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1.  A TRIAL OF B VITAMINS AND COGNITIVE FUNCTION AMONG WOMEN AT HIGH RISK OF CARDIOVASCULAR DISEASE 
Background
High homocysteine levels may be neurotoxic and contribute to cognitive decline in older persons.
Objective
Examine the effect of supplementation with folic acid, vitamin B12 and vitamin B6 on cognitive change among women with cardiovascular disease (CVD) or CVD risk factors.
Design
The Women's Antioxidant and Folic Acid Cardiovascular Study is a randomized, placebo-controlled trial to test a combination of B vitamins (folic acid 2.5 mg, vitamin B6 50 mg, and vitamin B12 1 mg, daily) for secondary prevention of CVD. Randomization took place among 5,442 female health professionals, 40+ years, with CVD or at least three coronary risk factors in 1998 (after folic acid fortification began in the US). Shortly after randomization (mean=1.2 years), a cognitive function substudy was initiated among 2009 participants aged 65+ years. Telephone cognitive function testing was administered up to four times over 5.4 years with 5 tests of general cognition, verbal memory and category fluency. Repeated measures analyses were conducted. The primary outcome was a global composite score averaging all tests.
Results
Mean cognitive change from baseline did not differ between the B vitamin and placebo groups (difference in change in global score= 0.03, 95% CI −0.03, 0.08; p=0.30). However, supplementation appeared to confer benefits in preserving cognition among women with low baseline dietary intake of B vitamins.
Conclusions
Combined B vitamin supplementation did not delay cognitive decline among women with CVD or CVD risk factors. Possible cognitive benefits of supplementation among women with low dietary intake of B vitamins warrant further study.
doi:10.3945/ajcn.2008.26404
PMCID: PMC3470481  PMID: 19064521
2.  Physical activity and cognition in women with vascular conditions 
Archives of internal medicine  2011;171(14):1244-1250.
Background
Individuals with vascular disease or risk factors have substantially higher rates of cognitive decline, yet little is known on means of maintaining cognition in this group.
Methods
We examined the relation between physical activity and cognitive decline in participants of the Women’s Antioxidant Cardiovascular Study (WACS), a cohort of women with prevalent vascular disease or ≥3 coronary risk factors. Recreational physical activity was assessed at baseline (1995–1996) and every two years thereafter. In 1998–2000, participants aged ≥65 years underwent a telephone cognitive battery including five tests of global cognition, verbal memory, and category fluency (n=2809). Tests were administered three additional times over 5.4 years. We used multivariable-adjusted generalized linear models for repeated measures to compare the annual rates of cognitive score changes across levels of total physical activity and on walking, as assessed at WACS baseline.
Results
We found a significant trend (p-trend<0.001) of slower rates of cognitive decline with increasing energy expenditure. Compared to the bottom quintile of total physical activity, significant differences in rates of cognitive decline were observed from the fourth quintile (p=0.04 for fourth quintile, p<0.001 for fifth quintile) or the equivalent of daily 30-minute walks at a brisk pace. This difference was equivalent to the difference in cognitive decline observed for women who were younger by 5–7 years. Walking was also strongly related to slower rates of cognitive decline (p-trend=0.003).
Conclusions
Regular physical activity, including walking, was associated with better preservation of cognitive function in older women with vascular disease or risk factors.
doi:10.1001/archinternmed.2011.282
PMCID: PMC3153432  PMID: 21771894
3.  Dietary fat intake in relation to cognitive change in high-risk women with cardiovascular disease or vascular factors 
European journal of clinical nutrition  2010;64(10):1134-1140.
Background/Objectives
Dietary fat intake may influence the rate of cognitive change among those at high risk due to vascular disease or risk factors.
Subjects/Methods
Women’s Antioxidant Cardiovascular Study began in 1995-96 as a randomized trial of antioxidants and B vitamin supplementation for secondary prevention in women with cardiovascular disease or ≥ 3 coronary risk factors. From 1998-99, eligible participants aged ≥ 65 years were administered a telephone cognitive battery including five tests of general cognition, memory and category fluency (n=2 551). Tests were administered four times over 5.4 years. The primary outcome was a global composite score averaging z-scores of all tests. Multivariable generalized linear models for repeated measures were used to evaluate the difference in cognitive decline rates across tertiles of total fat and various types of fat.
Results
Total fat intake or different types of fat were not related to cognitive decline. However, older age significantly modified the association: among the oldest participants, higher intakes of mono- and poly-unsaturated fat were inversely related to cognitive decline (p-interaction: 0.06 and 0.04, respectively), and the rate differences between the highest and lowest tertiles were cognitively equivalent to the rate differences observed with being 4-6 years younger.
Conclusions
In women at high risk of cognitive decline due to vascular disease or risk factors, dietary fat intake was not associated with 5-year cognitive change. However, a possible protective relation of unsaturated fats with cognitive decline in the oldest women warrants further study.
doi:10.1038/ejcn.2010.113
PMCID: PMC3095099  PMID: 20648044
cognition; epidemiology; fats; risk factors; women; cardiovascular disease
4.  Vitamin E, vitamin C and β-carotene and cognitive function among women with or at risk of cardiovascular disease: the WACS study 
Circulation  2009;119(21):2772-2780.
Background
Cardiovascular factors are associated with cognitive decline. Antioxidants may be beneficial.
