Iron deficiency protects against severe Plasmodium falciparum malaria and death in young children.

BACKGROUND: Iron supplementation may increase malaria morbidity and mortality, but the effect of naturally occurring variation in iron status on malaria risk is not well studied. METHODS: A total of 785 Tanzanian children living in an area of intense malaria transmission were enrolled at birth, and intensively monitored for parasitemia and illness including malaria for up to 3 years, with an average of 47 blood smears. We assayed plasma samples collected at routine healthy-child visits, and evaluated the impact of iron deficiency (ID) on future malaria outcomes and mortality. RESULTS: ID at routine, well-child visits significantly decreased the odds of subsequent parasitemia (23% decrease, P < .001) and subsequent severe malaria (38% decrease, P = .04). ID was also associated with 60% lower all-cause mortality (P = .04) and 66% lower malaria-associated mortality (P = .11). When sick visits as well as routine healthy-child visits are included in analyses (average of 3 iron status assays/child), ID reduced the prevalence of parasitemia (6.6-fold), hyperparasitemia (24.0-fold), and severe malaria (4.0-fold) at the time of sample collection (all P < .001). CONCLUSIONS: 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.

Malaria severity and human nitric oxide synthase type 2 (NOS2) promoter haplotypes.

Nitric oxide (NO) mediates host resistance to severe malaria and other infectious diseases. NO production and mononuclear cell expression of the NO producing enzyme-inducible nitric oxide synthase (NOS2) have been associated with protection from severe falciparum malaria. The purpose of this study was to identify single nucleotide polymorphisms (SNPs) and haplotypes in the NOS2 promoter, to identify associations of these haplotypes with malaria severity and to test the effects of these polymorphisms on promoter activity. We identified 34 SNPs in the proximal 7.3 kb region of the NOS2 promoter and inferred NOS2 promoter haplotypes based on genotyping 24 of these SNPs in a population of Tanzanian children with and without cerebral malaria. We identified 71 haplotypes; 24 of these haplotypes comprised 82% of the alleles. We determined whether NOS2 promoter haplotypes were associated with malaria severity in two groups of subjects from Dar es Salaam (N = 185 and N = 250) and in an inception cohort of children from Muheza-Tanga, Tanzania (N = 883). We did not find consistent associations of NOS2 promoter haplotypes with malaria severity or malarial anemia, although interpretation of these results was potentially limited by the sample size of each group. Furthermore, cytokine-induced NOS2 promoter activity determined using luciferase reporter constructs containing the proximal 7.3 kb region of the NOS2 promoter and the G-954C or C-1173T SNPs did not differ from NOS2 promoter constructs that lacked these polymorphisms. Taken together, these studies suggest that the relationship between NOS2 promoter polymorphisms and malaria severity is more complex than previously described.

No effect of aspirin on mammographic density in a randomized controlled clinical trial.

BACKGROUND: Epidemiologic studies suggest a reduced risk of breast cancer among women who regularly use aspirin; a plausible mechanism is through aspirin effect on mammographic breast density, a breast cancer risk factor, possibly mediated through aspirin interference with estrogen synthesis. METHODS: In a 2-arm randomized placebo-controlled clinical trial, we evaluated the effects of 6-month administration of 325 mg/day aspirin on total mammographic breast dense area and percent of the mammographic breast image occupied by dense areas (% density) in 143 postmenopausal women. Eligible women, recruited from 2005 to 2007, were healthy, not taking hormone therapy, with elevated mammographic breast density (American College of Radiology Breast Imaging Reporting and Data System density category 2, 3, or 4) within 6 months before enrollment. RESULTS: Women were a mean (SD) 59.5 (5.5) years. Geometric mean baseline percent density was 17.6% (95% confidence interval, 14.8-20.9) in women randomized to aspirin and 19.2% (95% confidence interval, 16.3-22.7) in women randomized to placebo. Percent density decreased in women randomized to aspirin by an absolute 0.8% versus an absolute decrease of 1.2% in controls (P = 0.84). Total breast area and dense area decreased to a similar degree in women assigned to aspirin and in those assigned to placebo, with no statistically significant differences between trial arms. CONCLUSIONS: A single daily administration of adult-dose aspirin for 6 months had no effect on mammographic density in postmenopausal women. If aspirin affects breast cancer risk in postmenopausal women, it may do so through alternative pathways than mammographic breast density.

