Human exposure to diesel exhaust induces CYP1A1 expression and AhR activation without a coordinated antioxidant response.

BACKGROUND: Diesel exhaust (DE) induces neutrophilia and lymphocytosis in experimentally exposed humans. These responses occur in parallel to nuclear migration of NF-κB and c-Jun, activation of mitogen activated protein kinases and increased production of inflammatory mediators. There remains uncertainty regarding the impact of DE on endogenous antioxidant and xenobiotic defences, mediated by nuclear factor erythroid 2-related factor 2 (Nrf2) and the aryl hydrocarbon receptor (AhR) respectively, and the extent to which cellular antioxidant adaptations protect against the adverse effects of DE. METHODS: Using immunohistochemistry we investigated the nuclear localization of Nrf2 and AhR in the epithelium of endobronchial mucosal biopsies from healthy subjects six-hours post exposure to DE (PM10, 300 µg/m3) versus post-filtered air in a randomized double blind study, as a marker of activation. Cytoplasmic expression of cytochrome P450s, family 1, subfamily A, polypeptide 1 (CYP1A1) and subfamily B, Polypeptide 1 (CYP1B1) were examined to confirm AhR activation; with the expression of aldo-keto reductases (AKR1A1, AKR1C1 and AKR1C3), epoxide hydrolase and NAD(P)H dehydrogenase quinone 1 (NQO1) also quantified. Inflammatory and oxidative stress markers were examined to contextualize the responses observed. RESULTS: DE exposure caused an influx of neutrophils to the bronchial airway surface (p = 0.013), as well as increased bronchial submucosal neutrophil (p < 0.001), lymphocyte (p = 0.007) and mast cell (p = 0.002) numbers. In addition, DE exposure enhanced the nuclear translocation of the AhR and increased the CYP1A1 expression in the bronchial epithelium (p = 0.001 and p = 0.028, respectively). Nuclear translocation of AhR was also increased in the submucosal leukocytes (p < 0.001). Epithelial nuclear AhR expression was negatively associated with bronchial submucosal CD3 numbers post DE (r = -0.706, p = 0.002). In contrast, DE did not increase nuclear translocation of Nrf2 and was associated with decreased NQO1 in bronchial epithelial cells (p = 0.02), without affecting CYP1B1, aldo-keto reductases, or epoxide hydrolase protein expression. CONCLUSION: These in vivo human data confirm earlier cell and animal-based observations of the induction of the AhR and CYP1A1 by diesel exhaust. The induction of phase I xenobiotic response occurred in the absence of the induction of antioxidant or phase II xenobiotic defences at the investigated time point 6 h post-exposures. This suggests DE-associated compounds, such as polycyclic aromatic hydrocarbons (PAHs), may induce acute inflammation and alter detoxification enzymes without concomitant protective cellular adaptations in human airways.

Sex-related differences among young adults with heart failure in Sweden.

BACKGROUND: Differences between the sexes among the non-elderly with heart failure (HF) have been insufficiently evaluated. This study aims to investigate sex-related differences in early-onset HF. METHODS: Patients aged 18 to 54 years who were registered from 2003 to 2014 in the Swedish Heart Failure Register were included. Each patient was matched with two controls from the Swedish Total Population Register. Data on comorbidities and outcomes were obtained through the National Patient Register and Cause of Death Register. RESULTS: We identified 3752 patients and 7425 controls. Of the patients, 971 (25.9%) were women and 2781 (74.1%) were men with a mean (standard deviation) age of 44.9 (8.4) and 46.4 (7.3) years, respectively. Men had more hypertension and ischemic heart disease, whereas women had more congenital heart disease and obesity. During the median follow-up of 4.87 years, 26.5 and 24.7 per 1000 person-years male and female patients died, compared with 3.61 and 2.01 per 1000 person-years male and female controls, respectively. The adjusted hazard ratios for all-cause mortality, compared with controls, were 4.77 (3.78-6.01) in men and 7.84 (4.85-12.7) in women (p for sex difference = 0.11). When HF was diagnosed at 30, 35, 40, and 45 years, women and men lost up to 24.6 and 24.2, 24.4 and 20.9, 20.5 and 18.3, and 20.7 and 16.5 years of life, respectively. CONCLUSION: Long-term mortality was similar between the sexes. Women lost more years of life than men.

