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1.  Obesity and Survival to Age 85 Years without Major Disease or Disability in Older Women 
JAMA internal medicine  2014;174(1):98-106.
The impact of obesity on late-age survival without disease or disability in women is unknown.
To investigate if higher baseline body mass index and waist circumference affects women’s survival to age 85 years without major chronic disease (coronary disease, stroke, cancer, diabetes, or hip fracture) and mobility disability.
Design, Setting, Participants
Examination of 36,611 women from the Women’s Health Initiative who could have reached age 85 years or older if they survived to the last outcomes evaluation on September 17, 2012. Recruitment was from 40 US Clinical Centers from October 1993–December 1998. Multinomial logistic regression models were used to estimate odds ratios and 95% confidence intervals for the association of baseline body mass index and waist circumference with the outcomes, adjusting for demographic, behavioral, and health characteristics.
Main Outcome Measures
Mutually-exclusive classifications: 1) survived without major chronic disease and without mobility disability (“healthy”); 2) survived with ≥1 major chronic disease at baseline, but without new disease or disability (“prevalent diseased”); 3) survived and developed ≥1 major chronic disease but not disability during study follow-up (“incident diseased”); 4) survived and developed mobility disability with or without disease (“disabled”); and 5) did not survive (“died”).
Mean (SD) baseline age was 72.4 (3.0) years (range: 66–81). The distribution of women classified as healthy, prevalent diseased, incident diseased, disabled, and died was 19%, 15%, 23%, 18%, and 25%, respectively. Compared to normal-weight women, underweight and obese women were more likely to die before age 85 years. Overweight and obese women had higher risks of incident disease and mobility disability. Disability risks were striking. Relative to normal-weight women, adjusted odds ratios (95% confidence intervals) of mobility disability was 1.6 (1.5–1.8) for overweight women and 3.2 (2.9–3.6), 6.6 (5.4–8.1), and 6.7 (4.8–9.2), for class I, II, and III obesity, respectively. Waist circumference >88 centimeters was also associated with higher risk of earlier death, incident disease, and mobility disability.
Overall and abdominal obesity were important and potentially modifiable factors associated with dying or developing mobility disability and major chronic disease before age 85 years in older women.
PMCID: PMC3963496  PMID: 24217806
2.  Association of Total Marine Fatty Acids, Eicosapentaenoic and Docosahexaenoic Acids, With Aortic Stiffness in Koreans, Whites, and Japanese Americans 
American Journal of Hypertension  2013;26(11):1321-1327.
Few previous studies have reported the association of aortic stiffness with marine n-3 fatty acids (Fas) in the general population. The aim of this study was to determine the combined and independent associations of 2 major marine n-3 FAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), with aortic stiffness evaluated using carotid–femoral pulse wave velocity (cfPWV) in Korean, white, and Japanese American men.
A population-based sample of 851 middle-aged men (299 Koreans, 266 whites, and 286 Japanese Americans) was examined for cfPWV during 2002–2006. Serum FAs, including EPA and DHA, were measured as a percentage of total FAs using gas chromatography. Multiple regression analysis was used to examine the association of EPA and DHA with cfPWV after adjusting for blood pressure and other confounders.
Mean EPA and DHA levels were 1.9 (SD = 1.0) and 4.8 (SD = 1.4) for Koreans, 0.8 (SD = 0.6) and 2.4 (SD = 1.2) for whites, and 1.0 (SD = 1.0) and 3.2 (SD = 1.4) for Japanese Americans. Both EPA and DHA were significantly higher in Koreans than in the other 2 groups (P < 0.01). Multiple regression analyses in Koreans showed that cfPWV had a significant inverse association with total marine n-3 FAs and with EPA alone after adjusting for blood pressure and other potential confounders. In contrast, there was no significant association of cfPWV with DHA. Whites and Japanese Americans did not show any significant associations of cfPWV with total marine n-3 FAs, EPA, or DHA.
High levels of EPA observed in Koreans have an inverse association with aortic stiffness.
PMCID: PMC3790451  PMID: 23820020
aortic stiffness; blood pressure; carotid femoral pulse wave velocity; docosahexaenoic acid; eicosapentaenoic acid; fish oil; hypertension.
3.  Do Differences in Risk Factors Explain the Lower Rates of Coronary Heart Disease in Japanese Versus U.S. Women? 
Journal of Women's Health  2013;22(11):966-977.
Mortality from coronary heart disease (CHD) in women in Japan is one of the lowest in developed countries. In an attempt to shed some light on possible reasons of lower CHD in women in Japan compared with the United States, we extensively reviewed and analyzed existing national data and recent literature.
We searched recent epidemiological studies that reported incidence of acute myocardial infarction (AMI) and examined risk factors for CHD in women in Japan. Then, we compared trends in risk factors between women currently aged 50–69 years in Japan and the United States, using national statistics and other available resources.
Recent epidemiological studies have clearly shown that AMI incidence in women in Japan is lower than that reported from other countries, and that lipids, blood pressure (BP), diabetes, smoking, and early menopause are independent risk factors. Comparing trends in risk factors between women in Japan and the United States, current levels of serum total cholesterol are higher in women in Japan and levels have been similar at least since 1990. Levels of BP have been higher in in Japan for the past 3 decades. Prevalence of type 2 diabetes has been similar in Japanese and white women currently aged 60–69 for the past 2 decades. In contrast, rates of cigarette smoking, although low in women in both countries, have been lower in women in Japan.
Differences in risk factors and their trends are unlikely to explain the difference in CHD rates in women in Japan and the United States. Determining the currently unknown factors responsible for low CHD mortality in women in Japan may lead to new strategy for CHD prevention.
PMCID: PMC3820126  PMID: 24073782
4.  Antihypertensive medication use and risk of cognitive impairment 
Neurology  2013;81(10):888-895.
