Publications

OBJECTIVES This study evaluated safety and efficacy of excimer laser angioplasty for treatment of restenosed or occluded coronary stents. BACKGROUND Balloon angioplasty of in-stent restenosis is limited by a high recurrence rate. Debulking by laser angioplasty is a novel concept to treat in-stent restenosis. METHODS A total of 440 patients with restenoses or occlusions in 527 stents were enrolled for treatment with concentric or eccentric laser catheters and adjunctive balloon angioplasty. RESULTS Laser angioplasty success (≤50% diameter stenosis after laser treatment or successful passage with a 2.0-mm or 1.7-mm eccentric laser catheter) was achieved in 92% of patients. Adjunctive balloon angioplasty was performed in 99%. Procedural success (laser angioplasty success followed by ≤30% stenosis with or without balloon angioplasty) was 91%. There was neither a significant difference in success with respect to lesion length, nor were there differences between small and large vessels or native vessels and vein grafts. Success was higher and residual stenosis lower using large or eccentric catheters. Serious adverse events included death (1.6%, not directly laser catheter related), Q-wave myocardial infarction (0.5%), non–Q-wave infarction (2.7%), cardiac tamponade (0.5%) and stent damage (0.5%). Perforations after laser treatment occurred in 0.9% of patients and after balloon angioplasty in 0.2%. Dissections were visible in 4.8% of patients after laser treatment and in 9.3% after balloon angioplasty. Reinterventions during hospitalization were necessary in 0.9% of patients; bypass surgery was performed in 0.2%. CONCLUSIONS Excimer laser angioplasty with adjunctive balloon angioplasty is a safe and efficient technology to treat in-stent restenoses. These data justify a randomized comparison with balloon angioplasty.

Cyclo‐oxygenase metabolizes arachidonic acid to prostaglandin H 2 (PGH 2 ) and exists in at least two isoforms. Cyclo‐oxygenase‐1 (COX‐1) is expressed constitutively whereas COX‐2 is induced by lipopolysaccharide (LPS) and some cytokines in vitro and at the site of inflammation in vivo . Epithelial cells may be an important source of prostaglandins in the airways and we have, therefore, investigated the expression of COX‐1 or COX‐2 isoforms in primary cultures of human airway epithelial cells or in a human pulmonary epithelial cell line (A549). COX‐1 or COX‐2 protein was measured by western blot analysis using specific antibodies to COX‐2 and selective antibodies to COX‐1. The activity of COX was assessed by the conversion of either endogenous or exogenous arachidonic acid to four metabolites, PGE 2 , PGF 2α , thromboxane B 2 or 6‐oxo PGF 1α measured by radioimmunoassay. Thus, COX‐1 or COX‐2 activity was measured under two conditions; initially the accumulation of the COX metabolites formed from endogenous arachidonic acid was measured after 24 h. In other experiments designed to measure COX activity directly, cells were treated with cytokines for 12 h before fresh culture medium was added containing exogenous arachidonic acid (30 μ m ) for 15min after which COX metabolites were measured. Untreated primary cells or A549 cells contained low amounts of COX‐1 or COX‐2 protein. Bacterial LPS (1 μg ml −1 for 24 h) induced COX‐2 protein in the primary cells, a process which was enhanced by interferon‐γ, with no further increase in the presence of a mixture of cytokines (interleukin‐1β, tumour necrosis factor‐α and interferon‐γ, 10 ng ml −1 for all). In contrast, A549 cells contained only low levels of COX‐2 protein after exposure to LPS or LPS plus interferon‐γ, but contained large amounts of COX‐2 protein after exposure to the mixture of cytokines. Untreated human pulmonary primary cells or A549 cells released low levels of all COX metabolites measured over a 24 h incubation period. This release was enhanced by treatment of either cell type with the mixture of cytokines (interleukin‐10, tumour necrosis factor‐α and interferon‐γ, 10ng ml −1 for all). PGE2 was the principal COX metabolite released by cytokine‐activated epithelial cells. The release of PGE 2 induced by cytokines occurred after a lag period of more than 6 h. The glucocorticosteroid, dexamethasone (1 μ m ; 30 min prior to cytokines) completely suppressed the cytokine‐induced expression of COX‐2 protein and activity in both primary cells and A549 cells. In experiments where COX‐2 activity was supported by endogenous stores of arachidonic acid, treatment of A549 cells with interleukin‐10 but not tumour necrosis factor‐α or interferon‐γ alone caused a similar release of PGE 2 to that seen when the cytokines were given in combination. However, both interleukin‐10 and necrosis factor‐α alone produced similar increases in COX‐2 activity (measured in the presence of exogenous arachidonic acid) as seen when the mixture of interleukin‐1β, tumour necrosis factor‐α and interferon‐γ were used to stimulate the cells. These findings show that COX‐2 expression correlates with the exaggerated release of prostaglandins from cytokine‐activated human pulmonary epithelial cells and that the induction of the enzyme is suppressed by a glucocorticosteroid. These findings may be relevant to inflammatory diseases of the lung, such as asthma.

