Living near traffic adversely affects health outcomes. Traffic exposure metrics include distance to high-traffic roads, traffic volume on nearby roads, traffic within buffer distances, measured pollutant concentrations, land-use regression estimates of pollution concentrations, and others. We used Geographic Information System software to explore a new approach using traffic count data and a kernel density calculation to generate a traffic density surface with a resolution of 50?m. The density value in each cell reflects all the traffic on all the roads within the distance specified in the kernel density algorithm. The effect of a given roadway on the raster cell value depends on the amount of traffic on the road segment, its distance from the raster cell, and the form of the algorithm. We used a Gaussian algorithm in which traffic influence became insignificant beyond 300?m. This metric integrates the deleterious effects of traffic rather than focusing on one pollutant. The density surface can be used to impute exposure at any point, and it can be used to quantify integrated exposure along a global positioning system route. The traffic density calculation compares favorably with other metrics for assessing traffic exposure and can be used in a variety of applications.Journal of Exposure Science and Environmental Epidemiology advance online publication, 18 September 2013; doi:10.1038/jes.2013.51.
In 2008, the statute authorizing the Minnesota Pollution Control Agency (MPCA) to issue air permits was amended to include a unique requirement to analyze and consider "cumulative levels and effects of past and current environmental pollution from all sources on the environment and residents of the geographic area within which the facilitys emissions are likely to be deposited." Data describing the Statute Area suggest it is challenged by environmental and socioeconomic concerns, i.e., concerns which are often described by the phrase environmental equity. With input from diverse stakeholders, the MPCA developed a methodology for implementing a cumulative levels and effects analysis when issuing air permits in the designated geographic area. A Process Document was created defining explicit steps a project proposer must complete in the analysis. An accompanying Reference Document compiles all available environmental health data relevant to the Statute Area that could be identified. The final cumulative levels and effects methodology is organized by health endpoint and identifies hazard, exposure and health indices that require further evaluation. The resulting assessment is summarized and presented to decision makers for consideration in the regulatory permitting process. We present a description of the methodology followed by a case study summary of the first air permit processed through the "cumulative levels and effects analysis".
Three modeling systems were used to estimate human health risks from air pollution: two versions of MNRiskS (for Minnesota Risk Screening), and the USEPA National Air Toxics Assessment (NATA). MNRiskS is a unique cumulative risk modeling system used to assess risks from multiple air toxics, sources, and pathways on a local to a state-wide scale. In addition, ambient outdoor air monitoring data were available for estimation of risks and comparison with the modeled estimates of air concentrations. Highest air concentrations and estimated risks were generally found in the Minneapolis-St. Paul metropolitan area and lowest risks in undeveloped rural areas. Emissions from mobile and area (nonpoint) sources created greater estimated risks than emissions from point sources. Highest cancer risks were via ingestion pathway exposures to dioxins and related compounds. Diesel particles, acrolein, and formaldehyde created the highest estimated inhalation health impacts. Model-estimated air concentrations were generally highest for NATA and lowest for the AERMOD version of MNRiskS. This validation study showed reasonable agreement between available measurements and model predictions, although results varied among pollutants, and predictions were often lower than measurements. The results increased confidence in identifying pollutants, pathways, geographic areas, sources, and receptors of potential concern, and thus provide a basis for informing pollution reduction strategies and focusing efforts on specific pollutants (diesel particles, acrolein, and formaldehyde), geographic areas (urban centers), and source categories (nonpoint sources). The results heighten concerns about risks from food chain exposures to dioxins and PAHs. Risk estimates were sensitive to variations in methodologies for treating emissions, dispersion, deposition, exposure, and toxicity.
