De novo mutations in histone-modifying genes in congenital heart disease.

Congenital heart disease (CHD) is the most frequent birth defect, affecting 0.8% of live births. Many cases occur sporadically and impair reproductive fitness, suggesting a role for de novo mutations. Here we compare the incidence of de novo mutations in 362 severe CHD cases and 264 controls by analysing exome sequencing of parent-offspring trios. CHD cases show a significant excess of protein-altering de novo mutations in genes expressed in the developing heart, with an odds ratio of 7.5 for damaging (premature termination, frameshift, splice site) mutations. Similar odds ratios are seen across the main classes of severe CHD. We find a marked excess of de novo mutations in genes involved in the production, removal or reading of histone 3 lysine 4 (H3K4) methylation, or ubiquitination of H2BK120, which is required for H3K4 methylation. There are also two de novo mutations in SMAD2, which regulates H3K27 methylation in the embryonic left-right organizer. The combination of both activating (H3K4 methylation) and inactivating (H3K27 methylation) chromatin marks characterizes 'poised' promoters and enhancers, which regulate expression of key developmental genes. These findings implicate de novo point mutations in several hundreds of genes that collectively contribute to approximately 10% of severe CHD.

The Congenital Heart Disease Genetic Network Study: rationale, design, and early results.

Congenital heart defects (CHD) are the leading cause of infant mortality among birth defects, and later morbidities and premature mortality remain problematic. Although genetic factors contribute significantly to cause CHD, specific genetic lesions are unknown for most patients. The National Heart, Lung, and Blood Institute-funded Pediatric Cardiac Genomics Consortium established the Congenital Heart Disease Genetic Network Study to investigate relationships between genetic factors, clinical features, and outcomes in CHD. The Pediatric Cardiac Genomics Consortium comprises 6 main and 4 satellite sites at which subjects are recruited, and medical data and biospecimens (blood, saliva, cardiovascular tissue) are collected. Core infrastructure includes an administrative/data-coordinating center, biorepository, data hub, and core laboratories (genotyping, whole-exome sequencing, candidate gene evaluation, and variant confirmation). Eligibility includes all forms of CHD. Annual follow-up is obtained for probands <1-year-old. Parents are enrolled whenever available. Enrollment from December 2010 to June 2012 comprised 3772 probands. One or both parents were enrolled for 72% of probands. Proband median age is 5.5 years. The one third enrolled at age <1 year are contacted annually for follow-up information. The distribution of CHD favors more complex lesions. Approximately, 11% of probands have a genetic diagnosis. Adequate DNA is available from 97% and 91% of blood and saliva samples, respectively. Genomic analyses of probands with heterotaxy, atrial septal defects, conotruncal, and left ventricular outflow tract obstructive lesions are underway. The scientific community's use of Pediatric Cardiac Genomics Consortium resources is welcome.

The contribution of de novo and rare inherited copy number changes to congenital heart disease in an unselected sample of children with conotruncal defects or hypoplastic left heart disease.

Congenital heart disease (CHD) is the most common congenital malformation, with evidence of a strong genetic component. We analyzed data from 223 consecutively ascertained families, each consisting of at least one child affected by a conotruncal defect (CNT) or hypoplastic left heart disease (HLHS) and both parents. The NimbleGen HD2-2.1 comparative genomic hybridization platform was used to identify de novo and rare inherited copy number variants (CNVs). Excluding 10 cases with 22q11.2 DiGeorge deletions, we validated de novo CNVs in 8 % of 148 probands with CNTs, 12.7 % of 71 probands with HLHS and none in 4 probands with both. Only 2 % of control families showed a de novo CNV. We also identified a group of ultra-rare inherited CNVs that occurred de novo in our sample, contained a candidate gene for CHD, recurred in our sample or were present in an affected sibling. We confirmed the contribution to CHD of copy number changes in genes such as GATA4 and NODAL and identified several genes in novel recurrent CNVs that may point to novel CHD candidate loci. We also found CNVs previously associated with highly variable phenotypes and reduced penetrance, such as dup 1q21.1, dup 16p13.11, dup 15q11.2-13, dup 22q11.2, and del 2q23.1. We found that the presence of extra-cardiac anomalies was not related to the frequency of CNVs, and that there was no significant difference in CNV frequency or specificity between the probands with CNT and HLHS. In agreement with other series, we identified likely causal CNVs in 5.6 % of our total sample, half of which were de novo.

