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Characterization of blunt chest trauma in a long-term porcine model of severe multiple trauma
(2016)
Horst, Klemens ; Simon, Tim-Philipp ; Pfeifer, Roman ; Teuben, Michel Paul Johan ; Almahmoud, Khalid ; Qiao, Zhi ; Aguiar Santos, Susana ; Castelar Wembers, Carlos Emilio ; Leonhardt, Steffen ; Heussen, Nicole ; Störmann, Philipp ; Auner, Birgit ; Relja, Borna ; Marzi, Ingo ; Haug, Alexander Tobias ; Griensven, Martijn van ; Kalbitz, Miriam ; Huber-Lang, Markus ; Tolba, René H. ; Reiss, Lucy Kathleen ; Uhlig, Stefan ; Marx, Gernot ; Pape, Hans-Christoph ; Hildebrand, Frank
Chest trauma has a significant relevance on outcome after severe trauma. Clinically, impaired lung function typically occurs within 72 hours after trauma. However, the underlying pathophysiological mechanisms are still not fully elucidated. Therefore, we aimed to establish an experimental long-term model to investigate physiological, morphologic and inflammatory changes, after severe trauma. Male pigs (sus scrofa) sustained severe trauma (including unilateral chest trauma, femur fracture, liver laceration and hemorrhagic shock). Additionally, non-injured animals served as sham controls. Chest trauma resulted in severe lung damage on both CT and histological analyses. Furthermore, severe inflammation with a systemic increase of IL-6 (p = 0.0305) and a local increase of IL-8 in BAL (p = 0.0009) was observed. The pO2/FiO2 ratio in trauma animals decreased over the observation period (p < 0.0001) but not in the sham group (p = 0.2967). Electrical Impedance Tomography (EIT) revealed differences between the traumatized and healthy lung (p < 0.0001). In conclusion, a clinically relevant, long-term model of blunt chest trauma with concomitant injuries has been developed. This reproducible model allows to examine local and systemic consequences of trauma and is valid for investigation of potential diagnostic or therapeutic options. In this context, EIT might represent a radiation-free method for bedside diagnostics.
Combined diabetes-obesity syndromes severely impair regeneration of acute skin wounds in mouse models. This study assessed the contribution of subcutaneous adipose tissue to exacerbated wound inflammatory conditions. Genetically obese (ob/ob) mice showed an increased expression of positive transcriptional effectors of adipocyte differentiation such as Krüppel-like factor (KLF)-5 and peroxisome proliferator-activated receptor (PPAR)-γ and an associated expression of leptin and fatty acid-binding protein (FABP)-4, but also CXCL2 in isolated subcutaneous fat. This observation in obese mice is in keeping with differentially elevated levels of KLF-5, PPAR-γ, leptin, FABP-4 and CXCL2 in in vitro-differentiated 3T3-L1 adipocytes. Notably, CXCL2 expression restrictively appeared upon cytokine (IL-1β/TNF-α) stimulation only in mature, but not immature 3T3-L1 adipocytes. Of importance, the critical regulator of adipocyte maturation, PPAR-γ, was merely expressed in the final phase of in-vitro induced adipocyte differentiation from 3T3-L1 pre-adipocytes. Consistently, the PPAR-γ agonist rosiglitazone suppressed cytokine-induced CXCL2 release from mature adipocytes, but not from early 3T3-L1 adipocyte stages. The inhibitory effect of PPAR-γ activation on CXCL2 release appeared to be a general anti-inflammatory effect in mature adipocytes, as cytokine-induced cyclooxygenase (Cox)-2 was simultaneously repressed by rosiglitazone. In accordance with these findings, oral administration of rosiglitazone to wounded obese mice significantly changed subcutaneous adipocyte morphology, reduced wound CXCL2 and Cox-2 expression and improved tissue regeneration. Thus, our data suggest that PPAR-γ might provide a target to suppress inflammatory signals from mature adipocytes, which add to the prolonged wound inflammation observed in diabetes-obesity conditions.
