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2.  Short-Term Exposure to Air Pollution and Digital Vascular Function 
American Journal of Epidemiology  2014;180(5):482-489.
We investigated associations between ambient air pollution and microvessel function measured by peripheral arterial tonometry between 2003 and 2008 in the Framingham Heart Study Offspring and Third Generation Cohorts. We measured particulate matter with aerodynamic diameter ≤2.5 µm (PM2.5), black carbon, sulfates, particle number, nitrogen oxides, and ozone by using fixed monitors, and we determined moving averages for 1–7 days preceding vascular testing. We examined associations between these exposures and hyperemic response to ischemia and baseline pulse amplitude, a measure of arterial tone (n = 2,369). Higher short-term exposure to air pollutants, including PM2.5, black carbon, and particle number was associated with higher baseline pulse amplitude. For example, higher 3-day average PM2.5 exposure was associated with 6.3% higher baseline pulse amplitude (95% confidence interval: 2.0, 10.9). However, there were no consistent associations between the air pollution exposures assessed and hyperemic response. Our findings in a community-based sample exposed to relatively low pollution levels suggest that short-term exposure to ambient particulate pollution is not associated with vasodilator response, but that particulate air pollution is associated with baseline pulse amplitude, suggesting potentially adverse alterations in baseline vascular tone or compliance.
PMCID: PMC4143083  PMID: 25100647
air pollutants; endothelium, vascular; particulate matter; vascular diseases
3.  Allergens on Desktop Surfaces in Preschools and Elementary Schools of Urban Children with Asthma 
Allergy  2014;69(7):960-963.
Desktop dust has been studied as a source of food allergen, but not as a source of potential aeroallergen exposure.
36 wiped samples from desktop surfaces were collected from preschools and schools. Samples were analyzed for detectable levels of common aeroallergens including Alternaria, cockroach, dog, dust mite, cat, mouse, and rat allergens by immunoassay.
Mouse allergen was the most prevalent, detectable in 97.2% of samples. Cat allergen was detectable in 80.6% of samples and dog allergen was detectable in 77.8% of samples. Other allergens were not as prevalent. Mouse was the only allergen that was highly correlated with settled floor dust collected from the same rooms (r=0.721, p<0.001).
This is the first study to detect aeroallergens on desktop surfaces by using moist wipes. Allergens for mouse, cat, and dog were highly detectable in wipes with mouse desktop surface levels correlating with levels in vacuumed floor dust.
PMCID: PMC4047193  PMID: 24750034
Allergen; asthma; inner-city children; school; desktop
4.  Systemic inflammation, heart rate variability and air pollution in a cohort of senior adults 
Short-term elevation of ambient particulate air pollution has been associated with autonomic dysfunction and increased systemic inflammation, but the interconnections between these pathways are not well understood. We examined the association between inflammation and autonomic dysfunction and effect modification of inflammation on the association between air pollution and heart rate variability (HRV) in elderly subjects.
25 elderly subjects in Steubenville, Ohio, were followed up to 24 times with repeated 30-min ECG Holter monitoring (545 observations). C-reactive protein (CRP), fibrinogen, interleukin-6 (IL-6), soluble inter-cellular adhesion molecule 1 (sICAM-1), and white blood cell and platelet counts were measured in peripheral blood samples collected in the first month of the study. Increased systemic inflammation was defined for subjects within the upper 20% of the distribution for each marker. A central ambient monitoring station provided daily fine particle (PM2.5) and sulphate (SO42−) data. Linear mixed models were used to identify associations between inflammatory markers and HRV and to assess effect modification of the association between air pollution and HRV due to inflammatory status.
A 5.8 mg/l elevation in CRP was associated with decreases of between −8% and −33% for time and frequency domain HRV outcomes. A 5.1 μg/m3 increase in SO42− on the day before the health assessment was associated with a decrease of −6.7% in the SD of normal RR intervals (SDNN) (95% CI −11.8% to −1.3%) in subjects with elevated CRP, but not in subjects with lower CRP (p value interaction=0.04), with similar findings for PM2.5.
Increased systemic inflammation is associated with autonomic dysfunction in the elderly. Air pollution effects on reduced SDNN are stronger in subjects with elevated systemic inflammation.
PMCID: PMC4472481  PMID: 20519749
5.  Relation of Long-term Exposure to Air Pollution to Brachial Artery Flow-Mediated Dilation and Reactive Hyperemia 
The American journal of cardiology  2014;113(12):2057-2063.
Long-term exposure to ambient air pollution has been associated with cardiovascular morbidity and mortality. Impaired vascular responses may in part explain these findings, but the association of such long-term exposure with measures of both conduit artery and microvascular function have not been widely reported. We evaluated the association between residential proximity to a major roadway (primary or secondary highway) and spatially resolved average fine particulate matter (PM2.5) and baseline brachial artery diameter and mean flow velocity, flow mediated dilation % and hyperemic flow velocity, in the Framingham Offspring and Third Generation Cohorts. We examined 5,112 participants (2,731 (53%) women, mean age 49±14 years). Spatially resolved average PM2.5 was associated with lower flow mediated dilation% and hyperemic flow velocity. An interquartile range difference in PM2.5 (1.99 μg/m3) was associated with −0.16% (95%CI: −0.27%, −0.05%) lower FMD% and −0.72 (95%CI: −1.38, −0.06) cm/s lower hyperemic flow velocity %. Residential proximity to a major roadway was negatively associated with flow mediated dilation %. Compared to living ≥400 m away, living <50 m from a major roadway was associated with 0.32% lower flow mediated dilation (95% confidence interval (CI): −0.58%, −0.06%), but results for hyperemic flow velocity had wide confidence intervals −0.68 cm/s (95%CI: −2.29, 0.93). In conclusion, residential proximity to a major roadway and higher levels of spatially resolved estimates of PM2.5 at participant residences are associated with impaired conduit artery and microvascular function in this large community-based cohort of middle-aged and elderly adults.
