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1.  Small high-density lipoprotein is associated with monocyte subsets in stable coronary artery disease 
Atherosclerosis  2014;237(2):589-596.
Objective: High-density lipoprotein (HDL) particles are heterogeneous in structure and function and the role of HDL subfractions in atherogenesis is not well understood. It has been suggested that small HDL may be dysfunctional in patients with coronary artery disease (CAD). Monocytes are considered to play a key role in atherosclerotic diseases. Circulating monocytes can be divided into three subtypes according to their surface expression of CD14 and CD16. Our aim was to examine whether monocyte subsets are associated with HDL subfractions in patients with atherosclerosis. Methods: We included 90 patients with angiographically stable CAD. Monocyte subsets were defined as classical monocytes (CD14++CD16-; CM), intermediate monocytes (CD14++CD16+; IM) and non-classical monocytes (CD14+CD16++; NCM). HDL subfractions were measured by electrophoresis on polyacrylamide gel. Results: Serum levels of small HDL correlated with circulating pro-inflammatory NCM and showed an inverse relationship to circulating CM independently from other lipid parameters, risk factors, inflammatory parameters or statin treatment regime, respectively. IM were not associated with small HDL. In particular, patients with small HDL levels in the highest tertile showed dramatically increased levels of NCM (14.7 ± 7% vs. 10.7 ± 5% and 10.8 ± 5%; p = 0.006) and a decreased proportion of CM (79.3 ± 7% vs. 83.7 ± 6% and 83.9 ± 6%; p = 0.004) compared to patients in the two lower tertiles. In contrast, intermediate HDL, large HDL and total HDL were not associated with monocyte subset distribution. Conclusion: Small HDL levels are associated with pro-inflammatory NCM and inversely correlated with CM. This may suggest that small HDL could have dysfunctional anti-inflammatory properties in patients with established CAD.
Highlights
•Small HDL levels are associated with non-classical monocytes in stable CAD.•Classical monocytes are inversely associated with small HDL levels.•Associations are independent of other lipid parameters, risk factors, inflammatory parameters or statin treatment regime.•Inflammatory markers do not vary according to small HDL levels.
doi:10.1016/j.atherosclerosis.2014.10.015
PMCID: PMC4270455  PMID: 25463093
HDL; Small HDL; Atherosclerosis; Monocytes; Monocyte subsets; Inflammation
2.  Components of the interleukin-33/ST2 system are differentially expressed and regulated in human cardiac cells and in cells of the cardiac vasculature 
Interleukin-33 (IL-33) is a recently described member of the IL-1 family of cytokines, which was identified as a ligand for the ST2 receptor. Components of the IL-33/ST2 system were shown to be expressed in normal and pressure overloaded human myocardium, and soluble ST2 (sST2) has emerged as a prognostic biomarker in myocardial infarction and heart failure. However, expression and regulation of IL-33 in human adult cardiac myocytes and fibroblasts was not tested before. In this study we found that primary human adult cardiac fibroblasts (HACF) and human adult cardiac myocytes (HACM) constitutively express nuclear IL-33 that is released during cell necrosis. Tumor necrosis factor (TNF)-α, interferon (IFN)-γ and IL-1β significantly increased both IL-33 protein and IL-33 mRNA expression in HACF and HACM as well as in human coronary artery smooth muscle cells (HCASMC). The nuclear factor-κB (NF-κB) inhibitor dimethylfumarate inhibited TNF-α- and IL-1β-induced IL-33 production as well as nuclear translocation of p50 and p65 NF-κB subunits in these cells. Mitogen-activated protein/extracellular signal-regulated kinase inhibitor U0126 abrogated TNF-α-, IFN-γ-, and IL-1β-induced and Janus-activated kinase inhibitor I reduced IFN-γ-induced IL-33 production. We detected IL-33 mRNA in human myocardial tissue from patients undergoing heart transplantation (n = 27) where IL-33 mRNA levels statistically significant correlated with IFN-γ (r = 0.591, p = 0.001) and TNF-α (r = 0.408, p = 0.035) mRNA expression. Endothelial cells in human heart expressed IL-33 as well as ST2 protein. We also reveal that human cardiac and vascular cells have different distribution patterns of ST2 isoforms (sST2 and transmembrane ST2L) mRNA expression and produce different amounts of sST2 protein. Both human macrovascular (aortic and coronary artery) and heart microvascular endothelial cells express specific