Inhibition of Pim1 kinase activation attenuates allergen-induced airway hyperresponsiveness and inflammation.

Pim kinases are a family of serine/threonine kinases whose activity can be induced by cytokines involved in allergy and asthma. These kinases play a role in cell survival and proliferation, but have not been examined, to the best of our knowledge, in the development of allergic disease. This study sought to determine the role of Pim1 kinase in the development of allergic airway responses. Mice were sensitized and challenged with antigen (primary challenge), or were sensitized, challenged, and rechallenged with allergen in a secondary model. To assess the role of Pim1 kinase, a small molecule inhibitor was administered orally after sensitization and during the challenge phase. Airway responsiveness to inhaled methacholine, airway and lung inflammation, cell composition, and cytokine concentrations were assessed. Lung Pim1 kinase concentrations were increased after ovalbumin sensitization and challenge. In the primary allergen challenge model, treatment with the Pim1 kinase inhibitor after sensitization and during airway challenges prevented the development of airway hyperresponsiveness, eosinophilic airway inflammation, and goblet cell metaplasia, and increased Th2 cytokine concentrations in bronchoalveolar fluid in a dose-dependent manner. These effects were also demonstrated after a secondary allergen challenge, where lung allergic disease was established before treatment. After treatment with the inhibitor, a significant reduction was evident in the number of CD4(+) and CD8(+) T cells and concentrations of cytokines in the airways. The inhibition of Pim1 kinase was effective in preventing the development of airway hyperresponsiveness, airway inflammation, and cytokine production in allergen-sensitized and allergen-challenged mice. These data identify the important role of Pim1 kinase in the full development of allergen-induced airway responses.

The role of PIM kinases in human and mouse CD4+ T cell activation and inflammatory bowel disease.

PIM kinases are a family of three serine/threonine kinases expressed following T cell activation. Using potent selective small molecule antagonists of PIM-1/3 kinases, we demonstrate a potential role for these enzymes in naïve and effector CD4+ T cell activation. PIM-1/3 inhibition prevented CD4+ T cell proliferation by inducing a G0/G1 cell cycle arrest without affecting cellular survival. In the absence of PIM-1/3 kinase activity, naïve CD4+ T cells failed to fully differentiate into effector cells both in vitro and in vivo. Therapeutic dosing of a PIM-1/3 inhibitor was efficacious in a CD4+ T cell-mediated model of inflammatory bowel disease suggesting that PIM-1 and PIM-3 kinase activity contributes to sustained disease severity. These results demonstrate that PIM-1/3 kinases have an important role in CD4+ T cell responses and inhibition of this activity may provide a therapeutic benefit in T cell-mediated diseases.

TLR4-mediated signaling induces MMP9-dependent cleavage of B cell surface CD23.

IgE production is inversely regulated by circulating and B cell surface levels of the low affinity IgE receptor, CD23. To begin to understand physiologic determinants of CD23 expression, we analyzed effects of BCR and TLR stimulation on CD23 levels. BCR and TLR 2, 3, 4, 6, and 9 agonists induced CD23 down-modulation from the cell surface. However, among the ligands only TLR4 agonists induced transcriptional activation of CD23 and generation of significant soluble CD23. These responses were induced by LPS both in vitro and in vivo, and were seen in both murine and human B cells. LPS also induced expression of matrix metalloprotease 9 (MMP9) and failed to induce CD23 cleaving activity in MMP9(-/-) cells, thus implicating MMP9 in the LPS-induced release of CD23 from the cell surface. Finally, type 1 transitional B cells uniquely produce MMP9 in response to LPS, suggesting a mechanism wherein endotoxin induces T1 cell expression of MMP9, which mediates cleavage of CD23 on distinct, mature B cells.

Assessment of benefits of a universal screen for maternal alcohol use during pregnancy.

