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Biomedical subjects

Christian J Wiedermann

Publications and source records attributed to Christian J Wiedermann.

At least 19 recordsLinked to original sources
PubMed2007

Emergency correction of coagulation before major surgery in two elderly patients on oral anticoagulation.

Recommendations for urgent reversal of oral anticoagulation with vitamin K1 antagonists are largely derived from case series employing empirical dosing regimens with vitamin K1 and prothrombin complex concentrates. Data on the use of prothrombin complex concentrates in this indication are scarce in the elderly who are at high risk of both hemorrhagic and thrombotic complications. The two cases presented here describe patients older than 75 years who underwent rapid International Normalized Ratio (INR) reversal with prothrombin complex concentrates for surgical treatment of a bleeding ruptured spleen and for emergency surgery of a dissecting aorta. Both patients had their INRs rapidly corrected to <or= 1.6 and underwent operation without complications. Evidence on treatment of patients who present with elevated INR and who have major bleeding or need to undergo emergency surgery is based mainly on observational studies. The two elderly patients presented here underwent successful emergency surgery after their INRs had been corrected with the intravenous use of vitamin K1 in combination with prothrombin complex concentrate that was administered according to current guideline recommendations.

Journal Article↗
PubMed2007

Co-infection with two Chlamydophila species in a case of fulminant myocarditis.

OBJECTIVE: The aim of this study is to describe a case of fulminant myocarditis caused by co-infection with Chlamydophila pneumoniae and Chlamydophila psittaci in order to facilitate diagnosis and clinical management of patients suffering from this rare but life-threatening condition. DESIGN: Case report. SETTING: Intensive care unit of Innsbruck Medical University. PATIENT: A 24-yr-old patient admitted with septicemia and cardiac failure. INTERVENTIONS: Cardiopulmonary resuscitation, extracorporal membrane oxygenation, implantation of an extracorporal cardiac assist device, and antibiotic treatment with erythromycin. MEASUREMENTS AND MAIN RESULTS: Cp. pneumoniae and Cp. psittaci were identified by means of polymerase chain reaction and electron microscopy in the patient's myocytes. Successful weaning off the ventricular assist device was performed within 2 wks after commencement of antibiotic therapy. CONCLUSIONS: This case report demonstrates co-infection with Cp. pneumoniae and Cp. psittaci to be a hitherto unknown cause of fulminant myocarditis. There is a particular risk of misdiagnosis of viral myocarditis, which must be avoided. Patients should be transferred to a center where extracorporal membrane oxygenation therapy and molecular diagnosis of all members of the family Chlamydiaceae are available.

Adult↗
PubMed2006

Heparan sulfate proteoglycan-dependent neutrophil chemotaxis toward PR-39 cathelicidin.

Cathelicidins are mammalian proteins containing a C-terminal cationic antimicrobial domain. Porcine PR-39 cathelicidin affects leukocyte biology. Mechanisms of action may involve alteration of heparan sulfate proteoglycan-dependent functions in inflammatory cells. It was tested whether PR-39 affects human neutrophil migration and if such effects involve heparan sulphate proteoglycans. Neutrophils were from forearm venous blood of healthy donors. Migration was tested in modified Boyden chamber assays. Involvement of heparan sulfate proteoglycans was tested by their chemical modification and by the use of specific antibodies. PR-39 induced migration in neutrophils in a concentration dependent manner. Modification of heparan sulfate proteoglycans with sodium chlorate inhibited migration whereas chemotaxis toward the chemoattractant formyl-Met-Leu-Phe was not affected. Removal of heparan sulfates or chondroitin sulfates from the surface of neutrophils by heparinase or chondroitinase inhibited migration toward PR-39. In conclusion, antimicrobial PR-39 stimulates human neutrophil chemotaxis in a heparan sulfate proteoglycan-dependent manner. Involvement of syndecans is likely as both heparinase and chondroitinase were abrogating. Data suggest active participation of heparan sulfate proteoglycans of neutrophils in cathelicidin peptide-mediated regulation of the antimicrobial host defense.

Journal Article↗
PubMed2006

Genetic and acquired inflammatory conditions are synergistically associated with early carotid atherosclerosis.

