Publications

Loop Diuretics Inhibit Cholinergic and Noncholinergic Nerves in Guinea Pig Airways

Furosemide, a loop diuretic, is known to inhibit the response to a variety of indirect bronchial challenges in humans but does not inhibit bronchoconstriction induced by inhaled methacholine or histamine. We have investigated the effects of the two loop diuretics, furosemide (10−6 to 10−3 M) and bumetanide (10−7 to 10−4 M), on airway smooth muscle contraction in vitro induced by electrical field stimulation (EFS), or exogenously applied acetylcholine (ACh) or substance P (SP) in guinea pig tracheal and bronchial smooth muscle strips pretreated with indomethacin (10−5 M) and propranolol (10−6 M). Both furosemide and bumetanide caused a concentration-dependent inhibition of cholinergically mediated neural contraction in the trachea. The effect of furosemide was not influenced by the presence of airway epithelium. Furthermore, both furosemide and bumetanide inhibited in a concentration-dependent fashion nonadrenergic, noncholinergic (NANC) contraction induced by electrical field stimulation of bronchi pretreated with atropine (10−6 M). Neither drug at the highest concentration inhibited the responses to exogenous acetylcholine (10−8 to 10−2 M) or substance P (10−9 to 10−5 M). Thus loop diuretics inhibit the neurally induced contraction of guinea pig airways without a direct effect on airway smooth muscle. We conclude that loop diuretics inhibit both cholinergic and excitatory NANC neurotransmission in guinea pig airways and that this effect may be related to their inhibitory effects on the sodium-potassium-chloride cotransporter.

210-Day follow-up of the RAVEL study: a randomized study with the sirolimus-eluting Bx VELOCITY™ balloon-expandable stent in the treatment of patients with de novo native coronary artery lesions

No abstract is provided for this article.

Corticosteroid Inhibition of Airway Microvascular Leakage

We studied the effect of dexamethasone on microvascular leakage (using Evans blue dye as a marker of plasma exudation) induced in rat airways by platelet-activating factor (PAF). Intravenously administered PAF caused a dose-related increase in plasma leakage over the range 0.1 to 1 ng/kg. At 500 ng/kg PAF, the response was maximal in the extrapulmonary airways examined with increases in leakage above those in control animals of 312% in the larynx, 295% in the trachea, and 167% in the main bronchi. A maximal response was not achieved in the intrapulmonary airways at the doses of PAF tested: at 1 µg/kg the increase was 206% above that in control animals. Dexamethasone, given by intraperitoneal injection 24 h and 4 h before PAF at a dose of 0.2 mg/kg on each occasion, partially inhibited leakage induced by PAF (1 µg/kg) in all airway levels studied by 43 to 65%. At each level the tissue concentration of dye was reduced to a value that was significantly (p < 0.05) different from either PAF or control values. We also determined whether a high dose (8 mg/kg) of dexamethasone given intraperitoneally would inhibit plasma leakage of dye induced by either PAF or antigen-challenge of sensitized rats. When given 4 h before antigen, dexamethasone completely prevented allergen-induced leakage in the airways showing significant leakage (larynx, trachea, and intrapulmonary airways). Similarly, dexamethasone (4 h before) partially inhibited PAF-induced leakage in the trachea and main bronchi. In summary, in rat airways, both low and high doses of dexamethasone markedly inhibit mediator-induced plasma exudation. This effect may contribute to the beneficial action of corticosteroids in allergic disease, including asthma.

