Walter Fürst

B.R.A.H.M.S. GmbH, Stadt Hennigsdorf, Brandenburg, Germany

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Publications (21)45.75 Total impact

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    ABSTRACT: The breakdown of mucosal barrier function due to intestinal hypo-perfusion is the earliest dysfunction of ischaemic colitis. Severe colon ischaemia after aortic reconstruction is associated with mortality rates up to 90%. Therefore, early detection and treatment of patients with extensive ischaemic colitis is of crucial importance. In experimental studies, both D-lactate and bacterial endotoxin have been reported as markers of intestinal mucosal barrier impairment. However, evidence of their value in clinical practice is lacking. The aim of this pilot prospective cohort study was to assess the association between ischaemia of the colon (assessed histologically) and plasma levels of D-lactate and endotoxin in patients undergoing open aortic reconstruction. Twelve consecutive patients underwent surgery between February and April 2003. Six patients underwent emergency surgery and six patients elective aortic surgery. D-Lactate and endotoxin levels were measured in blood samples collected according to a standardised protocol. For histological examination biopsies were obtained by sigmoidoscopy on days 4-6 after surgery, or earlier if indicated clinically. As early as 2 h postoperatively, elevated plasma levels of d-lactate were measured in patients with histologically proven ischaemic colitis. The peak of D-lactate elevation was on postoperative days 1 and 2. Concentration of plasma endotoxin was not significantly different in patients with or without ischaemic colitis. Our data suggest that plasma D-lactate levels are a useful marker for early detection of ischaemic colitis secondary to aortic surgery.
    European Journal of Vascular and Endovascular Surgery 06/2006; 31(5):470-4. · 2.82 Impact Factor
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    ABSTRACT: Multiple trauma patients have an impaired immune system and thus frequently develop life-threatening septic complications. Because there is an ongoing debate on which are the most predictive immunologic parameters of clinical outcome, we prospectively studied 19 multiple trauma patients with sepsis (mean age, 38.7 +/- 15.8 years; mean Injury Severity Score, 40.6 +/- 11.6) over a period of 14 days. The following parameters were measured daily after admission to the intensive care unit: ex vivo lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-alpha) production, monocyte human leukocyte antigen (HLA)-DR expression, constitutive interleukin (IL) 6 secretion, white blood cell count, and C-reactive protein. In addition, procalcitonin, neopterin, LPS-binding protein, and constitutive TNF-alpha secretion were measured every third day. Immediately after trauma, all patients had significantly lower levels of HLA-DR and ex vivo LPS-stimulated TNF-alpha secretion than healthy controls (n = 7; P < 0.001). On the day after clinical diagnosis of sepsis, before any other parameter differed between survivors (n = 13) and nonsurvivors (n = 6), ex vivo LPS-induced TNF-alpha secretion was significantly lower (P < 0.05) in nonsurvivors than in survivors. We conclude that ex vivo LPS-induced TNF-alpha production is an earlier predictor of clinical outcome in multiple trauma patients with sepsis than monocyte HLA-DR expression, constitutive IL-6 secretion, or any other parameter assessed.
    Shock 03/2006; 25(2):129-34. · 2.61 Impact Factor
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    ABSTRACT: Rat bone morphogenetic protein-4 (rBMP-4) cDNA was cloned from rat osteoblasts by RT-PCR and expressed in E. coli. Monomeric, dimeric and polymeric forms of recombinant rat BMP-4 (rrBMP-4) were obtained from inclusion bodies after solubilization with urea. The dimer was separated from the remaining polymer and host cell contaminants using size exclusion chromatography. Furthermore, purified rrBMP-4 was stabilized at low urea concentration (40 mM) and at pH 8.5 through the addition of bovine serum albumin. Both, rrBMP-4 dimer and polymer were biologically active as tested by the induction of alkaline phosphatase activity in MC3T3-E1 cells.
    Biotechnology Letters 11/2005; 27(20):1559-64. · 1.85 Impact Factor
  • Walter Fürst, Heinz Redl
    The Annals of thoracic surgery 10/2005; 80(3):1159. · 3.45 Impact Factor
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    ABSTRACT: To identify sepsis-related dysregulations of protein expression in the liver, we used a baboon model of acute endotoxemia and performed comparative proteome analysis. Treatment with lipopolysaccharide (LPS) was followed by an early but long-lasting (5-48 h) generation of N-terminal fragments of carbamoyl phosphate synthase-1 (CPS-1), an abundant enzyme of the hepatic urea cycle, which is normally located in the mitochondrial matrix. In addition, we developed a new sandwich immunoassay to determine circulating CPS-1 in human and baboons. We found CPS-1 to be induced by LPS and to be released into the circulation of healthy humans and baboons as early as 4 to 5 h after stimulation. Similarly, CPS-1 levels increased after injection of gram-positive bacteria in another baboon model. Enhanced CPS-1 levels were also detected in serum of patients with sepsis. Our data demonstrate fragmentation of CPS-1 in the liver and early increase in circulating CPS-1 levels under septic conditions. We suggest that circulating CPS-1 might serve as a novel serum marker indicating mitochondrial impairment of the liver and/or the small intestine in critically ill patients.
