Mary K. Townsend

Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development.

Most patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed with advanced disease and survive less than 12 months. PDAC has been linked with obesity and glucose intolerance, but whether changes in circulating metabolites are associated with early cancer progression is unknown. To better understand metabolic derangements associated with early disease, we profiled metabolites in prediagnostic plasma from individuals with pancreatic cancer (cases) and matched controls from four prospective cohort studies. We find that elevated plasma levels of branched-chain amino acids (BCAAs) are associated with a greater than twofold increased risk of future pancreatic cancer diagnosis. This elevated risk was independent of known predisposing factors, with the strongest association observed among subjects with samples collected 2 to 5 years before diagnosis, when occult disease is probably present. We show that plasma BCAAs are also elevated in mice with early-stage pancreatic cancers driven by mutant Kras expression but not in mice with Kras-driven tumors in other tissues, and that breakdown of tissue protein accounts for the increase in plasma BCAAs that accompanies early-stage disease. Together, these findings suggest that increased whole-body protein breakdown is an early event in development of PDAC.

Specific Subjective Memory Complaints in Older Persons May Indicate Poor Cognitive Function

OBJECTIVES: To examine the association between the type and number of subjective memory complaints (SMCs) and performance on objective cognitive tests.

Association of Urinary Concentrations of Bisphenol A and Phthalate Metabolites with Risk of Type 2 Diabetes: A Prospective Investigation in the Nurses’ Health Study (NHS) and NHSII Cohorts

Background: Prospective evidence regarding associations for exposures to bisphenol A (BPA) and phthalates with type 2 diabetes (T2D) is lacking. Objective: We prospectively examined urinary concentrations of BPA and phthalate metabolites with T2D risk. Methods: We measured BPA and eight major phthalate metabolites among 971 incident T2D case–control pairs from the Nurses’ Health Study (NHS) (mean age, 65.6 years) and NHSII (mean age, 45.6 years). Results: In the NHSII, BPA levels were not associated with incident T2D in multivariate-adjusted analysis until body mass index was adjusted: odds ratio (OR) comparing extreme BPA quartiles increased from 1.40 (95% CI: 0.91, 2.15) to 2.08 (95% CI: 1.17, 3.69; ptrend = 0.02) with such an adjustment. In contrast, BPA concentrations were not associated with T2D in the NHS (OR = 0.81; 95% CI: 0.48, 1.38; ptrend = 0.45). Likewise, urinary concentrations of total phthalate metabolites were associated with T2D in the NHSII (OR comparing extreme quartiles = 2.14; 95% CI: 1.19, 3.85; ptrend = 0.02), but not in the NHS (OR = 0.87; 95% CI: 0.49, 1.53; ptrend = 0.29). Summed metabolites of butyl phthalates or di-(2-ethylhexyl) phthalates were significantly associated with T2D only in the NHSII; ORs comparing extreme quartiles were 3.16 (95% CI: 1.68, 5.95; ptrend = 0.0002) and 1.91 (95% CI: 1.04, 3.49; ptrend = 0.20), respectively. Conclusions: These results suggest that BPA and phthalate exposures may be associated with the risk of T2D among middle-aged, but not older, women. The divergent findings between the two cohorts might be explained by menopausal status or simply by chance. Clearly, these results need to be interpreted with caution and should be replicated in future studies, ideally with multiple urine samples collected prospectively to improve the measurement of these exposures with short half-lives. Citation: Sun Q, Cornelis MC, Townsend MK, Tobias DK, Eliassen AH, Franke AA, Hauser R, Hu FB. 2014. Association of urinary concentrations of bisphenol A and phthalate metabolites with risk of type 2 diabetes: a prospective investigation in the Nurses’ Health Study (NHS) and NHSII Cohorts. Environ Health Perspect 122:616–623; http://dx.doi.org/10.1289/ehp.1307201

Adiposity and weight change in mid-life in relation to healthy survival after age 70 in women: prospective cohort study

