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1.  Breast Cancer after Use of Estrogen plus Progestin in Postmenopausal Women 
The New England journal of medicine  2009;360(6):573-587.
BACKGROUND
Following the release of the 2002 report of the Women’s Health Initiative (WHI) trial of estrogen plus progestin, the use of menopausal hormone therapy in the United States decreased substantially. Subsequently, the incidence of breast cancer also dropped, suggesting a cause-and-effect relation between hormone treatment and breast cancer. However, the cause of this decrease remains controversial.
METHODS
We analyzed the results of the WHI randomized clinical trial — in which one study group received 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxy-progesterone acetate daily and another group received placebo — and examined temporal trends in breast-cancer diagnoses in the WHI observational-study cohort. Risk factors for breast cancer, frequency of mammography, and time-specific incidence of breast cancer were assessed in relation to combined hormone use.
RESULTS
In the clinical trial, there were fewer breast-cancer diagnoses in the group receiving estrogen plus progestin than in the placebo group in the initial 2 years of the study, but the number of diagnoses increased over the course of the 5.6-year intervention period. The elevated risk decreased rapidly after both groups stopped taking the study pills, despite a similar frequency of mammography. In the observational study, the incidence of breast cancer was initially about two times as high in the group receiving menopausal hormones as in the placebo group, but this difference in incidence decreased rapidly in about 2 years, coinciding with year-to-year reductions in combined hormone use. During this period, differences in the frequency of mammography between the two groups were unchanged.
CONCLUSIONS
The increased risk of breast cancer associated with the use of estrogen plus progestin declined markedly soon after discontinuation of combined hormone therapy and was unrelated to changes in frequency of mammography.
doi:10.1056/NEJMoa0807684
PMCID: PMC3963492  PMID: 19196674
2.  Patterns of Compensation and Vulnerability in Normal Subjects at Risk of Alzheimer’s Disease 
Journal of Alzheimer's disease : JAD  2013;33(0 1):S427-S438.
Alzheimer’s disease (AD) is the most frequent form of dementia in elderly individuals and its incidence and prevalence increases with age. This risk of AD is increased in the presence of genetic and demographic factors including apolipoprotein E 4 allele, lower education, and family history of AD. There are medical risk modifiers including systemic hypertension, diabetes mellitus, cardiovascular disease, and cerebrovascular disease that increase the vulnerability for AD. By contrast, there are lifestyle risk modifiers that reduce the effects of AD risk factors include diet and physical and cognitive activity. Our research has consistently shown that it is the interactions among these risk factors with the pathobiological cascade of AD that determine the likelihood of a clinical expression of AD—either as dementia or mild cognitive impairment. However, the association between “vulnerability” and “protective” factors varies with age, since the effects of these factors on the risk for AD may differ in younger (age < 80) versus older (age > 80) individuals. The understanding of the dynamic of these factors at different age periods will be essential for the implementation of primary prevention treatments for AD.
doi:10.3233/JAD-2012-129015
PMCID: PMC3951098  PMID: 22669014
Alzheimer’s disease; cardiovascular disease; cerebrovascular disease; mild cognitive impairment
3.  Effect of Dementia on the Use of Drugs for Secondary Prevention of Ischemic Heart Disease 
Journal of Aging Research  2014;2014:897671.
Background. Dementia and cardiovascular disease (CVD) are frequently comorbid. The presence of dementia may have an effect on how CVD is treated. Objective. To examine the effect of dementia on the use of four medications recommended for secondary prevention of ischemic heart disease (IHD): angiotensin-converting enzyme inhibitors, beta-blockers, lipid-lowering medications, and antiplatelet medications. Design. Retrospective analysis of data from the Cardiovascular Health Study: Cognition Study. Setting and Subjects. 1,087 older adults in four US states who had or developed IHD between 1989 and 1998. Methods. Generalized estimating equations to explore the association between dementia and the use of guideline-recommended medications for the secondary prevention of IHD. Results. The length of follow-up for the cohort was 8.7 years and 265 (24%) had or developed dementia during the study. Use of medications for the secondary prevention of IHD for patients with and without dementia increased during the study period. In models, subjects with dementia were not less likely to use any one particular class of medication but were less likely to use two or more classes of medications as a group (OR, 0.60; 95% CI, 0.36–0.99). Conclusions. Subjects with dementia used fewer guideline-recommended medications for the secondary prevention of IHD than those without dementia.
doi:10.1155/2014/897671
PMCID: PMC3955600  PMID: 24719764
4.  Self-reported and accelerometer physical activity levels and coronary artery calcification progression in older women: Results from the Healthy Women Study 
Menopause (New York, N.Y.)  2013;20(2):152-161.
