Publications

Therapeutic approaches to asthma–chronic obstructive pulmonary disease overlap syndromes

Ezrin, a Membrane Cytoskeleton Cross-Linker Protein, as a Marker of Epithelial Damage in Asthma

Bronchial epithelial cell damage occurs in patients with bronchial asthma. Ezrin, a membrane-cytoskeleton protein, maintains cellular morphology and intercellular adhesion and protects the barrier function of epithelial cells.To study the role of ezrin in bronchial epithelial cells injury and correlate its expression with asthma severity.Levels of ezrin were measured in exhaled breath condensate (EBC) and serum in patients with asthma and BAL fluid (BALF) from a mouse model of asthma by ELISA. The regulation of IL-13 on ezrin protein levels was studied in primary bronchial epithelial cells. Ezrin knockdown using shRNA was studied in human bronchial epithelial 16HBE cells.Ezrin levels were decreased in asthmatic EBC (92.7 ± 34.99 vs. 150.5 ± 10.22 pg/ml, P < 0.0001) and serum (700.7 ± 55.59 vs. 279.2 ± 25.83 pg/ml, P < 0.0001) compared with normal subjects. Levels were much lower in uncontrolled (P < 0.001) and partly controlled patients (P < 0.01) compared with well-controlled subjects. EBC and serum ezrin levels correlated with lung function in patients with asthma and serum ezrin levels were negatively correlated with serum IL-13 and periostin. IL-13-induced downregulation of ezrin expression in primary bronchial epithelial cells was significantly attenuated by the Janus tyrosine kinase 2 inhibitor, TG101348. Ezrin knockdown changed 16HBE cell morphology, enlarged intercellular spaces, and increased their permeability. Ezrin expression was decreased in the lung tissue and BALF of "asthmatic" mice and negatively correlated with BALF IL-13 level.Ezrin downregulation is associated with IL-13-induced epithelial damage and might be a potential biomarker of asthma control.

Stability Design of Stainless Steel Structures

The direct analysis method (DAM), featuring second-order elastic analysis with two stiffness reduction factors (τb and τg), is the primary means of stability design for steel structures in AISC 360 and AISI S100. The equivalent provisions for stainless steel structures, which are due to be incorporated into the upcoming AISC 370 and ASCE-8 specifications, are developed in this paper. Stainless steel exhibits a rounded stress–strain response, typically described by the Ramberg–Osgood formulation. The slope of this function (i.e., the tangent modulus), adjusted to consider the influence of residual stresses, is used to define the stiffness reduction factor τb at a given axial load level to be applied to members in compression to allow for the adverse influence of the spread of plasticity and residual stresses. The dependency of the degree of stiffness reduction on the roundedness of the stress–strain curve, which varies between the different grades of stainless steel is also directly captured through the strain hardening exponent n that features in the Ramberg–Osgood formulation. Values of 0.7 for AISC 370 and 0.9 for ASCE-8 are proposed for the general stiffness reduction factor τg to be applied to all member stiffnesses to account for the development and spread of plasticity, and to ensure a suitable reduction in stiffness for slender members with low axial load levels. The different τg values between the two specifications are required to reflect the different buckling curves and axial-bending interaction expressions employed. The accuracy of the proposed method for the design of stainless steel members and frames is assessed through comparisons with benchmark shell finite-element results. Comparisons are also made against the new provisions in AISC 370 for design by second-order inelastic analysis. The reliability of the design proposals is demonstrated through statistical analyses, where it is shown that a resistance factor ϕ of 0.9 can be adopted.

Does an occluded RCA affect prognosis in patients undergoing PCI or CABG for left main coronary artery disease? Analysis from the EXCEL trial

The impact of an occluded right coronary artery (RCA) in patients with left main coronary artery disease (LMCAD) undergoing revascularisation is unknown. We compared outcomes for patients with LMCAD randomised to percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) according to the presence of an occluded RCA in the EXCEL trial.The EXCEL trial randomised 1,905 patients with LMCAD and SYNTAX scores ≤32 to PCI with everolimus-eluting stents versus CABG. Patients were categorised according to whether they had an occluded RCA at baseline, and their outcomes were examined using multivariable Cox proportional hazards regression. The primary endpoint was a composite of death, stroke, or myocardial infarction at three years. Among 1,753 patients with a dominant RCA by core laboratory analysis, the RCA was occluded in 130 (7.4%) at baseline. PCI was attempted in 34 of 65 patients with an occluded RCA (52.3%) and was successful in 27 (79.4% of those attempted; 41.5% of all RCAs recanalised). The RCA was bypassed in 42 of 65 patients with an occluded RCA (64.6%; p=0.0008 versus PCI). The three-year absolute and relative rates of the primary endpoint were similar between PCI and CABG, in patients with or without an occluded RCA (pinteraction=0.92).In the EXCEL trial, the presence of an occluded RCA at baseline did not confer a worse three-year prognosis in patients undergoing revascularisation for LMCAD and did not affect the relative outcomes of PCI versus CABG in this high-risk patient cohort.