INTRODUCTION: The objective of this report is to estimate the benefits of universal meconium screening for maternal drinking during pregnancy. Fetal alcohol spectrum disorder (FASD), including its most severe manifestation fetal alcohol syndrome (FAS), is preventable and remains a public health tragedy. The incidences of FAS and FASD have been conservatively estimated to be 0.97 and 10 per 1000 births, respectively. Meconium testing has been demonstrated to be a promising at-birth method for detection of drinking during pregnancy. METHODS: The current costs of FAS and FASD, alcohol treatment programs, and meconium screening were estimated by literature review. Monetary values were converted roughly to equal dollars in 2006. RESULTS: Costs of adding meconium analysis to the current newborn screening program and of treatment for the identified mothers were estimated and compared to potential averted costs that may result from identification and intervention for mothers and affected infants. Three potential maternal treatment strategies are analyzed. Depending on the treatment type, the savings may range from $6 to $97 for every $1 spent on screening and treatment. DISCUSSION: It needs to be emphasized, however, that such screening is premature and that to be effective this screening can be implemented only if there is a societal willingness to institute prevention and intervention programs to improve both women's and children's health. Future research should be directed at improving detection and developing in-depth prevention and remedial intervention programs. A thorough consideration of the ethical issues involved in such a screening program is also needed.

Consumption of alcoholic beverages among pregnant urban Ugandan women.

The World Health Organization estimated alcohol consumption in Uganda to be one of the highest in the world. We examined alcohol consumption among Ugandan women prior to and after learning of pregnancy. We developed a screening algorithm using factors that predicted alcohol consumption in this study. In 2006, we surveyed 610 women attending antenatal care at the national referral hospital in Kampala, Uganda about consumption of traditional and commercial alcoholic beverages before and after learning of pregnancy. Predictors of alcohol consumption during pregnancy were examined and a practical screening algorithm was developed for use in antenatal clinics. One hundred eighty women (30%) drank alcohol at least monthly before learning of their pregnancy. Among these women, almost one-third reported usual consumption of at least one beverage type at quantities that equal binging levels for women. Overall, 151 women (25%) consumed alcohol after learning of pregnancy. Commercial beverages, particularly beer, were consumed more often than traditional drinks. A two-stage screening algorithm asking women about their religion, male partner or friends' drinking, and any lifetime drinking predicted self-reported consumption of alcohol during pregnancy with 97% sensitivity and 89% specificity. Alcohol consumption among pregnant Ugandan women attending antenatal care is high. A feasible screening algorithm can help providers target education and counseling to women who are likely drinking during pregnancy. Given the preference for commercial alcoholic beverages, it is recommended that labels be placed prominently on bottled alcoholic beverages warning of the adverse effects of consuming alcohol during pregnancy.

Impact of Glatiramer Acetate on B Cell-Mediated Pathogenesis of Multiple Sclerosis.

Growing evidence indicates that B cells play a key role in the pathogenesis of multiple sclerosis (MS). B cells occupy distinct central nervous system (CNS) compartments in MS, including the cerebrospinal fluid and white matter lesions. Also, it is now known that, in addition to entering the CNS, B cells can circulate into the periphery via a functional lymphatic system. Data suggest that the role of B cells in MS mainly involves their in situ activation in demyelinating lesions, leading to altered pro- and anti-inflammatory cytokine secretion, and a highly effective antigen-presenting cell function, resulting in activation of memory or naïve T cells. Clinically, B cell-depleting agents show significant efficacy in MS. In addition, many disease-modifying therapies (DMTs) traditionally understood to target T cells are now known to influence B cell number and function. One of the earliest DMTs to be developed, glatiramer acetate (GA), has been shown to reduce the total frequency of B cells, plasmablasts, and memory B cells. It also appears to promote a shift toward reduced inflammation by increasing anti-inflammatory cytokine release and/or reducing pro-inflammatory cytokine release by B cells. In the authors' opinion, this may be mediated by cross-reactivity of B cell receptors for GA with antigen (possibly myelin basic protein) expressed in the MS lesion. More research is required to further characterize the role of B cells and their bidirectional trafficking in the pathogenesis of MS. This may uncover novel targets for MS treatments and facilitate the development of B cell biomarkers of drug response.

