A cross-sectional study of seven-year-old children was conducted to explore the relationship between damp, mouldy housing and childhood asthma, and the effects of passive tobacco smoke exposure upon respiratory symptoms, lung function and middle ear effusion. A random cluster sample of 1095 school children were contacted. Following a postal questionnaire to parents, 892 children were examined. Baseline spirometry, exercise-induced brochospasm (EIB), and impedance tympanograms were measured. Salivary cotinine concentration was determined for 770 children. Bedroom temperature and relative humidity were monitored continuously for 7 days in the homes of 317 children. The repeatability of each of the measurements was assessed. Among 1000 children with questionnaire data, 123 (12.3%) were reported to have wheezed in the previous year. Recent wheeze was strongly associated with report of mould in the home (odds ratio 3.70, 95&37 CI 2.22-6.15, X<SUP>2</SUP> 27.7, 1df), and this association was substantially independent of other aspects of the home environment. However, reported dampness and mould growth were only weakly associated with EIB and impaired baseline spirometry. Differences in adjusted weekly mean temperature and relative humidity between the bedrooms of wheezy and non-wheezy children were small and non-significant, although in the expected direction (-0.4 degC, t -1.3, 315df; +1.1% RH, t +1.1, 315df). Tympanometric findings were unrelated to bedroom conditions. At every level of measured EIB, recent wheeze was reported more commonly for children from mouldy homes, and the association between mould and wheeze was substantially independent of EIB. These findings confirm those of a preliminary study and suggest that the association between damp or mouldy housing and childhood asthma may be principally due to greater awareness of respiratory symptoms by parents who consider their home to be mouldy. Further studies of this association will benefit from objective measurements of both exposure and disease. Cotinine was detected in the saliva of 85% (658/770) children. Six children had levels greater than 15 ng/ml, which may indicate experimentation with active smoking. Cotinine concentrations were strongly related to the number of smokers in the household, female sex and rented housing. Most respiratory symptoms, including wheeze, were not associated with salivary cotinine. All spirometric indices except FVC were inversely correlated with cotinine level, the effect being greatest for end-expiratory flow rates. Adjusting for sex, height, test conditions and housing tenure, differences in FEF75-85% and FEF75% between the top and bottom quintiles of salivary cotinine were each about 7%, equivalent to a reduction of 1.1% (95% CI 0.1% -2.1%) per doubling of cotinine concentration. Further cross-sectional studies of passive smoking in childhood should include measures of end-expiratory airflow. The long-term significance of these spirometric changes can only be assessed by longitudinal studies, preferably using biochemical markers of tobacco smoke exposure in subjects who have never actively smoked. Tympanograms indicating middle ear effusion (Type B) were found in 9.4% (82/872) children. The housing characteristic most strongly related to effusion was the number of smokers in the household, the odds ratio for two or more smokers (compared to none) being 1.9 (95% CI 1.1-3.4, X<SUP>2</SUP> 4.1, 1df). Tympanometric abnormalities were strongly related to salivary cotinine level, the odds ratio for effusion being 1.14 per doubling of the cotinine concentration (95% CI 1.03-1.27, X<SUP>2</SUP> 6.6, 1df). Adjustment for sex, housing tenure and a range of specific housing variables made little difference to this result. At least one-third of middle ear effusions in this population were statistically attributable to passive smoke exposure. These findings are consistent with three case-control studies and one population survey of this age-group, and suggest that middle ear effusion should be added to the list of hazards attributable to passive smoking.

No description available.

No description available.

Primary spontaneous pneumothorax (PSP) is a common clinical problem affecting previously healthy individuals. It is a condition in which air is present in the pleural space in the absence of a precipitating event such as trauma or lung disease (Painter et al., 2005). The pathogenesis is poorly understood but is related to the rupture of apical pleural blebs. The tissue injury that accumulates within the lung prior to PSP is thought to arise through the action of activated alveolar macrophages. These cells, once stimulated, release matrix degrading metalloproteinases within the lung postulated to result in increased breakdown of collagen and elastin causing alveolar destruction, distal emphysema and formation of blebs. The proteases of most interest are a family of zinc dependant proteinases, collectively known as matrix metalloproteinases, (MMP' s). Of particular interest in this setting are MMP's 1, 2 and 9 due to their association with matrix degradation and remodelling and their ability to digest both type I and type IV Collagen. The study aims to investigate whether PSP occurs as a result of increased expression of MMP-1, MMP-2 and MMP-9 from activated alveolar macrophages. Immunohistochemistry was performed on apical lung tissue samples from 51 patients presenting with PSP to determine the level of expression of MMP-1, MMP-2 and MMP-9. Semiquantitative analysis revealed decreased expression ofMMP-2 and MMP-9 in comparison to controls. No alteration in MMP-1 expression was observed in comparison to controls. In vitro experiments were conducted using two cell lines; A549 a lung type 11 epithelial cell line and U937 a human macrophage cell line to map physiological responses to varying environmental stimuli, postulated to represent risk factors of PSP. In addition evaluation of cytokine expression was performed on these samples to further assess the effects of the cellular stimulation The A549 cell line was most sensitive to treatments with CO2 and tobacco particulate while the U937 cell line showed fluctuating responses to all of the treatments investigated. Despite this, it was not possible to positively correlate the production ofMMP-l, 2 and 9 in the individual cell treatments with that observed for the in-vivo patient samples. Measurement of cytokine expression demonstrated a varying response in both A549 and U937 cell lines, the greatest of which was observed for Interleukin 8 (IL-8) and Tumour Necrosis Factor a (TNF-a). Decreased levels ofMMP-2 and MMP-9 may limit the deposition of matrix construct causing a weakness in type IV collagen. This decrease in MMP activity may alter the proteolysis/antiproteolysis balance reflecting defective repair of the extracellular matrix. Sustained production of MMP-l under these conditions may further contribute, pushing the remodelling process towards matrix destruction further promoting the tissue damage associated with bleb formation.

