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Biomedical subjects

G Schlag

Publications and source records attributed to G Schlag.

At least 55 records · Page 3Linked to original sources
PubMed1996

Nailing versus plating in thoracic trauma: an experimental study in sheep.

In this study, femoral intramedullary pressure, fat embolization, and pulmonary response were measured during reamed and unreamed nailing and plating of femoral fractures after blunt thoracic trauma. Intramedullary peak pressures of 425 mm Hg (mean 205 mm Hg) occurred in the reamed nail group (group I) during reaming with the 9-mm reamer, while in the unreamed nail group (group II) peak values were seen during nail insertion (330 mm Hg) with a mean of 203 mm Hg. Plating never led to a pressure rise over 67 mm Hg (mean 37 mm Hg). In reamed nailing, the most intense embolism was identified under ultrasound imaging with the large awl and with the 9.0-mm reamer (mean 2.2) and in the unreamed nail group during nail insertion (mean 2.8). Minimal echoes appeared during plating. The pulmonary arterial pressure did not vary significantly postoperatively between the three groups (p < 0.08). Our findings indicate that intramedullary fracture fixation causes a higher increase of intramedullary pressure and more fat and bone marrow embolization than extramedullary ones. Nevertheless, only minimal differences in the pulmonary hemodynamic response (pulmonary arterial pressure) were noted even in the presence of thoracic trauma.

Animals↗
PubMed1996

Comparison of the efficacy of pentoxifylline and albifyllin (HWA 138) on endotoxin-induced cytokine production, coagulation disturbances, and mortality.

We have evaluated two different xanthine derivatives, pentoxifylline (POF) and albifyllin (HWA), in rat endotoxemia for their ability to reduce 1) cytokine formation, 2) coagulation disturbances, and 3) mortality. The animals were injected with lipopolysaccharide (LPS) (15 mg/kg i.p.) and received HWA or POF (25, 50, or 100 mg/kg) or saline 30 min before LPS administration. The plasma tumor necrosis factor levels were significantly reduced and in a similar manner by pretreatment with HWA or POF in vivo as well as in vitro. Neither the coagulation disturbance nor the characteristic leukopenia that follow an LPS challenge were significantly influenced by the xanthine derivatives. At a dose of 100 mg/kg, the 6 day mortality was significantly reduced by HWA to 36% but only attenuated by POF to 55% as compared to 80% in the control group. The similar effect of both agents on cytokine formation and coagulation disturbances indicate that, at least to a substantial degree, other mechanisms may account for the significant protection of rats against endotoxin-induced mortality by HWA only. HWA 138 may, therefore, be a new powerful agent against endotoxin-related disorders and mortality.

Animals↗
PubMed1996

Pteridine and nitrite/nitrate formation in experimental septic and traumatic shock.

Bacterial lipopolysaccharides (LPS) induce the activity of guanosine triphosphate (GTP)-cyclohydrolase I (GTP-CHI), the first enzyme in the biosynthesis of tetrahydrobiopterin (H4bip) from GTP in endothelial cells and macrophages. In these and other cells, LPS also acts costimulatory with cytokines, i.e., mainly tumor necrosis factor-alpha (TNF-alpha). H4bip is the cofactor for nitric oxide synthase (NOS). We were interested in comparing the pteridine and nitrate levels in two baboon models: a hyperdynamic sepsis model and a hemorrhagic traumatic shock model. Our results show a similar response of pteridines (H4bip, neopterin) and nitrite/nitrate levels to an immune stimulus. LPS, which peaks rapidly, induces a sustained increase in pteridine levels in septic animals. Since hemorrhagic animals show very little response in terms of cytokine production, it was not possible to measure the induction of neopterin and nitrite/nitrate. This information could aid our understanding of the regulatory mechanisms in various forms of experimental shock.

Animals↗
PubMed1996

Effects on complement activation and cytokine (TNF-alpha and IL-8) release of infusion of anti-TNF-antibodies or a xanthine derivative (HWA 138) in septic baboons.