Sputum proteomic signature of gastro-oesophageal reflux in patients with severe asthma.

Gastro-oesophageal reflux disease (GORD) has long been associated with poor asthma control without an established cause-effect relationship. 610 asthmatics (421 severe/88 mild-moderate) and 101 healthy controls were assessed clinically and a subset of 154 severe asthmatics underwent proteomic analysis of induced sputum using untargeted mass spectrometry, LC-IMS-MSE. Univariate and multiple logistic regression analyses (MLR) were conducted to identify proteins associated with GORD in this cohort. When compared to mild/moderate asthmatics and healthy individuals, respectively, GORD was three- and ten-fold more prevalent in severe asthmatics and was associated with increased asthma symptoms and oral corticosteroid use, poorer quality of life, depression/anxiety, obesity and symptoms of sino-nasal disease. Comparison of sputum proteomes in severe asthmatics with and without active GORD showed five differentially abundant proteins with described roles in anti-microbial defences, systemic inflammation and epithelial integrity. Three of these were associated with active GORD by multiple linear regression analysis: Ig lambda variable 1-47 (p = 0·017) and plasma protease C1 inhibitor (p = 0·043), both in lower concentrations, and lipocalin-1 (p = 0·034) in higher concentrations in active GORD. This study provides evidence which suggests that reflux can cause subtle perturbation of proteins detectable in the airways lining fluid and that severe asthmatics with GORD may represent a distinct phenotype of asthma.

Incidence of and risk factors for nephrolithiasis in patients with gout and the general population, a cohort study.

BACKGROUND: Nephrolithiasis (NL) is known to be associated with gout, although there are few comparative studies on risk and risk factors for NL in gout compared to population cohorts. In this cohort study we investigated: (1) overall incidence of NL in gout (cases) and general population controls; (2) risk and risk factors (common comorbidities and medications) for first-time NL in cases and controls separately. METHODS: Cases (n = 29,968) and age-matched and sex-matched controls (n = 138,678) were identified from the regional healthcare database in western Sweden (VEGA). The analyzed risk factors (comorbidities and current medication use) for first-time NL, and socioeconomic factors were retrieved from VEGA and other national Swedish registers. For cases, follow up began on 1 January 2006 or on the first diagnosis of gout if this occurred later, and for controls on their index patient's first diagnosis of gout. Follow up ended on death, emigration or 31 December 2012. Incidence rates (IR) per 1000 person-years and hazard ratios (HR) were calculated. The incidence calculations were performed for cases (regardless of prior NL) and their controls. HRs with first occurrence of NL as outcome were calculated only in those without previous NL. RESULTS: In cases there were 678 NL events (IR: 6.16 events per 1000 person-years (95% CI: 5.70-6.64) and in controls 2125 NL events (IR 3.85 events per 1000 person-years (95% CI: 3.69-4.02), resulting in an age-sex-adjusted incidence rate ratio of 1.60 (95% CI:1.47-1.74). Point estimates for predictive factors were similar in cases and controls, except for a significant interaction for losartan which increased the risk of NL only in controls (HR = 1.49 (95% CI: 1.03-2.14). Loop diuretics significantly decreased the risk of NL by 30-34% in both cases and controls. Further significant predictors of NL in gout cases were male sex, diabetes and obesity and in controls male sex and kidney disease. CONCLUSIONS: The risk (age and sex adjusted) of NL was increased by 60% in cases compared to controls. None of the commonly used medications increased the risk of NL in gout patients.

Assessment of energy intake in women with chronic obstructive pulmonary disease: a doubly labeled water method study.