    Shock 07/2005; 23(6):533-8. · 2.61 Impact Factor
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    Walter Fürst, Asmita Banerjee
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    ABSTRACT: A two-component sealant composed of bovine serum albumin and glutaraldehyde (BioGlue) is used to treat aortic dissections. Although glutaraldehyde guarantees strong adherence to tissues and synthetic materials, its toxic potential should be considered. The aim of this study was to determine the amount of glutaraldehyde released from BioGlue, its cytotoxic effects on cultured cells, and the local reaction of lung, liver, and aortic tissues to BioGlue. BioGlue was prepared according to the product insert, allowed to polymerize, and then overlaid with saline solution. The supernatant was analyzed for its content of glutaraldehyde. The cytotoxic effect of BioGlue was evaluated by adding the supernatants to either cultured human embryo fibroblasts (MRC5) or mouse myoblasts (C2C12). In vivo toxicity was assessed on three different tissues by applying BioGlue onto a partial lung resection, a liver abrasion, or an intact abdominal aorta in rabbits. Tissue samples were histologically evaluated 2 and 7 days after application. Saline supernatants from polymerized BioGlue contained 100 to 200 mug/mL glutaraldehyde and were cytotoxic to both cell lines tested. Application of BioGlue to lung and liver tissue evoked serious adverse effects consisting of high-grade inflammation, edema, and toxic necrosis. Intact aortic tissue showed only low-grade or medium-grade inflammation. Polymerized BioGlue releases amounts of glutaraldehyde that are capable of inducing cytotoxic effects both in vitro and in vivo. Use of BioGlue should be restricted to the aortic dissection procedure, as other tissues are sensitive to the amounts of glutaraldehyde released from the glue.
    The Annals of thoracic surgery 06/2005; 79(5):1522-8; discussion 1529. · 3.45 Impact Factor
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    ABSTRACT: A lipopolysaccharide (LPS) dose-response study in an experimental baboon endotoxemia model is presented to define the relevance of this model compared with human endotoxemia. We describe acute and subacute endotoxemic models in baboons, the first evoked by bolus injection of LPS (1 mg, 0.1 mg, or 4 ng per kg of Escherichia coli LPS), and the second evoked by infusion of 1.5 mg/kg of E. coli LPS over 30 min. We report the analysis of LPS clearance, the kinetics of tumor necrosis factor, interleukin (IL) 6, and IL-8 expression on the protein as well as on the mRNA level, change in blood counts (white and red blood cells and circulating platelets), and several hemodynamic parameters such as temperature, cardiac index, heart rate, and mean arterial pressure via multiple sampling. The resulting data are compared with previously published human data. Our results show that the LPS-induced kinetics of cytokine release, as well as of hemodynamic and hematologic changes in baboons, were similar to those observed in humans, even though baboons required a approximately 104-fold higher initial LPS dose to develop these manifestations. Hence, we demonstrate that endotoxemia in baboons qualitatively, yet not quantitatively, resembles endotoxemia in humans and, therefore, proves to constitute a useful model for studying the pathogenic mechanisms of sepsis in relation to humans.
    Shock 12/2003; 20(5):431-6. · 2.61 Impact Factor
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    ABSTRACT: D-lactate is produced by indigenous bacteria in the gastrointestinal tract. Mammals do not have the enzyme systems to metabolize D-lactate rapidly. The present study was designed to determine the kinetics of circulating D-lactate levels and to examine whether the severity of shock affects circulating D-lactate levels in rats subjected to hemorrhagic/traumatic shock. Anesthetized rats underwent midline laparotomy (duration 30 min) and were bled to 30-35 mmHg mean arterial pressure (MAP). After the onset of decompensation, MAP was either increased to 40-45 mmHg immediately by administration of Ringer's solution (moderate shock) or after 40% of shed blood volume had been re-infused as Ringer's solution (severe shock). MAP was then maintained at 40-45 mmHg for 40 min by further administration of Ringer's solution (inadequate resuscitation). Subsequently, adequate resuscitation was performed for 60 min with shed blood and additional Ringer's solution. Metabolic acidosis was significantly more pronounced in severe than in moderate hemorrhagic/traumatic shock. Plasma D-lactate levels were already significantly increased at the end of severe hemorrhagic/traumatic shock and remained high during inadequate resuscitation. D-lactate levels were significantly higher after severe than after moderate shock. Endotoxin levels did not correlate with shock severity. Damage to the intestinal mucosa was more profound in severe shock than in moderate shock. Our data suggest that hemorrhagic/traumatic shock is associated with mucosal damage and increased plasma D-lactate levels. The severity of shock affects D-lactate concentrations in plasma. Plasma D-lactate may be a useful marker of intestinal injury after hemorrhagic/traumatic shock.
