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1.  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
2.  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
3.  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
4.  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+
5.  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
6.  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
7.  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
8.  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
9.  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

10.  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
12.  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
13.  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
14.  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
15.  Exposure to dust mite allergen and endotoxin in early life and asthma and atopy in childhood 
There has been no longitudinal study of the relation between concurrent exposure to dust mite allergen and endotoxin in early life and asthma and atopy at school age.
To examine the relation between exposure to dust mite allergen and endotoxin at age 2 to 3 months and asthma, wheeze, and atopy in high-risk children.
Birth cohort study of 440 children with parental history of atopy in the Boston metropolitan area.
In multivariate analyses, early exposure to high levels of dust mite allergen (≥10 μg/g) was associated with increased risks of asthma at age 7 years (odds ratio [OR], 3.0; 95% CI, 1.1-7.9) and late-onset wheeze (OR, 5.0; 95% CI, 1.5-16.4). Exposure to endotoxin levels above the lowest quartile at age 2 to 3 months was associated with reduced odds of atopy at school age (OR, 0.5; 95% CI, 0.2-0.9). In contrast with its inverse association with atopy, endotoxin exposure in early life was associated with an increased risk of any wheeze between ages 1 and 7 years that did not change significantly with time (hazard ratio for each quartile increment in endotoxin levels, 1.23; 95% CI, 1.07-1.43).
Among children at risk of atopy, early exposure to high levels of dust mite allergen is associated with increased risks of asthma and late-onset wheeze. In these children, endotoxin exposure is associated with a reduced risk of atopy but an increased risk of wheeze.
Clinical implications
Early endotoxin exposure may be a protective factor against atopy but a risk factor for wheeze in high-risk children.
PMCID: PMC3737770  PMID: 17507083
Endotoxin; dust mite; wheeze; atopy; asthma
16.  Multiple Microbial Exposures in the Home May Protect Against Asthma or Allergy in Childhood 
Experimental animal data on the gram-negative bacterial biomarker endotoxin suggest that persistence, dose and timing of exposure are likely to influence its effects on allergy and wheeze. In epidemiologic studies, endotoxin may be a sentinel marker for a microbial milieu, including gram-positive as well as gram-negative bacteria, that may influence allergy and asthma through components (pathogen-associated molecular patterns) that signal through innate Toll-like receptor pathways.
To determine the influence of current gram-negative and gram-positive bacterial exposures on asthma and allergic sensitization in school-aged children.
We examined the relationship between bacterial biomarkers and current asthma and allergic sensitization in 377 school-aged children in a birth-cohort study. We then evaluated the effects of school-age endotoxin, after controlling for exposure in early life.
Exposure to gram-negative bacteria was inversely associated with asthma and allergic sensitization at school-age (for > median endotoxin: prevalence odds ratio [POR] =0.34 [95% CI=0.2 to 0.7] for current asthma and prevalence ratio [PR]=0.77 [95% CI=0.6 to 0.97] for allergic sensitization). In contrast, elevated gram-positive bacteria in the bed was inversely associated with current asthma (POR= 0.41, 95% CI=0.2 to 0.9) but not with allergic sensitization (POR=1.07, 95% CI=0.8 to 1.4). School-age endotoxin exposure remained protective in models for allergic disease adjusted for early-life endotoxin.
Both gram-negative and gram-positive bacterial exposures are associated with decreased asthma symptoms, but may act through different mechanisms to confer protection. Endotoxin exposure in later childhood is not simply a surrogate of early life exposure; it has independent protective effects on allergic disease.
PMCID: PMC3730840  PMID: 20412140
childhood asthma; allergic sensitization; endotoxin; peptidoglycan
17.  Effect of physical activity on heart rate variability in normal weight, overweight and obese subjects: results from the SAPALDIA study 
Many studies have demonstrated an association of both a sedentary lifestyle and a high body mass index (BMI) with greater risk for cardiovascular disease. Within the prospective SAPALDIA cohort (Swiss cohort study on Air Pollution and Lung Diseases in Adults), we investigated whether regular exercise was protective against reduced heart rate variability (HRV), a clinically relevant predictor of cardiovascular morbidity and mortality, and whether adverse effects of obesity and weight gain on HRV were modified by regular exercise. 24-hour electrocardiograms were recorded in 1712 randomly selected SAPALDIA participants aged ≥50, for whom BMI was assessed in the years 1991 and 2001–2003. Other examinations included an interview investigating health status (especially respiratory and cardiovascular health and health relevant behaviours including physical activity) and measurements of blood pressure, body height and weight. The association between regular physical activity and HRV and interactions with BMI and BMI change was assessed in multivariable linear regression analyses.
