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.

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.

Intermediate CGG repeat length at the FMR1 locus is not associated with hormonal indicators of ovarian age.

OBJECTIVE: Premutation and intermediate CGG repeat length at the fragile X mental retardation 1 (FMR1) locus have been associated with premature ovarian failure. We tested whether intermediate length is associated with indicators of ovarian age in a sample of fertile women. Our primary measures of ovarian age were antimüllerian hormone (AMH) and follicle-stimulating hormone (FSH) levels. METHODS: The cross-sectional sample comprised 258 women with karyotyped spontaneous abortions (140 trisomic spontaneous abortions and 118 chromosomally normal spontaneous abortions or spontaneous abortions with anomalies other than trisomy) and 325 women with recent live births (LBs). We analyzed data from the total sample and data from LBs only. We defined CGG repeat length by the length (both continuous and categorical) on the longer allele. RESULTS: CGG repeat length was not significantly associated with either hormone measure. A repeat length of 35 to 54 CGG, versus the modal category of 30 CGG, was associated with an approximately 7% increase in median AMH level and a 3% increase in median FSH level. Results were unaltered when analyses were limited to LBs. Analyses of hormone levels using cutpoints to define older ovarian age showed no associations with repeat length. Among 10 women with repeat lengths of 35 to 54 CGG analyzed for AGG sequences, the uninterrupted CGG length was not significantly longer among women with hormonal indicators of "old" versus "young" ovarian age. CONCLUSIONS: Our data do not support an association between intermediate CGG repeat length and levels of AMH or FSH among fertile women.

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.

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.

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.

Menopausal transition: predicting time to menopause for women 44 years or older from simple questions on menstrual variability.

OBJECTIVE: To assess whether menstrual variability predicts time to menopause. DESIGN: Analyses drew on 326 menstruating women, aged 44 to 56, who were followed until they reached menopause or the study ended. The women provided data on their menstrual characteristics at intake. We evaluated the utility of six definitions of menstrual variability for predicting time to ascertained menopause (final menstrual period + 12 months): (1) more than 90 days since the most recent menstrual period (n = 20); (2) 60 or more days of amenorrhea during the previous year (n = 71); (3) cycle lengths that varied by 19 or more days (n = 106); (4) cycle lengths too variable to report a usual length (n = 29); (5) cycles less regular than they had been at age 40 (n = 107); and (6) change in the duration or heaviness of menstrual flow compared with age 40 (n = 255). In addition, we evaluated hot flashes or night sweats during the previous week (n = 50) and age 50 or more years (n = 60) as predictors. RESULTS: Definitions 1 to 5 predicted time to menopause; definition 6 did not. Definition 1 had the highest positive predictive value for ascertained menopause within 2 years and within 4 years; definitions 2 and 4 had low to moderate positive predictive values for ascertained menopause within 2 years but good positive predictive values for ascertained menopause within 4 years. For ascertained menopause within 2 years, definition 2 showed the best balance of sensitivity (94%) and specificity (91%). CONCLUSION: Simple questions about menstrual variability elicit information that is informative about proximity to menopause.

Onset of dementia is associated with age at menopause in women with Down's syndrome.

Women with Down's syndrome experience early onset of both menopause and Alzheimer's disease. This timing provides an opportunity to examine the influence of endogenous estrogen deficiency, indicated by age at menopause, on risk of Alzheimer's disease. A community-based sample of 163 postmenopausal women with Down's syndrome, 40 to 60 years of age, was ascertained through the New York State Developmental Disability service system. Information from cognitive assessments, medical record review, neurological evaluation, and caregiver interviews was used to establish ages for onset of menopause and dementia. We used survival and multivariate regression analyses to determine the relation of age at menopause to age at onset of Alzheimer's disease, adjusting for age, level of mental retardation, body mass index, and history of hypothyroidism or depression. Women with early onset of menopause (46 years or younger) had earlier onset and increased risk of Alzheimer's disease (AD) compared with women with onset of menopause after 46 years (rate ratio, 2.7; 95% confidence interval [CI], 1.2-5.9). Demented women had higher mean serum sex hormone binding globulin levels than nondemented women (86.4 vs 56.6 nmol/L, p = 0.02), but similar levels of total estradiol, suggesting that bioavailable estradiol, rather than total estradiol, is associated with dementia. Our findings support the hypothesis that reductions in estrogens after menopause contribute to the cascade of pathological processes leading to AD.

The relationship between blood lead, bone lead and child intelligence.

We report associations between serial measures of blood lead and intelligence in children age 10-12 years, half heavily exposed to lead from the prenatal period onward, and half relatively unexposed. For a subsample, we examine bone lead-IQ associations, comparing them with bone lead associations. Both blood and bone lead levels were associated with intelligence decrements, small relative to the contribution of social factors. For each doubling of Tib-Pb, Full Scale, Performance, and Verbal IQ decreased by an estimated 5.5, 6.2, and 4.1 points, respectively. Bone lead-IQ associations were stronger than those for blood lead, which nonetheless provide robust analogues. Current BPb, easy to obtain, provides a useful means for assessing Pb exposure/IQ associations.