To determine the associations between classes of antihypertensive medication use and the risk of cognitive impairment among elderly hypertensive men.
The Honolulu-Asia Aging Study is a prospective, community-based cohort study of Japanese American men conducted in Honolulu, Hawaii. We examined 2,197 participants (mean age 77 years at cohort entry, 1991–1993, followed through September 2010) with hypertension and without dementia or cognitive impairment at baseline, who provided information on medication use. Cognitive function was assessed at 7 standardized examinations using the Cognitive Abilities Screening Instrument (CASI). Cognitive impairment was defined as a CASI score <74.
A total of 854 men developed cognitive impairment (median follow-up, 5.8 years). β-Blocker use as the sole antihypertensive drug at baseline was consistently associated with a lower risk of cognitive impairment (incidence rate ratio [IRR] 0.69; 95% confidence interval [CI] 0.50–0.94), as compared with men not taking any antihypertensive medications, adjusting for multiple potential confounders. The use of diuretics, calcium channel blockers, angiotensin-converting enzyme inhibitors, or vasodilators alone was not significantly associated with cognitive impairment. Results were similar excluding those with cardiovascular disease or <1 year of follow-up, and additionally adjusting for pulse pressure, heart rate, baseline and midlife systolic blood pressure, and midlife antihypertensive treatment (IRR 0.65; 95% CI 0.45–0.94). The association between β-blocker use and cognitive impairment was stronger among men with diabetes, men aged >75 years, and those with pulse pressure ≥70 mm Hg.
β-blocker use is associated with a lower risk of developing cognitive impairment in elderly Japanese American men.
PMCID: PMC3885214  PMID: 23911753
5.  Total and Differential White Blood Cell Counts Predict Eight-Year Incident Stoke in Elderly Japanese-American Men: The Honolulu Heart Program 
Previous studies have found that a higher white blood cell (WBC) count is associated with incident stroke. There have been few studies examining differential WBC counts in elderly or Asian populations. We studied the association between total and differential WBC counts and incident stroke in an older Asian population.
The Honolulu Heart Program is a prospective population-based study of cardiovascular diseases in Japanese-American men that started in 1965. At exam 4 (1991–93), 3,741 men ages 71–93 years participated, and total and differential WBC counts were measured in 3,569 men using a Coulter counter machine. Data on incident stroke (all strokes [ALL-CVA], thromboembolic [TE-CVA] and hemorrhagic [HEM-CVA]) were available through December 1999 (8 years follow-up) from a comprehensive hospital surveillance system. After excluding 227 subjects with prevalent stroke, 3,342 subjects were divided into quartiles of total WBC, neutrophil (segmented and band), granulocyte (neutrophil, eosinophil and basophil), lymphocyte, and monocyte counts for separate analyses.
Age-adjusted incident ALL-CVA rates increased significantly with total WBC quartiles (7.68, 9.04, 9.26, 14.1, per 1,000 person years follow-up, respectively, P = .0014). Relative risks for ALL-CVA for each quartile of total and differential WBC counts were obtained using Cox proportional hazards, using the lowest quartile as the reference group. After full adjustment including age, cardiovascular risk factors, fibrinogen, prevalent CHD, cancer or COPD, and aspirin/NSAID use, the relative risks in the highest quartiles of total WBC, neutrophil, and granulocyte counts were 1.63 (95%CI = 1.05–2.54, P = .03), 2.19 (95%CI = 1.41–3.39, P < .001) and 1.91 (95%CI = 1.25–2.92, P = .003), respectively. These significant associations were also seen for TE-CVA, but not for HEM-CVA. No significant associations were found between lymphocyte or monocyte counts and incident stroke or subtypes.
In elderly Japanese-American men, higher total WBC, neutrophil, and granulocyte counts were independent predictors of overall stroke, as well as thromboembolic stroke. Further studies are needed to establish cut-points and treatment options.
PMCID: PMC4175930
6.  A cross-sectional association of obesity with coronary calcium among Japanese, Koreans, Japanese Americans, and US Whites 
Conflicting evidence exists regarding whether obesity is independently associated with coronary artery calcium (CAC), a measure of coronary atherosclerosis. We examined an independent association of obesity with prevalent CAC among samples of multi-ethnic groups whose background populations have varying levels of obesity and coronary heart disease (CHD).
Methods and results
We analysed a population-based sample of 1212 men, aged 40–49 years free of clinical cardiovascular disease recruited in 2002–06; 310 Japanese in Japan (JJ), 294 Koreans in South Korea (KN), 300 Japanese Americans (JA), and 308 Whites in the USA (UW). We defined prevalent CAC as an Agatston score of ≥10. Prevalent CAC was calculated by tertile of the body mass index (BMI) in each ethnic group and was plotted against the corresponding median of tertile BMI. Additionally, logistic regression was conducted to examine whether an association of the BMI was independent of conventional risk factors. The median BMI and crude prevalence of CAC for JJ, KN, JA, and UW were 23.4, 24.4, 27.4, and 27.1 (kg/m2); 12, 11, 32, and 26 (%), respectively. Despite the absolute difference in levels of BMI and CAC across groups, higher BMI was generally associated with higher prevalent CAC in each group. After adjusting for age, smoking, alcohol, hypertension, lipids, and diabetes mellitus, the BMI was positively and independently associated with prevalent CAC in JJ, KN, UW, but not in JA.
In this multi-ethnic study, obesity was independently associated with subclinical stage of coronary atherosclerosis among men aged 40–49 years regardless of the BMI level.
PMCID: PMC3738098  PMID: 23764486
Coronary artery calcium; Obesity; Body mass index; Multi-ethnic; Men; Risk factors
7.  Pre-Stroke Factors Associated with Post-Stroke Mortality and Recovery in Older Women in the Women’s Health Initiative 
We sought to examine pre-stroke lifestyle factorsassociated with post-stroke mortalityand recovery in older women.
