Novel insights into presenilin 1 mutation associated with a distinctive dementia phenotype and cotton wool plaques.

BACKGROUND: The mutations in the presenilin 1 gene (PSEN1) are the main cause of familial Alzheimer's disease. PSEN1 mutations affect amyloid-beta peptide production, which accumulates in the brain as senile plaque and cotton wool plaques (CWPs) and relates to other neurodegenerative disorders. Here we report the second case of the PSEN1 G266S mutation, which showed distinctive neuropathological features, including abundant CWPs. Lewy body pathology, and altered amyloid-beta production. METHOD: Using the proband's samples, we performed genetic analysis of the PSEN1, APP, MAPT, and APOE genes, histopathological and immunohistochemical analysis of the brain tissue, and biochemical analysis of Aß production in COS cells transfected with wild-type or mutant PSEN1. RESULTS: The patient presented with memory loss, abnormal behavior, and visual hallucinations. Brain scans showed reduced blood flow, mild atrophy, and white matter lesions. Genetic analysis revealed a heterozygous mutation at codon 266 (G266S) of PSEN1 and polymorphism of MAPT (Q230R). The brain had many CWPs, severe cerebral amyloid angiopathy (CAA), senile plaque, Lewy bodies, and neurites. Electron microscopy displayed myelinated fiber degeneration, mitochondrial damage, and amyloid fibrils in the white matter. The production level of Aß42 in PSEN1 G266S-transfected cells significantly increased. CONCLUSION: Our findings suggest that the PSEN1 G266S mutation may cause a heterogeneous clinical and pathological phenotype, influenced by other genetic or environmental factors.

Genome-wide association study of plasma resistin levels identified rs1423096 and rs10401670 as possible functional variants in the Japanese population.

Resistin is a cytokine inducing insulin resistance in mice. We previously identified single nucleotide polymorphisms (SNPs) at -420 (rs1862513) and -358 (rs3219175) located in the human resistin gene (RETN) promoter as strong determinants for circulating resistin in the Japanese population. The objective was to identify additional functional variants for circulating resistin. We conducted a genome-wide association study in 448 Japanese subjects. A peak association signal was found on chromosome 19 where RETN is located. The top-hit SNP was SNP -358 G>A, followed by rs1423096 C>T, SNP -420 C>G, and rs10401670 C>T (P = 5.39×10-47, 1.81×10-22, 2.09×10-16, and 9.25×10-15, respectively). Meta-analysis including another two independent general Japanese populations showed that circulating resistin was most strongly associated with SNP-358, followed by SNP-420, rs1423096, and rs10401670. Rs1423096 and rs10401670 were located in the 3'-region of RETN and were in strong linkage disequilibrium. Although these SNPs were also in linkage disequilibrium with the promoter SNPs, conditional and haplotype association analyses identified rs1423096 and rs10401670 as independent determinants for circulating resistin. Functionally, nuclear proteins specifically recognized T but not C at rs10401670 as evidenced by an electrophoretic mobility shift assay. The promoter activity of a luciferase reporter with T at either rs1423096 or rs10401670 was lower than that with C in THP-1 human monocytes. Therefore, rs1423096 and rs10401670, in addition to SNP-420 and SNP-358, were identified as possible functional variants affecting circulating resistin by the genome-wide search in the Japanese population.

Identification of three novel genetic variations associated with electrocardiographic traits (QRS duration and PR interval) in East Asians.

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).

A meta-analysis of genome-wide association studies for adiponectin levels in East Asians identifies a novel locus near WDR11-FGFR2.

