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Biomedical subjects

H Darius

Publications and source records attributed to H Darius.

At least 55 records · Page 3Linked to original sources
PubMed1998

Clinical and morphological characteristics in Streptococcus bovis endocarditis: a comparison with other causative microorganisms in 177 cases.

AIM: To compare the clinical and morphological characteristics of patients with Streptococcus bovis endocarditis with those of patients with endocarditis caused by other microorganisms. METHODS: 177 consecutive patients (Streptococcus bovis, 22; other streptococci, 94; staphylococci, 44; other, 17) with definite infective endocarditis according to the Duke criteria were included. All patients underwent transthoracic and transoesophageal echocardiography. In 88 patients, findings from surgery/necropsy were obtained. RESULTS: S bovis endocarditis was associated with older patients, with a higher mortality (p = 0.04), and with a higher rate of cardiac surgery (p < 0.001) than other microorganisms, although embolic events were observed less often (p = 0.02). Pathological gastrointestinal lesions were detected in 45% of the patients. Multiple valves were affected in 68% of the patients with S bovis endocarditis and in 20% of those with other organisms (p < 0.001). Moderate or severe regurgitation occurred more often in S bovis endocarditis than with other microorganisms (p = 0.05). When surgery or necropsy was performed, infectious myocardial infiltration of the left ventricle was confirmed histopathologically in 36% of the patients with S bovis endocarditis and in 10% of those with other organisms (p = 0.002). CONCLUSIONS: S bovis endocarditis is a severe illness because of the more common involvement of multiple valves, and of the frequent occurrence of haemodynamically relevant valvar regurgitation and infectious myocardial infiltration.

Adult↗
PubMed1998

Differential regulation of endothelial cell adhesion molecule expression by nitric oxide donors and antioxidants.

Although nitric oxide (NO) and antioxidants inhibit adhesion molecule expression, their inhibitory effects on nuclear factor kappaB (NF-kappaB) activation may differ. The NO donors, but not 8-bromo-cGMP, decreased tumor necrosis factor alpha (TNF-alpha)-induced VCAM-1, ICAM-1, and E-selectin expression by 11-70%. In contrast, NAC completely abolished VCAM-1 and E-selectin expression and decreased ICAM-1 expression by 56%. Gel shift assays demonstrate that NF-kappaB activation was inhibited by both NO and antioxidants. The activation of NF-kappaB involves the phosphorylation and degradation of its cytoplasmic inhibitor IkappaB-alpha by 26S proteasomes. The 26S proteasome inhibitor MG132 prevented the degradation of phosphorylated IkappaB-alpha. NAC inhibited IkappaB kinase (IKK) activity and prevented IkappaB-alpha phosphorylation and degradation. In contrast, NO did not inhibit IKK activity, IkappaB-alpha phosphorylation, or IkappaB-alpha degradation. However, NO, but not antioxidants, induced IkappaB-alpha promoter activity. The inhibitory effects of NO on adhesion molecule expression, therefore, differs from that of antioxidants in terms of the mechanism by which NF-kappaB is inactivated.

Animals↗
PubMed1998

Blocking of classical complement pathway inhibits endothelial adhesion molecule expression and preserves ischemic myocardium from reperfusion injury.