BACKGROUND: Sepsis and septic shock lead to activation of the complement cascade and to the release of pro-inflammatory cytokines. METHODS: The effects of E coli infusion and of infusion of anti-TNF antibodies and a xanthine derivative (HWA 138) on complement activation and cytokine release was evaluated in 17 baboons. All animals received 5 x 10(8) live bacteria per kg body weight. Five animals received only bacteria, five received in addition 0.5 mg per kg body weight of anti-TNF-antibody, and seven received an infusion of 6 mg per kg body weight of HWA 138 in addition to the bacteria. RESULTS: In baboons receiving 5 x 10(8) live E coli per kg body weight increased plasma levels of TCC, TNF-alpha and IL-8 were found. The release of TNF-alpha was lower in the group receiving HWA 138 at 2 h after the infusion. In baboons receiving an infusion of anti-TNF antibody the concentration of IL-8 was lower at 2 and 4 h than in animals receiving just E coli or HWA 138. CONCLUSION: Infusion of anti-TNF-antibody before E coli infusion will decrease the formation of IL-8. Infusion of HWA 138 before the E coli infusion will also inhibit the formation of TNF-alpha.

Animals↗
PubMed1996

Significance of NO in hemorrhage-induced hemodynamic alterations, organ injury, and mortality in rats.

In an attempt to evaluate the role of nitric oxide (NO) in pathophysiological alterations and multiple organ damage caused by hemorrhagic shock, we employed NG-monomethyl-L-arginine (L-NMMA), an inhibitor of NO synthase, in anesthetized rats subjected to a prolonged hypovolemic insult (30-35 mmHg for 180 min). Infusion of 2.0 mg/kg L-NMMA at the end of resuscitation diminished the fall in mean arterial pressure (MAP) and significantly increased the cardiac index and stroke volume, together with remarkable protection from multiple organ damage compared with the controls. The 48-h survival rate was significantly improved from 26.7% in the control group to 68.8% in the treatment group (P < 0.05). In contrast, the high dose of 20.0 mg/kg L-NMMA resulted in a strong blood pressure response, but a marked reduction in cardiac index and stroke volume concomitant with an increased total peripheral resistance index within the observation period, and tended to increase damage to various organs at 2 h after treatment. In addition, marked elevation in both endotoxin and tumor necrosis factor levels were observed in animals subjected to shock insult. The results suggest that NO induced by hemorrhagic shock in rats is an important mediator for pathophysiological alterations associated with cardiovascular abnormalities, multiple organ dysfunction, and even lethality. Regulation of NO generation and use of NO inhibitors might provide new aspects in the treatment of hemorrhage-related disorders, whereas the administration of L-NMMA would be either deleterious or salutary in a dose-dependent manner.

Animals↗
PubMed1996

Endogenous modulators of TNF and IL-1 response are under partial control of TNF in baboon bacteremia.

Tumor necrosis factor (TNF) and interleukin (IL)-1 are two cytokines for which naturally occurring inhibitors have been identified. The present study was undertaken to evaluate the extent to which scavenging of TNF in bacteremia attenuates the plasma levels of IL-1 receptor antagonist (IL-1ra) and soluble TNF receptors (sTNFR). Ten male baboons received 2 x 10(9) colony-forming units/kg live Escherichia coli over 2 h and were subjected to either placebo or anti-TNF antibody (anti-TNF Ab) treatment (1 mg/kg CDP571, Celltech, UK) 2 h before E. coli infusion (observation time: 72h). IL-1ra (range: 50-100 ng/ml) and sTNFR (range: 55kDa, 20-25 ng/ml; 75 kDa, 30-35 ng/ml) release was more sustained than that of IL-1 and TNF and was significantly attenuated by anti-TNF treatment, as were the circulating levels of IL-1, IL-8, and monocyte chemotactic peptide-1 (MCP-1) in the anti-TNF Ab group. We conclude that the increase in circulating natural cytokine modulators observed in nonhuman primate bacteremia is under the partial control of endogenous TNF because it was influenced by anti-TNF pretreatment. This attenuation is comparable to the anti-TNF effect on the chemokine MCP-1.

