Publications

1. The molecular mechanisms involved in the regulation of muscarinic receptor gene expression are poorly understood. We have investigated the effect of homologous stimulation on the regulation of M2 muscarinic receptor protein and gene in human embryonic lung fibroblasts (HEL 299 cells). 2. Saturation studies performed with the non-selective hydrophilic ([3H]-N-methyl-scopolamine, [3H]-NMS) and lipophilic (3H]-quinuclidinyl benzilate, [3H]-QNB) muscarinic antagonists revealed a single class of high affinity binding sites. 3. Carbachol (1 mM) induced a rapid down-regulation of [3H]-NMS binding sites. Within 12 h, the process had approached steady state with 40 to 60% loss of receptors at 12 and 24 h. 4. The loss of [3h]-QNB binding sites (40% reduction at 24 h) occurred at a slower rate than did loss of [3H]-NMS binding sites as a result of receptor sequestration. 5. Carbachol treatment was accompanied by a functional desensitization of the receptor after 24 h of agonist treatment. In untreated cells, forskolin induced a large increase in cyclic AMP accumulation which was inhibited significantly by carbachol. The inhibitory effect of carbachol on forskolin-induced cyclic AMP accumulation was lost following 24 h carbachol stimulation. 6. The steady state level of muscarinic m2 mRNA measured by Northern blot analysis was not affected by carbachol had no effect on the stability of m2 mRNA. 7. The rate of transcription of m2 muscarinic receptor gene as measured by nuclear RNA run-on assay was unaltered by carbachol stimulation. 8. These results suggest that homologous sequestration, desensitization, and down-regulation of M2 modifications of m2 muscarinic receptor mRNAs.

No abstract is provided for this article.

An experimental study into the structural behaviour of Directed Energy Deposition-arc or wire arc additively manufactured (DED-arc AM and WAAM, respectively) steel double-lap shear bolted connections is presented. The mechanical properties of the material, which had a nominal yield stress of 420 MPa, were first determined by means of tensile coupon tests. Sixty connection specimens of two different nominal thicknesses and two print layer orientations were then tested to failure. The geometry of the test specimens was determined by 3D laser scanning, while the deformation and strain fields were measured during testing using digital image correlation. The observed failure modes included shear-out, net section tension, bearing and end-splitting, while a new hybrid mode of shear-out and net section tension was identified for the first time. The test results were compared against the predictions of current design specifications, namely AISI S100 and AS/NZS 4600 for cold-formed steel and AISC 360 and Eurocode 3 for structural steel, to evaluate their applicability to WAAM elements. Overall, the structural behaviour of the tested specimens followed the anticipated trends, and the predicted resistances determined from the current design specifications were generally reasonable. There were, however, a number of exceptions to this, highlighting the need for new design provisions, together with appropriate safety factors, that are specific to this form of manufacture.

Wire-Arc Directed Energy Deposition (DED-Arc) or Wire Arc Additive Manufacturing (WAAM) is a metal 3D printing method offering the ability to produce large-scale structural components with complex geometries in an efficient and cost-effective manner. To date, only a limited number of experimental studies on the structural behaviour of slender DED-Arc hollow sections have been conducted. To fill this gap, new experimental evidence on the behaviour of DED-Arc shell structures is thus reported. A comprehensive experimental programme investigating the local buckling response of DED-Arc high strength steel circular hollow sections (CHS) over a wide range of cross-sectional slendernesses has been conducted. In total, twelve DED-Arc CHS stub columns with a series of diameter-to-thickness ratios were produced using ER120S-G wire. The undulating as-built geometry and the initial geometric imperfections of the stub columns were captured using 3D laser scanning. During the stub column tests, the deformation fields were captured by means of digital image correlation. In the present paper, following the description of the specimen production, the experimental programme is described, the test results are analysed and the applicability of the current Eurocode 3 rules to the design of DED-Arc CHS is assessed by comparing the test results with the EN 1993-1-1 and EN 1993-1-6 design provisions. The test results show that the structural behaviour of DED-Arc CHS is similar to that of conventionally-produced (i.e. cold-formed and hot-rolled) steel CHS. Both EN 1993-1-1 and EN 1993-1-6 yield safe-sided resistance predictions, with the latter being more accurate since it incorporates the influences of both the fabrication quality and of the initial geometric imperfections. • Experimental study on local buckling behaviour of DED-Arc high strength steel CHS. • 3D laser scanning and characterisation of local imperfection patterns of DED-Arc CHS. • Coupon tests and microstructure characterisation of DED-Arc high strength steel. • Applicability of EN 1993-1-1 and EN 1993-1-6 provisions assessed using test data.

