Publications

Despite increased numbers o f alveolar macrophages (mΦ) in stable COPD patients, lower airway bacterial colonisation (LABC) is often seen. We investigated the relationship between LABC status, airway inflammation & monocyte-derived mΦ (MDMs) phagocytosis. Whole blood & sputa were collected from stable COPD patients. MDMs were cultured & phagocytosis of fluorescently-labeled inert beads, or heat-killed Haemophilus influenzae (HI) & Streptococcus pneumoniae (SP) measured. Sputa were analysed by qPCR for HI, SP & Moraxella catarrhalis & airway cytokines by ELISA. Clinical characteristics are shown in Table 1. 19/40 patients had evidence of LABC on qPCR & had significantly higher levels of IL-8 and IL-1β, but not MPO, than non-LABC patients. There was a trend towards increasing airway inflammation with increasing bacterial load. Phagocytosis of HI & SP, but not beads, significantly increased with increasing airway IL-8 & IL-1β (Figure 1). There was no significant relationship between airway MPO and phagocytosis of any prey. Higher levels of airway IL-8 and IL-1β are associated with increased phagocytic response by MDMs to HI & SP but not beads. Higher bacterial loads seen in LABC patients may increase airway inflammation & this may in turn influence phagocytic ability.

We have studied the effects of tachykinin‐depletion on airway microvascular leakage induced by allergen challenge in ovalbumin‐sensitised guinea pigs, Tachykinin‐depletion was obtained by capsacin pretreatment 1 week before inhaled allergen challenge. Capsaicin pretreatment did not change airway microvascular permeability induced by allergen challenge. Capsaicin pretreatment did not change airway microvascular permeability induced by allergen challenge. Thus, sensory neuropeptides may not be important in allergen induced acute airway microvascular leakage in guinea pig in vivo.

COPD (chronic obstructive pulmonary disease) is associated with sustained inflammation, excessive injury, and accelerated lung aging. Human Klotho (KL) is an anti-aging protein that protects cells against inflammation and damage. In the present study, we quantified KL expression in the lungs of COPD patients and in an ozone-induced mouse model of COPD, and investigated the mechanisms that control KL expression and function in the airways. KL distribution and levels in human and mouse airways were measured by immunohistochemistry and Western blotting. The effect of CSE (cigarette smoke extract) on KL expression was detected in human bronchial epithelial cells. Moreover, the effect of KL on CSE-mediated inflammation and hydrogen peroxide-induced cellular injury/apoptosis was determined using siRNAs. KL expression was decreased in the lungs of smokers and further reduced in patients with COPD. Similarly, 6 weeks of exposure to ozone decreased KL levels in airway epithelial cells. CSE and TNFα (tumour necrosis factor α) decreased KL expression and release from airway epithelial cells, which was associated with enhanced pro-inflammatory cytokine expression. Moreover, KL depletion increased cell sensitivity to cigarette smoke-induced inflammation and oxidative stress-induced cell damage. These effects involved the NF-κB (nuclear factor κB), MAPK (mitogen-activated protein kinase) and Nrf2 (nuclear factor erythroid 2-related factor 2) pathways. Reduced KL expression in COPD airway epithelial cells was associated with increased oxidative stress, inflammation and apoptosis. These data provide new insights into the mechanisms associated with the accelerated lung aging in COPD development.

Objectives : To study the effect of endothelial progenitor cell (EPC) capture on the vascular response to coronary stenting. Background : The introduction of drug‐eluting stents has reduced the need for target lesion revascularization, but their effect on delayed healing, inflammation, and vascular dysfunction has emphasized the need to design strategies that improve current DES. One such strategy is to improve endothelialization by capturing CD34‐positive cells (EPC) by the stent surface. The first human clinical trial using coronary EPC capture stents showed stent safety but neointimal thickness (NIT) was not reduced compared to bare metal stents (BMS). To understand these responses we studied the coronary response to the EPC capture stent in swine. Methods and Results : The stent, coated with murine antihuman monoclonal CD34 antibodies, was assessed with QCA guided stent implantation in normal swine coronary arteries for early endothelialization at 2 and 5 days, and NIT at 28 and 90 days in comparison to control stents carrying a non‐specific murine antibody or to BMS. The main finding was that while the EPC capture stent significantly improved early endothelialization it did not reduce NIT at 28 and 90 days. Conclusions : The EPC capture stent improves early endothelialization in swine but this does not affect neointimal thickness as compared to control stents at 28 and 90 days. © 2011 Wiley Periodicals, Inc.