Correlates of circulating C-reactive protein and serum amyloid A concentrations in breast cancer survivors.

INTRODUCTION: Inflammatory status may be an important prognostic factor for breast cancer. Correlates of markers of inflammation in breast cancer survivors have not been thoroughly evaluated. METHODS: Using data from, the Health, Eating, Activity, and Lifestyle (HEAL) Study (a population-based, multiethnic prospective cohort study of female breast cancer patients) we evaluated the associations between circulating markers of inflammation (C-reactive protein [CRP] and serum amyloid A [SAA], measured approximately 31 months after diagnosis) and several demographic, lifestyle, and clinical characteristics in 741 disease-free breast cancer survivors. Analysis of variance and regression methods were used for statistical analyses of log-transformed values of CRP and SAA. RESULTS: After adjusting for age, BMI, ethnicity, and study site, higher concentrations of CRP were associated with increasing concentration of SAA (P-trend < 0.0001), increasing age (P-trend < 0.0001), increasing BMI (P-trend < 0.0001), increasing waist circumference (P-trend < 0.0001), positive history of heart failure (P = 0.0007), decreasing physical activity (P-trend = 0.005), Hispanic ethnicity (P = 0.05 vs. non-Hispanic white), and current smoking (P = 0.03 vs. never smoking). Vitamin E supplementation (P = 0.0005), tamoxifen use (P = 0.008), and radiation treatment (compared to no chemotherapy or radiation; P = 0.04) were associated with reduced CRP. Associations of CRP with clinical characteristics were not significant in the adjusted models. In a multivariate analysis, CRP showed significant associations with waist circumference, BMI, age, history of heart failure, tamoxifen use, and vitamin E supplementation (R (2) = 0.35). Similar, yet fewer, associations were observed for SAA (R (2) = 0.19). CONCLUSIONS: This study highlights important correlates of inflammatory status in breast cancer patients. Our results are consistent with those from similar studies of healthy women.

Effect of exercise on in vitro immune function: a 12-month randomized, controlled trial among postmenopausal women.

Cross-sectional studies suggest that moderate physical activity is associated with enhanced resting immune function; however, few randomized controlled trials have investigated this link. We investigated the effect of 12-mo aerobic exercise, relative to stretching control, on in vitro immune function in a randomized, controlled trial of 115 postmenopausal, overweight, or obese sedentary women, aged 50-75 yr. The exercise goal was > or =45 min/day, 5 days/wk. Control women participated in 1 day/wk stretching classes. Immune markers (natural killer cell cytotoxicity, T-lymphocyte proliferation, immune cell counts and phenotypes, and serum immunoglobulins) were assessed at baseline, 3 mo, and 12 mo under strict blood-draw criteria. General estimation equations evaluated intervention effects at 3 and 12 mo, controlling for baseline. Of the 115 women who began the trial, blood samples were available from 109 at 3 mo (95%) and 108 at 12 mo (94%). From baseline to 12 mo, the exercise group participated in 87% of the prescribed physical activity minutes per week and increased maximal O(2) uptake by 13.8%; controls experienced no change in fitness. The main outcomes, natural killer cell cytotoxicity and T-lymphocyte proliferation, did not differ between groups at 3 and 12 mo. Secondary outcome and subgroup (e.g., stratification by baseline categories of body mass index, immune status, C-reactive protein, and age) analyses did not show any clear patterns of association. This 12-mo randomized, controlled trial showed no effect of aerobic exercise on in vitro immune function, despite excellent retention, high adherence, and demonstrable efficacy of the exercise intervention.

Predictors of diet quality among overweight and obese postmenopausal women.

Previous studies have shown that sociodemographic characteristics can be determinants of healthful eating. However, health characteristics such as smoking status have not been well studied. The objective of this research, therefore, was to determine predictors of diet quality in postmenopausal women. We included 164 overweight or obese postmenopausal women aged 50 to 75 years living in and around Seattle, WA, and intake, measured by food frequency questionnaire, was used to calculate scores for the Diet Quality Index and Healthy Eating Index. Information on sociodemographic factors and health behaviors was collected by self-administered questionnaire. Body mass index was computed using duplicate measures of height and weight. Percent body fat was measured by dual-energy x-ray absorptiometry. Following data collection, one-way analysis of variance, chi(2), and Pearson correlations were used to compare means of diet quality scores across participant characteristics. We found that predictors of better diet quality in this study population were higher education and former smoking history (compared to never-smokers); there was no evidence for a relationship with income level. Individuals with higher-quality diets were more likely to have lower body mass index or percent body fat. Based on the results of this study, education level and smoking history are predictors of diet quality among overweight and obese postmenopausal women. These findings add to the increasing evidence for targeting public health interventions to individuals with lower education because this group stands to benefit from improved dietary intake. In addition, these results suggest that the timing of smoking cessation is a possible teachable moment for food and nutrition professionals.