Objective To examine the hypothesis that mid-life adiposity is associated with a reduced probability of maintaining an optimal health status among those who survive to older ages. Design Prospective cohort study. Setting The Nurses’ Health Study, United States. Participants 17 065 women who survived until at least the age of 70, provided information on occurrence of chronic disease, cognitive function, physical function, and mental health at older ages, and were free from major chronic diseases at mid-life (mean age was 50 at baseline in 1976). Main outcome measures Healthy survival to age 70 and over was defined as having no history of 11 major chronic diseases and having no substantial cognitive, physical, or mental limitations. Results Of the women who survived until at least age 70, 1686 (9.9%) met our criteria for healthy survival. Increased body mass index (BMI) at baseline was significantly associated with linearly reduced odds of healthy survival compared with usual survival, after adjustment for various lifestyle and dietary variables (P<0.001 for trend). Compared with lean women (BMI 18.5-22.9), obese women (BMI ≥30) had 79% lower odds of healthy survival (odds ratio 0.21, 95% confidence interval 0.15 to 0.29). In addition, the more weight gained from age 18 until mid-life, the less likely was healthy survival after the age of 70. The lowest odds of healthy survival were among women who were overweight (BMI ≥25) at age 18 and gained ≥10 kg weight (0.18, 0.09 to 0.36), relative to women who were lean (BMI 18.5-22.9) and maintained a stable weight. Conclusions These data provide evidence that adiposity in mid-life is strongly related to a reduced probability of healthy survival among women who live to older ages, and emphasise the importance of maintaining a healthy weight from early adulthood.

Body mass index, weight gain, and incident urinary incontinence in middle-aged women.

OBJECTIVE: To describe the relations between body mass index (BMI; kg/m2), weight gain, and incident urinary incontinence in middle-aged women. METHODS: This was a prospective study in the Nurses’ Health Study II. Participants reported their weight at age 18 years, and current weight and height in 1989; weight was updated on subsequent biennial questionnaires. From 2001–2003, incident cases with at least monthly incontinence were identified among 30,982 women aged 37 to 54 years who reported no incontinence in 2001. Information on incontinence type was collected from incident cases with at least weekly incontinence. Multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between BMI in 2001, weight change from age 18 years to 2001, and incident incontinence were estimated using multivariable logistic regression models. RESULTS: Increasingly higher BMI was related to increasing odds of developing incontinence (P for trend<.001). Comparing women with BMI greater than or equal to 35 kg/m2 with lean women (BMI 21–22.9 kg/m2), the OR for at least monthly incontinence was 2.11 (95% CI 1.84–2.42). These increases were similar for all incontinence types. The odds of incontinence also increased with increasing adult weight gain (P for trend<.001); compared with women who maintained their weight within 2 kg, the OR for at least weekly incontinence was 1.44 (95% CI 1.05–1.97) among women who gained 5.1 to 10 kg and 4.04 (95% CI 2.93–5.56) among women who had gained more than 30 kg since early adulthood. We found no effect modification by initial weight in analyses of weight gain from age 18 years to 2001. CONCLUSION: Adiposity and weight gain seem to be strong independent risk factors for incontinence development in middle-aged women. LEVEL OF EVIDENCE: II

The Epidemiology of Urinary Incontinence in Older Women: Incidence, Progression, and Remission

OBJECTIVES: To examine the epidemiology of urinary incontinence (UI) in older women.

Risk Factors for Fecal Incontinence in Older Women

OBJECTIVES:The objectives of this study were to estimate the prevalence of fecal incontinence (FI) in older women and examine associations between potential risk factors and prevalent FI.METHODS:We conducted a cross-sectional study of prevalent FI in 64,559 women, aged 62–87 years, in the Nurses’ Health Study. Since 1976, participants provided information on health and lifestyle on mailed biennial questionnaires. Data on FI were collected in 2008. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for FI were calculated using logistic regression models.RESULTS:The reported prevalence of liquid or solid stool incontinence at least monthly increased from 9% in women aged 62 to 64 years to 17% in women aged 85 to 87 years. Prevalent FI was 50% less common in black women compared with white women (6% vs. 12%, respectively). Other variables associated with increased odds of FI at least monthly were pregnancy, higher body mass index (BMI), lower physical activity, functional limitations, current cigarette smoking, type 2 diabetes, high blood pressure, and neurologic disease. Urinary incontinence (UI) was a strong correlate of FI, with 63% of women with FI reporting UI at least monthly compared with 45% of women in the whole study population.CONCLUSIONS:FI is a common condition among older women, and often co-occurs with UI. Potentially modifiable risk factors include BMI, physical activity, and cigarette smoking.