OBJECTIVES: To maintain energy balance, reliable methods for assessing energy intake and expenditure should be used in patients with chronic obstructive pulmonary disease (COPD). The purpose of this study was to validate the diet history and 7-day food diary methods of assessing energy intake (EI) using total energy expenditure (TEE) with the doubly labeled water (DLW) method (TEEDLW) as the criterion method in outpatient women with COPD. METHODS: EI was assessed by diet history (EIDH) and a 7-day food diary (EIFD) in 19 women with COPD, using TEEDLW as the criterion method. The three methods were compared using intra-class correlation coefficients (ICC) and Bland-Altman analyses. The participants were classified according to their reporting status (EI/TEE) as valid-reporters 0.79-1.21, under-reporters < 0.79 or over-reporters > 1.21. RESULTS: Diet history underestimated reported EI by 28%, and 7-day food diary underestimated EI by approximately 20% compared with TEEDLW. The ICC analysis showed weak agreement between TEEDLW and EIDH (ICC=-0.01; 95%CI-0.10 to 0.17) and between TEEDLW and EIFD (ICC=0.11; 95%CI -0.16 to 0.44). The Bland-Altman plots revealed a slight systematic bias for both methods. For diet history, six women (32%) were identified as valid-reporters, and for the 7-day food diary, twelve women (63%) were identified as valid-reporters. The accuracy of reported EI was only related to BMI. CONCLUSION: The diet history and 7-day food diary methods underestimated energy intake in women with COPD compared with the DLW method. Individuals with higher BMIs are prone to underreporting. Seven-day food diaries should be used with caution in assessing EI in women with COPD.

Sex-specific trends in 4-year survival in 37 276 men and women with acute myocardial infarction before the age of 55 years in Sweden, 1987-2006: a register-based cohort study.

OBJECTIVE: To examine sex-specific trends in 4-year mortality among young patients with first acute myocardial infarction (AMI), 1987-2006. DESIGN: Prospective cohort study. SETTING: Sweden. PARTICIPANTS: We identified 37 276 cases (19.4% women; age, 25-54 years) from the Swedish Inpatient Register, 1987-2006, who had survived 28 days after an AMI. OUTCOME MEASURES: 4-year mortality from all causes and standard mortality ratio (SMR). RESULTS: From the first to last 5-year period, the absolute excess risk decreased from 1.38 to 0.50 and 1.53 to 0.59 per 100 person-years among men aged 25-44 and 45-54 years, respectively. Corresponding figures for women were a decrease from 2.26 to 1.17 and from 1.93 to 1.45 per 100 person-years, respectively. Trends for women were non-linear, decreasing to the same extent as those for men until the third period, then increasing. For the last 5-year period, the standardised mortality ratio for young survivors of AMI compared with the general population was 4.34 (95% CI 3.04 to 5.87) and 2.43 (95% CI 2.12 to 2.76) for men aged 25-44 and 45-54 years, respectively, and 13.53 (95% CI 8.36 to 19.93) and 6.42 (95% CI 5.24 to 7.73) for women, respectively. Deaths not associated with cardiovascular causes increased from 21.5% to 44.6% in men and 41.5% to 65.9% in women. CONCLUSIONS: Young male survivors of AMI have low absolute long-term mortality rates, but these rates remain twofold to fourfold that of the general population. After favourable development until 2001, women now have higher absolute mortality than men and a 6-fold to 14-fold risk of death compared with women in the general population.

Cardiovascular effects of particulate air pollution exposure: time course and underlying mechanisms.

Air pollution is now recognized as an important independent risk factor for cardiovascular morbidity and mortality and may be responsible for up to 3 million premature deaths each year worldwide. The mechanisms underlying the observed effects are poorly understood but are likely to be multifactorial. Here, we review the acute and chronic effects of air pollution exposure on the cardiovascular system and discuss how these effects may explain the observed increases in cardiovascular morbidity and mortality.

Cytokine mRNA profile of alveolar T lymphocytes and macrophages in patients with systemic sclerosis suggests a local Tr1 response.