Effect of exercise on serum sex hormones in men: a 12-month randomized clinical trial.

PURPOSE: The effect of exercise on androgens in middle-aged to older men is poorly understood, and it could have implications for several aspects of health. This analysis was conducted to examine the effects of long-term aerobic exercise on serum sex hormones in middle-aged to older men. METHODS: One hundred two sedentary men, ages 40-75 yr, were randomly assigned to a 12-month exercise intervention or a control group (no change in activity). The combined facility- and home-based exercise program consisted of moderate/vigorous-intensity aerobic activity for 60 min.d(-1), 6 d.wk(-1). Serum concentrations of testosterone, free testosterone, dihydrotestosterone (DHT), 3alpha-androstanediol glucuronide (3alpha-Diol-G), estradiol, free estradiol, and sex hormone-binding globulin (SHBG) were measured at baseline, 3, and 12 months. RESULTS: Exercisers trained a mean of 370 min.wk(-1) (102% of goal), with only two dropouts. Cardiopulmonary fitness (.VO(2max)) increased 10.8% in exercisers and decreased by 1.8% in controls (P < 0.001). DHT increased 14.5% in exercisers versus 1.7% in controls at 3 months (P = 0.04); at 12 months, it remained 8.6% above baseline in exercisers versus a 3.1% decrease in controls (P = 0.03). SHBG increased 14.3% in exercisers versus 5.7% in controls at 3 months (P = 0.04); at 12 months, it remained 8.9% above baseline in exercisers versus 4.0% in controls (P = 0.13). There were significant trends toward increasing DHT and SHBG, with greater increases in .VO(2max) at 3 and 12 months in exercisers. No statistically significant differences were observed for testosterone, free testosterone, 3alpha-Diol-G, estradiol, or free estradiol in exercisers versus controls. CONCLUSIONS: A year-long, moderate-intensity aerobic exercise program increased DHT and SHBG, but it had no effect on other androgens in middle-aged to older men.

Associations between healthy eating patterns and immune function or inflammation in overweight or obese postmenopausal women.

BACKGROUND: The link between poor nutritional status and impaired immune function is well established; however, most studies have focused on individual nutrients instead of overall dietary patterns. OBJECTIVE: Our objective was to investigate associations between 3 indexes of overall diet quality [the Diet Quality Index (DQI), the DQI including supplementary calcium (DQI-Ca), and the Healthy Eating Index (HEI)] and biomarkers of inflammation and immunity. DESIGN: This cross-sectional study included 110 overweight or obese postmenopausal women. Dietary intake measured by food-frequency questionnaire was used to calculate diet quality scores. C-reactive protein (CRP) and serum amyloid A (SAA) were measured by latex-enhanced nephelometry. Flow cytometry was used to measure natural killer (NK) cell cytotoxicity and to enumerate and phenotype lymphocyte subsets. T lymphocyte proliferation was assessed by (3)H-thymidine incorporation as well as by the carboxyfluorescein-succinimidyl ester method of cell division tracking. Multivariable-adjusted linear regression analysis was used to investigate associations between diet quality scores and markers of inflammation and immune function. RESULTS: Higher diet quality was associated with increased proportions of cytotoxic and decreased proportions of helper T lymphocytes. CRP and SAA concentrations were higher among women with a lower-quality diet; these associations became nonsignificant after adjustment for body mass index or percentage body fat. We observed limited evidence for an association between healthy eating patterns and greater lymphocyte proliferation and no evidence for an association with NK cell cytotoxicity. CONCLUSION: Our results provide limited evidence that healthy eating patterns contribute to enhanced immune function and reduced inflammation in overweight and obese postmenopausal women.

Effect of a 12-month randomized clinical trial of exercise on serum prolactin concentrations in postmenopausal women.

