Publications

Histone deacetylase-2 and airway disease

The increased expression of inflammatory genes in inflammatory lung diseases is regulated by acetylation of core histones, whereas histone deacetylase-2 (HDAC2) suppresses inflammatory gene expression. Corticosteroids suppress inflammatory genes in asthma by inhibiting histone acetyltransferase and in particular by recruiting HDAC2 to the nuclear factor-kappaB-activated inflammatory gene complex. This involves deacetylation of the acetylated glucocorticoid receptor. In COPD, severe asthma and asthmatics who smoke, HDAC2 is reduced, thus preventing corticosteroids from suppressing inflammation. The reduction in HDAC2 appears to be secondary to increased oxidative and nitrative stress in the lungs. Antioxidants and inhibitors of nitric oxide synthesis may therefore restore corticosteroid sensitivity in COPD, but this can also be achieved by low concentrations of theophylline and curcumin, which act as HDAC activators. Theophylline is a direct inhibitor of oxidant-activated phosphoinositide-3-kinase-delta, which is involved in inactivation of HDAC2. In the future selective PI3Kdelta inhibitors and more direct activators of HDAC2 may be used to treat corticosteroid-resistant inflammatory diseases of the lung, including COPD, severe asthma and asthma in smokers.

[Hemodynamic effects of nifedipine after intravenous or intracoronary injection].

No abstract is provided for this article.

Was the Ball Inside or Outside the Court?

No abstract is provided for this article.

Involvement Of P38MAPK Gamma On Corticosteroid Refractory Airway Inflammation Induced By Tobacco Smoke In Mice

Asthma guidelines: recommendations versus reality

Relation between Coronary Flow Reserve and Severity of Coronary Obstruction, Both Assessed from Coronary Cineangiogram

No abstract is provided for this article.

Molecular Mechanisms and Cellular Effects of Glucocorticosteroids

Physiological phenotype of coronary artery disease on short-term angina status in patients with CCS after PCI: perspective from PIONEER IV trial

Background The hemodynamic impact of PCI on major epicardial conductance vessels is the results of a complex interplay between diffuseness and focality of coronary artery atherosclerosis. The pre-procedural identification of these two phenotypes (diffuseness vs. focality) may have important implication on the angina relief after PCI. Purpose The aim of this study was to determine the differential improvement in patient-reported outcomes after PCI in focal and diffuse CAD as defined by the pullback pressure gradient index (PPGi) derived from angiography. Methods The PIONEER IV trial is a prospective, all-comers, multi-center trial, randomizing patients to PCI guided by angiography-derived physiology or usual care, with both arms using the Healing-Targeted Supreme sirolimus-eluting stent. Pre-procedural PPGi derived from angiography was documented. The 7-item Seattle Angina Questionnaire (SAQ-7) was administered at baseline and 30 days after PCI. The median PPG value was used to define focal and diffuse CAD. Residual angina was defined as a SAQ-AF score ≤ 90. Results A total of 203 patients were analyzed, in which 105 patients with focal CAD and 98 diffuse. Focal disease had larger pre-procedure QFR and post-procedure QFR value than patients with diffuse disease (0.71 ± 0.13 vs 0.59 ± 0.19, P < 0.001; 0.96 ± 0.04 vs 0.91 ± 0.08, P < 0.001). The median of PPGi was 0.73 (Figure 1A). In the restricted cubic spline model, the risk of residual angina rises substantially when the pre-procedural PPGi was below 0.74 (Figure 1B). Patients with focal disease who underwent PCI for focal CAD had significantly higher angina frequency score and quality of life score at follow-up than those with diffuse CAD (94.10 ± 11.58 vs 89.80 ± 16.31, P = 0.031; 75.77 ± 26.01 vs 67.17 ± 25.86, P=0.024; Figure 2). After PCI, residual angina was present in 35.0% but was significantly less in those with treated focal CAD (26.7 % vs 43.9 %; P = 0.015; Figure 1C-D). Conclusion Residual angina after PCI was higher in patients with diffuse CAD, whereas patients with focal CAD reported greater improvement in angina and quality of life. Whether pre-procedural physiological phenotyping should alter the therapeutic decision making to perform PCI, and could influence the procedure planning warrants further study.Figure 1Figure 2

The p70-S6K inhibitor LY2584702 reverses oxidative stress-induced senescence in small airway epithelial cells.