Myocardial injury after ischemia (I) and reperfusion (R) is related to leukocyte activation with subsequent release of cytokines and oxygen-derived free radicals as well as complement activation. In our study, the cardioprotective effects of exogenous C1 esterase inhibitor (C1 INH) were examined in a rat model of myocardial I + R (i.e., 20 min + 24 hr or 48 hr). The C1 INH (10, 50 and 100 U/kg) administered 2 min before reperfusion significantly attenuated myocardial injury after 24 hr of R compared to vehicle treated rats (P < .001). Further, cardiac myeloperoxidase activity (i.e., a marker of PMN [polymorphonuclear leukocyte] accumulation) in the ischemic area was significantly reduced after C1 INH treatment compared to vehicle treated animals (0.81 +/- 0.1, 0.34 +/- 0.13, 0.13 +/- 0.1 vs. 1.44 +/- 0.3 U/100 mg tissue, P < .001). In addition, C1 INH (100 U/kg) significantly attenuated myocardial injury and neutrophil infiltration even after 48 hr of reperfusion compared to vehicle treatment. Immunohistochemical analysis of ischemic-reperfused myocardial tissue demonstrated activation of classical complement pathway by deposition of C1q on cardiac myocytes and cardiac vessels. In addition, expression of the endothelial adhesion molecules P-selectin and intercellular adhesion molecule 1 (ICAM-1) was observed after reperfusion of the ischemic myocardium. In this regard, C1 INH administration abolished expression of P-selectin and ICAM-1 on the cardiac vasculature after myocardial ischemia and reperfusion. Blocking the classical complement pathway by exogenous C1 INH appears to be an effective means to preserve ischemic myocardium from injury after 24 and 48 hr of reperfusion. The mechanisms of this cardioprotective effect appears to be due to blocking of complement activation and reduced endothelial adhesion molecule expression with subsequent reduced PMN-endothelium interaction, resulting in diminished cardiac necrosis.

Animals↗
PubMed1997

Phosphodiesterase inhibitors piroximone and enoximone inhibit platelet aggregation in vivo and in vitro.

The phosphodiesterase type III inhibitors piroximone (PIR) and enoximone (ENO) exert positive inotropic and vasodilating effects in patients with severe heart failure. PIR and ENO raise cyclic AMP levels in cardiac and vascular smooth muscle cells. Platelet activity is also regulated by intracellular levels of cyclic AMP. In this study we have investigated the effects of PIR and ENO on platelet activity in vivo and in vitro. PIR and ENO inhibited ADP induced platelet aggregation in a time- and concentration-dependent manner with IC50-values of 67 +/- 14 mumol/l and 129 +/- 6 mumol/l, respectively. Coincubation of PIR with the adenylate cyclase activator iloprost resulted in a synergistic potentiation of the platelet inhibitory effect. In anesthetized rats PIR and ENO (2 mg/kg bw) exerted an effective inhibition of collagen induced reduction in peripheral platelet count (vehicle 49 +/- 7%, PIR 22 +/- 8%, ENO 30 +/- 6%; P < 0.01). In washed human platelets incubation with PIR and ENO resulted in a time- and concentration-dependent increase of the intracellular second messenger cyclic AMP. In Fura-2 AM loaded platelets PIR and ENO diminished PAF induced Ca2+ mobilization concentration dependently. Thus, the observed antiplatelet effects following PIR and ENO might exert beneficial effects in patients with cardiovascular disease.

Animals↗
PubMed1997

Prostacyclin receptor desensitization is a reversible phenomenon in human platelets.

BACKGROUND: Long-term exposure of platelets to endogenous or exogenous prostacyclin or its analogues might result in desensitization of the platelet prostacyclin receptor in vitro and in vivo accompanied by a loss in receptor density on the platelet surface and a reduced sensitivity toward the inhibitory effects of prostacyclins. However, the reversibility of this process in platelets has not yet been investigated. METHODS AND RESULTS: Human platelets desensitized by the chemically stable prostacyclin analogue iloprost showed a significant reduction in [3H]-iloprost binding sites that was reversed by saponin permeabilization. This indicates functionally active internalized prostacyclin receptors. To assess whether the internalized prostacyclin receptors recycle to the cell surface after withdrawal of the agonist, iloprost sensitivity and prostacyclin receptor binding properties of iloprost (30 nmol/L, 2 hours) desensitized platelets incubated in iloprost-free autologous plasma were investigated. While desensitized platelets showed a significant increase in IC50 for iloprost inhibition of thrombin-induced platelet aggregation, serotonin release, and p-selectin expression and a reduced iloprost-stimulated cAMP formation, platelet iloprost sensitivity was restored 3 hours after iloprost withdrawal. In addition, the significant reduction in Bmax and the increase in K(D) of prostacyclin receptors in desensitized platelets as revealed by [3H]-iloprost binding studies also returned to the initial values. CONCLUSIONS: These results indicate that prostacyclin receptors internalized during short-term desensitization are not degraded but can be recycled rapidly to the platelet surface in a functionally active form after withdrawal of the agonist.