Gut Microbiota Metabolites of Dietary Lignans and Risk of Type 2 Diabetes: A Prospective Investigation in Two Cohorts of U.S. Women

OBJECTIVE To examine urinary levels of enterolactone and enterodiol, intestinal microbial metabolites of dietary lignans, in relation to type 2 diabetes (T2D) risk. RESEARCH DESIGN AND METHODS Urinary concentrations of the lignan metabolites were assayed by liquid chromatography-mass spectrometry among 1,107 T2D and 1,107 control subjects in a nested case-control study conducted in participants from the Nurses’ Health Study (NHS) and NHSII. Subjects were free of diabetes, cardiovascular disease, and cancer at urine sample collection in 1995–2001. Incident self-reported T2D cases identified through 2008 were confirmed with a validated questionnaire. RESULTS In both cohorts, T2D subjects had significantly lower concentrations of both enterolactone and enterodiol than control subjects. After multivariate adjustment for lifestyle and dietary risk factors of T2D, urinary concentrations of enterolactone were significantly associated with a lower risk of T2D (pooled odds ratio [OR] comparing the extreme quartiles 0.62 [95% CI 0.44, 0.88], P for trend = 0.003). Higher urinary concentrations of enterodiol were also marginally significantly associated with a lower T2D risk (pooled OR comparing extreme quartiles 0.67 [95% CI 0.48, 0.96], P for trend = 0.08). When concentrations of both metabolites were combined to reflect total lignan intake, the OR was 0.70 (95% CI 0.53, 0.92) for each SD increment of total lignan metabolites. CONCLUSIONS These results indicate that lignan metabolites, especially enterolactone, are associated with a lower risk of T2D in U.S. women. Further studies are needed to replicate these findings and to explore potential mechanisms underlying the observed association.

A prospective study of smoking, caffeine, and alcohol as risk factors for seizures or epilepsy in young adult women: Data from the Nurses' Health Study II

Purpose:  Seizures and epilepsy are associated with significant disability and substantial treatment costs, yet little is known about primary prevention. We prospectively examined the association of cigarette smoking, caffeine use, and alcohol intake with risk of seizure or epilepsy among women, aged 25–42 years, in the Nurses’ Health Study II.

Circulating Metabolites and Survival Among Patients With Pancreatic Cancer.

BACKGROUND Pancreatic tumors cause changes in whole-body metabolism, but whether prediagnostic circulating metabolites predict survival is unknown. METHODS We measured 82 metabolites by liquid chromatography-mass spectrometry in prediagnostic plasma from 484 pancreatic cancer case patients enrolled in four prospective cohort studies. Association of metabolites with survival was evaluated using Cox proportional hazards models adjusted for age, cohort, race/ethnicity, cancer stage, fasting time, and diagnosis year. After multiple-hypothesis testing correction, a P value of .0006 or less (.05/82) was considered statistically significant. Based on the results, we evaluated 33 tagging single-nucleotide polymorphisms (SNPs) in the ACO1 gene, requiring a P value of less than .002 (.05/33) for statistical significance. All statistical tests were two-sided. RESULTS Two metabolites in the tricarboxylic acid (TCA) cycle--isocitrate and aconitate--were statistically significantly associated with survival. Participants in the highest vs lowest quintile had hazard ratios (HRs) for death of 1.89 (95% confidence interval [CI] = 1.06 to 3.35, Ptrend < .001) for isocitrate and 2.54 (95% CI = 1.42 to 4.54, Ptrend < .001) for aconitate. Isocitrate is interconverted with citrate via the intermediate aconitate in a reaction catalyzed by the enzyme aconitase 1 (ACO1). Therefore, we investigated the citrate to aconitate plus isocitrate ratio and SNPs in the ACO1 gene. The ratio was strongly associated with survival (P trend < .001) as was the SNP rs7874815 in the ACO1 gene (hazard ratio for death per minor allele = 1.37, 95% CI = 1.16 to 1.61, P < .001). Patients had an approximately three-fold hazard for death when possessing one or more minor alleles at rs7874851 and high aconitate or isocitrate. CONCLUSIONS Prediagnostic circulating levels of TCA cycle intermediates and inherited ACO1 genotypes were associated with survival among patients with pancreatic cancer.