Antiplatelet therapy is the mainstay of pharmacologic treatment to prevent thrombotic or ischemic events in patients with coronary artery disease treated with percutaneous coronary intervention and those treated medically for an acute coronary syndrome. The use of antiplatelet therapy comes at the expense of an increased risk of bleeding complications. Defining the optimal intensity of platelet inhibition according to the clinical presentation of atherosclerotic cardiovascular disease and individual patient factors is a clinical challenge. Modulation of antiplatelet therapy is a medical action that is frequently performed to balance the risk of thrombotic or ischemic events and the risk of bleeding. This aim may be achieved by reducing (ie, de-escalation) or increasing (ie, escalation) the intensity of platelet inhibition by changing the type, dose, or number of antiplatelet drugs. Because de-escalation or escalation can be achieved in different ways, with a number of emerging approaches, confusion arises with terminologies that are often used interchangeably. To address this issue, this Academic Research Consortium collaboration provides an overview and definitions of different strategies of antiplatelet therapy modulation for patients with coronary artery disease, including but not limited to those undergoing percutaneous coronary intervention, and consensus statements on standardized definitions.

Non-specific interstitial pneumonia (NSIP) and fibrosing alveolitis associated with systemic sclerosis (FASSc) are diseases of unknown aetiology that are characterised by the accumulation of mononuclear cells, followed by the progressive deposition of collagen within the interstitium and subsequent destruction of lung airspace. Better understanding of mediators involved in fibrosis may be useful for early diagnosis and in clinical monitoring of disease progression.The aim of this study was to investigate the presence of two profibrotic markers, the vitronectin and the endothelin-1 (ET-1) in the airways of NSIP and FASSc patients.Ten NSIP (6 males, age 57 +/- 2 years) and 15 FASSc (8 males, age 55 +/- 4 years) patients were recruited along with 10 normal subjects (4 male, age 52 +/- 2 years). Vitronectin and ET-1 concentrations were measured in their breath condensate, using a specific enzyme immunoassay.Higher levels of vitronectin and ET-1 were observed in NSIP and FASSc patients [median 92.8 (91.7-93.9) microg/ml; median 8.3 (7.9-9.3) pg/ml] than in control subjects [median 80.3 (89.3-91.4) microg/ml; p < 0.01; median 5.3 (4.9-5.9) pg/ml, p < 0.0001]. We also found increased concentrations of vitronectin in patients with clinical deterioration compared to those remaining stable and in ex-smokers compared to non-smokers and, increased vitronectin and ET-1 in patients treated with steroids compared to untreated patients.These findings justify further studies of vitronectin and ET-1 levels in exhaled breath condensate, as a means of monitoring activity and predicting progression of pulmonary fibrosis.

Objectives. This study was designed to examine whether oversized implantation of the new, less shortening Wallstent provides a more favorable long-term clinical and angiographic outcome in chronic total occlusions than does conventional coronary balloon angioplasty. Background. Restenosis and reocclusion remain major limitations of balloon angioplasty for chronic total occlusions. Enforced mechanical remodeling by implantation of the oversized Wallstent may prevent elastic recoil and improve accommodation of intimal hyperplasia. Methods. Lumen dimension was measured by a computerbased quantitative coronary angiography system (CAAS II). These measurements (before and after intervention and at 6-month follow-up) were compared between the groups with Wallstent implantation (20 lesions, 20 patients) and conventional balloon angioplasty (266 lesions, 249 patients) for treatment of chronic total occlusion. Acute gain (minimal lumen diameter after intervention minus that before intervention), late loss (minimal lumen diameter after intervention minus that at follow-up) and net gain (acute gain minus late loss) were examined. Results. Wallstent deployment was successful in all patients. High pressure intra-Wallstent balloon inflation (mean ± SD 14 ± 3 atm) was performed in all lesions. Although vessel size did not differ between the Wallstent and balloon angioplasty groups, acute gain was significantly greater in the Wallstent group (2.96 ± 0.55 vs. 1.61 ± 0.34 mm, p < 0.0001). Although late loss was also significantly larger in the Wallstent group (0.81 ± 0.95 vs. 0.43 ± 0.68 mm, p < 0.05), net gain was still significantly greater in this group (2.27 ± 1.00 vs. 1.18 ± 0.69 mm, p < 0.0001). Angiographic restenosis (≥50% diameter stenosis) occurred at 6 months in 29% of lesions in the Wallstent group and in 45% of those in the balloon angioplasty group (p = 0.5150). Conclusions. Implantation of the oversized Wallstent, with full coverage of the lesion length, ensures resetting of the vessel size to its original caliber before disease and allows greater accommodation of intimal hyperplasia and chronic vessel recoil. Wallstent implantation provides a more favorable short- and long-term clinical and angiographic outcome than does conventional balloon angioplasty for chronic total occlusions.