Blood levels of adiponectin, an adipocyte-secreted protein correlated with metabolic and cardiovascular risks, are highly heritable. Genome-wide association (GWA) studies for adiponectin levels have identified 14 loci harboring variants associated with blood levels of adiponectin. To identify novel adiponectin-associated loci, particularly those of importance in East Asians, we conducted a meta-analysis of GWA studies for adiponectin in 7827 individuals, followed by two stages of replications in 4298 and 5954 additional individuals. We identified a novel adiponectin-associated locus on chromosome 10 near WDR11-FGFR2 (P = 3.0 × 10(-14)) and provided suggestive evidence for a locus on chromosome 12 near OR8S1-LALBA (P = 1.2 × 10(-7)). Of the adiponectin-associated loci previously described, we confirmed the association at CDH13 (P = 6.8 × 10(-165)), ADIPOQ (P = 1.8 × 10(-22)), PEPD (P = 3.6 × 10(-12)), CMIP (P = 2.1 × 10(-10)), ZNF664 (P = 2.3 × 10(-7)) and GPR109A (P = 7.4 × 10(-6)). Conditional analysis at ADIPOQ revealed a second signal with suggestive evidence of association only after conditioning on the lead SNP (Pinitial = 0.020; Pconditional = 7.0 × 10(-7)). We further confirmed the independence of two pairs of closely located loci (<2 Mb) on chromosome 16 at CMIP and CDH13, and on chromosome 12 at GPR109A and ZNF664. In addition, the newly identified signal near WDR11-FGFR2 exhibited evidence of association with triglycerides (P = 3.3 × 10(-4)), high density lipoprotein cholesterol (HDL-C, P = 4.9 × 10(-4)) and body mass index (BMI)-adjusted waist-hip ratio (P = 9.8 × 10(-3)). These findings improve our knowledge of the genetic basis of adiponectin variation, demonstrate the shared allelic architecture for adiponectin with lipids and central obesity and motivate further studies of underlying mechanisms.

Association of postural instability with asymptomatic cerebrovascular damage and cognitive decline: the Japan Shimanami health promoting program study.

BACKGROUND AND PURPOSE: Asymptomatic cerebral small-vessel disease (cSVD) in elderly individuals are potent risk factors for stroke. In addition to common clinical risk factors, postural instability has been postulated to be associated with cSVD in older frail patients. Here, we conducted a cross-sectional study to understand the possible link between postural instability and asymptomatic cSVD further, namely periventricular hyperintensity, lacunar infarction, and microbleeds, as well as cognitive function, in a middle-aged to elderly general population (n=1387). METHODS: Postural instability was assessed based on one-leg standing time (OLST) and posturography findings. cSVD was evaluated by brain MRI. Mild cognitive impairment was assessed using a computer-based questionnaire, and carotid intima-media thickness as an index of atherosclerosis was measured via ultrasonography. RESULTS: Frequency of short OLST, in particular <20 s, increased linearly with severity of cSVD (lacunar infarction lesion: none, 9.7%; 1, 16.0%; >2, 34.5%; microbleeds lesion: none, 10.1%; 1, 15.3%; >2, 30.0%; periventricular hyperintensity grade: 0, 5.7%; 1, 11.5%; >2, 23.7%). The association of short OLST with lacunar infarction and microbleeds but not periventricular hyperintensity remained significant even after adjustment for possible covariates (lacunar infarction, P=0.009; microbleeds, P=0.003; periventricular hyperintensity, P=0.601). In contrast, no significant association was found between posturographic parameters and cSVD, whereas these parameters were linearly associated with OLST. Short OLST was also significantly associated with reduced cognitive function independent of covariates, including cSVD (P=0.002). CONCLUSIONS: Postural instability was found to be associated with early pathological changes in the brain and functional decline, even in apparently healthy subjects.

Brachial-ankle pulse wave velocity is a predictor of walking distance in community-dwelling adults.

Arterial stiffness represents the cumulative effects of cardiovascular risk factors, including aging, on the arterial wall, and has been found to be a surrogate marker of cardiovascular disease. However, it remains unknown whether baseline arterial stiffness is independently associated with improvement in functional abilities after exercise training. The subjects were 72 adults (9 men and 63 women) aged 67 ± 7 years from a rural village. Before and at the end of a 12-week Nordic walking program, 6-min walk distance (6MWD) as functional abilities, metabolic characteristics, and the mean of the right and left brachial-ankle pulse wave velocity (baPWV) as a marker of arterial stiffness were measured. Higher baseline mean baPWV levels correlated significantly with shorter baseline 6MWD (P < 0.001), and also with the follow-up 6MWD (P < 0.001) and change rate (P = 0.019) in 6MWD after the 12-week training program. Multivariate linear regression analysis was employed to evaluate the contribution of baseline mean baPWV for 6MWD parameters showing that baseline mean baPWV values were significantly and independently associated with follow-up 6MWD (ß = -0.523, P < 0.001) and change rate in 6MWD (ß = -0.399, P < 0.001) as well as baseline 6MWD (ß = -0.522, P < 0.001), but was not associated with change after the 12-week training program. Higher baPWV, a measurement of arterial stiffness, might be a predictor of functional abilities after exercise training, independent of confounding factors, in the general population.