No abstract is provided for this article.

Pathological studies suggest that calcified coronary nodules are a rare cause of thrombotic events. The frequency, distribution, predictors, and outcomes of calcified nodules have never been described.After successful stenting in 697 patients (167 female; median age, 58.1 years) with acute coronary syndromes, 3-vessel gray-scale and virtual histology intravascular ultrasound was performed in the proximal-mid segments of all 3 coronary arteries as part of a prospective, multicenter study. On the basis of recent histological validation, an independent core laboratory identified calcified nodules as distinct calcification with an irregular, protruding, and convex luminal surface. Patients were followed up for 3 years (median). Overall, 314 calcified nodules were detected in 250 of 1573 analyzable arteries (185 of 623 patients). Thus, the prevalence of calcified nodules was 17% per artery and 30% per patient. Two or more calcified nodules were detected in 48 coronary arteries (3%) in 76 patients (12%). The calcified nodules were located <40 mm from the ostium of the coronary artery in 85% of left anterior descending arteries and 86% of left circumflex arteries, whereas calcified nodules within the right coronary arteries were evenly and more distally distributed. Patients with calcified nodules were significantly older and had more plaque volume, more thick-cap fibroatheroma, but fewer nonculprit lesion major adverse events on follow-up.Calcified nodules in untreated nonculprit coronary segments in patients with acute coronary syndromes were more prevalent than previously recognized. Although their distribution mirrored the origin of most thrombotic events, calcified nodules caused fewer major adverse events during 3 years of follow-up.

Background: Elevated B-type natriuretic peptide (BNP) is reflective of impaired cardiac function and is associated with worse prognosis among patients with coronary artery disease (CAD). We sought to assess the association between baseline BNP, adverse outcomes, and the relative efficacy of percutaneous coronary intervention (PCI) versus coronary artery bypass grafting (CABG) in patients with left main CAD. Methods: The EXCEL trial (Evaluation of XIENCE Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) randomized patients with left main CAD and low or intermediate SYNTAX scores (Synergy Between PCI With TAXUS and Cardiac Surgery) to PCI with everolimus-eluting stents versus CABG. The primary end point was the composite of all-cause death, myocardial infarction, or stroke. We used multivariable Cox proportional hazards regression to assess the associations between normal versus elevated BNP (≥100 pg/mL), randomized treatment, and the 3-year risk of adverse events. Results: BNP at baseline was elevated in 410 of 1037 (39.5%) patients enrolled in EXCEL. Patients with elevated BNP levels were older and more frequently had additional cardiovascular risk factors and lower left ventricular ejection fraction than those with normal BNP, but had similar SYNTAX scores. Patients with elevated BNP had significantly higher 3-year rates of the primary end point (18.6% versus 11.7%; adjusted hazard ratio [HR], 1.62; 95% confidence interval [CI], 1.16–2.28; P =0.005) and higher mortality (11.5% versus 3.9%; adjusted HR, 2.49; 95% CI, 1.48–4.19; P =0.0006), both from cardiovascular and noncardiovascular causes. In contrast, there were no significant differences in the risks of myocardial infarction, stroke, ischemia-driven revascularization, stent thrombosis, graft occlusion, or major bleeding. A significant interaction ( P interaction =0.03) was present between elevated versus normal BNP and treatment with PCI versus CABG for the adjusted risk of the primary composite end point at 3 years among patients with elevated BNP (adjusted HR for PCI versus CABG, 1.54; 95% CI, 0.96–2.47) versus normal BNP (adjusted HR, 0.74; 95% CI, 0.46–1.20). This interaction was stronger when log(BNP) was modeled as a continuous variable ( P interaction =0.002). Conclusions: In the EXCEL trial, elevated baseline BNP levels in patients with left main CAD undergoing revascularization were independently associated with long-term mortality but not nonfatal adverse ischemic or bleeding events. The relative long-term outcomes after PCI versus CABG for revascularization of left main CAD may be conditioned by the baseline BNP level. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01205776.

