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Asthma, rhinitis, and eczema are complex diseases with multiple genetic and environmental factors interlinked through IgE-associated and non-IgE-associated mechanisms. Mechanisms of the Development of ALLergy (MeDALL; EU FP7-CP-IP; project no: 261357; 2010-2015) studied the complex links of allergic diseases at the clinical and mechanistic levels by linking epidemiologic, clinical, and mechanistic research, including in vivo and in vitro models. MeDALL integrated 14 European birth cohorts, including 44,010 participants and 160 cohort follow-ups between pregnancy and age 20 years. Thirteen thousand children were prospectively followed after puberty by using a newly standardized MeDALL Core Questionnaire. A microarray developed for allergen molecules with increased IgE sensitivity was obtained for 3,292 children. Estimates of air pollution exposure from previous studies were available for 10,000 children. Omics data included those from historical genome-wide association studies (23,000 children) and DNA methylation (2,173), targeted multiplex biomarker (1,427), and transcriptomic (723) studies. Using classical epidemiology and machine-learning methods in 16,147 children aged 4 years and 11,080 children aged 8 years, MeDALL showed the multimorbidity of eczema, rhinitis, and asthma and estimated that only 38% of multimorbidity was attributable to IgE sensitization. MeDALL has proposed a new vision of multimorbidity independent of IgE sensitization, and has shown that monosensitization and polysensitization represent 2 distinct phenotypes. The translational component of MeDALL is shown by the identification of a novel allergic phenotype characterized by polysensitization and multimorbidity, which is associated with the frequency, persistence, and severity of allergic symptoms. The results of MeDALL will help integrate personalized, predictive, preventative, and participatory approaches in allergic diseases., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The Strategic Implementation Plan of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) proposed six Action Groups. After almost three years of activity, many achievements have been obtained through commitments or collaborative work of the Action Groups. However, they have often worked in silos and, consequently, synergies between Action Groups have been proposed to strengthen the triple win of the EIP on AHA. The paper presents the methodology and current status of the Task Force on EIP on AHA synergies. Synergies are in line with the Action Groups' new Renovated Action Plan (2016-2018) to ensure that their future objectives are coherent and fully connected. The outcomes and impact of synergies are using the Monitoring and Assessment Framework for the EIP on AHA (MAFEIP). Eight proposals for synergies have been approved by the Task Force: Five cross-cutting synergies which can be used for all current and future synergies as they consider overarching domains (appropriate polypharmacy, citizen empowerment, teaching and coaching on AHA, deployment of synergies to EU regions, Responsible Research and Innovation), and three cross-cutting synergies focussing on current Action Group activities (falls, frailty, integrated care and chronic respiratory diseases).

The Allergic Rhinitis and its Impact on Asthma (ARIA) initiative commenced during a World Health Organization workshop in 1999. The initial goals were (1) to propose a new allergic rhinitis classification, (2) to promote the concept of multi-morbidity in asthma and rhinitis and (3) to develop guidelines with all stakeholders that could be used globally for all countries and populations. ARIA-disseminated and implemented in over 70 countries globally-is now focusing on the implementation of emerging technologies for individualized and predictive medicine. MASK [MACVIA ( Contre les Maladies Chroniques pour un Vieillissement Actif )-ARIA Sentinel NetworK] uses mobile technology to develop care pathways for the management of rhinitis and asthma by a multi-disciplinary group and by patients themselves. An app (Android and iOS) is available in 20 countries and 15 languages. It uses a visual analogue scale to assess symptom control and work productivity as well as a clinical decision support system. It is associated with an inter-operable tablet for physicians and other health care professionals. The scaling up strategy uses the recommendations of the European Innovation Partnership on Active and Healthy Ageing. The aim of the novel ARIA approach is to provide an active and healthy life to rhinitis sufferers, whatever their age, sex or socio-economic status, in order to reduce health and social inequalities incurred by the disease.

Background: Profiles of allergic sensitization are poorly documented in infancy. Relations between early sensitization and allergic morbidity need to be clarified., Methods: This study dealt with children involved in the Pollution and Asthma Risk: an Infant Study (PARIS), a population-based prospective birth cohort. Allergic sensitization to twelve food and four inhalant allergens was assessed at 18 months and defined by a specific immunoglobulin E (IgE) level ≥0.35 kU A /l. Health data were collected by standardized questionnaires at 2 and 6 years. Early allergic profiles were identified by an unsupervised cluster analysis based on health data at 2 years and IgE measurements. Profiles were compared with regard to allergic morbidity and multimorbidity at 6 years., Results: Sensitization to any allergen concerned 13.6% of infants. By cluster analysis, 1525 infants were grouped into three profiles: 89.2% not or rarely sensitized (only 3.7% of sensitized), 9.2% mainly sensitized to one or few allergens (45.2% of monosensitized and 45.9% of paucisensitized) and 1.6% all polysensitized. The prevalence of doctor-diagnosed asthma, rhinitis, eczema, food allergy and multimorbidity at 2 years increased from profile one to profile three (p-trend <0.001). At 6 years, symptoms of current asthma, rhinitis, eczema and multimorbidity were significantly more frequent in the last two profiles., Conclusions: This study highlights, as early as 18 months of age, three profiles of increasing severity with regard to allergic sensitization and diseases. These profiles also differ in terms of allergic morbidity at 6 years. Early sensitization can predict allergic multimorbidity in childhood, and in the case of early polysensitization, multimorbidity is more frequent as soon as infancy., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Allergic sensitisation is poorly documented in infants. This study aims to provide new insights into allergic sensitisation patterns and related factors in infancy., Methods: This study concerns 1860 infants involved in the Pollution and Asthma Risk: an Infant Study (PARIS) population-based birth cohort who had a standardised health examination when 18 months old, from 2004 to 2008. Sensitisation was assessed by measurements of serum specific IgE to 12 food and 4 inhalant allergens and defined by IgE≥0.35kU A /L. Information regarding lifestyle and environment were obtained from questionnaires prospectively administered., Results: Prevalence of allergic sensitisation to any allergen, to food allergens, and to aeroallergens was 13.8%, 12.3%, and 2.3%, respectively. Multiple sensitisation (to at least two allergens) concerned 6.2% of toddlers. Intrinsic factors such as male gender, family history of allergy, and high birth weight increased the risk of food allergen sensitisation and multiple sensitisation. Caesarean section was also positively associated with multiple sensitisation. Day-care attendance was negatively related to food allergen, aeroallergen, and multiple sensitisation. A cat entering the baby's room in early life was strongly associated with aeroallergen sensitisation (ORa 3.21, 95%CI: 1.29-8.01). An introduction of meat in infant's diet after 6 months of age was negatively related to food allergen sensitisation (ORa 0.46, 95%CI: 0.24-0.91)., Conclusion: Our results suggest that intrinsic factors and indicators of exposure to microorganisms such as caesarean section and day-care attendance may be associated with inhalant as well as food allergen sensitisation in infancy. For example, male gender, family history of allergy, high birth weight, and caesarean section could be positively related whereas day-care attendance could be negatively related to both aeroallergen and food allergen sensitisation. Conversely, early life exposure to inhalant allergens or food allergens may be specifically linked to either aeroallergen sensitisation or food allergen sensitisation, respectively., (Copyright © 2016 Elsevier GmbH. All rights reserved.)