Coronary bypass surgery guided by computed tomography in a low-risk population

Background and Aims In patients with three-vessel disease and/or left main disease, selecting revascularization strategy based on coronary computed tomography angiography (CCTA) has a high level of virtual agreement with treatment decisions based on invasive coronary angiography (ICA). Methods In this study, coronary artery bypass grafting (CABG) procedures were planned based on CCTA without knowledge of ICA. The CABG strategy was recommended by a central core laboratory assessing the anatomy and functionality of the coronary circulation. The primary feasibility endpoint was the percentage of operations performed without access to the ICA. The primary safety endpoint was graft patency on 30-day follow-up CCTA. Secondary endpoints included topographical adequacy of grafting, major adverse cardiac and cerebrovascular (MACCE), and major bleeding events at 30 days. The study was considered positive if the lower boundary of confidence intervals (CI) for feasibility was ≥75% (NCT04142021). Results The study enrolled 114 patients with a mean (standard deviation) anatomical SYNTAX score and Society of Thoracic Surgery score of 43.6 (15.3) and 0.81 (0.63), respectively. Unblinding ICA was required in one case yielding a feasibility of 99.1% (95% CI 95.2%–100%). The concordance and agreement in revascularization planning between the ICA- and CCTA-Heart Teams was 82.9% with a moderate kappa of 0.58 (95% CI 0.50–0.66) and between the CCTA-Heart Team and actual treatment was 83.7% with a substantial kappa of 0.61 (95% CI 0.53–0.68). The 30-day follow-up CCTA in 102 patients (91.9%) showed an anastomosis patency rate of 92.6%, whilst MACCE was 7.2% and major bleeding 2.7%. Conclusions CABG guided by CCTA is feasible and has an acceptable safety profile in a selected population of complex coronary artery disease.

Impact of TCFA on Unanticipated Ischemic Events in Medically Treated Diabetes Mellitus

Objectives This study sought to investigate the relationship between thin-cap fibroatheromas (TCFAs) on major adverse cardiac events (MACEs) arising from medically treated nonculprit lesions (NCLs) in patients with acute coronary syndromes (ACS) with and without diabetes mellitus (DM). Background MACEs occur frequently in patients with DM and ACS. The impact of plaque composition on subsequent MACEs in DM patients with ACS is unknown. Methods In the PROSPECT (Providing Regional Observations Study Predictors of Events in the Coronary Tree) study, using 3-vessel radiofrequency intravascular ultrasound, we analyzed the incidence of NCL-MACE in 2 propensity-matched groups according to the presence of DM and TCFA. Results Among 697 patients, 119 (17.7%) had DM. The 3-year total MACE rate (29.4% vs. 18.8%; p = 0.01) was significantly higher in patients with versus without DM, driven by a higher rate of NCL-MACE in DM (18.7% vs. 10.4%; p = 0.02). Propensity score matching generated 2 balanced groups with and without DM of 82 patients each. Among DM patients, the presence of ≥1 TCFA was associated with higher NCL-MACE at 3 years (27.8% vs. 8.9% in patients without a TCFA, hazard ratio: 3.56; 95% confidence interval: 0.98 to 12.96; p = 0.04). DM patients without a TCFA had a similar 3-year rate of NCL-MACE as patients without DM (8.9% vs. 8.9%; hazard ratio: 1.09; 95% confidence interval: 0.27 to 4.41; p = 0.90). Conclusions ACS patients with DM and ≥1 TCFA have a high rate of NCL-MACE at 3 years. In contrast, the prognosis of ACS patients with DM but no TCFAs is favorable and similar to patients without DM.

Stent fracture and restenosis of a paclitaxel-eluting stent.

Glucocorticoids induce beta2-adrenergic receptor function in human nasal mucosa.

Glucocorticoids are hypothesized to induce beta2-adrenergic receptors (beta2-R) and their functions. The ability of dexamethasone (DEX) in vitro and beclomethasone dipropionate (BDP) in vivo to induce beta2-R messenger RNA (mRNA) and function was investigated in human nasal mucosa. In this tissue, albuterol does not stimulate exocytosis either in vivo or in vitro (Mullol and coworkers, 1992). Therefore, induction of beta2-R-mediated glandular exocytosis by glucocorticoids was proposed as an unambiguous outcome measure. Human nasal mucosa was cultured for 3 d with and without 1 microM DEX, then challenged with media or 100 microM albuterol. Culture supernatants were collected for measurement of exocytosed glandular products. Explant mRNA was extracted for reverse transcriptase-polymerase chain reaction (RT-PCR), and in situ hybridization of beta2-R mRNA performed. In vivo, normal subjects received saline or BDP for 3 d before albuterol nasal provocation. Concentrations of exocytosed products were measured in nasal secretions. RNA was extracted from nasal epithelial scrapings for RT-PCR. In vitro, DEX treatment induced albuterol-mediated glandular exocytosis (p < 0.04), and increased the steady-state beta2-R/beta-actin mRNA ratio (p < 0.05), and expression of beta2-R mRNA in glands. In vivo, BDP increased the beta2-R/beta-actin mRNA ratio in epithelial scrapings (p < 0.04), but did not induce albuterol-mediated glandular secretion. We conclude that glucocorticoids increase steady-state beta2-R mRNA levels in vivo and in vitro, and can induce beta2-R function as assessed by submucosal gland exocytosis in vitro. While topical BDP induced epithelial beta2-R mRNA, it did not modulate exocytosis from the deeper submucosal glands.

