William Dana Flanders

Dietary Intake of ω-6 and ω-3 Fatty Acids and Risk of Colorectal Cancer in a Prospective Cohort of U.S. Men and Women

Background: ω-6 and ω-3 polyunsaturated fatty acids intakes may play opposing roles in inflammation-driven colorectal carcinogenesis. We examined the relationship of these polyunsaturated fatty acids and the ratio of their intake with colorectal cancer risk in a large U.S. prospective cohort. Design: Participants in the Cancer Prevention Study-II Nutrition Cohort completed a detailed questionnaire on diet, medical history, and lifestyle in 1999. Between 1999 and 2005, 869 incident colorectal cancer cases (452 men and 417 women) were identified among 99,080 participants (43,108 men and 55,972 women). Multivariate-adjusted rate ratios were calculated using Cox proportional hazards models. Results: The ratio of total ω-6 to total ω-3 intake was not associated with colorectal cancer risk in either sex. Contrary to our initial hypothesis, total ω-6 intake was inversely related to colorectal cancer risk in men [multivariate relative risk (95% confidence interval) for highest to lowest quartile, 0.81 (0.61-1.07); Ptrend = 0.07], and α-linolenic acid, the primary contributor to total ω-3 intake, was associated with increased risk in women for quartiles 2 through 4 versus the lowest quartile [relative risk (95% confidence interval), 1.50 (1.12-2.01), 1.40 (1.04-1.87), and 1.38 (1.02-1.85), respectively; Ptrend = 0.13]. In women, total ω-6 and marine ω-3 intake appeared to be associated with higher and lower risk, respectively, but associations were attenuated with adjustment for other risk factors. Conclusions: The ratio of ω-6 to ω-3 intake was not related to colorectal cancer risk in this cohort, which may be due to unexpected findings for the individual components. Differential associations by sex warrant further investigation. (Cancer Epidemiol Biomarkers Prev 2009;18(2):516–25)

Physical activity and fertility in women: the North-Trøndelag Health Study

BACKGROUND Changes in the state of energy balance owing to changes in physical activity may affect the reproductive system. We evaluated the association between physical activity (PA) and fertility and parity in healthy women. METHODS A population-based health survey (HUNT 1) was conducted during 1984-1986 in Nord-Trøndelag county, Norway, with follow-up from 1995 to 1997 (HUNT 2). The study included 3887 women, <45 years old in HUNT 2. PA was assessed by baseline questionnaire, and fertility and parity by questionnaire at follow-up. Data focused on overall occurrence of infertility in the population (without biological confirmation). RESULTS Increased frequency, duration and intensity of PA were associated with increased subfertility, and frequency of PA was associated with voluntary childlessness (P < 0.01). After adjusting for age, parity, smoking, and marital status, women who were active on most days were 3.2 times more likely to have fertility problems than inactive women. Exercising to exhaustion was associated with 2.3 times the odds of fertility problems versus low intensity. Women with highest intensity of PA at baseline had the lowest frequency of continuing nulliparity and highest frequency of having three or more children during follow-up (P < 0.05). Sensitivity analysis including body mass index as confounder did not alter the results. No associations were found between lower activity levels and fertility or parity. CONCLUSION Increased risk of infertility was only found for the small group of women reporting the highest levels of intensity and frequency of PA. Awareness of the possible risks of infertility should be highlighted among non-athletic women who exercise vigorously.

Predictors of treatment error for children with uncomplicated malaria seen as outpatients in Blantyre district, Malawi

Background  Past studies have shown that health workers in developing countries often do not follow clinical guidelines, though few studies have explored with appropriate methods why errors occur. To develop interventions that improve health worker performance, factors affecting treatment practices must be better understood.

TGF-α Expression as a Potential Biomarker of Risk Within the Normal-appearing Colorectal Mucosa of Patients with and without Incident Sporadic Adenoma

Background: Transforming growth factor-α (TGF-α), a stimulatory growth factor and member of the epidermal growth factor family, is a mediator of oncogenesis and malignant progression in colorectal carcinogenesis. Limited evidence suggests its utility as a growth-related biomarker of risk for colorectal cancer. Methods: We measured expression of TGF-α in biopsies of normal-appearing colorectal mucosa using automated immunohistochemistry and quantitative image analysis in a subsample of 29 cases and 31 controls from a colonoscopy-based case-control study (n = 203) of biomarkers of risk for incident sporadic colorectal adenoma. Diet, lifestyle, and medical history were assessed with validated questionnaires. Results: TGF-α expression in the rectum was 51% higher in cases compared with controls (P = 0.05) and statistically significantly associated with accepted risk factors for colorectal neoplasms (36% lower among nonsteroidal anti-inflammatory drug users, 49% lower among women using hormone replacement therapy, 79% higher among persons with a family history of colorectal cancer). Conclusions: TGF-α expression in the normal-appearing rectal mucosa shows promise as an early, potentially modifiable biomarker of risk for colorectal cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(1):65–73)