More than a barrier against environmental agents, skin reflects individual health and is a visible sign of ageing with the progressive loss of skin integrity. In order to evaluate the consequences of an environmental complex mixture, with tobacco smoke (TS) as model, on cellular and morphological changes, a 3D skin model was used. Morphologically, tissue integrity was intact after one TS-exposure while the superficial layers were drastically reduced after two TS-exposures. However, TS modified epidermal organisation at the molecular level after just one exposure. A decrease in loricrin protein staining was showed in the epidermis, while production of inflammatory cytokines (IL-8, IL-1α, IL-18) and metalloproteinase (MMP-1, MMP-3) were stimulated. Oxidative stress was also illustrated with an increase in 4-HNE protein staining. Moreover, terminal differentiation, cell-cell junction and anchorage gene expression was down-regulated in our model after one TS-exposure. In conclusion, tobacco smoke impacted the fundamental functions of skin, namely tissue anchorage, cornification and skin desquamation. Oxidative stress resulted in skin ageing. The tissue was even reactive with the inflammatory pathways, after one TS-exposure. The 3D-RHE model is appropriate for evaluating the impact of environmental pollutants on skin ageing., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Action Plan B3 of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) focuses on the integrated care of chronic diseases. Area 5 (Care Pathways) was initiated using chronic respiratory diseases as a model. The chronic respiratory disease action plan includes (1) AIRWAYS integrated care pathways (ICPs), (2) the joint initiative between the Reference site MACVIA-LR (Contre les MAladies Chroniques pour un VIeillissement Actif) and ARIA (Allergic Rhinitis and its Impact on Asthma), (3) Commitments for Action to the European Innovation Partnership on Active and Healthy Ageing and the AIRWAYS ICPs network. It is deployed in collaboration with the World Health Organization Global Alliance against Chronic Respiratory Diseases (GARD). The European Innovation Partnership on Active and Healthy Ageing has proposed a 5-step framework for developing an individual scaling up strategy: (1) what to scale up: (1-a) databases of good practices, (1-b) assessment of viability of the scaling up of good practices, (1-c) classification of good practices for local replication and (2) how to scale up: (2-a) facilitating partnerships for scaling up, (2-b) implementation of key success factors and lessons learnt, including emerging technologies for individualised and predictive medicine. This strategy has already been applied to the chronic respiratory disease action plan of the European Innovation Partnership on Active and Healthy Ageing.

Considering the impact of respiratory diseases around the world, appropriate experimental tools to help understand the mechanisms involved in such diseases are becoming essential. Our aim was to investigate the cellular and morphological reactivity of a human Reconstituted Nasal Epithelium (hRNE) to evaluate the impact of environmental complex mixture (ECM), with tobacco smoke as a model, after three weeks of repeated exposures. Staining of hRNE showed a multilayered ciliated epithelium, with a regular cilia beats, and a mucus production. When hRNE was exposed to ECM for 5 min once or twice a week, during 3 weeks, significant changes occurred: IL-8 production significantly increased 24h after the first exposure compared with Air-exposure and only during the first week, without any loss of tissue integrity. Immunostaining of F-actin cytoskeleton showed a modification in cellular morphology (number and diameter). Taken together our results indicate that hRNE is well suited to study the cellular and morphological effects of repeated exposures to an environmental complex mixture. Human reconstituted epithelium models are currently the best in vitro representation of human respiratory tract physiology, and also the most robust for performing repeated exposures to atmospheric pollutants., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Several unmet needs have been identified in allergic rhinitis: identification of the time of onset of the pollen season, optimal control of rhinitis and comorbidities, patient stratification, multidisciplinary team for integrated care pathways, innovation in clinical trials and, above all, patient empowerment. MASK-rhinitis (MACVIA-ARIA Sentinel NetworK for allergic rhinitis) is a simple system centred around the patient which was devised to fill many of these gaps using Information and Communications Technology (ICT) tools and a clinical decision support system (CDSS) based on the most widely used guideline in allergic rhinitis and its asthma comorbidity (ARIA 2015 revision). It is one of the implementation systems of Action Plan B3 of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA). Three tools are used for the electronic monitoring of allergic diseases: a cell phone-based daily visual analogue scale (VAS) assessment of disease control, CARAT (Control of Allergic Rhinitis and Asthma Test) and e-Allergy screening (premedical system of early diagnosis of allergy and asthma based on online tools). These tools are combined with a clinical decision support system (CDSS) and are available in many languages. An e-CRF and an e-learning tool complete MASK. MASK is flexible and other tools can be added. It appears to be an advanced, global and integrated ICT answer for many unmet needs in allergic diseases which will improve policies and standards., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Health is a multi-dimensional concept, capturing how people feel and function. The broad concept of Active and Healthy Ageing was proposed by the World Health Organisation (WHO) as the process of optimizing opportunities for health to enhance quality of life as people age. It applies to both individuals and population groups. A universal Active and Healthy Ageing definition is not available and it may differ depending on the purpose of the definition and/or the questions raised. While the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) has had a major impact, a definition of Active and Healthy Ageing is urgently needed. A meeting was organised in Montpellier, France, October 20-21, 2014 as the annual conference of the EIP on AHA Reference Site MACVIA-LR (Contre les Maladies Chroniques pour un Vieillissement Actif en Languedoc Roussillon) to propose an operational definition of Active and Healthy Ageing including tools that may be used for this. The current paper describes the rationale and the process by which the aims of the meeting will be reached.

Allergic diseases [asthma, rhinitis and atopic dermatitis (AD)] are complex. They are associated with allergen-specific IgE and nonallergic mechanisms that may coexist in the same patient. In addition, these diseases tend to cluster and patients present concomitant or consecutive diseases (multimorbidity). IgE sensitization should be considered as a quantitative trait. Important clinical and immunological differences exist between mono- and polysensitized subjects. Multimorbidities of allergic diseases share common causal mechanisms that are only partly IgE-mediated. Persistence of allergic diseases over time is associated with multimorbidity and/or IgE polysensitization. The importance of the family history of allergy may decrease with age. This review puts forward the hypothesis that allergic multimorbidities and IgE polysensitization are associated and related to the persistence or re-occurrence of foetal type 2 signalling. Asthma, rhinitis and AD are manifestations of a common systemic immune imbalance (mesodermal origin) with specific patterns of remodelling (ectodermal or endodermal origin). This study proposes a new classification of IgE-mediated allergic diseases that allows the definition of novel phenotypes to (i) better understand genetic and epigenetic mechanisms, (ii) better stratify allergic preschool children for prognosis and (iii) propose novel strategies of treatment and prevention., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Prenatal and peri-natal events play a fundamental role in health, development of diseases and ageing (Developmental Origins of Health and Disease (DOHaD)). Research on the determinants of active and healthy ageing is a priority to: (i) inform strategies for reducing societal and individual costs of an ageing population and (ii) develop effective novel prevention strategies. It is important to compare the trajectories of respiratory diseases with those of other chronic diseases., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: During the last decades, a large number of phenotypes and disease classifications of allergic diseases have been proposed. Despite the heterogeneity across studies, no systematic review has been conducted on phenotype classification and the criteria that define allergic diseases. We aimed to identify clinically expressed, population-based phenotypes of allergic diseases and their interrelationships, to explore disease heterogeneity and to evaluate the measurements employed in disease diagnosis., Methods: We conducted a search of MEDLINE up to December 2012, to identify relevant original studies published in the English language that examine at least one objective of this systematic review in subjects aged 0-18 years. The screening of titles and abstracts and the extraction of data were conducted independently by two reviewers., Results: From a total of 13,767 citations, 197 studies met the criteria for inclusion, with 54% being cohort studies. Allergic diseases were studied as a single entity in 55% (109/197) of the studies or in the context of multimorbidity in 45%. Asthma accounted for 81.7% of the studies examining single diseases. Overall, up to 33 different phenotypes of allergic disease were reported. Transient early, late-onset and persistent wheeze were the most frequently reported phenotypes. Most studies (78%) used questionnaires. The skin-prick test was the preferred measurement of sensitization (64%). Spirometry and bronchial hyperresponsiveness were assessed in one third of the studies, peak flow rate in 8.6% and disease severity in 35%., Conclusions: Studies reporting phenotypes of allergic diseases in children are highly heterogeneous and often lack objective phenotypical measures. A concerted effort to standardize methods and terminology is necessary., (© 2015 S. Karger AG, Basel.)

