymorphism, resistin SNP-420, and plasma resistin. Design, patients and measurements We cross-sectionally analysed 2077 community-dwelling subjects attending an annual medical check-up. Genotypes were determined by TaqMan analysis. Fasting plasma resistin was measured using ELISA. Results Plasma resistin appeared to be higher in subjects with the Pro/Pro genotype of PPARγ than those with Pro/Ala and Ala/Ala genotypes (mean ± SE, 11·6 ± 0·2 vs. 10·4 ± 0·5 μg/l). Multiple regression analysis, adjusted for age, gender, BMI, and resistin SNP-420, revealed that the Pro/Pro genotype was a positive predictor of plasma resistin (PPARγ , Pro/Pro vs. Pro/Ala + Ala/Ala, unstandardized regression coefficient (β) = 1·03, P = 0·0384). The effects of the Pro/Pro genotype of PPARγ (Pro/Pro vs. Pro/Ala + Ala/Ala) and the G/G genotype of resistin SNP-420 (G/G vs. C/C) on plasma resistin were synergistic (β = 4·76, P = 0·011). Conclusions The PPARγ Pro12Ala Pro/Pro and resistin SNP-420 G/G genotypes were synergistically associated with plasma resistin, when adjusted for age, gender, and BMI, in the Japanese general population.

OBJECTIVE—The present study was conducted to confirm possible associations between candidate genes from genome-wide association studies and type 2 diabetes in Japanese diabetic patients and a community-based general population. A total of 11 previously reported single-nucleotide polymorphisms (SNPs) from the TCF7L2, CDKAL1, HHEX, IGF2BP2, CDKN2A/B, SLC30A8, and KCNJ11 genes were analyzed. RESEARCH DESIGN AND METHODS—Candidate SNPs were genotyped in 506 type 2 diabetic patients and 402 control subjects and meta-analyzed with six previous association studies in Japanese patients. Associations with fasting plasma insulin levels were investigated in a general population sample (n = 1,963, 61 ± 13 years). RESULTS—In our case-control subjects, susceptibility to type 2 diabetes was replicated in TCF7L2 (rs12255372), CDKAL1 (rs7756992, rs7754840), HHEX (rs7923837), IGF2BP2 (rs4402960 and rs1470579), CDKN2A/B (rs10811661), and SLC30A8 (rs13266634). In addition to these polymorphisms, meta-analysis confirmed the association of type 2 diabetes susceptibility with KCNJ11 rs5219, TCF7L2 rs7903146, and HHEX rs1111875. The TCF7L2 rs12255372 polymorphism showed the highest odds ratio (OR) for type 2 diabetes (OR 1.714 [1.298–2.263]). Odds ratio of other polymorphisms ranged from 1.13 to 1.41. The risk allele of CDKAL1 rs7756992 was significantly associated with lower insulin levels in type 2 diabetic patients after adjustment for other confounding factors. CONCLUSIONS—Type 2 diabetes susceptibility of seven candidate genes was confirmed in Japanese. Conservation of susceptible loci for type 2 diabetes was independent of ethnic background.

Central aortic blood pressure (BP), obtained from radial arterial waveform using the transfer function method (TFM), has been shown to have prognostic value independently of brachial BP. In this study, the relationship between peripheral systolic BP (SBP) and aortic SBP was evaluated. We further investigated whether TFM-derived aortic SBP can be estimated by information obtained from the radial waveform. The radial waveform was analysed to obtain the first peak of radial SBP (SBP1), second peak of radial SBP (SBP2), radial augmentation index (AI) (radial (SBP2-DBP)/(SBP1-DBP) x 100 and aortic SBP and AI using TFM in 233 subjects in the supine position. Measurements were repeated after changing position to the prone position. The constructed equation was validated in 149 community residents with different backgrounds. Radial SBP2 was closer to TFM-derived aortic SBP compared with brachial SBP. TFM-derived aortic SBP was approximated by the equation: aortic SBP=18.9-radial SBP2-0.03 x HR-0.214 x radial AI (r2=0.992). The equation was also applicable to predicting aortic SBP in the prone position as well as in different populations (mean difference between predicted aortic SBP and TFM-derived aortic SBP: -0.01+/-1.34 and 1.05+/-1.47 mm Hg, respectively). Radial arterial waveform analysis can be used for estimation of TFM-derived aortic SBP.

