Publications

cAMP immunocytochemistry provides evidence for functional VIP receptors in trachea

Vasoactive intestinal peptide (VIP), first isolated from porcine intestine (S. I. Said and V. Mutt, Science Wash. DC 169: 1217-1218, 1970), has been identified in postganglionic autonomic axons of many tissues. VIP has potent regulatory effects on the function of various cell types within these tissues, ranging from relaxation of smooth muscle to ion transport. Recently, VIP has been implicated in the regulation of mucus secretion in the respiratory tract, a process involving release of macromolecules from exocrine cells and transport of ions and water across the airway mucosa. However, because airway glands and mucosa both consist of mixed cell populations, it was unclear which specific cells contained VIP receptors and contributed to VIP-evoked responses. We identified these specific cells by using immunocytochemical techniques to monitor concentration changes in adenosine 3',5'-cyclic monophosphate (cAMP), the intracellular compound known to mediate VIP responses. Serous and mucous cells of ferret tracheal submucosal glands and ciliated and basal cells of dog tracheal mucosa all increased cAMP in response to VIP stimulation. We conclude that these cell types possess VIP receptors and thus participate in VIP-stimulated responses. In contrast, ferret tracheal epithelium and dog epithelial goblet cells showed little or no reactivity after VIP, and thus we believe that these cells lack VIP receptors.

Five‐year long‐term clinical follow‐up of the XIENCE V everolimus eluting coronary stent system in the treatment of patients with <i>de novo</i> coronary artery lesions: The SPIRIT FIRST trial

Drug-eluting stents have shown to be superior over bare metal stents in clinical and angiographic outcomes after percutaneous treatment of coronary artery stenosis. However, long-term follow-up data are scarce and only available for sirolimus- and paclitaxel-eluting stents.To assess the feasibility and performance of the XIENCE V everolimus-eluting stent (EES) versus an identical bare metal stent after a 5-year follow-up period.SPIRIT FIRST was a First in Man, multicentre, prospective, single-blind, clinical trial, randomizing 60 patients with a single de novo coronary artery lesion in a ratio of 1:1 to either an everolimus eluting or a bare metal control stent.At 5-year clinical follow-up, data were available in 89% and 86% of patients in the everolimus and control arm, respectively. In the everolimus arm, no additional death, myocardial infarction, clinically driven target lesion revascularization (TLR), or clinically driven target vessel revascularization (TVR) events were observed between 1- and 5-year follow-up. The 5-year hierarchical major adverse cardiac events (MACE) and target vessel failure (TVF) rates for the everolimus arm were 16.7% (4/24) for both endpoints. In the control group, no additional cardiac death, myocardial infarction, or clinically driven TLR events were observed between 2- and 5-year follow-up. No additional clinically driven TVR events were observed between 3- and 5-year follow-up. The 5-year hierarchical MACE and TVF rates for the control arm were 28.0% (7/25) and 36.0% (9/25), respectively. No stent thromboses were observed in either the everolimus arm or the control arm up to 5 years.The favorable 5-year long term clinical outcome of the EES is consistent with the results from other studies of the EES with shorter follow-up.

Measurement of Exhaled Hydrocarbons

Oxidative stress is implicated in the pathogenesis and progression of asthma (1,2), chronic obstructive respiratory disease (COPD) (3), and cystic fibrosis (4). Reactive oxygen species (ROS) are unstable compounds with unpaired electrons, capable of initiating oxidation. Several of the inflammatory cells which participate in the inflammatory response, such as macrophages, neutrophils, and eosinophils release increased amounts of ROS (1,5) exceeding the already reduced tissue antioxidant defences of asthmatic and COPD patients (2).

The Hidden Burden of Severe Asthma: From Patient Perspective to New Opportunities for Clinicians

Severe asthma is an important topic in respiratory diseases, due to its high impact on morbidity and mortality as well as on health-care resources. The many challenges that still exist in the management of the most difficult-to-treat forms of the disease, and the acknowledgement of the existence of unexplored areas in the pathophysiological mechanisms and the therapeutic targets represent an opportunity to gather experts in the field with the immediate goals to summarize current understanding about the natural history of severe asthma and to identify gaps in knowledge and research opportunities, with the aim to contribute to improved medical care and health outcomes. This article is a consensus document from the “International Course on Severe Asthma” that took place in Palermo, Italy, on May 10–11, 2019. Emerging topics in severe asthma were addressed and discussed among experts, with special focus on patient’s needs and research opportunities, with the aim to highlight the unanswered questions in the diagnostic process and therapeutic approach.