This paper describes the first reported attempt to develop a real-time intravascular ultrasonic palpation system. We also report on our first experience in the catherization laboratory with this new elastographic imaging technique. The prototype system was based on commercially available intravascular ultrasound (US) scanner that was equipped with a 20-MHz array catheter. Digital beam-formed radiofrequency (RF) echo data (i.e., 12 bits, 100 Hz) was captured at full frame rate from the scanner and transferred to personal computer (PC) memory using a fast data-acquisition system. Composite palpograms were created by applying a one-dimensional (1-D) echo tracking technique in combination with global motion compensation and multiframe averaging to several pairs of RF echo frames that were obtained in the diastolic phase of the cardiac cycle. The quality of palpograms was assessed by conducting experiments on vessel phantoms and on patients. The results demonstrated that robust and consistent palpograms could be generated in almost real-time using the proposed system. Good correlation was observed between low strain values and regions of calcification as identified from the intravascular US (IVUS) sonograms. Although the clinical results are clearly preliminary, it was concluded that the prototype system performed sufficiently well to warrant further and more in-depth clinical investigation. (E-mail: dekorte@tch.fgg.eur.nl)

Background New-generation drug-eluting stents (DES) have mostly been investigated in head-to-head non-inferiority trials against early-generation DES and have typically shown similar efficacy and superior safety. How the safety profile of new-generation DES compares with that of bare-metal stents (BMS) is less clear. Methods We did an individual patient data meta-analysis of randomised clinical trials to compare outcomes after implantation of new-generation DES or BMS among patients undergoing percutaneous coronary intervention. The primary outcome was the composite of cardiac death or myocardial infarction. Data were pooled in a one-stage random-effects meta-analysis and examined at maximum follow-up and a 1-year landmark. Risk estimates are reported as hazard ratios (HRs) with 95% CIs. This study is registered in PROSPERO, number CRD42017060520. Findings We obtained individual data for 26 616 patients in 20 randomised trials. Mean follow-up was 3·2 (SD 1·8) years. The risk of the primary outcome was reduced in DES recipients compared with BMS recipients (HR 0·84, 95% CI 0·78–0·90, p<0·001) owing to a reduced risk of myocardial infarction (0·79, 0·71–0·88, p<0·001) and a possible slight but non-significant cardiac mortality benefit (0·89, 0·78–1·01, p=0·075). All-cause death was unaffected (HR with DES 0·96, 95% CI 0·88–1·05, p=0·358), but risk was lowered for definite stent thrombosis (0·63, 0·50–0·80, p<0·001) and target-vessel revascularisation (0·55, 0·50–0·60, p<0·001). We saw a time-dependent treatment effect, with DES being associated with lower risk of the primary outcome than BMS up to 1 year after placement. While the effect was maintained in the longer term, there was no further divergence from BMS after 1 year. Interpretation The performance of new-generation DES in the first year after implantation means that BMS should no longer be considered the gold standard for safety. Further development of DES technology should target improvements in clinical outcomes beyond 1 year. Funding Bern University Hospital.