The reaction of nitric oxide (NO) and superoxide anions (O(2)(-)) in the airway results in the formation of peroxynitrite, a highly reactive oxidant species. Peroxynitrite reacts with tyrosine residues in proteins to form the stable product nitrotyrosine. We investigated whether nitrotyrosine in exhaled breath condensates may be increased in patients with asthma. Four groups of nonsmoking subjects were studied. We measured exhaled NO, nitrotyrosine, and leukotrienes concentrations in breath condensate in healthy nonatopic subjects (n = 15) and in patients with mild asthma (steroid naive, n = 15), moderate asthma (inhaled steroid treatment, n = 12), and severe asthma (oral steroid treatment, n = 12). Exhaled NO was increased significantly in patients with mild (19.2 +/- 2.7 ppb, p < 0.01) and moderate asthma (14.0 +/- 1.53 ppb, p < 0.05), as compared with normal control (6.58 +/- 0.61 ppb). The levels of LTC(4)/D(4)/E(4) and LTB(4) were increased significantly in patients with moderate and severe asthma treated with steroids. Nitrotyrosine concentrations were detectable (6.3 +/- 0.8 ng/ml) in breath condensate of normal subjects, and were increased significantly in patients with mild asthma (15.3 +/- 2.0 ng/ml, p < 0.01). However, the levels of nitrotyrosine in exhaled condensate were lower in patients with moderate (5.0 +/- 0.6 ng/ml) and severe asthma (3.3 +/- 0.6 ng/ml, p < 0.05). There was a significant correlation between nitrotyrosine in breath condensate and exhaled NO in patients with mild asthma (r = 0.65, p < 0.05). We conclude that nitrotyrosine formation in exhaled breath condensates may be a marker of oxidative stress in airways of asthma.
Opioid drugs have been shown to inhibit neurogenic plasma exudation in skin by a presynaptic mechanism. We determined whether a similar inhibitory effect operates in the airways of anesthetized guinea pigs in vivo with the use of Evans blue dye as a marker of plasma leakage. Stimulation of the vagus nerve significantly increased leakage of dye in trachea and main bronchi (by approximately 300 and 600%, respectively). Similar increases in leakage were seen in the presence of atropine and propranolol. Morphine (1–30 mg/kg iv) inhibited leakage in a dose-related manner with complete inhibition in the trachea at a dose of 30 mg/kg. The inhibition was blocked by the opioid receptor-antagonist naloxone (1 mg/kg iv). Intravenous substance P significantly increased leakage but was not inhibited by morphine. We conclude that morphine inhibits neurogenic plasma leakage by presynaptic inhibition of release of neuropeptides from sensory nerve endings. If similar mechanisms are operative in human airways, inhibition of neurogenic plasma leakage by opioid drugs devoid of central effects may be of value in the therapy of asthma.
A 73-year-old woman with hypertension, hyperlipidemia and positive familial history of coronary artery disease presented with Canadian Cardiovascular Society class III angina and underwent coronary angiography, which showed a chronic occluded right coronary artery (Panel A). The vessel was recanalized and treated with three paclitaxel-eluting stents (TAXUS®, Boston Scientific: 3.5 x 32 mm distally, 3.5 x 28 mm in the middle part, 3.5 x 12 mm proximally). Postintervention coronary angiography showed a good result (Panel B). Twelve-month follow-up angiography revealed focal in-stent restenosis (Panel C). Intracoronary optical coherence tomography (OCT: LightLabImagingTM, Boston, MA, USA) pullback displayed well-expanded stents covered with a thin, homogenous, highly reflective neointimal layer (Panel D, E). In contrast, the narrowest lesion site (minimal lumen area 1.1 mm2; stent area 9.0 mm2) showed a three-layer appearance of the neointima (Panel F). The inner luminal layer appeared concentric, homogenous and signal-rich (maximal thickness 0.27 mm). A second layer consisting of a low-reflective area with poorly delineated borders followed. The third layer was in direct contact with the stent struts and revealed only minimal signal intensity. These signal-poor areas (maximal thickness 1.18 mm) might represent acellular fibrinoid deposition that has been well described in experimental studies. The patient was re-treated with repeat paclitaxel-eluting stent implantation. OCT is an analogue of intravascular ultrasound with an ultra-high resolution (10 μm) superior to any current available imaging modalities. This imaging device may be useful in visualizing neointimal growth in drug-eluting stents and improve our understanding of its underlying physiopathology in the future.
