Asthma and atopy show epidemiological association and are biologically linked by T-helper type 2 (T(h)2) cytokine-driven inflammatory mechanisms. IL-4 operates through the IL-4 receptor (IL-4R, a heterodimer of IL-4Ralpha and either gammac or IL-13Ralpha1) and IL-13 operates through IL-13R (a heterodimer of IL-4Ralpha and IL-13Ralpha1) to promote IgE synthesis and IgE-based mucosal inflammation which typify atopy. Recent animal model data suggest that IL-13 is a central cytokine in promoting asthma, through the stimulation of bronchial epithelial mucus secretion and smooth muscle hyper-reactivity. We investigated the role of common genetic variants of IL-13 and IL-13Ralpha1 in human asthma, considering IgE levels. A novel variant of human IL-13, Gln110Arg, on chromosome 5q31, associated with asthma rather than IgE levels in case-control populations from Britain and Japan [peak odds ratio (OR) = 2.31, 95% CI 1.33-4.00]; the variant also predicted asthma and higher serum IL-13 levels in a general, Japanese paediatric population. Immunohistochemistry demonstrated that both subunits of IL-13R are prominently expressed in bronchial epithelium and smooth muscle from asthmatic subjects. Detailed molecular modelling analyses indicate that residue 110 of IL-13, the site of the charge-modifying variants Arg and Gln, is important in the internal constitution of the ligand and crucial in ligand-receptor interaction. A non-coding variant of IL-13Ralpha1, A1398G, on chromosome Xq13, associated primarily with high IgE levels (OR = 3. 38 in males, 1.10 in females) rather than asthma. Thus, certain variants of IL-13 signalling are likely to be important promoters of human asthma; detailed functional analysis of their actions is needed.

Background Escherichia coli are widespread in the environment and pathogenic strains cause diseases of mucosal surfaces including the female genital tract. Pelvic inflammatory disease (PID; metritis) or endometritis affects ∼40% of cattle after parturition. We tested the expectation that multiple genetically diverse E. coli from the environment opportunistically contaminate the uterine lumen after parturition to establish PID.Methodology/Principal FindingsDistinct clonal groups of E. coli were identified by Random Amplification of Polymorphic DNA (RAPD) and Multilocus sequence typing (MLST) from animals with uterine disease and these differed from known diarrhoeic or extra-intestinal pathogenic E. coli. The endometrial pathogenic E. coli (EnPEC) were more adherent and invasive for endometrial epithelial and stromal cells, compared with E. coli isolated from the uterus of clinically unaffected animals. The endometrial epithelial and stromal cells produced more prostaglandin E2 and interleukin-8 in response to lipopolysaccharide (LPS) purified from EnPEC compared with non-pathogenic E. coli. The EnPEC or their LPS also caused PID when infused into the uterus of mice with accumulation of neutrophils and macrophages in the endometrium. Infusion of EnPEC was only associated with bacterial invasion of the endometrium and myometrium. Despite their ability to invade cultured cells, elicit host cell responses and establish PID, EnPEC lacked sixteen genes commonly associated with adhesion and invasion by enteric or extraintestinal pathogenic E. coli, though the ferric yersiniabactin uptake gene (fyuA) was present in PID-associated EnPEC. Endometrial epithelial or stromal cells from wild type but not Toll-like receptor 4 (TLR4) null mice secreted prostaglandin E2 and chemokine (C-X-C motif) ligand 1 (CXCL1) in response to LPS from EnPEC, highlighting the key role of LPS in PID.Conclusions/SignificanceThe implication arising from the discovery of EnPEC is that development of treatments or vaccines for PID should focus specifically on EnPEC and not other strains of E. coli.

Introduction There is epidemiological evidence to suggest that events in childhood influence lung growth and constitute a significant risk for adult COPD. The aim of the study is to evaluate for an association between childhood asthma and adult COPD. Methods This longitudinal, prospective study of 6-7-year-old children with asthma has been regularly reviewed every 7 years to the current analysis at 50 years of age. Participants completed respiratory questionnaires and lung function spirometry with postbronchodilator response. At the age of 50, subjects were classified to the following subgroups: non-asthmatics, asthma remission, current asthma and COPD which was defined by FEV 1 to FVC ratio postbronchodilator of less than 0.7. Results Of the remaining survivors, 346 participated in the current study ( participation rate of 76%) of whom 197 completed both questionnaire and lung function testing. As compared with children without symptoms of wheeze to the age of 7, (non-asthmatics) children with severe asthma had an adjusted 32 times higher risk for developing COPD (95% CI 3.4 to 269). In this cohort, 43% of the COPD group had never smoked. There was no evidence of a difference in the rate of decline in FEV 1 (mL/year, 95th CI) between the COPD group (17, 10 to 23) and the other groups: non-asthmatics (16, 12 to 21), asthma remission (20, 16 to 24) and current asthma (19, 13 to 25). Conclusions Children with severe asthma are at increased risk of developing COPD.

