Early-life residential green spaces and traffic exposure in association with young adult body composition: a longitudinal birth cohort study of twins.

BACKGROUND: Globally, the rapid increase of obesity is reaching alarming proportions. A new approach to reduce obesity and its comorbidities involves tackling the built environment. Environmental influences seem to play an important role, but the environmental influences in early life on adult body composition have not been thoroughly investigated. This study seeks to fill the research gap by examining early-life exposure to residential green spaces and traffic exposure in association with body composition among a population of young adult twins. METHODS: As part of the East Flanders Prospective Twin Survey (EFPTS) cohort, this study included 332 twins. Residential addresses of the mothers at time of birth of the twins were geocoded to determine residential green spaces and traffic exposure. To capture body composition, body mass index, waist-to-hip ratio (WHR), waist circumference, skinfold thickness, leptin levels, and fat percentage were measured at adult age. Linear mixed modelling analyses were conducted to investigate early-life environmental exposures in association with body composition, while accounting for potential confounders. In addition, moderator effects of zygosity/chorionicity, sex and socio-economic status were tested. RESULTS: Each interquartile range (IQR) increase in distance to highway was found associated with an increase of 1.2% in WHR (95%CI 0.2-2.2%). For landcover of green spaces, each IQR increase was associated with 0.8% increase in WHR (95%CI 0.4-1.3%), 1.4% increase in waist circumference (95%CI 0.5-2.2%), and 2.3% increase in body fat (95%CI 0.2-4.4%). Stratified analyses by zygosity/chorionicity type indicated that in monozygotic monochorionic twins, each IQR increase in land cover of green spaces was associated with 1.3% increase in WHR (95%CI 0.5-2.1%). In monozygotic dichorionic twins, each IQR increase in land cover of green spaces was associated with 1.4% increase in waist-circumference (95%CI 0.6-2.2%). CONCLUSIONS: The built environment in which mothers reside during pregnancy might play a role on body composition among young adult twins. Our study revealed that based on zygosity/chorionicity type differential effects of prenatal exposure to green spaces on body composition at adult age might exist.

Association between outdoor air pollution and chronic rhinosinusitis patient reported outcomes.

BACKGROUND: The aetiology of chronic rhinosinusitis (CRS) is multifactorial with a complex interplay between environmental, microbial endogenous and genetic factors. The impact of outdoor air pollution on prevalence or severity of CRS remains largely unknown. METHODS: Real-life geolocation data (2017-2018, Belgium) from 278 CRS patients (2576 health records) using the mySinusitisCoach mobile application were analysed to calculate the patients' individual exposure to outdoor air pollutants (ozone (O3), black carbon (BC), nitrogen dioxide (NO2) and particulate matter with diameter < 2.5 µm (PM2.5)) and to associate these pollutants with the patients' sinus related symptoms measured at multiple occasions by visual analogue scale (VAS). RESULTS: The adjusted seasonal model for the spring-summer (n = 1000 health entries, N = 83 patients) population revealed an increase of 6.07 (p < 0.0001) in overall CRS symptom scoring for an interquartile range (IQR) increase in exposure to O3 (26.9 µg/m3). An increase of 1.69 (p = 0.05) in total CRS symptom scoring was observed for an IQR increase of PM2.5 (7.1 µg/m3) exposure. Sex-stratified analysis in the spring-summer population showed significant interaction between air pollution and sex with male patients having higher total CRS symptom scores for an IQR increase in exposure to PM2.5 (3.52, p = 0.001), and O3 (8.33, p < 0.0001), while no significant association with symptom severity was seen in the female patients. In the analysis stratified by comorbid asthma, CRS patients with comorbid asthma had higher total CRS symptoms for an IQR increase in exposure to PM2.5 (2.58, p = 0.04) and O3 (7.72, p < 0.0001) while the patients without comorbid asthma had no significant symptom increases. CONCLUSION: Exposure to outdoor air pollution is associated with increased symptom severity in CRS patients. The extent to which CRS patients are sensitive to outdoor air pollution exposure varies per season and depends on their sex and comorbid asthma status. mHealth technology has the potential to reveal novel insights on the patients' exposome and disease severity in the real-life situation.

Internal exposure of Flemish teenagers to environmental pollutants: Results of the Flemish Environment and Health Study 2016-2020 (FLEHS IV).