Methods
The Women’s Antioxidant Cardiovascular Study was a trial of vitamin E (402 mg every other day), β-carotene (50 mg every other day) and vitamin C (500 mg daily) for the secondary prevention of cardiovascular disease (CVD). From 1995–1996, women 40+ years, with CVD or ≥3 coronary risk factors were randomized. From 1998–1999, a cognitive function substudy was initiated among 2824 participants aged 65+ years. With 5 cognitive tests, cognition was assessed by telephone four times over 5.4 years. The primary outcome was a global composite score averaging all scores; repeated measures analyses were used to examine cognitive change over time.
Results
Vitamin E and β-carotene supplementation were not associated with slower rates of cognitive change (mean difference in change for vitamin E versus placebo = −0.01, 95% CI −0.05, 0.04, p=0.78; for β-carotene=0.03, 95% CI −0.02, 0.07, p=0.28). Although vitamin C supplementation was associated with better performance at the last assessment (mean difference = 0.13, 95% CI 0.06, 0.20, p=0.0005), it was not associated with cognitive change over time (mean difference in change = 0.02, 95% CI −0.03, 0.07, p=0.39). Vitamin C was more protective against cognitive change among those with new cardiovascular events during the trial (p-interaction= 0.009).
Conclusions
Antioxidant supplementation did not slow cognitive change among women with preexisting CVD or CVD risk factors. A possible late effect of vitamin C or of β-carotene among those with low dietary intake on cognition warrant further study.
doi:10.1161/CIRCULATIONAHA.108.816900
PMCID: PMC2752297  PMID: 19451353
5.  Plasma Carotenoids and Tocopherols and Cognitive Function: a prospective study 
Neurobiology of aging  2007;29(9):1394-1403.
As a site of high metabolic activity, the brain is particularly susceptible to oxidative damage. We explored the association between plasma antioxidants and cognition. In 858 female participants of the Nurses’ Health Study, aged 70+ years, we measured plasma carotenoids and tocopherols in 1989–1990, and assessed cognitive function by telephone beginning in 1995–2001; assessments were repeated twice at two-year intervals. We used linear regression to estimate multivariable-adjusted mean cognitive performance at the initial assessment by quartile of antioxidants, and longitudinal models for analyzing cognitive decline over four years. Higher antioxidant levels were not associated with initial performance or decline. Mean difference in initial global composite score (averaging all 6 cognitive tests) for the top versus bottom quartile of total carotenoids was −0.05 standard units (95% confidence interval [CI] −0.19, 0.09), and 0.04 units for total tocopherols (95% CI −0.10, 0.18). Individual antioxidants were not associated with cognition. Overall, total plasma carotenoids or tocopherols were not related to cognition in women.
doi:10.1016/j.neurobiolaging.2007.03.006
PMCID: PMC2533579  PMID: 17433501
6.  A survey of preoperative blood tests in primary open-angle glaucoma patients versus cataract surgery patients 
Purpose
To investigate biomarker differences in routine preoperative blood tests performed on primary open-angle glaucoma (POAG) case and control patients presenting for anterior segment eye surgery.
Methods
POAG cases and age-related cataract surgery patients (controls) who underwent anterior segment surgery at Massachusetts Eye and Ear from January 2009 through March 2012 were identified by retrospective record review. Patients with diabetes mellitus, secondary glaucoma, and cataract due to trauma or steroid exposure were excluded. Data on demographic features, preoperative ophthalmological and medical diagnosis, blood pressure, anthropometric measures, basic metabolic panel, and complete blood count were extracted from the medical records. Univariate differences in lab values between POAG cases and controls were assessed using unpaired t tests. Multivariate logistic regression analysis was completed to determine the independent associations of biomarkers with POAG.
Results
A total of 150 cases and 150 age-related controls were included. In multivariate analysis, higher AG was inversely associated with POAG (odds ratio [OR] = 0.90; 95% confidence interval [CI], 0.80–1.00), and higher Cl− level was positively associated with POAG (OR = 1.15; 95% CI, 1.02–1.29). The lower AG in POAG patients could be explained by higher IgG levels as the available data in post hoc analysis showed a nonsignificant trend toward higher IgG in cases compared to controls (17 vs 23; 1142 ± 284 mg/dl vs 1028 ± 291 mg/dl; P = 0.22). Furthermore, in multivariable analysis, a higher red blood cell count was also associated with POAG (OR = 1.91; 95% CI, 1.11–3.28).
Conclusions
Patients with POAG presenting for anterior segment surgery had a lower AG compared to age-related cataract surgery patients. The etiology of this reduced gap is unclear but the possible contribution of IgG warrants further exploration. The etiology of higher red blood cell counts in POAG cases is unknown and deserves further exploration.
doi:10.5693/djo.01.2014.02.002
PMCID: PMC4120802  PMID: 25097461
7.  Dietary intake of berries and flavonoids in relation to cognitive decline 
Annals of neurology  2012;72(1):135-143.
Objective
Berries are high in flavonoids, especially anthocyanidins, and improve cognition in experimental studies. We prospectively evaluated whether greater long-term intakes of berries and flavonoids are associated with slower rates of cognitive decline in older women.
Methods
Beginning in 1980, a semi-quantitative food frequency questionnaire was administered every four years to Nurses’ Health Study participants. In 1995–2001, we began measuring cognitive function in 16,010 participants, aged ≥70 years; follow-up assessments were conducted twice, at two-year intervals. To ascertain long-term diet, we averaged dietary variables from 1980 through the initial cognitive interview. Using multivariable-adjusted, mixed linear regression, we estimated mean differences in slopes of cognitive decline by long-term berry and flavonoid intakes.
