No abstract is provided for this article.
No abstract is provided for this article.
Rationale: The treatment effect of golimumab, a human monoclonal antibody against tumor necrosis factor (TNF)-α, in severe persistent asthma is unknown.Objectives: To assess the safety and efficacy of golimumab in a large population of patients with uncontrolled, severe persistent asthma.Methods: From 2004 to 2006, 309 patients with severe and uncontrolled asthma, despite high-dose inhaled corticosteroids and long-acting β2 agonists, were randomized 1:1:1:1 to monthly subcutaneous injections of placebo or golimumab (50, 100, or 200 mg) through Week 52. Coprimary endpoints were the change from baseline through Week 24 in prebronchodilator percent-predicted FEV1 and the number of severe asthma exacerbations through Week 24.Measurements and Main Results: No significant differences were observed for the change in percent-predicted FEV1 (least squares mean: placebo, 2.44 [95% confidence interval (CI) −0.574 to 5.461]; combined 100-mg and 200-mg, 2.91 [0.696–5.116]) or severe exacerbations (mean ± SD: placebo, 0.5 ± 1.07 vs. combined 100-mg and 200-mg 0.5 ± 0.97) through week 24. Through Week 24, 2.6% of patients treated with placebo vs. 19.5% of those treated with golimumab discontinued the study agent, and 1.3% and 7.8% discontinued study participation, respectively. An unfavorable risk–benefit profile led to early discontinuation of study-agent administration after the Week-24 database lock. Through Week 76, 20.5% of patients treated with placebo and 30.3% of patients treated with golimumab experienced serious adverse events, with serious infections occurring more frequently in golimumab-treated patients. One death and all eight malignancies occurred in the active groups.Conclusions: Overall, treatment with golimumab did not demonstrate a favorable risk–benefit profile in this study population of patients with severe persistent asthma.Clinical trial registered with www.clinicaltrials.gov (NCT00207740).
Lyso-platelet-activating factor (PAF), the precursor and metabolite of PAF, is considered inactive, although it may be converted to PAF by airway cells. We have investigated the effects of inhaled lyso-PAF on bronchoconstriction and airway microvascular leakage in anesthetized guinea pigs. Lung resistance (RL) was measured for 6 min after inhalation of lyso-PAF (0.3, 1, and 3 mM; 30 breaths) followed by measurement of extravasation of intravenous Evans blue dye into airway tissues, which was used as an index of airway microvascular leakage. Inhaled lyso-PAF caused an increase in RL and leakage of dye at all airway levels in a dose-dependent fashion, but intravenous lyso-PAF (0.25 mg/kg) had no airway effect. The maximum dose of inhaled lyso-PAF increased RL significantly by approximately 200%. The amount of extravasation of dye induced was 96 +/- 4 (SE) ng/mg of tissue in trachea, 77 +/- 8 ng/mg in main bronchi, and 65 +/- 7 and 25 +/- 1 ng/mg in proximal and distal intrapulmonary airways respectively; these values were all significantly higher (P < 0.01) than control values. These responses were completely abolished by a specific PAF-receptor antagonist WEB-2086 (2 mg/kg iv). Our results show that inhaled lyso-PAF is potent in increasing airway microvascular leakage. The effects of lyso-PAF may result from its metabolic transformation to PAF by lyso-PAF:acetyl-CoA acetyltransferase in the airway.
