PubMed Health⌕ Search

Biomedical subjects

Paul Erne

Publications and source records attributed to Paul Erne.

At least 19 recordsLinked to original sources
PubMed2006

Oxidized phospholipids stimulate angiogenesis via autocrine mechanisms, implicating a novel role for lipid oxidation in the evolution of atherosclerotic lesions.

Angiogenesis is a common feature observed in advanced atherosclerotic lesions. We hypothesized that oxidized phospholipids (OxPLs), which accumulate in atherosclerotic vessels can stimulate angiogenesis. We found that oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (OxPAPC) stimulated the formation of sprouts from endothelial cell spheroids and promoted growth of capillaries into Matrigel plugs in mice. OxPLs stimulated expression of vascular endothelial growth factor (VEGF) in vivo and in several normal and tumor cell types in vitro. In addition, OxPAPC upregulated cyclooxygenase (COX)-2 and interleukin (IL)-8. COX-2 inhibitors, as well as blocking antibodies to IL-8 suppressed activation of sprouting by OxPAPC. We conclude that OxPAPC stimulates angiogenesis via autocrine mechanisms involving VEGF, IL-8, and COX-2-generated prostanoids. Our data suggest that accumulation of OxPLs may contribute to increased growth of blood capillaries in advanced lesions, thus leading to progression and destabilization of atherosclerotic plaques.

ADAM Proteins↗
PubMed2006

S100A1-deficient male mice exhibit increased exploratory activity and reduced anxiety-related responses.

S100 proteins comprise a family of Ca(2+) binding proteins of at least 21 members. They are distinctly expressed in a variety of cell types and tissues and are thought to play unique roles, although they share a high degree of sequence homology and expression overlap. S100A1 is prominently expressed in the heart, where it takes part in Ca(2+)-cycling. Its role in the central nervous system (CNS) is largely unknown. We have generated S100A1-deficient mice by gene trap mutagenesis to study the involvement of S100A1 in the cytoarchitecture of the brain, in learning and memory, and in avoidance-approach behavior. S100A1 knock out (KO) mice develop well and their brains present with normal morphology. In wild type (Wt) mice, S100A1 protein was found in the hippocampus, cerebral cortex and amygdala, and partially co-localized with the astrocyte marker glial fibrillary acidic protein (GFAP) in the stratum radiatum of the hippocampus. Astrocytes and neurons of S100A1KO mice did not differ from those of Wt mice regarding shape, distribution and density. In the water maze, S100A1KO mice performed equally well as Wt, implying that S100A1 is not involved in spatial learning and memory. In avoidance-approach tests, predominantly male S100A1KO mice showed reduced anxiety-like responses and enhanced explorative activities. We conclude that S100A1 plays a role in modulating innate fear and exploration of novel stimuli.

Animals↗
PubMed2006

Atypical GPI-anchored T-cadherin stimulates angiogenesis in vitro and in vivo.

OBJECTIVE: T-cadherin (T-cad) is an atypical GPI-anchored member of the cadherin superfamily. In vascular tissue, T-cad expression is increased during atherosclerosis, restenosis, and tumor neovascularization. In vitro, overexpression and/or homophilic ligation of T-cad on endothelial cells (ECs) facilitates migration, proliferation, and survival. This study investigated T-cad effects on angiogenesis. METHODS AND RESULTS: In vitro, T-cad homophilic ligation induced arrangement of ECs into a capillary-like network in a 2-dimensional model of EC differentiation and stimulated in-gel endothelial sprout outgrowth in an EC spheroid model and a modified Nicosia tissue assay. Sprouting from spheroids composed of adenoviral-infected T-cad overexpressing ECs or T-cad siRNA transfected ECs were significantly increased or reduced, respectively. In vivo, T-cad potentiated VEGF effects on neovascularization in a model of myoblast-mediated gene transfer to mouse skeletal muscle; vessel caliber after co-delivery of T-cad and VEGF was significantly greater than after delivery of VEGF alone. CONCLUSIONS: We unequivocally identify T-cad as a novel modulator of angiogenesis and suggest that this molecule can be exploited as a target for modulation of therapeutic angiogenesis, as well as for prevention of pathological conditions associated with abnormal neovascularization.

Angiogenesis Inducing Agents↗
PubMed2006

ECG changes amongst patients with alcohol withdrawal seizures and delirium tremens.

