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Stephen Bruinsma, Declan J James, Melanie Quintana Serrano, Joseph Esquibel, Sang Su Woo, Elle Kielar-Grevstad, Ellen Crummy, Rehan Qurashi, Judy A Kowalchyk, Thomas F J Martin
Ca2+ -dependent secretory granule fusion with the plasma membrane is the final step for the exocytic release of inflammatory mediators, neuropeptides, and peptide hormones. Secretory cells use a similar protein machinery at late steps in the regulated secretory pathway, employing protein isoforms from the Rab, Sec1/Munc18, Munc13/CAPS, SNARE, and synaptotagmin protein families. However, no small-molecule inhibitors of secretory granule exocytosis that target these proteins are currently available but could have clinical utility...
May 25, 2018: Journal of Biological Chemistry
Jakob Hessel Andersen, Pia Jaeger, Tobias Laier Sonne, Jørgen Berg Dahl, Ole Mathiesen, Ulrik Grevstad
BACKGROUND: Clonidine used as an adjuvant to ropivacaine have been shown to prolong the duration of peripheral nerve blocks. The mechanism of action remains unclear. We hypothesized, that clonidine used as an adjuvant to ropivacaine extends the duration of an adductor canal block (ACB) by a peripheral mechanism, compared to ropivacaine alone when controlling for systemic effects. METHODS: We conducted a paired, blinded, randomized trial in healthy volunteers. Participants received bilateral ACBs containing 20 ml ropivacaine 0...
2017: PloS One
P Jæger, U Grevstad, Z J Koscielniak-Nielsen, A R Sauter, J K Sørensen, J B Dahl
BACKGROUND: Dexamethasone prolongs block duration. Whether this is achieved via a peripheral or a central mechanism of action is unknown. We hypothesized that perineural dexamethasone added as an adjuvant to ropivacaine prolongs block duration compared with ropivacaine alone, by a locally mediated effect when controlled for a systemic action. METHODS: We performed a paired, blinded, randomized trial, including healthy men. All subjects received bilateral blocks of the saphenous nerve with ropivacaine 0...
November 2016: British Journal of Anaesthesia
Jakob H Andersen, Ulrik Grevstad, Hanna Siegel, Jørgen B Dahl, Ole Mathiesen, Pia Jæger
BACKGROUND: Dexmedetomidine used as an adjuvant to local anesthetics may prolong the duration of peripheral nerve blocks. Whether this is mediated by a perineural or systemic mechanism remains unknown. The authors hypothesized that dexmedetomidine has a peripheral mechanism of action. METHODS: The authors conducted a randomized, paired, triple-blind trial in healthy volunteers. All received bilateral saphenous nerve blocks with 20 ml ropivacaine, 0.5%, plus 1 ml dexmedetomidine, 100 µg/ml, in one thigh and 20 ml ropivacaine 0...
January 2017: Anesthesiology
Pia Jæger, Zbigniew J Koscielniak-Nielsen, Karen Lisa Hilsted, Ulrik Grevstad, Volkert Siersma, Maria Louise Fabritius, Jørgen Berg Dahl
BACKGROUND: The binary aims of this study were to investigate the effect of total dose of lidocaine on duration of an adductor canal block (ACB) and to validate different methods used to assess nerve blocks. METHODS: We performed 2 blinded, randomized, controlled crossover trials, including healthy, young men. In study 1, 14 subjects received 4 ACBs with saline and 40, 80, and 160 mg lidocaine. In study 2, 14 new subjects received 2 ACBs with 100 and 300 mg lidocaine...
October 2016: Anesthesia and Analgesia
Ulrik Grevstad, Pia Jæger, Johan Kløvgaard Sørensen, Bo Gottschau, Brian Ilfeld, Martin Ballegaard, Mike Hagelskjaer, Jørgen Berg Dahl
BACKGROUND: Single-injection adductor canal block (ACB) provides analgesia after knee surgery. Which nerves that are blocked by an ACB and what influence-if any-local anesthetic volume has on the effects remain undetermined. We hypothesized that effects on the nerve to the vastus medialis muscle (which besides being a motor nerve innervates portions of the knee) are volume-dependent. METHODS: In this assessor- and subject-blinded randomized trial, 20 volunteers were included...
August 2016: Anesthesia and Analgesia
Ø Jans, U Grevstad, H Mandøe, H Kehlet, P I Johansson
BACKGROUND: Total hip arthroplasty (THA) is associated with both intraoperative and postoperative blood loss resulting in anaemia and, in some patients, transfusion of red blood cells. Epinephrine enhances coagulation by several mechanisms. We evaluated the effect of intraoperative low dose infusion of epinephrine on intraoperative and early postoperative blood loss. METHODS: After consent, 106 subjects undergoing THA under spinal anaesthesia were randomly assigned to receive an i...
