8 results
Effect of REL-1017 (Esmethadone) on Cholesterol, Triglycerides, PCSK9, and hs-CRP in a Phase 2a Double-Blind Randomized Trial in Patients with MDD
- Nicola Ferri, Marco Pappagallo, Sheetal Patel, Franco Folli, Sara De Martin, Maria Giovanna Lupo, Sergio Traversa, Paolo L. Manfredi
-
- Journal:
- CNS Spectrums / Volume 27 / Issue 2 / April 2022
- Published online by Cambridge University Press:
- 28 April 2022, pp. 246-247
-
- Article
-
- You have access Access
- Export citation
-
Background
Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of morbidity and mortality. Hyperlipidemia and vascular subinflammation play critical roles in the pathogenesis of atherosclerosis. Patients with Major Depressive Disorder (MDD) are at higher risk for ASCVD and current antidepressant therapies may carry ASCVD risks. REL-1017 is a novel NMDAR channel blocker which showed rapid, robust, and sustained antidepressant effects, currently in Phase 3 clinical trials for MDD.
MethodsWe analyzed total cholesterol (TC), triglycerides (TG), Proprotein Convertase Subtilisin/Kexin 9 (PCSK9), and high-sensitivity C-reactive protein (hs-CRP) from patients enrolled in a Phase-2, multicenter, randomized, double-blind, placebo-controlled, 7-day, 3-arm trial to assess safety, tolerability, pharmacokinetics, and efficacy of REL-1017. Patients were randomized in a 1:1:1 ratio to either placebo, REL-1017 25 mg QD, or REL-1017 50 mg QD. TC, TG, PCSK9, and hs-CRP levels were measured in patients at baseline, day 7 and day 14, 7 days after treatment discontinuation. 6 out of 21 (28% of patients), 6 out of 16 (37%), and 1 out of 19 (5%), were under statin therapy in the placebo, REL-1017 25 and 50 mg groups, respectively.
ResultsAt baseline, day 7, day 14 TC levels (mg/dL) were 117.8 ± 30.8, 124.7 ± 34.1, 114.2 ± 18.1; 123.7 ± 59.3, 119.0 ± 28.1, 115.1 ± 14.8; 113.9 ± 22.9, 118.6 ± 29.5, 115.8 ± 25.5 for placebo (n = 21), REL-1017 25 mg (n = 16) and REL-1017 50 mg (n = 19), respectively. Considering the subgroup not on statins, TC levels were 127.5 ± 28.6, 134.2 ± 35.0, 117.8 ± 14.8; 131.0 ± 71.7, 121.1 ± 32.9, 118.6 ± 15.4; 115.5 ± 22.1, 121.4 ± 27.1, 119.0 ± 21.9 for placebo (n = 15, 72% of patients), REL-1017 25 mg (n = 10, 63%) and REL-1017 50 mg (n = 18, 95%), respectively. TG were 57.0 ± 25.6, 55.7 ± 20.0, 58.0 ± 34.1; 62.7 ± 52.1, 56.0 ± 31.0, 59.5 ± 32.6; 48.5 ± 25.3, 50.2 ± 18.4, 55.1 ± 21.9 for placebo (n = 21), REL-1017 25 mg (n = 16) and REL-1017 50 mg (n = 19), respectively. Considering the group not on statins, TG were 52.9 ± 27.6, 55.7 ± 23.1, 51.3 ± 26.8; 70.6 ± 63.3, 57.6 ± 38.9, 65.2 ± 38.9; 47.4 ± 25.4, 48.9 ± 17.9, 52.6 ± 19.5 for placebo (n = 15), REL-1017 25 mg (n = 10), and REL-1017 50 mg (n = 18), respectively. Levels of PCSK9, a key player of LDL cholesterol levels, significantly (P < .05) increased from baseline to day 7 and did not further change by day 14 for placebo, with similar results for REL-1017 25 or 50 mg groups, suggesting fluctuations unrelated to treatment. A total of 30% of the patients had hs-CRP plasma levels higher than 2 mg/L, thus potentially associated with a higher incidence of CV events. However, 7 days of treatment with REL-1017 did not alter hs-CRP plasma levels, neither at 25 mg/day nor at 50 mg/day. In summary, REL-1017 of 25 or 50 mg for 7 days did not affect TC, TG, PCSK9 and hs-CRP levels.