Longitudinal prospective cohort study.
The Women’s Health Initiative (clinical trials and observational study), 40 clinical centers in the U.S.
WHI participants, women aged 50–79, who were stroke-free at baseline 1993–1998, with incident stroke prior to 2005.
Participants were followed for mortality through 2010. Pre-stroke characteristics were from the most proximal examination before the stroke event. Annual follow-up for clinical events ascertained hospitalization for stroke which was subsequently physician-adjudicated with medical records. Multivariable regression models analyzed factors associated with post-stroke mortality and post-stroke recovery at hospital discharge (post-stroke Glasgow score), adjusting for stroke type.
Of 3,173 women with incident stroke, 1,111 (35%) died. Overweight and obese BMI pre-stroke was associated with reduced post-stroke mortality (vs. normal BMI, obese BMI hazards ratio, HR=0.69, 95% confidence interval (CI)=0.53–0.88; overweight BMI: HR=0.72, 95%CI=0.58–0.90); underweight pre-stroke BMI had borderline increased post-stroke mortality (HR=2.02, 95%CI=0.98–4.16).Other pre-stroke factors associated with post-stroke mortality included diabetes (HR=1.28, 95%CI=1.01–1.64), current smoking (vs. nonsmoker, hazard ratio (HR)=2.13, 95%CI=1.53–3.00), physical inactivity (vs. >150 minutes exercise/week, HR=1.39, 95%CI=1.09–1.78) and lowest physical function quartile (vs. highest, HR=1.54, 95%CI=1.18–2.02). Pre-stroke diabetes was associated with reduced odds of good recovery post-stroke (odds ratio (OR)= 0.60, 95%CI= 0.44–0.82). Current hormone use pre-stroke was associated with increased odds of moderate vs. severe disability post-stroke (OR=1.29, 95%CI=1.00–1.66).
Potentially modifiable factors pre-stroke, including smoking, diabetes and underweight BMI, were associated with increased post-stroke mortality in older women. Pre-stroke overweight or obese BMI and physical activity were associated with reduced post-stroke mortality in older women.
PMCID: PMC3743941  PMID: 23869842
stroke; mortality; women; BMI; recovery; diabetes
8.  Particle Numbers of Lipoprotein Subclasses and Arterial Stiffness among Middle-aged men from the ERA JUMP study 
Journal of human hypertension  2013;28(2):111-117.
We examined the association between serum lipoprotein subclasses and the three measures of arterial stiffness i.e. (i) carotid-femoral pulse wave velocity (cfPWV) which is a gold standard measure of central arterial stiffness, (ii) brachial-ankle PWV (baPWV) which is emerging as a combined measure of central and peripheral arterial stiffness, and (iii) femoral-ankle PWV (faPWV) which is a measure of peripheral arterial stiffness. Among a population-based sample of 701 apparently healthy Caucasian, Japanese American and Korean men aged 40–49 years, concentrations of lipoprotein particles were assessed by nuclear magnetic resonance (NMR) spectroscopy, and PWV was assessed with an automated waveform analyzer (VP2000, Omron, Japan). Multiple linear regressions were performed to analyze the association between each NMR lipoprotein subclasses and PWV measures, after adjusting for cardiovascular risk factors and other confounders. A cut-off of p<0.01 was used for determining significance. All PWV measures had significant correlations with total and small low-density lipoprotein particle number (LDL-P) (all p<0.0001) but not LDL-cholesterol (LDL-C) (all p>0.1), independent of race and age. In multivariate regression analysis, no NMR lipoprotein subclass was significantly associated with cfPWV (all p>0.01). However, most NMR lipoprotein subclasses had significant associations with both baPWV and faPWV (p<0.01). In this study of healthy middle-aged men, as compared to cfPWV, both baPWV and faPWV had stronger associations with particle numbers of lipoprotein subclasses. Our results may suggest that both baPWV and faPWV are related to arterial stiffness and atherosclerosis, whereas cfPWV may represent arterial stiffness alone.
PMCID: PMC3800263  PMID: 23823580
lipoproteins; lipoprotein fractions; pulse wave velocity; atherosclerosis
9.  The Associations of Indices of Obesity with Lipoprotein Subfractions in Japanese American, African American and Korean Men 
Global heart  2013;8(3):273-280.
Both indices of obesity and lipoprotein subfractions contribute to coronary heart disease risk. However, associations between indices of obesity and lipoprotein subfractions remain undetermined across different ethnic groups. This study aims to examine the associations of indices of obesity in Japanese Americans (JA), African Americans (AA) and Koreans with lipoprotein subfractions.
A population-based sample of 230 JA, 91 AA, and 291 Korean men aged 40–49 was examined for indices of obesity, i.e., visceral and subcutaneous adipose tissue (VAT and SAT, respectively), waist circumference (WC), and body-mass index (BMI), and for lipoprotein subfractions by nuclear-magnetic-resonance spectroscopy. Multiple regression analyses were performed in each of the three ethnic groups to examine the associations of each index of obesity with lipoprotein.
VAT had significant positive associations with total and small low-density lipoprotein (LDL) and a significant negative association with large high-density lipoprotein (HDL) in all three ethnicities (p < 0.01). SAT, WC, and BMI had significant positive associations with total and small LDL in only JA and Koreans, while these indices had significant inverse associations with large HDL in all ethnic groups (p < 0.01). Compared to SAT, VAT had larger R2 values in the associations with total and small LDL and large HDL in all three ethnic groups.
VAT is significantly associated with total and small LDL and large HDL in all three ethnic groups. The associations of SAT, WC, and BMI with lipoprotein subfractions are weaker compared to VAT in all three ethnic groups.
