Genotype-phenotype correlations in children with HHT

Hereditary hemorrhagic telangiectasia (HHT), a rare autosomal dominant disease mostly caused by mutations in three known genes

A quantile-based g-computation approach to addressing the effects of exposure mixtures

Exposure mixtures frequently occur in data across many domains, particularly in the fields of environmental and nutritional epidemiology. Various strategies have arisen to answer questions about mixtures, including methods such as weighted quantile sum (WQS) regression that estimate a joint effect of the mixture components.We demonstrate a new approach to estimating the joint effects of a mixture: quantile g-computation. This approach combines the inferential simplicity of WQS regression with the flexibility of g-computation, a method of causal effect estimation. We use simulations to examine whether quantile g-computation and WQS regression can accurately and precisely estimate effects of mixtures in common scenarios. We examine the bias, confidence interval coverage, and bias-variance tradeoff of quantile g-computation and WQS regression, and how these quantities are impacted by the presence of non-causal exposures, exposure correlation, unmeasured confounding, and non-linear effects. Quantile g-computation, unlike WQS regression allows inference on mixture effects that is unbiased with appropriate confidence interval coverage at sample sizes typically encountered in epidemiologic studies and when the assumptions of WQS regression are not met. Further, WQS regression can magnify bias from unmeasured confounding that might occur if important components of the mixture are omitted. Unlike inferential approaches that examine effects of individual exposures, methods like quantile g-computation that can estimate the effect of a mixture are essential for understanding effects of potential public health actions that act on exposure sources. Our approach may serve to help bridge gaps between epidemiologic analysis and interventions such as regulations on industrial emissions or mining processes, dietary changes, or consumer behavioral changes that act on multiple exposures simultaneously.Comment: Main manuscript (3 figures, 4 tables, 7000 words) + appendi

Exposure to fogger trucks and breast cancer incidence in the Long Island Breast Cancer Study Project: a case-control study

Background: Few studies have supported an association between breast cancer and DDT, usually assessed with biomarkers that cannot discern timing of exposure, or differentiate between the accumulation of chronic low-dose versus acute high-dose exposures in the past. Previous studies suggest that an association may be evident only among women exposed to DDT during biologically susceptible windows, or among those diagnosed with estrogen receptor/progesterone receptor-positive (ER+PR+) breast cancer subtypes. Self-reported acute exposure to a fogger truck, which sprayed DDT prior to 1972, was hypothesized to increase the risk of breast cancer, particularly among women exposed at a young age or diagnosed with ER+PR+ breast cancer. Methods: We examined these possibilities in the Long Island Breast Cancer Study Project (LIBCSP) (1,508 cases, 1,556 controls), which included exposure assessment by structured questionnaire and serum samples collected between 1996–1998, using adjusted logistic and polytomous regression to estimate ORs and 95% CIs. Results: Women with ER+PR+ breast cancer had a 44% increased odds of ever seeing a pre-1972 fogger truck compared to other subtypes (OR = 1.44; 95% CI 1.08-1.93). However, there was little variation in the observed increase in breast cancer risk when considering all women who reported seeing a pre-1972 fogger truck at their residence (OR = 1.16; 95% CI 0.98, 1.37), or during hypothesized susceptible windows. Self-reported acute exposure was not correlated with serum concentrations, a biomarker of long-term exposure. Conclusions: These findings support the hypothesis that seeing a fogger truck, a proxy measure for acute DDT exposure, may be associated with ER+PR+ tumors, the most commonly diagnosed breast cancer subtype among American women

Childhood and Adolescent Pesticide Exposure and Breast Cancer Risk

To date, epidemiological studies have not strongly supported an association between pesticide exposure and breast cancer. However, few previous studies had the ability to assess specific time periods of exposure. Studies that relied on adult serum levels of metabolites of organochlorine pesticides may not accurately reflect exposure during developmental periods. Further, exposure assessment often occurred after diagnosis and key tumor characteristics, such as hormone receptor status, have rarely been available to evaluate tumor-subtype specific associations. We examine the association between pesticide exposure during childhood and adolescence and breast cancer risk in the prospective Sister Study cohort (N=50,844 women) to assess this relation by tumor subtype

Antimüllerian hormone in relation to tobacco and marijuana use and sources of indoor heating/cooking

To evaluate exposure to tobacco, marijuana and indoor heating/cooking sources in relation to anti-Müllerian hormone (AMH) levels

ZnII(atsm) is protective in amyotrophic lateral sclerosis model mice via a copper delivery mechanism

AbstractMutations in the metalloprotein Cu,Zn-superoxide dismutase (SOD1) cause approximately 20% of familial cases of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease for which effective therapeutics do not yet exist. Transgenic rodent models based on over-expression of mutant SOD1 have been developed and these have provided opportunity to test new therapeutic strategies and to study the mechanisms of mutant SOD1 toxicity. Although the mechanisms of mutant SOD1 toxicity are yet to be fully elucidated, incorrect or incomplete metallation of SOD1 confers abnormal folding, aggregation and biochemical properties, and improving the metallation state of SOD1 provides a viable therapeutic option. The therapeutic effects of delivering copper (Cu) to mutant SOD1 have been demonstrated recently. The aim of the current study was to determine if delivery of zinc (Zn) to SOD1 was also therapeutic. To investigate this, SOD1G37R mice were treated with the metal complex diacetyl-bis(4-methylthiosemicarbazonato)zincII [ZnII(atsm)]. Treatment resulted in an improvement in locomotor function and survival of the mice. However, biochemical analysis of spinal cord tissue collected from the mice revealed that the treatment did not increase overall Zn levels in the spinal cord nor the Zn content of SOD1. In contrast, overall levels of Cu in the spinal cord were elevated in the ZnII(atsm)-treated SOD1G37R mice and the Cu content of SOD1 was also elevated. Further experiments demonstrated transmetallation of ZnII(atsm) in the presence of Cu to form the Cu-analogue CuII(atsm), indicating that the observed therapeutic effects for ZnII(atsm) in SOD1G37R mice may in fact be due to in vivo transmetallation and subsequent delivery of Cu