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1. Paired associative stimulation demonstrates alterations in motor cortical synaptic plasticity in patients with hepatic encephalopathy

Author

Nikolov, Petyo, Baumgarten, Thomas J., Hassan, Shady Safwat, Füllenbach, Nur-Deniz, Kircheis, Gerald, Häussinger, Dieter, Jördens, Markus, Butz, Markus, Schnitzler, Alfons, and Groiss, Stefan J.

Subjects
Quantitative Biology - Neurons and Cognition
Abstract

Objective: Hepatic encephalopathy (HE) is a potentially reversible brain dysfunction caused by liver failure. Altered synaptic plasticity is supposed to play a major role in the pathophysiology of HE. Here, we used paired associative stimulation with an inter-stimulus interval of 25 ms (PAS25), a transcranial magnetic stimulation (TMS) protocol, to test synaptic plasticity of the motor cortex in patients with manifest HE. Methods: 23 HE-patients and 23 healthy controls were enrolled in the study. Motor evoked potential (MEP) amplitudes were assessed as measure for cortical excitability. Time courses of MEP amplitude changes after the PAS25 intervention were compared between both groups. Results: MEP-amplitudes increased after PAS25 in the control group, indicating PAS25-induced synaptic plasticity in healthy controls, as expected. In contrast, MEP-amplitudes within the HE group did not change and were lower than in the control group, indicating no induction of plasticity. Conclusion: Our study revealed reduced synaptic plasticity of the primary motor cortex in HE. Significance: Reduced synaptic plasticity in HE provides a link between pathological changes on the molecular level and early clinical symptoms of the disease. This decrease may be caused by disturbances in the glutamatergic neurotransmission due to the known hyperammonemia in HE patients., Comment: number of pages: 33; number of tables: 1; number of figures: 5; References: 94

Published
2022
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5. Bile Acids and TGR5 (Gpbar1) Signaling

Author

Keitel, Verena, Gertzen, Christoph G. W., Schäfer, Sven, Klindt, Caroline, Wöhler, Christina, Deutschmann, Kathleen, Reich, Maria, Gohlke, Holger, Häussinger, Dieter, Rozman, Damjana, editor, and Gebhardt, Rolf, editor

Published
2020
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6. Targeting FXR in Cholestasis

Author

Keitel, Verena, Dröge, Carola, Häussinger, Dieter, Barrett, James E., Editor-in-Chief, Flockerzi, Veit, Editorial Board Member, Frohman, Michael A., Editorial Board Member, Geppetti, Pierangelo, Editorial Board Member, Hofmann, Franz B., Editorial Board Member, Michel, Martin C., Editorial Board Member, Page, Clive P., Editorial Board Member, Rosenthal, Walter, Editorial Board Member, Wang, KeWei, Editorial Board Member, Fiorucci, Stefano, editor, and Distrutti, Eleonora, editor

Published
2019
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7. Bile Acid-Activated Receptors: GPBAR1 (TGR5) and Other G Protein-Coupled Receptors

Author

Keitel, Verena, Stindt, Jan, Häussinger, Dieter, Barrett, James E., Editor-in-Chief, Flockerzi, Veit, Editorial Board Member, Frohman, Michael A., Editorial Board Member, Geppetti, Pierangelo, Editorial Board Member, Hofmann, Franz B., Editorial Board Member, Michel, Martin C., Editorial Board Member, Page, Clive P., Editorial Board Member, Rosenthal, Walter, Editorial Board Member, Wang, KeWei, Editorial Board Member, Fiorucci, Stefano, editor, and Distrutti, Eleonora, editor

Published
2019
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10. Norursodeoxycholic acid versus placebo in the treatment of non-alcoholic fatty liver disease: a double-blind, randomised, placebo-controlled, phase 2 dose-finding trial