The Flemish Environment and Health Study (FLEHS) collects information on internal exposure to a broad range of environmental chemicals in the general population in Flanders, the Northern region of Belgium. The aim is to establish biomonitoring exposure distributions for the general population in support of public health and environmental policy, environmental risk assessment and risk management decisions. In 2017-2018, urine and blood samples were collected from 428 teenagers by a stratified clustered two stage randomized design. Samples were analyzed for a broad range of biomarkers related to exposure to chlorinated and newer pesticides, brominated and organophosphate flame retardants (BFR/OPFR), polychlorinated biphenyls (PCBs), bisphenols, phthalates and alternative plasticizers, per-and polyfluoroalkyl substances (PFAS), polycyclic aromatic hydrocarbons (PAHs), benzene, metals and trace elements. The geometric mean levels and percentiles of the distribution were estimated for each biomarker, for the whole study population and following stratification for sex, the household educational attainment and the residence area's urbanicity. Geometric means of biomarkers of lead, dichlorodiphenyltrichloroethane (DDT), PCBs, PAHs, regulated phthalates and bisphenol A (BPA) were lower than in the previous FLEHS cycles. Most biomarker levels were below health-based guidance values (HB-GVs). However, HB-GVs of urinary arsenic, blood lead, blood cadmium, sum of serum perfluorooctane sulfonate (PFOS) and perfluoro-1-hexanesulfonate (PFHxS) and the urinary pyrethroid metabolite (3-PBA) were exceeded in respectively 25%, 12%, 39.5%, 10% and 22% of the teenagers. These results suggest that the levels of exposure in the Flemish population to some environmental chemicals might be of concern. At the same time, we noticed that biomarkers for BPA substitutes, metabolites of OPFRs, an expanded list of PFAS, glyphosate and its metabolite could be measured in substantial proportions of participants. Interpretation of these levels in a health-risk context remains uncertain as HB-GVs are lacking. Household educational attainment and residential urbanicity were significant exposure determinants for many biomarkers and could influence specific biomarker levels up to 70% as shown by multiple regression analysis. The research consortium also took care of the broader external communication of results with participants, policy makers, professional groups and civil society organizations. Our study demonstrated that teenagers are exposed to a wide range of chemicals, it demonstrates the success of public policies to reduce exposure but also points to concern and further priorities and needs for follow up.

Pooled analysis of genotoxicity markers in relation to exposure in the Flemish Environment and Health Studies (FLEHS) between 1999 and 2018.

BACKGROUND: The Flemish Environment and Health Studies (FLEHS) are human biomonitoring surveys running in Flanders since 1999. Additionally to biomarkers of exposure, markers of genotoxicity and oxidative stress have been measured, including the alkaline comet and micronucleus assay in peripheral whole blood cells, and urinary concentrations of 8-oxo-2'-deoxyguanosine (8-oxodG). AIM: Exposure-effect associations were explored in a pooled dataset of nine different cross-sectional FLEHS surveys. Data of adolescents collected in a time frame of about 20 years (1999-2018) were compiled. The aim of the study was to examine whether increased variation in exposure, lifestyle and environmental factors would lead to more powerful and robust exposure-effect associations. MATERIALS & METHODS: The biomarkers were measured in 2283 adolescents in the age range of 14-18 years. Exposure to polycyclic aromatic hydrocarbons [1-hydroxypyrene (1-OHP)], benzene (tt'-muconic acid), metals (arsenic, cadmium, copper, nickel, thallium, lead, chromium), persistent organochlorines and phthalates were assessed in blood or urine. Furthermore, outdoor air levels of particulate matter (PM10 and PM2.5) at the residences of the youngsters were calculated. Pooled statistical analysis was done using mixed models. Study-specific differences in the genotoxicity markers and in the strength/direction of the association were accounted for. This was done by incorporating the random factor 'study' and a random study slope (if possible). The exposure markers were centered around the study-specific mean in order to correct for protocol changes over time. RESULTS: A significant association was observed for the urinary oxidative stress marker 8-oxodG, which was positively associated with 1-OHP (5% increase for doubling of 1-OHP levels, p = 0.001), and with urinary copper (26% increase for doubling of copper levels, p = 0.001), a metal involved in the Fenton reaction in biological systems. 8-oxodG was also associated with the sum of the metabolites of the phthalate di(2-ethylhexyl) phthalate (DEHP) (3% increase for doubling of the DEHP levels, p = 0.02). For those associations, data pooling increased the statistical power. However, some of the associations in the individual surveys, were not confirmed in the pooled analysis (such as comet assay and 8-oxodG vs. atmospheric PM; and 8-oxodG vs. urinary nickel). This may be due to inconsistencies in exposure-effect relations and/or variations in the pollutant mix over time and regions. CONCLUSION: Pooled analysis including a large population of 2283 Flemish adolescents showed that 8-oxodG, a marker of oxidative DNA damage is a valuable marker to assess impact of daily life pollutants, such as PAHs, Cu and the phthalate DEHP.