Forced expiratory flow (FEF) at low lung volumes are supposed to be better at detecting lung-function impairment in asthmatic children than a forced volume. The aim of this study was to examine whether FEF results could modify the interpretation of baseline and post-bronchodilator spirometry in asthmatic schoolchildren in whom forced expiratory volumes are within the normal range. Spirometry, with post-bronchodilator vital capacity within 10% of that of baseline in healthy and asthmatic children, was recorded prospectively. We defined abnormal baseline values expressed as z-scores <-1.645, forced expiratory volume in 1 s (FEV1) reversibility as a baseline increase >12%, FEF reversibility as an increase larger than the 2.5th percentile of post-bronchodilator changes in healthy children. Among 66 healthy and 50 asthmatic schoolchildren, only two (1.7%) children with normal vital capacity and no airways obstruction had abnormal baseline forced expiratory flow at 25-75% of forced vital capacity (FEF25-75%). After bronchodilation, among the 45 asthmatic children without FEV1 reversibility, 5 (11.1%) had an FEF25-75% increase that exceeded the reference interval. Isolated abnormal baseline values or significant post-bronchodilator changes in FEF are rare situations in asthmatic schoolchildren with good spirometry quality., (Copyright ©ERS 2015.)

Missing data are unavoidable in environmental epidemiologic surveys. The aim of this study was to compare methods for handling large amounts of missing values: omission of missing values, single and multiple imputations (through linear regression or partial least squares regression), and a fully Bayesian approach. These methods were applied to the PARIS birth cohort, where indoor domestic pollutant measurements were performed in a random sample of babies' dwellings. A simulation study was conducted to assess performances of different approaches with a high proportion of missing values (from 50% to 95%). Different simulation scenarios were carried out, controlling the true value of the association (odds ratio of 1.0, 1.2, and 1.4), and varying the health outcome prevalence. When a large amount of data is missing, omitting these missing data reduced statistical power and inflated standard errors, which affected the significance of the association. Single imputation underestimated the variability, and considerably increased risk of type I error. All approaches were conservative, except the Bayesian joint model. In the case of a common health outcome, the fully Bayesian approach is the most efficient approach (low root mean square error, reasonable type I error, and high statistical power). Nevertheless for a less prevalent event, the type I error is increased and the statistical power is reduced. The estimated posterior distribution of the OR is useful to refine the conclusion. Among the methods handling missing values, no approach is absolutely the best but when usual approaches (e.g. single imputation) are not sufficient, joint modelling approach of missing process and health association is more efficient when large amounts of data are missing.

Airway epithelium lining the nasal cavity plays a pivotal role in respiratory tract defense and protection mechanisms. Air pollution induces alterations linked to airway diseases such as asthma. Only very few in vitro studies to date have succeeded in reproducing physiological conditions relevant to cellular type and chronic atmospheric pollution exposure. We therefore, set up an in vitro model of human Airway Epithelial Cells of Nasal origin (hAECN) close to real human cell functionality, specifically adapted to study the biological effects of exposure to indoor gaseous pollution at the environmental level. hAECN were exposed under air-liquid interface, one, two, or three-times at 24 h intervals for 1 h, to air or formaldehyde (200 μg/m(3)), an indoor air gaseous pollutant. All experiments were ended at day 4, when both cellular viability and cytokine production were assessed. Optimal adherence and confluence of cells were obtained 96 h after cell seeding onto collagen IV-precoated insert. Direct and repeated exposure to formaldehyde did not produce any cellular damage or IL-6 production change, although weak lower IL-8 production was observed only after the third exposure. Our model is significantly better than previous ones due to cell type and the repeated exposure protocol., (Copyright © 2014. Published by Elsevier Ireland Ltd.)

The objective of Integrated Care Pathways for Airway Diseases (AIRWAYS-ICPs) is to launch a collaboration to develop multi-sectoral care pathways for chronic respiratory diseases in European countries and regions. AIRWAYS-ICPs has strategic relevance to the European Union Health Strategy and will add value to existing public health knowledge by: 1) proposing a common framework of care pathways for chronic respiratory diseases, which will facilitate comparability and trans-national initiatives; 2) informing cost-effective policy development, strengthening in particular those on smoking and environmental exposure; 3) aiding risk stratification in chronic disease patients, using a common strategy; 4) having a significant impact on the health of citizens in the short term (reduction of morbidity, improvement of education in children and of work in adults) and in the long-term (healthy ageing); 5) proposing a common simulation tool to assist physicians; and 6) ultimately reducing the healthcare burden (emergency visits, avoidable hospitalisations, disability and costs) while improving quality of life. In the longer term, the incidence of disease may be reduced by innovative prevention strategies. AIRWAYSICPs was initiated by Area 5 of the Action Plan B3 of the European Innovation Partnership on Active and Healthy Ageing. All stakeholders are involved (health and social care, patients, and policy makers).

Objective: IgE-mediated allergic asthma phenotype appears to be heterogeneous. We set out to define distinct allergic phenotypes by unsupervised cluster analysis., Study Design: A total of 18 variables were analyzed: sex and age, eczema and food allergy, asthma duration, asthma severity and control, severe exacerbations, total IgE level, allergic sensitization, fractional exhaled nitric oxide, and functional parameters. Clusters obtained were cross-tabulated with environmental parameters., Results: Four clusters were identified in 125 children (average age 8.9 years): (1) 57 children constituted the "House dust mite Sensitization and Mild Asthma" cluster, 98% of these were monosensitized and had mild asthma (74%); (2) 12 children had "Pollen Sensitization with Severe Exacerbations," 92 % with severe exacerbations and pollen sensitization; (3) 20 children had "Multiple Allergies and Severe Asthma," with 95% having moderate to severe asthma, and a significantly decreased forced expiratory flow rate at 25%-75% of forced vital capacity, 100% had eczema and higher values of IgE (1123 kU/L) and fractional exhaled nitric oxide (67 ppb) (this cluster was associated with molds at home [P = .004]); and (4) 36 children had "Multiple Allergic Sensitizations and Mild Asthma," 97% of these with multiple sensitizations and 100% mild asthma., Conclusions: The identification of 2 novel severe allergic asthma phenotypes "Pollen Sensitization with Severe Exacerbations"and "Multiple Allergies and Severe Asthma" could lead to specific targeted treatment., (Copyright © 2014 Mosby, Inc. All rights reserved.)