Author

Vogel, Wolfgang, Aigner, Elmar, Datz, Christian, Tilg, Herbert, Gerken, Guido, Rust, Christian, Cordes, Hans-Jörg, Steib, Christian, Pathil-Warth, Anita, Prinz, MD, Christian, Lammert, Frank, Antoni, Christoph, Klausmann, Gerhard, Häussinger, Dieter, Zipprich, Alexander, Traussnigg, Stefan, Schattenberg, Jörn M, Demir, Münevver, Wiegand, Johannes, Geier, Andreas, Teuber, Gerlinde, Hofmann, Wolf Peter, Kremer, Andreas E, Spreda, Frank, Kluwe, Johannes, Petersen, Jörg, Boettler, Tobias, Rainer, Florian, Halilbasic, Emina, Greinwald, Roland, Pröls, Markus, Manns, Michael P, Fickert, Peter, and Trauner, Michael

Published
2019
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13. Inhibiting Glutamine-Dependent mTORC1 Activation Ameliorates Liver Cancers Driven by β-Catenin Mutations

Author

Adebayo Michael, Adeola O., Ko, Sungjin, Tao, Junyan, Moghe, Akshata, Yang, Hong, Xu, Meng, Russell, Jacquelyn O., Pradhan-Sundd, Tirthadipa, Liu, Silvia, Singh, Sucha, Poddar, Minakshi, Monga, Jayvir S., Liu, Pin, Oertel, Michael, Ranganathan, Sarangarajan, Singhi, Aatur, Rebouissou, Sandra, Zucman-Rossi, Jessica, Ribback, Silvia, Calvisi, Diego, Qvartskhava, Natalia, Görg, Boris, Häussinger, Dieter, Chen, Xin, and Monga, Satdarshan P.

Published
2019
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14. Favourable Outcome in Two Pregnancies in a Patient with 3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency

Author

Santosa, David, Donner, Markus G., vom Dahl, Stephan, Fleisch, Markus, Hoehn, Thomas, Mayatepek, Ertan, Heldt, Katrin, Niehues, Tim, Häussinger, Dieter, Baumgartner, Matthias, Series editor, Patterson, Marc, Series editor, Rahman, Shamima, Series editor, Peters, Verena, Series editor, Morava, Eva, Editor-in-chief, and Zschocke, Johannes, Series editor

Published
2017
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20. Overview

Author

Häussinger, Dieter, Lammert, Eckhard, editor, and Zeeb, Martin, editor

Published
2014
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22. Helicobacter pylori Coinfection Is Associated With Decreased Markers of Immune Activation in ART-Naive HIV-Positive and in HIV-Negative Individuals in Ghana

Author

Eberhardt, Kirsten Alexandra, Sarfo, Fred Stephen, Dompreh, Albert, Kuffour, Edmund Osei, Geldmacher, Christof, Soltau, Mareike, Schachscheider, Marei, Drexler, Jan Felix, Eis-Hübinger, Anna Maria, Häussinger, Dieter, Bedu-Addo, George, Phillips, Richard Odame, Norman, Betty, Burchard, Gerd Dieter, and Feldt, Torsten

Published
2015

28. Hepatische Enzephalopathie

Author

Wettstein, Matthias, Häussinger, Dieter, Schölmerich, Jürgen, editor, Burdach, S., editor, Drexler, H., editor, Hallek, M., editor, Hiddemann, W., editor, Hörl, W.H., editor, Klein, H., editor, Landthaler, M., editor, Lenz, K., editor, Mann, K., editor, Mössner, J., editor, Müller-Ladner, U., editor, Reichen, J., editor, Schmiegel, W., editor, Schröder, J.O., editor, Seeger, W., editor, Stremmel, W., editor, Suttorp, N., editor, Weilemann, L.S., editor, and Wöhrle, J.C., editor

Published
2005
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30. Erkrankungen von Leber, Gallenwegen und Pankreas

Author

Mössner, Joachim, Stremmel, Wolfgang, Gerken, Guido, Jochum, Christoph, Strassburg, Christian P., Vogel, Arndt, Manns, Michael P., Grothe, Wilfried, Fleig, Wolfgang E., Pape, Ulrich-Frank, Berg, Thomas, Wiedenmann, Bertram, Bahr, Matthias J., Böker, Klaus H. W., Steudel, Norbert, Wettstein, Matthias, Häussinger, Dieter, Schölmerich, Jürgen, Berr, Frieder, Schiefke, Ingolf, Sauerbruch, Tilman, Terjung, Birgit, Keim, Volker, Graeven, Ullrich, Schmiegel, Wolff, Böhmig, Michael, Schölmerich, Jürgen, editor, Burdach, Stefan, editor, Diehl, Volker, editor, Drexler, Helmut, editor, Hiddemann, Wolfgang, editor, Hörl, Walter H., editor, Klein, Helmfried, editor, Landthaler, Michael, editor, Lenz, Kurt, editor, Mann, Klaus, editor, Mössner, Joachim, editor, Müller-Ladner, Ulf, editor, Reichen, Jürg, editor, Schmiegel, Wolff, editor, Schröder, Johann Oltmann, editor, Seeger, Werner, editor, Stremmel, Wolfgang, editor, Suttorp, Norbert, editor, and Weilemann, L. Sacha, editor