INTRODUCTION: Alcohol withdrawal seizures and delirium tremens (DT) are serious complications of alcohol dependence. The prevalence of arrhythmias and other electrocardiographic (ECG) changes occurring in these clinical situations is not well studied. METHODS: We performed a retrospective analysis of clinical data and ECG's from patients discharged between 1995 and 2005 with the diagnosis of DT (ICD-Code F10.4) or alcohol withdrawal seizures (F10.3). Measurement of the ECG intervals was done in lead II. The corrected QT interval (QTc) was obtained using Bazett's formula. RESULTS: 49 patients (38 males; 11 females) with a mean age of 48 years were included in the study. 23 patients with DT and 16 with convulsions were admitted to the hospitals. Ten patients developed DT while being hospitalised for other reasons. The QTc interval was prolonged (>440 ms and >460 ms in males and females, respectively) in 31 patients (63%). Five patients (10%) developed tachyarrhythmias (two torsade de pointes, one sustained ventricular tachycardia, two supraventricular tachycardia, one atrial fibrillation). All returned to sinus rhythm after appropriate treatment. CONCLUSIONS: Tachyarrhythmias are common amongst patients with severe alcohol withdrawal syndromes. The majority of the patients had an acquired long QT syndrome which led to a torsade de pointes in two cases. No patient died in the hospital and all were discharged in sinus rhythm. Clinicians should possibly avoid QT prolonging drugs and carefully monitor the rhythm in patients with severe alcohol withdrawal syndromes.

Adult↗
PubMed2006

Cost-effectiveness of eplerenone in patients with left ventricular dysfunction after myocardial infarction--an analysis of the EPHESUS study from a Swiss perspective.

OBJECTIVE: The EPHESUS study demonstrated that aldosterone blockade with eplerenone decreased mortality in patients with left ventricular systolic dysfunction (LVSD) and heart failure after acute myocardial infarction (AMI). The EPHESUS pharmacoeconomic analysis was performed to evaluate the cost-effectiveness of eplerenone in the Swiss setting. MATERIALS AND METHODS: A total of 6,632 patients with LVSD and heart failure after AMI were randomized to eplerenone or placebo and followed for a mean of 16 months. The co-primary endpoints were all-cause death and the composite of cardiovascular death/cardiovascular hospitalization. The evaluation of resource use included hospitalizations, outpatient services, and medications. Survival beyond the trial period was estimated using data from the Framingham Heart Study, the Saskatchewan Health database, and the Worcester Heart Attack Registry. The incremental cost-effectiveness of eplerenone in cost per life-year and quality-adjusted life-year gained was estimated. The perspective of the Swiss third party payers was used. Daily treatment costs of eplerenone were set at CHF 3.88. All other resources were valued on the basis of official tariffs. Discounting of the results was performed at a rate of 3%. RESULTS: The number of life-years gained with eplerenone was 0.1083 based on Framingham, 0.0661 with Saskatchewan and 0.1518 with Worcester survival estimates. Total costs were CHF 1,028 higher over the trial period in the eplerenone arm, due to drug cost. The incremental cost-effectiveness ratio was CHF 10,145 per life-year gained with Framingham, CHF 16,178 with Saskatchewan, and CHF 7,693 with Worcester survival estimates. The corresponding costs per QALY were CHF 15,219, CHF 23,965 and CHF 11,337, respectively. CONCLUSION: Eplerenone is effective in reducing mortality and, in Switzerland, is also cost-effective in increasing years of life for patients with LVSD after AMI.

Adult↗
PubMed2006

Psychological distress in patients with ICD recall.

BACKGROUND: Multiple clinical trials have shown that a properly functioning implantable cardioverter-defibrillator (ICD) is capable of interrupting sudden death caused by ventricular tachyarrhythmias. However, ICDs are complex medical devices, and they do not always perform as expected or they may fail completely. Exposure of ICD recipients to professional or media reports that their specific device type is potentially malfunctioning could negatively influence their psychological status. METHODS: This study aimed to evaluate and quantify psychological distress in patients implanted with an ICD-recall device. Thirty patients implanted with ICD-recall devices (ICD-recall group) and 25 patients with unaffected ICD devices (ICD-control group) were interviewed using the Brief Symptom Inventory (a psychological self-report symptom scale). RESULTS: Mean values of all primary psychiatric distress symptom dimensions and global indices were within the normal range for both the ICD-recall and the ICD-control group. New York Heart Association (NYHA)class was a predictor of higher distress symptoms in all categories, independently of the ICD group. NYHA II group patients tended toward higher stress levels than the NYHA I group, but only somatization was significantly different. An upward, but not significant, trend in 7 of the 12 scales was associated with symptomatic shock experience. CONCLUSION: This study demonstrates that psychological distress was not significantly increased in patients recently informed about a potential malfunction of their device.