Contaminated vermiculite ore from Libby, Montana was processed in northeast Minneapolis from 1936 to 1989 in a densely populated urban residential neighborhood, resulting in non-occupational exposure scenarios from plant stack and fugitive emissions as well as from activity-based scenarios associated with use of the waste rock in the surrounding community. The objective of this analysis was to estimate potential cumulative asbestos exposure for all non-occupationally exposed members of this community. Questionnaire data from a neighborhood-exposure assessment ascertained frequency of potential contact with vermiculite processing waste. Monte Carlo simulation was used to develop exposure estimates based on activity-based concentration estimates and contact durations for four scenarios: S1, moved asbestos-contaminated waste; S2, used waste at home, on lawn or garden; S3, installed/removed vermiculite insulation; S4, played in or around waste piles at the plant. The simulation outputs were combined with air-dispersion model results to provide total cumulative asbestos exposure estimates for the cohort. Fiber emissions from the plant were the largest source of exposure for the majority of the cohort, with geometric mean cumulative exposures of 0.02 fibers/cc × month. The addition of S1, S2 and S3 did not significantly increase total cumulative exposure above background exposure estimates obtained from dispersion modeling. Activity-based exposures were a substantial contributor to the upper end of the exposure distribution: 90th percentile S4 exposure estimates are ?10 times higher than exposures from plant emissions. Pile playing is the strongest source of asbestos exposure in this cohort, with other activity scenarios contributing less than from plant emissions.
Ecm29 is a 200-kDa HEAT repeat protein that binds the 26 S proteasome. Genome-wide two-hybrid screens and mass spectrometry have identified molecular motors, endosomal components, and ubiquitin-proteasome factors as Ecm29-interacting proteins. The C-terminal half of human Ecm29 binds myosins and kinesins; its N-terminal region binds the endocytic proteins, Vps11, Rab11-FIP4, and rabaptin. Whereas full-length FLAG-Ecm29, its C-terminal half, and a small central fragment of Ecm29 remain bound to glycerol-gradient-separated 26 S proteasomes, the N-terminal half of Ecm29 does not. Confocal microscopy showed that Ecm-26 S proteasomes are present on flotillin-positive endosomes, but they are virtually absent from caveolin- and clathrin-decorated endosomes. Expression of the small central fragment of Ecm29 markedly reduces proteasome association with flotillin-positive endosomes. Identification of regions within Ecm29 capable of binding molecular motors, endosomal proteins, and the 26 S proteasome supports the hypothesis that Ecm29 serves as an adaptor for coupling 26 S proteasomes to specific cellular compartments.
The innate antiviral response is mediated, at least in part, by Toll-like receptors (TLRs). TLR3 signaling is activated in response to viral infection, and the absence of TLR3 in mice significantly increases mortality after infection with enteroviruses that cause myocarditis and/or dilated cardiomyopathy. We screened TLR3 in patients diagnosed with enteroviral myocarditis/cardiomyopathy and identified a rare variant in one patient as well as a significantly increased occurrence of a common polymorphism compared with controls. Expression of either variant resulted in significantly reduced TLR3-mediated signaling after stimulation with synthetic double-stranded RNA. Furthermore, Coxsackievirus B3 infection of cell lines expressing mutated TLR3 abrogated activation of the type I interferon pathway, leading to increased viral replication. TLR3-mediated type I interferon signaling required cellular autophagy and was suppressed by 3-methyladenine and bafilomycin A1, by inhibitors of lysosomal proteolysis, and by reduced expression of Beclin 1, Atg5, or microtubule-associated protein 1 light chain 3beta (MAP1LC3beta). However, TLR3-mediated signaling was restored upon exogenous expression of Beclin 1 or a variant MAP1LC3beta fusion protein refractory to RNA interference. These data suggest that individuals harboring these variants may have a blunted innate immune response to enteroviral infection, leading to reduced viral clearance and an increased risk of cardiac pathology.
The best method for identifying the epidural space for neuraxial blocks is controversial. We conducted this meta-analysis to test the hypothesis that loss of resistance with liquid reduces complications with epidural placement.
Diabetic patients with lower literacy or numeracy skills are at greater risk for poor diabetes outcomes. This study evaluated the impact of providing literacy- and numeracy-sensitive diabetes care within an enhanced diabetes care program on A1C and other diabetes outcomes.