Results
Greater intakes of blueberries and strawberries were associated with slower rates of cognitive decline (e.g., for a global score averaging all six cognitive tests, for blueberries: p-trend=0.014 and mean difference=0.04 [95% CI=0.01, 0.07] comparing extreme categories of intake; for strawberries: p-trend= 0.022 and mean difference=0.03 [95% CI=0.00, 0.06] comparing extreme categories of intake), after adjusting for multiple potential confounders. These effect estimates were equivalent to those we find for approximately 1.5 to 2.5 years of age in our cohort, indicating that berry intake appears to delay cognitive aging by up to 2.5 years. Additionally, in further supporting evidence, greater intakes of anthocyanidins and total flavonoids were associated with slower rates of cognitive decline (p-trends= 0.015 and 0.053, respectively, for the global score).
Interpretation
Higher intake of flavonoids, particularly from berries, appears to reduce rates of cognitive decline in older adults.
doi:10.1002/ana.23594
PMCID: PMC3582325  PMID: 22535616
8.  Demographic and Geographic Features of Exfoliation Glaucoma in Two United States-based Prospective Cohorts 
Ophthalmology  2011;119(1):27-35.
Purpose
To prospectively examine the association between demographic and geographic factors in relation to exfoliation glaucoma or exfoliation glaucoma suspect (EG/EGS).
Design
Prospective cohort study.
Participants
We included 78,955 women in the Nurses’ Health Study and 41,191 men in the Health Professionals Follow-up Study.
Methods
Female and male health professionals were prospectively followed during the periods 1980–2008 and 1986–2008, respectively. Eligible participants were 40+ years old, did not have EG/EGS at baseline and reported receiving eye examinations during follow-up. Information regarding demographic features, lifetime geographic residence and potential confounders was collected. During follow-up, 348 EG/EGS cases were confirmed with medical record review. We estimated the relative risk of EG/EGS in each cohort separately and pooled the results with meta-analysis.
Main outcome measures
Multivariable rate ratios (MVRR) of EG/EGS and their 95% confidence intervals (95% CI).
Results
EG/EGS was strongly age-related with subjects ≥ 75 years old at 46.22-fold (95% CI, 22.77 – 93.80) increased risk compared to those between aged 40–55 years. While men were 68% less likely to develop EG/EGS than women (MVRR = 0.32; 95% CI, 0.23 – 0.46), no predisposition to EG/EGS by ancestry, particularly Scandinavian ancestry, emerged. Compared to a lifetime of living in the Northern tier of the continental US, lifetime residence in the middle geographical tier (MVRR = 0.53; 95% CI, 0.40 – 0.71) and in the southern geographical tier (MVRR = 0.25; 95% CI, 0.09 – 0.71) was associated with markedly reduced risks of EG/EGS.
Conclusions
In this mainly Caucasian cohort from the United States (US), increasing age and female gender were significant risk factors for EG/EGS; however, Scandinavian heritage was not. Living in the middle or southern regions of the US relative to living in the northern region was associated with a reduced risk of EG/EGS.
doi:10.1016/j.ophtha.2011.06.018
PMCID: PMC3251653  PMID: 21982415
9.  Clinical characteristics of acute appendiceal diverticulitis 
Purpose
Diverticulitis of vermiform appendix is known as a rare cause of acute appendicitis, most of which are diagnosed after surgery. We compared appendiceal diverticulitis with acute appendicitis to study the clinical characteristics of appendiceal diverticulitis.
Methods
Among 1,029 patients who received appendectomy from January 2009 to May 2011, 38 patients with appendiceal diverticulitis (diverticulitis group) were compared with 98 randomly collected patients with acute appendicitis (appendicitis group) during the same period. Patients' characteristics, clinical features, laboratory findings, operative findings, and postoperative course were compared between the two groups.
Results
Thirty-eight patients (3.7%) were pathologically diagnosed with acute appendiceal diverticulitis among 1,029 cases of appendectomy. The mean age of patients in the diverticulitis group was significantly older than that of the appendicitis group (49.0 ± 15.2 years vs. 25.4 ± 14.2 years, P < 0.05). Mean duration of preoperative symptoms was longer in the diverticulitis group (3.6 ± 3.8 days vs. 1.8 ± 3.2 days, P < 0.05). The site of abdominal pain, fever, signs of localized peritonitis, accompanying gastrointestinal symptoms, and white blood cell count showed no differences between the two groups. Twenty-five patients (65.8%) of the diverticulitis group and 10 patients (10.2%) of the appendicitis group showed perforation of appendix (P < 0.05). Mean operating time and postoperative hospital stay were longer in the diverticulitis group (55.3 ± 28.8 minutes vs. 41.4 ± 17.8 minutes, 6.8 ± 3.4 days vs. 4.9 ± 1.5 days, P < 0.05).
Conclusion
Acute diverticulitis of the appendix can be classified into quite different disease entities compared with acute appendicitis. Regarding high rates of perforation, immediate surgical treatment is needed for patients with a high index of suspicion of acute diverticulitis of the appendix.
doi:10.4174/jkss.2013.84.1.33
PMCID: PMC3539107  PMID: 23323233
Appendiceal diverticulitis; Appendix; Diverticulitis; Appendicitis
10.  Geographic and Climatic Factors Associated with the Exfoliation Syndrome 
Archives of ophthalmology  2011;129(8):1053-1060.
