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1.  Indigenous health and environmental risk factors: an Australian problem with global analogues? 
Global Health Action  2014;7:10.3402/gha.v7.23766.
Indigenous people experience poorer health than non-Indigenous people, and this well-described inequality has been observed in many countries. The contribution of different risk factors to the health ‘gap’ has understandably focussed on those factors for which there are sufficient data. However, this has precluded environmental risk factors – those present in air, water, food, and soil – due to a lack of data describing exposures and outcomes. These risk factors are demonstrably important at the global scale, as highlighted by the 2010 Global Burden of Disease study. Here, we describe how a greater focus on environmental risk factors is required in order to define their role in the Indigenous health gap. We use the Australian context as a case study of an issue we feel has global analogues and relevance. Suggestions for how and why this situation should be remedied are presented and discussed.
doi:10.3402/gha.v7.23766
PMCID: PMC4007027  PMID: 24802385
environmental health; Indigenous peoples; Australia; health; environment
2.  Rhinovirus Exacerbates House-Dust-Mite Induced Lung Disease in Adult Mice 
PLoS ONE  2014;9(3):e92163.
Human rhinovirus is a key viral trigger for asthma exacerbations. To date, murine studies investigating rhinovirus-induced exacerbation of allergic airways disease have employed systemic sensitisation/intranasal challenge with ovalbumin. In this study, we combined human-rhinovirus infection with a clinically relevant mouse model of aero-allergen exposure using house-dust-mite in an attempt to more accurately understand the links between human-rhinovirus infection and exacerbations of asthma. Adult BALB/c mice were intranasally exposed to low-dose house-dust-mite (or vehicle) daily for 10 days. On day 9, mice were inoculated with human-rhinovirus-1B (or UV-inactivated human-rhinovirus-1B). Forty-eight hours after inoculation, we assessed bronchoalveolar cellular inflammation, levels of relevant cytokines/serum antibodies, lung function and responsiveness/sensitivity to methacholine. House-dust-mite exposure did not result in a classical TH2-driven response, but was more representative of noneosinophilic asthma. However, there were significant effects of house-dust-mite exposure on most of the parameters measured including increased cellular inflammation (primarily macrophages and neutrophils), increased total IgE and house-dust-mite-specific IgG1 and increased responsiveness/sensitivity to methacholine. There were limited effects of human-rhinovirus-1B infection alone, and the combination of the two insults resulted in additive increases in neutrophil levels and lung parenchymal responses to methacholine (tissue elastance). We conclude that acute rhinovirus infection exacerbates house-dust-mite-induced lung disease in adult mice. The similarity of our results using the naturally occurring allergen house-dust-mite, to previous studies using ovalbumin, suggests that the exacerbation of allergic airways disease by rhinovirus infection could act via multiple or conserved mechanisms.
doi:10.1371/journal.pone.0092163
PMCID: PMC3954893  PMID: 24632596
3.  Using Mathematical Transmission Modelling to Investigate Drivers of Respiratory Syncytial Virus Seasonality in Children in the Philippines 
PLoS ONE  2014;9(2):e90094.
We used a mathematical transmission model to estimate when ecological drivers of respiratory syncytial virus (RSV) transmissibility would need to act in order to produce the observed seasonality of RSV in the Philippines. We estimated that a seasonal peak in transmissibility would need to occur approximately 51 days prior to the observed peak in RSV cases (range 49 to 67 days). We then compared this estimated seasonal pattern of transmissibility to the seasonal patterns of possible ecological drivers of transmissibility: rainfall, humidity and temperature patterns, nutritional status, and school holidays. The timing of the seasonal patterns of nutritional status and rainfall were both consistent with the estimated seasonal pattern of transmissibility and these are both plausible drivers of the seasonality of RSV in this setting.
doi:10.1371/journal.pone.0090094
PMCID: PMC3937436  PMID: 24587222
4.  Airway, but not serum or urinary, levels of YKL-40 reflect inflammation in early cystic fibrosis lung disease 
Background
Cystic fibrosis (CF) lung disease begins in early life and is progressive with the major risk factor being an exaggerated inflammatory response. Currently, assessment of neutrophilic inflammation in early cystic fibrosis (CF) lung disease relies on bronchoalveolar lavage (BAL). The chitinase-like protein YKL-40 is raised in sputum and serum of adults with CF. We investigated YKL-40 in BAL, serum and urine to determine whether this reflected inflammation and infection in young children with CF.
Methods
YKL-40 was measured in matched samples of BAL, serum and urine obtained from 36 infants and young children with CF participating in an early surveillance program. Levels were compared to clinical data and markers of inflammation detected in the lung.
Results
YKL-40 in BAL correlated with pulmonary infection [β=1.30 (SE 0.34), p < 0.001] and BAL markers of inflammation [macrophage number: r2 = 0.34, p < 0.001; neutrophil number: r2 = 0.74, p < 0.001; neutrophil elastase: r2 = 0.47, p < 0.001; CXCL8: r2 = 0.45, p < 0.001; IL-β: r2 = 0.62, p < 0.001]. YKL-40 was detectable in serum but levels did not correlate with BAL levels in the same individuals (r2 = 0.04, p = 0.14) or with inflammatory markers. YKL-40 was below the limit of detection in urine (30 pg/ml).
Conclusions
This study demonstrates that levels of the chitinase-like protein YKL-40 reflect airway inflammation and infection in early CF lung disease. The lack of increased YKL-40 in serum in the absence of systemic inflammation limits the benefit of this potential biomarker in early disease.
doi:10.1186/1471-2466-14-28
PMCID: PMC3946043  PMID: 24576297
Cystic fibrosis; YKL-40; Biomarker; Lung disease
5.  Prenatal determinants of cord blood total immunoglobulin E levels in Mexican newborns 
Allergy and Asthma Proceedings  2013;34(5):e27-e34.