Association Between Genetic Variation in the SCN10A Gene and Cardiac Conduction Abnormalities in Patients With Hypertrophic Cardiomyopathy.

Arrhythmias are associated with reduced quality of life and poor prognosis in patients with hypertrophic cardiomyopathy (HCM). Recent genome-wide association studies revealed that a nonsynonymous single nucleotide polymorphism, rs6795970, in the SCN10A gene was associated with the PR interval. We examined whether the PR prolonging allele (A allele) in the SCN10A gene may be associated with cardiac conduction abnormalities in HCM patients.We genotyped the polymorphism in 149 HCM patients. Conduction abnormalities were defined as first-degree heart block, bundle-branch block, and bifascicular heart block. Patients were divided into two groups: group A consisted of 122 patients (82%) without a conduction abnormality; and group B consisted of 27 patients (18%) with one or more cardiac conduction abnormalities. The frequency distribution of the SCN10A genotypes (G/G, G/A, and A/A) among the patients with HCM was 71%, 26%, and 3%, respectively. A cardiac conduction abnormality was documented in 9% with G/G and 40% with G/A or A/A. There was a significant difference in the genotype distribution between the two groups (P = 0.0002). In the dominant A allele model, there was a significant difference in genotypes between the two groups (P < 0.0001). In addition, the A allele remained significant after adjusting for other covariates in a multivariate model (odds ratio = 6.30 [95% confidence interval: 2.24 to 19.09], P = 0.0005).The rs6795970 in the SCN10A gene, which is reported to carry a high risk of heart block, might be associated with cardiac conduction abnormalities in HCM patients.

[The differences in speciality preferences and career determinant factors between first- and fifth-year medical school students].

AIM: In Japan, the imbalance in the medical workforce has caused a deterioration of rural medicine. We explored the differences in speciality preferences and career determinant factors among students to identify keys to increase the recruitment of physicians to rural areas. METHODS: We conducted a survey of first- and fifth-year medical students, using a questionnaire enquiring about their specialty preference and career determinant factors. The data were analyzed with a chi-square test. RESULTS: A higher percentage of first-year students preferred to be basic medicine scientists, while fifth-year students considered internal medicine subspecialities, obstetrics and gynecology, anesthesia, and ophthalmology to be the most desirable. The factor analysis yielded five factors responsible for these findings; high social approval of the specialty, working hours, income, advice from senior classmates and doctors, and the work environment. The percentage of students who considered rural practice as a choice for thier future plan and had an awareness of the collapse of rural medicine was lower in the fifth-year students than in the first-year students. CONCLUSION: To increase the medical work force in provincial areas, it is necessary to strengthen not only the medical system with regard to general medicine, but also to offer better medical education in rural areas. More information about rural practice should therefore be transmitted to medical students.

Mechanical stresses, arterial stiffness, and brain small vessel diseases: Shimanami Health Promoting Program Study.

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<0.0001) and negatively with SS (P=0.0007) even after correction for confounding parameters including baPWV. SVD was associated with significantly higher WT (P<0.0001) and lower SS (P<0.0001). After adjustment for confounding parameters (including baPWV), second peak of systolic blood pressure WT (odds ratio, 1.30; 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 (ß=0.02; P<0.0001). CONCLUSIONS: These findings indicate that SVD is phenotype-specifically associated with alterations in WT and SS independently of arterial stiffness.

Interaction between serum uric acid and triglycerides in relation to prehypertension in community-dwelling Japanese adults.

