Investigation of fMRI activation in the internal capsule

<p>Abstract</p> <p>Background</p> <p>Functional magnetic resonance imaging (fMRI) in white matter has long been considered controversial. Recently, this viewpoint has been challenged by an emerging body of evidence demonstrating white matter activation in the corpus callosum. The current study aimed to determine whether white matter activation could be detected outside of the corpus callosum, in the internal capsule. Data were acquired from a 4 T MRI using a specialized asymmetric spin echo spiral sequence. A motor task was selected to elicit activation in the posterior limb of the internal capsule.</p> <p>Results</p> <p>White matter fMRI activation was examined at the individual and group levels. Analyses revealed that activation was present in the posterior limb of the internal capsule in 80% of participants. These results provide further support for white matter fMRI activation.</p> <p>Conclusions</p> <p>The ability to visualize functionally active tracts has strong implications for the basic scientific study of connectivity and the clinical assessment of white matter disease.</p

Imputation method for lifetime exposure assessment in air pollution epidemiologic studies

Background: Environmental epidemiology, when focused on the life course of exposure to a specific pollutant, requires historical exposure estimates that are difficult to obtain for the full time period due to gaps in the historical record, especially in earlier years. We show that these gaps can be filled by applying multiple imputation methods to a formal risk equation that incorporates lifetime exposure. We also address challenges that arise, including choice of imputation method, potential bias in regression coefficients, and uncertainty in age-at-exposure sensitivities. Methods: During time periods when parameters needed in the risk equation are missing for an individual, the parameters are filled by an imputation model using group level information or interpolation. A random component is added to match the variance found in the estimates for study subjects not needing imputation. The process is repeated to obtain multiple data sets, whose regressions against health data can be combined statistically to develop confidence limits using Rubin’s rules to account for the uncertainty introduced by the imputations. To test for possible recall bias between cases and controls, which can occur when historical residence location is obtained by interview, and which can lead to misclassification of imputed exposure by disease status, we introduce an “incompleteness index,” equal to the percentage of dose imputed (PDI) for a subject. “Effective doses” can be computed using different functional dependencies of relative risk on age of exposure, allowing intercomparison of different risk models. To illustrate our approach, we quantify lifetime exposure (dose) from traffic air pollution in an established case–control study on Long Island, New York, where considerable in-migration occurred over a period of many decades. Results: The major result is the described approach to imputation. The illustrative example revealed potential recall bias, suggesting that regressions against health data should be done as a function of PDI to check for consistency of results. The 1% of study subjects who lived for long durations near heavily trafficked intersections, had very high cumulative exposures. Thus, imputation methods must be designed to reproduce non-standard distributions. Conclusions: Our approach meets a number of methodological challenges to extending historical exposure reconstruction over a lifetime and shows promise for environmental epidemiology. Application to assessment of breast cancer risks will be reported in a subsequent manuscript

Validation and Calibration of a Model Used to Reconstruct Historical Exposure to Polycyclic Aromatic Hydrocarbons for Use in Epidemiologic Studies

OBJECTIVES: We previously developed a historical reconstruction model to estimate exposure to airborne polycyclic aromatic hydrocarbons (PAHs) from traffic back to 1960 for use in case–control studies of breast cancer risk. Here we report the results of four exercises to validate and calibrate the model. METHODS: Model predictions of benzo[a]pyrene (BaP) concentration in soil and carpet dust were tested against measurements collected at subjects’ homes at interview. In addition, predictions of air intake of BaP were compared with blood PAH–DNA adducts. These same soil, carpet, and blood measurements were used for model optimization. In a separate test of the meteorological dispersion part of the model, predictions of hourly concentrations of carbon monoxide from traffic were compared with data collected at a U.S. Environmental Protection Agency monitoring station. RESULTS: The data for soil, PAH–DNA adducts, and carbon monoxide concentrations were all consistent with model predictions. The carpet dust data were inconsistent, suggesting possible spatial confounding with PAH-containing contamination tracked in from outdoors or unmodeled cooking sources. BaP was found proportional to other PAHs in our soil and dust data, making it reasonable to use BaP historical data as a surrogate for other PAHs. Road intersections contributed 40–80% of both total emissions and average exposures, suggesting that the repertoire of simple markers of exposure, such as traffic counts and/or distance to nearest road, needs to be expanded to include distance to nearest intersection