ConclusionA 7-day treatment course with REL-1017 did not significantly alter TC, TG, PCSK9, or hs-CRP, suggesting the absence of detrimental effects on ASCVD risk. These data should be confirmed in longer and larger trials.
FundingRelmada Therapeutics, Inc.
Mechanisms of glyphosate resistance in common ragweed (Ambrosia artemisiifolia): patterns of absorption, translocation, and metabolism
- Holly P. Byker, Nadar Soltani, Scott J. Nissen, Todd A. Gaines, Philip E. Westra, Sara L. Martin, François J. Tardif, Darren E. Robinson, Mark B. Lawton, Peter H. Sikkema
-
- Journal:
- Weed Science / Volume 70 / Issue 2 / March 2022
- Published online by Cambridge University Press:
- 20 January 2022, pp. 151-159
-
- Article
-
- You have access Access
- Open access
- HTML
- Export citation
-
Glyphosate’s efficacy is influenced by the amount absorbed and translocated throughout the plant to inhibit 5-enolpyruvyl shikimate-3-phosphate synthase (EPSPS). Glyphosate resistance can be due to target-site (TS) or non–target site (NTS) resistance mechanisms. TS resistance includes an altered target site and gene overexpression, while NTS resistance includes reduced absorption, reduced translocation, enhanced metabolism, and exclusion/sequestration. The goal of this research was to elucidate the mechanism(s) of glyphosate resistance in common ragweed (Ambrosia artemisiifolia L.) from Ontario, Canada. The resistance factor for this glyphosate-resistant (GR) A. artemisiifolia biotype is 5.1. No amino acid substitutions were found at positions 102 or 106 of the EPSPS enzyme in this A. artemisiifolia biotype. Based on [14C]glyphosate studies, there was no difference in glyphosate absorption or translocation between glyphosate-susceptible (GS) and GR A. artemisiifolia biotypes. Radio-labeled glyphosate metabolites were similar for GS and GR A. artemisiifolia 96 h after application. Glyphosate resistance in this A. artemisiifolia biotype is not due to an altered target site due to amino acid substitutions at positions 102 and 106 in the EPSPS and is not due to the NTS mechanisms of reduced absorption, reduced translocation, or enhanced metabolism.
Definition of important early morbidities related to paediatric cardiac surgery
- Katherine L. Brown, Christina Pagel, Rhian Brimmell, Kate Bull, Peter Davis, Rodney C. Franklin, Aparna Hoskote, Natasha Khan, Warren Rodrigues, Sara Thorne, Liz Smith, Linda Chigaru, Martin Utley, Jo Wray, Victor Tsang, Andrew Mclean
-
- Journal:
- Cardiology in the Young / Volume 27 / Issue 4 / May 2017
- Published online by Cambridge University Press:
- 29 September 2016, pp. 747-756
-
- Article
-
- You have access Access
- Open access
- HTML
- Export citation
-
Background
Morbidity is defined as a state of being unhealthy or of experiencing an aspect of health that is “generally bad for you”, and postoperative morbidity linked to paediatric cardiac surgery encompasses a range of conditions that may impact the patient and are potential targets for quality assurance.
MethodsAs part of a wider study, a multi-disciplinary group of professionals aimed to define a list of morbidities linked to paediatric cardiac surgery that was prioritised by a panel reflecting the views of both professionals from a range of disciplines and settings as well as parents and patients.