Animals↗
PubMed1995

Thrombomodulin release in baboon sepsis: its dependence on the dose of Escherichia coli and the presence of tumor necrosis factor.

This study was designed to test whether thrombomodulin is shed in septic baboons and whether shedding is blocked by antibody to tumor necrosis factor (anti-TNF). Live Escherichia coli were injected intravenously into 24 baboons according to one of the following regimens: 5 x 10(8) or 2 x 10(9) cfu/kg (n = 6/8), 2 x 10(9) cfu/kg with placebo (n = 5), or pretreatment with 1 mg/kg anti-TNF 2 h before E. coli injection (n = 5). E. coli administration resulted in a significant release of thrombomodulin in a dose-dependent manner; however, thrombomodulin release was significantly attenuated (180 to 40 ng/mL) by anti-TNF pretreatment. This is parallel to the reduction of neutrophil activation (elastase). These results provide evidence for an E. coli dose-related and TNF-dependent thrombomodulin release into the plasma of septic baboons and suggest a possible role of anti-TNF in protection of the endothelium.

Alanine Transaminase↗
PubMed1995

Kinetics of endotoxin and tumor necrosis factor appearance in portal and systemic circulation after hemorrhagic shock in rats.

OBJECTIVE: This study was performed to investigate gut-derived bacterial translocation and the time course of endotoxin (lipopolysaccharide [LPS]) and tumor necrosis factor (TNF) appearance, both in portal and systemic circulation. SUMMARY BACKGROUND DATA: The significance of intestinal bacteria/endotoxin translocation or TNF formation in the development of systemic sepsis has been disputed. METHODS: A rat model of hemorrhagic shock (30-35 mm Hg for 90 min) and resuscitation was used. RESULTS: Bacterial translocation was histologically observed in the small intestinal wall 30 minutes after resuscitation. A significant increase in LPS concentrations was found in the portal vein (91.7 +/- 30.6 pg/mL) at 90 minutes, which remained steady until 150 minutes after shock. Lipopolysaccharide increased in the systemic circulation, the levels became significant at 120 minutes, and peaked (66.5 +/- 39.2 pg/mL) 150 minutes after shock. Tumor necrosis factor concentrations were found to be significantly elevated in both portal and systemic circulation (75.6 +/- 22.1 vs. 58.4 +/- 14.1 pg/mL) at 90 minutes post-shock. Although there was no further increase in TNF concentration in the portal blood. TNF peaked (83.5 +/- 17.7 pg/mL) in systemic circulation at 120 minutes and still was markedly increased at 150 minutes post-shock. In addition, higher LPS and TNF concentrations in systemic circulation were found in the nonsurvivors than in the surviving animals at the end of resuscitation. CONCLUSIONS: These results suggest that hemorrhagic shock may lead to early bacterial translocation in the intestinal wall and transient access of gut-derived LPS and LPS-induced mediators into the circulation predominantly via the portal circulation.

Animals↗
PubMed1995

Pathogenesis of hemorrhage-induced bacteria/endotoxin translocation in rats. Effects of recombinant bactericidal/permeability-increasing protein.

OBJECTIVES: This study was conducted to determine the role of gut-derived bacteria/endotoxin in the pathogenesis of the multiple-organ damage and mortality, the possible beneficial effect of recombinant bactericidal/permeability-increasing protein (rBPl21), and whether neutralizing endotoxemia by rBPl21 treatment influences tumor necrosis factor (TNF) formation in rats after hemorrhagic shock and resuscitation. SUMMARY BACKGROUND DATA: Hypovolemic shock might be associated with bacterial or endotoxin translocation as well as systemic sepsis. Similar to bactericidal/permeability-increasing (BPl) protein, rBPl21 has been found to bind endotoxin and inhibit TNF production. METHODS: A rat model of prolonged hemorrhagic shock (30 to 35 mm Hg for 180 min) followed by adequate resuscitation was employed. Recombinant bactericidal/permeability-increasing protein was administered at 5 mg/kg intravenously. The control group was treated similarly to the BPl group, but received thaumatin as a protein-control preparation in the same dose as rBPl21. RESULTS: Immediately after resuscitation (230 min), plasma endotoxin levels in the control group (61.0 +/- 16.3 pg/mL) were almost neutralized by rBPl21 treatment (13.8 +/- 4.8 pg/mL, p < 0.05). Plasma TNF levels were not significantly influenced by rBPl21 treatment. The 48-hour survival rate was 68.8% in the treatment group versus 37.5% in the control group (p = 0.08). Microscopic histopathologic examination revealed relatively minor damage to various organs in the treatment group. CONCLUSIONS: These data suggest that hemorrhagic shock may lead to bacterial/endotoxin translocation with concomitant TNF formation, endogenous endotoxemia may play an important role in the pathogenesis of multiple-organ failure after shock and trauma, TNF formation at an early stage might be related mainly to mechanisms other than Kupffer's cells activation via lipopolysaccharide, and rBPl21 might be a useful therapeutic agent against endogenous bacteria/endotoxin related disorders in severe hemorrhagic shock.