Polycyclic Aromatic Hydrocarbon-DNA Adducts and Breast Cancer: A Pooled Analysis

Polycyclic aromatic hydrocarbon (PAH)-DNA adducts have been associated with breast cancer in several small studies. The authors' pooled analysis included 873 cases and 941 controls from a population-based case-control study. Competitive enzyme-linked immunosorbent assay in peripheral mononuclear cells was conducted in 2 rounds, and results were pooled on the basis of round-specific quantiles. The odds ratio for breast cancer was elevated in relation to detectable PAH-DNA adducts (1.29 as compared with nondetectable adduct levels; 95% confidence interval = 1.05, 1.58), but there was no apparent dose-response relationship with increasing quantiles. No consistent pattern emerged when the results were stratified by PAH sources (e.g., active cigarette smoking or PAH-containing foods), or when the cases were categorized by stage of disease or hormone receptor status. These data provide only modest support for an association between PAH-DNA adducts and breast cancer development

Indoor air pollution exposure from use of indoor stoves and fireplaces in association with breast cancer: a case-control study

Background: Previous studies suggest that polycyclic aromatic hydrocarbons (PAHs) may adversely affect breast cancer risk. Indoor air pollution from use of indoor stoves and/or fireplaces is an important source of ambient PAH exposure. However, the association between indoor stove/fireplace use and breast cancer risk is unknown. We hypothesized that indoor stove/fireplace use in a Long Island, New York study population would be positively associated with breast cancer and differ by material burned, and the duration and timing of exposure. We also hypothesized that the association would vary by breast cancer subtype defined by p53 mutation status, and interact with glutathione S-transferases GSTM1, T1, A1 and P1 polymorphisms. Methods: Population-based, case-control resources (1,508 cases/1,556 controls) were used to conduct unconditional logistic regression to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI). Results: Breast cancer risk was increased among women reporting ever burning synthetic logs (which may also contain wood) in their homes (OR = 1.42, 95% CI 1.11, 1.84), but not for ever burning wood alone (OR = 0.93, 95% CI 0.77, 1.12). For synthetic log use, longer duration >7 years, older age at exposure (>20 years; OR = 1.65, 95% CI 1.02, 2.67) and 2 or more variants in GSTM1, T1, A1 or P1 (OR = 1.71, 95% CI 1.09, 2.69) were associated with increased risk. Conclusions: Burning wood or synthetic logs are both indoor PAH exposure sources; however, positive associations were only observed for burning synthetic logs, which was stronger for longer exposures, adult exposures, and those with multiple GST variant genotypes. Therefore, our results should be interpreted with care and require replication. Electronic supplementary material The online version of this article (doi:10.1186/1476-069X-13-108) contains supplementary material, which is available to authorized users

Vehicular Traffic–Related Polycyclic Aromatic Hydrocarbon Exposure and Breast Cancer Incidence: The Long Island Breast Cancer Study Project (LIBCSP)

