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Biomedical subjects

J E Fish

Publications and source records attributed to J E Fish.

At least 19 recordsLinked to original sources
PubMed2001

Summarizing methacholine challenges in clinical research.

In clinical trials in asthma, airway reactivity is commonly assessed by performing a methacholine challenge. Airway reactivity is thought to vary in proportion to asthma severity, and methacholine causes the airways of asthma subjects to constrict, thus lowering forced expiratory volume in 1 second (FEV(1)). A dose-response curve is obtained for each subject who meets standardized eligibility requirements to proceed with a methacholine challenge. When data from a methacholine challenge are used as an outcome variable in analysis, a univariate measure called the PC(20), the concentration of methacholine needed to produce a 20% fall in FEV(1) from baseline, is typically used to summarize the dose-response curve. Questions that arise regarding data generated from the methacholine challenge include: how to express data that do not yield a PC(20) value; whether PC(20) actually represents the best way to capture airway activity as expressed in a methacholine challenge; and whether the baseline FEV(1) is defined appropriately in calculation of PC(20). The impact of these issues on the statistical analysis of methacholine challenge data is described in this article. Some adjustments to the usual estimates of PC(20) and parametric modeling of the entire dose-response curve are proposed as alternatives that address some of the shortcomings of PC(20).

Asthma↗
PubMed2001

Mechanisms of cytokine effects on G protein-coupled receptor-mediated signaling in airway smooth muscle.

Numerous in vitro and in vivo studies have implicated the cytokines interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) as mediators of airway inflammation and therefore potentially important substances in the pathogenesis of asthma. In this study, we examined the mechanisms by which IL-1 beta and TNF-alpha affect inhibition of cell growth, G protein-coupled receptor (GPCR) desensitization, and the recently reported adenylyl cyclase sensitization in human airway smooth muscle (HASM) cultures. Our findings demonstrate that adenylyl cyclase sensitization is independent of cytokine-mediated cyclooxygenase type 2 (COX-2) and prostaglandin E(2) (PGE(2)) induction, whereas COX-2 induction appears to be required for both growth inhibition and GPCR desensitization. However, GPCR desensitization was highly dependent on the presence of EGF during chronic treatment with cytokines, which could be explained by a synergistic effect of EGF on cytokine-mediated COX-2 and PGE(2) induction. Interestingly, various agents (including inhibitors of p42/p44 and p38 mitogen-activated protein kinase signaling) were significantly more effective in inhibiting cytokine-mediated PGE(2) induction, GPCR desensitization, and cell growth inhibition than in inhibiting COX-2 induction. These data demonstrate disparity in the requirement and sufficiency of COX-2 induction in promoting different functional effects of IL-1 beta and TNF-alpha in HASM.

Adenylyl Cyclases↗
PubMed2001

Safety and reproducibility of sputum induction in asthmatic subjects in a multicenter study.

The safety of sputum induction and the reproducibility of measurements in induced sputum in multicenter studies is unknown. We examined the safety of sputum induction in a two-visit, six-center study in 79 subjects with moderate to severe asthma (mean +/- SD FEV(1) 71 +/- 12% predicted, 67% taking inhaled corticosteroids). In addition, we compared the reproducibility of markers of inflammation in induced sputum with the reproducibility of the FEV(1) and the methacholine PC(20). The FEV(1) decreased > or = 20% from the postbronchodilator baseline in 14% of all subjects and in 25% of subjects whose initial prebronchodilator baseline was 40 to 60% of predicted. All subjects responded promptly to additional albuterol treatment, and no subject developed refractory bronchoconstriction requiring treatment other than reversal of bronchospasm in the study laboratory. The reproducibility of measurements of the eosinophil percentage, eosinophil cationic protein, tryptase, and methacholine PC(20) were similar (concordance correlation coefficients of 0.74, 0.81, 0.79, and 0.74, respectively), without any significant among-center effect. We conclude that sputum induction can be performed safely in subjects with moderate to severe asthma in multicenter clinical trials when carried out under carefully monitored conditions. Importantly, we demonstrate that measurement of markers of inflammation in induced sputum is as reproducible as methacholine PC(20) and should prove useful in the assessment of airway inflammation in multicenter clinical trials.

Aged↗
PubMed2001

The utility of peak flow, symptom scores, and beta-agonist use as outcome measures in asthma clinical research.