Defibrillators, Implantable↗
PubMed2005

T-cadherin protects endothelial cells from oxidative stress-induced apoptosis.

In vascular tissue, T-cadherin (T-cad) is up-regulated in vivo under disease conditions associated with oxidative stress and concomitant cell migration, proliferation and apoptosis/survival. Using cultures of human umbilical vein endothelial cells (HUVEC), we examined whether there is a functional relationship between oxidative stress, T-cad expression, and cell survival status. Culture of HUVEC under conditions of oxidative stress (e.g., serum deprivation, inclusion of H2O2) resulted in increased T-cad expression. Oxidative stress-induced increases in T-cad were inhibited by the free radical-scavenging antioxidant, N-acetylcysteine, and the flavin-containing oxidase inhibitor, diphenyleneiodonium. Thus reactive oxygen species (ROS) contribute to stress-induced elevation of T-cad in HUVEC. Compared with control cells, HUVEC overexpressing T-cad (T-cad+-HUVEC) had higher phosphorylation levels for phosphatidylinositol 3-kinase (PI3K) target Akt and mTOR target p70(S6K) (survival pathway regulators), but lower levels for p38MAPK (death pathway regulator). T-cad+-HUVEC exposed to stress (serum-deprivation, TNF-alpha, actinomycin D, staurosporine) exhibited reduced caspase activation together with increased cell survival. Protection against stress-induced apoptosis in T-cad+-HUVEC was abrogated by either PI3K-inhibitor wortmannin or mTOR-inhibitor rapamycin. We conclude that T-cad overexpression in HUVEC protects against stress-induced apoptosis through activation of the PI3K/Akt/mTOR survival signal pathway and concomitant suppression of the p38 MAPK proapoptotic pathway. ROS-induced changes in T-cad expression may play an important role in controlling tissue cellularity during vascular remodeling.

Adenoviridae↗
PubMed2005

Vascular risk factors in the Swiss population.

BACKGROUND AND PURPOSE: Identification of the population at risk of stroke remains the best approach to assess the burden of cardiovascular morbidity and mortality. METHODS: The prevalence of hypertension (HT), hypercholesterolemia (HCh), diabetes mellitus (DM), overweight (OW), obesity (OB), tobacco use (SM), and their combinations was examined in 4,458 Swiss persons (1,741 men and 2,717 women, mean age 57.8 +/- 15 years), who volunteered for the present survey. RESULTS: OW was the most prevalent risk factor (50 %), followed by HT (47%), HCh (33%), SM (13 %) and DM (1.6 %). The proportion of persons without risk factors (RF) was 19.9%, with 1 RF 41.5%, 2 RF 33.8%, 3 RF 4%, and 4 RF 0.9%. OW was more prevalent in men than in women (53% vs. 41%, P=0.02). More men than women aged 41-50 years and 51-60 years had HT (49 % vs. 36%, P=0.01, and 52 % vs. 42%, P=0.02). The prevalence of HCh and DM did not show any sex-related differences. HT, OW and HCh were not only the most common single risk factors, but were also most likely to aggregate with each other. CONCLUSIONS: The majority of Swiss people have one or two vascular risk factors. OW and HT are by far most common and are likely to aggregate with each other. A small modification of these two factors would reduce the incidence of stroke and myocardial infarction significantly.

Adult↗
PubMed2005

RhoA and Rac mediate endothelial cell polarization and detachment induced by T-cadherin.