mRNA for both ST2 isoforms (ST2L and sST2) and are a source for sST2 protein, whereas cardiac myocytes, cardiac fibroblasts and vascular SMC express only minor amounts of ST2 mRNA and do not secrete detectable amounts of sST2 antigen. In accordance with the cellular distribution of ST2 receptor, human cardiac fibroblasts and myocytes as well as HCASMC did not respond to treatment with IL-33, as recombinant human IL-33 did not induce NF-κB p50 and p65 subunits nuclear translocation or increase IL-6, IL-8, and monocyte chemoattractant protein (MCP-1) level in HACF, HACM and HCASMC. In summary, we found that endothelial cells seem to be the source of sST2 and the target for IL-33 in the cardiovascular system. IL-33 is expressed in the nucleus of human adult cardiac fibroblasts and myocytes and released during necrosis. Proinflammatory cytokines TNF-α, IFN-γ and IL-1β increase IL-33 in these cells in vitro, and IL-33 mRNA levels correlated with TNF-α and IFN-γ mRNA expression in human myocardial tissue.
Highlights
•IL-33 is in nucleus of cardiac myocytes, cardiac fibroblasts and smooth muscle cells.•TNF-α, IFN-γ, IL-1β increase IL-33 expression in these cells.•IL-33 is released during necrosis by these cells.•Endothelial cells in myocardial tissue predominantly express IL-33 and ST2.•Endothelial cells express the IL-33 receptor ST2 and secrete soluble ST2.
doi:10.1016/j.yjmcc.2013.03.020
PMCID: PMC3683148  PMID: 23567618
Interleukin-33; ST2; Cardiac fibroblasts; Cardiac myocytes; Cytokines
3.  A Hierarchical Method for Removal of Baseline Drift from Biomedical Signals: Application in ECG Analysis 
The Scientific World Journal  2013;2013:896056.
Noise can compromise the extraction of some fundamental and important features from biomedical signals and hence prohibit accurate analysis of these signals. Baseline wander in electrocardiogram (ECG) signals is one such example, which can be caused by factors such as respiration, variations in electrode impedance, and excessive body movements. Unless baseline wander is effectively removed, the accuracy of any feature extracted from the ECG, such as timing and duration of the ST-segment, is compromised. This paper approaches this filtering task from a novel standpoint by assuming that the ECG baseline wander comes from an independent and unknown source. The technique utilizes a hierarchical method including a blind source separation (BSS) step, in particular independent component analysis, to eliminate the effect of the baseline wander. We examine the specifics of the components causing the baseline wander and the factors that affect the separation process. Experimental results reveal the superiority of the proposed algorithm in removing the baseline wander.
doi:10.1155/2013/896056
PMCID: PMC3673325  PMID: 23766720
6.  Highly Defined, Colloid-Like Ionic Clusters in Solution 
ChemistryOpen  2012;1(5):211-214.
doi:10.1002/open.201200025
PMCID: PMC3922591  PMID: 24551510
dynamic light scattering; molecular dynamics; Monte Carlo simulations; nanoscale electrostatics; self-assembly
7.  The anti-angiogenic factor PEDF is present in the human heart and is regulated by anoxia in cardiac myocytes and fibroblasts 
Cardiac diseases such as myocardial infarction and heart failure are among the leading causes of death in western societies. Therapeutic angiogenesis has been suggested as a concept to combat these diseases. The biology of angiogenic factors expressed in the heart such as vascular endothelial growth factor (VEGF) is well studied, whereas data on anti-angiogenic mediators in the heart are scarce. Here we study the expression of the anti-angiogenic factor pigment epithelium-derived factor (PEDF) in the human heart and in human cardiac cells. PEDF expression could be detected in human cardiac tissue on the protein and mRNA levels. PEDF mRNA levels were significantly lower in explanted human ischemic hearts as compared to healthy hearts. Our in vitro experiments showed that human adult cardiac myocytes and fibroblasts constitutively secrete PEDF. In addition to anoxic conditions, cobalt chloride, 2,2′dipyridyl and dimethoxally glycine, which stabilize hypoxia inducible factor-α decreased PEDF expression. Furthermore we show that PEDF inhibits VEGF-induced sprouting. We have identified PEDF in healthy and ischemic human hearts and we show that PEDF expression is down-regulated by low oxygen levels. Therefore, we suggest a role for PEDF in the regulation of angiogenesis in the heart and propose PEDF as a possible therapeutic target in heart disease.