Background: Eczema, rhinitis, and asthma often coexist (comorbidity) in children, but the proportion of comorbidity not attributable to either chance or the role of IgE sensitisation is unknown. We assessed these factors in children aged 4-8 years., Methods: In this prospective cohort study, we assessed children from 12 ongoing European birth cohort studies participating in MeDALL (Mechanisms of the Development of ALLergy). We recorded current eczema, rhinitis, and asthma from questionnaires and serum-specific IgE to six allergens. Comorbidity of eczema, rhinitis, and asthma was defined as coexistence of two or three diseases in the same child. We estimated relative and absolute excess comorbidity by comparing observed and expected occurrence of diseases at 4 years and 8 years. We did a longitudinal analysis using log-linear models of the relation between disease at age 4 years and comorbidity at age 8 years., Findings: We assessed 16 147 children aged 4 years and 11 080 aged 8 years in cross-sectional analyses. The absolute excess of any comorbidity was 1·6% for children aged 4 years and 2·2% for children aged 8 years; 44% of the observed comorbidity at age 4 years and 50·0% at age 8 years was not a result of chance. Children with comorbidities at 4 years had an increased risk of having comorbidity at 8 years. The relative risk of any cormorbidity at age 8 years ranged from 36·2 (95% CI 26·8-48·8) for children with rhinitis and eczema at age 4 years to 63·5 (95% CI 51·7-78·1) for children with asthma, rhinitis, and eczema at age 4 years. We did longitudinal assessment of 10 107 children with data at both ages. Children with comorbidities at 4 years without IgE sensitisation had higher relative risks of comorbidity at 8 years than did children who were sensitised to IgE. For children without comorbidity at age 4 years, 38% of the comorbidity at age 8 years was attributable to the presence of IgE sensitisation at age 4 years., Interpretation: Coexistence of eczema, rhinitis, and asthma in the same child is more common than expected by chance alone-both in the presence and absence of IgE sensitisation-suggesting that these diseases share causal mechanisms. Although IgE sensitisation is independently associated with excess comorbidity of eczema, rhinitis, and asthma, its presence accounted only for 38% of comorbidity, suggesting that IgE sensitisation can no longer be considered the dominant causal mechanism of comorbidity for these diseases., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Numerous birth cohorts have been initiated in the world over the past 30 years using heterogeneous methods to assess the incidence, course and risk factors of asthma and allergies. The aim of the present work is to provide the stepwise proceedings of the development and current version of the harmonized MeDALL-Core Questionnaire (MeDALL-CQ) used prospectively in 11 European birth cohorts., Methods: The harmonization of questions was accomplished in 4 steps: (i) collection of variables from 14 birth cohorts, (ii) consensus on questionnaire items, (iii) translation and back-translation of the harmonized English MeDALL-CQ into 8 other languages and (iv) implementation of the harmonized follow-up., Results: Three harmonized MeDALL-CQs (2 for parents of children aged 4-9 and 14-18, 1 for adolescents aged 14-18) were developed and used for a harmonized follow-up assessment of 11 European birth cohorts on asthma and allergies with over 13,000 children., Conclusions: The harmonized MeDALL follow-up produced more comparable data across different cohorts and countries in Europe and will offer the possibility to verify results of former cohort analyses. Thus, MeDALL can become the starting point to stringently plan, conduct and support future common asthma and allergy research initiatives in Europe., (© 2014 S. Karger AG, Basel.)

Background: During the past 25 years, many pregnancy and birth cohorts have been established. Each cohort provides unique opportunities for examining associations of early-life exposures with child development and health. However, to fully exploit the large amount of available resources and to facilitate cross-cohort collaboration, it is necessary to have accessible information on each cohort and its individual characteristics. The aim of this work was to provide an overview of European pregnancy and birth cohorts registered in a freely accessible database located at http://www.birthcohorts.net., Methods: European pregnancy and birth cohorts initiated in 1980 or later with at least 300 mother-child pairs enrolled during pregnancy or at birth, and with postnatal data, were eligible for inclusion. Eligible cohorts were invited to provide information on the data and biological samples collected, as well as the timing of data collection., Results: In total, 70 cohorts were identified. Of these, 56 fulfilled the inclusion criteria encompassing a total of more than 500,000 live-born European children. The cohorts represented 19 countries with the majority of cohorts located in Northern and Western Europe. Some cohorts were general with multiple aims, whilst others focused on specific health or exposure-related research questions., Conclusion: This work demonstrates a great potential for cross-cohort collaboration addressing important aspects of child health. The web site, http://www.birthcohorts.net, proved to be a useful tool for accessing information on European pregnancy and birth cohorts and their characteristics., (© 2013 John Wiley & Sons Ltd.)

Although formaldehyde is a common indoor pollutant, its impact on respiratory symptoms in childhood remains unclear. The aim of this study was to examine the relation between domestic formaldehyde exposure and occurrence of coughing, one of the most prevalent respiratory symptoms during the first year of life of infants from the PARIS birth cohort involving 3840 healthy full-term babies. The presence of respiratory symptoms, including dry cough at night apart from a cold or chest infection in the past 12 months was reported on a standardized health questionnaire. Formaldehyde exposure was estimated for all infants using a predictive model established from data (both repeated measurements and information about determinants of levels) collected in a random sample of infants from the cohort. An unconditional logistic regression was fitted to study the relation between annual domestic formaldehyde exposure and dry cough at night, adjusting for all potential risk factors/confounders. The prevalence of dry cough at night was 14.9%. Parental history of allergy was found to modify the relation between environmental factors and dry cough. Cockroaches, used mattresses, and family stressor events were associated with dry cough in infants with parental allergy history. Conversely, domestic formaldehyde exposure tended to increase occurrence of dry cough at night only among babies without parental history of allergy (adjusted OR per 10 µg/m(3) increase in levels, single imputation approach: 1.45, 95% CI: 1.08-1.96, and Bayesian approach: 1.12, 0.91-1.36). This study suggests that the impact of indoor environmental exposure on dry cough at night in infancy is different depending on the presence or not of parental history of allergy., (Copyright © 2013. Published by Elsevier Inc.)

Background: Early detection of children at risk for developing allergy is an important challenge. Our first analyses in infants from the Pollution and Asthma Risk: an Infant Study (PARIS) birth cohort suggested that dry night cough was associated with parental-reported allergic disorders. The aim of the present study was to refine this finding by investigating the time course of dry night cough from birth to age 4 yr in relation to blood markers of atopy and allergic morbidity., Methods: Health outcomes were regularly assessed by parental self-administered questionnaires. Blood markers of atopy were measured at age 18 months. Children with similar patterns of dry night cough over the first 4 yr of life were grouped together using k-means clustering. Associations with atopy/allergy were studied using multinomial logistic regression., Results: Three trajectories of dry night cough were identified in 1869 children. Besides the never/infrequent pattern (72.4%), the transient pattern (8.8%) was composed of children who coughed in the first year and recovered by age 4 yr, while the rising pattern (18.8%) included all symptomatic children at age 4 yr, whether they were persistent or late coughers. Compared with the never/infrequent pattern, the rising pattern was significantly associated with elevated total immunoglobulin E (IgE) level (odds ratio [OR] = 1.70, 95% confidence interval [CI] = 1.21-2.39) and inhalant allergens sensitization (OR = 2.66, 95% CI = 1.26-5.61) at age 18 months, and with doctor-diagnosed allergic diseases over the first 4 yr such as hay fever (OR = 2.52, 95% CI = 1.49-4.26) and eczema (OR = 1.29, 95% CI = 1.00-1.66)., Conclusions: This study provides evidence that persistent/late dry night cough may indicate allergy in preschool children., (© 2013 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.)