Regulatory agencies are frequently called upon to assess the potential for significant environmental impacts from air pollution emissions. These assessments often entail air dispersion modeling to estimate air concentrations that can be compared with standards or health benchmarks. Some air pollutants can also impact human health through pathways in media besides air. Risk assessment models are available that consider pollutant deposition, movement, uptake, and other processes on land and water and in biota, but they are typically effort-intensive. A screening-level assessment of potential multipathway effects would be useful. We developed multipathway screening factors (MPSFs) that can be applied to inhalation risk estimates to give screening estimates of risks via ingestion pathways. The MPSFs were generated using a generic multipathway risk assessment, consisting of air dispersion and deposition modeling followed by risk modeling for 42 persistent, bioaccumulative air pollutants. MPSFs are defined as the ratio of ingestion risks to inhalation risks. We report here the results of a sensitivity analysis that evaluates the effects on the MPSF ratio of varying inputs to the air dispersion and deposition modeling analysis. Model input parameters were systematically varied and multipathway risks recalculated. From the sensitivity analysis results, reasonable upper-bound values for the ratio of ingestion risks to inhalation risks for each pollutant were selected. The particle size distribution and the method of calculating particle deposition had the most disproportionate effect on inhalation versus ingestion risks and the greatest effect on MPSFs. Risk calculations are often done at the points of maximum air concentration and maximum deposition. In this study, the MPSFs were usually highest at the location of the maximum inhalation risk.
Diabetes self-management education is an important component of comprehensive diabetes care. Patients with low health literacy and numeracy may have difficulty translating information from traditional diabetes educational programs and materials into effective self-care.
CryAB (HspB5) and HspB2, two small heat shock genes located adjacently in the vertebrate genome, are hypothesized to play distinct roles. Mice lacking both cryab and hspb2 (DKO) are viable and exhibit adult-onset degeneration of skeletal muscle but confounding results from independent groups were reported for cardiac responses to different stressful conditions (i.e., ischemia/reperfusion or pressure overload). To determine the specific requirements of HSPB2 in heart, we generated cardiac-specific HSPB2 deficient (HSPB2cKO) mice and examined their cardiac function under basal conditions and following cardiac pressure overload.
Aims: The human mutation R120G in the ?B-crystallin causes a multisystemic disease characterized by hypertrophic cardiomyopathy and cytoplasmic protein aggregates. In transgenic mice, human R120GCRYAB (hR120GTg) expression in heart sequentially modifies the REDOX status, in part by the activation of the nuclear factor, erythroid derived 2, like 2 (Nrf2). Thioredoxin System (TS) components are NRF2 target genes so it could be hypothesized that TS was affected in hR120GTg mice. Results: Transgenic hearts overexpressed thioredoxin1 (Trx1), which was identified by Isotope Coded Affinity Tag-Mass Spectrometry (ICAT), among hundreds of peptides displaying an increased reduced/oxidized ratio. Coupled to this higher level of reduced cysteines, the activity of thioredoxin reductase 1 (TrxR1) was augmented by 2.5 fold. Combining mutiple experimental approaches, the enzymatic regulation of TrxR1 by a HDAC3-dependent level of acetylation was confirmed. In vitro and in vivo functional tests established that TrxR1 activity is required to mitigate aggregate development and this could be mediated by BAG3 as a potential TS substrate. Innovation and Conclusions: This study uncovers the compartmentalized changes and the involvement of TS in the cardiac stress response elicited by misfolded proteins such as R120GCRYAB. Our work suggests that R120GCRYAB triggers a defensive pathway acting through the newly identified interacting partners HDAC3, TrxR1 and BAG3 to counter aggregate growth. Therefore, those interactors may function as modifier genes contributing to the variable onset and expressivity of such human diseases. Furthermore, our work underscores the potential organismal effects of pharmacological interventions targeting TS and HDAC.
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