Publications

Unstimulated peripheral blood mononuclear cells (PBMCs) from corticosteroid-resistant (CR) but not corticosteroid-sensitive (CS) asthmatics demonstrate increased activating peptide-1 (AP-1)- and decreased glucocorticoid receptor (GR)-DNA binding. We test whether these abnormalities are associated with excessive generation of c-fos, the inducible component of AP-1. The c-fos transcription rate, mRNA and protein levels, and GR-DNA binding were quantitated in PBMCs, T cells, and monocytes from CS, CR, and nonasthmatic subjects. There was a 1.7-, 4.2-, and 2.3-fold greater increase in the baseline c-fos transcription rate, mRNA expression, and protein levels, respectively, in PBMCs derived from CR compared with CS patients. At optimal stimulation with PMA, there was a 5.7-, 3.4-, and 2-fold greater increase in the c-fos transcription rate, mRNA accumulation, and protein levels, respectively, in CR compared with CS PBMCs. These abnormalities were detected in both the T cell and monocyte subpopulations. PMA stimulation converted PBMCs from a CS to a CR phenotype and was associated with direct interaction between c-Fos and the GR. Pretreatment of PBMCs from CR patients with c-fos antisense oligonucleotides enhanced GR-DNA binding activity in CR PBMCs stimulated with dexamethasone. We suggest that increased c-fos synthesis provides a major mechanism for the increased AP-1- and decreased GR- DNA binding seen in CR asthma.

Objectives This study sought to evaluate the impact of chronic kidney disease (CKD) on coronary atherosclerotic plaque composition, morphology, and outcomes in patients with acute coronary syndromes (ACS). Background CKD patients presenting with ACS are at increased risk for adverse events. Whether or not this increased risk reflects differences in coronary plaque composition remains unknown. Methods In the PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) study, patients presenting with ACS in whom percutaneous coronary intervention was successful underwent 3-vessel grayscale and radiofrequency intravascular ultrasound imaging. Lesions were prospectively characterized, and patients were followed for a median of 3.4 years. We conducted a patient-level and lesion-level analysis of study participants by comparing intravascular ultrasound parameters of untreated nonculprit lesions in patients with and without CKD. Results Patients with CKD (n = 73, 11.3%) were older, more often female and diabetic compared to those without CKD (n = 573). Nonculprit lesions in patients with (n = 280) versus without (n = 2,390) CKD were more likely to have plaque burden ≥70% (11.8% vs. 8.5%, p = 0.05) and minimal luminal area ≤4.0 mm2 (25.9% vs. 19.2%, p = 0.005). The percentage of plaque comprised of necrotic core (15.0% vs. 13.0%, p = 0.0001) and dense calcium (8.2% vs. 6.4%, p < 0.0001) was higher while fibrous tissue (57.7% vs. 59.8%, p < 0.0001) was lower in CKD versus non-CKD lesions. The 3-year composite rate of cardiac death, cardiac arrest, or myocardial infarction (15.1% vs. 3.3%, p < 0.0001) was significantly higher in patients with than in those without CKD, although there were no differences in the rates of events adjudicated to nonculprit lesions. Conclusions Following percutaneous coronary intervention of all culprit lesions in ACS, patients with versus without CKD have more extensive and severe atherosclerosis remaining in their coronary tree with plaque composed of greater necrotic core and less fibrous tissue. These influences resulted in nonsignificantly different rates of non-culprit lesion–related adverse events, although cardiac death, arrest, or myocardial infarction were more common in patients with CKD.