PMCID: PMC4110345  PMID: 25068101
visceral adipose tissue; subcutaneous adipose tissue; body-mass index; waist circumference; lipoprotein subfractions
10.  The Prevalence of Aortic Calcification in Japanese Compared to White and Japanese-American Middle-Aged Men is Confounded by the Amount of Cigarette Smoking 
International journal of cardiology  2012;167(1):134-139.
Prevalence of coronary artery calcification (CAC) in Japanese men is lower than in white and Japanese-American men. It is unclear if aortic calcification (AC) strongly linked to smoking is also lower in Japanese men who have many times higher smoking prevalence compared to US men.
We conducted a population-based study of 903 randomly-selected men aged 40–49 years: 310 Japanese men in Kusatsu, Japan, 301 white men in Allegheny County, U.S., and 292 Japanese men in Hawaii, U.S. (2002–2006). The presence of AC was assessed by electron-beam tomography. AC was defined as Agatston aortic calcium scores (AoCaS) >0 and ≥100.
Japanese (35.8%) had significantly less AoCaS>0 compared to both white (68.8%, p<0.001) and Japanese-American (62.3%, p<0.001) but similar AoCaS≥100 (19.4%, 18.3%, 22.6%, respectively, p=0.392). Pack-years of smoking, which was highest in Japanese, was the most important single associate of AC in all populations. Additionally age, low-density-lipoprotein cholesterol (LDL-C), and triglycerides in Japanese; body-mass index (BMI) in white; and BMI, LDL-C, hypertension, diabetes, and lipid medications in Japanese-American were independent associates of AC. The risk of AC using either cut points adjusted for pack-years of smoking and additional risk factors was lower in Japanese compared to both white and Japanese-American. AC and CAC had moderately positive and significant correlations in Japanese (r=0.26), white (r=0.39), and Japanese-American (r=0.45).
Prevalence of AC defined both >0 and ≥100 was significantly lower in Japanese than in white and Japanese-American men after adjusting for cigarette smoking and additional risk factors
PMCID: PMC3328605  PMID: 22240754
Epidemiology; risk factors; atherosclerosis; aorta; calcification; electron-beam tomography; Caucasian; Japanese; Japanese American
11.  Shorter Men Live Longer: Association of Height with Longevity and FOXO3 Genotype in American Men of Japanese Ancestry 
PLoS ONE  2014;9(5):e94385.
To determine the relation between height, FOXO3 genotype and age of death in humans.
Observational study of 8,003 American men of Japanese ancestry from the Honolulu Heart Program/Honolulu-Asia Aging Study (HHP/HAAS), a genetically and culturally homogeneous cohort followed for over 40 years. A Cox regression model with age as the time scale, stratified by year of birth, was used to estimate the effect of baseline height on mortality during follow-up. An analysis of height and longevity-associated variants of the key regulatory gene in the insulin/IGF-1 signaling (IIS) pathway, FOXO3, was performed in a HHP-HAAS subpopulation. A study of fasting insulin level and height was conducted in another HHP-HAAS subpopulation.
A positive association was found between baseline height and all-cause mortality (RR = 1.007; 95% CI 1.003–1.011; P = 0.002) over the follow-up period. Adjustments for possible confounding variables reduced this association only slightly (RR = 1.006; 95% CI 1.002–1.010; P = 0.007). In addition, height was positively associated with all cancer mortality and mortality from cancer unrelated to smoking. A Cox regression model with time-dependent covariates showed that relative risk for baseline height on mortality increased as the population aged. Comparison of genotypes of a longevity-associated single nucleotide polymorphism in FOXO3 showed that the longevity allele was inversely associated with height. This finding was consistent with prior findings in model organisms of aging. Height was also positively associated with fasting blood insulin level, a risk factor for mortality. Regression analysis of fasting insulin level (mIU/L) on height (cm) adjusting for the age both data were collected yielded a regression coefficient of 0.26 (95% CI 0.10–0.42; P = 0.001).
Height in mid-life is positively associated with mortality, with shorter stature predicting longer lifespan. Height was, moreover, associated with fasting insulin level and the longevity genotype of FOXO3, consistent with a mechanistic role for the IIS pathway.
PMCID: PMC4013008  PMID: 24804734
12.  Long-chain n-3 polyunsaturated fatty acids and incidence rate of coronary artery calcification in Japanese in Japan and United States whites – population-based prospective cohort study 
Heart (British Cardiac Society)  2013;100(7):569-573.
To determine whether serum levels of long-chain n-3 polyunsaturated fatty acids (LCn3PUFAs) contribute to the difference in incidence rate of coronary artery calcification (CAC) between Japanese in Japan and U.S. whites.
In a population-based prospective-cohort study, 214 Japanese and 152 white men aged 40–49 years at baseline (2002–2006) with coronary calcium score (CCS) = 0 were reexamined for CAC in 2007–2010. Among these, 175 Japanese and 113 whites participated in the follow-up exam. Incident cases were defined as participants with CCS ≥ 10 at follow-up. A relative risk regression analysis was used to model incidence rate ratio between Japanese and whites. The incidence rate ratio was first adjusted for potential confounders at baseline and then further adjusted for serum LCn3PUFAs at baseline.
Mean (standard deviation) serum percentage of LCn3PUFA was > 100% higher in Japanese than in whites (9.08 (2.49) versus 3.84 (1.79), respectively, p<0.01). Japanese had a significantly lower incidence rate of CAC compared to whites (0.9 versus 2.9/100 person-years, respectively, p < 0.01). Incidence rate ratio of CAC taking follow-up time into account between Japanese and white men was 0.321 (95% confidence interval (CI) 0.150, 0.690: p<0.01). After adjusting for age, systolic-blood pressure, low-density-lipoprotein cholesterol, diabetes, and other potential confounders, the ratio remained significant: 0.262 (95% CI: 0.094, 0.731, p=0.01). After further adjusting for LCn3PUFAs, however, the ratio was attenuated and became non-significant (0.376 (95% CI: 0.090, 1.572, p=0.18).
