Makoto Daimon

Prevalence and Risk Factors for Age-Related Macular Degeneration in an Adult Japanese Population : The Funagata Study

OBJECTIVE To describe the prevalence and risk factors for age-related macular degeneration (AMD) in a Japanese population and to compare these with data from a white population. DESIGN Population-based cross-sectional epidemiologic study. PARTICIPANTS A population-based sample of Japanese persons 35 years or older from Funagata, Japan. METHODS The Funagata study is a population-based study of 1758 (43% of eligible) Japanese persons 35 years or older from Funagata, Japan. In 2000 to 2002, 1625 (92.4%) participants had a nonmydriatic fundus photograph of one eye with sufficient quality for grading of AMD lesions, using the Wisconsin protocol. Age-standardized prevalence rates compared with the Blue Mountains Eye Study (BMES) population, odds ratios (ORs), and 95% confidence intervals (CIs) were calculated. Risk factors were assessed by logistic regression. MAIN OUTCOME MEASURES Early and late AMD. RESULTS Of 1625 participants, early AMD and late AMD were present in 3.5% and 0.5%, respectively. Age-standardized early AMD prevalence in right eyes was 4.1%, similar to the corresponding prevalence of 4.4% in the BMES. For men, age-standardized prevalences of late AMD in right eyes were 1.1% and 1.2% in the BMES; for women, the corresponding prevalences were 0.3% and 2.1%, respectively. Increasing age (per 10 years; gender-adjusted OR, 2.27; 95% CI, 1.10-4.67) and current cigarette smoking (age- and gender-adjusted OR, 5.03; 95% CI, 1.00-25.47) were associated with late AMD. CONCLUSIONS In this Japanese population, prevalence of early AMD was similar to that for whites in the BMES. Although the late AMD prevalence was lower in Japanese women, in Japanese men it was similar to that in whites. This could have resulted from the substantially high proportion of Japanese men who are smokers. Cigarette smoking and increasing age were the 2 principal factors found associated with late AMD.

The Role of G-Protein-Coupled Receptor Kinase 5 in Pathogenesis of Sporadic Parkinson's Disease

Sporadic Parkinsons disease (sPD) is a common neurodegenerative disorder, characterized by selective degeneration of dopaminergic neurons in the substantia nigra. Although the pathogenesis of the disease remains undetermined, phosphorylation of α-synuclein and its oligomer formation seem to play a key role. However, the protein kinase(s) involved in the phosphorylation in the pathogenesis of sPD has not been identified. Here, we found that G-protein-coupled receptor kinase 5 (GRK5) accumulated in Lewy bodies and colocalized with α-synuclein in the pathological structures of the brains of sPD patients. In cotransfected cells, GRK5 phosphorylated Ser-129 of α-synuclein at the plasma membrane and induced translocation of phosphorylated α-synuclein to the perikaryal area. GRK5-catalyzed phosphorylation also promoted the formation of soluble oligomers and aggregates of α-synuclein. Genetic association study revealed haplotypic association of the GRK5 gene with susceptibility to sPD. The haplotype contained two functional single-nucleotide polymorphisms, m22.1 and m24, in introns of the GRK5 gene, which bound to YY1 (Yin Yang-1) and CREB-1 (cAMP response element-binding protein 1), respectively, and increased transcriptional activity of the reporter gene. The results suggest that phosphorylation of α-synuclein by GRK5 plays a crucial role in the pathogenesis of sPD.