Asthma and allergic diseases have increased worldwide; however, etilogic factors for this increase are still poor. Prenatal consumptions of fatty acids are hypothesized, although few clinical trials in developing countries have been performed. This study was designed to identify predictors of immunoglobulin E (IgE) levels in cord blood of Mexican newborns. Total IgE was measured in umbilical cord blood from 613 infants whose mothers participated in a double-blind randomized controlled trial of 400 mg of docosahexaenoic acid or placebo from 18 to 22 weeks gestation through delivery. During pregnancy, information on sociodemographic characteristics, environmental exposures, and perceived maternal stress were obtained; a maternal blood sample was also collected to determine atopy via specific IgE levels. Logistic regression models were used to identify the main prenatal predictors of detectable total IgE levels in cord blood. IgE was detectable in cord blood from 344 (53.7%) infants; the main predictors in multivariate analyses were maternal atopy (odds ratio [OR] = 1.69; 95% CI, 1.19–2.42; p < 0.05) and pesticide use in the home (OR = 1.49; 95% CI, 1.04–2.14; p < 0.05). When stratified by maternal atopy, season of birth was a significant predictor in the atopic group only (OR = 2.48; 95% CI, 1.00–6.16; p < 0.05), and pesticide use was a significant predictor for infants born to nonatopic mothers (OR = 1.64; 95% CI, 1.07–2.51; p < 0.05). No differences were seen in the proportion of infants with detectable IgE by treatment group. Prenatal supplementation with omega-3 polyunsaturated fatty acid did not alter the detectable cord blood IgE levels. Maternal atopy and pesticide use during pregnancy are strong predictors of cord blood IgE levels in newborns. Clinical trial NCT00646360, www.clinicaltrials.gov.
doi:10.2500/aap.2013.34.3688
PMCID: PMC3973815  PMID: 23998234
Clinical trial; cord blood; maternal atopy; newborn; omega-3 polyunsaturated fatty acid; pregnancy supplementation; total immunoglobulin E
6.  Early Life Arsenic Exposure and Acute and Long-term Responses to Influenza A Infection in Mice 
Environmental Health Perspectives  2013;121(10):1187-1193.
Background: Arsenic is a significant global environmental health problem. Exposure to arsenic in early life has been shown to increase the rate of respiratory infections during infancy, reduce childhood lung function, and increase the rates of bronchiectasis in early adulthood.
Objective: We aimed to determine if early life exposure to arsenic exacerbates the response to early life influenza infection in mice.
Methods: C57BL/6 mice were exposed to arsenic in utero and throughout postnatal life. At 1 week of age, a subgroup of mice were infected with influenza A. We then assessed the acute and long-term effects of arsenic exposure on viral clearance, inflammation, lung structure, and lung function.
Results: Early life arsenic exposure reduced the clearance of and exacerbated the inflammatory response to influenza A, and resulted in acute and long-term changes in lung mechanics and airway structure.
Conclusions: Increased susceptibility to respiratory infections combined with exaggerated inflammatory responses throughout early life may contribute to the development of bronchiectasis in arsenic-exposed populations.
Citation: Ramsey KA, Foong RE, Sly PD, Larcombe AN, Zosky GR. 2013. Early life arsenic exposure and acute and long-term responses to influenza A infection in mice. Environ Health Perspect 121:1187–1193; http://dx.doi.org/10.1289/ehp.1306748
doi:10.1289/ehp.1306748
PMCID: PMC3801203  PMID: 23968752
7.  Poor Growth and Pneumonia Seasonality in Infants in the Philippines: Cohort and Time Series Studies 
PLoS ONE  2013;8(6):e67528.
Children with poor nutrition are at increased risk of pneumonia. In many tropical settings seasonal pneumonia epidemics occur during the rainy season, which is often a period of poor nutrition. We have investigated whether seasonal hunger may be a driver of seasonal pneumonia epidemics in children in the tropical setting of the Philippines. In individual level cohort analysis, infant size and growth were both associated with increased pneumonia admissions, consistent with findings from previous studies. A low weight for age z-score in early infancy was associated with an increased risk of pneumonia admission over the following 12 months (RR for infants in the lowest quartile of weight for age z-scores 1.28 [95% CI 1.08 to 1.51]). Poor growth in smaller than average infants was also associated with an increased risk of pneumonia (RR for those in the lowest quartile of growth in early infancy 1.31 [95%CI 1.02 to 1.68]). At a population level, we found that seasonal undernutrition preceded the seasonal increase in pneumonia and respiratory syncytial virus admissions by approximately 10 weeks (pairwise correlation at this lag was −0.41 [95%CI −0.53 to −0.27] for pneumonia admissions, and −0.63 [95%CI −0.72 to −0.51] for respiratory syncytial virus admissions). This lag appears biologically plausible. These results suggest that in addition to being an individual level risk factor for pneumonia, poor nutrition may act as a population level driver of seasonal pneumonia epidemics in the tropics. Further investigation of the seasonal level association, in particular the estimation of the expected lag between seasonal undernutrition and increased pneumonia incidence, is recommended.
doi:10.1371/journal.pone.0067528
PMCID: PMC3695907  PMID: 23840731
8.  Assessment of bronchodilator responsiveness in preschool children using forced oscillations 
Thorax  2007;62(9):814-819.