Air pollution-induced placental alterations: an interplay of oxidative stress, epigenetics, and the aging phenotype?

According to the "Developmental Origins of Health and Disease" (DOHaD) concept, the early-life environment is a critical period for fetal programming. Given the epidemiological evidence that air pollution exposure during pregnancy adversely affects newborn outcomes such as birth weight and preterm birth, there is a need to pay attention to underlying modes of action to better understand not only these air pollution-induced early health effects but also its later-life consequences. In this review, we give an overview of air pollution-induced placental molecular alterations observed in the ENVIRONAGE birth cohort and evaluate the existing evidence. In general, we showed that prenatal exposure to air pollution is associated with nitrosative stress and epigenetic alterations in the placenta. Adversely affected CpG targets were involved in cellular processes including DNA repair, circadian rhythm, and energy metabolism. For miRNA expression, specific air pollution exposure windows were associated with altered miR-20a, miR-21, miR-146a, and miR-222 expression. Early-life aging markers including telomere length and mitochondrial DNA content are associated with air pollution exposure during pregnancy. Previously, we proposed the air pollution-induced telomere-mitochondrial aging hypothesis with a direct link between telomeres and mitochondria. Here, we extend this view with a potential co-interaction of different biological mechanisms on the level of placental oxidative stress, epigenetics, aging, and energy metabolism. Investigating the placenta is an opportunity for future research as it may help to understand the fundamental biology underpinning the DOHaD concept through the interactions between the underlying modes of action, prenatal environment, and disease risk in later life. To prevent lasting consequences from early-life exposures of air pollution, policy makers should get a basic understanding of biomolecular consequences and transgenerational risks.

Body fat evolution as predictor of retinal microvasculature in children.

OBJECTIVES: Microvascular changes may represent an underlying mechanism through which overweight contributes to cardiovascular disease development. Therefore, the aim of this study was to investigate whether changes in children's body fat over time are associated with the retinal microvasculature, a marker of cardiovascular aging. METHODS: In a longitudinal design, 171 healthy Flemish children (53.8% boys) were followed-up for 7 years (2008-2015), aged 2.7-8.1 years at baseline.Z-scores of body mass index (zBMI; 4.1% overweight), waist circumference (zWC) and fat mass index (zFMI by BODPOD) were obtained using standardized protocols during each visit. Retinal arteriolar (central retinal arteriolar equivalent (CRAE)) and venular equivalents (central retinal venular equivalent (CRVE)) were measured from digital retinal photographs (2015) using IVAN software. Cross-sectional and longitudinal associations between changes in body fat and retinal microvasculature were explored using multivariable regression analysis, while controlling for age, sex, mean arterial pressure, alternate retinal caliber, physical activity, diet and birth weight. RESULTS: In cross-sectional analysis, children with high zFMI had a higher CRVE, but only in boys (ß=0.25, P=0.02). In addition, boys with high zFMI had also a lower CRAE to CRVE ratio (ß=-0.26, P=0.03). No associations were seen with the CRAE, or between zBMI or zWC and the retinal microvasculature. Only changes in zFMI over time were found to be positively associated with the CRVE in boys (ß=0.38, P=0.01). CONCLUSIONS: Our analysis over a 7-year period shows that changes in body fat during childhood are already associated with the CRVE (especially in boys).

Continuous alternating inhaled antibiotic therapy in CF: A single center retrospective analysis.