Glycated Hemoglobin Measurement and Prediction of Cardiovascular Disease

IMPORTANCE The value of measuring levels of glycated hemoglobin (HbA1c) for the prediction of first cardiovascular events is uncertain. OBJECTIVE To determine whether adding information on HbA1c values to conventional cardiovascular risk factors is associated with improvement in prediction of cardiovascular disease (CVD) risk. DESIGN, SETTING, AND PARTICIPANTS Analysis of individual-participant data available from 73 prospective studies involving 294,998 participants without a known history of diabetes mellitus or CVD at the baseline assessment. MAIN OUTCOMES AND MEASURES Measures of risk discrimination for CVD outcomes (eg, C-index) and reclassification (eg, net reclassification improvement) of participants across predicted 10-year risk categories of low (<5%), intermediate (5% to <7.5%), and high (≥ 7.5%) risk. RESULTS During a median follow-up of 9.9 (interquartile range, 7.6-13.2) years, 20,840 incident fatal and nonfatal CVD outcomes (13,237 coronary heart disease and 7603 stroke outcomes) were recorded. In analyses adjusted for several conventional cardiovascular risk factors, there was an approximately J-shaped association between HbA1c values and CVD risk. The association between HbA1c values and CVD risk changed only slightly after adjustment for total cholesterol and triglyceride concentrations or estimated glomerular filtration rate, but this association attenuated somewhat after adjustment for concentrations of high-density lipoprotein cholesterol and C-reactive protein. The C-index for a CVD risk prediction model containing conventional cardiovascular risk factors alone was 0.7434 (95% CI, 0.7350 to 0.7517). The addition of information on HbA1c was associated with a C-index change of 0.0018 (0.0003 to 0.0033) and a net reclassification improvement of 0.42 (-0.63 to 1.48) for the categories of predicted 10-year CVD risk. The improvement provided by HbA1c assessment in prediction of CVD risk was equal to or better than estimated improvements for measurement of fasting, random, or postload plasma glucose levels. CONCLUSIONS AND RELEVANCE In a study of individuals without known CVD or diabetes, additional assessment of HbA1c values in the context of CVD risk assessment provided little incremental benefit for prediction of CVD risk.

Microalbuminuria is a risk factor for cerebral small vessel disease in community-based elderly subjects

Microalbuminuria (MA) is known as a marker for generalized vascular dysfunction. It occurs most commonly in the setting of diabetes and hypertension; however, its association with cerebral small vessel disease (SVD) in community-based elderly remains to be clarified. In this cross-sectional analysis, we evaluated the association between MA and cerebral SVD in total 651 community-based elderly subjects. We assessed cardiovascular risk factors by interviews and physical examinations, including an evaluation of urinary albumin creatinine ratio (UACR). All subjects underwent brain magnetic resonance imaging (MRI) and carotid ultrasonography. As endothelial markers, the serum levels of thrombomodulin (TM) and a tissue-type plasminogen activator/ plasminogen activator inhibitor-1 complex were also studied. The mean TM and UACR were higher in subjects with lacunar infarcts or with moderate white matter hyperintensities (mWMH) on MRI than in those without them. Additionally, the prevalence of lacunar infarcts or mWMH was higher in the highest tertile of UACR level than in the lowest or middle tertile. Furthermore, in logistic regression analysis, the elevation of logarithmically transformed UACR (log UACR) was associated with the higher likelihood for total lacunar infarcts (odds ratio [OR], 1.85 per one log UACR increase), multiple lacunar infarcts (OR, 1.89 per one log UACR increase), and mWMH (OR, 2.15 per one log UACR increase). The present study revealed that levels of urinary albumin are associated with cerebral SVD, independently of traditional cerebrovascular risk factors, in community-based elderly.

Lateral and Medial Medullary Infarction A Comparative Analysis of 214 Patients

Background and Purpose— No large-scale study has ever compared the clinical and radiological features of lateral medullary infarction (LMI) and medial medullary infarction (MMI). The aim of this study was to investigate them through the use of cooperatively collected cases. Methods— Medical information on all patients from 1996 to 2000 with medullary infarction (MI) proven by brain MR images at 35 stroke centers in the Tohoku district, Japan, was collected, and their clinical and radiological features were analyzed. Results— A total of 214 cases of MI were registered. They included 167 cases (78%) of LMI, 41 (19%) of MMI, and 6 (3%) of LMI plus MMI. The mean age of onset and the male-to-female ratio were 60.7 years and 2.7:1 in LMI and 65.0 years and 3.6:1 in MMI, respectively. The middle medulla was most frequently affected in LMI, and the upper medulla was most frequently affected in MMI. Dissection of the vertebral artery was observed in 29% of LMI and 21% of MMI. Prognosis, assessed by the Barthel Index, was favorable in both LMI and MMI. Diabetes mellitus was more frequently associated with MMI than with LMI. Conclusions— The present study surveyed a large number of MI cases and revealed that (1) the mean age of onset of MMI is higher than that of LMI, (2) the dissection of the vertebral artery is an important cause not only of LMI but also of MMI, and (3) diabetes mellitus is frequently associated with MMI.