Haskamp, Stefan ; Horowitz, Joseph Simon ; Oji, Vinzenz ; Philipp, Sandra ; Sticherling, Michael ; Schäkel, Knut ; Schuhmann, Sarah Laetissia ; Prinz, Jörg C. ; Burkhardt, Harald ; Behrens, Frank ; Böhm, Beate ; Köhm, Michaela ; Rech, Jürgen ; Simon, David ; Schett, Georg ; Morrison, Kirsten ; Gerdes, Sascha ; Aßmann, Gunter ; Nimeh, Ali ; Schuster, Volker ; Jacobi, Arnd ; Weyergraf, Ansgar J. ; Reis, André ; Uebe, Steffen ; Wilsmann-Theis, Dagmar Irmgard ; Mößner, Rotraut ; Hüffmeier, Ulrike
Werner, Volker ; Santamaria, C. ; Louchart, C. ; Obertelli, Alexandre ; Doornenbal, Pieter ; Nowacki, Frédéric ; Authelet, Gilles ; Baba, Hidetada ; Calvet, Denis ; Château, F. ; Corsi, Anna ; Delbart, Alain ; Gheller, Jean-Marc ; Gillibert, Alain ; Isobe, Tadaaki ; Lapoux, Valérie ; Matsushita, M. ; Momiyama, S. ; Motobayashi, Tohru ; Niikura, Megumi ; Otsu, Hideaki ; Péron, Cedric ; Peyaud, Alan ; Pollacco, Emanuel C. ; Roussé, Jean-Yves Andre ; Sakurai, Hiroyoshi ; Sasano, Masaki ; Shiga, Y. ; Takeuchi, Satoshi ; Taniuchi, Ryo ; Uesaka, Tomohiro ; Wang, Haohao ; Yoneda, Ken-ichiro ; Browne, Frank ; Chung, L.X. ; Dombrádi, Zsolt ; Franchoo, Serge ; Giacoppo, F. ; Gottardo, A. ; Hadyńska-Kęk, Katarzyna ; Korkulu, Zeren ; Koyama, Shunpei ; Kubota, Yuichi ; Lee, J. ; Lettmann, Marc ; Lozeva, R. ; Matsui, K. ; Miyazaki, T. ; Nishimura, Shunji ; Olivier, L. ; Ota, S. ; Patel, Z. ; Pietralla, Norbert ; Sahin, E. ; Shand, C. ; Söderström, Pär-Anders ; Stefan, I. ; Steppenbeck, David ; Sumikama, Toshiyuki ; Suzuki, Daisuke ; Vajta, Zs. ; Wu, J. ; Xu, Z.
Within the SEASTAR project at RIKEN-RIBF, 66Cr and 70,72Fe have been produced via protonknockout reactions, and their first excited 2+ and 4+ states have been discovered. The combination of the liquid-hydrogen target and TPC system MINOS has been used in combination with the DALI2 detector array for the first time. A 345 MeV/u 238U beam with a mean intensity of about 12 pnA impinged on a Be target. Fission fragments were separated and identified using the BigRIPS spectrograph, and reaction products were analyzed using the ZeroDegree spectrograph. A plateau of excitation energies, with a small change in the systematic trends past N = 44, reveals an extension of the N = 40 region of collectivity toward N = 50. Hence, the isotopes of interest are located within the N = 40 island of inversion. An interpretation of the observed trends is offered through large scale shell model calculations.
Pathophysiological role of prostanoids in coagulation of the portal venous system in liver cirrhosis
(2019)
Queck, Alexander David Roger ; Thomas, Dominique Jeanette ; Jansen, Christian ; Schreiber, Yannick ; Rüschenbaum, Sabrina ; Praktiknjo, Michael ; Schwarzkopf, Katharina ; Mücke, Marcus Maximilian ; Schierwagen, Robert ; Uschner, Frank Erhard ; Meyer, Carsten ; Clària, Joan ; Zeuzem, Stefan ; Geisslinger, Gerd ; Trebicka, Jonel ; Lange, Christian
Background: Prostanoids are important regulators of platelet aggregation and thrombotic arterial diseases. Their involvement in the development of portal vein thrombosis, frequent in decompensated liver cirrhosis, is still not investigated.
