Publications

Bronchial antigen challenge of sensitized atopic patients with asthma results in an early fall in FEV1, followed in a proportion of patients by a late (4 to 24 hours) fall. The late response is accompanied by an increase in bronchial reactivity, which is widely believed to reflect local influx and degranulation of inflammatory cells, particularly eosinophils, in association with elevated local secretion of cytokines. We hypothesized that the development of a late-phase bronchoconstrictor response and airway eosinophilia after allergen challenge of sensitized atopic patients with asthma is associated with elevated induced sputum concentrations of the eosinophil-active cytokines IL-5 and granulocyte-macrophage colony-stimulating factor and the proinflammatory cytokine tumor necrosis factor-alpha. We counted inflammatory leukocytes and measured cytokine concentrations in induced sputum at baseline and 24 hours after inhalational allergen challenge of 15 atopic patients with asthma who had previously demonstrated a late response. We observed significant increases in the numbers of eosinophils and the concentrations of their granule products, eosinophil cationic protein and eosinophil peroxidase. In contrast, the numbers of neutrophils and concentrations of two of their products, myeloperoxidase and human neutrophil lipocalin, did not significantly change. The numbers of sputum eosinophils correlated with the maximal late-phase fall in FEV1. Concentrations of IL-5 and tumor necrosis factor-alpha, but not granulocyte-macrophage colony-stimulating factor, were significantly elevated after allergen challenge. We conclude that the relatively noninvasive technique of induced sputum production can be used to monitor the effect of bronchial provocation on cytokine concentrations in asthma.

The appropriate modelling of initial imperfections, in terms of both amplitude and shape/direction, is a key challenge in the design of structures by geometrically and materially nonlinear analysis with imperfections (GMNIA). While recent research has addressed the amplitude aspect of imperfection modelling, there remains a lack of clear guidance for determining the appropriate imperfection shape. This is tackled herein through the establishment of comprehensive rules for introducing global sway and member bow imperfections in the in-plane stability design of steel frames. The proposed rules cover the two most commonly used imperfection definition approaches – the direct definition (DD) method and the elastic buckling mode (EBM) method. In the DD method recommended herein, the directions of global sway and member bow imperfections are introduced following a set of prescribed rules. Two EBM methods are recommended. In the first EBM method, the ultimate capacity is taken as the lowest among n values obtained by considering the first n buckling modes as imperfection shapes individually, with n = 6 recommended. In the second EBM method, the bow and sway components of the imperfection shape are determined separately from different LBA in which loads are applied on the key load paths. The bow components are established by combining the first buckling mode for each key vertical and horizontal load path, while the sway component is based on the first mode – provided it is a sway mode – obtained from an LBA considering the maximum gravity load case. The consequences of using no imperfections are also explored. The accuracy of the proposed methods is verified based on a series of moment frames and braced frames considering both regular and irregular configurations.

Objectives The aim of this study was to assess whether residual nonculprit (NC) lesions, defined as visual diameter stenosis ≥30% after successful percutaneous coronary intervention, affect the rate of future events in patients with acute coronary syndromes. Background In patients with acute coronary syndromes, approximately one-half of recurrent events after percutaneous coronary intervention arise from untreated lesions. Methods Patients enrolled in PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) were divided into 3 groups: those with no NC lesions, 1 NC lesion, or ≥2 NC lesions. Time to events for major adverse cardiac events was estimated up to 3 years. Results Among 697 patients, 13.3% had no NC lesions, 19.7% had 1 NC lesion, and 67.0% had ≥2 NC lesions. The median diameter stenoses of the NC lesions in the latter 2 groups were 36.7% (interquartile range: 31.0% to 43.4%) and 37.4% (interquartile range: 32.0% to 46.5%), respectively (p = 0.22). At least 1 thin-cap fibroatheroma was present in one-half the patients in each group. At 3 years, the incidence of major adverse cardiac events was 8.5%, 15.2%, and 24.3%, respectively (p = 0.0009). NC lesion–related events occurred in 0%, 5.0%, and 15.9% of patients, respectively (p < 0.0001). Of 105 NC lesion–related clinical events occurring during follow-up, 73 (69.5%) originated from angiographically evident baseline NC lesions (of which 36 had diameter stenosis >50%), while the other 32 arose from normal or near normal segments. Conclusions Residual NC lesions are common after percutaneous coronary intervention for acute coronary syndromes and portend a higher rate of recurrent ischemic events within 3 years, especially when angiographically more severe. Conversely, the absence of NC lesions by angiography is highly predictive of freedom from events not related to the originally treated culprit lesion(s).

No abstract is provided for this article.

Background — Intravascular ultrasound elastography assesses the local strain of the atherosclerotic vessel wall. In the present study, the potential to identify different plaque components in vivo was investigated. Methods and Results — Atherosclerotic external iliac and femoral arteries (n=24) of 6 Yucatan pigs were investigated. Before termination, elastographic data were acquired with a 20-MHz Visions catheter. Two frames acquired at end-diastole with a pressure differential of ≈4 mm Hg were acquired to obtain the elastograms. Before dissection, x-ray was used to identify the arterial segments that had been investigated by ultrasound. Specimens were stained for collagen, fat, and macrophages. Plaques were classified as absent, early fibrous lesion, early fatty lesion, or advanced fibrous plaque. The average strains in the plaque-free arterial wall (0.21%) and the early (0.24%) and advanced fibrous plaques (0.22%) were similar. Higher average strain values were observed in fatty lesions (0.46%) compared with fibrous plaques ( P =0.007). After correction for confounding by lipid content, no additional differences in average strain were found between plaques with and without macrophages ( P =0.966). Receiver operating characteristic analysis revealed a sensitivity and a specificity of 100% and 80%, respectively, to identify fatty plaques. The presence of a high-strain spot (strain &gt;1%) has 92% sensitivity and 92% specificity to identify macrophages. Conclusions — To the best of our knowledge, this is the first time that intravascular ultrasound elastography has been validated in vivo. Fatty plaques have an increased mean strain value. High-strain spots are associated with the presence of macrophages.

