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Frankfurt am Main, Germany

Kanczkowski W.,TU Dresden | Tymoszuk P.,TU Dresden | Ehrhart-Bornstein M.,TU Dresden | Wirth M.P.,TU Dresden | And 2 more authors.
Journal of Clinical Endocrinology and Metabolism

Context: Adrenocortical carcinoma (ACC) is a rare tumor with poor prognosis. The expression of innate immunity receptor Toll-like receptor 4 (TLR4) was recently reported in various human tumors, and TLR4 was shown to regulate tumor immune escape processes, proliferation, and resistance to chemotherapeutical agents. Objective: The aim of this study was to investigate TLR4 expression, signaling, and function in the process of tumorigenesis in the human adrenal cortex. Measurements and Main Results: Real-time PCR analysis of human ACC (n = 8), adenoma (n = 8), and ACC cell lines (SW13, NCI-H295R, and HAC15) revealed a significant down-regulation of TLR4, MD2 (myeloid differentiation protein-2), and cluster of differentiation 14 (CD14) mRNA compared with normal human adrenal cortex and adrenocortical cells in primary culture. Furthermore, immunohistochemistry revealed an abrogation of TLR4 and CD14 expression in ACC but notadenoma tissues. Western blot analysis of MAPK, AKT, activator protein-1, and nuclear factor-κB signaling revealed that the ACC cell lines are unresponsive to lipopolysaccharide action. Restoration of TLR4 signaling by stable transfection of TLR4-CD14 plasmid into NCI-H295R cells sensitized them to lipopolysaccharide incubation as shown by nuclear factor-κB activation and decreased cell viability and induced apoptosis in these cells. Conclusion: Our results demonstrate a significant reduction in the expression of TLR4 and CD14 and an inactivation of TLR4 signaling in ACCs. Furthermore, our data show that reintroduction of TLR4 expression in ACCs may provide a novel therapeutic strategy for adrenal cancer. Copyright © 2010 by The Endocrine Society. Source

Pape A.,University Hospital Frankfurt | Steche M.,University Hospital Frankfurt | Laout M.,University Hospital Frankfurt | Wedel M.,University Hospital Frankfurt | And 4 more authors.
European Surgical Research

Background: During acellular replacement of an acute blood loss, hyperoxic ventilation (HV) increases the amount of O2 physically dissolved in the plasma and thereby improves O2 supply to the tissues. While this effect could be demonstrated for HV with inspiratory O2 fraction (FiO2) 0.6, it was unclear whether HV with pure oxygen (FiO 2 1.0) would have an additional effect on the physiological limit of acute normovolemic anemia. Methods: Seven anesthetized domestic pigs were ventilated with FiO2 1.0 and subjected to an isovolemic hemodilution protocol. Blood was drawn and replaced by a 6% hydroxyethyl starch (HES) solution (130/0.4) until a sudden decrease of total body O2 consumption (VO2) indicated the onset of O2 supply dependency (primary endpoint). The corresponding hemoglobin (Hb) concentration was defined as 'critical Hb' (Hbcrit). Secondary endpoints were parameters of myocardial function, central hemodynamics, O2 transport and tissue oxygenation. Results: HV with FiO2 1.0 enabled a large blood-for-HES exchange (156 ± 28% of the circulating blood volume) until Hbcrit was met at 1.3 ± 0.3 g/dl. After termination of the hemodilution protocol, the contribution of O2 physically dissolved in the plasma to O2 delivery and VO2 had significantly increased from 11.7 ± 2 to 44.2 ± 9.7% and from 29.1 ± 4.2 to 66.2 ± 11.7%, respectively. However, at Hbcrit, cardiovascular performance was found to have severely deteriorated. Conclusion: HV with FiO2 1.0 maintains O2 supply to tissues during extensive blood-for-HES exchange. In acute situations, where profound anemia must be tolerated (e.g. bridging an acute blood loss until red blood cells become available for transfusion), O2 physically dissolved in the plasma becomes an essential source of oxygen. However, compromised cardiovascular performance might require additional treatment. © 2013 S. Karger AG, Basel. Source

Pape A.,Goethe University Frankfurt | Kutschker S.,Goethe University Frankfurt | Kertscho H.,Goethe University Frankfurt | Stein P.,Goethe University Frankfurt | And 4 more authors.
Critical Care

