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1. The effect of needle tip tracking on procedural time of ultrasound‐guided lumbar plexus block: a randomised controlled trial

Author

Luis Romundstad, Leiv Arne Rosseland, Axel R. Sauter, Morten W. Fagerland, Paul Kessler, Kyrre Ullensvang, Erika Rolfsen Bjørnå, and Trine Kåsine

Subjects
Adult, Male, medicine.medical_treatment, Lumbosacral Plexus, Tracking (particle physics), law.invention, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Match moving, 030202 anesthesiology, law, Lumbar plexus block, Humans, Medicine, 030212 general & internal medicine, Anesthetics, Local, Ultrasonography, Interventional, Aged, Dry needling, Cross-Over Studies, Lumbar plexus, business.industry, Ultrasound, Nerve Block, Middle Aged, Anesthesiology and Pain Medicine, Needles, Nerve block, Female, Nuclear medicine, business
Abstract

Technology that facilitates performance of deep peripheral nerve blocks is of clinical interest. The Onvision™ is a new device for ultrasonographic needle tip tracking that incorporates an ultrasound sensor on the needle tip that is then represented by a green circle on the ultrasound screen. The primary aim of this study was to investigate the effect of needle tip tracking on procedural time in the first human volunteer study. Secondary outcome measures included: number of hand movements; hand movement path length; block success rate; block onset time; block duration; discomfort experienced by the volunteers; and the anaesthetists’ confidence as to whether their block would be successful. Two anaesthetists performed ultrasound‐guided lumbar plexus blocks with an out‐of‐plane technique, with and without the use of needle tip tracking. In total, data from 25 volunteers were studied. Mean (SD) procedural time was 163 (103) s with needle tip tracking and 216 (117) s without (p = 0.10). Hand motion analysis showed that needle tip tracking was associated with a significant decrease in the mean (SD) number of intended needling hand movements (39 (29) vs. 59 (36); p = 0.03) and path lengths (3.2 (3.1) m vs. 5.5 (4.5) m; p = 0.03). No differences were found for any other secondary outcomes. The use of Onvision needle tip tracking did not reduce procedural time for out‐of‐plane ultrasound‐guided lumbar plexus block but did reduce the number of hand movements and path lengths. This may indicate improved needle control but further studies are needed to confirm this finding.

Published
2019
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2. Needle tip tracking for ultrasound‐guided peripheral nerve block procedures—An observer blinded, randomised, controlled, crossover study on a phantom model

Author

Per Kristian Hol, Luis Romundstad, Paul Kessler, Leiv Arne Rosseland, Kyrre Ullensvang, Axel R. Sauter, Trine Kåsine, and Morten W. Fagerland

Subjects
Observer (quantum physics), Swine, Regional Anaesthesia and Pain Therapy, Peripheral nerve block, Hand movements, Imaging phantom, 03 medical and health sciences, 0302 clinical medicine, Primary outcome, Outcome Assessment, Health Care, Animals, Humans, Medicine, 030212 general & internal medicine, Ultrasonography, Interventional, Cross-Over Studies, business.industry, Ultrasound, Nerve Block, 030208 emergency & critical care medicine, General Medicine, Crossover study, Ultrasound guided, Anesthesiology and Pain Medicine, Needles, Original Article, Clinical Competence, business, Nuclear medicine
Abstract

Background The Onvision needle tip tracking (NTT) is a new technology consisting of a needle with an ultrasound sensor close to the needle tip and a console for computerised signal processing. The aim of the study was to evaluate NTT technology during ultrasound-guided simulated peripheral nerve block procedures in a porcine phantom model. Methods Forty anaesthesiologists performed in-plane and out-of-plane simulated nerve blocks with and without NTT guidance. The primary outcome measure was procedure time. Secondary outcomes were hand movements and the path length travelled by the hands measured by motion analysis, precision of the needle tip related to the target structure, success rates and violations of the target structure, and the participants confidence whether their procedure would be successful or not. Results Procedure time was reduced from 66.7 (SD = 47.5) seconds to 43.8 (SD = 29.2) seconds when NTT was used for out-of-plane procedures (P = 0.002). The number of hand movements of the probe hand was 13.9 (SD = 30.2) with NTT and 22.8 (SD = 30.0) without NTT (P = 0.019). No significant differences were registered during the performance of in-plane procedures. The participants confidence in a presumed block success was increased with both in-plane procedures (8.50 (SD = 1.18) with NTT vs 7.65 (SD = 1.96), P = 0.004) and out-of-plane procedures (8.50 (SD = 1.09) vs 7.10 (SD = 1.89), P = 0.0001). Conclusions The new NTT technology significantly reduced the procedure time and the number of hand movements for ultrasound-guided out-of-plane PNB procedures. No significant differences were found for the in-plane procedures.

Published
2019

4. First Experience With Rectus Sheath Block for Postoperative Analgesia After Pancreas Transplant: A Retrospective Observational Study

Author

Håkon Haugaa, Kristina Elisabeth Rydenfelt, Rune Horneland, John Hausken, Tor Inge Tønnessen, Gisle Kjøsen, and Kyrre Ullensvang

Subjects
Adult, Male, Transplantasjon, medicine.drug_class, Analgesi, Rectus Abdominis, Patient satisfaction, Bolus (medicine), Interquartile range, medicine, Humans, Pain Management, Anesthetics, Local, Aged, Retrospective Studies, Transplantation, Pain, Postoperative, business.industry, Local anesthetic, Retrospective cohort study, Nerve Block, Rectus sheath, Middle Aged, Analgesia, Epidural, Catheter, medicine.anatomical_structure, Treatment Outcome, Patient Satisfaction, Anesthesia, Surgery, Female, Pancreas Transplantation, business, Oxycodone, medicine.drug
Abstract

Background Standard of care for postoperative analgesia after pancreas transplant has been thoracic epidural analgesia (TEA). A high incidence of venous graft thrombosis necessitated a change to a more aggressive anticoagulation protocol. To minimize the risk of epidural hemorrhages, we changed from TEA to rectus sheath block (RSB) in 2017. Methods From June 2016 to December 2017, a total of 29 consecutive pancreas transplant recipients were included. Sixteen were treated with TEA and 13 were treated with RSB. In the TEA group, the catheter was inserted before induction of general anesthesia, and an epidural infusion was started intraoperatively. An ultrasound-guided RSB was performed bilaterally, and a bolus of local anesthetic was administered before an 18G catheter was inserted. The patients received intermittent local anesthetic boluses every 4 hours in addition to an intravenous patient-controlled analgesia with oxycodone. Both groups received oral acetaminophen and additional rescue opioids. Results The administered amount of intravenous morphine equivalents (MEQ) was not significantly different between the RSB and TEA groups. The median MEQ consumption per day during the stay at the surgical ward was 23 mg MEQ/d (interquartile range [IQR], 14–33 mg MEQ/d) in the TEA group compared with 19 mg MEQ/d (IQR, 14–32 mg MEQ/d) in the RSB group (P = .4). The duration of the pain catheters was significantly longer in the RSB group. We had no complications related to insertion, use, or removal of the RSB or the TEA catheters, and overall patient satisfaction and comfort was good. Conclusion Compared with TEA, RSB was equally effective and safe for postoperative analgesia in heavily anticoagulated pancreas transplant patients.