PMCID: PMC4066389  PMID: 24793676
Air Pollution; Brachial Artery; Microvessels; Endothelium; Vascular
6.  Effects of Ambient Coarse, Fine, and Ultrafine Particles and Their Biological Constituents on Systemic Biomarkers: A Controlled Human Exposure Study 
Environmental Health Perspectives  2015;123(6):534-540.
Ambient coarse, fine, and ultrafine particles have been associated with mortality and morbidity. Few studies have compared how various particle size fractions affect systemic biomarkers.
We examined changes of blood and urinary biomarkers following exposures to three particle sizes.
Fifty healthy nonsmoking volunteers, mean age of 28 years, were exposed to coarse (2.5–10 μm; mean, 213 μg/m3) and fine (0.15–2.5 μm; mean, 238 μg/m3) concentrated ambient particles (CAPs), and filtered ambient and/or medical air. Twenty-five participants were exposed to ultrafine CAP (< 0.3 μm; mean, 136 μg/m3) and filtered medical air. Exposures lasted 130 min, separated by ≥ 2 weeks. Blood/urine samples were collected preexposure and 1 hr and 21 hr postexposure to determine blood interleukin-6 and C-reactive protein (inflammation), endothelin-1 and vascular endothelial growth factor (VEGF; vascular mediators), and malondialdehyde (lipid peroxidation); as well as urinary VEGF, 8-hydroxy-deoxy-guanosine (DNA oxidation), and malondialdehyde. Mixed-model regressions assessed pre- and postexposure differences.
One hour postexposure, for every 100-μg/m3 increase, coarse CAP was associated with increased blood VEGF (2.41 pg/mL; 95% CI: 0.41, 4.40) in models adjusted for O3, fine CAP with increased urinary malondialdehyde in single- (0.31 nmol/mg creatinine; 95% CI: 0.02, 0.60) and two-pollutant models, and ultrafine CAP with increased urinary 8-hydroxydeoxyguanosine in single- (0.69 ng/mg creatinine; 95% CI: 0.09, 1.29) and two-pollutant models, lasting < 21 hr. Endotoxin was significantly associated with biomarker changes similar to those found with CAPs.
Ambient particles with various sizes/constituents may influence systemic biomarkers differently. Endotoxin in ambient particles may contribute to vascular mediator changes and oxidative stress.
Liu L, Urch B, Poon R, Szyszkowicz M, Speck M, Gold DR, Wheeler AJ, Scott JA, Brook JR, Thorne PS, Silverman FS. 2015. Effects of ambient coarse, fine, and ultrafine particles and their biological constituents on systemic biomarkers: a controlled human exposure study. Environ Health Perspect 123:534–540;
PMCID: PMC4455587  PMID: 25616223
7.  β-2 adrenergic receptor gene methylation is associated with decreased asthma severity in Inner-City School Children 
Genetic variation in the β-2 adrenergic receptor gene (ADRB2) has been implicated in asthma severity and control with conflicting results. Epigenetic variation in the β-2 adrenergic receptor gene (ADRB2) may play an important role in asthma phenotype.
We aimed to evaluate whether DNA methylation of ADRB2 is associated with asthma phenotypes in inner city school aged children.
Multiple CpG sites in the promoter region of ADRB2 gene were analyzed in 177 children enrolled in the School Inner-City Asthma Study (SICAS). Blood or saliva-derived DNA was measured by bisulfite-polymerase chain reaction pyrosequencing assay. Average percent DNA methylation across the sites was evaluated for association with asthma severity (report of dyspnea, nighttime symptoms, rescue medication use, and baseline spirometry) and morbidity (school absences and unscheduled healthcare visits). Three clades composed of highly correlated methylation sites within the methylated segment of ADRB2 were further analyzed.
Methylation of individual sites generally ranged from 0 – 6% with average percent methylation across sites of 2.4%. Univariate analyses strongly favored the association of higher percent methylation with lower asthma severity measured by report of dyspnea. Furthermore, there was a non-significant trend toward less rescue medication use, nighttime symptoms, school absences, activity limitation due to asthma, and improved lung function measurements with increased methylation. Multivariate analysis demonstrated methylation of ADRB2 gene significantly associated with less dyspnea (odds ratio (OR) 0.2, 95%confidence interval (CI), 0.1 – 0.6, P = 0.002). Each of the 3 clades of methylation sites showed a strong, but not statistically significant, effect on decreased dyspnea.
Conclusions and Clinical Relevance
DNA methylation in the ADRB2 gene is associated with decreased asthma symptom severity, suggesting a role for methylation in asthma phenotypes.
PMCID: PMC3989375  PMID: 24131275
8.  Peanut, milk, and wheat intake during pregnancy is associated with reduced allergy and asthma in children 
Maternal diet during pregnancy may influence childhood allergy and asthma.
To examine the associations between maternal intake of common childhood food allergens during early pregnancy and childhood allergy and asthma.