ResultsWe present a set of definitions of morbidity for use in routine audit after paediatric cardiac surgery. These morbidities are ranked in priority order as acute neurological event, unplanned re-operation, feeding problems, the need for renal support, major adverse cardiac events or never events, extracorporeal life support, necrotising enterocolitis, surgical site of blood stream infection, and prolonged pleural effusion or chylothorax. It is recognised that more than one such morbidity may arise in the same patient and these are referred to as multiple morbidities, except in the case of extracorporeal life support, which is a stand-alone constellation of morbidity.
ConclusionsIt is feasible to define a range of paediatric cardiac surgical morbidities for use in routine audit that reflects the priorities of both professionals and parents. The impact of these morbidities on the patient and family will be explored prospectively as part of a wider ongoing, multi-centre study.
Contributors
-
- By Peter J. D. Andrews, Sandeep Ankolekar, Issam A. Awad, Omar Ayoub, Philip Bath, Jürgen Bardutzky, Alexander Beck, Patrícia Canhão, J. Ricardo Carhuapoma, Winward Choy, Mahua Dey, Rajat Dhar, Michael C. Diringer, Arnd Dörfler, Joshua R. Dusick, Justin A. Dye, Corina Epple, José M. Ferro, Reiner Fietkau, Anthony Frattalone, Philippe Gailloud, Oliver Ganslandt, Anil Gholkar, Philipp Gölitz, Barbara A. Gregson, Daniel Hanley, Thomas M. Hemmen, Dan Holmes, Hagen B. Huttner, Jennifer Jaffe, Olav Jansen, Eric Jüttler, Karl L. Kiening, Martin Köhrmann, Rainer Kollmar, Kara L. Krajewski, Joji B. Kuramatsu, Perttu J. Lindsberg, Andrew Losiniecki, Patrick Lyden, Neil A. Martin, Heinrich P. Mattle, A. David Mendelow, Patrick Mitchell, Daniel T. Nagasawa, Neeraj S. Naval, Jan-Oliver Neumann, Tim Nowe, Berk Orakcioglu, Soenke Peters, Sara Pitoni, François Proust, Adnan I. Qureshi, Martin Radvany, Elise Rowan, Tiina Sairanen, Oliver W. Sakowitz, Edgar Santos, Peter D. Schellinger, Stefan Schwab, Günter Seidel, Sabine Semrau, Louise Sinclair, Dimitre Staykov, Thorsten Steiner, Jeanne Teitelbaum, Wondwossen G. Tekle, Andreas W. Unterberg, Katayoun Vahedi, H. Bart van der Worp, Paul M. Vespa, Raghu Vindlacheruvu, Jens Witsch, Isaac Yang, Wendy C. Ziai, Mario Zuccarello, Klaus Zweckberger
- Edited by Stefan Schwab, Daniel Hanley, A. David Mendelow
-
- Book:
- Critical Care of the Stroke Patient
- Published online:
- 05 June 2014
- Print publication:
- 05 June 2014, pp viii-xii
-
- Chapter
- Export citation
GWAS of DNA Methylation Variation Within Imprinting Control Regions Suggests Parent-of-Origin Association
- Miguel E. Rentería, Marcel W. Coolen, Aaron L. Statham, R. Seong Min Choi, Wenjia Qu, Megan J. Campbell, Sara Smith, Anjali K. Henders, Grant W. Montgomery, Susan J. Clark, Nicholas G. Martin, Sarah E. Medland
-
- Journal:
- Twin Research and Human Genetics / Volume 16 / Issue 4 / August 2013
- Published online by Cambridge University Press:
- 03 June 2013, pp. 767-781
-
- Article
-
- You have access Access
- HTML
- Export citation
-
