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Biomedical subjects

H Darius

Publications and source records attributed to H Darius.

At least 37 records · Page 2Linked to original sources
PubMed2000

A functional role of I kappa B-epsilon in endothelial cell activation.

The NF-kappa B inhibitor I kappa B-epsilon is a new member of the I kappa B protein family, but its functional role in regulating NF-kappa B-mediated induction of adhesion molecule expression is unknown. In vascular endothelial cells, I kappa B-epsilon associates predominantly with the NF-kappa B subunit Rel A and to a lesser extent with c-Rel, whereas I kappa B-alpha and I kappa B-beta associate with Rel A only. Following stimulation with TNF-alpha, pyrrolidine dithiocarbamate (PDTC), N-acetylcysteine, and dexamethasone prevented I kappa B kinase-induced I kappa B-alpha, but not I kappa B-beta or I kappa B-epsilon phosphorylation and degradation. Since the activation of NF-kappa B is required for the induction of adhesion molecule expression, we examined the role of I kappa B-epsilon in the transactivation of promoters from VCAM-1, ICAM-1, and E-selectin. Using reporter gene constructs of adhesion molecule promoters, PDTC inhibited VCAM-1 and E-selectin, but to a lesser extent, ICAM-1 promoter activity. Subcloning of kappa B cis-acting elements of VCAM-1, E-selectin, and ICAM-1 into a heterologous promoter construct revealed that PDTC inhibited VCAM-1 and E-selectin, but to a lesser extent, ICAM-1 kappa B promoter activity. By electrophoretic mobility shift assay, NF-kappa B heterodimers containing c-Rel specifically bind to the kappa B motif in the ICAM-1, but not VCAM-1 or E-selectin promoter. Indeed, overexpression of c-Rel induced ICAM-1 kappa B promoter activity to a greater extent than that of E-selectin and overexpression of I kappa B-epsilon inhibited ICAM-1 and VCAM-1 promoter activity in endothelial cells. These findings indicate that c-Rel-associated I kappa B-epsilon is involved in the induction of ICAM-1 expression.

Animals↗
PubMed2000

NO reduces PMN adhesion to human vascular endothelial cells due to downregulation of ICAM-1 mRNA and surface expression.

Reperfusion damage is largely due to the adherence of polymorphonuclear leukocytes to the endothelium initiated by adhesion molecule upregulation. The reduced endothelial nitric oxide release during ischemia may be involved in the upregulation of intercellular adhesion molecule 1. In this study, we tested if nitric oxide donors suppress polymorphonuclear leukocyte adherence to activated endothelial cells by inhibition of the intercellular adhesion molecule 1 surface expression. Confluent human umbilical vein endothelial cells were stimulated with tumor necrosis factor alpha (300 U/mL) after preincubation with increasing concentrations of the nitric oxide donors CAS 1609 (0.005-5 mM/L) and 3-(4-morpholinyl)-sydnonimine (0.01-1 mM/L). Intercellular adhesion molecule 1 surface expression was measured in a cell surface enzyme-linked immunosorbent assay, intercellular adhesion molecule 1 mRNA by Northern analysis. Human saphenous vein endothelial cells were transfected with the inducible nitric oxide synthase gene and stimulated with tumor necrosis factor alpha (300 U/mL). Fluorescein green-labeled polymorphonuclear leukocytes adhering to activated human umbilical vein endothelial cells/human saphenous vein endothelial cells were quantified by epifluorescent microscopy. The intercellular adhesion molecule 1 surface expression of activated human umbilical vein endothelial cells/human saphenous vein endothelial cells was significantly diminished to 40 to 60% of the maximum after treatment with CAS 1609, 3-(4-morpholinyl)-sydnonimine, or transfection with the inducible nitric oxide synthase gene. Intercellular adhesion molecule 1 mRNA was diminished by CAS 1609 and 3-(4-morpholinyl)-sydnonimine in the same manner. The functional relevance of our data was shown by reduction of polymorphonuclear leukocyte adherence to activated human umbilical vein endothelial cells/human saphenous vein endothelial cells following treatment with CAS 1609 and 3-(4-morpholinyl)-sydnonimine or transfection with inducible nitric oxide synthase. Tumor necrosis factor-induced polymorphonuclear leukocyte adherence was abolished by blocking antibody against intercellular adhesion molecule 1. Thus, exogenous or endogenous substitution of nitric oxide diminishes the expression of endothelial intercellular adhesion molecule 1 and its mRNA following tumor necrosis factor alpha stimulation. This results in a reduced polymorphonuclear leukocyte adherence to activated endothelium.