There is growing public health concern about indoor air quality. Tetrachloroethylene (PERC), a chlorinated volatile organic compound widely used as a solvent in dry cleaning facilities, can be a residential indoor air pollutant. As part of an environmental investigation included in the PARIS (Pollution and asthma Risk: an Infant Study) birth cohort, this study firstly aimed to document domestic PERC levels, and then to identify the factors influencing these levels using standardized questionnaires about housing characteristics and living conditions. Air samples were collected in the child's bedroom over one week using passive devices when infants were 1, 6, 9, and 12 months. PERC was identified and quantified by gas chromatography/mass spectrometry. PERC annual domestic level was calculated by averaging seasonal levels. PERC was omnipresent indoors, annual levels ranged from 0.6 to 124.2 μg/m3. Multivariate linear and logistic regression models showed that proximity to dry cleaning facilities, do-it-yourself activities (e.g.: photographic development, silverware), presence of air vents, and building construction date (<1945) were responsible for higher domestic levels of PERC. This study, conducted in an urban context, provides helpful information on PERC contamination in dwellings, and identifies parameters influencing this contamination., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Unsupervised approaches can be used to analyze complex respiratory and allergic disorders., Objective: We investigated the respiratory and allergic phenotypes of children followed in the Pollution and Asthma Risk: An Infant Study (PARIS) birth cohort., Methods: Information on respiratory and allergic disorders, medical visits, and medications was collected during medical examinations of children at 18 months of age; biomarker data were also collected (total and allergen-specific IgE levels and eosinophilia). Phenotypes were determined by using latent class analysis. Associated risk factors were determined based on answers to questionnaires about environmental exposures., Results: Apart from a reference group, which had a low prevalence of respiratory symptoms or allergies (n=1271 [69.4%]), 3 phenotypes were identified. On the basis of clinical signs of severity and use of health care resources, we identified a mild phenotype (n=306 [16.7%]) characterized by occasional mild wheeze and 2 severe phenotypes separated by atopic status. The atopic severe phenotype (n=59 [3.2%]) included 49 (83%) children with wheezing and was characterized by a high prevalence of atopy (61% with allergenic sensitization) and atopic dermatitis (78%). In contrast, atopy was rare among children with the nonatopic severe phenotype (n=195 [11%]); this group included 88% of the children with recurrent wheezing. Risk factors for respiratory disease included parental history of asthma, male sex, siblings, day care attendance, exposure to tobacco smoke or molds, indoor renovations, and being overweight, although these factors did not have similar affects on risk for all phenotypes., Conclusion: Atopy should be taken into account when assessing the risk of severe exacerbations (that require hospital-based care) in wheezing infants; precautions should be taken against respiratory irritants and molds and to prevent children from becoming overweight., (Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

The two main difficulties when assessing the role and action mechanism of environmental pollutant exposure on the respiratory tract using in vitro methodology are firstly to create exposure conditions that closely mimic the human situation, and secondly to choose an experimental model that accurately represents lung compartment complexity, with different types of cell interaction. The aim of this study was to resolve these two challenges. The first of our difficulties was to find the closest experimental conditions to mimic respiratory environmental pollutant exposure. We compared the effects of formaldehyde (FA) on two cellular models, alveolar and bronchial cell lines, respectively A549 and BEAS-2B. The cells were exposed for 30 min to an environmental dose of gaseous FA (50 μg/m³) at the air-liquid interface. In order to mimic macrophage-epithelial cell cooperation, sensitizations (with TNFα or with conditioned medium from macrophages--CM) prior to gas exposure were applied. After toxicity evaluation, local inflammation was assessed by IL-8 and MCP-1 production 24h after exposure. In our experimental conditions FA had no effects on alveolar and bronchial epithelial cells without any sensitization. FA exposure after TNFα sensitization alone induced a moderate increase of IL-8 by A549 cells. After sensitization with CM, FA exposure induced a strong increase of IL-8 production by A549 cells in comparison to air, whereas a decrease of MCP-1 production was observed on BEAS-2B cells. It appears that the response of alveolar and bronchial epithelial cells to FA was moderate and that complex sensitization refines the inflammatory response to environmental stresses. When sensitized with CM, these cell lines responded differently to FA exposure. Finally by interacting with the respiratory epithelium, FA could exacerbate the inflammation of airways that occurs in severe asthma, and even synergize the effects of other air pollutants such as allergens. Evaluation of nasal cell inflammatory response could shed further light on the effects of FA on respiratory epithelium., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Asthma symptoms are non-specific during infancy, making the identification of different subgroups among preschool children with early respiratory manifestations an important challenge. We previously used a clustering approach to identify bronchial obstructive phenotypes in 1-yr-old infants from the Pollution and Asthma Risk: an Infant Study (PARIS) birth cohort. In the present study, we examined whether these phenotypes were stable at 3 yr and studied their comorbidity and risk factors. Partitioning around medoids (PAM) method was applied at 1 and 3 yr of age to cluster children according to wheezing, dry night cough, dyspnoea with sleep disturbance and breathlessness. The resulting groups were used to derive phenotypes in 2084 children during their first 3 yr of life. Analysis of associated comorbidity and risk factors was conducted using multinomial logistic regression. PAM groups were similarly defined at both ages so that two respiratory phenotypes were identified between birth and 3 yr: cough phenotype (CP) and dyspnoea phenotype (DP) including 14.1% and 30.7% of children, respectively. CP infants experienced more often allergic features than DP, dominated by respiratory infections. Parental history of allergy, potential allergen exposure and psychosocial factors were associated with CP. Day care centre attendance was more frequent in DP as well as exposure to domestic chemical pollution, suggesting a greater vulnerability to pathogens. Finally, dry night cough and dyspnoea disturbing the sleep appear to be markers of two respiratory profiles potentially allergic and infectious before 3 yr old., (© 2012 John Wiley & Sons A/S.)

Mechanisms of the Development of Allergy (MeDALL), a Seventh Framework Program European Union project, aims to generate novel knowledge on the mechanisms of initiation of allergy. Precise phenotypes of IgE-mediated allergic diseases will be defined in MeDALL. As part of MeDALL, a scientific seminar was held on January 24, 2011, to review current knowledge on the IgE-related phenotypes and to explore how a multidisciplinary effort could result in a new integrative translational approach. This article provides a summary of the meeting. It develops challenges in IgE-related phenotypes and new clinical and epidemiologic approaches to the investigation of allergic phenotypes, including cluster analysis, scale-free models, candidate biomarkers, and IgE microarrays; the particular case of severe asthma was reviewed. Then novel approaches to the IgE-associated phenotypes are reviewed from the individual mechanisms to the systems, including epigenetics, human in vitro immunology, systems biology, and animal models. The last chapter deals with the understanding of the population-based IgE-associated phenotypes in children and adolescents, including age effect in terms of maturation, observed effects of early-life exposures and shift of focus from early life to pregnancy, gene-environment interactions, cohort effects, and time trends in patients with allergic diseases. This review helps to define phenotypes of allergic diseases in MeDALL., (Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: While wheezing disorders are common in preschool children, their management is not well defined. The aim of this study was to assess the use of medical health care resources due to wheezing disorders in infants aged 18 months followed up in the Pollution and Asthma Risk: an Infant Study (PARIS) birth cohort., Methods: Data on wheezing disorders, medical visits and medication on account of respiratory disorders during the previous 12 months were collected with a standardized questionnaire, administered by a paediatrician, during the health check offered to every child aged 18 months included in the PARIS birth cohort., Results: The prevalence of wheezing disorders during the past 12 months amounted to 560/1974 (28.4%). Among wheezers, 493 (89.3%) required a medical visit because of difficult breathing; 61 (11.0%) went to the emergency room, 35 (6.4%) were admitted to the hospital and 375 (67.2%) received an inhaled anti-asthmatic medication. Recourse to chest physiotherapy was reported in 472 of them (85.1%)., Conclusion: This study confirms the high use of healthcare resources because of wheezing disorders in infants and suggests a higher use of anti-asthmatic medications in France compared to other European countries., (Copyright © 2011 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Concepts of disease severity, activity, control and responsiveness to treatment are linked but different. Severity refers to the loss of function of the organs induced by the disease process or to the occurrence of severe acute exacerbations. Severity may vary over time and needs regular follow-up. Control is the degree to which therapy goals are currently met. These concepts have evolved over time for asthma in guidelines, task forces or consensus meetings. The aim of this paper is to generalize the approach of the uniform definition of severe asthma presented to WHO for chronic allergic and associated diseases (rhinitis, chronic rhinosinusitis, chronic urticaria and atopic dermatitis) in order to have a uniform definition of severity, control and risk, usable in most situations. It is based on the appropriate diagnosis, availability and accessibility of treatments, treatment responsiveness and associated factors such as comorbidities and risk factors. This uniform definition will allow a better definition of the phenotypes of severe allergic (and related) diseases for clinical practice, research (including epidemiology), public health purposes, education and the discovery of novel therapies., (Copyright © 2012 S. Karger AG, Basel.)