Blood Platelets↗
PubMed1997

Intracoronary application of C1 esterase inhibitor improves cardiac function and reduces myocardial necrosis in an experimental model of ischemia and reperfusion.

BACKGROUND: Myocardial injury from ischemia can be aggravated by reperfusion of the jeopardized area. The precise underlying mechanisms have not been clearly defined, but proinflammatory events, including complement activation, leukocyte adhesion, and infiltration and release of diverse mediators, probably play important roles. The present study addresses the possibility of reducing reperfusion damage by the application of C1 esterase inhibitor (C1-INH). METHODS AND RESULTS: Cardioprotection by C1-INH 20 IU/kg IC was examined in a pig model with 60 minutes of coronary occlusion, followed by 120 minutes of reperfusion. C1-INH was administered during the first 5 minutes of coronary reperfusion Compared with the NaCl controls, C1-INH reduced myocardial injury (48.8 +/- 7.8% versus 73.4 +/- 4.0% necrosis of area at risk, P < or = .018). C1-INH treatment significantly reduced circulating C3a and slightly attenuated C5a plasma concentrations. Myocardial protection was accompanied by reduced plasma concentration of creatine kinase and troponin-T. C1-INH had no effect on global hemodynamic parameters, but local myocardial contractility was markedly improved in the ischemic zone. In the short-axis view, 137 degrees of the anteroseptal region showed significantly improved wall motion at early and 29 degrees at late reperfusion with C1-INH treatment. CONCLUSIONS: C1-INH significantly protects ischemic tissue from reperfusion damage, reduces myocardial necrosis, and improves local cardiac function.

Anaphylatoxins↗
PubMed1997

Effect of antibiotic treatment on vegetation size and complication rate in infective endocarditis.

BACKGROUND: Infective endocarditis is associated with significant morbidity and mortality, with valvular destruction, and with congestive heart failure. Embolic events are more common in patients with echocardiographically discernible vegetations, especially when vegetations are > 10 mm in diameter. HYPOTHESIS: The objective of the study was to follow vegetation morphology during native valve endocarditis, to compare it with the clinical course and antibiotic treatment chosen, and to evaluate whether the impact on vegetation size and complication rate of antibiotic regimens differed in patients with positive and negative blood cultures. METHODS: The effect of different antibiotic regimes on vegetation size monitored by using transesophageal echocardiography was evaluated in 183 patients with echocardiographic evidence of infective endocarditis. A total of 223 vegetations attached to the aortic or mitral valves were detected using the transesophageal approach. The patients were followed for a mean of 76 weeks and underwent a minimum of two consecutive transesophageal echocardiographic examinations. RESULTS: Treatment with different kinds of antibiotics corresponded with significant differences in vegetation size; vancomycin-associated treatment was related to a 45% reduction, ampicillin to a 19% reduction, penicillin to a 5% reduction, penicillase-resistant drugs to a 15% increase, and cephalosporin to a 40% increase in vegetation size. Multivariate analysis showed that penicillin, cephalosporin, and penicillase-resistant drug treatments were associated with an increased embolic risk, vancomycin treatment with abscess formation, and cephalosporin medication with increased mortality. Plotting changes in vegetation size against the incidence of embolism and mortality, linear regression analysis suggested a 40-50% reduction in vegetation size, thereby greatly reducing the risk of embolism and mortality. CONCLUSION: Our study shows that different antibiotics have different effects on vegetation size. The highest complication rate was observed when vegetations significantly increased in size during antibiotic treatment. Especially in culture-negative patients, monitoring vegetation size by means of transesophageal echocardiography may prove to be useful for estimating the efficacy of antibiotic treatment.