Published
2003
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33. Involvement of Toso in activation of monocytes, macrophages, and granulocytes

Author

Lang, Karl S., Lang, Philipp A., Meryk, Andreas, Pandyra, Aleksandra A., Boucher, Louis-Martin, Pozdeev, Vitaly I., Tusche, Michael W., Göthert, Joachim R., Haight, Julian, Wakeham, Andrew, You-Ten, Annick J., MclIwain, David R., Merches, Katja, Khairnar, Vishal, Recher, Mike, Nolan, Garry P., Hitoshi, Yasumichi, Funkner, Pauline, Navarini, Alexander A., Verschoor, Admar, Shaabani, Namir, Honke, Nadine, Penn, Linda Z., Ohashi, Pamela S., Häussinger, Dieter, Lee, Kyeong-Hee, and Mak, Tak W.

Published
2013

34. Characterization of HIV-1 drug resistance among patients with failure of second-line combined antiretroviral therapy in central Ethiopia

Author

Tufa, Tafese Beyene, Fuchs, Andre, Orth, Hans Martin, Luebke, Nadine, Knops, Elena, Heger, Eva, Jarso, Godana, Hurissa, Zewdu, Eggers, Yannik, Haeussinger, Dieter, Luedde, Tom, Jensen, Bjoern-Erik Ole, Kaiser, Rolf, Feldt, Torsten, Tufa, Tafese Beyene, Fuchs, Andre, Orth, Hans Martin, Luebke, Nadine, Knops, Elena, Heger, Eva, Jarso, Godana, Hurissa, Zewdu, Eggers, Yannik, Haeussinger, Dieter, Luedde, Tom, Jensen, Bjoern-Erik Ole, Kaiser, Rolf, and Feldt, Torsten

Abstract

Background As a consequence of the improved availability of combined antiretroviral therapy (cART) in resource-limited countries, an emergence of HIV drug resistance (HIVDR) has been observed. We assessed the prevalence and spectrum of HIVDR in patients with failure of second-line cART at two HIV clinics in central Ethiopia. Methods HIV drug resistance was analysed in HIV-1-infected patients with virological failure of second-line cART using the geno2pheno application. Results Among 714 patients receiving second-line cART, 44 (6.2%) fulfilled the criteria for treatment failure and 37 were eligible for study inclusion. Median age was 42 years [interquartile range (IQR): 20-45] and 62.2% were male. At initiation of first-line cART, 23 (62.2%) were WHO stage III, mean CD4 cell count was 170.6 (range: 16-496) cells/mu L and median (IQR) HIV-1 viral load was 30 220 (7963-82 598) copies/mL. Most common second-line cART regimens at the time of failure were tenofovir disoproxil fumarate (TDF)-lamivudine (3TC)-ritonavir-boosted atazanavir (ATV/r) (19/37, 51.4%) and zidovudine (ZDV)-3TC-ATV/r (9/37, 24.3%). Genotypic HIV-1 resistance testing was successful in 35 (94.6%) participants. We found at least one resistance mutation in 80% of patients and 40% carried a protease inhibitor (PI)-associated mutation. Most common mutations were M184V (57.1%), Y188C (25.7%), M46I/L (25.7%) and V82A/M (25.7%). High-level resistance against the PI ATV (10/35, 28.6%) and lopinavir (LPV) (5/35, 14.3%) was reported. As expected, no resistance mutations conferring integrase inhibitor resistance were detected. Conclusions We found a high prevalence of resistance mutations, also against PIs (40%), as the national standard second-line cART components. Resistance testing before switching to second- or third-line cART is warranted.

