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1.  Is Chronic Asthma Associated with Shorter Leukocyte Telomere Length at Midlife? 
Rationale: Asthma is prospectively associated with age-related chronic diseases and mortality, suggesting the hypothesis that asthma may relate to a general, multisystem phenotype of accelerated aging.
Objectives: To test whether chronic asthma is associated with a proposed biomarker of accelerated aging, leukocyte telomere length.
Methods: Asthma was ascertained prospectively in the Dunedin Multidisciplinary Health and Development Study cohort (n = 1,037) at nine in-person assessments spanning ages 9–38 years. Leukocyte telomere length was measured at ages 26 and 38 years. Asthma was classified as life-course-persistent, childhood-onset not meeting criteria for persistence, and adolescent/adult-onset. We tested associations between asthma and leukocyte telomere length using regression models. We tested for confounding of asthma-leukocyte telomere length associations using covariate adjustment. We tested serum C-reactive protein and white blood cell counts as potential mediators of asthma-leukocyte telomere length associations.
Measurements and Main Results: Study members with life-course-persistent asthma had shorter leukocyte telomere length as compared with sex- and age-matched peers with no reported asthma. In contrast, leukocyte telomere length in study members with childhood-onset and adolescent/adult-onset asthma was not different from leukocyte telomere length in peers with no reported asthma. Adjustment for life histories of obesity and smoking did not change results. Study members with life-course-persistent asthma had elevated blood eosinophil counts. Blood eosinophil count mediated 29% of the life-course-persistent asthma-leukocyte telomere length association.
Conclusions: Life-course-persistent asthma is related to a proposed biomarker of accelerated aging, possibly via systemic eosinophilic inflammation. Life histories of asthma can inform studies of aging.
doi:10.1164/rccm.201402-0370OC
PMCID: PMC4214127  PMID: 24956257
asthma; telomere; aging; longitudinal; developmental phenotype
2.  Asthma: epidemiology, etiology and risk factors 
doi:10.1503/cmaj.080612
PMCID: PMC2764772  PMID: 19752106
3.  Association between children’s experience of socioeconomic disadvantage and adult health: a life-course study 
Lancet  2002;360(9346):1640-1645.
Summary
Background
Research into social inequalities in health has tended to focus on low socioeconomic status in adulthood. We aimed to test the hypothesis that children’s experience of socioeconomic disadvantage is associated with a wide range of health risk factors and outcomes in adult life.
Methods
We studied an unselected cohort of 1000 children (born in New Zealand during 1972–73) who had been assessed at birth and ages 3, 5, 7, 9, 11, 13, and 15 years. At age 26 years, we assessed these individuals for health outcomes including body-mass index, waist:hip ratio, blood pressure, cardiorespiratory fitness, dental caries, plaque scores, gingival bleeding, periodontal disease, major depression, and tobacco and alcohol dependence, and tested for associations between these variables and childhood and adult socioeconomic status.
Findings
Compared with those from high socioeconomic status backgrounds, children who grew up in low socioeconomic status families had poorer cardiovascular health. Significant differences were also found on all dental health measures, with a threefold increase in adult periodontal disease (31·1% vs 11·9%) and caries level (32·2% vs 9·9%) in low versus high childhood socioeconomic status groups. Substance abuse resulting in clinical dependence was related in a similar way to childhood socioeconomic status (eg, 21·5% vs 12·1% for adult alcohol dependence). The longitudinal associations could not be attributed to life-course continuity of low socioeconomic status, and upward mobility did not mitigate or reverse the adverse effects of low childhood socioeconomic status on adult health.
Interpretation
Protecting children against the effects of socioeconomic adversity could reduce the burden of disease experienced by adults. These findings provide strong impetus for policy makers, practitioners, and researchers to direct energy and resources towards childhood as a way of improving population health.
doi:10.1016/S0140-6736(02)11602-3
PMCID: PMC3752775  PMID: 12457787
4.  Links Between Anxiety and Allergies: Psychobiological Reality or Possible Methodological Bias? 
Journal of personality  2009;77(2):347-362.
The objective of the study was to examine the link between anxiety and allergies to establish whether it reflects a psychobiological reality or a possible methodological bias. A cohort of 1,037 children enrolled in the study. Anxiety disorders were assessed between 11 and 21 years. Anxious personality was assessed at 18 years. Allergies were examined at 21 years by (a) self reports, (b) skin pricks, and (c) serum total immunoglobulin E (IgE). Self-reported allergies were predicted by recurrent anxiety disorders (OR [95% CI]=1.56 [1.06–2.30], p=.023) and self-reports of anxious personality (OR [95% CI]=1.67 [1.17–2.37], p=.004): Objectively verified allergies were not. These results suggest that the link between anxiety and allergies may reflect a methodological artifact rather than a psychobiological reality.
doi:10.1111/j.1467-6494.2008.00550.x
PMCID: PMC3752790  PMID: 19192077
6.  Gut microbiota of healthy Canadian infants: profiles by mode of delivery and infant diet at 4 months 
Background:
The gut microbiota is essential to human health throughout life, yet the acquisition and development of this microbial community during infancy remains poorly understood. Meanwhile, there is increasing concern over rising rates of cesarean delivery and insufficient exclusive breastfeeding of infants in developed countries. In this article, we characterize the gut microbiota of healthy Canadian infants and describe the influence of cesarean delivery and formula feeding.