There are few data available on the association between serum uric acid (SUA) levels and blood pressure (BP) categories earlier in the disease continuum, when efforts for its prevention may be applicable. We performed a cross-sectional study to examine the association between SUA and prehypertension in a community-dwelling sample of Japanese adults. Study participants without hypertension aged 19 to 90 years [567 men aged 56 ± 15 (mean ± standard deviation) years and 808 women aged 58 ± 13 years] were recruited for a survey at the community based annual medical check-up. The main outcome was the presence of prehypertension [systolic BP (SBP) 120-139 mmHg and/or diastolic BP (DBP) 80-89 mmHg]. After adjustments by gender and age, both SBP (p<0.001) and DBP (p<0.001) increased significantly and progressively with increasing SUA and triglycerides (TG) as well as body mass index, LDL cholesterol, and fasting plasma glucose (FPG). Compared to those with normotension, the multivariate-adjusted odds ratio (95% confidence interval) for participants with prehypertension was 1.15 (1.05-1.26) for SUA and 3.19 (1.66-6.14) for TG. The interaction between increased SUA and TG was a significant and independent determinant for SBP (ß=-2.474, p=0.008), but not for DBP (ß=-0.608, p=0.349). Higher SUA levels are associated with prehypertension in participants without hypertriglyceridemia (<150 mg/dL), but not in participants with hypertriglyceridemia (≥ 150 mg/dL). TG levels may modify the association between SUA and prehypertension.

Positive natural selection of TRIB2, a novel gene that influences visceral fat accumulation, in East Asia.

Accumulation of visceral fat increases cardiovascular mortality in industrialized societies. However, during the evolution of the modern human, visceral fat may have acted as energy storage facility to survive in times of famine. Therefore, past natural selection might contribute to shaping the variation of visceral fat accumulation in present populations. Here, we report that the gene encoding tribbles homolog 2 (TRIB2) influenced visceral fat accumulation and was operated by recent positive natural selection in East Asians. Our candidate gene association analysis on 11 metabolic traits of 5,810 East Asians revealed that rs1057001, a T/A transversion polymorphism in 3'untranslated region (UTR) of TRIB2, was strongly associated with visceral fat area (VFA) and waist circumference adjusted for body mass index (P = 2.7 × 10(-6) and P = 9.0 × 10(-6), respectively). rs1057001 was in absolute linkage disequilibrium with a conserved insertion-deletion polymorphism in the 3'UTR and was associated with allelic imbalance of TRIB2 transcript levels in adipose tissues. rs1057001 showed high degree of interpopulation variation of the allele frequency; the low-VFA-associated A allele was found with high frequencies in East Asians. Haplotypes containing the rs1057001 A allele exhibited a signature of a selective sweep, which may have occurred 16,546-27,827 years ago in East Asians. Given the predominance of the thrifty gene hypothesis, it is surprising that the apparently non-thrifty allele was selectively favored in the evolution of modern humans. Environmental/physiological factors other than famine would be needed to explain the non-neutral evolution of TRIB2 in East Asians.

Visit-to-visit variability in systolic blood pressure is a novel risk factor for the growth of intracranial aneurysms.