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The platelet-activating factor (PAF) represents a phospholipid with complex biological functions, including involvement in inflammatory processes. The degrading enzyme PAF acetylhydrolase (PAFAH) represents a candidate for asthma and other atopic diseases. Two loss-of-function mutations of PAFAH are associated with severe asthma in Japanese individuals. Our aim was to look for further PAFAH variants in white populations, their possible association with atopic and asthmatic phenotypes, and their functional importance. We picked up three common variants in the PAFAH gene: Arg92His (exon 4), Ile198Thr (exon 7), and Ala379Val (exon 11). The known loss-of-function mutations were not seen. The variant allele Thr198 was found to be highly associated with total IgE concentrations in an atopic population (P=.009) and with "atopic asthma" in an asthmatic population (P=.008). The variant allele Val379 was found to be highly associated with "specific sensitization" in the atopic population (P=.002) and with "asthma" in the asthmatic population (P=.003). By use of recombinant PAFAH enzymes, the variant Val379 showed increased (14 microM) and Thr198 markedly increased (42 microM) KM values compared to the wild type (7 microM); furthermore, Vmax of Val379 was highly increased (132%). Thr198 and Val379 influence plasmatic PAFAH toward lower substrate affinities and therefore are very likely to prolong the activities of PAF. At the same time, they are associated with an increased risk to develop asthma and atopy. Thus, two PAFAH variants seem to play a key role in atopic and asthmatic processes in Caucasian populations.

Objective: To determine the change in prevalence of asthma, eczema and allergic rhinitis in Australian schoolchildren between 1993 and 2002. Design: Questionnaire based survey, using the protocol of the International Study of Asthma and Allergy in Childhood. Setting: Metropolitan Melbourne primary schools within a 20 km radius of the GPO in 1993 and 2002. Subjects: All children in school years 1 and 2 (ages 6 and 7) attending a random sample of 84 schools in 1993 and 63 schools in 2002. Main outcome measures: Parent‐reported symptoms of atopic disease; treatment for asthma; country of birth. Results: There was a 26% reduction in the 12‐month period prevalence of reported wheeze, from 27.2% in 1993 to 20.0% in 2002. The magnitude of reduction was similar for boys (27%) and girls (25%). The 12‐month period prevalence of reported eczema increased from 11.1% in 1993 to 17.2% in 2002, and rhinitis increased from 9.7% to 12.7%. There were reductions in the proportion of children attending an emergency department for asthma in the previous year (3.6% to 2.3%), the proportion admitted to hospital (1.7% to 1.1%) and the proportion taking asthma medication (18.5% to 13.4%). Of those who reported frequent wheeze, there was an increase in the proportion taking regular inhaled steroids (34.5% to 40.9%). Conclusion: There has been a significant reduction in the prevalence of reported asthma in Melbourne schoolchildren, whereas the prevalence of eczema and allergic rhinitis has continued to increase.

Background/aims: Few studies have reported on the change in visual acuity (VA) in patients with choroideraemia. In order to determine the degree and rate of VA impairment associated with this disease, the central VA was analysed in a large group of patients with choroideraemia. Methods: The authors completed a retrospective, cross sectional review of 115 patients with choroideraemia from three tertiary care centres. A longitudinal analysis was performed on 45 of these patients who met the inclusion criteria of at least three visits over a minimum period of 4.5 years. Multiple linear regression analysis was used to explore the 5 year rate of VA change while controlling for initial VA and initial age. Multiple logistic regression was also used to investigate VA impairment. Conclusion:In this cohort of patients with choroideraemia, there was typically a slow rate of VA loss and the prognosis for central VA retention was, as a group, favourable until the seventh decade.

BackgroundAscending infections of the female genital tract with bacteria causes pelvic inflammatory disease (PID), preterm labour and infertility. Lipopolysaccharide (LPS) is the main component of the cell wall of Gram-negative bacteria. Innate immunity relies on the detection of LPS by Toll-like receptor 4 (TLR4) on host cells. Binding of LPS to TLR4 on immune cells stimulates secretion of pro-inflammatory cytokines such as IL-6, chemokines such as CXCL1 and CCL20, and prostaglandin E2. The present study tested the hypothesis that TLR4 on endometrial epithelial and stromal cells is essential for the innate immune response to LPS in the female genital tract.Methodology/Principal FindingsWild type (WT) mice expressed TLR4 in the endometrium. Intrauterine infusion of purified LPS caused pelvic inflammatory disease, with accumulation of granulocytes throughout the endometrium of WT but not Tlr4−/− mice. Intra-peritoneal infusion of LPS did not cause PID in WT or Tlr4−/− mice, indicating the importance of TLR4 in the endometrium for the detection of LPS in the female genital tract. Stromal and epithelial cells isolated from the endometrium of WT but not Tlr4−/− mice, secreted IL-6, CXCL1, CCL20 and prostaglandin E2 in response to LPS, in a concentration and time dependent manner. Co-culture of combinations of stromal and epithelial cells from WT and Tlr4−/− mice provided little evidence of stromal-epithelial interactions in the response to LPS.Conclusions/SignificanceThe innate immune response to LPS in the female genital tract is dependent on TLR4 on the epithelial and stromal cells of the endometrium.