The development of an autoimmune disease like systemic sclerosis (SSc) is suspected to be driven by an activated T lymphocyte subset, expressing a cytokine profile specific to the disease. To further characterize the type of immune reaction in SSc, we searched for a broad panel of cytokine messenger ribonucleic acids (mRNAs) in T lymphocytes and monocytes/macrophages from paired samples of bronchoalveolar lavage fluid and peripheral blood in 18 patients and 16 age- and sex-matched controls. RNA from CD3(+) T lymphocytes and CD14(+) monocytes/macrophages was examined by means of the reverse transcriptase polymerase chain reaction. SSc alveolar T lymphocytes expressed a cytokine profile suggestive of a mixed Th1/Th2 reaction, showing an increased frequency of mRNA for interleukin (IL)-10, IL-6 and interferon (IFN)γ, while IL-1ß, IFNγ and tumour necrosis factor ß were expressed in blood T lymphocytes in a higher percentage of patients with SSc than controls. SSc alveolar T cells expressed IL-10 mRNA more often than peripheral T cells, a phenomenon not found in controls and which may point at local IL-10 activation/response in SSc lung. Transforming growth factor ß mRNA was present in all alveolar as well as peripheral blood T cell samples in patients and controls. The cytokine mRNA profile in SSc with interstitial lung disease (ILD) was similar to the profile found in SSc without ILD. Our findings point at a mixed Th1/Th2 reaction in SSc and may indicate regulatory T 1 cell activation/response in the lungs of patients with SSc.

Factor XII activation is essential to sustain the procoagulant effects of particulate matter.

BACKGROUND: Particulate matter (PM) is a key component of ambient air pollution and has been associated with an increased risk of thrombotic events and mortality. The underlying mechanisms remain unclear. OBJECTIVES: To study the mechanisms of PM-driven procoagulant activity in human plasma and to investigate mainly, the coagulation driven by ultrafine particles (UFPs; < 0.1 µm) in genetically modified mice. METHODS: Thrombin generation in response to PM of different sizes was assessed in normal human platelet-poor plasma, as well as in plasmas deficient in the intrinsic pathway proteases factors XII (FXII) or XI (FXI). In addition, UFPs were intratracheally instilled in wild-type (WT) and FXII-deficient (FXII(-/-) ) mice and plasma thrombin generation was analyzed in plasma from treated mice at 4 and 20 h post-exposure. RESULTS: In normal human plasma, thrombin generation was enhanced in the presence of PM, whereas PM-driven thrombin formation was completely abolished in FXII- and FXI-deficient plasma. UFPs induced a transient increase in tissue factor (TF)-driven thrombin formation at 4 h post-instillation in WT mice compared with saline instillation. Intratracheal instillation of UFPs resulted in a procoagulant response in WT mice plasma at 20 h, whereas it was entirely suppressed in FXII(-/-) mice. CONCLUSIONS: Overall, the data suggest that PM promotes its early procoagulant actions mostly through the TF-driven extrinsic pathway of coagulation, whereas PM-driven long lasting thrombogenic effects are predominantly mediated via formation of activated FXII. Hence, FXII-driven thrombin formation may be relevant to an enhanced thrombotic susceptibility upon chronic exposure to PM in humans.

Ozone exposure enhances mast-cell inflammation in asthmatic airways despite inhaled corticosteroid therapy.

Asthmatics are recognised to be more susceptible than healthy individuals to adverse health effects caused by exposure to the common air pollutant ozone. Ozone has been reported to induce airway neutrophilia in mild asthmatics, but little is known about how it affects the airways of asthmatic subjects on inhaled corticosteroids. We hypothesised that ozone exposure would exacerbate the pre-existent asthmatic airway inflammation despite regular inhaled corticosteroid treatment. Therefore, we exposed subjects with persistent asthma on inhaled corticosteroid therapy to 0.2 ppm ozone or filtered air for 2 h, on 2 separate occasions. Lung function was evaluated before and immediately after exposure, while bronchoscopy was performed 18 h post exposure. Compared to filtered air, ozone exposure increased airway resistance. Ozone significantly enhanced neutrophil numbers and myeloperoxidase levels in airway lavages, and induced a fourfold increase in bronchial mucosal mast cell numbers. The present findings indicate that ozone worsened asthmatic airway inflammation and offer a possible biological explanation for the epidemiological findings of increased need for rescue medication and hospitalisation in asthmatic people following exposure to ambient ozone.

Time trends in asthma and wheeze in Swedish children 1996-2006: prevalence and risk factors by sex.