Published
2019

5. The Analgesic Effect of Ultrasound-guided Quadratus Lumborum Block After Cesarean Delivery: A Randomized Clinical Trial

Author

Eldrid Langesæter, Leiv Arne Rosseland, Axel R. Sauter, Kyrre Ullensvang, and Anders Krohg

Subjects
Adult, musculoskeletal diseases, Analgesic effect, medicine.medical_specialty, medicine.drug_class, 610 Medicine & health, Thoracolumbar fascia, law.invention, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, Randomized controlled trial, Pregnancy, 030202 anesthesiology, law, medicine, Humans, 030212 general & internal medicine, Transversus abdominis, Anesthetics, Local, Cesarean delivery, Ultrasonography, Interventional, Abdominal Muscles, Pain, Postoperative, Cesarean Section, Local anesthetic, business.industry, Nerve Block, musculoskeletal system, Ultrasound guided, Surgery, Analgesics, Opioid, body regions, Treatment Outcome, Anesthesiology and Pain Medicine, surgical procedures, operative, medicine.anatomical_structure, Anesthesia, Female, Ultrasonography, business, 030217 neurology & neurosurgery
Abstract

BACKGROUND Landmark and ultrasound-guided transversus abdominis plane blocks have demonstrated an opioid-sparing effect postoperatively after cesarean delivery. The more posterior quadratus lumborum (QL) might provide superior local anesthetic spread to the thoracolumbar fascia and paravertebral space. The aim of our study was to evaluate the efficacy of the QL block after cesarean delivery. METHODS A randomized, double-blind, controlled trial was performed. Forty parturients undergoing cesarean delivery received bilateral ultrasound-guided QL blocks with either 2 mg/mL ropivacaine or saline postoperatively. All patients received spinal anesthesia with bupivacaine and sufentanil and a postoperative analgesic regimen of paracetamol, ibuprofen, and ketobemidone administered by a patient-controlled analgesic pump. The ketobemidone consumption and time of each dose administered were recorded. The primary outcome was ketobemidone consumption during the first 24 hours postoperatively. Secondary and exploratory analyses compared repeated measures of pain scores, nausea, and fatigue, and total differences in time until patients were able to stand and able to walk 5 m, and the interaction between the effective analgesic score and time. RESULTS All 40 patients completed the trial, 20 in each group. The cumulative ketobemidone consumption in 24 hours was reduced in the active group compared with the control group (P = .04; ratio of means = 0.60; 95% confidence interval, 0.37-0.97). The effective analgesic scores were significantly better in the treatment group compared with the placebo group both at rest (P < .01) and during coughing (P < .01). CONCLUSIONS QL block with ropivacaine reduces the postoperative ketobemidone consumption and pain intensity as a part of a multimodal analgesic regimen that excludes neuraxial morphine.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Published
2018
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6. Ultrasound-guided lumbar plexus block in volunteers; a randomized controlled trial

Author

Axel R. Sauter, Kjeld Søballe, Mathias Alrø Fichtner Bendtsen, Kyrre Ullensvang, Jennie Maria Christin Strid, Morten Daugaard, Jens Børglum, Thomas Fichtner Bendtsen, Morten Andersen, and Erik Morre Pedersen

Subjects
Adult, Male, Time Factors, Lidocaine, medicine.medical_treatment, Lumbosacral Plexus, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Lumbar, Reference Values, 030202 anesthesiology, Journal Article, Humans, Medicine, Single-Blind Method, Anesthetics, Local, 610 Medicine & health, Ultrasonography, Interventional, Cross-Over Studies, medicine.diagnostic_test, Lumbar plexus, business.industry, Ultrasound, Nerve Block, Magnetic resonance imaging, Crossover study, Lumbosacral plexus, Anesthesiology and Pain Medicine, Nerve block, business, Nuclear medicine, 030217 neurology & neurosurgery, medicine.drug
Abstract

Background: The currently best-established ultrasound-guided lumbar plexus block (LPB) techniques use a paravertebral location of the probe, such as the lumbar ultrasound trident (LUT). However, paravertebral ultrasound scanning can provide inadequate sonographic visibility of the lumbar plexus in some patients. The ultrasound-guided shamrock LPB technique allows real-time sonographic viewing of the lumbar plexus, various anatomical landmarks, advancement of the needle, and spread of local anaesthetic injectate in most patients. We aimed to compare block procedure outcomes, effectiveness, and safety of the shamrock vs LUT.Methods: Twenty healthy men underwent ultrasound-guided shamrock and LUT LPBs (2% lidocaine–adrenaline 20 ml, with 1 ml diluted contrast added) in a blinded randomized crossover study. The primary outcome was block procedure time. Secondary outcomes were procedural discomfort, number of needle insertions, injectate spread assessed with magnetic resonance imaging, sensorimotor effects, and lidocaine pharmacokinetics.Results: The shamrock LPB procedure was faster than LUT (238 [sd 74] vs 334 [156] s; P=0.009), more comfortable {numeric rating scale 0–10: 3 [interquartile range (IQR) 2–4] vs 4 [3–6]; P=0.03}, and required fewer needle insertions (2 [IQR 1–3] vs 6 [2–12]; P=0.003). Perineural injectate spread seen with magnetic resonance imaging was similar between the groups and consistent with motor and sensory mapping. Zero/20 (0%) and 1/19 (5%) subjects had epidural spread after shamrock and LUT (P=1.00), respectively. The lidocaine pharmacokinetics were similar between the groups.Conclusions: Shamrock was faster, more comfortable, and equally effective compared with LUT.Clinical trial registration: NCT02255591

Published
2017
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7. Incidence of severe critical events in paediatric anaesthesia (APRICOT): a prospective multicentre observational study in 261 hospitals in Europe