A cross-sectional study of well water arsenic and child IQ in Maine schoolchildren.

BACKGROUND: In recent studies in Bangladesh and elsewhere, exposure to arsenic (As) via drinking water is negatively associated with performance-related aspects of child intelligence (e.g., Perceptual Reasoning, Working Memory) after adjustment for social factors. Because findings are not easily generalizable to the US, we examine this relation in a US population. METHODS: In 272 children in grades 3-5 from three Maine school districts, we examine associations between drinking water As (WAs) and intelligence (WISC-IV). RESULTS: On average, children had resided in their current home for 7.3 years (approximately 75% of their lives). In unadjusted analyses, household well WAs is associated with decreased scores on most WISC-IV Indices. With adjustment for maternal IQ and education, HOME environment, school district and number of siblings, WAs remains significantly negatively associated with Full Scale IQ and Perceptual Reasoning, Working Memory and Verbal Comprehension scores. Compared to those with WAs < 5 µg/L, exposure to WAs ≥ 5 µg/L was associated with reductions of approximately 5-6 points in both Full Scale IQ (p < 0.01) and most Index scores (Perceptual Reasoning, Working Memory, Verbal Comprehension, all p's < 0.05). Both maternal IQ and education were associated with lower levels of WAs, possibly reflecting behaviors (e.g., water filters, residential choice) limiting exposure. Both WAs and maternal measures were associated with school district. CONCLUSIONS: The magnitude of the association between WAs and child IQ raises the possibility that levels of WAs ≥ 5 µg/L, levels that are not uncommon in the United States, pose a threat to child development.

Incidence of subsequent pancreatic adenocarcinoma in patients with a history of nonpancreatic primary cancers.

BACKGROUND: Several environmental risk factors are known to predispose individuals to pancreatic cancer, and up to 15% of pancreatic cancers have an inherited component. Understanding metachronous cancer associations can modify pancreas cancer risk. The objective of this study was to investigate the association of nonpancreatic cancers with subsequent pancreatic adenocarcinoma. METHODS: The authors used data from the US Surveillance, Epidemiology, and End Results (SEER) registries to identify 1,618,834 individuals who had a primary malignancy and subsequent pancreatic adenocarcinoma (n = 4013). Standardized incidence ratios were calculated as an approximation of relative risk (RR) for the occurrence of pancreatic adenocarcinoma after another primary malignancy. RESULTS: Among patients who were diagnosed with a first primary malignancy at ages 20 to 49 years, the risk of subsequent pancreatic adenocarcinoma was increased among patients who had cancers of the ascending colon (relative risk [RR], 4.62; 95% confidence interval [CI], 1.86-9.52), hepatic flexure (RR, 5.42; 95% CI, 1.12-15.84), biliary system (RR, 13.14; 95% CI, 4.27-30.66), breast (RR, 1.32; 95% CI, 1.09-1.59), uterine cervix (RR, 1.61; 95% CI, 1.02-2.41), testes (RR, 2.78; 95% CI, 1.83-4.05), and hematopoietic system (RR, 1.83; 95% CI, 1.28-2.53). Among patients who had a first malignancy at ages 50 to 64 years, the risk was increased after cancers of the stomach (RR, 1.88; 95% CI, 1.13-2.93), hepatic flexure (RR, 2.25; 95% CI, 1.08-4.13), lung and bronchus (RR, 1.46; 95% CI, 1.16-1.82), pharynx (RR, 2.26; 95% CI, 1.13-4.04), and bladder (RR, 1.24; 95% CI, 1.03-1.48). Among patients who had a primary cancer after age 65 years, the risk was increased after cancers of the stomach (RR, 1.79; 95% CI, 1.23-2.53), hepatic flexure (RR, 1.76; 95% CI, 1.06-2.75), biliary system (RR, 2.35; 95% CI, 1.17-4.20), and uterus (RR, 1.23; 95% CI, 1.03-1.47). CONCLUSIONS: The results from the current population-based data set suggested that pancreatic adenocarcinoma is associated with certain primary cancers. Genetic predisposition and common environmental and behavioral risk factors all may contribute to this observation. Specific tumor associations will guide future risk-stratification efforts.

Skewed X chromosome inactivation and trisomic spontaneous abortion: no association.