BACKGROUND: Recent data suggest that the previously rising trend in childhood wheezing symptoms has plateaued in some regions. We sought to investigate sex-specific trends in wheeze, asthma, allergic conditions, allergic sensitization and risk factors for wheeze. METHODS: We compared two population-based cohorts of 7 to 8-year olds from the same Swedish towns in 1996 and 2006 using parental expanded ISAAC questionnaires. In 1996, 3430 (97%) and in 2006, 2585 (96%) questionnaires were completed. A subset was skin prick tested: in 1996, 2148 (88%) and in 2006, 1700 (90%) children participated. RESULTS: No significant change in the prevalence of current wheeze (P = 0.13), allergic rhinitis (P = 0.18) or eczema (P = 0.22) was found despite an increase in allergic sensitization (20.6-29.9%, P < 0.01). In boys, however, the prevalence of current wheeze (12.9-16.4%, P < 0.01), physician-diagnosed asthma (7.1-9.3%, P = 0.03) and asthma medication use increased. In girls the prevalence of current symptoms and conditions tended to decrease. The prevalence of all studied risk factors for wheeze and asthma increased in boys relative to girls from 1996 to 2006, thus increasing the boy-to-girl prevalence ratio in risk factors. CONCLUSIONS: The previously reported increase in current wheezing indices has plateaued in Sweden. Due to increased diagnostic activity, physician diagnoses continue to increase. Time trends in wheezing symptoms differed between boys and girls, and current wheeze increased in boys. This was seemingly explained by the observed increases in the prevalence of risk factors for asthma in boys compared with girls. In contrast to the current symptoms of wheeze, rhinitis or eczema, the prevalence of allergic sensitization increased considerably.

Diesel exhaust exposure enhances the ozone-induced airway inflammation in healthy humans.

Exposure to particulate matter and ozone cause adverse airway reactions. Individual pollutant effects are often addressed separately, despite coexisting in ambient air. The present investigation was performed to study the effects of sequential exposures to diesel exhaust (DE) and ozone on airway inflammation in human subjects. Healthy subjects underwent bronchoscopy with bronchoalveolar lavage (BAL) and bronchial wash (BW) sampling on two occasions. Once following a DE exposure (with 300 mug.m(-3) particles with a 50% cut-off aerodynamic diameter of 10 mum) with subsequent exposure to O(3) (0.2 ppm) 5 h later. The other bronchoscopy was performed after a filtered air exposure followed by an ozone exposure, using an identical protocol. Bronchoscopy was performed 24 h after the start of the initial exposure. Significant increases in neutrophil and macrophage numbers were found in BW after DE followed by ozone exposure versus air followed by ozone exposure. DE pre-exposure also raised eosinophil protein X levels in BAL compared with air. The present study indicates additive effects of diesel exhaust on the ozone-induced airway inflammation. Together with similar results from a recent study with sequential diesel exhaust and ozone exposures, the present data stress a need to consider the interaction and cumulative effects of different air pollutants.

Lower airways inflammation in allergic rhinitics: a comparison with asthmatics and normal controls.

BACKGROUND: Allergic rhinitis (AR) and asthma represent a continuum of atopic disease. AR is believed to pre-dispose an individual to asthma. Compared with asthmatics and normal controls, the inflammatory response in the lower airways of rhinitics is not fully elucidated. To test the hypothesis that the inflammatory response in the airways of subjects with AR is at a level intermediate between that in normal controls and asthmatics, we have characterized bronchial inflammation and cytokine mRNA levels in non-asthmatic allergic rhinitics and compared it with subjects with allergic asthma and with normal controls. METHODS: Endobronchial mucosal biopsies were obtained at bronchoscopy from 14 allergic rhinitics, 16 asthmatics and 21 normal controls. Biopsies were embedded into glycol methacrylate resin for immunohistochemical analysis of cellular inflammation and snap frozen for semi-quantitative PCR analysis of cytokine mRNA levels. RESULTS: Airway inflammation in rhinitic subjects was characterized by an increase in submucosal eosinophils, mast cells and the mRNA expression of TNF-alpha, at an intermediate level between healthy and asthmatics. In addition, CD3(+) and CD8(+) lymphocytes in the epithelium, the endothelial expression of vascular adhesion molecule-1 and IL-1 beta mRNA were higher in the allergic rhinitics compared with both normal controls and asthmatics, whereas growth-related oncogene alpha-mRNA was decreased in AR compared with both healthy and asthmatics. Airway inflammation in the asthmatic group was characterized by higher numbers of eosinophils and mast cells, together with an increase in TNF-alpha-mRNA compared with both healthy and rhinitics. IFN-gamma mRNA was the highest in normal controls and lowest in the asthmatics. CONCLUSIONS: In individuals with AR the present data suggest an intermediate state of airway inflammation between that observed in normal individuals and subjects with clinical asthma. It is also indicated that IFN-gamma production by CD8(+) T lymphocytes could be protective against the development of airway hyperresponsiveness. Further work is needed to evaluate this hypothesis.

