Publications

Background ACEF score has been shown to have predictive ability in the patients undergoing percutaneous coronary intervention (PCI). The ACEF II score has recently been developed to predict short-term mortality after cardiac surgery. We compared the predictive ability of the ACEF and ACEF II scores to predict mortality after PCI in the all-comers population. Methods The ACEF and ACEF II scores were calculated in 15,968 patients enrolled in the GLOBAL LEADERS study. Discrimination and calibration were assessed for outcomes after PCI. Recalibration of the regression model by updating the intercept and slope were performed to adjust the original ACEF model to the PCI setting. In a stratified approach, patients were divided into quintiles according to the score. Outcomes were compared between quintiles. Results The ACEF and ACEF II score were available in 14,941 and 14,355 patients respectively. Discrimination for 30-day all-cause mortality was acceptable for both scores (C-statistic ACEF 0.75 and ACEF II 0.77). For 2-year all-cause mortality, the discrimination of ACEF score was acceptable (C-statistic 0.72) while the discrimination of ACEF II score was moderate (C-statistic 0.69). Both scores identified patients at high risk of mortality but overestimated all-cause mortality at 30 days in all quintiles. After recalibration, agreement between predicted and observed 30-day all-cause mortality in both scores are close to the identity line. Conclusions The ACEF II model did not improve the predictive ability of the ACEF score. Recalibrated ACEF model can be used to estimated all-cause mortality rate at 30 days after PCI.

Objectives: To describe a method for the estimation of transaortic flow from multidetector computer tomography (MDCT). Background: Cardiac MDCT may not allow instantaneous flow measurement yet the components of flow, namely, volume change over time and lumenal area are recorded. Methods: In 36 patients, the transaortic flow velocity was determined on transthoracic echocardiography and also with cardiac MDCT as follows: On MDCT an axial orientation through the aortic root was obtained so that the nadir of all three aortic leaflets could be seen simultaneously in one axial image. Aortic valve area (AVA) was determined by planimetry and left ventricular volumes by endocardial border mapping at every 5% increment of the RR intervals. Flow velocity was then calculated as the incremental ejection volume ÷ duration of the increment ÷ AVA. Results: The transthoracic echocardiography (TTE) peak velocity and MDCT peak velocity were highly correlated ( r = 0.75, P < 0.01). Transaortic peak velocity was higher when measured by MDCT as compared to TTE, with respectively a median [IQ‐range] of 4.5 [2.9–5.3] and 4.0 [3.0–4.6], P < 0.01. For the diagnosis of severe aortic stenosis greater concordance with TTE peak velocity was seen with MDCT peak velocity (sensitivity 100%, specificity 76%) than with MDCT AVA (sensitivity 74%, specificity 76%). Conclusions: We show for the first time that transaortic flow velocity can be estimated by dual‐source MDCT and has a better sensitivity for the detection of severe aortic stenosis than AVA planimetry when compared to the gold standard of TTE peak flow velocity. © 2011 Wiley‐Liss, Inc.

Abstract Epigenetics is the term used to describe heritable changes in gene expression that are not coded in the DNA sequence itself but by post-translational modifications in DNA and histone proteins. These modifications include histone acetylation, methylation, ubiquitination, sumoylation and phosphorylation. Epigenetic regulation is not only critical for generating diversity of cell types during mammalian development, but it is also important for maintaining the stability and integrity of the expression profiles of different cell types. Until recently, the study of human disease has focused on genetic mechanisms rather than on non-coding events. However, it is becoming increasingly clear that disruption of epigenetic processes can lead to several major pathologies, including cancer, syndromes involving chromosomal instabilities, and mental retardation. Furthermore, the expression and activity of enzymes that regulate these epigenetic modifications have been reported to be abnormal in the airways of patients with respiratory disease. The development of new diagnostic tools might reveal other diseases that are caused by epigenetic alterations. These changes, despite being heritable and stably maintained, are also potentially reversible and there is scope for the development of 'epigenetic therapies' for disease.

Wire arc additive manufacturing (WAAM) is a metal 3D printing method that allows the cost-effective and efficient production of large-scale elements, and has thus gained great interest from architects and structural engineers. Integration of this novel technology into the construction industry, however, requires the development of a clear understanding of the mechanical behaviour of WAAM materials. To this end, a comprehensive experimental study into the mechanical properties and microstructure of WAAM plates made of normal- and high-strength steels has been undertaken and is reported herein. A total of 137 as-built and machined tensile coupons were tested, extracted in various directions relative to the print layer orientation from WAAM plates of two nominal thicknesses, built using different deposition strategies. The influence of the geometric undulations inherent to the WAAM process and deposition strategy on the resulting mechanical properties was investigated. Microstructural characterisation was also performed by means of optical microscopy (OM) and electron backscatter diffraction (EBSD). The WAAM normal-strength steel plates exhibited a principally ferritic-pearlitic microstructure, while the WAAM high-strength steel plates displayed a mixed microstructure featuring ferrite, bainite and martensite. The EBSD analysis revealed a weak crystallographic texture, which explained the observed mechanical properties being almost isotropic. No significant differences in tensile properties were observed with the different deposition strategies, except for some variation in ductility. The geometric undulations of the as-built coupons resulted in some reduction in effective mechanical properties and a degree of anisotropy. Overall, the examined WAAM material exhibited consistent mechanical properties, a Young's modulus comparable to conventionally-produced steel plates, marginally lower strength, reflecting the slower cooling conditions than is customary, and good ductility.