BACKGROUND: Although rupture of unruptured intracranial aneurysms (UIAs) is closely associated with UIA growth during follow-up, few studies have investigated how UIAs grow during observation. Hypertension appears to affect the formation of intracranial aneurysms. However, few studies have investigated the association of blood pressure variability with UIA growth. Visit-to-visit variability (VVV) in systolic blood pressure (SBP) is a newly defined concept which appears to be a good predictor of stroke. With this factor in mind, here we conducted a prospective analysis of the results of 2 years of observation of UIAs by magnetic resonance angiography (MRA) and sought to identify risk factors for UIA growth and rupture. METHODS: From December 2006 through June 2010, two hundred patients with 212 UIAs were followed for 2 years. Patient ages ranged from 31 to 91 years. Putative risk factors for the growth of UIAs were evaluated. Subjects were divided into two groups: a UIA growth group consisting of patients whose UIAs increased by 1 mm or more in size or who developed subarachnoid hemorrhage (SAH), and an unchanged group. Brachial blood pressure values were recorded at the time of diagnosis and during follow-up in the outpatient clinic. All blood pressure values were then averaged, and the VVV of SBP was defined as the standard deviation (SD) of a minimum of 5 blood pressure measurements at outpatient visits. RESULTS: UIA growth occurred in 20 patients and SAH occurred in 1 patient. Current smoking tended to be more prevalent in the UIA growth group (p < 0.01). Five of the 12 patients with multiple UIAs showed UIA growth within 2 years and multiplicity was a significant risk factor for UIA growth (p < 0.01). The mean baseline size in the UIA growth group was larger than that in the unchanged group (p = 0.01) and 7 of the 18 patients with large UIAs, categorized as having an initial diameter of 7 mm or more, had an increase in UIA size over the 2 years (p < 0.01). On multivariable logistic regression analysis, current smoking, multiplicity, and UIA size ≥7 mm were significant risk factors for UIA growth. Although no significant difference was seen between the UIA growth and unchanged groups in office SBP during the observation period, VVV in SBP was significantly higher in the UIA growth group than in the unchanged group, and it was significantly and independently associated with UIA growth. CONCLUSIONS: VVV in SBP is a novel risk factor for the growth of UIAs and may be a key factor for the prevention of UIA rupture. Future research is needed to confirm that SBP stability prevents UIA rupture.

A slightly high-normal glucose level is associated with increased arterial stiffness in Japanese community-dwelling persons with pre-diabetes.

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 (ß=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: <90 mg/dL; Group 2: 90-94 mg/dL) (p<0.001 and p=0.009, respectively). Slightly high-normal glucose levels were associated with arterial stiffness in Japanese community-dwelling persons.

Alanine aminotransferase/aspartate aminotransferase ratio is the best surrogate marker for insulin resistance in non-obese Japanese adults.

BACKGROUND: The aim of the present study was to examine how liver markers are associated with insulin resistance in Japanese community-dwelling adults. METHODS: This cross-sectional study included 587 men aged 58 ± 14 (mean ± standard deviation; range, 20-89) years and 755 women aged 60 ± 12 (range, 21-88) years. The study sample consisted of 998 (74.4%) non-obese [body mass index (BMI) <25.0 kg/m2] and 344 (25.6%) overweight (BMI ≥ 25 kg/m2) subjects. Insulin resistance was defined by homeostasis model assessment of insulin resistance (HOMA-IR) of at least 2.5, and HOMA-IR and potential confounders were compared between the groups. Areas under the curve (AUC) of the receiver operating characteristic curves (ROC) were used to compare the power of these serum markers. RESULTS: In non-obese subjects, the best marker of insulin resistance was alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ratio of 0.70 (95% confidence interval (CI), 0.63-0.77). In overweight subjects, AUC values for the ALT/AST ratio and ALT were 0.66 (0.59-0.72) and 0.66 (0.59-0.72), respectively. Multiple linear regression analyses for HOMA-IR showed that ALT/AST ratios were independently and significantly associated with HOMA-IR as well as other confounding factors in both non-obese and overweight subjects. The optimal cut-off point to identifying insulin resistance for these markers yielded the following values: ALT/AST ratio of ≥ 0.82 in non-obese subjects and ≥ 1.02 in overweight subjects. In non-obese subjects, the positive likelihood ratio was greatest for ALT/AST ratio. CONCLUSIONS: In non-obese Japanese adults, ALT/AST ratio may be the best reliable marker of insulin resistance.

Impact of synergistic polymorphisms in adrenergic receptor-related genes and cardiovascular events in patients with dilated cardiomyopathy.