Cerebral small vessel disease and chronic kidney disease (CKD): results of a cross-sectional study in community-based Japanese elderly.

Chronic kidney disease (CKD) is known as a risk factor for cardiovascular disease. In recent years, several experimental and epidemiological studies have suggested that CKD is associated with endothelial dysfunction; thereby, a CKD state may initiate both large and small vessel damage. The association between renal dysfunction and asymptomatic lacunar infarction was reported in a hospital-based study, whereas the relationship between cerebral small vessel disease (SVD)-related lesions and CKD could not be clarified in a community-based study. We performed a cross-sectional study to determine the relationship between silent cerebral SVD-related lesions and CKD in a total of 625 community-based Japanese elderly. In this study, subjects with lower estimated glomerular filtration rate levels tended to have more lacunar infarcts and higher grades of white matter lesions (WMLs). In addition, the mean grades of WMLs or the mean numbers of lacunar infarction in the subjects with albuminuria were greater than those in subjects without albuminuria. In the logistic regression analysis, the association between the presence of CKD and lacunar infarction or moderate WMLs (Fazekas grades 2 and 3) was statistically significant (odds ratio [OR]: 1.86 and 1.50, respectively). Furthermore, as we performed additional analysis, excluding the subjects with stage 2 hypertension (those with casual blood pressure >or=160/100 mm Hg) or diabetes, CKD remained to be an independent risk for cerebral SVD-related lesions. This is the first study showing the relationship between silent SVD-related brain lesions and the presence of CKD, independently of conventional cardiovascular risk factors, in community-based elderly.

Hypersecretion of Truncated Glucagon‐like Peptide‐1 and Gastric Inhibitory Polypeptide in Obese Patients

Postprandial insulin secretion is modulated by both neural and humoral gastrointestinal insulinotropic factors in addition to the absorbed nutrient. To investigate the involvement of the potent insulinotropic hormones gastric inhibitory polypeptide (GIP) and truncated glucagon‐like peptide‐1 (tGLP‐1) in the postprandial hyperinsulinaemia of obesity, we examined the changes in plasma levels of GIP and tGLP‐1 by an oral glucose tolerance test (OGTT) in nine normal subjects (controls), nine obese subjects without glucose intolerance (Group A), and six obese mild diabetic patients (Group B). Following the OGTT, plasma GIP levels in Group B were increased more markedly than those in the other two groups. Plasma levels of tGLP‐1 were estimated by the difference between the values measured with the N‐terminal directed antiserum (GLP‐1NT) and those with the C‐terminal directed antiserum (GLP‐1 CT). Plasma levels of GLP‐1 NT were increased in Group B, but decreased in the other two groups. Plasma GLP‐1 CT levels were increased in all groups with the highest response in Group B. These results suggest that the combined augmentation of plasma GIP and tGLP‐1 responses were involved in the delayed and considerable increases in plasma insulin after glucose ingestion in obese diabetic patients. Since tGLP‐1 is suppressed in the hyperglycaemic hyperinsulinaemic state in normal subjects, the augmented tGLP‐1 response appears to be characteristic of obese Type 2 diabetes.

Calpain 10 gene polymorphisms are related, not to type 2 diabetes, but to increased serum cholesterol in Japanese