INTRODUCTION: The efficacy of inhaled antibiotics to treat chronic Pseudomonas aeruginosa pulmonary infection in patients with cystic fibrosis (CF) has been well established. Few data are available on the value of continuous alternating inhaled antibiotic therapy (CAIT), a strategy increasingly used in the management of CF. OBJECTIVE: To investigate the effect of CAIT on clinical outcome in adult CF patients treated at the University Hospital Leuven. METHODS: Patients with a documented CF diagnosis who received inhaled antibiotics between March 2010 and January 2015 were retrospectively evaluated. In patients receiving CAIT patient characteristics, recorded spirometry data and number of IV antibiotic days were collected retrospectively at fixed time intervals, from 6months before to one year after the start of the 2nd inhaled antibiotic. For patients on inhaled antibiotic monotherapy (IAMT), the same data were obtained at similar intervals during the study period. RESULTS: A total of 49 of 89 patients using chronic inhaled antibiotic therapy received CAIT. Patients receiving CAIT had a lower baseline FEV1 and were more likely to be homozygous for F508del compared to patients receiving IAMT. FEV1 deteriorated on average by a factor of 0.904 per year (95% CI: 0.851-0.960) prior to the start of CAIT. The initiation of CAIT was associated with an average improvement in FEV1 by a factor of 1.148 per year (95% CI: 1.068-1.236, p=0.0002). The analysis of specific types of antibiotics revealed evidence of positive effects of adding COLI to TOBI and COLI to AZLI. We found no effect of the initiation of CAIT on the number of IV antibiotic days (p=0.80). CONCLUSION: CF patients with more advanced lung disease are more likely to receive CAIT. In this patient group, CAIT was associated with a significant improvement in FEV1. Further data are warranted to identify the value of CAIT.

Early-life house dust mite allergens, childhood mite sensitization, and respiratory outcomes.

BACKGROUND: Exposure to indoor allergens during early life may play a role in the development of the immune system and inception of asthma. OBJECTIVE: To describe the house dust mite (HDM) allergen concentrations in bedroom dust during early life and to evaluate its associations with HDM sensitization, wheezing, and asthma, from birth to school age, in 5 geographically spread European birth cohorts. METHODS: We included 4334 children from INMA-Menorca (Spain), BAMSE (Sweden), LISAplus and MAS (Germany), and PIAMA-NHS (the Netherlands). Dust samples were collected from bedrooms during early life and analyzed for Dermatophagoides pteronyssinus (Der p1) and Dermatophagoides farinae (Der f1). HDM concentrations were divided into four categories. Sensitization was determined by specific IgE. Wheezing and asthma information up to 8/10 years was collected through questionnaires. We performed mixed-effects logistic regression models and expressed associations as odds ratios with 95% confidence intervals. RESULTS: House dust mite concentrations varied across cohorts. Mean allergen concentrations were highest in INMA-Menorca (geometric mean (GM) Der p1 = 3.3 µg/g) and LISAplus (GM Der f1 = 2.1 µg/g) and lowest in BAMSE (GM Der p1 = 0.1 µg/g, Der f1 = 0.3 µg/g). Moderate and high HDM concentrations were significantly (P-values < 0.05) associated with 50-90% higher prevalence of HDM sensitization. No significant associations were observed with respiratory outcomes. CONCLUSION: Our study based on geographically spread regions, a large sample size, and a wide range of allergen concentration shows that HDM allergen concentrations vary across regions and that exposure during early life plays a role in the development of allergic sensitization but not in the development of respiratory outcomes.

Variation of DNA methylation in candidate age-related targets on the mitochondrial-telomere axis in cord blood and placenta.