Objective
Regardless of the well-supported biological link between PA and atherosclerosis, most previous studies report a null association between PA and CAC. To examine the relation between physical activity (PA) and coronary artery calcification (CAC) progression in 148 Healthy Women Study (HWS) participants over 28 years of observation.
Methods
The HWS was designed to examine cardiovascular risk factor changes from pre- to post-menopause. Based on CAC scores collected at two follow-up visits (EBT1 and EBT4) scheduled 12 years apart, participants were classified into one of three groups: 1) no detectable CAC (n=37; 0 CAC at both visits), 2) incident CAC (n=46; 0 CAC at the first- and >0 CAC at the last- visit), or 3) prevalent CAC (n=65; >0 CAC at both visits). PA data were collected regularly throughout the study using self-report questionnaires and accelerometers at EBT4.
Results
The percentage of HWS participants with no detectible CAC decreased from 56.1% at EBT1 to 25.0% at EBT4. Time spent per day in accumulated and bouts of moderate- to vigorous-intensity (MV)PA were each significantly higher in the no detectable CAC group when compared to the prevalent CAC group (both p≤.01). After covariate adjustment, these differences remained statistically significant (both p<.05). Although self-reported summary estimates collected throughout the study were significantly associated with accelerometer data at EBT4, there were no significant differences in self-reported physical activity levels by CAC groups after covariate adjustment.
Conclusions
Study findings suggest that low levels of accelerometer-derived MVPA may be indicative of subclinical disease in older women.
doi:10.1097/gme.0b013e31826115af
PMCID: PMC3897237  PMID: 22914209
coronary heart disease; motor activity; ambulatory monitoring; coronary calcification; women
5.  A Self-Report Risk Index to Predict Occurrence of Dementia in Three Independent Cohorts of Older Adults: The ANU-ADRI 
PLoS ONE  2014;9(1):e86141.
Background and Aims
The Australian National University AD Risk Index (ANU-ADRI, http://anuadri.anu.edu.au) is a self-report risk index developed using an evidence-based medicine approach to measure risk of Alzheimer's disease (AD). We aimed to evaluate the extent to which the ANU-ADRI can predict the risk of AD in older adults and to compare the ANU-ADRI to the dementia risk index developed from the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study for middle-aged cohorts.
Methods
This study included three validation cohorts, i.e., the Rush Memory and Aging Study (MAP) (n = 903, age ≥53 years), the Kungsholmen Project (KP) (n = 905, age ≥75 years), and the Cardiovascular Health Cognition Study (CVHS) (n = 2496, age ≥65 years) that were each followed for dementia. Baseline data were collected on exposure to the 15 risk factors included in the ANU-ADRI of which MAP had 10, KP had 8 and CVHS had 9. Risk scores and C-statistics were computed for individual participants for the ANU-ADRI and the CAIDE index.
Results
For the ANU-ADRI using available data, the MAP study c-statistic was 0·637 (95% CI 0·596–0·678), for the KP study it was 0·740 (0·712–0·768) and for the CVHS it was 0·733 (0·691–0·776) for predicting AD. When a common set of risk and protective factors were used c-statistics were 0.689 (95% CI 0.650–0.727), 0.666 (0.628–0.704) and 0.734 (0.707–0.761) for MAP, KP and CVHS respectively. Results for CAIDE ranged from c-statistics of 0.488 (0.427–0.554) to 0.595 (0.565–0.625).
Conclusion
A composite risk score derived from the ANU-ADRI weights including 8–10 risk or protective factors is a valid, self-report tool to identify those at risk of AD and dementia. The accuracy can be further improved in studies including more risk factors and younger cohorts with long-term follow-up.
doi:10.1371/journal.pone.0086141
PMCID: PMC3900468  PMID: 24465922
6.  Monthly Variation in Physical Activity Levels in Post-Menopausal Women 
Medicine and science in sports and exercise  2009;41(2):10.1249/MSS.0b013e3181864c05.
INTRODUCTION
Month-to-month variation in physical activity levels in a cohort of post-menopausal women participating in a single site clinical trial undergoing lifestyle intervention was investigated prior to and after lifestyle intervention.
METHODS
Participants were Caucasian and African-American women (mean age 57.0 ± 3.0) from the Women On the Move through Activity and Nutrition (WOMAN) study. Physical activity was measured subjectively by questionnaire and objectively by pedometer at baseline and at the 18-month follow-up.
RESULTS
At baseline, prior to intervention, pedometer steps were highest in the summer months (7,616 steps/day), lower in the fall (6,293 steps/day), lowest in winter (5,304 steps/day), and then rebounded in the spring (5,850 steps/day). Physical activity estimates from the past-week subjective measure followed the same seasonal pattern. After 18-months, the lifestyle change group significantly increased their pedometer step counts when compared to the health education group (p<0.0001). At 18-months, pedometer step counts for the health education group followed a pattern similar to that found in the entire group prior to intervention, whereas, month-to-month step counts for the lifestyle change group appeared to remain consistent throughout the year.
