Publications

Effect of 5-HTA receptor agonist, 8-OH-DPAT, on cough responses in the conscious guinea-pig

Drugs for airway disease

Editorial

ESC Journals working together

cardiology. However, the mood of the meeting was not primarily celebratory; rather, we were there to discuss the vision of the ESC Journal Family within an increasingly competitive landscape. More new journals are expected to enter the field within the coming months and it will be our fundamental task as ESC Journal Editors to keep on differentiating our journals from the rest of the pack. The foremost “weapon” in our armoury is the speed and quality of the reviews – almost all journals showed increases in the review turnaround time – but with this increase, coupled with an increase of submissions will lead to obviously higher rejection rates, there is – after all – only so much you can publish in any given year. What is obvious is that the “accept-to-publish” time is a parameter that will become just as important as the “review-turnaround” time. It is here, looking at this particular aspect, that there is definitely room to improve our journal in the future. The growth of open-access journals is another aspect that may impact on our publications – although we might add that EuroIntervention still has open access with all PDFs being freely available for download. However, how does the publisher generate enough funds to cover costs, particularly if the journal is online only? With this in mind, we look forward to the imminent launch and initial experiences of BMJ’s Open Heart, an online-only, open-access journal under the Editorship of Pascal Meier. Is the PLoS ONE model – charging the author a fee, usually per article published – something we should consider to cover costs? Should reviewers be paid for their work? Would this potentiality bias their comments or review outcomes? Finally on this point, and somewhat paradoxically, a recent study concluded that overall citation rates were 30% higher for subscription journals as compared to open-access journals 1

TCT-304 Non-Invasive Assessment of Microvascular Dysfunction After Optimal Coronary Artery Stent Deployment; Insight From Acetyl Salicylic Elimination Trial (ASET) Japan

No abstract is provided for this article.

Elevated CCL2 responses in COPD and attenuation by selective chemokine receptor antagonists

Monocyte (M¤) recruitment into the lungs of COPD can drive excessive macrophage inflammation. Increased CCL2 in sputum and BALF in COPD may drive this response; novel therapies that attenuate M¤ migration would be beneficial. The effect of CCL2 stimulation was investigated on PBMC and M¤ by measuring chemotaxis, [Ca²⁺]_i signalling and activation by up-regulation of CD11b and the effect of receptor antagonists on these responses. Chemotaxis was measured using Boyden chamber, CD11b expression was measured in whole blood by flow cytometry and [Ca2+]_i release fluorimetrically with cells from non-smokers (NS), smokers (S) and COPD. Basal CD11b did not differ in M¤ however, CCL2 (10nM) increased CD11b expression in COPD M¤ compared with S (232.1±24.1(n=5) <i>vs</i> 148.1±11.5(n=5 % change MFI respectively p&lt;0.05). There was increased COPD M¤ chemotaxis to CCL2 (3nM)(COPD:67.7±7.5 n=4, NS:48.5±7.9 n=6, S:53.5±4.5 n=5 cells/field). In contrast, [Ca²⁺]_i was similar across groups (EC₅₀ NS:1.9±0.5 n=5, S:1.4±0.2 n=4 COPD:1.4±0.5 n=3 x10^-8M). These effects were inhibited by the CCR2 antagonist, PF0413, (EC₅₀ NS:3.0±1.4 n=6, S:7.3±6.8 n=6, COPD:5.1±3.7 n=5 x10^-8M) and the dual CCR2/5 antagonist, PF04173 (EC₅₀ NS:2.8±1.4 n=6, S:4.0±1.6 n=6 COPD:1.6±0.6 n=6 x10^-8M). In contrast, a CCR1 (CP4817) and CCR5 (UK4278) antagonist had no effect against CCL2 induced [Ca²⁺]_i. CCL2 highly activated COPD M¤ and is associated with increased migration, however this is not coupled with increased [Ca²⁺]_i. This response is mediated by CCR2 and can be abrogated by selective receptor antagonists. These data suggest that blocking CCR2 may be a potential anti-inflammatory therapy to prevent macrophage accumulation in COPD.