<b>Background:</b> Overactivation of the mammalian target of rapamycin (mTOR) pathway induced by oxidative stress leads to downregulation of the anti-ageing protein sirtuin-1 (SIRT1), resulting in cellular senescence similar to that seen in COPD. P70 S6 kinase (p70-S6K) acts downstream of mTOR to regulate the cell cycle and DNA damage response. Inhibiting p70-S6K may be able to reverse cell cycle arrest and senescence and identify a therapeutic target for diseases of lung ageing. <b>Aim:</b> To examine the effect of inhibiting p70-S6K on SIRT1 and markers of senescence in H₂O₂-treated small airway epithelial cells (SAECs). <b>Methods:</b> SAECs isolated from non-smokers were cultured with or without 300µM H₂O₂ for 48h, followed by treatment with 10^-12-10^-5M LY2584702 (p70-S6K inhibitor) or 0.1% DMSO for 24h. Protein expression of SIRT1 was quantified using Western blot. Senescence associated-β-Galactosidase staining was used to determine senescent cells and ELISA for CXCL8 release. <b>Results:</b> H₂O₂ treatment significantly reduced SIRT1 protein (65%, p&amp;lt;0.01, n=3), increased CXCL8 (75%, p&amp;lt;0.01, n=5) and SA-β-Gal staining (51%, p&amp;lt;0.05, n=3). LY2584702 exhibited a concentration dependent effect, 10^-5M treatment increased SIRT1 protein expression (70%, p&amp;lt;0.01, n=3), reduced CXCL8 protein release (57%, p&amp;lt;0.01, n=3) and SA-β-Gal staining (30%, p&amp;lt;0.01, n=3). <b>Conclusion:</b> Inhibition of p70-S6K reverses oxidative stress-induced senescence in SAECs. Further investigation into the mechanism of p70-S6K in regulating SIRT1 may help identify further drug targets to combat cellular senescence in COPD.

Association of Serum PCSK9 with Near-Infrared Spectroscopy Derived Lipid Core Burden Index and Long-Term Cardiac Outcome

Background: We aimed to study the association between serum proprotein convertase subtilisin/kexin type 9 (PCSK9) levels, and near-infrared spectroscopy (NIRS)-derived lipid core burden index (LCBI) and the occurrence of major adverse cardiac events (MACE) in patients with coronary artery disease (CAD).Methods: Serum PCSK9 levels were measured in 576 CAD patients who underwent diagnostic coronary angiography (CAG). NIRS imaging was performed in a subset of 203 patients, in a non-culprit coronary artery segment of at least 40 mm in length. LCBI was assessed in a core laboratory. Data on all-cause mortality, nonfatal ACS or unplanned coronary revascularization was collected during a median follow-up of 4·7 years.Findings: In multivariable analysis, after adjustment for cardiac risk factors, statin use at time of hospital admission and serum LDL cholesterol levels, serum PCSK9 was positively associated with LCBI (mean increase of 0·390 (95% CI [0·011-0·769] ZlnLCBI per unit increase in lnPCSK9 level p =0·044)). During a median follow-up of 4·7 years, 155 patients (27%) had MACE. After multivariable adjustment, serum PCSK9 levels showed a tendency towards an association with MACE (HR [95%CI]: 1·64[0·99-2·71], p=0·055) and a positive association with the composite of death or ACS (HR [95%CI]: 1·88[1·01-3·51], p=0·047). Patients admitted with serum PCSK9 levels above the median of 270 μg/L had 53% higher risk of MACE and 67% higher risk of death or ACS than those with levels below the median.Interpretation: CAD patients with elevated serum PCSK9 levels had a higher NIRS-derived LCBI and higher incidence of adverse cardiac outcome than those with lower levels.Funding Statement: This ATHEROREMO-IVUS study was supported by the European Commission, Seventh Framework Programme (theme FP7-HEALTH-2007-2.4.2-1). The current study was also funded by BBMRI-NL (a research infrastructure financed by the Dutch government, NWO 184.021.007) and the Netherlands Heart Foundation (NHS2007B012 to R.M.O.). The funders had no role in study design, data collection, data analysis, interpretation, and/or writing of the report.Declaration of Interests:The authors report no relationships that could be construed as a conflict of interest.Ethics Approval Statement: The medical ethics committee of Erasmus MC approved the ATHEROREMO-IVUS study and its NIRS sub-study and written informed consent was obtained from all patients. The ATHEROREMO-IVUS study and its NIRS sub-study were performed in accordance with the declaration of Helsinki.

The immediate and long-term effect of balloon coronary angioplasty on the distal coronary flow velocity reserve

No abstract is provided for this article.