BACKGROUND AND PURPOSE: If chronic inflammation plays a causal role in atherogenesis, individuals with proinflammatory gene variants would be expected to develop more atherosclerosis. We recently found a synergistic association between 3 functional proinflammatory gene polymorphisms/haplotypes and smoking on carotid intima-media thickness (IMT). We replicated this finding in a second large population and extended the analysis by inclusion of other inflammatory conditions (chronic infection and obesity/abnormal glucose tolerance). METHODS: Common carotid and femoral artery IMT was determined in the Bruneck Study population (n=810). Proinflammatory variants were determined in 3 genes (IL-6 [-174C, -572G, -597A haplotype], IL-1-receptor antagonist [VNTR *2], and endotoxin receptor CD-14 [-159C]). RESULTS: There was a significant relationship between gene-variant score and carotid IMT: age- and sex-adjusted mean IMT in subjects with 0, 1, and >or=2 gene variants was 936, 987 and 1047 microm, respectively (P=0.001), and synergistic effects of gene-variant score and smoking on IMT measurements (P=0.040). Analogous findings were obtained for obesity/abnormal glucose tolerance and chronic infection. Interactive effects of gene-variant score and a risk factor score composed of the acquired inflammatory conditions were highly significant (P<0.001 each). Results were similar for femoral artery IMT. CONCLUSIONS: These results provide support for a causal role of inflammation in carotid atherosclerosis, and emphasize the importance of gene-gene and gene-environment interactions in this pathogenic pathway. This may help to explain the substantial variability of disease expression in subjects with proinflammatory risk factors such as smoking, diabetes and chronic infection.

Aged↗
PubMed2006

Mechanisms of neutrophil transmigration across renal proximal tubular HK-2 cells.

BACKGROUND: Adhesion of intratubular leukocytes to proximal tubules in biopsies of patients with rapidly progressive glomerulonephritis and the appearance of leukocytes in the urine in interstitial nephritis suggest interactions between leukocytes and tubular epithelia in renal diseases. The aim of this study was to investigate the effect of cytokines and endotoxin on leukocyte migration through proximal tubular epithelial cells and also to determine the role of the transmembrane adhesion molecules ICAM-1 and CD47 in this process. METHODS: Experiments determined transepithelial migration (TEM) of PMN (polymorphonuclear) leukocytes through monolayers of HK-2. Expression of ICAM-1 and CD47 was assessed via confocal immunofluorescence, FACS analysis and western blotting. The effect of antibodies against ICAM-1 and CD47 on TEM was examined. Furthermore measurements of cytokine release (IL- 6 and IL-8) were performed. RESULTS: Preincubation of HK-2 cells with either TNFalpha or LPS resulted in stimulation of PMN migration through monolayers of HK-2 cells. There was no preferred direction of transmigration. ICAM-1 was expressed by HK-2 cells and expression was increased after 4 h stimulation with TNFalpha or LPS. Application of ICAM-1 antibodies inhibited TEM. CD47 was expressed in both HK-2 cells and PMN. CD47 antibodies inhibited predominantly basolateral-to-apical TEM. HK-2 cells released IL-8 and IL-6 preferably into the apical compartment. Additionally, we showed that fMLP induced transmigration through monolayers of HK-2 cells was associated with significant increased CD47 expression on PMN cell surfaces. CONCLUSIONS: Inflammatory mediators stimulate TEM of PMN through monolayers of HK-2 cells without a clearly discernible preference of direction. Mechanisms involved in TEM stimulated by cytokines or endotoxin appear to be mainly changes in surface receptor densities of HK-2 cells with ICAM-1 and CD47 playing an essential role.

Antibodies, Monoclonal↗
PubMed2006

Amphotericin B tissue distribution in autopsy material after treatment with liposomal amphotericin B and amphotericin B colloidal dispersion.

OBJECTIVES: Tissue concentrations of amphotericin B were determined in autopsy material of patients who had been treated with liposomal amphotericin B or amphotericin B colloidal dispersion (colloidal amphotericin B) for suspected or proven invasive fungal infection. PATIENTS AND METHODS: Amphotericin B tissue levels were measured in liver, spleen, lung, kidney, and myocardial and brain tissue of 20 patients who had been treated with lipid-formulated amphotericin B, before they died from multi-organ failure. Seven patients had been treated with liposomal amphotericin B (AmBisome) and thirteen with colloidal amphotericin B (Amphocil). Tissue samples were obtained during routine autopsy, homogenized and extracted with methanol. Amphotericin B concentrations were measured using HPLC after purification by solid phase extraction. RESULTS: The highest amphotericin B levels were found in liver and spleen, followed by kidney, lung, myocardium and brain. In the lung higher amphotericin B concentrations were found after treatment with amphotericin B colloidal dispersion than after therapy with liposomal amphotericin B. CONCLUSIONS: The choice of lipid formulation may influence amphotericin B penetration into the lung.