BACKGROUND We have earlier identified a quantitative trait locus (QTL) on rat chromosome 5 that appears to be primarily under the control of the sympathetic nervous system. Because sympathetic overactivity is related to both hypertension and insulin resistance, FABP3 is a candidate gene for the link between this QTL and blood pressure regulation. In this study, therefore, we explored the role of FABP3 genetic variations in essential hypertension (EH) in humans. METHODS We evaluated two single-nucleotide polymorphisms (SNPs) (rs2279885 and rs2271072) in 758 patients with EH and 726 controls. Polymorphism-related genotypes were determined using TaqMan assays, while haplotypes were estimated from the genotype data. RESULTS The frequencies of occurrence of the G allele of rs2279885 and the C allele of rs2271072 were significantly higher in subjects with EH than in normotensive (NT) subjects (P = 0.0339, P = 0.0209, respectively). However, the genotype distributions did not exhibit any significant differences. CONCLUSION We found an association between FABP3 gene polymorphisms and EH in a Japanese population, thereby suggesting that FABP3 is a susceptibility locus for EH.

So-called metabolic syndrome (MetS) is, in Western countries, one of the most promising modifiable targets for preventing cardiovascular disease. Elements of MetS include abdominal obesity, elevated blood pressure, hypertriglyceridemia, and impaired glucose tolerance. Numerous epidemiologic studies have found significant associations between MetS and both coronary artery disease and stroke. Adiponectin is an adipose tissue-specific plasma protein that is able to suppress atherosclerotic vascular changes. Levels of adiponectin reportedly are reduced in obese individuals and those with MetS. One of several molecular isoforms of adiponectin, high-molecular-weight (HMW) complex, is thought to be the active form. Adiponectin may influence plasma levels of C-reactive protein (CRP), a marker of inflammation reflecting early-stage atherosclerosis. Increased serum levels of high-sensitivity CRP (hsCRP) also are associated with MetS. This study measured plasma HMW adiponectin concentrations using an enzyme-linked immunosorbent assay, as well as levels of hsCRP, in 1845 middle-aged to elderly subjects dwelling in the community. Significantly reduced plasma levels of HMW adiponectin were documented, in both men and women, for each component of MetS other than elevated blood pressure. Plasma levels of hsCRP were significantly higher in those with metabolic disorders. Levels of high-density lipoprotein-cholesterol correlated positively with adiponectin levels. There was an inverse association between body mass index and hsCRP. After adjusting for possible confounding factors by logistic regression analysis, concentrations of both HMW adiponectin and hsCRP were identified as independent determinants of MetS. In addition to these direct associations there was a synergistic effect between these substances. Both HMW adiponectin and hsCRP were independently associated with insulin resistance. These findings demonstrate that reduced concentrations of HMW adiponectin and elevated levels of hsCRP are synergistically associated with the accumulation of metabolic disorders as exemplified by MetS. Estimating concentrations of these marker substances might help to identify populations at increased risk.

Alzheimer disease (AD) is characterized by progressive cognitive decline caused by synaptic dysfunction and neurodegeneration in the brain, and late-onset AD (LOAD), genetically classified as a polygenetic disease, is the major form of dementia in the elderly. It has been shown that beta amyloid, deposited in the AD brain, interacts with dynamin 1 and that the dynamin 2 (DNM2) gene homologous to the dynamin 1 gene is encoded at chromosome 19p13.2 where a susceptibility locus has been detected by linkage analysis. To test the genetic association of LOAD with the DNM2 gene, we performed a case-control study of 429 patients with LOAD and 438 sex- and age-matched control subjects in a Japanese population. We found a significant association of LOAD with single nucleotide polymorphism markers of the DNM2 gene, especially in non-carriers of the apolipoprotein E-epsilon4 allele. Even though subjects with the genotype homozygous for the risk allele at rs892086 showed no mutation in exons of the DNM2 gene, expression of DNM2 mRNA in the hippocampus was decreased in the patients compared to non-demented controls. We propose that the DNM2 gene is a novel susceptibility gene for LOAD.