BACKGROUND: Epigenetics is tissue-specific and potentially even cell-specific, but little information is available from human reproductive studies about the concordance of DNA methylation patterns in cord blood and placenta, as well as within-placenta variations. We evaluated methylation levels at promoter regions of candidate genes in biological ageing pathways (SIRT1, TP53, PPARG, PPARGC1A, and TFAM), a subtelomeric region (D4Z4) and the mitochondrial genome (MT-RNR1, D-loop). METHODS: Ninety individuals were randomly chosen from the ENVIRONAGE birth cohort to evaluate methylation concordance between cord blood and placenta using highly quantitative bisulfite-PCR pyrosequencing. In a subset of nineteen individuals, a more extensive sampling scheme was performed to examine within-placenta variation. RESULTS: The DNA methylation levels of the subtelomeric region and mitochondrial genome showed concordance between cord blood and placenta with correlation coefficients ranging from r = 0.31 to 0.43, p ≤ 0.005, and also between the maternal and foetal sides of placental tissue (r = 0.53 to 0.72, p ≤ 0.05). For the majority of targets, an agreement in methylation levels between four foetal biopsies was found (with intra-class correlation coefficients ranging from 0.16 to 0.72), indicating small within-placenta variation. CONCLUSIONS: The methylation levels of the subtelomeric region (D4Z4) and mitochondrial genome (MT-RNR1, D-loop) showed concordance between cord blood and placenta, suggesting a common epigenetic signature of these targets between tissues. Concordance was lacking between the other genes that were studied. In placental tissue, methylation patterns of most targets on the mitochondrial-telomere axis were not strongly influenced by sample location.

Mortality in non-cystic fibrosis bronchiectasis: a prospective cohort analysis.

INTRODUCTION: There is limited data on mortality and associated morbidity in non-cystic fibrosis bronchiectasis (NCFB). Our aim was to analyze the overall mortality for all newly diagnosed patients from June 2006 onwards and to evaluate risk factors for mortality in this cohort. METHODS: 245 patients who had a new diagnosis of NCFB between June 2006 and October 2012 at the University Hospital of Leuven, Belgium, were included in the analysis. Death was analyzed until end of November 2013. All patients had chest HRCT scan confirming the presence of bronchiectatic lesions and had symptoms of chronic productive cough. Univariate and multivariate Cox proportional hazard survival regression analysis was used to estimate hazard ratios (HR) and their 95% confidence intervals (CI) of variables possibly predicting mortality. RESULTS: Overall mortality in NCFB patients who had a median follow-up of 5.18 years was 20.4%. Patients with NCFB and associated chronic obstructive pulmonary disease (COPD) had a mortality of 55% in that period. Univariate analysis showed higher mortality according to age, gender, smoking history, Pseudomonas aeruginosa status, spirometry, radiological extent, total number of sputum bacteria and underlying etiology. Multivariate analysis showed significant higher mortality with increasing age (HR = 1.045; p = 0.004), with increasing number of lobes affected (HR = 1.53; p = 0.009) and when patients had COPD associated NCFB (HR = 2.12; p = 0.038). The majority of the 50 deaths were respiratory related (n = 29; 58%). CONCLUSION: NCFB patients with associated COPD disease had the highest mortality rates compared to the other NCFB patients. Additional risk factors for lower survival were increasing age and number of lobes affected.

Lymphocytic bronchiolitis after lung transplantation is associated with daily changes in air pollution.

Acute rejection represents a major problem after organ transplantation, being a recognized risk for chronic rejection and mortality. Recently, it became clear that lymphocytic bronchiolitis (LB, B-grade acute rejection) is more important than previously thought, as it predisposes to chronic rejection. We aimed to verify whether daily fluctuations of air pollution, measured as particulate matter (PM) are related to histologically proven A-grade rejection and/or LB and bronchoalveolar lavage (BAL) fluid cellularity after lung transplantation. We fitted a mixed model to examine the association between daily variations in PM(10) and A-grade rejection/LB on 1276 bronchoscopic biopsies (397 patients, 416 transplantations) taken between 2001 and 2011. A difference of 10 µg/m(3) in PM(10) 3 days before diagnosis of LB was associated with an OR of 1.15 (95% CI 1.04-1.27; p = 0.0044) but not with A-grade rejection (OR = 1.05; 95% CI 0.95-1.15; p = 0.32). Variations in PM(10) at lag day 3 correlated with neutrophils (p = 0.013), lymphocytes (p = 0.0031) and total cell count (p = 0.024) in BAL. Importantly, we only found an effect of PM10 on LB in patients not taking azithromycin. LB predisposed to chronic rejection (p < 0.0001). The risk for LB after lung transplantation increased with temporal changes in particulate air pollution, and this was associated with BAL neutrophilia and lymphocytosis. Azithromycin was protective against this PM effect.

Air pollution-associated procoagulant changes: the role of circulating microvesicles.