Imprinting control regions (ICRs) play a fundamental role in establishing and maintaining the non-random monoallelic expression of certain genes, via common regulatory elements such as non-coding RNAs and differentially methylated regions (DMRs) of DNA. We recently surveyed DNA methylation levels within four ICRs (H19-ICR, IGF2-DMR, KvDMR, and NESPAS-ICR) in whole-blood genomic DNA from 128 monozygotic (MZ) and 128 dizygotic (DZ) human twin pairs. Our analyses revealed high individual variation and intra-domain covariation in methylation levels across CpGs and emphasized the interaction between epigenetic variation and the underlying genetic sequence in a parent-of-origin fashion. Here, we extend our analysis to conduct two genome-wide screenings of single nucleotide polymorphisms (SNPs) underlying either intra-domain covariation or parent-of-origin-dependent association with methylation status at individual CpG sites located within ICRs. Although genome-wide significance was not surpassed due to sample size limitations, the most significantly associated SNPs found through multiple-trait genome-wide association (MQFAM) included the previously described rs10732516, which is located in the vicinity of the H19-ICR. Similarly, we identified an association between rs965808 and methylation status within the NESPAS-ICR. This SNP is positioned within an intronic region of the overlapping genes GNAS and GNAS-AS1, which are imprinted genes regulated by the NESPAS-ICR. Sixteen other SNPs located in regions apart from the analyzed regions displayed suggestive association with intra-domain methylation. Additionally, we identified 13 SNPs displaying parent-of-origin association with individual methylation sites through family-based association testing. In this exploratory study, we show the value and feasibility of using alternative GWAS approaches in the study of the interaction between epigenetic state and genetic sequence within imprinting regulatory domains. Despite the relatively small sample size, we identified a number of SNPs displaying suggestive association either in a domain-wide or in a parent-of-origin fashion. Nevertheless, these associations will require future experimental validation or replication in larger and independent samples.
List of contributors
-
- By H. Elliott Albers, Reut Avinun, Karen L. Bales, Jorge A. Barraza, Michael T. Bowen, Sunny K. Boyd, Heather K. Caldwell, Elena Choleris, Amy E. Clipperton-Allen, Bruce S. Cushing, Monica B. Dhakar, Riccardo Dore, Richard P. Ebstein, Craig F. Ferris, Sara M. Freeman, James L. Goodson, Joshua J. Green, Haruhiro Higashida, Eric Hollander, Salomon Israel, Martin Kavaliers, Keith M. Kendrick, Ariel Knafo, Yoav Litvin, Olga Lopatina, David Mankuta, Iain S. McGregor, Richard H. Melloni, Inga D. Neumann, Jerome H. Pagani, Cort A. Pedersen, Donald W. Pfaff, Anna Phan, Benjamin J. Ragen, Amina Sarwat, Idan Shalev, Erica L. Stevenson, Bonnie Taylor, Richmond R. Thompson, Florina Uzefovsky, Erwin H. van den Burg, James C. Walton, Scott R. Wersinger, Nurit Yirmiya, Larry J. Young, W. Scott Young, Paul J. Zak
- Edited by Elena Choleris, University of Guelph, Ontario, Donald W. Pfaff, Rockefeller University, New York, Martin Kavaliers, University of Western Ontario
-
- Book:
- Oxytocin, Vasopressin and Related Peptides in the Regulation of Behavior