We studied 1277 mother-child pairs from a United States pre-birth cohort unselected for any disease. Using food frequency questionnaires administered during the first and second trimesters, we assessed maternal intake of common childhood food allergens during pregnancy. In mid-childhood (mean age 7.9 years), we assessed food allergy, asthma, allergic rhinitis, and atopic dermatitis by questionnaire and serum specific IgE levels. We examined the associations between maternal diet during pregnancy and childhood allergy and asthma. We also examined the cross-sectional associations between specific food allergies, asthma, and atopic conditions in mid-childhood.
Food allergy was common (5.6%) in mid-childhood, as was sensitization to at least one food allergen (28.0%). Higher maternal peanut intake (each additional z-score) during the first trimester was associated with 47% reduced odds of peanut allergic reaction (OR 0.53, 95%CI 0.30–0.94). Higher milk intake during the first trimester was associated with reduced asthma (OR 0.83, 95%CI 0.69–0.99) and allergic rhinitis (OR 0.85, 95%CI 0.74–0.97). Higher maternal wheat intake during the second trimester was associated with reduced atopic dermatitis (OR 0.64, 95%CI 0.46–0.90). Peanut, wheat, and soy allergy were each cross-sectionally associated with increased childhood asthma, atopic dermatitis, and allergic rhinitis (ORs 3.6 to 8.1).
Higher maternal intake of peanut, milk, and wheat during early pregnancy was associated with reduced odds of mid-childhood allergy and asthma.
PMCID: PMC4004710  PMID: 24522094
maternal diet; pregnancy; food allergy; sensitization; asthma; allergic rhinitis; peanut; milk; wheat; childhood
9.  Maternal intake of vitamin D during pregnancy and risk of recurrent wheeze in children at 3 y of age1–3 
Vitamin D deficiency and asthma are common at higher latitudes. Although vitamin D has important immunologic effects, its relation with asthma is unknown.
We hypothesized that a higher maternal intake of vitamin D during pregnancy is associated with a lower risk of recurrent wheeze in children at 3 y of age.
The participants were 1194 mother-child pairs in Project Viva—a prospective prebirth cohort study in Massachusetts. We assessed the maternal intake of vitamin D during pregnancy from a validated food-frequency questionnaire. The primary outcome was recurrent wheeze, ie, a positive asthma predictive index (≥2 wheezing attacks among children with a personal diagnosis of eczema or a parental history of asthma).
The mean (±SD) total vitamin D intake during pregnancy was 548 ± 167 IU/d. By age 3 y, 186 children (16%) had recurrent wheeze. Compared with mothers in the lowest quartile of daily intake (median: 356 IU), those in the highest quartile (724 IU) had a lower risk of having a child with recurrent wheeze [odds ratio (OR): 0.39; 95% CI: 0.25, 0.62; P for trend <0.001]. A 100-IU increase in vitamin D intake was associated with lower risk (OR: 0.81; 95% CI: 0.74, 0.89), regardless of whether vitamin D was from the diet (OR: 0.81; 95% CI: 0.69, 0.96) or supplements (OR: 0.82; 95% CI: 0.73, 0.92). Adjustment for 12 potential confounders, including maternal intake of other dietary factors, did not change the results.
In the northeastern United States, a higher maternal intake of vitamin D during pregnancy may decrease the risk of recurrent wheeze in early childhood.
PMCID: PMC4406411  PMID: 17344501
Vitamin D; pregnancy; dietary intake; childhood wheeze; asthma
10.  Prenatal Air Pollution Exposure and Newborn Blood Pressure 
Environmental Health Perspectives  2015;123(4):353-359.
Air pollution exposure has been associated with increased blood pressure in adults.
We examined associations of antenatal exposure to ambient air pollution with newborn systolic blood pressure (SBP).
We studied 1,131 mother–infant pairs in a Boston, Massachusetts, area pre-birth cohort. We calculated average exposures by trimester and during the 2 to 90 days before birth for temporally resolved fine particulate matter (≤ 2.5 μm; PM2.5), black carbon (BC), nitrogen oxides, nitrogen dioxide, ozone (O3), and carbon monoxide measured at stationary monitoring sites, and for spatiotemporally resolved estimates of PM2.5 and BC at the residence level. We measured SBP at a mean age of 30 ± 18 hr with an automated device. We used mixed-effects models to examine associations between air pollutant exposures and SBP, taking into account measurement circumstances; child’s birth weight; mother’s age, race/ethnicity, socioeconomic position, and third-trimester BP; and time trend. Estimates represent differences in SBP associated with an interquartile range (IQR) increase in each pollutant.
Higher mean PM2.5 and BC exposures during the third trimester were associated with higher SBP (e.g., 1.0 mmHg; 95% CI: 0.1, 1.8 for a 0.32-μg/m3 increase in mean 90-day residential BC). In contrast, O3 was negatively associated with SBP (e.g., –2.3 mmHg; 95% CI: –4.4, –0.2 for a 13.5-ppb increase during the 90 days before birth).
Exposures to PM2.5 and BC in late pregnancy were positively associated with newborn SBP, whereas O3 was negatively associated with SBP. Longitudinal follow-up will enable us to assess the implications of these findings for health during later childhood and adulthood.
van Rossem L, Rifas-Shiman SL, Melly SJ, Kloog I, Luttmann-Gibson H, Zanobetti A, Coull BA, Schwartz JD, Mittleman MA, Oken E, Gillman MW, Koutrakis P, Gold DR. 2015. Prenatal air pollution exposure and newborn blood pressure. Environ Health Perspect 123:353–359;
PMCID: PMC4384198  PMID: 25625652
11.  Associations between arrhythmia episodes and temporally and spatially resolved black carbon and particulate matter in elderly patients 
Ambient air pollution has been associated with sudden deaths, some of which are likely due to ventricular arrhythmias. Defibrillator discharge studies have examined the association of air pollution with arrhythmias in sensitive populations. No studies have assessed this association using residence-specific estimates of air pollution exposure.
