is the etiological agent of the zoonotic disease Anthrax. Reservoirs for anthrax are wild and domestic grass-eating animals, most commonly sheep, goats and cattle and their proximity to humans within an agricultural setting can cause infection and disease. Disease may also be contracted through either direct contact with infected animals or through contact with animal by-products such as wool, skins or bone meal, where spores can survive in the environment for decades. Disease can occur when spores enter the body through breaks in the skin, via ingestion or by inhalation and has a number of clinical presentations. The Anthrax bacillus expresses a number of proteins responsible for the pathology of disease, including the protein toxins lethal factor (LF), oedema factor (OA) and protective antigen (PA). Other proteins are likely to be expressed during infection, which may contribute to the disease process.

Anaerobic bacteria have been identified in abundance in the airways of cystic fibrosis (CF) subjects. The impact their presence and abundance has on lung function and inflammation is unclear. The aim of this study was to investigate the relationship between the colony count of aerobic and anaerobic bacteria, lung clearance index (LCI), spirometry and C-Reactive Protein (CRP) in patients with CF. Sputum and blood were collected from CF patients at a single cross-sectional visit when clinically stable. Community composition and bacterial colony counts were analysed using extended aerobic and anaerobic culture. Patients completed spirometry and a multiple breath washout (MBW) test to obtain LCI. An inverse correlation between colony count of aerobic bacteria (n = 41, r = -0.35; p = 0.02), anaerobic bacteria (n = 41, r = -0.44, p = 0.004) and LCI was observed. There was an inverse correlation between colony count of anaerobic bacteria and CRP (n = 25, r = -0.44, p = 0.03) only. The results of this study demonstrate that a lower colony count of aerobic and anaerobic bacteria correlated with a worse LCI. A lower colony count of anaerobic bacteria also correlated with higher CRP levels. These results indicate that lower abundance of aerobic and anaerobic bacteria may reflect microbiota disruption and disease progression in the CF lung.

Objectives: An Annual Review, including a chest X-ray (CXR), is mandatory for all CF patients to ensure that treatment of their complex disease is optimized. Since the CXR involves potentially harmful ionizing radiation, we assessed the value of its routine use at annual assessment. Methods: We looked at 65 adult CF patients who had undergone a CXR solely as part of their annual review and compared the results with previous radiological and clinical parameters, looking for potential changes in management.

Objectives: Repeated cycles of pulmonary exacerbation of chronic infection cause tissue damage and progressive drop in lung function for CF patients so making effective treatment and prevention strategies imperative. Our study aims to better understand the response to antibiotics and identify biomarker targets suitable for improved therapeutic or preventative treatments. Methods: Multidimensional LC-MS/MS and relative quantitation was employed to investigate the changes in sputum cellular proteome following antibiotic treatment in 12 CF patients chronically infected with Pseudomonas aeruginosa. Conclusions: 1989 human proteins were identified in total. 37 proteins out of the 318 detected in >80% samples were differentially expressed (p<0.05) after antibiotic treatment. Of these, 22 exhibited a strong correlation (r = 0.969) between their pre-antibiotic/post-antibiotic ratios and ratios for the same proteins comparing CF/healthy control cohorts, thus suggesting that successful treatment promotes a proteome shift towards a non-CF profile. Ingenuity Pathway Analysis software showed antibiotic treatment to most affect the molecular and cellular function categories of Cellular Movement (particularly Immune Cell Trafficking), Organismal Injury and Abnormalities, Cell Death and Free Radical Scavenging. 67 P. aeruginosa proteins and 17 proteins from other bacterial species were also detected. Bacterial proteins accounted for 0.5−35% of CF sputum cellular protein. Although total cellular protein (per g sputum) decreased following antibiotic treatment, the percentage attributable to bacteria did not alter and no bacterial proteins were detected as differentially expressed.