Avancées thérapeutiques pouvant modifier l’évolution clinique de la BPCO

Inhibition of neurogenic plasma exudation and bronchoconstriction by a K+ channel activator, BRL 38227, in guinea pig airways in vivo

Attenuation of Inhaled Allergen-induced Airway Microvascular Leakage and Airflow Obstruction in Guinea Pigs by a 5-Lipoxygenase Inhibitor (A-63162)

Leukotrienes, products of the 5-lipoxygenase pathway in the metabolism of arachidonic acid, are potent mediators of airway microvascular leakage and smooth muscle contraction in guinea pigs. We studied the effect of a specific 5-lipoxygenase inhibitor, A-63162, on airway microvascular leakage and airflow obstruction following inhaled ovalbumin in actively sensitized guinea pigs. Airway microvascular leakage was assessed by extravasation of Evans blue dye Into airway tissues. Inhaled ovalbumin caused increased lung resistance (Rl) with decreased dynamic compliance (Cl) and increased extravasation of Evans blue dye at all airway levels. A-63162 reduced the changes in Rl and Cl at 1.0 µmol/kg (p < 0.05) but not at lower doses of 0.1 and 0.3 µmol/kg. A-63162 reduced Evans blue dye extravasation in airway tissues at all three doses, however, being most effective in the distal airways (p < 0.01), and these reductions were greater than those in Rl and Cl. A 5-lipoxygenase inhibitor thus reduced airway microvascular leakage to a greater extent than airflow obstruction, suggesting that leukotrienes have a larger contribution to changes in airway microvascular permeability than smooth muscle contraction following inhaled allergen challenge in actively sensitized guinea pigs in vivo.

Inhibition of cutaneous and platelet responses to platelet-activating factor by oral WEB 2086 in man

Influence of load and high temperature on the post‐fire behaviour of high‐strength structural steels

Abstract In this work, an experimental campaign was carried out to evaluate the post‐fire mechanical performance of high‐strength steel specimens (grade S700) when being subjected simultaneously to different combinations of tensile load and elevated temperature. To this end, transient‐state tests were firstly carried out to obtain the ‘critical temperature’, i.e., the temperature at which a specimen failed while being simultaneously subjected to tensile load and heated at a constant temperature rate. Secondly, post‐fire tests were performed on unloaded as well as loaded specimens. For that purpose, specimens were heated to temperatures below the critical temperature, cooled down in air and finally submitted to tensile testing. In order to investigate the influence of production route, specimens were extracted from cold‐formed circular hollow sections and hot‐rolled sheets. Moreover, coupons with five different thicknesses were tested to investigate the influence of section thickness on the post‐fire behaviour. Residual values of yield strength, ultimate strength, elastic modulus and ductility were determined from the tests and discussed.

Relationship of Isoniazid Resistance to Human Immunodeficiency Patients with Tuberculosis

To investigate the relationship between isoniazid resistance and HIV infection in patients with tuberculosis, the authors evaluated data in the Los Angeles County tuberculosis registry on 1,506 patients for whom drug susceptibility results were available.

Relationship Between Neointimal Thickness and Shear Stress After Wallstent Implantation in Human Coronary Arteries

Background —In-stent restenosis by excessive intimal hyperplasia reduces the long-term clinical efficacy of coronary stents. Because shear stress (SS) is related to plaque growth in atherosclerosis, we investigated whether variations in SS distribution are related to variations in neointima formation. Methods and Results —In 14 patients, at 6-month follow-up after coronary Wallstent implantation, 3D stent and vessel reconstruction was performed with a combined angiographic and intravascular ultrasound technique (ANGUS). The bare stent reconstruction was used to calculate in-stent SS at implantation, applying computational fluid dynamics. The flow was selected to deliver an average SS of 1.5 N/m 2 . SS and neointimal thickness (Th) values were obtained with a resolution of 90° in the circumferential and 2.5 mm in the longitudinal direction. For each vessel, the relationship between Th and SS was obtained by linear regression analysis. Averaging the individual slopes and intercepts of the regression lines summarized the overall relationship. Average Th was 0.44±0.20 mm. Th was inversely related to SS: Th=(0.59±0.24)−(0.08±0.10)×SS (mm) ( P &lt;0.05). Conclusions —These data show for the first time in vivo that the Th variations in Wallstents at 6-month follow-up are inversely related to the relative SS distribution. These findings support a hemodynamic mechanism underlying in-stent neointimal hyperplasia formation.