CONCLUSIONS
These results confirm previous reports that suggest physical activity levels fluctuate throughout the year. Lifestyle intervention, which includes a physical activity component, not only increases step counts, but appears to reduce some of variation in physical activity levels over the course of a year in post-menopausal women.
doi:10.1249/MSS.0b013e3181864c05
PMCID: PMC3880933  PMID: 19127194
pedometer; seasonality; post-menopause; lifestyle intervention
7.  Use of Interrupted Time-Series Method to Evaluate the Impact of Cigarette Excise Tax Increases in Pennsylvania, 2000–2009 
Introduction
Scientific evidence shows that cigarette price increases can significantly reduce smoking prevalence and smoking initiation among adolescents and young adults. However, data are lacking regarding the effectiveness of increasing Pennsylvania’s cigarette tax to reduce smoking and/or adverse health effects of smoking. The objective of our study was to assess the impact of cigarette tax increases and resulting price increases on smoking prevalence, acute myocardial infarction (AMI) and asthma hospitalization rates, and sudden cardiac death (SCD) rates in Pennsylvania.
Methods
We used segmented regression analyses of interrupted time series to evaluate the level and trend changes in Pennsylvania adults’ current smoking prevalence, age-adjusted AMI and asthma hospitalization rates, age-specific asthma hospitalization rates, and age-adjusted SCD rates following 2 cigarette excise tax increases.
Results
After the first excise tax increase, no beneficial effects were noted on the outcomes of interest. The second tax increase was associated with significant declines in smoking prevalence for people aged 18 to 39, age-adjusted AMI hospitalization rates for men, age-adjusted asthma hospitalizations rates, and SCD rates among men. Overall smoking prevalence declined by 5.2% (P = .01), with a quarterly decrease of 1.4% (P = .01) for people aged 18 to 39 years. The age-adjusted AMI hospitalization rate for men showed a decline of 3.87/100,000 population (P = .04). The rate of age-adjusted asthma hospitalizations decreased by 10.05/100,000 population (P < .001), and the quarterly trend decreased by 3.21/100,000 population (P < .001). Quarterly SCD rates for men decreased by 1.34/100,000 population (P < .001).
Conclusion
An increase in the price of cigarettes to more than $4 per 20-cigarette pack was associated with a significant decrease in smoking among younger people (aged 18–39). Decreases were also seen in asthma hospitalizations and men’s age-adjusted AMI hospitalization and SCD rates. Further research and policy development regarding the effect of cigarette taxes on tobacco consumption should be cognizant of the psychological tipping points at which overall price affects smoking patterns.
doi:10.5888/pcd10.120268
PMCID: PMC3804017  PMID: 24135393
8.  Cardiovascular Disease and Cognitive Decline in Postmenopausal Women: Results From the Women's Health Initiative Memory Study 
Background
Data on cardiovascular diseases (CVD) and cognitive decline are conflicting. Our objective was to investigate if CVD is associated with an increased risk for cognitive decline and to examine whether hypertension, diabetes, or adiposity modify the effect of CVD on cognitive functioning.
Methods and Results
Prospective follow‐up of 6455 cognitively intact, postmenopausal women aged 65 to 79 years old enrolled in the Women's Health Initiative Memory Study (WHIMS). CVD was determined by self‐report. For cognitive decline, we assessed the incidence of mild cognitive impairment (MCI) or probable dementia (PD) via modified mini‐mental state examination (3 MS) score, neurocognitive, and neuropsychiatric examinations. The median follow‐up was 8.4 years. Women with CVD tended to be at increased risk for cognitive decline compared with those free of CVD (hazard ratio [HR], 1.29; 95% CI: 1.00, 1.67). Women with myocardial infarction or other vascular disease were at highest risk (HR, 2.10; 95% CI: 1.40, 3.15 or HR, 1.97; 95% CI: 1.34, 2.87). Angina pectoris was moderately associated with cognitive decline (HR 1.45; 95% CI: 1.05, 2.01) whereas no significant relationships were found for atrial fibrillation or heart failure. Hypertension and diabetes increased the risk for cognitive decline in women without CVD. Diabetes tended to elevate the risk for MCI/PD in women with CVD. No significant trend was seen for adiposity.
Conclusions
CVD is associated with cognitive decline in elderly postmenopausal women. Hypertension and diabetes, but not adiposity, are associated with a higher risk for cognitive decline. More research is warranted on the potential of CVD prevention for preserving cognitive functioning.
doi:10.1161/JAHA.113.000369
PMCID: PMC3886762  PMID: 24351701
cardiovascular diseases; cognitive decline; postmenopausal women
9.  Distribution of 10-Year and Lifetime Predicted Risk for Cardiovascular Disease Prior to Surgery in the Longitudinal Assessment of Bariatric Surgery-2 Study 
The American journal of cardiology  2012;110(8):1130-1137.