Methods: Therefore, we used pro-thrombotic venous milieu generation by bare metal stent transjugular intrahepatic portosystemic shunt insertion, to study the role of prostanoids in decompensated liver cirrhosis. Here, 89 patients receiving transjugular intrahepatic portosystemic shunt insertion were included in the study, and baseline levels of thromboxane B2, prostaglandin D2 and prostaglandin E2 were measured in the portal and the hepatic vein.
Results: While the hepatic vein contained higher levels of thromboxane B2 than the portal vein, levels of prostaglandin E2 and D2 were higher in the portal vein (all P<0.0001). Baseline concentrations of thromboxane B2 in the portal vein were independently associated with an increase of portal hepatic venous pressure gradient during short term follow-up, as an indirect sign of thrombogenic potential (multivariable P = 0.004). Moreover, severity of liver disease was inversely correlated with portal as well as hepatic vein levels of prostaglandin D2 and E2 (all P<0.0001).
Conclusions: Elevated portal venous thromboxane B2 concentrations are possibly associated with the extent of thrombogenic potential in patients with decompensated liver cirrhosis.
Trial registration: ClinicalTrials.gov identifier: NCT03584204.
Jakob, Carolin Ellen Marianne ; Mahajan, Ujjwal Mukund ; Oswald, Marcus ; Stecher, Melanie ; Schons, Maximilian ; Mayerle, Julia ; Rieg, Siegbert ; Pletz, Mathias ; Merle, Uta ; Wille, Kai ; Borgmann, Stefan ; Spinner, Christoph Daniel ; Dolff, Sebastian Conrad Johannes ; Scherer, Clemens Martin ; Pilgram, Lisa ; Rüthrich, Maria Madeleine ; Hanses, Frank ; Hower, Martin ; Strauß, Richard ; Maßberg, Steffen ; Er, Ahmet Görkem ; Jung, Norma ; Vehreschild, Jörg Janne ; Stubbe, Hans Christian ; Tometten, Lukas ; König, Rainer
Purpose: While more advanced COVID-19 necessitates medical interventions and hospitalization, patients with mild COVID-19 do not require this. Identifying patients at risk of progressing to advanced COVID-19 might guide treatment decisions, particularly for better prioritizing patients in need for hospitalization.
Methods: We developed a machine learning-based predictor for deriving a clinical score identifying patients with asymptomatic/mild COVID-19 at risk of progressing to advanced COVID-19. Clinical data from SARS-CoV-2 positive patients from the multicenter Lean European Open Survey on SARS-CoV-2 Infected Patients (LEOSS) were used for discovery (2020-03-16 to 2020-07-14) and validation (data from 2020-07-15 to 2021-02-16).
Results: The LEOSS dataset contains 473 baseline patient parameters measured at the first patient contact. After training the predictor model on a training dataset comprising 1233 patients, 20 of the 473 parameters were selected for the predictor model. From the predictor model, we delineated a composite predictive score (SACOV-19, Score for the prediction of an Advanced stage of COVID-19) with eleven variables. In the validation cohort (n = 2264 patients), we observed good prediction performance with an area under the curve (AUC) of 0.73 ± 0.01. Besides temperature, age, body mass index and smoking habit, variables indicating pulmonary involvement (respiration rate, oxygen saturation, dyspnea), inflammation (CRP, LDH, lymphocyte counts), and acute kidney injury at diagnosis were identified. For better interpretability, the predictor was translated into a web interface.
Conclusion: We present a machine learning-based predictor model and a clinical score for identifying patients at risk of developing advanced COVID-19.