Prolactin is associated with an increased risk of postmenopausal breast cancer; however, few modifiable factors are known to reduce prolactin concentrations. Therefore, we examined the effect of a 12-month moderate-intensity exercise intervention on serum prolactin concentrations as a secondary end point (primary end points were estrogens and androgens). We randomly assigned 173 postmenopausal women who were sedentary, overweight (body mass index >24 kg/m(2), body fat >33%), ages 50 to 75 years, and not using hormone therapy to an exercise intervention or stretching control group. The intervention was facility- and home-based (45 min, 5 days/wk moderate-intensity sports/recreational exercise). One hundred and seventy (98%) women completed the study. Prolactin concentrations were similar at baseline (P = 0.25, geometric mean exercisers = 6.9 and controls = 7.5 ng/mL). Overall, the intervention was not associated with changes in prolactin concentrations between exercisers and controls at 3 months (P = 0.46) or 12 months (P = 0.29). The intervention effect did not vary by baseline age, body mass index, parity, or change in percent body fat during the intervention. Among exercisers, there was a significant difference in prolactin concentrations by change in fitness (VO(2)max) between baseline and 12 months. Exercisers whose VO(2)max changed by <5% had a 5% increase in prolactin concentrations, whereas those who increased their VO(2)max by 5% to 15% and >15% had a 11% (P = 0.03) and 7% (P = 0.01) decrease in prolactin concentrations, respectively. Although the exercise intervention had little effect on prolactin concentrations overall, increasing physical fitness was associated with reduced prolactin concentrations among postmenopausal women.

No effect of exercise on colon mucosal prostaglandin concentrations: a 12-month randomized controlled trial.

BACKGROUND: Epidemiologic studies provide evidence that exercise is associated with reduced risk of colon cancer. Exercise may exert protective effects on the colon by influencing prostaglandin production. We hypothesized that an exercise intervention would decrease prostaglandin E(2) concentrations and increase prostaglandin F(2alpha) in colon biopsies compared with controls. METHODS: A 12-month randomized controlled trial testing the effects of exercise on colon mucosal prostaglandin concentrations was conducted in men (n=95) and women (n=89). The exercise intervention included moderate-to-vigorous aerobic activity, 60 min/d, 6 days/wk versus controls. Prostaglandin E(2) and F(2alpha) concentrations were measured in colon biopsies using an enzyme-linked immunoassay at baseline and at 12 months to assess changes in mean concentration for each group. RESULTS: Baseline colon prostaglandin E(2) and F(2alpha) concentrations were not correlated with age, race, education, family history of colon cancer, previous polyps, body size, diet, smoking, nonsteroidal antiinflammatory drug use, metabolic factors, or sex hormone levels. For both men and women, the exercise and control groups showed no change in mean prostaglandin E(2) or F(2alpha) between the baseline and 12-month biopsies. There was no difference in mean prostaglandin concentrations between exercisers and controls when exercisers were grouped by level of intervention adherence. Results were not modified by baseline age, body mass index, percentage of body fat, nonsteroidal antiinflammatory drug use, history of adenomatous polyps, or family history of colon cancer. CONCLUSION: A 12-month moderate-to-vigorous intensity aerobic exercise intervention did not result in significant changes in colon mucosal prostaglandin concentrations.

Effect of a 12-month exercise intervention on the apoptotic regulating proteins Bax and Bcl-2 in colon crypts: a randomized controlled trial.

BACKGROUND: Cellular proliferation and apoptosis (cell death) are highly regulated in the colon as insufficient apoptosis may lead to polyps and cancer. Physical activity decreases risk of colon cancer in observational studies, but the biological basis is not well defined. The objective of this study is to examine the effects of a 12-month aerobic exercise program on expression of proteins that promote (Bax) or inhibit (Bcl-2) apoptosis in colon crypts. METHODS: Two hundred two sedentary participants, 40 to 75 years, were randomly assigned to moderate-to-vigorous intensity exercise for 60 min per day, 6 days per week for 12 months, or usual lifestyle. Colon crypt samples were obtained at baseline and 12 months. Bcl-2 and Bax expression was measured by immunohistochemistry. RESULTS: Bax density at the bottom of crypts increased in male exercisers versus controls (+0.87 versus -0.18; P = 0.05), whereas the ratio of Bcl-2 to Bax at the bottom and middle of crypts decreased as aerobic fitness (VO(2)max) increased (P trend = 0.02 and 0.05, respectively). In female exercisers, Bax density in the middle of crypts decreased (-0.36 versus +0.69; P = 0.03) and Bcl-2 to Bax ratio at the top of crypts increased versus controls (+0.46 versus -0.85; P = 0.03). Bax density in the middle of crypts also decreased as minutes per week of exercise increased (P trend = 0.03). CONCLUSIONS: A 12-month exercise intervention resulted in greater expression of proteins that promote apoptosis at the bottom of colon crypts in men and decreased expression of proteins that promote apoptosis at the middle and top of colon crypts in women. The difference in effect by gender and location of observed changes warrants further study.