Primary prevention guidelines recommend calculation of lifetime cardiovascular disease (CVD) predicted risk among individuals who may not meet criteria for high short-term (10-year) ATP-III risk for coronary heart disease (CHD). Both extreme obesity and bariatric surgery are more common among women, who often have low short-term predicted CHD risk. The distribution and correlates of lifetime CVD predicted risk, however, have not yet been evaluated among bariatric surgery candidates. Using established 10-year (ATP-III) CHD and lifetime CVD risk prediction algorithms and pre-surgery risk factors, participants from the Longitudinal Assessment of Bariatric Surgery-2 study without prevalent CVD (n=2070) were stratified into 3 groups: low 10-year (<10%)/low lifetime (<39%) predicted risk, low 10-year (<10%)/high lifetime (≥39%) predicted risk, and high 10-year (≥10% predicted risk or diagnosed diabetes.) Participants were predominantly white (86%), women (80%), with a median age of 45 years and median BMI of 45.6 kg/m2. High 10-year CHD predicted risk was common (36.5%), and associated with diabetes, male sex and older age, but not with higher BMI or hs-c-reactive protein. Most (76%) participants with low 10-year predicted risk had high lifetime CVD predicted risk, which was associated with dyslipidemia and hypertension, but not with BMI, waist circumference, HDL cholesterol or hs-C-reactive protein. In conclusion, bariatric surgery candidates without diabetes or existing CVD are likely to have low short-term, but high lifetime CVD predicted risk. Current data support the need for long-term monitoring and treatment of elevated CVD risk factors among bariatric surgery patients, to maximize lifetime CVD risk reduction.
Clinical Trial Registration
Long-term Effects of Bariatric Surgery, #NCT00465829, http://www.clinicaltrials.gov/ct2/results?term=%23NCT00465829
doi:10.1016/j.amjcard.2012.05.054
PMCID: PMC3462227  PMID: 22742719
Cardiovascular disease; extreme obesity; bariatric surgery; lipids
11.  Lower Levels of Adiponectin in Japanese than in American Men despite much Less Levels of Obesity in the Japanese 
Metabolism: clinical and experimental  2006;55(12):1561-1563.
Levels of adiponectin are inversely associated with obesity levels. We examined the levels of adiponectin in American (n = 98) and Japanese (n = 92) men aged 40 to 49 years. Contrary to our expectations, the American men had higher evels of adiponectin than the Japanese men (13.3 ± 5.8 vs 7.3 ± 4.2 (μg/ml) despite higher levels of obesity. Smaller areas of visceral adipose tissue in American than in Japanese men may have resulted in the higher levels of adiponectin.
doi:10.1016/j.metabol.2006.08.004
PMCID: PMC3713636  PMID: 17142124
12.  Serum ghrelin levels are higher for men 40-49 years of age in the U.S. than Japan 
Diabetes, obesity & metabolism  2007;9(4):591-593.
Background
Ghrelin, a 28-amino-acid gastric peptide hormone, has an appetite-stimulating effect and controls the energy balance. Serum ghrelin levels inversely correlate with body mass index. Recently, several papers reported the ethnic difference in the ghrelin levels. To our knowledge, however, no studies have compared the serum ghrelin levels between Caucasian in the United States (U.S.) and the Japanese in Japan.
Methods
We conducted a cross-sectional study of 189 men 40-49 years of age (91 Caucasian in the U.S. and 98 Japanese in Japan) to examine serum ghrelin levels and metabolic and other factors.
Results
Serum ghrelin levels correlated with waist circumferences and lipid profiles among Caucasian American and the Japanese. Serum ghrelin levels were significantly higher among Caucasian Americans than among the Japanese (904.5 (632.0, 1132.0) pg/mL, 508.0 (399.0, 1378.3) pg/mL (median and 95% confidence interval), respectively, P<0.01), although Caucasian Americans were much more obese (BMI: 26.9±3.3 kg/m2 versus 23.3±3.1kg/m2 respectively, P<0.01). The ethnic difference remained after adjusting for metabolic factors, smoking status, and other factors (P<0.01).
Conclusions
We have shown in our population-based study that serum ghrelin levels among men aged 40-49 are significantly higher in Caucasian Americans than in the Japanese in Japan. Reasons for the ethnic difference in the ghrelin levels are largely unknown and warrant further investigation.
doi:10.1111/j.1463-1326.2006.00627.x
PMCID: PMC3682931  PMID: 17587401
gut hormones; ghrelin; ethinic difference
13.  New-onset breast tenderness after initiation of estrogen plus progestin therapy and breast cancer risk 
Archives of internal medicine  2009;169(18):1684-1691.