Bacteria in chronic infections can form complex, interacting communities. These communities diversify as a result of interactions with both the environment and each other. The Cystic Fibrosis lung facilitates the cohabitation of diverse microbial organisms and we are only just beginning to understand the extent of this diversity. Objective: We aimed to study the community structure and interspecies interactions, particularly those affecting virulence, in greater detail by using both an in vitro model and deep sequencing of patient samples. Methods: We have developed co-culture multispecies biofilm models in which microbial interactions can be investigated. Results: Using an artificial sputum medium, pathogens such as Pseudomoas aeruginosa, Staphylococcus aureus, Burkholderia sp and Candida albicans have been studied in a free-floating biofilm system to determine whether interspecies interactions facilitate the virulence of P. aeruginosa. In addition, metabolic footprinting of these cultures was used to determine changes in small-molecule metabolites. To further characterise the CF lung microbiome, we have collected longitudinal sputum samples from adult CF patients and sequenced 16S rRNA sequences using an Illumina MiSeq. This enables the microbial community in each sample to be identified and compared to determine whether additional factors influence the microbial composition of the lung. Considerable differences in the microbial population could be found between samples. Conclusion: Understanding complex interactions may uncover novel therapeutic targets and ultimately lead to altered CF patient management. We acknowledge the Leverhulme Trust for funding.

We prefer to receive all responses electronically, sent directly to our website. Processing your letter will be delayed unless it arrives in an electronic form. We are now posting all direct submissions to our website within 24 hours of receipt and our intention is to post all other electronic submissions there as well. All responses will be eligible for publication in the paper journal. Responses should be under 400 words and relate to articles published in the preceding month. They should include <5 references, in the Vancouver style, including one to the BMJ article to which they relate. We welcome illustrations.

This supplement has been commissioned and funded by Reckitt Benckiser Healthcare (UK) Ltd. The authors have received an honorarium from Reckitt Benckiser Healthcare (UK) Ltd for writing their articles. Reckitt Benckiser Healthcare (UK) Ltd did not have editorial control over the content of the articles prior to publication. The articles have been reviewed by three guest editors who each received an honorarium from Reckitt Benckiser Healthcare (UK) Ltd.

Persistent activation of NF-kB is central to the pathogenesis of many inflammatory lung disorders, including cystic fibrosis, asthma, and chronic obstructive pulmonary disease. A20 is an endogenous negative regulator of NF-kB signaling, which has been widely described in autoimmune and inflammatory disorders, including diabetes and Crohn's disease, but which has received little attention in terms of chronic lung disorders. This review examines the existing body of research on A20 regulation of NF-kB signaling and details the mechanism and regulation of A20 action focusing, where possible, on pulmonary inflammation. A20 and its associated signaling molecules are highlighted as being of potential therapeutic interest for the treatment of inflammatory disorders, and a proposed model of A20 activity in inflammatory lung disease is provided.

Background: In asthma there is increased expression of the Th2-type cytokine interleukin-4 (IL-4). IL-4 is important in immunoglobulin isotype switching to immunoglobulin E and adhesion of eosinophils to endothelium. Objective: We hypothesized that levels of IL-4 in bronchoalveolar lavage (BAL) fluid would be increased in stable, atopic asthmatic children compared with controls and that levels of its physiologic inhibitor IL-4 soluble receptor ␣ (IL-4sR␣) would be correspondingly decreased. Methods: One hundred sixteen children attending a children's hospital for elective surgery were recruited. A nonbronchoscopic BAL was performed, and IL-4 and IL-4sR␣ were measured in the BAL supernatants. Results: There was no significant difference in IL-4 concentrations between atopic asthmatic children, atopic normal controls, and nonatopic normal controls [0.13 pg/mL (0.13 to 0.87) vs 0.13 pg/mL (0.13 to 0.41) vs 0.13 pg/mL (0.13 to 0.5), P ϭ 0.65]. IL-4sR␣ levels were significantly increased in asthmatic patients compared with atopic controls [6.4 pg/mL (5.0 to 25.5) vs 5.0 pg/mL (5.0 to 9.9), P ϭ 0.018], but not when compared with the nonatopic controls [5.2 pg/mL (5.0 to 10.6), P ϭ 0.19]. Conclusions: Contrary to expectation, IL-4sR␣ levels are increased in BAL from stable asthmatic children compared with nonatopic controls, and we speculate that IL-4sR␣ is released by inflammatory cells in the airways to limit the proinflammatory effects of IL-4.