Purpose : To measure the effect of cardiac motion on coronary artery stent position during the cardiac cycle as a first step toward exploring the feasibility of stereotactic external beam radiation therapy targeted at restenotic stented coronary arteries. Methods and Materials : The three-dimensional (3D) position of eight coronary artery stents in 8 patients immobilized in a stereotactic body frame was studied noninvasively by single-breathhold ECG-gated multislice spiral computed tomography (MSCT) during 10 retrospectively selected phases, equally distributed throughout the R-R interval of consecutive cardiac cycles. The volume encompassing all measured 3D positions of the stent was measured. Results : Stent volumes measured by MSCT closely agreed with measurements by quantitative coronary angiography (r > 0.99). The mean of the maximum 3D stent center of mass displacement between any two phases during the cardiac cycle for all eight coronary arteries was 7.5 mm (range 3.3–20.5 mm) in the lateral direction, 8.6 mm (range 2.7–21.6 mm) in the ventrodorsal direction, and 8.2 mm (range 2.5–19.7 mm) in the craniocaudal direction. As was anticipated, the volume encompassing all measured 3D positions of the stent represented only a fraction of the whole heart volume in all patients, i.e., less than 0.6%. Conclusions : ECG-gated MSCT allowed the measurement of the volume encompassing multiphase 3D positions of coronary artery stents during the cardiac cycle. This volume, a measure of the cardiac motion effect on coronary artery stent position during the cardiac cycle, represents a moving gross target for stereotactic external beam radiation therapy.

When a lesion is unstable, it may rupture and cause an acute thrombotic reaction. A rupture prone plaque contains a large lipid pool covered by a thin fibrous cap. Intravascular ultrasound (IVUS) elastography can assess the presence of lipid pools and identify high stress regions. The deformation of the tissue is determined using ultrasound. For intravascular purposes, the intraluminal pressure is used as the excitation force. The radial strain in the tissue is obtained by cross-correlation techniques on the radio frequency (rf) signal. The strain is colour-coded and plotted as a complimentary image to the IVUS echogram , or , in case of palpography, as a ring on the lumen vessel boundary.

Background and purpose Intracoronary brachytherapy after percutaneous transluminal coronary angioplasty (PTCA) is usually performed with catheter-based treatment techniques in a straight vessel segment. There is a growing interest for treatment of bifurcations, which requires consecutive positioning of the source in main vessel and side branch. Materials and methods In-house developed software (IC-BT doseplan) is used to explore the optimal positioning of the source in modelled bifurcations with different shape for the source types available in our hospital, i.e. 90Sr/90Y, 32P and 192Ir. The results were summarised in look-up tables. The usefulness of these look-up tables was tested on various clinical examples. Results Tabulated results for the modelled bifurcations yield an estimation of the distance between the sources (gap width) in relation to the geometry and source type: 90Sr/90Y gap range 3–8.5 mm, 32P gap range 2–7 mm and 192Ir gap range 3.5–8 mm. The average dose relative to 2 mm from the source axis is: 90Sr/90Y, (mean±SD) 120±40%; 32P, 125±50% and 192Ir, 120±22%. The look-up tables also provide the coarse location and value of maximum and minimum dose: 90Sr/90Y, 220–60%, 32P, 230–55% and 192Ir, 170–85%. It appeared that the look-up tables provide a good approximation of the optimal gap width in the clinical examples. Conclusions Tabulated optimal gap widths are very useful for quick estimation of the required gap width for a given bifurcation and source type, in case the prescribed dose in both vessels is the same. In unfavourable geometries there is a risk of local underdosage. Individual treatment planning using a program such as IC-BT doseplan is then recommended.