STUDY OBJECTIVES: Several methods of utilizing peak expiratory flow (PEF) and other markers of disease activity have been suggested as useful in the management of asthma. It remains unclear, however, as to which surrogate markers of disease status are discriminative indicators of treatment failure, suitable for use in clinical trials. DESIGN: We analyzed the operating characteristics of 66 surrogate markers of treatment failure using a receiver operating characteristic (ROC) curve analysis. PARTICIPANTS: Information regarding FEV(1), symptoms, beta(2)-agonist use, and PEF was available from 313 subjects previously enrolled in two Asthma Clinical Research Network trials, in which 71 treatment failures occurred (defined by a 20% fall in FEV(1) from baseline). INTERVENTIONS: None. MEASUREMENTS AND RESULTS: None of the measures had an acceptable ability to discriminate subjects with a > or % fall in FEV(1) from those without, regardless of the duration of the period of analysis or the criteria for test positivity employed. Areas under the ROC curves generated ranged from 0.51 to 0.79, but none were statistically superior. Sensitivity and specificity combinations were generally poor at all cutoff values; true-positive rates could not be raised without unacceptably elevating false-positive rates concurrently. CONCLUSIONS: Studies that seek to detect treatment failure defined by a significant fall in FEV(1) should not use such individual surrogate measures to estimate disease severity.

Adolescent↗
PubMed2001

Salmeterol powder provides significantly better benefit than montelukast in asthmatic patients receiving concomitant inhaled corticosteroid therapy.

STUDY OBJECTIVES: Comparison of inhaled salmeterol powder vs oral montelukast treatment in patients with persistent asthma who remained symptomatic while receiving inhaled corticosteroids. DESIGN: Randomized, double-blind, double-dummy, parallel-group, multicenter trials of 12-week duration. SETTING: Outpatients in private and university-affiliated clinics. PATIENTS: Male and female patients > or = 15 years of age with a diagnosis of asthma (baseline FEV(1) of 50 to 80% of predicted) and symptomatic despite receiving inhaled corticosteroids. INTERVENTIONS: Inhaled salmeterol xinafoate powder, 50 microg bid, or oral montelukast, 10 mg qd. MEASUREMENTS AND RESULTS: Treatment with salmeterol powder resulted in significantly greater improvements from baseline compared with montelukast for most efficacy measurements, including morning peak expiratory flow (35.0 L/min vs 21.7 L/min; p < 0.001), percentage of symptom-free days (24% vs 16%; p < 0.001), and the percentage of rescue-free days (27% vs 20%; p = 0.002). Total supplemental albuterol use was decreased significantly more in the salmeterol group compared with the montelukast group (- 1.90 puffs per day vs - 1.66 puffs per day; p = 0.004) and nighttime awakenings per week decreased significantly more with salmeterol than with montelukast (- 1.42 vs - 1.32; p = 0.015). Patients treated with inhaled salmeterol were significantly more satisfied with their treatment regimen and how well, how fast, and how long it worked than were patients who were treated with oral montelukast. The safety profiles for the two treatments were similar. CONCLUSION: In patients with persistent asthma who remain symptomatic while receiving inhaled corticosteroids, adding inhaled salmeterol powder provided significantly greater improvement in lung function and asthma symptoms and was preferred by patients over oral montelukast.

Acetates↗
PubMed2000

Effect of IL-5, glucocorticoid, and Fas ligation on Bcl-2 homologue expression and caspase activation in circulating human eosinophils.

IL-5 is a potent eosinophil viability-enhancing factor that has been strongly implicated in the pathogenesis of IgE-mediated inflammation in vivo. Recently published data have suggested that IL-5 (and related cytokines) may act by altering the expression of the anti-apoptotic regulator Bcl-2 or its homologues, but this is controversial. The behaviour of the recently described pro-apoptotic cysteine proteases (caspases) in eosinophils after IL-5 treatment has not been explored. We examined the effect of IL-5 on the expression of four major Bcl-2 homologues, as well as on the expression/activation of key members of the caspase cell death cascade in cultured circulating human eosinophils. The effect of relevant inducers of eosinophil apoptosis (glucocorticoid and Fas ligation) on these regulatory proteins was also examined. We observed baseline expression of the anti-apoptotic Mcl-1 and pro-apoptotic Bax proteins in immunoblots of eosinophil lysates, but not Bcl-x, Bcl-2. IL-5 treatment had the effect of maintaining this basal level of expression over time without altering the balance of Bcl-2 homologues. The (upstream) caspase 8 and (downstream) caspase 3 proenzymes were detected in eosinophils at baseline, and were processed during spontaneous and stimulated eosinophil death. IL-5 completely blocked caspase processing in spontaneous and dexamethasone-induced cell death, and significantly slowed processing during Fas ligation. Our data do not support the theory that IL-5 acts by altering the balance of anti-apoptotic and pro-apoptotic Bcl-2 homologues, but suggest that it may act by regulating activation of the caspase cell death cascade.

