A computerized decision support tool to implement asthma guidelines for children and adolescents

1. Download : Download high-res image (226KB)
2. Download : Download full-size image

     

Attenuated innate mechanisms of interferon-gamma production in rats susceptible to postviral airway dysfunction

After Sendai virus (SeV)-induced bronchiolitis as weanlings, BN, but not F344, rats develop a postbronchiolitis asthma-like phenotype, which can be prevented by supplemental interferon (IFN)-gamma treatment. We have shown that splenocytes from BN weanlings, compared with those from F344 weanlings, have a markedly reduced capacity for IFN-gamma production. We hypothesized that SeV-induced IFN-gamma production occurs via innate mechanisms that are attenuated in BN weanlings. Therefore, we investigated potential mechanisms of SeV-induced IFN-gamma production in BN and F344 weanlings. SeV-stimulated splenocytes secreted the IFN-gamma-inducing cytokines, interleukin (IL)-12 and IL-18. BN splenocytes produced significantly less IL-12 (P = 0.001) and IL-18 (P < 0.001) than did F344 splenocytes. Depletion studies demonstrated that natural killer cells were the primary source of SeV-induced IFN-gamma production. Anti-IL-12 antibody, IL-12 p40 homodimer, and IL-18 binding protein each inhibited SeV-induced IFN-gamma production by 82-94%, and the combination of IL-12 p40 homodimer and IL-18 binding protein abolished SeV-induced IFN-gamma production, demonstrating synergism between IL-12 and IL-18. Therefore, SeV-induced IFN-gamma production occurred via innate IL-12-, IL-18-, and natural killer cell-dependent mechanisms, which were attenuated in BN weanlings. Attenuation of innate IFN-gamma-producing responses to SeV in BN weanlings may be a critical factor in their susceptibility to postbronchiolitis chronic airway dysfunction.     

Outcome assessment of pain: functional status measures and quality of life as therapeutic endpoints

These studies and others will provide tools for cancer treatment centers to integrate pain management into comprehensive care strategies. Pharmacists in all health care settings where the cancer patient with pain is being treated should take leadership roles in the improvement of therapeutic outcomes. This leadership is essential, because drug therapy remains the mainstay of palliation.     

Relationship of exhaled nitric oxide to clinical and inflammatory markers of persistent asthma in children

BACKGROUND: Exhaled nitric oxide (eNO) is a noninvasive test that measures airway inflammation. Insufficient information is available concerning correlations between eNO and biologic, physiologic, and clinical characteristics of asthma in children currently not taking controller medications. OBJECTIVE: The aim of this study was to find correlations between eNO and other characteristics of children with mild to moderate asthma currently not taking medications. METHODS: Children aged 6 to 17 years with mild to moderate persistent asthma, taking only albuterol as needed, were characterized during 2 visits 1 week apart before being randomly assigned into a clinical trial. At the screening visit, online measurements of eNO, spirometry before and after bronchodilator, and biomarkers of peripheral blood eosinophils, serum eosinophil cationic protein, total serum IgE, and urinary leukotriene E4 were obtained. During a week characterization period before randomization, symptoms were recorded on a diary and peak expiratory flows were measured twice daily using an electronic device. At the randomization visit, eNO was repeated followed by a methacholine challenge and aeroallergen skin testing. Correlations and rank regression analyses between eNO and clinical characteristics, pulmonary function, and biomarkers were evaluated. RESULTS: eNO was significantly correlated with peripheral blood eosinophils (r =.51, P <.0001), IgE (r =.48, P <.0001), and serum eosinophil cationic protein (r =.31, P =.0003) but not with urinary leukotriene E4 (r =.16, P =.08). A moderate correlation was found between eNO and the number of positive aeroallergen skin tests (r =.45, P <.0001). eNO did not correlate with FEV1% predicted but was weakly correlated with FEV1/forced vital capacity (r = -.19, P =.032), bronchodilator response (r =.20, P =.023), and FEV1 PC20 methacholine (r = -.31, P =.0005). No significant correlations were found between eNO and clinical characteristics or morning or evening peak expiratory flow measurements. The rank regression analysis demonstrated that 5 variables accounted for an R square of.52 (eosinophils [P <.0001], IgE [P =.0023], age [P <.0001], months of inhaled corticosteroid use in the year before study entry [P =.01], and FEV1 PC20 [P =.0061]). CONCLUSIONS: These findings suggest that eNO provides information about the asthmatic state consistent with information from other markers of inflammation. It is a noninvasive technique that could be used in decisional management of children with asthma.     

