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Background: To prospectively apply an automated, quantitative three-dimensional approach to imaging and airway analysis to assess airway remodeling in asthma patients., Methods: Using quantitative software (Pulmonary Workstation, version 0.139; VIDA Diagnostics; Iowa City, IA) that enables quantitative airway segment measurements of low-dose, thin-section (0.625 to 1.25 mm), multidetector-row CT (MDCT) scans, we compared airway wall thickness (WT) and wall area (WA) in 123 subjects participating in a prospective multicenter cohort study, the National Institutes of Health Severe Asthma Research Program (patients with severe asthma, n = 63; patients with mild-to-moderate asthma, n = 35); and healthy subjects, n = 25). A subset of these subjects underwent fiberoptic bronchoscopy and endobronchial biopsies (n = 32). WT and WA measurements were corrected for total airway diameter and area: WT and WA, respectively., Results: Subjects with severe asthma had a significantly greater WT% than patients with mild-to-moderate asthma and healthy subjects (17.2 +/- 1.5 vs 16.5 +/- 1.6 [p = 0.014] and 16.3 +/- 1.2 [p = 0.031], respectively) and a greater WA percentage (WA%) compared to patients with mild-to-moderate asthma and healthy subjects (56.6 +/- 2.9 vs 54.7 +/- 3.3 [p = 0.005] and 54.6 +/- 2.4 [p = 0.003], respectively). Both WT% and WA% were inversely correlated with baseline FEV(1) percent predicted (r = -0.39, p < 0.0001 and r = -0.40, p < 0.0001, respectively) and positively correlated with response to a bronchodilator (r = 0.28, p = 0.002 and r = 0.35, p < 0.0001, respectively). The airway epithelial thickness measure on the biopsy sample correlated with WT% (r = 0.47; p = 0.007) and WA% (r = 0.52; p = 0.003). In the same individual, there is considerable regional heterogeneity in airway WT., Conclusion: Patients with severe asthma have thicker airway walls as measured on MDCT scan than do patients with mild asthma or healthy subjects, which correlates with pathologic measures of remodeling and the degree of airflow obstruction. MDCT scanning may be a useful technique for assessing airway remodeling in asthma patients, but overlap among the groups limits the diagnostic value in individual subjects.

The asthmatic response to the common cold is highly variable, and early characteristics that predict worsening of asthma control following a cold have not been identified. In this prospective multicentric cohort study of 413 adult subjects with asthma, the mini-Asthma Control Questionnaire (mini-ACQ) was used to quantify changes in asthma control and the Wisconsin Upper Respiratory Symptom Survey-21 (WURSS-21) to measure cold severity. Univariate and multivariable models were used to examine demographic, physiological, serological and cold-related characteristics for their relationship to changes in asthma control following a cold. Clinically significant worsening of asthma control was observed following a cold (mean+/-SD increase in mini-ACQ score of 0.69+/-0.93). Univariate analysis demonstrated that season, centre location, cold duration and cold severity measurements were all associated with a change in asthma control. Multivariable analysis of the covariates available within the first 2 days of cold onset revealed that the day 2 and cumulative sum of day 1 and 2 WURSS-21 scores were significant predictors of the subsequent changes in asthma control. In asthmatic subjects, cold severity within the first 2 days can be used to predict subsequent changes in asthma control. This information may help clinicians prevent deterioration in asthma control following a cold.

Background: Immune response after viral infection usually involves T(H)1-mediated response; however, severe respiratory syncytial virus (RSV) infection appears to be associated with the development of asthma, a T(H)2-predominant phenotype., Objective: To understand the early and subsequent immunologic response to a serious RSV infection in children over time., Methods: A total of 206 previously healthy infants hospitalized with severe RSV bronchiolitis were enrolled in a prospective cohort called the RSV Bronchiolitis in Early Life study. Peripheral blood T cells were obtained immediately after RSV infection and at 2, 4, and 6 years of age, stimulated with phorbol 12-myristate 13-acetate and ionomycin, and analyzed for IL-2, IL-4, IL-13, and IFN-gamma by flow cytometry and real-time PCR., Results: Of the children, 48% (n = 97) developed asthma (physician-diagnosed), and 48% (n = 97) had eczema by age 6 years; 32% (n = 48 of 150) developed allergic sensitization by 3 years of age. Children with asthma had lower IL-13 expression at 6 years of age than those without (P = .001). IFN-gamma, IL-2, and IL-4 levels did not differ by asthma or eczema status during follow-up (all P > .05). Allergic sensitization was not associated with differences in cytokine levels during follow-up (all P > .05)., Conclusion: Severe RSV infection early in life is associated with a high incidence of asthma and eczema. Contrary to expectations, subsequent immunologic development in those who developed asthma, eczema, or allergic sensitization was not associated with a T(H)2 phenotype in the peripheral blood.

The recognition of growth factors and other cell signaling agents by their cognate cell surface receptors triggers a cascade of signal transducing events. Ligand binding and subsequent activation of many signal transducing receptors increases their rate of internalization. Endocytosis of the receptor has always been viewed as primarily a mechanism for signal attenuation and receptor degradation, but recent evidence suggests that internalization may result in the formation of specialized signaling platforms on intracellular vesicles. Thus, understanding how interactions between receptors and intracellular signaling molecules, such as adaptors, GTPases, and kinases, are regulated will undoubtedly provide insight into the ways that cells sense and adapt to the extracellular milieu.

The expression of glutamic acid decarboxylase (GAD) is a basic characteristic of a wide array of inhibitory neurons the use gamma-aminobutyric acid as a neurotransmitter. Clonal cell models will be essential for investigating the mechanisms which are responsible for the selective expression of GAD. P19 embryonal carcinoma cells are an important model for the analysis of neuronal gene expression. Depending on culture conditions, undifferentiated cells can be induced to form cells as widely divergent as cardiac muscle-like cells and neuron-like and glial-like cells. P19 cells are amendable to a number of powerful genetic manipulations including transformation with foreign DNA and selection of mutants. In this study we used nuclease protection assays and Northern blot analysis to determine if P19 cells express the GAD1 and GAD2 genes. The results show that uninduced P19 cells express these genes at very low but easily detectable levels. When the cells are induced to differentiate along the neuronal pathway with retinoic acid, the levels of transcripts for both GAD genes rise dramatically. At least some RNA transcripts of both genes from induced cells comigrate with the corresponding mRNA from the brain and thus probably represent processed mRNA. The expression of GAD genes in undifferentiated cultures of embryonal stem (ES) cells was also investigated. These cultures express levels of GAD1 transcripts that are higher than uninduced P19 cells. In contrast, expression of the GAD2 gene was barely detectable. These results indicate that P19 EC cells and ES cells will be useful for the investigation of the mechanisms that regulate the expression of the GAD1 and GAD2 genes.