Compressive Behaviour of Concrete-filled Elliptical Hollow Sections

Chronic mucosal inflammation

State of the art: role of intravascular imaging in the evolution of percutaneous coronary intervention – a 30-year review

It has been 40 years since percutaneous coronary intervention (PCI) was introduced into the clinical setting. Over these years significant advances in device technology and the invention of new therapeutic strategies have broadened its applications in the clinical arena, rendering this treatment the first-line therapy for patients with obstructive coronary artery disease. The evolution of PCI would not have been possible without intravascular imaging which provided unique insights about coronary artery pathology, enabled evaluation of vessel wall response following PCI and allowed meticulous evaluation of the advantages and limitations of emerging devices. This review article appraises the role of intravascular imaging in the evolution of PCI, summarises the findings of invasive imaging studies that examined the efficacy of new therapies and endovascular devices, presents the evidence that supports its use in current clinical practice and discusses its future potential in PCI.

Proliferation and matrix protein synthesis of human coronary smooth muscle cells in culture

No abstract is provided for this article.

Randomized Trials of Coronary Stenting

No abstract is provided for this article.

“Haemoxygenase-1 induction and exhaled markers of oxidative stress in lung diseases”, summary of the ERS Research Seminar in Budapest, Hungary, September, 1999

In recent years, there has been increasing interest in noninvasive monitoring of airway inflammation and oxidative stress. Several volatile and nonvolatile substances can be measured in exhaled breath and have been suggested as potential biomarkers of these events. Exhaled gases, including carbon monoxide (CO), alkanes (ethane, pentane), and substances measured in breath condensate, such as hydrogen peroxide (H 2 O 2 ) and isoprostanes were all suggested as potential markers of oxidative stress in the lung. A European Respiratory Society (ERS) International Research Seminar entitled “Haemoxygenase-1 induction and exhaled markers of oxidative stress in lung diseases” was organized by the Airway Regulation and Provocation Group of the Clinical Allergy and Immunology Assembly in Budapest, Hungary in September, 1999 to integrate the latest knowledge on these issues and accelerate further improvement in this area. During this 2-day event several issues were raised about: the use and standardization of measurements in exhaled breath; problems of measuring expired H 2 O 2 and other mediators in breath condensate; role and regulation of haemoxygenase (HO)-1 in the lung; and conditions and factors influencing exhaled CO. This report is a summary of the main presentations at the seminar, together with the current areas of research in this rapidly expanding field.

Two‐dimensional quantitative coronary angiographic models for bifurcation segmental analysis

Quantitative coronary angiography (QCA) analysis for bifurcation lesions needs to be standardized.In vitro validation of two models for bifurcation QCA segmental analysis.In the latest edition of the Cardiovascular angiography analysis system (CAAS 5v8, Pie Medical Imaging, Maastricht, The Netherlands) a 6-segment model for two-dimensional coronary bifurcation analysis was implemented next to the currently available 11-segment model. Both models were validated against 6 precision manufactured plexiglas phantoms, each of them mimicking a vessel with three successive bifurcation lesions with variable anatomy and Medina class. The phantoms were filled with 100% contrast agent and imaged with a biplane gantry. Images acquired in antero-posterior (AP) direction by either C-arm and at 30° right and left anterior oblique angulation were analyzed by two independent analysts, blinded to the actual dimensions. Manual correction of the contours was not allowed. Measurements for minimal lumen diameter (MLD), reference vessel diameter (RVD), percent diameter stenosis (DS) and bifurcation angle (BA) were compared with the true phantom dimensions.In AP views the accuracy and precision (mean difference ± SD) of 11- and 6-segment model for MLD, RVD, and DS were 0.065 ± 0.128 mm vs. 0.058 ± 0.142 mm, -0.021 ± 0.032 mm vs. -0.022 ± 0.030 mm, and -2.45% ± 5.07% vs. -2.28% ± 5.29%, respectively. Phantom MLD values ≤ 0.7 mm were systematically overestimated; if excluded, MLD accuracy and precision became 0.015 ± 0.106 mm and 0.004 ± 0.125 mm for the 11- and 6-segment model, respectively. Accuracy and precision for BA were -2.2° ± 3.3°. Interobserver variability for MLD, RVD, DS, and BA for either model was ≤ 0.049 mm, ≤ 0.056 mm, ≤ 2.77%, and 1.6°, respectively. Agreement between models for MLD, RVD, and DS was ± 0.079 mm, ± 0.011 mm, and ± 2.07%. Accuracy and precision for diameter-derived parameters were slightly decreased in angulated projections; precision for BA measurements dropped to 6.1°.The results of both models are highly reproducible and for phantom MLD values >0.7 mm in excellent agreement with the true dimensions.