Background
The use of estrogen plus progestin therapy increases both breast cancer incidence and breast tenderness. Whether breast tenderness during estrogen plus progestin therapy is associated with breast cancer risk is uncertain.
Methods
We analyzed data from the Women’s Health Initiative Estrogen plus Progestin Clinical Trial, which randomized postmenopausal women with an intact uterus to conjugated equine estrogens 0.625 mg plus medroxyprogesterone acetate 2.5 mg daily (CEE + MPA, N=8506) or placebo (N=8102). At baseline and annually, participants underwent mammography and clinical breast exam. Self-report of breast tenderness was assessed at baseline and 12 months. Invasive breast cancer incidence was confirmed by medical record review (mean 5.6 years of follow-up).
Results
Among women without baseline breast tenderness (N=14538), significantly more women assigned to CEE + MPA than placebo experienced new-onset breast tenderness after 12 months (36.1% vs. 11.8%, P<0.001). Among women in the CEE + MPA group, breast cancer risk was significantly higher in those with new-onset breast tenderness compared to those without new-onset breast tenderness (Hazard Ratio 1.48, 95% confidence interval 1.08–2.03, P=0.02). Among women in the placebo group, breast cancer risk was not significantly associated with new-onset breast tenderness.
Conclusions
New-onset breast tenderness during use of CEE + MPA was associated with increased breast cancer risk. The sensitivity and specificity for the association between breast tenderness and breast cancer were similar in magnitude to those of the Gail model.
doi:10.1001/archinternmed.2009.303
PMCID: PMC3670683  PMID: 19822825
14.  Vital Records and Dementia 
Neuroepidemiology  2008;32(1):70-71.
doi:10.1159/000170909
PMCID: PMC3049957  PMID: 19001799
15.  Incident Coronary Artery Calcium Among Postmenopausal Women 
Atherosclerosis  2008;200(2):278-285.
Recent studies have shown that individuals with 0 coronary artery calcium (CAC) scores have very low risk of coronary heart disease. In the Healthy Women Study, we evaluated development of new CAC among postmenopausal women (n=272) over a 6 year period, age 62 at the 1st and 68 at the 3rd electron beam tomography (EBT) examination. At the 1st EBT, 155 of 272 (57%) women had 0 CAC. By the 3rd, 56 (36%) of these women had developed new CAC, including 38 with >5 Agatston units. There was practically no regression from having CAC at with the 1st EBT to no CAC at the 3rd EBT. The risk of developing new CAC over 6 years among women with 0 CAC on their 1st EBT was strongly and significantly related to presence of both aortic calcium and carotid plaque at the time of 1st EBT. Baseline premenopausal risk factors, age 47, apolipoprotein B, body mass index (BMI) and triglycerides, were significant predictors of incident CAC as were the changes in BMI and low density lipoprotein cholesterol between premenopause and the 1st post exam, age 53. Risk factors measured premenopause and change in risk factors from premenopause to the 1st post exam and the extent of subclinical disease in other vascular beds are primary determinants of the risk of developing incident CAC in women over a 6 year period.
doi:10.1016/j.atherosclerosis.2007.12.057
PMCID: PMC2577772  PMID: 18289547
16.  Coronary Artery Calcification in Japanese Men in Japan and Hawaii 
American journal of epidemiology  2007;166(11):1280-1287.
Explanations for the low prevalence of atherosclerosis in Japan versus United States are often confounded with genetic variation. To help remove such confounding, coronary artery calcification (CAC), a marker of subclinical atherosclerosis, was compared between Japanese men in Japan and Japanese men in Hawaii. Findings are based on risk factor and CAC measurements that were made from 2001 to 2005 in 311 men in Japan and 300 men in Hawaii. Men were aged 40 to 50 years and without cardiovascular disease. After age-adjustment, there was a 3-fold excess in the odds of prevalent CAC scores ≥10 in Hawaii versus Japan (relative odds [RO] = 3.2; 95% confidence interval [CI] = 2.1,4.9). While men in Hawaii had a generally poorer risk factor profile, men in Japan were 4-times more likely to smoke cigarettes (49.5 vs. 12.7%, p<0.001). In spite of marked risk factor differences between the samples, none of the risk factors provided an explanation for the low amounts of CAC in Japan. After risk factor adjustment, the RO of CAC scores ≥10 in Hawaii versus Japan was 4.0 (95% CI = 2.2,7.4). Further studies are needed to identify factors that offer protection against atherosclerosis in Japanese men in Japan.
doi:10.1093/aje/kwm201
PMCID: PMC3660555  PMID: 17728270
Atherosclerosis; cohort studies; coronary disease; Japan; men; risk factors
17.  The Determinants of Plasma Plasminogen Activator Inhibitor 1 Levels Differ for American and Japanese Men Aged 40–49 
Background
Elevated plasma plasminogen activator inhibitor-1 (PAI-1) levels were associated with higher incidence of type II diabetes. Elucidating the determinants of PAI-1 in various ethnicities may help to understand the susceptibility to developing diabetes. The aim of our study was to compare PAI-1 levels between Americans and the Japanese in the post-war generation and to elucidate the determinants of the PAI-1 levels.