Physical Activity and Depressive Symptoms Among Norwegian Adults Aged 20-50

INTRODUCTION To analyze the association between physical activity (PA) and occurrence of depressive symptoms in The Nord-Trøndelag Health Survey (HUNT 1 1984-1986, HUNT 2 1995-1997). METHODS In this prospective follow-up study, we studied men and women who were 21-40 years old in HUNT 1, and participated in HUNT 2. The sample consisted of 3,353 women and 3,308 men. We used logistic regression and calculated odds ratios (OR) to assess the association between physical activity and depression (Hospital Anxiety and Depression Scale depression subscale [HADS-D]). Confounding was addressed by excluding those with relevant health conditions and adjustment. RESULTS Among women 272 (8.1%) and among men 293 (8.9%) scored higher than 8 on the HADS-D scale. We found a higher mean on HADS-D in men and women who were inactive. Men participating in low PA had significantly lower scores on depression (OR=0.63, confidence interval [CI]=0.43-0.93, p=.02) than inactive men. Women participating in medium PA had significantly lower scores on depression (OR=0.69, CI=0.49-0.97, p=.03) than inactive women. CONCLUSIONS Young men and women who exercised were less likely to have a high depression score, compared with inactive people. Our prospective, observational study included a large population and indicated some significant associations between physical activity and depression.

Serum folate and cancer mortality among U.S. adults: findings from the Third National Health and Nutritional Examination Survey linked mortality file.

Background: The relation between folate status and cancer is controversial. Several epidemiologic studies have suggested that increased folate intake is associated with reduced risk of various cancers, others have found no such associations, and a few have suggested that high folate intake might increase the risk of certain cancers. Methods: Using data from the Third National Health and Nutrition Examination Survey (NHANES III) Mortality File, a prospective cohort study of a nationally representative sample of 14,611 U.S. adults, we conducted Cox proportional hazards regression modeling to investigate the association of baseline serum folate concentrations and all-cancer mortality determined from linked death certificate data. Results: Relative to the lowest quintile of serum folate (<3.0 ng/mL), the multivariable-adjusted hazard ratios across quintiles 2 to 5 were: 1.61 [95% confidence interval (95% CI), 1.11-2.32], 1.00 (95% CI, 0.65-1.49), 1.39 (95% CI, 0.96-2.03), and 0.85 (95% CI, 0.59-1.22). These findings did not differ substantially by age or sex, but the higher risk for those in the second quintile appeared limited to non-Hispanic whites. Conclusion: These findings suggest that there may be a nonlinear relationship between folate status and the risk of all-cancer mortality such that persons with low, but not grossly deficient, serum blood folate concentrations may be at increased risk. Further study is needed to determine whether these findings are due to chance, and if not, to clarify their biological basis. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1439–47)

First-trimester maternal plasma cytokine levels, pre-pregnancy body mass index, and spontaneous preterm delivery.

Objective. To examine associations between first‐trimester plasma cytokines and spontaneous preterm delivery (sPTD). Design. A case‐control study was nested within the Danish National Birth Cohort, a cohort of women with 101,042 pregnancies from 1997 to 2002 who were recruited during pregnancy and followed prospectively. Sample. Subjects included 107 women delivering singleton infants at 24–29 weeks, 353 at 30–33 weeks, 422 at 34–36 weeks, and 1,372 at ≥37 weeks. Methods. Maternal plasma interleukin (IL)‐2, IL‐6, tumor necrosis factor (TNF)‐α, interferon (IFN)‐γ, and granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) were measured at a median of eight weeks gestation using multiplex flow cytometry. Adjusted odds ratios (ORs) were obtained using polytomous logistic regression. Main outcome measures. sPTD categorized as: 24–29 weeks, 30–33 weeks, 34–36 weeks, and ≥37 weeks (controls). Results. Elevated TNF‐α and GM‐CSF were associated with an increased risk of delivery at 34–36 weeks. In underweight women, sPTD <34 weeks was associated with elevated (>75th percentile) IL‐6 (OR = 5.62, 95% confidence interval (CI): 1.73, 18.26) and TNF‐α (OR = 3.02, CI: 1.02, 8.91) compared with term delivery. Conversely, among obese women, elevated IL‐2 (OR = 0.30, CI: 0.11, 0.78) and TNF‐α (OR = 0.15, CI: 0.05, 0.47) were associated with a reduced risk of delivering at <34 weeks. Cytokines were not related to delivery at <34 weeks in normal‐weight and overweight women. Conclusions. These findings suggest that the association between first‐trimester plasma cytokine levels and sPTD may depend on pre‐pregnancy body mass index.