Published
2022

38. Natural killer cell activation enhances immune pathology and promotes chronic infection by limiting CD8⁺ T-cell immunity

Author

Lang, Philipp A., Lang, Karl S., Xu, Haifeng C., Grusdat, Melanie, Parish, Ian A., Recher, Mike, Elford, Alisha R., Dhanji, Salim, Shaabani, Namir, Tran, Charles W., Dissanayake, Dilan, Rahbar, Ramtin, Ghazarian, Magar, Brüstle, Anne, Fine, Jason, Chen, Peter, Weaver, Casey T., Klose, Christoph, Diefenbach, Andreas, Häussinger, Dieter, Carlyle, James R., Kaech, Susan M., Mak, Tak W., and Ohashi, Pamela S.

Published
2012

48. Granulocyte-colony stimulating factor (G-CSF) to treat acute-on- chronic liver failure: A multicenter randomized trial (GRAFT study)

Author

Engelmann, Cornelius, Herber, Adam, Franke, Annegret, Bruns, Tony, Reuken, Philipp, Schiefke, Ingolf, Zipprich, Alexander, Zeuzem, Stefan, Goeser, Tobias, Canbay, Ali, Berg, Christoph, Trebicka, Jonel, Uschner, Frank E., Chang, Johannes, Mueller, Tobias, Aehling, Niklas, Schmelzle, Moritz, Splith, Katrin, Lammert, Frank, Lange, Christian M., Sarrazin, Christoph, Trautwein, Christian, Manns, Michael, Haeussinger, Dieter, Pfeiffenberger, Jan, Galle, Peter R., Schmiedeknecht, Anett, Berg, Thomas, Engelmann, Cornelius, Herber, Adam, Franke, Annegret, Bruns, Tony, Reuken, Philipp, Schiefke, Ingolf, Zipprich, Alexander, Zeuzem, Stefan, Goeser, Tobias, Canbay, Ali, Berg, Christoph, Trebicka, Jonel, Uschner, Frank E., Chang, Johannes, Mueller, Tobias, Aehling, Niklas, Schmelzle, Moritz, Splith, Katrin, Lammert, Frank, Lange, Christian M., Sarrazin, Christoph, Trautwein, Christian, Manns, Michael, Haeussinger, Dieter, Pfeiffenberger, Jan, Galle, Peter R., Schmiedeknecht, Anett, and Berg, Thomas

Abstract

Background & Aims: Based on positive results from small single center studies, granulocyte-colony stimulating factor (G-CSF) is being widely used for the treatment of patients with acute-on chronic liver failure (ACLF). Herein, we aimed to evaluate the safety and efficacy of G-CSF in patients with ACLF. Methods: In this multicenter, prospective, controlled, open-label phase II study, 176 patients with ACLF (EASL-CLIF criteria) were randomized to receive G-CSF (5 mu g/kg daily for the first 5 days and every third day thereafter until day 26) plus standard medical therapy (SMT) (n = 88) or SMT alone. The primary effi- cacy endpoint was 90-day transplant-free survival analyzed by Cox regression modeling. The key secondary endpoints were overall and transplant-free survival after 360 days, the development of ACLF-related complications, and the course of liver function scores during the entire observation period. Results: Patients treated with G-CSF had a 90-day transplant free survival rate of 34.1% compared to 37.5% in the SMT group (hazard ratio [HR] 1.05; 95% CI 0.711-1.551; p = 0.805). Transplant-free and overall survival at 360 days did not differ between the 2 arms (HR 0.998; 95% CI 0.697-1.430; p = 0.992 and HR 1.058; 95% CI 0.727-1.548; p = 0.768, respectively). G-CSF did not improve liver function scores, the occurrence of infections, or survival in subgroups of patients without infections, with alcohol-related ACLF, or with ACLF defined by the APASL criteria. Sixty-one serious adverse events were reported in the GCSF+SMT group and 57 were reported in the SMT group. In total, 7 drug-related serious adverse reactions occurred in the G-CSF group. The study was prematurely terminated due to futility after conditional power calculation. Conclusions: In contrast to previous findings, G-CSF had no significant beneficial effect on patients with ACLF in this multicenter controlled trial, which suggests that it should not be used as a standard treatment for ACLF. Clinic