BackgroundPolycyclic aromatic hydrocarbons (PAHs) are widespread environmental pollutants, known human lung carcinogens, and potent mammary carcinogens in laboratory animals. However, the association between PAHs and breast cancer in women is unclear. Vehicular traffic is a major ambient source of PAH exposure.ObjectivesOur study aim was to evaluate the association between residential exposure to vehicular traffic and breast cancer incidence.MethodsResidential histories of 1,508 participants with breast cancer (case participants) and 1,556 particpants with no breast cancer (control participants) were assessed in a population-based investigation conducted in 1996–1997. Traffic exposure estimates of benzo[a]pyrene (B[a]P), as a proxy for traffic-related PAHs, for the years 1960–1995 were reconstructed using a model previously shown to generate estimates consistent with measured soil PAHs, PAH–DNA adducts, and CO readings. Associations between vehicular traffic exposure estimates and breast cancer incidence were evaluated using unconditional logistic regression.ResultsThe odds ratio (95% CI) was modestly elevated by 1.44 (0.78, 2.68) for the association between breast cancer and long-term 1960–1990 vehicular traffic estimates in the top 5%, compared with below the median. The association with recent 1995 traffic exposure was elevated by 1.14 (0.80, 1.64) for the top 5%, compared with below the median, which was stronger among women with low fruit/vegetable intake [1.46 (0.89, 2.40)], but not among those with high fruit/vegetable intake [0.92 (0.53, 1.60)]. Among the subset of women with information regarding traffic exposure and tumor hormone receptor subtype, the traffic–breast cancer association was higher for those with estrogen/progesterone-negative tumors [1.67 (0.91, 3.05) relative to control participants], but lower among all other tumor subtypes [0.80 (0.50, 1.27) compared with control participants].ConclusionsIn our population-based study, we observed positive associations between vehicular traffic-related B[a]P exposure and breast cancer incidence among women with comparatively high long-term traffic B[a]P exposures, although effect estimates were imprecise.CitationMordukhovich I, Beyea J, Herring AH, Hatch M, Stellman SD, Teitelbaum SL, Richardson DB, Millikan RC, Engel LS, Shantakumar S, Steck SE, Neugut AI, Rossner P Jr., Santella RM, Gammon MD. 2016. Vehicular traffic–related polycyclic aromatic hydrocarbon exposure and breast cancer incidence: the Long Island Breast Cancer Study Project (LIBCSP). Environ Health Perspect 124:30–38; http://dx.doi.org/10.1289/ehp.130773

Residential Environmental Exposures and other Characteristics Associated with Detectable PAH-DNA Adducts in Peripheral Mononuclear Cells in a Population-Based Sample of Adult Females

The detection of polycyclic aromatic hydrocarbon (PAH)-DNA adducts in human lymphocytes may be useful as a surrogate end point for individual cancer risk prediction. In this study, we examined the relationship between environmental sources of residential PAH, as well as other potential factors that may confound their association with cancer risk, and the detection of PAH-DNA adducts in a large population-based sample of adult women. Adult female residents of Long Island, New York, aged at least 20 years were identified from the general population between August 1996 and July 1997. Among 1556 women who completed a structured questionnaire, 941 donated sufficient blood (25+ ml) to allow use of a competitive ELISA for measurement of PAH-DNA adducts in peripheral blood mononuclear cells. Ambient PAH exposure at the current residence was estimated using geographic modeling (n=796). Environmental home samples of dust (n=356) and soil (n=360) were collected on a random subset of long-term residents (15+ years). Multivariable regression was conducted to obtain the best-fitting predictive models. Three separate models were constructed based on data from : (A) the questionnaire, including a dietary history; (B) environmental home samples; and (C) geographic modeling. Women who donated blood in summer and fall had increased odds of detectable PAH-DNA adducts (OR=2.65, 95% confidence interval (CI)=1.69, 4.17; OR=1.59, 95% CI=1.08, 2.32, respectively), as did current and past smokers (OR=1.50, 95% CI=1.00, 2.24; OR=1.46, 95% CI=1.05, 2.02, respectively). There were inconsistent associations between detectable PAH-DNA adducts and other known sources of residential PAH, such as grilled and smoked foods, or a summary measure of total dietary benzo-[a]-pyrene (BaP) intake during the year prior to the interview. Detectable PAH-DNA adducts were inversely associated with increased BaP levels in dust in the home, but positively associated with BaP levels in soil outside of the home, although CIs were wide. Ambient BaP estimates from the geographic model were not associated with detectable PAH-DNA adducts. These data suggest that PAH-DNA adducts detected in a population-based sample of adult women with ambient exposure levels reflect some key residential PAH exposure sources assessed in this study, such as cigarette smoking