Markers of the APC/β-Catenin Signaling Pathway as Potential Treatable, Preneoplastic Biomarkers of Risk for Colorectal Neoplasms

Background: Malfunctioning of the adenomatous polyposis coli (APC)/β-catenin signaling pathway is both an early and common event in sporadic colorectal cancer. To assess the potential of APC/β-catenin signaling pathway markers as treatable, preneoplastic biomarkers of risk for colorectal neoplasms, we conducted a pilot colonoscopy-based case–control study (51 cases and 154 controls) of incident, sporadic colorectal adenoma. Methods: We evaluated APC, β-catenin, and E-cadherin expression in normal mucosa from the rectum and ascending and sigmoid colon using automated immunohistochemical and quantitative image analysis. Diet, lifestyle, and medical history were assessed with validated questionnaires. Results: In the normal rectal mucosa, the ratio of the proportion of APC expression in the upper 40% of crypts with total β-catenin expression (APC/β-catenin score) was 14.3% greater in controls than in cases [P = 0.02; OR, 0.40; 95% confidence interval (CI), 0.14–1.14]. Compared with controls, in cases, APC expression was 3.2% lower, β-catenin expression was 3.0% higher, and E-cadherin expression was 0.7% lower; however, none of these differences were statistically significant. The APC/β-catenin score statistically significantly differed according to categories of plausible risk factors for colorectal cancer [e.g., it was 17.7% higher among those with 25(OH) vitamin D3 concentrations ≥ 27 ng/mL]. Conclusions: These preliminary data suggest that the combined expression of APC and β-catenin in the normal rectal mucosa may be associated with risk for incident, sporadic colorectal neoplasms, as well as with modifiable risk factors for colorectal neoplasms. Impact: Our results may help advance the development of treatable, preneoplastic biomarkers of risk for colorectal neoplasms. Cancer Epidemiol Biomarkers Prev; 21(6); 969–79. ©2012 AACR.

Physical activity and cardiovascular risk factors at menopause: The Nord-Trøndelag health study

Abstract Background Lowered physical activity levels may partially explain changes in metabolic risk factors in women after menopause. Objectives To evaluate the association between physical activity and metabolic risk factors at baseline and after 11 years, as well as the change in that association over time in women who were premenopausal and ≥ 40 years at baseline. Methods Subjects in a Norwegian population-based health survey answered questionnaires and had body and serum measurements during 1995–1997 (HUNT 2) and in a follow-up study during 2006–2008 (HUNT 3). Repeated-measures analyses were used to estimate the association between physical activity and metabolic factors, adjusting for age, smoking status, education, alcohol intake, and parity. Adjustment for hormonal treatment and medication was made, as appropriate. Results In women remaining premenopausal, a higher physical activity score in HUNT 3 was associated with lower weight (p < 0.01) and waist–hip ratio (p < 0.01) and higher high density lipoprotein (HDL) cholesterol in HUNT 3 (p < 0.01). In women that were postmenopausal by the time of follow-up, a higher physical activity score in HUNT 3 was associated with lower weight (p < 0.01), waist–hip ratio (p < 0.01), triglycerides (p < 0.01), and higher total cholesterol (p < 0.05), HDL cholesterol (p < 0.01), and diastolic blood pressure (p < 0.05) in HUNT 3. The association of total physical activity score with weight and waist–hip ratio was stronger in HUNT 3 than in HUNT 2 (p < 0.01). Conclusion Increased physical activity may reduce the risk of adverse outcomes and use of pharmacological management in women of menopausal age.

Healthy Postmenopausal Women–Physical Activity and Forearm Bone Mineral Density: The Nord-Trøndelag Health Survey

ABSTRACT The aim of this study was to analyze the association between Physical Activity (PA) and forearm bone mineral density (BMD) in healthy postmenopausal women. During 1984–1986, a population-based health survey (HUNT-1) was conducted in Nord-Trøndelag county, Norway. The second follow-up survey (HUNT-2) was conducted during 1995–1997. The subjects consist of all healthy postmenopausal women (N = 2,924). Higher intensity of recreational PA in HUNT-1 was associated with higher BMD ultradistally (slope = +0.0084, p = 0.0009). The summary score of duration, frequency and intensity of recreational PA in HUNT-1 was associated with lower risk of being below the 20th percentile ultradistally (OR = 0.90, p = 0.01, after adjustment for covariates). The trends for mean distal and ultradistal BMD and percent low BMD lacked statistical significance when we used the PA score that combined the recreational and occupational PA in HUNT-1 and HUNT-2. Conclusion: Higher intensity of prior recreational PA (HUNT-1) was associated with a protective effect on BMD measured in the forearm (HUNT-2).