T-cadherin (T-cad) is an atypical GPI-anchored member of the cadherin superfamily. Ligation of T-cad receptors on endothelial cells prevents cell spreading, promotes elongation and polarization, decreases adhesion to the matrix, and facilitates migration. This study investigates involvement of Rho GTPases in T-cad signaling. Human umbilical vein endothelial cells were infected with adenoviral vectors expressing dominant-negative and/or constitutively active mutants of RhoA (N19RhoA/RhoA63), ROCK (RB/PH(TT)/CAT), and Rac1 (N17RAC). Mutant-infected and empty vector-infected cells were compared with respect to their ability to detach and polarize when plated on substratum containing recombinant T-cad protein used as a ligand mimicking homophilic T-cad interactions. ROCK involvement was also studied using specific inhibitor Y-27632. Adhesion assays, analysis of cell phenotype, and actin cytoskeleton organization using TRITC-labeled phalloidin demonstrated that T-cad-induced cell polarization includes two complementary components: RhoA/ROCK pathway is necessary for cell contraction, stress fiber assembly, and inhibition of spreading, whereas Rac is required for formation of actin-rich lamellipodia at the leading edges of polarized cells. Individual repression of either pathway only partially prevented cell polarization and detachment, while simultaneous repression of RhoA and Rac pathways fully eliminated responses to homophilic T-cad ligation. In conclusion, these data suggest that T-cad induces cell deadhesion and polarization via RhoA-ROCK- and Rac-dependent mechanisms.

Cadherins↗
PubMed2005

The catalytically active secretory phospholipase A2 type IIA is involved in restenosis development after PTCA in human coronary arteries and generation of atherogenic LDL.

Secretory phospholipase A2 type IIA (sPLA2) may actively contribute to atherogenesis, acting either within the arterial wall or in plasma. Proinflammatory eicosanoids and lysophospholipids, generated through hydrolysis of cell membrane phospho-lipids by sPLA2, initiate and prolong the inflammatory process. In the present study we examined the possible involvement of sPLA2 in development of restenosis in patients undergoing percutaneous transluminal coronary angioplasty (PTCA). We also investigated whether serum sPLA2 could catalyze accumulation of lysophosphatidylcholine (LPC) in LDL. Concentrations and catalytic activities of sPLA2 were measured in blood serum of 49 consenting patients immediately before, 1-7 and 180 days after PTCA. All patients had repeat angiograms at 180-day follow-up. Restenosis was registered in 19 patients. Accumulation of LPC in LDL was evaluated by thin-layer chromatography after incubation of blood serum with LDL. Serum sPLA2 concentrations increased in all study patients by day 1 post-PTCA, but the increase was significantly greater and more protracted in patients who developed restenosis. Catalytic activities increased significantly 6 days post-PTCA in patients who developed restenosis, whereas for patients without restenosis there was no change in serum sPLA2 activity throughout the study period in spite of the sPLA2 presence in blood. Incubation of blood serum (6 days post-PTCA) with LDL resulted in accumulation of LPC only for those patients who subsequently developed restenosis. Manoalide, a specific inhibitor of sPLA2, completely blocked the LPC accumulation. The data indicate that elevated serum sPLA2 activity after PTCA is associated with restenosis development and may be involved in atherogenic modification of LDL in blood serum.

Angioplasty↗
PubMed2005

Long-term benefits and limitations of combined antianginal drug therapy in elderly patients with symptomatic chronic coronary artery disease.

BACKGROUND: Chronic angina is a common and disabling disorder in the elderly. Combined antianginal drug treatment represents the mainstay of therapy in this population. However, there is a paucity of data regarding the effect of this strategy on long-term outcome in the elderly. METHODS: To assess the long-term effect of combined antianginal drug therapy in elderly individuals, we performed a long-term follow-up analysis of all 148 patients of the Trial of Invasive versus Medical therapy in Elderly (TIME) patients with chronic symptomatic coronary-artery disease assigned to an optimized medical therapy strategy. Angina severity, measures of quality of life (QOL), and survival were assessed after a median of 3.7 (0.1-6.9) years. RESULTS: At baseline, patients were 79.8 +/- 3.5 years old with Canadian Cardiovascular Society (CCS) class angina 3.0 +/- 0.7 despite the use of 2.4 +/- 0.6 antianginal drugs. Although antianginal drugs were increased to 2.8 +/- 0.9 (P < .01), 63 (43%) patients needed revascularization for refractory symptoms during the first year of observation (REVASC). At baseline, REVASC patients had more frequently CCS class 4 angina (37% vs 20%, P < 0.05) but reported less prior heart failure (5% vs 20%, P < 0.01), fewer prior cerebral events (3% vs 13%, P < .05) and a lower rate of two or more comorbidities (10% vs 33%, P < .01) than patients on continued drug therapy (DRUG). At long-term follow-up, angina severity was still higher in DRUG compared to REVASC patients (CCS class, 1.8 +/- 1.6 vs 1.0 +/- 1.4, P < .05) despite more antianginal drugs (2.1 +/- 1.1 vs 1.5 +/- 1.0, P < .01), whereas measures of QOL had improved similarly in both groups. In addition, long-term mortality was significantly higher in DRUG than in REVASC patients (38% vs 13%, P < .01). CONCLUSION: Combined antianginal drug therapy successfully relieved symptoms in most elderly patients with chronic angina but failed to do so in 43%. Patients who needed revascularization for refractory symptoms reported less angina, despite lower drug use during long-term follow-up and had a better long-term survival. Thus, the widely used strategy to increase antianginal drug therapy in elderly patients instead of evaluating them for revascularization should be reconsidered.