Methods
We conducted a cross-sectional study on a total of 198 men aged 40–49 in the U.S. (Body-mass index (BMI): 27.0 ± 3.3 kg/m2) and Japan (BMI: 23.3 ± 3.1 kg/m2). Examination included physique measurement (BMI and waist girth), blood analysis (lipid profiles, glucose, insulin, C-reactive protein, and PAI-1), and life-style assessment by self-administered questionnaires.
Results
PAI-1 levels were significantly lower in American than in Japanese men, even after adjustment for age, waist girth, cigarette smoking, habitual alcohol drinking, and other factors. In the Americans, waist girth, insulin, and cigarette smoking were significantly associated with PAI-1 levels, while waist girth and triglycerides were significantly associated with PAI-1 levels in the Japanese.
Conclusions
PAI-1 levels were significantly lower in American than in Japanese men and the determinants of PAI-1 levels differ for American and Japanese men aged 40–49.
doi:10.1016/j.diabres.2005.10.015
PMCID: PMC3660558  PMID: 16325297
PAI-1; US; Japan; epidemiology; post-war generation
18.  Less subclinical atherosclerosis in Japanese men in Japan than in white men in the United States in the post World-War-II birth cohort 
American journal of epidemiology  2007;165(6):617-624.
Coronary heart disease (CHD) incidence and mortality remain very low in Japan despite major dietary changes and increases in CHD risk factors that should have resulted in substantial increase in CHD rates (Japanese paradox). Primary genetic effects are unlikely, given the substantial increase in CHD in migrant Japanese to the U.S. For men aged 40–49, levels of total cholesterol and blood pressure have been similar in Japan and the U.S. throughout their lifetime. The authors tested the hypothesis that levels of subclinical atherosclerosis, coronary artery calcification and intima-media thickness of the carotid artery (IMT), in men aged 40–49 are similar in Japan and the U.S. The authors conducted a population-based study of 493 randomly-selected men: 250 men in Kusatsu, Shiga, Japan, and 243 white men in Allegheny County, Pennsylvania, U.S. in 2002–2005. The Japanese had a less favorable profile of many risk factors than the whites. Prevalence ratio for the presence of coronary calcium score ≥10 in the Japanese compared to the whites was 0.52 (95% CI, 0.35, 0.76). Mean (SE) IMT was significantly lower in the Japanese (0.616 (0.005) versus 0.672 (0.005) mm, p<0.01). Both associations remained significant after adjusting for risk factors. The findings warrant further investigations.
doi:10.1093/aje/kwk053
PMCID: PMC3660737  PMID: 17244636
Atherosclerosis; epidemiology; men; risk factors
19.  Association of lipoprotein-associated phospholipase A2 with coronary calcification among American and Japanese men 
BACKGROUND
We have previously reported that the prevalence of coronary artery calcification (CAC) was substantially lower among Japanese than American men despite a less favorable profile of many traditional risk factors in Japanese men.
OBJECTIVES
To determine whether lipoprotein-associated phospholipase A2 (Lp-PLA2) levels are related to the difference in the prevalence of CAC between the two populations.
METHODS
A total of 200 men aged 40-49 were examined: 100 residents in Allegheny County, Pennsylvania, United States, and 100 residents in Kusatsu City, Shiga, Japan. Coronary calcium score (CCS) was evaluated by electron-beam tomography, Lp-PLA2 levels, nuclear magnetic resonance (NMR) lipoprotein subclasses and other factors were assessed centrally in the United States.
RESULTS
Lp-PLA2 levels were higher among American than Japanese men (Mean±SD 301.7±82.6 versus 275.9±104.7 ng/mL, respectively, p=0.06). Among all Japanese men and those with low density lipoprotein (LDL) cholesterol ≥130 mg/dL, there was an inverse association of the prevalence of CCS>0 with the tertile groups of Lp-PLA2 levels (p=0.08 and p=0.03, respectively). American men did not have any association between CCS>0 with the tertile groups of Lp-PLA2 (p=0.62). Although Lp-PLA2 among both populations correlated positively with LDL and total cholesterol, American and Japanese men had different correlations with NMR lipoprotein subclasses. Reported high odds ratio for CCS>0 among American compared to Japanese men was not reduced after adjusting for Lp-PLA2 levels.