- Published online:
- 05 April 2013
- Print publication:
- 11 April 2013, pp xi-xiv
-
- Chapter
- Export citation
Contributors
-
- By Isabella Aboderin, W. Andrew Achenbaum, Katherine R. Allen, Toni C. Antonucci, Sara Arber, Claudine Attias‐Donfut, Paul B. Baltes, Sandhi Maria Barreto, Vern L. Bengtson, Simon Biggs, Joanna Bornat, Julie B. Boron, Mike Boulton, Clive E. Bowman, Marjolein Broese van Groenou, Edna Brown, Robert N. Butler, Bill Bytheway, Neena L. Chappell, Neil Charness, Kaare Christensen, Peter G. Coleman, Ingrid Arnet Connidis, Neal E. Cutler, Sara J. Czaja, Svein Olav Daatland, Lia Susana Daichman, Adam Davey, Bleddyn Davies, Freya Dittmann‐Kohli, Glen H. Elder, Carroll L. Estes, Mike Featherstone, Amy Fiske, Alexandra Freund, Daphna Gans, Linda K. George, Roseann Giarrusso, Chris Gilleard, Jay Ginn, Edlira Gjonça, Elena L. Grigorenko, Jaber F. Gubrium, Sarah Harper, Jutta Heckhausen, Akiko Hashimoto, Jon Hendricks, Mike Hepworth, Charlotte Ikels, James S. Jackson, Yuri Jang, Bernard Jeune, Malcolm L. Johnson, Randi S. Jones, Alexandre Kalache, Robert L. Kane, Rosalie A. Kane, Ingrid Keller, Rose Anne Kenny, Thomas B. L. Kirkwood, Kees Knipscheer, Martin Kohli, Gisela Labouvie‐Vief, Kristina Larsson, Shu‐Chen Li, Charles F. Longino, Ariela Lowenstein, Erick McCarthy, Gerald E. McClearn, Brendan McCormack, Elizabeth MacKinlay, Alfons Marcoen, Michael Marmot, Tom Margrain, Victor W. Marshall, Elizabeth A. Maylor, Ruud ter Meulen, Harry R. Moody, Robert A. Neimeyer, Demi Patsios, Margaret J. Penning, Stephen A. Petrill, Chris Phillipson, Leonard W. Poon, Norella M. Putney, Jill Quadagno, Pat Rabbitt, Jennifer Reid Keene, Sandra G. Reynolds, Steven R. Sabat, Clive Seale, Merril Silverstein, Hannes B. Staehelin, Ursula M. Staudinger, Robert J. Sternberg, Debra Street, Philip Taylor, Fleur Thomése, Mats Thorslund, Jinzhou Tian, Theo van Tilburg, Fernando M. Torres‐Gil, Josy Ubachs‐Moust, Christina Victor, K. Warner Shaie, Anthony M. Warnes, James L. Werth, Sherry L. Willis, François‐Charles Wolff, Bob Woods
- Edited by Malcolm L. Johnson, University of Bristol
- Edited in association with Vern L. Bengtson, University of Southern California, Peter G. Coleman, University of Southampton, Thomas B. L. Kirkwood, University of Newcastle upon Tyne
-
- Book:
- The Cambridge Handbook of Age and Ageing
- Published online:
- 05 June 2016
- Print publication:
- 01 December 2005, pp xii-xvi
-
- Chapter
- Export citation
Looking Backward, Looking Forward: MLA Members Speak
- April Alliston, Elizabeth Ammons, Jean Arnold, Nina Baym, Sandra L. Beckett, Peter G. Beidler, Roger A. Berger, Sandra Bermann, J.J. Wilson, Troy Boone, Alison Booth, Wayne C. Booth, James Phelan, Marie Borroff, Ihab Hassan, Ulrich Weisstein, Zack Bowen, Jill Campbell, Dan Campion, Jay Caplan, Maurice Charney, Beverly Lyon Clark, Robert A. Colby, Thomas C. Coleman III, Nicole Cooley, Richard Dellamora, Morris Dickstein, Terrell Dixon, Emory Elliott, Caryl Emerson, Ann W. Engar, Lars Engle, Kai Hammermeister, N. N. Feltes, Mary Anne Ferguson, Annie Finch, Shelley Fisher Fishkin, Jerry Aline Flieger, Norman Friedman, Rosemarie Garland-Thomson, Sandra M. Gilbert, Laurie Grobman, George Guida, Liselotte