Background
The forced oscillation technique (FOT) requires minimal patient cooperation and is feasible in preschool children. Few data exist on respiratory function changes measured using FOT following inhaled bronchodilators (BD) in healthy young children, limiting the clinical applications of BD testing in this age group. A study was undertaken to determine the most appropriate method of quantifying BD responses using FOT in healthy young children and those with common respiratory conditions including cystic fibrosis, neonatal chronic lung disease and asthma and/or current wheeze.
Methods
A pseudorandom FOT signal (4–48 Hz) was used to examine respiratory resistance and reactance at 6, 8 and 10 Hz; 3–5 acceptable measurements were made before and 15 min after the administration of salbutamol. The post‐BD response was expressed in absolute and relative (percentage of baseline) terms.
Results
Significant BD responses were seen in all groups. Absolute changes in BD responses were related to baseline lung function within each group. Relative changes in BD responses were less dependent on baseline lung function and were independent of height in healthy children. Those with neonatal chronic lung disease showed a strong baseline dependence in their responses. The BD response in children with cystic fibrosis, asthma or wheeze (based on both group mean data and number of responders) was not greater than in healthy children.
Conclusions
The BD response assessed by the FOT in preschool children should be expressed as a relative change to account for the effect of baseline lung function. The limits for a positive BD response of −40% and 65% for respiratory resistance and reactance, respectively, are recommended.
doi:10.1136/thx.2006.071290
PMCID: PMC2117298  PMID: 17412777
9.  Respiratory function in healthy young children using forced oscillations 
Thorax  2007;62(6):521-526.
Background
Monitoring of respiratory function is important in the diagnosis and management of respiratory disease. The forced oscillation technique requires minimal patient cooperation and is ideal for the determination of respiratory function in young children. This study aimed to develop reference ranges and to document the repeatability in healthy young children using commercially available forced oscillation equipment.
Methods
The forced oscillation technique, which uses a pseudo‐random noise forcing signal between 4 and 48 Hz, was used to measure respiratory function in healthy young children. Repeatability over a 15 min period was also assessed. Regression equations and standardised Z scores were determined for respiratory resistance (Rrs) and reactance (Xrs) at 6, 8 and 10 Hz.
Results
Respiratory function was obtained in 158 healthy children aged two to seven years and between 92 and 127 cm in height. Oscillatory respiratory mechanics exhibited linear relationships with height. Within‐test variability for resistance ranged between 6% and 9% and between 17% and 20% for reactance. Resistance and reactance did not change significantly over a 15 min period.
Conclusions
Reference ranges for respiratory impedance variables in healthy children aged two to seven years are presented. The short‐term repeatability of forced oscillatory variables in this age group is reported, allowing appropriate cut‐off values for therapeutic interventions to be defined.
doi:10.1136/thx.2006.067835
PMCID: PMC2117207  PMID: 17251315
10.  In utero exposure to low dose arsenic via drinking water impairs early life lung mechanics in mice 
Background
Exposure to arsenic via drinking water is a significant environmental issue affecting millions of people around the world. Exposure to arsenic during foetal development has been shown to impair somatic growth and increase the risk of developing chronic respiratory diseases. The aim of this study was to determine if in utero exposure to low dose arsenic via drinking water is capable of altering lung growth and postnatal lung mechanics.
Methods
Pregnant C57BL/6 mice were given drinking water containing 0, 10 (current World Health Organisation (WHO) maximum contaminant level) or 100μg/L arsenic from gestational day 8 to birth. Birth outcomes and somatic growth were monitored. Plethysmography and the forced oscillation technique were used to collect measurements of lung volume, lung mechanics, pressure-volume curves and the volume dependence of lung mechanics in male and female offspring at two, four, six and eight weeks of age.
Results
In utero exposure to low dose arsenic via drinking water resulted in low birth weight and impaired parenchymal lung mechanics during infancy. Male offspring were more susceptible to the effects of arsenic on growth and lung mechanics than females. All alterations to lung mechanics following in utero arsenic exposure were recovered by adulthood.
Conclusions
Exposure to arsenic at the current WHO maximum contaminant level in utero impaired somatic growth and the development of the lungs resulting in alterations to lung mechanics during infancy. Deficits in growth and lung development in early life may contribute to the increased susceptibility of developing chronic respiratory disease in arsenic exposed human populations.
doi:10.1186/2050-6511-14-13
PMCID: PMC3584853  PMID: 23419080
Animal model; Arsenic; Environmental exposure; Growth & development; Lung function
11.  In Utero Exposure to Arsenic Alters Lung Development and Genes Related to Immune and Mucociliary Function in Mice 
Environmental Health Perspectives  2012;121(2):244-250.
Background: Exposure to arsenic via drinking water is a global environmental health problem. In utero exposure to arsenic via drinking water increases the risk of lower respiratory tract infections during infancy and mortality from bronchiectasis in early adulthood.
Objectives: We aimed to investigate how arsenic exposure in early life alters lung development and pathways involved in innate immunity.
Methods: Pregnant BALB/c, C57BL/6, and C3H/HeARC mice were exposed to 0 (control) or 100 μg/L arsenic via drinking water from gestation day 8 until the birth of their offspring. We measured somatic growth, lung volume, and lung mechanics of mice at 2 weeks of age. We used fixed lungs for structural analysis and collected lung tissue for gene expression analysis by microarray.