A G-to-A (UCSNP-43) polymorphism of the calpain-10 gene was significantly associated with type 2 diabetes (DM) in Mexican-American, and was postulated, together with a T-to-C (UCSNP-44) polymorphism, as a risk factor for DM. We examined the association of these genotypes with DM in Japanese. Eighty-one subjects with DM and 81 non-diabetic subjects (NGT) were recruited. The number of subjects with genotypes UCSNP-43 G/G, G/A and A/A were 76, 5 and 0, respectively, for the DM and NGT groups. The number of subjects with genotypes UCSNP-44 T/T, T/C and C/C were 66, 14 and 1 for the DM group and 64, 17 and 0 for the NGT group. There was no difference between the groups in terms of frequency of any genotype combinations. No association between the genotypes and DM was observed. We next examined the differences between the genotypes or genotype combinations in terms of the traits related to DM, obesity, hypertension and dyslipidemia. No differences were observed between the genotypes UCSNP43 G/G and G/A, between UCSNP-44 T/T and the others, or between the genotype combination UCSNP-43 G/G and UCSNP-44 T/T and the others, except that the individuals with the genotype combination had significantly increased serum cholesterol levels (212.6 +/- 34.3 vs. 198.5 +/- 29.9, P=0.020). The genotype combination might be a risk factor, not for DM, obesity and hypertension, but for increased serum cholesterol.

The metabolic syndrome and retinal microvascular signs in a Japanese population: the Funagata study

Aims: To determine the relationship of metabolic syndrome and its components with retinopathy and other retinal microvascular signs in a Japanese population. Methods: The Funagata study recruited 1961 (53.3% of eligible) Japanese aged 35 or older. The metabolic syndrome was diagnosed primarily using definitions of the International Diabetes Federation. Retinopathy and retinal microvascular signs were assessed from fundus photographs. Retinal arteriolar and venular diameters were measured using a computer-assisted programme. Results: Data were available for analysis in 1638 persons for retinopathy and retinal microvascular signs and 921 persons for retinal vessel diameters. Various components of the metabolic syndrome were associated with retinal microvascular signs: a larger waist circumference was associated with wider venular diameter and retinopathy lesions; a higher blood pressure level was associated with focal arteriolar narrowing, arteriovenous nicking, enhanced arteriolar wall reflex and narrower arteriolar diameter; and a higher triglyceride level was associated with enhanced arteriolar wall reflex. Overall, persons with the metabolic syndrome were more likely to have retinopathy (odds ratio 1.64, 95% CI: 1.02 to 2.64) and wider venular diameter 4.69 μm (95% CI: 1.20 to 8.19 μm) than persons without the metabolic syndrome. Conclusion: We report associations of metabolic syndrome components with retinopathy and wider venular diameter in Japanese adults. These data suggest that metabolic abnormalities, indicated by metabolic syndrome components, are associated with microvascular changes in the retina. There was no synergistic effect of the metabolic syndrome on retinal microvascular changes beyond its individual components.

Nifedipine suppresses neointimal thickening by its inhibitory effect on vascular smooth muscle cell growth via a MEK-ERK pathway coupling with Pyk2

The aim of this study was to determine whether nifedipine could suppress an atherogenic process such as balloon‐injured intimal thickening in vivo and the proliferation of vascular smooth muscle cells (VSMC) in vitro. First, we examined the in vivo effect of nifedipine to determine whether it could suppress intimal thickening induced by balloon catheterization. Sprague‐Dawley (SD) rats were divided into three groups (L, nifedipine 0.3 mg kg−1 day−1; H, nifedipine 3 mg kg−1 day−1; C, no nifedipine), and Alzet® osmotic pumps were implanted in their backs for continuous administration. The neointimal layers were completely occupied by proliferated VSMC, and the area ratios of neointima/media treated with nifedipine significantly decreased dose‐dependently compared to those of the control. Neither blood pressure nor lipid levels changed among the three groups. We next evaluated the in vitro effect of nifedipine on the proliferation of cultured rat VSMC. Nifedipine decreased the values of [3H]‐thymidine incorporation and total cellular protein content as well as the levels of phosphorylated extracellular signal‐regulated protein kinase (ERK) 1/2, mitogen‐activated protein kinase kinase (MEK) 1/2, and even the phosphorylation of Pyk2, in dose‐dependent fashions. In addition, nifedipine suppressed the levels of proliferative cell nuclear antigen (PCNA) dose‐dependently in both VSMC and balloon‐injured thoracic aortae. These results indicate that nifedipine has an inhibitory effect on intimal thickening by attenuating intimal VSMC proliferation, suggesting that nifedipine could be effective for preventing the progression of atherosclerotic plaque as in restenosis after angioplasty.