BACKGROUND: Epidemiological studies suggest an association between exposure to particulate matter (PM) in air pollution and the risk of venous thromboembolism (VTE). OBJECTIVES: To investigate the underlying pathophysiological pathways linking PM exposure and VTE. PATIENTS AND METHODS: We assessed potential associations between PM exposure and coagulation and inflammation parameters, including circulating microvesicles, in a group of 233 patients with diabetes. RESULTS: The numbers of circulating blood platelet-derived and annexin V-binding microvesicles were inversely associated with the current levels of PM(2.5) or PM(10), measured on the day of sampling. Recent past exposure to PM(10), up to 1 week prior to blood sampling, estimated at the patients' residential addresses, was associated with elevated high-sensitivity C-reactive protein (CRP), leukocytes and fibrinogen, as well as with tissue factor (TF)-dependent procoagulant changes in thrombin generation assays. When longer windows of past exposure were considered, up to 1 year preceding blood sampling, procoagulant changes were evident from the strongly increased numbers of red blood cell-derived circulating microvesicles and annexin V-binding microvesicles, but they no longer associated with TF. Past PM exposure was never associated with activated partial thromboplastin time (aPTT), prothrombin time (PT), or factor (F) VII, FVIII, FXII or D-dimers. Residential distance to a major road was only marginally correlated with procoagulant changes in FVIII and thrombin generation. CONCLUSIONS: Increases in the number of microvesicles and in their procoagulant properties, rather than increases in coagulation factors per se, seem to contribute to the risk of VTE, developing during prolonged exposure to air pollutants.

Quantification of PCDD/Fs and dioxin-like PCBs in small amounts of human serum using the sensitive H1L7.5c1 mouse hepatoma cell line: optimization and analysis of human serum samples from adolescents of the Flemish human biomonitoring program FLEHS II.

Since the CALUX (Chemically Activated LUciferase gene eXpression) bioassay is a fast and inexpensive tool for the throughput analysis of dioxin-like compounds in a large number of samples and requires only small sample volumes, the use of this technique in human biomonitoring programs provides a good alternative to GC-HRMS. In this study, a method for the separate analysis of PCDD/Fs and dioxin-like PCBs (dl-PCBs) in human serum with the new sensitive H1L7.5c1 mouse hepatoma cell line was optimized. Sample dilution factors of 5 and 2.4 were selected for routine analysis of respectively the PCDD/Fs and dl-PCBs. The validation studies showed that repeatability and within-lab reproducibility for the quality control (QC) standard were within the in-house criteria. A long-term within-lab reproducibility of 25% for the PCDD/F fraction and 41% for the dl-PCB fraction for the analysis of pooled serum samples, expressed as pg BEQ/g fat, was determined. CALUX recoveries of the spiked procedural blanks were within the acceptable in-house limits of 80-120% for both fractions and the LOQ was 30.3 pg BEQ/g fat for the PCDD/Fs and 14.5 pg BEQ/g fat for the dl-PCBs. The GC-HRMS recovery of a C13-spiked pooled serum sample was between 60 and 90% for all PCDD/F congeners and between 67 and 82% for the non-ortho PCBs. An adequate separation between both fractions was found. The CALUX/GC-HRMS ratio for a pooled serum sample was respectively 2.0 and 1.4 for the PCDD/Fs and the dl-PCBs, indicating the presence of additional AhR active compounds. As expected, a correlation was found between human serum samples analyzed with both the new H1L7.5c1 cell line and the more established H1L6.1c3 cell line. The geometric mean CALUX-BEQ values, reported for the adolescents of the second Flemish Environment and Health Study (FLEHS II) recruited in 2009-2010, were 108 (95% CI: 101-114) pg CALUX-BEQ/g fat for the PCDD/Fs and 32.1 (30.1-34.2) pg CALUX-BEQ/g fat for the dioxin-like PCBs.

No exercise-induced increase in serum BDNF after cycling near a major traffic road.