The main objective of the present randomized pilot study was to explore the effects of upstream prasugrel or ticagrelor or clopidogrel for patients with ST-segment-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI).Administration of clopidogrel "as soon as possible" has been advocated for STEMI. Pretreatment with prasugrel and ticagrelor may improve reperfusion. Currently, the angiographic effects of upstream administration of these agents are poorly understood.A total of 132 patients with STEMI within the first 12 hr of chest pain referred to primary angioplasty were randomized to upstream clopidogrel (600 mg), prasugrel (60 mg), or ticagrelor (180 mg) while still in the emergency room. All patients underwent protocol-mandated thrombus aspiration.Macroscopic thrombus material was retrieved in 79.5% of the clopidogrel group, 65.9% of the prasugrel group, and 54.3% of the ticagrelor group (P = 0.041). At baseline angiography, large thrombus burden was 97.7% vs. 87.8% vs. 80.4% in the clopidogrel, prasugrel, and ticagrelor groups, respectively (P = 0.036). Also, at baseline, 97.7% presented with an occluded target vessel in the clopidogrel group, 87.8% in the prasugrel group and 78.3% in the ticagrelor group (P = 0.019). At the end of the procedure, the percentages of patients with combined TIMI grade III flow and myocardial blush grade III were 52.3% for clopidogrel, 80.5% for prasugrel, and 67.4% for ticagrelor (P = 0.022).In patients with STEMI undergoing primary PCI within 12 hr, upstream clopidogrel, prasugrel or ticagrelor have varying angiographic findings, with a trend toward better results for the latter two agents. © 2015 Wiley Periodicals, Inc.

Corticosteroid insensitivity is a major therapeutic problem for some inflammatory diseases including chronic obstructive pulmonary disease (COPD), and it is known to be induced by reduced histone deacetylase (HDAC)-2 activities via activation of the phosphoinositide 3-kinase (PI3K) pathway. The aim of this study is to evaluate effects of a novel macrolide/fluoroketolide, solithromycin (SOL, CEM-101), on corticosteroid sensitivity induced by oxidative stress.Corticosteroid sensitivity was determined by IC50/EC50 of dexamethasone (Dex) on TNF-α-induced CXCL8 production in U937 monocytic cell line and peripheral blood mononuclear cells (PBMC) from COPD patients. Activities of HDAC and protein phosphatase 2A (PP2A) were measured by fluorescence-based assay in cells exposed to hydrogen peroxide (H2O2). We also investigated steroid insensitive airway neutrophilia in cigarette smoke exposed mice in vivo.SOL (10 μM) restored Dex sensitivity in PBMC from COPD patients, H2O2-treated U937 cells and phorbol 12-myristate 13-acetate-differentiated U937 cells. In addition, SOL restored HDAC activity with concomitant inhibition of Akt phosphorylation as surrogate marker of PI3K activation. The inhibition of Akt phosphorylation by SOL was due to increased PP2A phosphatase activity, which was reduced in COPD and oxidative stress model. Other known macrolides, such as eryhthromycin, clarithromycin and azithromycin, were significantly less effective in these responses. In cigarette smoke-exposed mice, SOL (100 mg kg(-1), po) showed significant but weak inhibition of neutrophilia, whereas Dex (10 mg kg(-1), p.o.) showed no such effect. However, a combination of SOL and Dex inhibited neutrophilia by over 50%.SOL has potential as novel therapy for corticosteroid-insensitive diseases such as COPD.

No abstract is provided for this article.

OBJECTIVES This study was performed to assess whether angiography six months after coronary balloon angioplasty or stent implantation has an influence on clinical management and one-year outcome. BACKGROUND The Benestent II study randomized 827 patients to balloon angioplasty or stent implantation. A subrandomization was undertaken allocating patients to six-month clinical follow-up (CF) or clinical and angiographic follow-up (AF). METHODS Seven hundred and six patients (349 CF and 357 AF) had no intercurrent angiography, so that restenosis and disease progression elsewhere remained unknown until the time of six-month follow-up. These two groups, which were well matched at enrolment, were compared with respect to symptoms, medication and major cardiac events defined as death, myocardial infarction and need for revascularization at six and 12 months. RESULTS At six-month follow-up, 53 (15%) of the CF and 76 (21%) of the AF patients had stable angina (p = 0.041), while 5 (1%) and 4 (1%) had symptoms of unstable angina. At 12-month follow-up, 44 (13%) patients in both groups had stable angina, and only 1 patient in the CF group had unstable angina. Seventy-seven patients (27 CF and 50 AF; p < 0.01) had major cardiac events between 6 and 12 months. Of the 349 patients in the CF group, 21 underwent repeat percutaneous transluminal coronary angioplasty or coronary artery bypass graft surgery between 6 and 12 months, compared with 44 of the 357 patients in the AF group (relative risk 2.05 [1.24 to 3.37], p = 0.003). CONCLUSIONS Patients who had AF six months after balloon angioplasty or stent implantation experienced more repeat revascularization procedures than those who had CF. They also had significantly more angina at six-month follow-up but this may be due to bias.