Anti-Bacterial Agents↗
PubMed1997

[Local drug delivery and gene therapy].

One of the most important problems in clinical cardiology is still unresolved, i.e., the development of a restenosis following coronary balloon angioplasty. Our knowledge about the sequelae of pathophysiologic events occurring during neointima formation is still far from complete (Figure 1) and numerous therapeutic trials using systemic administration of drugs with different mechanisms of action have failed. Possible innovative strategies are the local administration of high doses of drugs into the coronary arteries and local gene therapeutic interventions to inhibit neointima formation by reducing the proliferation of vascular smooth muscle cells. Numerous catheter devices were developed (Figure 2) in order to enable the local application of high doses of a drug or DNA. Additionally, galenic techniques are being developed to guarantee a steady release of locally administered drugs, e.g. from drug containing liposomes or microcarriers (Figure 3). There are already several animal models in which the development of a neointima was reduced by injecting antisense oligonucleotides directed towards the RNA encoding cell cycle regulatory proteins or peptides. Alternatively, the transfer of cDNA encoding proteins or protein products which inhibit the cellular proliferation and migration are being tested in vitro and in vivo with the help of reporter genes (Figure 4). Although, gene transfer techniques are believed to offer great therapeutic options for the future, the clinical data available today regarding this method are very limited and are derived from studies in patients with peripheral arterial disease. Thus, it is still questionable if gene transfer techniques will ever be able to become an integral part of our standard treatment for patients with vascular diseases.

Coronary Disease↗
PubMed1997

A randomized controlled trial of epoprostenol therapy for severe congestive heart failure: The Flolan International Randomized Survival Trial (FIRST).

This trial evaluated the effects of epoprostenol on patients with severe left ventricular failure. Patients with class IIIB/IV congestive heart failure and decreased left ventricular ejection fraction were eligible for enrollment if angiography documented severely compromised hemodynamics while the patient was receiving a regimen of digoxin, diuretics, and an angiotensin-converting enzyme inhibitor. We randomly assigned 471 patients to epoprostenol infusion or standard care. The primary end point was survival; secondary end points were clinical events, congestive heart failure symptoms, distance walked in 6 minutes, and quality-of-life measures. The median dose of epoprostenol was 4.0 ng/kg/min, resulting in a significant increase in cardiac index (1.81 to 2.61 L/min/m2), a decrease in pulmonary capillary wedge pressure (24.5 to 20.0 mm Hg), and a decrease in systemic vascular resistance (20.76 to 12.33 units). The trial was terminated early because of a strong trend toward decreased survival in the patients treated with epoprostenol. Chronic intravenous epoprostenol therapy is not associated with improvement in distance walked, quality of life, or morbid events and is associated with an increased risk of death.

Aged↗
PubMed1996

Clinical assessment of periodontal conditions in patients treated with nifedipine.

Calcium antagonists are widely used in treating acute and chronic coronary insufficiency disorders. A major side effect of long-term treatment is gingival hyperplasia. In the present study, 70 patients taking nifedipine for at least six months and 70 controls similar in age, gender, approximal hygiene and systemic disease with at least 6 anterior teeth in upper and lower arches were examined. Their periodontal conditions were determined by modified Sulcus-Bleeding-Index (mSBI), modified Approximal-Plaque-Index (mAPI), Community Periodontal Index of Treatment Needs (CPITN), a hyperplasia index quantifying the extent of gingival overgrowth, probing depths, clinical attachment loss and the modified Phenytoin-Gingival-Inflammation-Index (mPGI). A mild to moderate gingival hyperplasia was diagnosed in 21 of 70 patients resulting in a prevalence of 30% compared to 8.5% in controls. The hyperplastic changes were situated mainly in the anterior region of the dentition. Significant differences between both groups could be found comparing the severity of the gingival hyperplasia, the CPITN, mSBI, probing depths and the part of mPGI evaluating colour and turgor of the gingiva (p < 0.05). The severity of gingival overgrowth was strongly correlated with the inflammatory gingival changes, probing depths, the periodontal treatment need and the approximal hygiene of the patients. No statistically significant correlation could be found between the severity of gingival hyperplasia and the age and gender of the patient, or the dose or duration of nifedipine therapy. Gingival changes seemed to be more pronounced in patients with cardiovascular disorders than in patients under hemodialysis. The high incidence of gingival hyperplasia in patients receiving nifedipine on a long-term basis emphasises the role of the dentist and general practitioner in the early detection and prophylaxis of gingival changes and requires a thorough information to the patient concerning periodontal side effects.