Aged↗
PubMed2004

Brachytherapy: potential therapy for refractory coronary spasm.

OBJECTIVES: We sought to demonstrate that brachytherapy reduces coronary spasm in refractory and highly symptomatic variant angina. BACKGROUND: In some patients with variant angina due to extensive vasoconstriction, intensive drug therapy fails to sufficiently relieve symptoms. METHODS: In 18 patients with frequent angina episodes despite triple anti-anginal therapy, coronary spasm was induced by intracoronary acetylcholine (ACh) infusion. Five patients had spasm in a second vessel. Intracoronary radiation (20 Gy) was applied to vasospastic segments using a beta-emitting ((32)P) wire source centered within a Galileo balloon. Parameters of vessel function before and after brachytherapy were investigated. RESULTS: Before brachytherapy, artery diameters decreased (p < 0.0001) from 2.8 +/- 0.4 mm to 1.0 +/- 0.4 mm for the first vessels and from 3.1 +/- 0.3 mm to 1.0 +/- 0.2 mm for the second vessels. After brachytherapy (143 +/- 106 and 80 +/- 52 days for first and second vessels, respectively), ACh-induced vasoconstriction was significantly reduced. The ACh-induced changes in artery diameter before and after brachytherapy were -1.5 +/- 0.5 mm and -0.5 +/- 0.3 mm (p < 0.0001) for the first vessels and -1.4 +/- 0.3 mm and -0.4 +/- 0.2 mm (p < 0.01) for the second vessels, respectively. In non-irradiated spastic vessels, ACh-induced vasoconstriction remained unchanged (e.g., -1.7 +/- 0.6 mm, -1.6 +/- 0.3 mm, and -1.5 +/- 0.5 mm for second vessels, at first investigation, first follow-up, and immediately before brachytherapy, respectively). Angina frequency decreased from 15.6 +/- 6.0 to 2.2 +/- 2.4 angina episodes/week (p < 0.001) in treated patients. CONCLUSIONS: Brachytherapy is a potential therapy in patients with highly symptomatic variant angina.

Adult↗
PubMed2004

T-cadherin upregulation correlates with cell-cycle progression and promotes proliferation of vascular cells.

OBJECTIVE: In vascular tissue, T-cadherin (T-cad) levels correlate with the progression of atherosclerosis, restenosis and tumour neovascularization. This study investigates whether T-cad influences proliferation of vascular cells. METHODS AND RESULTS: Cultures of human umbilical vein endothelial cells (HUVEC) and rat and human aortic smooth muscle cells (rSMC, hSMC) were used. T-cad was overexpressed in HUVEC and hSMC using an adenoviral expression system. In cultures released from G(1)/G(0) synchrony parallel immunoblot analysis of T-cad and cell cycle phase specific markers (p27(Kip1), cyclin D1, E2F1, PCNA, cyclin B) showed increased T-cad protein levels subsequent to entry into early S-phase with sustained elevation through S-and M-phases. T-cad was increased in G(2)/M-phase (colchicine) synchronized cultures. In FACS-sorted cell populations, expression of T-cad in S-and G(2)/M-phase was higher than G(1)/G(0)-phase. Compared with empty-and LacZ-vector infected controls, HUVEC and hSMC overexpressing T-cad exhibited increased proliferation as assessed in enumeration and DNA synthesis assays. Additionally, following release from G(1)/G(0) synchrony, HUVEC and hSMC overexpressing T-cad enter S-phase more rapidly. Flow cytometry after BrdU/propidium labelling confirmed increased cell cycle progression in T-cad overexpressing cells. CONCLUSION: In vascular cells, T-cad is dynamically regulated during the cell cycle and its expression functions in the promotion of proliferation. T-cad may facilitate progression of proliferative vascular disorders such as atherosclerosis, restenosis and tumour angiogenesis.

Animals↗