We previously demonstrated that angiotensin II acts as a crucial neuroprotective factor after neural injury through angiotensin II type-2 (AT2) receptor signaling. Although the pathway is known to play an important role in the development of experimental autoimmune encephalomyelitis, cerebrospinal fluid (CSF) angiotensin II levels in patients with multiple sclerosis (MS) have never been studied. To clarify the significance of angiotensin II in MS, we assayed angiotensin II concentrations using an established enzyme-linked immunoabsorbent assay in CSF samples from patients with MS ( n = 21), patients with inflammatory neuropathies (IN) ( n = 23) and control individuals who did not have either of the neurological diseases or any other disease that might affect the angiotensin II levels in the CSF (control) ( n = 24). Angiotensin II levels in the CSF were 3.79 ± 1.54 pg/ml in the MS group, 5.13 ± 2.27 pg/ml in the IN group and 6.71 ± 2.65 pg/ml in the control group. The angiotensin II levels in the CSF of the MS group were significantly lower than in the control group ( p = 0.00057). Angiotensin II concentration in the CSF tended to have a negative correlation with the Kurtzke’s Expanded Disability Status Scale scores during MS relapse ( p = 0.0847). These findings suggest that reduced levels of intrathecal angiotensin II may be related to the abnormal neural damage and repair processes in MS.

Exaggerated blood pressure (BP) response to mental stress has been known to be a prognostic factor for cardiovascular disease. It has been argued that such unusual vascular reactivity to mental stress may arise from insulin resistance. To examine the vascular responses to mental stress, we evaluated the stress-related changes in BP and the augmentation index (AI), an index of arterial stiffness, in normotensive young males. Changes in late systolic BP (SBP2) representing central aortic pressure were also examined. Subjects were 86 males (21+/-2 years), 13 of whom were classified as obese (>or=25 kg/m(2)). AI was obtained from the radial arterial waveform as a ratio of the height of the late systolic peak to that of the first peak. Blood pressure and AI measurements were taken before, during and after a simple mental arithmetic test (MAT) lasting 3 min. Systolic BP (baseline 125+/-13, during MAT 133+/-13, post-MAT 124+/-11 mmHg; p

Obesity is a complex trait reflecting numerous genetic and environmental factors. Recently, a common genetic polymorphism (rs7566605) associated with a higher BMI was found in proximity to the insulin induced protein 2 (INSIG2 ) gene, with replication in four unrelated populations living in Western countries. We investigated the susceptibility to the polymorphism amongst the general Japanese population (n = 1976). The frequency of appearance of the single-nucleotide polymorphism (SNP) in the Japanese (G allele; 0.652, C allele; 0.348) was not different from that found in subjects of European origin as reported previously. However, the BMI levels in each of these genotypes did not differ significantly (GG; 23 +/- 3, GC; 24 +/- 3, CC; 24 +/- 3 kg/m(2), P = 0.906). In a separate analysis according to sex (male; P = 0.462, female; P = 0.879), age decade (40s; P = 0.057, 50s; P = 0.998, 60s; P = 0.622, 70s; 0.425, respectively), and tertiles of the BMI (1st; P = 0.409, 2nd; P = 0.088, 3rd; P = 0.780), the differences did not achieve statistical significance. The frequency of obesity did not differ among the genotypes (25 kg/m(2); 30.3, 30.8, 28.2%, P = 0.729, 30 kg/m(2); 2.9, 3.8, 2.8%, P = 0.549). No associations were also observed for related plasma markers; high-molecular weight (HMW) adiponectin (P = 0.510), high-sensitive C-reactive protein (P = 0.788), resistin (P = 0.937) and homeostasis of minimal assessment of insulin resistance (P = 0.634). These results indicate a lack of association between SNP rs7566605 and being overweight among the Japanese (in the middle-aged and elderly population).

Masked hypertension (HT) is a known risk factor for cardiovascular outcomes. Postural blood pressure (BP) dysregulation is another BP phenomenon representing cardiovascular frailty. Given their several shared risk factors, we suspected an inter-relationship between these two BP phenomena. Here we investigated a possible relationship between masked HT and postural BP dysregulation in a general population. Study subjects were 884 apparently healthy individuals (aged 66.3±8.9 years). Masked HT was assessed on the basis of the ambulatory monitored average awake BP and office-measured BP values. Orthostatic BP change was measured at our office after a subject was asked to actively stand up. A strong inverse relationship was noted for orthostatic systolic BP (SBP) change and office-to-awake SBP differences (office-awake BP) (r=-0.422, P0.001), and these relationships were replicated in the second-visit measurements (n=101, r=-0.326, P=0.001). Multivariate analysis revealed that the inverse association was independent (β=-0.23, P0.001) of possible covariates, including baseline office BP and antihypertensive treatment. Orthostatic HT (OHT), which is defined as postural increases in SBP10 mm Hg, 3 min after standing (P=0.001), but not transient HT at only 1 min (P=0.767), was associated with greater office-to-awake SBP differences than in orthostatic normotensive subjects. Among apparently normotensive subjects, the frequency of masked HT was therefore significantly greater in subjects who showed OHT 3 min after standing (52.1%) compared with controls (27.5%) (odds ratio=3.01, P=0.001). We observed an intra-individual relationship between the postural BP change and the office-to-awake BP differences, and subjects who showed OHT were likely to have masked HT irrespective of antihypertensive treatment.