In the Normative Aging Study, we investigated the association between temporally-and spatially-resolved black carbon (BC) and PM2.5 and arrhythmia episodes (bigeminy, trigeminy or couplets episodes) measured as ventricular ectopy (VE) by 4-min electrocardiogram (ECG) monitoring in repeated measures of 701 subjects, during the years 2000 to 2010.
We used a binomial distribution (having or not a VE episode) in a mixed effect model with a random intercept for subject, controlling for seasonality, temperature, day of the week, medication use, smoking, having diabetes, BMI and age. We also examined whether these associations were modified by genotype or phenotype.
We found significant increases in VE with both pollutants and lags; for the estimated concentration averaged over the three days prior to the health assessment we found increases in the odds of having VE with an OR of 1.52 (95% CI: 1.19–1.94) for an IQR (0.30 μg/m3) increase in BC and an OR of 1.39 (95% CI: 1.12–1.71) for an IQR (5.63 μg/m3) increase in PM2.5. We also found higher effects in subjects with the GSTT1 and GSTM1 variants and in obese (P-values<0.05).
Increased levels of short-term traffic related pollutants may increase the risk of ventricular arrhythmia in elderly subjects.
PMCID: PMC4371778  PMID: 24142987
arrhythmia episodes; spatially-resolved black carbon and particulate matter; traffic pollution; elderly
12.  Associations of cord blood fatty acids with lymphocyte proliferation, IL-13, and IFN-γ 
Background. N-3 and n-6 polyunsaturated fatty acids (PUFAs) have been hypothesized to have opposing influences on neonatal immune responses that might influence the risk of allergy or asthma. However, both n-3 eicosapentaenoic acid (EPA) and n-6 arachidonic acid (AA) are required for normal fetal development.
Objective. We evaluated whether cord blood fatty acid levels were related to neonatal immune responses and whether n-3 and n-6 PUFA responses differed.
Methods. We examined the relation of cord blood plasma n-3 and n-6 PUFAs (n = 192) to antigen- and mitogen-stimulated cord blood lymphocyte proliferation (n = 191) and cytokine (IL-13 and IFN-γ; n = 167) secretion in a US birth cohort.
Results. Higher levels of n-6 linoleic acid were correlated with higher IL-13 levels in response to Bla g 2 (cockroach, P = .009) and Der f 1 (dust mite, P = .02). Higher n-3 EPA and n-6 AA levels were each correlated with reduced lymphocyte proliferation and IFN-γ levels in response to Bla g 2 and Der f 1 stimulation. Controlling for potential confounders, EPA and AA had similar independent effects on reduced allergen-stimulated IFN-γ levels. If neonates had either EPA or AA levels in the highest quartile, their Der f 1 IFN-γ levels were 90% lower (P = .0001) than those with both EPA and AA levels in the lowest 3 quartiles. Reduced AA/EPA ratio was associated with reduced allergen-stimulated IFN-γ level.
Conclusion. Increased levels of fetal n-3 EPA and n-6 AA might have similar effects on attenuation of cord blood lymphocyte proliferation and IFN-γ secretion.
Clinical implications. The implications of these findings for
PMCID: PMC1508138  PMID: 16630954
Asthma; child; cord blood; cytokine; fatty acids; lymphocyte proliferation; AA: Arachidonic acid; BMI: Body mass index; CBMC: Cord blood mononuclear cell; CI: Confidence interval; DHA: Docosohexaenoic acid; EPA: Eicosapentaenoic acid; FA: Fatty acid; LA: Linoleic acid; NICU: Neonatal intensive care unit; OVA: Ovalbumin; PG: Prostaglandin; PUFA: Polyunsaturated fatty acid; SI: Stimulation index
13.  Perceived Neighborhood Safety and Asthma Morbidity in the School Inner-City Asthma Study 
Pediatric pulmonology  2014;50(1):17-24.
Aim: The aim of this study was to investigate whether neighborhood safety as perceived by primary caregivers is associated with asthma morbidity outcomes among inner-city school children with asthma. Methods: School children with asthma were recruited from 25 inner-city schools between 2009 and 2012 for the School Inner-City Asthma Study (N = 219). Primary caregivers completed a baseline questionnaire detailing their perception of neighborhood safety and their children’s asthma symptoms, and the children performed baseline pulmonary function tests. In this cross-sectional analysis, asthma control was compared between children whose caregivers perceived their neighborhood to be unsafe versus safe. Results: After adjusting for potential confounders, those children whose primary caregivers perceived the neighborhood to be unsafe had twice the odds of having poorly controlled asthma (odds ratio [OR] adjusted = 2.2, 95% confidence interval [CI] = 1.2–3.9, P = 0.009), four times the odds of dyspnea and rescue medication use (OR adjusted = 4.7; 95% CI = 1.7–13.0, P = 0.003, OR adjusted = 4.0; 95% CI = 1.8–8.8, P < 0.001, respectively), three times as much limitation in activity (OR adjusted = 3.2; 95% CI = 1.4–7.7, P = 0.008), and more than twice the odds of night-time symptoms (OR adjusted = 2.2; 95% CI = 1.3–4.0, P = 0.007) compared to participants living in safe neighborhoods. There was no difference in pulmonary function test results between the two groups. Conclusions: Primary caregivers’ perception of neighborhood safety is associated with childhood asthma morbidity among inner-city school children with asthma. Further study is needed to elucidate mechanisms behind this association, and future intervention studies to address social disadvantage may be important.