Background: Global Initiative for Asthma (GINA) guidelines recommend a gradual step-down of asthma therapy if asthma has been well-controlled for at least 3 months. In real life, however, many well-controlled patients are prescribed high doses of inhaled corticosteroids (ICS), and are therefore unnecessarily at risk of systemic side effects associated with long-term ICS use. To encourage and facilitate step-down in a clinical setting, further pragmatic studies are required to demonstrate that good control of asthma can be maintained with a lower dose of ICS in stable and controlled patients, and to explore potential predictors for response to step-down.To test if good control of asthma can be maintained in adult patients previously stable on Flutiform® 250 (250 mcg fluticasone/10 mcg formoterol) for 12 weeks, after step-down to Flutiform® 125 (250 mcg fluticasone/5 mcg formoterol). Methods: This was the second phase of a pragmatic, open-label, randomised controlled, non-inferiority trial in adult patients with asthma. Patients eligible for this phase had been on Flutiform® 250 for 12 weeks, had had no exacerbations during this period and were considered suitable for step-down by their GP. A total of 116 patients from 23 sites in the UK were randomised 1:1 to continue on Flutiform® 250 or to step down to Flutiform® 125. The primary outcome was asthma control assessed using the 7-item Asthma Control Questionnaire (ACQ7). Non-inferiority limit on the ACQ7 was set at 0.3. Patients were eligible for the non-inferiority analysis if they stayed on the randomised treatment for at least 8 weeks and did not change treatment before outcome visit. Secondary outcomes included forced expiratory volume in the first second (FEV1) % predicted, the Mini-Asthma Quality of Life Questionnaire (Mini-AQLQ), asthma control (according to GINA) and absence of exacerbations during outcome period. Analyses of secondary outcomes included all randomised patients [Full Analysis Set (FAS)]. Adherence was calculated based on dose counter values for patients who returned the study inhalers. Results: Of the 107 patients who completed the study 48 (45%) were male and the mean [standard deviation (SD)] age was 54 (13) years. Of those randomised, 52 (90%) patients in each arm were eligible for the non-inferiority analysis (see figure for details of the FAS). At week 12, Flutiform® 125 was non-inferior to Flutiform® 250 in terms of asthma control assessed by ACQ7, with an upper confidence limit of 0.22, which is less than the pre-defined limit of 0.3 [mean difference 0.01; 95% confidence interval (CI), −0.20 to 0.22]. No significant differences between the groups were found for GINA asthma control, absence of exacerbations, Mini-AQLQ, or FEV1% predicted (see Table for treatment effect estimates). Adherence was high in both groups [median (inter-quartile range) 94% (88% to 106%) and 98% (77% to 103%) for the Flutiform® 125 and Flutiform® 250 groups, respectively] and there was no significant difference in distribution of adherence between the groups (P=0.20, Mann-Whitney U-test). Conclusions: This study showed that real-life patients previously controlled on Flutiform® 250 can be stepped down to Flutiform® 125 and maintain good asthma control. Additional analyses are ongoing to investigate biomarkers [blood eosinophils, fractional exhaled nitric oxide (FeNO)] and other factors that might predispose patients to exacerbations or worsening of asthma control following ICS step-down. In the future, such predictors could help physicians to make more informed decisions on stepping down therapy in a real-life setting.

Objective : The objective of this study is to compare magnetic guidewire navigation in percutaneous coronary intervention (MPCI) to conventional percutaneous coronary intervention (CPCI) for the elective treatment of a single discrete stenosis. Background : Magnetic navigation actively steers an angioplasty wire‐tip and may improve PCI procedures, but it is not known whether the intricacy and increased preparation necessary for using the system negatively influences the performance of simple procedures in terms of time and contrast use. Methods : The procedures of 44 patients (mean age 65 ± 10 year) undergoing elective single vessel MPCI of a single discrete stenosis were matched for age, gender, and lesion location with 44 concurrent patients (mean age 65 ± 10 year) undergoing CPCI. The major endpoint was procedural time. Results : Technical success was defined as an intraluminal wire position distal to the stenosis. Procedural outcome, contrast use, and costs were evaluated. Clinical demographics and angiographic characteristics of the two groups were similar, except for a higher incidence of previous MI and class III angina pectoris in the conventional group. The technical success rate was high and identical in both groups (97.7%). Procedural and fluoroscopy times were not significantly different for MPCI compared to CPCI (21.0 ± 14.5 min vs. 24.7 ± 14.0 min; 4.9 ± 4.8 min vs. 7.3 ± 10.3 min, P = NS). There was a significant reduction in median contrast use [60 ml/patient (41–100) vs. 100 ml/patient (64–130); P = 0.006]. Conclusion : Magnetic navigation does not increase procedural time, irradiation, equipment use, or cost compared to conventional PCI of a single discrete stenosis. It proved feasible, yielding high rates of procedural success with less contrast use. © 2009 Wiley‐Liss, Inc.