LCn3PUFAs significantly contributed to the difference in CAC incidence between Japanese and white men.
PMCID: PMC3949146  PMID: 24352736
long-chain n-3 fatty acids; coronary artery calcification; prospective cohort study; incidence; risk factors
13.  Regional pulse wave velocities and their cardiovascular risk factors among healthy middle-aged men: a cross-sectional population-based study 
Both carotid-femoral (cf) pulse wave velocity (PWV) and brachial-ankle (ba) PWV employ arterial sites that are not consistent with the path of blood flow. Few previous studies have reported the differential characteristics between cfPWV and baPWV by simultaneously comparing these with measures of pure central (aorta) and peripheral (leg) arterial stiffness, i.e., heart-femoral (hf) PWV and femoral-ankle (fa) PWV in healthy populations. We aimed to identify the degree to which these commonly used measures of cfPWV and baPWV correlate with hfPWV and faPWV, respectively, and to evaluate whether both cfPWV and baPWV are consistent with either hfPWV or faPWV in their associations with cardiovascular (CV) risk factors.
A population-based sample of healthy 784 men aged 40–49 (202 white Americans, 68 African Americans, 202 Japanese-Americans, and 282 Koreans) was examined in this cross-sectional study. Four regional PWVs were simultaneously measured by an automated tonometry/plethysmography system.
cfPWV correlated strongly with hfPWV (r = .81, P < .001), but weakly with faPWV (r = .12, P = .001). baPWV correlated moderately with both hfPWV (r = .47, P < .001) and faPWV (r = .62, P < .001). After stepwise regression analyses with adjustments for race, cfPWV shared common significant correlates with both hfPWV and faPWV: systolic blood pressure (BP) and body mass index (BMI). However, BMI was positively associated with hfPWV and cfPWV, and negatively associated with faPWV. baPWV shared common significant correlates with hfPWV: age and systolic BP. baPWV also shared the following correlates with faPWV: systolic BP, triglycerides, and current smoking.
Among healthy men aged 40 – 49, cfPWV correlated strongly with central PWV, and baPWV correlated with both central and peripheral PWVs. Of the CV risk factors, systolic BP was uniformly associated with all the regional PWVs. In the associations with factors other than systolic BP, cfPWV was consistent with central PWV, while baPWV was consistent with both central and peripheral PWVs.
PMCID: PMC3893368  PMID: 24410766
Arterial stiffness; Aorta; Carotid arteries; Brachial artery; Femoral artery
14.  Influence of Type 2 Diabetes on Brain Volumes and Changes in Brain Volumes 
Diabetes Care  2012;36(1):90-97.
To study how type 2 diabetes adversely affects brain volumes, changes in volume, and cognitive function.
Regional brain volumes and ischemic lesion volumes in 1,366 women, aged 72–89 years, were measured with structural brain magnetic resonance imaging (MRI). Repeat scans were collected an average of 4.7 years later in 698 women. Cross-sectional differences and changes with time between women with and without diabetes were compared. Relationships that cognitive function test scores had with these measures and diabetes were examined.
The 145 women with diabetes (10.6%) at the first MRI had smaller total brain volumes (0.6% less; P = 0.05) and smaller gray matter volumes (1.5% less; P = 0.01) but not white matter volumes, both overall and within major lobes. They also had larger ischemic lesion volumes (21.8% greater; P = 0.02), both overall and in gray matter (27.5% greater; P = 0.06), in white matter (18.8% greater; P = 0.02), and across major lobes. Overall, women with diabetes had slightly (nonsignificant) greater loss of total brain volumes (3.02 cc; P = 0.11) and significant increases in total ischemic lesion volumes (9.7% more; P = 0.05) with time relative to those without diabetes. Diabetes was associated with lower scores in global cognitive function and its subdomains. These relative deficits were only partially accounted for by brain volumes and risk factors for cognitive deficits.
Diabetes is associated with smaller brain volumes in gray but not white matter and increasing ischemic lesion volumes throughout the brain. These markers are associated with but do not fully account for diabetes-related deficits in cognitive function.
PMCID: PMC3526228  PMID: 22933440
15.  Calcium and Vitamin D Supplementation and Cognitive Impairment in the Women’s Health Initiative 
Calcium and vitamin D are thought to play important roles in neuronal functioning. Studies have found associations between low serum vitamin D levels and reduced cognitive functioning, as well as high serum calcium levels and reduced cognitive functioning.
To examine the effects of vitamin D and calcium on cognitive outcomes in elderly women.
Post-hoc analysis of a randomized double-blinded placebo-controlled trial.
40 Women’s Health Initiative clinical centers across the U.S.
4143 women aged 65 years and older without probable dementia at baseline who participated in the WHI Calcium and Vitamin D trial and the Women’s Health Initiative Memory Study.
2034 women were randomized to 1000 mg of calcium carbonate combined with 400 IU of vitamin D3; 2109 women were randomized to placebo.
Primary: classifications of probable dementia or mild cognitive impairment via a 4-phase protocol that included central adjudication. Secondary: global cognitive function and individual cognitive subtests.
Mean age of participants was 71 years. During mean follow-up of 7.8 years, there were 39 cases of incident dementia among calcium plus vitamin D subjects compared to 37 cases among placebo subjects (hazard ratio=1.11, 95% CI: 0.71–1.74, p=0.64). Likewise, there were 98 cases of incident mild cognitive impairment among calcium plus vitamin D subjects compared to 108 cases among placebo subjects (hazard ratio=0.95, 95% CI: 0.72–1.25, p=0.72). There were no significant differences in incident dementia or mild cognitive impairment, or in global or domain-specific cognitive function between groups.