    Shock 10/2003; 20(3):245-50. · 2.61 Impact Factor
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    ABSTRACT: Toll-like receptors (TLR) play a pivotal role in the innate immune response, and the expression levels of these receptors may reflect the sensitivity of immune cells to infections. The binding of lipopolysaccharide (LPS) to TLR-4 triggers human monocytes to produce cytokines, which play a dominant role in the inflammatory response, as can be observed during sepsis and after polytrauma. Here, we evaluated TLR-4 expression of isolated monocytes in the presence of tumor necrosis factor (TNF)-alpha, interleukin (IL) 6, IL-8, and IL-10, and we investigated cellular activation of this treatment. TNF-alpha significantly down-regulated TLR-4 mRNA expression after 6 h (100% vs. 38.5% +/- 4%; P < 0.05). This down-regulation was followed by a dose- and time-dependent diminished expression of TLR-4 surface protein (100% vs. 8.0% +/- 5%; P < 0.01). Forty-eight hours after TNF-alpha treatment, a reduced nuclear factor (NF)-kappaB translocation and a diminished IL-6 secretion after LPS stimulation were found (100% vs. 42.0% +/- 23%; P < 0.05). In contrast, IL-6 incubation upregulated TLR-4 cell surface protein (100% vs. 165.8% +/- 24%; P < 0.05) and increased the ability to activate NF-kappaB and AP-1 after LPS stimulation. Stimulation with IL-8 or IL-10 had no significant effects. We conclude that not only LPS but also TNF-alpha and IL-6 have the potency to regulate the immune response via TLR-4. Down-regulation of TLR-4 by TNF-alpha is associated with LPS hyporeactivity for NF-kappaB formation, whereas upregulation of TLR-4 via IL-6 can increase the responsiveness of mononuclear phagocytes.
    Shock 09/2003; 20(3):224-9. · 2.61 Impact Factor
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    ABSTRACT: There is criticism that the major line of evidence regarding posttraumatic inflammatory response and bacterial translocation has mainly come from experiments in rodents. The aim of this study was therefore to investigate the very early bacteremia/endotoxemia and inflammatory response in nonhuman primates. Six baboons were subjected to hemorrhagic shock (40 mm Hg mean arterial pressure) preceded by infusion of zymosan-activated plasma (to simulate trauma-associated complement activation) followed by reinfusion for 1 h. Measurements of complement and granulocyte (PMN) activation, cytokines of the inflammatory network, soluble cytokine receptors, and bacteria/endotoxin translocation (BT) were performed. There were significantly increased levels of PMN elastase, interleukin-6, and soluble tumor necrosis factors (TNF) receptors, but not of TNF. BT was evident from positive blood cultures, and from trendwise increased endotoxin plasma levels. Early liver damage was shown from elevated glutathione S-transferase (GST) plasma levels. Complement activation and hemorrhagic shock lead to an early inflammatory response together with bacteremia/endotoxemia as evidence of translocation from the gut already during the shock period in subhuman primates.
    European Journal of Trauma 11/2000; 26(6):300-307.
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    ABSTRACT: We studied the effects of a novel pterin antagonist of NO synthase, the 4-amino analogue of tetrahydrobiopterin (4-ABH4), in a rat model of endotoxic shock and compared its properties with those of N(G)-monomethyl L-arginine (L-NMMA). Treatment with a bolus dose of 4-ABH4 at 2 h after LPS challenge significantly improved the 6-day survival rate, compared with the controls treated with saline. L-NMMA treatment did not significantly influence the survival rate. This bolus treatment, using either compound, had no effect on the plasma nitrite + nitrate or plasma IL-6 levels. The continuous infusion of 4-ABH4 efficiently suppressed the enhanced calcium-dependent/independent NO synthase activities induced by endotoxin in lung homogenates and completely suppressed the increase in plasma nitrite + nitrate caused by endotoxin at 5 h, with no significant difference compared with the L- NMMA treatment. Treatment of RAW264.7 murine macrophages with 4-ABH4 but not with L-NMMA suppressed endotoxin-induced tumor necrosis factor-alpha release by the cells, whereas nitrite in the supernatant decreased in a dose-dependent fashion in both assay systems. Our data show that 4-ABH4, an inhibitor of inducible NO synthase, significantly improves survival in a rat model of endotoxic shock when administered in a bolus dose that does not reduce plasma total nitrite + nitrate levels. Because we observed no overt signs of toxicity and no influence on organ-specific tetrahydrobiopterin levels, we conclude that the novel compound 4-ABH4 is a promising drug candidate for protection against endotoxin-related mortality.