Animals↗
PubMed1995

Inflammatory mediators in relation to the development of multiple organ failure in patients after severe blunt trauma.

OBJECTIVE: To evaluate the posttraumatic course of several inflammatory mediators or markers (complement components C3, C3a, terminal complement complex, thromboxane B2, C-reactive protein, elastase, and neopterin) in relation to the development of multiple organ failure and mortality. DESIGN: Prospective study of a selected patient group. SETTING: Surgical intensive care units in three European trauma hospitals. PATIENTS: Patients (n = 56) with severe blunt trauma (Injury Severity Score of > or = 33). INTERVENTIONS: Arterial blood samples were sequentially obtained. MEASUREMENTS AND MAIN RESULTS: Nonsurvivors (n = 8) had significantly higher circulating C3a and elastase concentrations on the first postinjury day, compared with survivors (n = 48). No differences between these groups were found for terminal complement complex, thromboxane B2, C-reactive protein, and the neopterin/creatinine ratio. Five patients died before day 5. Eighteen patients developed multiple organ failure, which was diagnosed from day 5 onward, leaving 33 patients without multiple organ failure. The patients with subsequent multiple organ failure showed significantly higher mean circulating concentrations of C3a (914 +/- 190 [SEM] ng/mL), terminal complement complex (57 +/- 17 U/mL), and thromboxane B2 (275 +/- 37 pg/mL) at the first postinjury day than the patients without multiple organ failure (566 +/- 110 ng/mL, 27 +/- 2 U/mL, and 169 +/- 14 pg/mL, respectively). In patients with multiple organ failure, elastase concentrations were significantly higher on days 2, 3, 4, and 5 postinjury. Neopterin/creatinine ratios, on the other hand, were significantly higher in patients with multiple organ failure when the multiple organ failure had already become established (on days 8 and 10). CONCLUSION: In multiple trauma patients, excessive triggering of the inflammatory cascade-as expressed by complement activation and stimulation of neutrophils producing elastase--plays an important and early role in the development of multiple organ failure.

Adolescent↗
PubMed1995

Does lung contusion affect both the traumatized and the noninjured lung parenchyma? A morphological and morphometric study in the pig.

Isolated unilateral lung contusion (LC) was induced in 12 pigs to determine the pathophysiological role of LC in the high mortality after multiple injury. The Horovitz quotient, pulmonary vascular resistance, mean pulmonary artery pressure, mixed venous oxygen consumption, inspiratory pressure and compliance were significantly decreased in the LC group as compared to controls. The number of polymorphonuclear granulocytes, the microvascular permeability of albumine and the Wilhelmy balance as determined by bronchoalveolar lavage were significantly increased after lung contusion. As indicators of a systemic reaction we found elevated plasma levels of the terminal complement complex and decreased levels of the complement factor 3a after LC. The morphological assessment revealed changes such as those encountered during the early phase of adult respiratory distress syndrome, with granulocyte sticking, endothelial cell adhesion and transendothelial diapedesis. Morphometric analysis demonstrated a significant decrease in alveolar diameter in both the injured and the contralateral lung due to impaired surfactant surface activity. A distinct increase in septal diameter, related to edema and caused by increased microvascular permeability, was found in the injured lungs. These findings emphasize that LC leads to a generalized impairment of the entire lung, which may lead to progressive lung failure.