Commuting by bike has a clear health enhancing effect. Moreover, regular exercise is known to improve brain plasticity, which results in enhanced cognition and memory performance. Animal research has clearly shown that exercise upregulates brain-derived neurotrophic factor (BDNF - a neurotrophine) enhancing brain plasticity. Studies in humans found an increase in serum BDNF concentration in response to an acute exercise bout. Recently, more evidence is emerging suggesting that exposure to air pollution (such as particulate matter (PM)) is higher in commuter cyclists compared to car drivers. Furthermore, exposure to PM is linked to negative neurological effects, such as neuroinflammation and cognitive decline. We carried-out a cross-over experiment to examine the acute effect of exercise on serum BDNF, and the potential effect-modification by exposure to traffic-related air pollution. Thirty eight physically fit, non-asthmatic volunteers (mean age: 43, 26% women) performed two cycling trials, one near a major traffic road (Antwerp Ring, R1, up to 260,000 vehicles per day) and one in an air-filtered room. The air-filtered room was created by reducing fine particles as well as ultrafine particles (UFP). PM10, PM2.5 and UFP were measured. The duration (∼20min) and intensity of cycling were kept the same for each volunteer for both cycling trials. Serum BDNF concentrations were measured before and 30min after each cycling trial. Average concentrations of PM10 and PM2.5 were 64.9µg/m(3) and 24.6µg/m(3) in cycling near a major ring way, in contrast to 7.7µg/m(3) and 2.0µg/m(3) in the air-filtered room. Average concentrations of UFP were 28,180 particles/cm(3) along the road in contrast to 496 particles/cm(3) in the air-filtered room. As expected, exercise significantly increased serum BDNF concentration after cycling in the air-filtered room (+14.4%; p=0.02). In contrast, serum BDNF concentrations did not increase after cycling near the major traffic route (+0.5%; p=0.42). Although active commuting is considered to be beneficial for health, this health enhancing effect could be negatively influenced by exercising in an environment with high concentrations of PM. Whether this effect is also present with chronic exercise and chronic exposure must be further elucidated.

A randomised controlled trial of azithromycin to prevent chronic rejection after lung transplantation.

Azithromycin reduces airway inflammation and improves forced expiratory volume in 1 s (FEV1) in chronic rejection or bronchiolitis obliterans syndrome (BOS) after lung transplantation (LTx). Azithromycin prophylaxis might prevent BOS. A double-blind randomised controlled trial of azithromycin (n = 40) or placebo (n = 43), initiated at discharge and administered three times a week for 2 yrs, was performed in 2005-2009 at the Leuven University Hospital (Leuven, Belgium). Primary end-points were BOS-free and overall survival 2 yrs after LTx; secondary end-points were acute rejection, lymphocytic bronchiolitis and pneumonitis rate, prevalence of pseudomonal airway colonisation or gastro-oesophageal reflux, and change in FEV1, airway and systemic inflammation over time. Patients developing BOS were assessed for change in FEV1 with open-label azithromycin. BOS occurred less in patients receiving azithromycin: 12.5 versus 44.2% (p = 0.0017). BOS-free survival was better with azithromycin (hazard ratio 0.27, 95% CI 0.092-0.816; p = 0.020). Overall survival, acute rejection, lymphocytic bronchiolitis, pneumonitis, colonisation and reflux were comparable between groups. Patients receiving azithromycin demonstrated better FEV1 (p = 0.028), and lower airway neutrophilia (p = 0.015) and systemic C-reactive protein levels (p = 0.050) over time. Open-label azithromycin for BOS improved FEV1 in 52.2% patients. No serious adverse events were noted. Azithromycin prophylaxis attenuates local and systemic inflammation, improves FEV1 and reduces BOS 2 yrs after LTx.

Arterial properties in relation to genetic variation in alpha-adducin and the renin-angiotensin system in a White population.

Earlier studies have demonstrated the interaction between ADD1 and ACE in relation to arterial properties. We investigated whether arterial characteristics might also be related to interactions of ADD1 with other renin-angiotensin system genes. Using a family-based sampling frame, we randomly recruited 1064 Flemish subjects (mean age, 43.6 years; 50.4% women). By means of a wall-tracking ultrasound system, we measured the properties of the carotid, femoral and brachial arteries. In multivariate-adjusted analyses, we assessed the multiple gene effects of ADD1 (Gly460Trp), AGT (C-532T and G-6A) and AT1R (A1166C). In ADD1 Trp allele carriers, but not in ADD1 GlyGly homozygotes (P-value for interaction < or =0.014), femoral cross-sectional compliance was significantly higher (0.74 vs 0.65 mm(2) kPa(-1); P=0.020) in carriers of the AT1R C allele than in AT1R AA homozygotes, with a similar trend for femoral distensibility (11.3 vs 10.2 x 10(-3) kPa(-1); P=0.055). These associations were independent of potential confounding factors, including age. Family-based analyses confirmed these results. Brachial diameter (4.35 vs 4.18 mm) and plasma renin activity (PRA) (0.23 vs 0.14 ng ml(-1) h(-1)) were increased (P< or =0.005) in AGT CG haplotype homozygotes compared with non-carriers, whereas the opposite was true for brachial distensibility (12.4 vs 14.4 x 10(-3) kPa(-1); P=0.011). There was no interaction between AGT and any other gene in relation to the measured phenotypes. ADD1 and AT1R interactively determine the elastic properties of the femoral artery. There is a single-gene effect of the AGT promoter haplotypes on brachial properties and PRA.