Adult↗
PubMed2000

[A case report: suppurative pericardial effusion].

We present the case of a 67 year old woman who was resuscitated due to cardiac tamponade. Examination of the pus fluid showed a bacterial infection with streptococcus milleri. Four days before resuscitation the patient experienced weakness, dyspnoea, increased temperature (39 degrees C), swelling of the neck, and pain on swallowing. Using computed tomography, examination revealed an infection extending from the right tonsil to the mediastinum and into the pericardium. After surgery to remove the retropharyngeal abscess, the patient healed well. Therefore, on presentation of a cardiac tamponade, possible hematogenous or lymphogenous causes or per continuitatem infections should always be considered. In this case the germs in the fluid and the typical patient history indicated an oropharyngeal reason.

Aged↗
PubMed2000

MIC trial: metoprolol in patients with mild to moderate heart failure: effects on ventricular function and cardiopulmonary exercise testing.

UNLABELLED: Beta-blocker therapy results in a functional benefit in patients with heart failure (CHF) due to idiopathic dilated cardiomyopathy (DCM). This study assessed if similar effects were observed in patients with ischemic heart disease (CAD), NYHA II-III after 6 months of therapy with metoprolol. METHODS AND RESULTS: Fifty-two patients with CHF secondary to DCM (26 patients) and CAD (26 patients) and a left ventricular ejection fraction (EF)<40% were enrolled in the placebo-controlled study. The study medication was titrated over 6 weeks, the mean final dosage was 135 mg/day. Three patients died due to cardiogenic shock, two received placebo and one metoprolol. Eight patients did not complete the study due to non-compliance. Metoprolol significantly reduced heart rate at rest and after submaximal and maximal exercise. Vo(2)-max and Vo(2)-AT as well as the 6-min walk test improved significantly after metoprolol treatment. There was a significant increase in EF at rest (27.3-35. 2%), submaximal (28.5-37.7%) and maximal exercise (28.7-40.9%) in the metoprolol-treated patients. No differences were found between patients with CAD and DCM. We also observed reduced left ventricular volumes. CONCLUSION: The additional therapy with metoprolol improved cardiac function and the cardiopulmonary exercise capacity in patients with CHF.

Adrenergic beta-Antagonists↗
PubMed2000

Argatroban and alteplase in patients with acute myocardial infarction: the ARGAMI Study.

ARGAMI was designed to assess safety and efficacy of argatroban compared with heparin as adjunctive treatment to alteplase in the treatment of patients with acute myocardial infarction. ARGAMI consisted of an open-dose finding study (35 patients) followed by a placebo-controlled study with double dummy technique and 2:1 (argatroban:heparin) randomization. An argatroban dosage of 100 microg/kg bolus plus 3 microg/kg/min infusion for 72 hours was selected for the randomized study in which 82 patients were allocated to argatroban and 45 to heparin (5000 U intravenous bolus, 1000 U/h infusion). Patency of the infarct-related artery (Thrombolysis in Myocardial Infarction [TIMI] grade 2 or 3 flow) after 90 minutes was obtained in 62 patients (76%) allocated to argatroban versus 37 patients (82%) allocated to heparin (p=ns). Angiograms after 24 hours and 5 to 10 days showed low reocclusion rates in both groups. Bleeding complications were observed in 16 patients allocated to argatroban (19.5%) and in 9 patients allocated to heparin (20.0%). One patient allocated to heparin suffered from hemorrhage stroke. Argatroban, given as adjunctive treatment to alteplase, is tolerated well in patients with acute myocardial infarction. Safety and efficacy of the combination alteplase and argatroban (with this dose regimen) are similar to those of alteplase and heparin.

Aged↗
PubMed2000

Effects of local delivery of trapidil on neointima formation in a rabbit angioplasty model.