Bicuspid↗
PubMed1996

[Comparison of NYHA classification with cardiopulmonary function in patients with chronic heart failure].

In this study a correlation was sought between the NYHA class, the results of cardiopulmonary exercise testing (CPX) and the ejection fraction (EF) measured by echocardiography and scintigraphy. Of 36 patients enrolled, CHF in 20 patients was due to CAD and in 16 patients due to DCM. The NYHA class was determined independently by two cardiologists who were blinded to the CPX, echocardiography or scintigraphy results. Sixteen patients were classified as class II and 20 as class III. As a control, 23 patients without cardiopulmonary disease were examined. The CPX was done according to a ramp protocol with continuous measurement of respiratory gases, maximal oxygen consumption (VO2-max) and oxygen consumption at the anaerobic threshold (VO2-AT). A correlation (p = 0.0425) between the NYHA classification and the Weber classification for VO2-AT was found. There was no correlation for VO2-max. VO2-AT was significantly higher in NYHA II patients as compared to NYHA III patients. No significant difference was seen in relation to the VO2-max. In comparison to the normal group, the VO2-AT and VO2-max were significantly lower in NYHA II and III patients. There was no significant correlation between VO2-AT and EF, VO2-max and EF, or between NYHA class and EF. During a 16-month follow-up period lethality was 8/14 patients with VO2-AT < 10 ml/kg/min. Although the NYHA classification provides a valid method for determining the prognosis of CHF patients, if feasible, the CPX examinations should be used to provide updates of the disease progress.

Adult↗
PubMed1996

[Effect of intracoronary and intravenous iloprost on coronary blood flow velocity in patients with coronary heart disease].

Prostacyclin and its stable analog iloprost (ILO) are able to induce vasomotor effects in smooth muscle cells. These vasodilator effects have been demonstrated in several types of vessels, even in coronary arteries. Bugiardini et al. have previously claimed to have evidence for a coronary steal phenomenon in patients with coronary artery disease receiving ILO. They conclude the steal phenomenon from the appearance of angina and ST-segment changes. The aim of our trial was to study the coronary circulation by measuring coronary vessel diameter, coronary blood flow velocity (CBFV), heart rate and blood pressure in patients with high degree LAD stenosis following i.v. and i.c. infusion of ILO and papaverine (PAPA i.c.). Infusion of ILO i.v. (2 ng kg-1 min-1) induced no significant change in vessel diameter measured in the stenotic and in normal vessel segments. Following ILO i.c. (0.5 ng kg-1 min-1) and PAPA coronary vessel diameter increased proximal to the stenosis by 25.8 +/- 5.6% and 24.8 +/- 4.6% and within the stenosis by 50.1 +/- 10% and 56.2 +/- 11%, respectively (p < 0.01). At the end of the i.c. ILO infusion CBFV increased by 103.7 +/- 24.9% and was further elevated by PAPA (217 +/- 57.2%, p < 0.01). The elevated flow velocity with increased vessel diameter following ILO i.c. (0.5 ng kg-1 min-1) implicated an increased flow in the stenotic vessel and thus there was no evidence for a decreased perfusion or coronary steal phenomenon.

Blood Flow Velocity↗
PubMed1995

Synergistic interaction of adenylate cyclase activators and nitric oxide donor SIN-1 on platelet cyclic AMP.