Several studies suggest that highly skewed X chromosome inactivation (HSXI) is associated with recurrent spontaneous abortion. We hypothesized that this association reflects an increased rate of trisomic conceptions due to anomalies on the X chromosome that lead both to HSXI and to a diminished oocyte pool. We compared the distribution of X chromosome inactivation (XCI) skewing percentages (range: 50%-100%) among women with spontaneous abortions in four karyotype groups-trisomy (n = 154), chromosomally normal male (n = 43), chromosomally normal female (n = 38), nontrisomic chromosomally abnormal (n = 61)-to the distribution for age-matched controls with chromosomally normal births (n = 388). In secondary analyses, we subdivided the nontrisomic chromosomally abnormal group, divided trisomies by chromosome, and classified women by reproductive history. Our data support neither an association of HSXI with all trisomies nor an association of HSXI with chromosomally normal male spontaneous abortions. We also find no association between HSXI and recurrent abortion (n = 45).

Using FISH to increase the yield and accuracy of karyotypes from spontaneous abortion specimens.

OBJECTIVE: Cytogenetic analysis of spontaneous abortions is frequently complicated by culture failure and maternal cell contamination (MCC). The objective of the study is to demonstrate that multiplex fluorescence in situ hybridization (FISH) can increase the yield and accuracy of karyotypes from spontaneous abortion specimens. METHOD: A multiplex interphase FISH probe set was used to analyze two sample sets. (1) Uncultured tissues from 153 abortions samples with a normal 46,XX karyotype and (2) a series of 171 samples that either failed to grow or were contaminated. MCC studies were performed on 70 cultures where both karyotype and FISH indicated a normal female karyotype. RESULTS: FISH showed 31% (53/171) of the specimens karyotyped as 46,XX were either male or abnormal; 23% (40/118) of these specimens were found to have an abnormal chromosome complement. In specimens with culture failure, FISH showed an abnormal complement in 44.4% (68/153). MCC studies showed 41.49% (29/70) cultures of maternal origin, 45.7% (32/70) fetal, 11.4% (8/70) a maternal/fetal mixture and 1 diploid mole. CONCLUSION: Results demonstrate the utility of a simple FISH panel in increasing the detection rate of abnormal karyotypes. They also reveal the high frequency of overgrowth of maternal cells in cultured specimens from villi after embryonic loss.

Embryonic lethal genetic variants and chromosomally normal pregnancy loss.

OBJECTIVE: To examine whether rare damaging genetic variants are associated with chromosomally normal pregnancy loss and estimate the magnitude of the association. DESIGN: Case-control. SETTING: Cases were derived from a consecutive series of karyotyped losses at one New Jersey hospital. Controls were derived from the National Database for Autism Research. PATIENT(S): Cases comprised 19 chromosomally normal loss conceptus-parent trios. Controls comprised 547 unaffected siblings of autism case-parent trios. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The rate of damaging variants in the exome (loss of function and missense-damaging) and the proportions of probands with at least one such variant among cases vs. controls. RESULTS: The proportions of probands with at least one rare damaging variant were 36.8% among cases and 22.9% among controls (odds ratio, 2.0; 99% confidence interval, 0.5-7.3). No case had a variant in a known fetal anomaly gene. The proportion with variants in possibly embryonic lethal genes increased in case probands (odds ratio, 14.5; 99% confidence interval, 1.5-89.7); variants occurred in BAZ1A, FBN2, and TIMP2. CONCLUSION(S): Rare genetic variants in the conceptus may be a cause of chromosomally normal pregnancy loss. A larger sample is needed to estimate the magnitude of the association with precision and identify relevant biologic pathways.

Body size at birth, early-life growth and the timing of the menopausal transition and natural menopause.

BACKGROUND: Whether birth weight and early-life growth are associated with age at menopause has not been resolved. METHODS: We conducted a prospective study in two U.S. birth cohorts to investigate the relation of weight at birth and weight and growth trajectory through age 4 years to menstrual status among 1001 women ages 39-49 years. We used logistic regression models with GEE. RESULTS: Women who weighed more at birth and at one year were less likely to have experienced the menopausal transition or natural menopause by age 39-49 years (odds ratio(OR) = 0.50, 95% confidence interval(CI) = 0.32, 0.77 and OR = 0.82, 95%CI = 0.68, 0.99 per kilogram increase at birth and age one, respectively). CONCLUSIONS: Women who had a lighter weight at birth and women who were lighter than their peers through infancy experienced the menopausal transition or natural menopause at an earlier age.