1. Smooth muscle cell (SMC) proliferation can result in luminal reduction of a vessel following balloon angioplasty. This study was designed (i) to determine if local administration of trapidil (triazolopyrimidine) into a vessel wall reduces neointima formation, and (ii) to explore the mechanism involved in the subsequent reduction in cell proliferation. 2. Following balloon angioplasty in 40 anaesthetized New Zealand White rabbits, trapidil (50-200 mg) or its vehicle (saline) was injected into the dilated vessel wall of the right femoral artery. Experimental groups and time of investigation: (I) vehicle (2 weeks, n = 3), (II) trapidil-100 mg (2 weeks, n = 3), (III) vehicle (3 weeks, n = 8), (IV) trapidil-50 mg (3 weeks, n = 5); (V) trapidil-100 mg (3 weeks, n = 9) or (V) trapidil-200 mg (3 weeks, n = 7). 3. After 2 weeks, there was a significant reduction of intimal hyperplasia (expressed as intima to media area ratio) in the trapidil group compared with vehicle (0.44 +/- 0.04 vs 0.93 +/- 0.04, *P < 0.05) and also a significant reduction in cell proliferation (% ratio of BrdU-positive cells to total cell number: vehicle 14 +/- 2% vs trapidil 6 +/- 1%, *P < 0.05). 4. After 3 weeks, there was a dose-dependent reduction of intimal hyperplasia in the trapidil groups compared with vehicle (trapidil 50 mg 1.14 +/- 0.04; trapidil 100 mg 0.91 +/- 0.09*; trapidil 200 mg 0.77 +/- 0.09* vs vehicle 1.67 +/- 0.23, *P < 0.05). 5. Thus, the local administration of trapidil to the rabbit femoral artery reduces the neointima formation, which occurs 2 or 3 weeks after balloon angioplasty via a mechanism, which is dependent on inhibition of cell proliferation.

Angioplasty, Balloon↗
PubMed2000

Temperature-controlled high frequency ablation for creation of transmyocardial channels: in vivo validation of a novel method.

OBJECTIVE: We investigated the feasibility and short-term effects of a novel procedure to create intramyocardial channels by means of high frequency (HF) ablation in a rabbit in vivo model. METHODS: A flexible catheter ending in a cylindrical electrode (diameter 0.7 mm) with a sharpened tip was used for HF energy application following transmyocardial insertion. Power-controlled or energy-controlled energy applications were performed in 16 anesthetized rabbits after thoracotomy with a follow-up for 3 h. Assessment of myocardial channels and the necrotic zone was performed by morphometric quantification in serial sections. The ferret diameter was used to compare channel dimensions and the extent of necrosis. RESULTS: Thirty-nine power-controlled and 54 temperature-controlled HF applications were performed. The shape of identified channels was round in 71% and 69% had a lumen patency of > or =2/3 of the channel. Ferret diameter of the channels was 414 +/- 180 microm and of the necrotic zone 3,558 +/- 1,200 microm. In temperature-controlled applications, channel dimensions were strongly influenced by the maximum tissue temperature and the duration of energy delivery (T(max): p = 0.0006; duration: p = 0. 003). Channel and necrosis dimensions correlated better with biometric parameters in temperature-controlled compared with power-controlled applications. CONCLUSION: Mechanically created transmyocardial channels can be stabilized by HF heating of the surrounding tissue. A high percentage of these channels remain patent. The channel dimensions are closely correlated with maximum temperature and duration of energy delivery in a temperature-controlled application mode.

Animals↗
PubMed1999

A nonhealing ulcer diagnosed as extramedullary plasmocytoma of the limb eight years after cardiac transplantation.

A 63-year-old man was hospitalized for a nonhealing ulcer of the left lower leg that appeared 8 years after orthotopic cardiac transplantation under immunosuppressive therapy including cyclosporine. Serum protein electrophoresis, immunofixation, and urinalysis revealed a monoclonal gammopathy IgG kappa. The final diagnosis of an extramedullary plasmocytoma was made by biopsy of the ulcer, which showed formations of plasmablastic cells. We report a rare case of extramedullary plasmocytoma as a posttransplantational malignancy.

Cyclosporine↗
PubMed1999

Highly efficient liposome-mediated gene transfer of inducible nitric oxide synthase in vivo and in vitro in vascular smooth muscle cells.