Published
2021

49. Downregulation of TGR5 (GPBAR1) in biliary epithelial cells contributes to the pathogenesis of sclerosing cholangitis

Author

Reich, Maria, Spomer, Lina, Klindt, Caroline, Fuchs, Katharina, Stindt, Jan, Deutschmann, Kathleen, Hohne, Johanna, Liaskou, Evaggelia, Hov, Johannes R., Karlsen, Tom H., Beuers, Ulrich, Verheij, Joanne, Ferreira-Gonzalez, Sofia, Hirschfield, Gideon, Forbes, Stuart J., Schramm, Christoph, Esposito, Irene, Nierhoff, Dirk, Fickert, Peter, Fuchs, Claudia Daniela, Trauner, Michael, Garcia-Beccaria, Maria, Gabernet, Gisela, Nahnsen, Sven, Mallm, Jan-Philipp, Vogel, Marina, Schoonjans, Kristina, Lautwein, Tobias, Koehrer, Karl, Haeussinger, Dieter, Luedde, Tom, Heikenwalder, Mathias, Keitel, Verena, Reich, Maria, Spomer, Lina, Klindt, Caroline, Fuchs, Katharina, Stindt, Jan, Deutschmann, Kathleen, Hohne, Johanna, Liaskou, Evaggelia, Hov, Johannes R., Karlsen, Tom H., Beuers, Ulrich, Verheij, Joanne, Ferreira-Gonzalez, Sofia, Hirschfield, Gideon, Forbes, Stuart J., Schramm, Christoph, Esposito, Irene, Nierhoff, Dirk, Fickert, Peter, Fuchs, Claudia Daniela, Trauner, Michael, Garcia-Beccaria, Maria, Gabernet, Gisela, Nahnsen, Sven, Mallm, Jan-Philipp, Vogel, Marina, Schoonjans, Kristina, Lautwein, Tobias, Koehrer, Karl, Haeussinger, Dieter, Luedde, Tom, Heikenwalder, Mathias, and Keitel, Verena

Abstract

Background & Aims: Primary sclerosing cholangitis (PSC) is characterized by chronic inflammation and progressive fibrosis of the biliary tree. The bile acid receptor TGR5 (GPBAR1) is found on biliary epithelial cells (BECs), where it promotes secretion, proliferation and tight junction integrity. Thus, we speculated that changes in TGR5-expression in BECs may contribute to PSC pathogenesis. Methods: TGR5-expression and-localization were analyzed in PSC livers and liver tissue, isolated bile ducts and BECs from Abcb4(-/-) , Abcb4(-/-)/Tgr5(Tg) and ursodeoxycholic acid (UDCA)-or 24-norursodeoxycholic acid (norUDCA)-fed Abcb(4-/-) mice. The effects of IL8/IL8 homologues on TGR5 mRNA and protein levels were studied. BEC gene expression was analyzed by single-cell transcriptomics (scRNA-seq) from distinct mouse models. Results: TGR5 mRNA expression and immunofluorescence staining intensity were reduced in BECs of PSC and Abcb4(-/-) livers, in Abcb4(-/-) extrahepatic bile ducts, but not in intrahepatic macrophages. No changes in TGR5 BEC fluorescence intensity were detected in liver tissue of other liver diseases, including primary biliary cholangitis. Incubation of BECs with IL8/IL8 homologues, but not with other cytokines, reduced TGR5 mRNA and protein levels. BECs from Abcb4(-/-) mice had lower levels of phosphorylated Erk and higher expression levels of Icam1, Vcam1 and Tgfb2. Overexpression of Tgr5 abolished the activated inflammatory phenotype characteristic of Abcb4(-/-) BECs. NorUDCA-feeding restored TGR5-expression levels in BECs in Abcb4(-/-) livers. Conclusions: Reduced TGR5 levels in BECs from patients with PSC and Abcb4(-/-) mice promote development of a reactive BEC phenotype, aggravate biliary injury and thus contribute to the pathogenesis of sclerosing cholangitis. Restoration of biliary TGR5-expression levels represents a previously unknown mechanism of action of norUDCA. Lay summary: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver dis

Published
2021

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