The objectives of the present study are to describe the algorithm for VH® IVUS using the 45-MHz rotational IVUS catheter and the associated ex vivo validation in comparison to the gold standard histology. The first phase of the present study was to construct the 45 MHz VH IVUS algorithm by using a total of 55 human coronary artery specimens [111 independent coronary lesions and 510 homogenous regions of interest (ROIs)], obtained at autopsy. Regions were selected from histology and matched with their corresponding IVUS data to build the plaque classification system using spectral analysis and statistical random forests. In the second phase, the ex vivo validation of the VH IVUS algorithm assessed a total of 1060 ROIs (120 lesions from 60 coronary arteries) in comparison with histology. In an independent manner, two interventional cardiologists also classified a randomly selected subset of the ROIs for assessment of inter- and intra-observer reproducibility of VH IVUS image interpretation. When including all ROIs, the predictive accuracies were 90.8% for fibrous tissue, 85.8% for fibro fatty tissue, 88.3% for necrotic core, and 88.0% for dense calcium. The exclusion of ROIs in the acoustically attenuated areas improved the predictive accuracies, ranging from 91.9 to 96.8%. The independent analysis of randomly selected 253 ROIs showed substantial agreement for inter-observer (k = 0.66) and intra-observer (k = 0.88) reproducibility. Tissue classification by 45 MHz VH IVUS technology, when not influenced by calcium-induced acoustic attenuation, provided combined tissue accuracy >88% to identify tissue types compared with the gold standard histologic assessment, with high inter- and intra-observer reproducibility.
A variational model that describes the interactive buckling of a thin-walled equal-leg angle strut under pure axial compression is presented. A formulation combining the Rayleigh–Ritz method and continuous displacement functions is used to derive a system of differential and integral equilibrium equations for the structural component. Solving the equations using numerical continuation reveals progressive cellular buckling (or snaking) arising from the nonlinear interaction between the weak-axis flexural buckling mode and the strong-axis flexural–torsional buckling mode for the first time—the resulting behaviour being highly unstable. Physical experiments conducted on 10 cold-formed steel specimens are presented and the results show good agreement with the variational model.
Although theophylline has side effects when used in bronchodilator doses, increasing evidence shows that it has significant antiinflammatory effects in chronic obstructive pulmonary disease at lower plasma concentrations. These antiinflammatory effects are unlikely to be accounted for by phosphodiesterase inhibition or adenosine receptor antagonism, which require higher concentrations. There is now evidence that theophylline at low therapeutic concentrations is an activator of histone deacetylases and that this activation enhances the antiinflammatory effect of corticosteroids. There appears to be a marked reduction in histone deacetylase-2 in macrophages and peripheral lung of patients with chronic obstructive pulmonary disease, which accounts for amplified inflammation and steroid resistance. Theophylline has been shown to restore steroid sensitivity in vitro. The effect of theophylline on histone deacetylase activity appears to be enhanced by oxidative stress. The mechanism whereby theophylline activat...
The effect of tachykinins on cholinergic neurotransmission was studied in an innervated tracheal tube preparation isolated from guinea‐pigs anaeshetized with urethane. The tracheal tube was bathed in Krebs‐Henseleit solution containing 5 μ m indomethacin. Neurokinin A (NKA), eledoisin (El) and substance P (SP) caused concentration‐dependent increases in intraluminal pressure (ILP), with an order of potency NKA > El >> SP. Low concentrations of tachykinins, that had little effect on ILP, caused an increase in the contractions elicited by stimulation of the preganglionic vagal nerve fibres and by postganglionic (transmural) stimulation. The order of potency was NKA ≤ El > SP. Contractions induced by exogenous acetylcholine (ACh) were not increased by the tachykinins. The magnitude of the tachykinin‐induced augmentation of responses to nerve stimulation was inversely related to stimulation voltage and frequency. These results suggest that tachykinins act on NK 2 receptors, both on the trachealis muscle and on postganglionic pulmonary parasympathetic nerve terminals. Activation of the neuronal receptors may increase the probability of transmitter release from the nerve terminals.