There was no association between treatment assignment and incident cognitive impairment. Further studies are needed to investigate the effects of vitamin D and calcium separately, on men and in other age and ethnic groups, and with other doses.
PMCID: PMC3521077  PMID: 23176129
Vitamin D; Calcium; Dementia; Cognition; Mild Cognitive Impairment
16.  Relation of Serum Leptin and Adiponectin Level to Serum C-Reactive Protein: The INTERLIPID Study 
Objective. Despite considerable study, the relevance of leptin and adiponectin for atherosclerosis development is still unsettled. We investigated relations of serum leptin and adiponectin to serum C-reactive protein (CRP), using the INTERLIPID dataset on Japanese emigrants living in Hawaii and Japanese in Japan. Design and Methods. Serum leptin, adiponectin, and CRP were measured by standardized methods in men and women of ages 40 to 59 years from two population samples, one Japanese-American in Hawaii (83 men, 89 women) and the other Japanese in central Japan (111 men, 104 women). Participants with CRP >10 mg/L were excluded. Results. Sex-specific multiple linear regression analyses, with log-transformed leptin and adiponectin (log-leptin, log-adipo), site (Hawaii = 1, Japan = 0), SBP, HbA1c, smoking (cigarettes/day), and physical activity index score of the Framingham Offspring Study as covariates, showed that log-leptin directly related and log-adipo inversely related to log-CRP for both sexes (Ps < 0.05 to <0.01). Addition to the model of BMI and interaction terms (BMI × log-leptin, BMI × log-adipo, SITE × log-leptin, SITE × log-adipo) resulted in disappearance of statistical significance except for direct relation of log-leptin to log-CRP in men (P = 0.006). Conclusions. Leptin directly related to CRP independent of BMI and other confounding factors in men but not in women.
PMCID: PMC3859203  PMID: 24371525
17.  Correlation of a Self-Report and Direct Measure of Physical Activity Level in the Electron-Beam Tomography and Risk Assessment Among Japanese and US Men in the Post World War II Birth Cohort (ERA JUMP) Study 
Journal of Epidemiology  2013;23(6):411-417.
Physical activity (PA) is complex and a difficult behavior to assess as there is no ideal assessment tool(s) that can capture all contexts of PA. Therefore, it is important to understand how different assessment tools rank individuals. We examined the extent to which self-report and direct assessment PA tools yielded the same ranking of PA levels.
PA levels were measured by the Modifiable Activity Questionnaire (MAQ) and pedometer at baseline among 855 white (W), African-American (AA), Japanese-American (JA), and Korean (K) men (mean age 45.3 years) in 3 geographic locations in the ERA JUMP study.
Korean men were more active than W, AA, and JA men, according to both the MAQ and pedometer (MAQ total PA [mean ± SD]: 41.6 ± 17.8, 20.9 ± 9.9, 20.0 ± 9.1, and 29.4 ± 10.3 metabolic equivalent [MET] hours/week, respectively; pedometer: 9584.4 ± 449.4, 8363.8 ± 368.6, 8930.3 ± 285.6, 8335.7 ± 368.6 steps/day, respectively). Higher levels of total PA in Korean men, as shown by MAQ, were due to higher occupational PA. Spearman correlations between PA levels reported on the MAQ and pedometer indicated positive associations ranging from rho = 0.29 to 0.42 for total activity, rho = 0.13 to 0.35 for leisure activity, and rho = 0.10 to 0.26 for occupational activity.
The 2 assessment methods correlated and were complementary rather than interchangeable. The MAQ revealed why Korean men were more active. In some subpopulations it may be necessary to assess PA domains other than leisure and to use more than 1 assessment tool to obtain a more representative picture of PA levels.
PMCID: PMC3834277  PMID: 24064592
ethnic groups; exercise; pedometry; self-report; occupational activity
18.  Reducing Cost by Reducing Polypharmacy: The Polypharmacy Outcomes Project 
PMCID: PMC3489959  PMID: 22959733
Polypharmacy; Long-term care; Nursing homes
19.  FOXO3 Gene Variants and Human Aging: Coding Variants May Not Be Key Players 
FOXO3 is generally recognized as a “master” gene in aging since its association with longevity has been replicated in multiple organisms and human populations. A group of single nucleotide polymorphisms in linkage disequilibrium with a coding region has been associated with human longevity, but the actual functional variant is unidentified. Therefore, we sequenced the coding region in our long-lived Japanese American population in order to enhance resources for fine mapping this region. We demonstrate that of 38 published variants, 6 are misalignments with homologous nonallelic sequences from FOXO3B (ZNF286B), a pseudogene on a different chromosome; 2 are attributable to ZNF286B only, and the remaining 30 were unconfirmed, indicating that they are very rare and not likely involved in longevity. Furthermore, we identified a novel, unique, nonsynonymous coding variant in exon 3 (Gly566Ala; rs138174682) that is prevalent in multiple ethnic groups but appeared too rare for major longevity effects in our study populations.
PMCID: PMC3668389  PMID: 22459618
Aging; FOXO3; Genetic; Human longevity
20.  Brain Organochlorines and Lewy Pathology: The Honolulu-Asia Aging Study 
Although organochlorines have been reported more frequently in Parkinson’s disease (PD) brains than controls, the association with brain Lewy pathology is unknown. Honolulu-Asia Aging Study (HAAS) participants, exposed to organochlorines from a variety of sources during mid-life, represent a population well suited to determine the relationship of brain organochlorines with Lewy pathology in decedents from the longitudinal HAAS.