Objective
To identify geographic and climatic risk factors associated with exfoliation syndrome (ES).
Methods
This is a retrospective, observational study of 626901 beneficiaries in a managed-care network throughout the continental United States (excluding California) under ophthalmic surveillance from 2001–2007. International Classification of Disease (ICD-9CM) codes (365.52, 366.11) were used to identify 3367 incident ES cases. We assessed the risk for ES by geographic latitude tier in the continental United States and then assigned state-level climatic data (e.g., ambient temperatures, elevation, sun exposure) to individuals based on their place of residence. Multivariable-adjusted Cox regression models were used to assess associations with the hazard of developing ES.
Results
Compared with living in the middle geographic tier of the United States, residing in the northern tier (above 42°N) was associated with an increased hazard of developing ES (adjusted Hazard Ratio (HR)=2.14 [Confidence Interval (CI)=1.94–2.35]). Conversely, living in the southern geographic tier (below 37°N) was associated with a reduced hazard of ES (HR=0.83 [CI=0.75–0.93]). These associations did not materially change after excluding whites. After adjusting for joint environmental effects, for every one-degree increase in July high temperature, the hazard of ES decreased by 9% (HR=0.91 [CI=0.89–0.93]) and for every one-degree increase in January low temperature, the hazard decreased 3% (HR=0.97 [CI=0.96–0.98]. For each additional day of sunshine exposure annually, the hazard of ES increased by 1.5% (HR=1.02 [CI=1.01–1.02]) for persons living with average levels of other climatic factors.
Conclusion
Ambient temperature and sun exposure may be important environmental triggers of ES.
doi:10.1001/archophthalmol.2011.191
PMCID: PMC3198850  PMID: 21825188
11.  Endothelial Nitric Oxide Synthase Gene Variants and Primary Open-Angle Glaucoma: Interactions with Hypertension, Alcohol, and Cigarette Smoking 
Archives of Ophthalmology  2011;129(6):773-780.
Objective
To evaluate whether the associations with any of the factors of hypertension, alcohol intake and cigarette smoking and risk of primary open-angle glaucoma (POAG) depended on nitric oxide synthase gene (NOS3) variants.
Methods
Two functional and two tagging single nucleotide polymorphisms (SNPs) (T-786C: rs2070744, Glu298Asp: rs1799983; rs7830; rs3918188) were evaluated in nested case-control studies from the Nurses’ Health Study (followed 1980–2002) and the Health Professionals’ Follow-up Study (followed 1986–2002). Participants were aged ≥ 40 years and Caucasian, who were followed biennially. We included 527 incident cases of POAG and 1539 controls, matched on cohort, age and eye exam at the matched cases’ diagnosis dates. Cohort–specific relative risks (RR) were estimated using multivariable conditional logistic regression and pooled with meta-analyses.
Results
The association between hypertension and POAG depended on T-786C SNP variants. Compared with TT homozygotes without hypertension, the TT homozygotes with hypertension were at significantly higher risk (RR=1.45, 95% CI = 1.01, 2.08); however, among carriers of the variant (C) allele hypertension was not associated, or even showed protective associations (p-interaction = 0.007). Similarly, compared with CC homozygotes in the rs7830 tagging SNP who never smoked, CC homozygotes who were past or current smokers were at significantly higher risk (RR=1.63, 95% CI = 1.15, 2.31); however, among carriers of the variant allele (A), smoking was not associated (p-interaction=0.004). Interactions were not observed with alcohol intake.
Conclusions
The associations between hypertension and cigarette smoking in relation to POAG depended on NOS3 SNP polymorphisms.
doi:10.1001/archophthalmol.2011.118
PMCID: PMC3337676  PMID: 21670344
12.  Phenotype harmonization and cross-study collaboration in GWAS consortia: the GENEVA experience 
Genetic epidemiology  2011;35(3):159-173.
Genome-wide association study (GWAS) consortia and collaborations formed to detect genetic loci for common phenotypes or investigate gene-environment (G*E) interactions are increasingly common. While these consortia effectively increase sample size, phenotype heterogeneity across studies represents a major obstacle that limits successful identification of these associations. Investigators are faced with the challenge of how to harmonize previously collected phenotype data obtained using different data collection instruments which cover topics in varying degrees of detail and over diverse time frames. This process has not been described in detail. We describe here some of the strategies and pitfalls associated with combining phenotype data from varying studies. Using the Gene Environment Association Studies (GENEVA) multi-site GWAS consortium as an example, this paper provides an illustration to guide GWAS consortia through the process of phenotype harmonization and describes key issues that arise when sharing data across disparate studies. GENEVA is unusual in the diversity of disease endpoints and so the issues it faces as its participating studies share data will be informative for many collaborations. Phenotype harmonization requires identifying common phenotypes, determining the feasibility of cross-study analysis for each, preparing common definitions, and applying appropriate algorithms. Other issues to be considered include genotyping timeframes, coordination of parallel efforts by other collaborative groups, analytic approaches, and imputation of genotype data. GENEVA's harmonization efforts and policy of promoting data sharing and collaboration, not only within GENEVA but also with outside collaborations, can provide important guidance to ongoing and new consortia.