March 2016: British Journal of Anaesthesia
Greg Kabachinski, D Michelle Kielar-Grevstad, Xingmin Zhang, Declan J James, Thomas F J Martin
The Ca(2+)-dependent exocytosis of dense-core vesicles in neuroendocrine cells requires a priming step during which SNARE protein complexes assemble. CAPS (aka CADPS) is one of several factors required for vesicle priming; however, the localization and dynamics of CAPS at sites of exocytosis in live neuroendocrine cells has not been determined. We imaged CAPS before, during, and after single-vesicle fusion events in PC12 cells by TIRF micro-scopy. In addition to being a resident on cytoplasmic dense-core vesicles, CAPS was present in clusters of approximately nine molecules near the plasma membrane that corresponded to docked/tethered vesicles...
February 15, 2016: Molecular Biology of the Cell
Johan Kløvgaard Sørensen, Pia Jæger, Jørgen Berg Dahl, Bo Gottschau, Snorre Læssøe Stephensen, Ulrik Grevstad
BACKGROUND: Using peripheral nerve block after total knee arthroplasty (TKA), without impeding mobility, is challenging. We hypothesized that the analgesic effect of adductor canal block (ACB) could increase the maximum voluntary isometric contraction (MVIC) of the quadriceps femoris muscle after TKA. METHODS: We included 64 patients on the first postoperative day. Group A received an ACB with 30 mL ropivacaine 0.75% at t0 and with 30 mL saline 60 minutes later (t60)...
February 2016: Anesthesia and Analgesia
Fritzi S Grevstad, Leonard B Coop
A change in climate is known to affect seasonal timing (phenology) of the life stages of poikilothermic organisms whose development depends on temperature. Less understood is the potential for even greater disruption to the life cycle when a phenology shift exposes photoperiod-sensitive life stages to new day lengths. We present a conceptual framework and model to investigate the ways that photoperiod-cued diapause can interact with a change in climate or latitude to influence voltinism in poikilothermic organisms...
September 2015: Ecological Applications: a Publication of the Ecological Society of America
M Christensen, A H Sparre-Ulrich, B Hartmann, U Grevstad, M M Rosenkilde, J J Holst, T Vilsbøll, F K Knop
Treatment with liraglutide leads to weight loss. We investigated whether blood-to-cerebrospinal fluid (CSF) transfer of liraglutide occurs, and if so, whether it associates with clinical weight loss following liraglutide treatment in humans. We performed lumbar puncture and blood sampling in eight patients with type 2 diabetes (mean (range)): age 63 (54-79) years; actual body weight: 90 (75-118) kg treated with 1.8 mg liraglutide for 14 (5-22) months and with a treatment-induced weight loss of 8.4 (7-11) kg...
November 2015: International Journal of Obesity: Journal of the International Association for the Study of Obesity
Simon Hyttel-Sorensen, Adelina Pellicer, Thomas Alderliesten, Topun Austin, Frank van Bel, Manon Benders, Olivier Claris, Eugene Dempsey, Axel R Franz, Monica Fumagalli, Christian Gluud, Berit Grevstad, Cornelia Hagmann, Petra Lemmers, Wim van Oeveren, Gerhard Pichler, Anne Mette Plomgaard, Joan Riera, Laura Sanchez, Per Winkel, Martin Wolf, Gorm Greisen
OBJECTIVE: To determine if it is possible to stabilise the cerebral oxygenation of extremely preterm infants monitored by cerebral near infrared spectroscopy (NIRS) oximetry. DESIGN: Phase II randomised, single blinded, parallel clinical trial. SETTING: Eight tertiary neonatal intensive care units in eight European countries. PARTICIPANTS: 166 extremely preterm infants born before 28 weeks of gestation: 86 were randomised to cerebral NIRS monitoring and 80 to blinded NIRS monitoring...
January 5, 2015: BMJ: British Medical Journal
Ulrik Grevstad, Ole Mathiesen, Laura Staun Valentiner, Pia Jaeger, Karen Lisa Hilsted, Jørgen B Dahl
BACKGROUND AND OBJECTIVES: Total knee arthroplasty (TKA) is often associated with severe pain. Different regional anesthetic techniques exist, all with varying degrees of motor blockade. We hypothesized that pain relief provided by the adductor canal block (ACB) could increase functional muscle strength. METHODS: We included 50 TKA patients with severe movement-related pain; defined as having visual analog scale pain score of greater than 60 mm during active flexion of the knee...
January 2015: Regional Anesthesia and Pain Medicine
M Espelund, U Grevstad, P Jaeger, P Hölmich, L Kjeldsen, O Mathiesen, J B Dahl
BACKGROUND: The analgesic effect of the adductor canal block (ACB) after knee surgery has been evaluated in a number of trials. We hypothesized that the ACB would provide substantial pain relief to patients responding with moderate to severe pain after arthroscopic knee surgery. METHODS: Fifty subjects with moderate to severe pain after arthroscopic knee surgery were enrolled in this placebo-controlled, blinded trial. All subjects received two ACBs; an initial ACB with either 30 ml ropivacaine 7...