Adult↗
PubMed2006

Endothelial protein C receptor-dependent inhibition of migration of human lymphocytes by protein C involves epidermal growth factor receptor.

The protein C pathway is an important regulator of the blood coagulation system. Protein C may also play a role in inflammatory and immunomodulatory processes. Whether protein C or activated protein C affects lymphocyte migration and possible mechanisms involved was tested. Lymphocyte migration was studied by micropore filter assays. Lymphocytes that were pretreated with protein C (Ceprotin) or activated protein C (Xigris) significantly reduced their migration toward IL-8, RANTES, MCP-1, and substance P, but not toward sphingosine-1-phosphate. The inhibitory effects of protein C or activated protein C were reversed by Abs against endothelial protein C receptor and epidermal growth factor receptor. Evidence for the synthesis of endothelial protein C receptor by lymphocytes is shown by demonstration of receptor mRNA expression and detection of endothelial protein C receptor immunoreactivity on the cells' surface. Data suggest that an endothelial protein C receptor is expressed by lymphocytes whose activation with protein C or activated protein C arrests directed migration. Exposure of lymphocytes to protein C or activated protein C stimulates phosphorylation of Tyr845 of epidermal growth factor receptor, which may be relevant for cytoprotective effects of the protein C pathway.

Antigens↗
PubMed2006

High-dose antithrombin III in the treatment of severe sepsis in patients with a high risk of death: efficacy and safety.

OBJECTIVE: To explore if patients with severe sepsis and with a predicted high risk of death (according to the Simplified Acute Physiology Score II) might have a treatment benefit from high-dose antithrombin III. DESIGN: Subgroup analysis of a randomized, placebo-controlled, double-blind, prospective phase III study. SETTING: Unifactorial and multifactorial reanalysis of prospectively defined populations from the KyberSept trial. PATIENTS: We studied 1,008 patients (43.6% of the overall intention-to-treat population, n = 2,314) with a predicted mortality rate of 30-60% at study entry as defined by the Simplified Acute Physiology Score II. INTERVENTIONS: Patients were randomized in a 1:1 fashion to receive either high-dose antithrombin III (30,000 IU intravenously over the period of 4 days) or placebo. MEASUREMENTS AND MAIN RESULTS: In a Kaplan-Meier analysis of patients with a predicted mortality of 30-60%, the survival time when followed up for 90 days after admission was increased in the high-dose antithrombin III group compared with placebo (p = .04). If heparin was avoided during the 4-day treatment phase with high-dose antithrombin III (n = 140) or placebo (n = 162), the treatment effect appeared to be even more pronounced: 28-day mortality rate, 35.7% vs. 44.4% (risk ratio, 0.804; 95% confidence interval, 0.607-1.064); 56-day mortality rate, 39.9% vs. 52.2% (risk ratio, 0.764; 95% confidence interval, 0.593-0.984); 90-day mortality rate, 42.8% vs. 55.1% (risk ratio, 0.776; 95% confidence interval, 0.614-0.986). Like in the overall population, the percentage with any bleeding was increased in patients receiving high-dose antithrombin III compared with placebo. Survival rates were in favor of high-dose antithrombin III in patients both with and without bleeding complications. CONCLUSIONS: Treatment with high-dose antithrombin III may increase survival time up to 90 days in patients with severe sepsis and high risk of death. This benefit may even be stronger when concomitant heparin is avoided.

APACHE↗
PubMed2006

A systematic review of antithrombin concentrate use in patients with disseminated intravascular coagulation of severe sepsis.

The objective was to estimate the effect of antithrombin therapy on mortality in disseminated intravascular coagulation (DIC) of severe sepsis and septic shock. Randomized clinical trials (RCT) on patients with DIC and severe sepsis or septic shock assigned to intravenous antithrombin or placebo were searched. Eligible studies reported death as the outcome measure. Of 35 RCT, 32 trials were excluded because patients were not randomized to antithrombin versus placebo, or no separate data on patients with DIC were given. In three RCT, 364 patients with severe sepsis or septic shock and DIC were randomized. The disease severity, definition of DIC, dose and duration of treatment varied among the trials. In two of the three RCT, data were from subgroup analyses (patients not stratified by DIC). The combined odds ratio for short-term all-cause mortality in those who received antithrombin was 0.649 (95% confidence interval, 0.422-0.998). Data on bleeding complications in patients treated with antithrombin were reported only in one of the RCT and were not considered suitable for systematic safety estimation. In sepsis patients with DIC, administration of antithrombin concentrate may increase overall survival. Current available evidence, however, is not suited to sufficiently inform clinical practice.