Inflammatory activities

Increased 8-Isoprostane and Interleukin-6 in Breath Condensate of Obstructive Sleep Apnea Patients

Effect of a nitric oxide synthase inhibitor and a glucocorticosteroid on exhaled nitric oxide.

Nitric oxide (NO) is produced by a variety of cells within the respiratory tract, including inflammatory epithelial cells. NO has been detected in the exhaled air of normal human subjects, and its concentration is raised in asthmatic patients. To study whether exhaled NO arises from the respiratory tract, we administered a NO synthase (NOS) inhibitor, NG-monomethyl-L-arginine (L-NMMA), by inhalation (490 mg) in a double-blind randomized manner in nine normal and six asthmatic subjects. Because exhaled NO may arise from an inducible isoform of NO synthase that may be inhibited by glucocorticosteroids, we also studied the effects of oral prednisolone (30 mg orally for 3 d) in seven normal and six asthmatic subjects in a separate double-blind crossover study with matched placebo. After nebulized L-NMMA, there was a significant fall in peak exhaled NO compared with saline control values, with a mean fall of 43.6 +/- 5.6% in normal subjects (p < 0.01) and of 39.7 +/- 6.5% (p < 0.01) in asthmatic subjects, which persisted for 4 h. There were no effects of L-NMMA inhalation on heart rate, blood pressure, or FEV1 in either normal or asthmatic patients. Administration of oral prednisolone (30 mg) resulted in a fall in exhaled NO concentrations in asthmatic subjects by 21.6 +/- 5.0% at 48 h (p < 0.01) but no significant change in normal subjects. These data suggest that NOS inhibitors may be safely given in normal and asthmatic patients and that the increased exhaled NO seen in asthmatic patients is likely to be caused by induction of inducible NOS.

Review in depth: Elastography

A New Approach to the Treatment of Asthma

ASTHMA affects more than 5 percent of the population in industrialized countries, yet it is underdiagnosed and undertreated. There is evidence that the prevalence and severity of asthma are rising.1 The number of deaths from asthma may also be rising,2 3 4 5 contrary to the trend for other common treatable conditions.6 These alarming increases are occurring despite a marked increase in prescribed asthma therapy,7 , 8 which suggests that currently available therapy is inadequate or is not being used optimally. In the past, attention has been concentrated on bronchoconstrictor mechanisms and possible abnormalities of airway smooth muscle in asthma, with consequent emphasis on bronchodilator . . .

Dual Transmembrane Signalling Mechanisms in Eosinophils: Evidence for Two Functionally Distinct Receptors for Platelet-Activating Factor

The effect of PAF on eosinophil activation was investigated. TxB2 release required a lower concentration of PAF (ED50 = 17.2 nM) whereas for superoxide anion (O2) production doses in excess of 1 μM (ED50 = 31.7 μM) were needed. The PAF-induced O2 release occurred in the absence of increased [Ca2+]i whereas the production of TxB2 paralleled the magnitude of the [Ca2+]i increase. Pretreatment of the eosinophils with pertussis toxin (PTX) reduced both the PAF-induced release of TxB2 and the PAF-induced rise in [Ca2+]i. However, PTX failed to inhibit PAF-induced O2 generation. Experiments with the microsomal (100,000 g) fraction from these cells demonstrated that PTX pretreatment had ADP-ribosylated a 41-kD protein in the membrane, confirming that GTP binding proteins are present in eosinophil membranes. Scatchard plot analysis of radioligand binding to eosinophil membranes indicated the presence or two binding sites with an apparent Kd of 0.33 and 11.5 nM, respectively. The results suggest that two distinct forms of the PAF receptor can be identified in eosinophil membranes.