Gulf War veterans' health: medical evaluation of a U.S. cohort.

BACKGROUND: United States military personnel reported various symptoms after deployment to the Persian Gulf during the 1991 Gulf War. However, the symptoms' long-term prevalence and association with deployment remain controversial. OBJECTIVE: To assess and compare the prevalence of selected medical conditions in a national cohort of deployed and nondeployed Gulf War veterans who were evaluated by direct medical and teledermatologic examinations. DESIGN: A cross-sectional prevalence study performed 10 years after the 1991 Gulf War. SETTING: Veterans were examined at 1 of 16 Veterans Affairs medical centers. PARTICIPANTS: Deployed (n = 1061) and nondeployed (n = 1128) veterans of the 1991 Gulf War. MEASUREMENTS: Primary outcome measures included fibromyalgia, the chronic fatigue syndrome, dermatologic conditions, dyspepsia, physical health-related quality of life (Short Form-36 [SF-36]), hypertension, obstructive lung disease, arthralgias, and peripheral neuropathy. RESULTS: Of 12 conditions, only 4 conditions were more prevalent among deployed than nondeployed veterans: fibromyalgia (deployed, 2.0%; nondeployed, 1.2%; odds ratio, 2.32 [95% CI, 1.02 to 5.27]); the chronic fatigue syndrome (deployed, 1.6%; nondeployed 0.1%; odds ratio, 40.6 [CI, 10.2 to 161]); dermatologic conditions (deployed, 34.6%; nondeployed, 26.8%; odds ratio, 1.38 [CI, 1.06 to 1.80]), and dyspepsia (deployed, 9.1%; nondeployed, 6.0%; odds ratio, 1.87 [CI, 1.16 to 2.99]). The mean physical component summary score of the SF-36 for deployed and nondeployed veterans was 49.3 and 50.8, respectively. LIMITATIONS: Relatively low participation rates introduce potential participation bias, and deployment-related illnesses that resolved before the research examination could not, by design, be detected. CONCLUSIONS: Ten years after the Gulf War, the physical health of deployed and nondeployed veterans is similar. However, Gulf War deployment is associated with an increased risk for fibromyalgia, the chronic fatigue syndrome, skin conditions, dyspepsia, and a clinically insignificant decrease in the SF-36 physical component score.

Spouses of Persian Gulf War I veterans: medical evaluation of a U.S. cohort.

Ten years after the 1991 Persian Gulf War (GW I), a comprehensive evaluation of a national cohort of deployed veterans (DV) demonstrated a higher prevalence of several medical conditions, in comparison to a similarly identified cohort of nondeployed veterans (NDV). The present study determined the prevalence of medical conditions among nonveteran spouses of these GW I DV and NDV. A cohort of 490 spouses of GW I DV and 537 spouses of GW I NDV underwent comprehensive face-to-face examinations. No significant differences in health were detected except that spouses of DV were less likely to have one or more of a group of six common skin conditions. We conclude that, 10 years after GW I, the general physical health of spouses of GW I DV is similar to that of spouses of NDV.

The relationship of blood lead with immunoglobulin E, eosinophils, and asthma among children: NHANES 2005-2006.

