A pathogenic role for tumor necrosis factor-related apoptosis-inducing ligand in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a life-threatening inflammatory respiratory disorder, often induced by cigarette smoke (CS) exposure. The development of effective therapies is impaired by a lack of understanding of the underlining mechanisms. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine with inflammatory and apoptotic properties. We interrogated a mouse model of CS-induced experimental COPD and human tissues to identify a novel role for TRAIL in COPD pathogenesis. CS exposure of wild-type mice increased TRAIL and its receptor messenger RNA (mRNA) expression and protein levels, as well as the number of TRAIL(+)CD11b(+) monocytes in the lung. TRAIL and its receptor mRNA were also increased in human COPD. CS-exposed TRAIL-deficient mice had decreased pulmonary inflammation, pro-inflammatory mediators, emphysema-like alveolar enlargement, and improved lung function. TRAIL-deficient mice also developed spontaneous small airway changes with increased epithelial cell thickness and collagen deposition, independent of CS exposure. Importantly, therapeutic neutralization of TRAIL, after the establishment of early-stage experimental COPD, reduced pulmonary inflammation, emphysema-like alveolar enlargement, and small airway changes. These data provide further evidence for TRAIL being a pivotal inflammatory factor in respiratory diseases, and the first preclinical evidence to suggest that therapeutic agents that target TRAIL may be effective in COPD therapy.

Elevated IL-33 expression is associated with pediatric eosinophilic esophagitis, and exogenous IL-33 promotes eosinophilic esophagitis development in mice.

We tested whether the T helper (Th) type 2 (Th2) cell agonist and allergenic ligand IL-33 was associated with eosinophilic esophagitis (EoE) development in a pediatric cohort and whether IL-33 protein could induce disease symptoms in mice. Biopsies from EoE patients or controls were used to measure IL-33 mRNA and protein expression. Increased expression of IL-33 mRNA was found in the esophageal mucosa in EoE. IL-33 protein was detected in cells negative for CD45, mast cells, and epithelial cell markers near blood vessels. Circulating levels of IL-33 were not increased. The time course for IL-33 gene expression was quantified in an established Aspergillus fumigatus allergen mouse model of EoE. Because IL-33 induction was transient in this model and chronicity of IL-33 expression has been demonstrated in humans, naive mice were treated with recombinant IL-33 for 1 wk and esophageal pathology was evaluated. IL-33 application produced changes consistent with phenotypically early EoE, including transmural eosinophilia, mucosal hyperproliferation, and upregulation of eosinophilic genes and chemokines. Th2 cytokines, including IL-13, along with innate lymphoid cell group 2, Th1/17, and M2 macrophage marker genes, were increased after IL-33 application. IL-33-induced eosinophilia was ablated in IL-13 null mice. In addition, IL-33 induced a profound inhibition of the regulatory T cell gene signature. We conclude that IL-33 gene expression is associated with pediatric EoE development and that application of recombinant protein in mice phenocopies the early clinical phase of the human disease in an IL-13-dependent manner. IL-33 inhibition of esophageal regulatory T cell function may induce loss of antigenic tolerance, thereby providing a mechanistic rationale for EoE development.

The fraction of exhaled nitric oxide improves prediction of clinical allergic reaction to peanut challenge in children.

BACKGROUND: Retrospective studies of childhood peanut allergy demonstrate serum-specific IgE (IgE) levels against the peanut allergen Ara h2 may help predict a clinical reaction at food challenge. Fraction of exhaled nitric oxide (FeNO) is a non-invasive tool correlating to allergic airways inflammation and has been independently associated with increased food-specific IgE. OBJECTIVE: To assess the validity of serum-specific Ara h2 IgE measured prospectively to diagnose peanut allergy and explore the utility of FeNO as a non-invasive screening tool for childhood food challenge. METHODS: We recruited 53 participants from a cohort of consecutive children scheduled for an open-labelled peanut food challenge (OFC) by their paediatric allergist. Participants underwent skin prick test (SPT) measurement for sensitization to whole peanut extract, and serum was collected for Ara h2-specific IgE. FeNO was also measured in all cooperative children before the challenge. OFC and assessment of reaction were undertaken by clinicians blinded to test results. RESULTS: Ara h2-specific IgE and FeNO each showed improved diagnostic accuracy when compared to SPT. Receiver operator characteristic curve analysis gave an area under the curve (AUC) for Ara h2 sIgE of 0.84 (95% CI, 0.72-0.96). The AUC for FeNO, 0.83 (95% CI, 0.71-0.95), was equivalent to that of Ara h2. Combined AUC for SPT, sIgE to Ara h2 and FeNO was 0.96 (95% CI 0.90-1.00). There was no correlation between FeNO and serum nitrite levels (rs = -0.13, P = 0.6, n = 18). CONCLUSION AND CLINICAL RELEVANCE: Prospectively measured Ara h2-specific IgE improves diagnostic accuracy and reduces unsuccessful challenge to peanut. FeNO levels may provide improved diagnostic accuracy in a paediatric population undergoing OFC. The proposed FeNO-based diagnostic algorithm requires further validation studies.