The Congenital Heart Disease Genetic Network Study: Cohort description.

The Pediatric Cardiac Genomics Consortium (PCGC) designed the Congenital Heart Disease Genetic Network Study to provide phenotype and genotype data for a large congenital heart defects (CHDs) cohort. This article describes the PCGC cohort, overall and by major types of CHDs (e.g., conotruncal defects) and subtypes of conotrucal heart defects (e.g., tetralogy of Fallot) and left ventricular outflow tract obstructions (e.g., hypoplastic left heart syndrome). Cases with CHDs were recruited through ten sites, 2010-2014. Information on cases (N = 9,727) and their parents was collected through interviews and medical record abstraction. Four case characteristics, eleven parental characteristics, and thirteen parent-reported neurodevelopment outcomes were summarized using counts and frequencies and compared across CHD types and subtypes. Eleven percent of cases had a genetic diagnosis. Among cases without a genetic diagnosis, the majority had conotruncal heart defects (40%) or left ventricular outflow tract obstruction (21%). Across CHD types, there were significant differences (p<0.05) in the distribution of all four case characteristics (e.g., sex), four parental characteristics (e.g., maternal pregestational diabetes), and five neurodevelopmental outcomes (e.g., learning disabilities). Several characteristics (e.g., sex) were also significantly different across CHD subtypes. The PCGC cohort is one of the largest CHD cohorts available for the study of genetic determinants of risk and outcomes. The majority of cases do not have a genetic diagnosis. This description of the PCGC cohort, including differences across CHD types and subtypes, provides a reference work for investigators who are interested in collaborating with or using publically available resources from the PCGC.

A cross-sectional study of water arsenic exposure and intellectual function in adolescence in Araihazar, Bangladesh.

BACKGROUND: Exposure to inorganic arsenic (As) from drinking water is associated with modest deficits in intellectual function in young children; it is unclear whether deficits occur during adolescence, when key brain functions are more fully developed. OBJECTIVES: We sought to determine the degree to which As exposure is associated with adolescent intelligence, and the contributory roles of lead, cadmium, manganese and selenium. METHODS: We recruited a cross-section of 726 14-16 year olds (mean age = 14.8 years) whose mothers are participants in the Bangladesh Health Effects of Arsenic Longitudinal Study (HEALS), and whose household well water As levels, which varied widely, were well characterized. Using a culturally modified version of the WISC-IV, we examined raw Full Scale scores, and Verbal Comprehension, Perceptual Reasoning, Working Memory and Processing Speed Indices. Blood levels of As (BAs), Mn, Pb, Cd and Se were assessed at the time of the visit, as was creatinine-adjusted urinary As (UAs/Cr). RESULTS: Linear regression analyses revealed that BAs was significantly negatively associated with all WISC-IV scores except for Perceptual Reasoning. With UAs/Cr as the exposure variable, we observed significantly negative associations for all WISC-IV scores. Except for Se, blood levels of other metals, were also associated with lower WISC-IV scores. Controlling for covariates, doubling BAs, or UAs/Cr, was associated with a mean decrement (95% CI) of 3.3 (1.1, 5.5), or 3.0 (1.2, 4.5) points, respectively, in raw Full scale scores with a sample mean of 177.6 (SD = 36.8). Confirmatory analyses using Bayesian Kernel Machine Regression, which identifies important mixture members, supported these findings; the primary contributor of the mixture was BAs, followed by BCd. CONCLUSIONS: Our data indicate that the adverse consequences of As exposure on neurodevelopment observed in other cross-sectional studies of younger children are also apparent during adolescence. They also implicate Cd as a neurotoxic element that deserves more attention.

Water arsenic exposure and intellectual function in 6-year-old children in Araihazar, Bangladesh.