Study design included the measurement of 21 organochlorine levels in frozen occipital lobe samples from HAAS decedents. Alpha-synuclein immunostaining performed on 225 brains was used to identify Lewy bodies and Lewy neurites.
With the potential for spurious associations to appear between Lewy pathology and 17 organochlorine compounds found to be present in at least one brain, initial assessments identified heptachlor epoxide isomer b, methoxychlor, and benzene hexachloride b as being most important. Prevalence of Lewy pathology was 75% (6/8) among brains with any 2 of the 3 compounds, 48.8% (79/162) among those with 1, and 32.7% (18/55) for those with neither (P=0.007 test for trend). While findings persisted after removing cases with PD and dementia with Lewy bodies, and when adjustments were made for age at death, body mass index, pack-years of cigarette smoking, and coffee intake (p=0.013), results were insignificant when correcting for multiple testing.
While consistent with earlier accounts of an association between organochlorines and clinical PD, associations with Lewy pathology warrant further study.
PMCID: PMC3474594  PMID: 22976848
Parkinson’s disease; epidemiology; Lewy body; organochlorines; pesticides
21.  Association of Vitamin D Deficiency with Functional Disability and Chronic Diseases Among Veterans Entering a Nursing Home 
Nursing home residents are at high risk of vitamin D deficiency. There has been only one previous study about vitamin D status on admission to the nursing home, and limited data are available about associations with functional disability and chronic diseases.
Data were collected by retrospective chart review of electronic medical records and Minimum Data Set (MDS) for all veterans admitted to a VA nursing home in Honolulu, Hawai‘i, between January 2011 and June 2012. All veterans had a comprehensive geriatric assessment and measurement of serum 25-hydroxyvitamin D level within 7 days of admission. Females, hospice patients, vitamin D supplement users, and those transferred from other nursing homes were excluded, leaving a final analytic sample of 104 patients. Vitamin D deficiency was defined as serum 25-hydroxyvitamin D level <20 ng/mL. Baseline data collected included age, ethnicity, BMI, functional disability (mobility, bathing, dressing, toileting, continence, and feeding) and prevalent chronic diseases to study cross-sectional associations of vitamin D deficiency using logistic regression.
Prevalence of vitamin D deficiency on admission to the nursing home was 49.0% (51/104) among male veterans not taking supplements. The mean age was 70.6 years (range 35–95), with ethnicity as follows: 51 (49.0%) White, 34 (32.7%) Asian, and 6 (5.8%) Black. In multiple logistic regression models adjusted for age, ethnicity and BMI, vitamin D deficiency was significantly associated with number of ADL disabilities (OR = 1.36 for each increase in ADL disability, 95%CI = 1.03–1.78, P = .03) and prevalent diabetes (OR = 2.99, 95%CI = 1.12–7.99, P = .03). When all six ADL disabilities were entered separately into the multivariate logistic regression model instead of total number of ADL disabilities, only the disability in feeding (OR = 4.74, 95%CI = 0.97–23.23, P = .05) and prevalent diabetes (OR = 2.92, 95%CI = 1.03–8.24, P = .04) remained significant. There were no significant associations between vitamin D deficiency and prevalent hypertension, hypercholesterolemia, coronary artery disease, stroke, cancer, depression or dementia.
Almost half the male patients entering a nursing home in Hawai‘i had vitamin D deficiency. A high number of ADL disabilities, disability in feeding, and prevalent diabetes were independently associated with vitamin D deficiency. Future studies should focus on targeting these patients for screening and intervention with supplementation to possibly prevent adverse health outcomes of vitamin D deficiency.
PMCID: PMC3764550
22.  Prevalence and Factors Associated with Percutaneous Endoscopic Gastrostomy (PEG) Tube Feeding Among Nursing Home Patients 
Unnecessary percutaneous endoscopic gastrostomy (PEG) tube feeding in nursing homes (NH) is a growing concern and an important area of research. Hawaii has one of the highest rates of PEG tube feeding in NH patients in the US, yet has lower rates than many NHs in Asian countries. We examined prevalence and factors associated with PEG tube feeding in NH patients in Hawaii.
We conducted an observational cohort study of all patients admitted between 2003 and 2006 to an urban 180-bed hospital-affiliated NH in Honolulu, Hawaii. Data were collected from time of admission until discharge or death through 6/30/2011, from electronic and paper medical records and Minimum Data Set (MDS). Data included demographic characteristics, baseline medical conditions, functional status, cognitive status and code status. We created a Charlson Comorbidity Index (CCI) score based on baseline medical conditions on admission, and a disability score (ADL score) and Cognitive Performance Score (CPS) using baseline MDS data. Multivariable logistic regression was used to analyze factors associated with PEG tube feeding.
Of 238 NH patients aged 45–104 years (mean 83 years), 35 (14.7%) had PEG tube feeding. Of the NH cohort, 130 (54.6%) were female, 218 (92.3%) were Asian, 123 (51.9%) had a prior stroke and 163 (72%) had dementia based on CPS score. Among the 35 PEG tube fed patients, 23 (66%) had PEG placement prior to NH admission, 12 (34%) had PEG placement after NH admission, and 26 (74%) patients had PEG tube feeding until death or the end of follow-up (61 days to 8.4 years, mean 2.4 years). Prior stroke was associated with increased likelihood of PEG tube feeding (aOR = 2.52, 95%CI = 1.03–6.17, P = .04); with borderline increased likelihood for high comorbidity index (aOR = 2.21, 95%CI = 0.89–5.52, P = .09) and high ADL disability score (aOR = 2.03, 95%CI = 0.87–4.73, P = .10). DNR status was inversely associated with PEG tube feeding (aOR = 0.31, 95%CI = 0.11–0.85, P = .02). Age, dementia, Medicaid status, previous speech or physical therapy, and weight loss were not significantly associated with PEG tube feeding.