Author

Walid Habre, Nicola Disma, Katalin Virag, Karin Becke, Tom G Hansen, Martin Jöhr, Brigitte Leva, Neil S Morton, Petronella M Vermeulen, Marzena Zielinska, Krisztina Boda, Francis Veyckemans, Walter Klimscha, Regina Konecny, Robert Luntzer, Ulrike Morawk-Wintersperger, Franz Neiger, Lydia Rustemeyer, Christian Breschan, Denise Frey, Manuela Platzer, Reinhard Germann, Joachim Oeding, Birgit Stoegermüller, Bernhard Ziegler, Philipp Brotatsch, Anton Gutmann, Gerlinde Mausser, Brigitte Messerer, Wolfgang Toller, Maria Vittinghoff, Gregor Zangl, Natascha Seidel-Ahyai, Christoph Hochhold, Ruth Kroess, Peter Paal, Steven Cnudde, Patricia Coucke, Birgit Loveniers, John Mitchell, David Kahn, Thierry Pirotte, Caroline Pregardien, Marc Coppens, Stefan De Hert, Björn Heyse, Martine Neckebroek, Aliaksandra Parashchanka, Jurgen Van Limmen, Nancy Van Den Eynde, Caroline Vanpeteghem, Piet Wyffels, Michaël Lalot, Jean-Paul Lechat, France Stevens, Sari Casaer, Françoise De Groote, Françoise De Pooter, Andrée De Villé, Marc Gerin, Natalia Magasich, Cristel Sanchez Torres, Denise Van Deenen, Johan Berghmans, Dirk Himpe, Eva Roofthooft, Ellen Joukes, Carine Smitz, Veronique Van Reeth, Christel Huygens, Julie Lauweryns, Karen De Smet, Nadia Najafi, Jan Poelaert, Anne Van de Velde, Veerle Van Mossevelde, Ivan Bekavac, Diana Butkovic, Dubravka Heli Litvic, Ivana Kerovec Soric, Hrvoje Maretic, Djurdjica Moscatello, Ljiljana Popovic, Slobodan Micici, Ivana Stuck Tus, Lada Kalagac Fabris, Tatjana Simurina, Nina Sulen, Gordana Kesic-Valpotic, Dajana Djapic, Jirí Žurek, Lucie Jureckova, Iveta Mackova, Monika Skacel, Stanislava Weinlichova, Jan Divák, Michal Frelich, René Urbanec, Vera Biskupova, Vladimir Mixa, Jana Pavlickova, Arash Afshari, Morten Bøttger, Marguerite B. Ellekvist, Mathias Johansen, Birgitte Ingeborg Madsen, Jens Christian Nilsson, Birgitte MB Schousboe, Nicola G. Clausen, Tom G. Hansen, Nick Phaff Steen, Mari-Liis Ilmoja, Virge Tonise, Juri Karjagin, Reet Kikas, Mika Isohanni, Anniina Lyly, Annika Takala, Johanna Happo, Kai Kiviluoma, Kati Martikainen, Riku Aantaa, Tuula Manner, Sanna Vilo, Catherine Amory, Hugues Ludot, Patricia Lambotte, René Busche, Olivier Jacqmarcq, Corinne Lejus, Julien Corouge, Christian Erb, Delphine Garrigue, Patricia Gillet, Anne Laffargue, Veronique Lambelin, Hélène Le Freche, Daliana Peresbota, Pierre Richart, Jerome Berton, Catherine Chapotte, Laurent Colbus, Thierry Lehousse, Jean Monrigal, Catherine Baujard, Philippe Roulleau, Giuseppe Staiti, Hélène Batoz, Maryline Bordes, Anne Didier, Yann Hamonic, Sylvaine Lagarde, Karine Nouette-Gaulain, François Semjen, Brigitte Zaghet, Jacky Dekens, Axelle Delcuze, Hervé Dupont, Aurélien Legrand, Celine Raffoflandreur, Noémie Audren, Blandine Camus, Marielle Cartal, Chantal Chazelet, Isabelle Davin, Marion Guillier, Luc Desjeux, Claire Larcher, Elodie Grein, Mickeal Leclercq, Roxana Levitchi, Lilica Rosu, Dominique Simon, Aurélien Zang, Anne Migeon, Anne-Charlotte Gagey, Nathalie Bourdaud, Anne-Charlotte Carre, Frédéric Duflo, Jean-Claude Riche, Philippe Robert, Emilie Druot, Olivier Maupain, Gilles Orliaguet, Lucie Sabau, Hanna Taright, Lynn Uhrig, Juliette Verchere-Montmayeur, Lise Debrabant, Clotaire Pilla, Alexandre Podvin, Benjamin Roth, Souhayl Dahmani, Florence Julien-Marsollier, Nada Sabourdin, Bogdan Alexandri, Gilles Brezac, Francois de la Brière, Catherine Hayem, Elizabeth Lhubat, Jean Paul Mission, Charlotte Rémond, Christophe Dadure, Maud Maniora, Anais Marie, Philippe Pirat, Anne-Charlotte Saour, Chrystelle Sola, Claude Ecoffey, Eric Wodey, Christian Adam, Thomas Standl, Ehrenfried Schindler, Tomohiro Yamamoto, Michael Brackhahn, Christoph Bernhard Eich, Holger Guericke, Petra Kindermann, Michael Laschat, Cornel Schink, Frank Wappler, Claudia Hoehne, Natalia Skordou, Johanna Ulrici, Martin Jetzek-Zader, Peter Kienbaum, Tanja Meyer-Treschan, Olaf Picker, Maximilian S. Schaefer, Golo Mielke, Sabine Baethge, Axel Ramminger, Martin Bauer, Matthias Bollinger, José Hinz, Michael Quintel, Sebastian G. Russo, Michael Bauer, Dfominik Geil, Andreas Kortgen, Niels-Peter Preussler, Ulrich Hofmann, Manfred Raber, Doris Reindl, Karin Oppenrieder, Bettina Schierlinger, Jens Roth, Wolfgang Funk, Thomas Fischer, Christian Gernoth, Christina Wiefelspütz, Hauke Volger, Nicole Zederer, Anja Diers, Matthias Huber, Clemens Schorer, Andreas Weyland, Konrad Schwarzkopf, Catharina Grau, Winfried Roth, Rolf Holy, Thomas Mader, Laura Peter, Hauke Supthut, Thomas Kuehhirt, Alexander Milde, Fritz Fiedler, Carsten Isselhorst, Ulrich Grundmann, Alexander Pattar, Jennifer Reinert, Birgit Ehm, Katrin Fritzsche, Ralf Gaebler, Patrick Meybohm, Maximilian Hein, Ines Guzman, Johanna Jokinen, Peter Kranke, Ulrich Goebel, Sarah Harris, Christoph Eisner, Miriam Ochsenreiter, Michael Schoeler, Elke Thil, Richard Ellerkmann, Andreas Hoeft, Claudia Neumann, Stefan Weber, Julia Keilhauer, Jan Kloessing, Michael Schramm, Uwe Trieschmann, Kristina Knauss, Barbara Sinner, Johannes Steinmann, Herbert Koessler, Evagelia Kalliardou, Anna Malisiova, Adelais Tsiotou, Pelagia Chloropoulou, Mpratzou Chrysi, Despoina Iordanidou, Merkourios Ntavlis, Krisztina B Boda, Christilynn Guerin, Janice Irwin, Claire Magner, Solmaz Nakhjavani, Brendan O'Hare, Deborah Galvin, Yosry Jamil, Carlos Lesmes, Yuri Barak, Haran Fisher, Ludmyla Kachko, Jacob Katz, Dmitry Kirilov, Michael Levinzon, Yair Manevich, Konstantin Nekrasov, Elia Peled, Elena Sanko, Dmitri Schmain, Olga Sheinkin, Eliahu Simhi, Alex Tarabikin, Evelina Trabkin, Irena Yagudaev, Yelena Zeitlin, Igor Zunser, Elisabetta Cerutti, Maria Maddalena Schellino, Silvia Valzan, Rosa Lucia Pinciroli, Luciano Bortone, Giorgia Cerati, Fabiana Salici, Leonardo Bussolin, Giuliana Rizzo, Francesca Rossetti, Laura Marchesini, Simonetta Tesoro, Brita De Lorenzo, Fabio Guarracino, Beate Kuppers, Marinella Astuto, Sofia Pitino, Rita Scalisi, Lucia Scordo, Sandra D'Alessandro, Luigi Dei Giudici, Ivano Farinelli, Giuseppe Lofino, Giuliano Marchetti, Sergio Giuseppe Picardo, Simone Reali, Alessandro Vittori, Francesco Antonio Idone, Maria Sammartino, Fabio Sbaraglia, Cinzia Barbera, Michela Bevilacqua, Valeria Cento, Svetlana Kotzeva, Leila Mameli, Giovanni Montobbio, Leandro Passariello, Cinzia Punzo, Rosanna Sileo, Rosanna Viacava, Claudia Volpe, Clelia Zanaboni, Edoardo