Inappropriate elevation of matrix metalloproteinase-9 (MMP9) is reported to be involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). The object of this study was to identify the molecular mechanism underlying this increase of MMP9 expression, and here we show that oxidative stress-dependent reduction of a protein deacetylase, SIRT1, known as a putative antiaging enzyme, causes elevation of MMP9 expression. A sirtuin inhibitor, splitomycin, and SIRT1 knockdown by RNA interference led an increase in MMP9 expression in human monocytic U937 cells and in primary sputum macrophages, which was detected by RT-PCR, Western blot, activity assay, and zymography. In fact, the SIRT1 level was significantly decreased in peripheral lungs of patients with COPD, and this increase was inversely correlated with MMP9 expression and MMP9 promoter activation detected by a chromatin immunoprecipitation assay. H(2)O(2) reduced SIRT1 expression and activity in U937 cells; furthermore, cigarette smoke exposure also caused reduction of SIRT1 expression in lung tissue of A/J mice, with concomitant elevation of MMP9. Intranasal treatment of a selective and novel SIRT1 small molecule activator, SRT2172, blocked the increase of MMP9 expression in the lung as well as pulmonary neutrophilia and the reduction in exercise tolerance. Thus, SIRT1 is a negative regulator of MMP9 expression, and SIRT1 activation is implicated as a novel therapeutic approach to treating chronic inflammatory diseases, in which MMP9 is abundant.

A number of techniques have been proposed for circulatory support during high‐risk percutaneous coronary interventions (PCI), but no single approach has achieved wide acceptance so far. We report on a patient with severe left ventricular (LV) impairment who underwent a PCI with the use of a new left ventricular assist device, the Impella Recover LP 2.5 system. The effects on global cardiac output were determined by thermodilution (TD) and LV pressure‐volume loops obtained by conductance catheter. The activation of the pump resulted in a rapid and sustained unloading effect of the LV. At the same time, the continuous expulsion of blood into ascending aorta throughout the cardiac cycle produced by the pump resulted in an increase of systemic overall CO, measured by the TD technique, of 1.43 L/min. The procedure was uncomplicated and the patient remained uneventful at follow‐up. Our single experience gives new input for future trials to assess the effect of the Impella Recover LP 2.5 assist device on outcome in this subset of patients. © 2005 Wiley‐Liss, Inc.

3527 Y. Kobayashi, C. Rossios, P. J. Barnes, K. Ito Airway Disease Section, NHLI, Imperial College London, UK Rationale: We have recently demonstrated that the reduction of histone deacetylase (HDAC)2 activity via PI3K activation causes corticosteroid (CS) insensitivity in COPD (ATS 2007). Here we show that CEM-101, a novel macrolide/fluoroketolide, which has potent activities against many bacteria causing pneumonia (starting Phase 2), reverses oxidative stress-dependent CS insensitivity via inhibition of PI3K signaling. Methods: CS sensitivity was determined by calculation of IC50 value of dexamethasone on TNFα-induced IL8 production in U937 monocytic cell line. HDAC activity and phosphorylation level of Akt as a marker of PI3K activation were measured by fluorescence based activity assay and western blotting, respectively. HDAC2 mRNA expression were also determined in A549 type II alveolar epithelial cell line. Cells were exposed to oxidative stress such as hydrogen peroxide (H2O2) or cigarette smoke extract (CSE) to induce steroid insensitivity. Results: Oxidative stress decreased CS sensitivity with concomitant down-regulation of total HDAC activity/HDAC2 expression and increased Akt phosphorylation. Treatment with CEM-101 (10 μM) restored CS sensitivity in H2O2 exposed cells. In addition, CEM-101 (10 100 μM) restored HDAC activity and HDAC2 expression reduced under oxidative stress and also inhibited Akt phosphorylation, which effects were more potent than those of any macrolides currently used clinically. Conclusions: CEM-101 restores CS sensitivity in oxidative stress-dependent CS insensitive model via enhancement of HDAC activity/expression due to PI3K signaling inhibition. This novel fluoroketolide, CEM-101, has potential for a novel treatment of COPD or severe asthma, which are steroid insensitive.

No abstract is provided for this article.

No abstract is provided for this article.