Results: The response to arsenic was genetically determined, and C57BL/6 mice were the most susceptible. Arsenic-exposed C57BL/6 mice were smaller in size, had smaller lungs, and had impaired lung mechanics compared with controls. Exposure to arsenic in utero up-regulated the expression of genes in the lung involved in mucus production (Clca3, Muc5b, Scgb3a1), innate immunity (Reg3γ, Tff2, Dynlrb2, Lplunc1), and lung morphogenesis (Sox2). Arsenic exposure also induced mucous cell metaplasia and increased expression of CLCA3 protein in the large airways.
Conclusions: Alterations in somatic growth, lung development, and the expression of genes involved in mucociliary clearance and innate immunity in the lung are potential mechanisms through which early life arsenic exposure impacts respiratory health.
doi:10.1289/ehp.1205590
PMCID: PMC3569690  PMID: 23221970
gene expression; growth and development; innate immunity; mucociliary clearance; toxicity
12.  INCENTIVE DEVICE IMPROVES SPACER TECHNIQUE BUT NOT CLINICAL OUTCOME IN PRESCHOOL CHILDREN WITH ASTHMA 
Background
Inhaled corticosteroid use reduces respiratory symptoms in young children with recurrent wheeze. Delivery of steroids with pressurised metered dose inhalers and spacers is influenced by children’s proficiency/technique in using delivery devices.
Objectives
To investigate the influence of an incentive device, the Funhaler®, on spacer technique and symptom control in young children with asthma and recurrent wheeze.
Methods
Randomised controlled trial where 132 2–6 year old asthmatic children received regular inhaled fluticasone through Aerochamber Plus®, or Funhaler®. The setting was a research clinic at Princess Margaret Hospital for Children, Perth, Australia. Subjects were followed up for a year. The main outcome measure was asthma symptoms. Proficiency in spacer technique was measured as salbutamol inhaled from spacer onto filter. Quality of life was measured three-monthly. Groups were compared in terms of spacer technique, symptoms and quality of life. The relationship between spacer technique and clinical outcome was examined.
Results
There was no difference between Funhaler and Aerochamber groups in wheeze free days, cough free days, bronchodilator free days or quality of life (p = 0.90, 0.87, 0.74 and 0.11 respectively). Spacer technique was better in the Funhaler group (p = 0.05), particularly in subjects younger than 4 years of age (p = 0.002). Drug dose on filter (as the mean of five 100μg doses) ranged from zero to 136μg.
Conclusion
Use of Funhaler® incentive device does not improve clinical outcome, but improves spacer technique in children younger than 4 years. Variability in drug delivery is large in young children using pMDI-spacers.
doi:10.1111/j.1440-1754.2011.02190.x
PMCID: PMC3261303  PMID: 22040259
Asthma; wheeze; children; preschool; spacer technique; device technique; inhaled corticosteroids
13.  Respiratory viral infections in children with asthma: do they matter and can we prevent them? 
BMC Pediatrics  2012;12:147.
Background
Asthma is a major public health problem with a huge social and economic burden affecting 300 million people worldwide. Viral respiratory infections are the major cause of acute asthma exacerbations and may contribute to asthma inception in high risk young children with susceptible genetic background. Acute exacerbations are associated with decreased lung growth or accelerated loss of lung function and, as such, add substantially to both the cost and morbidity associated with asthma.
Discussion
While the importance of preventing viral infection is well established, preventive strategies have not been well explored. Good personal hygiene, hand-washing and avoidance of cigarette smoke are likely to reduce respiratory viral infections. Eating a healthy balanced diet, active probiotic supplements and bacterial-derived products, such as OM-85, may reduce recurrent infections in susceptible children. There are no practical anti-viral therapies currently available that are suitable for widespread use.
Summary
Hand hygiene is the best measure to prevent the common cold. A healthy balanced diet, active probiotic supplements and immunostimulant OM-85 may reduce recurrent infections in asthmatic children.
doi:10.1186/1471-2431-12-147
PMCID: PMC3471019  PMID: 22974166
Acute respiratory infections; Childhood asthma; Common cold; Acute exacerbations; Rhinovirus
14.  Genome-wide association and large scale follow-up identifies 16 new loci influencing lung function 
Artigas, María Soler | Loth, Daan W | Wain, Louise V | Gharib, Sina A | Obeidat, Ma’en | Tang, Wenbo | Zhai, Guangju | Zhao, Jing Hua | Smith, Albert Vernon | Huffman, Jennifer E | Albrecht, Eva | Jackson, Catherine M | Evans, David M | Cadby, Gemma | Fornage, Myriam | Manichaikul, Ani | Lopez, Lorna M | Johnson, Toby | Aldrich, Melinda C | Aspelund, Thor | Barroso, Inês | Campbell, Harry | Cassano, Patricia A | Couper, David J | Eiriksdottir, Gudny | Franceschini, Nora | Garcia, Melissa | Gieger, Christian | Gislason, Gauti Kjartan | Grkovic, Ivica | Hammond, Christopher J | Hancock, Dana B | Harris, Tamara B | Ramasamy, Adaikalavan | Heckbert, Susan R | Heliövaara, Markku | Homuth, Georg | Hysi, Pirro G | James, Alan L | Jankovic, Stipan | Joubert, Bonnie R | Karrasch, Stefan | Klopp, Norman | Koch, Beate | Kritchevsky, Stephen B | Launer, Lenore J | Liu, Yongmei | Loehr, Laura R | Lohman, Kurt | Loos, Ruth JF | Lumley, Thomas | Al Balushi, Khalid A | Ang, Wei Q | Barr, R Graham | Beilby, John | Blakey, John D | Boban, Mladen | Boraska, Vesna | Brisman, Jonas | Britton, John