Nitric oxide as a neurotransmitter in human airways.

Human airway smooth muscle possesses a prominent nonadrenergic noncholinergic (i-NANC) bronchodilator response. Nitric oxide (NO) appears to account for all the i-NANC response in human central and peripheral airways in vitro. Furthermore, it appears that i-NANC relaxations in human trachea are associated with a concomitant selective elevation of cGMP, but not cAMP levels, which are inhibited by an NO synthase (NOS) inhibitor. This confirms the hypothesis that the L-arginine/NO/cGMP pathway is responsible for mediating the i-NANC response in this tissue. It is not certain from where the NO is formed or the location of the NOS enzyme. However, in human trachea, NOS immunoreactivity (NOS-IR) has been described in nerve fibres originating from intrinsic neurons. In addition, the density of NOS-IR is reduced from proximal to distal airways and this correlates with functional data describing a reduced i-NANC relaxation response from central to peripheral airways. The i-NANC bronchodilator nerves are the only neural relaxant pathway in human airways and, therefore, it is important to determine whether there is any defect in the ability of these nerves to function in diseased airways. In fact, functional and immunohistochemical data suggest that there may be a deficiency in NOS-IR nerves leading to a decreased i-NANC response in tissue from patients with cystic fibrosis. NOS inhibitors appear to enhance the cholinergic bronchoconstriction in human airways in vitro. Therefore, if the nitrergic innervation is dysfunctional in inflammatory conditions, its absence may lead to exaggerated bronchoconstriction.

Pressure-mediated versus pharmacologic treatment of radial artery spasm during cardiac catheterisation: a randomised pilot study

The aim of the study was to determine the effectiveness of a novel strategy to treat radial artery spasm (RAS).We conducted a prospective, randomised, single-centre, open-label trial comparing a novel strategy of pressure-mediated dilatation versus intra-arterial administration of a combination of nitroglycerine plus verapamil for the treatment of RAS. The primary endpoint was radial artery intraluminal diameter acute gain assessed by quantitative radial angiography. After screening two hundred and twenty consecutive cases, twenty patients presented with RAS and were randomised 1:1 to either strategy. Overall the mean age was 60.8±11.5 years and 53% were females. Pre-treatment angiographic characteristics were similar between the groups. The primary endpoint of radial artery acute gain was significantly greater in the pressure-mediated dilatation group (0.85±0.46 mm vs. 0.03±0.24 mm, p<0.001). Blood pressure drop was significantly lower in the pressure-mediated dilatation group (ΔBP -3.8±24 vs. -31.6±19 mmHg, p<0.001). There was one case of radial artery occlusion in the pressure-mediated dilatation group at follow-up. Short-duration pain was observed during the application of pressure.Pressure-mediated dilatation for the treatment of RAS was feasible, with superior angiographic results compared to a pharmacologic vasodilator strategy, with no impact on blood pressure. This novel approach proved to be safe and effective and should be tested in a large randomised trial.