A 64-year-old man presented with high fever, deep coma, neck stiffness and decorticate rigidity on admission to our hospital. Laboratory findings revealed liver dysfunction, and serial brain computer tomography revealed a right cerebellar hematoma, a small hemorrhage in the left frontal lobe and ischemia of the left corona radiata. Electroencephalogram (EEG) showed periodic synchronous discharge (PSD) patterns on the first occasion, but these disappeared in later EEG. Based on the cerebrospinal fluid findings of increased total protein (1183 mg/dL), increased cells (71/μL) and decreased glucose concentration (1 mg/dL), and the culture result of pure growth of Streptococcus pneumoniae, he was diagnosed as having pneumococcal meningoencephalitis. PSD patterns, though seldom found in bacterial meningoencephalitis, presented in this case probably due to severe infection of the central nervous system and hepatic encephalopathy. We report this case to emphasize that PSD can emerge on EEG in the early stage of pneumococcal meningoencephalitis.

Reelin plays an important role in the migration of embryonic neurons, but its continuing presence suggests additional functions in the brain. We now report a novel function where reelin protects P19 embryonal cells from apoptosis during retinoic acid-induced neuronal differentiation. This increased survival is associated with reelin activation of the phosphatidyl-inositol-3-kinase (PI3 K)/Akt pathway. When PI3 K was inhibited with LY294002, reelin failed to protect against this retinoic acid-induced apoptosis. The protective effect of reelin includes activating the Src-family kinases/PI3 K/Akt pathway which then led to selective phosphorylation of Bcl-2/Bcl-XL associated death promoter (BAD) at serine-136, while the phosphorylation-incompetent mutation of BAD (S136A) suppressed this protection. These and additional studies define a novel pathway where reelin binds apoE receptors, significantly activates the PI3 K/Akt pathway causing phosphorylation of BAD which helps to protect cells from apoptosing, thus serving an important role in promoting the survival of maturing neurons in the brain.

OBJECTIVE—Resistin, secreted from adipocytes, causes insulin resistance in rodents. We previously reported that the G/G genotype of a resistin gene promoter single nucleotide polymorphism (SNP) at −420 increases type 2 diabetes susceptibility by enhancing promoter activity. We report here on the relation between plasma resistin and either SNP −420 genotype or factors related to insulin resistance. RESEARCH DESIGN AND METHODS—We cross-sectionally analyzed 2,078 community-dwelling Japanese subjects attending a yearly medical checkup. The SNP −420 genotype was determined by TaqMan analysis. Fasting plasma resistin was measured using an enzyme-linked immunosorbent assay kit. RESULTS—Plasma resistin was associated with the SNP −420 genotype (P < 0.0001), which was highest in G/G followed by C/G and C/C. Plasma resistin was higher in elderly individuals, female subjects, nondrinkers, and subjects with high blood pressure (P < 0.001, 0.003, CONCLUSIONS—Plasma resistin was associated with SNP −420 and was correlated with insulin resistance, low serum HDL cholesterol, and high hs-CRP in the Japanese general population.

Nicastrin interacts with gamma-secretase complex components predominantly via the N-terminal third of the transmembrane domain. The authentic transmembrane domain is critically required for the interaction with gamma-secretase complex components and for formation of an active gamma-secretase complex. In this study, we have identified a novel alternatively spliced transcript of nicastrin in human brain tissue. This transcript (NCSTN-DeltaE16) lacks exon 16 of nicastrin mRNA, which leads to deletion of 71 amino acids just upstream of its transmembrane domain. Its expression pattern was analyzed in the hippocampus of patients with pathologically diagnosed Alzheimer disease (cases) and non-Alzheimer dementia (controls). In patients with the APOE-epsilon4 allele, the frequency of Alzheimer disease appeared to be increased in the NCSTN-DeltaE16-positive group, but the association was not statistically significant. In conclusion, the expression of NCSTN-DeltaE16 transcript may confer some additional risk for developing Alzheimer disease beyond the risk due to ApoE-epsilon4 allele. Further investigation in larger scale population would be necessary to address its potential implication in Alzheimer disease.