Although indoor air has wide ranging effects on human health, the effects of environmental, chemical, and biological pollutants on the respiratory system are not fully understood. In order to clarify the health effects of airborne pollutant exposure, it would appear that toxicological evidence is needed to complement epidemiological observations to support by providing biological plausibility. The aim of this study is to manage air-liquid successive exposures to different pollutants such as a chemical pollutant (formaldehyde--FA), and a biological contaminant (Aspergillus fumigatus--Asp) using our in vitro model. Human alveolar cells (A549) were exposed at the air-liquid interface in an exposure module, firstly to an environmental level of FA (50 μg/m³) (or air) for 30 min, and 14 h later to Asp (7×10⁸ spores/m³) (or air) for 30 min. After 10 h post-incubation, cellular viability was assessed. Inflammation biomarkers (IL-8, MCP-1) were assayed by ELISA and by RT-PCR. Whatever the conditions, no cytotoxic effect was observed. FA followed by air exposure did not induce modification of production and expression of cytokines, confirming results with a unique FA exposure. Air followed by Asp exposure tended to induce IL-8 expression whereas IL-8 production tended to increase after FA and Asp exposure compared to FA and air exposure. The reaction of cells to sequential exposure to FA and Asp was moderate. These results show the feasibility of our model for sequential exposures to different types of environmental pollutants, allowing using it for preliminary assessment of cellular activity modification induced by airborne contaminants., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: Children are sensitive to indoor environmental pollution. Up until now there has been a lack of data on air quality in child day care centers., Objectives: The aim of this study is to document the indoor environment quality of Paris child day care centers by repeated measurements, and to compare pollutant levels in child day care centers with levels in Paris dwellings., Methods: We selected 28 child day care centers frequented by a random sample of babies who participated in the PARIS birth cohort environmental investigation, and visited the child day care centers for one week twice in one year. Biological contaminants assessed were fungi, endotoxin, dust mite allergens, and chemical pollutants: aldehydes, volatile organic compounds and nitrogen dioxide (NO2). Relative humidity, temperature, and carbon dioxide levels were measured simultaneously. A standardized questionnaire was used to gather information about the buildings and their inhabitants., Results: Airborne endotoxin levels in child day care centers were higher than those found in Paris dwellings. Dust mite allergens in child day care centers were below the threshold level for sensitization in the majority of samples, and in common with dwelling samples. Penicillium and Cladosporium were the most commonly identified genera fungi. The child day care center indoor/outdoor ratio for most chemical pollutants was above unity except for NO2, the levels for NO2 being significantly higher than those measured in homes., Conclusion: Chemical and biological contamination in child day care centers appears to be low, apart from endotoxin and NO2. Failure to take child exposure in child day care centers into account could result in an overestimation of children's exposure to other pollutants., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Certain chemical pollutants can exacerbate lower respiratory tract infections (LRIs), a common childhood ailment. Although formaldehyde (FA) is one of the most common air pollutants found in indoor environments, its impact on infant health is uncertain., Objective: Our aim was to determine the impact of FA exposure on the LRI incidence during the first year of life of infants from the Pollution and Asthma Risk: an Infant Study (PARIS) birth cohort., Methods: FA was measured in a random sample of 196 infants' dwellings, and exposure to this pollutant was estimated for 2,940 infants using predictive models based on measurements and data about potential determinants of FA levels. Health data were collected from parents by regular self-administered questionnaires. We used multivariate logistic regressions to estimate associations between FA exposure and the occurrence of LRI and wheezy LRI (wLRI), adjusting for potential confounders/risk factors., Results: During the first year of life, 45.8% of infants had at least one LRI, and LRI occurred simultaneously with wheezing in 48.7% of cases. The FA predictive models correctly classified 70% of dwellings as having high or low exposure, and we estimated that 43.3% of infants were exposed throughout the first year to levels of FA > 19.5 µg/m3. FA exposure was significantly associated with LRI and wLRI before and after adjustment for known LRI risk factors/confounders. For an interquartile increase in FA levels (12.4 μg/m3), we estimated a 32% [95% confidence interval (CI): 11, 55] and 41% (95% CI: 14, 74) increase in the incidence of LRI and wLRI, respectively., Conclusion: The findings of this study suggest that infants exposed to FA at an early age have an increased incidence of LRI.

Indoor aldehydes may result from ozone-initiated chemistry, mainly documented by experimental studies. As part of an environmental investigation included in the PARIS birth cohort, the aim of this study was to examine ozone contribution to airborne aldehyde formation in Paris homes. Formaldehyde, acetaldehyde and hexaldehyde levels, as well as styrene, nitrogen dioxide and nicotine concentrations, comfort parameters and carbon dioxide levels, were measured twice during the first year of life of the babies. Ambient ozone concentrations were collected from the closest background station of the regional air monitoring network. Traffic-related nitrogen oxide concentrations in front of the dwellings were estimated by an air pollution dispersion model. Home characteristics and families' way of life were described by questionnaires. Stepwise multiple linear regression models were used to link aldehyde levels with ambient ozone concentrations and a few aldehyde precursors involved in oxidation reactions, adjusting for other indoor aldehyde sources, comfort parameters and traffic-related nitrogen oxides. A 4 and 11% increase in formaldehyde and hexaldehyde levels was pointed out when 8-hour ozone concentrations increased by 20 μg/m(3). The influence of potential precursors such as indoor styrene level and frequent use of air fresheners, containing unsaturated volatile organic compounds as terpenes, was also found. Thus, our results suggest that ambient ozone can significantly impact indoor air quality, especially with regard to formaldehyde and hexaldehyde levels., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The origin of the epidemic of IgE-associated (allergic) diseases is unclear. MeDALL (Mechanisms of the Development of ALLergy), an FP7 European Union project (No. 264357), aims to generate novel knowledge on the mechanisms of initiation of allergy and to propose early diagnosis, prevention, and targets for therapy. A novel phenotype definition and an integrative translational approach are needed to understand how a network of molecular and environmental factors can lead to complex allergic diseases. A novel, stepwise, large-scale, and integrative approach will be led by a network of complementary experts in allergy, epidemiology, allergen biochemistry, immunology, molecular biology, epigenetics, functional genomics, bioinformatics, computational and systems biology. The following steps are proposed: (i) Identification of 'classical' and 'novel' phenotypes in existing birth cohorts; (ii) Building discovery of the relevant mechanisms in IgE-associated allergic diseases in existing longitudinal birth cohorts and Karelian children; (iii) Validation and redefinition of classical and novel phenotypes of IgE-associated allergic diseases; and (iv) Translational integration of systems biology outcomes into health care, including societal aspects. MeDALL will lead to: (i) A better understanding of allergic phenotypes, thus expanding current knowledge of the genomic and environmental determinants of allergic diseases in an integrative way; (ii) Novel diagnostic tools for the early diagnosis of allergy, targets for the development of novel treatment modalities, and prevention of allergic diseases; (iii) Improving the health of European citizens as well as increasing the competitiveness and boosting the innovative capacity of Europe, while addressing global health issues and ethical issues., (© 2011 John Wiley & Sons A/S.)