R | Brusselle, Guy G | Cooper, Cyrus | Curjuric, Ivan | Dahgam, Santosh | Deary, Ian J | Ebrahim, Shah | Eijgelsheim, Mark | Francks, Clyde | Gaysina, Darya | Granell, Raquel | Gu, Xiangjun | Hankinson, John L | Hardy, Rebecca | Harris, Sarah E | Henderson, John | Henry, Amanda | Hingorani, Aroon D | Hofman, Albert | Holt, Patrick G | Hui, Jennie | Hunter, Michael L | Imboden, Medea | Jameson, Karen A | Kerr, Shona M | Kolcic, Ivana | Kronenberg, Florian | Liu, Jason Z | Marchini, Jonathan | McKeever, Tricia | Morris, Andrew D | Olin, Anna-Carin | Porteous, David J | Postma, Dirkje S | Rich, Stephen S | Ring, Susan M | Rivadeneira, Fernando | Rochat, Thierry | Sayer, Avan Aihie | Sayers, Ian | Sly, Peter D | Smith, George Davey | Sood, Akshay | Starr, John M | Uitterlinden, André G | Vonk, Judith M | Wannamethee, S Goya | Whincup, Peter H | Wijmenga, Cisca | Williams, O Dale | Wong, Andrew | Mangino, Massimo | Marciante, Kristin D | McArdle, Wendy L | Meibohm, Bernd | Morrison, Alanna C | North, Kari E | Omenaas, Ernst | Palmer, Lyle J | Pietiläinen, Kirsi H | Pin, Isabelle | Polašek, Ozren | Pouta, Anneli | Psaty, Bruce M | Hartikainen, Anna-Liisa | Rantanen, Taina | Ripatti, Samuli | Rotter, Jerome I | Rudan, Igor | Rudnicka, Alicja R | Schulz, Holger | Shin, So-Youn | Spector, Tim D | Surakka, Ida | Vitart, Veronique | Völzke, Henry | Wareham, Nicholas J | Warrington, Nicole M | Wichmann, H-Erich | Wild, Sarah H | Wilk, Jemma B | Wjst, Matthias | Wright, Alan F | Zgaga, Lina | Zemunik, Tatijana | Pennell, Craig E | Nyberg, Fredrik | Kuh, Diana | Holloway, John W | Boezen, H Marike | Lawlor, Debbie A | Morris, Richard W | Probst-Hensch, Nicole | Kaprio, Jaakko | Wilson, James F | Hayward, Caroline | Kähönen, Mika | Heinrich, Joachim | Musk, Arthur W | Jarvis, Deborah L | Gläser, Sven | Järvelin, Marjo-Riitta | Stricker, Bruno H Ch | Elliott, Paul | O’Connor, George T | Strachan, David P | London, Stephanie J | Hall, Ian P | Gudnason, Vilmundur | Tobin, Martin D
Nature Genetics  2011;43(11):1082-1090.
Pulmonary function measures reflect respiratory health and predict mortality, and are used in the diagnosis of chronic obstructive pulmonary disease (COPD). We tested genome-wide association with the forced expiratory volume in 1 second (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) in 48,201 individuals of European ancestry, with follow-up of top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P<5×10−8) with pulmonary function, in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1, and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.
doi:10.1038/ng.941
PMCID: PMC3267376  PMID: 21946350
15.  Air Trapping on Chest CT Is Associated with Worse Ventilation Distribution in Infants with Cystic Fibrosis Diagnosed following Newborn Screening 
PLoS ONE  2011;6(8):e23932.
Background
In school-aged children with cystic fibrosis (CF) structural lung damage assessed using chest CT is associated with abnormal ventilation distribution. The primary objective of this analysis was to determine the relationships between ventilation distribution outcomes and the presence and extent of structural damage as assessed by chest CT in infants and young children with CF.
Methods
Data of infants and young children with CF diagnosed following newborn screening consecutively reviewed between August 2005 and December 2009 were analysed. Ventilation distribution (lung clearance index and the first and second moment ratios [LCI, M1/M0 and M2/M0, respectively]), chest CT and airway pathology from bronchoalveolar lavage were determined at diagnosis and then annually. The chest CT scans were evaluated for the presence or absence of bronchiectasis and air trapping.
Results
Matched lung function, chest CT and pathology outcomes were available in 49 infants (31 male) with bronchiectasis and air trapping present in 13 (27%) and 24 (49%) infants, respectively. The presence of bronchiectasis or air trapping was associated with increased M2/M0 but not LCI or M1/M0. There was a weak, but statistically significant association between the extent of air trapping and all ventilation distribution outcomes.
Conclusion
These findings suggest that in early CF lung disease there are weak associations between ventilation distribution and lung damage from chest CT. These finding are in contrast to those reported in older children. These findings suggest that assessments of LCI could not be used to replace a chest CT scan for the assessment of structural lung disease in the first two years of life. Further research in which both MBW and chest CT outcomes are obtained is required to assess the role of ventilation distribution in tracking the progression of lung damage in infants with CF.
doi:10.1371/journal.pone.0023932
PMCID: PMC3158781  PMID: 21886842
16.  Ethical Issues in Measuring Biomarkers in Children’s Environmental Health 
Environmental Health Perspectives  2009;117(8):1185-1190.
Background
Studying the impact of environmental exposures is important in children because they are more vulnerable to adverse effects on growth, development, and health. Assessing exposure in children is difficult, and measuring biomarkers is potentially useful. Research measuring biomarkers in children raises a number of ethical issues, some of which relate to children as research subjects and some of which are specific to biomarker research.
Objective
As an international group with experience in pediatric research, biomarkers, and the ethics of research in children, we highlight the ethical issues of undertaking biomarker research in children in these environments.