BACKGROUND: Sustained cardiac adrenergic stimulation has been implicated in the progression of cardiovascular events in patients with dilated cardiomyopathy (DCM). Our group hypothesized that a combination of polymorphisms that result in increased synaptic norepinephrine release and enhanced receptor function would predispose patients with DCM to cardiovascular events. The effect of polymorphisms in adrenergic receptor-related genes on cardiovascular event-free survival in patients with idiopathic DCM was evaluated. METHODS AND RESULTS: Genotyping at 3 loci (ADRB1 Ser49Gly and Arg389Gly, and NET T-182C) was performed in 83 patients with DCM. Patients were followed prospectively to the endpoint of cardiovascular events (mean follow-up, 45 months). Cardiovascular events were defined as cardiac death and emergent hospitalization as a result of congestive heart failure, arrhythmia, and cerebrovascular events. Analyses were conducted based on the number of predicted risk genotypes a patient carried. The ADRB1 Ser49 allele carrier, ADRB1 Arg389 allele carrier, and NET-182CC genotype were defined as the predicted risk genotypes. Cardiovascular event-free survival was compared based on the number of predicted risk genotypes. Cardiovascular event-free survival was significantly better in patients with fewer than 3 predicted risk genotypes than in those with 3 predicted risk genotypes. CONCLUSIONS: Genotyping at these 3 loci might be a useful approach for identification of patients with DCM at risk for cardiovascular events.

A slightly low hemoglobin level is beneficially associated with arterial stiffness in Japanese community-dwelling women.

Pulse wave velocity (PWV) is a simple and noninvasive method of measuring arterial stiffness for the assessment of cardiovascular disease in high-risk populations. This association may be further confounded by hemoglobin status, which is involved in the development of atherosclerosis. We randomly recruited 120 men and 223 women aged 69 ± 9 and 68 ± 7 years, respectively, during their annual health examination in a single community. Arterial stiffness was evaluated by brachial-ankle PWV (baPWV). The value of baPWV was different from men and women. In men, baPWV was not related to hemoglobin levels (r = 0.013, P = .886), but in women baPWV increased significantly and progressively with increased hemoglobin levels (r = 0.276, P < .001). Stepwise multiple regression analysis using the baPWV as objective variables, adjusted for confounding factors as explanatory variables, showed that only in women, hemoglobin levels (ß = 0.165, P = .001) as well as age (ß = 0.268, P < .001), body mass index (BMI; ß = -0.165, P < .001), systolic blood pressure (SBP; ß = 0.429, P < .001), prevalence of antihypertensive (ß = 0.154, P = .002), heart rate (HR; ß = 0.108, P = .017), and antilipidemic medication (ß = 0.094, P = .036), and estimated glomerular filtration rate (eGFR; ß = -0.147, P = .003) were significantly and independently associated with baPWV. Multivariate-adjusted baPWV was significantly higher in hemoglobin groups of ≥12.7 g/dL (Group-2, Group-4) than in the lowest hemoglobin group (10.0-12.6 g/dL; P = .032). A slightly low hemoglobin level was beneficially associated with arterial stiffness in community-dwelling women but not men.

[A case of Fisher syndrome with multiple cranial neuropathy and abnormal EEG findings].

A 69-year-old woman was admitted because of unconsciousness and multiple cranial neuropathy. She had suffered diarrhea 2 weeks previously. On examination, she was noted to have total external and internal ophthalmoplegia, bilateral facial palsy, dysphagia, dysarthria, neck weakness, distal motor weakness of all limbs, and ataxia. She had also presented with hyporeflexia and hypoesthesia, but with a bilateral pyramidal tract sign. A study of her cerebrospinal fluid revealed albuminocytologic dissociation, and nerve conduction study revealed demyelination of her peripheral nerves. Moreover, electroencephalography findings were abnormal and anti-GQ1b antibody was positive. We diagnosed Fisher syndrome with Guillain-Barré syndrome and Bickerstaff brainstem encephalitis. We administered intravenous immunoglobulin treatment for 5 days and her symptoms gradually improved. However, her external ophthalmoplegia continued for several months.

Association between fasting plasma glucose and high-sensitivity C-reactive protein: gender differences in a Japanese community-dwelling population.