Background:   Early onset of allergic rhinitis (AR) is poorly described, and rhinitis symptoms are often attributed to infections. This study analyses the relations between AR-like symptoms and atopy in infancy in the PARIS (Pollution and Asthma Risk: an Infant Study) birth cohort., Methods:   Data on AR-like symptoms (runny nose, blocked nose, sneezing apart from a cold) were collected using a standardized questionnaire administered during the health examination at age 18 months included in the follow-up of the PARIS birth cohort. Parental history of allergy and children's atopy blood markers (blood eosinophilia ≥470 eosinophils/mm(3) , total immunoglobulin E ≥45 U/ml and presence of allergen-specific IgE) were assessed. Associations were studied using multivariate logistic regression models adjusted for potential confounders., Results:   Prevalence of AR-like symptoms in the past year was 9.1% of the 1850 toddlers of the study cohort. AR-like symptoms and dry cough apart from a cold were frequent comorbid conditions. Parental history of AR in both parents increased the risk of suffering from AR-like symptoms with an OR 2.09 (P=0.036). Significant associations were found with the presence of concurrent biological markers of atopy, especially blood eosinophilia and sensitization to house dust mite (OR 1.54, P=0.046 and OR 2.91, P=0.042) whereas there was no relation with sensitization to food., Conclusions:   These results support the hypothesis that AR could begin as early as 18 months of life. Suspicion of AR should be reinforced in infants with parental history of AR or biological evidence of atopy, particularly blood eosinophilia and sensitization to inhalant allergens., (© 2010 John Wiley & Sons A/S.)

Asthma is a public health problem worldwide, and indoor air pollution considered to be a potential etiology. New tools need to be developed to study the effects of air pollutants in vitro and modelize inhalation exposure. This study was thus set up to design an in vitro model, using a direct exposure device to study the cellular effects of air pollutants at environmental doses on lung epithelial cells, and apply this to gaseous formaldehyde (FA). A549 cells were exposed using the direct exposure device (air/liquid interface) to FA without, after and before TNFalpha (1 ng/mL) sensitization. 24h after exposure, cellular viability (XTT) and inflammation (IL-6, IL-8 and MCP-1) were assessed. No effects on cellular viability were observed for concentrations < or =50 microg/m(3). After TNFalpha sensitization, FA-exposure induced a significant increase in IL-8 (p<0.001), which could lead to the initiation or pathogenesis of non-specific respiratory inflammation. The results of this study demonstrate the feasibility and sensitivity of the exposure system for testing inflammatory cellular effects of indoor gaseous compounds at environmental doses directly on human respiratory cells., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

A cross sectional study was carried out to evaluate arsenic exposure of residents living in an area with a soil naturally rich in arsenic (As), through urinary measurements. During the summer of 2007, 322 people aged over 7 years and resident in the study area for at least 4 days prior to the investigation were recruited. The sum of urinary inorganic arsenic and metabolites (iAs+MMA+DMA) and speciation were determined by graphite furnace atomic absorption spectrometry and high performance liquid chromatography coupled to inductively coupled plasma mass spectrometry, respectively. Geometric means levels of iAs+MMA+DMA were 3.6 microg/L or 4.4 microg/g creatinine. The percent of DMA, As(III) and MMA contribution to urinary arsenic concentrations was respectively 84.2%, 12% and 3.7%. We found significant associations between urinary arsenic concentrations and the consumption of seafood (p=0.03), the consumption of wine (p=0.03) and beer (p=0.001), respectively 3 and 4 days before the investigation. When we focus on the various species, As(V) was rarely detected and DMA is the predominant metabolite composing the majority of measurable inorganic-related As in the urine. Considering the percent of DMA contribution to iAs+MMA+DMA urinary concentrations, almost half of the subjects had 100% of DMA contribution whatever the concentration of urinary As whereas the others had a lower DMA contribution, between 39 and 90%. Arsenic levels reported in this original study in France were between 2 and 4 times lower than in other studies dealing with iAs+MMA+DMA levels associated with soil arsenic exposure. Arsenic levels were similar to those observed in unexposed individuals in European countries, although 10% were above the French guideline values for the general population., (Copyright 2009 Elsevier B.V. All rights reserved.)

As the natural history of respiratory and allergic manifestations is unclear, our ongoing Paris birth cohort study prospectively assesses the onset of these symptoms in early childhood. Data were collected by five questionnaires sent at regular intervals during the first year of life. Partitioning around medoids (PAM) was used to classify infants according to their bronchial obstructive symptoms. A polytomous logistic regression was performed to assess the eventual predictable power of various respiratory events and perinatal factors. Results are given for 2698 infants. Atopic dermatitis occurred in 17.9% of infants. The main respiratory symptoms in infancy were wheeze in the chest (22%), dyspnoea responsible for sleep disturbance (23.7%), nocturnal dry cough (14.5%) and shortness of breath (4.2%). The PAM method identified three groups of infants. Apart from the G0 group of infants mostly asymptomatic, two distinct clinical phenotypes (G1 and G2: 8.7% and 23.5% of total infants respectively) emerged. G2 was defined by severe bronchial obstructive disorders as all cases of dyspnoea with sleep disturbance were included in this group, while all infants assigned in G1 suffered from nocturnal dry cough. G2 group infants had significantly higher rates of respiratory events while a parental history of asthma, symptoms suggestive of rhino-conjunctivitis and birth season clearly differentiated the G1 group. Finally, G1 and G2 group infants should be closely followed up as they are expected to develop allergic and asthmatic phenotypes, possibly in relation to environmental and behavioural risk factors.

Public health aims at preventing, promoting and restoring populations' health. As a public health actor, the chemist must be aware of the collective and social dimension of health problems. Moreover, in the exercise of his/her duties, the chemist has specific public health actions either in a dispensary, or in a hospital, or in industries or in new trades related to risk assessment. To fulfil these needs, public health teaching tries to pass on both a knowledge, an ability and a method. Lectures given all along the pharmaceutical formation will be presented. Concerning research and experts' report in public health, pharmacoepidemiology and environmental risks assessment and management are the most suitable fields for chemists' intervention.

Indoor mould growth can affect health, especially in early childhood. As part of a birth cohort follow-up, the purpose of this study was firstly to examine spectrum and levels of airborne fungi in 190 Paris newborns' dwellings, and secondly to identify predictors of these levels. Sequential duplicate air samples were collected twice a year in the newborn's bedroom and outside the building. A single-stage multi-holed impactor (Air Ideal) was used with chloramphenicol/MEA agar. Housing characteristics were assessed using a questionnaire administered by a trained interviewer. Cladosporium and Penicillium were isolated in, respectively, 77% and 93% of homes in the cold season, and in 95% and 83% of homes in the hot season. Aspergillus and Alternaria were recovered from indoor air in, respectively, 60% and less than 20% of homes. Geometric means (geometric standard deviation) of indoor total airborne fungal concentrations at two different visits were, respectively, 232.4 (3.2) and 186.7 (2.7)cfu/m(3). In the GEE multivariate analysis, outdoor fungal concentrations were the best predictors for variability of indoor total fungal and Cladosporium concentrations (respectively, R(2)=32% and 31%). Levels of total airborne fungal and Cladosporium concentrations were significantly higher during the hot season (respectively, p=0.003 and p<0.001) and were positively correlated with the duration of bedroom aeration (respectively, p=0.004 and p<0.001). Signs of dampness were associated with higher total airborne fungi (p=0.031) and Aspergillus levels (p=0.055). This study provides for the first time indoor airborne fungal spectrum and concentrations in Paris. Outdoor levels and season largely contributed to the variability of indoor total airborne fungal concentrations, which also depended on aeration and signs of dampness.

Introduction: Allergic disorders of the respiratory tract have been the subject of many epidemiological studies, especially during infancy which is known to be a critical period for development of the immune system. This paper aims to describe the prevalence of allergic respiratory disorders in children below three years of age in the general population, despite the lack of shared definition of asthma and allergic rhinitis among studies., State of Art: Doctor-diagnosed asthma occurs in 5% of children below two years of age. One third of children below three years of age experience wheeze during a lower respiratory tract infection, but only 7% of children wheeze apart from a respiratory infection. Asthma-like cough and bronchial obstruction symptoms are reported in respectively 15% and 9% of children below two years of age. Depending on the definition of allergic rhinitis used, its prevalence varies from 1 to 30% among two years old children., Perspectives: Definitions of allergic respiratory tract disorders in infants become more elaborate involving parental and personal history of allergy and medication; epidemiological research now attempts to identify, using biological evidence of atopy, infants at risk of persistent allergic disorders., Conclusions: A better definition of allergic respiratory disorders in infants may help epidemiological research and early care management.

