Publications

No abstract is provided for this article.

Objectives This study sought to study the efficacy and safety of newer-generation drug-eluting stents (DES) compared with bare-metal stents (BMS) in an appropriately powered population of patients with ST-segment elevation myocardial infarction (STEMI). Background Among patients with STEMI, early generation DES improved efficacy but not safety compared with BMS. Newer-generation DES, everolimus-eluting stents, and biolimus A9-eluting stents, have been shown to improve clinical outcomes compared with early generation DES. Methods Individual patient data for 2,665 STEMI patients enrolled in 2 large-scale randomized clinical trials comparing newer-generation DES with BMS were pooled: 1,326 patients received a newer-generation DES (everolimus-eluting stent or biolimus A9-eluting stent), whereas the remaining 1,329 patients received a BMS. Random-effects models were used to assess differences between the 2 groups for the device-oriented composite endpoint of cardiac death, target-vessel reinfarction, and target-lesion revascularization and the patient-oriented composite endpoint of all-cause death, any infarction, and any revascularization at 1 year. Results Newer-generation DES substantially reduce the risk of the device-oriented composite endpoint compared with BMS at 1 year (relative risk [RR]: 0.58; 95% confidence interval [CI]: 0.43 to 0.79; p = 0.0004). Similarly, the risk of the patient-oriented composite endpoint was lower with newer-generation DES than BMS (RR: 0.78; 95% CI: 0.63 to 0.96; p = 0.02). Differences in favor of newer-generation DES were driven by both a lower risk of repeat revascularization of the target lesion (RR: 0.33; 95% CI: 0.20 to 0.52; p < 0.0001) and a lower risk of target-vessel infarction (RR: 0.36; 95% CI: 0.14 to 0.92; p = 0.03). Newer-generation DES also reduced the risk of definite stent thrombosis (RR: 0.35; 95% CI: 0.16 to 0.75; p = 0.006) compared with BMS. Conclusions Among patients with STEMI, newer-generation DES improve safety and efficacy compared with BMS throughout 1 year. It remains to be determined whether the differences in favor of newer-generation DES are sustained during long-term follow-up.

We have studied the effects of tachykinin‐depletion on airway microvascular leakage induced by allergen challenge in ovalbumin‐sensitised guinea pigs, Tachykinin‐depletion was obtained by capsacin pretreatment 1 week before inhaled allergen challenge. Capsaicin pretreatment did not change airway microvascular permeability induced by allergen challenge. Capsaicin pretreatment did not change airway microvascular permeability induced by allergen challenge. Thus, sensory neuropeptides may not be important in allergen induced acute airway microvascular leakage in guinea pig in vivo.

Despite increased numbers o f alveolar macrophages (mΦ) in stable COPD patients, lower airway bacterial colonisation (LABC) is often seen. We investigated the relationship between LABC status, airway inflammation & monocyte-derived mΦ (MDMs) phagocytosis. Whole blood & sputa were collected from stable COPD patients. MDMs were cultured & phagocytosis of fluorescently-labeled inert beads, or heat-killed Haemophilus influenzae (HI) & Streptococcus pneumoniae (SP) measured. Sputa were analysed by qPCR for HI, SP & Moraxella catarrhalis & airway cytokines by ELISA. Clinical characteristics are shown in Table 1. 19/40 patients had evidence of LABC on qPCR & had significantly higher levels of IL-8 and IL-1β, but not MPO, than non-LABC patients. There was a trend towards increasing airway inflammation with increasing bacterial load. Phagocytosis of HI & SP, but not beads, significantly increased with increasing airway IL-8 & IL-1β (Figure 1). There was no significant relationship between airway MPO and phagocytosis of any prey. Higher levels of airway IL-8 and IL-1β are associated with increased phagocytic response by MDMs to HI & SP but not beads. Higher bacterial loads seen in LABC patients may increase airway inflammation & this may in turn influence phagocytic ability.

No abstract is provided for this article.

To develop a simplified approach of virtual functional assessment of coronary stenosis from routine angiographic data and test it against fractional flow reserve using a pressure wire (wire-FFR).Three-dimensional quantitative coronary angiography (3D-QCA) was performed in 139 vessels (120 patients) with intermediate lesions assessed by wire-FFR (reference standard: ≤0.80). The 3D-QCA models were processed with computational fluid dynamics (CFD) to calculate the lesion-specific pressure gradient (ΔP) and construct the ΔP-flow curve, from which the virtual functional assessment index (vFAI) was derived. The discriminatory power of vFAI for ischaemia- producing lesions was high (area under the receiver operator characteristic curve [AUC]: 92% [95% CI: 86-96%]). Diagnostic accuracy, sensitivity and specificity for the optimal vFAI cut-point (≤0.82) were 88%, 90% and 86%, respectively. Virtual-FAI demonstrated superior discrimination against 3D-QCA-derived % area stenosis (AUC: 78% [95% CI: 70- 84%]; p<0.0001 compared to vFAI). There was a close correlation (r=0.78, p<0.0001) and agreement of vFAI compared to wire-FFR (mean difference: -0.0039±0.085, p=0.59).We developed a fast and simple CFD-powered virtual haemodynamic assessment model using only routine angiography and without requiring any invasive physiology measurements/hyperaemia induction. Virtual-FAI showed a high diagnostic performance and incremental value to QCA for predicting wire-FFR; this "less invasive" approach could have important implications for patient management and cost.