Compared to sedentary obese subjects, SDNN (standard deviation of all RR intervals) was 14% (95% CI: 8–20%) higher in sedentary normal weight subjects; 19% (CI: 12–27%) higher in normal weight subjects exercising regularly ≥ 2h/week; and 19% (CI:11–28%) higher in obese subjects exercising regularly ≥ 2h/week.
Compared with sedentary subjects who gained weight, those who gained weight but did exercise regularly had a 13% higher SDNN (CI: 7–20%).
Regular physical exercise has strong beneficial effects on cardiac autonomic nervous function and thus appears to offset the negative effect of obesity on HRV.
PMCID: PMC3705554  PMID: 18597107
heart rate variability; autonomic nervous system; body mass index; obesity; body weight change; exercise
18.  Spatial Cluster Detection for Longitudinal Outcomes using Administrative Regions 
This manuscript proposes a new spatial cluster detection method for longitudinal outcomes that detects neighborhoods and regions with elevated rates of disease while controlling for individual level confounders. The proposed method, CumResPerm, utilizes cumulative geographic residuals through a permutation test to detect potential clusters which are are defined as sets of administrative regions, such as a town, or group of administrative regions. Previous cluster detection methods are not able to incorporate individual level data including covariate adjustment, while still being able to define potential clusters using informative neighborhood or town boundaries. Often it is of interest to detect such spatial clusters because individuals residing in a town may have similar environmental exposures or socioeconomic backgrounds due to administrative reasons, such as zoning laws. Therefore these boundaries can be very informative and more relevant than arbitrary clusters such as the standard circle or square. Application of the CumResPerm method will be illustrated by the Home Allergens and Asthma prospective cohort study analyzing the relationship between area or neighborhood residence and repeated measured outcome, occurrence of wheeze in the last 6 months, while taking into account mobile locations.
PMCID: PMC3705764  PMID: 23847392
Asthma; Cluster Detection; Cumulative Residuals; Repeated Measures; Wheeze
19.  Association of variants in innate immune genes with asthma and eczema 
The innate immune pathway is important in the pathogenesis of asthma and eczema. However, only a few variants in these genes have been associated with either disease. We investigate the association between polymorphisms of genes in the innate immune pathway with childhood asthma and eczema. In addition, we compare individual associations with those discovered using a multivariate approach.
Using a novel method, case control based association testing (C2BAT), 569 single nucleotide polymorphisms (SNPs) in 44 innate immune genes were tested for association with asthma and eczema in children from the Boston Home Allergens and Asthma Study and the Connecticut Childhood Asthma Study. The screening algorithm was used to identify the top SNPs associated with asthma and eczema. We next investigated the interaction of innate immune variants with asthma and eczema risk using Bayesian networks.
After correction for multiple comparisons, 7 SNPs in 6 genes (CARD25, TGFB1, LY96, ACAA1, DEFB1, and IFNG) were associated with asthma (adjusted p-value<0.02), while 5 SNPs in 3 different genes (CD80, STAT4, and IRAKI) were significantly associated with eczema (adjusted p-value < 0.02). None of these SNPs were associated with both asthma and eczema. Bayesian network analysis identified 4 SNPs that were predictive of asthma and 10 SNPs that predicted eczema. Of the genes identified using Bayesian networks, only CD80 was associated with eczema in the single-SNP study. Using novel methodology that allows for screening and replication in the same population, we have identified associations of innate immune genes with asthma and eczema. Bayesian network analysis suggests that additional SNPs influence disease susceptibility via SNP interactions.
Our findings suggest that innate immune genes contribute to the pathogenesis of asthma and eczema, and that these diseases likely have different genetic determinants.
PMCID: PMC3412627  PMID: 22192168
asthma; Bayesian network; genetic association; eczema; innate immunity
20.  Maternal intestinal flora and wheeze in early childhood 
Increasing evidence links altered intestinal flora in infancy to eczema and asthma. No studies have investigated the influence of maternal intestinal flora on wheezing and eczema in early childhood.