PMCID: PMC4096619  PMID: 24421055
asthma; pediatrics; inner-city; socioeconomic factors; stress; psychological; disparities
14.  Short-Term Exposure to Air Pollution and Lung Function in the Framingham Heart Study 
Rationale: Short-term exposure to ambient air pollution has been associated with lower lung function. Few studies have examined whether these associations are detectable at relatively low levels of pollution within current U.S. Environmental Protection Agency (EPA) standards.
Objectives: To examine exposure to ambient air pollutants within EPA standards and lung function in a large cohort study.
Methods: We included 3,262 participants of the Framingham Offspring and Third Generation cohorts living within 40 km of the Harvard Supersite monitor in Boston, Massachusetts (5,358 examinations, 1995–2011) who were not current smokers, with previous-day pollutant levels in compliance with EPA standards. We compared lung function (FEV1 and FVC) after previous-day exposure to particulate matter less than 2.5 μm in diameter (PM2.5), nitrogen dioxide (NO2), and ozone (O3) in the “moderate” range of the EPA Air Quality Index to exposure in the “good” range. We also examined linear relationships between moving averages of pollutant concentrations 1, 2, 3, 5, and 7 days before spirometry and lung function.
Measurements and Main Results: Exposure to pollutant concentrations in the “moderate” range of the EPA Air Quality Index was associated with a 20.1-ml lower FEV1 for PM2.5 (95% confidence interval [CI], −33.4, −6.9), a 30.6-ml lower FEV1 for NO2 (95% CI, −60.9, −0.2), and a 55.7-ml lower FEV1 for O3 (95% CI, −100.7, −10.8) compared with the “good” range. The 1- and 2-day moving averages of PM2.5, NO2, and O3 before testing were negatively associated with FEV1 and FVC.
Conclusions: Short-term exposure to PM2.5, NO2, and O3 within current EPA standards was associated with lower lung function in this cohort of adults.
PMCID: PMC3919078  PMID: 24200465
chronic obstructive pulmonary disease; asthma; air pollutants; U.S. Environmental Protection Agency
15.  Longitudinal Relationship of Early-Life Immunomodulatory T-cell Phenotype and Function to Development of Allergic Sensitization in an Urban Cohort 
Immunomodulatory T-cells are thought to influence development of allergy and asthma, but early-life longitudinal data on their phenotype and function are lacking.
As part of the Urban Environment and Childhood Asthma (URECA) study, we investigated the development of immunomodulatory T-cell phenotype and function, and characterized their relation to allergic disease progression from birth through to age two years.
Immunomodulatory T-cell phenotype and function in cord blood mononuclear cells and peripheral blood mononuclear cells at age 1 and 2 years were characterized by analyzing CD25bright and FoxP3+ expression; proliferative responses and cytokine production. The relation of immunomodulatory T-cell characteristics to allergic sensitization and disease at 1- and 2-years was investigated.
The proportion of CD4+CD25bright and CD4+CD25+FoxP3+ T-cells (n=114, 83, 82 at birth, 1- and 2-years respectively) increased significantly, while there were no significant changes in the suppressive function of CD25+ T-cells (n=78, 71, 81 at birth, 1- and 2-years respectively). Birth immunomodulatory T-cell characteristics were not related to subsequent allergic sensitization or disease. However, increases in the numbers of CD4+CD25bright cells and their ability to suppress lymphoproliferative responses at 1 year of age were associated with reduced allergic sensitization at ages 1 (p<0.03) and 2 (p<0.02) years. Production of the anti-inflammatory cytokine IL-10 by CD25+ T-cells appeared to mediate this protective suppressive function. In contrast, by two years of age, we observed the emergence of a positive association of CD4+CD25+FoxP3+ T-cell numbers with allergic sensitization (p=0.05) and eczema (p=0.02).
Conclusions and Clinical Relevance
These findings suggest that the relationship between immunomodulatory T-cell subsets, allergic sensitization, and eczema is developmentally regulated. In the first year of life CD4+CD25+ IL-10 producing T-cells are associated with a reduced incidence of allergic sensitization. Once allergic sensitization or eczema are established, CD4+CD25+FoxP3+ T-reg cell expand to potentially counteract the allergic inflammatory response. Understanding the relationship between development of immunoregulatory T cells and early-onset atopy could lead to new preventive strategies for allergic diseases.
PMCID: PMC4162345  PMID: 22092655
T regulatory cells; asthma; allergy; IL-10; newborn; suppressive index; toddler; CD4+CD25+FoxP3+
16.  Diagnostic accuracy of the bronchodilator response in children 
The bronchodilator response (BDR) reflects the reversibility of airflow obstruction and is recommended as an adjunctive test to diagnose asthma. The validity of the commonly used definition of BDR, a 12% or greater change in FEV1 from baseline, has been questioned in childhood.
We sought to examine the diagnostic accuracy of the BDR test by using 3 large pediatric cohorts.
Cases include 1041 children with mild-to-moderate asthma from the Childhood Asthma Management Program.