Cyclo‐oxygenase (COX) is the enzyme that converts arachidonic acid to prostaglandin H 2 (PGH 2 ) which can then be further metabolized to prostanoids which modulate various airway functions. COX exists in at least two isoforms. COX‐1 is expressed constitutively, whereas COX‐2 is expressed in response to pro‐inflammatory stimuli. Prostanoids are produced under physiological and pathophysiological conditions by many cell types in the lung. However, the regulation of the different COX isoforms in human airway smooth muscle (HASM) cells has not yet been determined. COX‐1 and COX‐2 protein were measured by Western blot analysis with specific antibodies for COX‐1 and COX‐2. COX‐2 mRNA levels were assessed by Northern blot analysis by use of a COX‐2 cDNA probe. COX activity was determined by measuring conversion of either endogenous or exogenous arachidonic acid to three metabolites, PGE 2 , thromboxane B 2 or 6‐ketoPGF 1α by radioimmunoassay. Under control culture conditions HASM cells expressed COX‐1, but not COX‐2, protein. However, a mixture of cytokines (interleukin‐1β (IL‐1β), tumour necrosis factor α (TNFα) and interferon γ (IFNγ) each at 10 ng ml −1 ) induced COX‐2 mRNA expression, which was maximal at 12 h and inhibited by dexamethasone (1 μ m ; added 30 min before the cytokines). Furthermore, COX‐2 protein was detected 24 h after the cytokine treatment and the expression of this protein was also inhibited by dexamethasone (1 μ m ) and cyclohexamide (10 μg ml −1 ; added 30 min before the cytokines). Untreated HASM cells released low or undetectable amounts of all COX metabolites measured over a 24 h period. Incubation of the cells with the cytokine mixture (IL‐1β, TNFα, IFNγ each at 10 ng ml −1 for 24 h) caused the accumulation of PGE 2 and 6‐keto‐PGF 1α . In experiments where COX‐2 metabolized endogenous stores of arachidonic acid, treatment of HASM cells with IL‐1β in combination with TNFα caused a similar release of PGE 2 to that when the three cytokines were given in combination. In other experiments designed to measure COX‐2 activity directly, cells were treated with cytokines for 24 h before fresh culture medium was added containing exogenous arachidonic acid (30 μ m for 15 min) after which PGE 2 was measured. IL‐1β and TNFα increased COX‐2 activity and an additional small increase was produced by the three cytokines in combination. These findings suggest that the increased expression of COX‐2 is intimately involved in the exaggerated release of prostanoids from HASM cells exposed to pro‐inflammatory cytokines. These data indicate a role for airway smooth muscle cells, in addition to their contractile function, as inflammatory cells involved in the production of mediators which may contribute to the inflammatory response seen in diseases such as asthma. British Journal of Pharmacology (1997) 120 , 910–916; doi: 10.1038/sj.bjp.0700963

textabstractSeventeen patients with coronary artery disease were studied with cineangiography and simultaneous tip manometry at resting heart rate and maximal tachycardia induced by atrial pacing. During early diastole, defined as the interval from the opening of the mitral valve to the point of minimal left ventricular pressure, 20 percent of total ventricular filling took place at resting heart rate, but 62 percent occurred during tachycardia. Minimal pressure was significantly correlated with the time constant of pressure decay during the isovolumic phase (r = 0.75 at resting heart rate and r = 0.81 during tachycardia). The measured minimal pressure could be predictd by extrapolating the exponential decay of ventricular isovolumic pressure to the time of occurence of the minimal pressure, which occurred on average 2.7 time constants from the peak negative rate of change of pressure. At resting heart rate the time constant of relaxation was inversely correlated with ventricular inflow volume (r = -0.64) and inflow rate (r = -0.72). It is concluded that left ventricular relaxatin has a relevant role in early diastolic pressure-volume relations and increases during tachycardia.