New Therapies for Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is a major global health problem which is increasing throughout the world and a major cause of death. However, current therapies fail to prevent disease progression or mortality. The mainstay of current drug therapy are long-acting bronchodilators; several longer-acting inhaled β&lt;sub&gt;2&lt;/sub&gt;-agonists and muscarinic antagonists (and combinations) are now in development. No treatments have so far been shown to suppress chronic inflammation in COPD lungs. With better understanding of the inflammatory and destructive process in the pathophysiology of COPD, several new targets have been identified. Several mediator antagonists tested in COPD have so far been disappointing, but CXCR2 antagonists that block pulmonary neutrophil and monocyte recruitment may be more promising. Broad-spectrum anti-inflammatory drugs may be more effective, and include inhibitors of the enzymes phosphodiesterase-4, p38 mitogen-activated protein kinase, NF-ĸB kinase and phosphoinositide 3 kinase-γ and -δ, but side effects will be a major limitation so that inhaled delivery may be necessary. Perhaps the most promising approach is reversal of corticosteroid resistance through increasing histone deacetylase-2 activity. This might be achieved by theophylline-like drugs, phosphoinositide 3 kinase-δ inhibitors, more effective antioxidants and non-antibiotic macrolides.

TCT-196 Outcomes of Radial Compared with Femoral Artery Access in Patients Undergoing PCI for Left Main Disease: Analysis from the EXCEL Trial

No abstract is provided for this article.

Roflumilast potently inhibits CXCL1 mediated neutrophil migration in COPD patients

Chronic obstructive pulmonary disease (COPD) is associated with glucocorticosteroid insensitive inflammation. Neutrophils from COPD patients migrate more in response to CXCL1 than cells from control subjects. Roflumilast, a PDE4 inhibitor recently approved for COPD in the EU, reduces neutrophil numbers in sputum from COPD patients. The mechanism of this anti-inflammatory effect is not clear, but may be due to inhibition of neutrophil migration. Thus this study investigated the effects of roflumilast N-oxide (RNO), the active metabolite of roflumilast, on neutrophil migration in comparison with another PDE4 inhibitor, rolipram. Neutrophils were isolated from whole blood samples from healthy subjects and COPD patients. Chemotaxis was measured using 48-well Boyden chambers and [Ca 2+ ] i by fluorimetry. Both RNO and rolipram completely inhibited migration of neutrophils from healthy subjects towards CXCL1 (3nM) with EC 50 values of 0.18±0.13 nM and 2.8±0.51 nM, n=4, respectively. A similar response was seen with neutrophils obtained from patients with COPD (EC 50 RNO: 0.74±0.89 nM; rolipram 42±45.9 nM, n=3). Having established that cell migration was attenuated by PDE4 inhibitors, the effects of these compounds on CXCL1 stimulated [Ca 2+ ] i was investigated. RNO (1μM) inhibited the peak of [Ca 2+ ] i and area under the curve (AUC) by 83.0±2.6% and 90.3±2.1%, n=6. Rolipram (1μM) also inhibited these responses by 80.7±3.2% and 86.3±2.1%, n=6. These data indicate that oral PDE4 inhibitors may have added anti-inflammatory effects by reducing CXCL1 stimulated neutrophil migration into the lung via regulation of [Ca 2+ ] i and this could contribute to the anti-inflammatory effects of roflumilast in the treatment of COPD.

Aneurysm of the Abdominal Aorta

No abstract is provided for this article.

Dynamics and Chemistry of Dense Gas in the Core of Orion B

Left ventricular performance, regional blood flow, wall motion, and lactate metabolism during transluminal angioplasty.