Control subjects (nonasthmatic and nonwheezing) were chosen from Project Viva and Home Allergens, 2 population-based pediatric cohorts. Receiver operating characteristic curves were constructed, and areas under the curve were calculated for different BDR cutoffs.
A total of 1041 cases (59.7% male; mean age, 8.9 ± 2.1 years) and 250 control subjects (46.8% male; mean age, 8.7 ± 1.7 years) were analyzed, with mean BDRs of 10.7% ± 10.2% and 2.7% ± 8.4%, respectively. The BDR test differentiated asthmatic patients from nonasthmatic patients with a moderate accuracy (area under the curve, 73.3%).
Despite good specificity, a cutoff of 12% was associated with poor sensitivity (35.6%). A cutoff of less than 8% performed significantly better than a cutoff of 12% (P = .03, 8% vs 12%).
Our findings highlight the poor sensitivity associated with the commonly used 12% cutoff for BDR. Although our data show that a threshold of less than 8% performs better than 12%, given the variability of this test in children, we conclude that it might be not be appropriate to choose a specific BDR cutoff as a criterion for the diagnosis of asthma.
PMCID: PMC3759549  PMID: 23683464
Asthma; bronchodilator response; diagnosis
17.  Acute Exposure to Air Pollution Triggers Atrial Fibrillation 
The aim of the present study is to evaluate the association of air pollution with the onset of atrial fibrillation (AF).
Air pollution in general and more specifically particulate matter has been associated with cardiovascular events. Although ventricular arrhythmias are traditionally thought to convey the increased cardiovascular risk, AF may also contribute.
Patients with dual chamber implantable cardioverter defibrillators (ICDs) were enrolled and followed prospectively. The association of AF onset with air quality including ambient PM2.5, black carbon, sulfate, particle number, NO2, SO2, and O3 in the 24 hours prior to the arrhythmia was examined utilizing a case-crossover analysis. In sensitivity analyses, associations with air pollution between 2 and 48 hours prior to the AF were examined.
Of 176 patients followed for an average of 1.9 years, 49 patients had 328 episodes of AF lasting ≥ 30 seconds. Positive but nonsignificant associations were found for PM2.5 in the prior 24 hours, but stronger associations were found with shorter exposure windows. The odds of AF increased by 26% (95% CI 8% to 47%) for each 6.0 µg/m3 increase in PM2.5 in the 2 hours prior to the event (p=0.004). The odds of AF was highest at the upper quartile of mean PM2.5.
Particulate matter was associated with increased odds of AF onset within hours following exposure in patients with known cardiac disease. Air pollution is an acute trigger of AF, likely contributing to the pollution-associated adverse cardiac outcomes observed in epidemiological studies.
PMCID: PMC3752319  PMID: 23770178
Air pollution; Atrial fibrillation; Particulate matter; Traffic
18.  Air Pollution Exposure and Abnormal Glucose Tolerance during Pregnancy: The Project Viva Cohort 
Environmental Health Perspectives  2014;122(4):378-383.
Background: Exposure to fine particulate matter (PM with diameter ≤ 2.5 μm; PM2.5) has been linked to type 2 diabetes mellitus, but associations with hyperglycemia in pregnancy have not been well studied.
Methods: We studied Boston, Massachusetts–area pregnant women without known diabetes. We identified impaired glucose tolerance (IGT) and gestational diabetes mellitus (GDM) during pregnancy from clinical glucose tolerance tests at median 28.1 weeks gestation. We used residential addresses to estimate second-trimester PM2.5 and black carbon exposure via a central monitoring site and spatiotemporal models. We estimated residential traffic density and roadway proximity as surrogates for exposure to traffic-related air pollution. We performed multinomial logistic regression analyses adjusted for sociodemographic covariates, and used multiple imputation to account for missing data.
Results: Of 2,093 women, 65 (3%) had IGT and 118 (6%) had GDM. Second-trimester spatiotemporal exposures ranged from 8.5 to 15.9 μg/m3 for PM2.5 and from 0.1 to 1.7 μg/m3 for black carbon. Traffic density was 0–30,860 vehicles/day × length of road (kilometers) within 100 m; 281 (13%) women lived ≤ 200 m from a major road. The prevalence of IGT was elevated in the highest (vs. lowest) quartile of exposure to spatiotemporal PM2.5 [odds ratio (OR) = 2.63; 95% CI: 1.15, 6.01] and traffic density (OR = 2.66; 95% CI: 1.24, 5.71). IGT also was positively associated with other exposure measures, although associations were not statistically significant. No pollutant exposures were positively associated with GDM.
Conclusions: Greater exposure to PM2.5 and other traffic-related pollutants during pregnancy was associated with IGT but not GDM. Air pollution may contribute to abnormal glycemia in pregnancy.
Citation: Fleisch AF, Gold DR, Rifas-Shiman SL, Koutrakis P, Schwartz JD, Kloog I, Melly S, Coull BA, Zanobetti A, Gillman MW, Oken E. 2014. Air pollution exposure and abnormal glucose tolerance during pregnancy: the Project Viva Cohort. Environ Health Perspect 122:378–383;
PMCID: PMC3984217  PMID: 24508979
19.  Brachial Artery Responses to Ambient Pollution, Temperature, and Humidity in People with Type 2 Diabetes: A Repeated-Measures Study 
Environmental Health Perspectives  2014;122(3):242-248.
Background: Extreme weather and air pollution are associated with increased cardiovascular risk in people with diabetes.
Objectives: In a population with diabetes, we conducted a novel assessment of vascular brachial artery responses both to ambient pollution and to weather (temperature and water vapor pressure, a measure of humidity).