Calderini, Daniele Genco, Simona Neri, Davide Ottolina, Anna Camporesi, Francesca Izzo, Ida Salvo, Andrea Wolfler, Andrea Sanna, Angela Sciascia, Paolo Stoia, Annamaria Guddo, Maria Lapi, Giorgio Ivani, Annalisa Longobardo, Valeria Mossetti, Dino Pedrotti, Maurizia Grazzini, Luisa Meneghini, Salvatore Metrangolo, Stefania Michelon, Carmelo Minardi, Costanza Tognon, Nicola Zadra, Ilaria Busi, Magda Khotcholava, Bruno Guido Locatelli, Valter Sonzogni, Giusi Starita, Nicole Almenrader, Caterina Aurilio, Pasquale Sansone, Raffaella Albarello, Paolo Bracci, Mariateresa Cecini, Maria Cristina Mondardini, Lorena Pasini, Milo Vason, Gianluca Zani, Roberto Zoppellari, Laura Pistidda, Andrea Cortegiani, Santi Maurizio Raineri, Antigona Hasani, Medita Hashimi, Agris Ancupans, Arta Barzdina, Zane Straume, Anda Zundane, Mikhail Chlopin, Dalia Gestautaite, Laura Lukosiene, Evelina Paliokaite, Ilona Razlevice, Inesa Armoniene, Aurelija Bernotiene, Vidunas Daugelavicius, Ilona Dockiene, Lina Gaidelyte, Nijole Saviciene, Jolita Krikstaponiene, Dominika Sidlovskaite-Baltake, Vladyslav Stasevski, Agne Vaitoskaite, David Gatt, Stephanie Mifsud, Simone Zammit, Celia Allison, Hamid Aslami, Susanne Eberl, Mireille F M van Stijn, Markus F Stevens, Kees Punt, Rob van Osch, Arthur Bauwman, Harm Scholten, Vesna Svircevic, Veronique Adriaens, Maaike Dirckx, Jaap Dogger, Ilse Dons-Sinke, Andreas Machotta, Xavier Moors, Mandana Rad, Lonneke Staals, Anouk van der Knijff - van Dortmont, Caroline van der Marel, Anne Sieben, Tim van der Zwan, Marianne Veldhuizen, David Alders, Wolfgang Buhre, Nicole Engel, Carine Vossen, Ravin Mahadewsing, Patrick Meijer, Volker Gerling, Roelof van der Schatte Olivier, Thea van Doorn, Kristy Vons Mark Hendriks, Sandra Lako, Gert jan Scheffer, Luc Tielens, Marieke Voet, Anthony Absalom, Margot Bergsma, Vera Spanjer, Rob Spanjersberg, Yvette van de Riet, Martin Volkers, Jurgen C. de Graaff, Geranne A.J. Hopman, Teus H. Kappen, J. Hannie, A.M. Megens, Sandra C. Numan, Anton N.J. Schouten, Nigel M. Turner, Désirée B.M. Van Der Werff, Renee T.M. Wensing, Erik Ephraim, Claire Nolte, Tore Reikvam, Ole Fredrik Lund, Lene Skaaden, Kari Marthe Ballovarre, Wenche Bakken Boerke, Guro Grindheim, Pal H H Lindenskov, Anne Beate Solas, Sjur Sponheim, Kyrre Ullensvang, Oddbjorn Viken, Inger Marie Drage, Kasper Gymoese Berthelsen, Bjørn Anders Kroken, Unni Bergland, Miroslaw Pryzmont, Mariola Talalaj, Malgorzata Wasiluk, Dorota Zalewska, Maria Damps, Jadzia Siemek-Mitela, Pawel Wieczorek, Magdalena Juzwa, Jowita Rosada-Kurasinska, Alicja Bartkowska-Sniatkowska, Maciej Cettler, Renata Kopycinska, Iwona Rudewicz, Jaek Sobczyk, Dariusz Wojciechowski, Artur Baranowski, Ewa Basiewicz, Magdalena Mierzewska-Schmidt, Wlodzimierz Retka, Piotr Sawicki, Magdalena Checinska, Magdalena Zurawska, Teresa Leal, Catia Mascarenhas, António Pedro Pina, Maria Joao Susano, Antonio Moniz, Maria Teresa Rocha, Carolina Calvao Santos, M Domingas Patuleia, Ricardo Pereira, Helena Roxo, Rosa Amaral, Isabel Guedes, Cristina Gomes, Marta Gonçalves, Helena Salgado, Maria Santos, Sara Rodrigues, Angela Sa, Elvira Machado, Sandra Pé d'Arca, Manuel Seabra, Ligia Mihaela Gheorghe, Constantin Ivascu, Lucia Moraru-Draghici, Mirela Suvejan, Remus Babici, Kovacs Eniko, Cristiana Hogea, Dubau Mihaela, Daraban Nicoleta, Danut Barbunc, Alina Maria Nistor, Violeta Stefan, Gabriela Catalina Ionescu, Irina Davidescu, Alina Teodora Nastase, Florin Dumitru Rusu, Victoria Badarau, Iulia Cindea, Melania Moscaliuc, Dana Olteanu, Luxita Petrescu, Daniela Ceuca, Irena Galinescu, Rodica Badeti, Alin Capusan, Cosmina Cucui-Cozma, Barbura Popescu, Luminita Cimpeanu, Mihaela-Petronela Birliba, Magdalena Miulescu, Stefania Balamat, Adriana Gurita, Luminita Ilie, Gabriel Mocioiu, Darina Pick, Rodica Sirghie, Radu Tabacaru, Irinel Trante, Lucian Horhota, Daniela Bandrabur, Tudor Ciobanu, Veaceslav Cuciuc, Valentin Munteanu, Valentin Olaru, Corneliu Paiu, Anca Savu, Oana Trifan, Anca Elena Malos, Anton Glazunov, Alexander Ivanov, Evgeny Poduskov, Alexander Popov, Igor Guskov, Alexander Lugovoy, Vladislav Nechaev, Alexey Ovezov, Mikhail Basov, Vladimir Kochkin, Vladimir Lazarev, Dmitri Chizhov, Ivan Ostreikov, Konstantin Tolasov, Ivana Budic, Vesna Marjanovic, Biljana Draskovic, Marina Pandurov, Jovana Simin, Vladimir Dolinaj, Dusanka Janjevic, Ana Mandras, Maja Mircetic, Sladjana Petrovic, Vlatka Rebac, Bojana Slavkovic, Vesna Stevanovic, Ana Velcev, Mirjana Knezevic, Irina Milojevic, Selena Puric, Irena Simic, Marija Stevic, Vladimir Stranjanac, Dusica Simic, Barbora Cabanova, Miloslav Hanula, Andry Grynyuk, Jelena Berger, Uros Cerne, Andraz Nastran, Dejan Pirc, Rok Popic, Spela Stupnik, Paloma Rubio, Cristina del Río, Pilar Benito, Gema Pino, Ignacio Gutierrez, Andrea Gutierrez Valcarcel, Irene León Carsi, Anibal Perez Garcia, Sílvia López Galera, Joan Marco Valls, Laura Ricol Lainez, Andrea Vallejo Tarrat, David Artes, Ester Banus, Luca Chirichiello, Leidy De Abreu, Belen De Josemaria, M Helena Gaitan, Antonio Garces, Juan J Lazaro, Ferran Manen Berga, Dolors Molies, Enric Monclus, Montserrat Navaro, Carmen Pamies, Marina Perelló, Mar Prat, Laura Ribo, M Angeles Sanz, Silvia Serrano, Eva Sola Ruiz, Blanca Anuncia Escontrela Rodríguez, Andrea Maria Gago Martinez, Alberto Martínez Ruiz, Fausto De La Cruz Benito, Gustavo Gabilondo Garcia, Ever Martinez Maldonado, Bryant Noriega, Lara Oller Duque, Alberto Olmos Mendez, Antonio Perez- Ferrer, Francisco Reinoso Barbero, Ismael Acevedo Bambaren, Fernando Domínguez, Teresa Franco, Anabel Jiménez, Alicia Melero, Montserrat Feliu, Irene García, Núria Montferrer, Francisca Munar, Cristina Muro, Rosario Nuño, Remel Perera, Erika Schmucker, Glenda Börjesson, Lars Gillberg, Albert Castellheim, Kerstin Sandström, Annette Bauer, Torbjörn Roos, Lars Hedlund, Yann Boegli, Mirko Dolci, Carine Marcucci, Isabelle Spahr-Schopfer, Michel Pellegrini, Malte Book, Loreen Errass, Christine Riggenbach, Mattias Casutt, Martin Hölzle, Thomas Hurni, Jacqueline Mauch, Luciano Anselmi, Irene Anselmi, Alfred Jacomet, Markus Oberhauser, Stephanie Wossner, Angelika Zettl, Thomas Erb, Tomasz Mackiewicz, Helena Simitzes, Yetkin Ozer, Arzu Takil, Zekeriyya Alanoglu, Onat Bermede, K.Sanem Cakar Turhan, Neslihan Alkis, Cigdem Yildirim Guclu, Basak Ceyda Meco, Zehra Hatipoglu, Dilek