Methods:
We included a subset of 24 term infants from the Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort. Mode of delivery was obtained from medical records, and mothers were asked to report on infant diet and medication use. Fecal samples were collected at 4 months of age, and we characterized the microbiota composition using high-throughput DNA sequencing.
Results:
We observed high variability in the profiles of fecal microbiota among the infants. The profiles were generally dominated by Actinobacteria (mainly the genus Bifidobacterium) and Firmicutes (with diverse representation from numerous genera). Compared with breastfed infants, formula-fed infants had increased richness of species, with overrepresentation of Clostridium difficile. Escherichia–Shigella and Bacteroides species were underrepresented in infants born by cesarean delivery. Infants born by elective cesarean delivery had particularly low bacterial richness and diversity.
Interpretation:
These findings advance our understanding of the gut microbiota in healthy infants. They also provide new evidence for the effects of delivery mode and infant diet as determinants of this essential microbial community in early life.
doi:10.1503/cmaj.121189
PMCID: PMC3602254  PMID: 23401405
7.  Exposure Assessment in Cohort Studies of Childhood Asthma 
Environmental Health Perspectives  2010;119(5):591-597.
Background
The environment is suspected to play an important role in the development of childhood asthma. Cohort studies are a powerful observational design for studying exposure–response relationships, but their power depends in part upon the accuracy of the exposure assessment.
Objective
The purpose of this paper is to summarize and discuss issues that make accurate exposure assessment a challenge and to suggest strategies for improving exposure assessment in longitudinal cohort studies of childhood asthma and allergies.
Data synthesis
Exposures of interest need to be prioritized, because a single study cannot measure all potentially relevant exposures. Hypotheses need to be based on proposed mechanisms, critical time windows for effects, prior knowledge of physical, physiologic, and immunologic development, as well as genetic pathways potentially influenced by the exposures. Modifiable exposures are most important from the public health perspective. Given the interest in evaluating gene–environment interactions, large cohort sizes are required, and planning for data pooling across independent studies is critical. Collection of additional samples, possibly through subject participation, will permit secondary analyses. Models combining air quality, environmental, and dose data provide exposure estimates across large cohorts but can still be improved.
Conclusions
Exposure is best characterized through a combination of information sources. Improving exposure assessment is critical for reducing measurement error and increasing power, which increase confidence in characterization of children at risk, leading to improved health outcomes.
doi:10.1289/ehp.1002267
PMCID: PMC3094407  PMID: 21081299
childhood asthma; cohort studies; exposure assessment
9.  A Cohort Study of Traffic-Related Air Pollution and Mortality in Toronto, Ontario, Canada 
Environmental Health Perspectives  2009;117(5):772-777.
Background
Chronic exposure to traffic-related air pollution (TRAP) may contribute to premature mortality, but few studies to date have addressed this topic.
Objectives
In this study we assessed the association between TRAP and mortality in Toronto, Ontario, Canada.
Methods
We collected nitrogen dioxide samples over two seasons using duplicate two-sided Ogawa passive diffusion samplers at 143 locations across Toronto. We calibrated land use regressions to predict NO2 exposure on a fine scale within Toronto. We used interpolations to predict levels of particulate matter with aerodynamic diameter ≤ 2.5 μm (PM2.5) and ozone levels. We assigned predicted pollution exposures to 2,360 subjects from a respiratory clinic, and abstracted health data on these subjects from medical billings, lung function tests, and diagnoses by pulmonologists. We tracked mortality between 1992 and 2002. We used standard and multilevel Cox proportional hazard models to test associations between air pollution and mortality.
Results
After controlling for age, sex, lung function, obesity, smoking, and neighborhood deprivation, we observed a 17% increase in all-cause mortality and a 40% increase in circulatory mortality from an exposure contrast across the interquartile range of 4 ppb NO2. We observed no significant associations with other pollutants.