Road tunnel air pollution induces bronchoalveolar inflammation in healthy subjects.

Traffic-related air pollution is associated with adverse respiratory effects. The aim of the present study was to investigate whether exposure to air pollution in a road tunnel causes airway inflammatory and blood coagulation responses. A total of 16 healthy subjects underwent bronchoscopy with bronchial mucosal biopsies and bronchoalveolar lavage (BAL) on two occasions, in random order: once at 14 h after a 2-h exposure to air pollution in a busy road tunnel, and once after a control day with subjects exposed to urban air during normal activities. Peripheral blood was sampled prior to bronchoscopy. The road tunnel exposures included particulate matter with a 50% cut-off aerodynamic diameter of 2.5 microm, particulate matter with a 50% cut-off aerodynamic diameter of 10 mum and nitrogen dioxide which had median concentrations of 64, 176 and 230 microg.m(-3), respectively. Significantly higher numbers of BAL fluid total cell number, lymphocytes and alveolar macrophages were present after road tunnel exposure versus control. Significantly higher nuclear expression of the transcription factor component c-Jun was found in the bronchial epithelium after exposure. No upregulation of adhesion molecules or cellular infiltration was present and blood coagulation factors were unaffected. In conclusion, exposure of healthy subjects to traffic-related air pollution resulted in a lower airway inflammatory response with cell migration, together with signs of an initiated signal transduction in the bronchial epithelium.

The economic value of anti-IgE in severe persistent, IgE-mediated (allergic) asthma patients: adaptation of INNOVATE to Sweden.

BACKGROUND: Severe allergic asthma patients may not be controlled even with guideline recommended care, including inhaled corticosteroids, long-acting beta-2 agonists, theophylline, oral steroids and anti-leukotrienes. They experience exacerbations requiring intensive healthcare use and which may be fatal. Omalizumab, a new monoclonal antibody for use in IgE-mediated allergic diseases, reduces exacerbations and daily symptoms in this patient population. The aim of this study is to estimate the cost effectiveness of adding omalizumab to optimized standard therapy (ST) in patients with severe persistent IgE-mediated (allergic) asthma. METHODS: A Markov model comparing lifelong ST with a treatment period of omalizumab add-on therapy followed by ST, was developed based on efficacy data from the INNOVATE trial (28 weeks, N = 419) and Swedish life table and cost data. This model assumes that patients are at risk of having an exacerbation every 2 weeks and are at risk of dying from a clinically significant severe asthma exacerbation. Patients in a steady-state of having no exacerbations are defined to be in an 'optimized asthma control' state. Resource use data and utilities were obtained from INNOVATE and from a UK observational study. Costs from a societal perspective include estimates for drugs, routine care, exacerbations and costs in added years of life; benefits are expressed in QALYs. The response to omalizumab was evaluated after 16 weeks of trial, and non-responders stopped taking omalizumab for the remaining time. RESULTS: Total lifetime discounted costs and QALYs on ST were 52,702 euros and 11.60. Omalizumab add-on therapy cost an additional 42,754 euros for 0.76 additional QALYs, resulting in an incremental cost-effectiveness ratio of 56,091 euros. A probabilistic sensitivity analysis indicates that the 95% CI around the ICER is [31,328 euros; 120,552 euros]. One-way analyses indicate that the results are sensitive to the exacerbation-related mortality rate, the time horizon and the discount rates. CONCLUSIONS: Based on the model and the assumptions used, our results suggest that omalizumab provides cost offsets, improves quality of life and may have an attractive ICER in treating the severe allergic asthma population.