The response of left ventricular function, coronary blood flow, and myocardial lactate metabolism during percutaneous transluminal coronary angioplasty (PTCA) was studied in a series of patients undergoing the procedure. From four to six balloon inflation procedures per patient were performed with an average duration per occlusion of 51 +/- 12 sec (mean +/- SD) and a total occlusion time of 252 +/- 140 sec. Analysis of left ventricular hemodynamics in 19 patients showed that the relaxation parameters, peak negative rate of change in pressure, and early time constants of relaxation, responded earliest to short-term coronary occlusion (peak effect at 17 +/- 7 sec) while other parameters, such as peak pressure, left ventricular end-diastolic pressure, and peak positive rate of change in pressure, responded more gradually, suggesting a progressive depression of myocardial mechanics throughout the procedure. Left ventricular angiograms, available for 14 patients, indicated an early onset of asynchronous relaxation concurrent with the early response in peak negative dP/dt and the time constant of early relaxation. All hemodynamic functions fully recovered within minutes after the end of PTCA. Mean blood flow in the great cardiac vein and proximal coronary sinus and the hyperemic response were measured in 20 patients. Before PTCA mean flow in the great cardiac vein was 69 +/- 17 ml/min and in the coronary sinus it was 129 +/- 34 ml/min. Reactive hyperemia (great cardiac vein) was 55% after the first PTCA and 91% after the third. A more pronounced reaction was observed when the residual functional coronary stenosis was reduced in subsequent dilatations. Arteriovenous lactate difference appeared constant during the first two occlusions (control +0.11 mmol/liter, first PTCA -0.87 mmol/liter, and second PTCA -0.82 mmol/liter) and did not increase during subsequent occlusions. Within minutes after the procedure lactate balance was again positive, demonstrating the reversibility of the metabolic disturbances after repeated ischemia. The results of this study indicate that there is no permanent dysfunction of global or regional myocardial mechanics, myocardial blood flow, or lactate metabolism after PTCA with four to six coronary occlusions of 40 to 60 sec.

Pacemaker dependency after transcatheter aortic valve implantation with the self-expanding Medtronic CoreValve System

Background/objectives To determine pacemaker (PM) dependency at follow-up visit in patients who underwent new permanent pacemaker implantation (PPI) following transcatheter aortic valve implantation (TAVI). Methods Single center prospective observational study including 167 patients without previous PM implantation who underwent TAVI with the self-expanding Medtronic CoreValve System (MCS) between November 2005 and February 2011. PM dependency was defined by the presence of a high degree atrioventricular block (HDAVB; second [AV2] and third degree [AV3B]), or a slow (<30bpm) or absent ventricular escape rhythm during follow-up PM interrogation. Results A total of 36 patients (21.6%) received a new PM following TAVI. The indication for PM was AV2B (n=2, 5.6%), AV3B (n=28, 77.8%), postoperative symptomatic bradycardia (n=3, 8.3%), brady–tachy syndrome (n=1, 2.8%), atrial fibrilation with slow response (n=1, 2.8%) and left bundle branch block (n=1, 2.8%). Long term follow-up was complete for all patients and ranged from 1 to 40months (median (IQR): 11.5 (5.0–18.0months). Of those patients with a HDAVB, 16 out of the 30 patients (53.3%) were PM independent at follow-up visit (complete or partial resolution of the AV conduction abnormality). Overall, 20 out of the 36 patients (55.6%) who received a new PM following TAVI were PM independent at follow-up. Conclusion Partial and even complete resolution of peri-operative AV conduction abnormalities after MCS valve implantation occurred in more than half of the patients.

Greater late lumen loss after successful coronary balloon angioplasty in the proximal left anterior descending coronary artery is not explained by extent of vessel wall damage or plaque burden

