Exposure information in environmental health research: Current opportunities and future directions for particulate matter, ozone, and toxic air pollutants

Understanding and quantifying outdoor and indoor sources of human exposure are essential but often not adequately addressed in health-effects studies for air pollution. Air pollution epidemiology, risk assessment, health tracking and accountability assessments are examples of health-effects studies that require but often lack adequate exposure information. Recent advances in exposure modeling along with better information on time-activity and exposure factors data provide us with unique opportunities to improve the assignment of exposures for both future and ongoing studies linking air pollution to health impacts. In September 2006, scientists from the US Environmental Protection Agency (EPA) and the Centers for Disease Control and Prevention (CDC) along with scientists from the academic community and state health departments convened a symposium on air pollution exposure and health in order to identify, evaluate, and improve current approaches for linking air pollution exposures to disease. This manuscript presents the key issues, challenges and recommendations identified by the exposure working group, who used cases studies of particulate matter, ozone, and toxic air pollutant exposure to evaluate health-effects for air pollution. One of the over-arching lessons of this workshop is that obtaining better exposure information for these different health-effects studies requires both goal-setting for what is needed and mapping out the transition pathway from current capabilities to meeting these goals. Meeting our long-term goals requires definition of incremental steps that provide useful information for the interim and move us toward our long-term goals. Another over-arching theme among the three different pollutants and the different health study approaches is the need for integration among alternate exposure assessment approaches. For example, different groups may advocate exposure indicators, biomonitoring, mapping methods (GIS), modeling, environmental media monitoring, and/or personal exposure modeling. However, emerging research reveals that the greatest progress comes from integration among two or more of these efforts

Association of FEV1 in asthmatic children with personal and microenvironmental exposure to airborne particulate matter.

Exposure to particulate matter (PM) air pollution has been shown to exacerbate children's asthma, but the exposure sources and temporal characteristics are still under study. Children's exposure to PM is likely to involve both combustion-related ambient PM and PM related to a child's activity in various indoor and outdoor microenvironments. Among 19 children with asthma, 9-17 years of age, we examined the relationship of temporal changes in percent predicted forced expiratory volume in 1 sec (FEV1) to personal continuous PM exposure and to 24-hr average gravimetric PM mass measured at home and central sites. Subjects were followed for 2 weeks during either the fall of 1999 or the spring of 2000, in a southern California region affected by transported air pollution. FEV(subscript)1(/subscript) was measured by subjects in the morning, afternoon, and evening. Exposure measurements included continuous PM using a passive nephelometer carried by subjects; indoor, outdoor home, and central-site 24-hr gravimetric PM2.5 (PM of aerodynamic diameter < 2.5 microm) and PM10; and central-site hourly PM10, nitrogen dioxide, and ozone. Data were analyzed with linear mixed models controlling for within-subject autocorrelation, FEV1 maneuver time, and exposure period. We found inverse associations of FEV1 with increasing PM exposure during the 24 hr before the FEV1 maneuver and with increasing multiday PM averages. Deficits in percent predicted FEV1 (95% confidence interval) for given PM interquartile ranges measured during the preceding 24-hr were as follows: 128 microg/m3 1-hr maximum personal PM, -6.0% (-10.5 to -1.4); 30 microg/m3 24-hr average personal PM, -5.9% (-10.8 to -1.0); 6.7 microg/m3 indoor home PM2.5, -1.6% (-2.8 to -0.4); 16 microg/m3 indoor home PM10, -2.1% (-3.7 to -0.4); 7.1 microg/m3 outdoor home PM2.5, -1.1% (-2.4 to 0.1); and 7.5 microg/m3 central-site PM2.5, -0.7% (-1.9 to 0.4). Stronger associations were found for multiday moving averages of PM for both personal and stationary-site PM. Stronger associations with personal PM were found in boys allergic to indoor allergens. FEV1 was weakly associated with NO2 but not with O3. Results suggest mixed respiratory effects of PM in asthmatic children from both ambient background exposures and personal exposures in various microenvironments

Transplantation tolerance: lessons from experimental rodent models

Immunological tolerance or functional unresponsiveness to a transplant is arguably the only approach that is likely to provide long-term graft survival without the problems associated with life-long global immunosuppression. Over the past 50 years, rodent models have become an invaluable tool for elucidating the mechanisms of tolerance to alloantigens. Importantly, rodent models can be adapted to ensure that they reflect more accurately the immune status of human transplant recipients. More recently, the development of genetically modified mice has enabled specific insights into the cellular and molecular mechanisms that play a key role in both the induction and maintenance of tolerance to be obtained and more complex questions to be addressed. This review highlights strategies designed to induce alloantigen specific immunological unresponsiveness leading to transplantation tolerance that have been developed through the use of experimental models

A Method for Assaying Deubiquitinating Enzymes

A general method for the assay of deubiquitinating enzymes was described in detail using (125)I-labeled ubiquitin-fused αNH-MHISPPEPESEEEEEHYC (referred to as Ub-PESTc) as a substrate. Since the tyrosine residue in the PESTc portion of the fusion protein was almost exclusively radioiodinated under a mild labeling condition, such as using IODO-BEADS, the enzymes could be assayed directly by simple measurement of the radioactivity released into acid soluble products. Using this assay protocol, we could purify six deubiquitinating enzymes from chick skeletal muscle and yeast and compare their specific activities. Since the extracts of E. coli showed little or no activity against the substrate, the assay protocol should be useful for identification and purification of eukaryotic deubiquitinating enzymes cloned and expressed in the cells

CRIM1 is localized to the podocyte filtration slit diaphragm of the adult human kidney

Background. CRIM1 is a plasma membrane bound protein containing six cysteine-rich repeats (CRR). Through these, CRIM1 has been shown to interact with a subgroup of the TGF-β superfamily, the bone morphogenic proteins (BMP) isoforms 2, 4 and 7. The probable action is to modulate the signalling properties of these factors. CRIM1 has also been shown to regulate the release of VEGFA by podocytes during renal organogenesis. Knock-out studies in mice have shown that CRIM1 is critically involved in the development of the central nervous system, eye and kidney. Replacement of CRIM1 with a defective version leads to renal dysgenesis and perinatal death. We have analysed the distribution of CRIM1 in adult human renal tissue

A genome-wide screen for essential yeast genes that affect telomere length maintenance

Telomeres are structures composed of repetitive DNA and proteins that protect the chromosomal ends in eukaryotic cells from fusion or degradation, thus contributing to genomic stability. Although telomere length varies between species, in all organisms studied telomere length appears to be controlled by a dynamic equilibrium between elongating mechanisms (mainly addition of repeats by the enzyme telomerase) and nucleases that shorten the telomeric sequences. Two previous studies have analyzed a collection of yeast deletion strains (deleted for nonessential genes) and found over 270 genes that affect telomere length (Telomere Length Maintenance or TLM genes). Here we complete the list of TLM by analyzing a collection of strains carrying hypomorphic alleles of most essential genes (DAmP collection). We identify 87 essential genes that affect telomere length in yeast. These genes interact with the nonessential TLM genes in a significant manner, and provide new insights on the mechanisms involved in telomere length maintenance. The newly identified genes span a variety of cellular processes, including protein degradation, pre-mRNA splicing and DNA replication