Introduction: The correction of hypovolemia with acellular fluids results in acute normovolemic anemia. Whether the choice of the infusion fluid has an impact on the maintenance of oxygen (O 2) supply during acute normovolemic anemia has not been investigated so far.Methods: Thirty-six anesthetized and mechanically ventilated pigs were hemodiluted to their physiological limit of anemia tolerance, reflected by the individual critical hemoglobin concentration (Hb crit). Hb critwas defined as the Hb-concentration corresponding with the onset of supply-dependency of total body O 2-consumption (VO 2). The hemodilution protocol was randomly performed with either tetrastarch (6% HES 130/0.4, TS-group, n = 9), gelatin (3.5% urea-crosslinked polygeline, GEL-group, n = 9), hetastarch (6% HES 450/0.7, HS-group, n = 9) or Ringer's solution (RS-group, n = 9). The primary endpoint was the dimension of Hb crit, secondary endpoints were parameters of central hemodynamics, O 2transport and tissue oxygenation.Results: In each animal, normovolemia was maintained throughout the protocol. Hb critwas met at 3.7 ± 0.6 g/dl (RS), 3.0 ± 0.6 g/dl (HS P < 0.05 vs. RS), 2.7 ± 0.6 g/dl (GEL, P < 0.05 vs. RS) and 2.1 ± 0.4 g/dl (TS, P < 0.05 vs. GEL, HS and RS). Hemodilution with RS resulted in a significant increase of extravascular lung water index (EVLWI) and a decrease of arterial oxygen partial pressure (paO 2), and O 2extraction ratio was increased, when animals of the TS-, GEL- and HS-groups met their individual Hb crit.Conclusions: The choice of the intravenous fluid has an impact on the tolerance of acute normovolemic anemia induced by acellular volume replacement. Third-generation tetrastarch preparations (e.g., HES 130/0.4) appear most advantageous regarding maintenance of tissue oxygenation during progressive anemia. The underlying mechanism includes a lower degree of extravasation and favourable effects on microcirculatory function. © 2012 Pape et al.; licensee BioMed Central Ltd. Source

Keilhoff G.,Otto Von Guericke University of Magdeburg | Ebmeyer U.,Clinic of Anesthesiology | Schild L.,Otto Von Guericke University of Magdeburg

Vijlbrief et al. [Neonatology 2012;102:243-248] reported a beneficial effect of hypothermia on cardiac function after perinatal asphyxia indicated by low levels of B-type natriuretic peptide (BNP). Elevated troponin I plasma levels, however, reflects impairment of cardiomyocytes under hypothermic conditions. The importance of BNP and cardiac troponin I as biomarkers of cardiac dysfunction that may supplement or substitute Doppler echocardiography has been outlined. Using an asphyxia cardiac arrest (ACA) animal model under spontaneous hypothermia, we found a decrease in the activities of NADH-cytochrome c-oxidoreductase and succinate-cytochrome c-oxidoreductase in comparison to normothermic sham-operated controls. This observation indicates the impairment of the respiratory chain of heart mitochondria, which is accompanied by morphological changes in these mitochondria. Changed cardiac troponin I levels and respiratory chain complexes activity represent different but corresponding steps within the process of cardiomyocyte injury. Interestingly, liver and brain mitochondria remained unchanged under this condition. Patients could benefit from the control of mitochondrial function during hypothermic intervention. When indicated, substances could be supplemented that support mitochondrial function, e.g. antioxidative-acting vitamins and ubiquinone. Copyright © 2012 S. Karger AG, Basel. Source

Pape A.,University Hospital Frankfurt | Weber C.F.,University Hospital Frankfurt | Laout M.,University Hospital Frankfurt | Steche M.,University Hospital Frankfurt | And 4 more authors.

Background: The initial treatment of an acute blood loss with acellular fluids leads to the dilution of the red cell mass remaining in the vasculature, that is, to acute normovolemic anemia. Whether the compensation and, thus, the tolerance of acute anemia, are affected by sympathetic block induced by thoracic epidural anesthesia has not yet been investigated.Methods: Eighteen anesthetized and mechanically ventilated pigs were instrumented with thoracic epidural catheters and randomly assigned to receive an epidural injection of either 5-ml ropivacaine 0.2% (n = 9) aiming for a Th5-Th10 block or saline (n = 9) followed by continuous epidural infusion of 5 ml/h of either fluid. Subsequently, acute normovolemic anemia was induced by replacement of whole blood with 6% hydroxyethyl starch solution until a "critical" limitation of oxygen transport capacity was reached as indicated by a sudden decrease in oxygen consumption. The critical hemoglobin concentration quantified at this time point was the primary endpoint; secondary endpoints were hemodynamic and oxygen transport parameters.Results:Thoracic epidural anesthesia elicited only a moderate decrease in mean arterial pressure and cardiac index and a transient decrease in oxygen extraction ratio. During progressive anemia, the compensatory increases in cardiac index and oxygen extraction ratio were not compromised by thoracic epidural anesthesia. Critical hemoglobin concentration was reached at identical levels in both groups (ropivacaine group: 2.5 ± 0.6 g/dl, saline group: 2.5 ± 0.6 g/dl).Conclusion: Thoracic epidural anesthesia with ropivacaine 0.2% does not decrease the tolerance to acute normovolemic anemia in healthy pigs. The hemodynamic compensation of acute anemia is fully preserved despite sympathetic block, and the critical hemoglobin concentration remains unaffected. Copyright © 2014, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins. Source

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