Early life lead exposure may alter immune function and predispose a child to develop asthma. In an initial exploration of this hypothesis, we examined the association between blood lead, and serum immunoglobulin E (IgE), eosinophils, and asthma prevalence in a cross-sectional study of 1788 children from the National Health and Nutrition Examination Survey 2005-2006. Geometric mean blood lead, serum IgE, and percent eosinophils were 1.13 µg/dL (95% confidence interval (CI): 1.04, 1.22), 46.3 kU/L (95% CI: 40.3, 53.1), and 2.82 percent (95% CI 2.67, 2.98), respectively. Prevalence of asthma, atopic asthma, and atopy were 11.8% (95% CI: 9.5, 14.2), 8.1% (6.2, 9.9), and 44.4% (40.1, 48.7), respectively. Regression models controlled for season, age, sex, race/ethnicity, education, passive smoke exposure, and body mass index. Based on these models, there was an 11.1% (95% CI: 5.6, 16.9) increase in IgE and a 4.9% (95% CI: 2.3, 7.6) increase in eosinophils per 1 µg/dL increase in blood lead. In independent stratified analyses, lead was found to increase IgE and eosinophils among non-Hispanic whites, but not other children; and stronger associations were observed among children who lived with a smoker vs. not. Lead was not associated with asthma, atopic asthma, or general atopy. This study provides additional evidence of a cross-sectional association between lead with IgE and new evidence for eosinophils. This may be a mechanism for development of downstream allergic disease. The mechanisms that determine ultimate development of allergic disease are currently unknown, but are the focus of ongoing studies.

Colorectal cancer predicted risk online (CRC-PRO) calculator using data from the multi-ethnic cohort study.

BACKGROUND: Better risk predictions for colorectal cancer (CRC) could improve prevention strategies by allowing clinicians to more accurately identify high-risk individuals. The National Cancer Institute's CRC risk calculator was created by Freedman et al using case control data. METHODS: An online risk calculator was created using data from the Multi-Ethnic Cohort Study, which followed >180,000 patients for the development of CRC for up to 11.5 years through linkage with cancer registries. Forward stepwise regression tuned to the c statistic was used to select the most important variables for use in separate Cox survival models for men and women. Model accuracy was assessed using 10-fold cross-validation. RESULTS: Patients in the cohort experienced 2762 incident cases of CRC. The final model for men contained age, ethnicity, pack-years of smoking, alcoholic drinks per day, body mass index, years of education, regular use of aspirin, family history of colon cancer, regular use of multivitamins, ounces of red meat intake per day, history of diabetes, and hours of moderate physical activity per day. The final model for women included age, ethnicity, years of education, use of estrogen, history of diabetes, pack-years of smoking, family history of colon cancer, regular use of multivitamins, body mass index, regular use of nonsteroidal anti-inflammatory drugs, and alcoholic drinks per day. The calculator demonstrated good accuracy with a cross-validated c statistic of 0.681 in men and 0.679 in women, and it seems to be well calibrated graphically. An electronic version of the calculator is available at http://rcalc.ccf.org. CONCLUSION: This calculator seems to be accurate, is user friendly, and has been internally validated in a diverse population.

Defining incident cases of epilepsy in administrative data.

PURPOSE: To determine the minimum enrollment duration for identifying incident cases of epilepsy in administrative data. METHODS: We performed a retrospective dynamic cohort study using Ohio Medicaid data from 1992 to 2006 to identify a total of 5037 incident epilepsy cases who had at least 1 year of follow-up prior to epilepsy diagnosis (epilepsy-free interval). The incidence for epilepsy-free intervals from 1 to 8 years, overall and stratified by pre-existing disability status, was examined. The graphical approach between the slopes of incidence estimates and the epilepsy-free intervals was used to identify the minimum epilepsy-free interval that minimized misclassification of prevalent as incident epilepsy cases. RESULTS: As the length of epilepsy-free interval increased, the incidence rates decreased. A graphical plot showed that the decline in incidence of epilepsy became nearly flat beyond the third epilepsy-free interval. CONCLUSION: The minimum of 3-year epilepsy-free interval is needed to differentiate incident from prevalent cases in administrative data. Shorter or longer epilepsy-free intervals could result in over- or under-estimation of epilepsy incidence.

Activity change in response to bad air quality, National Health and Nutrition Examination Survey, 2007-2010.