doi:10.1002/gepi.20564
PMCID: PMC3055921  PMID: 21284036
phenotype; harmonization; genome-wide association studies; GENEVA; consortia
13.  Small-cell neuroendocrine carcinoma of the breast 
A small-cell carcinoma is one of the histologic subtypes of primary neuroendocrine carcinomas of the breast. A small-cell carcinoma is a rare entity of the breast and exhibits similar morphologic features as neuroendocrine tumors of the gastrointestinal tract and lung. We present the imaging and pathologic findings of a primary small-cell neuroendocrine carcinoma of the breast. This is the first report of a primary small-cell carcinoma arising from the breast in Korea.
doi:10.4174/jkss.2012.82.2.116
PMCID: PMC3278633  PMID: 22347714
Breast neoplasms; Neuroendocrine carcinoma; Small cell carcinoma
14.  Female reproductive factors and primary open-angle glaucoma in the Nurses’ Health Study 
Eye (London, England)  2011;25(5):633-641.
Purpose
We explored the relation between age at menarche, parity and oral contraceptive (OC) use and primary open-angle glaucoma (POAG).
Methods
We followed 79,440 women in the Nurses’ Health Study prospectively from 1980 to 2006 and identified 813 cases of incident POAG. Eligible participants were ≥ 40 years old, free of POAG at baseline, had information on reproductive history and reported receiving eye examinations during follow-up. Relevant exposure data and POAG risk factors were updated using biennial questionnaires. We used proportional hazards models to calculate multivariable rate ratios (MVRR) of POAG and 95% confidence intervals (CI).
Results
In multivariable analysis, there were no significant linear trends between age at menarche (p for trend = 0.65) or reproductive duration defined as time between age at menarche and menopause (p for trend = 0.30) and POAG. While ever using OCs was not associated with POAG risk (MVRR = 1.14; 95% CI, 0.98, 1.34), five or more years of OC use was associated with a modest 25% increased risk of POAG (MVRR = 1.25; 95% CI, 1.02, 1.53; p for linear trend = 0.04). Furthermore, among past OC users, a shorter time since stopping OC use was also associated with an increased risk of POAG (p for linear trend = 0.02). Parity was not associated with POAG risk.
Conclusion
Five or more years of OC use was associated with a modestly increased risk of POAG. These data add further support for a role of circulating estrogen in the pathogenesis of POAG.
doi:10.1038/eye.2011.34
PMCID: PMC3093442  PMID: 21336255
Female reproductive factors; age at menarche; parity; oral contraceptives; primary open angle glaucoma
15.  Anthropometric Measures and their Relation to Incident Primary Open-Angle Glaucoma 
Ophthalmology  2010;117(8):1521-1529.
Purpose
To assess the relation between anthropometric measures and incident primary open-angle glaucoma (POAG).
Design
Prospective cohort study.
Participants
We included 78,777 women in the Nurses Health Study and 41,352 men in the Health Professionals Follow-up Study.
Methods
Females and male health professionals were prospectively followed during the periods 1980–2004 and 1986–2004, respectively. Eligible participants were 40+ years old, did not have POAG at baseline and reported receiving eye examinations during follow-up. Information regarding anthropometric measures, potential confounders and ophthalmic status was updated using biennial questionnaires. During follow-up, 980 self-reported POAG cases were confirmed with medical record review.
Main outcome measures
Multivariable rate ratios (MVRR) of POAG and their 95% confidence intervals [95% CI].
Results
There was no significant relation between cumulatively averaged body mass index (BMI) in kg/m2 and POAG overall (p for trend = 0.06). However, in relation to POAG with intraocular pressure (IOP) < 22 mm Hg at diagnosis, each unit increase in BMI was associated with a 6% reduced risk in women (MVRR = 0.94 [0.91–0.98]; p=0.01) but not for men (MVRR = 1.02 [0.96–1.09]; p=0.57); this gender difference was significant (p-heterogeneity =0.03). In multivariable analyses to explore the independent effects of height and weight, weight (as height-adjusted weight residuals; p for trend = 0.002), but not height (p for trend = 0.10) appeared to account for most of the inverse association between BMI and POAG with IOP ≤ 21 mm Hg at diagnosis in women. There was no association between BMI and POAG with IOP > 21 mm Hg at diagnosis for either gender (p for trend ≥ 0.26). Among women, analyses found that the relations between anthropometric parameters and the two POAG subtypes (POAG with IOP ≤ 21 mm Hg versus POAG with IOP > 21 mm Hg when diagnosed) were significantly different (p ≤ 0.0001).
Conclusions
Among women, higher BMI was associated with a lower risk of POAG with IOP ≤ 21 mm Hg at diagnosis. The factors contributing to this tendency may yield insight into the pathogenesis of POAG.
doi:10.1016/j.ophtha.2009.12.017
PMCID: PMC2904416  PMID: 20382429
16.  Antioxidant Intake and Risks of Rheumatoid Arthritis and Systemic Lupus Erythematosus in Women 
American Journal of Epidemiology  2010;172(2):205-216.