Ozcengiz, Zekine Begec, Huseyin Ilksen Toprak, Pinar Kendigelen, Ayse Cigdem Tütüncü, Meltem Savran Karadeniz, Tulay Seyhan Ozkan, Nuket Sivrikoz, Mustafa Kemal Arslantas, Ayse Hizal, Gülbin Tore Altun, Tumay Umuroglu, Sibel Baris, Zuleyha Kazak Bengisun, Galyna Goncharenko, Maksym Khrapak, Tetyana Klymenko, Vitaliy Pavlenko, Dmytro Prysiazhniuk, Olga Rudio, Mykhailo Varyvoda, Sergii Vodianytskyi, Ivanna Boryshkevych, Iryna Kyselova, Nikolay Trikash, Andrew Albokrinov, Valentina Perova-Sharonova, Vitaliy Sklyar, Denis Surkov, Amr Abdelaal, Nicola Barber, Sarah Checuti, Leisha Godsiff, Lynch Johanne, Joanna Simpson, Helen Underhill, Rishi Diwan, Nivedita Kelgeri, Nuria Masip, Radha Ravi, Steve Roberts, Annagrazia 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Sanem, Alkis, Neslihan, Yildirim Guclu, Cigdem, Ceyda Meco, Basak, Hatipoglu, Zehra, Ozcengiz, Dilek, Begec, Zekine, Ilksen Toprak, Huseyin, Kendigelen, Pinar, Cigdem Tütüncü, Ayse, Karadeniz, Meltem Savran, Seyhan Ozkan, Tulay, Sivrikoz, Nuket, Kemal Arslantas, Mustafa, Hizal, Ayse, Tore Altun, Gülbin, Umuroglu, Tumay, Baris, Sibel, Kazak Bengisun, Zuleyha, Goncharenko, Galyna, Khrapak, Maksym, Klymenko, Tetyana, Pavlenko, Vitaliy, Prysiazhniuk, Dmytro, Rudio, Olga, Varyvoda, Mykhailo, Vodianytskyi, Sergii, Boryshkevych, Ivanna, Kyselova, Iryna, Trikash, Nikolay, Albokrinov, Andrew, Perova Sharonova, Valentina, Sklyar, Vitaliy, Surkov, Deni, Abdelaal, Amr, Barber, Nicola, Checuti, Sarah, Godsiff, Leisha, Johanne, Lynch, Simpson, Joanna, Underhill, Helen, Diwan, Rishi, Kelgeri, Nivedita, Masip, Nuria, Ravi, Radha, Roberts, Steve, Cillis, Annagrazia, Marcus, Ritchie, Merella, Federica, Love, David, Baraggia, Paolo, Bird, Victoria, Hussey, Joseph, Alderson, Peter, Bartholomew, Karen, Moncreiff, Michael, Davidson, Sarah, Hare, Alison, Kotecha, Ami, Lee, Corina, Liyanage, Ganga, Patel, Shivali, Samani, Amee, Abou Samra, Mark, Boyd, Matthew, Hullatt, Laurence, Levy, David, Pauling, Mark, Sharman, Sarah Jane, Smith, Natalie, Rutherford, John, Cavalier, Alison, Locke, Christie, Sage, Frederic, Bapat, Smita, Hammerschlag, Jacinda, Ioannou, Ioanni, King, Stephanie, Pegg, Rachel, Salota, Vishal, Sketcher, Jonathan, Thadsad, Muthu, Zeitlin, Deborah, Jack, Ewan, Lang, Colin, Ahmed, Samira, Ayyash, Reema, Bari, Francoise, Bell, Sarah J, Elizabeth Biercamp, Claire, Briggs, Sandra, Gabriella Elena Clement, Maria, Dalton, Mark, Ali Eissa Eid, Mohamed, Gandhi, Monica, Harmen Herrema, Idse, Khaffaf, Ranj, Jeng Min Law, Savio, Mcclintock, Joanna, Ireland, Nichola, Majid Saleem, Mohammed, Smith, Fiona, Cohen, Marc, Lee, Clover Ann, O'Donahue, Lizanne, Powell, Alex, Rawlinson, Ellen, Snoek, Aarjan, Weiss, Katja, Wellesley, Hugo, Crawford, Michael, Abdel Hafiz, Mostafa, Day, Alexandra, Rajamani, Balaji, Saha, Rita, Wright, Dave, Chee, Lew Chin, Bew, Stephanie, Homer, Rachel, Malarkkan, Nalini, Wolfe Barry, Juliet, Angadi, Pradeep, Cagney, Brid, De Melo, Eric, Dekker, Elsa, Helm, Emma, Jones, Gareth, Peiris, Kawshala, Russell, William, Slater, Patricia, Sodhi, Puja, Browning, Mike, Phillips, Trudie, Van Hecke, Rachel, Muir, Vimty, Singh, Piyush, Soskova, Tereza, Cumming, Craig, Farquharson, Pamela, Pearson, Karen, Shaw, Neil, Whiteside, Jonathan, Whyte, Emma, Byers, Gordon, Davies, Kay, Engelhardt, Thoma, Faliszewski, Isabella, Johnston, Graham, Kaufmann, Nil, Kusnirikova, Zuzana, Wilson, Graham, Carachi, Peter, Makin, Andrew, Foster, Brian, Lipczynski, Dariusz, Mawer, Rebecca, Rutherford, William, Rogerson, David, Rushman, Sarah, Taylor, Christopher, Tomlinson, William, Dix, Philippa, Woodward, Tom, Bell, Graham, Boyle, David, Cloherty, Marianne, Cullen, Julia, Cullen, Pauline, Fairgrieve, Ro, Ghent, Robert, Glasgow, Russell, Gordeeva, Elena, Harden, Alison, Hivey, Sarah, Jerome, Kevin, Mckee, Lesley, Morton, Neil, Pribul, Vicky, Sinclair, John, Steiner, Maria, Steward, Heather, Sweeney, Lorraine, Thomson, Wendy, Whiteside, Jeanette, Dalton, Andrew, Ross, Mark, Smith, Carolyn, Allen, Claire, Anders, Nicola, Barlow, Victoria, Bassett, Mike, Darwin, Leanne, Davison, Rachel, Diacono, Jacque, Hobbs, Amy, Hutchinson, Adel, Lomas, Bernadette, Lonsdale, Hannah, Nasser, Leila, Oshan, Vimmi, Patel, Pradip, Raistrick, Christopher, Scott Warren, Victoria, Talbot, Laura, Wai, Carolynn, Childs, Sophie, Dickinson, Matthew, Bloomfield, Tom, Garrioch, Sweyn, Watson, Karen, Gaynor, Jame, Harrison, Richard, Lee, Juliette, Blythe, Elizabeth, Dorman, Teresa, Eissa, Ayman, Ellwood, Jame, Gooch, Ingrid, Hearn, Robert, Hodgetts, Vanessa, John, Robert, Kirton, Christine, Ladak, Nadia, Morgan, Judith, Plant, Nina, Shepherd, Elizabeth, Short, Judith, Stack, Charle, Steel, Simon, Taylor, Matthew, Thomas, Deborah, Wilson, Catharine, Wilson Smith, Elaine, Bradbury, Carol L., Hussain, Nageena, Mayell, Antonia, Mesbah, Ahmed, Qureshi, Arif, Vaidyanath, Chandra, Geary, Tim, Hawksworth, Chri, Parasuraman, Tamaraichelvi, Perry, Nicole, Banerjee, Indrani, Barr, Katharine, Butler, Patrick, Davies, Jack, Flewin, Lisa, Gande, Richard, Montague, Jame, Plumb, Jame, Pratt, Thoma, Sutherland, Paul, Vail, Hannah, Wilkins, Andrew, Hunter, Catherine, Russell, Susan, Thomas, Alun, Mifsud, Mark, Strachan, Dominic, Plichon, Benoit, Harlet, Pierre, Child and Adolescent Psychiatry / Psychology, Morawk-Wintersperger, Ulrike, Seidel-Ahyai, Natascha, Lechat, Jean-Paul, Kesic-Valpotic, Gordana, Ilmoja, Mari-Lii, Nouette-Gaulain, Karine, Gagey, Anne-Charlotte, Carre, Anne-Charlotte, Riche, Jean-Claude, Verchere-Montmayeur, Juliette, Julien-Marsollier, Florence, Saour, Anne-Charlotte, Jetzek-Zader, Martin, Meyer-Treschan, Tanja, Preussler, Niels-Peter, Sidlovskaite-Baltake, Dominika, van Stijn, Mireille F M, Dons-Sinke, Ilse, van der Knijff - van Dortmont, Anouk, Hopman, Geranne A.J., Megens, A.M., Schouten, Anton N.J., Van Der Werff, Désirée B.M., Wensing, Renee T.M., Lindenskov, Pal H H, Siemek-Mitela, Jadzia, Rosada-Kurasinska, Jowita, Bartkowska-Sniatkowska, Alicja, Mierzewska-Schmidt, Magdalena, Moraru-Draghici, Lucia, Cucui-Cozma, Cosmina, Birliba, Mihaela-Petronela, Perez- Ferrer, Antonio, Spahr-Schopfer, Isabelle, Cakar Turhan, K.Sanem, Perova-Sharonova, Valentina, Abou-Samra, Mark, Sharman, Sarah-Jane, McClintock, Joanna, Lee, Clover-Ann, Abdel-Hafiz, Mostafa, Chee, Lew-Chin, McKee, Lesley, Scott-Warren, Victoria, and Wilson-Smith, Elaine