In this predominantly Asian-American NH cohort with high prevalence of PEG tube feeding, prior stroke was strongly associated with PEG tube feeding, while dementia was not. Further study is needed to examine ways to identify and reduce unnecessary tube feeding in this population.
PMCID: PMC3764570
23.  Factors Associated with 30-Day Hospital Readmission Among Nursing Home Residents 
Hospital readmissions within 30 days are increasingly targeted as a quality parameter. Frail nursing home patients are at high risk for hospitalization. The purpose of this study was to examine baseline prevalent chronic diseases associated with hospital readmission within 30 days.
We collected data on demographics and prevalent diseases for all patients admitted to one hospital-affiliated nursing home between January 2003 and December 2006, with follow-up data on pneumonia episodes and hospitalizations through June 2011. Multivariable logistic regression models identified baseline prevalent chronic diseases associated with hospital readmission within 30 days of nursing home admission.
Of 238 patients (mean age 83.4, range 45-103) admitted to the nursing home, 156 (65.5%) originally came from hospitals, 54.6% were female, 92.4% were Asian, 43.6% were on Medicaid, and 76.5% were first admitted for intermediate care and 23.5% for skilled nursing care. Although recent pneumonia was the factor most strongly associated with hospital readmission (OR = 14.5, P <.0001), in the model without pneumonia, chronic diseases associated with 30-day hospital readmission included pulmonary disease (OR = 2.2, 95%CI = 1.1–4.3, P = .019) and congestive heart failure (OR = 1.8, 95%CI = 1.0–3.4, P = .055). There were no significant associations between hospital readmission and myocardial infarction, stroke, cancer, diabetes, and dementia.
Among nursing home patients, although recent pneumonia was the strongest risk factor for 30-day hospital readmission, those with baseline chronic pulmonary disease and congestive heart failure were at especially high risk for hospital readmission within 30 days of nursing home admission. These patients may benefit from care focused on preventing hospital readmissions.
PMCID: PMC3764574
24.  Low Dietary Vitamin D Predicts 34-Year Incident Stroke: The Honolulu Heart Program 
Background and Purpose
Vitamin D deficiency has been reported to contribute to the risk of cardiovascular disease, especially stroke. We examined the relationship between dietary vitamin D intake and 34-year incident stroke.
The Honolulu Heart Program is a prospective population-based cohort study of 8,006 Japanese-American men in Hawaii who were 45-68 years old at the baseline examination in 1965-68. Dietary vitamin D intake was calculated using the Nutritionist IV v3 software from a 24-hour dietary recall. Subjects with prevalent stroke were excluded, leaving 7,385 men followed through 1999 for incident stroke. Subjects were divided into quartiles of dietary vitamin D for analyses.
During 34 years of follow-up, 960 subjects developed stroke. Age-adjusted rates of incident stroke were significantly higher in the lowest dietary vitamin D quartile compared to the highest (all stroke: 6.38 vs. 5.14 per 1,000 person-years follow-up, p=0.030; thromboembolic stroke: 4.36 vs. 3.30, p=0.033). Using Cox regression, adjusting for age, total kilocalories, BMI, hypertension, diabetes mellitus, pack-years smoking, physical activity index, serum cholesterol, and alcohol intake, those in the lowest quartile had a significantly increased risk of incident stroke (all stroke HR=1.22, 95% CI=1.01-1.47, p=0.038; thromboembolic stroke HR=1.27, 95% CI=1.01-1.59, p=0.044), with the highest as reference. We found no significant associations between dietary vitamin D and hemorrhagic stroke.
Low dietary vitamin D intake was an independent risk factor for 34-year incidence of all stroke and thromboembolic stroke in Japanese-American men. Additional research is needed on vitamin D supplementation to prevent stroke.
PMCID: PMC3404239  PMID: 22627988
dietary vitamin D intake; incident stroke; Japanese-American men; longitudinal cohort study
25.  Ethnic difference in liver fat content: A cross-sectional observation among Japanese American in Hawaii, Japanese in Japan, and non-Hispanic whites in United States 
We recently reported that Japanese had higher liver fat at a lower level of BMI compared with non-Hispanic whites (NHW).
We hypothesize that ethnic difference in fat storage capacity contributes to this ethnic difference in liver fat.
To examine this, we assessed liver fat among 244 Japanese-American aged 40-49, using regional computed-tomography images, along with metabolic variables.
Despite the similar BMI between Japanese-Americans and NHW men, Japanese-Americans had more liver fat (liver to spleen attenuation ratio: 1.03 ± 0.22 for Japanese-Americans, and 1.07 ± 0.15 for NHW men; p<0.05) and tended to have a greater disposition for fatty liver with an increase in BMI than NHW, indicating a clear difference between the two groups. In addition, liver fat is less in Japanese-Americans compared with Japanese men (1.03 ± 0.22 vs. 1.01 ± 0.16; p<0.05), despite of a much higher BMI. These ethnic differences support the hypothesis that higher fat storage capacity indeed seems to be associated with less liver fat. In all the groups, liver fat content strongly correlated with triglycerides, homeostasis model assessment-insulin resistance, and C-reactive protein (CRP). Nevertheless, these metabolic variables were worse in Japanese-Americans, despite of less liver fat, compared with Japanese. Moreover, CRP levels were least among Japanese with highest liver fat, and highest among NHW men with least liver fat, despite of a strong positive association between CRP and fatty liver within each population.
Fat content in the liver is intermediate for Japanese-Americans compared with Japanese and NHW men, which supports the hypothesis of less fat storage capacity among Japanese, closely linked to ethnic difference in predisposition to fatty liver.
PMCID: PMC3664948  PMID: 23697588
Ethnicity; Fatty liver; Genetic; Environmental; CRP

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