Infliximab is used increasingly as maintenance therapy for inflammatory bowel disease (IBD); however, the effects of a single maintenance dose of infliximab are unclear with respect to the quality of life and hormones related to growth and puberty. The aim of the present study was to determine the time course of inflammatory, hormonal, and quality-of-life changes following a single dose of infliximab in the context of ongoing therapy, as related to presence of IBD symptoms at time of administration.Children and adolescents with IBD receiving ongoing therapy with infliximab for clinical indications were recruited. The Pediatric Crohn's Disease Activity Index was determined at baseline and laboratory measures of high-sensitivity C-reactive protein (hsCRP) and hormones of growth and puberty were determined on days 0, 2, and 14. IBD-related quality of life (IMPACT III questionnaire) was tested on days 0 and 14. Subjects who had symptoms of IBD were compared with asymptomatic subjects.Subjects overall and in the symptomatic group exhibited improved hsCRP by day 2 following treatment. Symptomatic subjects had higher Pediatric Crohn's Disease Activity Index scores and lower quality-of-life scores than asymptomatic subjects on day 0, whereas at day 14 there were no significant differences in quality-of-life scores between the 2 groups.Even in the context of ongoing treatment, a single dose of infliximab results in decreased hsCRP, an improvement that is particularly noted among subjects who are symptomatic at the time of treatment. Although randomized trials are needed, these observational data may assist clinicians, patients, and families regarding expectations about timing and extent of these changes following a single treatment dose.
We assessed the effect of nedocromil sodium on bronchoconstriction and airway responsiveness induced by platelet-activating factor (PAF) in eight normal subjects, in a double-blind, placebo-controlled cross-over study. Subjects inhaled PAF by a dosimeter method in 5 doses of 18 micrograms each, separated by an interval of 15 min, (total dose of 90 micrograms). Airway calibre was measured by partial expiratory flow at 30% of vital capacity (Vp30) before and at 1, 3, 5, 10 and 15 min after each dose of PAF. The bronchoconstrictor response was assessed by measuring the area under the curve of the percentage fall in Vp30 over time. There was a significant reduction in PAF-induced bronchoconstriction after nedocromil sodium (1,225 +/- 392 arbitrary units; mean +/- SEM) compared to placebo (2,395 +/- 598; p < 0.01). There was no significant difference in the fall in peripheral neutrophil count measured at 5 min after PAF with nedocromil sodium (48.5 +/- 9.5%) compared to placebo (43.3 +/- 6.8%). In conclusion, nedocromil sodium significantly attenuates PAF-induced bronchoconstriction but not the peripheral neutropenia in normal subjects. Since PAF is not a direct constrictor of human airway smooth muscle, this effect of nedocromil sodium may indicate inhibition of release of bronchoconstrictor mediators.
Abstract Wire arc additive manufacturing (WAAM) is a method of metal 3D printing which, when strategically combined with traditional methods of manufacture, has the potential to make a significant impact on the construction sector. To illustrate this potential, an experimental investigation into the flexural buckling response of 13 hot‐rolled I‐section columns, strengthened by WAAM, has been undertaken and is presented herein. The WAAM material was added at the flange tips and distributed non‐uniformly along the member length. Complementary material tests on the conventional and WAAM steels were also carried out. 3D laser scanning was employed to determine the geometry and global geometric imperfections of all specimens, while digital image correlation measurements were taken to provide a detailed insight into the surface deformation characteristics of the specimens during testing. The beneficial effects of the WAAM stiffeners were an increased cross‐sectional area and second moment of area, enhanced local buckling capacity and a more favourable residual stress pattern. Increases in axial capacity of between 17% and 54% for increases of mass between 2% and 26% were achieved, highlighting the tremendous potential in terms of structural efficiency and material savings that can be realised by the combination of WAAM with traditional manufacturing methods.
No abstract is provided for this article.
Studies have reported benefit of oral therapy with the phosphodiesterase inhibitor, trapidil, in reducing restenosis after coronary angioplasty. Coronary stenting is associated with improved late outcome compared with balloon angioplasty, but significant neointimal hyperplasia still occurs in a considerable proportion of patients. The aim of this study was to investigate the safety and efficacy of trapidil 200 mg in preventing in-stent restenosis.Patients with a single native coronary lesion requiring revascularization were randomized to placebo or trapidil at least 1 h before, and continuing for 6 months after, successful implantation of a coronary Wallstent. The primary end-point was in-stent neointimal volume measured by three-dimensional reconstruction of intravascular ultrasound images recorded at the 6 month follow-up catheterization.Of 312 patients randomized at 21 centres in nine countries, 303 (148 trapidil, 155 placebo) underwent successful Wallstent implantation, and 139 patients (90%) in the placebo group and 130 (88%) in the trapidil group had repeat catheterization at 26+/-2 weeks. There was no significant difference between trapidil and placebo-treated patients regarding in-stent neointimal volume (108.6+/- 95.6 mm(3)vs 93.3+/-79.1 mm(3);P=0.16) or % obstruction volume (38+/-18% vs 36+/-21%;P=0.32), in angiographic minimal luminal diameter at follow-up (1.63+/-0.61 mm vs 1.74+/-0.69 mm;P=0.17), restenosis rate (31% vs 24%;P=0.24), cumulative incidence of major adverse cardiac events at 7 months (22% vs 20%;P=0.71) or anginal complaints (30% vs 24%;P=0.29).Oral trapidil 600 mg daily for 6 months did not reduce in-stent hyperplasia or improve clinical outcome after successful Wallstent implantation and is not indicated for this purpose.