BACKGROUND: High sensitivity C-reactive protein (hsCRP) is an acute phase reactant and a sensitive marker of inflammation. Hyperglycemia can potentially promote the production of CRP. The aim of this study was to determine whether increased fasting plasma glucose (FPG) levels are associated with elevated hsCRP concentrations by gender. METHODS: We recruited 822 men (mean age, 61 ± 14 years) and 1,097 women (63 ± 12 years) during their annual health examination from a single community. We cross-sectionally examined whether FPG levels are associated with hsCRP concentrations, and whether this association is independent of gender, body mass index (BMI) and other components of the metabolic syndrome. RESULTS: In women only, hsCRP increased significantly and progressively with increasing FPG (r = 0.169, P < 0.001). The stepwise multiple linear regression analysis using hsCRP as an objective variable, adjusted for confounding factors as explanatory variables, showed that FPG as well as age, BMI, systolic blood pressure, high-density lipoprotein cholesterol (HDL-C), uric acid, and high molecular weight adiponectin were significantly associated with hsCRP in women, but not in men. There was significant gender interaction, and an increase in hsCRP levels that was greater in women with BMI ≥ 25 kg/m2 and higher FPG than in men. CONCLUSIONS: These results suggested that hsCRP levels increase continuously across the FPG spectrum starting from the lowest FPG in both men and women. However, increase in hsCRP levels was greater in women than men.

Relationships between lipid profiles and metabolic syndrome, insulin resistance and serum high molecular adiponectin in Japanese community-dwelling adults.

BACKGROUND: There are few studies to demonstrate the associations between newly addressed lipid profiles and metabolic syndrome (MetS)-associated variables. METHODS: Study participants without medications for hypertension, diabetes, or dyslipidemia {614 men aged 58 ± 14 (mean ± standard deviation; range, 20-89) years and 779 women aged 60 ± 12 (range, 21-88) years} were randomly recruited from a single community at the time of their annual health examination. The association between lipid profiles (total cholesterol (T-C), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-HDL-C, T-C/HDL-C, TG/HDL-C, LDL-C/HDL-C ratio and MetS, Insulin resistance by homeostasis model assessment of insulin resistance (HOMA-IR), and serum HMW adiponectin were analyzed. RESULTS: In multiple linear regression analysis, TG/HDL-C and T-C/HDL-C ratios as well as TG showed significantly strong associations with all three MetS-associated variables in both men and women. In men, the ROC curve analyses showed that the best marker for these variables was TG/HDL-C ratio, with the AUC for presence of MetS (AUC, 0.82; 95% CI, 0.77-0.87), HOMA-IR (AUC, 0.75; 95% CI, 0.70-0.80), and serum HMW adiponectin (AUC, 0.67; 95% CI, 0.63-0.71), respectively. The T-C/HDL-C ratio, TG, HDL-C, LDL-C/HDL-C ratio, and non-HDL-C also discriminated these markers; however all their AUC estimates were lower than TG/HDL-C ratio. These results were similar in women. CONCLUSION: In Japanese community-dwelling adults, lipid ratios of TG/HDL-C, T-C/HDL-C, LDL-C/HDL-C as well as TG and HDL-C were consistently associated with MetS, insulin resistance and serum HMW adiponectin. Lipid ratios may be used as reliable markers.

Association of serum high molecular weight adiponectin and blood pressure among non-diabetic community-dwelling men.

Adiponectin is one of the important molecules in the development of metabolic syndrome, and its concentration is decreased in obesity, type-2 diabetes, and cardiovascular disease. We aim to determine whether serum high-molecular weight (HMW) adiponectin, which is thought to represent the biological active form, was associated with a risk for the prevalence of prehypertension and hypertension. The cross-sectional study was carried out in 2002. A total of 614 men, aged 58 ± 14 (range, 20-89) years, and 779 women, aged 62 ± 12 (range, 21-88) years without medications for hypertension, diabetes, or dyslipidemia were recruited from a single community at the time of their annual health examination. In men, nonadjusted and age-adjusted mean serum HMW adiponectin were significantly lower in subjects with prehypertension and hypertension than those with normotension. In women, only nonadjusted values were higher in subjects with hypertension than those with normotension. Multiple linear regression analysis using systolic blood pressure (SBP) and diastolic blood pressure (DBP) as an objective variable, adjusted for risk factors as explanatory variables, showed that only in men, log serum HMW adiponectin were significantly and independently associated with SBP and DBP. In men, lower serum HMW adiponectin categories were positively associated with prehypertension and hypertension in an age-adjusted model, and hypertension in an age- and BMI-adjusted model. Serum HMW adiponectin concentrations were inversely associated with blood pressure (BP) in the general male population.