Gumpel, R. K. Gupta, Florence Howe, Cathy L. Jrade, Richard A. Kaye, Calhoun Winton, Murray Krieger, Robert Langbaum, Richard A. Lanham, Marilee Lindemann, Paul Michael Lützeler, Thomas J. Lynn, Juliet Flower MacCannell, Michelle A. Massé, Irving Massey, Georges May, Christian W. Hallstein, Gita May, Lucy McDiarmid, Ellen Messer-Davidow, Koritha Mitchell, Robin Smiles, Kenyatta Albeny, George Monteiro, Joel Myerson, Alan Nadel, Ashton Nichols, Jeffrey Nishimura, Neal Oxenhandler, David Palumbo-Liu, Vincent P. Pecora, David Porter, Nancy Potter, Ronald C. Rosbottom, Elias L. Rivers, Gerhard F. Strasser, J. L. Styan, Marianna De Marco Torgovnick, Gary Totten, David van Leer, Asha Varadharajan, Orrin N. C. Wang, Sharon Willis, Louise E. Wright, Donald A. Yates, Takayuki Yokota-Murakami, Richard E. Zeikowitz, Angelika Bammer, Dale Bauer, Karl Beckson, Betsy A. Bowen, Stacey Donohue, Sheila Emerson, Gwendolyn Audrey Foster, Jay L. Halio, Karl Kroeber, Terence Hawkes, William B. Hunter, Mary Jambus, Willard F. King, Nancy K. Miller, Jody Norton, Ann Pellegrini, S. P. Rosenbaum, Lorie Roth, Robert Scholes, Joanne Shattock, Rosemary T. VanArsdel, Alfred Bendixen, Alarma Kathleen Brown, Michael J. Kiskis, Debra A. Castillo, Rey Chow, John F. Crossen, Robert F. Fleissner, Regenia Gagnier, Nicholas Howe, M. Thomas Inge, Frank Mehring, Hyungji Park, Jahan Ramazani, Kenneth M. Roemer, Deborah D. Rogers, A. LaVonne Brown Ruoff, Regina M. Schwartz, John T. Shawcross, Brenda R. Silver, Andrew von Hendy, Virginia Wright Wexman, Britta Zangen, A. Owen Aldridge, Paula R. Backscheider, Roland Bartel, E. M. Forster, Milton Birnbaum, Jonathan Bishop, Crystal Downing, Frank H. Ellis, Roberto Forns-Broggi, James R. Giles, Mary E. Giles, Susan Blair Green, Madelyn Gutwirth, Constance B. Hieatt, Titi Adepitan, Edgar C. Knowlton, Jr., Emanuel Mussman, Sally Todd Nelson, Robert O. Preyer, David Diego Rodriguez, Guy Stern, James Thorpe, Robert J. Wilson, Rebecca S. Beal, Joyce Simutis, Betsy Bowden, Sara Cooper, Wheeler Winston Dixon, Tarek el Ariss, Richard Jewell, John W. Kronik, Wendy Martin, Stuart Y. McDougal, Hugo Méndez-Ramírez, Ivy Schweitzer, Armand E. Singer, G. Thomas Tanselle, Tom Bishop, Mary Ann Caws, Marcel Gutwirth, Christophe Ippolito, Lawrence D. Kritzman, James Longenbach, Tim McCracken, Wolfe S. Molitor, Diane Quantic, Gregory Rabassa, Ellen M. Tsagaris, Anthony C. Yu, Betty Jean Craige, Wendell V. Harris, J. Hillis Miller, Jesse G. Swan, Helene Zimmer-Loew, Peter Berek, James Chandler, Hanna K. Charney, Philip Cohen, Judith Fetterley, Herbert Lindenberger, Julia Reinhard Lupton, Maximillian E. Novak, Richard Ohmann, Marjorie Perloff, Mark Reynolds, James Sledd, Harriet Turner, Marie Umeh, Flavia Aloya, Regina Barreca, Konrad Bieber, Ellis Hanson, William J. Hyde, Holly A. Laird, David Leverenz, Allen Michie, J. Wesley Miller, Marvin Rosenberg, Daniel R. Schwarz, Elizabeth Welt Trahan, Jean Fagan Yellin
-
- Journal:
- PMLA / Publications of the Modern Language Association of America / Volume 115 / Issue 7 / December 2000
- Published online by Cambridge University Press:
- 23 October 2020, pp. 1986-2078
- Print publication:
- December 2000
-
- Article
- Export citation