Subjects
Male, Pediatrics, Health Status, OPERATING-ROOM, Respiratory Tract Diseases, CHILDREN, 0302 clinical medicine, REGIONAL ANESTHESIA, Postoperative Complications, 030202 anesthesiology, CARDIAC-ARREST, Medicine, General anaesthesia, Prospective Studies, Prospective cohort study, Child, Intraoperative Complications, COMPLICATIONS, ddc:617, Incidence (epidemiology), Mortality rate, musculoskeletal, neural, and ocular physiology, Incidence, Age Factors, Hospitals, Europe, Cardiovascular Diseases, Child, Preschool, RESPIRATORY ADVERSE EVENTS, Female, Clinical Competence, Cohort study, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Adolescent, macromolecular substances, Anesthesia, General, Drug Hypersensitivity, 03 medical and health sciences, MORBIDITY, Journal Article, Humans, business.industry, Infant, Newborn, Infant, 030208 emergency & critical care medicine, Perioperative, nervous system, PROSPECTIVE COHORT, Relative risk, RISK-FACTORS, Observational study, Human medicine, Nervous System Diseases, business, SYSTEM
Abstract

Background Little is known about the incidence of severe critical events in children undergoing general anaesthesia in Europe. We aimed to identify the incidence, nature, and outcome of severe critical events in children undergoing anaesthesia, and the associated potential risk factors. Methods The APRICOT study was a prospective observational multicentre cohort study of children from birth to 15 years of age undergoing elective or urgent anaesthesia for diagnostic or surgical procedures. Children were eligible for inclusion during a 2-week period determined prospectively by each centre. There were 261 participating centres across 33 European countries. The primary endpoint was the occurence of perioperative severe critical events requiring immediate intervention. A severe critical event was defined as the occurrence of respiratory, cardiac, allergic, or neurological complications requiring immediate intervention and that led (or could have led) to major disability or death. This study is registered with ClinicalTrials.gov, number NCT01878760. Findings Between April 1, 2014, and Jan 31, 2015, 31 127 anaesthetic procedures in 30 874 children with a mean age of 6·35 years (SD 4·50) were included. The incidence of perioperative severe critical events was 5·2% (95% CI 5·0–5·5) with an incidence of respiratory critical events of 3·1% (2·9–3·3). Cardiovascular instability occurred in 1·9% (1·7–2·1), with an immediate poor outcome in 5·4% (3·7–7·5) of these cases. The all-cause 30-day in-hospital mortality rate was 10 in 10 000. This was independent of type of anaesthesia. Age (relative risk 0·88, 95% CI 0·86–0·90; p