To investigate the link between maternal intestinal flora during pregnancy and development of wheeze and eczema in infancy.
Sixty pregnant women from the Boston area gave stool samples during the third trimester of their pregnancy and answered questions during pregnancy about their own health, and about their children’s health when the child was 2 and 6 months of age. Quantitative culture was performed on stool samples and measured in log10colony-forming units(CFU)/gram stool. Primary outcomes included infant wheeze and eczema in the first 6 months of life. Atopic wheeze, defined as wheeze and eczema, was analyzed as a secondary outcome.
In multivariate models adjusted for breastfeeding, daycare attendance and maternal atopy, higher counts of maternal total aerobes (TA) and enterococci (E) were associated with increased risk of infant wheeze (TA: OR 2.32 for 1 log increase in CFU/g stool [95% CI 1.22, 4.42]; E: OR 1.57 [95% CI 1.06, 2.31]). No organisms were associated with either eczema or atopic wheeze.
Conclusions & Clinical Relevance
In our cohort, higher maternal total aerobes and enterococci were related to increased risk of infant wheeze. Maternal intestinal flora may be an important environmental exposure in early immune system development.
PMCID: PMC3428746  PMID: 22909161
infant wheeze; eczema; asthma; microbiota; intestinal flora; maternal flora
21.  Ozone exposure, vitamin C intake, and genetic susceptibility of asthmatic children in Mexico City: a cohort study 
Respiratory Research  2013;14(1):14.
We previously reported that asthmatic children with GSTM1 null genotype may be more susceptible to the acute effect of ozone on the small airways and might benefit from antioxidant supplementation. This study aims to assess the acute effect of ozone on lung function (FEF25-75) in asthmatic children according to dietary intake of vitamin C and the number of putative risk alleles in three antioxidant genes: GSTM1, GSTP1 (rs1695), and NQO1 (rs1800566).
257 asthmatic children from two cohort studies conducted in Mexico City were included. Stratified linear mixed models with random intercepts and random slopes on ozone were used. Potential confounding by ethnicity was assessed. Analyses were conducted under single gene and genotype score approaches.
The change in FEF25-75 per interquartile range (60 ppb) of ozone in persistent asthmatic children with low vitamin C intake and GSTM1 null was −91.2 ml/s (p = 0.06). Persistent asthmatic children with 4 to 6 risk alleles and low vitamin C intake showed an average decrement in FEF25-75 of 97.2 ml/s per 60 ppb of ozone (p = 0.03). In contrast in children with 1 to 3 risk alleles, acute effects of ozone on FEF25-75 did not differ by vitamin C intake.
Our results provide further evidence that asthmatic children predicted to have compromised antioxidant defense by virtue of genetic susceptibility combined with deficient antioxidant intake may be at increased risk of adverse effects of ozone on pulmonary function.
PMCID: PMC3579760  PMID: 23379631
Air pollution; Asthmatic children; Antioxidant genes; Mexico City; Vitamin C
22.  Controlled Exposure Study of Air Pollution and T-Wave Alternans in Volunteers without Cardiovascular Disease 
Environmental Health Perspectives  2012;120(8):1157-1161.
Background: Epidemiological studies have assessed T-wave alternans (TWA) as a possible mechanism of cardiac arrhythmias related to air pollution in high-risk subjects and have reported associations with increased TWA magnitude.
Objective: In this controlled human exposure study, we assessed the impact of exposure to concentrated ambient particulate matter (CAP) and ozone (O3) on T-wave alternans in resting volunteers without preexisting cardiovascular disease.
Methods: Seventeen participants without preexisting cardiovascular disease were randomized to filtered air (FA), CAP (150 μg/m3), O3 (120 ppb), or combined CAP + O3 exposures for 2 hr. Continuous electrocardiograms (ECGs) were recorded at rest and T-wave alternans (TWA) was computed by modified moving average analysis with QRS alignment for the artifact-free intervals of 20 beats along the V2 and V5 leads. Exposure-induced changes in the highest TWA magnitude (TWAMax) were estimated for the first and last 5 min of each exposure (TWAMax_Early and TWAMax_Late respectively). ΔTWAMax (Late–Early) were compared among exposure groups using analysis of variance.