Asthma during the primary school ages--prevalence, remission and the impact of allergic sensitization.

BACKGROUND: Childhood is the most important time for asthma development. The aims of this study were to study changes in prevalence of asthma and wheeze, remission of asthma and changes in risk factor pattern from age 7-8 to age 11-12 in a cohort of school children. METHODS: In 1996, 3525 children aged 7-8 years in northern Sweden were invited to participate in a parental expanded ISAAC questionnaire survey. The cohort has been followed prospectively with yearly follow-ups to age 11-12, with a 97% yearly response rate. Skin prick tests were conducted at age 7-8 and 11-12. RESULTS: The prevalence of physician-diagnosed asthma increased from 5.7% at age 7-8 to 7.7% at age 11-12. Life-time prevalence of wheeze was 34.7% at age 11-12. The remission of asthma was 10% yearly and inversely related to allergic sensitization. Relapses were common, and remission persisting throughout the observation period was 5% yearly. Allergic sensitization was associated with current asthma at age 7-8 [adjusted odds ratio (OR) 4.9 (95% confidence interval (CI) 3.3-7.3)] and when the children were 4 years older [OR 5.6 (3.9-8.2)]. A family history of asthma was associated with current asthma at age 7-8 [OR 3.0 (2.1-4.5)] and 11-12 (OR 2.8 [2.0-3.9]). Ever having lived with a cat was significantly negatively associated with current asthma. CONCLUSIONS: The prevalence of asthma increased continuously during the primary school ages. Among several significant risk factors, allergic sensitization and a family history of asthma were the most important. With increasing age many known risk factors lost significance. Remission was inversely related to allergic sensitization.

Airway antioxidant and inflammatory responses to diesel exhaust exposure in healthy humans.

Pulmonary cells exposed to diesel exhaust (DE) particles in vitro respond in a hierarchical fashion with protective antioxidant responses predominating at low doses and inflammation and injury only occurring at higher concentrations. In the present study, the authors examined whether similar responses occurred in vivo, specifically whether antioxidants were upregulated following a low-dose DE challenge and investigated how these responses related to the development of airway inflammation at different levels of the respiratory tract where particle dose varies markedly. A total of 15 volunteers were exposed to DE (100 microg x m(-3) airborne particulate matter with a diameter of <10 microm for 2 h) and air in a double-blinded, randomised fashion. At 18 h post-exposure, bronchoscopy was performed with lavage and mucosal biopsies taken to assess airway redox and inflammatory status. Following DE exposure, the current authors observed an increase in bronchial mucosa neutrophil and mast cell numbers, as well as increased neutrophil numbers, interleukin-8 and myeloperoxidase concentrations in bronchial lavage. No inflammatory responses were seen in the alveolar compartment, but both reduced glutathione and urate concentrations were increased following diesel exposure. In conclusion, the lung inflammatory response to diesel exhaust is compartmentalised, related to differing antioxidant responses in the conducting airway and alveolar regions.

Airway inflammation in iron ore miners exposed to dust and diesel exhaust.

The aim of the present study was to investigate if underground miners exposed to dust and diesel exhaust in an iron ore mine would show signs of airway inflammation as reflected in induced sputum. In total, 22 miners were studied, once after a holiday of at least 2 weeks and the second time after 3 months of regular work. Control subjects were 21 "white-collar" workers. All subjects completed a questionnaire regarding medical and occupational history, and underwent lung function testing and induced sputum collection. Total and differential cell counts and analyses of the fluid phase of the induced sputum were performed. Sampling of personal exposure to elemental carbon, nitrogen dioxide and inhalable dust was recorded. The average concentrations of inhalable dust, nitrogen dioxide and elemental carbon were 3.2 mg.m-3, 0.28 mg.m-3 and 27 microg.m-3, respectively. Miners had increased numbers of inflammatory cells, mainly alveolar macrophages and neutrophils, and increased concentrations of fibronectin, metalloproteinase-9 and interleukin-10 in induced sputum compared with controls. In conclusion, miners in an underground iron ore mine demonstrated persistent airway inflammation that was as pronounced after a 4-week holiday as after a 3-month period of work underground in the mine.