Air pollution contributes to poor respiratory and cardiovascular health. Susceptible individuals may be advised to mitigate effects of air pollution through actions such as reducing outdoor physical activity on days with high pollution. Our analysis identifies the extent to which susceptible individuals changed activities due to bad air quality. This cross-sectional study included 10,898 adults from the National Health and Nutrition Examination Survey (NHANES) 2007-2010. Participants reported if they did something differently when air quality was bad. Susceptible categories included respiratory conditions, cardiovascular conditions and older age (≥ 65 years). Analyses accounted for complex survey design; logistic regression models controlled for gender, race, education, smoking, and body mass index. 1305 individuals reported doing something differently (12.0%, 95% confidence interval (CI): 10.9, 13.1). This percentage was 14.2% (95% CI: 11.6, 16.8), 25.1% (95% CI: 21.7, 28.6), and 15.5% (95% CI: 12.2, 18.9) among older adults, those with a respiratory condition, and those with a cardiovascular condition, respectively. In adjusted regression models the following were significantly more likely to have changed activity compared to those who did not belong to any susceptible group: respiratory conditions (adjusted odds ratio (aOR): 2.61, 95% CI: 2.03, 3.35); respiratory and cardiovascular conditions (aOR: 4.36, 95% CI: 2.47, 7.69); respiratory conditions and older age (aOR: 3.83; 95% CI: 2.47, 5.96); or all three groups (aOR: 3.52; 95% CI: (2.33, 5.32). Having cardiovascular conditions alone was not statistically significant. Some individuals, especially those with a respiratory condition, reported changing activities due to poor air quality. However, efforts should continue to educate the public about air quality and health.

Evaluation of the recommended core components of cardiac rehabilitation practice: an opportunity for quality improvement.

PURPOSE: Guidelines have been established that describe recommended core components for cardiac rehabilitation (CR) programs; yet, there are no national efforts to monitor the integration of the guidelines. The purpose of this research was to describe incorporation of core components in CR programs. METHODS: This was a cross-sectional study using the Ohio Phase II Cardiac Rehabilitation Survey. Descriptive analyses were stratified on American Association of Cardiovascular and Pulmonary Rehabilitation (AACVPR) certification, case management, and staff mix. RESULTS: Sixty-six percent (n = 94) of programs responded, 39% (n = 37) were AACVPR certified, 40% (n = 38) used case management, and 73% (n = 75) staffed an exercise physiologist. Notable findings included that only 44% of programs obtained/performed a 12-lead electrocardiogram and 36% screened for depression. AACVPR-certified programs compared with uncertified programs were more likely to manage overweight/obesity (100% vs 84% instruct on weight control, respectively, P = .02) and perform health assessments upon admission (89% vs 70% respectively, P = .04). Programs using case management when compared with programs that did not use case management were more likely to administer a health survey (92% vs 65%, respectively, P = .003) and risk stratify (100% vs 84%, respectively, P = .02). Programs with an exercise physiologist were more likely to administer/obtain a stress test when compared with those without an exercise physiologist (78% vs 56%, respectively, P = .04). CONCLUSIONS: There was a lack of consistency in the incorporation of core component guidelines; certification, case management, and staff mix offered little improvement. This study provides direction for statewide quality improvement initiatives to improve care delivered in CR programs.

Polycystic ovary syndrome and diabetes screening: a survey of gynecologists and reproductive endocrinologists.