Discussion
Significant issues include undertaking research in vulnerable communities, especially in developing countries; managing community expectations; obtaining appropriate consent to conduct the research; the potential conflicts of obtaining permission from an ethics review board in an economically developed country to perform research in a community that may have different cultural values; returning research results to participants and communities when the researchers are uncertain of how to interpret the results; and the conflicting ethical obligations of maintaining participant confidentiality when information about harm or illegal activities mandate reporting to authorities.
Conclusion
None of these challenges are insurmountable and all deserve discussion. Pediatric biomarker research is necessary for advancing child health.
doi:10.1289/ehp.0800480
PMCID: PMC2721859  PMID: 19672395
biobanks; biomarkers; children; environmental exposure; genetics; infants; informed consent; research ethics
17.  Children's environmental health: an under-recognised area in paediatric health care 
BMC Pediatrics  2009;9:10.
The knowledge that the environment in which we live, grow and play, can have negative or positive impacts on our health and development is not new. However the recognition that adverse environments can significantly and specifically affect the growth and development of a child from early intrauterine life through to adolescence, as well as impact their health later in adulthood, is relatively recent and has not fully reached health care providers involved in paediatric care.
Over the past 15 years, world declarations and statements on children's rights, sustainable development, chemical safety and most recently climate change, have succeeded in cultivating a global focus on children's health and their right to a healthy environment. Many international calls for research in the area, have also been able to identify patterns of environmental diseases in children, assess children's exposures to many environmental toxicants, identify developmental periods of vulnerability, and quantify the cost benefits to public health systems and beyond, of addressing environmentally related diseases in children. Transferring this information to front-line health care providers and increasing their awareness about the global burden of disease attributed to the environment and children's especial vulnerability to environmental threats is the salient aim of this commentary.
doi:10.1186/1471-2431-9-10
PMCID: PMC2645393  PMID: 19196484
18.  Reversal of airway hyperresponsiveness by induction of airway mucosal CD4+CD25+ regulatory T cells 
The Journal of Experimental Medicine  2006;203(12):2649-2660.
An important feature of atopic asthma is the T cell–driven late phase reaction involving transient bronchoconstriction followed by development of airways hyperresponsiveness (AHR). Using a unique rat asthma model we recently showed that the onset and duration of the aeroallergen-induced airway mucosal T cell activation response in sensitized rats is determined by the kinetics of functional maturation of resident airway mucosal dendritic cells (AMDCs) mediated by cognate interactions with CD4+ T helper memory cells. The study below extends these investigations to chronic aeroallergen exposure. We demonstrate that prevention of ensuing cycles of T cell activation and resultant AHR during chronic exposure of sensitized rats to allergen aerosols is mediated by CD4+CD25+Foxp3+LAG3+ CTLA+CD45RC+ T cells which appear in the airway mucosa and regional lymph nodes within 24 h of initiation of exposure, and inhibit subsequent Th-mediated upregulation of AMDC functions. These cells exhibit potent regulatory T (T reg) cell activity in both in vivo and ex vivo assay systems. The maintenance of protective T reg activity is absolutely dependent on continuing allergen stimulation, as interruption of exposure leads to waning of T reg activity and reemergence of sensitivity to aeroallergen exposure manifesting as AMDC/T cell upregulation and resurgence of T helper 2 cytokine expression, airways eosinophilia, and AHR.
doi:10.1084/jem.20060155
PMCID: PMC2118157  PMID: 17088431
19.  Dendritic Cell Immaturity during Infancy Restricts the Capacity To Express Vaccine-Specific T-Cell Memory  
Infection and Immunity  2006;74(2):1106-1112.
The capacity of the immune system in infants to develop stable T-cell memory in response to vaccination is attenuated, and the mechanism(s) underlying this developmental deficiency in humans is poorly understood. The present study focuses on the capacity for expression of in vitro recall responses to tetanus and diphtheria antigens in lymphocytes from 12-month-old infants vaccinated during the first 6 months of life. We demonstrate that supplementation of infant lymphocytes with “matured” dendritic cells (DC) cultured from autologous CD14+ precursors unmasks previously covert cellular immunity in the form of Th2-skewed cytokine production. Supplementation of adult lymphocytes with comparable prematured autologous DC also boosted vaccine-specific T-cell memory expression, but in contrast to the case for the infants, these cytokine responses were heavily Th1 skewed. Compared to adults, infants had significantly fewer circulating myeloid DC (P < 0.0001) and plasmacytoid DC (P < 0.0001) as a proportion of peripheral blood mononuclear cells. These findings suggest that deficiencies in the numbers of antigen-presenting cells and their functional competence at 12 months of age limit the capacity to express effector memory responses and are potentially a key factor in reduced vaccine responsiveness in infants.
doi:10.1128/IAI.74.2.1106-1112.2006
PMCID: PMC1360347  PMID: 16428758
20.  Induction of Asthma and the Environment: What We Know and Need to Know 
Environmental Health Perspectives  2006;114(4):615-619.