Apoptosis↗
PubMed2000

Kinetics of IL-10 production after segmental antigen challenge of atopic asthmatic subjects.

BACKGROUND: IL-10 is an anti-inflammatory cytokine made by lymphocytes, monocytes-macrophages, and eosinophils, and it may have an important role in regulating the asthmatic inflammatory response. IL-10 levels have been reported to be reduced in asthmatic airways, potentially contributing to more intense inflammation. OBJECTIVE: We sought to determine whether IL-10 levels were deficient in patients with mild asthma compared with controls and to determine whether IL-10 levels were associated with the resolution of eosinophilic inflammation. METHODS: We quantified IL-10 levels in the bronchoalveolar lavage (BAL) fluid (ELISA), BAL cells (quantitative immunocytochemistry), purified alveolar macrophages-monocytes studied ex vivo (ELISA), before (day 1) and after (24 hours [day 2], 1 week [day 9], and 2 weeks [day 16]) segmental antigen challenge (SAC), and investigated the effect of glucocorticoid treatment on ex vivo macrophage-monocyte IL-10 production. RESULTS: IL-10 levels were significantly higher in the BAL fluid of mild asthmatic subjects who demonstrated a dual reaction (both early and late) after whole lung ragweed inhalation challenge compared with nonallergic, nonasthmatic control subjects before and 24 hours and 1 week after SAC. Macro-phages-monocytes obtained before and after SAC from asthmatic patients also secreted increased amounts of IL-10 ex vivo than those from controls. Dexamethasone did not significantly change spontaneous IL-10 secretion from macrophages-monocytes in vitro. Quantitative immunocytochemical analysis of BAL cells demonstrated increased IL-10 in macrophages 24 hours after SAC and a similar trend in eosinophils. CONCLUSION: IL-10 is not deficient in mild asthma. Furthermore, BAL IL-10 levels are significantly higher in asthmatic subjects with a dual response than in control subjects before and after SAC. The increase in IL-10 was coincident with the initial increase in BAL eosinophils, although BAL eosinophilia persisted after IL-10 levels had returned to baseline, suggesting that the increased IL-10 levels could not promptly terminate this localized eosinophilic response.

Allergens↗
PubMed2000

Inhaled mometasone furoate reduces oral prednisone requirements while improving respiratory function and health-related quality of life in patients with severe persistent asthma.

BACKGROUND: Inhaled corticosteroid therapy in severe persistent asthma has been shown to reduce or eliminate oral corticosteroid (OCS) use while retaining effective asthma control. OBJECTIVE: We sought to evaluate the ability of mometasone furoate (MF) delivered by means of dry powder inhaler to reduce daily oral prednisone requirements in OCS-dependent patients with severe persistent asthma. METHODS: We performed a 12-week, double-blind, placebocontrolled trial (21 centers, 132 patients) comparing 2 doses of MF (400 and 800 microg administered twice daily) with placebo, followed by a 9-month open-label phase in which 128 patients received treatment with MF. RESULTS: At the endpoint of the double-blind trial, MF 400 and 800 mg twice daily reduced daily OCS requirements by 46.0% and 23.9%, respectively, whereas placebo increased OCS requirements by 164.4% (P <.01). Oral steroids were eliminated in 40%, 37%, and 0% of patients in the MF 400 and 800 mg twice daily and placebo groups, respectively. Pulmonary function and quality of life significantly increased for MF-treated patients. Further reductions in OCS requirements were achieved with long-term MF treatment in the open-label phase. CONCLUSION: MF inhaled orally as a dry powder is an effective alternative to systemic corticosteroids in patients with severe persistent asthma.

Administration, Inhalation↗
PubMed2000

The effect of polymorphisms of the beta(2)-adrenergic receptor on the response to regular use of albuterol in asthma.