November 2014: Acta Anaesthesiologica Scandinavica
Pernille Kähler, Berit Grevstad, Thomas Almdal, Christian Gluud, Jørn Wetterslev, Søren Søgaard Lund, Allan Vaag, Bianca Hemmingsen
OBJECTIVE: To assess the benefits and harms of targeting intensive versus conventional glycaemic control in patients with type 1 diabetes mellitus. DESIGN: A systematic review with meta-analyses and trial sequential analyses of randomised clinical trials. DATA SOURCES: The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded and LILACS to January 2013. STUDY SELECTION: Randomised clinical trials that prespecified different targets of glycaemic control in participants at any age with type 1 diabetes mellitus were included...
August 19, 2014: BMJ Open
Kristiana Nikolova, Christian Gluud, Berit Grevstad, Janus C Jakobsen
BACKGROUND: Hepatitis C infection is a disease of the liver caused by the hepatitis C virus. The estimated number of chronically infected people with hepatitis C virus worldwide is about 150 million people. Every year, another three to four million people acquire the infection. Chronic hepatitis C is a leading cause of liver-related mortality and morbidity. It is estimated that around 5% to 20% of people with the infection will develop liver cirrhosis, which increases the risk of hepatocellular carcinoma and liver failure...
April 6, 2014: Cochrane Database of Systematic Reviews
U Grevstad, O Mathiesen, T Lind, J B Dahl
BACKGROUND: Total knee arthroplasty (TKA) is associated with varying degrees of pain. A considerable proportion (25-40%) of patients experience severe pain, despite a comprehensive multimodal analgesic regimen. We hypothesized that adductor canal block (ACB) would reduce pain in this patient category compared with placebo. METHODS: Fifty patients with severe pain, defined as having a visual analogue scale (VAS) pain score of >60 during active flexion of the knee on the first or the second postoperative day after TKA, were included in this randomized, double-blind, placebo-controlled trial...
May 2014: British Journal of Anaesthesia
Greg Kabachinski, Masaki Yamaga, D Michelle Kielar-Grevstad, Stephen Bruinsma, Thomas F J Martin
Phosphoinositides provide compartment-specific signals for membrane trafficking. Plasma membrane phosphatidylinositol 4,5-bisphosphate (PIP2) is required for Ca(2+)-triggered vesicle exocytosis, but whether vesicles fuse into PIP2-rich membrane domains in live cells and whether PIP2 is metabolized during Ca(2+)-triggered fusion were unknown. Ca(2+)-dependent activator protein in secretion 1 (CAPS-1; CADPS/UNC31) and ubMunc13-2 (UNC13B) are PIP2-binding proteins required for Ca(2+)-triggered vesicle exocytosis in neuroendocrine PC12 cells...
February 2014: Molecular Biology of the Cell
Leo Heyndrickx, Guillaume Stewart-Jones, Marianne Jansson, Hanneke Schuitemaker, Emma Bowles, Luigi Buonaguro, Berit Grevstad, Lasse Vinner, Katleen Vereecken, Joe Parker, Meghna Ramaswamy, Priscilla Biswas, Guido Vanham, Gabriella Scarlatti, Anders Fomsgaard
BACKGROUND: Ten to 30% of HIV-1 infected subjects develop broadly neutralizing antibodies (bNAbs) during chronic infection. We hypothesized that immunizing rabbits with viral envelope glycoproteins (Envs) from these patients may induce bNAbs, when formulated as a trimeric protein and in the presence of an adjuvant. METHODS: Based on in vitro neutralizing activity in serum, patients with bNAbs were selected for cloning of their HIV-1 Env. Seven stable soluble trimeric gp140 proteins were generated from sequences derived from four adults and two children infected with either clade A or B HIV-1...
2013: PloS One
Maria Luisa Visciano, Maria Tagliamonte, Guillaume Stewart-Jones, Leo Heyndrickx, Guido Vanham, Marianne Jansson, Anders Fomsgaard, Berit Grevstad, Meghna Ramaswamy, Franco M Buonaguro, Maria Lina Tornesello, Priscilla Biswas, Gabriella Scarlatti, Luigi Buonaguro
Trimeric soluble forms of HIV gp140 envelope glycoproteins represent one of the closest molecular structures compared to native spikes present on intact virus particles. Trimeric soluble gp140 have been generated by several groups and such molecules have been shown to induce antibodies with neutralizing activity against homologous and heterologous viruses. In the present study, we generated a recombinant trimeric soluble gp140, derived from a previously identified Ugandan A-clade HIV field isolate (gp14094UG018)...
2013: Journal of Translational Medicine
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