2213Impact of BMI on clinical outcomes in all-comers patients with coronary artery disease undergoing PCI: insights from the Global Leaders study

Background It is uncertain if the obesity paradox still exists in contemporary PCI practice. Purposes We aimed to assess an association between baseline BMI and clinical outcomes at 2 years after PCI and to determine if the outcomes between two antiplatelet strategies depend on baseline BMI. Methods Global Leaders study compared 23-month ticagrelor monotherapy after 1 month of dual antiplatelet therapy (experimental strategy) with 12-month aspirin monotherapy after 12 months of conventional DAPT (reference strategy) in patients undergoing PCI with biolimus-A9 eluting stent. Primary outcome of current study was 2-year all-cause mortality after PCI. Secondary outcomes were net adverse clinical event (NACE) and individual components of the composite endpoint. Association between baseline BMI and outcomes were determined in the Cox model. Non-linearity was assessed using restrict cubic spline function. Patients were categorized according to WHO BMI categories; underweight (BMI &lt;18.5), healthy weight (BMI 18.5–24.9), pre-obese state (BMI 25–29.9) and obesity (BMI ≥30). Interaction between BMI categories and antiplatelet strategies were assessed. Results BMI was available in 15,966 out of 15,968 patients with a median of 27.7 kg/m2 (IQR 25.0–30.7). Baseline BMI had a reverse J-shaped association with 2-year all-cause mortality. 3901 patients (24.4%) were in the group of healthy weight, 79 patients (0.5%) were under-weight, 7220 patients (45.2%) were pre-obese and 4766 patients (29.8%) were obese. Due to small number of underweight patients, outcomes after PCI were compared among three groups; healthy weight, overweight, and obesity. Pre-obese and obese patients had lower risk of 2-year all-cause mortality than healthy-weight patients (HR pre-obesity vs. healthy-weight 0.71, 95% CI 0.58–0.88, HR obesity vs. healthy-weight 0.69, 95% CI 0.54–0.87). The risk of 2-year NACE was similar among three groups (healthy weight vs. pre-obesity; HR 1.04, 95% CI 0.94–1.16, healthy weight vs. obesity; HR 1.04, 95% CI 0.93–1.16). No significant difference in risk of any stroke, any MI, and BARC3 or 5 bleeding was found among three groups. Pre-obese patients had higher risk of revascularization than patients with healthy weight (HR 1.19, 95% CI 1.04–1.35). The risk of revascularization in obese patients was numerically higher than healthy-weight patients (HR 1.14, 95% CI 0.99–1.31). For BARC 3 or 5 bleeding at 2 years, ticagrelor monotherapy was more favorable in obese patients (HR reference/experimental 1.63, 95% CI 1.06–2.52) while conventional DAPT strategy was more favorable in pre-obese patients (HR experimental/reference 0.76, 95% CI 0.55–1.05) (P interaction 0.02). No interaction between treatment strategy, BMI, and other outcomes was seen. BMI and all-cause mortality and NACE Conclusions An obesity paradox, an association between elevated BMI and lower mortality, is still evident in this large PCI population. Effect of two antiplatelet strategies on bleeding may depend on baseline BMI.

Unmet clinical needs in asthma: Childhood to old age

Site-Specific Intracoronary Delivery of Octreotide in Humans: A Pharmacokinetic Study to Determine Dose-Efficacy in Restenosis Prevention

Somatostatin analogues have been shown to inhibit smooth muscle cell proliferation after local administration in vivo in animal models and in vitro using human coronary smooth muscle cell cultures. However, the optimal dosage for attaining effective site-specific administration remains undefined. This study was performed to determine the required theoretical dose of the somatostatin analogue, octreotide, to be delivered site specifically, for prevention of restenosis after coronary angioplasty in humans using a previously described methodology to determine regional pharmacokinetics of site-specific intracoronary administrated compounds. In 7 patients, 111In-octreotide, a γ-labeled somatostatin analogue, was infused post angioplasty at the site of dilatation via a coil-balloon and quantified using a radio-isotopic technique. Efficiency of delivery ranged from 0.1% to 2.7% of the total infused dose of 0.18 μg, corresponding to a mean peak delivered amount of 1.8 ± 1.9 ng. Total locally bioavailable 111In-octreotide reached 2.28 ± 2.15 ng h. Based on current in vitro bioavailability and peak concentration data to inhibit proliferation and thymidine incorporation in human coronary smooth muscle cells, a 4000× higher averaged dose (∼700 μg) should be infused site specifically to obtain a biologic efficacy in 50% of the treated patients (ED50). Quantification of regional pharmacokinetics enables the determination of a theoretical site-specific dose for achieving appropriate bioavailablility above the therapeutic threshold concentration for smooth muscle cell inhibition. This approach is proposed for the determination of the appropriate site-specific coronary infusion dose for the inhibition of restenosis after balloon angioplasty.