The effects of vagal stimulation on pulmonary vascular permeability were studied in guinea pigs in vivo using 125I-labeled albumin as a marker of plasma extravasation. Bilateral vagus nerve stimulation (NS) significantly increased the plasma leakage index in both parenchyma and tracheobronchial tissues. The NS-induced plasma leakage in the parenchyma was unaffected by the alpha-adrenoceptor antagonist phentolamine, the muscarinic receptor antagonist atropine, the ganglionic blocker hexamethonium, or pretreatment with 6-hydroxydopamine or capsaicin, but it was significantly potentiated by the beta-adrenoceptor antagonist propranolol. NS-induced tracheobronchial vascular leakage was markedly inhibited by pretreatment with atropine, hexamethonium, or capsaicin, although it was unaffected by pretreatment with phentolamine, propranolol, or 6-hydroxydopamine. By itself, NG-nitro L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthase, had no effect on pulmonary vascular leakage, but it significantly enhanced the NS-induced plasma leakage to parenchyma in a dose-related and L-arginine-reversible manner. Elevation of blood pressure to a similar extent as that induced by L-NAME by a phenylephrine infusion had no significant effect on the increased plasma leakage induced by NS. These results suggest that vagal stimulation increases plasma extravasation in lung parenchyma through the release of unidentified transmitter(s) in a process that is modulated by endogenous NO and catecholamines (via activation of beta-adrenoceptors), and that different mechanisms are involved in the vagally induced plasma extravasation in the pulmonary and tracheobronchial vascular beds.

Bipyridine derivatives have recently been introduced as a new class of inodilator drugs in the intravenous therapy of heart failure. A member of this class is milrinone, which improves the inotropic state and reduces ventricular afterload, leading to improved hemodynamics. Because systolic and diastolic function are intimately related, it can be expected that the diastolic muscle properties are influenced by changes in systolic function and therefore by milrinone therapy. Since end-diastolic pressure may shift as a result of a change in ventricular volume alone, a complete left ventricular diastolic pressure volume (LVDPV) relationship must always be measured before one can make firm conclusions regarding changes in diastolic function. After a LVDPV relationship is obtained, one should identify the variables that can modify this relationship without directly affecting the intrinsic diastolic muscle properties. These variables can be divided into static effects (coronary vascular bed volume, right ventricular pressure, and pericardial pressure) and dynamic effects (viscoelasticity and myocardial active relaxation). Increments in coronary perfusion pressure of perfusion flow (vascular bed volume) are known to stiffen the cardiac wall (turgor effect). Changes in right ventricular pressure or pericardial pressure are other factors affecting the LVDPV relationship by changing transmural pressure. This effect is more pronounced when the ventricle is already stiff, such as in patients with myocardial hypertrophy. Dynamic effects become important when a LVDPV relationship is measured during isolated cardiac cycles; they include viscoelasticity and abnormal myocardial relaxatlon. Clinical assessment of diastolic cardiac performance assumes a model in which the heart is considered an elastic body (while in fact it is viscoelastic). Therefore any increment in filling rate (dv/dt) will decrease the distensibility and result in a higher end-diastolic pressure. Abnormal relaxation is consistently present in patients with heart failure. It increases early diastolic myocardial stiffness caused by longer muscle activation (passive), and thus the LVDPV relationship will shift upward. In view of these considerations, how does one interpret the effects of milrinone on diastolic performance? The improved contractility increases cardiac metabolism and coronary blood flow. As a result, the cardiac wall stiffens by the erectile effect. An increase in atrial contractility must also be considered. This will increase the filling rate and will stiffen the wall further because of a viscoelastic effect in late diastole. The relaxation rate is affected by changes in afterload (vasodilation) and level of contractility. Both of these effects tend to increase the relaxation rate and distensibility of the left ventricle measured from the LVDPV relationship. This change in relaxation rate is independent of the direct changes in muscle properties. The erectile and viscoelastic effects counteract active relaxation, reflecting a direct milrinone effect. These effects probably explain why in our study there was an increase in distensibility in some patients and a decrease in distensibility in others after milrinone therapy. In view of the problems in controlling the variables in humans affecting the LVDPV relationship, the present results make it difficult to draw firm conclusions regarding the effect of milrinone on cardiac performance.