Background. Nitrosative and oxidative stress are involved in the pathogenesis of COPD but their role in acute exacerbations of COPD (AECOPD) is unclear. We used experimental rhinovirus (RV) infection to examine the role of RNS and oxidative stress in AECOPD. Methods. 9 COPD subjects, 9 smokers (SMK) and 8 non-smokers (NS) were successfully infected with RV. Induced sputum (IS) was collected prior to infection and on days 3, 5, 9, 12, 15, 21 and 42 post-infection. Markers of nitrosative and oxidative stress 3-nitrotyrosine (3-NT), 8-hydroxy-29-deoxyguanosine (8-OHDG) and 8-isoprostane, and inflammatory mediators were measured in IS supernatants. Results. At baseline 3-NT levels were significantly higher in the COPD group compared to both NS (P Conclusions. Following RV infection nitrosative and oxidative stress are increased in COPD. The marker of nitrosative stress 3-NT correlates with levels of inflammatory mediators in sputum. Oxidative and nitrosative stress are potential targets for the development of novel therapies for AECOPD.

It has recently been shown that the triazolodiazepine WEB 2086 inhibits the platelet-activating factor (PAF)-induced platelet aggregation, bronchoconstriction (J. Pharmacol. Exp. Therap. 1987; 241:974) and microvascular leakage (Br. J. Pharm. 1987; in press) in guinea pigs. In the present study we have determined the PAF antagonistic properties of WEB 2086 in human neutrophil and eosinophil leukocytes. In addition, we have characterized [3H] WEB 2086 as a radioligand in direct binding experiments with these cell types. PAF increased the beta-glucuronidase release from neutrophils with an EC50 of 138 nM. WEB 2086 caused a concentration-dependent inhibition of this PAF effect with an inhibition constant (Ki) of 11.9 nM. Binding of [3H] WEB 2086 to neutrophils was specific, reversible and saturable with a dissociation constant (KD) of 18.9 nM and a maximal number of binding sites of 40000 sites per cell. The characteristics of the binding sites were identical to those of PAF receptors. In human eosinophils PAF induced an increase in lucigenin-enhanced chemiluminescence with an EC50 of 2.5 nM. WEB 2086 competitively inhibited this response with a Ki of 16.4 nM. [3H] WEB 2086 bound to eosinophils with a KD of 18.5 nM, which is in good agreement with the Ki from the functional studies. Our results show that WEB 2086 is a potent and specific antagonist of PAF in human neutrophils and eosinophils. Also, [3H] WEB 2086 appears to be a suitable antagonist radioligand for labelling of PAF receptors in these inflammatory cells. WEB 2086 should be of value in further elucidation of the role of endogenous PAF in asthma through activation of inflammatory cells recruited to the lung.

T lymphocytes may play a regulatory role in the development of allergic airway hyperresponsiveness (AHR). We have studied the relationship between airway responsiveness and a number of immunological changes in Brown-Norway rats sensitized intraperitoneally and repeatedly exposed to ovalbumin (OVA) aerosol. Acetylcholine provocation concentration (PC)150 (the concentration of acetylcholine causing a 150% increase of base-line lung resistance) was measured and peripheral blood and bronchoalveolar lavage (BAL) cells were collected 18-24hr after the final exposure. Total and OVA-specific IgE in serum was measured by enzyme-linked immunosorbent assay (ELISA). Mononuclear cells were analysed by flow cytometry after labelling with monoclonal antibodies against CD2 (pan T-cell marker), CD4, CD8 (T-cell subsets) or CD25 (interleukin-2 receptor). There were significant differences in PC150 (P < 0.05) and in OVA-specific IgE levels in serum (P < 0.002); CD4+ T cells expressed a significantly increased level of CD25 immunoreactivity in BAL, but not in peripheral blood, of rats sensitized and exposed to OVA, compared with saline-exposed controls (P < 0.02). There was a significant correlation between CD25 expression and BAL eosinophil numbers (r = 0.74, P < 0.001), PC150 (r = 0.63, P < 0.003) and OVA-specific IgE (r = 0.77, P < 0.001). These data suggest that activated T cells may be involved in the regulation of allergen-induced AHR in a relevant animal model of allergic asthma.