PURPOSE Chronic inflammation is believed to contribute to the development and progression of breast cancer. Systemic C-reactive protein (CRP) and serum amyloid A (SAA) are measures of low-grade chronic inflammation and potential predictors of cancer survival. PATIENTS AND METHODS We evaluated the relationship between circulating markers of inflammation and breast cancer survival using data from the Health, Eating, Activity, and Lifestyle (HEAL) Study (a multiethnic prospective cohort study of women diagnosed with stage 0 to IIIA breast cancer). Circulating concentrations of CRP and SAA were measured approximately 31 months after diagnosis and tested for associations with disease-free survival (approximately 4.1 years of follow-up) and overall survival (approximately 6.9 years of follow-up) in 734 disease-free breast cancer survivors. Cox proportional hazards models were used with adjustment for potential confounding factors to generate hazard ratios (HRs) and 95% CIs. Results Elevated SAA and CRP were associated with reduced overall survival, regardless of adjustment for age, tumor stage, race, and body mass index (SAA P trend < .0001; CRP P trend = .002). The HRs for SAA and CRP tertiles suggested a threshold effect on survival, rather than a dose-response relationship (highest v lowest tertile: SAA HR = 3.15; 95% CI, 1.73 to 5.65; CRP HR = 2.27; 95% CI, 1.27 to 4.08). Associations were similar and still significant after adjusting for self-reported history of cardiovascular events and censoring cardiovascular disease deaths. Elevated CRP and SAA were also associated with reduced disease-free survival, although these associations were of borderline significance (SAA P trend = .04; CRP P trend = .07). CONCLUSION Circulating SAA and CRP may be important prognostic markers for long-term survival in breast cancer patients, independent of race, tumor stage, and body mass index.

Folic acid (FA) supplements and food fortification are used to prevent neural tube defects and to lower plasma homocysteine. Through exposure to food fortification and vitamin supplement use, large populations in the United States and elsewhere have an unprecedented high FA intake. We evaluated dietary and supplemental intakes of folate and FA in relation to an index of immune function, natural killer cell (NK) cytotoxicity, among 105 healthy, postmenopausal women. Among women with a diet low in folate (<233 microg/d), those who used FA-containing supplements had significantly greater NK cytotoxicity (P = 0.01). However, those who consumed a folate-rich diet and in addition used FA supplements > 400 microg/d had reduced NK cytotoxicity compared with those consuming a low-folate diet and no supplements (P = 0.02). Prompted by this observation, we assessed the presence of unmetabolized FA in plasma as a biochemical marker of excess FA. Unmetabolized folic acid was detected in 78% of plasma samples from fasting participants. We found an inverse relation between the presence of unmetabolized FA in plasma and NK cytotoxicity. NK cytotoxicity was approximately 23% lower among women with detectable folic acid (P = 0.04). This inverse relation was stronger among women >or= 60 y old and more pronounced with increasing unmetabolized FA concentrations (P-trend = 0.002). Because of the increased intake of FA in many countries, our findings highlight the need for further studies on the effect of long-term high FA intake on immune function and health.

Elevated circulating estrogens and a sedentary lifestyle increase risk for breast cancer. The effect of exercise on circulating estrogens in sedentary postmenopausal women is unknown. The objective of this study was to examine the effects of a 12-month moderate-intensity exercise intervention on serum estrogens. We randomly assigned 173 sedentary, overweight (body mass index > 24.0 kg/m 2 , body fat > 33%), postmenopausal women, ages 50 -75 years, not using hormone therapy, living in the Seattle, Washington, area for the next year, and willing to be randomly assigned to an exercise intervention or stretching control group. The exercise intervention included facility and home-based exercise (45 min, 5 days/ week moderate intensity sports/recreational exercise). A total of 170 (98.3%) women completed the study with exercisers averaging 171 min/ week of exercise. After 3 months, exercisers experienced declines in estrone, estradiol, and free estradiol of 3.8, 7.7, and 8.2%, respectively, versus no change or increased concentrations in controls (P ‫؍‬ 0.03, 0.07, and 0.02, respectively). At 12 months, the direction of effect remained the same, although the differences were no longer statistically significant. The effect was limited to women who lost body fat: women whose percentage of body fat [by dual energy x-ray absortiometry (DEXA)] decreased by >2% had statistically significant (comparing exercisers versus controls) decreases at 12 months of 11.9, 13.7, and 16.7% for serum estrone, estradiol, and free estradiol, respectively. We concluded that a 12-month moderate-intensity exercise intervention in postmenopausal women resulted in significant decreases in serum estrogens. The association between increased physical activity and reduced risk for postmenopausal breast cancer may be partly explained by effects on serum estrogens.