Inhaled beta-adrenergic agonists are the most commonly used medications for the treatment of asthma although there is evidence that regular use may produce adverse effects in some patients. Polymorphisms of the beta(2)-adrenergic receptor (beta(2)-AR) can affect regulation of the receptor. Smaller studies examining the effects of such polymorphisms on the response to beta-agonist therapy have produced inconsistent results. We examined whether polymorphisms at codon 16 (beta(2)-AR-16) and codon 27 (beta(2)-AR-27) of the beta(2)-AR might affect the response to regular versus as-needed use of albuterol by genotyping the 190 asthmatics who had participated in a trial examining the effects of regular versus as needed albuterol use. During the 16-wk treatment period there was a small decline in morning peak expiratory flow in patients homozygous for arginine at B(2)-AR-16 (Arg/Arg) who used albuterol regularly. This effect was magnified during a 4-wk run out period, during which all patients returned to using as-needed albuterol, so that by the end of the study Arg Arg patients who had regularly used albuterol had a morning peak expiratory flow 30. 5 +/- 12.1 L/min lower (p = 0.012) than Arg/Arg patients who had used albuterol on an as needed basis. There was no decline in peak flow with regular use of albuterol in patients who were homozygous for glycine at beta(2)-AR-16. Evening peak expiratory flow also declined in the Arg/Arg patients who used albuterol regularly but not in those who used albuterol on an as-needed basis. No significant differences in outcomes between regular and as-needed treatment were associated with polymorphisms at position 27 of the beta(2)-AR. No other differences in asthma outcomes that we investigated occurred in relation to these beta(2)-AR polymorphisms. Polymorphisms of the beta(2)-AR may influence airway responses to regular inhaled beta-agonist treatment.

Adolescent↗
PubMed1999

Airway remodeling and persistent airway obstruction in asthma.

There is growing recognition that some patients with long-standing asthma may possess a component of irreversible airflow obstruction despite optimal therapy. This persistent airflow obstruction is thought to be the result of structural changes in the airways that occur as a result of airway remodeling. The structural changes that lead to chronic obstruction are not known, nor are the intricacies of the remodeling process. Hence airway remodeling and its role in the evolution of irreversible airflow obstruction remain conceptual. Much work has been carried out to better define the histopathologic characteristics of asthma, including the characteristic features of airway inflammation. However, attempts to delineate the physiologic consequences of specific histologic findings are at an early stage of development. The thesis that airway remodeling is driven by chronic inflammatory processes has important implications for the way we make treatment decisions, especially in the patient with mild asthma. Abounding interest in airway remodeling has led to a growing literature on the subject, a literature that is largely speculative and perhaps too tautologic in the sense that remodeling is frequently defined by any observed histologic change, irrespective of its physiologic consequences. Careful attempts to link histologic observations with clinical, demographic, and physiologic findings will be necessary to unravel the causes of remodeling and identify who is at risk for development of irreversible airway obstruction.

Airway Obstruction↗
PubMed1999

Pharmaceutically-based severity stratification of an asthmatic population.

Algorithms designed to precisely identify disease severity for a given patient within a managed care population are helpful in organizing targeted interventions. These algorithms are also attracting considerable attention within the medical research community. Several health risk screening instruments have been developed; however, these involve survey methodologies and have several shortcomings. We present a valid and efficient method for predicting healthcare resource utilization among asthmatics in an Health Maintenance Organization (HMO) population. First, various diagnosis, procedure and pharmacy billing codes were used to identify the asthmatics within the database. The screening algorithm awards points each time one of these codes is identified for an HMO member. By varying the number of points necessary to consider a patient asthmatic, the sensitivity, specificity, positive and negative predictive values of the algorithm can be adjusted. Once identified as asthmatic, subjects were then stratified into severity levels based on pharmacy data. Severity stratification was validated directly by measuring asthma-related bed days utilized during the 12 months following the date of stratification. Our identification algorithm estimated an asthma prevalence of 3.84% within the studied population, with age-specific prevalence estimates that closely mirrored previously published survey data. There was a monotonic relationship between pharmacy severity levels and inpatient resource utilization. For example, asthmatics in severity level 1 used only 92 hospital days per 1000 asthmatics in the year following characterization, while those in levels 2-5 used 133, 156, 277 and 1168 hospital days (P < 0.001), respectively. Results from this model can be used as adjusters in other predictive models or stand alone to represent a patient's severity of illness.

Adolescent↗
PubMed1999

Asthma severity: histopathologic correlations.