OBJECTIVE: The efficient introduction of regulatory genes into vascular smooth muscle cells (SMCs) is one of the most promising options for gene therapy of cardiovascular diseases. Cationic liposome-mediated gene transfer may become a favorable transfection technique with regard to patient's safety for in vivo administration. However, this method until now has its limitation in a low transfection efficiency. Therefore, the present study was designed to improve cationic liposome-mediated transfection of rabbit vascular SMCs in vitro and in vivo, in order to enhance transfection efficiency and present an optimized system which may offer a potential therapeutic benefit for in vivo application. METHODS AND RESULTS: Optimized lipofection of rabbit SMCs with the mammalian expression vector pE-N1 and the reporter gene green fluorescent protein resulted in a mean transfection efficiency of about 50%. The unique transfection of rabbit SMCs in vitro and in vivo with the inducible isoform of human nitric oxide synthase (NOSII), using the same vector, resulted in a successful transient transcription and translation of a functionally active human NOSII in rabbit SMC, persisting 5-6 days. We could further demonstrate that the transfection procedure and the transgene product did neither induce necrosis nor apoptosis under the conditions chosen and did not result in the induction of endogenous NOSII of transfected SMCs. CONCLUSION(S): These findings indicate potential therapeutic relevance for this nonviral gene transfer system for in vivo gene therapy for cardiovascular diseases.

Animals↗
PubMed1999

Increased platelet sensitivity toward platelet inhibitors during physical exercise in patients with coronary artery disease.

Generalized atherosclerosis and coronary artery disease (CAD) are associated with endothelial dysfunction and during acute myocardial ischemia platelet activation has been reported. Activated platelets exert activated fibrinogen receptors (GP IIb/IIIa) and express CD 62p being regarded as reliable marker for platelet activation. Patients with angiographically proven CAD performed a bicycle exercise test until the onset of angina or ST-segment depression. We studied the ischemia-induced alterations in fibrinogen binding to activated platelet GP IIb/IIIa receptors and CD 62p expression. Therefore, the basal fibrinogen binding to GP IIb/IIIa and CD 62p expression and the thrombin-concentration for half-maximal platelet activation before and after exercise testing were determined. Additionally, inhibition of thrombin-induced platelet activation by increasing concentrations of the prostacyclin-analog iloprost and the NO-donor SIN-1 was examined. In patients with CAD, a significantly reduced basal activation and a highly significant reduction in sensitivity towards thrombin was measured. The thrombin-induced expression of GP IIb/IIIa and CD 62p was significantly diminished in patients with CAD after physical exercise and their platelets were significantly more sensitive towards the inhibitory effects of iloprost and SIN-1. These data demonstrate a significant reduction in platelet activation in response to physical exercise in patients with CAD and advanced atherosclerosis. Despite exercise induced myocardial ischemia as evidenced by angina and ECG-changes, the platelets are not generally activated, as it could be expected. Thus, patients with myocardial ischemia experienced a reduced platelet activity and enhanced sensitivity towards prostacyclin (PGI2) and nitric oxide, probably due to an augmented release of endogenous platelet inhibitory mediators.

Blood Platelets↗
PubMed1999

The presence of infection-related antiphospholipid antibodies in infective endocarditis determines a major risk factor for embolic events.

OBJECTIVES: The impact of infection-associated antiphospholipid antibodies (APA) on endothelial cell activation, blood coagulation and fibrinolysis was evaluated in patients with infective endocarditis with and without major embolic events. BACKGROUND: An embolic event is a common and severe complication of infective endocarditis. Despite the fact that APAs are known to be associated with infectious diseases, their pathogenic role in infective endocarditis has not been clearly defined. METHODS: The relationship among the occurrence of major embolic events, echocardiographic vegetation size, endothelial cell activation, thrombin generation, fibrinolysis and APA was examined in 91 patients with definite infective endocarditis, including 26 patients with embolic events and 65 control subjects without embolic events. RESULTS: Overall, 14.3% of patients exhibited elevated APA levels. Embolic events occurred more frequently in patients with elevated levels of APA than in patients without (61.5% vs. 23.1%; p = 0.008). Patients with elevated levels of APA showed higher levels of prothrombin-fragment F1 +2 (p = 0.005), plasminogen-activator inhibitor 1 (p = 0.0002), von Willebrand factor (p = 0.002) and lower levels of activated protein C (p = 0.001) than patients with normal levels of APA. Thrombin generation and endothelial cell activation were both positively correlated with levels of APA. The occurrence of elevated APA levels was frequently associated with structural valve abnormalities (p = 0.01) and vegetations >1.3 cm (p = 0.002). CONCLUSIONS: Infection-associated elevated APA levels in patients with infective endocarditis are related to endothelial cell activation, thrombin generation and impairment of fibrinolysis. This may contribute to the increased risk for major embolic events in these patients.

