The Early Development of Wheeze. Environmental Determinants and Genetic Susceptibility at 17q21.

Rationale: Growing up on a farm protects from childhood asthma and early wheeze. Virus-triggered wheeze in infancy predicts asthma in individuals with a genetic asthma risk associated with chromosome 17q21.

Objectives: To test environmental determinants of infections and wheeze in the first year of life, potential modifications of these associations by 17q21, and the implications for different trajectories of wheeze.

Lipocalin-2 Is a Disease Activity Marker in Inflammatory Bowel Disease Regulated by IL-17A, IL-22, and TNF-α and Modulated by IL23R Genotype Status.

Background: Lipocalin-2 (LCN2) is a potent bacteriostatic protein. We aimed to investigate its role as a disease activity marker in patients with inflammatory bowel disease (IBD) and its induction by the Th17 cytokines IL-17A, IL-22, and TNF-α in colonic epithelial cells. Moreover, we analyzed the influence of IBD-associated IL23R alleles on LCN2 serum levels in IBD patients.

European protocols for the diagnosis and initial treatment of interstitial lung disease in children.

Interstitial lung disease in children (chILD) is rare, and most centres will only see a few cases/year. There are numerous possible underlying diagnoses, with specific and non-specific treatment possibilities. The chILD-EU collaboration has brought together centres from across Europe to advance understanding of these considerations, and as part of this process, has created standard operating procedures and protocols for the investigation of chILD.

cCMP and cUMP occur in vivo.

Mammalian cells contain the cyclic pyrimidine nucleotides cCMP and cUMP. It is unknown whether these tentative new second messenger molecules occur in vivo. We used high performance liquid chromatography quadrupole tandem mass spectrometry to quantitate nucleoside 3',5'-cyclic monophosphates.

Transcriptome assessment reveals a dominant role for TLR4 in the activation of human monocytes by the alarmin MRP8.

The alarmins myeloid-related protein (MRP)8 and MRP14 are the most prevalent cytoplasmic proteins in phagocytes. When released from activated or necrotic phagocytes, extracellular MRP8/MRP14 promote inflammation in many diseases, including infections, allergies, autoimmune diseases, rheumatoid arthritis, and inflammatory bowel disease. The involvement of TLR4 and the multiligand receptor for advanced glycation end products as receptors during MRP8-mediated effects on inflammation remains controversial.

High variability in oral glucose tolerance among 1,128 patients with cystic fibrosis: a multicenter screening study.

Background: In cystic fibrosis, highly variable glucose tolerance is suspected. However, no study provided within-patient coefficients of variation. The main objective of this short report was to evaluate within-patient variability of oral glucose tolerance.

Impaired TLR4 and HIF expression in cystic fibrosis bronchial epithelial cells downregulates hemeoxygenase-1 and alters iron homeostasis in vitro.

Hemeoxygenase-1 (HO-1), an inducible heat shock protein, is upregulated in response to multiple cellular insults via oxidative stress, lipopolysaccharides (LPS), and hypoxia. In this study, we investigated in vitro the role of Toll-like receptor 4 (TLR4), hypoxia-inducible factor 1α (HIF-1α), and iron on HO-1 expression in cystic fibrosis (CF). Immunohistochemical analysis of TLR4, HO-1, ferritin, and HIF-1α were performed on lung sections of CFTR-/- and wild-type mice.

Current concepts: host-pathogen interactions in cystic fibrosis airways disease.

Chronic infection and inflammation are defining characteristics of cystic fibrosis (CF) airway disease. Conditions within the airways of patients living with CF are conducive to colonisation by a variety of opportunistic bacterial, viral and fungal pathogens. Improved molecular identification of microorganisms has begun to emphasise the polymicrobial nature of infections in the CF airway microenvironment.

In vivo imaging of bioluminescent Pseudomonas aeruginosa in an acute murine airway infection model.

Non-invasive bioluminescence imaging allows the analysis of infectious diseases in small animal models. In this study, an acute airway infection of C3H/HeN mice with luxCDABE transformed Pseudomonas aeruginosa TBCF10839 and an isogenic transposon mutant was followed by optical imaging in vivo. Using the disease-causing dose of 2.

Assessing Pseudomonas virulence using mammalian models: acute infection model.

The acute murine lung infection model monitors Pseudomonas aeruginosa airway infections by multiple continuous and endpoint parameters. After intratracheal or intranasal infection it characterizes the course of infection via head-out spirometry, rectal temperature, weight loss, a body condition score based on nine physiological parameters, lung bacterial numbers, organ dissemination of bacteria, and a semiquantitative assessment of lung inflammation and further analysis. The generated data allows a robust classification of virulence of mutant or wild-type P.

Genotyping methods.

Genotyping allows for the identification of bacterial isolates to the strain level and provides basic information about the evolutionary biology, population biology, taxonomy, ecology, and genetics of bacteria. Depending on the underlying question and available resources, Pseudomonas aeruginosa strains may be typed by anonymous fingerprinting techniques or electronically portable sequence-based typing methods such as multiple locus variable number tandem repeat (VNTR) analysis (MLVA), multilocus sequence typing, or oligonucleotide microarray. Macrorestriction fragment pattern analysis is a genotyping method that is globally applicable to all bacteria and hence has been and still is the reference method for strain typing in bacteriology.

Molecular epidemiology of chronic Pseudomonas aeruginosa airway infections in cystic fibrosis.

Background/methods: The molecular epidemiology of the chronic airway infections with Pseudomonas aeruginosa in individuals with cystic fibrosis (CF) was investigated by cross-sectional analysis of bacterial isolates from 51 CF centers and by longitudinal analysis of serial isolates which had been collected at the CF centers Hanover and Copenhagen since the onset of airway colonization over 30 years.

Results: Genotyping revealed that the P. aeruginosa population in CF is dominated by a few ubiquitous clones.

Acute intratracheal Pseudomonas aeruginosa infection in cystic fibrosis mice is age-independent.

Background: Since the discovery of the human CFTR gene in 1989 various mouse models for cystic fibrosis (CF) have been generated and used as a very suitable and popular tool to approach research on this life-threatening disease. Age related changes regarding the course of disease and susceptibility towards pulmonary infections have been discussed in numerous studies.

Methods: Here, we investigated CftrTgH(neoim)Hgu and Cftrtm1Unc-Tg(FABPCFTR)1Jaw/J CF mice and their non-CF littermates during an acute lung infection with Pseudomonas aeruginosa for age dependent effects of their lung function and immune response.

Unifying candidate gene and GWAS Approaches in Asthma.

The first genome wide association study (GWAS) for childhood asthma identified a novel major susceptibility locus on chromosome 17q21 harboring the ORMDL3 gene, but the role of previous asthma candidate genes was not specifically analyzed in this GWAS. We systematically identified 89 SNPs in 14 candidate genes previously associated with asthma in >3 independent study populations. We re-genotyped 39 SNPs in these genes not covered by GWAS performed in 703 asthmatics and 658 reference children.

Genetic variations in toll-like receptor pathway genes influence asthma and atopy.

Innate immunity is a pivotal defence system of higher organisms. Based on a limited number of receptors, it is capable of recognizing pathogens and to initiate immune responses. Major components of these innate immunity pathogen recognition receptors are the toll-like receptors (TLRs), a family of 11 in humans.