Effects of an exercise intervention on other health behaviors in overweight/obese post-menopausal women.

BACKGROUND: Little is known about whether initiating physical activity induces change in other health-related behaviors. If other behaviors do change with increasing physical activity, this would complicate interpretation of differences in study outcomes in exercise intervention trials. DESIGN: Randomized controlled trial. SETTING/PARTICIPANTS: 173 sedentary, overweight (body mass index between 24.0 and 25.0 kg/m2 with body fat>33% or BMI>or=25.0 kg/m2), postmenopausal women, ages 50 to 75 years, not using hormone therapy, and living in the Seattle, WA area. INTERVENTION: Participants were randomly assigned to an exercise intervention (n=87) or a stretching-control group (n=86). The exercise intervention included facility and home-based moderate-intensity exercise. MAIN OUTCOME MEASURES: Changes in dietary intake, alcohol consumption, and medication and supplement use were compared from baseline to 3- and 12-month follow-up between exercise and control groups, and by tertiles of exercise adherence. Data were collected between January 1998 and July 2001. RESULTS: In general, changes in dietary intake between the exercise and control group were not statistically different. The exercise group had a greater increase in the proportion of participants who used multivitamins (+5%) compared to the control group (-10%) at 3 months (p-interaction=0.04), but not at 12 months (p-interaction=0.58). Furthermore, there were few differences when comparing changes in health behaviors across exercise adherence tertiles. CONCLUSIONS: Our results suggest that participation in a year-long exercise intervention trial among post-menopausal women has little effect on other health behaviors. These findings suggest that additional behavior changes in exercise trials are minimal and unlikely to bias primary study results.

Effect of a 12-month exercise intervention on patterns of cellular proliferation in colonic crypts: a randomized controlled trial.

BACKGROUND: Colon crypt architecture and proliferation may be appropriate biomarkers for testing prevention interventions. A hypothesized mechanism for exercise-induced colon cancer risk reduction might be through alterations in colon crypt cell architecture and proliferation. METHODS: Healthy, sedentary participants with a colonoscopy within the previous 3 years were recruited through gastroenterology practices and media. We randomly assigned 100 women and 102 men, ages 40 to 75 years, to a control group or a 12-month exercise intervention of moderate-to-vigorous aerobic exercise, 60 minutes per day, 6 days per week, and assessed change in number and relative position of Ki67-stained cells in colon mucosal crypts. RESULTS: Exercisers did a mean 370 min/wk (men) and 295 min/wk (women) of exercise (seven dropped the intervention). In men, the mean height of Ki67-positive nuclei relative to total crypt height was related to amount of exercise, with changes from baseline of 0.0% (controls), +0.3% (exercisers <250 min/wk), -1.7% (exercisers 250-300 min/wk), and -2.4% (exercisers >300 min/wk; P(trend) = 0.03). In male exercisers whose cardiopulmonary fitness (V(O(2))max) increased >5%, the mean height of Ki67-positive nuclei decreased by 2% versus 0.9% in other exercisers, and versus no change in controls (P(trend) = 0.05). Similar trends were observed in other proliferation markers. In women, increased amount of exercise or V(O(2))max did not result in notable changes in proliferation markers. CONCLUSIONS: A 12-month moderate-to-vigorous intensity aerobic exercise intervention resulted in significant decreases in colon crypt cell proliferation indices in men who exercised a mean of >/=250 min/wk or whose V(O(2))max increased by >/=5%.

Serum lipoproteins in overweight/obese postmenopausal women: a one-year exercise trial.