Regional Lung Deposition and Bronchodilator Response as a Function of β₂-Agonist Particle Size

Aerosol particle size influences the extent, distribution, and site of inhaled drug deposition within the airways.We hypothesized that targeting albuterol to regional airways by altering aerosol particle size could optimize inhaled bronchodilator delivery.In a randomized, double-blind, placebo-controlled study, 12 subjects with asthma (FEV1, 76.8 +/- 11.4% predicted) inhaled technetium-99m-labeled monodisperse albuterol aerosols (30-microg dose) of 1.5-, 3-, and 6-microm mass median aerodynamic diameter, at slow (30-60 L/min) and fast (> 60 L/min) inspiratory flows. Lung and extrathoracic radioaerosol deposition were quantified using planar gamma-scintigraphy. Pulmonary function and tolerability measurements were simultaneously assessed. Clinical efficacy was also compared with unlabeled monodisperse albuterol (15-microg dose) and 200 microg metered-dose inhaler (MDI) albuterol.Smaller particles achieved greater total lung deposition (1.5 microm [56%], 3 microm [50%], and 6 microm [46%]), farther distal airways penetration (0.79, 0.60, and 0.36, respective penetration index), and more peripheral lung deposition (25, 17, and 10%, respectively). However, larger particles (30-microg dose) were more efficacious and achieved greater bronchodilation than 200 microg MDI albuterol (deltaFEV1 [ml]: 6 microm [551], 3 microm [457], 1.5 microm [347], MDI [494]). Small particles were exhaled more (1.5 microm [22%], 3 microm [8%], 6 microm [2%]), whereas greater oropharyngeal deposition occurred with large particles (15, 31, and 43%, respectively). Faster inspiratory flows decreased total lung deposition and increased oropharyngeal deposition for the larger particles, with less bronchodilation. A shift in aerosol distribution to the proximal airways was observed for all particles.Regional targeting of inhaled beta2-agonist to the proximal airways is more important than distal alveolar deposition for bronchodilation. Altering intrapulmonary deposition through aerosol particle size can appreciably enhance inhaled drug therapy and may have implications for developing future inhaled treatments.

TCT-70 Ability of the bioresorbable vascular scaffold to re-cap the underlying plaque. A serial optical coherence tomography study

No abstract is provided for this article.

50. PRELIMINARY LIPID ANALYSES OF CORE SECTIONS 18, 24, AND 30 FROM HOLE 402A

A preliminary analysis of the solvent-extractable lipids from three samples from the Aptian-Albian core sections of Hole 402A, which was drilled on the mid-continental slope of the Bay of Biscay (47°52.48'N, 08°50.44'W), has been carried out. The aliphatic and aromatic hydrocarbons, carboxylic acids and free hydroxy acids have been examined by gas chromatography and gas chromatography-mass spectrometry . A list of the samples is given in Table 1, together with relevant background data taken from the Summary Log. Core 402A-18 was a composite sample of Sections 1-4, obtained via the Institut Francais du Petrole; Cores 402A-24 and 30 were collected from the Scripps Institute of Oceanography. An additional core, 401-5 (supplied in a frozen state by the shipboard geochemist via British Petroleum Ltd.), was extracted, but the low concentrations of extractable lipids at comparable concentrations to a blank analysis precluded further investigations. A preliminary attempt has been made to relate the extractable lipids of these black shales to the extent of diagenesis/maturation and to the paleoenvironment of deposition.

TCT-67 Predictors and Outcomes After Stent Failure Is Treated With Either CABG or PCI: An Individual Patient-Data Pooled Analysis From 32,880 Patients

No abstract is provided for this article.

Chronic obstructive pulmonary disease in non-smokers