The spatial distribution of urban population exposures to ambient air particles was investigated as part of the Genotox'ER study conducted in four metropolitan areas (Grenoble, Paris, Rouen and Strasbourg) in France. In each city, 60 to 90 non-smoking adult and children volunteers were selected. Subjects lived in three different urban sectors: one highly exposed to traffic emissions, one influenced by local industrial sources, and a background urban environment. The Harvard Chempass multi-pollutant personal sampler was used to sample PM10 and PM2.5 particles during 48 h during two different seasons ('hot' and 'cold'). The elemental composition of the filters was analysed by Particle-Induced X-ray Emission (PIXE). Sixteen elements were found to be over the method detection limits: Al, Si, P, S, Cl, K, Ca, Ti, V, Cr, Mn, Fe, Ni, Cu, Zn and Pb. The relative concentrations of elements of crustal origin (Si, Al, Ca) were higher in the coarse fraction of PM10 filters, while elements associated with combustion processes (traffic emissions or industrial combustion) presented higher relative concentrations in the PM2.5 fraction (S, Ni, V, Pb). Spatial heterogeneity of elemental exposures by urban sector is substantial for some metals of health concern, with 20% to 90% greater exposure values, on average, in the traffic proximity or industrial sectors, compared to the background sector, for Fe, Zn, Cu, V and Cr. This spatial heterogeneity should not be overlooked in epidemiological or risk assessment studies.

The Paris prospective birth cohort study was implemented in 2003 to assess environmental/behavioural factors associated with respiratory and allergic disorder occurrence in early childhood. This paper describes the design and sociodemographic features of eligible/enrolled families. Full-term newborns without any medical problem at birth were recruited in five Paris maternity hospitals. They resided in the Paris area and had French speaking mothers. Sample size is at least 3500 infants, and children are followed-up until their sixth birthday. Data collection is based on regular medical and environmental self-administered questionnaires to parents. Information on dwellings is gathered by means of phone questionnaires, and standardized medical examinations are carried out at 18 months and 6 years. Exposure to traffic-related pollution is modelled. At inclusion, some information concerning refusals is gathered in order to describe sociodemographic features of participating families as compared with eligible children. 4115 (63%) out of the 6493 eligible infants are now participating in this study. Participation rate is higher in parents with a high SES (socioeconomic status), for French and European parents, and for > or =25-year-old mothers, but decreases with sibship size. Similar determinants are associated with the distribution of reasons for non-participation. The participation rate in the Paris study is comparable with other similar studies. Finally, giving detailed explanation of the study aims at inclusion, establishing regular mailed and phoned contacts with families, offering free complete medical examinations for the participant child and re-sent missing questionnaires are very important to improve participation at inclusion and during follow-up.

The purpose of the study was to assess non-dietary exposure of workers and the general population in the Paris area to some organophosphorus (OP) pesticides. In total, 21 workers from different occupational places (two greenhouses, three florist shops and three veterinary departments) and 20 subjects assumed to be non-occupationally exposed were recruited. Indoor air, hand wipes, and three first morning urine samples were collected. Seven OPs were measured by GC/ECD and GC/TSD, and six urinary dialkylphosphate metabolites by GC/PFPD. All indoor air samples from the workplaces and only one-third of the samples from the residences contained at least one of the seven OPs. However, almost all participants were dermally exposed to OPs. Total OP indoor air and cutaneous levels were significantly higher for workers than for the general population (air median = 185 pmol/m3 versus nondetectable, P < 0.0001; hands median = 1250 pmol/hands versus 475 pmol/hands, P = 0.03). From the air, gardeners and florists were mainly exposed to methyl-OPs and veterinary staff to ethyl-OPs (mainly diazinon). From their hands, all subjects were exposed to methyl-OPs, with gardeners and florists exposed to somewhat but not significantly higher levels. Ethyl-OPs were more found frequently and at higher levels on the hands of veterinary workers. Total OP levels in indoor air and from hand wipes were significantly correlated (Spearman R = 0.34, P = 0.03). DAP detection frequencies and levels were not different between workers and the general population (workers median=168 nmol/g creat and general population median = 241 nmol/g creat, P = 0.31), and did not correlate with air or hand levels. Subjects not occupationally exposed showed significant residential exposure to OPs, more frequently from their hands than from the air. Different occupations were associated with different exposure profiles and levels. The lack of differences in DAP levels between the different groups of exposure suggests that dietary exposure to OP residues and exposure to other OPs are involved.

This study applies a traffic exhaust air dispersion model (the ExTra index) to 403 children enrolled in a French multicentric case-control study, the VESTA study (Five [V] Epidemiological Studies on Transport and Asthma). The ExTra index (previously validated by our team) was used to assess lifelong average traffic-related air pollutant (TAP) concentrations (nitrogen oxides) children in the study were exposed to in front of their living places. ExTra index took into account traffic density, topographical parameters (building height, road and pavement width), weather conditions (wind direction and strength) and background pollution levels. Topographical and traffic data were collected, using a specific questionnaire for each home, school or nursery address, attended by children. The assessment of time-weighted NOx levels in front of the children's living places highlighted significant disparities: mean ExTra index values and share attributable to proximity traffic were, respectively, 70+/-42 and 14+/-22 microg/m3 NOx equivalent NO2 for the 403 children in our study. Not only would this diversity not have been revealed using urban background pollution data provided by air quality networks, it would have resulted in 40% of the children being misclassified with regard to their TAP exposure by underestimating it in half of the cases and overestimating it in the other half. Such errors of classification, which are highly prejudicial in epidemiology, argue strongly for the use of an index such as the ExTra, which enables TAP exposure to be reconstructed within the framework of retrospective or prospective epidemiological studies.

Associations between average total personal exposures to PM2.5, PM10, and NO2 and concomitant outdoor concentrations were assessed within the framework of the Genotox ER study. It was carried out in four French metropolitan areas (Grenoble, Paris, Rouen, and Strasbourg) with the participation, in each site, of 60-90 nonsmoking volunteers composed of two groups of equal size (adults and children) who carried the personal Harvard Chempass multipollutant sampler during 48 h along two different seasons ("hot" and "cold"). In each center, volunteers were selected so as to live (home and work/school) in three different urban sectors contrasted in terms of air pollution (one highly exposed to traffic emissions, one influenced by local industrial sources, and a background urban environment). In parallel to personal exposure measurements, a fixed ambient air monitoring station surveyed the same pollutants in each local sector. A linear regression model was accommodated where the dependent pollutant-specific variable was the difference, for each subject, between the average ambient air concentrations over 48 h and the personal exposure over the same period. The explanatory variables were the metropolitan areas, the three urban sectors, season, and age group. While average exposures to particles were underestimated by outdoor monitors, in almost all cities, seasons, and age groups, differences were lower for NO2 and, in general, in the other direction. Relationships between average total personal exposures and ambient air levels varied across metropolitan areas and local urban sectors. These results suggest that using ambient air concentrations to assess average exposure of populations, in epidemiological studies of long-term effects or in a risk assessment setting, calls for some caution. Comparison of personal exposures to PM or NO2 with ambient air levels is inherently disturbed by indoor sources and activities patterns. Discrepancies between measurement devices and local and regional sources of pollution may also strongly influence how the ambient air concentrations relate to population exposure. Much attention should be given to the selection of the most appropriate monitoring sites according to the study objectives.