Association of mononuclear cells and eosinophils with airway resistance and responsiveness in rat pulmonary inflammatory responses

To evaluate the association of various leukocytes with pulmonary resist ance and methacholine responsiveness, we induced pulmonary eosi-nophil-rich inflammation in IgE-sensitized (ovalbumin) Sprague Dawlcy rats. Sensitized rats were challenged with either relevant (OA) or irrele vant antigen by tracheal insufflation a) with no other treatment, b) in conjunction with intravenous Sephadex beads pretrcatment, or c) with antigen coupled covalently to Sepharose heads. About 24 h after antigen challenge, respiratory system resistance (Rrs), response to aerosolized methacholine, and pulmonary histopathology were evaluated. Challenge with OA, insufflation with Sepharose, and treatment with i. v. Sephadex all independently increased inflammatory cell infiltrates, but the combi nation of OA with the other agents did not significantly enhance the inflammatory response over OA alone. Interactive stepwise regression techniques were utilized to identify correlates for Rrs and methacholine responsiveness. Mononuclear cell score was a significant predictor (p < 0.1) for Rrs, and insufflation of Sepharose had a significant inde pendent effect on Rrs (p=. 01) above that predicted by mononuclear cell infiltrates. Conversely, eosinophil score and neutrophil score were not significant predictors for Rrs, and challenges with antigen or Sephadex had no significant independent effect on Rrs beyond that predicted from mononuclear cell infiltrates. Eosinophil score was the only significant histological predictor for methacholine responsiveness (p <0.001). Chal lenges with Sephadex, antigen and Sepharose did not significantly change methacholine responsiveness independently of the changes asso ciated with eosinophil infiltrates. These findings suggest that mononucle ar cells and eosinophils contribute to increases in airway resistance and responsiveness, respectively, following the induction of pulmonary inflammation by both allergic and non-allergic stimuli.     

Effect of ICAM-1 blockade on lung inflammation and physiology during acute viral bronchiolitis in rats

Viral respiratory infections cause acute bronchiolitis and physiologic dysfunction in human infants and in animals. It is possible that the pulmonary dysfunction is a consequence of the inflammatory cells that are recruited during viral illness. We hypothesized that blockade of intercellular adhesion molecule-1 (ICAM-1), a major cell adhesion molecule, would impede the ingress of leukocytes during viral infection and attenuate virus-induced pulmonary dysfunction. Adult male rats were inoculated with parainfluenza type 1 (Sendai) virus or sterile vehicle, and treated with blocking or nonblocking MAb specific for rat ICAM-1. Respiratory system resistance, oxygenation (PaO2), methacholine responsiveness, and bronchoalveolar lavage (BAL) leukocyte counts were measured in anesthetized, paralyzed, ventilated rats. Treatment with the blocking ICAM-1 antibody reduced virus-induced increases in BAL neutrophils and lymphocytes by 70% (p < 0.001), but did not affect BAL monocytes/macrophages. Peripheral blood leukocyte counts were elevated in anti-ICAM-1 blocking antibody-treated rats (p = 0.0003). Although virus-induced increases in resistance and decreases in PaO2 were not affected by anti-ICAM-1 treatment, there was a small but significant attenuation of virus-induced methacholine hyperresponsiveness (p = 0.02). We conclude that ICAM-1 has an important role in neutrophil and lymphocyte infiltration during respiratory viral illness, and that virus-induced changes in pulmonary physiology are not related directly to the numbers of neutrophils and lymphocytes that migrate to the air spaces during infection.