INTRODUCTION: This analysis was conducted to study the effect of a 1-yr moderate-intensity aerobic exercise program on serum lipoproteins among overweight/obese postmenopausal women. METHODS: We randomized 173 sedentary (VO2max = 20.2 mL.kg(-1).min(-1)), overweight/obese women (body mass index (BMI) 25.0-42.0 kg.m(-2) or body fat > 33% if BMI 24.0-25.0) aged 50-75 yr, not using hormone therapy, living in the Seattle area, to an exercise intervention or stretching control group. The exercise intervention included facility and home-based exercise (45 min, 5 d.wk(-1) of moderate-intensity sports or recreational exercise). Total cholesterol (TC), triglycerides, and high-density lipoprotein (HDL) were determined by chemical assay; low-density lipoprotein (LDL) was then calculated. RESULTS: Of the 173 women, 170 (98.3%) completed the study with exercisers averaging 176 (SD 91) min.wk(-1) of moderate- to vigorous-intensity (60%-75% HRmax) exercise, expending approximately 3828 kJ.wk(-1) (SD 2053). Exercisers, compared with stretchers, significantly increased their VO2max (+11%, P<0.001) and lost more body weight (-1.4 kg, P < 0.05), DEXA-% total body fat (-1.0, P < 0.005), L4-5 computed tomography intraabdominal fat (-8.6 cm2, P < 0.05) and subcutaneous abdominal fat (-28.8 cm2, P < 0.005) after 12 months. Mean (SD) baseline lipoprotein levels for TC, LDL, HDL, and triglycerides were 231 (39), 152 (39), 52 (12), and 135 (65) mg.dL(-1), respectively. We observed no significant change in serum lipoprotein levels among exercisers compared with stretchers at either 3 or 12 months postrandomization. We did not observe a statistically significant effect of exercise on serum lipoproteins in subgroups that changed their intraabdominal and subcutaneous fat, percent total body fat, or VO2max the most, or that adhered to the exercise regimen the most over 1 yr. CONCLUSION: It appears that a year long moderate-intensity exercise program alone does not significantly alter serum lipoprotein levels among overweight/obese postmenopausal women.

Effect of exercise on bone mineral density and lean mass in postmenopausal women.

PURPOSE: To evaluate the effects of physical activity on bone mineral density, bone mineral content, and lean mass in postmenopausal, overweight/obese women. METHODS: We conducted a 12-month randomized controlled aerobic exercise intervention versus control in 173 sedentary, overweight/obese, postmenopausal women, aged 50-75 yr. The exercise prescription consisted of >or=45 min of moderate-intensity aerobic exercise (60-75% of maximal heart rate), 5 d.wk for 12 months. Control participants attended 45-min stretching sessions once a week. Ninety-eight percent (N=170) completed the trial. Exercisers averaged 172 min.wk (SD=89) of exercise and expended 3828 kJ.wk (SD=2053). We assessed body fat, total lean mass, and total body bone mineral density and content using dual-energy x-ray absortiometry (DXA). We compared baseline with 12-month changes in exercisers versus controls. RESULTS: Exercisers lost significantly more weight than stretchers (1.3-kg loss vs 0.1-kg gain, P=0.01). However, no differences between exercisers and controls in the change from baseline to 12 months were detected: exercisers' average bone mineral density increased by 0.005 g.cm and controls' by 0.003 g.cm (P=0.61). Similarly, no significant differences were detected for bone mineral content. Lean mass increased by 0.2 kg in both groups (P=0.84). CONCLUSION: Overall, the results from this randomized controlled study suggest that a yearlong moderate-intensity aerobic exercise intervention does not affect total body bone mineral density, bone mineral content, or lean mass in overweight/obese postmenopausal women.

Effect of exercise on serum estrogens in postmenopausal women: a 12-month randomized clinical trial.

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 >/==" BORDER="0">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.

HIV-1 shedding from the female genital tract is associated with increased Th1 cytokines/chemokines that maintain tissue homeostasis and proportions of CD8+FOXP3+ T cells.