CONCLUSION
Lp-PLA2 may have different mechanisms of action among American and Japanese men. Lp-PLA2 levels can not explain the observed CAC differences between the two populations.
PMCID: PMC3659786  PMID: 18094516
atherosclerosis; lipoprotein-associated phospholipase A2; coronary artery disease; coronary calcification; Japanese; Caucasian
21.  Conjugated Equine Oestrogen and Breast Cancer Incidence and Mortality in Postmenopausal Women with Hysterectomy: Extended Follow-up of the Women’s Health Initiative Randomised Trial 
The lancet oncology  2012;13(5):476-486.
Background
In contrast to many observational studies, women in the Women’s Health Initiative (WHI) trial randomised to oestrogen-alone had lower invasive breast cancer incidence than those assigned placebo. Influence of oestrogen use on breast cancer mortality has not been reported.
Methods
Between 1993 and 1998, the WHI enrolled 10,739 postmenopausal women from 40 US centres into a randomized, double-masked, placebo-controlled trial evaluating oral conjugated equine oestrogen (0·625 mg/d). Women aged 50–79 years with prior hysterectomy, anticipated 3-year survival, and mammography clearance were randomized by a computerized, permuted block algorithm, stratified by age group and centre, to receive oestrogen or matching placebo. The trial was terminated early, in 2004, for an adverse effect on stroke. In extended follow-up through August 2009, we assessed long-term effects of oestrogen use on invasive breast cancer incidence, tumor characteristics, and mortality. Cox regression models were used to estimate intention-to-treat hazard ratios [HRs].
Findings
After a median 11.8 (interquartile range [IQR], 9·1 to 12·9) years of follow-up, conjugated equine oestrogen-alone use for a median of 5·9 (IQR, 2·5 to 7·3) years was associated with lower invasive breast cancer incidence compared to placebo (151 vs. 199 breast cancers; annualized rates, 0·27% vs. 0·35%; HR, 0·77; 95% confidence interval [CI], 0·62 to 0·95; P=0·02) with no difference (P=0·76) between intervention-phase (HR, 0·79; 95% CI, 0·61 to 1·02) and post-intervention effects (HR, 0·75; 95% CI: 0·51 to 1·09) ). Potential effect modification by benign breast disease (P=0·01) and family history of breast cancer (P=0·02) was observed. In the oestrogen-alone group fewer women died from breast cancer (6 vs.16 deaths; annualized rates 0·009% vs. 0·024%; HR, 0·37; 95% CI, 0·13 to 0·91; P=0.03) and fewer died from all causes after a breast cancer diagnosis (30 vs. 50 deaths; annualized rates, 0·046% vs. 0·076%; HR, 0·62; 95% CI, 0·39 to 0·9;, P=0·04).
Interpretation
Women with hysterectomy seeking relief of climacteric symptoms may be given reassurance regarding breast cancer influence of oestrogen use consistent with durations observed in this trial. However, these findings do not support oestrogen use for breast cancer risk reduction since this benefit may not apply to populations at higher risk.
Funding
US National Heart, Lung and Blood Institute. Wyeth provided study medications.
doi:10.1016/S1470-2045(12)70075-X
PMCID: PMC3412626  PMID: 22401913
menopausal hormone therapy; breast neoplasms; breast cancer mortality; prevention trial
22.  Association Between Depression and Vascular Disease in Systemic Lupus Erythematosus 
The Journal of rheumatology  2011;39(2):262-268.
Objective
Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease with increased prevalence of cardiovascular disease (CVD) and depression. Although depression may contribute to CVD risk in population-based studies, its influence on cardiovascular morbidity in SLE has not been evaluated. We evaluated the association between depression and vascular disease in SLE.
Methods
A cross-sectional study was conducted from 2002–2005 in 161 women with SLE and without CVD. The primary outcome measure was a composite vascular disease marker consisting of the presence of coronary artery calcium and/or carotid artery plaque.
Results
In total, 101 women met criteria for vascular disease. In unadjusted analyses, several traditional cardiovascular risk factors, inflammatory markers, adiposity, SLE disease-related factors, and depression were associated with vascular disease. In the final multivariable model, the psychological variable depression was associated with nearly 4-fold higher odds for vascular disease (OR 3.85, 95% CI 1.37, 10.87) when adjusted for other risk factors of age, lower education level, hypertensive status, waist-hip ratio, and C-reactive protein.