The Long Island Breast Cancer Study Project: description of a multi-institutional collaboration to identify environmental risk factors for breast cancer

The Long Island Breast Cancer Study Project is a federally mandated, population-based case-control study to determine whether breast cancer risk among women in the counties of Nassau and Suffolk, NY, is associated with selected environmental exposures, assessed by blood samples, self-reports, and environmental home samples. This report describes the collaborative project’s background, rationale, methods, participation rates, and distributions of known risk factors for breast cancer by case-control status, by blood donation, and by availability of environmental home samples. Interview response rates among eligible cases and controls were 82.1% (n=1,508) and 62.8% (n=1,556), respectively. Among case and control respondents who completed the interviewer-administered questionnaire, 98.2 and 97.6% self-completed the food frequency questionnaire; 73.0 and 73.3% donated a blood sample; and 93.0 and 83.3% donated a urine sample. Among a random sample of case and control respondents who are long-term residents, samples of dust (83.6 and 83.0%); soil (93.5 and 89.7%); and water (94.3 and 93.9%) were collected. Established risk factors for breast cancer that were found to increase risk among Long Island women include lower parity, late age at first birth, little or no breast feeding, and family history of breast cancer. Factors that were found to be associated with a decreased likelihood that a respondent would donate blood include increasing age and past smoking; factors associated with an increased probability include white or other race, alcohol use, ever breastfed, ever use of hormone replacement therapy, ever use of oral contraceptives, and ever had a mammogram. Long-term residents (defined as 15+ years in the interview home) with environmental home samples did not differ from other long-term residents, although there were a number of differences in risk factor distributions between long-term residents and other participants, as anticipated

Polymorphisms in DNA repair genes, traffic-related polycyclic aromatic hydrocarbon exposure and breast cancer incidence: Polymorphisms in DNA

Vehicular traffic polycyclic aromatic hydrocarbons (PAHs) have been associated with breast cancer incidence in epidemiologic studies, including our own. Because PAHs damage DNA by forming adducts and oxidative lesions, genetic polymorphisms that alter DNA repair capacity may modify associations between PAH-related exposures and breast cancer risk. Our goal was to examine the association between vehicular traffic exposure and breast cancer incidence within strata of a panel of nine biologically plausible nucleotide excision repair (NER) and base excision repair (BER) genotypes. Residential histories of 1,508 cases and 1,556 controls were assessed in the Long Island Breast Cancer Study Project between 1996 and 1997 and used to reconstruct residential traffic exposures to benzo[a]pyrene, as a proxy for traffic-related PAHs. Likelihood ratio tests from adjusted unconditional logistic regression models were used to assess multiplicative interactions. A gene-traffic interaction was evident (p = 0.04) for ERCC2 (Lys751); when comparing the upper and lower tertiles of 1995 traffic exposure estimates, the odds ratio (95% confidence interval) was 2.09 (1.13, 3.90) among women with homozygous variant alleles. Corresponding odds ratios for 1960–1990 traffic were also elevated nearly 2–3-fold for XRCC1 (Arg194Trp), XRCC1(Arg399Gln) and OGG1(-Ser326Cys), but formal multiplicative interaction was not evident. When DNA repair variants for ERCC2, XRCC1 and OGG1 were combined, among women with 4–6 variants, the odds ratios were 2.32 (1.22, 4.49) for 1995 traffic and 2.96 (1.06, 8.21) for 1960–1990 traffic. Our study is first to report positive associations between traffic-related PAH exposure and breast cancer incidence among women with select biologically plausible DNA repair genotypes