    Shock 06/2000; 13(5):386-91. · 2.61 Impact Factor
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    ABSTRACT: A brief period of ischemia was used to evaluate an erythrocyte-enriched Krebs-Henseleit (KH) buffer (n=8) compared to KH only (n=8) in an isolated working rabbit heart. Experimental protocol was as follows: preischemic baseline, 5 min of global ischemia followed by 45 min of reperfusion. Preischemic heart rate was identical, coronary flow was significantly lower (2.7 versus 5.6 mL/min/g wet wt, p<0.01), the other hemodynamic and biochemical values were significantly higher in erythrocyte-perfused hearts: aortic flow 23.5 versus 12.0, p<0.01; cardiac output 26.2 versus 17.6, p<0.01; all in mL/min/g wet wt; dp/dt max 1286 versus 997 mmHg/s, p<0.01; myocardial oxygen consumption 3.5 versus 2.3 μmol/min/g wet wt, p<0.05. During early reperfusion, in the erythrocyte-perfused hearts, coronary flow further increased (p<0.003), the other hemodynamic parameters returned to baseline values in both groups. High-energy phosphates showed significantly higher values (ATP 2.0±0.1 versus 1.3±0.1, p<0.05; CrP 2.0±0.2 versus 1.6±0.1, p<0.05 all in μmol/g wct wt), water content was significantly lower (81% versus 74%, p<0.05) in erythrocyte-perfused hearts. It can be concluded that the erythrocyte-perfused working heart model provides excellent oxygenation, leading to superior hemodynamic and metabolic performance. Additionally, in the erythrocyte-perfused hearts preservation of coronary flow reserve underlines the physiological competency of this prepar-ation.
    Journal of Pharmacological and Toxicological Methods 03/1999; 41(1):9-15. · 2.15 Impact Factor
  • Walter Fürst, Anna Schiesser
    Analytical Biochemistry - ANAL BIOCHEM. 01/1999; 269(1):214-215.
  • Journal of Pharmacological and Toxicological Methods 01/1999; 03:9-15. · 2.15 Impact Factor
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    ABSTRACT: A brief period of ischemia was used to evaluate an erythrocyte-enriched Krebs-Henseleit (KH) buffer (n=8) compared to KH only (n=8) in an isolated working rabbit heart. Experimental protocol was as follows: preischemic baseline, 5 min of global ischemia followed by 45 min of reperfusion. Preischemic heart rate was identical, coronary flow was significantly lower (2.7 versus 5.6 mL/min/g wet wt, p
    Journal of Pharmacological and Toxicological Methods - J PHARMACOL TOXICOL METHOD. 01/1999; 41(1):9-15.
  • Shock 01/1995; 3(5). · 2.61 Impact Factor
  • Shock. 01/1995; 3(5).
  • W Fürst, S Hallström
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    ABSTRACT: An ion-pair reversed-phase high-performance liquid chromatographic method is described for the separation and quantification of myocardial nucleotides, nucleosides, their metabolites and creatine phosphate-related compounds in a single run. Separation of a standard mixture containing 21 compounds was achieved on a 5-microns Hypersil ODS column with a 5-min isocratic elution (buffer: 0.1 M NaH2PO4, pH 5.5, containing 5.9 mM tetrabutylammonium hydrogen-sulphate) followed by a slow linear gradient to 17% acetonitrile. The method was applied to extracts of freeze-clamped rat heart tissue samples as well as to extracts of neonatal rat heart cardiomyocytes, and it provided good resolution of high-energy phosphates, including creatine phosphate, as well as of their degradation products.
    Journal of Chromatography A 08/1992; 578(1):39-44. · 4.61 Impact Factor
  • Progress in clinical and biological research 02/1989; 308:345-50.
  • Advances in experimental medicine and biology 02/1988; 240:449-55. · 1.83 Impact Factor