Adult↗
PubMed1999

Role of nitrates for the therapy of coronary artery disease patients in the years beyond 2000.

Vasodilator therapy with nitrates has been used for almost a century to bring relief to patients suffering from angina. The acute anti-ischemic effects of nitro-vasodilators for the treatment and prevention of anginal attacks is unquestioned. In addition, nitrates are administered in order to reduce symptomatic and silent ischemic episodes, in patients with proven coronary heart disease who exert ST segment alterations on Holter monitoring. The reduction in total ischemic burden may result in an improved prognosis with regard to infarct prevention and possible prevention of deterioration of left ventricular function due to repetitive episodes of myocardial ischemia. In patients with unstable angina, administration of nitrates significantly diminishes ischemic episodes and reduces the number of clinically symptomatic anginal attacks. The prevention of left ventricular dilatation in patients within the first few days and months following acute myocardial infarction may be due to the reduced preload. In patients with heart failure, preload reduction with nitrates and afterload reduction with hydralazine was tested versus angiotensin converting enzyme (ACE) inhibitors. However, unfortunately, very few data are available concerning the combination therapy of ACE inhibitors and nitrates in heart failure and following acute myocardial infarction. Long-term continuous administration of high doses of nitrates may cause nitrate tolerance, thus reducing the vasodilator potency of these drugs. Since nitrates were introduced into medical therapy many decades before randomized controlled trials were performed, and evidence-based medicine became the basic principal for medical therapy, there are still indications and situations where the full therapeutic potential of nitrates is not being fully appreciated. During recent decades, other anti-ischemic drugs, i.e., beta-receptor agonists and calcium channel blockers, were introduced into the clinical setting and contributed to an optimized therapy for patients with coronary heart disease. Nevertheless, due to their proven and unsurmounted symptomatic efficacy, nitrates will remain one of the cornerstones of acute and long-term therapy of patients with coronary heart disease far beyond the year 2000.

Angina Pectoris↗
PubMed1999

Surgical procedure affects physiological parameters in rat myocardial ischemia: need for mechanical ventilation.

Several surgical approaches are being used to induce myocardial ischemia in rats. The present study investigated two different operative procedures in spontaneously breathing and mechanically ventilated rats under sham conditions. A snare around the left coronary artery (LCA) was achieved without occlusion. Left lateral thoracotomy was performed in spontaneously breathing and mechanically ventilated rats (tidal volume 8 ml/kg) with a respiratory rate of 90 strokes/min at different levels of O2 supplementation (room air and 30, 40, and 90% O2). All animals were observed for 60 min after thoracotomy. Rats operated with exteriorization of the heart through left lateral thoracotomy while breathing spontaneously developed severe hypoxia and hypercapnia despite an intrathoracic operation time of <1 min. Arterial O2 content decreased from 18.7 +/- 0.5 to 3.3 +/- 0.9 vol%. Lactate increased from 1.2 +/- 0.1 to 5.2 +/- 0.3 mmol/l. Significant signs of ischemia were seen in the electrocardiogram up to 60 min. Mechanically ventilated animals exhibited a spectrum ranging from hypoxia (room air) to hyperoxia (90% O2). In order not to jeopardize findings in experimental myocardial ischemia-reperfusion injury models, stable physiological parameters can be achieved in mechanically ventilated rats at an O2 application of 30-40% at 90 strokes/min.

Animals↗
PubMed1998

Changes of neurohumoral parameters and endothelin-1 in response to exercise in patients with mild to moderate congestive heart failure.