An increase in subepithelial mesenchymal cells and associated connective tissue is a feature of bronchial asthma. We determined whether neuropeptides could modulate fibroblast activity, particularly with respect to proliferation and chemotaxis. Human lung fibroblasts were cultured with neurokinin A (NKA), substance P (SP), vasoactive intestinal peptide (VIP), and calcitonin-gene-related peptide (CGRP). After 48 h, fibroblast proliferation was measured by a colorimetric assay based on the uptake and subsequent release of methylene blue. The chemotactic response to neuropeptides was determined with the use of a modified Boyden chamber. Both NKA and SP (10(-7)-10(-4) M) stimulated human lung fibroblast proliferation in HFL1 and IMR-90 fibroblasts. VIP and CGRP had no effect on fibroblast proliferation. NKA alone stimulated fibroblast chemotaxis maximally at 10(-10) M. Neutral endopeptidase (NEP) activity of 0.52 and 5.2 pmol/10(6) cells was assayed in IMR-90 and Hs68 fibroblasts, respectively. Phosphoramidon (5 x 10(-6)-10(-5) M), an NEP inhibitor, enhanced fibroblast proliferation in a dose-dependent manner. Thus neuropeptides have the potential to cause activation of mesenchymal cells, and neuropeptide release may contribute to the structural abnormalities observed in asthmatic airways.

No abstract is provided for this article.

The emergence of additive manufacture (AM) for metallic material enables components of near arbitrary complexity to be produced. This has potential to disrupt traditional engineering approaches. However, metallic AM components exhibit greater levels of variation in their geometric and mechanical properties compared to standard components, which is not yet well understood. This uncertainty poses a fundamental barrier to potential users of the material, since extensive post-manufacture testing is currently required to ensure safety standards are met. Taking an interdisciplinary approach that combines probabilistic mechanics and uncertainty quantification, we demonstrate that intrinsic variation in AM steel can be well described by a generative statistical model that enables the quality of a design to be predicted before manufacture. Specifically, the geometric variation in the material can be described by an anisotropic spatial random field with oscillatory covariance structure, and the mechanical behaviour by a stochastic anisotropic elasto-plastic material model. The fitted generative model is validated on a held-out experimental dataset and our results underscore the need to combine both statistical and physics-based modelling in the characterization of new AM steel products.

It has been suggested that cysteinyl leukotrienes (cysLTs) play an important role in airway remodeling. Previous reports have indicated that cysLTs augment human airway smooth muscle cell proliferation. Recently, cysLTs have been measured in exhaled breath condensate (EBC). The aim of this study was to evaluate the relationship between cysLTs in EBC and another marker of airway remodeling, reticular basement membrane (RBM) thickening, in endobronchial biopsies in children.29 children, aged 4-15 years, with moderate to severe persistent asthma, who underwent bronchoscopy as part of their clinical assessment, were included. Subjects underwent spirometry and EBC collection for cysLTs analysis, followed by bronchoscopy and endobronchial biopsy within 24 hours.EBC cysLTs were significantly lower in asthmatic children who were treated with montelukast than in those who were not (median (interquartile range) 36.62 (22.60-101.05) versus 249.1 (74.21-526.36) pg/ml, p = 0.004). There was a significant relationship between EBC cysLTs and RBM thickness in the subgroup of children who were not treated with montelukast (n = 13, r = 0.75, p = 0.003).EBC cysLTs appear to be associated with RBM thickening in asthma.

Glucocorticoids are the most effective antiinflammatory agents for the treatment of chronic inflammatory diseases even though some diseases, such as chronic obstructive pulmonary disease (COPD), are relatively glucocorticoid insensitive. However, the molecular mechanism of this glucocorticoid insensitivity remains uncertain. We show that a defect of glucocorticoid receptor (GR) deacetylation caused by impaired histone deacetylase (HDAC) 2 induces glucocorticoid insensitivity toward nuclear factor (NF)-κB–mediated gene expression. Specific knockdown of HDAC2 by RNA interference resulted in reduced sensitivity to dexamethasone suppression of interleukin 1β–induced granulocyte/macrophage colony-stimulating factor production. Loss of HDAC2 did not reduce GR nuclear translocation, GR binding to glucocorticoid response element (GRE) on DNA, or GR-induced DNA or gene induction but inhibited the association between GR and NF-κB. GR becomes acetylated after ligand binding, and HDAC2-mediated GR deacetylation enables GR binding to the NF-κB complex. Site-directed mutagenesis of K494 and K495 reduced GR acetylation, and the ability to repress NF-κB–dependent gene expression becomes insensitive to histone deacetylase inhibition. In conclusion, we show that overexpression of HDAC2 in glucocorticoid-insensitive alveolar macrophages from patients with COPD is able to restore glucocorticoid sensitivity. Thus, reduction of HDAC2 plays a critical role in glucocorticoid insensitivity in repressing NF-κB–mediated, but not GRE-mediated, gene expression.