The prevalence of asthma has increased dramatically over the last 25 years in the United States and in other nations as a result of ill-defined changes in living conditions in modern society. On 18 and 19 October 2004 the U.S. Environmental Protection Agency and the National Institute of Environmental Health Sciences sponsored the workshop “Environmental Influences on the Induction and Incidence of Asthma” to review current scientific evidence with respect to factors that may contribute to the induction of asthma. Participants addressed two broad questions: a) What does the science suggest that regulatory and public health agencies could do now to reduce the incidence of asthma? and b) What research is needed to improve our understanding of the factors that contribute to the induction of asthma and our ability to manage this problem? In this article (one of four articles resulting from the workshop), we briefly characterize asthma and its public health and economic impacts, and intervention strategies that have been successfully used to prevent induction of asthma in the workplace. We conclude with the findings of seven working groups that focus on ambient air, indoor pollutants (biologics), occupational exposures, early life stages, older adults, intrinsic susceptibility, and lifestyle. These groups found strong scientific support for public health efforts to limit in utero and postnatal exposure to cigarette smoke. However, with respect to other potential types of interventions, participants noted many scientific questions, which are summarized in this article. Research to address these questions could have a significant public health and economic impact that would be well worth the investment.
doi:10.1289/ehp.8376
PMCID: PMC1440790  PMID: 16581555
air pollution; allergy; asthma economic impact; asthma induction; asthma prevalence; biologics; indoor environment; occupational exposure; public health; susceptibility
21.  Hyperresponsiveness to inhaled but not intravenous methacholine during acute respiratory syncytial virus infection in mice 
Respiratory Research  2005;6(1):142.
Background
To characterise the acute physiological and inflammatory changes induced by low-dose RSV infection in mice.
Methods
BALB/c mice were infected as adults (8 wk) or weanlings (3 wk) with 1 × 105 pfu of RSV A2 or vehicle (intranasal, 30 μl). Inflammation, cytokines and inflammatory markers in bronchoalveolar lavage fluid (BALF) and airway and tissue responses to inhaled methacholine (MCh; 0.001 – 30 mg/ml) were measured 5, 7, 10 and 21 days post infection. Responsiveness to iv MCh (6 – 96 μg/min/kg) in vivo and to electrical field stimulation (EFS) and MCh in vitro were measured at 7 d. Epithelial permeability was measured by Evans Blue dye leakage into BALF at 7 d. Respiratory mechanics were measured using low frequency forced oscillation in tracheostomised and ventilated (450 bpm, flexiVent) mice. Low frequency impedance spectra were calculated (0.5 – 20 Hz) and a model, consisting of an airway compartment [airway resistance (Raw) and inertance (Iaw)] and a constant-phase tissue compartment [coefficients of tissue damping (G) and elastance (H)] was fitted to the data.
Results
Inflammation in adult mouse BALF peaked at 7 d (RSV 15.6 (4.7 SE) vs. control 3.7 (0.7) × 104 cells/ml; p < 0.001), resolving by 21 d, with no increase in weanlings at any timepoint. RSV-infected mice were hyperresponsive to aerosolised MCh at 5 and 7 d (PC200 Raw adults: RSV 0.02 (0.005) vs. control 1.1 (0.41) mg/ml; p = 0.003) (PC200 Raw weanlings: RSV 0.19 (0.12) vs. control 10.2 (6.0) mg/ml MCh; p = 0.001). Increased responsiveness to aerosolised MCh was matched by elevated levels of cysLT at 5 d and elevated VEGF and PGE2 at 7 d in BALF from both adult and weanling mice. Responsiveness was not increased in response to iv MCh in vivo or EFS or MCh challenge in vitro. Increased epithelial permeability was not detected at 7 d.
Conclusion
Infection with 1 × 105 pfu RSV induced extreme hyperresponsiveness to aerosolised MCh during the acute phase of infection in adult and weanling mice. The route-specificity of hyperresponsiveness suggests that epithelial mechanisms were important in determining the physiological effects. Inflammatory changes were dissociated from physiological changes, particularly in weanling mice.
doi:10.1186/1465-9921-6-142
PMCID: PMC1325022  PMID: 16324223
forced oscillation; airway resistance; physiology
22.  Th2-Associated Local Reactions to the Acellular Diphtheria-Tetanus-Pertussis Vaccine in 4- to 6-Year-Old Children  
Infection and Immunity  2005;73(12):8130-8135.
Acellular vaccines against diphtheria-tetanus-pertussis (acellular pertussis) (DTaP) are being progressively introduced into vaccination programs worldwide, with the aim of reducing T-helper 1 (Th1)-associated reactogenicity associated with the cellular diphtheria-tetanus-pertussis (whole-cell pertussis) (DTwP) vaccine. The DTaP vaccine has an improved safety profile in infants, but little information is available concerning the nature of the ensuing immunological memory in older children and how this may affect the reactogenicity of DTaP booster doses. We have addressed this question in the present study by assessing polyclonal and vaccine antigen-specific humoral and cellular immune responses to boosting with DTaP in 4- to 6-year-old children primed during infancy with DTaP (n = 30) or DTwP (n = 16) and by correlating these parameters, in particular cytokine responses, with expression of local side effects at the injection site. Large local reactions (≥50-mm diameter) 24 to 72 h after receiving the DTaP booster occurred in 43% of exclusively DTaP-primed children, in contrast to 6% of children primed with DTwP. These reactions were associated with vigorous T helper 2 (Th2)-polarized memory responses to vaccine antigen exemplified by interleukin 5 (IL-5), IL-6, and IL-13 production and log-scale boosting of tetanus-specific immunoglobulin E and occurred most frequently among children who are intrinsically “high Th2 responders” as detected by in vitro responsiveness to polyclonal mitogen. Our findings suggest that priming during infancy with DTaP promotes stable, boostable Th2-polarized immunity against vaccine antigens, which in a significant subset of children is subsequently associated with local reactions at the booster site. The time course of these reactions suggests that the underlying mechanism involves reactivation of Th2-polarized cellular immune memory.
doi:10.1128/IAI.73.12.8130-8135.2005
PMCID: PMC1307058  PMID: 16299307
23.  The pattern of methacholine responsiveness in mice is dependent on antigen challenge dose 
Respiratory Research  2004;5(1):15.