OBJECTIVES: Women with polycystic ovary syndrome (PCOS) are at high risk of developing type 2 diabetes mellitus. The purpose of this study was to assess self-reported methods used by specialists in obstetrics and gynecology (OB/GYN) and in reproductive endocrinology and infertility (REI) to screen for type 2 diabetes in women with PCOS. STUDY DESIGN: We analyzed responses to a web-based survey of from 123 OB/GYN and 223 REI physician members of the American Society for Reproductive Medicine. RESULTS: Initial diabetes screening of all women with PCOS was performed by fewer OB/GYNs (57%) than REIs (71%). Approximately 1/3 of both groups reported initial screening only for those with additional risk factors, and 3% reported no screening. Re-screening for diabetes was reportedly performed by similar numbers of OB/GYNs (49%) and REIs (53%). Re-screening was reportedly not performed by the remaining 51% of OB/GYNs and 47% of REIs. For initial screening, the 2h glucose tolerance test (GTT) was reportedly used by fewer OB/GYNs than REIs (59% vs 72%), fasting plasma glucose (FPG) by more OB/GYNs (22% vs 8%), and hemoglobin A1c (HbA1c) by a similar number (19% vs 20%). For re-screening, GTT was reportedly used by a similar proportion of OB/GYNs and REIs (27% vs 32%), FPG was used more by OB/GYNs (43% vs 23%), and HbA1c was used less (30% vs 45%). CONCLUSIONS: Not all OB/GYN and REI respondents followed diabetes screening guidelines for women with PCOS. Screening rates for women with PCOS might be increased by continued educational efforts concerning their high risk for diabetes, and by the recent recommendation to use HbA1c for diabetes screening in high-risk populations.

The effect of prenatal and postnatal exposure to polychlorinated biphenyls and child neurodevelopment at age twenty four months.

We examined the association between prenatal and postnatal exposure to PCBs and development at age 24 months as measured by the Bayley Scales of Infant Development II. 44 (85%) of 52 children had information available. When prenatal and postnatal exposure were modeled together, we found no association between total PCB exposure and the mental development index (MDI) or the physical development index (PDI). In examining PCB 153, we found no association between PCB 153 and MDI, while higher levels of postnatal exposure was associated with a decrease in PDI after adjustment [ß for highest tertile=-24.9; 95% CI (-44.3, -5.5)]. Higher levels of prenatal PCB 153 exposure were associated with a statistically significant increased odds of screening positive for a motor delay. In sum, when prenatal and postnatal exposures were considered together, breast milk exposure to PCB 153 appears to be associated with decrements in motor development; however, we cannot rule out that the finding was due to chance.

Metabolic syndrome: identification and management in cardiac rehabilitation.

PURPOSE: The prevalence of metabolic syndrome in cardiac rehabilitation (CR) makes CR an ideal place to offer interventions to address metabolic syndrome­related risk. There is a lack of research related to the metabolic syndrome practices in CR. Therefore, the purpose of this research was to describe practices to assess CR patients for metabolic syndrome, interventions specific to metabolic syndrome, and staff knowledge and beliefs related to metabolic syndrome. METHODS: This was a cross-sectional study of CR providers in Ohio (n = 94). Program practices and interventions and staff knowledge and beliefs were assessed and stratified on the program use of case management, program certification by the American Association of Cardiovascular and Pulmonary Rehabilitation, and staff profession. RESULTS: At CR entry, 26% of the programs assessed patients for the metabolic syndrome and 8% had written guidelines for metabolic syndrome. Less than half of the staff (47%) was able to name 3 or more risk factors for metabolic syndrome. Programs using case management were more likely to identify metabolic syndrome (P < .001), measure waist circumference (P < .001), order a new lipid profile (P = .04) at program entry, and have written guidelines for managing metabolic syndrome (P = .01) than programs not using case management. No differences were observed in stratified analyses for the program certification or staff profession. CONCLUSIONS: The majority of CR programs do not assess patients for metabolic syndrome or have written guidelines for the metabolic syndrome. Opportunities exist for better management of metabolic syndrome in CR.

Preterm labor and chorioamnionitis are associated with neonatal T cell activation.