Albumins↗
PubMed1995

Tumor necrosis factor antibody treatment of septic baboons reduces the production of sustained T-cell suppressive factors.

Post-traumatic septic complications result from impaired cell-mediated immune function, which is caused in part by circulating T-cell suppressive factors (TSFs). We examined whether tumor necrosis factor alpha (TNF-alpha) antibody treatment in a baboon sepsis model influences the production of TSFs, including interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta). Sepsis was induced in anesthetized baboons by Escherichia coli infusion, and caused an increase in plasma levels of TNF, TSF activity, IL-10, and active TGF-beta, as well as a decrease in latent TGF-beta. TNF antibody pretreatment reduced TNF levels by 98%. Transient TSF activity (0-4 h) was only marginally influenced, while sustained TSF activity (8-24 h) was markedly reduced. TSF activity at 24 h correlated with peak TNF levels. IL-10 levels, coinciding with early TSF activity, remained unchanged by anti-TNF treatment. Levels of active TGF-beta and the drop in latent TGF-beta were decreased. We conclude that anti-TNF treatment reduces sustained TSF activity and may partially restore impaired cell-mediated immune function.

Animals↗
PubMed1995

Tumor necrosis factor (TNF)-dependent shedding of the p55 TNF receptor in a baboon model of bacteremia.

We have tested the hypothesis that the tumor necrosis factor (TNF) plays a significant role in vivo in TNF receptor shedding and studied the release of TNF-binding protein 1 (TNF-BP1), the soluble fragment of the 55- to 60-kDa TNF alpha (TNF) receptor, in a baboon model of Escherichia coli bacteremia, using three different doses of bacteria in acute infection (8 h) experiments (n [animals] = 11) and a single dose in a subchronic infection (72 h) experiment. In the subchronic infection study, one group of animals (n = 6) was pretreated with a neutralizing murine monoclonal antibody to TNF (CB0006). Concentrations of TNF and TNF-BP1 in plasma were determined in specific, monoclonal antibody-based immunoassays. Untreated animals (n = 6) showed undetectable TNF concentrations (< 10 pg/ml at baseline), whereas TNF-BP1 levels in plasma were in the range of 2 ng/ml, similar to concentrations observed in humans. Infusion of bacteria resulted in a rapid, dose-dependent increase in plasma TNF concentrations that reached a maximal level after 2 h and returned to baseline within 6 h. TNF-BP1 concentrations also showed a dose-dependent increase to peak concentrations three- to fivefold above baseline within 2 h but, in contrast to TNF levels, remained significantly elevated for up to 48 h. In animals pretreated with antibody CB0006, circulating TNF was completely neutralized, and TNF-BP1 was significantly reduced. We conclude that TNF-BP1 is released in bacteremia and that release in vivo is partially dependent on the presence of TNF.

Acute Disease↗
PubMed1995

Fibrin sealant matrix supports outgrowth of peripheral sensory axons.

It has been suggested that fibrin-based matrix has an important role during the early stage of nerve regeneration. A fibrin sealant matrix, which was made by combining diluted human fibrinogen and thrombin, was used as a substrate for in vitro elongation of neurites and in vivo regeneration of axons. In the in vitro experiment, dissociated embryonic chick sensory neurons were cultured on dishes coated with fibrin sealant matrix and compared with the solution of thrombin/calcium chloride, or with poly-D-lysine (PDLctr). After 16 hours, cultures were stained immunohistochemically with a monoclonal antineurofilament antibody. The neurons survived well, and an abundant network of neurites, qualitatively similar to that on PDLctr, developed on the fibrin sealant matrix. The percentage of neurons that had outsprout at 16 hours was the same both in the fibrin sealant matrix and PDLctr groups. By contrast, all the neurons plated on the dishes treated with the solution of thrombin/calcium chloride were dead after 16 hours. Immunohistochemical staining of fibrinogen also showed an even distribution of fibrin matrix over the culture dishes. For the in vivo experiments, 48 rat sciatic nerves were cut and reconnected with two epineurial stitches. Fibrin sealant matrix or phosphate buffer solution was applied to the transsected and repaired region. Pinch reflex test showed that the regeneration of the leading sensory fibre was significantly faster in the fibrin sealant matrix group than in the control group at 3 and 4 days. These results indicate that fibrin sealant matrix accelerates regeneration of axons in vivo during the early phase, and also supports elongation of neurites in vitro.