BACKGROUND: We recently reported results of a cross-sectional investigation of intellectual function in 10-year-olds in Bangladesh, who had been exposed to arsenic from drinking water in their home wells. OBJECTIVES: We present results of a similar investigation of 301 randomly selected 6-year-olds whose parents participated in our ongoing prospective study of the health effects of As exposure in 12,000 residents of Araihazar, Bangladesh. METHODS: Water As and manganese concentrations of tube wells at each home were obtained by surveying all study region wells. Children and mothers were first visited at home, where the quality of home stimulation was measured, and then seen in our field clinic, where children received a medical examination wherein weight, height, and head circumference were assessed. We assessed children's intellectual function using subtests drawn from the Wechsler Preschool and Primary Scale of Intelligence, version III, by summing weighted items across domains to create Verbal, Performance, Processing Speed, and Full-Scale raw scores. Children provided urine specimens for measuring urinary As and were asked to provide blood samples for blood lead measurements. RESULTS: Exposure to As from drinking water was associated with reduced intellectual function before and after adjusting for water Mn, for blood lead levels, and for sociodemographic features known to contribute to intellectual function. With covariate adjustment, water As remained significantly negatively associated with both Performance and Processing Speed raw scores; associations were less strong than in our previously studied 10-year-olds. CONCLUSION: This second cross-sectional study of As exposure expands our concerns about As neurotoxicity to a younger age group.

The autism epidemic: fact or artifact?

OBJECTIVE: We provide an illustration of how changes in methodological factors may produce variations in the frequency of autistic disorder (AD) over time and project how much of the observed increase in the frequency of AD may be explained by methodological factors. METHOD: Using a prediction analysis, we calculate how broadening diagnostic criteria, younger age at diagnosis, and improved efficiency of case ascertainment could produce temporal trends in the incidence and prevalence of AD, measured by calendar year and by year of birth, in a hypothetical population of children 0 to 18 across the years 1950 to 2020. RESULTS: Time trend studies report an increase as large as 11.0-fold over a 13-year period for AD. Conservative changes in the three methodological factors produced increases in the frequency of AD ranging from 2.1- to 28.8-fold. Measures of frequency by year of birth show the largest magnitude of increase; predicted prevalence by calendar year and to age 4 by year of birth are influenced by changes in the distribution of age at diagnosis, but 1-year incidence and prevalence to age 12 are not. DISCUSSION: Methodological factors may explain the observed increases in AD over time. To increase confidence in reports of time trends, we recommend particular frequency measures and study circumstances.

Water manganese exposure and children's intellectual function in Araihazar, Bangladesh.

Exposure to manganese via inhalation has long been known to elicit neurotoxicity in adults, but little is known about possible consequences of exposure via drinking water. In this study, we report results of a cross-sectional investigation of intellectual function in 142 10-year-old children in Araihazar, Bangladesh, who had been consuming tube-well water with an average concentration of 793 microg Mn/L and 3 microg arsenic/L. Children and mothers came to our field clinic, where children received a medical examination in which weight, height, and head circumference were measured. Children's intellectual function was assessed on tests drawn from the Wechsler Intelligence Scale for Children, version III, by summing weighted items across domains to create Verbal, Performance, and Full-Scale raw scores. Children provided urine specimens for measuring urinary As and creatinine and were asked to provide blood samples for measuring blood lead, As, Mn, and hemoglobin concentrations. After adjustment for sociodemographic covariates, water Mn was associated with reduced Full-Scale, Performance, and Verbal raw scores, in a dose-response fashion; the low level of As in water had no effect. In the United States, roughly 6% of domestic household wells have Mn concentrations that exceed 300 microg Mn/L, the current U.S. Environmental Protection Agency lifetime health advisory level. We conclude that in both Bangladesh and the United States, some children are at risk for Mn-induced neurotoxicity.

Pilot randomized controlled trial of interpersonal counseling for subsyndromal depression following miscarriage.

OBJECTIVE: Miscarriage, which occurs in 10% to 20% of clinically recognized pregnancies, is associated with an increased risk for subsyndromal depression. We examined whether Interpersonal Counseling (IPC) was superior to treatment as usual (TAU) in reducing subsyndromal depression among miscarrying women and, secondarily, superior to TAU in improving role functioning. METHOD: Nineteen of 20 eligible women participated in a randomized controlled trial of 1 to 6 weekly telephone sessions of IPC versus TAU, which consisted of whatever lay counseling or professional care women sought on their own initiative, from October 2001 to April 2002. The 2 trial arms were compared on mean within-subject change in Hamilton Rating Scale for Depression-17-item (HAM-D-17) scores and in role functioning scale scores (a 5-item modification of the 36-item Medical Outcomes Study questionnaire) from baseline to post-intervention. RESULTS: In the primary intent-to-treat analysis, the baseline mean HAM-D-17 scores were 18.0 (SD +/- 8.4) and 14.8 (SD +/- 6.6) in the IPC (N = 10) and TAU (N = 9) arms, respectively; post-intervention, the corresponding means were 11.6 (SD +/- 8.2) and 12.9 (SD +/- 8.3). The mean within-subject decline in HAM-D-17 scores was significantly greater in the IPC (6.4) than in the TAU (1.9) arm (difference in mean within-subject score decline, adjusted for design features, baseline HAM-D-17 scores and for baseline ethnic imbalance between study arms, 6.2 [95% CI = 0.4 to 12.0]). In a subordinate completers' analysis (N = 15), the corresponding mean decline and difference in adjusted mean decline were 8.0, 2.4, and 6.7 (95% CI = 0.4 to 13.1), respectively. Treatment was unrelated to improved role functioning. CONCLUSION: The efficacy of telephone-administered IPC for subsyndromal depression after miscarriage warrants testing in a full-scale randomized controlled trial.