‘Outside‐in’ signalling mechanisms underlying CD11b/CD18‐mediated NADPH oxidase activation in human adherent blood eosinophils

Incubation of human eosinophils in BSA‐coated tissue culture plates resulted in time‐dependent adhesion and attendant activation of the NADPH oxidase that were both inhibited (by &gt;85%) by blocking antibodies raised against CD11b and CD18. SB 203580, an inhibitor of p38 mitogen‐activated protein (MAP) kinase, did not influence adhesion but inhibited superoxide anion generation (pIC 50 =−6.57). PP1, an inhibitor of the src‐family of protein tyrosine kinases, inhibited adhesion and CD11b/CD18‐mediated superoxide anion generation with similar potencies (pEC 50 s=−5.53 and −5.99 respectively) suggesting that inhibition of the NADPH oxidase was a direct consequence of blocking adhesion. The protein kinase C (PKC) inhibitors Ro‐31 8220 (broad spectrum inhibitor), GF 109203X (inhibitor of conventional and novel isoforms) and Gö 6976 (inhibitor of conventional isoforms) suppressed adhesion‐dependent NADPH oxidase activation (pIC 50 s=−6.61, −6.05 and −4.89 respectively) without affecting adhesion. Based upon the selectivity of these drugs PKCδ and PKCε are implicated in the suppression of oxidant production. Wortmannin, an inhibitor of phosphatidylinositol 3‐kinase (PtdIns 3‐kinase), abolished superoxide anion production in adherent eosinophils (pEC 50 =−9.06). Similarly, CD11b/CD18‐dependent adhesion was suppressed with the same potency (pEC 50 =−9.29) although the maximum effect did not exceed 50% implying that wortmannin also had an affect on those processes that govern adhesion‐driven oxidase activation. PD 098059 and piceatannol, inhibitors of MAP kinase kinase‐1 and the syk tyrosine kinase respectively, had no effect on CD11b/CD18‐mediated adhesion or NADPH oxidase activation. The results of this study demonstrate that human eosinophils adhere to BSA‐coated plastic by a CD11b/CD18‐dependent mechanism, which is responsible for activation of the NADPH oxidase. Although the signalling pathway(s) utilized by CD11b/CD18 is still to be elucidated, the data presented herein implicate p38 MAP kinase, novel PKCs and PtdIns 3‐kinase. British Journal of Pharmacology (1999) 128 , 1149–1158; doi: 10.1038/sj.bjp.0702892

Multislice Computed Tomography Angiography for Noninvasive Assessment of the 18-Month Performance of a Novel Radiolucent Bioresorbable Vascular Scaffolding Device

No abstract is provided for this article.

A Review of Optimised Additively Manufactured Steel Connections for Modular Building Systems

Aerosolized Antibiotics

No abstract is provided for this article.

Influence of plaque composition on mechanisms of percutaneous transluminal coronary balloon angioplasty assessed by ultrasound imaging

In this study the influence of plaque composition on mechanism of immediate lumen enlargement after PTCA were assessed by serial ultrasound imaging in 77 patients. According to the preprocedural ultrasonic plaque characteristics, the lesions were classified as soft (54.5%), diffusely calcified (14.3%), and mixed (31.2%). The total arc of calcium and plaque eccentricity were also calculated. The mean balloon/artery ratio was equal for all types of lesions (1.07 ± 0.19), but diffusely calcified lesions required a higher maximal balloon inflation pressure (11.3 ± 3.75 atm vs 9.0 ± 3.15 atm for calcified and soft lesions, respectively, p < 0.05). The increase in lumen area after PTCA was similar in soft and mixed lesions (3.49 ± 1.61 mm2 vs 3.56 ± 1.58 mm2, NS) and was slightly lower in diffusely calcified lesions (2.97 ± 1.33 mm2, NS). Reduction in plaque area was the main operative mechanism in lesions with soft plaque, explaining 77.9% of the acute lumen gain. Expansion of the total vessel area was the predominant mechanism of lumen area increase in lesions with calcified and mixed plaques (99.1% vs 74.2%, respectively, NS). In particular, lesions with a total arc of calcium >90 degrees showed a high prevalence of vessel expansion as a mechanism of lumen enlargement compared with lesions with a calcium arc <90° (79.3% vs 23.8%, respectively, p < 0.05). In the studied group, presence of calcification was highly associated with wall fracture and dissection after balloon dilatation (93.4% vs 6.6% in lesions with and without calcifications, respectively, p < 0.05). A trend toward a greater degree of plaque reduction in concentric lesions in comparison to eccentric lesions was observed (58.3% vs 48.5%, respectively, NS). In conclusion, immediate lumen enlargement after PTCA does not differ for soft and mixed plaques. Diffusely calcific plaques show a smaller lumen enlargement despite a higher balloon inflation pressure. Plaque compression or axial redistribution is the main operative mechanism of PTCA in soft plaques, whereas an increase in total vessel area determines the lumen enlargement in mixed/calcific plaques. Plaque fracture or wall dissection is almost invariably associated with presence of plaque calcification.