OBJECTIVES We investigated whether the greater late lumen loss after coronary balloon angioplasty in the proximal left anterior descending artery (P-LAD) compared with that in other segments might be related to differences in vascular dimensions or morphology as determined by angiography and intravascular ultrasound imaging. BACKGROUND The greater late lumen loss after angioplasty in the P-LAD that has been observed in several studies has not been explained. METHODS We studied 178 patients and 194 coronary artery lesions by quantitative angiography and 30 MHz intravascular ultrasound imaging after successful balloon angioplasty. Vessel wall morphology was compared among three proximal and three nonproximal segments. Follow-up quantitative angiography for late lumen loss calculation was performed in 168 lesions. Multivariate analysis was used to determine predictors of late lumen loss. RESULTS Absolute and relative late loss were significantly greater at the P-LAD compared with the pooled group of other segments (0.42 ± 0.60 mm vs. 0.10 ± 0.48 mm, p = 0.0008 and 0.14 ± 0.24 vs. 0.03 ± 0.17, p < 0.001). Also, a greater percentage of calcific lesions (65% vs. 44%, p = 0.034), a lower incidence of rupture (51% vs. 74%, p = 0.009) and a larger reference segment plaque area (5.4 ± 2.2 mm2vs. 4.7 ± 1.9 mm2, p = 0.05) were found in the P-LAD. In multivariate analysis however, these variables were not predictive of late loss. CONCLUSIONS Greater late lumen loss after coronary balloon angioplasty of the P-LAD is not explained by differences in atherosclerotic plaque burden or in vessel wall damage.

Modulation of Functional Pulmonary β2-Adrenoceptor by Tansforming Growth Factor-β1 in Human Bronchial Epithelial Cells

Finite element modelling and design of welded stainless steel I-section columns

Recent Advances in the Pathophysiology of COPD

Chronic obstructive pulmonary disease (COPD) ranges amongst the commonest diseases in the world. The relentless progression of the disease causes a pressing need for a better understanding of and ther

Nonantimicrobial aspects of therapy

Biomechanical stress in coronary atherosclerosis: emerging insights from computational modelling

Coronary plaque rupture is the most common cause of vessel thrombosis and acute coronary syndrome. The accurate early detection of plaques prone to rupture may allow prospective, preventative treatment; however, current diagnostic methods remain inadequate to detect these lesions. Established imaging features indicating vulnerability do not confer adequate specificity for symptomatic rupture. Similarly, even though experimental and computational studies have underscored the importance of endothelial shear stress in progressive atherosclerosis, the ability of shear stress to predict plaque progression remains incremental. This review examines recent advances in image-based computational modelling that have elucidated possible mechanisms of plaque progression and rupture, and potentially novel features of plaques most prone to symptomatic rupture. With further study and clinical validation, these markers and techniques may improve the specificity of future culprit plaque detection.

Developmental changes in endothelium‐dependent pulmonary vasodilatation in pigs

1. We compared in vitro endothelium-dependent vasorelaxant responses to acetylcholine (ACh) and the endothelium-independent vasodilator response to sodium nitroprusside (SNP) in prostaglandin F2 alpha (PGF2 alpha)-precontracted muscular pulmonary arteries (PA) from pigs aged 5 min to 2 h (neonatal), 3-10 days, 3-8 weeks and adults. 2. In the pulmonary artery (PA) rings from neonatal animals, the vasodilator response to ACh was negligible. However, responses to ACh were present in all PA rings from older animals, being greatest at 3-10 days and then decreasing with age (P less than 0.001, ANOVA). ACh (30 microM) induced a 1 +/- 1%, 92 +/- 9%, 62 +/- 5% and 51 +/- 6% reduction of the PGF2 alpha-generated tension in neonatal, 3-10 days, 3-8 weeks and adult groups, respectively. 3. The relaxant response to SNP was present in the PA rings from all age groups and increased with age (P less than 0.001, ANOVA). SNP (1 microM)-induced relaxation was 55 +/- 9%, 73 +/- 7%, 97 +/- 5% and 93 +/- 6% in neonatal, 3-10 days, 3-8 week and adult groups, respectively. 4. Removal of the vascular endothelium abolished the relaxant response to ACh but had no effect on the response to SNP in any groups. 5. NG-monomethyl-L-arginine (30 microM), a nitric oxide synthesis inhibitor, inhibited the response to ACh but not to SNP. The lipoxygenase inhibitor, nordihydroguaiaretic acid, had no significant effect on responses to ACh or SNP in any group.6. These findings suggest that the nitric oxide pathway may not play a part in dilating the pig pulmonary arteries at birth, but may be important during the transitional period of establishing a stable post-natal pulmonary circulation. The increase in response to SNP with age parallels the increase in smooth muscle cell myofilaments to which it may be related.