UNLABELLED: Plasma endothelin levels are increased in patients with moderate and severe CHF. Conflicting data exist about the endothelin-1 (ET) level in patients with mild to moderate CHF and the effect of maximal exercise on plasma ET levels. METHODS AND RESULTS: We determined the plasma levels of ET and various neurohumoral parameters in 93 patients with CHF in functional class II and III of the NYHA classification at rest and after maximal bicycle exercise. Baseline ET level was increased compared to an age-matched healthy volunteer group (6.95+/-0.31 vs 3.29+/-0.17 pg/ml, mean+/-S.E.M., P<0.05), without significant differences between NYHA class II and III patients. Maximal exercise did not increase the ET level. In contrast, the neurohumoral parameters were significantly increased with maximal exercise. In conclusion, plasma levels of ET are increased in patients with mild to moderate CHF. However, no further increase in response to exercise was observed. Thus, it is highly unlikely that exercise capacity may be limited by ET-mediated peripheral vasoconstriction.

Aged↗
PubMed1998

Comparison of antiplatelet effects of aspirin, ticlopidine, or their combination after stent implantation.

BACKGROUND: This study was performed to analyze the influence of either aspirin, ticlopidine, or their combination on platelet activation and aggregation parameters after stent implantation. METHODS AND RESULTS: Sixty-one patients with successful implantation of a single Palmaz-Schatz stent in a native coronary artery were randomly assigned to either group A (aspirin 300 mg/d+ticlopidine 2X250 mg/d), group B (ticlopidine 2X250 mg/d), or group C (aspirin 300 mg/d). Platelet activation was evaluated on days 1, 7, and 14 by flow cytometry measurement of expression of CD62p (p-selectin) and the binding of fibrinogen to the platelet surface glycoprotein IIb/IIIa receptor. Platelet aggregation was induced by addition of ADP or collagen. Differences between treatment groups were compared by ANOVA. Between days 1 and 14, we observed a significant decrease in collagen-induced platelet aggregation in group A (62.2+/-2.5% versus 36.9+/-3.1%), whereas an increase was seen in group B (58.3+/-2.5% versus 67.7+/-3.2%) and no change was seen in group C (P<.0001). The ADP-induced aggregation declined significantly in group A (74.7+/-1.4% versus 55.3+/-2.6%), whereas a delayed reduction was seen in group B (72.0+/-3.0% versus 52.6+/-4.2%) and no change was seen in group C (P=.0017). The CD62p expression declined significantly in groups A (68.2+/-2.7% versus 41.3+/-2.7%) and B (64.8+/-2.9% versus 39.3+/-3.5%) but not in group C (P<.0001). Moreover, the fibrinogen binding decreased significantly in group A (61.0+/-4.3% versus 36.3+/-4.2%) and with delay in group B (58.3+/-2.2% versus 39.4+/-3.0%), whereas no alterations were seen in group C (P=.012). CONCLUSIONS: Our results demonstrate synergistic and accelerated platelet inhibitory effects of ticlopidine plus aspirin in patients after stent implantation compared with a monotherapy with either ticlopidine or aspirin alone.

Angioplasty, Balloon, Coronary↗
PubMed1998

Transesophageal ultrasonographic imaging in rat hearts: visualization of aortic valve vegetations in non-bacterial thrombotic endocarditis.

The aim of this study was to test the feasibility of transesophageal ultrasonography in rats by using an intravascular ultrasound system for visualization of vegetations at the aortic valve in the animal model of experimental endocarditis. After anesthesia and preparation of the right carotid artery, a polyethylene catheter was advanced across the aortic valve into the left ventricle in 91 rats. For transesophageal ultrasonography an intravascular ultrasound catheter (3.5 French; 30 MHz) linked to an imaging system was introduced into the esophagus. Sonographic investigations were performed every 24 hours until death. The presence, size, and echogenicity of vegetations were evaluated. Presence and size were compared to autopsy findings. No complications occurred as a result of the sonographic investigation. Left-sided valvular structures were imaged regularly. For detection of vegetations, sensitivity and specificity were 93% and 88%, respectively. Comparing the measurements of the vegetation size the following regression equation was obtained: y = 0.74x + 0.04 (r = 0.89; standard error of estimate = 0.02 cm). Inter- and intraobserver variabilities for sonographic measurements were 8.3% and 6.2%, respectively. Transesophageal ultrasonography permits reliable detection and repetitive accurate quantification of vegetations in the rat model of endocarditis. The technique enhances longitudinal studies of the dynamic process of the growth of vegetations under defined microbial conditions.

Animals↗