BACKGROUND: HIV-1 shedding from the female genital tract is associated with increased sexual and perinatal transmission and has been broadly evaluated in cross-sectional studies. However, few longitudinal studies have evaluated how the immune microenvironment effects shedding. METHODS: Thirty-nine HIV-1-infected women had blood, cervicovaginal lavage, and biopsies of the uterine cervix taken quarterly for up to 5 years. Cytokines/chemokines were quantified by Luminex assay in cervicovaginal lavage, and cellular phenotypes were characterized using immunohistochemistry in cervical biopsies. Comparisons of cytokine/chemokine concentrations and the percent of tissue staining positive for T cells were compared using generalized estimating equations between non-shedding and shedding visits across all women and within a subgroup of women who intermittently shed HIV-1. RESULTS: Genital HIV-1 shedding was more common when plasma HIV-1 was detected. Cytokines associated with cell growth (interleukin-7), Th1 cells/inflammation (interleukin-12p70), and fractalkine were significantly increased at shedding visits compared with non-shedding visits within intermittent shedders and across all subjects. Within intermittent shedders and across all subjects, FOXP3 T cells were significantly decreased at shedding visits. However, there were significant increases in CD8 cells and proportions of CD8FOXP3 T cells associated with HIV-1 shedding. CONCLUSIONS: Within intermittent HIV-1 shedders, decreases in FOXP3 T cells at the shedding visit suggests that local HIV-1 replication leads to CD4 T-cell depletion, with increases in the proportion of CD8FOXP3 cells. HIV-1-infected cell loss may promote a cytokine milieu that maintains cellular homeostasis and increases immune suppressor cells in response to HIV-1 replication in the cervical tissues.

High prevalence of tuberculosis infection in HIV-1 exposed Kenyan infants.

BACKGROUND: Infants born to HIV-1 infected mothers may have increased risk for tuberculosis (TB), but the prevalence of TB infection in this population is undefined. In contrast to tuberculin skin tests that are confounded by recent bacille Calmette-Guérin (BCG) vaccination, TB interferon gamma release assays (IGRAs) do not cross-react with BCG and enable detection of TB infection in infancy. METHODS: In a nested observational cohort of HIV-1 infected Kenyan mothers and their infants, we conducted T-SPOT.TB assays on cryopreserved peripheral blood mononuclear cells from 6-month-old infants without prior active TB. Maternal and infant correlates of infant TB infection were assessed. RESULTS: One hundred and eight-two infants were tested with T-SPOT.TB. Of 128 infants with determinate T-SPOT.TB results, the prevalence of a positive T-SPOT.TB was 10.9% [95% confidence interval (CI): 6.1-17.7%]. All infants were BCG-vaccinated and 7.0% were HIV-1 infected. Positive infant T-SPOT.TB was associated with maternal active TB (odds ratio: 15.5, 95% CI: 1.3-184; P = 0.04) and prolonged infant fever (>1 month) (odds ratio: 18.8, 95% CI: 1.6-223; P = 0.03). CONCLUSIONS: We observed a high prevalence of TB infection in 6-month-old HIV-1 exposed infants. Improved TB detection and prevention are warranted in HIV-1 exposed infants at high risk for active TB disease.

Systematic review of the performance of rapid rifampicin resistance testing for drug-resistant tuberculosis.

INTRODUCTION: Rapid tests for rifampicin resistance may be useful for identifying isolates at high risk of drug resistance, including multidrug-resistant TB (MDR-TB). However, choice of diagnostic test and prevalence of rifampicin resistance may both impact a diagnostic strategy for identifying drug resistant-TB. We performed a systematic review to evaluate the performance of WHO-endorsed rapid tests for rifampicin resistance detection. METHODS: We searched MEDLINE, Embase and the Cochrane Library through January 1, 2012. For each rapid test, we determined pooled sensitivity and specificity estimates using a hierarchical random effects model. Predictive values of the tests were determined at different prevalence rates of rifampicin resistance and MDR-TB. RESULTS: We identified 60 publications involving six different tests (INNO-LiPA Rif. TB assay, Genotype MTBDR assay, Genotype MTBDRplus assay, Colorimetric Redox Indicator (CRI) assay, Nitrate Reductase Assay (NRA) and MODS tests): for all tests, negative predictive values were high when rifampicin resistance prevalence was ≤ 30%. However, positive predictive values were considerably reduced for the INNO-LiPA Rif. TB assay, the MTBDRplus assay and MODS when rifampicin resistance prevalence was < 5%. LIMITATIONS: In many studies, it was unclear whether patient selection or index test performance could have introduced bias. In addition, we were unable to evaluate critical concentration thresholds for the colorimetric tests. DISCUSSION: Rapid tests for rifampicin resistance alone cannot accurately predict rifampicin resistance or MDR-TB in areas with a low prevalence of rifampicin resistance. However, in areas with a high prevalence of rifampicin resistance and MDR-TB, these tests may be a valuable component of an MDR-TB management strategy.