Results: Mean ± SD values for ΔTWAMax were –2.1 ± 0.4, –2.7 ± 1.1, –1.9 ± 1.5, and –1.2 ± 1.5 in FA, CAP, O3, and CAP + O3 exposure groups, respectively. No significant differences were observed between pollutant exposures and FA.
Conclusion: In our study of 17 volunteers who had no preexisting cardiovascular disease, we did not observe significant changes in T-wave alternans after 2-hr exposures to CAP, O3, or combined CAP + O3. This finding, however, does not preclude the possibility of pollution-related effects on TWA at elevated heart rates, such as during exercise, or the possibility of delayed responses.
PMCID: PMC3440072  PMID: 22552907
air pollution; arrhythmia; controlled exposure; ozone; particulate matter; T-wave alternans
24.  Umbilical cord plasma 25-hydroxyvitamin D concentration and immune function at birth: the Urban Environment and Childhood Asthma (URECA) study 
Recent studies have reported conflicting data on the association between maternal intake of vitamin D during pregnancy and asthma.
Assess the influence of prenatal vitamin D status on immune function at birth.
In an inner-city birth cohort of 568 newborns, 520 of whom had at least one atopic parent, we measured umbilical cord (UC) plasma concentration of 25-hydroxy vitamin D (25(OH)D) and the cytokine responses of UC blood mononuclear cells (UCMCs) to stimuli including phytohemaglutinin (PHA), lipopolysaccharide (LPS), and peptidoglycan (PG). In a subset, UCMC expression of regulatory T-cell markers and the suppressive activity of CD4+CD25+ UCMCs was measured.
The 25th, 50th, and 75th percentiles of UC plasma 25(OH)D level were 15.0, 20.2, and 25.6 ng/mL, respectively. Most cytokine responses of UCMC were not correlated with UC 25(OH)D concentration; however, IFN-γ release after LPS stimulation was weakly positively correlated with UC 25(OH)D concentration (r = 0.11, p =0.01). PHA responses were not significantly correlated with 25(OH)D concentration. The UC plasma 25(OH)D concentration was inversely related to the number of CD25+ (r= -0.20, p=0.06), CD25Bright (r= -0.21, p=0.05), and CD25+FoxP3 (r= -0.29, p=0.06) cells as a proportion of CD4+ T cells in UC blood (r = -0.26, p = 0.04) but not to the suppressive activity of CD4+CD25+ cells (r=0.17, p=0.22).
Conclusion and Clinical Relevance
UC 25(OH)D concentration was not correlated with most UCMC cytokine responses to multiple stimuli. There was a suggestion of a weakly positive correlation with IFN-γ release after LPS stimulation. The proportions of CD25+, CD25bright, and CD25+FoxP3 cells to total CD4+ T cells were inversely correlated with UC 25(OH)D concentration. Our findings suggest that higher vitamin D levels at birth may be associated with a lower number of T regulatory cells. Vitamin D status in utero may influence immune regulation in early life.
PMCID: PMC3093441  PMID: 21481021
25.  Gut Microbiota, Probiotics, and Vitamin D: Interrelated Exposures Influencing Allergy, Asthma, and Obesity? 
Current evidence supports a role for gut colonization in promoting and maintaining a balanced immune response in early life. An altered or less diverse gut microbiota composition has been associated with atopic diseases and/or obesity. Moreover, certain gut microbial strain or strains have been shown to inhibit or attenuate immune responses associated with chronic inflammation in experimental models. However, there has been no fully adequate longitudinal study of the relation between the neonatal gut microbiota and the development of allergic diseases (e.g., atopic asthma) and obesity. The emergence of promising experimental studies has led to several clinical trials of probiotics (live bacteria given orally that allow for intestinal colonization) in humans. Probiotic trials thus far have failed to show a consistent preventive or therapeutic effect on asthma or obesity. Previous trials of probiotics have been limited by small sample size, short duration of follow-up, or lack state-of-the art analyses of the gut microbiota. Finally, there is emerging evidence that the vitamin D pathway may be important in gut homeostasis and in the signaling between the microbiota and the host. Given the complexity of the gut micriobiota, additional research is needed before we can confidently establish whether its manipulation in early life can prevent or treat asthma and/or obesity.
PMCID: PMC3085575  PMID: 21419479
microbiota; asthma; obesity; allergic; eczema; vitamin D; probiotics; cytokines

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