The Formoterol and Corticosteroids Establishing Therapy (FACET) study has provided the first opportunity to examine the long-term effects of inhaled steroids and long-acting beta2-agonists on asthma-specific quality of life. The objectives of the present study were to: evaluate the effects of long-term (1 yr) formoterol and increasing doses of budesonide on asthma quality of life; 2) to determine whether initial improvements in quality of life are sustained when improvements in clinical indices persist; and 3) to evaluate the long-term relationship between changes in clinical indices and changes in quality of life. Of the 852 asthmatic adults enrolled, 470 from five countries participated in this quality of life evaluation. After a 4-week run-in on 1,600 microg budesonide, patients were randomized to either 200 microg (Bud200) or 800 microg budesonide (Bud800) in combination with either 24 microg formoterol (F) or placebo daily for 1 yr. The Asthma Quality of Life Questionnaire (AQLQ) was completed and conventional clinical indices measured at enrolment and randomization and on seven occasions during the following 12 months. During the run-in, there was an improvement in AQLQ score (changes (delta) in overall score approximately 0.50; p&lt;0.0001). After randomization, there was a further improvement in the Bud800+F group (delta=0.21; p=0.028). One month post-randomization, improvements in all groups stabilized and were sustained throughout the 12 months in a pattern very similar to that observed for the conventional clinical indices. The correlation of individual patient changes in clinical indices and changes in AQLQ score during the 12-month randomized period were weak to moderate (maximum r=0.51). Improvements in quality of life, which were greatest in the 800 microg budesonide plus 24 microg formoterol group, were sustained throughout the 12 months in a similar manner to the clinical indices. Long-term changes in conventional clinical indices cannot be used to predict the effect of treatment on individual patient experience.

Patients with mild asthma often rely on inhaled short-acting β2-agonists for symptom relief and have poor adherence to maintenance therapy. Another approach might be for patients to receive a fast-acting reliever plus an inhaled glucocorticoid component on an as-needed basis to address symptoms and exacerbation risk.We conducted a 52-week, double-blind, multicenter trial involving patients 12 years of age or older who had mild asthma and were eligible for treatment with regular inhaled glucocorticoids. Patients were randomly assigned to receive twice-daily placebo plus budesonide-formoterol (200 μg of budesonide and 6 μg of formoterol) used as needed or budesonide maintenance therapy with twice-daily budesonide (200 μg) plus terbutaline (0.5 mg) used as needed. The primary analysis compared budesonide-formoterol used as needed with budesonide maintenance therapy with regard to the annualized rate of severe exacerbations, with a prespecified noninferiority limit of 1.2. Symptoms were assessed according to scores on the Asthma Control Questionnaire-5 (ACQ-5) on a scale from 0 (no impairment) to 6 (maximum impairment).A total of 4215 patients underwent randomization, and 4176 (2089 in the budesonide-formoterol group and 2087 in the budesonide maintenance group) were included in the full analysis set. Budesonide-formoterol used as needed was noninferior to budesonide maintenance therapy for severe exacerbations; the annualized rate of severe exacerbations was 0.11 (95% confidence interval [CI], 0.10 to 0.13) and 0.12 (95% CI, 0.10 to 0.14), respectively (rate ratio, 0.97; upper one-sided 95% confidence limit, 1.16). The median daily metered dose of inhaled glucocorticoid was lower in the budesonide-formoterol group (66 μg) than in the budesonide maintenance group (267 μg). The time to the first exacerbation was similar in the two groups (hazard ratio, 0.96; 95% CI, 0.78 to 1.17). The change in ACQ-5 score showed a difference of 0.11 units (95% CI, 0.07 to 0.15) in favor of budesonide maintenance therapy.In patients with mild asthma, budesonide-formoterol used as needed was noninferior to twice-daily budesonide with respect to the rate of severe asthma exacerbations during 52 weeks of treatment but was inferior in controlling symptoms. Patients in the budesonide-formoterol group had approximately one quarter of the inhaled glucocorticoid exposure of those in the budesonide maintenance group. (Funded by AstraZeneca; SYGMA 2 ClinicalTrials.gov number, NCT02224157 .).