Published
2017
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8. A quantitative assessment of glutamate uptake into hippocampal synaptic terminals and astrocytes: New insights into a neuronal role for excitatory amino acid transporter 2 (EAAT2)

Author

A.Q. Akhtar, David Attwell, Yun Zhou, Knut P. Lehre, David N. Furness, Kyrre Ullensvang, Vidar Gundersen, Marcin W. Wojewodzic, Martine Hamann, Nina Julie Grutle, Silvia Holmseth, David J. Rossi, Niels C. Danbolt, and Yvette Dehnes

Subjects
Male, Synaptic cleft, Presynaptic Terminals, Glutamic Acid, Neurotransmission, Hippocampal formation, Biology, Hippocampus, Article, Substrate Specificity, Mice, chemistry.chemical_compound, medicine, Animals, Rats, Wistar, Microscopy, Immunoelectron, Neurotransmitter, Mice, Knockout, Aspartic Acid, General Neuroscience, Cell Membrane, Glutamate receptor, Immunohistochemistry, Rats, Cell biology, Microscopy, Electron, medicine.anatomical_structure, Excitatory Amino Acid Transporter 2, nervous system, Biochemistry, chemistry, Astrocytes, NMDA receptor, Electrophoresis, Polyacrylamide Gel, Neurotransmitter transport, Neuroglia, Synaptosomes, Astrocyte
Abstract

The relative distribution of the excitatory amino acid transporter 2 (EAAT2) between synaptic terminals and astroglia, and the importance of EAAT2 for the uptake into terminals is still unresolved. Here we have used antibodies to glutaraldehyde-fixed D-aspartate to identify electron microscopically the sites of D-aspartate accumulation in hippocampal slices. About 3/4 of all terminals in the stratum radiatum CA1 accumulated D-aspartate-immunoreactivity by an active dihydrokainate-sensitive mechanism which was absent in EAAT2 glutamate transporter knockout mice. These terminals were responsible for more than half of all D-aspartate uptake of external substrate in the slices. This is unexpected as EAAT2-immunoreactivity observed in intact brain tissue is mainly associated with astroglia. However, when examining synaptosomes and slice preparations where the extracellular space is larger than in perfusion fixed tissue, it was confirmed that most EAAT2 is in astroglia (about 80%). Neither D-aspartate uptake nor EAAT2 protein was detected in dendritic spines. About 6% of the EAAT2-immunoreactivity was detected in the plasma membrane of synaptic terminals (both within and outside of the synaptic cleft). Most of the remaining immunoreactivity (8%) was found in axons where it was distributed in a plasma membrane surface area several times larger than that of astroglia. This explains why the densities of neuronal EAAT2 are low despite high levels of mRNA in CA3 pyramidal cell bodies, but not why EAAT2 in terminals account for more than half of the uptake of exogenous substrate by hippocampal slice preparations. This and the relative amount of terminal versus glial uptake in the intact brain remain to be discovered.

Published
2008
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9. The Glutamate Transporter EAAT4 in Rat Cerebellar Purkinje Cells: A Glutamate-Gated Chloride Channel Concentrated near the Synapse in Parts of the Dendritic Membrane Facing Astroglia

Author

Jon Storm-Mathisen, Niels C. Danbolt, Kyrre Ullensvang, Yvette Dehnes, Knut P. Lehre, and Farrukh A. Chaudhry

Subjects
Cerebellum, Excitatory Amino Acid Transporter 4, Amino Acid Transport System X-AG, Purkinje cell, Excitatory Amino Acid Transporter 3, Immunoblotting, Molecular Sequence Data, Glutamic Acid, Cell Communication, Glutamate Plasma Membrane Transport Proteins, Article, Purkinje Cells, Antibody Specificity, Chloride Channels, medicine, Glutamate aspartate transporter, Animals, Amino Acid Sequence, Rats, Wistar, Microscopy, Immunoelectron, Neurotransmitter Agents, biology, Symporters, Tissue Embedding, Aldolase C, General Neuroscience, Glutamate receptor, Biological Transport, Dendrites, Immunohistochemistry, Rats, Excitatory Amino Acid Transporter 1, medicine.anatomical_structure, Biochemistry, Excitatory Amino Acid Transporter 2, Receptors, Glutamate, Astrocytes, Synapses, biology.protein, Biophysics, ATP-Binding Cassette Transporters, Rabbits, Carrier Proteins
Abstract