Conclusions
Exposure to TRAP was significantly associated with increased all-cause and circulatory mortality in this cohort. A high prevalence of cardiopulmonary disease in the cohort probably limits inference of the findings to populations with a substantial proportion of susceptible individuals.
doi:10.1289/ehp.11533
PMCID: PMC2685840  PMID: 19479020
air pollution; GIS; mortality; nitrogen dioxide; traffic air pollution; Toronto
10.  Prevalence of asthma among Chinese adolescents living in Canada and in China 
Background
Studies of the prevalence of asthma among migrating populations may help in identifying environmental risk factors.
Methods
We analyzed data from Vancouver, Canada, and from Guangzhou, Beijing and Hong Kong, China, collected during phase 3 of the International Study of Asthma and Allergies in Childhood. We subdivided the Vancouver adolescents according to whether they were Chinese immigrants to Canada, Canadian-born Chinese or Canadian-born non-Chinese. We compared the prevalence of asthma and wheezing among Chinese adolescents born in Canada, Chinese adolescents who had immigrated to Canada and Chinese adolescents living in China.
Results
Of 7794 Chinese adolescents who met the inclusion criteria, 3058 were from Guangzhou, 2824 were from Beijing, and 1912 were from Hong Kong. Of 2235 adolescents in Vancouver, Canada, 475 were Chinese immigrants, 617 were Canadian-born Chinese, and 1143 were Canadian-born non-Chinese. The prevalence of current wheezing among boys ranged from 5.9% in Guangzhou to 11.2% in Canadian-born Chinese adolescents. For girls, the range was 4.3% in Guangzhou to 9.8% in Canadian-born Chinese adolescents. The prevalence of ever having had asthma ranged from 6.6% to 16.6% for boys and from 2.9% to 15.0% for girls. Prevalence gradients persisted after adjustment for other environmental variables (odds ratios for ever having had asthma among Canadian-born Chinese compared with native Chinese in Guangzhou: 2.72 [95% confidence interval 1.75–4.23] for boys and 5.50 [95% confidence interval 3.21–9.44] for girls; p < 0.001 for both). Among Chinese adolescents living in Vancouver, the prevalence of ever wheezing increased with duration of residence, from 14.5% among those living in Canada for less than 7 years to 20.9% among those living their entire life in Canada. The same pattern was observed for the prevalence of ever having had asthma, from 7.7% to 15.9%.
Interpretation
Asthma symptoms in Chinese adolescents were lowest among residents of mainland China, were greater for those in Hong Kong and those who had immigrated to Canada, and were highest among those born in Canada. These findings suggest that environmental factors and duration of exposure influence asthma prevalence.
doi:10.1503/cmaj.071797
PMCID: PMC2582762  PMID: 19015564
11.  Sex Differences in Factors Associated with Childhood- and Adolescent-Onset Wheeze 
Rationale: Factors predicting the development of wheeze may differ between sexes and between childhood and adolescence. Methods: A New Zealand birth cohort of 1,037 children was followed to age 26. For this analysis, those reporting recurrent wheezing at two or more assessments were classified as “wheezers.” We examined risk factors for development of wheeze before age 10 (childhood) and subsequently (adolescent-onset) for males and for females separately using Cox regression modeling. Results: Males more often developed childhood wheeze (p = 0.002) and females adolescent-onset wheeze (p < 0.001). Maternal atopy (asthma or hay fever) was a risk factor for childhood wheeze in both sexes (hazard ratio [HR], 1.48, p < 0.05 for males; HR, 2.37, p < 0.001 for females). Paternal atopy also influenced childhood wheeze, significantly for males (HR, 1.72; p = 0.01), and similarly but not significantly for females (HR, 1.70; p = 0.08). For adolescent-onset wheeze, neither maternal (HR, 1.41; p = 0.19) nor paternal history (HR, 0.73; p = 0.42) was a risk factor in males, but maternal history (HR, 2.08; p < 0.01) was a significant risk factor for females. When both age ranges were combined, providing greater power for analysis, paternal history was a stronger risk factor for wheeze in females (HR, 1.62; p = 0.02) than in males (HR, 1.35; p = 0.12). Conclusion: The influence of parental atopy on the development for wheeze differs between males and females and between childhood- and adolescent-onset wheeze.
doi:10.1164/rccm.200412-1738OC
PMCID: PMC2718447  PMID: 15805179
age of onset; asthma; parental history; risk factors; sex
12.  Relation between income, air pollution and mortality: a cohort study 
Background
Community levels of air pollution have been associated with variability in mortality rates, but previous studies have inferred exposure to pollutants on a citywide basis. We investigated mortality in relation to neighbourhood levels of income and air pollution in an urban area.