doi:10.1111/j.1582-4934.2009.00731.x
PMCID: PMC2883745  PMID: 19298519
PEDF; anoxia; heart; angiogenesis
8.  The inflammatory mediator oncostatin M induces angiopoietin 2 expression in endothelial cells in vitro and in vivo 
Summary
Objectives:
Members of the glycoprotein 130 (gp130) receptor–gp130 ligand family play a role in angiogenesis in different tissues. We tested the effect of this cytokine family on the angiopoietin (Ang)–Tie system, which is involved in blood vessel maturation, stabilization, and regression.
Results:
Oncostatin M (OSM) increased Ang2 expression in human umbilical vein endothelial cells via Janus kinase/signal transducer and activator of transcription (JAK/STAT) and mitogen-activated protein (MAP) kinase activation. Furthermore, OSM induced Ang2 expression in macrovascular endothelial cells isolated from the human aorta and in microvascular endothelial cells isolated from human heart. Our in vivo experiments revealed that mRNA expression of Ang2 in hearts of mice injected with OSM increased significantly, and levels of OSM mRNA significantly correlated with mRNA levels of Ang2 in human hearts. In addition, OSM increased the expression of its own receptors, gp130 and OSM receptor, in endothelial cells in vitro and in mice in vivo, and levels of OSM mRNA significantly correlated with mRNA levels of gp130 and OSM receptor in human hearts.
Conclusion:
Our data, showing the effects of OSM on the Ang–Tie system in endothelial cells, in hearts of mice, and in human heart tissue, provide yet another link between inflammation and angiogenesis.
doi:10.1111/j.1538-7836.2010.03741.x
PMCID: PMC2857505  PMID: 20088942
angiogenesis; angiopoietin; cytokine; oncostatin M
9.  No evidence for a direct role of Helicobacter pylori and Mycoplasma pneumoniae in carotid artery atherosclerosis 
Journal of Clinical Pathology  2006;59(11):1186-1190.
Background
That infections with certain pathogens, by initiating an inflammatory response, may contribute to the development of atherosclerosis is suggested by clinical and experimental evidence.
Aim
To analyse atherosclerotic plaques of the carotid artery, samples of apparently healthy greater saphenous veins and circulating leucocytes from the same individual patients for the presence of Helicobacter pylori and Mycoplasma pneumoniae.
Methods
Samples from 36 patients undergoing carotid endarterectomy for symptomatic carotid artery stenosis were analysed by polymerase chain reaction for the presence of DNA specific for H pylori and M pneumoniae. IgG antibody titres against H pylori and M pneumoniae and plasma levels of soluble E‐selectin, soluble intercellular adhesion molecule‐1 and soluble vascular cell adhesion molecule‐1 were determined.
Results
M pneumoniae‐specific DNA was detected in the atherosclerotic plaques of 13 of 36 (36.1%) patients, in the saphenous veins of 9 of 36 (25%) patients and in the leucocytes of 27 of 36 (75%) patients. No salient association was observed between the presence of M pneumoniae‐specific DNA in leucocytes and atherosclerotic plaques or veins. A marked correlation between the presence of M pneumoniae in the respective specimens and the studied inflammatory markers or the presence of anti‐M pneumoniae antibodies was not observed. H pylori‐specific DNA could not be detected in the specimens tested.