Tumor necrosis factor-related apoptosis-inducing ligand translates neonatal respiratory infection into chronic lung disease.

Respiratory infections in early life can lead to chronic respiratory disease. Chlamydia infections are common causes of respiratory disease, particularly pneumonia in neonates, and are linked to permanent reductions in pulmonary function and the induction of asthma. However, the immune responses that protect against early-life infection and the mechanisms that lead to chronic lung disease are incompletely understood. Here we identify novel roles for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in promoting Chlamydia respiratory infection-induced pathology in early life, and subsequent chronic lung disease. By infecting TRAIL-deficient neonatal mice and using neutralizing antibodies against this factor and its receptors in wild-type mice, we demonstrate that TRAIL is critical in promoting infection-induced histopathology, inflammation, and mucus hypersecretion, as well as subsequent alveolar enlargement and impaired lung function. This suggests that therapeutic agents that target TRAIL or its receptors may be effective treatments for early-life respiratory infections and associated chronic lung disease.

From abandoned warehouse to life-saving facility, Pakro, Ghana. The Accra PMM Team.

PRELIMINARY STUDIES: Focus group discussions in Akwapim South District, Ghana, highlighted a lack of accessible health facilities as an important factor contributing to maternal deaths. INTERVENTIONS: In 1991, a health center was established by rennovating an abandoned warehouse. The center was equipped with beds, a refrigerator, a safe water supply, drugs and supplies. With the posting of a community health nurse from the Ministry of Health (MOH), it began functioning as a maternal and child health/family planning clinic. A senior nurse-midwife was posted in 1992 and obstetric services were offered. Starting in 1994, community interventions focused on reducing the delay in seeking care. RESULTS: An average of nine women with major obstetric complications were seen each 12-month period between 1992 and 1995. Many minor complications and non-obstetric ailments were also treated. COSTS: The material costs of establishing the health center amounted to US $12,550: 47% came from the community, 43% came from non-governmental organizations (NGOs), 7% from PMM and 3% from MOH. The costs of staff salaries were paid by MOH. CONCLUSIONS: It is possible to mobilize communities, government and NGOs to help provide emergency obstetric services. If emergency obstetric services are available, women will use them, even before the launching of community information and education campaigns.

The maternity waiting home concept: the Nsawam, Ghana experience. The Accra PMM Team.

PRELIMINARY STUDIES: Focus group discussions with community members in Nsawam District, Ghana, identified poor roads, scarce transport and exorbitant fees for emergency transport as barriers to reaching the district hospital for treatment of an obstetric complication. INTERVENTIONS: To minimize delay in the event of a complication, a maternity waiting home (MWH) was established in Nsawam in 1994. One ward of an abandoned hospital was renovated and furnished for this purpose. The objective was to encourage women at high risk of obstetric complications to move to the MWH so they could be transferred to the hospital when labor began. RESULTS: Of 25 women referred to the MWH by health personnel over 12 months, only one complied, for one night. Focus group discussions with community members and hospital staff later revealed that cost and hardship of staying away from home, absence of health personnel, distance from hospital, desolate surroundings and lack of perceived need were reasons for poor utilization. COSTS: The intervention cost approximately US $10,500, shared approximately equally between the project and government. The main government contribution was the building. CONCLUSIONS: It is important to consult potential users not only to identify problems, but also to identify appropriate solutions. Careful 'market research' should be done before launching interventions.

A comparative study of hysterosalpingography and laparoscopy in the investigation of infertility

A comparison of Hysterosalpingography (HSG) with Laparoscopy in the evaluation of tubal factor in 105 infertile women is presented. Results of these tests showed agreement for tubal patency in 65.7 per cent of the cases. Both procedures are discussed with their limitations