Ba 679 BR [7(S)-(1 alpha, 2 beta, 4 beta, 5 alpha, 7 beta)-7-[(hydroxydi(2-thienyl) acetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0(2,4)]nonan e bromide] is a new long-acting muscarinic antagonist developed as a bronchodilator drug. In this study, we have evaluated its affinity, its selectively, and the distribution of its binding sites in human lung. [3H]Ba 679 BR binds to a homogeneous population of muscarinic receptors in human lung membranes, with affinities in the subnanomolar concentration range. Like ipratropium bromide, Ba 679 BR showed no selectivity in its interactions with rat cerebrocortical M1 receptors (labeled with [3H]telenzepine) or heart M2 and salivary gland M3 receptors [labeled with [N-methyl-3H]scopolamine ([3H)]. Ba 679 BR displayed 6-20-fold higher affinity, compared with ipratropium bromide. We also studied the rate of Ba 679 BR and ipratropium bromide dissociation from human lung muscarinic receptors, by monitoring [3H]NMS association. Unlike ipratropium bromide (100 nM), which dissociated so quickly that there was little difference in the [3H]NMS association, compared with vehicle-treated membranes, Ba 679 BR (1 nM) had a strong protective effect against [3H]NMS binding ( > 70%) that lasted for 90 min. Kinetic experiments conducted with [3H]Ba 679 BR confirmed the slow dissociation profile of this compound. The dissociation rate constant (k-1) for [3H]Ba 679 BR was 3.29 +/- 0.18 x 10(-3) min-1, corresponding to a half-life of the complex of 212 +/- 11 min. Autoradiographic studies revealed that [3H]Ba 679 BR binding sites were densely distributed in alveolar walls and submucosal glands. These results suggest that the slow dissociation profile of Ba 679 BR from human lung muscarinic receptors might be the underlying mechanism by which this drug achieves its long duration of action observed in functional tests.
Coronary angioplasty was performed in 23 patients in whom within 10 days after acute myocardial infarction severe angina recurred despite continuing maximal pharmacological therapy. Initial success was achieved in 83% (19 of 23 patients). In three of the four failures bypass surgery was carried out as an emergency. There were no deaths, but myocardial infarction was a complication in 13% (three of 23 patients). At 6 months follow-up angina had recurred in 32% (6 of 19 patients) despite initial successful angioplasty. In 16 of the 19 patients, angiography was repeated and restenosis was seen in 31%, 5 of 16 patients, all of whom had recurrent symptoms. We conclude that, while coronary angioplasty is an effective initial therapy for selected patients with early post-infarction angina, its exact long-term value remains to be decided.
In ageing populations many patients have multiple diseases characterised by acceleration of the normal ageing process. Better understanding of the signalling pathways and cellular events involved in ageing shows that these are characteristic of many chronic degenerative diseases, such as chronic obstructive pulmonary disease (COPD), chronic cardiovascular and metabolic diseases, and neurodegeneration. Common mechanisms have now been identified in these diseases, which show evidence of cellular senescence with telomere shortening, activation of PI3K–AKT–mTOR signalling, impaired autophagy, mitochondrial dysfunction, stem cell exhaustion, epigenetic changes, abnormal microRNA profiles, immunosenescence and low grade chronic inflammation (“inflammaging”). Many of these pathways are driven by chronic oxidative stress. There is also a reduction in anti-ageing molecules, such as sirtuins and Klotho, which further accelerates the ageing process. Understanding these molecular mechanisms has identified several novel therapeutic targets and several drugs have already been developed that may slow the ageing process, as well as lifestyle interventions, such as diet and physical activity. This indicates that in the future new treatment approaches may target the common pathways involved in multimorbidity and this area of research should be given high priority. Thus, COPD should be considered as a component of multimorbidity and common disease pathways, particularly accelerated ageing, should be targeted.