To determine the safety and effectiveness of CYPHER(R) sirolimus-eluting stent implantation in patients with multivessel disease; and to compare outcomes against the historical results of the two arms of the Arterial Revascularisation Therapies Study (ARTS I).ARTS II is a 45 center, 607 patient single arm trial; the1-year outcomes were compared to the historical controls of the ARTS I trial, using conventional and Bayesian statistical methods. Patients were stratified by clinical site to ensure that at least one-third had 3-vessel disease to achieve the number of treatable lesions per patient comparable to ARTS I. Multivessel stenting was performed with sirolimus-eluting stents according to local institutional practice with the goal of achieving complete revascularisation. The majority of patients (53.5%) had 3-vessel disease and diabetes was present in 26.2%. Mean stented length was 72.5mm, with 3.7 stents implanted per patient. The 1-year survival rate was 99.0%, the composite of death / stroke and MI-free survival was 96.9%, freedom from revascularisation was 91.5% and the composite endpoint of MACCE-free survival was 89.5% (the primary endpoint). Diabetic patients treated with sirolimus-eluting stents were more likely to undergo repeat revascularisation (RR 1.97, 95% CI 1.16 - 3.34) and experience a MACCE (RR 1.85, 95% CI 1.16 - 2.97) than non-diabetics at 1-year. In the unadjusted comparison with the historical control arms of ARTS-I-CABG and ARTS-I-PCI, the respective relative risks (RR) and associated 95% confidence intervals (CI) for the endpoints were: (1) freedom from repeat revascularisation RR 2.03 (1.23-3.34) and RR 0.44 (0.31-0.61) respectively; and (2) MACCE free survival RR 0.89 (0.65-1.23) and RR 0.39 (0.30-0.51) respectively.The low incidence of MACCE and repeat revascularisation in ARTS II suggests that contemporary PCI with sirolimus-eluting stents is safe and efficacious for the treatment of multivessel coronary artery disease. Compared to the historical population of ARTS I, surgery still afforded a lower need for repeat revascularisation although overall MACCE rates in ARTS II approached the surgical results and were significantly better than bare stenting in ARTS I.
The diagnostic performance of the SYNTAX score 2020 (SS-2020) when calculated using CCTA remains unknown. This study aimed to compare treatment recommendations based on the SS-2020 derived from coronary computed tomography angiography (CCTA) versus invasive coronary angiography (ICA). This interim analysis included 57 of the planned 114 patients with de-novo three-vessel disease, with or without left main coronary artery disease, enrolled in the ongoing FASTTRACK CABG trial. The anatomical SYNTAX scores derived from ICA or CCTA were evaluated by two separate teams of blinded core-lab analysts. Treatment recommendations were based on a maximal individual absolute risk difference in all-cause mortality between percutaneous coronary intervention (PCI) and coronary artery bypass graft (CABG) of 4.5% ([predicted PCI mortality] – [predicted CABG mortality]). The level of agreement was evaluated with Bland–Altman plots and Cohen’s Kappa. The mean age was 66.2 ± 9.2 years and 89.5% of patients were male. Mean anatomical SYNTAX scores derived from ICA and CCTA were 35.1 ± 11.5 and 35.6 ± 11.4 (p = 0.751), respectively. The Bland–Altman analysis showed mean differences of − 0.26 and − 0.93, with standard deviation of 3.69 and 5.23, for 5- and 10-year all-cause mortality, respectively. The concordance in recommended treatment for 5- and 10-year mortalities were 84.2% (48/57 patients) and 80.7% (46/57 patients), with Cohen’s κ coefficients of 0.672 and 0.551. There was moderate to substantial agreement between treatment recommendations based on the SS-2020 derived using CCTA and ICA, suggesting that CCTA could be used as an alternative to ICA when making decisions regarding the modality of revascularization.
Aging increases susceptibility to infection, in part because thymic involution culminates in reduced naïve T-lymphocyte output. Thymic epithelial cells (TECs) are critical to ensure normal maturation of thymocytes and production of peripheral T cells. The forkhead-class transcription factor, encoded by FoxN1, regulates development, differentiation, and function of TECs, both in the prenatal and postnatal thymus. We recently showed that expression of FoxN1, by keratin 14 (K14)-expressing epithelial cells is essential for maintenance of thymic medullary architecture, and deletion of FoxN1 in K14 promoter-driven TECs inhibited development of mature TECs and reduced the number of total thymocytes. These findings are reminiscent of changes observed during normal thymic aging. In the current report, we compared the effects of K14-driven FoxN1 deletion on peripheral T cell function in response to influenza virus infection with those associated with normal aging in a mouse model. FoxN1-deleted mice had reduced numbers of peripheral CD62L+CD44− naïve T-cells. In addition, during influenza infection, these animals had reduced antigen-specific CD8+ T-cell and IgG responses to influenza virus, combined with increased lung injury, weight loss and mortality. These findings paralleled those observed in aged wild type mice, providing the first evidence that K14-mediated FoxN1 deletion causes changes in T-cell function that mimic those in aging during an immune response to challenge with an infectious agent.