BACKGROUND: Preterm parturition is characterized by innate immune activation and increased proinflammatory cytokine levels. This well established association leads us to hypothesize that preterm delivery is also associated with neonatal T lymphocyte activation and maturation. METHODOLOGY/PRINCIPAL FINDINGS: Cord blood samples were obtained following term, preterm, and deliveries complicated by clinical chorioamnionitis. Activation marker expression was quantitated by flow cytometric analysis. Infants born following preterm delivery demonstrated enhanced CD4(+) T lymphocyte activation, as determined by CD25 (Term 9.72% vs. Preterm 17.67%, p = 0.0001), HLA-DR (Term 0.91% vs. Preterm 1.92%, p = 0.0012), and CD69 expression (Term 0.38% vs. Preterm 1.20%, p = 0.0003). Neonates delivered following clinical chorioamnionitis also demonstrated increased T cell activation. Preterm neonates had an increased frequency of CD45RO(+) T cells. CONCLUSION/SIGNIFICANCE: Preterm parturition is associated with neonatal CD4(+) T cell activation, and an increased frequency of CD45RO(+) T cells. These findings support the concept that activation of the fetal adaptive immune system in utero is closely associated with preterm labor.

Premature thelarche in infants and toddlers: prevalence, natural history and environmental determinants.

STUDY OBJECTIVE: The aim of this study was to measure the prevalence of premature thelarche in infant and toddler girls and to determine if environmental sources of estrogen were associated with early breast development. DESIGN: Observational with mixed methods: Retrospective chart review, cross-sectional component involving an interview survey, along with longitudinal follow-up of girls with thelarche up to six months. SETTING: A general pediatric clinic within a teaching hospital located in a large Midwestern city. PARTICIPANTS: Girls, between the ages of 12 and 48 months, and their mothers, presenting for well-child care. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Prevalence of premature thelarche; association of premature thelarche with selected environmental exposures. RESULTS: Among the 318 subjects, the overall prevalence of premature thelarche was measured at 4.7% (n = 15). The prevalence by race/ethnicity was 4.2% among White Non-Hispanics, 4.6% among Blacks and 6.5% among White Hispanics. The peak prevalence occurred between 12-17 months of age. All thelarche cases were Tanner stage 2. No statistically significant relationship was found between premature thelarche and environmental exposures. Upon follow-up, 44% of the cases of premature thelarche had persistent breast development. CONCLUSIONS: Our study demonstrated a higher prevalence of premature thelarche than has been previously reported. This study lacked power because of the small number of premature thelarche cases, the ubiquitous presence of environmental exposure as well as the potentially small effect of each environmental factor. Future studies need to employ a very large sample in order to accurately analyze the relationship between environmental toxicants and premature thelarche.

Association between bone turnover, micronutrient intake, and blood lead levels in pre- and postmenopausal women, NHANES 1999-2002.

BACKGROUND: Blood lead levels (BLLs) have been shown to increase during periods of high bone turnover such as pregnancy and menopause. OBJECTIVES: We examined the associations between bone turnover and micronutrient intake with BLLs in women 20-85 years of age (n = 2,671) participating in the National Health and Nutrition Examination Survey, 1999-2002. METHODS: Serum bone-specific alkaline phosphatase (BAP) and urinary cross-linked N-telopeptides (NTx) were measured as markers of bone formation and resorption, respectively. Lead was quantified in whole blood. The association between tertiles of BAP and NTx, and BLLs was examined using linear regression with natural log transformed BLLs as the dependent variable and interpreted as the percent difference in geometric mean BLLs. RESULTS: In adjusted analyses, mean BLLs among postmenopausal women in the upper tertiles of NTx and BAP were 34% [95% confidence interval (CI), 23%-45%] and 30% (95% CI, 17%-43%) higher than BLLs among women in the lowest tertiles of NTx and BAP, respectively. These associations were weaker, but remained statistically significant, among premenopausal women (NTx: 10%; 95% CI, 0.60%-19%; BAP: 14%; 95% CI, 6%-22%). Within tertiles of NTx and BAP, calcium intake above the Dietary Reference Intake (DRI), compared with below the DRI, was associated with lower mean BLLs among postmenopausal women but not premenopausal women, although most of the associations were not statistically significant. We observed similar associations for vitamin D supplement use. CONCLUSIONS: Bone resorption and bone formation were associated with a significant increase in BLLs among pre- and postmenopausal women.