Conclusion
In SLE, depression is independently associated with vascular disease, along with physical factors.
doi:10.3899/jrheum.110327
PMCID: PMC3632335  PMID: 22174200
SYSTEMIC LUPUS ERYTHEMATOSUS; CARDIOVASCULAR DISEASE; DEPRESSION CALCIFICATION; CAROTID PLAQUE; PSYCHOSOCIAL FACTORS
23.  The Women on the Move Through Activity and Nutrition (WOMAN) Study: Final 48-Month Results 
Obesity (Silver Spring, Md.)  2011;20(3):636-643.
The Women on the Move through Activity and Nutrition (WOMAN) study was designed to test whether a nonpharmacological intervention including qualitative and quantitative dietary changes to induce weight loss and increased physical activity levels would reduce blood triglyceride levels and number of low-density lipoprotein particles (LDL-P). Such decreases in lipoproteins and other risk factors could reduce or slow progression of subclinical cardiovascular disease (CVD). Study participants were randomized to either the intervention (Lifestyle Change) or assessment (Health Education) group. Most of the intervention ended at the 30-month visit. The last 48-month examination was completed in 9/2008. There was very substantial weight loss and increased exercise during the first 30 months of the trial resulting in significant decreases in CV risk factors. Most of the intervention effect was lost through 48 months. Weight loss was 3.4 kg in Lifestyle Intervention and 0.2 kg in the Health Education at 48 months (P = 0.000). There were no significant changes at 48 months in lipid levels, blood pressure (BP), glucose, insulin, or in the subclinical measures of coronary calcium, carotid intima media thickness, or plaque. There was a significant decrease in long-distance corridor walk time in the Lifestyle vs. Health Education groups. Significant lifestyle changes can be achieved that result in decreases in CV risk factors. Whether such changes reduce CV outcomes is still untested in clinical trials of weight loss or exercise. Long-term maintenance of successful lifestyle changes, weight loss and reduced risk factors is the hurdle for lifestyle interventions attempting to prevent CV and other chronic diseases.
doi:10.1038/oby.2011.80
PMCID: PMC3623568  PMID: 21494228
24.  The Clinical Trial of Women On the Move through Activity and Nutrition (WOMAN Study) 
Contemporary clinical trials  2006;28(4):370-381.
The Women On the Move through Activity and Nutrition (WOMAN) Study is the first randomized clinical trial of nonpharmacological intervention designed to modify lipoproteins, weight loss and exercise among postmenopausal women using noninvasive measures of atherosclerosis as the primary endpoint. The trial was initially designed to test whether intervention as compared to health education would be more effective in slowing progression of subclinical atherosclerosis among women on hormone therapy (HT), estrogen or estrogen+progestin. It was designed and implemented prior to the results of the Women's Health Initiative (WHI). The trial was since modified to include women who had been on HT but went off after the results of the WHI were reported. Eligible women were between the ages of 52-62, had waist circumference ≥80 cm, low density lipoprotein cholesterol between 100-160 mg% and controlled blood pressure. The intervention is low in total and saturated fat, trans fats, higher in fiber and promotes loss of 7-10% of body weight and includes at least 150 minutes of physical activity per week. The study has recruited 508 women. The primary endpoints are change in extent of carotid intima media wall thickness as measured by carotid ultrasound, pulse wave velocity as a measure of vascular stiffness and coronary artery calcium using electron beam computed tomography. Body composition is measured by dual-energy x-ray absorptiometry.
doi:10.1016/j.cct.2006.10.009
PMCID: PMC1941838  PMID: 17113831
25.  White Matter Lesions and Brain Gray Matter Volume in Cognitively Normal Elders 
Neurobiology of Aging  2011;33(4):834.e7-834.e16.
Objectives
Cerebral white matter lesions (WMLs) reflect small vessel disease, are common in elderly individuals and are associated with cognitive impairment. We sought to determine the relationships between WMLs, age, gray matter (GM) volume, and cognition in the Cardiovascular Health Study (CHS).
Methods
From the CHS we selected 740 cognitively normal controls with a 1.5 T MRI scan of the brain and a detailed diagnostic evaluation. WML severity was determined using a standardized visual rating system. GM volumes were analyzed using voxel-based morphometry implemented in the Statistical Parametric Mapping software.
Results
WMLs were inversely correlated with GM volume, with the greatest volume loss in the frontal cortex. Age related atrophy was observed in the hippocampus and posterior cingulate cortex. Regression analyses revealed links among age, APOE*4 allele, hypertension, WMLs, GM volume, and digit symbol substitution test scores.
Conclusions
Both advancing age and hypertension predict higher WML load, which is itself associated with GM atrophy. Longitudinal data are needed to confirm the temporal sequence of events leading to a decline in cognitive function.
doi:10.1016/j.neurobiolaging.2011.08.010
PMCID: PMC3248984  PMID: 21943959
White matter lesions; age; gray matter volume; cognition

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