The human nasopharynx is a reservoir of both commensal and pathogenic bacteria that can be easily transmitted from one individual to another. It has long been hypothesised that host commensal flora give protection from carriage of pathogens and invasive disease. The commensal Neisseria lactamica has previously been associated with protection against the closely related human pathogen Neisseria meningitidis, which is thought to be due to the acquisition of cross-reactive immunity to N. meningitidis. The objective of this study was to identify the extent of protection by N. lactamica in the absence of host immune cells, using an in vitro model of the human nasopharyngeal epithelium with the Detroit 562 (D562) cell line. N. lactamica has been demonstrated to attenuate the induction of innate inflammatory cytokines and chemokines from D562 cells challenged with N. meningitidis. For the first time in this study, N. lactamica was found to attenuate the induction of IL6, IL8 and TNFα from D562 cells challenged with the unrelated Gram-positive human pathogen Streptococcus pneumoniae. Attenuation by N. lactamica did not extend to suppression of MAPK pathways when stimulated with chemical agonists, but was able to suppress inflammation induced through the intracellular PAMP receptor TLR3, which is not involved in meningococcal or pneumococcal inflammation. This suggests a global mechanism of attenuation in host cells by N. lactamica. N. lactamica was further demonstrated to reduce association with and invasion of D562 epithelial cells by N. meningitidis serogroup B (MenB) by up to 60% and 90%, respectively. This suppression was dependent on live N. lactamica and did not require invasion of host cells by the commensal, suggesting an active mechanism employed by N. lactamica. The occasional human commensal coloniser Neisseria polysaccharea was found to reduce adhesion and invasion of MenB to a similar degree, however the related commensal Neisseria cinerea was not. The reduction in MenB association with host cells protected host cells from MenB-induced apoptosis, which was mediated by activation of caspase 3. This study demonstrates that commensal Neisseria spp. N. lactamica and N. polysaccharea protect the host at the nasopharyngeal epithelium from experimental colonisation and invasive disease by MenB. Additionally, commensal neisseriae protect against inflammation and cell death induced by the unrelated pathogen S. pneumoniae. Therefore, commensal neisseriae warrant further study to evaluate their effectiveness for use as probiotics to protect against bacterial pathogens responsible for meningitis.

No description available.

No description available.

Recently there has been interest in assessing airway inflammation using non-invasive tests as it has been shown that controlling eosinophilic airway inflammation, as measured in induced sputum in a population of patients with moderate to severe asthma, can lead to a reduction in asthma exacerbations, when compared to current guidelines.;Most patients have mild to moderate asthma and are treated solely in primary care, in a setting not suitable for induced sputum measurements; there exists a need for an easy, safe and inexpensive mechanism for monitoring airway inflammation.;Previous work has demonstrated that the fraction of nitric oxide in the exhaled breath (FENO) is elevated in asthma and that levels decrease after steroid use. These papers led to an explosion of interest in using FENO as a marker for eosinophilic airway inflammation in asthma. However, few studies have evaluated FENO in a clinical setting and compared its use to management protocols.;This thesis explores the relationship between airway inflammation and asthma, and focuses on induced sputum and FENO. I explore the relationship between sputum eosinophil counts and FENO in an observational study, and use these findings to calculate levels for FENO which best identify the presence and absence of a sputum eosinophilia. These levels are then used in a randomised clinical trial, assessing whether FENO measurements can help predict and prevent asthma exacerbations when compared to current clinical guidelines.;Lastly, a large cross sectional study explores the relationship between pre- and postbronchodilator FEV1 and measures of airway inflammation, allowing for the effect of confounding factors, using a multivariate analysis.

It was proposed that the lower airways of patients with asthmas and Chronic Obstructive Pulmonary Disease (COPD) might possess uncharacterised bacterial components absent from the healthy respiratory tract.;Total genomic DNA was extracted from induced sputum and broncho-alveolar lavage samples from healthy volunteers, mild asthmatics and COPD patients. Following this, clones containing bacterial 16S rDNA amplicons were produced using broad-range bacterial primers and the Polymerase Chain Reaction (PCR). These were grouped using restriction analysis and characterised by selective sequencing. The bacterial composition of each sample was then determined and the distribution of individual groups and overall sample group diversities derived and compared across the volunteer groups. Such analyses have not previously been applied to samples from humans.;Bacterial populations of surprising complexity were present, not only in respiratory disease, but also in respiratory health. This raises questions about the natural sterility of the lower respiratory tract and whether there is a genuine resident microbiota. While no single predominant organism showed a strong association, several organisms represented by low clone frequencies were differentially associated with health or disease. Moreover, the Bacterial diversity present in samples from healthy volunteers was significantly greater than that detected in samples from patients. Molecular characterisation of the bacteria present in lower airways revealed novel and potentially important aspects of the human-associated microbiota.

No description available.