The molecular mechanism of the synergistic platelet inhibition by activators of adenylate cyclase and guanylate cyclase in human platelets was investigated. The adenylate cyclase activators iloprost and prostaglandin E1 and the guanylate cyclase activator 3-morpholino-syndnonimine (SIN-1) dose-dependently inhibited thrombin-induced aggregation of washed human platelets. Furthermore, SIN-1 at a concentration inhibiting platelet aggregation by only 10% shifted the IC50 values of iloprost and prostaglandin E1 by one order of magnitude to the left, indicating a synergistic action of adenylate cyclase and guanylate cyclase activators. Iloprost and prostaglandin E1 dose-dependently elevated platelet cAMP without a significant influence on cGMP. In contrast, the platelet cGMP level was dose-dependently elevated by SIN-1. In addiiton, SIN-1 markedly increased cAMP level induced by low concentrations of adenylate cyclase activators (0.1-0.3 nM iloprost or 10-150 nM prostaglandin E1). In contrast, the rise in cAMP induced by higher adenylate cyclase activator concentrations (3 nM iloprost or 30 microM prostaglandin E1) was significantly reduced in the presence of SIN-1. The same biphasic mode of action of SIN-1 was observed with forskolin, an adenylate cyclase stimulator acting receptor independently, indicating a prostacyclin-receptor independent mechanism. The cAMP elevating effect of SIN-1 in the presence of low prostanoid concentrations was completely abolished by piroximone, a selective inhibitor of phosphodiesterase type III. Therefore, the inhibition of phosphodiesterase III by cGMP seems to be the mechanism for the elevation of cAMP levels by SIN-1 in the presence of low concentration of adenylate cyclase activators in human platelets.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1995

Diminished inhibition of adhesion molecule expression in prostacyclin receptor desensitized human platelets.

Long-term exposure of platelets to prostacyclin or iloprost (100nM, 3hr) results in receptor desensitization measured as decrease in 3H-iloprost binding sites by 47 +/- 14%. Desensitized platelets respond with an increased adhesion to endothelial cells. The mechanism of increased adhesiveness was studied by measuring the expression of the adhesion molecule CD62p (p-selectin; GMP140) on washed human platelets by flowcytometry. In thrombin stimulated platelets CD62p expression was dose-dependently reduced by iloprost. In receptor desensitized platelets IC50 for iloprost inhibition of thrombin-induced CD62p expression increased from 0.48 +/- 0.10 to 2.4 +/- 0.7 nM.

Analysis of Variance↗
PubMed1995

Aspirin therapy: optimized platelet inhibition with different loading and maintenance doses.

Inhibition of cyclooxygenase by aspirin has been shown to be beneficial in clinical situations such as acute myocardial infarction or unstable angina. The precise effect of various doses of aspirin on acute and long-term inhibition of platelet aggregation and thromboxane synthesis remains unclear. In this study we evaluated the effect of oral aspirin (0, 40, 100, 300, or 500 mg) as the initial loading dose in combination with different maintenance doses of aspirin (0, 40, or 100 mg/day) for 14 days on platelet function in healthy men. Bleeding time 2 or 24 hours after the first aspirin administration was significantly increased for 300 and 500 mg aspirin (p < 0.01). Two hours after the first administration of 100, 300, and 500 mg aspirin, a significant inhibition of collagen-induced platelet aggregation (ED50 collagen: from 3 +/- 1 to 17 +/- 2, 24 +/- 3, 22 +/- 3 micrograms/ml, respectively) was seen. At the same time serum thromboxane B2 synthesis was inhibited by more than 99% with 300 and 500 mg aspirin. At the end of the 14-day observation period, bleeding time was significantly prolonged for the different combinations of aspirin doses compared with initial values (p < 0.01). Collagen-induced platelet aggregation and serum thromboxane B2 synthesis were significantly inhibited for all aspirin combinations tested at 14 days (p < 0.05). The 40/40 mg aspirin combination was less effective, because it reached its maximal effect very late at day 7 of the observation period compared with the other combinations.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