Antioxidants may protect against development of rheumatoid arthritis or systemic lupus erythematosus by combating oxidative stress. The authors identified and confirmed incident cases of rheumatoid arthritis and systemic lupus erythematosus among 184,643 US women followed in the Nurses’ Health Study and Nurses’ Health Study II cohorts in 1980–2004. Semiquantitative food frequency questionnaires assessed intakes of vitamins A, C, and E and α-carotene, β-carotene, β-cryptoxanthin, lycopene, lutein, and zeaxanthin from foods and supplements. The authors examined total antioxidant intake by calculating a “ferric-reducing ability of plasma” score, a new method for quantifying the total antioxidant effect of a food based on the reduction of ferric to ferrous iron by antioxidants. Cumulative updated total energy-adjusted dietary intakes were used. Associations between intake of each nutrient and incident rheumatoid arthritis and systemic lupus erythematosus were examined in age-adjusted and Cox proportional hazards models, adjusted for confounders. Results from the cohorts were pooled meta-analytically by using random-effects models. The authors identified 787 incident rheumatoid arthritis cases and 192 systemic lupus erythematosus cases for whom prospective dietary information was available. In these large, prospective cohorts of women, antioxidant intake was not associated with the risk of developing either rheumatoid arthritis or systemic lupus erythematosus.
doi:10.1093/aje/kwq089
PMCID: PMC2900941  PMID: 20534819
antioxidants; arthritis, rheumatoid; diet; food; lupus erythematosus, systemic; risk factors; vitamins
17.  Endothelial Nitric Oxide Synthase Gene Variants and Primary Open-Angle Glaucoma: Interactions with Sex and Postmenopausal Hormone Use 
Purpose
To evaluate the association between nitric oxide synthase gene (NOS3) variants and primary open-angle glaucoma (POAG).
Methods
Two functional single nucleotide polymorphisms (SNPs)( T-786C: rs2070744, Glu298Asp: rs1799983) and three tagging SNPs (rs7830; rs3918188; rs1800779) were evaluated in nested case-control studies from the Nurses’ Health Study (followed 1980 – 2002) and the Health Professionals’ Follow-up Study (followed 1986 – 2002). Participants were aged ≥ 40 years and Caucasian. We included 527 incident cases and 1543 controls, matched on cohort, age and eye exam at the matched cases’ diagnosis dates. Cohort–specific relative risks (RR) were estimated using multivariable conditional logistic regression and pooled with meta-analysis.
Results
No NOS3 polymorphism was significantly associated with overall POAG. For high tension POAG (HTPOAG), rs3918188 was significantly inversely associated among women (AA vs. CC genotype: RR = 0.48; 95% CI=0.28, 0.82) but not among men (p-heterogeneity by gender= 0.02). The minor alleles of T-786C and rs1800779 showed positive associations with high tension POAG (p-trend<0.02) in women only, but the p-heterogeneity was not significant. In women, four of the five NOS3 SNPs showed significant interactions with postmenopausal hormone (PMH) use in relation to HTPOAG: e.g., among women with TT genotype in T-786C, PMH use was inversely associated (RR = 0.41; 95% CI = 0.22, 0.76), but among carriers of the minor allele, PMH use was not associated.
Conclusions
Interactions were observed between NOS3 SNPs and gender and postmenopausal hormone use in women in relation to HTPOAG. These findings should be confirmed in populations with different racial/ethnic groups.
doi:10.1167/iovs.09-4266
PMCID: PMC3094851  PMID: 19815736
18.  Reproductive factors and NOS3 variant interactions in primary open-angle glaucoma 
Molecular Vision  2011;17:2544-2551.
Purpose
To investigate whether associations with the nitric oxide synthase gene (NOS3) variants and risk of primary open-angle glaucoma (POAG) depend on female reproductive factors.
Methods
Two functional and two tagging single nucleotide polymorphisms (SNPs; T-786C: rs2070744, Glu298Asp: rs1799983, rs7830, and rs3918188) were evaluated in a nested case-control study from the Nurses’ Health Study (women followed 1980 – 2002). Participants were aged ≥40 years and Caucasian, who were followed biennially with update information on reproductive factors. We included 374 Nurses’ Health Study (NHS) cases and 1,085 controls, matched on age and eye exam at the matched cases’ diagnosis dates. Relative risks (RRs) were estimated using multivariable conditional logistic regression.
Results
Among women with age at menarche <13 years, compared with the CC homozygotes of the rs3918188 tagging SNP, the wild-type AA homozygotes were at significantly reduced risk of POAG (RR=0.31, 95% CI=0.16, 0.59); however, for women with age at menarche ≥13 years, the SNP was not associated with POAG (p-interaction=0.0007). Among parous women with 3+ children, carriers of the minor variant (T) allele of the functional Glu298Asp SNP were at increased risk, while among parous women with 1–2 children, they were not (p-interaction=0.003). No significant interactions between NOS3 SNPs and oral contraceptive use in POAG were detected.
Conclusions
These data provide further support for the notion that NOS3 genotype - female reproductive health interactions are important in POAG pathogenesis.
PMCID: PMC3198482  PMID: 22025889
19.  Physical Activity Levels and Cognition in Women With Type 2 Diabetes 
American Journal of Epidemiology  2009;170(8):1040-1047.