Conclusions
The absence of H pylori and the random distribution of M pneumoniae in tissue samples obtained from patients with symptomatic carotid artery stenosis do not support a role for these pathogens in the development of atherosclerosis due to a direct interaction of the bacteria with the vasculature.
doi:10.1136/jcp.2005.034314
PMCID: PMC1860507  PMID: 16644879
10.  Effects of pantoprazole 20 mg in mildgastroesophageal reflux disease: Once-daily treatment in the acute phase, and comparison of on-demand versus continuous treatment in the long term 
Background:
Gastroesophageal reflux disease (GERD) is a chronic disorder,and although effective short-term treatment strategies are known, the rate of relapse within 1 year is as high as 90% despite successful acute treatment. Consequently, most patients with GERD require an effective long-term management strategy to achieve adequate symptom control and maintain mucosal healing.
Objective:
The present study was undertaken to compare the control ofGERD symptoms during long-term (24-week) treatment with pantoprazole 20 mg used on-demand or continuously in patients with mild GERD after complete relief of acute GERD symptoms.
Methods:
Patients with endoscopically confirmed Savary/Miller grade 0(normal mucosa) or I (patchy red lesions without white coating or with central white coating) GERD were enrolled in this multinational, multicenter study comprising 2 phases. In the first phase, which was open label, patients were treated with pantoprazole 20 mg QD for 4 weeks. The presence and intensity of the symptoms of heartburn, acid regurgitation, and pain on swallowing were assessed. In the second phase, which was an open-label, 24-week, randomized design, only patients completely free of GERD symptoms after acute treatment were included. During this phase, on-demand treatment with pantoprazole 20 mg was directly compared with continuous treatment. The rate of failure to control GERD symptoms after 24 weeks of treatment was estimated using the Kaplan-Meier method. Subsequently, the difference between treatments (on-demand minus continuous) and its 95% CI were calculated, and the on-demand treatment was tested for noninferiority using a predefined noninferiority margin of 20%. The mean daily symptom loads were compared between the treatment groups using the 1-sided Wilcoxon rank sum test on a 5% α level. The point estimate of the difference was determined using the Hodges-Lehman estimator and the 1-sided 95% CI according to Moses. The number of patients unwilling to continue due to insufficient control of heartburn, acid regurgitation, and pain on swallowing was analyzed using the Kaplan-Meier (time-to-event) analysis. Analysis was performed in the same manner as for the rate of failure to control GERD symptoms, but the 95% CI was interpreted for statistical superiority.
Results:
A total of 558 patients were enrolled in this study. At the end of theacute phase, 82.1% of patients in the per-protocol (PP) population and 79.1% in the intent-to-treat (ITT) population were relieved of all GERD symptoms, and subsequently entered the long-term phase. After 24 weeks of treatment, analysis of the failure rates revealed that on-demand treatment was noninferior to continuous treatment because the 95% CI was completely below 20% (ITT, 12.1% difference [95% CI, −∞ to 18.9%]; PP, 10.1% difference [95% CI, −∞ to 17.7%]). The higher perceived mean (SD) daily symptom load in the on-demand group (ITT, 1.26 [1.491 vs 0.82 [1.341) was balanced by the reduced tablet intake in that group (PP, 0.51 [0.31 ] vs 0.97 [0.11 ] tablets/d; P < 0.001). With respect to the rate of patients unwilling to continue treatment, no statistically significant difference was observed between the on-demand and continuous groups (ITT/PP, 0.95/1.13 vs 0.95/1.26).
Conclusions:
In this study of pantoprazole 20 mg tablets in patients withmild GERD, patients receiving on-demand treatment benefited despite their higher symptom load. The similar rates of unwillingness to continue treatment in both groups might suggest that patients were satisfied with the on-demand treatment strategy. On-demand treatment with pantoprazole 20 mg was found to be noninferior compared with continuous therapy with regard to symptom control. Both on-demand and continuous treatments were well tolerated.
doi:10.1016/j.curtheres.2005.08.012
PMCID: PMC3964567  PMID: 24672134
drug administration schedule; follow-up study; gastroesophagealreflux/drug therapy; heartburn; long-term care; treatment outcome; pantoprazole; continuous; on-demand; as needed

Results 1-10 (10)