Alcohol, caffeine and smoking in relation to age at menopause.

OBJECTIVES: Exposures which might influence age at natural menopause have been extensively studied but, with the exception of cigarette smoking, results have been inconsistent. We sought to determine: (i) whether alcohol and caffeine intake are associated with age at menopause; (ii) whether the association of cigarette smoking with age at menopause is confined to current smokers. METHODS: Analyses drew on longitudinal data from 494 women, aged 44-60 in 1993, of whom 159 experienced menopause before intake or during follow-up. We used parametric logistic survival analysis to estimate shifts in median age at menopause for women who drink alcohol or caffeine or who smoke cigarettes. RESULTS: The estimated median age at menopause was 2.2 (95% confidence interval (CI) 0.5, 3.9) years later for women who drank alcohol 5-7 days/week (13% of the sample) than for women who did not drink alcohol (54%). For women who drank at least 1 day/week, the estimated shift was 1.3 (95% CI 0.2, 2.3) years. Caffeine intake in approximate quartiles of mg/day-0-100, >100-200, >200-400, 400+-was not related to age at menopause. Current smokers of 14+cigarettes/day (6%) experienced menopause 2.8 (95% CI -4.8, -0.8) years earlier than women who never smoked (51%). Current smokers of 1-13 cigarettes/day (5%) and former smokers (38%) experienced menopause at about the same age as women who never smoked. CONCLUSIONS: The results are compatible with a pro-estrogenic effect of moderate alcohol intake and an anti-estrogenic effect of current cigarette smoking of 14+cigarettes/day.

Child Intelligence and Reductions in Water Arsenic and Manganese: A Two-Year Follow-up Study in Bangladesh.

BACKGROUND: Arsenic (As) exposure from drinking water is associated with modest intellectual deficits in childhood. It is not known whether reducing exposure is associated with improved intelligence. OBJECTIVE: We aimed to determine whether reducing As exposure is associated with improved child intellectual outcomes. METHODS: Three hundred three 10-year-old children drinking from household wells with a wide range of As concentrations were enrolled at baseline. In the subsequent year, deep community wells, low in As, were installed in villages of children whose original wells had high water As (WAs ≥ 50 µg/L). For 296 children, intelligence was assessed by WISC-IV (Wechsler Intelligence Scale for Children, 4th ed.), with a version modified for the study population, at baseline and approximately 2 years later; analyses considered standardized scores for both Full Scale IQ and Verbal Comprehension, Perceptual Reasoning, Working Memory, and Processing Speed Indices. Creatinine-adjusted urinary arsenic (UAs/Cr), blood As (BAs), and blood manganese (BMn) were assessed at both times. RESULTS: UAs/Cr concentrations declined significantly by follow-up for both the high (≥ 50 µg/L) and low (< 50 µg/L) WAs subgroups. At baseline, adjusting for maternal age and intelligence, plasma ferritin, head circumference, home environment quality, school grade, and BMn, UAs/Cr was significantly negatively associated with Full Scale IQ, and with all Index scores (except Processing Speed). After adjustment for baseline Working Memory scores and school grade, each 100-µg/g reduction in UAs/Cr from baseline to follow-up was associated with a 0.91 point increase in Working Memory (95% CI: 0.14, 1.67). The change in UAs/Cr across follow-up was not significantly associated with changes in Full Scale IQ or Index scores. CONCLUSIONS: Installation of deep, low-As community wells lowered UAs, BAs, and BMn. A greater decrease in UAs/Cr was associated with greater improvements in Working Memory scores, but not with a greater improvement in Full Scale IQ. CITATION: Wasserman GA, Liu X, Parvez F, Factor-Litvak P, Kline J, Siddique AB, Shahriar H, Uddin MN, van Geen A, Mey JL, Balac O, Graziano JH. 2016. Child intelligence and reductions in water arsenic and manganese: a two-year follow-up study in Bangladesh. Environ Health Perspect 124:1114-1120; http://dx.doi.org/10.1289/ehp.1509974.