Persons with type 2 diabetes have a high risk of late-life cognitive impairment, and physical activity might be a potential target for modifying this risk. Therefore, the authors evaluated the association between physical activity level and cognition in women with type 2 diabetes. Beginning in 1995–2000, cognitive function was assessed in 1,550 Nurses’ Health Study participants aged ≥70 years with type 2 diabetes. Follow-up assessments were completed twice thereafter, at 2-year intervals. Multivariate-adjusted linear regression models were used to obtain mean differences in baseline cognitive scores and cognitive decline across tertiles of long-term physical activity. Initial results from age- and education-adjusted models indicated that greater physical activity levels were associated with better baseline cognition (for a global score averaging scores from 6 cognitive tests, P-trend = 0.02). However, results were substantially attenuated after adjustment for multiple potential confounders, largely because of physical disability indicators (global score: P-trend = 0.06); for example, the mean difference for the global score was 0.07 standard units (95% confidence interval: −0.01, 0.15) when comparing extreme tertiles. Results were similar for cognitive decline. These findings indicate little overall association between physical activity and cognition after adjustment for disability factors in older women with type 2 diabetes.
doi:10.1093/aje/kwp224
PMCID: PMC2765365  PMID: 19729385
cognition; cohort studies; diabetes mellitus, type 2; exercise; women
20.  The relation between moderate alcohol consumption and cognitive function in older women with type 2 diabetes 
Aims:
To examine the association between moderate drinking, cognitive function, and cognitive decline in women with type 2 diabetes.
Methods:
From 1995-2001, we assessed cognitive function in 1,698 women aged 71-80 years with type 2 diabetes in the Nurses' Health Study. Assessments were repeated twice at 2-year intervals. We used linear regression to estimate multivariable-adjusted mean differences in initial cognitive function and longitudinal models to estimate cognitive decline over 4 years, according to average alcohol intake between diagnosis with diabetes and the initial cognitive measurement.
Results:
At the initial assessment, the mean score on our test of general cognition was 0.31 (95% CI 0.02, 0.60) points higher in women who were moderate alcohol drinkers (those consuming 1.0-9.9 grams of alcohol, or about 1 drink, per day) compared with abstainers. However, moderate alcohol was not associated with cognitive decline. Higher alcohol consumption (10.0-30.0 grams of alcohol per day) was not associated with initial cognition or cognitive decline, although there was no apparent harm either.
Conclusions:
Among women with type 2 diabetes, moderate alcohol was associated with better initial cognition, but not reduced rates of cognitive decline. Thus, we found no clear and consistent cognitive benefits of moderate alcohol in diabetes.
doi:10.1016/j.diabres.2009.06.023
PMCID: PMC2748648  PMID: 19625098
Alcohol consumption; Cognitive function; Type 2 diabetes
21.  Lifestyle, Nutrition and Glaucoma 
Journal of glaucoma  2009;18(6):423-428.
The only proven strategy to prevent primary open-angle glaucoma (POAG) is the use of ocular hypotensive therapy among people diagnosed with ocular hypertension. In this review, various modifiable lifestyle factors, such as exercise, diet and cigarette smoking, that may influence intraocular pressure and that have been studied in relation to the risk of developing POAG are discussed. Epidemiologic studies on lifestyle factors are few, and the current evidence suggests that there are no environmental factors that are clearly associated with POAG; however, a few factors merit further study. This review also outlines future directions for research into the primary prevention of POAG.
doi:10.1097/IJG.0b013e31818d3899
PMCID: PMC2727664  PMID: 19680048
primary open-angle glaucoma; lifestyle factors; diet; semiquantitative food frequency questionnaire
22.  Endothelial Nitric Oxide Synthase Gene Variants and Primary Open-Angle Glaucoma: Interactions with Sex and Postmenopausal Hormone Use 
Endothelial dysfunction may play a key role in the pathogenesis of primary open-angle glaucoma, and estrogen may modulate endothelial function. The association between five single-nucleotide polymorphisms in the endothelial-derived nitric oxide synthase gene and postmenopausal hormone use in relation to glaucoma in a nested, matched case–control study of 527 incident cases and 1543 control subjects were investigated.
Purpose.
To evaluate the association between the nitric oxide synthase gene (NOS3) variants and primary open-angle glaucoma (POAG).
Methods.
Two functional single-nucleotide polymorphisms (SNPs) (T−786C: rs2070744; Glu298Asp: rs1799983) and three tagging SNPs (rs7830, rs3918188, and rs1800779) were evaluated in a nested case–control study from the Nurses' Health Study (1980–2002) and the Health Professionals' Follow-up Study (1986–2002). Participants were aged ≥40 years and Caucasian. Included were 527 incident cases and 1543 controls, matched by cohort, age, and eye examination at the matched cases' diagnosis dates. Cohort-specific relative risks (RR) were estimated by using multivariable conditional logistic regression and were pooled with meta-analysis.
Results.
No NOS3 polymorphism was significantly associated with overall POAG. For high-tension POAG (HTPOAG), rs3918188 was significantly inversely associated among the women (AA versus CC genotype: RR = 0.48; 95% CI, 0.28–0.82) but not among the men (P-heterogeneity by sex = 0.02). The minor alleles of T −786C and rs1800779 showed positive association with high-tension POAG (P-trend < 0.02) in the women only, but P-heterogeneity was not significant. In the women, four of the five NOS3 SNPs showed significant interactions with postmenopausal hormone (PMH) use in relation to HTPOAG: for example, among the women with the TT genotype in T −786C, PMH use was inversely associated (RR = 0.41; 95% CI, 0.22–0.76), but among carriers of the minor allele, use of PMH was not associated.
Conclusions.