Co-cultures of multiple cell types mimic pulmonary cell communication in response to urban PM10.

The current authors evaluated whether a system of co-cultures of relevant cells (pneumocytes (A549), macrophages (THP-1), mast cells (HMC-1) and endothelial cells (EAHY926)) would mimic the responses to particles with a 50% cut-off aerodynamic diameter of 10 microm (PM(10)) previously reported in vivo. The role of mast cells was considered of special interest. Single cultures, bicultures (A549 + HMC-1 in a 10:1 ratio; THP-1 + HMC-1 in a 2:1 ratio) and tricultures (A549 + THP-1 + HMC-1 in a 10:2:1 ratio) were exposed to urban PM(10) (24 h at 0, 10, 30 or 100 microg x cm(-2)). Additionally, EAHY926 cells were introduced in inserts above the tricultures. The released cytokines were evaluated with a fluorescence-activated cell sorter array system. THP-1 + HMC-1 bicultures and the tricultures released more granulocyte colony-stimulating factor (G-CSF), macrophage inflammatory protein (MIP)-1beta, interleukin (IL)-1beta, IL-8, IL-6, tumour necrosis factor-alpha and MIP-1alpha in response to PM(10) than the sum of the single cultures. Tricultures with EAHY926 released more G-CSF, MIP-1alpha, IL-8 and MIP-1beta than the EAHY926 single culture. The bicultures, tricultures and tricultures with EAHY926 provide results that are consistent with the local and systemic effects previously described for particulate matter effects, i.e. inflammation, endothelial dysfunction and bone marrow cell mobilisation. Mast cells seem to play a significant role in the co-culture responses.

Arterial structure and function and environmental exposure to cadmium.

OBJECTIVES: Few studies have addressed the effect of cadmium toxicity on arterial properties. METHODS: We investigated the possible association of 24 h urinary cadmium excretion (an index of lifetime exposure) with measures of arterial function in a randomly selected population sample (n = 557) from two rural areas with low and high environmental exposure to cadmium. RESULTS: 24 h urinary cadmium excretion was significantly higher in the high compared with the low exposure group (p<0.001). Even though systolic (p = 0.42), diastolic (p = 0.14) and mean arterial pressure (p = 0.68) did not differ between the high and low exposure groups, aortic pulse wave velocity (p = 0.008), brachial pulse pressure (p = 0.026) and femoral pulse pressure (p = 0.008) were significantly lower in the high exposure group. Additionally, femoral distensibility (p<0.001) and compliance (p = 0.001) were significantly higher with high exposure. Across quartiles of 24 h urinary cadmium excretion (adjusted for sex and age), brachial (p for trend = 0.015) and femoral (p for trend = 0.018) pulse pressure significantly decreased and femoral distensibility (p for trend = 0.008) and compliance (p for trend = 0.007) significantly increased with higher cadmium excretion. After full adjustment, the partial regression coefficients confirmed these associations. Pulse wave velocity (beta = -0.79+/-0.27; p = 0.004) and carotid (beta = -4.20+/-1.51; p = 0.006), brachial (beta = -5.43+/-1.41; p = 0.001) and femoral (beta = -4.72+/-1.74; p = 0.007) pulse pressures correlated negatively, whereas femoral compliance (beta = 0.11+/-0.05; p = 0.016) and distensibility (beta = 1.70+/-0.70; p = 0.014) correlated positively with cadmium excretion. CONCLUSION: Increased cadmium body burden is associated with lower aortic pulse wave velocity, lower pulse pressure throughout the arterial system, and higher femoral distensibility.