Animals↗
PubMed1995

Oxidatively modified plasma phospholipids containing reactive carbonyl functions measured by HPLC: evidence for phosphatidylcholine-bound aldehydes in plasma of burn patients.

A HPLC method has been developed to measure phosphatidylcholine (PC) containing reactive carbonyl functions in the sn-acyl residue in order to study processes in which such reactive carbonyls can be formed due to e.g. oxidative fragmentation. The method has been applied to determine PC-bound carbonyls as 2,4-dinitrophenylhydrazones (DNPH) in plasma of burn patients. Plasma from healthy volunteers served as controls. Additionally, in vitro oxidation experiments (A: plasma, buffer diluted; B: plasma + iron-EDTA complex and C: plasma + iron-EDTA complex + H2O2) have been performed to obtain and to identify 2,4-dinitrophenylhydrazine derivatizable carbonyl functions in plasma PC. Both, the PC-aldehydes and PC-aldehyde DNPH derivatives were cleavable with phospholipase C. Quantification was based on thin-layer chromatography purified soybean phosphatidylcholine, which was identically oxidized and derivatized as the plasma lipids in vitro.

Adult↗
PubMed1995

Release of cytokines, polymorphonuclear elastase and terminal C5b-9 complement complex by infusion of wound drainage blood.

25 patients undergoing total hip replacement surgery were studied in an investigation of release of cytokines (interleukin-1 beta, IL-1 beta; interleukin-6, IL-6; interleukin-8, IL-8; and tumor necrosis factor-alpha, TNF-alpha), PMN elastase and terminal C5b-9 complement complexes (TCC) at the time of collection and transfusion of autologous blood. 15 patients received wound blood that was washed and centrifuged before being transfused as an erythrocyte suspension. In this blood there were no elevations in the concentrations of cytokines, TNF-alpha, PMN elastase or TCC, and there was no increase in these variables in plasma after transfusion of wound blood. 10 patients received postoperatively-collected drainage blood. There were high amounts of cytokines, PMN elastase and TCC in this blood, and filtration of the collected drainage blood did not reduce the concentrations of these factors, except those of TCC. When the collected drainage blood was infused, elevated plasma concentrations of IL-6, IL-8 and PMN elastase were observed 1 and 60 minutes after completing the transfusion. No differences regarding blood pressure, oxygen saturation (SpO2), and hemoglobin concentration between the groups were recorded.

Aged↗
PubMed1995

Plasma glutathione S-transferase as an early marker of posttraumatic hepatic injury in non-human primates.

We have hypothesized that the measurement of alpha-glutathione S-transferase (alpha-GST) in serum may provide a suitable sensitive marker of shock-induced liver damage. Six male adult baboons were studied. Hemorrhage was induced by blood withdrawal of 60-70% of the total blood volume down to an arterial pressure of 35-40 mmHg. Then the reinfusion was performed with the heparinized shed blood plus the same amount of Ringer's solution over the next 4 h. Before the start of hemorrhage, 2 mL/kg zymosan-activated plasma was infused to simulate trauma-related complement activation. alpha-GST antigen levels were determined using an anti-human alpha-GST immunoassay (Hepkit). Concentrations of alpha-GST at baseline in baboon were found to be 3.1 +/- 1.8 ng/mL; at the end of the shock period a significant increase in alpha-GST serum levels (74.8 +/- 13.8 ng/mL) was found. In contrast, transaminase levels did not significantly change. From the current evidence in posttraumatic non-human primates, which resemble the clinical situation in several aspects, alpha-GST measurements are a suitable marker of early hepatocellular injury.

Animals↗