Interactions were observed between NOS3 SNPs and female sex and postmenopausal hormone use in the women in relation to HTPOAG. These findings should be confirmed in different racial/ethnic groups.
doi:10.1167/iovs.09-4266
PMCID: PMC3094851  PMID: 19815736
23.  Dietary Fat Intake and Cognitive Decline in Women With Type 2 Diabetes 
Diabetes Care  2009;32(4):635-640.
OBJECTIVE
Individuals with type 2 diabetes have high risk of late-life cognitive impairment, yet little is known about strategies to modify risk. Targeting insulin resistance and vascular complications—both associated with cognitive decline—may be a productive approach. We investigated whether dietary fat, which modulates glucose and lipid metabolism, might influence cognitive decline in older adults with diabetes.
RESEARCH DESIGN AND METHODS
Beginning in 1995–1999, we evaluated cognitive function in 1,486 Nurses' Health Study participants, aged ≥70 years, with type 2 diabetes; second evaluations were conducted 2 years later. Dietary fat intake was assessed regularly beginning in 1980; we considered average intake from 1980 (at midlife) through initial cognitive interview and also after diabetes diagnosis. We used multivariate-adjusted linear regression models to obtain mean differences in cognitive decline across tertiles of fat intake.
RESULTS
Higher intakes of saturated and trans fat since midlife, and lower polyunsaturated to saturated fat ratio, were each highly associated with worse cognitive decline in these women. On a global score averaging all six cognitive tests, mean decline among women in the highest trans fat tertile was 0.15 standard units worse than that among women in the lowest tertile (95% CI −0.24 to −0.06, P = 0.002); this mean difference was comparable with the difference we find in women 7 years apart in age. Results were similar when we analyzed diet after diabetes diagnosis.
CONCLUSIONS
These findings suggest that lower intakes of saturated and trans fat and higher intake of polyunsaturated fat relative to saturated fat may reduce cognitive decline in individuals with type 2 diabetes.
doi:10.2337/dc08-1741
PMCID: PMC2660474  PMID: 19336640
24.  Fasting Insulin Levels and Cognitive Decline in Older Women without Diabetes 
Neuroepidemiology  2008;30(3):174-179.
Background
Type 2 diabetes has been associated with an increased risk of dementia. To assess possible independent effects of insulin, we investigated the relation of insulin levels to cognitive decline in nondiabetic women.
Methods
Fasting plasma insulin levels were measured in mid-life in 1,416 nondiabetic Nurses’ Health Study participants, who also completed cognitive testing that began 10 years later (current age: 70–75 years). Over 4 years, 3 assessments of general cognition, verbal memory, category fluency and attention were administered. Primary outcomes were the Telephone Interview for Cognitive Status (TICS) performance, the global score (average of all tests) and verbal memory (average of verbal recall tests). Linear mixed-effects models were used to calculate the association between insulin and cognitive decline.
Results
Higher insulin levels were associated with a faster decline on the TICS and verbal memory. For analysis, batch-specific quartiles of insulin levels were constructed. Compared to the lowest quartile, adjusted differences in the annual rates of decline (with 95% CI values in parentheses) for the second, third and fourth quartiles were: TICS, −0.06 (−0.16, 0.03), −0.14 (−0.24, −0.04), and −0.09 (−0.19, 0.01) points (p trend = 0.04); verbal memory, −0.01 (−0.04, 0.02), −0.05 (−0.08, −0.02), and −0.02 (−0.05, 0.01) units (p trend = 0.02). These associations remained after multivariable adjustment.
Conclusions
Our study provides evidence for a potential role of higher fasting insulin levels in cognitive decline, possibly independent of diabetes.
doi:10.1159/000126909
PMCID: PMC2821443  PMID: 18421217
Diabetes; Insulin, cognitive performance; Aging, cognitive decline; Dementia
25.  Low dose aspirin and cognitive function in the women's health study cognitive cohort 
BMJ : British Medical Journal  2007;334(7601):987.
Objective To determine whether low dose aspirin protects women aged 65 or more against cognitive decline.
Design Cohort study within both arms of the women's health study, a randomised, double blind, placebo controlled trial of low dose aspirin for the primary prevention of cardiovascular disease and cancer, 1992-5.
Setting Women's health study, 1998-2004.
Participants 6377 women aged 65 or more.
Interventions Low dose aspirin (100 mg on alternate days) or placebo for a mean of 9.6 years.
Main outcome measures Women had three cognitive assessments at two year intervals by telephone. The battery to assess cognition included five tests measuring general cognition, verbal memory, and category fluency. The primary prespecified outcome was a global score, averaging performance across all tests. The key secondary outcome was a verbal memory score, averaging performance on four measures of verbal memory.
Results At the initial assessment (mean 5.6 years after randomisation) cognitive performance in the aspirin group was similar to that of the placebo group (mean difference in global score −0.01, 95% confidence interval −0.04 to 0.02). Mean decline in the global score from the first to the final cognitive assessment was also similar in the aspirin compared with placebo groups (mean difference 0.01, −0.02 to 0.04). The risk of substantial decline (in the worst 10th centile of decline) was also comparable between the groups (relative risk 0.92, 0.77 to 1.10). Findings were similar for verbal memory; however, a 20% lower risk was observed for decline in category fluency with aspirin (relative risk 0.80, 0.67 to 0.97).
Conclusion Long term use of low dose aspirin does not provide overall benefits for cognition among generally healthy women aged 65 or more.
doi:10.1136/bmj.39166.597836.BE
PMCID: PMC1867896  PMID: 17468120

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