Methods: Sixty-four 49- to 85-year-old Boston residents with type 2 diabetes completed up to five study visits (279 repeated measures). Brachial artery diameter (BAD) was measured by ultrasound before and after brachial artery occlusion [i.e., flow-mediated dilation (FMD)] and before and after nitroglycerin-mediated dilation (NMD). Ambient concentrations of fine particulate mass (PM2.5), black carbon (BC), organic carbon (OC), elemental carbon, particle number, and sulfate were measured at our monitoring site; ambient concentrations of carbon monoxide, nitrogen dioxide, and ozone were obtained from state monitors. Particle exposure in the home and during each trip to the clinic (home/trip exposure) was measured continuously and as a 5-day integrated sample. We used linear models with fixed effects for participants, adjusting for date, season, temperature, and water vapor pressure on the day of each visit, to estimate associations between our outcomes and interquartile range increases in exposure.
Results: Baseline BAD was negatively associated with particle pollution, including home/trip–integrated BC (–0.02 mm; 95% CI: –0.04, –0.003, for a 0.28 μg/m3 increase in BC), OC (–0.08 mm; 95% CI: –0.14, –0.03, for a 1.61 μg/m3 increase) as well as PM2.5, 5-day average ambient PM2.5, and BC. BAD was positively associated with ambient temperature and water vapor pressure. However, exposures were not consistently associated with FMD or NMD.
Conclusion: Brachial artery diameter, a predictor of cardiovascular risk, decreased in association with particle pollution and increased in association with ambient temperature in our study population of adults with type 2 diabetes.
Citation: Zanobetti A, Luttmann-Gibson H, Horton ES, Cohen A, Coull BA, Hoffmann B, Schwartz JD, Mittleman MA, Li Y, Stone PH, de Souza C, Lamparello B, Koutrakis P, Gold DR. 2014. Brachial artery responses to ambient pollution, temperature, and humidity in people with type 2 diabetes: a repeated-measures study. Environ Health Perspect 122:242–248;
PMCID: PMC3948021  PMID: 24398072
20.  Short-Term Changes in Ambient Temperature and Risk of Ischemic Stroke 
Despite consistent evidence of a higher short-term risk of cardiovascular mortality associated with ambient temperature, there have been discrepant findings on the association between temperature and ischemic stroke. Moreover, few studies have considered potential confounding by ambient fine particulate matter air pollution <2.5 μm in diameter (PM2.5) and none have examined the impact of temperature changes on stroke in the subsequent hours rather than days. The aim of this study was to evaluate whether changes in temperature trigger an ischemic stroke in the following hours and days and whether humid days are particularly harmful.
We reviewed the medical records of 1,705 patients residing in the metropolitan region of Boston, Mass., USA, who were hospitalized with neurologist-confirmed ischemic stroke, and we abstracted data on the time of symptom onset and clinical characteristics. We obtained hourly meteorological data from the National Weather Service station and hourly PM2.5 data from the Harvard ambient monitoring station. We used the time-stratified case-crossover design to assess the association between ischemic stroke and apparent temperature averaged over 1-7 days prior to stroke onset adjusting for PM2.5. We assessed whether differences in apparent temperature trigger a stroke within shorter time periods by examining the association between stroke onset and apparent temperature levels averaged in 2-hour increments prior to stroke onset (0-2 h through 36-38 h). We tested whether the association varied by health characteristics or by PM2.5, ozone or relative humidity.
The incidence rate ratio of ischemic stroke was 1.09 (95% confidence interval 1.01-1.18) following a 5°C decrement in average apparent temperature over the 2 days preceding symptom onset. The higher risk associated with cooler temperatures peaked in the first 14-34 h. There was no statistically significant difference in the association between temperature and ischemic stroke across seasons. The risk of ischemic stroke was not meaningfully different across subgroups of patients defined by health characteristics. The association between ischemic stroke and ambient temperature was stronger on days with higher levels of relative humidity.
Lower temperatures are associated with a higher risk of ischemic stroke onset in both warm and cool seasons, and the risk is higher on days with higher levels of relative humidity. Based on this study and the body of literature on ambient temperature and cardiovascular events, identifying methods for mitigating cardiovascular risk may be warranted.
PMCID: PMC3934677  PMID: 24575110
Ischemic stroke; Environment; Particulate matter; Epidemiology

21.  Food Allergy and Increased Asthma Morbidity in a School-Based Inner-City Asthma Study 
Children with asthma have increased prevalence of food allergies. The relationship between food allergy and asthma morbidity is unclear.
We aimed to investigate the presence of food allergy as an independent risk factor for increased asthma morbidity using the School Inner-City Asthma (SICAS), a prospective study evaluating risk factors and asthma morbidity among urban children.
We prospectively surveyed 300 children from inner-city schools with physician-diagnosed asthma, followed by clinical evaluation. Food allergies were reported including symptoms experienced within one hour of food ingestion. Asthma morbidity, pulmonary function, and resource utilization were compared between children with food allergies and without.
Seventy-three (24%) of 300 asthmatic children surveyed had physician- diagnosed food allergy, and 36 (12%) had multiple food allergies. Those with any food allergy independently had increased risk of hospitalization (OR: 2.35, 95% CI: 1.30–4.24, p=0.005), and use of controller medication (OR: 1.99, 95% CI: 1.06–3.74, p=0.03). Those with multiple food allergies also had an independently higher risk of hospitalization in the past year (OR: 4.10 95% CI: 1.47–11.45, p=0.007), asthma-related hospitalization (OR: 3.52, 95% CI: 1.12–11.03, p=0.03), controller medication use (OR: 2.38 95% CI: 1.00–5.66, p=0.05), and more provider visits (median 4.5 versus 3.0, p=0.008). Furthermore, lung function was significantly lower (% predicted FEV1 and FEV1/FVC ratios) in both food allergy category groups.