Editorial

Responses of Leukocytes to Chemokines in Whole Blood and Their Antagonism by Novel CC-Chemokine Receptor 3 Antagonists

CC-chemokine receptor 3 (CCR3)-stimulating chemokines are likely to have important in vivo roles in the regulation of eosinophil, basophil, and potentially helper T cell type 2 and mast cell recruitment. We have developed techniques to investigate the actions of eotaxin and other chemokines on multiple leukocyte populations in whole blood, without cell purification steps that might alter leukocyte responsiveness. We have shown that the potency of eotaxin in whole blood is limited by Duffy antigen binding, which may modulate the actions of this chemokine in vivo. We have also investigated the efficacy and potency of a new panel of small molecule antagonists of CCR3 on responses of eosinophils, neutrophils, basophils, and monocytes to chemokines, using whole blood assays of shape change, chemokine receptor internalization, and CD11b upregulation. These small molecule antagonists cause selective and potent inhibition of CCR3 on eosinophils and basophils, are bioavailable in blood, and are prototypic antagonists potentially of benefit in the treatment of human allergic disease. Such whole blood methods may also be employed in the investigation of other small molecule chemokine receptor antagonists.

High prevalence of developmental disorders in pediatric eosinophilic esophagitis (EoE): A single-center observational study

TUMOR NECROSIS FACTOR ALTERS HUMAN BRONCHIAL REACTIVITY AND INDUCES INFLAMMATORY CELL INFLUX

Effect Of Short-term (3 Day) Cigarette Smoke-exposure In Mice On Histone Deacetylase (HDAC)2 And Hypoxia Inducible Factor (HIF)-1± Function

Advances in stent drug delivery: the future is in bioabsorbable stents

This expert opinion review offers a perspective on the future developments in drug-eluting stent design. Initial efforts were focused on reduction of in-stent restenosis, which the drug-eluting stents addressed effectively. Current concerns are predominantly with regard to risk of stent thrombosis and delayed endothelialization. All three components of the stent have been modified to achieve the goal of endothelialization and vessel healing: drug, polymer and the platform. We review different approaches to reduce this risk from design of different drug combinations, through less traumatic metallic stent platforms, via biodegradable polymers and, finally, fully biodegradable stents. It seems at this time that fully biodegradable solutions to stenting hold the greatest promise, but larger long-term studies are needed to evaluate fully their safety and efficacy in 'all-comer' patient populations. At the time of this review, design of a safe drug-eluting stent still remains a challenge.

Do we still need to perform FFR and PCI?

No abstract is provided for this article.

The distribution and nature of the 2 m radiation of the inner Orion Nebula

We present a grey-scale map of a portion of the Orion Nebula made at a wavelength of 2.2 µm. Spatial chopping was not employed, so the map includes a true representation of the extended emission as well as the dense cluster of point infrared sources, Several features not previously recorded can be seen in this map. The nature of the point sources is discussed in relation to their near-infrared colours, and their magnitude distribution. We also describe our DC mapping technique and discuss its potential.

Mediators of Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is a major and increasing global health problem that is now a leading cause of death. COPD is associated with a chronic inflammatory response, predominantly in small airways and lung parenchyma, which is characterized by increased numbers of macrophages, neutrophils, and T lymphocytes. The inflammatory mediators involved in COPD have not been clearly defined, in contrast to asthma, but it is now apparent that many lipid mediators, inflammatory peptides, reactive oxygen and nitrogen species, chemokines, cytokines, and growth factors are involved in orchestrating the complex inflammatory process that results in small airway fibrosis and alveolar destruction. Many proteases are also involved in the inflammatory process and are responsible for the destruction of elastin fibers in the lung parenchyma, which is the hallmark of emphysema. The identification of inflammatory mediators and understanding their interactions is important for the development of anti-inflammatory treatments for this important disease.