Methods
We identified 5228 people in the Hamilton–Burlington area of southern Ontario who had been referred for pulmonary function testing between 1985 and 1999. Nonaccidental deaths that occurred in this group between 1992 and 1999 were ascertained from the Ontario Mortality Registry. Mean household income was estimated by linking the subjects' postal codes with the 1996 census. Mean neighbourhood levels of total suspended particulates and sulfur dioxide were estimated by interpolation from data from a network of sampling stations. We used proportional hazards regression models to compute mortality risk in relation to income and pollutant levels, while adjusting for pulmonary function, body mass index and diagnoses of chronic disease. Household incomes and pollutant levels were each divided into 2 risk categories (low and high) at the median.
Results
Mean pollutant levels tended to be higher in lower-income neighbourhoods. Both income and pollutant levels were associated with mortality differences. Compared with people in the most favourable category (higher incomes and lower particulate levels), those with all other income–particulate combinations had a higher risk of death from nonaccidental causes (lower incomes and higher particulate levels: relative risk [RR] 2.62, 95% confidence interval [CI] 1.67–4.13; lower incomes and lower particulate levels: RR 1.82, 95% CI 1.30–2.55; higher incomes and higher particulate levels: RR 1.33, 95% CI 1.12–1.57). Similar results were observed for sulfur dioxide. The relative risk was lower at older ages.
Interpretation
Mortality rates varied by neighbourhood of residence in this cohort of people whose lung function was tested. Two of the broader determinants of health — income and air pollution levels — were important correlates of mortality in this population.
PMCID: PMC183288  PMID: 12952800
13.  Prevalence of asthma symptoms among adults aged 20–44 years in Canada 
Background
Reported prevalence rates of asthma vary within and between countries around the world. These differences suggest environmental factors in addition to genetic factors in the cause of the disease and may provide clues for preventive strategies. We examined the variability of asthma-related symptoms and medication use among adults in 6 sites across Canada (Vancouver, Winnipeg, Hamilton, Montreal, Halifax and Prince Edward Island) and compared our findings with those from sites that had participated in a recent European survey.
Methods
We used the same sampling strategy and standardized questionnaire as those used in the European Community Respiratory Health Survey (ECRHS). The 6 Canadian sites were selected to represent different environments with respect to climate, air pollution and occupational exposure. Community-based samples of 3000 to 4000 people aged 20–44 years were randomly selected in each site. Subjects were asked to complete the questionnaire by mail between March 1993 and November 1994. Prevalence rates (and 95% confidence intervals [CIs]) of asthma symptoms, self-reported asthma attacks and use of asthma medication were compared across the Canadian sites and with sites that had participated in the ECRHS.
Results
The overall response rate of those selected to receive the questionnaire was 86.5% (range 74.5%–92.8%). The prevalence rates of most asthma symptoms varied significantly among the Canadian sites. For instance, 21.9% (Montreal) to 30.4% (Halifax) of the men and 24.0% (Vancouver) to 35.2% (Halifax) of the women reported wheezing in the year before the survey. Depending on the site, 4.4% to 6.3% of the men and 5.2% to 9.5% of the women reported an asthma attack in the last year, and 4.0% to 6.1% of the men and 4.9% to 9.7% of the women were currently using asthma medication. Prevalence rates of symptoms, asthma attacks and medication use did not change with age, but they were higher among women than among men. Compared with the results from the ECRHS sites, those from the Canadian sites were among the highest.
Interpretation
Significant variation in the prevalence of asthma symptoms, asthma attacks and use of asthma medication between Canadian sites and international sites suggests environmental influences. Different combinations of factors in different sites may be responsible for the high prevalence rates and should be the subject of further research to guide clinical management and public health intervention.
PMCID: PMC80927  PMID: 11314453
14.  Effect of Experimental Pneumococcal Meningitis on Respiration and Circulation in the Rabbit 
Pathophysiological studies in bacterial meningitis in man have been limited by clinical variability and the necessity for immediate therapy. After the development of a reliable animal model of pneumococcal meningitis, we studied respiration and circulation in 25 anesthetized New Zealand white rabbits during untreated pneumococcal meningitis and in 33 healthy controls. In meningitis, we found increased lactic acid in cerebrospinal fluid (CSF). Increased ventilation, perhaps due to CSF lactic acid accumulation, resulted in respiratory alkalosis; the concomitant lowering of Pco2 acted as a homeostatic mechanism to restore pH toward normality in the CSF. Hyperventilation increased with the duration of the illness. Cardiac output was also increased with decreased peripheral vascular resistance but with only slight reduction in mean systemic and pulmonary arterial pressures. In the final hour of life, peripheral vascular resistance fell further; ventilation declined and then abruptly ceased while cardiac activity continued. Lactic acid accumulation in the CSF, found in both experimental and human pneumococcal meningitis, may cause the hyperventilation found in this disease and may contribute to death.
PMCID: PMC301520  PMID: 4152001

Results 1-14 (14)