Alber, Thomas ; Appelshäuser, Harald ; Bächler, Joachim ; Bartke, Jerzy ; Białkowska, Helena ; Bieser, Fred ; Bloomer, Matthew A. ; Blyth, Charles O. ; Bock, Rudolf ; Bormann, Christian ; Brady, Franklin Paul ; Brockmann, Robert ; Bunčić, Predrag ; Caines, Helen Louise ; Cebra, Daniel A. ; Chan, Phaikying ; Cooper, Glenn E. ; Cramer, John G. ; Cramer, Pauline B. ; Csató, Péter ; Derado, Ivan ; Dunn, Jason ; Eckardt, Volker ; Eckhardt, Frank ; Euler, Sebastian ; Ferguson, M. I. ; Fischer, Hans Gerhard ; Fodor, Zoltán ; Foka, Panagiota ; Freund, Peter ; Fuchs, Matthias ; Gál, József ; Gaździcki, Marek ; Gładysz-Dziaduś, Ewa ; Grebieszkow, Jaroslaw ; Günther, Jörg ; Harris, John W. ; Heck, W. ; Hegyi, Sándor ; Hill, L. A. ; Huang, Isaac ; Howe, Mark A. ; Igo, George J. ; Irmscher, Detlef ; Jacobs, Peter Martin ; Jones, Peter Graham ; Kadija, Krešo ; Kecskemeti, J. ; Kowalski, Marek ; Kühmichel, Andreas ; Lasiuk, Brian ; Margetis, Spyridon ; Mitchell, J. W. ; Mock, Andreas ; Nelson, John M. ; Odyniec, Grazyna Janina ; Pálinkás, József ; Pálla, Gabriella ; Panagiotou, Apostolos D. ; Petridis, Athanasios ; Piper, Andreas ; Poskanzer, Arthur M. ; Prindle, Duncan J. ; Pühlhofer, Falk ; Rauch, Wolfgang Hans ; Renfordt, Rainer Arno Ernst ; Retyk, Waldemar ; Ritter, Hans Georg ; Röhrich, Dieter ; Rudolph, Heinrich ; Runge, Kay ; Sandoval, Andres ; Sann, Hans ; Schäfer, Erich ; Schmitz, Norbert ; Schönfelder, Stefan ; Seyboth, Peter ; Seyerlein, Jürgen ; Sikler, Ferenc ; Skrzypczak, Ewa ; Stock, Reinhard ; Ströbele, Herbert ; Szentpetery, Imre ; Sziklai, János ; Toy, Milton Y. ; Trainor, Thomas A. ; Trentalange, Stephen ; Vassiliou, Maria ; Vesztergombi, György ; Vranić, Danilo ; Wenig, Siegfried ; Whitten, Charles A. ; Wienold, Thomas ; Wood, Lindsay ; Zimanyi, József ; Zhu, X. -Z. ; Zybert, Ryszard
Lenz, Maximilian ; Eichler, Amelie ; Kruse, Pia ; Strehl, Andreas ; Rodriguez-Rozada, Silvia ; Goren, Itamar ; Yogev, Nir ; Frank, Stefan ; Waisman, Ari ; Deller, Thomas ; Jung, Steffen ; Maggio, Nicola ; Vlachos, Andreas
Systemic inflammation is associated with alterations in complex brain functions such as learning and memory. However, diagnostic approaches to functionally assess and quantify inflammation-associated alterations in synaptic plasticity are not well-established. In previous work, we demonstrated that bacterial lipopolysaccharide (LPS)-induced systemic inflammation alters the ability of hippocampal neurons to express synaptic plasticity, i.e., the long-term potentiation (LTP) of excitatory neurotransmission. Here, we tested whether synaptic plasticity induced by repetitive magnetic stimulation (rMS), a non-invasive brain stimulation technique used in clinical practice, is affected by LPS-induced inflammation. Specifically, we explored brain tissue cultures to learn more about the direct effects of LPS on neural tissue, and we tested for the plasticity-restoring effects of the anti-inflammatory cytokine interleukin 10 (IL10). As shown previously, 10 Hz repetitive magnetic stimulation (rMS) of organotypic entorhino-hippocampal tissue cultures induced a robust increase in excitatory neurotransmission onto CA1 pyramidal neurons. Furthermore, LPS-treated tissue cultures did not express rMS-induced synaptic plasticity. Live-cell microscopy in tissue cultures prepared from a novel transgenic reporter mouse line [C57BL/6-Tg(TNFa-eGFP)] confirms that ex vivo LPS administration triggers microglial tumor necrosis factor alpha (TNFα) expression, which is ameliorated in the presence of IL10. Consistent with this observation, IL10 hampers the LPS-induced increase in TNFα, IL6, IL1β, and IFNγ and restores the ability of neurons to express rMS-induced synaptic plasticity in the presence of LPS. These findings establish organotypic tissue cultures as a suitable model for studying inflammation-induced alterations in synaptic plasticity, thus providing a biological basis for the diagnostic use of transcranial magnetic stimulation in the context of brain inflammation.