Food allergy is highly prevalent in inner-city school-aged children with asthma. Children with food allergies have increased asthma morbidity and health resource utilization with decreased lung function, and this association is stronger in those with multiple food allergies.
PMCID: PMC3777668  PMID: 24058900
asthma; food allergy; hospitalization; morbidity; prevalence; resource utilization; risk
23.  Exposures to Molds in School Classrooms of Children with Asthma 
Students spend a large portion of their day in classrooms which may be a source of mold exposure. We examined the diversity and concentrations of molds in inner-city schools and described differences between classrooms within the same school.
Classroom airborne mold spores, collected over a 2 day period, were measured twice during the school year by direct microscopy.
There were 180 classroom air samples collected from 12 schools. Mold was present in 100% of classrooms. Classrooms within the same school had differing mold levels and mold diversity scores. The total mold per classroom was 176.6 ± 4.2 spores/m3 (geometric mean ± standard deviation) and ranged from 11.2 to 16,288.5 spores/m3. Mold diversity scores for classroom samples ranged from 1 to 19 (7.7 ± 3.5). The classroom accounted for the majority of variance (62%) in the total mold count, and for the majority of variance (56%) in the mold diversity score versus the school. The species with the highest concentrations and found most commonly included Cladosporium (29.3 ± 4.2 spores/m3), Penicillium/Aspergillus (15.0 ± 5.4 spores/m3), smut spores (12.6 ± 4.0 spores/m3), and basidiospores (6.6 ± 7.1 spores/m3).
Our study found that the school is a source of mold exposure, but particularly the classroom microenvironment varies in quantity of spores and species among classrooms within the same school. We also verified that visible mold may be a predictor for higher mold spore counts. Further studies are needed to determine the clinical significance of mold exposure relative to asthma morbidity in sensitized and non-sensitized asthmatic children.
PMCID: PMC3782748  PMID: 24112429
Asthma; children; fungus; inner-city; mold; school
24.  Allergens in Urban Schools and Homes of Children with Asthma 
Most studies of indoor allergens have focused on the home environment. However, schools may be an important site of allergen exposure for children with asthma. We compared school allergen exposure to home exposure in a cohort of children with asthma. Correlations between settled dust and airborne allergen levels in classrooms were examined.
Settled dust and airborne samples from 12 inner-city schools were analyzed for indoor allergens using multiplex array technology (MARIA). School samples were linked to students with asthma enrolled in the School Inner-City Asthma Study (SICAS). Settled dust samples from students’ bedrooms were analyzed similarly.
From schools, 229 settled dust and 197 airborne samples were obtained. From homes, 118 settled dust samples were obtained. Linear mixed regression models of log-transformed variables showed significantly higher settled dust levels of mouse, cat and dog allergens in schools than homes (545% higher for Mus m 1, estimated absolute difference 0.55 μg/g, p<0.0001; 198% higher for Fel d 1, estimated absolute difference 0.13 μg/g, p=0.0033; and 144% higher for Can f 1, estimated absolute difference 0.05 μg/g, p=0.0008). Airborne and settled dust Mus m 1 levels in classrooms were moderately correlated (r=0.48; p< 0.0001). There were undetectable to very low levels of cockroach and dust mite allergens in both homes and schools.
Mouse allergen levels in schools were substantial. In general, cat and dog allergen levels were low, but detectable, and were higher in schools. Aerosolization of mouse allergen in classrooms may be a significant exposure for students. Further studies are needed to evaluate the effect of indoor allergen exposure in schools on asthma morbidity in students with asthma.
PMCID: PMC3424376  PMID: 22672325
indoor allergens; asthma; inner city; urban; mouse; Mus m 1; Can f 1; Fel d 1; SICAS; school
25.  Modeling the Association Between Particle Constituents of Air Pollution and Health Outcomes 
American Journal of Epidemiology  2012;176(4):317-326.
There is increasing interest in evaluating the association between specific fine-particle (particles with aerodynamic diameters less than 2.5 µm; PM2.5) constituents and adverse health outcomes rather than focusing solely on the impact of total PM2.5. Because PM2.5 may be related to both constituent concentration and health outcomes, constituents that are more strongly correlated with PM2.5 may appear more closely related to adverse health outcomes than other constituents even if they are not inherently more toxic. Therefore, it is important to properly account for potential confounding by PM2.5 in these analyses. Usually, confounding is due to a factor that is distinct from the exposure and outcome. However, because constituents are a component of PM2.5, standard covariate adjustment is not appropriate. Similar considerations apply to source-apportioned concentrations and studies assessing either short-term or long-term impacts of constituents. Using data on 18 constituents and data from 1,060 patients admitted to a Boston medical center with ischemic stroke in 2003–2008, the authors illustrate several options for modeling the association between constituents and health outcomes that account for the impact of PM2.5. Although the different methods yield results with different interpretations, the relative rankings of the association between constituents and ischemic stroke were fairly consistent across models.
PMCID: PMC3491968  PMID: 22850792
case crossover; epidemiology; ischemic stroke; particle constituents; particulate matter; stroke

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