Intermittent preventive treatment in pregnancy (IPTp) is used to prevent Plasmodium falciparum malaria. However, parasites resistant to the IPTp drug sulfadoxine-pyrimethamine (SP) have emerged worldwide, and infections with mixed resistant and susceptible parasites are exacerbated by pyrimethamine in mice. In a prospective delivery cohort in Muheza, Tanzania, we examined the effects of SP IPTp on parasite resistance alleles, parasite diversity, level of parasitemia, and inflammation in the placenta. IPTp use was associated with an increased fraction of parasites carrying the resistance allele at DHPS codon 581, an increase in the level of parasitemia, and more intense placental inflammation. The lowest mean level of parasite diversity and highest mean level of parasitemia occurred in women after recent IPTp use. These findings support a model of parasite release and facilitation, whereby the most highly resistant parasites out-compete less fit parasite populations and overgrow under drug pressure. Use of partially effective anti-malarial agents for IPTp may exacerbate malaria infections in the setting of widespread drug resistance.evolution of drug resistance ͉ intermittent preventive treatment in pregnancy ͉ malaria drug resistance ͉ pregnancy malaria M alaria during pregnancy causes both maternal and fetal morbidity and mortality, including the deaths of an estimated 100,000 infants each year because of malaria-related low birth weight. The World Health Organization recommends that women living in sub-Saharan Africa receive at least two doses of intermittent preventive treatment (IPTp) with sulfadoxinepyrimethamine (SP) to prevent malaria and improve pregnancy outcomes (1-5) and this advice is widely followed. However, the rapid spread of SP-resistant parasites might undermine the efficacy of SP-IPTp, although it still confers benefits in areas with low to moderate levels of drug resistance (6). The effect of SP IPTp in areas where resistant parasites are more widespread has not been studied.Pyrimethamine and sulfadoxine target the parasite proteins DHFR and DHPS, respectively, and increasing resistance is conferred by ordered accumulating point mutations, of which DHPS codon 581 is one of the final to occur (7). The mutation at DHPS codon 581 has been associated with high-level in vitro resistance (8), as well as treatment failure in children (9, 10). Single-dose treatment of children with SP has been associated with an increase in parasite resistance alleles (11, 12), but little work has been done to examine the relationship between IPTp and selection for drug resistance alleles. One recent study observed an increased prevalence of placental infections harboring the DHFR triple mutant in women who had received pyrimethamine prophylaxis during pregnancy, as compared with women who had not (13). In contrast, IPTp use was not related to increased prevalence of resistance alleles at the same study site (14). Modeling studies have proposed that IPTp is less likely to contribute to accumulating drug resistance as...

Malaria risk is influenced by physiologic iron status, and therefore iron supplementation may have adverse effects even among children with ID. Future interventional studies should assess whether treatment for ID coupled with effective malaria control can mitigate the risks of iron supplementation for children in areas of malaria transmission.

Objective: This study examined the effects of exercise on metabolic risk variables insulin, leptin, glucose, and triglycerides in overweight/obese postmenopausal women. Research Methods and Procedures: Sedentary women (n ϭ 173) who were overweight or obese (BMI Ն 25 kg/m 2 or Ն24 kg/m 2 with Ն33% body fat), 50 to 75 years of age, were randomized to 12 months of exercise (Ն45 minutes of moderate-intensity aerobic activity 5 d/wk) or to a stretching control group. Body composition (DXA) and visceral adiposity (computed tomography) were measured at baseline and 12 months. Insulin, glucose, triglycerides, and leptin were measured at baseline and 3 and 12 months. Insulin resistance was evaluated by the homeostasis model assessment formula. Differences from baseline to follow-up were calculated and compared across groups. Results: Exercisers had a 4% decrease and controls had a 12% increase in insulin concentrations from baseline to 12 months (p ϭ 0.0002). Over the same 12-month period, leptin concentrations decreased by 7% among exercisers compared with remaining constant among controls (p ϭ 0.03). Homeostasis model assessment scores decreased by 2% among exercisers and increased 14% among controls from baseline to 12 months (p ϭ 0.0005). The exercise effect on insulin was modified by changes in total fat mass (trend, p ϭ 0.03), such that the exercise intervention abolished increases in insulin concentrations associated with gains in total fat mass. Discussion: Regular moderate-intensity exercise can be used to improve metabolic risk variables such as insulin and leptin in overweight/obese postmenopausal women. These results are promising for health care providers providing advice to postmenopausal women for lifestyle changes to reduce risk of insulin resistance, coronary heart disease, and diabetes.

Exercise effect on weight and body fat in men and women. Obesity. 2007;15: 1496 -1512. Objectives: The effect of national exercise recommendations on adiposity is unknown and may differ by sex. We examined long-term effects of aerobic exercise on adiposity in women and men. Research Methods and Procedures: This was a 12-month randomized, controlled clinical trial testing exercise effect on weight and body composition in men (N ϭ 102) and women (N ϭ 100). Sedentary/unfit persons, 40 to 75 years old, were recruited through physician practices and media. The intervention was facility-and home-based moderate-tovigorous intensity aerobic activity, 60 min/d, 6 days/wk vs. controls (no intervention). Results: Exercisers exercised a mean 370 min/wk (men) and 295 min/wk (women), and seven dropped the intervention. Exercisers lost weight (women, Ϫ1.4 vs. ϩ0.7 kg in controls, p ϭ 0.008; men, Ϫ1.8 vs. Ϫ0.1 kg in controls, p ϭ 0.03), BMI (women, Ϫ0.6 vs. ϩ0.3 kg/m 2 in controls, p ϭ 0.006; men, Ϫ0.5 kg/m 2 vs. no change in controls, p ϭ 0.03), waist circumference (women, Ϫ1.4 vs. ϩ2.2 cm in controls, p Ͻ 0.001; men, Ϫ3.3 vs. Ϫ0.4 cm in controls, p ϭ 0.003), and total fat mass (women, Ϫ1.9 vs. ϩ0.2 kg in controls, p ϭ 0.001; men, Ϫ3.0 vs. ϩ0.2 kg in controls, p Ͻ 0.001). Exercisers with greater increases in pedometer-measured steps per day had greater decreases in weight, BMI, body fat, and intra-abdominal fat (all p trend Ͻ 0.05 in both men and women). Similar trends were observed for increased minutes per day of exercise and for increases in maximal oxygen consumption. Discussion: These data support the U.S. Department of Agriculture and Institute of Medicine guidelines of 60 min/d of moderate-to-vigorous physical activity.

In these breast cancer survivors, the prevalence of vitamin D insufficiency was high. Clinicians might consider monitoring vitamin D status in breast cancer patients, together with appropriate treatments, if necessary.