ABSTRACTWe modeled nevirapine (NVP) pharmacokinetics in HIV-infected Malawian patients to assess the relationship between drug exposure and patient characteristics, genetic polymorphisms, and development of hypersensitivity reaction (HSR). One thousand one hundred seventeen patients were prospectively recruited and followed for 26 weeks with multiple or single serum samples obtained in a subset of patients for NVP quantification. Single nucleotide polymorphisms (SNPs) withinCYP2B6andCYP3A4genes were typed. Nonlinear mixed effects modeling was utilized to assess the influence of patient characteristics and host genetics on NVP apparent oral clearance (CL/F) and to explore the relationship between NVP CL/F and HSR. Published haplotype distributions were used to simulate NVP concentrations in Caucasians versus Africans. One hundred eighty patients (101 female) were included in the model; 25 experienced HSR. No associations between patient demographics or HSR and NVP CL/F were evident. ...

Pyloric muscle dimensions were measured in 1400 consecutive newborn infants. Nine of these subsequently developed pyloric stenosis. Their pyloric measurements at birth were all within the normal range. Congenital preformed muscular hypertrophy does not appear to be present in babies who later develop pyloric stenosis.

Meta-analysis of randomized controlled trials. N Engl J Med 1987;316:450-5. 3 Vandenbroucke-Grauls CMJE, Vandenbroucke JJ. Effect of selective decontamination of the digestive tract on respiratory tract infections and mortality in the intensise care unit. Lancet

We prefer to receive all responses electronically, sent directly to our website. Processing your letter will be delayed unless it arrives in an electronic form. We are now posting all direct submissions to our website within 24 hours of receipt and our intention is to post all other electronic submissions there as well. All responses will be eligible for publication in the paper journal. Responses should be under 400 words and relate to articles published in the preceding month. They should include <5 references, in the Vancouver style, including one to the BMJ article to which they relate. We welcome illustrations.

• Currently tacrolimus is the mainstay of immunosuppression for most children undergoing liver transplantation (LT). • The clinical use of this agent, however, is complicated by its various adverse effects (mainly nephrotoxicity), its narrow therapeutic-index and considerable pharmacokinetic variability. • The low and variable oral bioavailability of tacrolimus is thought to result from the action of the multidrug efflux-pump P-glycoprotein, encoded by the ABCB1 gene. WHAT THIS STUDY ADDS • A significant association between ABCB1 genetic polymorphisms and tacrolimus-associated nephrotoxicity in paediatric patients following LT is reported for the first time. Genotyping such polymorphisms may have the potential to individualize better initial tacrolimus therapy and enhance drug safety. • The long-term effect of ABCB1 polymorphisms on tacrolimus trough concentrations were investigated up to 5 years post-transplantation. A significant effect of intestinal P-glycoprotein genotypes on tacrolimus pharmacokinetics was found at 3 and 4 years post-transplantation suggesting that the effect is maintained long term.

Background Children born by Caesarean section have modified intestinal bacterial colonization and consequently may have an increased risk of developing asthma under the hygiene hypothesis. The results of previous studies that have investigated the association between Caesarean section and asthma have been conflicting. Objective To review published literature and perform a meta-analysis summarizing the evidence in support of an association between children born by Caesarean section and asthma. Methods MEDLINE, Web Science, Google Scholar and PubMed were searched to identify relevant studies. Odds ratio (OR) and 95% confidence interval (CI) were calculated for each study from the reported prevalence of asthma in children born by Caesarean section and in control children. Meta-analysis was then used to derive a combined OR and test for heterogeneity in the findings between studies. Results Twenty-three studies were identified. The overall meta-analysis revealed an increase in the risk of asthma in children delivered by Caesarean section (OR = 1.22, 95% CI 1.14, 1.29). However, in this analysis, there was evidence of heterogeneity (I 2 = 46%) that was statistically significant (P o 0.001). Restricting the analysis to childhood studies, this heterogeneity was markedly decreased (I 2 = 32%) and no longer attained statistical significance (P = 0.08). In these studies, there was also evidence of an increase (P o 0.001) in the risk of asthma after Caesarean section (OR = 1.20, 95% CI 1.14, 12.6). Conclusion In this meta-analysis, we found a 20% increase in the subsequent risk of asthma in children who had been delivered by Caesarean section.