Antithrombins↗
PubMed2006

Pharmacokinetics of liposomal amphotericin B during extracorporeal albumin dialysis.

Extracorporeal blood purification techniques such as hemofiltration or albumin dialysis can exert a significant, but not easily predictable influence on plasma pharmacokinetics of antimicrobial agents. The effect of albumin dialysis on the pharmacokinetics of liposomal amphotericin B (AMB) and other lipid-formulated drugs has not been investigated so far. Therefore, plasma concentrations of liberated and liposomal AMB were measured in a patient, who obtained liposomal AMB for suspected invasive mycosis and required albumin dialysis because of cholestatic liver failure caused by graft versus host disease after bone marrow transplantation. Liberated and liposomal AMB were separated by solid phase extraction and measured by high performance liquid chromatography. No excessive AMB elimination took place during albumin dialysis. Plasma levels of liposomal AMB exceeded those of liberated AMB. Pharmacokinetic data were comparable to those obtained previously in patients on hemofiltration and in critically ill patients without extracorporeal blood purification.

Adult↗
PubMed2006

Clinical review: molecular mechanisms underlying the role of antithrombin in sepsis.

In disseminated intravascular coagulation (DIC) there is extensive crosstalk between activation of inflammation and coagulation. Endogenous anticoagulatory pathways are downregulated by inflammation, thus decreasing the natural anti-inflammatory mechanisms that these pathways possess. Supportive strategies aimed at inhibiting activation of coagulation and inflammation may theoretically be justified and have been found to be beneficial in experimental and initial clinical studies. This review assembles the available experimental and clinical data on biological mechanisms of antithrombin in inflammatory coagulation activation. Preclinical research has demonstrated partial interference of heparin--administered even at low doses--with the therapeutic effects of antithrombin, and has confirmed--at the level of cellular mechanisms--a regulatory role for antithrombin in DIC. Against this biological background, re-analyses of data from randomized controlled trials of antithrombin in sepsis suggest that antithrombin has the potential to be developed further as a therapeutic agent in the treatment of DIC. Even though there is a lack of studies employing satisfactory methodology, the results of investigations conducted thus far into the mechanisms of action of antithrombin allow one to infer that there is biological plausibility in the value of this agent. Final assessment of the drug's effectiveness, however, must await the availability of positive, prospective, randomized and placebo-controlled studies.

Animals↗
PubMed2006

Benefit/risk profile of high-dose antithrombin in patients with severe sepsis treated with and without concomitant heparin.

A randomised, prospective, placebo-controlled phase III multicentre clinical trial (KyberSept) has been performed to test the efficacy of high-dose antithrombin therapy in patients with severe sepsis. Concomitant low-dose heparin has been routinely given in two thirds of patients for deep vein thrombosis prophylaxis. This study analyses heparin - antithrombin interactions in terms of long-term mortality, adverse events, and thromboembolic events. From a total of 2,314 patients with severe sepsis (placebo: n = 1,157; antithrombin: n = 1,157) 1,616 patients (placebo: 811, antithrombin: 805) received heparin concomitantly with study drug (antithrombin 30,000 IU) over four days, whereas 698 patients (346 and 352, respectively) did not. In patients with no concomitant heparin, 28-day mortality was lower with antithrombin than with placebo (37.8% vs. 43.6%; absolute reduction: 5.8%; risk ratio: 0.860 [0.725-1.019]), which increased until day-90 (44.9% vs. 52.5%; absolute reduction: 7.6%; risk ratio: 0.851 [0.735-0.987]). In patients with concomitant heparin, no effect of antithrombin on mortality was seen (28-day mortality: 39.4% vs. 36.6%; absolute increase: 2.8%; risk ratio: 1.08 [0.96-1.22]). Frequency of use of concomitant heparin increased during conduct of the study. Increased bleeding incidences were reported with antithrombin plus concomitant heparin as compared to antithrombin alone. Rates of thromboembolic events were similar when antithrombin was given with or without concomitant heparin. In the treatment of severe sepsis, high-dose antithrombin may sufficiently protect against development of venous thromboembolism when no concomitant heparin is given. Combined administration of the two increases bleeding risk and probably abolishes efficacy of antithrombin.

Adult↗