Asthma is a disorder characterized by inflammation of the airways which leads to variable airflow obstruction and symptoms of wheezing, chest tightness, cough, and dyspnea. Decisions concerning the type and intensity of therapy for asthma are generally based on the severity of the disease in a given individual. Guidelines for asthma management classify disease severity on the basis of symptom frequency and intensity as well as the degree of physiological impairment. Because treatment decisions are currently not based on markers of airway inflammation, it is important to know how well the underlying inflammatory pathology correlates with clinical and physiological variables and whether airway inflammation, if undertreated, leads to longer term adverse outcomes such as chronic persistent airway obstruction. Studies of asthma pathology reveal an inflammatory response characterized by infiltration of the airways with eosinophils, mast cells and lymphocytes; disruption of the epithelium; thickening of the reticular basement membrane; and increases in smooth muscle mass. These findings are qualitatively found in mild as well as severe asthmatics, and attempts to draw quantitative correlations between severity and intensity of inflammation have yielded discordant results. Although antiinflammatory therapy with corticosteroids decreases the intensity of the inflammation in association with improved clinical variables, the association is circumstantial and it is unclear which marker of inflammation correlates best with the severity of acute episodes or the severity of the disease in patients who are stable. Problems in relating the underlying pathology to disease severity are largely due to inadequate tissue sampling as bronchoscopically obtained specimens do not permit an evaluation of the outer airway wall or small airways and their surrounding parenchyma.

Journal Article↗
PubMed1997

Beta 2-agonist-elevated stress response in human bronchial epithelial cells in vivo and in vitro.

Recent studies report high baseline levels of stress (heat shock) proteins in bronchial epithelial cells from asthmatic individuals. The promoter of the gene encoding the 72-kDa heat shock protein has an element responsive to cAMP, which may be affected by beta-agonists. This study examined stress protein levels in subjects enrolled in a segmental lung allergen challenge study to determine whether beta-agonist medication could contribute to a stress response. Subjects were divided on the basis of no premedication (n = 17), metered dose inhalations of albuterol (n = 24), or placebo inhalation (n = 3) prior to bronchoscopy. Levels of the inducible stress protein Hsp72 and constitutive Hsp73 were quantitated in bronchial epithelial cells from brush biopsy of allergic nonasthmatic, allergic asthmatic, and normal individuals. Mean levels were increased significantly (p < 0.003 and p < 0.004, respectively) in those subjects who received albuterol premedication. No significant differences were found between clinical groups of individuals or for placebo inhalation vs nonpremedication. Albuterol in vitro increased the levels of Hsp72 and Hsp73 in epithelial cells from either nonpremedicated or placebo-treated donors; the Hsp72 levels correlated linearly with increased albuterol concentration (r = 0.81, p < 0.01). Therefore, beta-agonists elevate or prolong an elevated stress response in epithelial cells, possibly through cAMP-mediated effects.

Adrenergic beta-Agonists↗
PubMed1997

HSP27 elevated in mild allergic inflammation protects airway epithelium from H2SO4 effects.

Inflammation in allergic individuals is hypothesized to elevate stress proteins [heat shock proteins (HSP)] in airway epithelium, which may protect cells from further adverse conditions. Allergic, either asthmatic or not, and normal volunteers participated in a 2-day segmental allergen challenge bronchoscopic procedure. Bronchial epithelium was obtained before and after challenge. Epithelium was exposed to medium with H2SO4 (pH5), returned to medium at pH 7.4, and finally harvested for Western blotting with anti-27-kDa HSP (HSP27) antibody. Prechallenge epithelium of all subjects had significantly inhibited ciliary function by H2SO4 (pH 5) conditions (P < 0.001); only epithelium of normals recovered (P = 0.02). Allergic subjects with mild inflammation (< 50 micrograms/ml increase in albumin in bronchoalveolar lavage) had significantly increased HSP27 postchallenge (P = 0.01) and little ciliary dysfunction at pH 5, whereas subjects with severe inflammation (> 50 micrograms/ml increase in albumin) had little change in HSP27 and significant ciliary inhibition (P = 0.02). Normal epithelium had similar trends in HSP27 and equivalent inhibition of ciliary activity at pH 5 before and after allergen challenge. These data indicate that mild inflammation to allergen elevates HSP27 stress protein levels, thereby potentially protecting epithelial function from additional adverse conditions.

Adult↗