Antibodies to an excitatory amino acid transporter (EAAT4) label a glycoprotein of ∼65 kDa strongly in the cerebellum and weakly in the forebrain. Cross-linking of cerebellar proteins with bis(sulfosuccinimidyl) suberate before solubilization causes dimer bands of EAAT4 and both dimer and trimer bands of the other glutamate transporters GLAST (EAAT1) and GLT (EAAT2) to appear on immunoblots. In contrast to GLAST, GLT, and EAAC (EAAT3), EAAT4 is unevenly distributed in the cerebellar molecular layer, being strongly expressed in parasagittal zones. It is located in cerebellar Purkinje cells, and the highest concentrations are seen in ones expressing high levels of zebrin II (aldolase C). The labeling of Purkinje cell spines and thin dendrites is stronger than that of large diameter dendrites and cell bodies. EAAT4 is present at low concentrations in the synaptic membrane, but is highly enriched in the parts of the dendritic and spine membranes facing astrocytes (which express GLAST and GLT) compared with parts facing neuronal membranes, suggesting a functional relationship with glial glutamate transporters. The presence of EAAT4 in intracellular cisterns and multivesicular organelles may reflect turnover of transporter in the plasma membrane. The total Purkinje cell spine surface and the EAAT4 concentration were found to be 1.1 m2/cm3and 0.2 mg/cm3, respectively, in the molecular layer, corresponding to 1800 molecules/μm2. The juxtasynaptic location of EAAT4 may explain electrophysiological observations predicting the presence of a neuronal glutamate transporter near the release site at a Purkinje cell spine synapse. EAAT4 may function as a combined transporter and inhibitory glutamate receptor.

Published
1998

10. Brain glutamate transporter proteins form homomultimers

Author

Tage Honore, Kyrre Ullensvang, M. Nielsen, Knut P. Lehre, Farrukh A. Chaudhry, Niels C. Danbolt, Line M. Levy, and Øyvind Haugeto

Subjects
Macromolecular Substances, Amino Acid Transport System X-AG, Excitatory Amino Acid Transporter 3, Molecular Sequence Data, Excitotoxicity, Glutamate Plasma Membrane Transport Proteins, medicine.disease_cause, Transfection, Biochemistry, Oligomer, Hippocampus, Antibodies, Chromatography, Affinity, chemistry.chemical_compound, medicine, Animals, Humans, Amino Acid Sequence, Rats, Wistar, Microscopy, Immunoelectron, Molecular Biology, Gel electrophoresis, Cerebral Cortex, biology, SLC1A2, Brain, Transporter, Dose-Response Relationship, Radiation, Cell Biology, Peptide Fragments, Recombinant Proteins, Rats, Molecular Weight, Kinetics, Membrane, chemistry, Astrocytes, biology.protein, ATP-Binding Cassette Transporters, Female, Particle Accelerators, Protein Multimerization, HeLa Cells
Abstract

Removal of excitatory amino acids from the extracellular fluid is essential for synaptic transmission and for avoiding excitotoxicity. The removal is accomplished by glutamate transporters located in the plasma membranes of both neurons and astroglia. The uptake system consists of several different transporter proteins that are carefully regulated, indicating more refined functions than simple transmitter inactivation. Here we show by chemical cross-linking, followed by electrophoresis and immunoblotting, that three rat brain glutamate transporter proteins (GLAST, GLT and EAAC) form homomultimers. The multimers exist not only in intact brain membranes but also after solubilization and after reconstitution in liposomes. Increasing the cross-linker concentration increased the immunoreactivity of the bands corresponding to trimers at the expense of the dimer and monomer bands. However, the immunoreactivities of the dimer bands did not disappear, indicating a mixture of dimers and trimers. GLT and GLAST do not complex with each other, but as demonstrated by double labeling post-embedding electron microscopic immunocytochemistry, they co-exist side by side in the same astrocytic cell membranes. The oligomers are held together noncovalently in vivo. In vitro, oxidation induces formation of covalent bonds (presumably -S-S-) between the subunits of the oligomers leading to the appearance of oligomer bands on SDS-polyacrylamide gel electrophoresis. Immunoprecipitation experiments suggest that GLT is the quantitatively dominant glutamate transporter in the brain. Radiation inactivation analysis gives a molecular target size of the functional complex corresponding to oligomeric structure. We postulate that the glutamate transporters operate as homomultimeric complexes.

Published
1996

11. The competitive transport inhibitor L-trans-pyrrolidine-2, 4-dicarboxylate triggers excitotoxicity in rat cortical neuron-astrocyte co-cultures via glutamate release rather than uptake inhibition

Author

Niels C. Danbolt, Kyrre Ullensvang, Giorgio Racagni, Barbara Lodi Rizzini, Andrea Volterra, Davide Trotti, and Paola Bezzi

Subjects
Patch-Clamp Techniques, Pyrrolidines, Cell Survival, Excitotoxicity, Glutamic Acid, Tetrodotoxin, Biology, Neurotransmission, medicine.disease_cause, Binding, Competitive, medicine, Animals, Dicarboxylic Acids, Neurotransmitter Uptake Inhibitors, Neurons, General Neuroscience, Glutamate receptor, Biological Transport, Stereoisomerism, Transport inhibitor, Coculture Techniques, Rats, medicine.anatomical_structure, Biochemistry, Metabotropic glutamate receptor, Astrocytes, glutamate transporter, secretion, astrocytes, Biophysics, Excitatory postsynaptic potential, NMDA receptor, Calcium, Neuroglia, Astrocyte
Abstract

We studied the early and late effects of L-trans-pyrrolidine-2,4-dicarboxylate (PDC), a competitive inhibitor of glutamate uptake with low affinity for glutamate receptors, in co-cultures of rat cortical neurons and glia expressing spontaneous excitatory amino acid (EAA) neurotransmission. At 100 or 200 microM, PDC induced different patterns of electrical changes: 100 microM prolonged tetrodotoxin-sensitive excitation triggered by synaptic glutamate release; 200 microM produced sustained, tetrodotoxin-insensitive and EAA-mediated neuronal depolarization, overwhelming synaptic activity. At 200 microM, but not at 100 microM, PDC caused rapid elevation of the glutamate concentration ([Glu]o) in the culture medium, resulting in NMDA receptor-mediated excitotoxic death of neurons 24 h later. The increase in [Glu]o was largely insensitive to tetrodotoxin, independent of extracellular Ca2+, and present also in astrocyte-pure cultures. By the use of glutamate transporters functionally reconstituted in liposomes, we showed directly that PDC activates carrier-mediated release of glutamate via heteroexchange. Glutamate release and delayed neurotoxicity in our cultures were suppressed if PDC was applied in a Na(+)-free medium containing Li+. However, replacement of Na+ with choline instead of Li+ did not result in an identical effect, suggesting that Li+ does not act simply as an external Na+ substitute. In conclusion, our data indicate that alteration of glutamate transport by PDC has excitotoxic consequences and that active release of glutamate rather than just uptake inhibition is responsible for the generation of neuronal injury.

Published
1996

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