Life course exposure to smoke and early menopause and menopausal transition.

OBJECTIVE: Early age at menopause is associated with increased risk of cardiovascular disease, stroke, osteoporosis, and all-cause mortality. Cigarette smoke exposure in adulthood is an established risk factor for earlier age at natural menopause and may be related to age at the menopausal transition. Using data from two US birth cohorts, we examined the association between smoke exposure at various stages of the life course (prenatal exposure, childhood exposure to parental smoking, and adult smoke exposure) and menopause status in 1,001 women aged 39 to 49 years at follow-up. METHODS: We used logistic regression analysis (adjusting for age at follow-up) to estimate odds ratios (ORs) and 95% confidence intervals (CI) relating smoke exposure to natural menopause and the menopausal transition. RESULTS: The magnitudes of the associations for natural menopause were similar but not statistically significant after adjustment for confounders among (i) women with prenatal smoke exposure who did not smoke on adult follow-up (OR, 2.7; 95% CI, 0.8-9.4) and (ii) current adult smokers who were not exposed prenatally (OR, 2.8; 95% CI, 0.9-9.0). Women who had been exposed to prenatal smoke and were current smokers had three times the risk of experiencing earlier natural menopause (adjusted OR, 3.4; 95% CI, 1.1-10.3) compared with women without smoke exposure in either period. Only current smoking of long duration (>26 y) was associated with the timing of the menopausal transition. CONCLUSIONS: Our data suggest that exposure to smoke both prenatally and around the time of menopause accelerates ovarian aging.

Obesity enhances verbal memory in postmenopausal women with Down syndrome.

Several lines of evidence suggest that the loss of estrogen after menopause may play a role in cognitive declines associated with Alzheimer's disease (AD). In postmenopausal women, the principal source of estrogen is estrone, which is influenced by body mass index (BMI). Increased BMI in postmenopausal women is associated with higher levels of serum estradiol and estrone. We hypothesized that obesity could have a beneficial effect on cognition with advancing age. We compared the performance of healthy nondemented obese and non-obese women with Down syndrome (DS) on a broad spectrum of cognitive tests. Estrone levels were 66.9% higher in obese than in non-obese postmenopausal women, and 136% higher in obese than in non-obese premenopausal women. Obese postmenopausal women performed significantly better than non-obese women on measures of verbal memory and on an omnibus test of neuropsychological function, but did not differ significantly in verbal fluency, language, praxis or visuospatial functioning. Among premenopausal women, there was no difference in cognitive function between obese and non-obese women. Our results support the hypothesis that higher endogenous estrogen levels after menopause are associated with better performance on verbal memory.

Mercury derived from dental amalgams and neuropsychologic function.

There is widespread concern regarding the safety of silver-mercury amalgam dental restorations, yet little evidence to support their harm or safety. We examined whether mercury dental amalgams are adversely associated with cognitive functioning in a cross-sectional sample of healthy working adults. We studied 550 adults, 30-49 years of age, who were not occupationally exposed to mercury. Participants were representative of employees at a major urban medical center. Each participant underwent a neuropsychologic test battery, a structured questionnaire, a modified dental examination, and collection of blood and urine samples. Mercury exposure was assessed using a) urinary mercury concentration (UHg); b) the total number of amalgam surfaces; and c) the number of occlusal amalgam surfaces. Linear regression analysis was used to estimate associations between each marker of mercury exposure and each neuropsychologic test, adjusting for potential confounding variables. Exposure levels were relatively low. The mean UHg was 1.7 micro g/g creatinine (range, 0.09-17.8); the mean total number of amalgam surfaces was 10.6 (range, 0-46) and the mean number of occlusal amalgam surfaces was 6.1 (range, 0-19). No measure of exposure was significantly associated with the scores on any neuropsychologic test in analyses that adjusted for the sampling design and other covariates. In a sample of healthy working adults, mercury exposure derived from dental amalgam restorations was not associated with any detectable deficits in cognitive or fine motor functioning.