Background
Considerable variation exists in the protocols used to induce hyperresponsiveness in murine models of allergic sensitisation. We examined the effect of varying the number of antigen exposures at challenge on the development of methacholine responsiveness in systemically sensitised mice.
Methods
BALB/c mice were sensitised with ovalbumin (OVA), challenged with 1, 3 or 6 OVA aerosols. Lung function was measured using low frequency forced oscillations and partitioned into components representing the airways (Raw) and lung parenchyma (tissue damping (G) and tissue elastance (H)). Responsiveness to inhaled methacholine (MCh), inflammatory cell profile and circulating IgE were assessed 24 and 48 hours after challenge. The threshold dose of MCh required to elicit a detectable response (sensitivity) and response to 30 mg.mL-1 (maximal response) were determined for each compartment.
Results
Sensitivity; All three OVA protocols resulted in an increased sensitivity to MCh in Raw but not in G or H. These responses where present at 24 and 48 hrs, except 1 OVA aerosol in which changes had resolved by 48 hrs. Maximal response; 1 OVA aerosol increased maximal responses in Raw, G and H at 24 hrs, which was gone by 48 hrs. Three OVA aerosols increased responses in H at 48 hrs only. Six OVA challenges caused increases in Raw, G and H at both 24 and 48 hrs. Eosinophils increased with increasing antigen challenges. IgE was elevated by OVA sensitisation but not boosted by OVA aerosol challenge.
Conclusions
The pattern of eosinophilia, IgE and MCh responsiveness in mice was determined by antigen dose at challenge. In this study, increased sensitivity to MCh was confined to the airways whereas increases in maximal responses occurred in both the airway and parenchymal compartments. The presence of eosinophilia and IgE did not always coincide with increased responsiveness to inhaled MCh. These findings require further systematic study to determine whether different mechanisms underlie airway and parenchymal hyperresponsiveness post antigen challenge.
doi:10.1186/1465-9921-5-15
PMCID: PMC521690  PMID: 15385057
24.  Bidirectional Interactions between Antigen-bearing Respiratory Tract Dendritic Cells (DCs) and T Cells Precede the Late Phase Reaction in Experimental Asthma 
The airway mucosal response to allergen in asthma involves influx of activated T helper type 2 cells and eosinophils, transient airflow obstruction, and airways hyperresponsiveness (AHR). The mechanism(s) underlying transient T cell activation during this inflammatory response is unclear. We present evidence that this response is regulated via bidirectional interactions between airway mucosal dendritic cells (AMDC) and T memory cells. After aerosol challenge, resident AMDC acquire antigen and rapidly mature into potent antigen-presenting cells (APCs) after cognate interactions with T memory cells. This process is restricted to dendritic cells (DCs) in the mucosae of the conducting airways, and is not seen in peripheral lung. Within 24 h, antigen-bearing mature DCs disappear from the airway wall, leaving in their wake activated interleukin 2R+ T cells and AHR. Antigen-bearing activated DCs appear in regional lymph nodes at 24 h, suggesting onward migration from the airway. Transient up-regulation of CD86 on AMDC accompanies this process, which can be reproduced by coculture of resting AMDC with T memory cells plus antigen. The APC activity of AMDC can be partially inhibited by anti-CD86, suggesting that CD86 may play an active role in this process and/or is a surrogate for other relevant costimulators. These findings provide a plausible model for local T cell activation at the lesional site in asthma, and for the transient nature of this inflammatory response.
doi:10.1084/jem.20021328
PMCID: PMC2196086  PMID: 12835476
dendritic cells; asthma; respiratory mucosa; T cells; activation
25.  Environmental threats to children's health in Southeast Asia and the Western Pacific. 
Environmental Health Perspectives  2003;111(10):1340-1347.
The Southeast Asia and Western Pacific regions contain half of the world's children and are among the most rapidly industrializing regions of the globe. Environmental threats to children's health are widespread and are multiplying as nations in the area undergo industrial development and pass through the epidemiologic transition. These environmental hazards range from traditional threats such as bacterial contamination of drinking water and wood smoke in poorly ventilated dwellings to more recently introduced chemical threats such as asbestos construction materials; arsenic in groundwater; methyl isocyanate in Bhopal, India; untreated manufacturing wastes released to landfills; chlorinated hydrocarbon and organophosphorous pesticides; and atmospheric lead emissions from the combustion of leaded gasoline. To address these problems, pediatricians, environmental health scientists, and public health workers throughout Southeast Asia and the Western Pacific have begun to build local and national research and prevention programs in children's environmental health. Successes have been achieved as a result of these efforts: A cost-effective system for producing safe drinking water at the village level has been devised in India; many nations have launched aggressive antismoking campaigns; and Thailand, the Philippines, India, and Pakistan have all begun to reduce their use of lead in gasoline, with resultant declines in children's blood lead levels. The International Conference on Environmental Threats to the Health of Children, held in Bangkok, Thailand, in March 2002, brought together more than 300 representatives from 35 countries and organizations to increase awareness on environmental health hazards affecting children in these regions and throughout the world. The conference, a direct result of the Environmental Threats to the Health of Children meeting held in Manila in April 2000, provided participants with the latest scientific data on children's vulnerability to environmental hazards and models for future policy and public health discussions on ways to improve children's health. The Bangkok Statement, a pledge resulting from the conference proceedings, is an important first step in creating a global alliance committed to developing active and innovative national and international networks to promote and protect children's environmental health.
PMCID: PMC1241616  PMID: 12896856

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